Potassium binding agents for treating hypertension and hyperkalemia

Abstract

The present invention relates generally to methods of treating hypertension (HTN) in a patient in need thereof, wherein the patient optionally also has chronic kidney disease (CKD) or type II diabetes mellitus (T2DM). The present invention also relates to a method of treating hyperkalemia in a patient in need thereof, wherein the patient has CKD, T2DM, or HTN and is optionally treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent. The present invention also relates to methods of treating nephropathy in a patient in need thereof, wherein the patient is optionally treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent. The methods may include administering to the patient an effective amount of a potassium binding agent to reduce blood pressure and / or enhance or stabilize renal function in the patient.

Description

[0001] The present application is a divisional application of a patent application filed on October 8, 2013, with application number 201380063003.3 and titled “Potassium binders for treating hypertension and hyperkalemia”. Field of the Invention

[0002] The present invention generally relates to a method for treating hypertension (HTN) in a patient in need thereof, wherein the patient optionally also suffers from chronic kidney disease (CKD) or type II diabetes mellitus (T2DM). The present invention also relates to a method for treating nephropathy in a patient in need thereof, wherein the patient is optionally treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent. The present invention also relates to a method for treating hyperkalemia in a patient in need thereof, wherein the patient suffers from CKD, T2DM or HTN and is optionally treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent. The method may include administering to the patient an effective amount of a potassium binder to reduce the patient's blood pressure and / or enhance or stabilize the patient's renal function. Background of the Invention

[0004] Normal renal function is crucial to the maintenance of potassium homeostasis. The ability of the kidney to maintain potassium homeostasis depends on several factors, including normal aldosterone production, sodium delivery to the distal nephron and sufficient sodium-potassium exchange in the cortical collecting duct (Palmer, BF, N. Engl. J. Med. 2004, 351: 585-92). Among these factors, aldosterone production and action are closely controlled by the renin-angiotensin-aldosterone system (RAAS), which controls the elements of the regulatory components of blood pressure, blood volume and cardiovascular function. Therefore, RAAS inhibition designed to limit aldosterone production and function is an important treatment strategy for hypertension, diabetes, chronic kidney disease and heart failure. Several studies have demonstrated the renoprotective effect of angiotensin receptor blockers (ARBs), such as losartan or irbesartan (Brenner, BM et al., N. Engl. J. Med. 2001, 345:861-869; de Zeeuw, D. et al., Kidney Intl. 2004, 65:2309-2320; Miao, Y. et al., Diabetologia 2010; Lewis, EJ et al., N. Engl. J. Med. 2001, 345:851-860; Atkins, RC et al., Am. J. Kidney Intl. 2004, 65:2309-2320; Dis. 2005, 45: 281-287), while studies using dual blockade of the RAAS, adding an aldosterone antagonist (spironolactone or eplerenone) to angiotensin-converting enzyme inhibitor (ACEI) or ARB therapy have been shown to substantially reduce cardiovascular endpoints in patients with heart failure or post-myocardial infarction (Pitt, B. et al., N. Engl. J. Med. 1999, 341: 709-717; Pitt, B., Molecular & Cellular Endocrinol. 2004, 217: 53-58; Zannad, F. et al., European J. Heart Failure 2010).

[0005] Although the clinical benefits of RAAS inhibitors have been demonstrated, the basic mode of action of the drugs disrupts sodium-potassium exchange in the renal tubules. Therefore, potassium retention can contribute to hyperkalemia, defined as serum potassium values ​​>5.0 mEq / L. This is particularly problematic in patients with renal impairment caused by chronic kidney disease and common comorbidities such as hypertension, diabetes, and heart failure. In this case, the combination of RAAS inhibition and renal impairment can worsen the nascent positive potassium balance and trigger hyperkalemic events. Stopping or reducing the dose of RAAS inhibitors is a common intervention for patients taking RAAS inhibitors who show abnormally elevated serum potassium levels, which cause patients to lose the benefits of RAAS inhibitors. Therefore, it is necessary to control the patient's blood pressure and treat hyperkalemia. SUMMARY OF THE INVENTION

