U.S. patent application number 17/192701 was filed with the patent office on 2021-07-08 for compositions for treating acid-base disorders.
The applicant listed for this patent is Tricida, Inc.. Invention is credited to Kalpesh N. BIYANI, Jerry M. BUYSSE, Eric F. CONNOR, Michael J. COPE, Randi K. GBUR, Matthew J. KADE, Paul H. KIERSTEAD, Gerrit KLAERNER, Son H. NGUYEN, Scott M. TABAKMAN.
Application Number | 20210205351 17/192701 |
Document ID | / |
Family ID | 1000005478495 |
Filed Date | 2021-07-08 |
United States Patent
Application |
20210205351 |
Kind Code |
A1 |
KLAERNER; Gerrit ; et
al. |
July 8, 2021 |
COMPOSITIONS FOR TREATING ACID-BASE DISORDERS
Abstract
Pharmaceutical compositions for and methods of treating an
animal, including a human, and methods of preparing such
compositions. The pharmaceutical compositions contain nonabsorbable
compositions and may be used, for example, to treat diseases or
other metabolic conditions in which removal of protons, the
conjugate base of a strong acid and/or a strong acid from the
gastrointestinal tract would provide physiological benefits such as
normalizing serum bicarbonate concentrations and the blood pH in an
animal, including a human.
Inventors: |
KLAERNER; Gerrit;
(Hillsborough, CA) ; CONNOR; Eric F.; (Los Gatos,
CA) ; GBUR; Randi K.; (Brisbane, CA) ; KADE;
Matthew J.; (Berkeley, CA) ; KIERSTEAD; Paul H.;
(Oakland, CA) ; BUYSSE; Jerry M.; (Los Altos,
CA) ; COPE; Michael J.; (Berkeley, CA) ;
BIYANI; Kalpesh N.; (Dublin, CA) ; NGUYEN; Son
H.; (Milpitas, CA) ; TABAKMAN; Scott M.; (Palo
Alto, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Tricida, Inc. |
South San Francisco |
CA |
US |
|
|
Family ID: |
1000005478495 |
Appl. No.: |
17/192701 |
Filed: |
March 4, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16099029 |
Nov 5, 2018 |
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PCT/US2017/031378 |
May 5, 2017 |
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17192701 |
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62333059 |
May 6, 2016 |
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62350686 |
Jun 15, 2016 |
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62408885 |
Oct 17, 2016 |
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62414966 |
Oct 31, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 33/00 20130101;
A61P 13/12 20180101; C08F 226/02 20130101; A61P 3/12 20180101; C08F
8/02 20130101; C08F 226/04 20130101; A61K 9/0053 20130101; A61K
9/14 20130101; A61P 43/00 20180101; A61K 31/785 20130101 |
International
Class: |
A61K 31/785 20060101
A61K031/785; C08F 8/02 20060101 C08F008/02; A61K 9/14 20060101
A61K009/14; A61K 33/00 20060101 A61K033/00; A61P 43/00 20060101
A61P043/00; A61P 13/12 20060101 A61P013/12; A61K 9/00 20060101
A61K009/00; A61P 3/12 20060101 A61P003/12 |
Claims
1-237. (canceled)
238. A method of treating metabolic acidosis in an adult human
patient, said patient having a serum bicarbonate level of less than
18 mEq/L prior to treatment, said composition being a nonabsorbable
composition having the capacity to remove protons from the patient,
wherein about 3 g of the composition is administered to the patient
per day, the composition is administered once per day in order to
provide the total specified daily dose, and the composition is a
pharmaceutical composition comprising a proton-binding, crosslinked
amine polymer comprising the residue of an amine corresponding to
Formula 2b: ##STR00047## wherein m and n are independently
non-negative integers; each R.sub.12 is independently hydrogen,
substituted hydrocarbyl, or hydrocarbyl; R.sub.22 and R.sub.32 are
independently hydrogen substituted hydrocarbyl, or hydrocarbyl;
R.sub.42 is hydrogen, hydrocarbyl or substituted hydrocarbyl;
X.sub.1 is ##STR00048## X.sub.2 is alkyl, aminoalkyl, or alkanol;
each X.sub.13 is independently hydrogen, hydroxy, alicyclic, amino,
aminoalkyl, halogen, alkyl, heteroaryl, boronic acid or aryl; z is
a non-negative number; and the amine corresponding to Formula 2b
comprises at least one allyl group, and the crosslinked amine
polymer has (i) an equilibrium proton binding capacity of at least
5 mmol/g and a chloride ion binding capacity of at least 5 mmol/g
in an aqueous simulated gastric fluid buffer ("SGF") containing 35
mM NaCl and 63 mM HCl at pH 1.2 and 37.degree. C., and (ii) an
equilibrium swelling ratio in deionized water of about 2 or
less.
239. The method according to claim 238, wherein the patient's serum
bicarbonate level is less than (a) 17 mEq/L, (b) 16 mEq/L, or (c)
15 mEq/L prior to treatment.
240. The method according to claim 238 wherein said patient's serum
bicarbonate value is increased by at least 1 mEq/L over 15 days of
treatment.
241. The method according to claim 238 wherein the treatment
increases the individual's serum bicarbonate value to an increased
serum bicarbonate value that exceeds the baseline serum bicarbonate
value by: (a) at least 1.5 mEq/l, (b) at least 2 mEq/l, (c) at
least 2.5 mEq/l, (d) at least 3 mEq/l, (e) at least 3.5 mEq/l, or
(f) at least 4 mEq/l.
242. The method according to claim 238 wherein the adult human
patient has chronic kidney disease.
243. The method according to claim 238 wherein the nonabsorbable
composition is characterized by a chloride ion binding capacity in
a Simulated Small Intestine Inorganic Buffer ("SIB") assay of (a)
at least 2.5 mEq/g, (b) at least 3 mEq/g, (c) at least 3.5 mEq/g,
(d) at least 4 mEq/g, (e) at least 4.5 mEq/g, or (f) at least 5
mEq/g.
244. The method according to claim 238 wherein the crosslinked
amine polymer has an equilibrium swelling ratio in deionized water
of (a) about 1.5 or less, or (b) about 1 or less.
245. The method according to claim 238 wherein the crosslinked
amine polymer has a chloride ion to phosphate ion binding molar
ratio of (a) at least 0.5:1, respectively, (b) at least 1:1,
respectively, or (c) at least 2:1, respectively, in an aqueous
simulated small intestine inorganic buffer ("SIB") containing 36 mM
NaCl, 20 mM NaH.sub.2PO.sub.4, and 50 mM
2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5 and at
37.degree. C.
246. The method according to claim 238 wherein the crosslinked
amine polymer has (a) a proton binding capacity of at least 10
mmol/g and a chloride ion binding capacity of at least 10 mmol/g,
or (b) an equilibrium proton binding capacity of at least 12 mmol/g
and a chloride ion binding capacity of at least 12 mmol/g in an
aqueous simulated gastric fluid buffer ("SGF") containing 35 mM
NaCl and 63 mM HCl at pH 1.2 and 37.degree. C.
247. The method according to claim 238 wherein m and z are
independently 0-3 and n is 0 or 1.
248. The method according to claim 238 wherein (i) m is a positive
integer and R.sub.12, R.sub.22 and R.sub.42, in combination
comprise at least two allyl or vinyl moieties or (ii) n is a
positive integer and R.sub.12, R.sub.32 and R.sub.42, in
combination, comprise at least two allyl or vinyl moieties.
249. The method according to claim 238 wherein the crosslinked
amine polymer comprises the residue of an amine, or the salt
thereof, selected from 1,4-bis(allylamino)butane,
1,2-bis(allylamino)ethane,
2-(allylamino)-1-[2-(allylamino)ethylamino]ethane,
1,3-bis(allylamino)propane, 1,3-bis(allylamino)-2-propanol,
2-propen-1-ylamine, 1-(allylamino)-2-aminoethane,
1-[N-allyl(2-aminoethyl)amino]-2-aminoethane and
N,N,N-triallylamine.
250. The method according to claim 238 wherein the crosslinked
amine polymer comprises the residue of an amine, or the salt
thereof, selected from 1,3-bis(allylamino)propane and
2-propen-1-ylamine.
251. The method according to claim 238 wherein the crosslinked
amine polymer is crosslinked with a crosslinking agent selected
from bis(3-chloropropyl)amine, 1,3-dichloro-2-propanol,
1,2-dichloroethane, 1,3-dichloropropane, 1-chloro-2,3-epoxypropane,
tris[(2-oxiranyl)methyl]amine,
3-chloro-1-(3-chloropropylamino)-2-propanol, and
1,2-bis(3-chloropropylamino)ethane.
252. The method according to claim 238 wherein the composition is
in a dosage unit form, wherein the dosage unit form is a capsule,
tablet or sachet dosage form.
Description
[0001] The present invention generally relates to methods of
treating acid-base disorders that may be used, for example, in the
treatment of metabolic acidosis.
[0002] Metabolic acidosis is the result of metabolic and dietary
processes that in various disease states create a condition in
which non-volatile acids accumulate in the body, causing a net
addition of protons (H.sup.+) or the loss of bicarbonate
(HCO.sub.3.sup.-). Metabolic acidosis occurs when the body
accumulates acid from metabolic and dietary processes and the
excess acid is not completely removed from the body by the kidneys.
Chronic kidney disease is often accompanied by metabolic acidosis
due to the reduced capacity of the kidney to excrete hydrogen ions
secondary to an inability to reclaim filtered bicarbonate
(HCO.sub.3.sup.-), synthesize ammonia (ammoniagenesis), and excrete
titratable acids. Clinical practice guidelines recommend initiation
of alkali therapy in patients with non-dialysis-dependent chronic
kidney disease (CKD) when the serum bicarbonate level is <22
mEq/L to prevent or treat complications of metabolic acidosis.
(Clinical practice guidelines for nutrition in chronic renal
failure, K/DOQI, National Kidney Foundation, Am. J. Kidney Dis.
2000; 35:S1-140; Raphael, K L, Zhang, Y, Wei, G, et al. 2013, Serum
bicarbonate and mortality in adults in NHANES III, Nephrol. Dial.
Transplant 28: 1207-1213). These complications include malnutrition
and growth retardation in children, exacerbation of bone disease,
increased muscle degradation, reduced albumin synthesis, and
increased inflammation. (Leman, J, Litzow, J R, Lennon, E J. 1966.
The effects of chronic acid loads in normal man: further evidence
for the participation of bone mineral in the defense against
chronic metabolic acidosis, J. Clin. Invest. 45: 1608-1614; Franch
H A, Mitch W E, 1998, Catabolism in uremia: the impact of metabolic
acidosis, J. Am. Soc. Nephrol. 9: S78-81; Ballmer, P E, McNurlan, M
A, Hulter, H N, et al., 1995, Chronic metabolic acidosis decreases
albumin synthesis and induces negative nitrogen balance in humans,
J. Clin. Invest. 95: 39-45; Farwell, W R, Taylor, E N, 2010, Serum
anion gap, bicarbonate and biomarkers of inflammation in healthy
individuals in a national survey, CMAJ 182:137-141). Overt
metabolic acidosis is present in a large proportion of patients
when the estimated glomerular filtration rate is below 30
ml/min/1.73 m.sup.2. (KDOQI bone guidelines: American Journal of
Kidney Diseases (2003) 42:S1-S201. (suppl); Widmer B, Gerhardt R E,
Harrington J T, Cohen J J, Serum electrolyte and acid base
composition: The influence of graded degrees of chronic renal
failure, Arch Intern Med 139:1099-1102, 1979; Dobre M, Yang, W,
Chen J, et. al., Association of serum bicarbonate with risk of
renal and cardiovascular outcomes in CKD: a report from the chronic
renal insufficiency cohort (CRIC) study. Am. J. Kidney Dis. 62:
670-678, 2013; Yaqoob, M M. Acidosis and progression of chronic
kidney disease. Curr. Opin. Nephrol. Hypertens. 19: 489-492,
2010).
[0003] Metabolic acidosis, regardless of etiology, lowers
extracellular fluid bicarbonate and, thus, decreases extracellular
pH. The relationship between serum pH and serum bicarbonate is
described by the Henderson-Hasselbalch equation
pH=pK'+log [HCO.sub.3.sup.-]/[(0.03.times.PaCO.sub.2)]
where 0.03 is the physical solubility coefficient for CO.sub.2,
[HCO.sub.3.sup.-] and PaCO.sub.2 are the concentrations of
bicarbonate and the partial pressure of carbon dioxide,
respectively.
[0004] There are several laboratory tests that can be used to
define metabolic acidosis. The tests fundamentally measure either
bicarbonate (HCO.sub.3.sup.-) or proton (H.sup.+) concentration in
various biological samples, including venous or arterial blood.
These tests can measure either bicarbonate (HCO.sub.3.sup.-) or
proton (H.sup.+) concentration by enzymatic methodology, by ion
selective electrodes or by blood gas analysis. In both the
enzymatic and ion selective electrode methods, bicarbonate is
"measured." Using blood gas analysis, bicarbonate level can be
calculated using the Henderson-Hasselbalch equation.
[0005] Arterial blood gas (ABG) analysis is commonly performed for
clinical evaluation, but the procedure has certain limitations in
the form of reduced patient acceptability because of painful
procedure and the potential to cause complications such as arterial
injury, thrombosis with distal ischaemia, haemorrhage, aneurysm
formation, median nerve damage and reflex sympathetic dystrophy.
Venous blood gas (VBG) analysis is a relatively safer procedure as
fewer punctures are required thus reducing the risk of needle stick
injury to the health care workers. Therefore, as set out below,
when the invention requires assessment of metabolic acidosis, it is
preferred to complete this assessment using VBG analysis. Any
measurements specified herein are preferably achieved by VBG
analysis where possible, for example measurements of blood or serum
bicarbonate levels.
[0006] The most useful measurements for the determination of
acidosis rely on a measurement of the venous plasma bicarbonate (or
total carbon dioxide [tCO.sub.2]), or arterial plasma bicarbonate
(or total carbon dioxide [tCO.sub.2]), serum electrolytes Cl.sup.-,
K.sup.+, and Na.sup.+, and a determination of the anion gap. In the
clinical laboratory, measurement of venous plasma or serum
electrolytes includes an estimation of the tCO.sub.2. This
measurement reflects the sum of circulating CO.sub.2 [i.e., the
total CO.sub.2 represented by bicarbonate (HCO.sub.3.sup.-),
carbonic acid, (H.sub.2CO.sub.3) and dissolved CO.sub.2
(0.03.times.PCO.sub.2)]. tCo.sub.2 can also be related to
HCO.sub.3.sup.- by using a simplified and standardized form of the
Henderson-Hasselbalch equation: tCO.sub.2.dbd.HCO.sub.3.sup.-+0.03
PCO.sub.2, where PCO.sub.2 is the measured partial pressure of
CO.sub.2. Since HCO.sub.3.sup.- concentration is greater than 90%
of the tCO.sub.2, and there are small amounts of H.sub.2CO.sub.3,
then venous tCO.sub.2 is often used as a reasonable approximation
of the venous HCO.sub.3.sup.- concentration in the blood.
Especially during chronic kidney disease, an abnormal plasma
HCO.sub.3.sup.- value <22 mEq/L generally indicates metabolic
acidosis.
[0007] Changes in serum Cl concentration can provide additional
insights into possible acid-base disorders, particularly when they
are disproportionate to changes in serum Na.sup.+ concentration.
When this occurs, the changes in serum Cl.sup.- concentration are
typically associated with reciprocal changes in serum bicarbonate.
Thus, in metabolic acidosis with normal anion gap, serum Cl
increases >105 mEq/L as serum bicarbonate decreases <22
mEq/L.
[0008] Calculation of the anion gap [defined as the serum
Na.sup.+--(Cl.sup.-+HCO.sub.3.sup.-)]is an important aspect of the
diagnosis of metabolic acidosis. Metabolic acidosis may be present
with a normal or an elevated anion gap. However, an elevated anion
gap commonly signifies the presence of metabolic acidosis,
regardless of the change in serum HCO.sub.3.sup.-. An anion gap
greater than 20 mEq/L (normal anion gap is 8 to 12 mEq/L) is a
typical feature of metabolic acidosis.
[0009] Arterial blood gases are used to identify the type of an
acid-base disorder and to determine if there are mixed
disturbances. In general, the result of arterial blood gas measures
should be coordinated with history, physical exam and the routine
laboratory data listed above. An arterial blood gas measures the
arterial carbon dioxide tension (P.sub.aCO.sub.2), acidity (pH),
and the oxygen tension (P.sub.aO.sub.2). The HCO.sub.3.sup.-
concentration is calculated from the pH and the PaCO.sub.2.
Hallmarks of metabolic acidosis are a pH<7.35,
P.sub.aCO.sub.2<35 mm Hg and HCO.sub.3.sup.-<22 mEq/L. The
value of P.sub.aO.sub.2 (normal 80-95 mmHg) is not used in making
the diagnosis of metabolic acidosis but may be helpful in
determining the cause. Acid-base disturbance are first classified
as respiratory or metabolic. Respiratory disturbances are those
caused by abnormal pulmonary elimination of CO.sub.2, producing an
excess (acidosis) or deficit (alkalosis) of CO.sub.2 (carbon
dioxide) in the extracellular fluid. In respiratory acid-base
disorders, changes in serum bicarbonate (HCO.sub.3.sup.-) are
initially a direct consequence of the change in PCO.sub.2 with a
greater increase in PCO.sub.2 resulting in an increase in
HCO.sub.3.sup.-. (Adrogue H J, Madias N E, 2003, Respiratory
acidosis, respiratory alkalosis, and mixed disorders, in Johnson R
J, Feehally J (eds): Comprehensive Clinical Nephrology. London, C V
Mosby, pp. 167-182). Metabolic disturbances are those caused by
excessive intake of, or metabolic production or losses of,
nonvolatile acids or bases in the extracellular fluid. These
changes are reflected by changes in the concentration of
bicarbonate anion (HCO.sub.3.sup.-) in the blood adaptation in this
case involves both buffering (immediate), respiratory (hours to
days) and renal (days) mechanisms. (DuBose T D, MacDonald G A:
renal tubular acidosis, 2002, in DuBose T D, Hamm L L (eds):
Acid-base and electrolyte disorders: A companion to Brenners and
Rector's the Kidney, Philadelphia, WB Saunders, pp. 189-206).
[0010] The overall hydrogen ion concentration in the blood is
defined by the ratio of two quantities, the serum HCO.sub.3.sup.-
content (regulated by the kidneys) and the PCO.sub.2 content
(regulated by the lungs) and is expressed as follows:
[H.sup.+].varies.(PCO.sub.2/[HCO.sub.3.sup.-])
[0011] The consequence of an increase in the overall hydrogen ion
concentration is a decline in the major extracellular buffer,
bicarbonate. Normal blood pH is between 7.38 and 7.42,
corresponding to a hydrogen ion (H.sup.+) concentration of 42 to 38
nmol/L (Goldberg M: Approach to Acid-Base Disorders. 2005. In
Greenberg A, Cheung A K (eds) Primer on Kidney Diseases, National
Kidney Foundation, Philadelphia, Elsevier-Saunders, pp. 104-109.).
Bicarbonate (HCO.sub.3.sup.-) is an anion that acts to buffer
against pH disturbances in the body, and normal levels of plasma
bicarbonate range from 22-26 mEq/L (Szerlip H M: Metabolic
Acidosis, 2005, in Greenberg A, Cheung A K (eds) Primer on Kidney
Diseases, National Kidney Foundation, Philadelphia,
Elsevier-Saunders, pp. 74-89.). Acidosis is the process which
causes a reduction in blood pH (acidemia) and reflects the
accumulation of hydrogen ion (H.sup.+) and its consequent buffering
by bicarbonate ion (HCO.sub.3.sup.-) resulting in a decrease in
serum bicarbonate. Metabolic acidosis can be represented as
follows:
##STR00001##
(Clinical practice guidelines for nutrition in chronic renal
failure. K/DOQI, National Kidney Foundation. Am. J. Kidney Dis.
2000; 35:S1-140). Using this balance equation, the loss of one
HCO.sub.3.sup.- is equivalent to the addition of one H.sup.+ and
conversely, the gain of one HCO.sub.3.sup.- is equivalent to the
loss of one H.sup.+. Thus, changes in blood pH, particularly
increases in H.sup.+ (lower pH, acidosis) can be corrected by
increasing serum HCO.sub.3.sup.- or, equivalently, by decreasing
serum H.sup.+.
[0012] In order to maintain extracellular pH within the normal
range, the daily production of acid must be excreted from the body.
Acid production in the body results from the metabolism of dietary
carbohydrates, fats and amino acids. Complete oxidation of these
metabolic substrates produces water and CO.sub.2. The carbon
dioxide generated by this oxidation (.about.20,000 mmol/day) is
efficiently exhaled by the lungs, and represents the volatile acid
component of acid-base balance.
[0013] In contrast, nonvolatile acids (.about.50-100 mEq/day) are
produced by the metabolism of sulfate- and phosphate-containing
amino acids and nucleic acids. Additional nonvolatile acids (lactic
acid, butyric acid, acetic acid, other organic acids) arise from
the incomplete oxidation of fats and carbohydrates, and from
carbohydrate metabolism in the colon, where bacteria residing in
the colon lumen convert the substrates into small organic acids
that are then absorbed into the bloodstream. The impact of short
chain fatty acids on acidosis is somewhat minimized by anabolism,
for example into long-chain fatty acids, or catabolism to water and
CO.sub.2.
[0014] The kidneys maintain pH balance in the blood through two
mechanisms: reclaiming filtered HCO.sub.3.sup.- to prevent overall
bicarbonate depletion and the elimination of nonvolatile acids in
the urine. Both mechanisms are necessary to prevent bicarbonate
depletion and acidosis.
[0015] In the first mechanism, the kidneys reclaim HCO.sub.3.sup.-
that is filtered by the glomerulus. This reclamation occurs in the
proximal tubule and accounts for .about.4500 mEq/day of reclaimed
HCO.sub.3.sup.-. This mechanism prevents HCO.sub.3.sup.- from being
lost in the urine, thus preventing metabolic acidosis. In the
second mechanism, the kidneys eliminate enough H.sup.+ to equal the
daily nonvolatile acid production through metabolism and oxidation
of protein, fats and carbohydrates. Elimination of this acid load
is accomplished by two distinct routes in the kidney, comprising
active secretion of H.sup.+ ion and ammoniagenesis. The net result
of these two interconnected processes is the elimination of the
50-100 mEq/day of nonvolatile acid generated by normal
metabolism.
[0016] Thus, normal renal function is needed to maintain acid-base
balance. During chronic kidney disease, filtration and reclamation
of HCO.sub.3.sup.- is impaired as is generation and secretion of
ammonia. These deficits rapidly lead to chronic metabolic acidosis
which is, itself, a potent antecedent to end-stage renal disease.
With continued acid production from metabolism, a reduction in acid
elimination will disturb the H.sup.+/HCO.sub.3.sup.- balance such
that blood pH falls below the normal value of pH=7.38-7.42.
[0017] Treatment of metabolic acidosis by alkali therapy is usually
indicated to raise and maintain the plasma pH to greater than 7.20.
Sodium bicarbonate (NaHCO.sub.3) is the agent most commonly used to
correct metabolic acidosis. NaHCO.sub.3 can be administered
intravenously to raise the serum HCO.sub.3.sup.- level adequately
to increase the pH to greater than 7.20. Further correction depends
on the individual situation and may not be indicated if the
underlying process is treatable or the patient is asymptomatic.
This is especially true in certain forms of metabolic acidosis. For
example, in high-anion gap (AG) acidosis secondary to accumulation
of organic acids, lactic acid, and ketones, the cognate anions are
eventually metabolized to HCO.sub.3.sup.-. When the underlying
disorder is treated, the serum pH corrects; thus, caution should be
exercised in these patients when providing alkali to raise the pH
much higher than 7.20, to prevent an increase in bicarbonate above
the normal range (>26 mEq/L).
[0018] Citrate is an appropriate alkali therapy to be given orally
or IV, either as the potassium or sodium salt, as it is metabolized
by the liver and results in the formation of three moles of
bicarbonate for each mole of citrate. Potassium citrate
administered IV should be used cautiously in the presence of renal
impairment and closely monitored to avoid hyperkalemia.
[0019] Intravenous sodium bicarbonate (NaHCO.sub.3) solution can be
administered if the metabolic acidosis is severe or if correction
is unlikely to occur without exogenous alkali administration. Oral
alkali administration is the preferred route of therapy in persons
with chronic metabolic acidosis. The most common alkali forms for
oral therapy include NaHCO.sub.3 tablets where 1 g of NaHCO.sub.3
is equal to 11.9 mEq of HCO.sub.3.sup.-. However, the oral form of
NaHCO.sub.3 is not approved for medical use and the package insert
of the intravenous sodium bicarbonate solution includes the
following contraindications, warnings and precautions (Hospira
label for NDC 0409-3486-16): [0020] Contraindications: Sodium
Bicarbonate Injection, USP is contraindicated in patients who are
losing chloride by vomiting or from continuous gastrointestinal
suction, and in patients receiving diuretics known to produce a
hypochloremic alkalosis. [0021] Warnings: Solutions containing
sodium ions should be used with great care, if at all, in patients
with congestive heart failure, severe renal insufficiency and in
clinical states in which there exists edema with sodium retention.
In patients with diminished renal function, administration of
solutions containing sodium ions may result in sodium retention.
The intravenous administration of these solutions can cause fluid
and/or solute overloading resulting in dilution of serum
electrolyte concentrations, overhydration, congested states or
pulmonary edema. [0022] Precautions: [ . . . ] The potentially
large loads of sodium given with bicarbonate require that caution
be exercise in the use of sodium bicarbonate in patients with
congestive heart failure or other edematous or sodium-retaining
states, as well as in patients with oliguria or anuria.
[0023] Acid-base disorders are common in chronic kidney disease and
heart failure patients. Chronic kidney disease (CKD) progressively
impairs renal excretion of the approximately 1 mmol/kg body weight
of hydrogen ions generated in healthy adults (Yaqoob, M M. 2010,
Acidosis and progression of chronic kidney disease, Curr. Opin.
Nephrol. Hyperten. 19:489-492.). Metabolic acidosis, resulting from
the accumulation of acid (H.sup.+) or depletion of base
(HCO.sub.3.sup.-) in the body, is a common complication of patients
with CKD, particularly when the glomerular filtration rate (GFR, a
measure of renal function) falls below 30 ml/min/1.73 m.sup.2.
Metabolic acidosis has profound long term effects on protein and
muscle metabolism, bone turnover and the development of renal
osteodystrophy. In addition, metabolic acidosis influences a
variety of paracrine and endocrine functions, again with long term
consequences such as increased inflammatory mediators, reduced
leptin, insulin resistance, and increased corticosteroid and
parathyroid hormone production (Mitch W E, 1997, Influence of
metabolic acidosis on nutrition, Am. J. Kidney Dis. 29:46-48.). The
net effect of sustained metabolic acidosis in the CKD patient is
loss of bone and muscle mass, a negative nitrogen balance, and the
acceleration of chronic renal failure due to hormonal and cellular
abnormalities (De Brito-Ashurst I, Varagunam M, Raftery M J, et al,
2009, Bicarbonate supplementation slows progression of CKD and
improves nutritional status, J. Am. Soc. Nephrol. 20: 2075-2084).
Conversely, the potential concerns with alkali therapy in CKD
patients include expansion of extracellular fluid volume associated
with sodium ingestion, resulting in the development or aggravation
of hypertension, facilitation of vascular calcification, and the
decompensation of existing heart failure. CKD patients of moderate
degree (GFR at 20-25% of normal) first develop hyperchloremic
acidosis with a normal anion gap due to the inability to reclaim
filtered bicarbonate and excrete proton and ammonium cations. As
they progress toward the advanced stages of CKD the anion gap
increases, reflective of the continuing degradation of the kidney's
ability to excrete the anions that were associated with the
unexcreted protons. Serum bicarbonate in these patients rarely goes
below 15 mmol/L with a maximum elevated anion gap of approximately
20 mmol/L. The non-metabolizable anions that accumulate in CKD are
buffered by alkaline salts from bone (Lemann J Jr, Bushinsky D A,
Hamm L L Bone buffering of acid and base in humans. Am. J. Physiol
Renal Physiol. 2003 November, 285(5):F811-32).
[0024] The majority of patients with chronic kidney disease have
underlying diabetes (diabetic nephropathy) and hypertension,
leading to deterioration of renal function. In almost all patients
with hypertension a high sodium intake will worsen the
hypertension. Accordingly, kidney, heart failure, diabetes and
hypertensive guidelines strictly limit sodium intake in these
patients to less than 1.5 g or 65 mEq per day (HFSA 2010
guidelines, Lindenfeld 2010, J Cardiac Failure V16 No 6 P475).
Chronic anti-hypertensive therapies often induce sodium excretion
(diuretics) or modify the kidney's ability to excrete sodium and
water (such as, for example, Renin Angiotensin Aldosterone System
inhibiting "RAASi" drugs). However, as kidney function
deteriorates, diuretics become less effective due to an inability
of the tubule to respond. The RAASi drugs induce life-threatening
hyperkalemia as they inhibit renal potassium excretion. Given the
additional sodium load, chronically treating metabolic acidosis
patients with amounts of sodium-containing base that often exceed
the total daily recommended sodium intake is not a reasonable
practice. As a consequence, oral sodium bicarbonate is not commonly
prescribed chronically in these diabetic nephropathy patients.
Potassium bicarbonate is also not acceptable as patients with CKD
are unable to readily excrete potassium, leading to severe
hyperkalemia.
[0025] Despite these shortcomings, the role of oral sodium
bicarbonate has been studied in the small subpopulation of
non-hypertensive CKD patients. As part of the Kidney Research
National Dialogue, alkali therapy was identified as having the
potential to slow the progression of CKD, as well as to correct
metabolic acidosis. The annual age-related decline in glomerular
filtration rate (GFR) after the age of 40 is 0.75-1.0 ml/min/1.73
m.sup.2 in normal individuals. In CKD patients with fast
progression, a steeper decline of >4 ml/min/1.73 m.sup.2
annually can be seen. Glomerular filtration rate ("GFR") or
estimated glomerular filtration rate is typically used to
characterize kidney function and the stage of chronic kidney
disease. The five stages of chronic kidney disease and the GFR for
each stage is as follows: [0026] Stage 1 with normal or high GFR
(GFR>90 mL/min/1.73 m.sup.2) [0027] Stage 2 Mild CKD (GFR=60-89
mL/min/1.73 m.sup.2) [0028] Stage 3A Moderate CKD (GFR=45-59
mL/min/1.73 m.sup.2) [0029] Stage 3B Moderate CKD (GFR=30-44
mL/min/1.73 m.sup.2) [0030] Stage 4 Severe CKD (GFR=15-29
mL/min/1.73 m.sup.2) [0031] Stage 5 End Stage CKD (GFR<15
mL/min/1.73 m.sup.2).
[0032] In one outcome study, De Brito-Ashurst et al showed that
bicarbonate supplementation preserves renal function in CKD (De
Brito-Ashurst I, Varagunam M, Raftery M J, et al, 2009, Bicarbonate
supplementation slows progression of CKD and improves nutritional
status, J. Am. Soc. Nephrol. 20: 2075-2084). The study randomly
assigned 134 adult patients with CKD (creatinine clearance [CrCl]
15 to 30 ml/min per 1.73 m.sup.2) and serum bicarbonate 16 to 20
mmol/L to either supplementation with oral sodium bicarbonate or
standard of care for 2 years. The average dose of bicarbonate in
this study was 1.82 g/day, which provides 22 mEq of bicarbonate per
day. The primary end points were rate of CrCl decline, the
proportion of patients with rapid decline of CrCl (>3 ml/min per
1.73 m.sup.2/yr), and end-stage renal disease ("ESRD") (CrCl<10
ml/min). Compared with the control group, decline in CrCl was
slower with bicarbonate supplementation (decrease of 1.88 ml/min
per 1.73 m.sup.2 for patients receiving bicarbonate versus a
decrease of 5.93 ml/min per 1.73 m.sup.2 for control group;
P<0.0001). Patients supplemented with bicarbonate were
significantly less likely to experience rapid progression (9%
versus 45%; relative risk 0.15; 95% confidence interval 0.06 to
0.40; P<0.0001). Similarly, fewer patients supplemented with
bicarbonate developed ESRD (6.5% versus 33%; relative risk 0.13;
95% confidence interval 0.04 to 0.40; P<0.001).
[0033] Hyperphosphatemia is a common co-morbidity inpatients with
CKD, particularly in those with advanced or end-stage renal
disease. Sevelamer hydrochloride is a commonly used ion-exchange
resin that reduces serum phosphate concentration. However, reported
drawbacks of this agent include metabolic acidosis apparently due
to the net absorption of HCl in the process of binding phosphate in
the small intestine. Several studies in patients with CKD and
hyperphosphatemia who received hemodialysis or peritoneal dialysis
found decreases in serum bicarbonate concentrations with the use of
sevelamer hydrochloride (Brezina, 2004 Kidney Int. V66 S90 (2004)
S39-S45; Fan, 2009 Nephrol Dial Transplant (2009) 24:3794).
[0034] WO2014197725 A1 and WO2016094685 A1 disclose polymers for
oral administration that may be used in the treatment of acid-base
disorders, for example metabolic acidosis.
The Disclosed Therapies
[0035] Among the various aspects of the present disclosure, the
following is a useful guide for one method for treating metabolic
acidosis (without wishing to be bound by theory). When an H.sup.+
is pumped into the stomach a HCO.sub.3.sup.- enters the systemic
circulation and raises the serum bicarbonate concentration. The
initial binding of gastric H.sup.+ to a nonabsorbable composition
as described herein results in HCO.sub.3.sup.- entering the
systemic circulation and raising the serum bicarbonate
concentration. The more H.sup.+ bound the greater the increase in
systemic HCO.sub.3.sup.-. The binding of Cl.sup.- the nonabsorbable
composition prevents subsequent exchange of luminal Cl.sup.- for
HCO.sub.3.sup.- which would counteract the initial rise in
HCO.sub.3.sup.-. The analogous clinical situation to administering
the composition is vomiting. Administration of the composition is
essentially causing the loss of gastric HCl as in vomiting. If a
person vomits they lose gastric HCl and have an increase in serum
bicarbonate. The increase in serum bicarbonate persists only if
they are not given a lot of oral Cl.sup.-, for example as NaCl,
which would allow subsequent exchange of intestinal Cl.sup.- for
HCO.sub.3.sup.- and dissipate the increase in serum bicarbonate
concentration. The disclosure is not limited by these requirements,
and instead they are set out in full below.
[0036] The examples include the results from the first human trials
of a polymer specifically for treating metabolic acidosis by
binding HCl. Following this research, it is now possible to specify
a variety of new specific therapeutic uses for nonabsorbable
compositions. Therefore, the present invention relates to improved
specific methods for treating metabolic acidosis as set out
herein.
[0037] One aspect of the present disclosure is a composition for
use in a method of treating metabolic acidosis in an adult human
patient wherein in said treatment 0.1-12 g of said composition is
administered to the patient per day, said composition being a
nonabsorbable composition having the capacity to remove protons
from the patient, wherein the nonabsorbable composition is
characterized by a chloride ion binding capacity of at least 2.5
mEq/g in a Simulated Small Intestine Inorganic Buffer ("SIB")
assay. In this aspect, the composition may be administered orally,
and so would be an orally administered nonabsorbable composition as
defined herein. One advantage of such an aspect is that a
relatively low dose of the composition provides a significant
clinical improvement.
[0038] Another aspect of the present disclosure is a composition
for use in a method of treating metabolic acidosis in an adult
human patient by increasing that patient's serum bicarbonate value
by at least 1 mEq/L over 15 days of treatment (i.e., within 15 days
of treatment), said composition being a nonabsorbable composition
having the capacity to remove protons from the patient. In this
aspect, the composition may be administered orally, and so would be
an orally administered nonabsorbable composition as defined herein.
One advantage of such an aspect is that a relatively large increase
in the patient's serum bicarbonate value has been achieved in a
short period of time.
[0039] Another aspect of the present disclosure is a composition
for use in a method of treating metabolic acidosis in an adult
human patient, said patient having a serum bicarbonate level of
less than 20 mEq/L prior to treatment, said composition being a
nonabsorbable composition having the capacity to remove protons
from the patient. In this aspect, the composition may be
administered orally, and so would be an orally administered
nonabsorbable composition as defined herein. One advantage of this
aspect is that patients with a low serum bicarbonate level can be
successfully treated by following the teaching herein.
[0040] Another aspect of the present disclosure is a composition
for use in a method of treating metabolic acidosis in an adult
human patient by increasing that patient's serum bicarbonate value
by at least 1 mEq/L over 15 days of treatment, wherein in said
treatment >12-100 g of said polymer is administered to the
patient per day, said composition being a nonabsorbable composition
having the capacity to remove protons from the patient, wherein the
nonabsorbable composition is characterized by a chloride ion
binding capacity of at least 2.5 mEq/g in a Simulated Small
Intestine Inorganic Buffer ("SIB") assay. In this aspect, the
composition may be administered orally, and so would be an orally
administered nonabsorbable composition as defined herein. One
advantage of this aspect is that it provides values for the dosage
based on the performance of the material in the SIB assay and
desired improvement in patient serum bicarbonate level.
