U.S. patent application number 17/087439 was filed with the patent office on 2021-02-18 for potassium-binding agents for treating hypertension and hyperkalemia.
The applicant listed for this patent is Vifor (International) Ltd.. Invention is credited to Lance Berman, Gerrit Klaerner.
Application Number | 20210046104 17/087439 |
Document ID | / |
Family ID | 1000005191069 |
Filed Date | 2021-02-18 |
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United States Patent
Application |
20210046104 |
Kind Code |
A1 |
Klaerner; Gerrit ; et
al. |
February 18, 2021 |
POTASSIUM-BINDING AGENTS FOR TREATING HYPERTENSION AND
HYPERKALEMIA
Abstract
The present invention generally relates to methods of treating
hypertension (HTN) in patients in need thereof wherein the patient
optionally further suffers from chronic kidney disease (CKD) or
Type II diabetes mellitus (T2DM). The invention also relates to
methods of treating hyperkalemia in a patient in need thereof,
wherein the patient suffers from CKD, T2DM or HTN and are
optionally being treated with an effective amount of a
renin-angiotensin-aldosterone system (RAAS) agent. The invention
also relates to methods of treating kidney disease in a patient in
need thereof, wherein the patient is optionally being treated with
an effective amount of a renin-angiotensin-aldosterone system
(RAAS) agent. The methods can comprise administering an effective
amount of a potassium-binding agent to the patient to lower the
patient's blood pressure and/or increase or stabilize the patient's
kidney function.
Inventors: |
Klaerner; Gerrit; (Los
Gatos, CA) ; Berman; Lance; (San Francisco,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vifor (International) Ltd. |
St. Gallen |
|
CH |
|
|
Family ID: |
1000005191069 |
Appl. No.: |
17/087439 |
Filed: |
November 2, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15916617 |
Mar 9, 2018 |
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17087439 |
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15287179 |
Oct 6, 2016 |
9925212 |
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15916617 |
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14581698 |
Dec 23, 2014 |
9492476 |
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15287179 |
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PCT/US2013/063921 |
Oct 8, 2013 |
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14581698 |
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61711184 |
Oct 8, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 33/24 20130101;
A61K 33/06 20130101; A61K 9/14 20130101; B01J 39/20 20130101; A61K
31/7004 20130101; A61K 31/78 20130101 |
International
Class: |
A61K 31/78 20060101
A61K031/78; A61K 31/7004 20060101 A61K031/7004; A61K 9/14 20060101
A61K009/14; A61K 33/06 20060101 A61K033/06; A61K 33/24 20060101
A61K033/24; B01J 39/20 20060101 B01J039/20 |
Claims
1.-137. (canceled)
138. A method of treating hyperkalemia in a human patient in need
thereof optionally being treated with an effective amount of a
renin-angiotensin-aldosterone system (RAAS) agent, the method
comprising: administering to the human patient a zirconium silicate
or a zirconium germinate molecular sieve at a daily dose of between
10 g and 40 g; wherein the human patient was hyperkalemic before
treatment with the zirconium silicate or zirconium germinate
molecular sieve; and wherein the human patient had a decrease in
the patient's serum potassium level after 48 hours of treatment
with the zirconium silicate or zirconium germinate molecular sieve;
and wherein the human patient was normokalemic after 4 weeks of
treatment with the zirconium silicate or zirconium germinate
molecular sieve.
139. The method of claim 138, wherein the human patient suffers
from chronic kidney disease.
140. The method of claim 138, wherein the zirconium silicate or
zirconium germinate molecular sieve is administered three times per
day.
141. The method of claim 139, wherein the zirconium silicate or
zirconium germinate molecular sieve is administered three times per
day.
142. The method of claim 138, wherein the zirconium silicate or
zirconium germinate molecular sieve is administered at a daily dose
between 15 g and 40 g.
143. The method of claim 139, wherein the zirconium silicate or
zirconium germinate molecular sieve is administered at a daily dose
between 15 g and 40 g.
144. The method of claim 138, wherein the human patient was being
treated with an effective amount of a RAAS agent.
145. The method of claim 138, wherein the zirconium silicate
molecular sieve is administered to the patient.
146. A method of treating hyperkalemia in a human patient suffering
from chronic kidney disease in need thereof optionally being
treated with an effective amount of a renin-angiotensin-aldosterone
system (RAAS) agent, the method comprising: administering to the
human patient a zirconium silicate or a zirconium germinate
molecular sieve at a daily dose of between 10 g and 40 g; wherein
the human patient was hyperkalemic before treatment with the
zirconium silicate or zirconium germinate molecular sieve; wherein
the human patient was normokalemic after 4 weeks of treatment with
the zirconium silicate or zirconium germinate molecular sieve; and
the amount of zirconium silicate or zirconium germinate
administered was increased by 5 g daily if patient's serum
potassium level was greater than or equal to 5.1 mEq/L or decreased
by 5 g daily if the patient's serum potassium level was less than
4.0 mEq/L.
147. The method of claim 146, wherein the zirconium silicate or
zirconium germinate molecular sieve is administered once per
day.
148. The method of claim 147, wherein the zirconium silicate or
zirconium germinate molecular sieve is administered at a daily dose
between 15 g and 40 g.
149. The method of claim 146, wherein the zirconium silicate
molecular sieve is administered to the patient.
150. The method of claim 147, wherein the zirconium silicate
molecular sieve is administered to the patient.
151. The method of claim 148, wherein the zirconium silicate
molecular sieve is administered to the patient.
152. A method of treating hyperkalemia in a human patient in need
thereof and optionally treated with an effective amount of a
renin-angiotensin-aldosterone system (RAAS) agent, the method
comprising: administering to the human patient once per day a
zirconium silicate molecular sieve at a daily dose of between 10 g
and 40 g; wherein the human patient was hyperkalemic before
treatment with the zirconium silicate molecular sieve; wherein the
human patient was normokalemic after 4 weeks of treatment with the
zirconium silicate or zirconium germinate molecular sieve; and the
amount of zirconium silicate was increased by 5 g daily if
patient's serum potassium level was greater than or equal to 5.1
mEq/L or decreased by 5 g daily if the patient's serum potassium
level was less than 4.0 mEq/L.
153. The method of claim 152, wherein the human patient suffers
from chronic kidney disease.
154. The method of claim 152, wherein the human patient is being
treated with an effective amount of a RAAS agent.
155. The method of claim 153, wherein the human patient is being
treated with an effective amount of a RAAS agent.
156. The method of claim 152, wherein the zirconium silicate
molecular sieve is administered at a daily dose between 15 g and 40
g.
157. The method of claim 153, wherein the zirconium silicate
molecular sieve is administered at a daily dose between 15 g and 40
g.
158. The method of claim 154, wherein the zirconium silicate
molecular sieve is administered at a daily dose between 15 g and 40
g.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/916,617 filed Mar. 9, 2018, which is a
continuation of U.S. patent application Ser. No. 15/287,179 filed
Oct. 6, 2016 (issued as U.S. Pat. No. 9,925,212), which is a
continuation of U.S. patent application Ser. No. 14/581,698 filed
Dec. 23, 2014 (issued as U.S. Pat. No. 9,492,476) which is a
continuation of PCT Patent Application No. PCT/US2013/063921, filed
on Oct. 8, 2013 which claims the benefit of U.S. Provisional Patent
Application Ser. No. 61/711,184, filed on Oct. 8, 2012. The entire
content of the above applications are hereby incorporated by
reference.
FIELD OF THE INVENTION
[0002] The present invention generally relates to methods of
treating hypertension (HTN) in patients in need thereof wherein the
patient optionally further suffers from chronic kidney disease
(CKD) or Type II diabetes mellitus (T2DM). The invention also
relates to methods of treating kidney disease in a patient in need
thereof, wherein the patient is optionally being treated with an
effective amount of a renin-angiotensin-aldosterone system (RAAS)
agent. The invention also relates to methods of treating
hyperkalemia in a patient in need thereof, wherein the patient
suffers from CKD, T2DM or HTN and are optionally being treated with
an effective amount of a renin-angiotensin-aldosterone system
(RAAS) agent. The methods can comprise administering an effective
amount of a potassium-binding agent to the patient to lower the
patient's blood pressure and/or increase or stabilize the patient's
kidney function.
BACKGROUND OF THE INVENTION
[0003] Normal kidney function is critical for the maintenance of
potassium homeostasis. The ability of the kidney to maintain
potassium homeostasis depends on several factors, including the
normal production of aldosterone, sodium delivery to the distal
nephron, and adequate sodium-potassium exchange in the cortical
collecting duct (Palmer, B. F., N. Engl. J. Med. 2004, 351:585-92).
Of these factors, aldosterone production and action is closely
regulated by the renin-angiotensin-aldosterone system (RAAS), a
cornerstone of the regulatory components controlling blood
pressure, blood volume and cardiovascular function. RAAS
inhibition, designed to limit aldosterone production and function,
is therefore an important treatment strategy for hypertension,
diabetes, chronic kidney disease and heart failure. Several studies
have demonstrated the renal protective effects of angiotensin
receptor blockers (ARBs) such as losartan or irbesartan (Brenner,
B. M. et al., N. Engl. J. Med. 2001, 345:861-869; de Zeeuw, D. et
al. Kidney Intl. 2004, 65:2309-2320; Miao, Y. et al., Diabetologia
2010; Lewis, E. J. et al., N. Engl. J. Med. 2001, 345:851-860;
Atkins, R. C. et al., Am. J. Kidney Dis. 2005, 45:281-287), while
studies using dual blockade of the RAAS with an aldosterone
antagonist (spironolactone or eplerenone), added to either
angiotensin converting enzyme inhibitor (ACEI) or ARB therapy, were
shown to substantially reduce cardiovascular endpoints in heart
failure or post-myocardial infarction patients (Pitt, B. et al., N.
Engl. J. Med. 1999, 341:709-717; Pitt, B., Molecular & Cellular
Endocrinol. 2004, 217:53-58; Zannad, F. et al., European J. Heart
Failure 2010).
[0004] Despite the demonstrated clinical benefits of RAAS
inhibitors, the fundamental mode of action of the drugs disturbs
the exchange of sodium for potassium in the kidney tubule. As a
result, potassium retention can precipitate hyperkalemia, defined
as a serum potassium value >5.0 mEq/L. This is particularly
problematic in patients with reduced renal function resulting from
chronic kidney disease and common co-morbidities such as
hypertension, diabetes and heart failure. In this situation, the
combination of RAAS inhibition and reduced renal function can
aggravate the nascent positive potassium balance and trigger a
hyperkalemic event. The discontinuation or reduction in the dose of
RAAS inhibitors is a common intervention for patients taking RAAS
inhibitors who show abnormally elevated serum potassium levels,
which deprives patients of the benefits of RAAS inhibitors. Thus,
there is a need to control blood pressure in patients and treat
hyperkalemia.
SUMMARY OF THE INVENTION
[0005] One aspect of the invention is a method of treating
hypertension in a patient in need thereof. The method comprises
administering an effective amount of a medication that controls the
serum potassium of a patient in need thereof into the normal range.
The method comprises administering an effective amount of a
medication that controls the serum potassium of a patient in need
thereof into the normal range within two days of treatment, and in
particular with chronic dosing, and further with such chronic over
a period of at least one month, more specifically at least 3
months, preferably at least 6 months and more preferably at least 9
months. More specifically, the method comprises administering an
effective amount of a potassium binding agent, such as
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form, to the patient.
[0006] Another aspect is a method of treating hypertension in a
chronic kidney disease patient in need thereof. The patient is
optionally treated with an effective amount of a
renin-angiotensin-aldosterone system (RAAS) agent and the method
comprising administering an effective amount of a potassium binding
agent, such as 2-fluoroacrylate-divinylbenzene-1,7-octadiene
copolymer crosslinked in the salt or acid form, to the patient to
control the patient's serum potassium into the normal range.
[0007] A further aspect is a method of treating hypertension in a
heart failure patient in need thereof. The patient is optionally
treated with an effective amount of a renin-angiotensin-aldosterone
system (RAAS) agent and the method comprises administering an
effective amount of a potassium binding agent, such as
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form, to the patient to control the patient's
serum potassium into the normal range.
[0008] Yet another aspect is a method of treating hypertension in a
type 2 diabetes mellitus patient in need thereof. The patient is
optionally treated with an effective amount of a
renin-angiotensin-aldosterone system (RAAS) agent and the method
comprises administering an effective amount of a potassium binding
agent, such as 2-fluoroacrylate-divinylbenzene-1,7-octadiene
copolymer crosslinked in the salt or acid form, to the patient to
control the patient's serum potassium into the normal range.
[0009] Yet a further aspect is a method of treating hyperkalemia in
a chronic kidney disease patient in need thereof optionally being
treated with an effective amount of a renin-angiotensin-aldosterone
system (RAAS) agent. The method comprises administering an
effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene
copolymer crosslinked in the salt or acid form to the patient to
increase or stabilize the patient's kidney function by decreasing
the patient's serum creatinine level as compared to the patient's
serum creatinine level before treatment with
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form.
[0010] Another aspect of the invention is a method of treating
hyperkalemia in a chronic kidney disease patient in need thereof
optionally being treated with an effective amount of a
renin-angiotensin-aldosterone system (RAAS) agent. The method
comprises administering an effective amount of
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form to the patient to increase or stabilize
the patient's kidney function by increasing the time to progression
of end stage renal disease as compared to a chronic kidney disease
patient optionally treated with a RAAS agent but not treated with
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form.
[0011] A further aspect is a method of treating hyperkalemia in a
chronic kidney disease patient in need thereof optionally being
treated with an effective amount of a renin-angiotensin-aldosterone
system (RAAS) agent. The method comprises administering an
effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene
copolymer crosslinked in the salt or acid form to the patient to
increase or stabilize the patient's kidney function by increasing
survival as compared to a chronic kidney disease patient optionally
treated with a RAAS agent but not treated with
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form.
[0012] Yet another aspect is a method of treating hyperkalemia in a
chronic kidney disease patient in need thereof optionally being
treated with an effective amount of a renin-angiotensin-aldosterone
system (RAAS) agent. The method comprises administering an
effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene
copolymer crosslinked in the salt or acid form to the patient to
increase or stabilize the patient's kidney function by increasing
or stabilizing estimated glomerular filtration rate (eGFR) as
compared to the patient's eGFR before treatment with
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form.
[0013] Another aspect is a method of treating chronic kidney
disease in a patient in need thereof optionally being treated with
an effective amount of a renin-angiotensin-aldosterone system
(RAAS) agent. The method comprises administering an effective
amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer
crosslinked in the salt or acid form to the patient to increase or
stabilize the patient's kidney function by decreasing the patient's
serum creatinine level as compared to the patient's serum
creatinine level before treatment with
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form.
[0014] A further aspect is a method of treating chronic kidney
disease in a patient in need thereof optionally being treated with
an effective amount of a renin-angiotensin-aldosterone system
(RAAS) agent. The method comprises administering an effective
amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer
crosslinked in the salt or acid form to the patient to increase or
stabilize the patient's kidney function by increasing the time to
progression of end stage renal disease as compared to a chronic
kidney disease patient optionally treated with a RAAS agent but not
treated with 2-fluoroacrylate-divinylbenzene-1,7-octadiene
copolymer crosslinked in the salt or acid form.
[0015] Yet another aspect is a method of treating chronic kidney
disease in a patient in need thereof optionally being treated with
an effective amount of a renin-angiotensin-aldosterone system
(RAAS) agent. The method comprises administering an effective
amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer
crosslinked in the salt or acid form to the patient to increase or
stabilize the patient's kidney function by increasing survival as
compared to a chronic kidney disease patient optionally treated
with a RAAS agent but not treated with
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form.
[0016] Another aspect is a method of treating chronic kidney
disease in a patient in need thereof optionally being treated with
an effective amount of a renin-angiotensin-aldosterone system
(RAAS) agent. The method comprises administering an effective
amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer
crosslinked in the salt or acid form to the patient to increase or
stabilize the patient's kidney function by increasing or
stabilizing estimated glomerular filtration rate (eGFR) as compared
to the patient's eGFR before treatment with
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form.
[0017] Other objects and features will be in part apparent and in
part pointed out hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is a graph of the central lab serum potassium
concentration in mEq/L versus time of treatment for patients having
been treated for six months with the protocol described in Example
2 and having any albumin creatinine ratio (ACR), an ACR.gtoreq.30,
and ACR>300 and an estimated glomerular filtration rate (eGFR)
of 15-44 mL/min/1.73 m.sup.2.
[0019] FIG. 2 is a graph of the systolic blood pressure (SBP) in
mmHg versus time of treatment for patients having been treated for
six months with the protocol described in Example 2 and having any
albumin creatinine ratio (ACR), an ACR.gtoreq.30, and ACR>300
and an estimated glomerular filtration rate (eGFR) of 15-44
mL/min/1.73 m.sup.2.
[0020] FIG. 3 is a graph of the diastolic blood pressure (DBP) in
mmHg versus time of treatment for patients having been treated for
six months with the protocol described in Example 2 and having any
albumin creatinine ratio (ACR), an ACR.gtoreq.30, and ACR>300
and an estimated glomerular filtration rate (eGFR) of 15-44
mL/min/1.73 m.sup.2.
[0021] FIG. 4 is a graph of the urine ACR in mg/g versus time of
treatment for patients having been treated for six months with the
protocol described in Example 2 and having any albumin creatinine
ratio (ACR), an ACR.gtoreq.30, and ACR>300 and an estimated
glomerular filtration rate (eGFR) of 15-44 mL/min/1.73 m.sup.2.
[0022] FIG. 5 is a graph of the eGFR in mL/min/1.73 m.sup.2 versus
time of treatment for patients having been treated for six months
with the protocol described in Example 2 and having any albumin
creatinine ratio (ACR), an ACR.gtoreq.30, and ACR>300 and an
estimated glomerular filtration rate (eGFR) of 15-44 mL/min/1.73
m.sup.2.
[0023] FIG. 6 is a graph of eGFR versus time of treatment for a
cohort of patients having pre-existing hyperkalemia on a stable
dose of a RAAS inhibitor that came to the trial without a run-in
period that were treated for twelve months as described in Example
2. For FIGS. 6-9, the data is presented at baseline (BL), one month
(M1), two months (M2), six months (M6), and twelve months
(M12).
[0024] FIG. 7 is a graph of serum potassium versus time of
treatment for a cohort of patients having pre-existing hyperkalemia
on a stable dose of a RAAS inhibitor that came to the trial without
a run-in period that were treated for twelve months with as
described in Example 2.
[0025] FIG. 8 is a graph of urine ACR versus time of treatment for
a cohort of patients having pre-existing hyperkalemia on a stable
dose of a RAAS inhibitor that came to the trial without a run-in
period that were treated for twelve months as described in Example
2.