[0007] One aspect of the invention is a method for treating hypertension in a patient in need thereof. The method comprises administering an effective amount of an agent that controls the serum potassium of a patient in need thereof within a normal range. The method comprises administering an effective amount of an agent that controls the serum potassium of a patient in need thereof within a normal range within a two-day treatment period, and particularly for a long period of time, and further for at least 1 month, more particularly at least 3 months, preferably at least 6 months and more preferably at least 9 months. More specifically, the method comprises administering to the patient an effective amount of a potassium binder, such as a cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

[0008] Another aspect of the present invention is a method of treating hypertension in a patient in need thereof, the method comprising administering to a patient suffering from hyperkalemia or proteinuria an effective amount of a potassium binder. When the potassium binder is a polymer, the polymer comprises an aliphatic cross-linked cation exchange polymer and 5 to 15 mol % of the cross-linker of the polymer.

[0009] Yet another aspect of the present invention is a method of treating hypertension in a patient in need thereof, the method comprising administering to a patient suffering from hyperkalemia or proteinuria an effective amount of a potassium binder. When the potassium binder is a polymer, the polymer comprises a cross-linked cation exchange polymer other than a polystyrene cation exchange polymer and comprises 5 mol % to 12 mol % of a cross-linking agent.

[0010] Another aspect is a method of treating hypertension in a chronic kidney disease patient in need thereof. The patient is optionally treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent and the method comprises administering to the patient an effective amount of a potassium binder (e.g., cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form) to control the patient's serum potassium level within a normal range.

[0011] Yet another aspect is a method of treating hypertension in a heart failure patient in need thereof. The patient is optionally treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent and the method comprises administering to the patient an effective amount of a potassium binder (e.g., cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form) to control the patient's serum potassium level within a normal range.

[0012] Yet another aspect is a method of treating hypertension in a type 2 diabetic patient in need thereof. The patient is optionally treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent and the method comprises administering to the patient an effective amount of a potassium binder (e.g., cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form) to control the patient's serum potassium level within a normal range.

[0013] A further aspect is a method of treating hyperkalemia in a chronic kidney disease patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent. The method comprises administering to the patient an effective amount of a potassium binder (e.g., cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form) to enhance or stabilize the patient's renal function by reducing the patient's serum creatinine level compared to the patient's serum creatinine level prior to treatment with the potassium binder (e.g., cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form).

[0014] Another aspect of the invention is a method of treating hyperkalemia in a chronic kidney disease patient in need thereof, the patient being optionally treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent. The method comprises administering to the patient an effective amount of a potassium binder (e.g., cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form) to enhance or stabilize the patient's renal function by increasing the time to progression to end-stage renal disease compared to a chronic kidney disease patient who is optionally treated with a RAAS agent but not treated with a potassium binder.

[0015] Yet another aspect is a method of treating hyperkalemia in a chronic kidney disease patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent. The method comprises administering to the patient an effective amount of a potassium binder (e.g., cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form) to enhance or stabilize the patient's renal function by increasing survival compared to chronic kidney disease patients optionally being treated with a RAAS agent but not being treated with a potassium binder.

[0016] Yet another aspect is a method of treating hyperkalemia in a chronic kidney disease patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent. The method comprises administering to the patient an effective amount of a potassium binder (e.g., cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form) to enhance or stabilize the patient's renal function by increasing or stabilizing the estimated glomerular filtration rate (eGFR) compared to the patient's eGFR prior to treatment with the potassium binder.

[0017] Another aspect is a method of treating chronic kidney disease in a patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent. The method comprises administering to the patient an effective amount of a potassium binder (e.g., cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form) to enhance or stabilize the patient's renal function by reducing the patient's serum creatinine level compared to the patient's serum creatinine level prior to treatment with the potassium binder.

[0018] Yet another aspect is a method of treating chronic kidney disease in a patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent. The method comprises administering to the patient an effective amount of a potassium binder (e.g., cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form) to enhance or stabilize the patient's renal function by increasing the time to progression to end-stage renal disease compared to a chronic kidney disease patient optionally being treated with a RAAS agent but not being treated with a potassium binder.

[0019] Yet another aspect is a method of treating chronic kidney disease in a patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent. The method comprises administering to the patient an effective amount of a potassium binder (e.g., cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form) to enhance or stabilize the patient's renal function by increasing survival compared to chronic kidney disease patients optionally treated with RAAS agents but not treated with potassium binders.