[0041] Another aspect of the present disclosure is a composition
for use in a method of treating metabolic acidosis in an adult
human patient wherein in said treatment >12-100 g of said
composition is administered to the patient per day, said
composition being a nonabsorbable composition having the capacity
to remove protons from the patient, wherein the nonabsorbable
composition is characterized by a chloride ion binding capacity of
less than 2.5 mEq/g in a Simulated Small Intestine Inorganic Buffer
("SIB") assay. In this aspect, the composition may be administered
orally, and so would be an orally administered nonabsorbable
composition as defined herein. One advantage of this aspect is that
it provides values for the dosage based on the performance of the
material in the SIB assay.
[0042] In certain embodiments, the orally administered
nonabsorbable composition comprises cations (such as Na.sup.+,
K.sup.+, Mg.sup.2+, Ca.sup.2+Li.sup.+, or a combination thereof)
that are exchanged for protons as the nonabsorbable composition
transits the digestive system, and the protons are then excreted
from the body along with the nonabsorbable composition upon
defecation. The net effect is reduction in protons in the body, in
exchange for an increase in one or more cations. In this
embodiment, the pharmaceutical composition may also optionally
comprise a pharmaceutically acceptable carrier, diluent or
excipient, or a combination thereof that does not significantly
interfere with the proton-binding characteristics of the
nonabsorbable composition in vivo. Optionally, the pharmaceutical
composition may also comprise an additional therapeutic agent.
[0043] In certain embodiments, the orally administered
nonabsorbable composition comprises anions that are exchanged for
chloride ions and if the anion comprised by the orally administered
nonabsorbable composition is a stronger base (e.g., OH.sup.-) than
the removed base (e.g., Cl.sup.-, HSO.sub.4.sup.-, or
SO.sub.4.sup.2-), the net effect is the removal of a strong acid
from the body (e.g., HCl or H.sub.2SO.sub.4) in exchange for a weak
acid (e.g., H.sub.2O). In this embodiment, the pharmaceutical
composition may also optionally comprise a pharmaceutically
acceptable carrier, diluent or excipient, or a combination thereof
that does not significantly interfere with the chloride-binding
characteristics of the nonabsorbable composition in vivo.
Optionally, the pharmaceutical composition may also comprise an
additional therapeutic agent.
[0044] In certain embodiments, the orally administered
nonabsorbable composition is a neutral composition having the
capacity to bind and remove a strong acid, such as HCl or
H.sub.2SO.sub.4, from the body upon oral administration. The
nonabsorbable composition may, but does not necessarily, introduce
(i.e., by ion exchange) counterbalancing cations or anions in the
process of removing the acid. In this embodiment, binding of both
ionic species of HCl (H.sup.+ and Cl.sup.-) may be achieved through
favorable surface energy of the bulk material, which can include
hydrogen bonding and other interactions as well as ionic
interactions. Complexation of HCl can occur on functional groups
that are dehydrated and upon administration in an acidic aqueous
medium, result in the hydrochloride salt of the functional
group.
[0045] Among the various aspects of the present disclosure may
further be noted a method of treating an individual afflicted with
a chronic acid/base disorder comprising oral administration of a
pharmaceutical composition containing a nonabsorbable composition
having the capacity to bind protons and chloride ions as it
transits the digestive system and remove the bound protons and
chloride ions from the individual's digestive system via
defecation. In each of these embodiments, the pharmaceutical
composition may also optionally comprise a pharmaceutically
acceptable carrier, diluent or excipient, or a combination thereof
that does not significantly interfere with the chloride-binding
characteristics of the nonabsorbable composition in vivo.
Optionally, the pharmaceutical composition may also comprise an
additional therapeutic agent.
[0046] In those embodiments in which the nonabsorbable composition
binds chloride ions, it is generally preferred that the
nonabsorbable composition selectively bind chloride ions relative
to other physiologically significant competing anions such as
bicarbonate equivalent anions, phosphate anions, and the conjugate
bases of bile and fatty acids that are present in the GI tract.
Stated differently, it is generally preferred that the
nonabsorbable composition remove more chloride ions than any other
competing anion in the GI tract.
[0047] In those embodiments in which the nonabsorbable composition
binds protons, it is generally preferred that the nonabsorbable
composition bind protons without delivering sodium, potassium,
calcium, magnesium, and/or other electrolytes in exchange for the
protons in an amount that is physiologically detrimental. As a
result, treatment with the nonabsorbable composition will not
significantly contribute to edema, hypertension, hyperkalemia,
hypercalcemia or a similar disorder associated with an elevated
load of sodium, potassium, calcium or other electrolyte. Similarly,
in those embodiments in which the nonabsorbable composition binds
protons, it is generally preferred that the nonabsorbable
composition bind protons without removing an amount of sodium,
potassium, calcium, magnesium and/or other electrolytes along with
the protons. As a result, treatment with the nonabsorbable
composition will not significantly contribute to hypotension,
hypokalemia, hypocalcemia or other disorder associated with a
depressed serum concentration of sodium, potassium, calcium,
magnesium or other electrolyte.
[0048] In certain embodiments, the polymers preferably bind and
maintain their ability to bind proton and anions at the
physiological conditions found along the gastrointestinal (GI)
lumen. These conditions can change according to dietary intake
(see, for example, Fordtran J, Locklear T. Ionic constituents and
osmolality of gastric and small-intestinal fluids after eating.
Digest Dis Sci. 1966; 11(7):503-21) and location along the GI tract
(Binder, H et al. Chapters 41-45 in "Medical Physiology", 2nd
Edition, Elsevier [2011]. Boron and Boulpaep [Ed.]). Rapid binding
of proton and chloride in the stomach and small intestine is
desirable. High binding levels and selectivity for chloride later
in the GI tract (lower small intestine and large intestine) is also
desirable. In general, the polymers also preferably have a pK.sub.a
such that the majority of amines are protonated under the various
pH and electrolyte conditions encountered along the GI tract and
are thereby capable of removing proton, along with an appropriate
counter anion (preferably chloride), from the body into the
feces.
[0049] Since the stomach is an abundant source of HCl, and the
stomach is the first site of potential HCl binding (after the
mouth), and since residence time in the stomach is short (gastric
residence half-life of approximately 90 minutes), compared to the
rest of the GI tract (small intestine transit time of approximately
4 hours; whole gut transit time of 2-3 days; Read, N W et al.
Gastroenterology [1980] 79:1276), it is desirable for the polymer
of the present disclosure to demonstrate rapid kinetics of proton
and chloride binding in the lumen of this organ, as well as in in
vitro conditions designed to mimic the stomach lumen (e.g. SGF).
Phosphate is a potential interfering anion for chloride binding in
the stomach and small intestine, where phosphate is mostly absorbed
(Cross, H S et al Miner Electrolyte Metab [1990] 16:115-24).
Therefore rapid and preferential binding of chloride over phosphate
is desirable in the small intestine and in in vitro conditions
designed to mimic the small intestine lumen (e.g. SIB). Since the
transit time of the colon is slow (2-3 days) relative to the small
intestine, and since conditions in the colon will not be
encountered by an orally administered polymer until after stomach
and small intestine conditions have been encountered, kinetics of
chloride binding by a polymer of the present disclosure do not have
to be as rapid in the colon or in in vitro conditions designed to
mimic the late small intestine/colon. It is, however, important
that chloride binding and selectivity over other interfering anions
is high, for example, at 24 and/or 48 hours or longer.
[0050] Other aspects and features will be in part apparent and in
part pointed out hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0051] FIG. 1A-1C is a flow chart schematically depicting the
mechanism of action of the polymer when passing through the
gastrointestinal tract of an individual from oral ingestion/stomach
(FIG. 1A), to the upper GI tract (FIG. 1B) to the lower GI
tract/colon (FIG. 1C).
[0052] FIG. 2 is a graph of the effect of TRC101 on serum
bicarbonate in a rat model of adenine-induced nephropathy and
metabolic acidosis in Part 1 of the study described in Example
1.
[0053] FIGS. 3A, 3B and 3C are graphs of the effect of TRC101 on
fecal excretion of chloride (FIG. 3A), sulfate (FIG. 3B), and
phosphate (FIG. 3C) in a rat model of adenine-induced nephropathy
and metabolic acidosis in Part 1 of the study described in Example
1.
[0054] FIG. 4 is a graph of the effect of TRC101 on serum
bicarbonate in a rat model of adenine-induced nephropathy and
metabolic acidosis in Part 2 of the study described in Example
1.
[0055] FIGS. 5A, 5B and 5C are graphs of the effect of TRC101 on
fecal excretion of chloride (FIG. 5A), sulfate (FIG. 5B), and
phosphate (FIG. 5C) in a rat model of adenine-induced nephropathy
and metabolic acidosis in Part 2 of the study described in Example
1.
[0056] FIGS. 6A, 6B and 6C are graphs of the in vivo chloride (FIG.
6A), sulfate (FIG. 6B) and phosphate (FIG. 6C) binding capacities
of test compound and bixalomer in a pig with normal renal function
in the study described in Example 2.
[0057] FIG. 7 is a line graph showing the mean change in serum
bicarbonate (SBC) from baseline (BL) and standard error (SE) by
treatment group over time in a human study as described more fully
in Example 3 (Part 1).
[0058] FIG. 8 is a bar graph showing the least squares mean (LS
Mean) change from baseline (CFB) to end of treatment in serum
bicarbonate (SBC) by treatment group in a human study as described
more fully in Example 3 (Part 1). Single asterisk ("*") indicates
statistically significant difference (p<0.5) and double asterisk
("**") indicates highly statistically significant difference
(p<0.0001).
[0059] FIG. 9 is a bar graph showing the effect on serum
bicarbonate (SBC) levels and standard error (SE) at days 8 and 15
resulting from treatment (Tx=treatment) and upon withdrawal of
TRC101 in a human study as described more fully in Example 3 (Part
1).
[0060] FIG. 10 is a line graph showing the mean change in serum
bicarbonate (SBC) and standard error (SE) for the four TRC101
active arms and the two placebo arms (pooled) of the study
described more fully in Example 3 (Parts 1 and 2).
[0061] FIG. 11 is a bar graph showing the least squares mean (LS
Mean) change from baseline (CFB) in serum bicarbonate (SBC) by
treatment group over time for the four TRC101 active arms and the
two placebo arms (pooled) of the study described more fully in
Example 3 (Parts 1 and 2). Single asterisk ("*") indicates
statistically significant difference (p<0.5) and double asterisk
("**") indicates highly statistically significant difference
(p<0.0001).
[0062] FIG. 12 is a bar graph showing the treatment effect on serum
bicarbonate (SBC) levels and standard error (SE) at days 8 and 15
resulting from treatment (Tx=treatment) with and upon withdrawal of
TRC101 in a human study as described more fully in Example 3 (Parts
1 and 2).
[0063] FIGS. 13A, 13B, 13C and 13D are graphs showing the changes
in serum bicarbonate (FIG. 13A), serum chloride (FIG. 13B), serum
sodium (FIG. 13C) and serum potassium (FIG. 13D) for the four
TRC101 active arms (combined) vs the two placebo arms (pooled) over
time for the study described more fully in Example 3 (Parts 1 and
2).
[0064] FIG. 14 is a graph showing the changes in the calculated
anion gap for the four TRC101 active arms (combined) vs the two
placebo arms (pooled) over time for the study described more fully
in Example 3 (Parts 1 and 2).
ABBREVIATIONS AND DEFINITIONS
[0065] The following definitions and methods are provided to better
define the present invention and to guide those of ordinary skill
in the art in the practice of the present invention. Unless
otherwise noted, terms are to be understood according to
conventional usage by those of ordinary skill in the relevant
art.
[0066] The term "absorption capacity" as used herein in connection
with a polymer and a swelling agent (or in the case of a mixture of
swelling agents, the mixture of swelling agents) is the amount of
the swelling agent (or such mixture) absorbed during a period of at
least 16 hours at room temperature by a given amount of a dry
polymer (e.g., in the form of a dry bead) immersed in an excess
amount of the swelling agent (or such mixture).
[0067] The term "acrylamide" denotes a moiety having the structural
formula H.sub.2C.dbd.CH--C(O)NR--*, where * denotes the point of
attachment of the moiety to the remainder of the molecule and R is
hydrogen, hydrocarbyl, or substituted hydrocarbyl.
[0068] The term "acrylic" denotes a moiety having the structural
formula H.sub.2C.dbd.CH--C(O)O--*, where * denotes the point of
attachment of the moiety to the remainder of the molecule.
[0069] The term "adult" refers to an individual over 18 years of
age.
[0070] The term "alicyclic", "alicyclo" or "alicyclyl" means a
saturated monocyclic group of 3 to 8 carbon atoms and includes
cyclopentyl, cyclohexyl, cycloheptyl, and the like.
[0071] The term "aliphatic" denotes saturated and non-aromatic
unsaturated hydrocarbyl moieties having, for example, one to about
twenty carbon atoms or, in specific embodiments, one to about
twelve carbon atoms, one to about ten carbon atoms, one to about
eight carbon atoms, or even one to about four carbon atoms. The
aliphatic groups include, for example, alkyl moieties such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, iso-amyl, hexyl and the like, and alkenyl
moieties of comparable chain length.
[0072] The term "alkanol" denotes an alkyl moiety that has been
substituted with at least one hydroxyl group. In some embodiments,
alkanol groups are "lower alkanol" groups comprising one to six
carbon atoms, one of which is attached to an oxygen atom. In other
embodiments, lower alkanol groups comprise one to three carbon
atoms.
[0073] The term "alkenyl group" encompasses linear or branched
carbon radicals having at least one carbon-carbon double bond. The
term "alkenyl group" can encompass conjugated and non-conjugated
carbon-carbon double bonds or combinations thereof. An alkenyl
group, for example and without being limited thereto, can encompass
two to about twenty carbon atoms or, in a particular embodiment,
two to about twelve carbon atoms. In certain embodiments, alkenyl
groups are "lower alkenyl" groups having two to about four carbon
atoms. Examples of alkenyl groups include, but are not limited
thereto, ethenyl, propenyl, allyl, vinyl, butenyl and
4-methylbutenyl. The terms "alkenyl group" and "lower alkenyl
group", encompass groups having "cis" or "trans" orientations, or
alternatively, "E" or "Z" orientations.
[0074] The term "alkyl group" as used, either alone or within other
terms such as "haloalkyl group," "aminoalkyl group" and "alkylamino
group", encompasses saturated linear or branched carbon radicals
having, for example, one to about twenty carbon atoms or, in
specific embodiments, one to about twelve carbon atoms. In other
embodiments, alkyl groups are "lower alkyl" groups having one to
about six carbon atoms. Examples of such groups include, but are
not limited thereto, methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the
like. In more specific embodiments, lower alkyl groups have one to
four carbon atoms.
[0075] The term "alkylamino group" refers to amino groups directly
attached to the remainder of the molecule via the nitrogen atom of
the amino group and wherein the nitrogen atom of the alkylamino
group is substituted by one or two alkyl groups. In some
embodiments, alkylamino groups are "lower alkylamino" groups having
one or two alkyl groups of one to six carbon atoms, attached to a
nitrogen atom. In other embodiments, lower alkylamino groups have
one to three carbon atoms. Suitable "alkylamino" groups may be mono
or dialkylamino such as N-methylamino, N-ethylamino,
N,N-dimethylamino, N,N-diethylamino, pentamethyleneamine and the
like.
[0076] The term "allyl" denotes a moiety having the structural
formula H.sub.2C.dbd.CH--CH.sub.2--*, where * denotes the point of
attachment of the moiety to the remainder of the molecule and the
point of attachment is to a heteroatom or an aromatic moiety.
[0077] The term "allylamine" denotes a moiety having the structural
formula H.sub.2C.dbd.CH--CH.sub.2N(X.sub.8)(X.sub.9), wherein
X.sub.8 and X.sub.9 are independently hydrogen, hydrocarbyl, or
substituted hydrocarbyl, or X.sub.8 and X.sub.9 taken together form
a substituted or unsubstituted alicyclic, aryl, or heterocyclic
moiety, each as defined in connection with such term, typically
having from 3 to 8 atoms in the ring.
[0078] The term "amine" or "amino" as used alone or as part of
another group, represents a group of formula --N(X.sub.8)(X.sub.9),
wherein X.sub.8 and X.sub.9 are independently hydrogen,
hydrocarbyl, or substituted hydrocarbyl, heteroaryl, or
heterocyclo, or X.sub.8 and X.sub.9 taken together form a
substituted or unsubstituted alicyclic, aryl, or heterocyclic
moiety, each as defined in connection with such term, typically
having from 3 to 8 atoms in the ring.
[0079] The term "aminoalkyl group" encompasses linear or branched
alkyl groups having one to about ten carbon atoms, any one of which
may be substituted with one or more amino groups, directly attached
to the remainder of the molecule via an atom other than a nitrogen
atom of the amine group(s). In some embodiments, the aminoalkyl
groups are "lower aminoalkyl" groups having one to six carbon atoms
and one or more amino groups. Examples of such groups include
aminomethyl, aminoethyl, aminopropyl, aminobutyl and
aminohexyl.
[0080] The terms "anion exchange material" and "cation exchange
material" take their normal meaning in the art. For example, the
terms "anion exchange material" and "cation exchange material"
refer to materials that exchange anions and cations, respectively.
Anion and cation exchange materials are typically water-insoluble
substances which can exchange some of their cations or anions,
respectively, for similarly charged anions or cations contained in
a medium with which they are in contact. Anion exchange materials
may contain positively charged groups, which are fixed to the
backbone materials and allow passage of anions but reject cations.
A non-exhaustive list of such positively charged groups includes:
amino group, alkyl substituted phosphine, and alkyl substituted
sulphides. A non-exhaustive list of cation or anion exchange
materials includes: clays (e.g., bentonite, kaolinite, and illite),
vermiculite, zeolites (e.g., analcite, chabazite, sodalite, and
clinoptilolite), synthetic zeolites, polybasic acid salts, hydrous
oxides, metal ferrocyanides, and heteropolyacids. Cation exchange
materials can contain negatively charged groups fixed to the
backbone material, which allow the passage of cations but reject
anions. A non-exhaustive list of such negatively charged groups
includes: sulphate, carboxylate, phosphate, and benzoate.
[0081] The term "aromatic group" or "aryl group" means an aromatic
group having one or more rings wherein such rings may be attached
together in a pendent manner or may be fused. In particular
embodiments, an aromatic group is one, two or three rings.
Monocyclic aromatic groups may contain 5 to 10 carbon atoms,
typically 5 to 7 carbon atoms, and more typically 5 to 6 carbon
atoms in the ring. Typical polycyclic aromatic groups have two or
three rings. Polycyclic aromatic groups having two rings typically
have 8 to 12 carbon atoms, preferably 8 to 10 carbon atoms in the
rings. Examples of aromatic groups include, but are not limited to,
phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl,
phenanthryl, anthryl or acenaphthyl.
[0082] The term "bead" is used to describe a crosslinked polymer
that is substantially spherical in shape.
[0083] The term "bicarbonate equivalent" is used to describe an
organic acid or anion that yields bicarbonate when metabolized.
Citrate and succinate are exemplary bicarbonate equivalents.
[0084] The term "binds" as used herein in connection with a polymer
and one or more ions, that is, a cation (e.g. "proton-binding"
polymer) and an anion, is an "ion-binding" polymer and/or when it
associates with the ion, generally though not necessarily in a
non-covalent manner, with sufficient association strength that at
least a portion of the ion remains bound under the in vitro or in
vivo conditions in which the polymer is used for sufficient time to
effect a removal of the ion from solution or from the body.
[0085] The term "ceramic material" takes its normal meaning in the
art. In certain embodiments, the term "ceramic material" refers to
an inorganic, nonmetallic, solid material comprising metal,
nonmetal or metalloid atoms primarily held in ionic and covalent
bonds. A non-exhaustive list of examples of ceramic materials
includes: barium titanate, bismuth strontium calcium copper oxide,
boron oxide, earthenware, ferrite, lanthanum carbonate, lead
zirconate, titanate, magnesium diboride, porcelain, sialon, silicon
carbide, silicon nitride, titanium carbide, yttrium barium copper
oxide, zinc oxide, zirconium dioxide, and partially stabilised
zirconia. In certain embodiments, the term "clinically significant
increase" as used herein in connection with a treatment refers to a
treatment that improves or provides a worthwhile change in an
individual from a dysfunctional state back to a relatively normal
functioning state, or moves the measurement of that state in the
direction of normal functioning, or at least a marked improvement
to untreated. A number of methods can be used to calculate clinical
significance. A non-exhaustive list of methods for calculating
clinical significance includes: Jacobson-Truax,
Gulliksen-Lord-Novick, Edwards-Nunnally, Hageman-Arrindell, and
Hierarchical Linear Modeling (HLM).
[0086] The term "crosslink density" denotes the average number of
connections of the amine containing repeat unit to the rest of the
polymer. The number of connections can be 2, 3, 4 and higher.
Repeat units in linear, non-crosslinked polymers are incorporated
via 2 connections. To form an insoluble gel, the number of
connections should be greater than 2. Low crosslinking density
materials such as sevelamer have on average about 2.1 connections
between repeat units. More crosslinked systems such as bixalomer
have on average about 4.6 connections between the amine-containing
repeat units. "Crosslinking density" represents a semi-quantitative
measure based on the ratios of the starting materials used.
Limitations include the fact that it does not account for different
crosslinking and polymerization methods. For example, small
molecule amine systems require higher amounts of crosslinker as the
crosslinker also serves as the monomer to form the polymer backbone
whereas for radical polymerizations the polymer chain is formed
independent from the crosslinking reaction. This can lead to
inherently higher crosslinking densities under this definition for
the substitution polymerization/small molecule amines as compared
to radical polymerization crosslinked materials.
[0087] The term "crosslinker" as used, either alone or within other
terms, encompasses hydrocarbyl or substituted hydrocarbyl, linear
or branched molecules capable of reacting with any of the described
monomers, or the infinite polymer network, as described in Formula
1, more than one time. The reactive group in the crosslinker can
include, but is not limited to alkyl halide, epoxide, phosgene,
anhydride, carbamate, carbonate, isocyanate, thioisocyanate,
esters, activated esters, carboxylic acids and derivatives,
sulfonates and derivatives, acyl halides, aziridines,
.alpha.,.beta.-unsaturated carbonyls, ketones, aldehydes,
pentafluoroaryl groups, vinyl, allyl, acrylate, methacrylate,
acrylamide, methacrylamide, styrenic, acrylonitriles and
combinations thereof. In one exemplary embodiment, the
crosslinker's reactive group will include alkyl halide, epoxide,
anhydrides, isocyanates, allyl, vinyl, acrylamide, and combinations
thereof. In one such embodiment, the crosslinker's reactive group
will be alkyl halide, epoxide, or allyl.
[0088] The term "diallylamine" denotes an amino moiety having two
allyl groups.
[0089] The terms "dry bead" and "dry polymer" refer to beads or
polymers that contain no more than 5% by weight of a non-polymer
swelling agent or solvent. Often the swelling agent/solvent is
water remaining at the end of a purification. This is generally
removed by lyophilization or oven drying before storage or further
crosslinking of a preformed amine polymer. The amount of swelling
agent/solvent can be measured by heating (e.g., heating to
100-200.degree. C.) and measuring the resulting change in weight.
This is referred to a "loss on drying" or "LOD."
[0090] The term "estimated glomerular filtration rate" or eGFR
refers to an estimate of the glomerular filtration rate and is
estimated from the serum level of an endogenous filtration marker.
Creatinine is a commonly used endogenous filtration marker in
clinical practice and several equations have been proposed for
estimating the glomerular filtration rate. As used herein, all eGFR
values may be determined according to the CKD-EPI equation (Levey
et al., A New Equation to Estimate Glomerular Filtration Rate. Ann
Intern Med. 2009; 150:604-612):
GFR=41*min(Scr/.kappa.,1).sup..alpha.*max(Scr/.kappa.,1).sup.-1.209*0.99-
3.sup.Age*1.018[if female]*1.159[if black]
wherein Scr is serum creatinine (mg/dL), .kappa. is 0.7 for females
and 0.9 for males, .alpha. is -0.329 for females and -0.411 for
males, min indicates the minimum of Scr/.kappa. or 1, and max
indicates the maximum of Scr/.kappa. or 1.
[0091] The term "ethereal" denotes a moiety having an oxygen bound
to two separate carbon atoms as depicted the structural formula
*--H.sub.xC--O--CH.sub.x--*, where * denotes the point of
attachment to the remainder of the moiety and x independently
equals 0, 1, 2, or 3.
[0092] The term "gel" is used to describe a crosslinked polymer
that has an irregular shape.
[0093] The term "glomerular filtration rate" or GFR is the volume
of fluid filtered from the renal (kidney) glomerular capillaries
into the Bowman's capsule per unit time. GFR cannot be measured
directly; instead, it is measured indirectly (mGFR) as the
clearance of an exogenous filtration marker (e.g., inulin,
iothalamate, iohexol, etc.) or estimated (eGFR) using an endogenous
filtration marker.
[0094] The term "halo" means halogens such as fluorine, chlorine,
bromine or iodine atoms.
[0095] The term "haloalkyl group" encompasses groups wherein anyone
or more of the alkyl carbon atoms is substituted with halo as
defined above. Specifically encompassed are monohaloalkyl,
dihaloalkyl and polyhaloalkyl groups including perhaloalkyl. A
monohaloalkyl group, for example, may have either an iodo, bromo,
chloro or fluoro atom within the group. Dihalo and polyhaloalkyl
groups may have two or more of the same halo atoms or a combination
of different halo groups. "Lower haloalkyl group" encompasses
groups having 1-6 carbon atoms. In some embodiments, lower
haloalkyl groups have one to three carbon atoms. Examples of
haloalkyl groups include fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl
and dichloropropyl.
[0096] The term "heteroaliphatic" describes a chain of 1 to 25
carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to
10 carbon atoms, and most typically 1 to 8 carbon atoms, and in
some embodiments 1 to 4 carbon atoms that can be saturated or
unsaturated (but not aromatic), containing one or more heteroatoms,
such as halogen, oxygen, nitrogen, sulfur, phosphorus, or boron. A
heteroatom atom may be a part of a pendant (or side) group attached
to a chain of atoms (e.g., --CH(OH)--CH(NH.sub.2)-- where the
carbon atom is a member of a chain of atoms) or it may be one of
the chain atoms (e.g., --ROR-- or --RNHR-- where each R is
aliphatic). Heteroaliphatic encompasses heteroalkyl and heterocyclo
but does not encompass heteroaryl.
[0097] The term "heteroalkyl" describes a fully saturated
heteroaliphatic moiety.
[0098] The term "heteroaryl" means a monocyclic or bicyclic
aromatic radical of 5 to 10 ring atoms, unless otherwise stated,
where one or more, (in one embodiment, one, two, or three), ring
atoms are heteroatom selected from N, O, or S, the remaining ring
atoms being carbon. Representative examples include, but are not
limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl,
indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl,
benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl,
pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. As
defined herein, the terms "heteroaryl" and "aryl" are mutually
exclusive. "Heteroarylene" means a divalent heteroaryl radical.
[0099] The term "heteroatom" means an atom other than carbon and
hydrogen. Typically, but not exclusively, heteroatoms are selected
from the group consisting of halogen, sulfur, phosphorous,
nitrogen, boron and oxygen atoms. Groups containing more than one
heteroatom may contain different heteroatoms.
[0100] The term "heterocyclo," "heterocyclic," or heterocyclyl"
means a saturated or unsaturated group of 4 to 8 ring atoms in
which one or two ring atoms are heteroatom such as N, O, B, P and
S(O)n, where n is an integer from 0 to 2, the remaining ring atoms
being carbon. Additionally, one or two ring carbon atoms in the
heterocyclyl ring can optionally be replaced by a --C(O)-- group.
More specifically the term heterocyclyl includes, but is not
limited to, pyrrolidino, piperidino, homopiperidino,
2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino,
tetrahydro-pyranyl, thiomorpholino, and the like. When the
heterocyclyl ring is unsaturated it can contain one or two ring
double bonds provided that the ring is not aromatic. When the
heterocyclyl group contains at least one nitrogen atom, it is also
referred to herein as heterocycloamino and is a subset of the
heterocyclyl group.
[0101] The term "hydrocarbon group" or "hydrocarbyl group" means a
chain of 1 to 25 carbon atoms, typically 1 to 12 carbon atoms, more
typically 1 to 10 carbon atoms, and most typically 1 to 8 carbon
atoms. Hydrocarbon groups may have a linear or branched chain
structure. Typical hydrocarbon groups have one or two branches,
typically one branch. Typically, hydrocarbon groups are saturated.
Unsaturated hydrocarbon groups may have one or more double bonds,
one or more triple bonds, or combinations thereof. Typical
unsaturated hydrocarbon groups have one or two double bonds or one
triple bond; more typically unsaturated hydrocarbon groups have one
double bond.
[0102] "Initiator" is a term used to describe a reagent that
initiates a polymerization.
[0103] The term "measured glomerular filtration rate" or "mGFR"
refers to a measurement of the glomerular filtration rate using any
chemical (e.g., inulin, iothalamate, iohexol, etc.) that has a
steady level in the blood, and is freely filtered but neither
reabsorbed nor secreted by the kidneys according to standard
technique.
[0104] The term "Michael acceptor" takes its normal meaning in the
art. In certain embodiments the term "Michael acceptor" refers to
activated olefins, such as .alpha.,.beta.-unsaturated carbonyl
compounds. A Michael acceptor can be a conjugated system with an
electron withdrawing group, such as cyano, keto or ester. A
non-exhaustive list of examples of Michael acceptors includes:
vinyl ketones, alkyl acrylates, acrylo nitrile, and fumarates.
[0105] The term "molecular weight per nitrogen" or "MW/N"
represents the calculated molecular weight in the polymer per
nitrogen atom. It represents the average molecular weight to
present one amine function within the crosslinked polymer. It is
calculated by dividing the mass of a polymer sample by the moles of
nitrogen present in the sample. "MW/N" is the inverse of
theoretical capacity, and the calculations are based upon the feed
ratio, assuming full reaction of crosslinker and monomer. The lower
the molecular weight per nitrogen the higher the theoretical
capacity of the crosslinked polymer.
[0106] The term "nonabsorbable" as used herein takes its normal
meaning in the art. Therefore, if something is nonabsorbable it is
not absorbed during its passage through the human GI tract. This
could be measured by any appropriate means. One option known to the
skilled person would be to examine faeces to see if the
nonabsorbable material is recovered after passing through the GI
tract. As a practical matter, the amount of a nonabsorbable
material recovered in this scenario will never be 100% of the
material administered. For example, about 90-99% of the material
might be recovered from the faeces. Another option known to the
skilled person would be to look for the presence of the material in
the lynph, blood, interstitial fluid, secretions from various
organs (eg, pancreas, liver, gut, etc) or in the body of organs
(eg, liver, kidney, lungs, etc) as oral administration of a
nonabsorbable material would not result in an increase in the
amount of that material in these matrices and tissues.
Nonabsorbable compositions may be particulate compositions that are
essentially insoluble in the human GI tract and have a particle
size that is large enough to avoid passive or active absorption
through the human GI tract. As an example, nonabsorbable
compositions is meant to imply that the substance does not enter
the lymph, blood, interstitial fluids or organs through the main
entry points of the human GI tract, namely by paracellular entry
between gut epithelial cells, by endocytic uptake through gut
epithelial cells, or through entry via M cells comprising the gut
epithelial antigen sampling and immune surveillance system (Jung,
2000), either through active or passive transport processes. There
is a known size limit for a particulate to be absorbed in the human
GI tract (Jung et al., European Journal of Pharmaceutics and
Biopharmaceutics 50 (2000) 147-160; Jani et al., Internation
Journal of Pharmaceutics, 84 (1992) 245-252; and Jani et al., J.
Pharm. Pharmacol. 1989, 41:809-812), so the skilled person would
know that materials that, when in the GI tract, have a size of at
least 1 micrometers would be nonabsorbable.
[0107] "Optional" or "optionally" means that the subsequently
described event or circumstance may but need not occur, and that
the description includes instances where the event or circumstance
occurs and instances in which it does not. For example,
"heterocyclyl group optionally substituted with an alkyl group"
means that the alkyl may but need not be present, and the
description includes embodiments in which the heterocyclyl group is
substituted with an alkyl group and embodiments in which the
heterocyclyl group is not substituted with alkyl.
[0108] "Particle size" is measured by wet laser diffraction using
Mie theory. Particles are dispersed in an appropriate solvent, such
as water or methanol, and added to the sample chamber to achieve
red channel obscuration of 10-20%. Sonication may be performed, and
a dispersing agent, such as a surfactant (e.g. Tween-80), may be
added in order to disrupt weak particle-particle interactions. The
refractive index setting of the particles used for size
distribution calculation is selected to minimize artifacts in the
results and the R parameter value, determined by the laser
diffraction software. The D(0.1), D(0.5), and D(0.9) values
characterizing the particle size distribution by volume-basis are
recorded.
[0109] "Pharmaceutically acceptable" as used in connection with a
carrier, diluent or excipient means a carrier, diluent or an
excipient, respectively, that is useful in preparing a
pharmaceutical composition that is generally safe, non-toxic and
neither biologically nor otherwise undesirable for veterinary use
and/or human pharmaceutical use.
[0110] The term "post polymerization crosslinking" is a term that
describes a reaction to an already formed bead or gel, where more
crosslinking is introduced to the already formed bead or gel to
create a bead or gel that has an increased amount of
crosslinking.
[0111] The term "post polymerization modification" is a term that
describes a modification to an already formed bead or gel, where a
reaction or a treatment introduces an additional functionality.
This functionality can be linked either covalently or
non-covalently to the already formed bead.
[0112] The term "quaternized amine assay" ("QAA") describes a
method to estimate the amount of quaternary amines present in a
given crosslinked polymer sample. This assay measures chloride
binding of a crosslinked polymer at a pH of 11.5. At this pH,
primary, secondary and tertiary amines are not substantially
protonated and do not substantially contribute to chloride binding.
Therefore, any binding observed under these conditions can be
attributed to the presence of permanently charged quaternary
amines. The test solution used for QAA assay is 100 mM sodium
chloride at a pH of 11.5. The concentration of chloride ions is
similar to that in the SGF assay which is used to assess total
binding capacity of crosslinked polymers. Quaternary amine content
as a percentage of total amines present is calculated as
follows:
% Quaternary amines = Chloride bound ( mmol / g ) in QAA Chloride
bound ( mmol / g ) in SGF .times. 100 ##EQU00001##
To perform the QAA assay, the free-amine polymer being tested is
prepared at a concentration of 2.5 mg/ml (e.g. 25 mg dry mas) in 10
mL of QAA buffer. The mixture is incubated at 37.degree. C. for
.about.16 hours with agitation on a rotisserie mixer. After
incubation and mixing, 600 microliters of supernatant is removed
and filtered using a 800 microliter, 0.45 micrometer pore size,
96-well poly propylene filter plate. With the samples arrayed in
the filter plate and the collection plate fitted on the bottom, the
unit is centrifuged at 1000.times.g for 1 minute to filter the
samples. After filtration into the collection plate, the respective
filtrates are diluted appropriately before measuring for chloride
content. The IC method (e.g. ICS-2100 Ion Chromatography, Thermo
Fisher Scientific) used for the analysis of chloride content in the
filtrates consists of a 15 mM KOH mobile phase, an injection volume
of 5 microliters, with a run time of three minutes, a washing/rinse
volume of 1000 microliters, and flow rate of 1.25 mL/min. To
determine the chloride bound to the polymer, the following
calculation is completed:
Binding capacity expressed as mmol chloride / g dry polymer = ( Cl
start - Cl eq ) 2.5 ##EQU00002##
where Cl start corresponds to the starting concentration of
chloride in the QAA buffer, C eq corresponds to the equilibrium
value of chloride in the measured filtrates after exposure to the
test polymer, and 2.5 is the polymer concentration in mg/ml.
[0113] The terms "short chain carboxylic acid" or "short chain
fatty acid" take their normal meaning in the art. In certain
embodiments, the terms "short chain carboxylic acid" or "short
chain fatty acid" refer to carboxylic acids having a chain length
of 0, 1, 2, 3, 4, 5 or 6 carbon atoms long. A non-exhaustive list
of examples of short chain carboxylic acids includes: formic acid,
acetic acid, propionic acid, butyric acid, isobutyric acid, valeric
acid, isovaleric acid, and lactic acid.