[0026] FIG. 9 is a graph of systolic and diastolic blood pressure
versus time of treatment for a cohort of patients having
pre-existing hyperkalemia on a stable dose of a RAAS inhibitor that
came to the trial without a run-in period that were treated for
twelve months as described in Example 2.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0027] Hyperkalemia, which can present chronically or acutely, can
lead to severe medical complications, including life-threatening
cardiac arrhythmias and sudden death. Hyperkalemia is typically
defined as a serum potassium level, or potassium in the blood,
greater than 5.0 milliequivalents per liter (mEq/L). Patients with
serum potassium levels greater than or equal to 5.5 mEq/L, which we
define as moderate-to-severe hyperkalemia, were found in an
independent study to have a 10-fold increase in their mortality
rate within 24 hours. Hyperkalemia occurs most frequently in
patients with chronic kidney disease, or CKD, where the ability of
the patient's kidney to excrete potassium has been compromised. The
normal range for serum potassium levels is from about 3.8 mEq/1 to
5.0 mEq/L.
[0028] Potassium-binding agents can remove potassium from the
gastrointestinal tract and reduce the serum potassium level and
treat hyperkalemia. In particularly, potassium-binding polymers can
remove potassium from the gastrointestinal tract and reduce the
serum potassium level (U.S. Pat. No. 7,566,799). Various studies
show that an increase in serum potassium level increases the
aldosterone level and a decrease in serum potassium level decreases
the aldosterone level (T. Himathongkam, et al., J. Clin.
Endocrinol. Metab. 1975, 41(1):153-159). These studies have shown
that a small increase or decrease in serum potassium level can
cause a larger change in the aldosterone level. Further, other
studies show that an increase in potassium intake can reduce blood
pressure (He, F. J., et al., Hypertension 2005, 45:571-574). It has
now been discovered, and clinically observed, that lowering of
serum potassium levels in patients also lowers blood pressure. This
finding was unexpected given that the intended primary benefit of
the potassium-binding polymer was to lower serum potassium. The
lowering of potassium and blood pressure using a potassium-binding
polymer is beneficial in patients with renal impairment,
hyperkalemia and hypertension given that these patients are at
significant risk of increased morbidity and mortality. Lowering of
blood pressure is also beneficial in patients without such
co-morbidities who suffer from hypertension.
[0029] The potassium-binding agents can be an agent that binds
potassium. One class of potassium-binding agents is
potassium-binding polymers. Various potassium-binding polymers can
be used in the methods described herein including crosslinked
cation exchange polymers. The potassium-binding agents can also be
zeolites, such as zirconium silicate or zirconium germanate
molecular sieves.
[0030] The crosslinked cation exchange polymers useful for the
methods described herein are in the form of substantially spherical
particles. As used herein, the term "substantially" means generally
rounded particles having an average aspect ratio of about 1.0 to
about 2.0. Aspect ratio is the ratio of the largest linear
dimension of a particle to the smallest linear dimension of the
particle. Aspect ratios may be easily determined by those of
ordinary skill in the art. This definition includes spherical
particles, which by definition have an aspect ratio of 1.0.
[0031] The particles can have an average aspect ratio of about 1.0,
1.2, 1.4, 1.6, 1.8 or 2.0. The particles may be round or elliptical
when observed at a magnification wherein the field of view is at
least twice the diameter of the particle.
[0032] The crosslinked cation exchange polymer particles have a
mean diameter of from about 20 .mu.m to about 200 .mu.m. Specific
ranges are where the crosslinked cation exchange particles have a
mean diameter of from about 20 .mu.m to about 200 .mu.m, from about
20 .mu.m to about 150 .mu.m, or from about 20 .mu.m to about 125
.mu.m. Other ranges include from about 35 .mu.m to about 150 .mu.m,
from about 35 .mu.m to about 125 .mu.m, or from about 50 .mu.m to
about 125 .mu.m. Particle sizes, including mean diameters,
distributions, etc. can be determined using techniques known to
those of skill in the art. For example, U.S. Pharmacopeia (USP)
<429> discloses methods for determining particle sizes.
[0033] Various crosslinked cation exchange polymer particles also
have less than about 4 volume percent of the particles that have a
diameter of less than about 10 .mu.m; particularly, less than about
2 volume percent of the particles that have a diameter of less than
about 10 .mu.m; more particularly, less than about 1 volume percent
of the particles that have a diameter of less than about 10 .mu.m;
and even more particularly, less than about 0.5 volume percent of
the particles that have a diameter of less than about 10 .mu.m. In
other cases, specific ranges are less than about 4 volume percent
of the particles that have a diameter of less than about 20 .mu.m;
less than about 2 volume percent of the particles that have a
diameter of less than about 20 .mu.m; less than about 1 volume
percent of the particles that have a diameter of less than about 20
.mu.m; less than about 0.5 volume percent of the particles that
have a diameter of less than about 20 .mu.m; less than about 2
volume percent of the particles that have a diameter of less than
about 30 .mu.m; less than about 1 volume percent of the particles
that have a diameter of less than about 30 .mu.m; less than about 1
volume percent of the particles that have a diameter of less than
about 30 .mu.m; less than about 1 volume percent of the particles
that have a diameter of less than about 40 .mu.m; or less than
about 0.5 volume percent of the particles that have a diameter of
less than about 40 .mu.m.
[0034] The crosslinked cation exchange polymer can have a particle
size distribution wherein not more than about 5 volume % of the
particles have a diameter less than about 30 .mu.m (i.e.,
D(0.05)<30 .mu.m), not more than about 5 volume % of the
particles have a diameter greater than about 250 .mu.m (i.e.,
D(0.05)>250 .mu.m), and at least about 50 volume % of the
particles have a diameter in the range from about 70 to about 150
.mu.m.
[0035] The particle distribution of the crosslinked cation exchange
polymer can be described as the span. The span of the particle
distribution is defined as (D(0.9)-D(0.1))/D(0.5), where D(0.9) is
the value wherein 90% of the particles have a diameter below that
value, D(0.1) is the value wherein 10% of the particles have a
diameter below that value, and D(0.5) is the value wherein 50% of
the particles have a diameter above that value and 50% of the
particles have a diameter below that value as measured by laser
diffraction. The span of the particle distribution is typically
from about 0.5 to about 1, from about 0.5 to about 0.95, from about
0.5 to about 0.90, or from about 0.5 to about 0.85. Particle size
distributions can be measured using Niro Method No. A 8 d (revised
September 2005), available from GEA Niro, Denmark, using the
Malvern Mastersizer.
[0036] Another desirable property that the crosslinked cation
exchange polymers may possess is a viscosity when hydrated and
sedimented of from about 10,000 Pas to about 1,000,000 Pas, from
about 10,000 Pas to about 800,000 Pas, from about 10,000 Pas to
about 600,000 Pas, from about 10,000 Pas to about 500,000 Pas, from
about 10,000 Pas to about 250,000 Pas, or from about 10,000 Pas to
about 150,000 Pas, from about 30,000 Pas to about 1,000,000 Pas,
from about 30,000 Pas to about 500,000 Pas, or from about 30,000
Pas to about 150,000 Pas, the viscosity being measured at a shear
rate of 0.01 sec.sup.-1. This viscosity is measured using a wet
polymer prepared by mixing the polymer thoroughly with a slight
excess of simulated intestinal fluid (per USP <26>), allowing
the mixture to sediment for 3 days at 37.degree. C., and decanting
free liquid from the sedimented wet polymer. The steady state shear
viscosity of this wet polymer can be determined using a Bohlin VOR
Rheometer (available from Malvern Instruments Ltd., Malvern, U.K.)
or equivalent with a parallel plate geometry (upper plate of 15 mm
diameter and lower plate of 30 mm diameter, and gap between plates
of 1 mm) and the temperature maintained at 37.degree. C.
[0037] The crosslinked cation exchange polymers may further have a
hydrated and sedimented yield stress of from about 150 Pa to about
4000 Pa, from about 150 Pa to about 3000 Pa, from about 150 Pa to
about 2500 Pa, from about 150 Pa to about 1500 Pa, from about 150
Pa to about 1000 Pa, from about 150 Pa to about 750 Pa, or from
about 150 Pa to about 500 Pa, from about 200 Pa to about 4000 Pa,
from about 200 Pa to about 2500 Pa, from about 200 Pa to about 1000
Pa, or from about 200 Pa to about 750 Pa. Dynamic stress sweep
measurements (i.e., yield stress) can be made using a Reologica
STRESSTECH Rheometer (available from Reologica Instruments AB,
Lund, Sweden) or equivalent in a manner known to those of skill in
the art. This rheometer also has a parallel plate geometry (upper
plate of 15 mm diameter, lower plate of 30 mm diameter, and gap
between plates of 1 mm) and the temperature is maintained at
37.degree. C. A constant frequency of 1 Hz with two integration
periods can be used while the shear stress is increased from 1 to
10.sup.4 Pa.
[0038] Crosslinked cation exchange polymers useful for the methods
described herein also have desirable compressibility and bulk
density when in the form of a dry powder. Some of the particles of
the crosslinked cation exchange polymers in the dry form have a
bulk density of from about 0.8 g/cm.sup.3 to about 1.5 g/cm.sup.3,
from about 0.82 g/cm.sup.3 to about 1.5 g/cm.sup.3, from about 0.84
g/cm.sup.3 to about 1.5 g/cm.sup.3, from about 0.86 g/cm.sup.3 to
about 1.5 g/cm.sup.3, from about 0.8 g/cm.sup.3 to about 1.2
g/cm.sup.3, or from about 0.86 g/cm.sup.3 to about 1.2 g/cm.sup.3.
The bulk density affects the volume of crosslinked cation exchange
polymer needed for administration to a patient. For example, a
higher bulk density means that a lower volume will provide the same
number of grams of crosslinked cation exchange polymer. This lower
volume can improve patient compliance by allowing the patient to
perceive they are taking a smaller amount due to the smaller
volume.
[0039] A powder composed of the particles of the crosslinked cation
exchange polymer in dry form has a compressibility index of from
about 3 to about 15, from about 3 to about 14, from about 3 to
about 13, from about 3 to about 12, from about 3 to about 11, from
about 5 to about 15, from about 5 to about 13, or from about 5 to
about 11. The compressibility index is defined as 100*(TD-BD)/TD,
wherein BD and TD are the bulk density and tap density,
respectively. The procedure for measuring bulk density and tap
density is described below in Example 3. Further, the powder form
of the cation exchange polymers settles into its smallest volume
more easily than polymers conventionally used to treat
hyperkalemia. This makes the difference between the bulk density
and the tap density (measured powder density after tapping a set
number of times) from about 3% to about 14%, from about 3% to about
13%, from about 3% to about 12%, from about 3% to about 11%, from
about 3% to about 10%, from about 5% to about 14%, from about 5% to
about 12%, or from about 5% to about 10% of the bulk density.
[0040] Generally the potassium-binding polymers in particle form
are not absorbed from the gastrointestinal tract. The term
"non-absorbed" and its grammatical equivalents is not intended to
mean that the entire amount of administered polymer is not
absorbed. It is expected that certain amounts of the polymer may be
absorbed. Particularly, about 90% or more of the polymer is not
absorbed, more particularly about 95% or more is not absorbed, even
more particularly about 97% or more is not absorbed, and most
particularly about 98% or more of the polymer is not absorbed.
[0041] The swelling ratio of the potassium-binding polymers in
physiological isotonic buffer, which is representative of the
gastrointestinal tract, is typically from about 1 to about 7,
particularly from about 1 to about 5, more particularly from about
1 to about 3, and more specifically, from about 1 to about 2.5.
[0042] The crosslinked cation exchange polymers can have a swelling
ratio of less than 5, less than about 4, less than about 3, less
than about 2.5, or less than about 2. As used herein, "swelling
ratio" refers to the number of grams of solvent taken up by one
gram of otherwise non-solvated crosslinked polymer when
equilibrated in an aqueous environment. When more than one
measurement of swelling is taken for a given polymer, the mean of
the measurements is taken to be the swelling ratio. The polymer
swelling can also be calculated by the percent weight gain of the
otherwise non-solvated polymer upon taking up solvent. For example,
a swelling ratio of 1 corresponds to polymer swelling of 100%.
[0043] Crosslinked cation exchange polymers having advantageous
surface morphology are polymers in the form of substantially
spherical particles with a substantially smooth surface. A
substantially smooth surface is a surface wherein the average
distance from the peak to the valley of a surface feature
determined at random over several different surface features and
over several different particles is less than about 2 .mu.m, less
than about 1 .mu.m, or less than about 0.5 .mu.m. Typically, the
average distance between the peak and the valley of a surface
feature is less than about 1 .mu.m.
[0044] The surface morphology can be measured using several
techniques including those for measuring roughness. Roughness is a
measure of the texture of a surface. It is quantified by the
vertical deviations of a real surface from its ideal form. If these
deviations are large, the surface is rough; if they are small the
surface is smooth. Roughness is typically considered to be the high
frequency, short wavelength component of a measured surface. For
example, roughness may be measured using contact or non-contact
methods. Contact methods involve dragging a measurement stylus
across the surface; these instruments include profilometers and
atomic force microscopes (AFM). Non-contact methods include
interferometry, confocal microscopy, electrical capacitance and
electron microscopy. These methods are described in more detail in
Chapter 4: Surface Roughness and Microtopography by L. Mattson in
Surface Characterization, ed. by D. Brune, R. Hellborg, H. J.
Whitlow, O. Hunderi, Wiley-VCH, 1997.
[0045] For three-dimensional measurements, the probe is commanded
to scan over a two-dimensional area on the surface. The spacing
between data points may not be the same in both directions. In this
way, a side view of the surface can be obtained and the relief of
the surface can be measured.
[0046] Surface roughness can be controlled in a number of ways. For
example, three approaches were determined for preparing
poly(.alpha.-fluoroacrylate) particles having a smoother surface.
The first approach was to include a solvent that was an acceptable
solvent for the monomers and the polymeric product. The second
approach was to decrease the solvation of the organic phase in the
aqueous phase by a salting out process. The third approach was to
increase the hydrophobicity of the starting fluoroacrylate monomer.
These approaches are described in more detail in Examples 4-7.
[0047] Dosing regimens for chronic treatment of hyperkalemia can
increase compliance by patients, particularly for crosslinked
cation exchange polymers that are taken in gram quantities. The
present invention is also directed to methods of chronically
removing potassium from a mammal in need thereof, and in particular
chronically treating hyperkalemia with a potassium binder that is a
crosslinked aliphatic carboxylic polymer, and preferably a salt of
such polymer stabilized with a linear polyol, wherein the polymer
is in the form of a substantially spherical particle.
[0048] Thus, the invention is directed to methods of treating
hypertension or hyperkalemia or kidney disease in a patient in need
thereof, the method comprising administering an effective amount of
a potassium-binding agent, to the patient. In particular, the
invention is directed to methods of treating hypertension and
hyperkalemia in a patient in need thereof. In particular also, the
invention is directed to methods of treating kidney disease and
hyperkalemia in a patient in need thereof.
[0049] In the methods described here, the potassium-binding agent
can be 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer,
crosslinked in the salt or acid form.
[0050] The methods of treating hypertension or kidney disease can
include chronic administration of the potassium-binding agent. The
potassium-binding agent exhibits long-term tolerability, long-term
safety, and/or long-term efficacy in the patient. The long-term
tolerability, long-term safety, and long-term efficacy are observed
over treatment periods of 12, 16, 20, 24, 28, 32, 36, 40, 44, 48,
52, or more weeks. The treatment period can also be 2 years, 3
years, 4 years, 5 years, or more. Particularly, the
potassium-binding agent can be administered to the patient daily
for more than 8 weeks or daily for more than one year.
[0051] In particular, the
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form exhibits long-term tolerability, long-term
safety, and/or long-term efficacy in the patient. The long-term
tolerability, long-term safety, and long-term efficacy are observed
over treatment periods of 12, 16, 20, 24, 28, 32, 36, 40, 44, 48,
52, or more weeks. The treatment period can also be 2 years, 3
years, 4 years, 5 years, or more. Particularly, the
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form can be administered to the patient daily
for more than 8 weeks or daily for more than one year.
[0052] The methods of treating hypertension and hyperkalemia can
also reduce the patient's systolic blood pressure by 5, 6, 7, 8
mmHg as compared to the patient's systolic blood pressure before
treatment with the potassium-binding agent, and/or reduce the
patient's diastolic blood pressure 2, 3, 4, 5, 6 mmHg as compared
to the patient's diastolic blood pressure before treatment with
potassium-binding agent.
[0053] The methods of treating hypertension and hyperkalemia can
also reduce the patient's systolic blood pressure by 9, 10, 11, 12,
13, 14, 15, 16, 17 mmHg or more as compared to the patient's
systolic blood pressure before treatment with potassium-binding
agent, and/or reduce the patient's diastolic blood pressure 7, 8,
9, 10, 11, 12, 13 mmHg or more as compared to the patient's
diastolic blood pressure before treatment with potassium-binding
agent.
[0054] The methods of treating hypertension and hyperkalemia can
also reduce the patient's systolic blood pressure by at least 6, 7,
8, 9, 10, 11, 12, or more percent as compared to the patient's
systolic blood pressure before treatment with potassium-binding
agent, and/or the patient's diastolic blood pressure is reduced by
at least 8, 9, 10, 11, 12, 13, 14, 15, or more percent as compared
to the patient's diastolic blood pressure before treatment with
potassium-binding agent.
[0055] The potassium-binding agent can be administered to a patient
having a systolic blood pressure greater than 130 mmHg or ranging
from 130 to 200 mmHg, 135 to 200 mmHg, 140 to 200 mmHg, 145 to 200
mmHg, or 150 to 180 mmHg before treatment with potassium-binding
agent.
[0056] The potassium-binding agent can be administered to a patient
having a systolic blood pressure greater than 143 mmHg or ranging
from 143 to 200 mmHg or 143 to 180 mmHg before treatment with
potassium-binding agent.
[0057] The systolic blood pressure of the patient can be maintained
below 130, 135, or 140 mmHg over at least 90% of the period of
treatment with potassium-binding agent. The diastolic blood
pressure of the patient can be maintained at below 80, 85, or 90
mmHg over at least 90% of the period of treatment with
potassium-binding agent.
[0058] The methods of treating hypertension can include
administering an effective amount of potassium-binding agent to a
heart failure patient, a type 2 diabetes mellitus patient, and/or a
chronic kidney disease patient in need of hypertension treatment,
the patient optionally being treated with an effective amount of a
renin-angiotensin-aldosterone system (RAAS) agent.
[0059] The methods of treatment of hypertension can be administered
to a patient suffering from chronic kidney disease, heart failure,
type 2 diabetes mellitus or a combination thereof.
[0060] The potassium-binding agent can be administered to a patient
that is not being treated with an aldosterone antagonist.
Particularly, the patient is not being treated with
spironolactone.
[0061] The methods of treating hypertension can include
administration of potassium-binding agent to a patient that does
not have another condition that causes hypertension such as Type 2
diabetes, chronic kidney disease, chronic heart failure or a
combination thereof. Particularly, the patient does not have type 2
diabetes mellitus, or the patient that does not have chronic kidney
disease (CKD).
[0062] The methods of treating hypertension can include
administration of potassium-binding agent to a patient that does
not have Class II or Class III heart failure (HF).