[0020] Another aspect is a method of treating chronic kidney disease in a patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent. The method comprises administering to the patient an effective amount of a potassium binder (e.g., cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form) to enhance or stabilize the patient's renal function by increasing or stabilizing the estimated glomerular filtration rate (eGFR) compared to the patient's eGFR prior to treatment with the potassium binder.

[0021] Other objects and features will in part be apparent and in part pointed out hereinafter. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 Patients who have been treated with the regimen described in Example 2 for 6 months and have any albumin-to-creatinine ratio (ACR), ACR ≥ 30, and ACR > 300 and an estimated glomerular filtration rate (eGFR) of 15-44 mL / min / 1.73 m 2 A graph of central laboratory serum potassium concentrations (mEq / L) versus treatment time for patients with

[0024] Figure 2 Patients who have been treated with the regimen described in Example 2 for 6 months and have any albumin-to-creatinine ratio (ACR), ACR ≥ 30, and ACR > 300 and an estimated glomerular filtration rate (eGFR) of 15-44 mL / min / 1.73 m 2 A graph of systolic blood pressure (SBP) (mmHg) versus treatment time for patients.

[0025] Figure 3 Patients who have been treated with the regimen described in Example 2 for 6 months and have any albumin-to-creatinine ratio (ACR), ACR ≥ 30, and ACR > 300 and an estimated glomerular filtration rate (eGFR) of 15-44 mL / min / 1.73 m 2 A graph of diastolic blood pressure (DBP) (mmHg) versus treatment time for a patient.

[0026] Figure 4 Patients who have been treated with the regimen described in Example 2 for 6 months and have any albumin-to-creatinine ratio (ACR), ACR ≥ 30, and ACR > 300 and an estimated glomerular filtration rate (eGFR) of 15-44 mL / min / 1.73 m 2 A graph of urine ACR (mg / g) versus treatment time for patients.

[0027] Figure 5 Patients who have been treated with the regimen described in Example 2 for 6 months and have any albumin-to-creatinine ratio (ACR), ACR ≥ 30, and ACR > 300 and an estimated glomerular filtration rate (eGFR) of 15-44 mL / min / 1.73 m 2 eGFR (mL / min / 1.73m 2 ) versus treatment time.

[0028] Figure 6A plot of eGFR versus treatment time for a group of patients with pre-existing hyperkalemia who were taking a stable dose of a RAAS inhibitor without a run-in period and were treated for 12 months as described in Example 2. Figure 6-9 , providing data at baseline (BL), 1 month (M1), 2 months (M2), 6 months (M6), and 12 months (M12).

[0029] Figure 7 Serum potassium versus treatment time for a group of patients with pre-existing hyperkalemia taking a stable dose of a RAAS inhibitor without a run-in period who were treated for 12 months as described in Example 2.

[0030] Figure 8 Plot of urine ACR versus treatment time for a group of patients with pre-existing hyperkalemia taking a stable dose of a RAAS inhibitor without a run-in period who were treated for 12 months as described in Example 2.

[0031] Fig. 9 Plots of systolic and diastolic blood pressure versus treatment time for a group of patients with pre-existing hyperkalemia taking a stable dose of a RAAS inhibitor without a run-in period who were treated for 12 months as described in Example 2.

[0032] DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] Hyperkalemia, which can present chronically or acutely, can lead to several medical complications, including life-threatening cardiac arrhythmias and sudden death. Hyperkalemia is generally defined as a serum potassium level, or potassium in the blood, above 5.0 milliequivalents per liter (mEq / L). In independent studies, patients with serum potassium levels greater than or equal to 5.5 mEq / L, which we define as moderate to severe hyperkalemia, were found to have a 10-fold increase in mortality within 24 hours. Hyperkalemia most often develops in patients with chronic kidney disease, or CKD, in whom the kidneys' ability to secrete potassium is already impaired. The normal range for serum potassium levels is approximately 3.8 mEq / l to 5.0 mEq / L.