[0114] "Simulated Gastric Fluid" or "SGF" Assay describes a test to
determine total chloride binding capacity for a test polymer using
a defined buffer that simulates the contents of gastric fluid as
follows: Simulated gastric fluid (SGF) consists of 35 mM NaCl, 63
mM HCl, pH 1.2. To perform the assay, the free-amine polymer being
tested is prepared at a concentration of 2.5 mg/ml (25 mg dry mass)
in 10 mL of SGF buffer. The mixture is incubated at 37.degree. C.
overnight for .about.12-16 hours with agitation on a rotisserie
mixer. Unless another time period is otherwise stated, SGF binding
data or binding capacities recited herein are determined in a time
period of this duration. After incubation and mixing, the tubes
containing the polymer are centrifuged for 2 minutes at
500-1000.times.g to pellet the test samples. Approximately 750
microliters of supernatant are removed and filtered using an
appropriate filter, for example a 0.45 micrometer pore-size syringe
filter or an 800 microliter, 1 micrometer pore-size, 96-well, glass
filter plate that has been fitted over a 96-well 2 mL collection
plate. With the latter arrangement, multiple samples tested in SGF
buffer can be prepared for analysis, including the standard
controls of free amine sevelamer, free amine bixalomer and a
control tube containing blank buffer that is processed through all
of the assay steps. With the samples arrayed in the filter plate
and the collection plate fitted on the bottom, the unit is
centrifuged at 1000.times.g for 1 minute to filter the samples. In
cases of small sample sets, a syringe filter may be used in lieu of
the filter plate, to retrieve .about.2-4 mL of filtrate into a 15
mL container. After filtration, the respective filtrates are
diluted 4.times. with water and the chloride content of the
filtrate is measured via ion chromatography (IC). The IC method
(e.g. Dionex ICS-2100, Thermo Scientific) consists of an AS11
column and a 15 mM KOH mobile phase, an injection volume of 5
microliters, with a run time of 3 minutes, a washing/rinse volume
of 1000 microliters, and flow rate of 1.25 mL/min. To determine the
chloride bound to the polymer, the following calculation is
completed:
( Cl start - Cl eq ) .times. 4 2.5 . ##EQU00003##
Binding capacity expressed as mmol chloride/g polymer: where Cl
start corresponds to the starting concentration of chloride in the
SGF buffer, Cl eq corresponds to the equilibrium value of chloride
in the diluted measured filtrates after exposure to the test
polymer, 4 is the dilution factor and 2.5 is the polymer
concentration in mg/ml.
[0115] "Simulated Small Intestine Inorganic Buffer" or "SIB" is a
test to determine the chloride and phosphate binding capacity of
free amine test polymers in a selective specific interfering buffer
assay (SIB). The chloride and phosphate binding capacity of free
amine test polymers, along with the chloride and phosphate binding
capacity of free amine sevelamer and bixalomer control polymers,
was determined using the selective specific interfering buffer
assay (SIB) as follows: The buffer used for the SIB assay comprises
36 mM NaCl, 20 mM NaH.sub.2PO.sub.4, 50 mM
2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5. The
SIB buffer contains concentrations of chloride, phosphate and pH
that are present in the human duodenum and upper gastrointestinal
tract (Stevens T, Conwell D L, Zuccaro G, Van Lente F, Khandwala F,
Purich E, et al. Electrolyte composition of endoscopically
collected duodenal drainage fluid after synthetic porcine secretin
stimulation in healthy subjects. Gastrointestinal endoscopy. 2004;
60(3):351-5, Fordtran J, Locklear T. Ionic constituents and
osmolality of gastric and small-intestinal fluids after eating.
Digest Dis Sci. 1966; 11(7):503-21) and is an effective measure of
the selectivity of chloride binding compared to phosphate binding
by a polymer. To perform the assay, the free amine polymer being
tested is prepared at a concentration of 2.5 mg/ml (25 mg dry mass)
in 10 mL of SIB buffer. The mixture is incubated at 37.degree. C.
for 1 hour with agitation on a rotisserie mixer. Unless another
time period is otherwise stated, SIB binding data or binding
capacities recited herein are determined in a time period of this
duration. After incubation and mixing, the tubes containing the
polymer are centrifuged for 2 minutes at 1000.times.g to pellet the
test samples. 750 microliter of supernatant is removed and filtered
using an 800 microliter, 1 micrometer pore-size, 96-well, glass
filter plate that has been fitted over a 96-well 2 mL collection
plate; with this arrangement multiple samples tested in SIB buffer
can be prepared for analysis, including the standard controls of
free amine sevelamer, free amine bixalomer and a control tube
containing blank buffer that is processed through all of the assay
steps. With the samples arrayed in the filter plate and the
collection plate fitted on the bottom, the unit is centrifuged at
1000.times.g for 1 minute to filter the samples. In cases of small
sample sets, a syringe filter (0.45 micrometer) may be used in lieu
of the filter plate, to retrieve .about.2-4 mL of filtrate into a
15 mL vial. After filtration into the collection plate, the
respective filtrates are diluted before measuring for chloride or
phosphate content. For the measurement of chloride and phosphate,
the filtrates under analysis are diluted 4.times. with water. The
chloride and phosphate content of the filtrate is measured via ion
chromatography (IC). The IC method (e.g. Dionex ICS-2100, Thermo
Scientific) consists of an AS24A column, a 45 mM KOH mobile phase,
an injection volume of 5 microliters, with a run time of about 10
minutes, a washing/rinse volume of 1000 microliter, and flow rate
of 0.3 mL/min. To determine the chloride bound to the polymer, the
following calculation is completed:
Binding capacity expressed as mmol chloride / g polymer = ( Cl
start - Cl final ) .times. 4 2.5 ##EQU00004##
where Cl.sub.star corresponds to the starting concentration of
chloride in the SIB buffer, Cl.sub.final corresponds to the final
value of chloride in the measured diluted filtrates after exposure
to the test polymer, 4 is the dilution factor and 2.5 is the
polymer concentration in mg/ml. To determine the phosphate bound to
the polymer, the following calculation is completed:
Binding capacity expressed as mmol p hosphate / g polymer = ( P
start - P final ) .times. 4 2.5 ##EQU00005##
where P.sub.start corresponds to the starting concentration of
phosphate in the SIB buffer, P.sub.final corresponds to the final
value of phosphate in the measured diluted filtrates after exposure
to the test polymer, 4 is the dilution factor and 2.5 is the
polymer concentration in mg/ml.
[0116] In certain embodiments, the term "statistically significant"
refers to the likelikhood that a relationship between two or more
variables is caused by something other than random chance. More
precisely, the significance level, a, defined for a study is the
probability of the study rejecting the null hypothesis, given that
it were true, and the p-value, p, of a result is the probability of
obtaining a result at least as extreme, given that the null
hypothesis were true. The result is statistically significant, by
the standards of the study, when p<a. The significance level for
a study is chosen before data collection, and typically set to
5%
[0117] The term "substituted hydrocarbyl," "substituted alkyl,"
"substituted alkenyl," "substituted aryl," "substituted
heterocyclo," or "substituted heteroaryl" as used herein denotes
hydrocarbyl, alkyl, alkenyl, aryl, heterocyclo, or heteroaryl
moieties which are substituted with at least one atom other than
carbon and hydrogen, including moieties in which a carbon chain
atom is substituted with a hetero atom such as nitrogen, oxygen,
silicon, phosphorous, boron, sulfur, or a halogen atom. These
substituents include halogen, heterocyclo, alkoxy, alkenoxy,
alkynoxy, aryloxy, hydroxy, keto, acyl, acyloxy, nitro, amino,
amido, nitro, cyano, thiol, ketals, acetals, esters and ethers.
[0118] "Swelling Ratio" or simply "Swelling" describes the amount
of water absorbed by a given amount of polymer divided by the
weight of the polymer aliquot. The Swelling Ratio is expressed as:
swelling=(g swollen polymer-g dry polymer)/g dry polymer. The
method used to determine the Swelling Ratio for any given polymer
comprised the following: [0119] a. 50-100 mg of dry (less than 5 wt
% water content) polymer is placed into an 11 mL sealable test tube
(with screw cap) of known weight (weight of tube=Weight A). [0120]
b. Deionized water (10 mL) is added to the tube containing the
polymer. The tube is sealed and tumbled for 16 hours (overnight) at
room temperature. After incubation, the tube is centrifuged at
3000.times.g for 3 minutes and the supernatant is carefully removed
by vacuum suction. For polymers that form a very loose sediment,
another step of centrifugation is performed. [0121] c. After step
(b), the weight of swollen polymer plus tube (Weight B) is
recorded. [0122] d. Freeze at -40.degree. C. for 30 minutes.
Lyophilize for 48 h. Weigh dried polymer and test tube (recorded as
Weight C). [0123] e. Calculate g water absorbed per g of polymer,
defined as: [(Weight B-Weight A)-(Weight C-Weight A)]/(Weight
C-Weight A).
[0124] A "target ion" is an ion to which the polymer binds, and
usually refers to the major ions bound by the polymer, or the ions
whose binding to the polymer is thought to produce the therapeutic
effect of the polymer (e.g., proton and chloride binding which
leads to net removal of HCl).
[0125] The term "theoretical capacity" represents the calculated,
expected binding of hydrochloric acid in an "SGF" assay, expressed
in mmol/g. The theoretical capacity is based on the assumption that
100% of the amines from the monomer(s) and crosslinker(s) are
incorporated in the crosslinked polymer based on their respective
feed ratios. Theoretical capacity is thus equal to the
concentration of amine functionalities in the polymer (mmol/g). The
theoretical capacity assumes that each amine is available to bind
the respective anions and cations and is not adjusted for the type
of amine formed (e.g. it does not subtract capacity of quaternary
amines that are not available to bind proton).
[0126] "Therapeutically effective amount" means the amount of a
proton-binding crosslinked polymer that, when administered to a
patient for treating a disease, is sufficient to effect such
treatment for the disease. The amount constituting a
"therapeutically effective amount" will vary depending on the
polymer, the severity of the disease and the age, weight, etc., of
the mammal to be treated.
[0127] "Treating" or "treatment" of a disease includes (i)
inhibiting the disease, i.e., arresting or reducing the development
of the disease or its clinical symptoms; or (ii) relieving the
disease, i.e., causing regression of the disease or its clinical
symptoms. Inhibiting the disease, for example, would include
prophylaxis.
[0128] The term "triallylamine" denotes an amino moiety having
three allyl groups.
[0129] The term "vinyl" denotes a moiety having the structural
formula R.sub.xH.sub.yC.dbd.CH--*, where * denotes the point of
attachment of the moiety to the remainder of the molecule wherein
the point of attachment is a heteroatom or aryl, X and Y are
independently 0, 1 or 2, such that X+Y=2, and R is hydrocarbyl or
substituted hydrocarbyl.
[0130] The term "weight percent crosslinker" represents the
calculated percentage, by mass, of a polymer sample that is derived
from the crosslinker. Weight percent crosslinker is calculated
using the feed ratio of the polymerization, and assumes full
conversion of the monomer and crosslinker(s). The mass attributed
to the crosslinker is equal to the expected increase of molecular
weight in the infinite polymer network after reaction (e.g.,
1,3-dichloropropane is 113 amu, but only 42 amu are added to a
polymer network after crosslinking with DCP because the chlorine
atoms, as leaving groups, are not incorporated into the polymer
network).
[0131] 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 not exclusive (i.e., there may be
other elements in addition to the recited elements).
EMBODIMENTS
[0132] In accordance with the present disclosure, acid-base
disorders may be treated using pharmaceutical compositions
comprising a nonabsorbable composition having the capacity to
remove clinically significant quantities of protons, the conjugate
base of one or more strong acids, and/or one or more strong acids.
An individual afflicted with a an acute or chronic acid/base
disorder characterized by a baseline serum bicarbonate value of
less than 22 mEq/l may thus be treated by oral administration of a
pharmaceutical composition comprising the nonabsorbable composition
which then transits the individual's digestive system, binds a
target species (protons, one or more conjugate base(s) of a strong
acid and/or one or more strong acid(s)) as it transits the
digestive system, and removes the bound target species by normal
biological function (defecation).
[0133] In general, the individual afflicted with an acute or
chronic acid/base disorder may be at any stage of chronic kidney
disease. For example, in one embodiment the afflicted individual
has not yet reached end stage renal disease ("ESRD") sometimes also
referred to as end stage chronic kidney disease and is not yet on
dialysis (i.e., the individual has a mGFR (or eGFR) of at least 15
mL/min/1.73 m.sup.2). In some embodiments, the afflicted individual
will be Stage 3B CKD (i.e., the individual has a mGFR (or eGFR) in
the range of 30-44 mL/min/1.73 m.sup.2 for at least three months).
In some embodiments, the afflicted individual will be Stage 3A CKD
(i.e., the individual has a mGFR (or eGFR) in the range of 45-59
mL/min/1.73 m.sup.2 for at least three months). Thus, for example,
in some embodiments the afflicted individual has a mGFR or an eGFR
of less than 60 mL/min/1.73 m.sup.2 for at least three months. By
way of further example, in some embodiments the afflicted
individual has a mGFR or an eGFR of less than 45 mL/min/1.73
m.sup.2 for at least three months. By way of further example, in
some embodiments the afflicted individual has a mGFR or an eGFR of
less than 30 mL/min/1.73 m.sup.2 for at least three months. By way
of further example, in some embodiments the afflicted individual
has a mGFR or an eGFR of 15-30, 15-45, 15-60, 30-45 or even 30-60
mL/min/1.73 m.sup.2 for at least three months.
[0134] The baseline serum bicarbonate value may be the serum
bicarbonate concentration determined at a single time point or may
be the mean or median value of two or more serum bicarbonate
concentrations determined at two or more time-points. For example,
in one embodiment the baseline serum bicarbonate value may be the
value of the serum bicarbonate concentration determined at a single
time point and the baseline serum bicarbonate value is used as a
basis to determine an acute acidic condition requiring immediate
treatment. In another embodiment, the baseline serum bicarbonate
treatment value is the mean value of the serum bicarbonate
concentration for serum samples drawn at different time points
(e.g., different days). By way of further example, in one such
embodiment the baseline serum bicarbonate treatment value is the
mean value of the serum bicarbonate concentration for serum samples
drawn on different days (e.g., at least 2, 3, 4, 5 or more days,
that may be consecutive or separated by one or more days or even
weeks). By way of further example, in one such embodiment the
baseline serum bicarbonate treatment value is the mean value of the
serum bicarbonate concentration for serum samples drawn on two
consecutive days preceding the initiation of treatment.
[0135] In one embodiment, the acid-base disorder being treated is
characterized by a baseline serum bicarbonate value of less than 21
mEq/l. For example, in one such embodiment the acid-base disorder
being treated is characterized by a baseline serum bicarbonate
value of less than 20 mEq/l. By way of further example, in one such
embodiment the acid-base disorder being treated is characterized by
a baseline serum bicarbonate value of less than 19 mEq/l. By way of
further example, in one such embodiment the acid-base disorder
being treated is characterized by a baseline serum bicarbonate
value of less than 18 mEq/l. By way of further example, in one such
embodiment the acid-base disorder being treated is characterized by
a baseline serum bicarbonate value of less than 17 mEq/l. By way of
further example, in one such embodiment the acid-base disorder
being treated is characterized by a baseline serum bicarbonate
value of less than 16 mEq/l. By way of further example, in one such
embodiment the acid-base disorder being treated is characterized by
a baseline serum bicarbonate value of less than 15 mEq/l. By way of
further example, in one such embodiment the acid-base disorder
being treated is characterized by a baseline serum bicarbonate
value of less than 14 mEq/l. By way of further example, in one such
embodiment the acid-base disorder being treated is characterized by
a baseline serum bicarbonate value of less than 13 mEq/l. By way of
further example, in one such embodiment the acid-base disorder
being treated is characterized by a baseline serum bicarbonate
value of less than 12 mEq/l. By way of further example, in one such
embodiment the acid-base disorder being treated is characterized by
a baseline serum bicarbonate value of less than 11 mEq/l. By way of
further example, in one such embodiment the acid-base disorder
being treated is characterized by a baseline serum bicarbonate
value of less than 10 mEq/l. By way of further example, in one such
embodiment the acid-base disorder being treated is characterized by
a baseline serum bicarbonate value of less than 9 mEq/l.
[0136] In general, however, the acid-base disorder being treated is
characterized by a baseline serum bicarbonate value of at least 9
mEq/l. For example, in one such embodiment, the acid-base disorder
is characterized by a baseline serum bicarbonate value of at least
10 mEq/l. By way of further example, in one such embodiment, the
acid-base disorder is characterized by a baseline serum bicarbonate
value of at least 11 mEq/l. By way of further example, in one such
embodiment, the acid-base disorder is characterized by a baseline
serum bicarbonate value of at least 12 mEq/l. By way of further
example, in one such embodiment, the acid-base disorder is
characterized by a baseline serum bicarbonate value of at least 13
mEq/l. By way of further example, in one such embodiment, the
acid-base disorder is characterized by a baseline serum bicarbonate
value of at least 14 mEq/l. By way of further example, in one such
embodiment, the acid-base disorder is characterized by a baseline
serum bicarbonate value of at least 15 mEq/l. By way of further
example, in one such embodiment, the acid-base disorder is
characterized by a baseline serum bicarbonate value of at least 16
mEq/l. By way of further example, in one such embodiment, the
acid-base disorder is characterized by a baseline serum bicarbonate
value of at least 17 mEq/l. By way of further example, in one such
embodiment, the acid-base disorder is characterized by a baseline
serum bicarbonate value of at least 18 mEq/l. By way of further
example, in one such embodiment, the acid-base disorder is
characterized by a baseline serum bicarbonate value of at least 19
mEq/l. By way of further example, in one such embodiment, the
acid-base disorder is characterized by a baseline serum bicarbonate
value of at least 20 mEq/l. By way of further example, in one such
embodiment, the acid-base disorder is characterized by a baseline
serum bicarbonate value of at least 21 mEq/l.
[0137] In certain embodiments, the acid-base disorder being treated
is characterized by a baseline serum bicarbonate value in the range
of 9 to 21 mEq/l. For example, in one such embodiment the acid-base
disorder is characterized by a baseline serum bicarbonate value in
the range of 12 to 20 mEq/l. By way of further example, in one such
embodiment the acid-base disorder is characterized by a baseline
serum bicarbonate value in the range of 12 to 19 mEq/l. By way of
further example, in one such embodiment the acid-base disorder is
characterized by a baseline serum bicarbonate value in the range of
12 to 18 mEq/l. By way of further example, in one such embodiment
the acid-base disorder is characterized by a baseline serum
bicarbonate value in the range of 12 to 17 mEq/l. By way of further
example, in one such embodiment the acid-base disorder is
characterized by a baseline serum bicarbonate value in the range of
12 to 16 mEq/l. By way of further example, in one such embodiment
the acid-base disorder is characterized by a baseline serum
bicarbonate value in the range of 9 to 11 mEq/l. By way of further
example, in one such embodiment the acid-base disorder is
characterized by a baseline serum bicarbonate value in the range of
12-14. By way of further example, in one such embodiment the
acid-base disorder is characterized by a baseline serum bicarbonate
value in the range of 15-17. By way of further example, in one such
embodiment the acid-base disorder is characterized by a baseline
serum bicarbonate value in the range of 18-21.
[0138] In certain embodiments, oral administration of a
pharmaceutical composition containing a nonabsorbable composition
increases the individual's serum bicarbonate value from baseline to
an increased serum bicarbonate value that exceeds the baseline
serum bicarbonate value by at least 1 mEq/l. For example, in one
such embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 1.5 mEq/l.
By way of further example in one such embodiment the treatment
increases the individual's serum bicarbonate value to an increased
serum bicarbonate value that exceeds the baseline serum bicarbonate
value by at least 2 mEq/l. By way of further example in one such
embodiment the treatment the individual's serum bicarbonate value
to an increased serum bicarbonate value that exceeds the baseline
serum bicarbonate value by at least 2.5 mEq/l. By way of further
example in one such embodiment the treatment increases the
individual's serum bicarbonate value to an increased serum
bicarbonate value that exceeds the baseline serum bicarbonate value
by at least at least 3 mEq/l. By way of further example in one such
embodiment the treatment increases the baseline serum bicarbonate
value to an increased serum bicarbonate value that exceeds the
baseline serum bicarbonate value by at least 3.5 mEq/l. By way of
further example in one such embodiment the treatment increases the
individual's serum bicarbonate value to an increased serum
bicarbonate value that exceeds the baseline serum bicarbonate value
by at least 4 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 5 mEq/l
but does not exceed 29 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 5 mEq/l
but does not exceed 28 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 5 mEq/l
but does not exceed 27 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 5 mEq/l
but does not exceed 26 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 6 mEq/l
but does not exceed 29 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 6 mEq/l
but does not exceed 28 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 6 mEq/l
but does not exceed 27 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 6 mEq/l
but does not exceed 26 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 7 mEq/l
but does not exceed 29 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 7 mEq/l
but does not exceed 28 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 7 mEq/l
but does not exceed 27 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 7 mEq/l
but does not exceed 26 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 8 mEq/l
but does not exceed 29 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 8 mEq/l
but does not exceed 28 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 8 mEq/l
but does not exceed 27 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 8 mEq/l
but does not exceed 26 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 9 mEq/l
but does not exceed 29 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 9 mEq/l
but does not exceed 28 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 9 mEq/l
but does not exceed 27 mEq/l. By way of further example in one such
embodiment the treatment increases the individual's serum
bicarbonate value to an increased serum bicarbonate value that
exceeds the baseline serum bicarbonate value by at least 9 mEq/l
but does not exceed 26 mEq/l. In each of the foregoing exemplary
embodiments recited in this paragraph, the treatment enables the
increased serum bicarbonate value to be sustained over a prolonged
period of at least one week, at least one month, at least two
months, at least three months, at least six months, or even at
least one year.
[0139] In certain embodiments, treatment with the nonabsorbable
composition increases the individual's serum bicarbonate value from
a baseline serum bicarbonate value in the range of 12 to 20 mEq/l
by at least 1 mEq/l. For example, in one such embodiment the
treatment increases the individual's serum bicarbonate value from a
baseline serum bicarbonate value in the range of 12 to 20 mEq/l by
at least 1.5 mEq/l. By way of further example, in one such
embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 12 to 20 mEq/l by at least 2 mEq/l. By way of further
example, in one such embodiment the treatment increases the
individual's serum bicarbonate value from a baseline serum
bicarbonate value in the range of 12 to 20 mEq/l by at least 2.5
mEq/l. By way of further example, in one such embodiment the
treatment increases the individual's serum bicarbonate value from a
baseline serum bicarbonate value in the range of 12 to 20 mEq/l by
at least 3 mEq/l. By way of further example, in one such embodiment
the treatment increases the individual's serum bicarbonate value
from a baseline serum bicarbonate value in the range of 12 to 20
mEq/l by at least 3.5 mEq/l. By way of further example, in one such
embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 12 to 20 mEq/l by at least 4 mEq/l. By way of further
example, in one such embodiment the treatment increases the
individual's serum bicarbonate value from a baseline serum
bicarbonate value in the range of 12 to 20 mEq/l by at least 4.5
mEq/l. By way of further example, in one such embodiment the
treatment increases the individual's serum bicarbonate value from a
baseline serum bicarbonate value in the range of 12 to 20 mEq/l by
at least 5 mEq/l. By way of further example, in one such embodiment
the treatment increases the individual's serum bicarbonate value
from a baseline serum bicarbonate value in the range of 12 to 20
mEq/l by at least 5.5 mEq/l. By way of further example, in one such
embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 12 to 20 mEq/l by at least 6 mEq/l. In each of the
foregoing exemplary embodiments recited in this paragraph, the
increased serum bicarbonate value preferably does not exceed 29
mEq/l. For example, in each of the foregoing exemplary embodiments,
the increased serum bicarbonate value may not exceed 28 mEq/l. By
way of further example, in each of the foregoing exemplary
embodiments, the increased serum bicarbonate value may not exceed
27 mEq/l. By way of further example, in each of the foregoing
exemplary embodiments, the increased serum bicarbonate value may
not exceed 26 mEq/l. Further, in each of the foregoing exemplary
embodiments recited in this paragraph, the treatment enables the
increased serum bicarbonate value to be sustained over a prolonged
period of at least one week, at least one month, at least two
months, at least three months, at least six months, or even at
least one year.
[0140] In certain embodiments, treatment with the nonabsorbable
composition increases the individual's serum bicarbonate value from
a baseline serum bicarbonate value in the range of 9 to 21 mEq/l by
at least 1 mEq/l. For example, in one such embodiment the treatment
increases the individual's serum bicarbonate value from a baseline
serum bicarbonate value in the range of 9 to 21 mEq/l by at least
1.5 mEq/l. By way of further example, in one such embodiment the
treatment increases the individual's serum bicarbonate value from a
baseline serum bicarbonate value in the range of 9 to 21 mEq/l by
at least 2 mEq/l. By way of further example, in one such embodiment
the treatment increases the individual's serum bicarbonate value
from a baseline serum bicarbonate value in the range of 9 to 21
mEq/l by at least 2.5 mEq/l. By way of further example, in one such
embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 9 to 21 mEq/l by at least 3 mEq/l. By way of further
example, in one such embodiment the treatment increases the
individual's serum bicarbonate value from a baseline serum
bicarbonate value in the range of 9 to 21 mEq/l by at least 3.5
mEq/l. By way of further example, in one such embodiment the
treatment increases the individual's serum bicarbonate value from a
baseline serum bicarbonate value in the range of 9 to 21 mEq/l by
at least 4 mEq/l. By way of further example, in one such embodiment
the treatment increases the individual's serum bicarbonate value
from a baseline serum bicarbonate value in the range of 9 to 21
mEq/l by at least 4.5 mEq/l. By way of further example, in one such
embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 9 to 21 mEq/l by at least 5 mEq/l. By way of further
example, in one such embodiment the treatment increases the
individual's serum bicarbonate value from a baseline serum
bicarbonate value in the range of 9 to 21 mEq/l by at least 5.5
mEq/l. By way of further example, in one such embodiment the
treatment increases the individual's serum bicarbonate value from a
baseline serum bicarbonate value in the range of 9 to 21 mEq/l by
at least 6 mEq/l. In each of the foregoing exemplary embodiments
recited in this paragraph, the increased serum bicarbonate value
preferably does not exceed 29 mEq/l. For example, in each of the
foregoing exemplary embodiments, the increased serum bicarbonate
value may not exceed 28 mEq/l. By way of further example, in each
of the foregoing exemplary embodiments, the increased serum
bicarbonate value may not exceed 27 mEq/l. By way of further
example, in each of the foregoing exemplary embodiments, the
increased serum bicarbonate value may not exceed 26 mEq/l. Further,
in each of the foregoing exemplary embodiments recited in this
paragraph, the treatment enables the increased serum bicarbonate
value to be sustained over a prolonged period of at least one week,
at least one month, at least two months, at least three months, at
least six months, or even at least one year.
[0141] In certain embodiments, the acid-base disorder is treated
with a pharmaceutical composition comprising the nonabsorbable
composition and the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 12 to 14 mEq/l by at least 1 mEq/l. For example, in one
such embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 12 to 14 mEq/l by at least 1.5 mEq/l. By way of further
example, in one such embodiment the treatment increases the
individual's serum bicarbonate value from a baseline serum
bicarbonate value in the range of 12 to 14 mEq/l by at least 2
mEq/l. By way of further example, in one such embodiment the
treatment increases the individual's serum bicarbonate value from a
baseline serum bicarbonate value in the range of 12 to 14 mEq/l by
at least 2.5 mEq/l. By way of further example, in one such
embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 12 to 14 mEq/l by at least 3 mEq/l. By way of further
example, in one such embodiment the treatment increases the
individual's serum bicarbonate value from a baseline serum
bicarbonate value in the range of 12 to 14 mEq/l by at least 3.5
mEq/l. By way of further example, in one such embodiment the
treatment increases the individual's serum bicarbonate value from a
baseline serum bicarbonate value in the range of 12 to 14 mEq/l by
at least 4 mEq/l. By way of further example, in one such embodiment
the treatment increases the individual's serum bicarbonate value
from a baseline serum bicarbonate value in the range of 12 to 14
mEq/l by at least 4.5 mEq/l. By way of further example, in one such
embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 12 to 14 mEq/l by at least 5 mEq/l. By way of further
example, in one such embodiment the treatment increases the
individual's serum bicarbonate value from a baseline serum
bicarbonate value in the range of 12 to 14 mEq/l by at least 6
mEq/l. By way of further example, in one such embodiment the
treatment increases the individual's serum bicarbonate value from a
baseline serum bicarbonate value in the range of 12 to 14 mEq/l by
at least 7 mEq/l. By way of further example, in one such embodiment
the treatment increases the individual's serum bicarbonate value
from a baseline serum bicarbonate value in the range of 12 to 14
mEq/l by at least 8 mEq/l. By way of further example, in one such
embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 12 to 14 mEq/l by at least 9 mEq/l. In each of the
foregoing exemplary embodiments recited in this paragraph, the
increased serum bicarbonate value preferably does not exceed 29
mEq/l. For example, in each of the foregoing exemplary embodiments,
the increased serum bicarbonate value may not exceed 28 mEq/l. By
way of further example, in each of the foregoing exemplary
embodiments, the increased serum bicarbonate value may not exceed
27 mEq/l. By way of further example, in each of the foregoing
exemplary embodiments, the increased serum bicarbonate value may
not exceed 26 mEq/l. Further, in each of the foregoing exemplary
embodiments recited in this paragraph, the treatment enables the
increased serum bicarbonate value to be sustained over a prolonged
period of at least one week, at least one month, at least two
months, at least three months, at least six months, or even at
least one year.
[0142] In certain embodiments, the treatment increases the
individual's serum bicarbonate value from a baseline serum
bicarbonate value in the range of 15 to 17 mEq/l by at least 1
mEq/l. For example, in one such embodiment the treatment increases
the individual's serum bicarbonate value from a baseline serum
bicarbonate value in the range of 15 to 17 mEq/l by at least 1.5
mEq/l. By way of further example, in one such embodiment the
treatment increases the individual's serum bicarbonate value from a
baseline serum bicarbonate value in the range of 15 to 17 mEq/l by
at least 2 mEq/l. By way of further example, in one such embodiment
the treatment increases the individual's serum bicarbonate value
from a baseline serum bicarbonate value in the range of 15 to 17
mEq/l by at least 2.5 mEq/l. By way of further example, in one such
embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 15 to 17 mEq/l by at least 3 mEq/l. By way of further
example, in one such embodiment the treatment increases the
individual's serum bicarbonate value from a baseline serum
bicarbonate value in the range of 15 to 17 mEq/l by at least 3.5
mEq/l. By way of further example, in one such embodiment the
treatment increases the individual's serum bicarbonate value from a
baseline serum bicarbonate value in the range of 15 to 17 mEq/l by
at least 4 mEq/l. By way of further example, in one such embodiment
the treatment increases the individual's serum bicarbonate value
from a baseline serum bicarbonate value in the range of 15 to 17
mEq/l by at least 4.5 mEq/l. By way of further example, in one such
embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 15 to 17 mEq/l by at least 5 mEq/l. By way of further
example, in one such embodiment the treatment increases the
individual's serum bicarbonate value from a baseline serum
bicarbonate value in the range of 15 to 17 mEq/l by at least 6
mEq/l. By way of further example, in one such embodiment the
treatment increases the individual's serum bicarbonate value from a
baseline serum bicarbonate value in the range of 15 to 17 mEq/l by
at least 7 mEq/l. By way of further example, in one such embodiment
the treatment increases the individual's serum bicarbonate value
from a baseline serum bicarbonate value in the range of 15 to 17
mEq/l by at least 8 mEq/l. By way of further example, in one such
embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 15 to 17 mEq/l by at least 9 mEq/l. In each of the
foregoing exemplary embodiments recited in this paragraph, the
increased serum bicarbonate value preferably does not exceed 29
mEq/l. For example, in each of the foregoing exemplary embodiments,
the increased serum bicarbonate value may not exceed 28 mEq/l. By
way of further example, in each of the foregoing exemplary
embodiments, the increased serum bicarbonate value may not exceed
27 mEq/l. By way of further example, in each of the foregoing
exemplary embodiments, the increased serum bicarbonate value may
not exceed 26 mEq/l. Further, in each of the foregoing exemplary
embodiments recited in this paragraph, the treatment enables the
increased serum bicarbonate value to be sustained over a prolonged
period of at least one week, at least one month, at least two
months, at least three months, at least six months, or even at
least one year.
[0143] In certain embodiments, the treatment increases the
individual's serum bicarbonate value from a baseline serum
bicarbonate value in the range of 18 to 21 mEq/l by at least 1
mEq/l. For example, in one such embodiment the treatment increases
the individual's serum bicarbonate value from a baseline serum
bicarbonate value in the range of 18 to 21 mEq/l by at least 1.5
mEq/l. By way of further example, in one such embodiment the
treatment increases the individual's serum bicarbonate value from a
baseline serum bicarbonate value in the range of 18 to 21 mEq/l by
at least 2 mEq/l. By way of further example, in one such embodiment
the treatment increases the individual's serum bicarbonate value
from a baseline serum bicarbonate value in the range of 18 to 21
mEq/l by at least 2.5 mEq/l. By way of further example, in one such
embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 18 to 21 mEq/l by at least 3 mEq/l. By way of further
example, in one such embodiment the treatment increases the
individual's serum bicarbonate value from a baseline serum
bicarbonate value in the range of 18 to 21 mEq/l by at least 3.5
mEq/l. By way of further example, in one such embodiment the
treatment increases the individual's serum bicarbonate value from a
baseline serum bicarbonate value in the range of 18 to 21 mEq/l by
at least 4 mEq/l. By way of further example, in one such embodiment
the treatment increases the individual's serum bicarbonate value
from a baseline serum bicarbonate value in the range of 18 to 21
mEq/l by at least 4.5 mEq/l. By way of further example, in one such
embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 18 to 21 mEq/l by at least 5 mEq/l. By way of further
example, in one such embodiment the treatment increases the
individual's serum bicarbonate value from a baseline serum
bicarbonate value in the range of 18 to 21 mEq/l by at least 5.5
mEq/l. By way of further example, in one such embodiment the
treatment increases the individual's serum bicarbonate value from a
baseline serum bicarbonate value in the range of 18 to 21 mEq/l by
at least 6 mEq/l. In each of the foregoing exemplary embodiments
recited in this paragraph, the increased serum bicarbonate value
preferably does not exceed 29 mEq/l. For example, in each of the
foregoing exemplary embodiments, the increased serum bicarbonate
value may not exceed 28 mEq/l. By way of further example, in each
of the foregoing exemplary embodiments, the increased serum
bicarbonate value may not exceed 27 mEq/l. By way of further
example, in each of the foregoing exemplary embodiments, the
increased serum bicarbonate value may not exceed 26 mEq/l. Further,
in each of the foregoing exemplary embodiments recited in this
paragraph, the treatment enables the increased serum bicarbonate
value to be sustained over a prolonged period of at least one week,
at least one month, at least two months, at least three months, at
least six months, or even at least one year.
[0144] In certain embodiments, the treatment increases the
individual's serum bicarbonate value from a baseline serum
bicarbonate value in the range of 12 to 21 mEq/l to an increased
value in the range of 22 mEq/l to 26 mEq/l. For example, in one
such embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 12 to 17 mEq/l to an increased value in the range of 22
mEq/l to 26 mEq/l. By way of further example, in one such
embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 12 to 14 mEq/l to an increased value in the range of 22
mEq/l to 26 mEq/l. By way of further example, in one such
embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 15 to 17 mEq/l to an increased value in the range of 22
mEq/l to 26 mEq/l. By way of further example, in one such
embodiment the treatment increases the individual's serum
bicarbonate value from a baseline serum bicarbonate value in the
range of 18 to 21 mEq/l to an increased value in the range of 22
mEq/l to 26 mEq/l. In each of the foregoing embodiments recited in
this paragraph, the treatment enables the increased serum
bicarbonate value to be sustained over a prolonged period of at
least one week, at least one month, at least two months, at least
three months, at least six months, or even at least one year.
[0145] In certain embodiments, the treatment achieves a clinically
significant increase is achieved within a treatment period of less
than one month. For example, in one such embodiment, the treatment
achieves a clinically significant increase within a treatment
period of 25 days. By way of further example, in one such
embodiment the treatment achieves the clinically significant
increase is achieved within a treatment period of 3 weeks. By way
of further example, in one such embodiment the treatment achieves
the clinically significant increase is achieved within a treatment
period of 15 days. By way of further example, in one such
embodiment the treatment achieves the clinically significant
increase is achieved within a treatment period of 2 weeks. By way
of further example, in one such embodiment the treatment achieves
the clinically significant increase is achieved within a treatment
period of 10 days. By way of further example, in one such
embodiment the treatment achieves the clinically significant
increase is achieved within a treatment period of 1 week. By way of
further example, in one such embodiment the treatment achieves the
clinically significant increase is achieved within a treatment
period of 6 days. By way of further example, in one such embodiment
the treatment achieves the clinically significant increase is
achieved within a treatment period of 5 days. By way of further
example, in one such embodiment the treatment achieves the
clinically significant increase is achieved within a treatment
period of 4 days. By way of further example, in one such embodiment
the treatment achieves the clinically significant increase is
achieved within a treatment period of 3 days. By way of further
example, in one such embodiment the treatment achieves the
clinically significant increase is achieved within a treatment
period of 2 days. By way of further example, in one such embodiment
the treatment achieves the clinically significant increase is
achieved within a treatment period of 1 day. By way of further
example, in one such embodiment the treatment achieves the
clinically significant increase is achieved within a treatment
period of 12 hours.
[0146] In certain embodiments, the treatment achieves a clinically
significant increase is achieved without any change in the
individual's diet or dietary habits relative to the period
immediately preceding the initiation of treatment. For example, in
one such embodiment the clinically significant increase is achieved
independent of the individual's diet or dietary habits.