[0063] The methods of treating hypertension can also include
administration of potassium-binding agent to a patient that is not
being treated with a heart failure therapy; the heart failure
therapy can be an angiotensin converting enzyme inhibitor (ACEI),
an angiotensin receptor blocker (ARB), a beta blocker (BB), or a
combination thereof.
[0064] The patients receiving the treatment methods of the
invention need not be treated with an antihypertensive agent
comprising a diuretic, a calcium channel blocker, an alpha blocker,
a nervous system inhibitor, a vasodilator, an angiotensin
converting enzyme inhibitor (ACEI), an angiotensin receptor blocker
(ARB), a beta blocker (BB), or a combination thereof.
[0065] The methods of treating hypertension of the invention can be
administered to patients that are normokalemic. Normokalemic
patients have a serum potassium level of 3.5 to 5.0 mEq/L.
[0066] The present invention is directed to methods of treating
hyperkalemia in a chronic kidney disease patient in need thereof
optionally being treated with an effective amount of a
renin-angiotensin-aldosterone system (RAAS) agent. The methods
generally comprise administering an effective amount of a
potassium-binding polymer to the patient to increase or stabilize
the patient's kidney function.
[0067] The present invention is directed to methods of treating
chronic kidney disease in a patient in need thereof optionally
being treated with an effective amount of a
renin-angiotensin-aldosterone system (RAAS) agent. The methods
generally comprise administering an effective amount of a
potassium-binding polymer to the patient to increase or stabilize
the patient's kidney function.
[0068] In the methods of treating kidney disease, there are several
ways in which the methods can exhibit an increase to or
stabilization of the patient's kidney function, such as by
decreasing the patient's serum creatinine level as compared to the
patient's serum creatinine level before treatment with a
potassium-binding agent; increasing the time to progression of end
stage renal disease as compared to a chronic kidney disease patient
optionally treated with a RAAS agent but not treated with a
potassium-binding agent; increasing survival as compared to a
chronic kidney disease patient optionally treated with a RAAS agent
but not treated with a potassium-binding agent; and/or increasing
or stabilizing estimated glomerular filtration rate (eGFR) as
compared to the patient's eGFR before treatment with a
potassium-binding agent.
[0069] For all of these methods of treatment including treating
hypertension, hyperkalemia, chronic kidney disease, end stage renal
disease, etc. the potassium-binding agent can be a
potassium-binding polymer.
[0070] For the methods of treatment described herein, the
potassium-binding polymer can be a crosslinked cation exchange
polymer.
[0071] For the methods of treatment described herein, the
potassium-binding polymer can be an aliphatic crosslinked cation
exchange polymer.
[0072] For the methods of treatment described herein, the
potassium-binding polymer can be
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form.
[0073] For the methods of treatment described herein, the
potassium-binding agent can be a zirconium silicate or a zirconium
germanate molecular sieve.
[0074] For the methods of treatment described herein, the
potassium-binding agent can be
Na.sub.2.19ZrSi.sub.3.01O.sub.9.11.2.71 H.sub.2O.
[0075] As detailed in Example 2, a Phase II clinical study
conducted in Type 2 diabetes mellitus (T2DM) patients with chronic
kidney disease (CKD) Phase 3/4 is instructive. All patients are
treated with a RAAS inhibitor, and about 40% of the patients also
have heart failure (HF). And, endpoints measure changes from
baseline at various time points. The trial is an 8-week,
open-label, randomized, dose ranging study to determine the optimal
starting dose(s) of 2-fluoroacrylate-divinylbenzene-1,7-octadiene
copolymer crosslinked in the salt or acid form. In addition, the
study contains a 44-week long-term safety extension component, in
order to collect 1-year safety data that will support chronic use
of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer
crosslinked in the salt or acid form. Patients with normal serum
K.sup.+ levels of 4.3-5.0 mEq/L were enrolled in a run-in period
during which they received the maximum labeled dose of losartan
and/or additional spironolactone as needed. Patients with serum
K.sup.+ levels>5.0 mEq/L at baseline entered the study without a
run-in period (data from some of these patients are shown in FIGS.
6-9). For treatment of hyperkalemia (serum K.sup.+>5.0 mEq/L),
two potassium strata were chosen (stratum 1=serum
K.sup.+>5.0-5.5 mEq/L; stratum 2=serum K.sup.+>5.5-<6.0
mEq/L), based on the National Kidney Foundation Kidney Disease
Outcomes Quality Initiative Guideline 11 (KDOQI, 2004) definition
of hyperkalemia and serum potassium cut-off points for ACEI/ARB
dose modification.
[0076] This Phase II Study was enrolled with a total of 306
subjects treated for an average duration of 9.5 months. All
subjects completed the trial, with 266 subjects completing 8 weeks,
226 subjects completing 6 months and 197 patients completing one
year.
[0077] Several key observations can be made. Looking at interim
data, and a statistically significant number of the 182 patients
had an albumin creatinine ratio (ACR) of .gtoreq.30 mg/g and others
had an ACR of >300 mg/g and an estimated glomerular filtration
rate (eGFR) of 15 to 44 mL/min/1.73 m.sup.2 at baseline. As shown
in FIG. 1, for all of these patients, the patient's serum potassium
concentration decreased from an average of 5.27 mEq/L at baseline
to an average of 4.57 mEq/L at 24 weeks. For patients having an
ACR.gtoreq.30 mg/g, the patient's serum potassium concentration
decreased from an average of 5.28 mEq/L at baseline to an average
of 4.60 mEq/L at 24 weeks. For patients having an ACR>300 mg/g,
the patient's serum potassium concentration decreased from an
average of 5.35 mEq/L at baseline to an average of 4.65 mEq/L at 24
weeks. For patients having an eGFR of 15 to 44 mL/min/1.73 m.sup.2,
the patient's serum potassium concentration decreased from an
average of 5.33 mEq/L at baseline to an average of 4.59 mEq/L at 24
weeks.
[0078] As shown in FIG. 2, for all of these patients, the patient's
systolic blood pressure decreased from an average of 154 at
baseline to an average of 137 at 24 weeks; for patients having an
ACR.gtoreq.30 mg/g, the patient's systolic blood pressure decreased
from an average of 154 at baseline to an average of 138 at 24
weeks; for patients having an ACR>300 mg/g, the patient's
systolic blood pressure decreased from an average of 154 at
baseline to an average of 137 at 24 weeks; and for patients having
an eGFR of 15 to 44 mL/min/1.73 m.sup.2, the patient's systolic
blood pressure decreased from an average of 152 at baseline to an
average of 135 at 24 weeks.
[0079] As shown in FIG. 3, for all of these patients, the patient's
diastolic blood pressure decreased from an average of 83 at
baseline to an average of 74 at 24 weeks; for patients having an
ACR.gtoreq.30 mg/g, the patient's diastolic blood pressure
decreased from an average of 84 at baseline to an average of 74 at
24 weeks; for patients having an ACR>300 mg/g, the patient's
diastolic blood pressure decreased from an average of 86 at
baseline to an average of 73 at 24 weeks; and or patients having an
eGFR of 15 to 44 mL/min/1.73 m.sup.2, the patient's diastolic blood
pressure decreased from an average of 82 at baseline to an average
of 73 at 24 weeks.
[0080] As shown in FIG. 4, for the patients in all groups and each
group separately (e.g., ACR of .gtoreq.30 mg/g, ACR of >300
mg/g, eGFR of 15 to 44 mL/min/1.73 m.sup.2), the ACR did not
significantly change over the 24 week treatment period.
[0081] As shown in FIG. 5, for patients having an eGFR of 15 to 44
mL/min/1.73 m.sup.2, the patient's eGFR increased from an average
of 32 mL/min/1.73 m.sup.2 at baseline to an average of 38
mL/min/1.73 m.sup.2 at 24 weeks. This increase in eGFR for these
patients was statistically significant.
[0082] As described above, FIGS. 6-9 show data from a certain
cohort of patients with pre-existing hyperkalemia taking a stable
dose of a RAAS inhibitor that came into the trial without a run-in
period. As shown in FIG. 6, the average of these patients' eGFR of
46 mL/min/1.73 m.sup.2 at baseline did not decrease over time, as
can be expected in these patients. Further data suggests that in a
subset of patients, the eGFR appears to increase at one year. As
shown in FIG. 7, the average of these patients' serum potassium
level decreased significantly from 5.3 mEq/L at baseline into the
normal range (to 4.6 mEq/L) at 12 months. As shown in FIG. 8, the
average of these patients' urine ACR of 853 mg/g at baseline was
not significantly different from the average of the patients' urine
ACR at any other time point. As shown in FIG. 9, the average of
these patients' systolic blood pressure decreased from 157 mmHg to
134 mmHg and the average of these patients' diastolic blood
pressure decreased from 85 mmHg to 77 mmHg.
[0083] Additional observations can be made from the study results.
First, the starting serum potassium is a factor in determining
efficacy of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer
crosslinked in the salt or acid form. The interim analysis of the
8-week Treatment Initiation Period performed for 304 subjects
showed a mean decrease in serum potassium from baseline to week 8
in subjects in the upper serum potassium stratum (Stratum 2: serum
K.sup.+>5.5 to <6.0 mEq/L) that was approximately twice that
in subjects in the lower serum potassium stratum (Stratum 1: serum
K.sup.+>5.0 to 5.5 mEq/L) (-0.90 mEq/L versus -0.47 mEq/L,
respectively). This baseline effect was seen within the first week
on treatment. Second, underlying RAAS inhibitor treatment does not
appear to influence the efficacy of
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form. Third, the efficacy of
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form appears to be independent of
comorbidities.
[0084] The potassium-binding polymers can be crosslinked cation
exchange polymers derived from at least one crosslinker and at
least one monomer containing acid groups in their protonated or
ionized form, such as sulfonic, sulfuric, carboxylic, phosphonic,
phosphoric, or sulfamic groups, or combinations thereof. In
general, the fraction of ionization of the acid groups of the
polymers used in this invention is greater than about 75% at the
physiological pH (e.g., about pH 6.5) in the colon and the
potassium binding capacity in vivo is greater than about 0.6
mEq/gram, more particularly greater than about 0.8 mEq/gram and
even more particularly greater than about 1.0 mEq/gram. Generally
the ionization of the acid groups is greater than about 80%, more
particularly it is greater than about 90%, and most particularly it
is about 100% at the physiological pH of the colon (e.g., about pH
6.5).
[0085] The acid containing polymers can contain more than one type
of acid group. In other instances, the acid containing polymers are
administered in their substantially anhydrous or salt form and
generate the ionized form when contacted with physiological fluids.
Representative structural units of these potassium-binding polymers
are shown in Table 1 wherein the asterisk at the end of a bond
indicates that bond is attached to another structural unit or to a
crosslinking unit.
TABLE-US-00001 TABLE 1 Examples of cation exchange structural units
- structures and theoretical binding capacities Fraction of
Fraction of Expected Expected Molar mass Theoretical titrable H
titrable H @ Capacity Capacity per charge capacity @ pH 3 pH 6 @ pH
3 @ pH 6 ##STR00001## 71 14.1 0.05 .35 0.70 4.93 ##STR00002## 87
11.49 0.2 0.95 2.3 10.92 ##STR00003## 53 18.9 0.25 0.5 4.72 9.43
##STR00004## 47.5 21.1 0.25 0.5 5.26 10.53 ##STR00005## 57 17.5 0.1
0.5 1.75 8.77 ##STR00006## 107 9.3 1 1 9.35 9.35 ##STR00007## 93
10.8 1 1 10.75 10.75 ##STR00008## 63 15.9 0 0.4 0 6.35 ##STR00009##
125 8 1 1 8 8 ##STR00010## 183 5.5 1 1 5.46 5.46 ##STR00011## 87
11.49 .1 .6 1.14 6.89
[0086] Other suitable cation exchange polymers contain repeat units
having the following structures:
##STR00012##
wherein R.sub.1 is a bond or nitrogen, R.sub.2 is hydrogen or Z,
R.sub.3 is Z or --CH(Z).sub.2, each Z is independently SO.sub.3H or
PO.sub.3H, x is 2 or 3, and y is 0 or 1, n is about 50 or more,
more particularly n is about 100 or more, even more particularly n
is about 200 or more, and most particularly n is about 500 or
more.
[0087] Sulfamic (i.e. when Z.dbd.SO.sub.3H) or phosphoramidic (i.e.
when Z.dbd.PO.sub.3H) polymers can be obtained from amine polymers
or monomer precursors treated with a sulfonating agent such as
sulfur trioxide/amine adducts or a phosphonating agent such as
P.sub.2O.sub.5, respectively. Typically, the acidic protons of
phosphonic groups are exchangeable with cations, like sodium or
potassium, at pH of about 6 to about 7.
[0088] Suitable phosphonate monomers include vinyl phosphonate,
vinyl-1,1-bis phosphonate, and ethylenic derivatives of
phosphonocarboxylate esters, oligo(methylenephosphonates), and
hydroxyethane-1,1-diphosphonic acid. Methods of synthesis of these
monomers are well known in the art.
[0089] The cation exchange structural units and repeat units
containing acid groups as described above are crosslinked to form
the crosslinked cation exchange polymers of the invention.
Representative crosslinking monomers include those shown in Table
2.
Table 2: Crosslinker Abbreviations and Structures
TABLE-US-00002 [0090] Molecular Abbreviation Chemical name
Structure Weight X-V-1 ethylenebisacrylamide ##STR00013## 168.2
X-V-2 N,N'-(ethane-1,2-diyl)bis(3- (N-vinylformamido) propanamide)
##STR00014## 310.36 X-V-3 N,N'-(propane-1,3-
diyl)diethenesulfonamide ##STR00015## 254.33 X-V-4
N,N'-bis(vinylsulfonylacetyl) ethylene diamine ##STR00016## 324.38
X-V-5 1,3-bis(vinylsulfonyl) 2- propanol ##STR00017## 240.3 X-V-6
vinylsulfone ##STR00018## 118.15 X-V-7 N,N'-methylenebisacrylamide
##STR00019## 154.17 ECH epichlorohydrin ##STR00020## 92.52 DVB
Divinyl benzene ##STR00021## 130.2 ODE 1,7-octadiene ##STR00022##
110.2 HDE 1,5-hexadiene ##STR00023## 82.15
The ratio of repeat units to crosslinker can be chosen by those of
skill in the art based on the desired physical properties of the
polymer particles. For example, the swelling ratio can be used to
determine the amount of crosslinking based on the general
understanding of those of skill in the art that as crosslinking
increases, the swelling ratio generally decreases.
[0091] The amount of crosslinker in the polymerization reaction
mixture can be in the range of 3 wt. % to 15 wt. %, more
specifically in the range of 5 wt. % to 15 wt. % and even more
specifically in the range of 8 wt. % to 12 wt. %, based on the
total weight of the monomers and crosslinkers added to the
polymerization reaction. Crosslinkers can include one or a mixture
of those in Table 2.
[0092] The crosslinked cation exchange polymer can also include a
pKa-decreasing group, preferably an electron-withdrawing
substituent, located adjacent to the acid group, preferably in the
alpha or beta position of the acid group. The preferred position
for the electron-withdrawing group is attached to the carbon atom
alpha to the acid group. Generally, electron-withdrawing
substituents are a hydroxyl group, an ether group, an ester group,
an acid group, or a halide atom. More preferably, the
electron-withdrawing substituent is a halide atom. Most preferably,
the electron-withdrawing group is fluoride and is attached to the
carbon atom alpha to the acid group. Acid groups are carboxylic,
phosphonic, phosphoric, or combinations thereof.
[0093] Other particularly preferred polymers result from the
polymerization of alpha-fluoro acrylic acid, difluoromaleic acid,
or an anhydride thereof. Monomers for use herein include
.alpha.-fluoroacrylate and difluoromaleic acid, with
.alpha.-fluoroacrylate being most preferred. This monomer can be
prepared from a variety of routes, see for example, Gassen et al,
J. Fluorine Chemistry, 55, (1991) 149-162, K F Pittman, C. U., M.
Ueda, et al. (1980). Macromolecules 13(5): 1031-1036.
Difluoromaleic acid is prepared by oxidation of fluoroaromatic
compounds (Bogachev et al, Zhurnal Organisheskoi Khimii, 1986,
22(12), 2578-83), or fluorinated furan derivatives (See U.S. Pat.
No. 5,112,993). A mode of synthesis of .alpha.-fluoroacrylate is
given in EP 415214.
[0094] Further, the potassium-binding polymer can be
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer,
crosslinked in the salt or acid form. Particularly, the
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form is in the salt form. The salt form
comprises the sodium, calcium, magnesium, ammonium, or a
combination thereof; preferably, the salt form comprises the
calcium salt form.
[0095] Also, the 2-fluoroacrylate-divinylbenzene-1,7-octadiene
copolymer, crosslinked in the salt form can be stabilized with a
linear polyol. Particularly, the
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer,
crosslinked in the salt form can be stabilized with 10 wt. % to
about 40 wt. % of a linear polyol based on the total weight of the
composition.
[0096] A linear polyol is added to the composition containing the
salt of a potassium-binding polymer (e.g.,
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer,
crosslinked in the salt form) in an amount effective to stabilize
the polymer salt, and generally from about 10 wt. % to about 40 wt.
% linear polyol based on the total weight of the composition.
[0097] The linear polyol is preferably a linear sugar (i.e., a
linear sugar alcohol). The linear sugar alcohol is preferably
selected from the group consisting of D-(+)arabitol, erythritol,
glycerol, maltitol, D-mannitol, ribitol, D-sorbitol, xylitol,
threitol, galactitol, isomalt, iditol, lactitol and combinations
thereof, more preferably selected from the group consisting of
D-(+)arabitol, erythritol, glycerol, maltitol, D-mannitol, ribitol,
D-sorbitol, xylitol, and combinations thereof, and most preferably
selected from the group consisting of xylitol, sorbitol, and a
combination thereof.
[0098] Preferably, the pharmaceutical composition contains from
about 15 wt. % to about 35 wt. % stabilizing polyol based on the
total weight of the composition. This linear polyol concentration
can be sufficient to reduce the release of fluoride ion from the
cation exchange polymer upon storage as compared to an otherwise
identical composition containing no stabilizing polyol at the same
temperature and storage time.
[0099] Further, the potassium-binding polymer can be a crosslinked
cation exchange polymer comprising units having Formulae 1, 2, and
3 as represented by the following structures:
##STR00024##
wherein R.sub.1 and R.sub.2 are independently selected from
hydrogen, alkyl, cycloalkyl, or aryl; A.sub.1 is carboxylic,
phosphonic, or phosphoric in its salt or acid form; X.sub.1 is
arylene; X.sub.2 is alkylene, an ether moiety or an amide moiety, m
is in the range of from about 85 to about 93 mol %, n is in the
range of from about 1 to about 10 mol % and p is in the range of
from about 1 to about 10 mol % calculated based on the ratio of
monomers and crosslinkers added to the polymerization mixture.