[0034] Potassium binders can remove potassium from the gastrointestinal tract and reduce serum potassium levels and treat hyperkalemia. Specifically, potassium-binding polymers can remove potassium from the gastrointestinal tract and reduce serum potassium levels (U.S. Pat. No. 7,566,799). Various studies have confirmed that increased serum potassium levels increase aldosterone levels and decreased serum potassium levels reduce aldosterone levels (T. Himathongkam et al., J. Clin. Endocrinol. Metab. 1975, 41 (1): 153-159). These studies have confirmed that small increases or decreases in serum potassium levels can cause larger changes in aldosterone levels. In addition, other studies have confirmed that increased potassium intake can reduce blood pressure (He, FJ et al., Hypertension 2005, 45: 571-574). It has been found and clinically observed that reduced serum potassium levels in patients also reduce blood pressure. Considering that the main expected benefit of potassium-binding polymers is to reduce serum potassium, this finding is unexpected. In patients with renal impairment, hyperkalemia, and hypertension, given that these patients are at significant risk for increased morbidity and mortality, lowering potassium and blood pressure with a potassium-binding polymer may be beneficial. Lowering blood pressure may also be beneficial in patients with hypertension who do not have such comorbidities.

[0035] The potassium binder can be an agent that binds potassium. One class of potassium binders is a potassium binding polymer. Various potassium binding polymers can be used in the methods described herein, including cross-linked cation exchange polymers. The potassium binder can also be a zeolite, such as a zirconium silicate or zirconium germanate molecular sieve.

[0036] The cross-linked cation exchange polymers used in the methods described herein are in the form of generally spherical particles. As used herein, the term "generally" means generally round particles having an average aspect ratio of about 1.0 to about 2.0. The aspect ratio is the ratio of the largest linear dimension of the particle to the smallest linear dimension of the particle. The aspect ratio can be easily determined by one of ordinary skill in the art. This definition includes spherical particles having an aspect ratio of 1.0 by definition.

[0037] The particles may have an average aspect ratio of about 1.0, 1.2, 1.4, 1.6, 1.8 or 2.0. The particles may be round or oval when viewed at a magnification where the field of view is at least 2 times the diameter of the particle.

[0038] The average diameter of the cross-linked cation exchange polymer particles is from about 20 μm to about 200 μm. Specific ranges are the ranges in which the average diameter of the cross-linked cation exchange particles is from about 20 μm to about 200 μm, from about 20 μm to about 150 μm, or from about 20 μm to about 125 μm. Other ranges include from about 35 μm to about 150 μm, from about 35 μm to about 125 μm, or from about 50 μm to about 125 μm. Particle size, including average diameter, distribution, etc., can be determined using techniques known to those skilled in the art. For example, the United States Pharmacopeia (USP) <429> Methods for determining particle size are disclosed.

[0039] The various crosslinked cation exchange polymer particles also have less than about 4% by volume of particles having a diameter less than about 10 μm; in particular, less than about 2% by volume of particles having a diameter less than about 10 μm; more particularly, less than about 1% by volume of particles having a diameter less than about 10 μm; even more particularly, less than about 0.5% by volume of particles having a diameter less than about 10 μm. In other cases, the specific ranges are less than about 4% by volume of particles having a diameter less than about 20 μm; less than about 2% by volume of particles having a diameter less than about 20 μm; less than about 1% by volume of particles having a diameter less than about 20 μm; less than about 0.5% by volume of particles having a diameter less than about 20 μm; less than about 2% by volume of particles having a diameter less than about 30 μm; less than about 1% by volume of particles having a diameter less than about 30 μm; less than about 1% by volume of particles having a diameter less than about 30 μm; less than about 1% by volume of particles having a diameter less than about 40 μm; or less than about 0.5% by volume of particles having a diameter less than about 40 μm.

[0040] The crosslinked cation exchange polymer may have a particle size distribution in which no more than about 5% by volume of the particles have a diameter less than about 30 μm (i.e., D(0.05)<30 μm), no more than about 5% by volume of the particles have a diameter greater than about 250 μm (i.e., D(0.05)>250 μm), and at least about 50% by volume of the particles have a diameter in the range of about 70 to about 150 μm.