[0147] In certain embodiments, the individual's serum bicarbonate
value returns to the baseline value.+-.2.5 mEq/l within 1 month of
the cessation of treatment. For example, in one such embodiment the
individual's serum bicarbonate value returns to the baseline
value.+-.2.5 mEq/l within 3 weeks of the cessation of treatment. By
way of further example, in one such embodiment the individual's
serum bicarbonate value returns to the baseline value.+-.2.5 mEq/l
within 2 weeks of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value returns to the baseline value.+-.2.5 mEq/l within 10 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value returns to the
baseline value.+-.2.5 mEq/l within 9 days of the cessation of
treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value returns to the baseline
value.+-.2.5 mEq/l within 8 days of the cessation of treatment. By
way of further example, in one such embodiment the individual's
serum bicarbonate value returns to the baseline value.+-.2.5 mEq/l
within 7 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value returns to the baseline value.+-.2.5 mEq/l within 6 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value returns to the
baseline value.+-.2.5 mEq/l within 5 days of the cessation of
treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value returns to the baseline
value.+-.2.5 mEq/l within 4 days of the cessation of treatment. By
way of further example, in one such embodiment the individual's
serum bicarbonate value returns to the baseline value.+-.2.5 mEq/l
within 3 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value returns to the baseline value.+-.2.5 mEq/l within 2 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value returns to the
baseline value.+-.2.5 mEq/l within 1 day of the cessation of
treatment.
[0148] In certain embodiments, the individual's serum bicarbonate
value returns to the baseline value.+-.2 mEq/l within 1 month of
the cessation of treatment. For example, in one such embodiment the
individual's serum bicarbonate value returns to the baseline
value.+-.2 mEq/l within 3 weeks of the cessation of treatment. By
way of further example, in one such embodiment the individual's
serum bicarbonate value returns to the baseline value.+-.2 mEq/l
within 2 weeks of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value returns to the baseline value.+-.2 mEq/l within 10 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value returns to the
baseline value.+-.2 mEq/l within 9 days of the cessation of
treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value returns to the baseline
value.+-.2 mEq/l within 8 days of the cessation of treatment. By
way of further example, in one such embodiment the individual's
serum bicarbonate value returns to the baseline value.+-.2 mEq/l
within 7 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value returns to the baseline value.+-.2 mEq/l within 6 days of the
cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value returns to the
baseline value.+-.2 mEq/l within 5 days of the cessation of
treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value returns to the baseline
value.+-.2 mEq/l within 4 days of the cessation of treatment. By
way of further example, in one such embodiment the individual's
serum bicarbonate value returns to the baseline value.+-.2 mEq/l
within 3 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value returns to the baseline value.+-.2 mEq/l within 2 days of the
cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value returns to the
baseline value.+-.2 mEq/l within 1 day of the cessation of
treatment.
[0149] In certain embodiments, the individual's serum bicarbonate
value returns to the baseline value.+-.1.5 mEq/l within 1 month of
the cessation of treatment. For example, in one such embodiment the
individual's serum bicarbonate value returns to the baseline
value.+-.1.5 mEq/l within 3 weeks of the cessation of treatment. By
way of further example, in one such embodiment the individual's
serum bicarbonate value returns to the baseline value.+-.1.5 mEq/l
within 2 weeks of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value returns to the baseline value.+-.1.5 mEq/l within 10 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value returns to the
baseline value.+-.1.5 mEq/l within 9 days of the cessation of
treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value returns to the baseline
value.+-.1.5 mEq/l within 8 days of the cessation of treatment. By
way of further example, in one such embodiment the individual's
serum bicarbonate value returns to the baseline value.+-.1.5 mEq/l
within 7 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value returns to the baseline value.+-.1.5 mEq/l within 6 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value returns to the
baseline value.+-.1.5 mEq/l within 5 days of the cessation of
treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value returns to the baseline
value.+-.1.5 mEq/l within 4 days of the cessation of treatment. By
way of further example, in one such embodiment the individual's
serum bicarbonate value returns to the baseline value.+-.1.5 mEq/l
within 3 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value returns to the baseline value.+-.1.5 mEq/l within 2 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value returns to the
baseline value.+-.1.5 mEq/l within 1 day of the cessation of
treatment.
[0150] In certain embodiments, the individual's serum bicarbonate
value returns to the baseline value.+-.1 mEq/l within 1 month of
the cessation of treatment. For example, in one such embodiment the
individual's serum bicarbonate value returns to the baseline
value.+-.1 mEq/l within 3 weeks of the cessation of treatment. By
way of further example, in one such embodiment the individual's
serum bicarbonate value returns to the baseline value.+-.1 mEq/l
within 2 weeks of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value returns to the baseline value.+-.1 mEq/l within 10 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value returns to the
baseline value.+-.1 mEq/l within 9 days of the cessation of
treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value returns to the baseline
value.+-.1 mEq/l within 8 days of the cessation of treatment. By
way of further example, in one such embodiment the individual's
serum bicarbonate value returns to the baseline value.+-.1 mEq/l
within 7 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value returns to the baseline value.+-.1 mEq/l within 6 days of the
cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value returns to the
baseline value.+-.1 mEq/l within 5 days of the cessation of
treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value returns to the baseline
value.+-.1 mEq/l within 4 days of the cessation of treatment. By
way of further example, in one such embodiment the individual's
serum bicarbonate value returns to the baseline value.+-.1 mEq/l
within 3 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value returns to the baseline value.+-.1 mEq/l within 2 days of the
cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value returns to the
baseline value.+-.1 mEq/l within 1 day of the cessation of
treatment.
[0151] In certain embodiments, upon the cessation of treatment the
individual's serum bicarbonate value decreases by at least 1 mEq/l
within 1 month of the cessation of treatment. For example, in one
such embodiment. For example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 1 mEq/l
within 3 weeks of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 1 mEq/l within 2 weeks of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 1 mEq/l
within 10 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 1 mEq/l within 9 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 1 mEq/l
within 8 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 1 mEq/l within 7 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 1 mEq/l
within 6 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 1 mEq/l within 5 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 1 mEq/l
within 4 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 1 mEq/l within 3 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 1 mEq/l
within 2 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 1 mEq/l within 1 day of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 1 mEq/l
within 12 hours of the cessation of treatment.
[0152] In certain embodiments, upon the cessation of treatment the
individual's serum bicarbonate value decreases by at least 1.5
mEq/l within 1 month of the cessation of treatment. For example, in
one such embodiment. For example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 1.5
mEq/l within 3 weeks of the cessation of treatment. By way of
further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 1.5 mEq/l within 2 weeks of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value decreases by at
least 1.5 mEq/l within 10 days of the cessation of treatment. By
way of further example, in one such embodiment the individual's
serum bicarbonate value decreases by at least 1.5 mEq/l within 9
days of the cessation of treatment. By way of further example, in
one such embodiment the individual's serum bicarbonate value
decreases by at least 1.5 mEq/l within 8 days of the cessation of
treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 1.5
mEq/l within 7 days of the cessation of treatment. By way of
further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 1.5 mEq/l within 6 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value decreases by at
least 1.5 mEq/l within 5 days of the cessation of treatment. By way
of further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 1.5 mEq/l within 4 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value decreases by at
least 1.5 mEq/l within 3 days of the cessation of treatment. By way
of further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 1.5 mEq/l within 2 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value decreases by at
least 1.5 mEq/l within 1 day of the cessation of treatment. By way
of further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 1.5 mEq/l within 12 hours
of the cessation of treatment.
[0153] In certain embodiments, upon the cessation of treatment the
individual's serum bicarbonate value decreases by at least 2 mEq/l
within 1 month of the cessation of treatment. For example, in one
such embodiment. For example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 2 mEq/l
within 3 weeks of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 2 mEq/l within 2 weeks of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 2 mEq/l
within 10 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 2 mEq/l within 9 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 2 mEq/l
within 8 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 2 mEq/l within 7 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 2 mEq/l
within 6 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 2 mEq/l within 5 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 2 mEq/l
within 4 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 2 mEq/l within 3 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 2 mEq/l
within 2 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 2 mEq/l within 1 day of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 2 mEq/l
within 12 hours of the cessation of treatment.
[0154] In certain embodiments, upon the cessation of treatment the
individual's serum bicarbonate value decreases by at least 2.5
mEq/l within 1 month of the cessation of treatment. For example, in
one such embodiment. For example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 2.5
mEq/l within 3 weeks of the cessation of treatment. By way of
further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 2.5 mEq/l within 2 weeks of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value decreases by at
least 2.5 mEq/l within 10 days of the cessation of treatment. By
way of further example, in one such embodiment the individual's
serum bicarbonate value decreases by at least 2.5 mEq/l within 9
days of the cessation of treatment. By way of further example, in
one such embodiment the individual's serum bicarbonate value
decreases by at least 2.5 mEq/l within 8 days of the cessation of
treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 2.5
mEq/l within 7 days of the cessation of treatment. By way of
further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 2.5 mEq/l within 6 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value decreases by at
least 2.5 mEq/l within 5 days of the cessation of treatment. By way
of further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 2.5 mEq/l within 4 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value decreases by at
least 2.5 mEq/l within 3 days of the cessation of treatment. By way
of further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 2.5 mEq/l within 2 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value decreases by at
least 2.5 mEq/l within 1 day of the cessation of treatment. By way
of further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 2.5 mEq/l within 12 hours
of the cessation of treatment.
[0155] In certain embodiments, upon the cessation of treatment the
individual's serum bicarbonate value decreases by at least 3 mEq/l
within 1 month of the cessation of treatment. For example, in one
such embodiment. For example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 3 mEq/l
within 3 weeks of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 3 mEq/l within 2 weeks of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 3 mEq/l
within 10 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 3 mEq/l within 9 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 3 mEq/l
within 8 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 3 mEq/l within 7 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 3 mEq/l
within 6 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 3 mEq/l within 5 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 3 mEq/l
within 4 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 3 mEq/l within 3 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 3 mEq/l
within 2 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 3 mEq/l within 1 day of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 3 mEq/l
within 12 hours of the cessation of treatment.
[0156] In certain embodiments, upon the cessation of treatment the
individual's serum bicarbonate value decreases by at least 3.5
mEq/l within 1 month of the cessation of treatment. For example, in
one such embodiment. For example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 3.5
mEq/l within 3 weeks of the cessation of treatment. By way of
further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 3.5 mEq/l within 2 weeks of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value decreases by at
least 3.5 mEq/l within 10 days of the cessation of treatment. By
way of further example, in one such embodiment the individual's
serum bicarbonate value decreases by at least 3.5 mEq/l within 9
days of the cessation of treatment. By way of further example, in
one such embodiment the individual's serum bicarbonate value
decreases by at least 3.5 mEq/l within 8 days of the cessation of
treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 3.5
mEq/l within 7 days of the cessation of treatment. By way of
further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 3.5 mEq/l within 6 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value decreases by at
least 3.5 mEq/l within 5 days of the cessation of treatment. By way
of further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 3.5 mEq/l within 4 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value decreases by at
least 3.5 mEq/l within 3 days of the cessation of treatment. By way
of further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 3.5 mEq/l within 2 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value decreases by at
least 3.5 mEq/l within 1 day of the cessation of treatment. By way
of further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 3.5 mEq/l within 12 hours
of the cessation of treatment.
[0157] In certain embodiments, upon the cessation of treatment the
individual's serum bicarbonate value decreases by at least 4 mEq/l
within 1 month of the cessation of treatment. For example, in one
such embodiment. For example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 4 mEq/l
within 3 weeks of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 4 mEq/l within 2 weeks of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 4 mEq/l
within 10 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 4 mEq/l within 9 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 4 mEq/l
within 8 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 4 mEq/l within 7 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 4 mEq/l
within 6 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 4 mEq/l within 5 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 4 mEq/l
within 4 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 4 mEq/l within 3 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 4 mEq/l
within 2 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 4 mEq/l within 1 day of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 4 mEq/l
within 12 hours of the cessation of treatment.
[0158] In certain embodiments, upon the cessation of treatment the
individual's serum bicarbonate value decreases by at least 4.5
mEq/l within 1 month of the cessation of treatment. For example, in
one such embodiment. For example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 4.5
mEq/l within 3 weeks of the cessation of treatment. By way of
further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 4.5 mEq/l within 2 weeks of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value decreases by at
least 4.5 mEq/l within 10 days of the cessation of treatment. By
way of further example, in one such embodiment the individual's
serum bicarbonate value decreases by at least 4.5 mEq/l within 9
days of the cessation of treatment. By way of further example, in
one such embodiment the individual's serum bicarbonate value
decreases by at least 4.5 mEq/l within 8 days of the cessation of
treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 4.5
mEq/l within 7 days of the cessation of treatment. By way of
further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 4.5 mEq/l within 6 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value decreases by at
least 4.5 mEq/l within 5 days of the cessation of treatment. By way
of further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 4.5 mEq/l within 4 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value decreases by at
least 4.5 mEq/l within 3 days of the cessation of treatment. By way
of further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 4.5 mEq/l within 2 days of
the cessation of treatment. By way of further example, in one such
embodiment the individual's serum bicarbonate value decreases by at
least 4.5 mEq/l within 1 day of the cessation of treatment. By way
of further example, in one such embodiment the individual's serum
bicarbonate value decreases by at least 4.5 mEq/l within 12 hours
of the cessation of treatment.
[0159] In certain embodiments, upon the cessation of treatment the
individual's serum bicarbonate value decreases by at least 5 mEq/l
within 1 month of the cessation of treatment. For example, in one
such embodiment. For example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 5 mEq/l
within 3 weeks of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 5 mEq/l within 2 weeks of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 5 mEq/l
within 10 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 5 mEq/l within 9 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 5 mEq/l
within 8 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 5 mEq/l within 7 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 5 mEq/l
within 6 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 5 mEq/l within 5 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 5 mEq/l
within 4 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 5 mEq/l within 3 days of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 5 mEq/l
within 2 days of the cessation of treatment. By way of further
example, in one such embodiment the individual's serum bicarbonate
value decreases by at least 5 mEq/l within 1 day of the cessation
of treatment. By way of further example, in one such embodiment the
individual's serum bicarbonate value decreases by at least 5 mEq/l
within 12 hours of the cessation of treatment.
[0160] In one embodiment, the baseline serum bicarbonate value is
the value of the serum bicarbonate concentration determined at a
single time point. In another embodiment, the baseline serum
bicarbonate value is the mean value of at least two serum
bicarbonate concentrations determined at different time-points. For
example, in one such embodiment the baseline serum bicarbonate
value is the mean value of at least two serum bicarbonate
concentrations for serum samples drawn on different days. By way of
further example, the baseline serum bicarbonate value is the mean
or median value of at least two serum bicarbonate concentrations
for serum samples drawn on non-consecutive days. By way of further
example, in one such method the non-consecutive days are separated
by at least two days. By way of further example, in one such method
the non-consecutive days are separated by at least one week. By way
of further example, in one such method the non-consecutive days are
separated by at least two weeks. By way of further example, in one
such method the non-consecutive days are separated by at least
three weeks.
[0161] In certain embodiments, the daily dose is no more than 100
g/day of the nonabsorbable composition. For example, in one such
embodiment the daily dose is no more than 90 g/day of the
nonabsorbable composition. By way of further example, in one such
embodiment the daily dose is no more than 75 g/day of the
nonabsorbable composition. By way of further example, in one such
embodiment the daily dose is no more than 65 g/day of the
nonabsorbable composition. By way of further example, in one such
embodiment the daily dose is no more than 50 g/day of the
nonabsorbable composition. By way of further example, in one such
embodiment the daily dose is no more than 40 g/day of the
nonabsorbable composition. By way of further example, in one such
embodiment the daily dose is no more than 30 g/day of the
nonabsorbable composition. By way of further example, in one such
embodiment the daily dose is no more than 25 g/day of the
nonabsorbable composition. By way of further example, in one such
embodiment the daily dose is no more than 20 g/day of the
nonabsorbable composition. By way of further example, in one such
embodiment the daily dose is no more than 15 g/day of the
nonabsorbable composition. By way of further example, in one such
embodiment the daily dose is no more than 10 g/day of the
nonabsorbable composition. By way of further example, in one such
embodiment the daily dose is no more than 5 g/day of the
nonabsorbable composition.
[0162] In certain embodiments, the individual is treated with the
daily dose for a period of at least one day. For example, in one
such embodiment the individual is treated with the daily dose for a
period of at least one week. By way of further example, in one such
embodiment the individual is treated with the daily dose for a
period of at least one month. By way of further example, in one
such embodiment the individual is treated with the daily dose for a
period of at least two months. By way of further example, in one
such embodiment the individual is treated with the daily dose for a
period of at least three months. By way of further example, in one
such embodiment the individual is treated with the daily dose for a
period of at least several months. By way of further example, in
one such embodiment the individual is treated with the daily dose
for a period of at least six months. By way of further example, in
one such embodiment the individual is treated with the daily dose
for a period of at least one year.
[0163] In certain embodiments of the method of the present
disclosure, the daily dose of the nonabsorbable composition has the
capacity to remove at least about 5 mEq/day of the target species.
For example, in one such embodiment the daily dose of the
nonabsorbable composition has the capacity to remove at least about
6 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition has
the capacity to remove at least about 7 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition has the capacity to
remove at least about 8 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition has the capacity to remove at least about
9 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition has
the capacity to remove at least about 10 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition has the capacity to
remove at least about 11 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition has the capacity to remove at least about
12 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition has
the capacity to remove at least about 13 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition has the capacity to
remove at least about 14 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition has the capacity to remove at least about
15 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition has
the capacity to remove at least about 16 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition has the capacity to
remove at least about 17 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition has the capacity to remove at least about
18 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition has
the capacity to remove at least about 19 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition has the capacity to
remove at least about 20 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition has the capacity to remove at least about
21 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition has
the capacity to remove at least about 22 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition has the capacity to
remove at least about 23 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition has the capacity to remove at least about
24 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition has
the capacity to remove at least about 25 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition has the capacity to
remove at least about 26 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition has the capacity to remove at least about
27 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition has
the capacity to remove at least about 28 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition has the capacity to
remove at least about 29 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition has the capacity to remove at least about
30 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition has
the capacity to remove at least about 31 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition has the capacity to
remove at least about 32 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition has the capacity to remove at least about
33 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition has
the capacity to remove at least about 34 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition has the capacity to
remove at least about 35 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition has the capacity to remove at least about
36 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition has
the capacity to remove at least about 37 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition has the capacity to
remove at least about 38 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition has the capacity to remove at least about
39 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition has
the capacity to remove at least about 40 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition has the capacity to
remove at least about 41 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition has the capacity to remove at least about
42 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition has
the capacity to remove at least about 43 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition has the capacity to
remove at least about 44 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition has the capacity to remove at least about
45 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition has
the capacity to remove at least about 46 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition has the capacity to
remove at least about 47 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition has the capacity to remove at least about
48 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition has
the capacity to remove at least about 49 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition has the capacity to
remove at least about 50 mEq/day of the target species.
[0164] In certain embodiments of the method of the present
disclosure, the daily dose of the nonabsorbable composition removes
at least about 5 mEq/day of the target species. For example, in one
such embodiment the daily dose of the nonabsorbable composition
removes at least about 6 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition removes at least about 7 mEq/day of the
target species. By way of further example, in one such embodiment
the daily dose of the nonabsorbable composition removes at least
about 8 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose of the nonabsorbable
composition removes at least about 9 mEq/day of the target species.
By way of further example, in one such embodiment the daily dose of
the nonabsorbable composition removes at least about 10 mEq/day of
the target species. By way of further example, in one such
embodiment the daily dose of the nonabsorbable composition removes
at least about 11 mEq/day of the target species. By way of further
example, in one such embodiment the daily dose of the nonabsorbable
composition removes at least about 12 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition removes at least about
13 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition
removes at least about 14 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition removes at least about 15 mEq/day of the
target species. By way of further example, in one such embodiment
the daily dose of the nonabsorbable composition removes at least
about 16 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose of the nonabsorbable
composition removes at least about 17 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition removes at least about
18 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition
removes at least about 19 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition removes at least about 20 mEq/day of the
target species. By way of further example, in one such embodiment
the daily dose of the nonabsorbable composition removes at least
about 21 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose of the nonabsorbable
composition removes at least about 22 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition removes at least about
23 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition
removes at least about 24 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition removes at least about 25 mEq/day of the
target species. By way of further example, in one such embodiment
the daily dose of the nonabsorbable composition removes at least
about 26 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose of the nonabsorbable
composition removes at least about 27 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition removes at least about
28 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition
removes at least about 29 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition removes at least about 30 mEq/day of the
target species. By way of further example, in one such embodiment
the daily dose of the nonabsorbable composition removes at least
about 31 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose of the nonabsorbable
composition removes at least about 32 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition removes at least about
33 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition
removes at least about 34 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition removes at least about 35 mEq/day of the
target species. By way of further example, in one such embodiment
the daily dose of the nonabsorbable composition removes at least
about 36 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose of the nonabsorbable
composition removes at least about 37 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition removes at least about
38 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition
removes at least about 39 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition removes at least about 40 mEq/day of the
target species. By way of further example, in one such embodiment
the daily dose of the nonabsorbable composition removes at least
about 41 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose of the nonabsorbable
composition removes at least about 42 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition removes at least about
43 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition
removes at least about 44 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition removes at least about 45 mEq/day of the
target species. By way of further example, in one such embodiment
the daily dose of the nonabsorbable composition removes at least
about 46 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose of the nonabsorbable
composition removes at least about 47 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose of the nonabsorbable composition removes at least about
48 mEq/day of the target species. By way of further example, in one
such embodiment the daily dose of the nonabsorbable composition
removes at least about 49 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose of the
nonabsorbable composition removes at least about 50 mEq/day of the
target species.
[0165] In certain embodiments of the method of the present
disclosure, the daily dose of the nonabsorbable composition removes
less than 60 mEq/day of the target species. For example, in one
such method the daily dose removes less than 55 mEq/day of the
target species. By way of further example, in one such embodiment
the daily dose removes less than 50 mEq/day of the target species.
By way of further example, in one such embodiment the daily dose
removes less than 45 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose removes less
than 40 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose removes less than 35 mEq/day
of the target species. By way of further example, in one such
embodiment the daily dose removes less than 34 mEq/day of the
target species. By way of further example, in one such embodiment
the daily dose removes less than 33 mEq/day of the target species.
By way of further example, in one such embodiment the daily dose
removes less than 32 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose removes less
than 31 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose removes less than 30 mEq/day
of the target species. By way of further example, in one such
embodiment the daily dose removes less than 29 mEq/day of the
target species. By way of further example, in one such embodiment
the daily dose removes less than 28 mEq/day of the target species.
By way of further example, in one such embodiment the daily dose
removes less than 27 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose removes less
than 26 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose removes less than 25 mEq/day
of the target species. By way of further example, in one such
embodiment the daily dose removes less than 24 mEq/day of the
target species. By way of further example, in one such embodiment
the daily dose removes less than 23 mEq/day of the target species.
By way of further example, in one such embodiment the daily dose
removes less than 22 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose removes less
than 21 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose removes less than 20 mEq/day
of the target species. By way of further example, in one such
embodiment the daily dose removes less than 19 mEq/day of the
target species. By way of further example, in one such embodiment
the daily dose removes less than 18 mEq/day of the target species.
By way of further example, in one such embodiment the daily dose
removes less than 17 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose removes less
than 16 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose removes less than 15 mEq/day
of the target species. By way of further example, in one such
embodiment the daily dose removes less than 14 mEq/day of the
target species. By way of further example, in one such embodiment
the daily dose removes less than 13 mEq/day of the target species.
By way of further example, in one such embodiment the daily dose
removes less than 12 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose removes less
than 11 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose removes less than 10 mEq/day
of the target species. By way of further example, in one such
embodiment the daily dose removes less than 9 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose removes less than 8 mEq/day of the target species. By
way of further example, in one such embodiment the daily dose
removes less than 7 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose removes less
than 6 mEq/day of the target species.
[0166] In certain embodiments of the method of the present
disclosure, the daily dose of the nonabsorbable composition has
insufficient capacity to remove more than 60 mEq/day of the target
species. For example, in one such method the daily dose has
insufficient capacity to remove more than 55 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose has insufficient capacity to remove more than 50 mEq/day
of the target species. By way of further example, in one such
embodiment the daily dose has insufficient capacity to remove more
than 45 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose has insufficient capacity to
remove more than 40 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose has
insufficient capacity to remove more than 35 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose has insufficient capacity to remove more than 34 mEq/day
of the target species. By way of further example, in one such
embodiment the daily dose has insufficient capacity to remove more
than 33 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose has insufficient capacity to
remove more than 32 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose has
insufficient capacity to remove more than 31 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose has insufficient capacity to remove more than 30 mEq/day
of the target species. By way of further example, in one such
embodiment the daily dose has insufficient capacity to remove more
than 29 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose has insufficient capacity to
remove more than 28 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose has
insufficient capacity to remove more than 27 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose has insufficient capacity to remove more than 26 mEq/day
of the target species. By way of further example, in one such
embodiment the daily dose has insufficient capacity to remove more
than 25 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose has insufficient capacity to
remove more than 24 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose has
insufficient capacity to remove more than 23 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose has insufficient capacity to remove more than 22 mEq/day
of the target species. By way of further example, in one such
embodiment the daily dose has insufficient capacity to remove more
than 21 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose has insufficient capacity to
remove more than 20 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose has
insufficient capacity to remove more than 19 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose has insufficient capacity to remove more than 18 mEq/day
of the target species. By way of further example, in one such
embodiment the daily dose has insufficient capacity to remove more
than 17 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose has insufficient capacity to
remove more than 16 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose has
insufficient capacity to remove more than 15 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose has insufficient capacity to remove more than 14 mEq/day
of the target species. By way of further example, in one such
embodiment the daily dose has insufficient capacity to remove more
than 13 mEq/day of the target species. By way of further example,
in one such embodiment the daily dose has insufficient capacity to
remove more than 12 mEq/day of the target species. By way of
further example, in one such embodiment the daily dose has
insufficient capacity to remove more than 11 mEq/day of the target
species. By way of further example, in one such embodiment the
daily dose has insufficient capacity to remove more than 10 mEq/day
of the target species. By way of further example, in one such
embodiment the daily dose has insufficient capacity to remove more
than 9 mEq/day of the target species. By way of further example, in
one such embodiment the daily dose has insufficient capacity to
remove more than 8 mEq/day of the target species. By way of further
example, in one such embodiment the daily dose has insufficient
capacity to remove more than 7 mEq/day of the target species. By
way of further example, in one such embodiment the daily dose has
insufficient capacity to remove more than 6 mEq/day of the target
species.
[0167] While the methods described above refer to daily dose, a
further aspect of the disclosure include the methods disclosed
herein in which the dose is administered less frequently than once
per day (while still being administered on a regular basis). In any
of the disclosure, the daily dose specified may, instead, be
administrated on a less frequent basis. For example, the doses
disclosed here may be administered once every two or three days. Or
the doses disclosed here may be administered once, twice or three
times a week.
[0168] In addition to (or as a surrogate for) serum bicarbonate,
other biomarkers of acid-base imbalance may be used as a measure of
acid-base status. For example, blood (serum or plasma) pH, total
CO.sub.2, anion gap, and/or the concentration of other electrolytes
(e.g., sodium, potassium, calcium, magnesium, chloride and/or
sulfate) may be used as an indicator of acid-base imbalance.
Similarly, net acid excretion ("NAE"), urine pH, urine ammonium
concentration, and/or the concentration of other electrolytes in
the urine (e.g., sodium, potassium, calcium, magnesium, chloride
and/or sulfate) may be used as an indicator of acid-base
imbalance.
TABLE-US-00001 Bio- marker of Fluid interest Normal/Target Value
Analytical Technique Blood Total 23-29 mmol/L Blood gas analyzer;
(serum CO.sub.2 enzymatic assay; ion or selective electrode plasma)
Anion 3-11 mEq/L Obtained from standard gap chemistry electrolyte
panel pH 7.36 to 7.44 Blood gas analyzer; enzymatic assay; ion
selective electrode Elec- Na = 135-145 mEq/L; Obtained from
standard trolytes K = 3.5-5 mEq/L; chemistry electrolyte Total Ca =
8-10.5 mEq/L, panel; depending on age and sex; ion selective
electrodes Mg = 1.5-2.5 mEq/L, can be used for Na, Cl depending on
age; and K Cl = 95-105 mEq/L; phosphate = 2.5-4.5 mEq/L; sulfate =
1 mEq/L urine pH 4.5-8.0 pH meter ammo- 3-65 mmol/L Enzymatic nium
150-1,191 mg/24-hour Enzymatic citrate urine collection; ranges for
20 to 60 years of age sodium 20 mEq/L in spot samples,
Ion-selective electrode 41-227 mEq/L per day (depending upon salt
and fluid intake) potas- 17-77 mmol/24 hours; Ion-selective
electrode sium spot sample is ~45 mmol/L calcium Urinary calcium is
<250 Enzymatic mg/24 hours in males, <200 mg/24 hours in
females magne- Urinary magnesium is Enzymatic sium 51-269 mg/24
hours; spot values are usually reported as a ratio with creatinine
and are >0.035 mg Mg/mg creatinine chloride Urinary chloride is
40-224 Ion-selective electrode mmol/24 hours Urine UAG = 0-10
mEq/L; UAG = (Na.sup.+ + K.sup.+)--Cl.sup.- Anion Metabolic
acidosis in urine. It is a measure Gap indicated when UAG > of
ammonium excretion, ("UAG") 20 mEq/L the primary mechanism for acid
excretion. Net Acid Urinary net acid excretion 24-hour urine
collection Excretion is the total amount of acid required; Direct
NAE excreted by the kidney per measurement (mEq/day) = day; the NAE
value [NH.sub.4.sup.+] + [TA]--[HCO.sub.3.sup.-], depends on the
age of the where TA is concentration subject, gender, and of
titratable acids protein intake; typical Indirect NAE NAE values
range from measurement (mEq/day) = 9 mEq/day to 38 mEq/day (Cl + P
+ SO.sub.4 + organic anions) - (Na + K + Ca + Mg).
[0169] In one embodiment, treatment of an individual as described
herein may improve an individuals' serum anion gap. For example,
treating an acid base imbalance with a neutral composition having
the capacity to bind both protons and anions (unaccompanied by the
delivery of sodium or potassium ions) can increase serum
bicarbonate without an accompanying increase in sodium or potassium
(see Example 3 and FIGS. 13A, 130 and 13D). Consequently, the serum
anion gap may be improved (decreased) by at least 1 mEq/l or more
(e.g., at least 2 mEq/l) within a period as short as 2 weeks (see
Example 3).
[0170] The various aspects and embodiments may have a range of
advantages, such as improved or successful treatment of metabolic
acidosis. Such improvements may also include reduced side effects,
increased patient compliance, reduced drug loads, increased speed
of treatment, increased magnitude of treatment, avoiding unwanted
changes to other electrolytes and/or reduced drug-drug
interactions. A further improvement may include reducing a
patient's anion gap (as defined above) as part of the methods and
other aspects disclosed herein. Further useful features of the
disclosed aspects can be found in the examples.
[0171] Certain Specific Compositions for Use in Treatment
[0172] As previously noted, one aspect disclosed here is a
composition for use in a method of treating metabolic acidosis in
an adult human patient wherein in said treatment 0.1-12 g of said
composition is administered to the patient per day, said
composition being a nonabsorbable composition having the capacity
to remove protons from the patient, wherein the nonabsorbable
composition is characterized by a chloride ion binding capacity of
at least 2.5 mEq/g in a Simulated Small Intestine Inorganic ("SIB")
assay. This aspect is based on the data in the examples showing the
absorption and removal of HCl to successfully treat patients,
allowing the amount of the composition to be set based on its
capacity to bind chloride in the SIB assay. As shown in the
examples, a composition with this specified level of chloride
binding in the "SIB" assay can be used in the specified dose range
to successfully treat metabolic acidosis in adult humans. In this
aspect, the composition may be administered orally, and so would be
an orally administered nonabsorbable composition as defined
herein.
[0173] This aspect is based on the data in the examples showing the
absorption and removal of HCl to successfully treat patients using
a composition according to this aspect, allowing the amount of the
composition to be set based on its capacity to bind chloride in the
SIB assay. Surprisingly, the amounts required for successful
treatment were relatively low.
[0174] Another aspect of the present disclosure is a composition
for use in a method of treating metabolic acidosis in an adult
human patient by increasing that patient's serum bicarbonate value
by at least 1 mEq/L over 15 days of treatment, said composition
being a nonabsorbable composition having the capacity to remove
protons from the patient. In this aspect, the composition may be
administered orally, and so would be an orally administered
nonabsorbable composition as defined herein.
[0175] This aspect is based on the data in the examples showing the
absorption and removal of HCl to successfully treat patients using
a composition according to this aspect which provides new detail
regarding the reductions possible using a composition of the
disclosure. This aspect includes surprisingly rapid increases in
the patient's serum bicarbonate level, for example in the first few
days, as well as surprisingly large increases in serum bicarbonate
level.
[0176] Another aspect of the present disclosure is a composition
for use in a method of treating metabolic acidosis in an adult
human patient, said patient having a serum bicarbonate level of
less than 20 mEq/L prior to treatment, said composition being a
nonabsorbable composition having the capacity to remove protons
from the patient. In this aspect, the composition may be
administered orally, and so would be an orally administered
nonabsorbable composition as defined herein.
[0177] This aspect is based on the data in the examples showing,
for the first time, the successful treatment of patients with a low
serum bicarbonate level, for example levels that have not been
shown to be so readily treated previously. The patients with lower
serum bicarbonate levels responded particularly well to the
treatment and this improvement for this subgroup is one advantage
of this aspect.
[0178] Another aspect of the present disclosure is a composition
for use in a method of treating metabolic acidosis in an adult
human patient by increasing that patient's serum bicarbonate value
by at least 1 mEq/L over 15 days of treatment, wherein in said
treatment >12-100 g of said polymer is administered to the
patient per day, said composition being a nonabsorbable composition
having the capacity to remove protons from the patient, wherein the
nonabsorbable composition is characterized by a chloride ion
binding capacity of at least 2.5 mEq/g in a Simulated Small
Intestine Inorganic Buffer ("SIB") assay. In this aspect, the
composition may be administered orally, and so would be an orally
administered nonabsorbable composition as defined herein.
[0179] Another aspect of the present disclosure is a composition
for use in a method of treating metabolic acidosis in an adult
human patient wherein in said treatment >12-100 g of said
composition is administered to the patient per day, said
composition being a nonabsorbable composition having the capacity
to remove protons from the patient, wherein the nonabsorbable
composition is characterized by a chloride ion binding capacity of
less than 2.5 mEq/g in a Simulated Small Intestine Inorganic Buffer
("SIB") assay. In this aspect, the composition may be administered
orally, and so would be an orally administered nonabsorbable
composition as defined herein.
[0180] The chloride ion binding capacity in the SIB assay is
affected by both the composition's selectivity for binding chloride
and the total space available for chloride binding. The term
"composition" refers to the active pharmaceutical ingredient,
including any counter ions, but not to excipients. So, the "amount"
of the composition is the amount of active pharmaceutical
ingredient without including other parts of any unit dose form.
[0181] More specifically in these aspects, the amount of
composition may be any amount disclosed herein in other sections
within the range 0.1 g-12 g. For example, 1-11 g, 2-10 g, 3-9 g,
3-8 g, 3-7 g, 3-6 g, 3.5-5.5 g, 4-5 g, or 4.5-5 g of said polymer
is administered to the patient per day, or 0.5 g, 1 g, 1.5 g, 2 g,
2.5 g, 3 g, 3.5 g, 4.0 g, 4.5 g or 5.0 g of the composition is
administered to the patient per day.
[0182] More specifically in these aspects, the chloride ion binding
capacity in a Simulated Small Intestine Inorganic Buffer ("SIB")
assay may be greater than 3, 3.5, 4, or 4.5 mEq/g. One upper limit
for the chloride ion binding capacity in a SIB assay is 10 mEq/g.
Other the upper limits may be 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9,
9.5 or 10 mEq/g, or there may be no upper limit specified.
[0183] All combinations of the amount of composition and the
chloride ion binding capacity mentioned here are also disclosed.
For example, in one embodiment, the composition has a chloride ion
binding capacity in a SIB assay is of at least 4.5 mEq/g and only
0.1-6 gs of composition is administered in the method of treating
metabolic acidosis.
[0184] The composition in these aspects can additionally have any
of the properties or features specified elsewhere herein. For
example, the composition may be a nonabsorbable composition as
described in the following section. In a similar fashion, the
methods of treatment specified in these aspects may include any of
the features disclosed in the preceding section regarding certain
methods of treatment.
[0185] Nonabsorbable Compositions
[0186] As previously noted, the nonabsorbable compositions having
the medical uses described herein possess the capacity to remove
clinically significant quantities of one or more target species:
(i) protons, (ii) the conjugate base(s) of one or more strong acids
(e.g., chloride, bisulfate (HSO.sub.4.sup.-) and/or sulfate
(SO.sub.4.sup.-) ions) and/or (iii) one or more strong acids (e.g.,
HCl and/or H.sub.2SO.sub.4).