[0100] When X.sub.2 is an ether moiety, the ether moiety can be
--(CH.sub.2).sub.d--O--(CH.sub.2).sub.e-- or
--(CH.sub.2).sub.d--O--(CH.sub.2).sub.e--O--(CH.sub.2).sub.d--,
wherein d and e are independently an integer of 1 through 5.
[0101] Preferably, d is an integer from 1 to 2 and e is an integer
from 1 to 3.
[0102] When X.sub.2 is an amide moiety, the amide moiety can be
--C(O)--NH--(CH.sub.2).sub.p--NH--C(O)-- wherein p is an integer of
1 through 8. Preferably, p is an integer of 4 to 6.
[0103] The unit corresponding to Formula 2 can be derived from a
difunctional crosslinking monomer having the formula
CH.sub.2.dbd.CH--X.sub.1--CH.dbd.CH.sub.2 wherein X.sub.1 is as
defined in connection with Formula 2.
[0104] The unit corresponding to Formula 3 can be derived from a
difunctional crosslinking monomer having the formula
CH.sub.2.dbd.CH--X.sub.2--CH.dbd.CH.sub.2 wherein X.sub.2 is as
defined in connection with Formula 3.
[0105] In connection with Formula 1, R.sub.1 and R.sub.2 are
hydrogen and A.sub.1 is carboxylic.
[0106] In connection with Formula 2, X.sub.1 is an optionally
substituted phenylene, and preferably phenylene.
[0107] In connection with Formula 3, X.sub.2 is optionally
substituted ethylene, propylene, butylene, pentylene, or hexylene;
more specifically, X.sub.2 is ethylene, propylene, butylene,
pentylene, or hexylene; and preferably X.sub.2 is butylene.
Specifically, R.sub.1 and R.sub.2 are hydrogen, A.sub.1 is
carboxylic acid, X.sub.1 is phenylene and X.sub.2 is butylene.
[0108] Generally, the Formulae 1, 2 and 3 structural units of the
terpolymer have specific ratios, for example, wherein the
structural units corresponding to Formula 1 constitute at least
about 80 wt. %, particularly at least about 85 wt. %, and more
particularly at least about 90 wt. % or from about 80 wt. % to
about 95 wt. %, from about 85 wt. % to about 95 wt. %, from about
85 wt. % to about 93 wt. % or from about 88 wt. % to about 92 wt. %
based on the total weight of structural units of Formulae 1, 2, and
3 in the polymer, calculated based on the monomers of Formulae 11,
22, and 33 used in the polymerization reaction, and the weight
ratio of the structural unit corresponding to Formula 2 to the
structural unit corresponding to Formula 3 is from about 4:1 to
about 1:4, or about 1:1.
[0109] Further, the ratio of structural units when expressed as the
mole fraction of the structural unit of Formula 1 in the polymer is
at least about 0.87 or from about 0.87 to about 0.94, or from about
0.9 to about 0.92 based on the total number of moles of the
structural units of Formulae 1, 2, and 3, and the mole ratio of the
structural unit of Formula 2 to the structural unit of Formula 3 is
from about 0.2:1 to about 7:1, from about 0.2:1 to about 3.5:1;
from about 0.5:1 to about 1.3:1, from about 0.8 to about 0.9, or
about 0.85:1; again these calculations are performed using the
amounts of monomers of Formulae 11, 22, and 33 used in the
polymerization reaction. It is not necessary to calculate
conversion.
[0110] In some aspects, the crosslinked cation exchange polymer
comprises units corresponding to Formulae 1A, 2A, and 3A, wherein
Formula 1A, Formula 2A and Formula 3A correspond to the following
structures.
##STR00025##
[0111] In Formula 1 or 1A, the carboxylic acid can be in the acid
form (i.e., balanced with hydrogen), in salt form (i.e., balanced
with a counter-ion such as Ca.sup.2+, Mg.sup.2+, Na.sup.+,
NH.sub.4.sup.+, and the like) or in an ester form (i.e., balanced
with an alkyl, such as methyl). Preferably, the carboxylic acid is
in the salt form and balanced with a Ca.sup.2+ counterion.
[0112] When the carboxylic acid of the crosslinked cation exchange
form is balanced with a divalent counterion, two carboxylic acid
groups can be associated with the one divalent cation.
[0113] The polymers described herein are generally random polymers
wherein the exact order of the structural units of Formulae 1, 2,
or 3 (derived from monomers of Formulae 11, 22, or 33), or 1A, 2A,
or 3A (derived from monomers of Formulae 11A, 22A, or 33A) is not
predetermined.
[0114] A cation exchange polymer derived from monomers of Formulae
11, 22, and 33, followed by hydrolysis, can have the structure as
follows:
##STR00026##
wherein R.sub.1, R.sub.2, A.sub.1, X.sub.1, and X.sub.2 are as
defined in connection with Formulae 1, 2, and 3 and m is in the
range of from about 85 to about 93 mol %, n is in the range of from
about 1 to about 10 mol % and p is in the range of from about 1 to
about 10 mol % calculated based on the ratio of monomers and
crosslinkers added to the polymerization mixture. The wavy bonds in
the polymer structures of Formula 40 are included to represent the
random attachment of structural units to one another wherein the
structural unit of Formula 1 can be attached to another structural
unit of Formula 1, a structural unit of Formula 2, or a structural
unit of Formula 3; the structural units of Formulae 2 and 3 have
the same range of attachment possibilities.
[0115] Using the polymerization process described herein, with
monomers of Formulae 11A, 22A and 33A, followed by hydrolysis and
calcium ion exchange, a polymer having the general structure shown
below is obtained:
##STR00027##
wherein m is in the range of from about 85 to about 93 mol %, n is
in the range of from about 1 to about 10 mol % and p is in the
range of from about 1 to about 10 mol %, calculated based on the
ratios of monomers and crosslinkers added to the polymerization
mixture. The wavy bonds in the polymer structures of Formula 40A
are included to represent the random attachment of structural units
to one another wherein the structural unit of Formula 1A can be
attached to another structural unit of Formula 1A, a structural
unit of Formula 2A, or a structural unit of Formula 3A; the
structural units of Formulae 2A and 3A have the same range of
attachment possibilities.
[0116] The crosslinked cation exchange polymer is generally a
reaction product of a polymerization mixture that is subjected to
polymerization conditions. The polymerization mixture may also
contain components that are not chemically incorporated into the
polymer. The crosslinked cation exchange polymer typically
comprises a fluoro group and an acid group that is the product of
the polymerization of three different monomer units where one
monomer comprises a fluoro group and an acid group, another monomer
is a difunctional arylene monomer and a third monomer is a
difunctional alkylene, ether- or amide-containing monomer. More
specifically, the crosslinked cation exchange polymer can be a
reaction product of a polymerization mixture comprising monomers of
Formulae 11, 22, 33. The monomer of Formula 11, the monomer of
Formula 22, and the monomer of Formula 33 have the general
formulas:
##STR00028##
wherein R.sub.1 and R.sub.2 are as defined in connection with
Formula 1, X.sub.1 is as defined in connection with Formula 2,
X.sub.2 is as defined in connection with Formula 3, and A.sub.11 is
an optionally protected carboxylic, phosphonic, or phosphoric.
[0117] Preferably, A.sub.11 is a protected carboxylic, phosphonic,
or phosphoric.
[0118] The polymerization mixture typically further comprises a
polymerization initiator.
[0119] The reaction product of the polymerization mixture
comprising Formulae 11, 22, 33 comprises a polymer having protected
acid groups and comprising units corresponding to Formula 10 and
units corresponding to Formulae 2 and 3. Polymer products having
protected acid groups can be hydrolyzed to form a polymer having
unprotected acid groups and comprising units corresponding to
Formulae 1, 2, and 3. The structural units corresponding to Formula
10 have the structure
##STR00029##
wherein R.sub.1, R.sub.2, and A.sub.11 are as defined in connection
with Formula 11 and m is as defined in connection with Formula
1.
[0120] In any of the methods of the invention wherein the
crosslinked cation exchange polymer is a reaction product of a
polymerization mixture of monomers, A.sub.11 can be a protected
carboxylic, phosphonic, or phosphoric. The polymer formed in the
polymerization reaction contains protected carboxylic, phosphonic,
or phosphoric groups. A hydrolysis agent can be added to the
polymer formed in the polymerization reaction to hydrolyze these
protected groups, converting them to carboxylic, phosphonic, or
phosphoric groups, or other methods of deprotection well known in
the art can be used. The hydrolyzed polymer is preferably subjected
to ion exchange to obtain a preferred polymer salt for therapeutic
use.
[0121] Generally, the polymerization reaction mixture comprises at
least about 85 wt. % or from about 80 wt. % to about 95 wt. % of
monomers corresponding to Formula 11 based on the total weight of
the monomers corresponding to Formulae 11, 22, and 33; and the
mixture having a weight ratio of the monomer corresponding to
Formula 22 to the monomer corresponding to Formula 33 from about
4:1 to about 1:4, from about 2:1 to 1:2, or about 1:1.
[0122] The polymerization reaction mixture can comprise a unit
corresponding to Formula 11 having a mole fraction of at least
about 0.87 or from about 0.87 to about 0.94 based on the total
number of moles of the monomers corresponding to Formulae 11, 22,
and 33 and the mixture having a mole ratio of the monomer
corresponding to Formula 22 to the monomer corresponding to Formula
33 of from about 0.2:1 to about 7:1, from about 0.2:1 to about
3.5:1; from about 0.5:1 to about 1.3:1, from about 0.8 to about
0.9, or about 0.85:1.
[0123] Particular crosslinked cation exchange polymers are the
reaction product of a monomer corresponding to Formula 11A, a
monomer corresponding to Formula 22A, a monomer corresponding to
Formula 33A, and a polymerization initiator. The monomers
corresponding to Formulae 11A, 22A, and 33A have the structure:
##STR00030##
wherein alkyl is preferably selected from methyl, ethyl, propyl,
iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl,
iso-pentyl, sec-pentyl, or tert-pentyl. Most preferably, the alkyl
group is methyl or tert-butyl. The --O-alkyl moiety protects the
carboxyl moiety from reacting with other reactive moieties during
the polymerization reaction and can be removed by hydrolysis or
other deprotection methods as described in more detail below.
[0124] Further, the reaction mixture contains at least about 80 wt.
%, particularly at least about 85 wt. %, and more particularly at
least about 90 wt. % or from about 80 wt. % to about 95 wt. %, from
about 85 wt. % to about 95 wt. %, from about 85 wt. % to about 93
wt. % or from about 88 wt. % to about 92 wt. % of monomers
corresponding to Formula 11A based on the total weight of monomers
of Formulae 11A, 22A, and 33A and has a weight ratio of the monomer
corresponding to Formula 22A to the monomer corresponding to
Formula 33A of from about 4:1 to about 1:4 or about 1:1.
Additionally, the reaction mixture can have a mole fraction of at
least about 0.87 or from about 0.87 to about 0.94 of the monomer of
Formula 11A based on the total number of moles of the monomers of
Formulae 11A, 22A, and 33A and the mixture has a mole ratio of the
monomer of Formula 22A to the monomer of Formula 33A of from about
0.2:1 to about 7:1, from about 0.2:1 to about 3.5:1; from about
0.5:1 to about 1.3:1, from about 0.8 to about 0.9, or about
0.85:1.
[0125] Generally, the reaction mixture contains from about 80 wt. %
to about 95 wt. % of monomers corresponding to Formula 11A based on
the total weight of monomers corresponding to Formulae 11A, 22A,
and 33A. Additionally, the weight ratio of the monomer
corresponding to Formula 22A to the monomer corresponding to
Formula 33A of from about 4:1 to about 1:4 or about 1:1. Further,
the reaction mixture can have a mole fraction of from about 0.9 to
about 0.92 of the monomer of Formula 11A based on the total number
of moles of the monomers of Formulae 11A, 22A, and 33A. Also, the
mixture has a mole ratio of the monomer of Formula 22A to the
monomer of Formula 33A of from about 0.2:1 to about 7:1, from about
0.2:1 to about 3.5:1; from about 0.5:1 to about 1.3:1, from about
0.8 to about 0.9, or about 0.85:1.
[0126] An initiated polymerization reaction is employed where a
polymerization initiator is used in the polymerization reaction
mixture to aid initiation of the polymerization reaction. When
preparing poly(methylfluoro acrylate) or (polyMeFA) or any other
crosslinked cation exchange polymer of the invention in a
suspension polymerization reaction, the nature of the free radical
initiator plays a role in the quality of the suspension in terms of
polymer particle stability, yield of polymer particles, and the
polymer particle shape. Use of water-insoluble free radical
initiators, such as lauroyl peroxide, can produce polymer particles
in a high yield. Without being bound by any particular theory, it
is believed that a water-insoluble free radical initiator initiates
polymerization primarily within the dispersed phase containing the
monomers of Formulae 11, 22, and 33. Such a reaction scheme
provides polymer particles rather than a bulk polymer gel. Thus,
the process uses free radical initiators with water solubility
lower than 0.1 g/L, particularly lower than 0.01 g/L.
Polymethylfluoroacrylate particles can be produced with a
combination of a low water solubility free radical initiator and
the presence of a salt in the aqueous phase, such as sodium
chloride.
[0127] The polymerization initiator can be chosen from a variety of
classes of initiators. For instance, initiators that generate
polymer initiating radicals upon exposure to heat include
peroxides, persulfates or azo type initiators (e.g.,
2,2'-azobis(2-methylpropionitrile), lauroyl peroxide (LPO),
tert-butyl hydro peroxide,
dimethyl-2,2'-azobis(2-methylpropionate),
2,2'-azobis[2-methyl-N-(2-hydroxyethyl)propionamide],
2,2'-azobis[2-(2-imidazolin-2-yl)propane], (2,2''-azo
bis(2,4-dimethylvaleronitrile), azobisisobutyronitrile (AIBN) or a
combination thereof. Another class of polymer initiating radicals
is radicals generated from redox reactions, such as persulfates and
amines. Radicals can also be generated by exposing certain
initiators to UV light or exposure to air.
[0128] For those polymerization reactions that contain additional
components in the polymerization mixture that are not intended to
be incorporated into the polymer, such additional components
typically comprise surfactants, solvents, salts, buffers, aqueous
phase polymerization inhibitors and/or other components known to
those of skill in the art.
[0129] When the polymerization is carried out in a suspension mode,
the additional components may be contained in an aqueous phase
while the monomers and initiator may be contained in an organic
phase. When an aqueous phase is present, the aqueous phase may be
comprised of water, surfactants, stabilizers, buffers, salts, and
polymerization inhibitors.
[0130] A surfactant may be selected from the group consisting of
anionic, cationic, nonionic, amphoteric, zwitterionic, or a
combination thereof. Anionic surfactants are typically based on
sulfate, sulfonate or carboxylate anions. These surfactants
include, sodium dodecyl sulfate (SDS), ammonium lauryl sulfate,
other alkyl sulfate salts, sodium laureth sulfate (or sodium lauryl
ether sulfate (SLES)), N-lauroylsarcosine sodium salt,
lauryldimethylamine-oxide (LDAO), ethyltrimethylammoniumbromide
(CTAB), bis(2-ethylhexyl)sulfosuccinate sodium salt, alkyl benzene
sulfonate, soaps, fatty acid salts, or a combination thereof.
[0131] Cationic surfactants, for example, contain quaternary
ammonium cations. These surfactants are cetyl trimethylammonium
bromide (CTAB or hexadecyl trimethyl ammonium bromide),
cetylpyridinium chloride (CPC), polyethoxylated tallow amine
(POEA), benzalkonium chloride (BAC), benzethonium chloride (BZT),
or a combination thereof.
[0132] Zwitterionic or amphoteric surfactants include dodecyl
betaine, dodecyl dimethylamine oxide, cocamidopropyl betaine, coco
ampho glycinate, or a combination thereof.
[0133] Nonionic surfactants include alkyl poly(ethylene oxide),
copolymers of poly(ethylene oxide) and poly(propylene oxide)
(commercially called Poloxamers or Poloxamines), alkyl
polyglucosides (including octyl glucoside, decyl maltoside) fatty
alcohols, cetyl alcohol, oleyl alcohol, cocamide MEA, cocamide DEA,
or a combination thereof. Other pharmaceutically acceptable
surfactants are well known in the art and are described in
McCutcheon's Emulsifiers and Detergents, N. American Edition
(2007).
[0134] Polymerization reaction stabilizers may be selected from the
group consisting of organic polymers and inorganic particulate
stabilizers. Examples include polyvinyl alcohol-co-vinylacetate and
its range of hydrolyzed products, polyvinylacetate,
polyvinylpyrolidinone, salts of polyacrylic acid, cellulose ethers,
natural gums, or a combination thereof.
[0135] Buffers may be selected from the group consisting of, for
example, 4-2-hydroxyethyl-1-piperazineethanesulfonic acid,
2-{[tris(hydroxymethyl)methyl]amino}ethanesulfonic acid,
3-(N-morpholino)propanesulfonic acid,
piperazine-N,N'-bis(2-ethanesulfonic acid), sodium phosphate
dibasic heptahydrate, sodium phosphate monobasic monohydrate or a
combination thereof.
[0136] Polymerization reaction salts may be selected from the group
consisting of potassium chloride, calcium chloride, potassium
bromide, sodium bromide, sodium bicarbonate, ammonium
peroxodisulfate, or a combination thereof.
[0137] Polymerization inhibitors may be used as known in the art
and selected from the group consisting of
1,1,3-tris(2-methyl-4-hydroxy-5-tert-butylphenyl)butane,
1,3,5-trimethyl-2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl)benzene,
1-aza-3,7-dioxabicyclo[3.3.0]octane-5-methanol,
2,2'-ethylidene-bis(4,6-di-tert-butylphenol),
2,2'-ethylidenebis(4,6-di-tert-butylphenyl) fluorophosphite,
2,2'-methylenebis(6-tert-butyl-4-ethylphenol),
2,2'-methylenebis(6-tert-butyl-4-methylphenol),
2,5-di-tert-butyl-4-methoxyphenol, 2,6-di-tert-butyl-4-(dimethyl
aminomethyl)phenol, 2-heptanone oxime,
3,3',5,5'-tetramethylbiphenyl-4,4'-diol,
3,9-bis(2,4-dicumylphenoxy)-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]unde-
cane, 4,4-dimethyloxazolidine, 4-methyl-2-pentanone oxime,
5-ethyl-1-aza-3,7-dioxabicyclo[3.3.0]octane,
6,6'-dihydroxy-5,5'-dimethoxy-[1,1'-biphenyl]-3,3'-dicarboxaldehyde,
distearyl-3,3'-thiodipropionate,
ditetradecyl-3,3'-thiodipropionate,
ditridecyl-3,3'-thiodipropionate,
octadecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate,
pentaerythritol
tetrakis(3,5-di-tert-butyl-4-hydroxyhydrocinnamate),
poly(1,2-dihydro-2,2,4-trimethylquinoline), sodium D-isoascorbate
monohydrate,
tetrakis(2,4-di-tert-butylphenyl)-4,4'-biphenyldiphosphonite,
tris(3,5-di-tert-butyl-4-hydroxybenzyl) isocyanurate,
tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl) isocyanurate,
sodium nitrite or a combination thereof.