[0041] The particle distribution of the crosslinked cation exchange polymer can be described as a span. The span of the particle distribution is defined as (D(0.9)-D(0.1)) / D(0.5), where D(0.9) is the value below which 90% of the particles have a diameter, D(0.1) is the value below which 10% of the particles have a diameter, and D(0.5) is the value above which 50% of the particles have a diameter and below which 50% of the particles have a diameter, as measured by laser diffraction. The span of the particle distribution is typically from about 0.5 to about 1, from about 0.5 to about 0.95, from about 0.5 to about 0.90, or from about 0.5 to about 0.85. The particle size distribution can be measured using the Niro Method No. A8d (revised September 2005), available from GEA Niro, using a Malvern Mastersizer.

[0042] Another desirable property that the crosslinked cation exchange polymer may have is a viscosity when hydrated and deposited of from about 10,000 Pa·s to about 1,000,000 Pa·s, from about 10,000 Pa·s to about 800,000 Pa·s, from about 10,000 Pa·s to about 600,000 Pa·s, from about 10,000 Pa·s to about 500,000 Pa·s, from about 10,000 Pa·s to about 250,000 Pa·s, or from about 10,000 Pa·s to about 150,000 Pa·s, from about 30,000 Pa·s to about 1,000,000 Pa·s, from about 30,000 Pa·s to about 500,000 Pa·s, or from about 30,000 Pa·s to about 150,000 Pa·s, wherein the viscosity is 0.01 sec. -1 The shear rate was measured by mixing the polymer with a slight excess of simulated intestinal fluid (according to USP <26> ), the mixture is allowed to settle at 37° C. for 3 days, and the viscosity is measured on a wet polymer prepared by decanting the free liquid from the settled wet polymer. The steady state shear viscosity of the wet polymer can be determined using a BohlinVOR rheometer (available from Malvern Instruments Ltd., Malvern, UK) or equivalent, using parallel plate geometry (upper plate diameter 15 mm, lower plate diameter 30 mm, gap between plates 1 mm) at a temperature maintained at 37° C.

[0043] The crosslinked cation exchange polymer may also have a hydration and sedimentation yield stress of about 150 Pa to about 4000 Pa, about 150 Pa to about 3000 Pa, about 150 Pa to about 2500 Pa, about 150 Pa to about 1500 Pa, about 150 Pa to about 1000 Pa, about 150 Pa to about 750 Pa, or about 150 Pa to about 500 Pa, about 200 Pa to about 4000 Pa, about 200 Pa to about 2500 Pa, about 200 Pa to about 1000 Pa, or about 200 Pa to about 750 Pa. Dynamic stress sweep measurements (i.e., yield stress) can be performed using a Reologica STRESSTECH rheometer (available from Reologica Instruments AB, Lund, Sweden) or an equivalent method known to those skilled in the art. This rheometer also has a parallel plate geometry (upper plate diameter 15 mm, lower plate diameter 30 mm, gap between plates 1 mm) and the temperature is maintained at 37°C. When the shear stress increases from 1Pa to 10 4 A fixed frequency of 1 Hz and a double integration period can be used for Pa.

[0044] The crosslinked cation exchange polymers used in the methods described herein also have desirable compressibility and bulk density when in dry powder form. Some crosslinked cation exchange polymer particles in dry form have a bulk density of about 0.8 g / cm 3 To about 1.5g / cm 3 , about 0.82g / cm 3 To about 1.5g / cm 3 , about 0.84g / cm 3 To about 1.5g / cm 3 , about 0.86g / cm 3 To about 1.5g / cm 3 , about 0.8g / cm 3 To about 1.2g / cm 3 or about 0.86g / cm 3 To about 1.2g / cm 3 The bulk density of the cross-linked cation exchange polymer is determined by the bulk density of the cross-linked cation exchange polymer. The bulk density affects the volume of the cross-linked cation exchange polymer that needs to be administered to the patient. For example, a higher bulk density means that a smaller volume will provide the same number of grams of the cross-linked cation exchange polymer. This smaller volume can improve patient compliance by making the patient feel that he or she is taking a smaller amount due to the smaller volume.