[0187] In general, the nonabsorbable composition has a preferred
particle size range that is (i) large enough to avoid passive or
active absorption through the GI tract and (ii) small enough to not
cause grittiness or unpleasant mouth feel when ingested as a
powder, sachet and/or chewable tablet/dosage form with a mean
particle size of at least 3 microns. For example, in one such
embodiment the nonabsorbable composition comprises a population of
particles having a mean particle size (volume distribution) in the
range of 5 to 1,000 microns. By way of further example, in one such
embodiment the nonabsorbable composition comprises a population of
particles having a mean particle size (volume distribution) in the
range of 5 to 500 microns. By way of further example, in one such
embodiment the nonabsorbable composition comprises a population of
particles having a mean particle size (volume distribution) in the
range of 10 to 400 microns. By way of further example, in one such
embodiment the nonabsorbable composition comprises a population of
particles having a mean particle size (volume distribution) in the
range of 10 to 300 microns. By way of further example, in one such
embodiment the nonabsorbable composition comprises a population of
particles having a mean particle size (volume distribution) in the
range of 20 to 250 microns. By way of further example, in one such
embodiment the nonabsorbable composition comprises a population of
particles having a mean particle size (volume distribution) in the
range of 30 to 250 microns. By way of further example, in one such
embodiment the nonabsorbable composition comprises a population of
particles having a mean particle size (volume distribution) in the
range of 40 to 180 microns. In certain embodiments, less than 7% of
the particles in the population (volume distribution) have a
diameter less than 10 microns. For example, in such embodiments
less than 5% of the particles in the particles in the population
(volume distribution) have a diameter less than 10 microns. By way
of further example, in such embodiments less than 2.5% of the
particles in the particles in the population (volume distribution)
have a diameter less than 10 microns. By way of further example, in
such embodiments less than 1% of the particles in the particles in
the population (volume distribution) have a diameter less than 10
microns. In all embodiments, the particle size may be measured
using the protocol set out in the abbreviations and definitions
section (above).
[0188] To minimize GI side effects inpatients that are often
related to a large volume polymer gel moving through the GI tract,
a low Swelling Ratio of the nonabsorbable composition is preferred
(0.5 to 10 times its own weight in water). For example, in one such
embodiment the nonabsorbable composition has a Swelling Ratio of
less than 9. By way of further example, in one such embodiment the
nonabsorbable composition has a Swelling Ratio of less than 8. By
way of further example, in one such embodiment the nonabsorbable
composition has a Swelling Ratio of less than 7. By way of further
example, in one such embodiment the nonabsorbable composition has a
Swelling Ratio of less than 6. By way of further example, in one
such embodiment the nonabsorbable composition has a Swelling Ratio
of less than 5. By way of further example, in one such embodiment
the nonabsorbable composition has a Swelling Ratio of less than 4.
By way of further example, in one such embodiment the nonabsorbable
composition has a Swelling Ratio of less than 3. By way of further
example, in one such embodiment the nonabsorbable composition has a
Swelling Ratio of less than 2.
[0189] The amount of the target species (proton, conjugate base of
a strong acid and/or strong acid) that is bound as the
nonabsorbable composition transits the GI tract is largely a
function of the binding capacity of the composition for the target
species (protons, the conjugate base of a strong acid, and/or a
strong acid) and the quantity of the nonabsorbable composition
administered per day as a daily dose. In general, the theoretical
binding capacity for a target species may be determined using a SGF
assay and determining the amount of a species that appeared in or
disappeared from the SGF buffer during the SGF assay. For example,
the theoretical proton binding capacity of a cation exchange resin
may be determined by measuring the increase in the amount of
cations (other than protons) in the buffer during a SGF assay.
Similarly, the theoretical anion binding capacity of an anion
exchange resin (in a form other than the chloride form) may be
determined by measuring the increase in the amount of anions (other
than chloride ions) in the buffer during a SGF assay. Additionally,
the theoretical anion binding capacity of a neutral composition for
protons and the conjugate base of a strong acid may be determined
by measuring the decrease in chloride concentration in the buffer
during a SGF assay.
[0190] In general, the nonabsorbable composition will have a
theoretical binding capacity for the target species of at least
about 0.5 mEq/g (as determined in an SGF assay). For example, in
some embodiments the nonabsorbable composition will have a
theoretical binding capacity for the target species of at least
about 1 mEq/g. By way of further example, in some embodiments the
nonabsorbable composition will have a theoretical binding capacity
for the target species of at least about 2 mEq/g. By way of further
example, in some embodiments the nonabsorbable composition will
have a theoretical binding capacity for the target species of at
least about 3 mEq/g. By way of further example, in some embodiments
the nonabsorbable composition will have a theoretical binding
capacity for the target species of at least about 4 mEq/g. By way
of further example, in some embodiments the nonabsorbable
composition will have a theoretical binding capacity for the target
species of at least about 5 mEq/g. By way of further example, in
some embodiments the nonabsorbable composition will have a
theoretical binding capacity for the target species of at least
about 7.5 mEq/g. By way of further example, in some embodiments the
nonabsorbable composition will have a theoretical binding capacity
for the target species of at least about 10 mEq/g. By way of
further example, in some embodiments the nonabsorbable composition
will have a theoretical binding capacity for the target species of
at least about 12.5 mEq/g. By way of further example, in some
embodiments the nonabsorbable composition will have a theoretical
binding capacity for the target species of at least about 15 mEq/g.
By way of further example, in some embodiments the nonabsorbable
composition will have a theoretical binding capacity for the target
species of at least about 20 mEq/g. In general, the nonabsorbable
composition will typically have a theoretical binding capacity for
the target species that is not in excess of about 35 mEq/g. For
example, in some embodiments, the theoretical binding capacity of
the nonabsorbable compositions for the target species that is not
be excess of 30 mEq/g. Thus, for example, the theoretical binding
capacity of the nonabsorbable compositions for the target species
may range from 2 to 25 mEq/g, 3 to 25 mEq/g, 5 to 25 mEq/g, 10 to
25 mEq/g, 5 to 20 mEq/g, 6 to 20 mEq/g, 7.5 to 20 mEq/g, or even 10
to 20 mEq/g. In those embodiments in which the target species
comprises protons and at least one conjugate base, the binding
capacities recited in this paragraph are the theoretical binding
capacities for protons and the theoretical binding capacities for
the conjugate base(s), independently and individually, and not the
sum thereof.
[0191] In general, the nonabsorbable composition will have a
theoretical binding capacity for protons of at least about 0.5
mEq/g (as determined in an SGF assay). For example, in some
embodiments the nonabsorbable composition will have a theoretical
binding capacity for protons of at least about 1 mEq/g. By way of
further example, in some embodiments the nonabsorbable composition
will have a theoretical binding capacity for protons of at least
about 2 mEq/g. By way of further example, in some embodiments the
nonabsorbable composition will have a theoretical binding capacity
for protons of at least about 3 mEq/g. By way of further example,
in some embodiments the nonabsorbable composition will have a
theoretical binding capacity for protons of at least about 4 mEq/g.
By way of further example, in some embodiments the nonabsorbable
composition will have a theoretical binding capacity for protons of
at least about 5 mEq/g. By way of further example, in some
embodiments the nonabsorbable composition will have a theoretical
binding capacity for protons of at least about 7.5 mEq/g. By way of
further example, in some embodiments the nonabsorbable composition
will have a theoretical binding capacity for protons of at least
about 10 mEq/g. By way of further example, in some embodiments the
nonabsorbable composition will have a theoretical binding capacity
for protons of at least about 12.5 mEq/g. By way of further
example, in some embodiments the nonabsorbable composition will
have a theoretical binding capacity for protons of at least about
15 mEq/g. By way of further example, in some embodiments the
nonabsorbable composition will have a theoretical binding capacity
for protons of at least about 20 mEq/g. In general, the
nonabsorbable composition will typically have a theoretical binding
capacity for protons that is not in excess of about 35 mEq/g. For
example, in some embodiments, the theoretical binding capacity of
the nonabsorbable compositions for protons that is not be excess of
30 mEq/g. Thus, for example, the theoretical binding capacity of
the nonabsorbable compositions for protons may range from 2 to 25
mEq/g, 3 to 25 mEq/g, 5 to 25 mEq/g, 10 to 25 mEq/g, 5 to 20 mEq/g,
6 to 20 mEq/g, 7.5 to 20 mEq/g, or even 10 to 20 mEq/g. In those
embodiments in which the target species comprises protons and at
least one conjugate base, the binding capacities recited in this
paragraph are the theoretical binding capacities for protons and
the theoretical binding capacities for the conjugate base(s),
independently and individually, and not the sum thereof.
[0192] Phosphate, bicarbonate, bicarbonate equivalents, the
conjugate bases of bile and fatty acids are potential interfering
anions for chloride or other conjugate bases of strong acids (e.g.,
HSO.sub.4.sup.- and SO.sub.4.sup.2-) in the stomach and small
intestine. Therefore, rapid and preferential binding of chloride
over phosphate, bicarbonate equivalents, and the conjugate bases of
bile and fatty acids in the small intestine is desirable and the
SIB assay may be used to determine kinetics and preferential
binding. Since the transit time of the colon is slow (2-3 days)
relative to the small intestine, and since conditions in the colon
will not be encountered by an orally administered nonabsorbable
composition until after stomach and small intestine conditions have
been encountered, kinetics of chloride binding by a nonabsorbable
composition do not need to be as rapid in the colon or under in
vitro conditions designed to mimic the late small intestine/colon.
It is, however, desirable that chloride binding and selectivity
over other interfering anions is high, for example, at 24 and/or 48
hours or longer.
[0193] In one embodiment, the nonabsorbable composition is
characterized by a chloride ion binding capacity of at least 1
mEq/g in a Simulated Small Intestine Inorganic Buffer ("SIB")
assay. For example, in one such embodiment the nonabsorbable
composition is characterized by a chloride ion binding capacity of
at least 1.5 mEq/g in a SIB assay. By way of further example, in
one such embodiment the nonabsorbable composition is characterized
by a chloride ion binding capacity of at least 2 mEq/g in a SIB
assay. By way of further example, in one such embodiment the
nonabsorbable composition is characterized by a chloride ion
binding capacity of at least 2.5 mEq/g in a SIB assay. By way of
further example, in one such embodiment the nonabsorbable
composition is characterized by a chloride ion binding capacity of
at least 3 mEq/g in a SIB assay. By way of further example, in one
such embodiment the nonabsorbable composition is characterized by a
chloride ion binding capacity of at least 3.5 mEq/g in a SIB assay.
By way of further example, in one such embodiment the nonabsorbable
composition is characterized by a chloride ion binding capacity of
at least 4 mEq/g in a SIB assay. By way of further example, in one
such embodiment the nonabsorbable composition is characterized by a
chloride ion binding capacity of at least 4.5 mEq/g in a SIB assay.
By way of further example, in one such embodiment the nonabsorbable
composition is characterized by a chloride ion binding capacity of
at least 5 mEq/g in a SIB assay. By way of further example, in one
such embodiment the nonabsorbable composition is characterized by a
chloride ion binding capacity of at least 5.5 mEq/g in a SIB assay.
By way of further example, in one such embodiment the nonabsorbable
composition is characterized by a chloride ion binding capacity of
at least 6 mEq/g in a SIB assay.
[0194] In one embodiment, the nonabsorbable composition binds a
significant amount of chloride relative to phosphate as exhibited,
for example, in a SIB assay. For example, in one embodiment the
ratio of the amount of bound chloride to bound phosphate in a SIB
assay is at least 0.1:1, respectively. By way of further example,
in one such embodiment the ratio of the amount of bound chloride to
bound phosphate in a SIB assay is at least 0.2:1, respectively. By
way of further example, in one such embodiment the ratio of the
amount of bound chloride to bound phosphate in a SIB assay is at
least 0.25:1, respectively. By way of further example, in one such
embodiment the ratio of the amount of bound chloride to bound
phosphate in a SIB assay is at least 0.3:1, respectively. By way of
further example, in one such embodiment the ratio of the amount of
bound chloride to bound phosphate in a SIB assay is at least
0.35:1, respectively. By way of further example, in one such
embodiment the ratio of the amount of bound chloride to bound
phosphate in a SIB assay is at least 0.4:1, respectively. By way of
further example, in one such embodiment the ratio of the amount of
bound chloride to bound phosphate in a SIB assay is at least
0.45:1, respectively. By way of further example, in one such
embodiment the ratio of the amount of bound chloride to bound
phosphate in a SIB assay is at least 0.5:1, respectively. By way of
further example, in one such embodiment the ratio of the amount of
bound chloride to bound phosphate in a SIB assay is at least 2:3,
respectively. By way of further example, in one such embodiment the
ratio of the amount of bound chloride to bound phosphate in a SIB
assay is at least 0.75:1, respectively. By way of further example,
in one such embodiment the ratio of the amount of bound chloride to
bound phosphate in a SIB assay is at least 0.9:1, respectively. By
way of further example, in one such embodiment the ratio of the
amount of bound chloride to bound phosphate in a SIB assay is at
least 1:1, respectively. By way of further example, in one such
embodiment the ratio of the amount of bound chloride to bound
phosphate in a SIB assay is at least 1.25:1, respectively. By way
of further example, in one such embodiment the ratio of the amount
of bound chloride to bound phosphate in a SIB assay is at least
1.5:1, respectively. By way of further example, in one such
embodiment the ratio of the amount of bound chloride to bound
phosphate in a SIB assay is at least 1.75:1, respectively. By way
of further example, in one such embodiment the ratio of the amount
of bound chloride to bound phosphate in a SIB assay is at least
2:1, respectively. By way of further example, in one such
embodiment the ratio of the amount of bound chloride to bound
phosphate in a SIB assay is at least 2.25:1, respectively. By way
of further example, in one such embodiment the ratio of the amount
of bound chloride to bound phosphate in a SIB assay is at least
2.5:1, respectively. By way of further example, in one such
embodiment the ratio of the amount of bound chloride to bound
phosphate in a SIB assay is at least 2.75:1, respectively. By way
of further example, in one such embodiment the ratio of the amount
of bound chloride to bound phosphate in a SIB assay is at least
3:1, respectively. By way of further example, in one such
embodiment the ratio of the amount of bound chloride to bound
phosphate in a SIB assay is at least 4:1, respectively. By way of
further example, in one such embodiment the ratio of the amount of
bound chloride to bound phosphate in a SIB assay is at least 5:1,
respectively.
[0195] In one embodiment, the orally administered nonabsorbable
composition is characterized by a proton-binding capacity and a
chloride binding capacity in Simulated Gastric Fluid of at least 1
mEq/g in a SGF assay. For example, in one such embodiment the
nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity in a SGF assay of at least
2 mEq/g. By way of further example, in one such embodiment the
nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity in a SGF assay of at least
3 mEq/g. By way of further example, in one such embodiment the
nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity in a SGF assay of at least
4 mEq/g. By way of further example, in one such embodiment the
nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity in a SGF assay of at least
5 mEq/g. By way of further example, in one such embodiment the
nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity in a SGF assay of at least
6 mEq/g. By way of further example, in one such embodiment the
nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity in a SGF assay of at least
7 mEq/g. By way of further example, in one such embodiment the
nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity in a SGF assay of at least
8 mEq/g. By way of further example, in one such embodiment the
nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity in a SGF assay of at least
9 mEq/g. By way of further example, in one such embodiment the
nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity in a SGF assay of at least
10 mEq/g. By way of further example, in one such embodiment the
nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity in a SGF assay of at least
11 mEq/g. By way of further example, in one such embodiment the
nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity in a SGF assay of at least
12 mEq/g. By way of further example, in one such embodiment the
nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity in a SGF assay of at least
13 mEq/g. By way of further example, in one such embodiment the
nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity in a SGF assay of at least
14 mEq/g. By way of further example, in one such embodiment the
nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity after 1 hour in SGF that
is at least 50% of the proton-binding capacity and the chloride
binding capacity, respectively, of the nonabsorbable composition at
24 hours in SGF. By way of further example, in one such embodiment
the nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity after 1 hour in SGF that
is at least 60% of the proton-binding capacity and the chloride
binding capacity, respectively, of the nonabsorbable composition at
24 hours in SGF. By way of further example, in one such embodiment
the nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity after 1 hour in SGF that
is at least 70% of the proton-binding capacity and the chloride
binding capacity, respectively, of the nonabsorbable composition at
24 hours in SGF. By way of further example, in one such embodiment
the nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity after 1 hour in SGF that
is at least 80% of the proton-binding capacity and the chloride
binding capacity, respectively, of the nonabsorbable composition at
24 hours in SGF. By way of further example, in one such embodiment
the nonabsorbable composition is characterized by a proton-binding
capacity and a chloride binding capacity after 1 hour in SGF that
is at least 90% of the proton-binding capacity and the chloride
binding capacity, respectively, of the nonabsorbable composition at
24 hours in SGF.
[0196] In those embodiments in which the nonabsorbable composition
binds chloride ions, it is generally preferred that the
nonabsorbable composition selectively bind chloride ions relative
to other counter ions such as bicarbonate equivalent anions,
phosphate anions, and the conjugate bases of bile and fatty acids.
Stated differently, it is generally preferred in these embodiments
that the nonabsorbable composition (i) remove more chloride ions
than bicarbonate equivalent anions (ii) remove more chloride ions
than phosphate anions, and (iii) remove more chloride ions than the
conjugate bases of bile and fatty acids. Advantageously, therefore,
treatment with the nonabsorbable composition does not induce or
exacerbate hypophosphatemia (i.e., a serum phosphorous
concentration of less than about 2.4 mg/dL, does not significantly
elevate low density lipoproteins ("LDL"), or otherwise negatively
impact serum or colon levels of metabolically relevant anions.
[0197] The nonabsorbable composition of the present invention can
be a polymer as defined anywhere herein, including Formulae 1-4
below.
[0198] In some embodiments, the pharmaceutical composition
comprises a crosslinked polymer containing the residue of an amine
corresponding to Formula 1:
##STR00002##
wherein R.sub.1, R.sub.2 and R.sub.3 are independently hydrogen,
hydrocarbyl, substituted hydrocarbyl provided, however, at least
one of R.sub.1, R.sub.2 and R.sub.3 is other than hydrogen. Stated
differently, at least one of R.sub.1, R.sub.2 and R.sub.3 is
hydrocarbyl or substituted hydrocarbyl, and the others of R.sub.1,
R.sub.2 and R.sub.3 are independently hydrogen, hydrocarbyl, or
substituted hydrocarbyl. In one embodiment, for example, R.sub.1,
R.sub.2 and R.sub.3 are independently hydrogen, aryl, aliphatic,
heteroaryl, or heteroaliphatic provided, however, each of R.sub.1,
R.sub.2 and R.sub.3 are not hydrogen. By way of further example, in
one such embodiment R.sub.1, R.sub.2 and R.sub.3 are independently
hydrogen, saturated hydrocarbons, unsaturated aliphatic,
unsaturated heteroaliphatic, heteroalkyl, heterocyclic, aryl or
heteroaryl, provided, however, each of R.sub.1, R.sub.2 and R.sub.3
are not hydrogen. By way of further example, in one such embodiment
R.sub.1, R.sub.2 and R.sub.3 are independently hydrogen, alkyl,
alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl,
hydroxyalkyl, ethereal, heteroaryl or heterocyclic provided,
however, each of R.sub.1, R.sub.2 and R.sub.3 are not hydrogen. By
way of further example, in one such embodiment R.sub.1, R.sub.2 and
R.sub.3 are independently hydrogen, alkyl, aminoalkyl, alkanol,
aryl, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic
provided, however, each of R.sub.1, R.sub.2 and R.sub.3 are not
hydrogen. By way of further example, in one such embodiment R.sub.1
and R.sub.2 (in combination with the nitrogen atom to which they
are attached) together constitute part of a ring structure, so that
the monomer as described by Formula 1 is a nitrogen-containing
heterocycle (e.g., piperidine) and R.sub.3 is hydrogen, or
heteroaliphatic. By way of further example, in one embodiment
R.sub.1, R.sub.2 and R.sub.3 are independently hydrogen, aliphatic
or heteroaliphatic provided, however, at least one of R.sub.1,
R.sub.2 and R.sub.3 is other than hydrogen. By way of further
example, in one embodiment R.sub.1, R.sub.2 and R.sub.3 are
independently hydrogen, allyl, or aminoalkyl.
[0199] In one embodiment, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 1 wherein R.sub.1,
R.sub.2, and R.sub.3 are independently hydrogen, heteroaryl, aryl,
aliphatic or heteroaliphatic provided, however, at least one of
R.sub.1, R.sub.2, and R.sub.3 is aryl or heteroaryl. For example,
in this embodiment R.sub.1 and R.sub.2, in combination with the
nitrogen atom to which they are attached, may form a saturated or
unsaturated nitrogen-containing heterocyclic ring. By way of
further example, R.sub.1 and R.sub.2, in combination with the
nitrogen atom to which they are attached may constitute part of a
pyrrolidino, pyrole, pyrazolidine, pyrazole, imidazolidine,
imidazole, piperidine, pyridine, piperazine, diazine, or triazine
ring structure. By way of further example, R.sub.1 and R.sub.2, in
combination with the nitrogen atom to which they are attached may
constitute part of a piperidine ring structure.
[0200] In one embodiment, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 1 wherein R.sub.1,
R.sub.2, and R.sub.3 are independently hydrogen, aliphatic, or
heteroaliphatic provided, however, at least one of R.sub.1,
R.sub.2, and R.sub.3 is other than hydrogen. For example, in this
embodiment R.sub.1, R.sub.2, and R.sub.3 may independently be
hydrogen, alkyl, alkenyl, allyl, vinyl, aminoalkyl, alkanol,
haloalkyl, hydroxyalkyl, ethereal, or heterocyclic provided,
however, at least one of R.sub.1, R.sub.2, and R.sub.3 is other
than hydrogen. By way of further example, in one such embodiment
R.sub.1 and R.sub.2, in combination with the nitrogen atom to which
they are attached, may form a saturated or unsaturated
nitrogen-containing heterocyclic ring. By way of further example,
in one such embodiment R.sub.1 and R.sub.2, in combination with the
nitrogen atom to which they are attached may constitute part of a
pyrrolidino, pyrole, pyrazolidine, pyrazole, imidazolidine,
imidazole, piperidine, piperazine, or diazine ring structure. By
way of further example, in one such embodiment R.sub.1 and R.sub.2,
in combination with the nitrogen atom to which they are attached
may constitute part of a piperidine ring structure. By way of
further example, in one such embodiment the amine corresponding to
Formula 1 is acyclic and at least one of R.sub.1, R.sub.2, and
R.sub.3 is aliphatic or heteroaliphatic. By way of further example,
in one such embodiment R.sub.1, R.sub.2, and R.sub.3 are
independently hydrogen, alkyl, allyl, vinyl, alicyclic, aminoalkyl,
alkanol, or heterocyclic, provided at least one of R.sub.1,
R.sub.2, and R.sub.3 is other than hydrogen.
[0201] In one embodiment, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 1 and the crosslinked
polymer is prepared by substitution polymerization of the amine
corresponding to Formula 1 with a polyfunctional crosslinker
(optionally also comprising amine moieties) wherein R.sub.1,
R.sub.2, and R.sub.3 are independently hydrogen, alkyl, aminoalkyl,
or alkanol, provided at least one of R.sub.1, R.sub.2, and R.sub.3
is other than hydrogen.
[0202] In some embodiments, the molecular weight per nitrogen of
the polymers of the present disclosure may range from about 40 to
about 1000 Daltons. In one embodiment, the molecular weight per
nitrogen of the polymer is from about 40 to about 500 Daltons. In
another embodiment, the molecular weight per nitrogen of the
polymer is from about 50 to about 170 Daltons. In another
embodiment, the molecular weight per nitrogen of the polymer is
from about 60 to about 110 Daltons.
[0203] In some embodiments, an amine-containing monomer is
polymerized and the polymer is concurrently crosslinked in a
substitution polymerization reaction in the first reaction step.
The amine reactant (monomer) in the concurrent polymerization and
crosslinking reaction can react more than one time for the
substitution polymerization. In one such embodiment, the amine
monomer is a linear amine possessing at least two reactive amine
moieties to participate in the substitution polymerization
reaction. In another embodiment, the amine monomer is a branched
amine possessing at least two reactive amine moieties to
participate in the substitution polymerization reaction.
Crosslinkers for the concurrent substitution polymerization and
crosslinking typically have at least two amine-reactive moieties
such as alkyl-chlorides, and alkyl-epoxides. In order to be
incorporated into the polymer, primary amines react at least once
and potentially may react up to three times with the crosslinker,
secondary amines can react up to twice with the crosslinkers, and
tertiary amines can only react once with the crosslinker. In
general, however, the formation of a significant number of
quaternary nitrogens/amines is generally not preferred because
quaternary amines cannot bind protons.
[0204] Exemplary amines that may be used in substitution
polymerization reactions described herein include
1,3-Bis[bis(2-aminoethyl)amino]propane,
3-Amino-1-{[2-(bis{2-[bis(3-aminopropyl)amino]ethyl}amino)ethyl](3-aminop-
ropyl)amino}propane, 2-[Bis(2-aminoethyl)amino]ethanamine,
Tris(3-aminopropyl)amine, 1,4-Bis[bis(3-aminopropyl)amino]butane,
1,2-Ethanediamine, 2-Amino-1-(2-aminoethylamino)ethane,
1,2-Bis(2-aminoethylamino)ethane, 1,3-Propanediamine,
3,3'-Diaminodipropylamine, 2,2-dimethyl-1,3-propanediamine,
2-methyl-1,3-propanediamine, N,N'-dimethyl-1,3-propanediamine,
N-methyl-1,3-diaminopropane, 3,3'-diamino-N-methyldipropylamine,
1,3-diaminopentane, 1,2-diamino-2-methylpropane,
2-methyl-1,5-diaminopentane, 1,2-diaminopropane,
1,10-diaminodecane, 1,8-diaminooctane, 1,9-diaminooctane,
1,7-diaminoheptane, 1,6-diaminohexane, 1,5-diaminopentane,
3-bromopropylamine hydrobromide, N,2-dimethyl-1,3-propanediamine,
N-isopropyl-1,3-diaminopropane,
N,N'-bis(2-aminoethyl)-1,3-propanediamine,
N,N'-bis(3-aminopropyl)ethylenediamine,
N,N'-bis(3-aminopropyl)-1,4-butanediamine tetrahydrochloride,
1,3-diamino-2-propanol, N-ethylethylenediamine,
2,2'-diamino-N-methyldiethylamine, N,N'-diethylethylenediamine,
N-isopropylethylenediamine, N-methylethylenediamine,
N,N'-di-tert-butylethylenediamine, N,N'-diisopropylethylenediamine,
N,N'-dimethylethylenediamine, N-butylethylenediamine,
2-(2-aminoethylamino)ethanol,
1,4,7,10,13,16-hexaazacyclooctadecane,
1,4,7,10-tetraazacyclododecane, 1,4,7-triazacyclononane,
N,N'-bis(2-hydroxyethyl)ethylenediamine, piperazine,
bis(hexamethylene)triamine, N-(3-hydroxypropyl)ethylenediamine,
N-(2-Aminoethyl)piperazine, 2-Methylpiperazine, Homopiperazine,
1,4,8,11-Tetraazacyclotetradecane,
1,4,8,12-Tetraazacyclopentadecane, 2-(Aminomethyl)piperidine,
3-(Methylamino)pyrrolidine
[0205] Exemplary crosslinking agents that may be used in
substitution polymerization reactions and post-polymerization
crosslinking reactions include, but are not limited to, one or more
multifunctional crosslinking agents such as: dihaloalkanes,
haloalkyloxiranes, alkyloxirane sulfonates, di(haloalkyl)amines,
tri(haloalkyl) amines, diepoxides, triepoxides, tetraepoxides, bis
(halomethyl)benzenes, tri(halomethyl)benzenes,
tetra(halomethyl)benzenes, epihalohydrins such as epichlorohydrin
and epibromohydrin poly(epichlorohydrin), (iodomethyl)oxirane,
glycidyl tosylate, glycidyl 3-nitrobenzenesulfonate,
4-tosyloxy-1,2-epoxybutane, bromo-1,2-epoxybutane,
1,2-dibromoethane, 1,3-dichloropropane, 1,2-dichloroethane,
1-bromo-2-chloroethane, 1,3-dibromopropane,
bis(2-chloroethyl)amine, tris(2-chloroethyl)amine, and
bis(2-chloroethyl)methylamine, 1,3-butadiene diepoxide,
1,5-hexadiene diepoxide, diglycidyl ether, 1,2,7,8-diepoxyoctane,
1,2,9,10-diepoxydecane, ethylene glycol diglycidyl ether, propylene
glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, 1,2
ethanedioldiglycidyl ether, glycerol diglycidyl ether,
1,3-diglycidyl glyceryl ether, N,N-diglycidylaniline, neopentyl
glycol diglycidyl ether, diethylene glycol diglycidyl ether,
1,4-bis(glycidyloxy)benzene, resorcinol digylcidyl ether,
1,6-hexanediol diglycidyl ether, trimethylolpropane diglycidyl
ether, 1,4-cyclohexanedimethanol diglycidyl ether,
1,3-bis-(2,3-epoxypropyloxy)-2-(2,3-dihydroxypropyloxy)propane,
1,2-cyclohexanedicarboxylic acid diglycidyl ester,
2,2'-bis(glycidyloxy) diphenylmethane, bisphenol F diglycidyl
ether, 1,4-bis(2',3'epoxypropyl)perfluoro-n-butane,
2,6-di(oxiran-2-ylmethyl)-1,2,3,5,6,7-hexahydropyrrolo[3,4-f]isoindol-1,3-
,5,7-tetraone, bisphenol A diglycidyl ether, ethyl
5-hydroxy-6,8-di(oxiran-2-ylmethyl)-4-oxo-4-h-chromene-2-carboxylate,
bis[4-(2,3-epoxy-propylthio)phenyl]-sulfide,
1,3-bis(3-glycidoxypropyl) tetramethyldisiloxane,
9,9-bis[4-(glycidyloxy)phenyl]fluorine, triepoxyisocyanurate,
glycerol triglycidyl ether, N,N-diglycidyl-4-glycidyloxyaniine,
isocyanuric acid (S,S,S)-triglycidyl ester, isocyanuric acid
(R,R,R)-triglycidyl ester, triglycidyl isocyanurate,
trimethylolpropane triglycidyl ether, glycerol propoxylate
triglycidyl ether, triphenylolmethane triglycidyl ether,
3,7,14-tris[[3-(epoxypropoxy)propyl]dimethylsilyloxy]-1,3,5,7,9,11,14-hep-
tacyclopentyltricyclo [7,3,3,15, 11]heptasiloxane,
4,4'methylenebis(N,N-diglycidylaniline), bis(halomethyl)benzene,
bis(halomethyl)biphenyl and bis(halomethyl)naphthalene, toluene
diisocyanate, acrylol chloride, methyl acrylate, ethylene
bisacrylamide, pyrometallic dianhydride, succinyl dichloride,
dimethylsuccinate, 3-chloro-1-(3-chloropropylamino-2-propanol,
1,2-bis(3-chloropropylamino)ethane, Bis(3-chloropropyl)amine,
1,3-Dichloro-2-propanol, 1,3-Dichloropropane,
1-chloro-2,3-epoxypropane, tris[(2-oxiranyl)methyl]amine.
[0206] In some embodiments, the carbon to nitrogen ratio of the
polymers of the present disclosure may range from about 2:1 to
about 6:1, respectively. For example, in one such embodiment, the
carbon to nitrogen ratio of the polymers of the present disclosure
may range from about 2.5:1 to about 5:1, respectively. By way of
further example, in one such embodiment, the carbon to nitrogen
ratio of the polymers of the present disclosure may range from
about 3:1 to about 4.5:1, respectively. By way of further example,
in one such embodiment, the carbon to nitrogen ratio of the
polymers of the present disclosure may range from about 3.25:1 to
about 4.25:1, respectively. By way of further example, in one such
embodiment, the carbon to nitrogen ratio of the polymers of the
present disclosure may range from about 3.4:1 to about 4:1,
respectively. In another embodiment, the molecular weight per
nitrogen of the polymer is from about 60 to about 110 Daltons.
[0207] In some embodiments, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 1a and the crosslinked
polymer is prepared by radical polymerization of an amine
corresponding to Formula 1a:
##STR00003##
wherein R.sub.4 and R.sub.5 are independently hydrogen,
hydrocarbyl, or substituted hydrocarbyl. In one embodiment, for
example, R.sub.4 and R.sub.5 are independently hydrogen, saturated
hydrocarbon, unsaturated aliphatic, aryl, heteroaryl, unsaturated
heteroaliphatic, heterocyclic, or heteroalkyl. By way of further
example, in one such embodiment R.sub.4 and R.sub.5 are
independently hydrogen, aliphatic, heteroaliphatic, aryl, or
heteroaryl. By way of further example, in one such embodiment
R.sub.4 and R.sub.5 are independently hydrogen, alkyl, alkenyl,
allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl,
ethereal, heteroaryl or heterocyclic. By way of further example, in
one such embodiment R.sub.4 and R.sub.5 are independently hydrogen,
alkyl, allyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl,
ethereal, or heterocyclic. By way of further example, in one such
embodiment R.sub.4 and R.sub.5 (in combination with the nitrogen
atom to which they are attached) together constitute part of a ring
structure, so that the monomer as described by Formula 1a is a
nitrogen-containing heterocycle (e.g., piperidine). By way of
further example, in one embodiment R.sub.4 and R.sub.5 are
independently hydrogen, aliphatic or heteroaliphatic. By way of
further example, in one embodiment R.sub.4 and R.sub.5 are
independently hydrogen, allyl, or aminoalkyl.
[0208] In some embodiments, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 1b and the crosslinked
polymer is prepared by substitution polymerization of the amine
corresponding to Formula 1b with a polyfunctional crosslinker
(optionally also comprising amine moieties):
##STR00004##
wherein R.sub.4 and R.sub.5 are independently hydrogen,
hydrocarbyl, or substituted hydrocarbyl, R.sub.6 is aliphatic and
R.sub.61 and R.sub.62 are independently hydrogen, aliphatic, or
heteroaliphatic. In one embodiment, for example, R.sub.4 and
R.sub.5 are independently hydrogen, saturated hydrocarbon,
unsaturated aliphatic, aryl, heteroaryl, heteroalkyl, or
unsaturated heteroaliphatic. By way of further example, in one such
embodiment R.sub.4 and R.sub.5 are independently hydrogen,
aliphatic, heteroaliphatic, aryl, or heteroaryl. By way of further
example, in one such embodiment R.sub.4 and R.sub.5 are
independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl,
aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl
or heterocyclic. By way of further example, in one such embodiment
R.sub.4 and R.sub.5 are independently hydrogen, alkyl, alkenyl,
aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ethereal,
heteroaryl or heterocyclic. By way of further example, in one such
embodiment R.sub.4 and R.sub.5 (in combination with the nitrogen
atom to which they are attached) together constitute part of a ring
structure, so that the monomer as described by Formula 1a is a
nitrogen-containing heterocycle (e.g., piperidine). By way of
further example, in one embodiment R.sub.4 and R.sub.5 are
independently hydrogen, aliphatic or heteroaliphatic. By way of
further example, in one embodiment R.sub.4 and R.sub.5 are
independently hydrogen, allyl, or aminoalkyl. By way of further
example, in each of the embodiments recited in this paragraph,
R.sub.6 may be methylene, ethylene or propylene, and R.sub.61 and
R.sub.62 may independently be hydrogen, allyl or aminoalkyl.
[0209] In some embodiments, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 1c:
##STR00005##
wherein R.sub.7 is hydrogen, aliphatic or heteroaliphatic and
R.sub.8 is aliphatic or heteroaliphatic. For example, in one such
embodiment, for example, R.sub.7 is hydrogen and R.sub.8 is
aliphatic or heteroaliphatic. By way of further example, in one
such embodiment R.sub.7 and R.sub.8 are independently aliphatic or
heteroaliphatic. By way of further example, in one such embodiment
at least one of R.sub.7 and R.sub.8 comprises an allyl moiety. By
way of further example, in one such embodiment at least one of
R.sub.7 and R.sub.8 comprises an aminoalkyl moiety. By way of
further example, in one such embodiment R.sub.7 and R.sub.8 each
comprise an allyl moiety. By way of further example, in one such
embodiment R.sub.7 and R.sub.8 each comprise an aminoalkyl moiety.
By way of further example, in one such embodiment R.sub.7 comprises
an allyl moiety and R.sub.8 comprises an aminoalkyl moiety.
[0210] In some embodiments, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 2:
##STR00006##
[0211] wherein
[0212] m and n are independently non-negative integers,
[0213] R.sub.10, R.sub.20, R.sub.30, and R.sub.40 are independently
hydrogen, hydrocarbyl, or substituted hydrocarbyl;
[0214] X.sub.1 is
##STR00007##
[0215] X.sub.2 is hydrocarbyl or substituted hydrocarbyl;
[0216] each X.sub.11 is independently hydrogen, hydrocarbyl,
substituted hydrocarbyl, hydroxyl, amino, boronic acid, or halo;
and
[0217] z is a non-negative number.
[0218] In one embodiment, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 2, the crosslinked
polymer is prepared by (i) substitution polymerization of the amine
corresponding to Formula 2 with a polyfunctional crosslinker
(optionally also comprising amine moieties) or (2) radical
polymerization of an amine corresponding to Formula 2, and m and n
are independently 0, 1, 2 or 3 and n is 0 or 1.