[0138] Generally, the polymerization mixture is subjected to
polymerization conditions. While suspension polymerization is
preferred, as already discussed herein, the polymers of this
invention may also be prepared in bulk, solution or emulsion
polymerization processes. The details of such processes are within
the skill of one of ordinary skill in the art based on the
disclosure of this invention. The polymerization conditions
typically include polymerization reaction temperatures, pressures,
mixing and reactor geometry, sequence and rate of addition of
polymerization mixtures and the like.
[0139] Polymerization temperatures are typically in the range of
from about 50 to 100.degree. C. Polymerization pressures are
typically run at atmospheric pressure, but can be run at higher
pressures (for example 130 PSI of nitrogen). Polymerization depends
on the scale of the polymerization and the equipment used, and is
within the skill of one of ordinary skill in the art. Various
alpha-fluoroacrylate polymers and the synthesis of these polymers
are described in U.S. Patent Application Publication No.
2005/0220752, herein incorporated by reference.
[0140] As described in more detail in connection with the examples
herein, the crosslinked cation exchange polymer can be synthesized
in a polymerization suspension polymerization reaction by preparing
an organic phase and an aqueous phase. The organic phase typically
contains a monomer of Formula 11, a monomer of Formula 22, a
monomer of Formula 33, and a polymerization initiator. The aqueous
phase contains a suspension stabilizer, a water soluble salt,
water, and optionally a buffer. The organic phase and the aqueous
phase are then combined and stirred under nitrogen. The mixture is
generally heated to about 60.degree. C. to about 80.degree. C. for
about 2.5 to about 3.5 hours, allowed to rise up to 95.degree. C.
after polymerization is initiated, and then cooled to room
temperature. After cooling, the aqueous phase is removed. Water is
added to the mixture, the mixture is stirred, and the resulting
solid is filtered. The solid is washed with water, alcohol or
alcohol/water mixtures.
[0141] As described above, polymerization suspension stabilizers,
such as polyvinyl alcohol, are used to prevent coalescence of
particles during the polymerization process. Further, it has been
observed that the addition of sodium chloride in the aqueous phase
decreased coalescence and particle aggregation. Other suitable
salts for this purpose include salts that are soluble in the
aqueous phase. Water soluble salts are added at a concentration of
from about 0.1 wt. % to about 10 wt. %, particularly from about 2
wt. % to about 5 wt. % and even more particularly from about 3 wt.
% to about 4 wt. %.
[0142] Preferably, an organic phase of methyl 2-fluoroacrylate (90
wt. %), 1,7-octadiene (5 wt. %) and divinylbenzene (5 wt. %) is
prepared and 0.5 wt. % of lauroyl peroxide is added to initiate the
polymerization reaction. Additionally, an aqueous phase of water,
polyvinyl alcohol, phosphates, sodium chloride, and sodium nitrite
is prepared. Under nitrogen and while keeping the temperature below
about 30.degree. C., the aqueous and organic phases are mixed
together. Once mixed completely, the reaction mixture is gradually
heated with continuous stirring. After the polymerization reaction
is initiated, the temperature of the reaction mixture is allowed to
rise up to about 95.degree. C. Once the polymerization reaction is
complete, the reaction mixture is cooled to room temperature and
the aqueous phase is removed. The solid can be isolated by
filtration after water is added to the mixture. The resulting
product is a crosslinked (methyl
2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer.
[0143] As discussed herein, after polymerization, the product may
be hydrolyzed or otherwise deprotected by methods known in the art.
For hydrolysis of the polymer having ester groups to form a polymer
having carboxylic acid groups, preferably, the polymer is
hydrolyzed with a strong base (e.g., NaOH, KOH, Mg(OH).sub.2, or
Ca(OH).sub.2) to remove the alkyl (e.g., methyl) group and form the
carboxylate salt. Depending on the pH of the hydrolysis mixture,
the proton form of the (2-fluoroacrylic
acid)-divinylbenzene-1,7-octadiene terpolymer is formed.
Alternatively, the polymer can be hydrolyzed with a strong acid
(e.g., HCl) to form the carboxylate salt. Preferably, the (methyl
2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer is
hydrolyzed with an excess of aqueous sodium hydroxide solution at a
temperature from about 30.degree. C. to about 100.degree. C. to
yield (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene
terpolymer. Typically, the hydrolysis reaction is carried out for
about 15 to 25 hours. After hydrolysis, the solid is filtered and
washed with water and/or an alcohol.
[0144] The cation of the polymer salt formed in the hydrolysis
reaction or other deprotection step depends on the base used in
that step. For example, when sodium hydroxide is used as the base,
the sodium salt of the polymer is formed. This sodium ion can be
exchanged for another cation by contacting the sodium salt with an
excess of an aqueous metal salt to yield an insoluble solid of the
desired polymer salt. After the desired ion exchange, the product
is washed with an alcohol and/or water and dried directly or dried
after a dewatering treatment with denatured alcohol; preferably,
the product is washed with water and dried directly. For example,
the sodium salt of the cation exchange polymer is converted to the
calcium salt by washing with a solution that substitutes calcium
for sodium, for example, by using calcium chloride, calcium
acetate, calcium lactate gluconate, or a combination thereof. And,
more specifically, to exchange sodium ions for calcium ions, the
(sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer
is contacted with an excess of aqueous calcium chloride to yield an
insoluble solid of crosslinked (calcium
2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer. If the
pH of the hydrolysis mixture is sufficiently low, the proton form
of the (2-fluoroacrylic acid)-divinylbenzene-1,7-octadiene
terpolymer is formed.
[0145] Using this suspension polymerization process, a cross-linked
polyMeFA polymer is isolated in good yield, generally above about
85%, more specifically above about 90%, and even more specifically
above about 93%. The yield of the second step (i.e., hydrolysis)
preferably occurs in 100%, providing an overall yield after
hydrolysis of above about 85%, more specifically above about 90%,
and even more specifically above about 93%.
[0146] To add the linear polyol to the composition, the salt of the
polymer is slurried with an aqueous solution of polyol (e.g.,
sorbitol), typically with the slurry containing an excess amount of
polyol based on polymer weight. Performing this step can reduce
inorganic fluoride in the composition. The slurry is maintained
under conditions known to those of skill in the art, such as for at
least 3 hours and ambient temperature and pressure. The solids are
then filtered off and dried to desired moisture content.
[0147] The methods of treatment of hypertension, hyperkalemia, and
chronic kidney disease can be used for a variety of treatment
periods including treatment periods of 1, 2, 4, 6, 8, 12, 16, 20,
24, 28, 32, 36, 40, 44, 48, 52, or more weeks. The treatment period
can also be 2 years, 3 years, 4 years, 5 years, or more.
[0148] When treating the patients for hyperkalemia or chronic
kidney disease using the methods of the invention, the patient can
have an estimated glomerular filtration rate (eGFR) from about 15
mL/min/1.73 m.sup.2 to about 44 mL/min/1.73 m.sup.2.
[0149] The methods of treating hyperkalemia, methods of treating
hypertension in a patient having chronic kidney disease, type 2
diabetes, heart failure or a combination thereof, and methods of
treating chronic kidney disease of the invention can cause several
improvements such as a decrease in the patient's serum potassium
level after 48 hours, or more of treatment as compared to the
patient's serum potassium level before treatment with the
potassium-binding agent; an increase in the patient's eGFR after 2,
3, 4, 5, 6, months or more of treatment as compared to the
patient's eGFR before treatment with the potassium-binding agent; a
decrease in the patient's urine albumin:creatinine ratio (ACR)
after 2, 3, 4, 5, 6, months or more of treatment as compared to the
patient's urine ACR before treatment with the potassium-binding
agent; a decrease in the patient's systolic and diastolic blood
pressure after 1, 2, 3, 4, 5, 6, 7 days or more of treatment as
compared to the patient's systolic and diastolic blood pressure
before treatment with the potassium-binding agent; a decrease in
the patient's serum aldosterone level after 6, 12, 24, 48, 72,
hours or more of treatment as compared to the patient's serum
aldosterone level before treatment with the potassium-binding
agent, or a combination thereof.
[0150] For the changes in serum potassium level, eGFR, blood
pressure, and ACR, it is understood that the potassium-binding
agent can be any one of the agents described herein even when the
method is described relating to administration of
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form.
[0151] The methods of treating hyperkalemia in a chronic kidney
disease patient in need thereof optionally being treated with an
effective amount of a renin-angiotensin-aldosterone system (RAAS)
agent comprise administering an effective amount of the
potassium-binding agent to the patient and observing either (i) a
decrease in the patient's serum creatinine level as compared to the
patient's serum creatinine level before treatment with the
potassium-binding agent, (ii) an increase in the time to
progression of end stage renal disease as compared to a chronic
kidney disease patient optionally treated with a RAAS agent but not
treated with the potassium-binding agent, (iii) an increase in
survival as compared to a chronic kidney disease patient optionally
treated with a RAAS agent but not treated with the
potassium-binding agent, or (iv) an increase or stabilization of
estimated glomerular filtration rate (eGFR) as compared to the
patient's eGFR before treatment with the potassium-binding agent,
all indicating an increase or stabilization of the patient's kidney
function.
[0152] The potassium-binding agent can be
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt or acid form.
[0153] The methods of treating hyperkalemia, methods of treating
hypertension in a patient having chronic kidney disease, type 2
diabetes, heart failure or a combination thereof, and methods of
treating chronic kidney disease can result in the patient's eGFR
after treatment with the potassium-binding agent being increased by
at least 4, 5, 6 mL/min/1.73 m.sup.2 or more as compared to the
patient's eGFR before treatment with the potassium-binding
agent
[0154] When treating hypertension, hyperkalemia, or chronic kidney
disease in patients in need thereof, the effective amount of the
potassium-binding agent comprises up to a maximum daily dose of 60
grams. The effective amount of the potassium-binding agent can be a
daily dose of from about 3 grams to about 60 grams; from about 5
grams to about 60 grams; from about 7 grams to about 60 grams; from
about 10 grams to about 60 grams; from about 12 grams to about 60
grams; or from about 15 grams to about 60 grams.
[0155] The effective amount of the potassium-binding agent can be a
daily dose of from about 3 grams to about 40 grams; from about 5
grams to about 40 grams; from about 10 grams to about 40 grams; or
from about 15 grams to about 40 grams.
[0156] Particularly, the effective amount of the potassium-binding
agent can be a daily dose of about 18 gram to about 60 grams or
about 18 grams to about 40 grams.
[0157] When the potassium binding agent is
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked
in the salt form, the dose in grams is calculated by determining
the amount of the salt form of crosslinked
2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer plus the
calcium counterion. So, this dose does not include the water and
sorbitol that may be contained in the powder that is administered
to the patient
[0158] Dosing can be once a day, twice a day or three times per
day, however, once a day or twice a day is preferred, with once a
day being most preferred.
[0159] The methods of treating hypertension, hyperkalemia, or
chronic kidney disease of the invention can further comprise
administering an effective amount of a
renin-angiotensin-aldosterone system (RAAS) agent to the patient;
determining the serum potassium level in the patient; and
increasing the amount of the potassium-binding agent subsequently
administered to the patient based on the serum potassium level if
greater than or equal to 5.1 mEq/L. The methods of hypertension,
hyperkalemia, or chronic kidney disease can further comprise a step
wherein the amount of the potassium-binding agent was increased by
5 g or 10 g per day.
[0160] The methods of treating hypertension, hyperkalemia, or
chronic kidney disease of the invention can further comprise
administering an effective amount of a
renin-angiotensin-aldosterone system (RAAS) agent to the patient;
determining the serum potassium level in the patient; decreasing
the amount of the potassium-binding agent subsequently administered
to the patient based on the serum potassium level if less than 4.0
mEq/L. The method of treating hypertension, hyperkalemia, or
chronic kidney disease can further comprise a step wherein the
amount of the potassium-binding agent was decreased by 5 g or 10 g
per day.
[0161] The methods hypertension, hyperkalemia, or chronic kidney
disease of the invention can further comprise treating
proteinuria.
[0162] Further, the methods of treating hypertension, hyperkalemia,
proteinuria, or chronic kidney disease may include treating the
patient with an effective amount of a RAAS agent, the RAAS agent
being an angiotensin converting enzyme (ACE) inhibitor, an
angiotensin receptor blocker (ARB), an aldosterone antagonist (AA),
an aldosterone synthase inhibitor, or a combination thereof.
Particularly, the patient may be treated with an effective amount
of a RAAS agent, the RAAS agent is an ACE inhibitor, an ARB, or a
combination thereof.
[0163] For the methods where the patient is being treated with an
effective amount of a RAAS agent, the effective amount of the RAAS
agent comprises up to a maximum daily tolerated dose.
[0164] The RAAS agent comprises fosinopril, ramipril, captopril,
lisinopril, trandolapril, moexipril, quinapril, enalapril,
benazepril, perindopril, eprosartan, olmesartan, losartan,
telmisartan, valsartan, candesartan, irbesartan, azilsartan
medoxomil, spironolactone, eplerenone, or a combination
thereof.
[0165] The maximum daily tolerated dose of specific RAAS agents is
4 mg/day (trandolapril), 8 mg/day (perindopril), 20 mg/day
(ramipril), 30 mg/day (moexipril), 32 mg/day (candesartan), 40
mg/day (fosinopril, lisinopril, enalapril, benazepril, olmesartan),
80 mg/day (quinapril telmisartan, azilsartan, medoxomil), 100
mg/day (losartan), 300 mg/day (captopril, irbesartan), 320 mg/day
(valsartan), or 800 mg/day (eprosartan).
[0166] When the RAAS agent comprises spironolactone, the maximum
daily tolerated dose is 200 mg/day.
[0167] When the RAAS agent comprises eplerenone, the maximum daily
tolerated dose is 50 mg/day.
[0168] Patients being treated with the methods of treating
hypertension, hyperkalemia or chronic kidney disease of the
invention can further be treated with an effective amount of a
beta-adrenergic blocking agent. The beta-adrenergic blocking agent
can comprise betaxolol, bisoprolol, atenolol, metoprolol,
nebivolol, metoprolol, esmolol, acebutolol, propranolol, nadolol,
carvedilol, labetalol, sotalol, timolol, carteolol, penbutolol,
pindolol, or a combination thereof.
[0169] In all of the methods described above, the potassium-binding
agent can be 2-fluoroacrylate-divinylbenzene-1,7-octadiene
copolymer crosslinked in the salt or acid form.
[0170] The term "treating" as used herein includes achieving a
therapeutic benefit. By therapeutic benefit is meant eradication,
amelioration, or prevention of the underlying disorder being
treated. For example, in a hyperkalemia patient, therapeutic
benefit includes eradication or amelioration of the underlying
hyperkalemia. Also, a therapeutic benefit is achieved with the
eradication, amelioration, or prevention of one or more of the
physiological symptoms associated with the underlying disorder such
that an improvement is observed in the patient, notwithstanding
that the patient may still be afflicted with the underlying
disorder. For example, administration of a potassium-binding
polymer to a patient experiencing hyperkalemia provides therapeutic
benefit not only when the patient's serum potassium level is
decreased, but also when an improvement is observed in the patient
with respect to other disorders that accompany hyperkalemia, like
renal failure. In some treatment regimens, the crosslinked cation
exchange polymer or composition of the invention may be
administered to a patient at risk of developing hyperkalemia or to
a patient reporting one or more of the physiological symptoms of
hyperkalemia, even though a diagnosis of hyperkalemia may not have
been made.
[0171] End stage renal disease is characterized by a patient being
on dialysis or having a renal transplant.
[0172] Proteinuria, also known as albuminuria or urine albuminis,
is a condition in which urine contains an abnormal amount of
protein. Albumin is the main protein in the blood. Proteins are the
building blocks for all body parts, including muscles, bones, hair,
and nails. Proteins in the blood also perform a number of important
functions. They protect the body from infection, help blood clot,
and keep the right amount of fluid circulating throughout the
body.
[0173] As blood passes through healthy kidneys, they filter out the
waste products and leave in the things the body needs, like
albumin. and other proteins. Most proteins are too big to pass
through the kidneys' filters into the urine. However, proteins from
the blood can leak into the urine when the filters of the kidney,
called glomeruli, are damaged.
[0174] Proteinuria is a sign of chronic kidney disease (CID), which
can result from diabetes, high blood pressure, and diseases that
cause inflammation in the kidneys. For this reason, testing for
albumin in the urine is part of a routine medical assessment for
everyone. Kidney disease is sometimes called renal disease. If CKD
progresses, it can lead to end-stage renal disease (ESRD), when the
kidneys fail completely. A person with ESRD must receive a kidney
transplant or regular blood-cleansing treatments called
dialysis.
[0175] The potassium-binding polymers used in the methods of the
invention can be administered as pharmaceutical compositions
containing an effective amount, i.e., in an amount effective to
achieve therapeutic or prophylactic benefit of the
potassium-binding polymer and a pharmaceutically acceptable
carrier. The actual amount effective for a particular application
will depend on the patient (e.g., age, weight, etc.), the condition
being treated, and the route of administration. Determination of an
effective amount is well within the capabilities of those skilled
in the art, especially in light of the disclosure herein. The
effective amount for use in humans can be determined from animal
models. For example, a dose for humans can be formulated to achieve
gastrointestinal concentrations that have been found to be
effective in animals.
[0176] The polymers and compositions described herein can be used
as food products and/or food additives. They can be added to foods
prior to consumption or while packaging.
[0177] The polymers or pharmaceutically acceptable salts thereof,
or compositions described herein, can be delivered to the patient
using a wide variety of routes or modes of administration. The most
preferred routes for administration are oral, intestinal, or
rectal. Rectal routes of administration are known to those of skill
in the art. Intestinal routes of administration generally refer to
administration directly into a segment of the gastrointestinal
tract, e.g., through a gastrointestinal tube or through a stoma.
The most preferred route for administration is oral.
[0178] The polymers (or pharmaceutically acceptable salts thereof)
may be administered per se or in the form of a pharmaceutical
composition wherein the active compound(s) is in admixture or
mixture with one or more pharmaceutically acceptable excipient.
Pharmaceutical compositions for use in accordance with the present
invention may be formulated in conventional manner using one or
more pharmaceutically acceptable excipients comprising carriers,
diluents, and auxiliaries which facilitate processing of the active
compounds into preparations which can be used physiologically.
Proper composition is dependent upon the route of administration
chosen.
[0179] For oral administration, the polymers or compositions of the
invention can be formulated readily by combining the polymer or
composition with pharmaceutically acceptable excipients well known
in the art. Such excipients enable the compositions of the
invention to be formulated as tablets, pills, dragees, capsules,
liquids, gels, syrups, slurries, suspensions, wafers, and the like,
for oral ingestion by a patient to be treated.
[0180] The oral composition can not have an enteric coating.
[0181] Pharmaceutical preparations for oral use can be obtained as
a solid excipient, optionally grinding a resulting mixture, and
processing the mixture of granules, after adding suitable
auxiliaries, if desired, to obtain tablets or dragee cores.