[0045] The compressibility index of the powder composed of crosslinked cation exchange polymer particles in dry form is about 3 to about 15, about 3 to about 14, about 3 to about 13, about 3 to about 12, about 3 to about 11, about 5 to about 15, about 5 to about 13, or about 5 to about 11. The compressibility index is defined as 100*(TD-BD) / TD, where BD and TD are the bulk density and the tap density, respectively. The procedure for measuring the bulk density and the tap density is described below in Example 3. In addition, the cation exchange polymer in powder form is easier to precipitate into its minimum volume than the polymers commonly used to treat hyperkalemia. This makes the difference between the bulk density and the tap density (the density of the powder measured after tapping a fixed number of times) about 3% to about 14%, about 3% to about 13%, about 3% to about 12%, about 3% to about 11%, about 3% to about 10%, about 5% to about 14%, about 5% to about 12%, or about 5% to about 10% of the bulk density.

[0046] Typically, potassium-binding polymers in particulate form are not absorbed from the gastrointestinal tract. The term "not absorbed" and its grammatical equivalents are not intended to mean that the entire amount of the administered polymer is not absorbed. It is expected that a certain amount of the polymer may be absorbed. In particular, about 90% or more of the polymer is not absorbed, more particularly about 95% or more is not absorbed, more particularly about 97% or more is not absorbed, and most particularly about 98% or more of the polymer is not absorbed.

[0047] The swelling ratio of the potassium binding polymer in a physiological isotonic buffer representative of the gastrointestinal tract is generally about 1 to about 7, specifically about 1 to about 5, more specifically about 1 to about 3, and more specifically, about 1 to about 2.5.

[0048] The swelling ratio of the crosslinked cation exchange polymer can be less than 5, less than about 4, less than about 3, less than about 2.5, or less than about 2. As used herein, "swelling ratio" refers to the grams of solvent absorbed by 1 gram of an otherwise non-solvated crosslinked polymer when in equilibrium in an aqueous environment. When more than one swelling measurement is made for a given polymer, the average of the measurements is taken as the swelling ratio. Polymer swelling can also be calculated by the percentage of weight gain after the otherwise non-solvated crosslinked polymer absorbs the solvent. For example, a swelling ratio of 1 corresponds to 100% polymer swelling.

[0049] The crosslinked cation exchange polymer having a favorable surface morphology is in the form of generally spherical particles having a generally smooth surface. A generally smooth surface is one in which the average distance from peak to valley of a surface feature measured randomly at several different surface features and on several different particles is less than about 2 μm, less than about 1 μm, or less than about 0.5 μm. Typically, the average distance between peaks and valleys of a surface feature is less than about 1 μm.

[0050] Several techniques, including those for measuring roughness, can be used to measure surface morphology. Roughness is a measure of surface texture. It is quantified by the vertical deviations of the actual surface from its ideal form. If these deviations are large, the surface is rough; if the deviations are small, the surface is smooth. Roughness is usually considered to be the high-frequency, short-wavelength component of the measured surface. For example, roughness can be measured using contact or non-contact methods. Contact methods involve dragging a measuring stylus across the surface; these instruments include profilometers and atomic force microscopes (AFMs). Non-contact methods include interferometry, confocal microscopy, capacitance, and electron microscopy. These methods are described in more detail in Chapter 4: Surface Roughness and Microtopography by L. Mattson in Surface Characterization, edited by D. Brune, R. Hellborg, HJ Whitlow, O. Hunderi, Wiley-VCH, 1997.

[0051] For 3D measurements, the probe is controlled to scan over a 2D area on the surface. The spacing between data points in the two directions can be different. In this way, a side view of the surface can be obtained and the relief of the surface can be measured.

[0052] Surface roughness can be controlled in many ways. For example, three methods were determined to prepare poly(α-fluoroacrylate) particles with smoother surfaces. The first method was to include a solvent that was an acceptable solvent for the monomer and polymer product. The second method was to reduce the solvation of the organic phase in the aqueous phase through a salting-out process. The third method was to increase the hydrophobicity of the starting fluoroacrylate monomer.

[0053] The dosing regimen for chronic treatment of hyperkalemia can increase patient compliance, particularly for crosslinked cation exchange polymers that are taken on a gram basis. The present invention also relates to methods for chronic removal of potassium from a mammal in need thereof, particularly methods for chronic treatment of hyperkalemia, by a potassium binder stabilized with a linear polyol, which is a crosslinked aliphatic carboxylic acid polymer and preferably a salt of such a polymer, wherein the polymer is in the form of generally spherical particles.