[0219] In one embodiment, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 2, the crosslinked
polymer is prepared by (i) substitution polymerization of the amine
corresponding to Formula 2 with a polyfunctional crosslinker
(optionally also comprising amine moieties) or (2) radical
polymerization of an amine corresponding to Formula 2, and
R.sub.10, R.sub.20, R.sub.30, and R.sub.40 are independently
hydrogen, aliphatic, aryl, heteroaliphatic, or heteroaryl. By way
of further example, in one such embodiment R.sub.10, R.sub.20,
R.sub.30, and R.sub.40 are independently hydrogen, aliphatic, or
heteroaliphatic. By way of further example, in one such embodiment
R.sub.10, R.sub.20, R.sub.30, and R.sub.40 are independently
hydrogen, alkyl, allyl, vinyl, or aminoalkyl. By way of further
example, in one such embodiment R.sub.10, R.sub.20, R.sub.30, and
R.sub.40 are independently hydrogen, alkyl, allyl, vinyl,
--(CH.sub.2).sub.dNH.sub.2,
--(CH.sub.2).sub.dN[(CH.sub.2).sub.eNH.sub.2)].sub.2 where d and e
are independently 2-4. In each of the foregoing exemplary
embodiments of this paragraph, m and z may independently be 0, 1, 2
or 3 and n is 0 or 1.
[0220] In one embodiment, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 2, the crosslinked
polymer is prepared by (i) substitution polymerization of the amine
corresponding to Formula 2 with a polyfunctional crosslinker
(optionally also comprising amine moieties) or (2) radical
polymerization of an amine corresponding to Formula 2, and X.sub.2
is aliphatic or heteroaliphatic. For example, in one such
embodiment X.sub.2 is aliphatic or heteroaliphatic and R.sub.10,
R.sub.20, R.sub.30, and R.sub.40 are independently hydrogen,
aliphatic, heteroaliphatic. By way of further example, in one such
embodiment X.sub.2 is alkyl or aminoalkyl and R.sub.10, R.sub.20,
R.sub.30, and R.sub.40 are independently hydrogen, aliphatic, or
heteroaliphatic. By way of further example, in one such embodiment
X.sub.2 is alkyl or aminoalkyl and R.sub.10, R.sub.20, R.sub.30,
and R.sub.40 are independently hydrogen, alkyl, allyl, vinyl, or
aminoalkyl. In each of the foregoing exemplary embodiments of this
paragraph, m and z may independently be 0, 1, 2 or 3 and n is 0 or
1.
[0221] In one embodiment, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 2, the crosslinked
polymer is prepared by (i) substitution polymerization of the amine
corresponding to Formula 2 with a polyfunctional crosslinker
(optionally also comprising amine moieties) or (2) radical
polymerization of an amine corresponding to Formula 2, and m is a
positive integer. For example, in one such embodiment m is a
positive integer, z is zero and R.sub.20 is hydrogen, aliphatic or
heteroaliphatic. By way of further example, in one such embodiment
m is a positive integer (e.g., 1 to 3), z is a positive integer
(e.g., 1 to 2), X.sub.11 is hydrogen, aliphatic or heteroaliphatic,
and R.sub.20 is hydrogen, aliphatic or heteroaliphatic. By way of
further example, in one such embodiment m is a positive integer, z
is zero, one or two, X.sub.11 is hydrogen alkyl, alkenyl, or
aminoalkyl, and R.sub.20 is hydrogen, alkyl, alkenyl, or
aminoalkyl.
[0222] In one embodiment, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 2, the crosslinked
polymer is prepared by (i) substitution polymerization of the amine
corresponding to Formula 2 with a polyfunctional crosslinker
(optionally also comprising amine moieties) or (2) radical
polymerization of an amine corresponding to Formula 2, and n is a
positive integer and R.sub.30 is hydrogen, aliphatic or
heteroaliphatic. By way of further example, in one such embodiment
n is 0 or 1, and R.sub.30 is hydrogen, alkyl, alkenyl, or
aminoalkyl.
[0223] In one embodiment, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 2, the crosslinked
polymer is prepared by (i) substitution polymerization of the amine
corresponding to Formula 2 with a polyfunctional crosslinker
(optionally also comprising amine moieties) or (2) radical
polymerization of an amine corresponding to Formula 2, and m and n
are independently non-negative integers and X.sub.2 is aliphatic or
heteroaliphatic. For example, in one such embodiment m is 0 to 2, n
is 0 or 1, X.sub.2 is aliphatic or heteroaliphatic, and R.sub.10,
R.sub.20, R.sub.30, and R.sub.40 are independently hydrogen,
aliphatic, or heteroaliphatic. By way of further example, in one
such embodiment m is 0 to 2, n is 0 or 1, X.sub.2 is alkyl or
aminoalkyl, and R.sub.10, R.sub.20, R.sub.30, and R.sub.40 are
independently hydrogen, aliphatic, or heteroaliphatic. By way of
further example, in one such embodiment m is 0 to 2, n is 0 or 1,
X.sub.2 is alkyl or aminoalkyl, and R.sub.10, R.sub.20, R.sub.30,
and R.sub.40 are independently hydrogen, alkyl, alkenyl, or
aminoalkyl.
[0224] In some embodiments, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 2a and the crosslinked
polymer is prepared by substitution polymerization of the amine
corresponding to Formula 2a with a polyfunctional crosslinker
(optionally also comprising amine moieties):
##STR00008##
[0225] wherein
[0226] m and n are independently non-negative integers;
[0227] each R.sub.11 is independently hydrogen, hydrocarbyl,
heteroaliphatic, or heteroaryl;
[0228] R.sub.21 and R.sub.31, are independently hydrogen or
heteroaliphatic;
[0229] R.sub.41 is hydrogen, substituted hydrocarbyl, or
hydrocarbyl;
[0230] X.sub.1 is
##STR00009##
[0231] X.sub.2 is alkyl or substituted hydrocarbyl;
[0232] each X.sub.12 is independently hydrogen, hydroxy, amino,
aminoalkyl, boronic acid or halo; and
[0233] z is a non-negative number.
[0234] In one embodiment, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 2a, the crosslinked
polymer is prepared by substitution polymerization of the amine
corresponding to Formula 1 with a polyfunctional crosslinker
(optionally also comprising amine moieties). For example, in one
such embodiment, m and z are independently 0, 1, 2 or 3, and n is 0
or 1.
[0235] In one embodiment, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 2a, the crosslinked
polymer is prepared by substitution polymerization of the amine
corresponding to Formula 2a with a polyfunctional crosslinker
(optionally also comprising amine moieties), and each R.sub.11 is
independently hydrogen, aliphatic, aminoalkyl, haloalkyl, or
heteroaryl, R.sub.21 and R.sub.31 are independently hydrogen or
heteroaliphatic and R.sub.41 is hydrogen, aliphatic, aryl,
heteroaliphatic, or heteroaryl. For example, in one such embodiment
each R.sub.11 is hydrogen, aliphatic, aminoalkyl, or haloalkyl,
R.sub.21 and R.sub.31 are independently hydrogen or heteroaliphatic
and R.sub.41 is hydrogen, alkylamino, aminoalkyl, aliphatic, or
heteroaliphatic. By way of further example, in one such embodiment
each R.sub.11 is hydrogen, aliphatic, aminoalkyl, or haloalkyl,
R.sub.21 and R.sub.31 are hydrogen or aminoalkyl, and R.sub.41 is
hydrogen, aliphatic, or heteroaliphatic. By way of further example,
in one such embodiment each R.sub.11 and R.sub.41 is independently
hydrogen, alkyl, or aminoalkyl, and R.sub.21 and R.sub.31 are
independently hydrogen or heteroaliphatic. By way of further
example, in one such embodiment each R.sub.11 and R.sub.41 is
independently hydrogen, alkyl, --(CH.sub.2).sub.dNH.sub.2,
--(CH.sub.2).sub.dN[(CH.sub.2).sub.eNH.sub.2)]2 where d and e are
independently 2-4, and R.sub.21 and R.sub.31 are independently
hydrogen or heteroaliphatic. In each of the foregoing exemplary
embodiments of this paragraph, m and z may independently be 0, 1, 2
or 3, and n is 0 or 1.
[0236] Exemplary amines for the synthesis of polymers comprising
repeat units corresponding to Formula 2a include, but are not
limited to, amines appearing in Table A.
TABLE-US-00002 TABLE A Abbre- MW viation IUPAC name Other names
(g/mol) C2A3BTA 1,3-Bis[bis(2-aminoethyl) amino]propane
##STR00010## 288.48 C2A3G2 3-Amino-1-{[2-(bis{2-[bis
(3-aminopropyl)amino] ethyl}amino)ethyl](3- aminopropyl)amino}
propane ##STR00011## 488.81 C2PW 2-[Bis(2-aminoethyl)
amino]ethanamine 2,2',2''-Triamino- triethylamine or
2,2',2''-Nitrilo- triethylamine ##STR00012## 146.24 C3PW
Tris(3-aminopropyl) amine ##STR00013## 188.32 C4A3BTA
1,4-Bis[bis(3-amino- propyl)amino]butane ##STR00014## 316.54 EDA1
1,2-Ethanediamine ##STR00015## 60.1 EDA2 2-Amino-1-(2-amino-
ethylamino)ethane Bis(2-aminoethyl) amine or 2,2'-Diamino-
diethylamine ##STR00016## 103.17 EDA3 1,2-Bis(2-aminoethyl-
amino)ethane N,N'-bis(2-amino- ethyl)ethane- 1,2-diamine
##STR00017## 146.24 PDA1 1,3-Propanediamine ##STR00018## 74.3 PDA2
3,3'-Diaminodi- propylamine ##STR00019## 131.22
[0237] Exemplary crosslinkers for the synthesis of polymers
comprising the residue of amines corresponding to Formula 2a
include but are not limited to crosslinkers appearing in Table
B.
TABLE-US-00003 TABLE B Abbre- MW viation Common name IUPAC name
(g/mol) BCPA Bis(3- chloropropyl) amine Bis(3- chloropropyl) amine
##STR00020## 206.54 DC2OH 1,3- dichloroiso- propanol 1,3-Dichloro-
2-propanol ##STR00021## 128.98 DCE dichloro- ethane 1,2- dichloro-
ethane ##STR00022## 98.96 DCP Dichloro- propane 1,3- Dichloro-
propane ##STR00023## 112.98 ECH Epichloro- hydrin 1-chloro-
2,3-epoxy- propane ##STR00024## 92.52 TGA Triglycidyl amine
Tris[(2- oxiranyl) methyl] amine ##STR00025## 185.22 BCPOH
Bis(3-chloro- propyl) amine-OH 3-Chloro- 1-(3- chloro- propyl-
amino)-2- ##STR00026## 186.08 propanol BCPEDA Bis(chloro- propyl)
ethylene- diamine 1,2-Bis(3- chloro- propyl- amino) ethane
##STR00027## 213.15
[0238] In some embodiments, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 2b and the crosslinked
polymer is prepared by radical polymerization of an amine
corresponding to Formula 2b:
##STR00028##
[0239] wherein
[0240] m and n are independently non-negative integers;
[0241] each R.sub.12 is independently hydrogen, substituted
hydrocarbyl, or hydrocarbyl;
[0242] R.sub.22 and R.sub.32 are independently hydrogen substituted
hydrocarbyl, or hydrocarbyl;
[0243] R.sub.42 is hydrogen, hydrocarbyl or substituted
hydrocarbyl;
[0244] X.sub.1 is
##STR00029##
[0245] X.sub.2 is alkyl, aminoalkyl, or alkanol;
[0246] each X.sub.13 is independently hydrogen, hydroxy, alicyclic,
amino, aminoalkyl, halogen, alkyl, heteroaryl, boronic acid or
aryl;
[0247] z is a non-negative number, and
[0248] the amine corresponding to Formula 2b comprises at least one
allyl group.
[0249] In one embodiment, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 2b, the crosslinked
polymer is prepared by radical polymerization of an amine
corresponding to Formula 2b, and m and z are independently 0, 1, 2
or 3, and n is 0 or 1.
[0250] In one embodiment, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 2b, the crosslinked
polymer is prepared by radical polymerization of an amine
corresponding to Formula 1, and (i) R.sub.12 or R.sub.42
independently comprise at least one allyl or vinyl moiety, (ii) m
is a positive integer and R.sub.22 comprises at least one allyl or
vinyl moiety, and/or (iii) n is a positive integer and R.sub.32
comprises at least one allyl moiety. For example, in one such
embodiment, m and z are independently 0, 1, 2 or 3 and n is 0 or 1.
For example, in one such embodiment R.sub.12 or R.sub.42, in
combination comprise at least two allyl or vinyl moieties. By way
of further example, in in one such embodiment, m is a positive
integer and R.sub.12, R.sub.22 and R.sub.42, in combination
comprise at least two allyl or vinyl moieties. By way of further
example, in in one such embodiment, n is a positive integer and
R.sub.12, R.sub.32 and R.sub.42, in combination comprise at least
two allyl or vinyl moieties. By way of further example, in in one
such embodiment, m is a positive integer, n is a positive integer
and R.sub.12, R.sub.22, R.sub.32 and R.sub.42, in combination,
comprise at least two allyl or vinyl moieties.
[0251] In one embodiment, the crosslinked polymer comprises the
residue of an amine corresponding to Formula 2b, the crosslinked
polymer is prepared by radical polymerization of an amine
corresponding to Formula 2b, and each R.sub.12 is independently
hydrogen, aminoalkyl, allyl, or vinyl, R.sub.22 and R.sub.32 are
independently hydrogen, alkyl, aminoalkyl, haloalkyl, alkenyl,
alkanol, heteroaryl, alicyclic heterocyclic, or aryl, and R.sub.42
is hydrogen or substituted hydrocarbyl. For example, in one such
embodiment each R.sub.12 is aminoalkyl, allyl or vinyl, R.sub.22
and R.sub.32 are independently hydrogen, alkyl, aminoalkyl,
haloalkyl, alkenyl, or alkanol, and R.sub.42 is hydrogen or
substituted hydrocarbyl. By way of further example, in one such
embodiment each R.sub.12 and R.sub.42 is independently hydrogen,
alkyl, allyl, vinyl, --(CH.sub.2).sub.dNH.sub.2 or
--(CH.sub.2).sub.dN[(CH.sub.2).sub.eNH.sub.2].sub.2 where d and e
are independently 2-4, and R.sub.22 and R.sub.32 are independently
hydrogen or heteroaliphatic.
[0252] Exemplary amines and crosslinkers (or the salts thereof, for
example the hydrochloric acid, phosphoric acid, sulfuric acid, or
hydrobromic acid salts thereof) for the synthesis of polymers
described by Formula 2b include but are not limited to the ones in
Table C.
TABLE-US-00004 TABLE C Abbre- MW viation Common name IUPAC name
(g/mol) DABDA1 Diallylbutyl- diamine 1,4-Bis (allylamino) butane
##STR00030## 241.2 DAEDA1 Diallylethyl- diamine 1,2-Bis
(allylamino) ethane ##STR00031## 213.15 DAEDA2 Diallyldiethyl-
enetriamine 2-(Allylamino)- 1-[2- (allylamino) ethylamino] ethane
##STR00032## 292.67 DAPDA Diallyl- propyl- diamine 1,3-Bis
(allylamino) propane ##STR00033## 227.17 POHDA Diallyl- amine- iso-
propanol 1,3-Bis (allylamino)- 2-propanol ##STR00034## 243.17 AAH
Allylamine 2-Propen- 1-ylamine ##STR00035## 93.5 AEAAH Amino-
ethylallyl- amine 1-(Allyl- amino)-2- amino- ethane ##STR00036##
173.08 BAEAAH Bis(2- aminoethyl) allylamine 1-[N-Allyl (2-amino-
ethyl) amino]-2- amino- ethane ##STR00037## 252.61 TAA Triallyl-
amine N,N,N- triallyl- amine ##STR00038## 137.22
[0253] In some embodiments, the crosslinked polymer is derived from
a reaction of the resulting polymers that utilize monomers
described in any of Formulae 1, 1a, 1b, 1c, 2, 2a and 2b or a
linear polymer comprised of a repeat unit described by Formula 3
with external crosslinkers or pre-existing polymer functionality
that can serve as crosslinking sites. Formula 3 can be a repeat
unit of a copolymer or terpolymer where X.sub.15 is either a
random, alternating, or block copolymer. The repeating unit in
Formula 3 can also represent the repeating unit of a polymer that
is branched, or hyperbranched, wherein the primary branch point can
be from any atom in the main chain of the polymer:
##STR00039##
wherein
[0254] R.sub.15, R.sub.16 and R.sub.17 are independently hydrogen,
hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid
or halo,
[0255] X.sub.1 is
##STR00040##
[0256] X.sub.5 is hydrocarbyl, substituted hydrocarbyl, oxo
(--O--), or amino and
[0257] z is a non-negative number.
[0258] In one embodiment, R.sub.15, R.sub.16 and R.sub.17 are
independently hydrogen, aryl, or heteroaryl, X.sub.5 is
hydrocarbyl, substituted hydrocarbyl, oxo or amino, and m and z are
non-negative integers. In another embodiment, R.sub.15, R.sub.16
and R.sub.17 are independently aliphatic or heteroaliphatic,
X.sub.5 is hydrocarbyl, substituted hydrocarbyl, oxo (--O--) or
amino, and m and z are non-negative integers. In another
embodiment, R.sub.15, R.sub.16 and R.sub.17 are independently
unsaturated aliphatic or unsaturated heteroaliphatic, X.sub.5 is
hydrocarbyl, substituted hydrocarbyl, oxo, or amino, and z is a
non-negative integer. In another embodiment, R.sub.15, R.sub.16 and
R.sub.17 are independently alkyl or heteroalkyl, X.sub.5 is
hydrocarbyl, substituted hydrocarbyl, oxo, or amino, and z is a
non-negative integer. In another embodiment, R.sub.15, R.sub.16 and
R.sub.17 are independently alkylamino, aminoalkyl, hydroxyl, amino,
boronic acid, halo, haloalkyl, alkanol, or ethereal, X.sub.5 is
hydrocarbyl, substituted hydrocarbyl, oxo, or amino, and z is a
non-negative integer. In another embodiment, R.sub.15, R.sub.16 and
R.sub.17 are independently hydrogen, hydrocarbyl, substituted
hydrocarbyl, hydroxyl, amino, boronic acid or halo, X.sub.5 is oxo,
amino, alkylamino, ethereal, alkanol, or haloalkyl, and z is a
non-negative integer.
[0259] Exemplary crosslinking agents that may be used in radical
polymerization reactions include, but are not limited to, one or
more multifunctional crosslinking agents such as:
1,4-bis(allylamino)butane, 1,2-bis(allylamino)ethane,
2-(allylamino)-1-[2-(allylamino)ethylamino]ethane,
1,3-bis(allylamino)propane, 1,3-bis(allylamino)-2-propanol,
triallylamine, diallylamine, divinylbenzene, 1,7-octadiene,
1,6-heptadiene, 1,8-nonadiene, 1,9-decadiene, 1,4-divinyloxybutane,
1,6-hexamethylenebisacrylamide, ethylene bisacrylamide,
N,N'-bis(vinylsulfonylacetyl)ethylene diamine,
1,3-bis(vinylsulfonyl) 2-propanol, vinylsulfone,
N,N'-methylenebisacrylamide polyvinyl ether, polyallylether,
divinylbenzene, 1,4-divinyloxybutane, and combinations thereof.
[0260] Crosslinked polymers derived from the monomers and polymers
in formulas 1 through 3 may be synthesized either in solution or
bulk or in dispersed media. Examples of solvents that are suitable
for the synthesis of polymers of the present disclosure include,
but are not limited to water, low boiling alcohols (methanol,
ethanol, propanol, butanol), dimethylformamide, dimethylsulfoxide,
heptane, chlorobenzene, toluene.
[0261] Alternative polymer processes may include, a lone
polymerization reaction, stepwise addition of individual starting
material monomers via a series of reactions, the stepwise addition
of blocks of monomers, combinations or any other method of
polymerization such as living polymerization, direct
polymerization, indirect polymerization, condensation, radical,
emulsion, precipitation approaches, spray dry polymerization or
using some bulk crosslinking reaction methods and size reduction
processes such as grinding, compressing, extrusion. Processes can
be carried out as a batch, semi-continuous and continuous
processes. For processes in dispersed media, the continuous phase
can be non-polar solvents, such as toluene, benzene, hydrocarbon,
halogenated solvents, super critical carbon dioxide. With a direct
suspension reaction, water can be used and salt can be used to tune
the properties of the suspension.
[0262] The starting molecules described in formulas 1 through 3 may
be copolymerized with one or more other monomers of the invention,
oligomers or other polymerizable groups. Such copolymer
architectures can include, but are not limited to, block or
block-like polymers, graft copolymers, and random copolymers.
Incorporation of monomers described by formulas 1 through 3 can
range from 1% to 99%. In some embodiments, the incorporation of
comonomer is between 20% and 80%.
[0263] Non-limiting examples of comonomers which may be used alone
or in combination include: styrene, allylamine hydrochloride,
substituted allylamine hydrochloride, substituted styrene, alkyl
acrylate, substituted alkyl acrylate, alkyl methacrylate,
substituted alkyl methacrylate, acrylonitrile, methacrylonitrile,
acrylamide, methacrylamide, N-alkylacrylamide,
N-alkylmethacrylamide, N,N-dialkylacrylamide,
N,N-dialkylmethacrylamide, isoprene, butadiene, ethylene, vinyl
acetate, N-vinyl amide, maleic acid derivatives, vinyl ether,
allyle, methallyl monomers and combinations thereof. Functionalized
versions of these monomers may also be used. Additional specific
monomers or comonomers that may be used in this invention include,
but are not limited to, 2-propen-1-ylamine,
1-(allylamino)-2-aminoethane,
1-[N-allyl(2-aminoethyl)amino]-2-aminoethane, methyl methacrylate,
ethyl methacrylate, propyl methacrylate (all isomers), butyl
methacrylate (all isomers), 2-ethylhexyl methacrylate, isobornyl
methacrylate, methacrylic acid, benzyl methacrylate, phenyl
methacrylate, methacrylonitrile, amethylstyrene, methyl acrylate,
ethyl acrylate, propyl acrylate (all isomers), butyl acrylate (all
isomers), 2-ethylhexyl acrylate, isobornyl acrylate, acrylic acid,
benzyl acrylate, phenyl acrylate, acrylonitrile, styrene, glycidyl
methacrylate, 2-hydroxyethyl methacrylate, hydroxypropyl
methacrylate (all isomers), hydroxybutyl methacrylate (all
isomers), N,N-dimethylaminoethyl methacrylate,
N,N-diethylaminoethyl methacrylate, triethyleneglycol methacrylate,
itaconic anhydride, itaconic acid, glycidyl acrylate,
2-hydroxyethyl acrylate, hydroxypropyl acrylate (all isomers),
hydroxybutyl acrylate (all isomers), N,N-dimethylaminoethyl
acrylate, N,N-diethylaminoethyl acrylate, triethyleneglycol
acrylate, methacrylamide, N-methylacrylamide,
N,N-dimethylacrylamide, N-tert-butylmethacrylamide,
N--N-butylmethacrylamide, N-methylolmethacrylamide,
N-ethylolmethacrylamide, N-tert-butylacryl amide,
N-Nbutylacrylamide, N-methylolacrylamide, N-ethylolacrylamide,
4-acryloylmorpholine, vinyl benzoic acid (all isomers),
diethylaminostyrene (all isomers), a-methylvinyl benzoic acid (all
isomers), diethylamino a-methylstyrene (all isomers),
p-vinylbenzene sulfonic acid, p-vinylbenzene sulfonic sodium salt,
trimethoxysilylpropyl methacrylate, triethoxysilylpropyl
methacrylate, tributoxysilylpropyl methacrylate,
dimethoxymethylsilylpropyl methacrylate, diethoxymethylsilylpropyl
methacrylate, dibutoxymethylsilylpropyl methacrylate,
diisopropoxymethylsilylpropyl methacrylate, dimethoxysilylpropyl
methacrylate, diethoxysilylpropyl methacrylate, dibutoxysilylpropyl
methacrylate, diisopropoxysilylpropyl methacrylate,
trimethoxysilylpropyl acrylate, triethoxysilylpropyl acrylate,
tributoxysilylpropyl acrylate, dimethoxymethylsilylpropyl acrylate,
diethoxymethylsilylpropyl acrylate, dibutoxymethylsilylpropyl
acrylate, diisopropoxymethylsilylpropyl acrylate,
dimethoxysilylpropyl acrylate, diethoxysilylpropyl acrylate,
dibutoxysilylpropyl acrylate, diisopropoxysilylpropyl acrylate,
maleic anhydride, N-phenylmaleimide, N-butylmaleimide,
N-vinylformamide, N-vinyl acetamide, allylamine, methallylamine,
allylalcohol, methyl-vinylether, ethylvinylether, butylvinyltether,
butadiene, isoprene, chloroprene, ethylene, vinyl acetate, and
combinations thereof.
[0264] Additional modification to the preformed crosslinked polymer
can be achieved through the addition of modifiers, including but
not limited to amine monomers, additional crosslinkers, and
polymers. Modification can be accomplished through covalent or
non-covalent methods. These modifications can be evenly or unevenly
dispersed throughout the preformed polymer material, including
modifications biased to the surface of the preformed crosslinked
polymer. Furthermore, modifications can be made to change the
physical properties of the preformed crosslinked polymer, including
but not limited to reactions that occur with remaining reactive
groups such as haloalkyl groups and allyl groups in the preformed
polymer. Reactions and modifications to the preformed crosslinked
polymer can include but are not limited to acid-base reactions,
nucleophilic substitution reactions, Michael reactions,
non-covalent electrostatic interactions, hydrophobic interactions,
physical interactions (crosslinking) and radical reactions.
[0265] In one embodiment, the post-polymerization crosslinked amine
polymer is a crosslinked amine polymer comprising a structure
corresponding to Formula 4:
##STR00041##
wherein each R is independently hydrogen or an ethylene crosslink
between two nitrogen atoms of the crosslinked amine polymer
##STR00042##
and a, b, c, and m are integers. Typically, m is a large integer
indicating an extended polymer network. In one such embodiment, a
ratio of the sum of a and b to c (i.e., a+b:c) is in the range of
about 1:1 to 5:1. For example, in one such embodiment a ratio of
the sum of a and b to c (i.e., a+b:c) is in the range of about
1.5:1 to 4:1. By way of further example, in one such embodiment a
ratio of the sum of a and b to c (i.e., a+b:c) is in the range of
about 1.75:1 to 3:1. For example, in one such embodiment a ratio of
the sum of a and b is 57, c is 24 and m is large integer indicating
an extended polymer network. In each of the foregoing embodiments a
ratio of the sum of a and b to c (i.e., a+b:c) may be in the range
of about 2:1 to 2.5:1. For example, in such embodiments the ratio
of the sum of a and b to c (i.e., a+b:c) may be in the range of
about 2.1:1 to 2.2:1. By way of further example, in such
embodiments the ratio of the sum of a and b to c (i.e., a+b:c) may
be in the range of about 2.2:1 to 2.3:1. By way of further example,
in such embodiments the ratio of the sum of a and b to c (i.e.,
a+b:c) may be in the range of about 2.3:1 to 2.4:1. By way of
further example, in such embodiments the ratio of the sum of a and
b to c (i.e., a+b:c) may be in the range of about 2.4:1 to 2.5:1.
In each of the foregoing embodiments, each R may independently be
hydrogen or an ethylene crosslink between two nitrogen atoms.
Typically, however, 35-95% of the R substituents will be hydrogen
and 5-65% will be an ethylene crosslink
##STR00043##
For example, in one such embodiment, 50-95% of the R substituents
will be hydrogen and 5-50% will be an ethylene crosslink
##STR00044##
For example, in one such embodiment 55-90% of the R substituents
are hydrogen and 10-45% are an ethylene crosslink
##STR00045##
By way of further example, in one such embodiment, 60-90% of the R
substituents are hydrogen and 10-40% are an ethylene crosslink. By
way of further example, in one such embodiment, 65-90% of the R
substituents are hydrogen and 10-35% are an ethylene crosslink.
##STR00046##
By way of further example, in one such embodiment, 70-90% of the R
substituents are hydrogen and 10-30% are an ethylene crosslink. By
way of further example, in one such embodiment, 75-85% of the R
substituents are hydrogen and 15-25% are an ethylene crosslink. By
way of further example, in one such embodiment, 65-75% of the R
substituents are hydrogen and 25-35% are an ethylene crosslink. By
way of further example, in one such embodiment, 55-65% of the R
substituents are hydrogen and 35-45% are an ethylene crosslink. In
some embodiments, a, b, c and R are such that the carbon to
nitrogen ratio of the polymer of Formula 4 may range from about 2:1
to about 6:1, respectively. For example, in one such embodiment,
the carbon to nitrogen ratio of the polymer of Formula 4 may range
from about 2.5:1 to about 5:1, respectively. By way of further
example, in one such embodiment, the carbon to nitrogen ratio of
the polymer of Formula 4 may range from about 3:1 to about 4.5:1,
respectively. By way of further example, in one such embodiment,
the carbon to nitrogen ratio of the polymer of Formula 4 may range
from about 3.25:1 to about 4.25:1, respectively. By way of further
example, in one such embodiment, the carbon to nitrogen ratio of
the polymer of Formula 4 may range from about 3.4:1 to about 4:1,
respectively. By way of further example, in one such embodiment,
the carbon to nitrogen ratio of the polymer of Formula 4 may range
from about 3.5:1 to about 3.9:1, respectively. By way of further
example, in one such embodiment, the carbon to nitrogen ratio of
the polymer of Formula 4 may range from about 3.55:1 to about
3.85:1, respectively. In each of the foregoing embodiments recited
in this paragraph, the polymer of Formula 4 is derived from
monomers and crosslinkers, each of which comprise less than 5 wt %
oxygen.
[0266] In certain embodiments, polymers in which crosslinking
and/or entanglement were increased were found to have lower
swelling than those with lower crosslinking and/or entanglement,
yet also had a binding capacity for target ion (e.g., chloride)
that was as great as or greater than the lower crosslinking and/or
entanglement polymers while binding of interfering ions such as
phosphate were significantly reduced. The selectivity effect may be
introduced in two different manners: 1) Overall capacity was
sacrificed for chloride specificity. Crosslinkers that don't
include chloride binding sites (e.g., epichlorohydrin) allow for
increased crosslinking while overall capacity is decreased
proportional to the amount of crosslinker incorporated into the
polymer. 2) Overall capacity is preserved for chloride specificity:
Crosslinkers that include chloride binding sites (e.g.,
diallylamines) allow for increased crosslinking while overall
capacity is staying the same or is reduced by only a small
amount.
[0267] As previously noted, crosslinked polymers having a high
capacity for chloride binding and high selectivity for chloride
over other competing anions such as phosphate may be prepared in a
two-step process in accordance with one embodiment of the present
disclosure. In general, the selectivity of the polymer is a
function of its crosslinking density and the capacity of the
polymer is a function of the free amine density of the crosslinked
polymer. Advantageously, the two-step process disclosed herein
provides both, high capacity for chloride binding, and high
selectivity for chloride over other competing ions by relying
primarily upon carbon-carbon crosslinking in the first step, and
nitrogen-nitrogen crosslinking in the second step.
[0268] In the first step, the crosslinking is preferably
capacity-sparing, i.e., free amine sparing, crosslinking from
carbon to carbon. In the second step, the crosslinking is
amine-consuming and is directed towards tuning for selectivity.
Based on the desired high capacity, the C--N ratio is preferably
optimized to maximize amine functionalities for HCl binding, while
still maintaining a spherical polymer particle of controlled
particle size to ensure nonabsorption and acceptable mouth feel
that is stable under GI conditions. The preferred extent of
carbon-carbon crosslinking achieved after the first step is
sufficient to permit the resulting bead to swell between 4.times.
and 6.times. in water (i.e., a Swelling Ratio of 4 to 6).
[0269] In one embodiment, crosslinked polymers having a high
capacity for chloride binding and high selectivity for chloride
over other competing anions such as phosphate may be prepared in a
two-step process, and the product of the first polymerization step
is preferably in the form of beads whose diameter is controlled in
the 5 to 1000 micromer range, preferably 10 to 500 micrometers and
most preferred 40-180 micrometers.
[0270] The product of the first polymerization step is preferably
in the form of beads whose Swelling Ratio in water is between 2 and
10, more preferably about 3 to about 8, and most preferably about 4
to about 6.
[0271] Additionally, if the crosslinked polymer beads resulting
from the first polymerization step are protonated, this may reduce
the amount of nitrogen-nitrogen crosslinking in the second
crosslinking step. Accordingly, in certain embodiments the
preformed amine polymer is at least partially deprotonated by
treatment with a base, preferably a strong base such as a hydroxide
base. For example, in one embodiment the base may be NaOH, KOH,
NH.sub.4OH, NaHCO.sub.3, Na.sub.2CO.sub.3, K.sub.2CO.sub.3, LiGH,
Li.sub.2CO.sub.3, CsOH or other metal hydroxides. If the charges
are removed from the preformed crosslinked amine polymer bead by
deprotonation, the bead will tend to collapse and the crosslinking
agent used in the second step may not be able to access binding
sites on the polymer unless the bead is prevented from collapsing.
One means of preventing the crosslinked polymer bead from
collapsing is the use of a swelling agent such as water to swell
the bead, thereby allowing the second-step crosslinker to access
binding sites.
[0272] The preformed polymer may be crosslinked to form the
post-polymerization crosslinked polymer using any of a range of
crosslinking compounds containing at least two amine-reactive
functional groups. In one such embodiment, the crosslinker is a
compound containing at least two amine-reactive groups selected
from the group consisting of halides, epoxides, phosgene,
anhydrides, carbamates, carbonates, isocyanates, thioisocyanates,
esters, activated esters, carboxylic acids and derivatives thereof,
sulfonates and derivatives thereof, acyl halides, aziridines,
.alpha.,.beta.-unsaturated carbonyls, ketones, aldehydes, and
pentafluoroaryl groups. The crosslinker may be, for example, any of
the crosslinkers disclosed herein, including a crosslinker selected
from Table B. By way of further example, in one such embodiment the
crosslinker is a dihalide such as a dichloroalkane.
[0273] As noted above, in certain embodiments a swelling agent for
the preformed amine polymer may be included in the reaction mixture
for the second polymerization step along with the crosslinking
agent. In general, the swelling agent and the crosslinking agent
may be miscible or immiscible and the swelling agent may be any
composition or combination of compositions that have the capacity
to swell the preformed amine polymer. Exemplary swelling agents
include polar solvents such as water, methanol, ethanol,
n-propanol, isopropanol, n-butanol, formic acid, acetic acid,
acetonitrile, dimethylformamide, dimethylsulfoxide, nitromethane,
propylene carbonate, or a combination thereof. Additionally, the
amount of swelling agent included in the reaction mixture will
typically be less than absorption capacity of the preformed amine
polymer for the swelling agent. For example, it is generally
preferred that the weight ratio of swelling agent to preformed
polymer in the reaction mixture be less than 4:1. By way of further
example, in some embodiments the weight ratio of swelling agent to
preformed polymer in the reaction mixture will be less than 3:1. By
way of further example, in some embodiments the weight ratio of
swelling agent to preformed polymer in the reaction mixture will be
less than 2:1. By way of further example, in some embodiments the
weight ratio of swelling agent to preformed polymer in the reaction
mixture will be less than 1:1. By way of further example, in some
embodiments the weight ratio of swelling agent to preformed polymer
in the reaction mixture will be less than 0.5:1. By way of further
example, in some embodiments the weight ratio of swelling agent to
preformed polymer in the reaction mixture will be less than 0.4:1.
By way of further example, in some embodiments the weight ratio of
swelling agent to preformed polymer in the reaction mixture will be
less than 0.3:1. In general, however, the weight ratio of swelling
agent to preformed polymer in the reaction mixture will typically
be at least 0.05:1, respectively.
[0274] In general, the crosslinked polymers may be crosslinked
homopolymers or crosslinked copolymers comprising free amine
moieties. The free amine moieties may be separated, for example, by
the same or varying lengths of repeating linker (or intervening)
units. In some embodiments, the polymers comprise repeat units
containing an amine moiety and an intervening linker unit. In other
embodiments, multiple amine-containing repeat units are separated
by one or more linker units. Additionally, the polyfunctional
crosslinkers may comprise HCl binding functional groups, e.g.,
amines, ("active crosslinkers") or may lack HCl binding functional
groups such as amines ("passive crosslinkers").
[0275] In a preferred embodiment, the first polymerization
(crosslinking) step yields preformed amine polymer beads having a
target size and chloride binding capacity. For example, in one such
embodiment the beads have a chloride binding capacity of at least
10 mmol/g in Simulated Gastric Fluid ("SGF") and a Swelling Ratio
in the range of 1 to 6. The resulting preformed amine polymer is
then preferably (at least partially) deprotonated with a base and
combined with a non-protonating swelling agent to swell the free
amine polymer without protonating the amine functions. Furthermore,
the amount of the non-protonating swelling agent is selected to
tune the subsequent degree of crosslinking effectively forming a
template that is then locked into place via the amine consuming
crosslinking step. In the second crosslinking step, the swollen,
deprotonated preformed amine polymer is crosslinked with a
crosslinker containing amine reactive moieties to form a
post-polymerization crosslinked polymer.
[0276] In general, selectivity for chloride over other competing
ions is achieved with highly crosslinked polymers. For example,
relatively high chloride binding capacity maybe be attained by
reacting a preformed amine polymer bead with neat crosslinker in
the presence of a swelling agent (water). While this
"non-dispersed" reaction provides access to high selectivity for
chloride over competing ions in the SIB assay, it also results in
macroscopically (and microscopically) aggregated polymer beads.