Suitable excipients are, in particular, fillers such as sugars,
including lactose or sucrose; cellulose preparations such as, for
example, maize starch, wheat starch, rice starch, potato starch,
gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose,
and/or polyvinyl pyrrolidone (PVP); and various flavoring agents
known in the art. If desired, disintegrating agents may be added,
such as the cross-linked polyvinyl pyrrolidone, agar, or alginic
acid or a salt thereof such as sodium alginate.
[0182] The active ingredient (e.g., polymer) can constitute over
about 20%, more particularly over about 40%, even more particularly
over about 50%, and most particularly more than about 60% by weight
of the oral dosage form, the remainder comprising suitable
excipient(s). In compositions containing water and linear polyol,
the polymer preferably constitutes over about 20%, more
particularly over about 40%, and even more particularly over about
50% by weight of the oral dosage form.
[0183] The polymers of the invention can be provided as
pharmaceutical compositions in the form of liquid compositions. The
pharmaceutical composition can contain a polymer dispersed in a
suitable liquid excipient. Suitable liquid excipients are known in
the art; see, e.g., Remington's Pharmaceutical Sciences.
[0184] Unless otherwise indicated, an alkyl group as described
herein alone or as part of another group is an optionally
substituted linear saturated monovalent hydrocarbon radical
containing from one to twenty carbon atoms and preferably one to
eight carbon atoms, or an optionally substituted branched saturated
monovalent hydrocarbon radical containing three to twenty carbon
atoms, and preferably three to eight carbon atoms. Examples of
unsubstituted alkyl groups include methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl,
s-pentyl, t-pentyl, and the like.
[0185] The term "amide moiety" as used herein represents a bivalent
(i.e., difunctional) group including at least one amido linkage
##STR00031##
such as --C(O)--NR.sub.A--R.sub.C--NR.sub.B--C(O)-- wherein R.sub.A
and R.sub.B are independently hydrogen or alkyl and R.sub.C is
alkylene. For example, an amide moiety can be
--C(O)--NH--(CH.sub.2).sub.p--NH--C(O)-- wherein p is an integer of
1 to 8.
[0186] The term "aryl" as used herein alone or as part of another
group denotes an optionally substituted monovalent aromatic
hydrocarbon radical, preferably a monovalent monocyclic or bicyclic
group containing from 6 to 12 carbons in the ring portion, such as
phenyl, biphenyl, naphthyl, substituted phenyl, substituted
biphenyl or substituted naphthyl. Phenyl and substituted phenyl are
the more preferred aryl groups. The term "aryl" also includes
heteroaryl.
[0187] The terms "carboxylic acid group", "carboxylic" or
"carboxyl" denote the monovalent radical --C(O)OH. Depending upon
the pH conditions, the monovalent radical can be in the form
--C(O)O.sup.-Q.sup.+ wherein Q.sup.+ is a cation (e.g., sodium), or
two of the monovalent radicals in close proximity can bond with a
divalent cation Q.sup.2+ (e.g., calcium, magnesium), or a
combination of these monovalent radicals and --C(O)OH are
present.
[0188] The term "cycloalkyl" as used herein denotes optionally an
optionally substituted cyclic saturated monovalent bridged or
non-bridged hydrocarbon radical containing from three to eight
carbon atoms in one ring and up to 20 carbon atoms in a multiple
ring group. Exemplary unsubstituted cycloalkyl groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, adamantyl, norbornyl, and the like.
[0189] The term "-ene" as used as a suffix as part of another group
denotes a bivalent radical in which a hydrogen atom is removed from
each of two terminal carbons of the group, or if the group is
cyclic, from each of two different carbon atoms in the ring. For
example, alkylene denotes a bivalent alkyl group such as methylene
(--CH.sub.2--) or ethylene (--CH.sub.2CH.sub.2--), and arylene
denotes a bivalent aryl group such as o-phenylene, m-phenylene, or
p-phenylene.
[0190] The term "ether moiety" as used herein represents a bivalent
(i.e., difunctional) group including at least one ether linkage
(i.e., --O--). For example, in Formulae 3 or 33 as defined herein,
the ether moiety can be --R.sub.AOR.sub.B-- or
--R.sub.AOR.sub.COR.sub.B-- wherein R.sub.A, R.sub.B and R.sub.C
are independently alkylene.
[0191] The term "heteroaryl," as used herein alone or as part of
another group, denotes an optionally substituted monovalent
monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms,
where one or more, preferably one, two, or three, ring atoms are
heteroatoms independently selected from N, O, and S, and the
remaining ring atoms are carbon. Exemplary heteroaryl moieties
include benzofuranyl, benzo[d]thiazolyl, isoquinolinyl, quinolinyl,
thiophenyl, imidazolyl, oxazolyl, quinolinyl, furanyl, thazolyl,
pyridinyl, furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl,
quinolinyl, isoquinolinyl, and the like.
[0192] The term "heterocyclo," as used herein alone or as part of
another group, denotes a saturated or unsaturated monovalent
monocyclic group of 4 to 8 ring atoms, in which one or two ring
atoms are heteroatom(s), independently selected from N, O, and S,
and the remaining ring atoms are carbon atoms. Additionally, the
heterocyclic ring may be fused to a phenyl or heteroaryl ring,
provided that the entire heterocyclic ring is not completely
aromatic. Exemplary heterocyclo groups include the heteroaryl
groups described above, pyrrolidino, piperidino, morpholino,
piperazino, and the like.
[0193] The term "hydrocarbon" as used herein describes a compound
or radical consisting exclusively of the elements carbon and
hydrogen.
[0194] The term "phosphonic" or "phosphonyl" denotes the monovalent
radical
##STR00032##
[0195] The term "phosphoric" or "phosphoryl" denotes the monovalent
radical
##STR00033##
[0196] The term "protected" as used herein as part of another group
denotes a group that blocks reaction at the protected portion of a
compound while being easily removed under conditions that are
sufficiently mild so as not to disturb other substituents of the
compound. For example, a protected carboxylic acid
group-C(O)OP.sub.g or a protected phosphoric acid group
--OP(O)(OH)OP.sub.g or a protected phosphonic acid group
--P(O)(OH)OP.sub.g each have a protecting group P.sub.g associated
with the oxygen of the acid group wherein P.sub.g can be alkyl
(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
s-butyl, t-butyl, n-pentyl, i-pentyl, s-pentyl, t-pentyl, and the
like), benzyl, silyl (e.g., trimethylsilyl (TMS), triethylsilyl
(TES), triisopropylsilyl (TIPS), triphenylsilyl (TPS),
t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS) and the
like. A variety of protecting groups and the synthesis thereof may
be found in "Protective Groups in Organic Synthesis" by T. W.
Greene and P. G. M. Wuts, John Wiley & Sons, 1999. When the
term "protected" introduces a list of possible protected groups, it
is intended that the term apply to every member of that group. That
is, the phrase "protected carboxylic, phosphonic or phosphoric" is
to be interpreted as "protected carboxylic, protected phosphonic or
protected phosphoric." Likewise, the phrase "optionally protected
carboxylic, phosphoric or phosphonic" is to be interpreted as
"optionally protected carboxylic, optionally protected phosphonic
or optionally protected phosphoric."
[0197] The term "substituted" as in "substituted aryl,"
"substituted alkyl," and the like, means that in the group in
question (i.e., the alkyl, aryl or other group that follows the
term), at least one hydrogen atom bound to a carbon atom is
replaced with one or more substituent groups such as hydroxy
(--OH), alkylthio, phosphino, amido (--CON(R.sub.A)(R.sub.B),
wherein R.sub.A and R.sub.B are independently hydrogen, alkyl, or
aryl), amino(-N(R.sub.A)(R.sub.B), wherein R.sub.A and R.sub.B are
independently hydrogen, alkyl, or aryl), halo (fluoro, chloro,
bromo, or iodo), silyl, nitro (--NO.sub.2), an ether (--OR.sub.A
wherein R.sub.A is alkyl or aryl), an ester (--OC(O)R.sub.A wherein
R.sub.A is alkyl or aryl), keto (--C(O)R.sub.A wherein R.sub.A is
alkyl or aryl), heterocyclo, and the like. When the term
"substituted" introduces a list of possible substituted groups, it
is intended that the term apply to every member of that group. That
is, the phrase "optionally substituted alkyl or aryl" is to be
interpreted as "optionally substituted alkyl or optionally
substituted aryl."
[0198] Having described the invention in detail, it will be
apparent that modifications and variations are possible without
departing from the scope of the invention defined in the appended
claims.
EXAMPLES
[0199] The following non-limiting examples are provided to further
illustrate the present invention.
Example 1: Sorbitol-Loaded, Crosslinked (calcium
2-fluoroacrylate)-divinylbenzene-1,7-octadiene Copolymer
[0200] Methyl 2-fluoroacrylate (MeFA) was purchased and was vacuum
distilled before use. Divinylbenzene (DVB) was purchased from
Aldrich, technical grade, 80%, mixture of isomers, and was used as
received. 1,7-octadiene (ODE), lauroyl peroxide (LPO), polyvinyl
alcohol (PVA) (typical molecular weight 85,000-146,000, 87-89%
hydrolyzed), sodium chloride (NaCl), sodium phosphate dibasic
heptahydrate (Na.sub.2HPO.sub.4.7H.sub.2O) and sodium phosphate
monobasic monohydrate (NaH.sub.2PO.sub.4.H.sub.2O) were purchased
from commercial sources and used as received.
[0201] In an appropriately sized reactor with appropriate stirring
and other equipment, a 90:5:5 weight ratio mixture of organic phase
of monomers was prepared by mixing methyl 2-fluoroacrylate,
1,7-octadiene, and divinylbenzene. One-half part of lauroyl
peroxide was added as an initiator of the polymerization reaction.
A stabilizing aqueous phase was prepared from water, polyvinyl
alcohol, phosphates, sodium chloride, and sodium nitrite. The
aqueous and monomer phases were mixed together under nitrogen at
atmospheric pressure, while maintaining the temperature below
30.degree. C. The reaction mixture was gradually heated while
stirring continuously. Once the polymerization reaction has
started, the temperature of the reaction mixture was allowed to
rise to a maximum of 95.degree. C.
[0202] After completion of the polymerization reaction, the
reaction mixture was cooled and the aqueous phase was removed.
Water was added, the mixture was stirred, and the solid material
was isolated by filtration. The solid was then washed with water to
yield a crosslinked (methyl
2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer. The
(methyl 2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer
was hydrolyzed with an excess of aqueous sodium hydroxide solution
at 90.degree. C. for 24 hours to yield (sodium
2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer. After
hydrolysis, the solid was filtered and washed with water. The
(sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer
was exposed at room temperature to an excess of aqueous calcium
chloride solution to yield insoluble cross-linked (calcium
2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer.
[0203] After the calcium ion exchange, the wet polymer is slurried
with 25-30% w/w aqueous solution of sorbitol at ambient temperature
to yield sorbitol-loaded polymer. Excess sorbitol was removed by
filtration. The resulting polymer was dried at 20-30.degree. C.
until the desired moisture content (10-25 w/w/%) was reached. This
provided a sorbitol-loaded, crosslinked (calcium
2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer
(5016CaS).
Example 2: Phase II Clinical Study
[0204] Study Design Overview. The study has two 5016CaS treatment
periods: a treatment initiation period for 8 weeks, followed by a
long-term maintenance period for an additional 44 weeks which
allows treatment with 5016CaS for up to a total of one year (i.e.,
52 weeks). Eligible non-hyperkalemic patients start a run-in period
of 1 to 4 weeks in duration (Cohorts 1 and 2). Eligible
hyperkalemic patients start treatment with 5016CaS immediately
(Cohort 3). At the first occurrence of serum potassium
(K.sup.+)>5.0-<6.0 mEq/L, eligible patients from all three
cohorts are assigned to one of two strata according to baseline
serum potassium and received 5016CaS treatment at randomly assigned
starting doses ranging from 10 to 40 g/day. The dose amount is
based on the amount of the polymer anion plus calcium (e.g., on a
water and sorbitol free basis). A 10 g dose of polymer anion plus
calcium is equivalent to an 8.4 g dose of the polymer anion. The
study duration is up to 62 weeks per patient (including screening
and follow-up procedures) and the study population is approximately
306 patients. The study variables included change in serum
potassium, blood pressure, estimated GFR and ACR.
[0205] Eligible patients are assigned to one of two 5016CaS
treatment strata wherein Stratum 1 includes patients with serum
K.sup.+>5.0-5.5 mEq/L, these patients are randomized in a 1:1:1
ratio to receive either 10 g/day, 20 g/day, or 30 g/day 5016CaS
starting doses within each study cohort. Stratum 2 includes
patients with serum K.sup.+>5.5-<6.0 mEq/L, these patients
are randomized in a 1:1:1 ratio to receive 20 g/day, 30 g/day, or
40 g/day 5016CaS starting doses within each study cohort.
[0206] Patients start 5016CaS treatment at their assigned dose
level on the evening of day 1. They continue taking losartan 100
mg/d (with or without spironolactone 25-50 mg/d) or pre-study ACEI
and/or ARB with spironolactone 25-50 mg/d, (as per their Cohort 1
or 2 assignment), as well as any other protocol-allowed
antihypertensive therapy. Patients in Cohort 3 continue their
pre-study ACEI and/or ARB.
[0207] Dose and Route of 5016CaS Administration. 5016CaS was taken
orally twice daily in equally divided doses for up to 52 weeks
starting on day 1 (the evening dose only). Patients take 5016CaS
twice a day with their regular meals (breakfast and dinner). The
5016CaS dose is adjusted as needed according to the appropriate
titration algorithm (treatment initiation or long-term maintenance)
starting on day 3 and up to the week 51 visit. The minimum allowed
dose is 0 g/d (no 5016CaS dispensed) and the maximum dose is 60
g/d.
[0208] FIGS. 1-5 look at potassium reduction, blood pressure
control, eGFR change and protein urea change by the following
patient subtypes: (1) patients with any amount of protein in the
urine (2) patients with microalbuminuria (3) patients with
macroalbuminuria and (4) patients with stage 4 chronic kidney
disease (CKD). FIG. 1 shows that a serum potassium reduction was
experienced by all of these patient types. FIGS. 2 and 3 showed
blood pressure reductions and that 5016CaS was as effective in
reducing blood pressure in all of the patient types. FIG. 4 shows
that there was no significant increase in protein urea levels in
any of the patient types, so 5016CaS effectively stabilized the
patient's protein excretion. FIG. 5 shows that renal function
appeared to stabilize in all patient types with a potential for
improvement in renal function in patients with stage 4 CKD.
[0209] The study protocol was completed by 182 patients for the
analysis following in this Example 2. A statistically significant
number of these patients had an albumin creatinine ratio (ACR) of
.gtoreq.30 mg/g and others had an ACR of >300 mg/g and an
estimated glomerular filtration rate (eGFR) of 15 to 44 mL/min/1.73
m.sup.2 at baseline. For all of these patients, the patient's serum
potassium concentration decreased from an average of 5.27 mEq/L at
baseline to an average of 4.57 mEq/L at 24 weeks. For patients
having an ACR.gtoreq.30 mg/g, the patient's serum potassium
concentration decreased from an average of 5.28 mEq/L at baseline
to an average of 4.60 mEq/L at 24 weeks. For patients having an
ACR>300 mg/g, the patient's serum potassium concentration
decreased from an average of 5.35 mEq/L at baseline to an average
of 4.65 mEq/L at 24 weeks. For patients having an eGFR of 15 to 44
mL/min/1.73 m.sup.2, the patient's serum potassium concentration
decreased from an average of 5.33 mEq/L at baseline to an average
of 4.59 mEq/L at 24 weeks.
[0210] For patients having an eGFR of 15 to 44 mL/min/1.73 m.sup.2,
the patient's eGFR increased from an average of 32 mL/min/1.73
m.sup.2 at baseline to an average of 38 mL/min/1.73 m.sup.2 at 24
weeks. This increase in eGFR for these patients was statistically
significant.
[0211] For the patients in all groups and each group separately
(e.g., ACR of .gtoreq.30 mg/g, ACR of >300 mg/g, eGFR of 15 to
44 mL/min/1.73 m.sup.2), the ACR did not significantly change over
the 24 week treatment period.
[0212] For all of these patients, the patient's systolic blood
pressure decreased from an average of 154 at baseline to an average
of 137 at 24 weeks and the patient's diastolic blood pressure
decreased from an average of 83 at baseline to an average of 74 at
24 weeks. For patients having an ACR>30 mg/g, the patient's
systolic blood pressure decreased from an average of 154 at
baseline to an average of 138 at 24 weeks and the patient's
diastolic blood pressure decreased from an average of 84 at
baseline to an average of 74 at 24 weeks. For patients having an
ACR>300 mg/g, the patient's systolic blood pressure decreased
from an average of 154 at baseline to an average of 137 at 24 weeks
and the patient's diastolic blood pressure decreased from an
average of 86 at baseline to an average of 73 at 24 weeks. For
patients having an eGFR of 15 to 44 mL/min/1.73 m.sup.2, the
patient's systolic blood pressure decreased from an average of 152
at baseline to an average of 135 at 24 weeks and the patient's
diastolic blood pressure decreased from an average of 82 at
baseline to an average of 73 at 24 weeks.
[0213] FIGS. 6-9 present one year data from a certain cohort of 90
patients with pre-existing hyperkalemia that were taking a stable
dose of a RAAS inhibitor that came into the trial without a run-in
period. These figures show that kidney function (FIG. 6) and
urinary protein excretion (FIG. 8) appeared to stabilize, with
reductions in serum potassium (FIG. 7) and blood pressure (FIG. 9).
When analyzing the twelve month data for these patients, the
average eGFR was 46 mL/min/1.73 m.sup.2 at baseline (BL), 49
mL/min/1.73 m.sup.2 at one month (M1), 51 mL/min/1.73 m.sup.2 at
two months (M2), 49 mL/min/1.73 m.sup.2 at six months (M6) and 48
mL/min/1.73 m.sup.2 at twelve months (M12) (FIG. 6). The eGFR for
these patients did not significantly change over the twelve month
treatment period. These patients also experienced a significant
decrease in serum potassium level. (FIG. 7) For example, the
average serum potassium level was 5.3 mEq/L at baseline (BL), 4.5
mEq/L at one month (M1), 4.5 mEq/L at two months (M2), 4.6 mEq/L at
six months (M6), and 4.6 mEq/L at twelve months (M12). These
patients also had an average urine ACR of 853 mg/g at baseline
(BL), 900 mg/g at one month (M1), 971 mg/g at two months (M2), 930
mg/g at six months (M6), and 802 mg/g at twelve months (M12). The
average systolic blood pressure of these patients was 157 mmHg at
baseline (BL), 138 mmHg at one month (M1), 139 mmHg at two months
(M2), 138 mmHg at six months (M6), and 134 mmHg at twelve months
(M12). The average diastolic blood pressure was 85 mmHg at baseline
(BL), 74 mmHg at one month (M1), 73 mmHg at two months (M2), 73
mmHg at six months (M6), and 77 mmHg at twelve months (M12).
[0214] The mean change in serum potassium from baseline to week 4
or first dose titration, whichever comes first, is presented by
stratum in Table 1. To be consistent with the study protocol, the
most recent non-missing measurement of serum potassium was used for
patients who did not titrate before the week 4 visit (last
observation carried forward, i.e., LOCF). 5016CaS lowered serum
potassium in all dose groups in both strata; the p-values indicate
that the reduction is statistically significantly different from
zero. The reference groups in both strata are the randomized
starting doses chosen for the Phase III study.
TABLE-US-00003 TABLE 1 Estimated mean change from baseline in
central serum K.sup.+ to week 4 or first dose titration, by
randomized starting dose within stratum Stratum 1 Local serum
K.sup.+ >5.0-5.5 mEq/L 10 g/d 20 g/d 30 g/d Overall At week 4 or
prior to first titration N = 74 N = 73 N = 73 N = 220 Change in
serum K.sup.+ (mEq/L) from baseline n.sup.a 73 73 72 218 Least
square mean .+-. standard error -0.35 .+-. 0.066 -0.51 .+-. 0.066
-0.54 .+-. 0.066 -0.47 .+-. 0.038 95% confidence interval -0.48,
-0.22 -0.64, -0.38 -0.67, -0.41 -0.54, -0.39 p-value.sup.b
<0.001 <0.001 <0.001 <0.001 Comparison to reference
Mean difference reference 0.17 0.19 95% confidence interval -0.018,
0.35 0.006, 0.37 p-value.sup.c 0.076 0.043 Stratum 2 Local serum
K.sup.+ >5.5-<6.0 mEq/L 20 g/d 30 g/d 40 g/d Overall At week
4 or prior to first titration N = 26 N = 28 N = 30 N = 84 Change in
serum K.sup.+ (mEq/L) from baseline n.sup.a 26 27 30 83 Least
square mean .+-. standard error -0.85 .+-. 0.136 -0.95 .+-. 0.132
-0.90 .+-. 0.127 -0.90 .+-. 0.076 95% confidence interval -1.12,
-0.58 -1.21, -0.68 -1.15, -0.65 -1.05, -0.75 p-value.sup.b
<0.001 <0.001 <0.001 <0.001 Comparison to reference
Mean difference reference 0.097 0.050 95% confidence interval
-0.28, 0.48 -0.32, 0.42 p-value.sup.c 0.61 0.79 Column header
counts include all randomized patients who received RLY5016
(intent-to-treat population) by each randomized starting dose
within stratum. Each stratum is analyzed separately using a
parallel lines analysis of covariance (ANCOVA) model where the
outcome is change in serum K.sup.+ from baseline. Each model
contains a fixedeffect for randomized starting dose, cohort, and
continuous baseline serum K.sup.+. Estimates and confidence
intervals for each randomized starting/dose gives were generated
using linear contrasts across the observed values of the
covariates. .sup.aNumber of patients in the intent-to-treat
population with non-missing baseline serum K.sup.+ at baseline.
.sup.bp-values test the hypothesis that the mean change in serum
K.sup.+ from baseline is 0. .sup.cp-values test the pairwise
difference in change in serum K.sup.+ from baseline between dose
groups. Positive values indicate lager reduction from baseline as
compared to the reference group.
[0215] 5016CaS lowered serum potassium in all dose groups in both
strata regardless of dose titration beginning as early as Day 3 and
stabilizing after approximately Week 2. Most patients were able to
maintain serum potassium before and after dose titration in the
range of 4.0 mEq/L to 5.0 mEq/L in all dose groups in both
strata.
[0216] The primary outcome, mean change from baseline in serum K
(mEq/L) at week 4 or first 5016CaS dose titration analyzed using a
parallel lines ANCOVA model, was -0.47.+-.0.038 (p<0.001) in S1
and -0.90.+-.0.076 (p<0.001) in S2. Mean K reduction after a
median 2 days of treatment was -0.29.+-.0.03 (S1) and -0.55.+-.0.05
mEq/L (S2). Table 2 summarizes the means and changes from baseline,
allowing titration.
TABLE-US-00004 TABLE 2 Stratum 1 ((S1), BL K >5.0-5.5 mEq/L)
Stratum 2 ((S2), BL K >5.5-<6.0 mEq/L) Baseline Week 4 Week 8
Baseline Week 4 Week8 (n = 217) (n = 197) (n = 185) (N = 84) (n =
70) (n = 70) Mean K (SE) 5.15 4.54 4.59 5.64 4.65 4.52 (mEq/L)
(0.02) (0.03) (0.03) (0.04) (0.06) (0.06) LS Mean change -- -0.61
-0.55 -- -0.97 -1.10 (SE) (mEq/L) (0.03) (0.03) (0.06) (0.06)
[0217] 5016CaS reduced serum K within days of treatment initiation,
an effect sustained over twelve months without significant adverse
effects.
Example 3: Analysis of Systolic Blood Pressure from Phase II
Clinical Study
[0218] The following section contains results of the repeated
measures analyses of mean systolic blood pressure during the 8-week
treatment initiation period of the Phase II Clinical Study
disclosed in Example 2. Table 3 through Table 6 present the
analyses of mean change from baseline. Tables 3 and 4 present the
results for all patients; Tables 5 and 6 present subsets of the
analyses according to hyperkalemia status at screening (Cohort 3).
In general, patients in Stratum 2 (patients with serum
K.sup.+>5.5-<6.0 mEq/L) experience smaller mean decreases in
blood pressure than patients in Stratum 1 (patients with serum
K.sup.+>5.0-5.5 mEq/L). Patients in Cohort 3, who entered the
study hyperkalemic and did not participate in the run-in phase,
contributed to the reduction in mean systolic blood pressure
(Tables 5 and 6).
[0219] For Tables 3-6, column header counts include all randomized
patients who received RLY5016 (intent-to-treat population) by each
randomized starting dose within stratum. The data were derived from
a mixed model for repeated measures where the outcome variable was
a change in systolic blood pressure (SBP) from baseline. Each
stratum was analyzed separately. Each model contained a fixed
effect for cohort, randomized starting dose, time (visit),
continuous baseline SBP, and randomized starting dose by visit
interaction. The within-patient correlation was modeled using
heterogeneous Toeplitz structure. Estimates, standard errors (SE),
and confidence intervals for each randomized starting dose were
generated using linear contrasts across the observed values of the
covariates. Overall estimates, standard errors, and confidence
intervals across randomized dosing groups assume equal distribution
across dosing groups. The total patients in the analysis, N, were
determined by the number of randomized patients who received
RLY5016, had a baseline measure, and contributed at least one
post-baseline measure to this analysis. Not all patients
contributed measures at each visit.
TABLE-US-00005 TABLE 3 Estimated mean change from baseline in
systolic blood pressure by randomized starting dose, all patients
Stratum 1 Stratum 1 - Local serum K+ >5.0-5.5 mEq/L Change in
SBP from 10 g/d 20 g/d 30 g/d Overall baseline (mmHg) N = 74 N = 73
N = 73 N = 220 Patients in analysis, N 74 73 73 220 Day 3, n 70 70
72 212 Least squares mean .+-. SE -9.3 .+-. 1.8 -4.9 .+-. 1.8 -10.3
.+-. 1.8 -8.2 .+-. 1.0 95% confidence interval -12.8, -5.7 -8.5,
-1.4 -13.9, -6.8 -10.2, -6.1 Week 1, n 72 71 72 215 Least squares
mean .+-. SE -11.1 .+-. 1.9 -8.8 .+-. 2.0 -12.0 .+-. 1.9 -10.6 .+-.
1.1 95% confidence interval -14.9, -7.3 -12.6, -4.9 -15.8, -8.2
-12.8, -8.4 Week 2, n 70 70 71 211 Least squares mean .+-. SE -12.4
.+-. 2.0 -5.7 .+-. 2.0 -13.8 .+-. 2.0 -10.6 .+-. 1.1 95% confidence
interval -16.3, -8.5 -9.6, -1.8 -17.7, -9.9 -12.9, -8.4 Week 3, n
64 69 71 204 Least squares mean .+-. SE -11.5 .+-. 2.1 -7.5 .+-.
2.0 -12.5 .+-. 2.0 -10.5 .+-. 1.2 95% confidence interval -15.6,
-7.4 -11.5, -3.5 -16.4, -8.6 -12.8, -8.2 Week 4, n 65 67 69 201
Least squares mean .+-. SE -13.3 .+-. 2.0 -8.0 .+-. 2.0 -12.4 .+-.
2.0 -11.2 .+-. 1.1 95% confidence interval -17.2, -9.3 -11.9, -4.1
-16.2, -8.5 -13.5, -9.0 Week 5, n 65 66 67 198 Least squares mean
.+-. SE -12.0 .+-. 2.0 -9.6 .+-. 2.0 -13.7 .+-. 2.0 -11.8 .+-. 1.2
95% confidence interval -15.9, -8.0 -13.5, -5.7 -17.7, -9.8 -14.0,
-9.5 Week 6, n 65 66 64 195 Least squares mean .+-. SE -13.3 .+-.
2.1 -6.9 .+-. 2.0 -12.8 .+-. 2.1 -11.0 .+-. 1.2 95% confidence
interval -17.3, -9.3 -10.9, -2.9 -16.8, -8.7 -13.3, -8.7 Week 7, n
64 64 65 193 Least squares mean .+-. SE -15.6 .+-. 2.0 -9.5 .+-.
2.0 -11.0 .+-. 2.0 -12.0 .+-. 1.2 95% confidence interval -19.5,
-11.6 -13.6, -5.5 -15.0, -7.0 -14.3, -9.7 Week 8, n 66 64 66 196
Least squares mean .+-. SE -16.3 .+-. 2.0 -12.0 .+-. 2.0 -13.8 .+-.
2.0 -14.0 .+-. 1.1 95% confidence interval -20.2, -12.5 -15.9, -8.1
-17.7, -10.0 -16.3, -11.8
TABLE-US-00006 TABLE 4 Estimated mean change from baseline in
systolic blood pressure by randomized starting dose, all patients
Stratum 2 Stratum 2 - Local serum K+ >5.5-<6.0 mEq/L Change
in SBP from 20 g/d 30 g/d 40 g/d Overall baseline (mmHg) N = 26 N =
28 N = 30 N = 84 Patients in analysis, N 26 28 29 83 Day 3, n 26 27
29 82 Least squares mean .+-. SE -7.3 .+-. 3.5 -9.6 .+-. 3.4 -6.6
.+-. 3.3 -7.8 .+-. 2.0 95% confidence interval -14.2, -0.4 -16.3,
-2.9 -13.1, -0.08 -11.7, -4.0 Week 1, n 24 28 28 80 Least squares
mean .+-. SE -6.2 .+-. 4.2 -11.5 .+-. 3.9 -4.8 .+-. 3.9 -7.5 .+-.
2.3 95% confidence interval -14.4, 1.9 -19.2, -3.9 -12.5, 2.8
-12.1, -3.0 Week 2, n 24 27 26 77 Least squares mean .+-. SE -5.8
.+-. 4.2 -7.7 .+-. 4.0 -3.3 .+-. 4.0 -5.6 .+-. 2.4 95% confidence
interval -14.2, 2.5 -15.6, 0.2 -11.3, 4.6 -10.3, -1.0 Week 3, n 24
25 25 74 Least squares mean .+-. SE -12.0 .+-. 3.8 -10.0 .+-. 3.6
-8.3 .+-. 3.6 -10.1 .+-. 2.1 95% confidence interval -19.4, -4.6
-17.2, -2.9 -15.5, -1.2 -14.3, -5.9 Week 4, n 24 25 24 73 Least
squares mean .+-. SE -9.6 .+-. 3.1 -10.7 .+-. 3.0 -3.8 .+-. 3.0
-8.1 .+-. 1.7 95% confidence interval -15.7, -3.5 -16.6, -4.9 -9.7,
2.1 -11.5, -4.6 Week 5, n 24 25 23 72 Least squares mean .+-. SE
-8.3 .+-. 3.6 -9.4 .+-. 3.5 -6.0 .+-. 3.5 -7.9 .+-. 2.0 95%
confidence interval -15.3, -1.2 -16.2, -2.7 -13.0, 0.9 -11.9, -3.9
Week 6, n 24 25 22 71 Least squares mean .+-. SE -7.5 .+-. 3.6
-11.4 .+-. 3.4 -5.4 .+-. 3.6 -8.1 .+-. 2.0 95% confidence interval
-14.5, -0.5 -18.1, -4.6 -12.4, 1.6 -12.1, -4.1 Week 7, n 24 25 22
71 Least squares mean .+-. SE -10.4 .+-. 3.4 -8.4 .+-. 3.3 -1.3
.+-. 3.4 -6.7 .+-. 1.9 95% confidence interval -17.1, -3.7 -14.8,
-1.9 -8.0, 5.4 -10.5, -2.9 Week 8, n 24 26 24 74 Least squares mean
.+-. SE -7.8 .+-. 3.5 -11.0 .+-. 3.4 -1.7 .+-. 3.5 -6.9 .+-. 2.0
95% confidence interval -14.8, -0.9 -17.6, -4.4 -8.5, 5.1 -10.8,
-3.0
TABLE-US-00007 TABLE 5 Estimated mean change from baseline in
systolic blood pressure by randomized starting dose, patients who
were hyperkalemic at screening Stratum 1 Stratum 1 - Local serum K+
>5.0-5.5 mEq/L Change in SBP from 10 g/d 20 g/d 30 g/d Overall
baseline (mmHg) N = 57 N = 57 N = 56 N = 170 Patients in analysis,
N 57 57 56 170 Day 3, n 56 56 56 168 Least squares mean .+-. SE
-9.8 .+-. 2.0 -5.6 .+-. 2.0 -12.5 .+-. 2.0 -9.3 .+-. 1.2 95%
confidence interval -13.8, -5.8 -9.6, -1.6 -16.5, -8.5 -11.6, -7.0
Week 1, n 55 55 55 165 Least squares mean .+-. SE -11.4 .+-. 2.2
-9.9 .+-. 2.2 -12.7 .+-. 2.2 -11.3 .+-. 1.3 95% confidence interval
-15.7, -7.1 -14.2, -5.6 -16.9, -8.4 -13.8, -8.9 Week 2, n 54 54 54
162 Least squares mean .+-. SE -12.3 .+-. 2.3 -5.8 .+-. 2.3 -15.2
.+-. 2.3 -11.1 .+-. 1.3 95% confidence interval -16.8, -7.8 -10.3,
-1.3 -19.8, -10.7 -13.7, -8.5 Week 3, n 49 53 54 156 Least squares
mean .+-. SE -11.6 .+-. 2.5 -10.2 .+-. 2.4 -13.8 .+-. 2.4 -11.9
.+-. 1.4 95% confidence interval -16.4, -6.7 -14.9, -5.5 -18.5,
-9.1 -14.6, -9.1 Week 4, n 51 52 53 156 Least squares mean .+-. SE
-13.4 .+-. 2.3 -10.8 .+-. 2.3 -14.2 .+-. 2.3 -12.8 .+-. 1.3 95%
confidence interval -18.0, -8.8 -15.4, -6.3 -18.7, -9.7 -15.4,
-10.2 Week 5, n 50 51 53 154 Least squares mean .+-. SE -11.4 .+-.
2.3 -10.5 .+-. 2.3 -15.0 .+-. 2.3 -12.3 .+-. 1.3 95% confidence
interval -16.0, -6.8 -15.1, -5.9 -19.5, -10.5 -14.9, -9.7 Week 6, n
50 51 52 153 Least squares mean .+-. SE -12.3 .+-. 2.2 -6.8 .+-.
2.2 -15.0 .+-. 2.2 -11.4 .+-. 1.3 95% confidence interval -16.6,
-7.9 -11.1, -2.5 -19.3, -10.7 -13.8, -8.9 Week 7, n 50 49 52 151
Least squares mean .+-. SE -14.5 .+-. 2.1 -9.0 .+-. 2.1 -13.2 .+-.
2.1 -12.2 .+-. 1.2 95% confidence interval -18.6, -10.3 -13.2, -4.8
-17.3, -9.1 -14.6, -9.8 Week 8, n 51 49 52 152 Least squares mean
.+-. SE -16.6 .+-. 2.2 -13.0 .+-. 2.3 -14.9 .+-. 2.2 -14.8 .+-. 1.3
95% confidence interval -21.0, -12.3 -17.4, -8.6 -19.2, -10.5
-17.3, -12.3
TABLE-US-00008 TABLE 6 Estimated mean change from baseline in
systolic blood pressure by randomized starting dose, patients who
were hyperkalemic at screening Stratum 2 Stratum 2 - Local serum
K.sup.+ >5.5-<6.0 mEq/L Change in SBP from 20 g/d 30 g/d 40
g/d Overall baseline (mmHg) N = 24 N = 24 N = 25 N = 73 Patients in
analysis, N 24 24 24 72 Day 3, n 24 23 24 71 Least squares mean
.+-. SE -10.2 .+-. 3.6 -11.2 .+-. 3.7 -6.5 .+-. 3.7 -9.3 .+-. 2.1
95% confidence interval -17.3, -3.0 -18.5, -3.9 -13.6, 0.7 -13.4,
-5.1 Week 1, n 22 24 23 69 Least squares mean .+-. SE -8.4 .+-. 4.4
-13.8 .+-. 4.3 -2.1 .+-. 4.3 -8.1 .+-. 2.5 95% confidence interval
-17.0, 0.3 -22.2, -5.4 -10.7, 6.4 -13.0, -3.2 Week 2, n 22 23 21 66
Least squares mean .+-. SE -8.0 .+-. 4.3 -10.4 .+-. 4.2 -0.3 .+-.
4.3 -6.2 .+-. 2.5 95% confidence interval -16.4, 0.4 -18.6, -2.1
-8.8, 8.2 -11.1, -1.4 Week 3, n 22 21 20 63 Least squares mean .+-.
SE -14.1 .+-. 3.9 -12.8 .+-. 3.9 -6.7 .+-. 4.0 -11.2 .+-. 2.3 95%
confidence interval -21.7, -6.4 -20.5, -5.1 -14.5, 1.2 -15.6, -6.7
Week 4, n 22 21 19 62 Least squares mean .+-. SE -12.0 .+-. 3.2
-13.6 .+-. 3.2 -4.0 .+-. 3.3 -9.9 .+-. 1.9 95% confidence interval
-18.3, -5.8 -19.9, -7.3 -10.6, 2.5 -13.5, -6.2 Week 5, n 22 21 18
61 Least squares mean .+-. SE -10.1 .+-. 3.7 -12.9 .+-. 3.8 -4.1
.+-. 4.0 -9.1 .+-. 2.2 95% confidence interval -17.5, -2.8 -20.3,
-5.5 -11.9, 3.7 -13.4, -4.7 Week 6, n 22 21 17 60 Least squares
mean .+-. SE -9.9 .+-. 3.5 -14.2 .+-. 3.6 -2.1 .+-. 3.8 -8.7 .+-.