Accordingly, it is advantageous to include a solvent (e.g.,
heptane) in the second crosslinking step to disperse the preformed
crosslinked polymer beads so as to avoid inter-bead reactions and
resulting aggregation. The use of too much solvent (dispersant),
however, can dilute the reaction solution to the point where the
resulting bead is not sufficiently crosslinked to have the desired
selectivity for chloride over other competing anions. By using a
crosslinking agent that also functions as a solvent (dispersant),
however, sufficient solvent (dispersant) may be included in the
reaction mixture to avoid inter-bead reactions and aggregation
without diluting the mixture to the point where the degree of
amine-consuming crosslinking is insufficient. For example, in an
effort to utilize the dispersing properties of a solvent (to avoid
aggregation during the reaction) while maintaining reactivity, DCE
and DCP were used neat, thus performing a dual purpose role, as
both solvent (dispersant) and crosslinker. Interestingly, DCE was
discovered to have excellent dispersal properties as a solvent,
when compared to similar reactions with DCP and/or heptane.
Additionally, less aggregation was observed when the beads were
first dispersed in DCE and then in a second operation, the water is
added to swell the beads. If water is added to the preformed amine
polymer before the bead is dispersed in the DCE, aggregation may
occur.
[0277] The use of 1,2-dichloroethane ("DCE") as the crosslinking
solvent also generates HCl molecules during the second step. These
HCl molecules protonate some of the free amine sites which block
the reaction sites for the crosslinking reaction and thereby limit
the number of binding sites available for crosslinking.
Consequently, the use of DCE creates a self-limiting effect on the
secondary crosslinking.
[0278] In each of the foregoing embodiments, the reaction mixture
may contain a wide range of amounts of crosslinking agents. For
example, in one embodiment the crosslinker may be used in large
excess relative to the amount of preformed amine polymer in the
reaction mixtures. Stated differently, in such embodiments the
crosslinking agent is a crosslinking solvent, i.e., it is both a
solvent for the reaction mixture and a crosslinking agent for the
preformed amine polymer. In such embodiments, other solvents may
optionally be included in the reaction mixture but are not
required. Alternatively, the preformed amine polymer, swelling
agent and crosslinker may be dispersed in a solvent that is
miscible with the crosslinker and immiscible with the swelling
agent. For example, in some embodiments the swelling agent may be a
polar solvent; in some such embodiments, for example, the swelling
agent may comprise water, methanol, ethanol, n-propanol,
isopropanol, formic acid, acetic acid, acetonitrile,
N,N-dimethylformamide, dimethylsulfoxide, nitromethane, or a
combination thereof. By way of further example, when the swelling
agent comprises a polar solvent, the solvent system for the
reaction mixture will typically comprise a non-polar solvent such
as pentane, cyclopentane, hexane, cyclohexane, benzene, toluene,
1,4-dioxane, chloroform, diethyl ether, dichloromethane,
dichloroethane, dichloropropane, dichlorobutane, or a combination
thereof. In certain embodiments, the crosslinker and the solvent
may be the same; i.e., the solvent is a crosslinking solvent such
as 1,2-dichloroethane, 1,3-dichloropropane, 1,4-dichlorobutane or a
combination thereof.
[0279] It is notable that in a crosslinking solvent (e.g., a
DCE-dispersed reaction), there is a large excess of crosslinker
regardless of the amount of crosslinking solvent (e.g., DCE) used
to disperse the bead (e.g., both 1 g:3 mL::bead:DCE and 1 g:10
mL::bead:DCE are a large excess of crosslinker, most of which is
not consumed during the reaction). Despite this, the relative
degree of crosslinking, and the performance in SIB assay, are
unaffected by changes in the ratio of reactive crosslinker to
polymer bead. This is possible because the reaction is limited by
the acid-neutralizing capacity of the polymer bead, rather than the
amount of crosslinker (e.g., DCE).
[0280] To more efficiently react with DCE or other crosslinker, the
amines of the preformed polymer bead preferably have a free
electron pair (neutral, deprotonated). As the free amines of the
preformed polymer bead react with the crosslinker (e.g., DCE), HCl
is produced and the amines become protonated, thus limiting the
reaction. For this reason, the preformed amine polymer beads
preferably start as the free amine in the second crosslinking step.
If the preformed amine polymer bead is protonated after the first
step of carbon-carbon crosslinking, amine-consuming crosslinking in
the second step will be limited, thus reducing the desired
selectivity for chloride over other competing ions. This has been
demonstrated by adding known quantities of HCl to preformed amine
polymer beads immediately before second step crosslinking with DCE
(TABLE 7). When less than 3 mol % HCl (to amine in preformed
polymer amine bead) is added prior to second step crosslinking,
total chloride capacity (SGF) and chloride selectivity in SIB are
similar to beads not treated with HCl in the second step. When
greater than 5 mol % HCl (to amine in preformed polymer amine bead)
is added prior to second step crosslinking, total chloride capacity
(SGF) increases and chloride selectivity in SIB decreases,
indicating lower incorporation of crosslinker.
[0281] The benefits of deprotonated preformed polymer beads in the
second step crosslinking highlights the advantages of using two
steps to achieve the final product. In the first step, to form the
amine polymer bead, all monomers (e.g., allylamine and DAPDA) are
protonated to remain in the aqueous phase and to avoid the radical
transfer reactions that severely limit the polymerization of
non-protonated allylamine (and derivatives). Once the bead is
formed through carbon-carbon crosslinks, the bead can then be
deprotonated and further crosslinked with an amine reactive
crosslinker in a second step.
[0282] Given the large excess of dual crosslinker/solvent,
mono-incorporation of this reagent can occur leading to alkyl
chloride functional groups on the crosslinked polymer bead that are
hydrophobic in nature and can increase non-specific interactions
with undesirable solutes other than HCl that are more hydrophobic
in nature. Washing with ammonium hydroxide solution converts the
alkyl-chloride to alkyl-amine functions that are hydrophilic and
minimize non-specific interactions with undesirable solutes. Other
modifications that yield more hydrophilic groups than alkyl
chloride such as --OH are suitable to quench mono-incorporated
crosslinker/solvent.
[0283] Any of a range of polymerization chemistries may be employed
in the first reaction step, provided that the crosslinking
mechanism is primarily carbon-carbon crosslinking. Thus, in one
exemplary embodiment, the first reaction step comprises radical
polymerization. In such reactions, the amine monomer will typically
be a mono-functional vinyl, allyl, or acrylamide (e.g., allylamine)
and crosslinkers will have two or more vinyl, allyl or acrylamide
functionalities (e.g., diallylamine). Concurrent polymerization and
crosslinking occurs through radically initiated polymerization of a
mixture of the mono- and multifunctional allylamines. The resulting
polymer network is thusly crosslinked through the carbon backbone.
Each crosslinking reaction forms a carbon-carbon bond (as opposed
to substitution reactions in which a carbon-heteroatom bond is
formed during crosslinking). During the concurrent polymerization
and crosslinking, the amine functionalities of the monomers do not
undergo crosslinking reactions and are preserved in the final
polymer (i.e., primary amines remain primary, secondary amines
remain secondary, and tertiary amines remain tertiary).
[0284] In those embodiments in which the first reaction step
comprises radical polymerization, a wide range of initiators may be
used including cationic and radical initiators. Some examples of
suitable initiators that may be used include: the free radical
peroxy and azo type compounds, such as azodiisobutyronitrile,
azodiisovaleronitrile, dimethylazodiisobutyrate, 2,2'azo
bis(isobutyronitrile),
2,2'-azobis(N,N'-dimethyl-eneisobutyramidine)dihydrochloride,
2,2'-azobis(2-amidinopropane)dihydrochloride,
2,2'-azobis(N,N'-dimethyleneisobutyramidine), 1,1'-azo
bis(I-cyclohexanecarbo-nitrile), 4,4'-azobis(4-cyanopentanoic
acid), 2,2'-azobis(isobutyramide)dihydrate,
2,2'-azobis(2-methylpropane), 2,2'-azobis(2-methylbutyronitrile),
VAZO 67, cyanopentanoic acid, the peroxypivalates, dodecylbenzene
peroxide, benzoyl peroxide, di-t-butyl hydroperoxide, t-butyl
peracetate, acetyl peroxide, dicumyl peroxide, cumylhydroperoxide,
dimethyl bis(butylperoxy)hexane.
[0285] Exemplary amine-containing polymers as described above are
more fully disclosed and exemplified in WO2016/094685 A1 and
WO2014/197725 A1, the entire contents of which are incorporated
herein by reference. Any polymer disclosed in these references
might be used in the present invention as a nonabsorbable
composition. Any of the methods of synthesis disclosed in these
references might be used to make polymers useful as nonabsorbable
compositions in the present invention.
[0286] In one embodiment, the pharmaceutical composition comprises
a mixture of any of the previously-identified nonabsorbable
materials. For example, in one embodiment the pharmaceutical
composition comprises a mixture of a cation exchange composition
with at least one anion exchange composition, amphoteric ion
exchange composition, or neutral composition having the capacity to
bind both protons and anions. In another embodiment, the
pharmaceutical composition comprises a mixture of an anion exchange
composition with at least one cation exchange composition,
amphoteric ion exchange composition, or neutral composition having
the capacity to bind both protons and anions. In yet another
embodiment, the pharmaceutical composition comprises a mixture of a
neutral composition having the capacity to bind both protons and
anions with at least one cation exchange composition, amphoteric
ion exchange composition, or anion exchange composition.
[0287] As schematically depicted in FIGS. 1A-1C and in accordance
with one embodiment, a nonabsorbable free-amine polymer of the
present disclosure is orally ingested and used to treat metabolic
acidosis (including by increasing serum bicarbonate and normalizing
blood pH) in a mammal by binding HCl in the gastrointestinal ("GI")
tract and removing HCl through the feces. Free-amine polymer is
taken orally (FIG. 1A) at compliance enhancing dose targeted to
chronically bind sufficient amounts of HCl to enable clinically
meaningful increase in serum bicarbonate of 3 mEq/L. In the stomach
(FIG. 1B), free amine becomes protonated by binding H.sup.+.
Positive charge on polymer is then available to bind Cl.sup.-; by
controlling access of binding sites through crosslinking and
hydrophilicity/hydrophobicity properties, other larger organic
anions (e.g., acetate, propionate, butyrate, etc., depicted as
X.sup.- and Y.sup.-) are bound to a lesser degree, if at all. The
net effect is therefore binding of HCl. In the lower GI tract/colon
(FIG. 1C), Cl.sup.- is not fully released and HCl is removed from
the body through regular bowel movement and fecal excretion,
resulting in net alkalinization in the serum. Cl.sup.- bound in
this fashion is not available for exchange via the
Cl.sup.-/HCO.sub.3.sup.- antiporter system.
[0288] In one embodiment, the polymer is designed to simultaneously
maximize efficacy (net HCl binding and excretion) and minimize GI
side effects (through low swelling particle design and particle
size distribution). Optimized HCl binding may be accomplished
through a careful balance of capacity (number of amine binding
sites), selectivity (preferred binding of chloride versus other
anions, in particular organic anions in the colon) and retention
(not releasing significant amounts of chloride in the lower GI
tract to avoid the activity of the Cl.sup.-/HCO.sub.3.sup.-
exchanger [antiporter] in the colon and intestine; if chloride is
not tightly bound to the polymer the Cl.sup.-/HCO.sub.3.sup.-
exchanger can mediate uptake of chloride ion from the intestinal
lumen and reciprocal exchange for bicarbonate from the serum, thus
effectively decreasing serum bicarbonate.
[0289] Competing anions that displace chloride lead to a decrease
in net bicarbonate through the following mechanisms. First,
displacement of chloride from the polymer in the GI lumen,
particularly the colon lumen, provides for a facile exchange with
bicarbonate in the serum. The colon has an anion exchanger
(chloride/bicarbonate antiporter) that moves chloride from the
luminal side in exchange for secreted bicarbonate. When free
chloride is released from the polymer in the GI tract it will
exchange for bicarbonate, which will then be lost in the stool and
cause a reduction in total extracellular bicarbonate (Davis, 1983;
D'Agostino, 1953). The binding of short chain fatty acids (SCFA) in
exchange for bound chloride on the polymer, will result in the
depletion of extracellular HCO.sub.3.sup.- stores. Short chain
fatty acids are the product of bacterial metabolism of complex
carbohydrates that are not catabolized by normal digestive
processes (Chemlarova, 2007). Short chain fatty acids that reach
the colon are absorbed and distributed to various tissues, with the
common metabolic fate being the generation of H.sub.2O and
CO.sub.2, which is converted to bicarbonate equivalents. Thus,
binding of SCFA to the polymer to neutralize the proton charge
would be detrimental to overall bicarbonate stores and buffering
capacity, necessitating the design of chemical and physical
features in the polymer that limit SCFA exchange. Finally,
phosphate binding to the polymer should be limited as well, since
phosphate represents an additional source of buffering capacity in
the situation where ammoniagenesis and/or hydrogen ion secretion is
compromised in chronic renal disease.
[0290] For each binding of proton, an anion is preferably bound as
the positive charge seeks to leave the human body as a neutral
polymer. "Binding" of an ion, is more than minimal binding, i.e.,
at least about 0.2 mmol of ion/g of polymer, at least about 1 mmol
of ion/g of polymer in some embodiments, at least about 1.5 mmol of
ion/g of polymer in some embodiments, at least about 3 mmol of
ion/g of polymer in some embodiments, at least about 5 mmol of
ion/g of polymer in some embodiments, at least about 10 mmol of
ion/g of polymer in some embodiments, at least about 12 mmol of
ion/g of polymer in some embodiments, at least about 13 mmol of
ion/g of polymer in some embodiments, or even at least about 14
mmol of ion/g of polymer in some embodiments. In one embodiment,
the polymers are characterized by their high capacity of proton
binding while at the same time providing selectivity for anions;
selectivity for chloride is accomplished by reducing the binding of
interfering anions that include but are not limited to phosphate,
citrate, acetate, bile acids and fatty acids. For example, in some
embodiments, polymers of the present disclosure bind phosphate with
a binding capacity of less than about 5 mmol/g, less than about 4
mmol/g, less than about 3 mmol/g, less than about 2 mmol/g or even
less than about 1 mmol/g. In some embodiments, polymers of the
invention bind bile and fatty acids with a binding capacity of less
than about less than about 5 mmol/g, less than about 4 mmol/g, less
than about 3 mmol/g, less than about 2 mmol/g, less than about 1
mmol/g in some embodiments, less than about 0.5 mmol/g in some
embodiments, less than about 0.3 mmol/g in some embodiments, and
less than about 0.1 mmol/g in some embodiments.
[0291] Pharmaceutical Compositions & Administration
[0292] In general, the dosage levels of the nonabsorbable
compositions for therapeutic and/or prophylactic uses may range
from about 0.5 g/day to about 100 g/day. To facilitate patient
compliance, it is generally preferred that the dose be in the range
of about 1 g/day to about 50 g/day. For example, in one such
embodiment, the dose will be about 2 g/day to about 25 g/day. By
way of further example, in one such embodiment, the dose will be
about 3 g/day to about 25 g/day. By way of further example, in one
such embodiment, the dose will be about 4 g/day to about 25 g/day.
By way of further example, in one such embodiment, the dose will be
about 5 g/day to about 25 g/day. By way of further example, in one
such embodiment, the dose will be about 2.5 g/day to about 20
g/day. By way of further example, in one such embodiment, the dose
will be about 2.5 g/day to about 15 g/day. By way of further
example, in one such embodiment, the dose will be about 1 g/day to
about 10 g/day. Optionally, the daily dose may be administered as a
single dose (i.e., one time a day), or divided into multiple doses
(e.g., two, three or more doses) over the course of a day. In
general, the nonabsorbable compositions may be administered as a
fixed daily dose or titrated based on the serum bicarbonate values
of the patient in need of treatment or other indicators of
acidosis. The titration may occur at the onset of treatment or
throughout, as required, and starting and maintenance dosage levels
may differ from patient to patient based on severity of the
underlying disease.
[0293] The effectiveness of the nonabsorbable composition may be
established in animal models, or in human volunteers and patients.
In addition, in vitro, ex vivo and in vivo approaches are useful to
establish HCl binding. In vitro binding solutions can be used to
measure the binding capacity for proton, chloride and other ions at
different pHs. Ex vivo extracts, such as the gastrointestinal lumen
contents from human volunteers or from model animals can be used
for similar purposes. The selectivity of binding and/or retaining
certain ions preferentially over others can also be demonstrated in
such in vitro and ex vivo solutions. In vivo models of metabolic
acidosis can be used to test the effectiveness of the nonabsorbable
composition in normalizing acid/base balance--for example 5/6
nephrectomized rats fed casein-containing chow (as described in
Phisitkul S, Hacker C, Simoni J, Tran R M, Wesson D E. Dietary
protein causes a decline in the glomerular filtration rate of the
remnant kidney mediated by metabolic acidosis and endothelin
receptors. Kidney international. 2008; 73(2):192-9), or adenine-fed
rats (Terai K, K Mizukami and M Okada. 2008. Comparison of chronic
renal failure rats and modification of the preparation protocol as
a hyperphosphatemia model. Nephrol. 13: 139-146).
[0294] In one embodiment, the nonabsorbable compositions are
provided (by oral administration) to an animal, including a human,
in a dosing regimen of one, two or even multiple (i.e., at least
three) doses per day to treat an acid-base disorder (e.g.,
metabolic acidosis) and achieve a clinically significant and
sustained increase of serum bicarbonate as previously described.
For example, in one embodiment a daily dose of the nonabsorbable
composition (whether orally administered in a single dose or
multiple doses over the course of the day) has sufficient capacity
to remove at least 5 mmol of protons, chloride ions or each per
day. By way of further example, in one such embodiment a daily dose
of the nonabsorbable composition has sufficient capacity to remove
at least 10 mmol of protons, chloride ions or each per day. By way
of further example, in one such embodiment a daily dose of the
nonabsorbable composition has sufficient capacity to remove at
least 20 mmol of protons, the conjugate base of a strong acid
(e.g., Cl.sup.-, HSO.sub.4.sup.- and SO.sub.4.sup.2-) and/or a
strong acid (e.g., HCl or H.sub.2SO.sub.4) each per day. By way of
further example, in one such embodiment a daily dose of the
nonabsorbable composition has sufficient capacity to remove at
least 30 mmol of protons, the conjugate base of a strong acid,
and/or a strong acid each per day. By way of further example, in
one such embodiment a daily dose of the nonabsorbable composition
has sufficient capacity to remove at least 40 mmol of protons, the
conjugate base of a strong acid, and/or a strong acid each per day.
By way of further example, in one such embodiment a daily dose of
the nonabsorbable composition has sufficient capacity to remove at
least 50 mmol of protons, the conjugate base of a strong acid,
and/or a strong acid each per day.
[0295] The dosage unit form of the pharmaceutical comprising the
nonabsorbable composition may be any form appropriate for oral
administration. Such dosage unit forms include powders, tablets,
pills, lozenges, sachets, cachets, elixirs, suspensions, syrups,
soft or hard gelatin capsules, and the like. In one embodiment, the
pharmaceutical composition comprises only the nonabsorbable
composition. Alternatively, the pharmaceutical composition may
comprise a carrier, a diluent, or excipient in addition to the
nonabsorbable composition. Examples of carriers, excipients, and
diluents that may be used in these formulations as well as others,
include foods, drinks, lactose, dextrose, sucrose, sorbitol,
mannitol, starches, gum acacia, alginates, tragacanth, gelatin,
calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, methyl cellulose, methylhydroxybenzoates,
propylhydroxybenzoates, propylhydroxybenzoates, and talc.
Pharmaceutical excipients useful in the pharmaceutical compositions
further include a binder, such as microcrystalline cellulose,
colloidal silica and combinations thereof (Prosolv 90), carbopol,
providone and xanthan gum; a flavoring agent, such as sucrose,
mannitol, xylitol, maltodextrin, fructose, or sorbitol; a
lubricant, such as magnesium stearate, stearic acid, sodium stearyl
fumurate and vegetable based fatty acids; and, optionally, a
disintegrant, such as croscarmellose sodium, gellan gum,
low-substituted hydroxypropyl ether of cellulose, sodium starch
glycolate. Other additives may include plasticizers, pigments,
talc, and the like. Such additives and other suitable ingredients
are well-known in the art; see, e.g., Gennaro A R (ed), Remington's
Pharmaceutical Sciences, 20th Edition.
[0296] In one embodiment, the nonabsorbable composition may be
co-administered with other active pharmaceutical agents depending
on the condition being treated. This co-administration may include
simultaneous administration of the two agents in the same dosage
form, simultaneous administration in separate dosage forms, and
separate administration. For example, for the treatment of
metabolic acidosis, the nonabsorbable composition may be
co-administered with common treatments that are required to treat
underlying co-morbidities including but not limited to edema,
hypertension, diabetes, obesity, heart failure and complications of
Chronic Kidney Disease. These medications and the nonabsorbable
composition can be formulated together in the same dosage form and
administered simultaneously as long as they do not display any
clinically significant drug-drug-interactions. Alternatively, these
treatments and the nonabsorbable composition may be separately and
sequentially administered with the administration of one being
followed by the administration of the other.
[0297] In one embodiment, the daily dose of the chronic metabolic
acidosis treatment is compliance enhancing (approximately 15 g or
less per day) and achieves a clinically significant and sustained
increase of serum bicarbonate of approximately 3 mEq/L at these
daily doses. The non-absorbed nature of the polymer and the lack of
sodium load and/or introduction of other deleterious ions for such
an oral drug enable for the first time a safe, chronic treatment of
metabolic acidosis without worsening blood pressure/hypertension
and/or without causing increased fluid retention and fluid
overload. Another benefit is further slowing of the progression of
kidney disease and time to onset of lifelong renal replacement
therapy (End Stage Renal Disease "ESRD" including 3 times a week
dialysis) or need for kidney transplants. Both are associated with
significant mortality, low quality of life and significant burden
to healthcare systems around the world. In the United States alone,
approximately 20% of the 400,000 ESRD patients die and 100,000 new
patients start dialysis every year.
[0298] Having described the invention in detail, it will be
apparent that modifications and variations are possible without
departing the scope of the invention defined in the appended
claims. Furthermore, it should be appreciated that all examples in
the present disclosure are provided as non-limiting examples.
Exemplary Synthetic Approaches for the Preparation of Nonabsorbed
Polymers for the Treatment of Acid-Base Imbalance (Reproduced from
WO2016/094685 A1)
[0299] Exemplary Synthesis A
[0300] Step 1: Two aqueous stock solutions of monomer (50% w/w)
were prepared by independently dissolving 43.83 g allylamine
hydrochloride and 45.60 g diallylpropyldiamine ("DAPDA") in water.
A 3-neck, 2 L round bottom flask with four side baffles equipped
with an overhead stirrer (stirring at 180 rpm), Dean-Stark
apparatus and condenser, and nitrogen inlet, was charged with 12 g
surfactant (Stepan Sulfonic 100) dissolved in 1,200 g of a
heptane/chlorobenzene solution (26/74 v/v), followed by the aqueous
stock solutions, and an additional portion of water (59.14 g). In a
separate vessel, a 15 wt % solution of initiator
2,2'-azobis(2-methylpropionamidine)-dihydrochloride ("V-50") (9.08
g) in water was prepared. The two mixtures were independently
sparged with nitrogen while the reaction vessel was brought to
67.degree. C. in an oil bath (approximately 30 min). Under inert
atmosphere, the initiator solution was added to the reaction
mixture, and subsequently heated at 67.degree. C. for 16 hours. A
second aliquot of initiator solution (equal to the first) and the
reaction mixture, were sparged with nitrogen for 30 minutes and
combined before increasing the temperature to 115.degree. C. for a
final dehydration step (Dean-Stark). The reaction was held at
115.degree. C. until water stopped collecting in the Dean-Stark
trap (6 h, 235 mL removed, >90% of total water,
T.sub.internal>99.degree. C.). The reaction was allowed to cool
to room temperature, and the stirring stopped to allow the beads to
settle. The organic phase was removed from the bead cake by
decanting. The beads were purified by washing (MeOH two times,
H.sub.2O once, 1N HCl two times, H.sub.2O once, 1N NaOH three
times, and then H.sub.2O until the pH of solution after washing was
7) and dried by lyophilization.
[0301] Step 2: Dry preformed amine polymer beads (15.00 g) prepared
in accordance with Step 1 were added to a 250 mL round bottom flask
equipped with a stir paddle and nitrogen gas inlet. To the beads
was added 1,2-dichloroethane (DCE) (90 mL, resulting in a 1:6 bead
to DCE (g/mL) ratio). The beads were dispersed in the DCE using
mechanical agitation (.about.150 rpm stirring). Water (3.75 mL,
resulting in a 0.25:1 water to bead mass ratio) was added directly
to the dispersion, and stirring was continued for 30 minutes. After
30 minutes, the flask was immersed into an oil bath held at
70.degree. C. The reaction was held in the oil bath and agitated
using mechanical stirring under a nitrogen atmosphere for 16 hours.
Methanol (100 mL) was added to the reaction and, solvent was
removed by decanting. The beads were then filtered, and then
purified by washing (MeOH two times, H.sub.2O once, 1N HCl two
times, H.sub.2O once, 1N NaOH three times, and then H.sub.2O until
the pH of solution after washing was 7). The purified beads were
then dried by lyophilization for 48 hours. Swelling ratio, particle
size, chloride binding capacity in SGF and chloride binding
capacity (SIB-Cl) and phosphate binding capacity (SIB-P) in SIB are
presented in Table S-1 for the resulting polymers.
TABLE-US-00005 TABLE S-1 Binding (mmol/g Particle Size dry weight)
Water: Swell- (microns) SIB- SIB- Unique ID Bead ing D10 D50 D90
SGF Cl P Averaged -- 5.0 79 129 209 13.9 2.0 6.0 from 019069- A1 FA
pooled batch* 030008- 0.00 1.9 NM NM NM 11.8 2.4 4.0 A1 FA 019070-
0.05 1.5 64 99 155 11.1 2.4 3.5 A1 FA 019070- 0.15 1.1 64 97 147
11.0 3.3 2.5 A2 FA 019070- 0.25 1.2 63 102 168 10.4 4.4 1.4 A3 FA
019070- 0.35 0.7 59 91 140 10.7 4.5 1.3 A4 FA 019070- 0.45 1.6 63
105 184 11.1 3.7 2.5 A5 FA *Averaged data from 4 batches of
preformed polyamine bead
[0302] Exemplary Syntheses B-E
[0303] Step 1 Exemplary Synthesis B: To a 500 mL round bottom
flask, polyallylamine (14 g, 15 kDa), and water (28 mL) were added.
The solution was purged with nitrogen and stirred overhead at 220
rpm for 1 hour to completely dissolve the polymer. Next, 30 wt %
aqueous NaOH (7 mL) was added and stirred for 5 minutes. A premade
solution of DCE (175 mL), n-heptane (105 mL), and Span 80 (2.8 g)
was added to the aqueous solution. The solution was heated to
70.degree. C. and stirred for 16 hours. The Dean-Stark step was
initiated by adding cyclohexane (100 mL) and heating the reaction
to 95.degree. C. to remove the water (>90%) from the beads.
Swelling ratio, chloride binding capacity in SGF and chloride
binding capacity (SIB-Cl) and phosphate binding capacity (SIB-P) in
SIB are presented in Table S-2 (entries 018013-A1 FA and 015026-A1
FA) for the resulting polymer with SGF, SIB-Cl and SIB-P values
expressed in mmol/g dry bead.
[0304] Step 1 Exemplary Synthesis C: To a 100 mL round bottom
flask, DCP (31 mL), n-heptane (19 mL), and Span 80 (0.5 g) were
added. A separate aqueous stock solution of polyallylamine (2.3 g,
900 kDa), Aq NaOH (1 mL, 30 wt %), and water (4 mL) was prepared.
The aqueous stock solution was added to the organic solution in the
round bottom flask. The solution was purged with nitrogen for 15
minutes, heated to 70.degree. C., and stirred for 16 hours.
Methanol (30 mL) was added to the reaction mixture and the organic
solvent removed by decanting. The resulting beads were purified and
isolated by washing the beads using, MeOH, HCl, aqueous sodium
hydroxide, and water. The beads were dried using lyophilization
techniques. Swelling ratio, chloride binding capacity in SGF and
chloride binding capacity (SIB-Cl) and phosphate binding capacity
(SIB-P) in SIB are presented in Table S-2 (018001-A2b FA) for the
resulting polymer with SGF, SIB-Cl and SIB-P values expressed in
mmol/g dry bead.
[0305] Step 1 Exemplary Synthesis D: Polyallylamine 15 kDa (3.0 g)
and water (9.05 g) were dissolved in a conical flask. Sodium
hydroxide (0.71 g) was added to the solution and the mixture was
stirred for 30 minutes. To a 100 mL round bottom flask, equipped
side arm and overhead stirrer was added 0.38 g of sorbitan
sesquioleate and 37.9 g of toluene. The overhead stirrer was
switched on to provide agitation to the reaction solution.
Dichloropropanol (0.41 g) was added directly to the polyallylamine
solution while stirring. The resulting aqueous polyallylamine
solution was added to the toluene solution in the 100 mL flask. The
reaction was heated to 50.degree. C. for 16 hours. After this time,
the reaction was heated to 80.degree. C. for 1 hour and then cooled
to room temperature. The resulting beads were purified and isolated
by washing the beads using, MeOH, HCl, aqueous sodium hydroxide,
and water. The beads were dried using lyophilization techniques.
Swelling ratio, chloride binding capacity in SGF and chloride
binding capacity (SIB-Cl) and phosphate binding capacity (SIB-P) in
SIB are presented in Table S-2 (entries 002054-A3 FA and 011021-A6
FA) for the resulting polymer with SGF, SIB-Cl and SIB-P values
expressed in mmol/g dry bead.
[0306] Step 1 Exemplary Synthesis E: Polyallylamine 15 kDa (3.1 g)
and water (9.35 g) were dissolved in a conical flask. Sodium
hydroxide (0.73 g) was added to the solution and the mixture was
stirred for 30 minutes. To a 100 mL round bottom flask, equipped
side arm and overhead stirrer was added 0.31 g of sorbitan
trioleate and 39.25 g of toluene. The overhead stirrer was switched
on to provide agitation to the reaction solution. The aqueous
polyallylamine solution was added to the toluene solution in the
100 mL flask. Epichlorohydrin (0.30 g) was added directly to the
reaction mixture using a syringe. The reaction was heated to
50.degree. C. for 16 hours. After this time the reaction was heated
to 80.degree. C. for 1 hour and then cooled to room temperature.
The resulting beads were purified and isolated by washing the beads
using, MeOH, HCl, aqueous sodium hydroxide, and water. The beads
were dried using lyophilization techniques. Swelling ratio,
chloride binding capacity in SGF and chloride binding capacity
(SIB-Cl) and phosphate binding capacity (SIB-P) in SIB are
presented in Table S-2 (entries 002050-A1 FA and 002050-A2 FA) for
the resulting polymer with SGF, SIB-Cl and SIB-P values expressed
in mmol/g dry bead.
TABLE-US-00006 TABLE S-2 Binding (mmol/g dry weight) Unique ID
Crosslinker Swelling SGF SIB-Cl SIB-P 018013-A1 FA DCE 6.1 16.9 2.2
7.3 015026-A1 FA DCE 5.9 16.6 2.0 7.2 018001-A2b FA DCP 4.6 15.9
1.9 7.1 002054-A3 FA DC2OH 6.5 14.3 1.6 7.1 011021-A6 FA DC2OH 3.0
14.3 1.5 6.1 002050-A1 FA ECH 8.3 14.4 1.7 7.0 002050-A2 FA ECH 8.8
14.2 1.6 7.1
[0307] Step 1 polymers selected from Exemplary Synthesis B and D
were subjected to Step 2 crosslinking according to the following
general procedure. Dry preformed amine polymer beads were added to
a reactor vessel equipped with a stir paddle and nitrogen gas
inlet. To the beads was added 1,2-dichloroethane (DCE). The beads
were dispersed in the DCE using mechanical agitation. Water was
added directly to the dispersion, and stirring was continued. The
flask was immersed into an oil bath held at a chosen temperature.
The reaction was held in the oil bath and agitated using mechanical
stirring under a nitrogen atmosphere for a chosen amount of time.
Methanol was added to the reaction and, solvent was removed by
decanting. The beads were then filtered, and then purified by
washing. Swelling ratio, chloride binding capacity in SGF and
chloride binding capacity (SIB-Cl) and phosphate binding capacity
(SIB-P) in SIB are presented in Table S-3.
TABLE-US-00007 TABLE S-3 Preformed Binding (mmol/ amine Step 1 g
dry weight) Unique ID polymer xlinker Swelling SGF SIB-Cl SIB-P
018022-A2 FA 018013-A1 FA DOE 1.7 14.9 4.0 4.6 015032-A1 FA
015026-A1 FA DOE 1.4 13.2 6.1 1.5 015032-B2 FA 015026-A1 FA DOE 1.2
13.0 6.1 1.5 002064-B4 FA 002054-A3 FA DC2OH 3.1 12.1 1.7 5.6
002064-B5 FA 002054-A3 FA DC2OH 2.7 12.3 1.7 5.5
[0308] Exemplary Synthesis F
[0309] Step 2 Exemplary Synthesis F: Dry preformed amine polymer
beads (3.00 g) (prepared as described in Step 1 of Exemplary
Synthesis A) were added to a 100 mL round bottom flask equipped
with a stir paddle and nitrogen gas inlet. To the beads was added
DCP (4.30 mL) and DCE (13.70 mL), resulting in a 1:6 bead to DCE
mass/volume ratio). The beads were dispersed in the DCE using
mechanical agitation (.about.150 rpm stirring). Water (3.00 mL,
resulting in a 1:1 water to bead mass ratio) was added directly to
the dispersion, and stirring was continued for 30 minutes. After 30
minutes, the flask was immersed into an oil bath held at 70.degree.
C. The reaction was held in the oil bath and agitated using
mechanical stirring under a nitrogen atmosphere for 16 hours.
Methanol (60 mL) was added to the reaction and, solvent was removed
by decanting. The beads were then filtered, and then purified by
washing (MeOH two times, H.sub.2O once, 1N HCl two times, H.sub.2O
once, 1N NaOH three times, and then H.sub.2O until the pH of
solution after washing was 7). The purified beads were then dried
by lyophilization for 48. Swelling ratio, chloride binding capacity
in SGF and chloride binding capacity (SIB-Cl) and phosphate binding
capacity (SIB-P) in SIB are presented in Table S-4.
TABLE-US-00008 TABLE S-4 Binding (mmol/g dry Vol % weight) Unique
ID DCE Swelling SGF SIB-Cl SIB-P 019031-B1 FA 100 1.1 11.3 5.2 1.3
019031-B2 FA 92 1.0 11.2 5.2 1.4 019031-B3 FA 84 0.9 11.3 4.9 1.7
019031-B4 FA 76 1.0 11.3 4.8 1.8 019031-B5 FA 68 1.0 11.4 4.6 1.9
019031-B6 FA 0 1.1 11.2 3.1 3.5
[0310] Exemplary Synthesis G:
[0311] Polyallylamine hydrochloride is dissolved in water. Sodium
hydroxide is added to partially deprotonate the polyallylamine
hydrochloride (preferably 50 mol %). The aqueous phase generated
has a water content (by weight) 2.42 times the weight of the
polyallylamine hydrochloride. A baffled 3 necked flask, equipped
with an overhead mechanical stirrer, nitrogen inlet, Dean Stark
apparatus with condenser is set up to conduct the suspension
reaction. A dichloroethane heptane mixture is prepared, such that
there is 3 times by weight dichloroethane to heptane. This
dichloroethane, heptane mixed solvent is added to the baffled 3
neck flask. The aqueous solution is added to the flask, such that
the ratio is 6.4 dichloroethane to one water by volume. The
reaction mixture is stirred and heated to 70.degree. C. for 16
hours. At this point beads are formed. The Dean Stark step is
initiated to remove all the water from the beads, while returning
the dichloromethane and heptane back to the reaction mixture. Once
no more water is removed the reaction mixture is cooled. Water and
sodium hydroxide is added back to the reaction mixture at a ratio
of 0.25 water to polyallylamine and up to 1 equivalent of sodium
hydroxide per chloride on allylamine added (both calculated from
polyallylamine hydrochloride added at the beginning of the
reaction). The reaction is heated for a further 16 hours at
70.degree. C. The reaction is cooled to room temperature. The beads
are purified using a filter frit with the following wash solvents;
methanol, water, aqueous solution of HCl, water, aqueous solution
of sodium hydroxide and 3 water washes or until the filtrate
measures a pH of 7.
Example 1
Efficacy of Trc101 in the Treatment of Acidosis in an
Adenine-Induced Model of Nephropathy in Rats
[0312] The drug substance, TRC101, is a non-absorbed free-flowing
powder composed of low-swelling, spherical beads, approximately 100
micrometers in diameter; each bead is a single crosslinked, high
molecular weight molecule. TRC101 is a highly crosslinked aliphatic
amine polymer that is synthesized by first copolymerizing two
monomers, allylamine hydrochloride and
N,N'-diallyl-1,3-diaminopropane dihydrochloride, followed by
crosslinking the polymer with 1,2-dichloroethane as described in
Exemplary Synthesis A and in WO2016/094685 A1. TRC101 is the
polymer with unique ID 019070-A3 FA in Table S-1 of Exemplary
Synthesis A.
[0313] TRC101 is administered as a free-amine polymer and contains
no counterion. TRC101 is insoluble in aqueous and non-aqueous
solvents. TRC101 has both high proton and chloride binding capacity
and chloride binding selectivity. The high amine content of the
polymer is responsible for the high proton and chloride binding
capacity of TRC101; the polymer's extensive crosslinking provides
size exclusion properties and selectivity over other potential
interfering anions, such as phosphate, citrate, bile acids, and
short-chain and long-chain fatty acids.