2.1 95% confidence interval -16.8, -3.0 -21.2, -7.2 -9.6, 5.5
-12.9, -4.6 Week 7, n 22 21 17 60 Least squares mean .+-. SE -12.7
.+-. 3.5 -11.9 .+-. 3.5 1.9 .+-. 3.8 -7.6 .+-. 2.1 95% confidence
interval -19.5, -5.9 -18.8, -5.0 -5.5, 9.4 -11.6, -3.5 Week 8, n 22
22 19 63 Least squares mean .+-. SE -11.4 .+-. 3.6 -14.4 .+-. 3.5
-0.3 .+-. 3.8 -8.7 .+-. 2.1 95% confidence interval -18.4, -4.4
-21.3, -7.4 -7.7, 7.1 -12.8, -4.6
Example 4: Analysis of Diastolic Blood Pressure from Phase II
Clinical Study
[0220] This section contains results of the repeated measures
analyses of diastolic blood pressure during the 8-week treatment
initiation period of the Phase II Clinical Study disclosed in
Example 2. Table 7 through Table 10 present the analyses of mean
change in diastolic blood pressure from baseline. Tables 7 and 8
present the results for all patients; Tables 9 and 10 present
subsets of the analyses according to hyperkalemia status at
screening (Cohort 3). Patients in both cohorts and strata
experienced modest mean reductions in diastolic blood pressure.
[0221] For Tables 7-10, column header counts include all randomized
patients who received RLY5016 (intent-to-treat population) by each
randomized starting dose within stratum. The data were derived from
a mixed model for repeated measures where the outcome variable was
a change in diastolic blood pressure (DBP) from baseline. Each
stratum was analyzed separately. Each model contained a fixed
effect for cohort, randomized starting dose, time (visit),
continuous baseline DBP, and randomized starting dose by visit
interaction. The within-patient correlation was modeled using
heterogeneous Toeplitz structure. Estimates, standard errors (SE),
and confidence intervals for each randomized starting dose were
generated using linear contrasts across the observed values of the
covariates. Overall estimates, standard errors, and confidence
intervals across randomized dosing groups assume equal distribution
across dosing groups. The total patients in the analysis, N, were
determined by the number of randomized patients who received
RLY5016, had a baseline measure, and contributed at least one
post-baseline measure to this analysis. Not all patients
contributed measures at each visit.
TABLE-US-00009 TABLE 7 Estimated mean change from baseline in
diastolic blood pressure by randomized starting/dose, all patients
Stratum 1 Stratum 1 - Local serum K.sup.+ >5.0-5.5 mEq/L Change
in DBP from 10 g/d 20 g/d 30 g/d Overall baseline (mmHg) N = 74 N =
73 N = 73 N = 220 Patients in analysis, N 74 73 73 220 Day 3, n 70
70 72 212 Least squares mean .+-. SE -3.8 .+-. 1.1 -3.1 .+-. 1.1
-5.8 .+-. 1.1 -4.2 .+-. 0.6 95% confidence interval -6.0, -1.7
-5.2, -1.0 -7.9, -3.7 -5.5, -3.0 Week 1, n 72 71 72 215 Least
squares mean .+-. SE -6.0 .+-. 1.2 -5.4 .+-. 1.2 -7.0 .+-. 1.2 -6.1
.+-. 0.7 95% confidence interval -8.3, -3.7 -7.7, -3.1 -9.3, -4.7
-7.4, -4.8 Week 2, n 70 70 71 211 Least squares mean .+-. SE -6.6
.+-. 1.3 -6.1 .+-. 1.3 -6.1 .+-. 1.3 -6.3 .+-. 0.7 95% confidence
interval -9.0, -4.1 -8.6, -3.6 -8.6, -3.7 -7.7, -4.8 Week 3, n 64
69 71 204 Least squares mean .+-. SE -5.0 .+-. 1.2 -6.0 .+-. 1.2
-8.0 .+-. 1.2 -6.3 .+-. 0.7 95% confidence interval -7.4, -2.5
-8.4, -3.6 -10.4, -5.7 -7.7, -4.9 Week 4, n 65 67 69 201 Least
squares mean .+-. SE -5.8 .+-. 1.2 -6.5 .+-. 1.2 -8.0 .+-. 1.2 -6.7
.+-. 0.7 95% confidence interval -8.1, -3.4 -8.8, -4.1 -10.3, -5.7
-8.1, -5.4 Week 5, n 65 66 67 198 Least squares mean .+-. SE -6.0
.+-. 1.3 -5.9 .+-. 1.3 -8.4 .+-. 1.3 -6.8 .+-. 0.7 95% confidence
interval -8.6, -3.5 -8.5, -3.4 -10.9, -5.9 -8.2, -5.3 Week 6, n 65
66 64 195 Least squares mean .+-. SE -5.7 .+-. 1.3 -6.4 .+-. 1.3
-6.6 .+-. 1.3 -6.2 .+-. 0.8 95% confidence interval -8.3, -3.1
-9.0, -3.8 -9.2, -4.0 -7.7, -4.8 Week 7, n 64 64 65 193 Least
squares mean .+-. SE -6.3 .+-. 1.4 -6.0 .+-. 1.4 -6.5 .+-. 1.3 -6.3
.+-. 0.8 95% confidence interval -8.9, -3.6 -8.7, -3.4 -9.2, -3.9
-7.8, -4.8 Week 8, n 66 64 66 196 Least squares mean .+-. SE -7.6
.+-. 1.4 -7.3 .+-. 1.4 -6.8 .+-. 1.4 -7.2 .+-. 0.8 95% confidence
interval -10.3, -4.9 -10.1, -4.6 -9.5, -4.1 -8.8, -5.7
TABLE-US-00010 TABLE 8 Estimated mean change from baseline in
diastolic blood pressure by randomized starting/dose, all patients
Stratum 2 Stratum 2 - Local serum K.sup.+ >5.5-<6.0 mEq/L
Change in DBP from 20 g/d 30 g/d 40 g/d Overall baseline (mmHg) N =
26 N = 28 N = 30 N = 84 Patients in analysis, N 26 28 29 83 Day 3,
n 26 27 29 82 Least squares mean .+-. SE -1.7 .+-. 2.0 -3.9 .+-.
2.0 -5.4 .+-. 1.9 -3.7 .+-. 1.1 95% confidence interval -5.6, 2.3
-7.8, -0.08 -9.1, -1.7 -5.9, -1.5 Week 1, n 24 28 28 80 Least
squares mean .+-. SE -1.4 .+-. 2.5 -5.3 .+-. 2.4 -4.4 .+-. 2.3 -3.7
.+-. 1.4 95% confidence interval -6.4, 3.5 -9.9, -0.7 -9.0, 0.2
-6.4, -1.0 Week 2, n 24 27 26 77 Least squares mean .+-. SE -7.2
.+-. 2.0 -3.0 .+-. 1.9 -5.5 .+-. 1.9 -5.3 .+-. 1.1 95% confidence
interval -11.2, -3.3 -6.8, 0.8 -9.4, -1.7 -7.5, -3.0 Week 3, n 24
25 25 74 Least squares mean .+-. SE -7.0 .+-. 2.1 -7.1 .+-. 2.0
-5.9 .+-. 2.0 -6.7 .+-. 1.2 95% confidence interval -11.1, -2.8
-11.1, -3.1 -9.9, -1.9 -9.0, -4.3 Week 4, n 24 25 24 73 Least
squares mean .+-. SE -7.7 .+-. 2.2 -6.3 .+-. 2.2 -1.9 .+-. 2.2 -5.3
.+-. 1.3 95% confidence interval -12.1, -3.3 -10.6, -2.0 -6.2, 2.4
-7.8, -2.8 Week 5, n 24 25 23 72 Least squares mean .+-. SE -8.2
.+-. 1.8 -6.8 .+-. 1.8 -4.4 .+-. 1.8 -6.5 .+-. 1.0 95% confidence
interval -11.8, -4.7 -10.3, -3.4 -8.0, -0.9 -8.5, -4.5 Week 6, n 24
25 22 71 Least squares mean .+-. SE -7.1 .+-. 2.0 -8.9 .+-. 2.0
-4.3 .+-. 2.0 -6.8 .+-. 1.2 95% confidence interval -11.1, -3.1
-12.8, -5.1 -8.4, -0.3 -9.1, -4.5 Week 7, n 24 25 22 71 Least
squares mean .+-. SE -7.3 .+-. 1.9 -9.0 .+-. 1.8 -3.4 .+-. 1.9 -6.6
.+-. 1.1 95% confidence interval -10.9, -3.6 -12.6, -5.4 -7.1, 0.3
-8.7, -4.5 Week 8, n 24 26 24 74 Least squares mean .+-. SE -4.5
.+-. 2.1 -7.0 .+-. 2.0 -1.8 .+-. 2.0 -4.4 .+-. 1.2 95% confidence
interval -8.5, -0.4 -10.9, -3.1 -5.8, 2.2 -6.7, -2.1
TABLE-US-00011 TABLE 9 Estimated mean change from baseline in
diastolic blood pressure by randomized starting/dose, patients who
were hyperkalemic at screening Stratum 1 Stratum 1 - Local serum
K.sup.+ >5.0-5.5 mEq/L Change in DBP from 10 g/d 20 g/d 30 g/d
Overall baseline (mmHg) N = 57 N = 57 N = 56 N = 170 Patients in
analysis, N 57 57 56 170 Day 3, n 56 56 56 168 Least squares mean
.+-. SE -3.7 .+-. 1.3 -4.5 .+-. 1.3 -7.1 .+-. 1.3 -5.1 .+-. 0.7 95%
confidence interval -6.1, -1.2 -7.0, -2.0 -9.6, -4.6 -6.5, -3.7
Week 1, n 55 55 55 165 Least squares mean .+-. SE -5.8 .+-. 1.3
-6.6 .+-. 1.3 -7.5 .+-. 1.3 -6.6 .+-. 0.8 95% confidence interval
-8.4, -3.2 -9.2, -3.9 -10.2, -4.9 -8.1, -5.1 Week 2, n 54 54 54 162
Least squares mean .+-. SE -7.1 .+-. 1.5 -7.4 .+-. 1.5 -6.5 .+-.
1.5 -7.0 .+-. 0.9 95% confidence interval -10.0, -4.1 -10.4, -4.5
-9.5, -3.6 -8.7, -5.3 Week 3, n 49 53 54 156 Least squares mean
.+-. SE -5.2 .+-. 1.5 -7.4 .+-. 1.4 -9.7 .+-. 1.4 -7.4 .+-. 0.8 95%
confidence interval -8.1, -2.2 -10.2, -4.5 -12.5, -6.8 -9.0, -5.7
Week 4, n 51 52 53 156 Least squares mean .+-. SE -5.6 .+-. 1.4
-8.5 .+-. 1.4 -10.0 .+-. 1.3 -8.0 .+-. 0.8 95% confidence interval
-8.2, -2.9 -11.2, -5.9 -12.6, -7.3 -9.6, -6.5 Week 5, n 50 51 53
154 Least squares mean .+-. SE -6.5 .+-. 1.5 -8.3 .+-. 1.5 -9.5
.+-. 1.4 -8.1 .+-. 0.8 95% confidence interval -9.4, -3.6 -11.1,
-5.4 -12.3, -6.7 -9.7, -6.4 Week 6, n 50 51 52 153 Least squares
mean .+-. SE -5.6 .+-. 1.5 -7.3 .+-. 1.5 -7.7 .+-. 1.5 -6.8 .+-.
0.9 95% confidence interval -8.6, -2.6 -10.3, -4.3 -10.7, -4.7
-8.6, -5.1 Week 7, n 50 49 52 151 Least squares mean .+-. SE -5.5
.+-. 1.6 -7.1 .+-. 1.6 -7.7 .+-. 1.5 -6.8 .+-. 0.9 95% confidence
interval -8.6, -2.4 -10.2, -4.0 -10.8, -4.7 -8.5, -5.0 Week 8, n 51
49 52 152 Least squares mean .+-. SE -7.2 .+-. 1.6 -8.1 .+-. 1.6
-8.1 .+-. 1.6 -7.8 .+-. 0.9 95% confidence interval -10.4, -4.1
-11.4, -4.9 -11.3, -5.0 -9.7, -6.0
TABLE-US-00012 TABLE 10 Estimated mean change from baseline in
diastolic blood pressure by randomized starting/dose, patients who
were hyperkalemic at screening Stratum 2 Stratum 2 - Local serum
K.sup.+ >5.5-<6.0 mEq/L Change in DBP from 20 g/d 30 g/d 40
g/d Overall baseline (mmHg) N = 24 N = 24 N = 25 N = 73 Patients in
analysis, N 24 24 24 72 Day 3, n 24 23 24 71 Least squares mean
.+-. SE -1.6 .+-. 2.2 -4.1 .+-. 2.2 -5.9 .+-. 2.2 -3.9 .+-. 1.3 95%
confidence interval -5.9, 2.6 -8.5, 0.3 -10.1, -1.6 -6.4, -1.4 Week
1, n 22 24 23 69 Least squares mean .+-. SE -1.5 .+-. 2.7 -6.4 .+-.
2.7 -4.4 .+-. 2.7 -4.1 .+-. 1.6 95% confidence interval -6.9, 3.9
-11.6, -1.2 -9.7, 0.9 -7.2, -1.1 Week 2, n 22 23 21 66 Least
squares mean .+-. SE -7.7 .+-. 2.2 -4.0 .+-. 2.2 -4.7 .+-. 2.2 -5.5
.+-. 1.3 95% confidence interval -12.0, -3.4 -8.3, 0.2 -9.0, -0.3
-7.9, -3.0 Week 3, n 22 21 20 63 Least squares mean .+-. SE -7.2
.+-. 2.3 -7.6 .+-. 2.3 -6.9 .+-. 2.3 -7.2 .+-. 1.3 95% confidence
interval -11.7, -2.7 -12.1, -3.1 -11.5, -2.3 -9.9, -4.6 Week 4, n
22 21 19 62 Least squares mean .+-. SE -8.0 .+-. 2.4 -6.9 .+-. 2.5
-2.6 .+-. 2.6 -5.8 .+-. 1.4 95% confidence interval -12.7, -3.2
-11.7, -2.0 -7.6, 2.4 -8.6, -3.0 Week 5, n 22 21 18 61 Least
squares mean .+-. SE -8.6 .+-. 1.9 -7.3 .+-. 2.0 -5.1 .+-. 2.1 -7.0
.+-. 1.1 95% confidence interval -12.4, -4.9 -11.2, -3.5 -9.1, -1.0
-9.3, -4.8 Week 6, n 22 21 17 60 Least squares mean .+-. SE -7.6
.+-. 2.1 -10.0 .+-. 2.2 -4.8 .+-. 2.3 -7.5 .+-. 1.3 95% confidence
interval -11.8, -3.4 -14.2, -5.8 -9.3, -0.2 -10.0, -5.0 Week 7, n
22 21 17 60 Least squares mean .+-. SE -7.5 .+-. 2.0 -9.4 .+-. 2.1
-3.0 .+-. 2.2 -6.6 .+-. 1.2 95% confidence interval -11.5, -3.5
-13.5, -5.4 -7.4, 1.4 -9.0, -4.3 Week 8, n 22 22 19 63 Least
squares mean .+-. SE -4.8 .+-. 2.2 -8.6 .+-. 2.2 -2.1 .+-. 2.3 -5.2
.+-. 1.3 95% confidence interval -9.1, -0.4 -12.9, -4.3 -6.7, 2.5
-7.7, -2.6
Example 5: Study of Relationship Between Serum Potassium and Serum
Aldosterone Levels
[0222] Male, unilaterally nephrectomized, spontaneously
hypertensive rats (SHR) (N=32) were used in the experimental groups
in this study. Non-manipulated SHR (N=6) were used as a control
group. Animals were acclimated on a low Ca.sup.2+ and Mg.sup.2+
diet (TD04498) for two weeks. The diet for the experimental groups
was then switched to one supplemented with spironolactone (0.4%
w/w, TD120436) and the drinking water was supplemented with
amiloride (0.05 mM) and quinapril (30 mg/L) for the duration of the
study.
[0223] Animals in the control group remained on the TD04498 diet
and unsupplemented water for the duration of the study.
[0224] A baseline blood draw was performed on all animals 16 days
later. The animals were randomized into 4 groups based on baseline
serum potassium levels and placed on a potassium binder treatment
regimen as described in the table below:
TABLE-US-00013 Group Treatment N 1 TD120436 (untreated) 8 2
TD120436 + 2% potassium binder 8 3 TD120436 + 4% potassium binder 8
4 TD120436 + 6% potassium binder 8 5 Control 6
[0225] Blood, feces, and urine were collected 9 and 15 days after
the treatment regimen was started. Proximal and distal
gastrointestinal segments were harvested at the end of the study.
Serum, fecal, and urine potassium levels and serum aldosterone
levels were determined at respective time points.
[0226] The serum potassium levels (mmol/L) for the control,
untreated, and experimental groups at baseline, day 9, and day 15
were analyzed. The average serum potassium reduction levels
compared to the untreated group were -9.1% (2% potassium binder),
-18.2% (4% potassium binder), and -20.3% (6% potassium binder) on
day 9 and -6.9% (2% potassium binder), -13.2% (4% potassium
binder), and -17.4% (6% potassium binder) on day 15. A significant
reduction in serum potassium levels in all groups treated with
potassium binder at day 9 and at the two higher doses on day 15 was
observed as compared to the untreated group. The analysis was
performed using a 2-way ANOVA plus Bonferroni post hoc test
(**P<0.01; ***P<0.001 vs. untreated).
[0227] The serum aldosterone levels (pg/mL) for the control,
untreated, and experimental groups at baseline, day 9, and day 15
were also analyzed. The average serum aldosterone reduction levels
compared to the untreated group were -22.7% (2% potassium binder),
-53.0% (4% potassium binder), and -57.6% (6% potassium binder) on
day 9 and -16.6% (2% potassium binder), -37.9% (4% potassium
binder), and -50.3 (6% potassium binder) % on day 15. A significant
reduction in serum aldosterone levels was observed in all groups
treated with potassium binder at day 9 and at the two higher doses
on day 15 as compared to the untreated group. The analysis was
performed using a 2-way ANOVA plus Bonferroni post-hoc test
(*P<0.05; **P<0.01; ***P<0.001 vs. untreated).
[0228] There was no difference in the urine potassium excretion
levels between all treatment groups.
[0229] The study showed that a reduction in serum aldosterone was
observed with a reduction in serum potassium.
[0230] When introducing elements of the present invention or the
preferred embodiments(s) thereof, the articles "a", "an", "the" and
"said" are intended to mean that there are one or more of the
elements. The terms "comprising", "including" and "having" are
intended to be inclusive and mean that there may be additional
elements other than the listed elements.
[0231] In view of the above, it will be seen that the several
objects of the invention are achieved and other advantageous
results attained.
[0232] As various changes could be made in the above methods
without departing from the scope of the invention, it is intended
that all matter contained in the above description and shown in the
accompanying figure[s] shall be interpreted as illustrative and not
in a limiting sense.
* * * * *