[0314] TRC101 was evaluated in vivo in an adenine-induced rat model
of chronic kidney disease (CKD) and metabolic acidosis. The study
was designed in two parts. In both parts, male Sprague-Dawley rats
weighing 260-280 g (10 per group) were first administered adenine
(0.75 wt % in casein diet) for 2 weeks to induce nephropathy. Study
Part 1 investigated the effect of early treatment with TRC101
administered in a casein diet with 0.25 wt % adenine for the 4
weeks following the 2-week nephropathy induction period. In
contrast, study Part 2 assessed the effect of TRC101 administered
after animals had been kept on casein diet with 0.25 wt % adenine
for 5 weeks following the induction period, before the 4-week
TRC101 treatment period was started. The dose levels of TRC101 were
0, 1.5, 3.0, and 4.5 wt % in the diet. Both study parts assessed
the effect of withdrawing TRC101 after the end of the Treatment
Phase with a 2-week Withdrawal Phase, in which TRC101 was
discontinued in the low (1.5 wt %) and high (4.5 wt %) TRC101 dose
groups, while dosing of TRC101 was continued in the mid dose group
(3.0 wt %). All animals received casein diet with 0.25 wt % adenine
during the Withdrawal Phase.
[0315] In both study parts, blood samples were taken from the tail
vein of animals before treatments started and weekly during the
Treatment and Withdrawal Periods for measurement of blood
bicarbonate (SBC) using a HESKA Element POC.TM. blood gas analyzer.
Animals were randomized based on SBC levels at baseline (i.e.,
following adenine induction of nephropathy and before initiation of
the dosing period) so that mean baseline SBC levels were comparable
across all dose groups. In addition, 24-h fecal collections were
performed for the untreated and 4.5 wt % TRC101 groups. Collected
fecal samples were stored at -20.degree. C. before drying in a
lyophilizer for 3 days followed by homogenization with a mortar and
pestle. Anions (Cl, SO.sub.4, and PO.sub.4) were extracted from
lyophilized, homogenized fecal samples by incubating the samples
with NaOH for 18 hours. Sample supernatants were analyzed for by
ion chromatography (IC).
[0316] In Part 1, early treatment with TRC101 resulted in a
significant, dose-dependent increase in SBC in all treated groups,
relative to the untreated controls (FIG. 2; statistical analysis:
2-way ANOVA with Dunnett's multiple comparisons test vs. untreated
group; horizontal dotted lines marked the normal SBC range for male
Sprague-Dawley rates of the same age). In contrast to the control
group, which had a progressive decline in mean SBC due to
adenine-induced renal insufficiency over the 4-week treatment
period, mean SBC levels increased and remained in the normal range
for low, mid and high treatment groups. Upon withdrawal of TRC101,
mean SBC levels fell below the normal range in the low and high
treatment groups and were similar to the untreated controls at the
end of the withdrawal period; whereas, continued treatment with
TRC101 (3.0 wt %) maintained SBC levels within the normal range,
with the mean value significantly higher than that of the untreated
controls.
[0317] Consistent with the results observed on SBC, recovered fecal
samples from animals treated with 4.5 wt % TRC101 in Part 1 of the
study demonstrated a significant 15-fold increase in fecal Cl
relative to untreated controls (FIG. 3). TRC101 also significantly
increased fecal SO.sub.4 and PO.sub.4 excretion, but the effect was
much less (3- and 2-fold increase, respectively, compared to
untreated controls) than that observed for Cl.
[0318] In Part 2 of the study, maintaining rats for a total of 7
weeks on adenine-containing diet prior to the start of the
Treatment Phase resulted in mean baseline SBC values that were
below the normal range in all treatment groups at a mean of
approximately 20 to 21 mEq/L. Treatments with TRC101 resulted in a
significant, dose-dependent increase in SBC in all treated groups,
relative to the untreated controls. At the end of the 4-week
treatment period, mean SBC levels in control animals remained below
the normal range. The mean SBC level at the low dose (1.5 wt %
TRC101) was only marginally below normal range. At the mid (3.0 wt
%) and high (4.5 wt %) doses of TRC101, mean SBC values remained
within the normal range (FIG. 4; 2-way ANOVA with Dunnett's
multiple comparisons test vs. untreated group; horizontal dotted
lines marked the normal SBC range for male Sprague-Dawley rates of
the same age). Similar to the results observed in Part 1 of the
study, withdrawal of TRC101 administration in Part 2 resulted in a
decrease in mean SBC to below the normal range in the low and high
doses treatment groups; whereas, continued treatment with 3.0 wt %
TRC101 maintained mean SBC levels within the normal range (FIG. 5).
The mean SBC level in the 3.0 wt % TRC101 group remained
significantly higher than that of the untreated control group
throughout the study.
[0319] Consistent with the results observed on SBC, recovered fecal
samples from animals treated with 4.5 wt % TRC101 in Part 2 of the
study demonstrated a significant 10-fold increase in fecal Cl
relative to controls, but only a 2-fold increase in fecal SO.sub.4
and PO.sub.4 excretion (FIG. 5).
Example 2
In Vivo Anion Binding of Polymers in a Pig with Normal Renal
Function
[0320] The anion binding capacities of TRC101 (as described in
Example 1) was evaluated in vivo in a female Yorkshire pig with
normal renal function. A comparative experiment was conducted using
the free amine form of bixalomer (approved in Japan), an
anion-binding resin designed to bind phosphate and available
commercially to treat hyperphosphatemia. TRC101 and the free amine
form of bixalomer were each individually sealed in nylon sachets
(with a 64 micrometer mesh size and differentiated for each polymer
by sachet shape), fed to a single pig at a total dose of 2 g for
each polymer (i.e., 10 sachets each), and then the polymers were
recovered from the sachets collected in the feces over a 10-day
period (seven and six sachets were recovered from feces for
bixalomer and TRC101, respectively). Bound anions were extracted
from the polymers by incubating with NaOH for 18 hours. The anion
concentrations in the samples were determined in supernatant by
IC.
[0321] Analysis of the anions bound to the polymers after recovery
from the feces revealed in vivo average binding of 2.62 and 0.50
mEq of chloride, 0.46 and 0.11 mmol of sulfate, and 0.37 and 0.95
mmol of phosphate per gram of TRC101 and bixalomer, respectively
(FIG. 61 statistical analysis unpaired T test; Mean.+-.standard
deviation; N=7 and 6 sachests for Bixalomer and TRC101,
respectively). Therefore, TRC101 removed 5- and 4-fold more
chloride and sulfate, respectively, than bixalomer removed from the
GI tract of the pig. On the other hand, bixalomer, a phosphate
binder, removed 2.5-fold more phosphate than TRC101 removed from
the GI tract of the pig.
Example 3
Efficacy of Trc101 in Subjects with Chronic Kidney Disease and Low
Serum Bicarbonate Levels
[0322] Part 1
[0323] TRC101 (as described in Example 1) was studied in a
double-blind, placebo-controlled, parallel-design, 4-arm, fixed
dose study to evaluate the ability of TRC101 to control serum
bicarbonate (SBC) in human subjects with marked metabolic acidosis.
A total of 101 subjects with chronic kidney disease (CKD) and low
SBC values were randomized into one of the four arms in an
approximately 1:1:1:1 ratio (total daily doses of 3, 6 or 9 g/day
TRC101 or 3 g/day placebo [microcrystalline cellulose],
administered twice daily [BID]).
[0324] Subjects were eligible for inclusion in the study if they
were 18 to 80 years of age, had Stage 3 or 4 CKD (estimated
glomerular filtration rate [eGFR], 20 to <60 mL/min/1.73 m.sup.2
of body surface area) and SBC levels of 12 to 20 mEq/L (inclusive)
at both Screening and study Day -1, had systolic blood pressure
(SBP) at Screening <170 mmHg, had a hemoglobin A1c (HbA1c) value
of s 9.0% and a fasting serum glucose (FSG) value of s 250 mg/dL
(13.9 mmol/L) at Screening. Key exclusion criteria were history of
anuria, dialysis, acute kidney injury, acute renal insufficiency or
>30% increase in serum creatinine or 30% decrease in eGFR in the
past 3 month, severe comorbid conditions (other than CKD) such as
congestive heart failure with maximum New York Heart Association
(NYHA) Class III or IV symptoms, unstable angina or acute coronary
syndrome, dementia, hypertensive urgency or emergency, transient
ischemic attack, stroke, or use of home oxygen during the 6 months
prior to Screening. Other exclusion criteria were serum potassium
values of <3.8 mEq/L or >5.9 mEq/L at Screening, Type 1
diabetes or chronic obstructive pulmonary disease, history or
current diagnosis of heart or kidney transplant, clinically
significant diabetic gastroparesis, bariatric surgery, bowel
obstruction, swallowing disorders, severe gastrointestinal
disorders, severe recurrent diarrhea or severe recurrent
constipation.
[0325] At the time of Screening, subjects who met all the entry
criteria were admitted to the Clinical Research Unit (CRU) on Day
-1 and placed on a study diet controlled for protein, caloric
content, anions, cations and fiber, in accordance with dietary
recommendations for patients with CKD (KDOQI, 2003). The potential
renal acid load (i.e., PRAL value) (Scialla, 2013) was calculated
for the daily meal plans to ensure that the study diet was neither
acidic nor basic; PRAL values for the four daily meal plans ranged
from -1.71 to +1.92 and averaged 0.82. The PRAL is calculated as
follows:
PRAL(mEq/d)=(0.49*protein [g/d])+(0.037*phosphorus
[mg/d])-(0.21*potassium [mg/d])-(0.26*magnesium
[mg/d])-0.013*(calcium [mg/d])
Four detailed meal plans were developed that specified the foods
(including measured quantities) provided at breakfast, lunch,
dinner and two light snacks each day (Table S-5). Care was taken to
ensure the diet closely approximated the subjects' typical diet so
that perturbations in serum bicarbonate related to a sudden change
in diet would be minimized. The dietary sources of protein were
predominantly plant-based. Meat (i.e., pork, fish) was served once
per day on two of the four meal plans. The sites rotated among the
four daily meal plans over the course of the treatment period. The
mean (.+-.standard deviation) serum bicarbonate level in the
placebo group was 17.6 (.+-.1.43) mEq/L at baseline and remained
constant during the 14-day treatment period (17.5[.+-.1.87] mEq/L
at Day 15), demonstrating that the study diet did not change the
level of serum bicarbonate.
TABLE-US-00009 TABLE S-5 Composition of Study Treatment Period Diet
Param- Protein Ca Mg P K Na Fiber eter Calories (g) (mg) (mg) (mg)
(mg) (mg) (g) PRAL Mean 2209.25 52.32 810 232.5 1008.125 2171.375
2249.5 27.022 0.82 Range 2129- 50.6- 778- 210- 991- 2048- 2076-
22.9- -1.71- 2246 53.4 849 235 1060 2277 2370 32.1 +1.92 Ca =
calcium; K = potassium; Mg = magnesium; Na = sodium; P =
phosphate
[0326] Enrolled subjects were randomized to one of three TRC101
doses or placebo on Day -1 and dosing was initiated in the morning
on Day 1 (next day) in accordance with the randomization
assignment. 101 subjects were randomized in an approximately
1:1:1:1 ratio to one of the following groups: Group 1. 3 g/day of
placebo administered in equally divided doses BID (twice daily) for
14 days (n=25); Group 2. 3 g/day of TRC101 administered in equally
divided doses BID for 14 days (n=25); Group 3. 6 g/day of TRC101
administered in equally divided doses BID for 14 days (n=25); Group
4. 9 g/day of TRC101 administered in equally divided doses BID for
14 days (n=26). TRC101 or placebo were administered orally as an
aqueous suspension BID, with breakfast and dinner. The first dose
of study drug was taken with breakfast. One hour prior to the
administration of the study drug, venous blood was drawn for a
pre-dose SBC (contributing to the baseline SBC value) and safety
laboratory measurements. Subjects remained in the CRU and continued
BID dosing with study drug (at breakfast and dinner) for 14 days.
On Day 15, subjects were discharged from the CRU. All subjects who
completed the study had a discharge assessment on Day 15 and
returned to the CRU on Day 17 and Day 21 for AE collection, blood
draws and safety assessments. A subset of patients (n=41) also
returned to the CRU on Day 28 for AE collection, blood draws and
safety assessments.
[0327] No subject was withdrawn early from the study for any
reason. The majority of subjects were male (65%), all subjects were
white, and the median age was 61 years (range: 30 to 79 years).
[0328] Subjects in the study had Stage 3-4 CKD (39% with Stage 4)
with a mean baseline eGFR of 36.4 mL/min/1.73 m.sup.2 (range 19.0
to 66.0 mL/min/1.73 m.sup.2) and metabolic acidosis characterized
by a mean SBC level of 17.6 mEq/L (range 14.1-20.4 mEq/L). At
baseline, 60% of subjects had an SBC value of 12-18 mEq/L and 40%
had an SBC value of >18-20 mEq/L.
[0329] Subjects had baseline comorbidities common in CKD patients
including hypertension (93%), diabetes (73%), left ventricular
hypertrophy (30%), and congestive heart failure (21%). As would be
expected in a CKD Stage 3-4 population, nearly all study subjects
had indications for sodium restriction: hypertension (93%),
congestive heart failure (21%), peripheral edema (15%) and use of
diuretics (41%).
[0330] Over a 2-week treatment period, TRC101 significantly
increased SBC levels in the study population of CKD patients with
baseline SBC levels ranging from 14 to 20 mEq/L. At Day 15, all
three doses tested (3, 6 and 9 g/day TRC101 BID) significantly
(p<0.0001) increased mean SBC levels from baseline and each dose
increased SBC levels to a significantly (p<0.0001) greater
extent than placebo.
[0331] FIG. 7 illustrates the steady increase in mean SBC observed
in all three TRC101 dose groups during the 14-day treatment period
with a mean increase at the end of treatment of approximately 3-4
mEq/L across all three active dose groups. Serum bicarbonate levels
in the placebo group remained essentially unchanged throughout the
study, suggesting that the diet with a controlled protein and
cation/anion content administered in the clinical research unit
matched well with what the subjects ate at home and, therefore, had
no significant impact on their SBC values.
[0332] TRC101 had a rapid onset of action (i.e., statistically
significant increase in mean within group change from baseline in
SBC; p<0.0001) within the first 24-48 hours following the
initiation of treatment for all three TRC101 dose groups combined.
The onset of action for between-group differences (active vs.
placebo) appear to occur between 48-72 hours after the initiation
of treatment with TRC101. At Day 4 (72 hours after the first dose
of TRC101), the mean increase in SBC from baseline for each TRC101
group was 1-2 mEq/L: 3 g/day (p=0.0011); 6 g/day (p=0.0001); 9
g/day (p<0.0001).
[0333] Each of the TRC101 dose groups showed a statistically
significant (p<0.0001) increase from baseline in SBC of
approximately 3-4 mEq/L after 2 weeks of treatment (see Table
1).
TABLE-US-00010 TABLE 1 Change from Baseline in SBC at Day 15 TRC101
TRC101 TRC101 TRC101 Placebo 3g/d BID 6g/d BID 9g/d BID Combined (N
= 25) (N = 25) (N = 25) (N = 26) (N = 76) Baseline n 25 25 25 26 76
Mean (SD) 17.30 18.02 17.77 17.48 17.75 (1.338) (1.009) (1.212)
(1.282) (1.180) Median 17.40 17.90 17.80 17.73 17.83 Min, Max 14.1,
19.6 15.6, 20.4 15.4, 19.9 14.5, 19.2 14.5, 20.4 Day 15 n 25 25 25
26 76 Mean (SD) 17.35 21.08 20.72 21.30 21.04 (1.958) (1.960)
(2.423) (2.977) (2.475) Median 17.00 21.30 20.50 21.45 21.20 Min,
Max 14.1, 21.7 17.3, 24.8 15.4, 25.9 15.1, 27.0 15.1, 27.0 Day 15
Change from Baseline (CFB) n 25 25 25 26 76 Mean (SD) 0.05 (1.955)
3.06 (2.209) 2.95 (2.625) 3.83 (2.372) 3.29 (2.408) Median -0.10
3.55 2.40 3.23 3.07 Min, Max -3.5, 4.6 -1.6, 7.5 -1.5, 8.6 -0.4,
9.2 -1.6, 9.2 Within Group CFB LS Mean (SEM) -0.10 (0.414) 3.21
(0.415) 3.04 (0.414) 3.74 (0.406) 3.33 (0.237) 95% CI of LS Mean
-0.91, 0.71 2.39, 4.02 2.23, 3.85 2.95, 4.54 2.86, 3.80 p-value
0.8109 <.0001 <.0001 <.0001 <.0001 Between Group CFB
Difference (TRC101- Placebo) LS Mean (SEM) NA 3.31 (0.588) 3.14
(0.587) 3.84 (0.579) 3.43 (0.478) 95% CI of LS Mean NA 2.15, 4.46
1.99, 4.29 2.70, 4.98 2.49, 4.37 p-value NA <.0001 <.0001
<.0001 <.0001 Note: baseline serum bicarbonate (SBC) is
defined as an average of two SBC values from samples collected on
Day -1 and at Day 1 pre-dose. Change from baseline (CFB) is defined
as post-baseline value minus baseline value. Note: Least squares
(LS) mean, standard error of LS mean (SEM). 95% CI of LS mean, and
p-values are based on the mixed-effect repeated measures model with
the CFB in SBC value as the dependent variable; treatment (placebo,
3 g/d BID, 6 g/d BID, and 9 g/d BID), time point (Days 2 through
15), and treatment by time point as fixed effects; subject as a
random effect; and baseline estimated glomerular filtration rate
(eGFR) and baseline SBC as continuous covariates. Within-subject
correlations are modeled assuming a first-order autoregressive
covariance structure.
[0334] There appeared to belittle difference inefficacy between the
3 g/day and 6 g/day TRC101 doses, however, subjects in the 9 g/day
TRC101 dose group demonstrated a more rapid and larger increase in
SBC. For example, the mean increases in SBC at Day 8 were 1.82,
2.00, and 2.79 mEq/L in the 3, 6 and 9 g/day TRC101 dose groups
respectively (i.e., -0.8-1.0 mEq/L difference between the 9 g/day
dose group and the other two TRC101 dose groups). At Day 15, the
comparable SBC increases were 3.21, 3.04, and 3.74 mEq/L,
respectively (i.e., .about.0.5-0.7 mEq/L difference between the 9
g/day dose group and the other two TRC101 dose groups) (FIG.
8)).
[0335] Statistically significant between-group (active vs. placebo)
differences in SBC change from baseline to Day 15 ranged from 3.14
to 3.84 mEq/L across the TRC101 treatment groups, with a combined
mean difference of 3.43 mEq/L between TRC101 and placebo
(p<0.0001) (see Table 1).
[0336] As shown in Table 2, after 2 weeks of treatment, SBC levels
increased by .gtoreq.3 mEq/L in over half of subjects (52.6%) in
the combined TRC101 group compared to 8.0% of subjects in the
placebo group (p<0.0001). In addition, 22.4% of all
TRC101-treated subjects had increases in SBC.gtoreq.5 mEq/L
compared to 0 subjects in the placebo group.
TABLE-US-00011 TABLE 2 Change in SBC by Category over Time Subjects
TRC101 TRC101 TRC101 TRC101 with Post Placebo 3 g/d 6 g/d 9 g/d
Combined Baseline SBC N = 25 N = 25 N = 25 N = 26 N = 76 Day 15
Increase from Baseline .gtoreq.2 mEq/L 4 (16.0%) 18 (72.0%) 14
(56.0%) 19 (73.1%) 1 (67.1%) .gtoreq.3 mEq/L 2 (8.0%) 14 (56.0%) 10
(40.0%) 16 (61.5%) 40 (52.6%) .gtoreq.4 mEq/L 1 (4.0%) 8 (32.0%) 10
(40.0%) 11 (42.3%) 29 (38.2%) .gtoreq.5 mEq/L 0 3 (12.0%) 6 (24.0%)
8 (30.8%) 17 (22.4%) .gtoreq.6 mEq/L 0 3 (12.0%) 3 (12.0%) 4
(15.4%) 10 (13.2%) .gtoreq.7 mEq/L 0 1 (4.0%) 2 (8.0%) 2 (7.7%) 5
(6.6%)
[0337] In the combined TRC101 treatment group, 35.5% of subjects
had their SBC corrected into the normal range (22-29 mEq/L) after 2
weeks of treatment, and at the end of the treatment period, 64.5%
of TRC101-treated subjects had SBC levels that were above the upper
limit of the baseline range (>20 mEq/L) (Table 3). The
proportion of subjects achieving an SBC>22 mEq/L was similar in
the 3, 6 and 9 g/day TRC101 dose groups (40.0%, 28.0%, and 38.5%,
respectively). At Day 8 of the treatment period, only about half of
the treatment effect was seen, again suggesting that the SBC
increase has not yet plateaued by the end of the 2-week treatment
period.
TABLE-US-00012 TABLE 3 Change in SBC by Category over Time Subjects
TRC101 TRC101 TRC101 TRC101 with Post Placebo 3 g/d 6 g/d 9 g/d
Combined Baseline SBC N = 25 N = 25 N = 25 N = 26 N = 76 Day 8 SBC
Values >20 mEq/L 3 (12.0%) 9 (36.0%) 7 (28.0%) 12 (46.2%) 28
(36.8%) >22 mEq/L 2 (8.0%) 2 (8.0%) 5 (20.0%) 6 (23.1%) 13
(17.1%) >27 mEq/L 0 0 0 0 0 >29 mEq/L 0 0 0 0 0 Day 15 SBC
Values >20 mEq/L 2 (8.0%) 16 (64.0%) 14 (56.0%) 19 (73.1%) 49
(64.5%) >22 mEq/L 0 10 (40.0%) 7 (28.0%) 10 (38.5%) 27 (35.5%)
>27 mEq/L 0 0 0 0 0 >29 mEq/L 0 0 0 0 0
[0338] The 2-week treatment period in the study was followed by a
2-week follow-up period in which subjects were off treatment. At
the end of the 2-week follow-up period, a withdrawal effect of
approximately 3 mEq/L was observed in the combined TRC101 group,
with SBC levels returning nearly to baseline (FIG. 9). These
results underscore the chronic nature of the underlying metabolic
acidosis in these CKD patients, and suggest that continued
treatment with TRC101 is needed to maintain elevated SBC
levels.
[0339] There were no mean changes in serum parameters (sodium,
calcium, potassium, phosphate, magnesium, low density lipoprotein)
observed in the study that would indicate off-target effects of
TRC101; there were also no mean changes in serum chloride.
[0340] Part 2
[0341] The double-blind, placebo-controlled, parallel-design, fixed
dose study of Part 1 was extended by the introduction of two
additional arms: a total of 34 subjects with chronic (CKD) and low
SBC values were randomized into one of two additional arms: total
daily dose of 6 g/day TRC101 (28 subjects) or 3 g/day placebo (6
subjects) [microcrystalline cellulose], administered once daily
[QD]). All subjects who completed Part 2 of the study had a
discharge assessment on Day 15 and returned to the CRU on Day 17,
Day 21, and Day 28 for AE collection, blood draws and safety
assessments. Part 2 of the study was otherwise unchanged from Part
1.
[0342] Discussion of Part 1 and Part 2 Study Results
[0343] There were no significant differences between the TRC101 and
placebo treatment groups with respect to demographics, baseline
eGFR or serum bicarbonate, or comorbidities (Table 4). Patients had
a mean baseline eGFR of 34.8 mL/min/1.73m2 and a mean baseline
serum bicarbonate level of 17.7 mEq/L. Study participants had
conditions common to CKD patients, including patients with
hypertension (93.3%), diabetes (69.6%), left ventricular
hypertrophy (28.9%), congestive heart failure (21.5%), peripheral
edema (14.1%) and stable diuretic use (42.2%).
[0344] Analysis of the mean serum bicarbonate level in the placebo
group over the course of the in-unit treatment period and
out-patient follow-up period demonstrated that the study diet did
not change the level of serum bicarbonate. The mean (.+-.standard
deviation) serum bicarbonate level in the placebo group was 17.6
(.+-.1.43) mEq/L at baseline and remained constant during the
14-day treatment period (17.5[.+-.1.87] mEq/L at Day 15).
[0345] There was a significant increase in mean serum bicarbonate
in all groups treated with TRC101 within the first 24-48 hours
compared to placebo (FIGS. 10 & 11). Within 72 hours after the
first dose of TRC101, the mean increase in serum bicarbonate from
baseline for each TRC101 group was 1-2 mEq/L
[0346] Over the 2-week treatment period, TRC101 increased serum
bicarbonate values over the respective baseline values for each
group, while placebo-treated patients had no change in serum
bicarbonate (FIGS. 10 & 11). At day 15, the between group
difference of serum bicarbonate versus placebo was 3.31 mEq/L (95%
Cl of LS mean 2.15 to 4.46; p<0.0001), 3.14 mEq/L (95% Cl of LS
mean 1.99 to 4.29; p<0.0001), 3.84 mEq/L (95% Cl of LS mean 2.70
to 4.98; p<0.0001), and 3.72 mEq/L (95% Cl of LS mean 2.70 to
4.74; p<0.0001), for TRC101 dose groups 1.5 g, 3.0 g, 4.5 g BID
and 6 g QD, respectively. By comparison, the placebo within group
change from baseline to day 15 was -0.21 mEq/L (95% Cl of LS mean
-0.91 to 0.49; p=0.56). The mean increase in the combined TRC101
dose groups was 3.57 mEq/L higher than in the placebo group at the
end of the 14-day treatment period (95% Cl of LS mean 2.75 to 4.38;
p<0.0001). At day 15 there was no significant difference in the
mean serum bicarbonate increase when TRC101 was given as a dose of
6.0 g once daily versus 3.0 g twice daily (-0.53 mEq/L; 95% Cl of
LS mean -1.61 to 0.56; p=0.34).
[0347] Treatment with TRC101 caused a steady increase in mean serum
bicarbonate in all TRC101 dose groups during the 14-day treatment
period. The slope of serum bicarbonate increase remained constant,
with no evidence of a plateau at the end of treatment, indicating
that the maximal increase in serum bicarbonate using the study
doses of TRC101 was not established. The change in serum
bicarbonate was similar in all groups treated with TRC101 at the
end of the treatment period (FIGS. 10 & 11).
[0348] After 2 weeks of treatment with TRC101, serum bicarbonate
increased by .gtoreq.3 mEq/L in over half of the patients (51.9%)
in the combined TRC101 dose group, compared to 6.5% of patients in
the placebo group (Table 5). In addition, 38.5% and 22.1% of all
TRC101-treated patients, compared to 3.2% and 0% of placebo-treated
patients, had increases in serum bicarbonate of .gtoreq.4 mEq/L and
.gtoreq.5 mEq/L, respectively.
[0349] At the end of TRC101 treatment, 34.6% of patients in the
combined TRC101 group had a serum bicarbonate in the normal range
(22-29 mEq/L) compared to no patients in the placebo group. At the
end of TRC101 dosing, the proportion of patients with a normal
serum bicarbonate was similar in the four TRC101 dose groups
(40.0%, 28.0%, and 38.5%, 32.1% for 1.5 g BID, 3.0 g BID, 4.5 g
BID, and 6.0 g QD, respectively) while none of the patients in the
placebo group had a normal serum bicarbonate (Table 6).
[0350] At the end of the 2-week, off-treatment, follow-up period, a
decrease in serum bicarbonate of approximately 3.0-3.5 mEq/L from
the end-of-treatment value was observed in all TRC101 dose groups,
with serum bicarbonate levels returning nearly to baseline value in
each respective group (FIGS. 10 & 11).
[0351] In contrast to serum bicarbonate, serum potassium, serum
sodium and serum chloride levels did not significantly change over
the course of the study (FIGS. 13A-13D), yielding a change in the
serum anion gap in excess of 2 mEq/l (FIG. 14) over the course of
the study.
[0352] All 135 randomized patients received TRC101 or placebo daily
for 14 consecutive days and were included in the safety analysis
population. No patients died during the study, or had any adverse
events resulting in treatment discontinuation, and no patients
suffered serious or severe adverse events. Gastrointestinal adverse
events were the most commonly reported events in TRC101-treated
patients, and all events were mild or moderate in severity (Table
7). Diarrhea was the most common adverse event; all diarrhea events
were mild, self-limited, of short duration, and none required
treatment. There were no trends suggesting an off-target effect of
TRC101 on electrolytes (i.e., sodium, potassium, magnesium, calcium
or phosphate). There were also no trends suggesting an effect of
TRC101 on vital signs or ECG intervals. No subject experienced
increases in serum bicarbonate that resulted in metabolic alkalosis
(i.e., serum bicarbonate >29 m Eq/L).
[0353] This two-part, double-blind, placebo-controlled,
parallel-design, 6-arm, fixed dose clinical study demonstrates that
ingestion of TRC101 highly significantly increases serum
bicarbonate level in patients with Stage 3 or 4 CKD and low SBC as
assessed both by change from baseline within group and by
comparisons between active and placebo groups. The rapid onset of
action (within 24-72 hours) and efficacy (>3.0 mEq/L increase in
SBC) observed in the study suggests that TRC101 is an effective
agent in controlling SBC level in the target patient population.
Unlike sodium bicarbonate, TRC101 does not introduce cations, such
as sodium or potassium, which are deleterious to sodium-sensitive
patients with common CKD comorbidities (e.g. hypertension, edema
and heart failure). Therefore, TRC101 is expected to provide a safe
treatment to control SBC in CKD patients with low SBC, including
those who are sodium-sensitive.
TABLE-US-00013 TABLE 4 Baseline demographics, dietary intake, renal
function, serum bicarbonate and co-morbidities TRC101 TRC101 TRC101
TRC101 Placebo 1.5 g 3.0 g 6 g 4.5 g TRC101 Combined BID BID QD BID
Combined Total N = 31 N = 25 N = 25 N = 28 N = 26 N = 104 N = 135
Age.sup.a (years) 65.0 59.0 61.0 65.0 66.0 62.5 63.0 Gender 19
(61.3%)/ 19 (76.0%)/ 17 (68.0%)/ 16 (57.1%)/ 15 (57.7%)/ 68
(65.4%)/ 87 (64.4%)/ (Male/Female) 12 (38.7%) 6 (24.6%) 8 (32.0%)
12 (42.9%) 11 (42.3%) 36 (34.6%) 48 (35.6%) Weight.sup.a, kg 81.0
80.0 84.70 84.2 81.2 83.0 82.0 Average Daily 0.64 0.65 0.61 0.62
0.64 0.63 0.63 Protein Intake.sup.a, g/kg/d Diabetes Mellitus 20
(64.5%)/ 18 (72.0%)/ 20 (80.0%)/ 17 (60.7%)/ 19 (73.1%)/ 74
(71.2%)/ 94 (69.6%)/ (Yes/No) 11 (35.5%) 7 (28.0%) 5 (20.0%) 11
(39.3%) 7 (26.9%) 30 (28.8%) 41 (30.4%) Hypertension 30 (96.8%)/ 24
(96.0%)/ 23 (92.0%)/ 26 (92.9%)/ 23 (88.5%)/ 96 (92.3%)/ 126
(93.3%)/ (Yes/No) 1 (3.2%) 1 (4.0%) 2 (8.0%) 2 (7.1%) 3 (11.5%) 8
(7.7%) 9 (6.7%) Heart Failure 7 (22.6%)/ 5 (20.0%)/ 7 (28.0%)/ 5
(17.9%)/ 5 (19.2%)/ 22 (21.1%)/ 29 (21.5%)/ (Yes/No) 24 (77.4%) 20
(80.0%) 18 (72.0%) 23 (82.1%) 21 (80.8%) 82 (78.9%) 106 (78.5%)
Left Ventricular 8 (25.8%)/ 7 (28.0%)/ 7 (28.0%)/ 8 (28.6%)/ 9
(34.6%)/ 31 (29.8%)/ 39 (28.9%)/ Hypertrophy 23 (74.2%) 18 (72.0%)
18 (72.0%) 20 (71.4%) 17 (65.4%) 73 (70.2%) 96 (71.1%) (Yes/No)
Peripheral Edema 4 (12.9%)/ 3 (12.0%)/ 4 (16.0%)/ 4 (14.3%)/ 4
(15.4%)/ 15 (14.4%)/ 19 (14.1%)/ (Yes/No) 27 (87.1%) 22 (88.0%) 21
(84.0%) 24 (85.7%) 22 (84.6%) 89 (85.6%) 116 (85.9%) SBP.sup.a,
mmHg 128.00 132.00 133.00 130.00 128.50 131.50 130.00 eGFR.sup.a, m
> /min/ 29.0 34.0 35.0 28.0 34.0 33.0 32.0 1.73 m.sup.2
SBC.sup.a, mEq/L 17.6 17.9 17.8 17.7 17.7 17.8 17.7 .sup.amedian
values
TABLE-US-00014 TABLE 5 Proportion of Patients by Serum Bicarbonate
Increase Category at Day 15 Patients with Post-baseline Pooled
TRC101 TRC101 TRC101 TRC101 TRC101 Serum Placebo 1.5 g BID 6 g QD
3.0 g BID 4.5 g BID Combined Bicarbonate N = 1 N = 25 N = 28 N = 25
N = 26 N = 104 .gtoreq.2 mEq/L 4 (12.9%) 18 (72.0%) 23 (82.1%) 14
(56.0%) 19 (73.1%) 74 (71.2%) .gtoreq.3 mEq/L 2 (6.5%) 14 (56.0%)
14 (50.0%) 10 (40.0%) 16 (61.5%) 54 (51.9%) .gtoreq.4 mEq/L 1
(3.2%) 8 (32.0%) 11 (39.3%) 10 (40.0%) 11 (42.3%) 40 (38.5%)
.gtoreq.5 mEq/L 0 3 (12.0%) 6 (21.4%) 6 (24.0%) 8 (30.8%) 23
(22.1%) .gtoreq.6 mEq/L 0 3 (12.0%) 5 (17.9%) 3 (12.0%) 4 (15.4%)
15 (14.4%) .gtoreq.7 mEq/L 0 1 (4.0%) 1 (3.6%) 2 (8.0%) 2 (7.7%) 6
(5.8%)
TABLE-US-00015 TABLE 6 Proportion of Patients by Serum Bicarbonate
Category (Days 8 and 15) Patients with Post-baseline Pooled TRC101
TRC101 TRC101 TRC101 TRC101 Serum Placebo 1.5 g BID 6 g QD 3.0 g
BID 4.5 g BID Combined Bicarbonate N = 31 N = 25 N = 28 N = 25 N =
26 N = 104 Day 8 Serum Bicarbonate Values >20 mEq/L 5 (16.1%) 9
(36.0%) 16 (57.1%) 7 (28.0%) 12 (46.2%) 44 (42.3%) >22 mEq/L 2
(6.5%) 2 (8.0%) 5 (17.9%) 5 (20.0%) 6 (23.1%) 18 (17.3%) >27
mEq/L 0 0 0 0 0 0 >29 mEq/L 0 0 0 0 0 0 Day 15 Serum Bicarbonate
Values >20 mEq/L 2 (6.5%) 16 (64.0%) 17 (60.7%) 14 (56.0%) 19
(73.1%) 69 (66.3%) >22 mEq/L 0 10 (40.0%) 9 (32.1%) 7 (28.0%) 10
(38.5%) 36 (34.6%) >27 mEq/L 0 0 0 0 0 0 >29 mEq/L 0 0 0 0 0
0
TABLE-US-00016 TABLE 7 Treatment-Emergent Adverse Events Occurring
in >5% of Patients in any Treatment Group (Safety Analysis Set)
TRC101 Pooled 1.5 g 6 g 3.0 g 4.5 g TRC101 Study Placebo BID QD BID
BID Combined Total (N = 31) (N = 25) (N = 28) (N = 25) (N = 26) (N
= 104) (N = 135) Preferred Term n (%) n (%) n (%) n (%) n (%) n (%)
n (%) Patients 14 (45.2) 13 (52.0) 17 (60.7) 9 (36.0) 17 (65.4) 56
(53.8) 70 (51.9) reporting any TEAE Diarrhea 4 (12.9) 9 (36.0) 3
(10.7) 3 (12.0) 6 (23.1) 21 (20.2) 25 (18.5) Headache 1 (3.2) 4
(16.0) 1 (3.6) 1 (4.0) 2 (7.7) 8 (7.7) 9 (6.7) Constipation 0 1
(4.0) 3 (10.7) 1 (4.0) 2 (7.7) 7 (6.7) 7 (5.2) Hyperglycemia 0 0 3
(10.7) 2 (8.0) 2 (7.7) 7 (6.7) 7 (5.2) Hypoglycemia 2 (6.5) 2 (8.0)
0 1 (4.0) 2 (7.7) 5 (4.8) 7 (5.2) Hypertension 1 (3.2) 1 (4.0) 2
(7.1) 0 2 (7.7) 5 (4.8) 6 (4.4) Glomerular 2 (6.5) 2 (8.0) 0 1
(4.0) 1 (3.8) 4 (3.8) 6 (4.4) filtration rate decreased Blood
glucose 2 (6.5) 1 (4.0) 1 (3.6) 0 0 2 (1.9) 4 (3.0) increased BID =
twice daily; GFR = glomerular filtration rate; QD = once daily;
TEAE = treatment-emergent adverse event.
* * * * *