[0054] Thus, the present invention relates to a method of treating hypertension or hyperkalemia or renal disease in a patient in need thereof, the method comprising administering to the patient an effective amount of a potassium binder. In particular, the present invention relates to a method of treating hypertension and hyperkalemia in a patient in need thereof. In particular, the present invention also relates to a method of treating renal disease and hyperkalemia in a patient in need thereof.

[0055] In the methods described herein, the potassium binding agent may be a cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

[0056] The method of treating hypertension or nephropathy may include long-term administration of a potassium binder. Potassium binders demonstrate long-term tolerability, long-term safety, and / or long-term efficacy in patients. Long-term tolerability, long-term safety, and long-term efficacy are observed over a treatment period of 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 weeks or more. The treatment period may also be 2 years, 3 years, 4 years, 5 years or longer. In particular, the potassium binder may be administered daily to the patient for more than 8 weeks or daily for more than one year.

[0057] Specifically, cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymers in salt or acid form show long-term tolerance, long-term safety and / or long-term efficacy in patients. Long-term tolerance, long-term safety and long-term efficacy are observed in treatment periods of 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 weeks or more. The treatment period can also be 2 years, 3 years, 4 years, 5 years or longer. In particular, cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymers in salt or acid form can be administered daily to patients for more than 8 weeks or daily for more than one year.

[0058] The method of treating hypertension and hyperkalemia can also reduce the patient's systolic blood pressure by 5, 6, 7, 8 mmHg compared to the patient's systolic blood pressure before treatment with the potassium binder, and / or reduce the patient's diastolic blood pressure by 2, 3, 4, 5, 6 mmHg compared to the patient's diastolic blood pressure before treatment with the potassium binder.

[0059] The methods of treating hypertension and hyperkalemia can also reduce the patient's systolic blood pressure by 9, 10, 11, 12, 13, 14, 15, 16, 17 mmHg or more, compared to the patient's systolic blood pressure prior to treatment with the potassium binder, and / or reduce the patient's diastolic blood pressure by 7, 8, 9, 10, 11, 12, 13 mmHg or more, compared to the patient's diastolic blood pressure prior to treatment with the potassium binder.

[0060] The methods of treating hypertension and hyperkalemia may also reduce the patient's systolic blood pressure by at least 6, 7, 8, 9, 10, 11, 12% or more percent compared to the patient's systolic blood pressure prior to treatment with the potassium binder and / or reduce the patient's diastolic blood pressure by at least 8, 9, 10, 11, 12, 13, 14, 15 or more percent compared to the patient's diastolic blood pressure prior to treatment with the potassium binder.

[0061] Potassium binders may be administered to patients whose systolic blood pressure prior to treatment with potassium binders is above 130 mmHg, or ranges from 130 to 220 mmHg, 135 to 200 mmHg, 140 to 200 mmHg, 145 to 200 mmHg, or 150 to 180 mmHg.

[0062] Potassium binders may be administered to patients whose systolic blood pressure prior to treatment with the potassium binder is above 143 mmHg, or ranges from 143 to 200 mmHg, or 143 to 180 mmHg.

[0063] The patient's systolic blood pressure is maintained below 130, 135 or 140 mmHg for at least 90% of the cycles treated with the potassium binder. The patient's diastolic blood pressure is maintained below 80, 85 or 90 mmHg for at least 90% of the cycles treated with the potassium binder.

[0064] A method of treating hypertension may comprise administering an effective amount of a potassium binder to a heart failure patient, a type 2 diabetes patient, and / or a chronic kidney disease patient in need of hypertension treatment, wherein the patient is optionally treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent.

[0065] The method of treating hypertension may be administered to a patient suffering from chronic kidney disease, heart failure, type 2 diabetes, or a combination thereof.

[0066] Potassium binders may be administered to patients who are not treated with an aldosterone antagonist. In particular, the patient is not treated with spironolactone.

[0067] The method of treating hypertension may comprise administering a potassium binder to a patient who does not have another condition causing hypertension, such as type 2 diabetes, chronic kidney disease, chronic heart failure, or a combination thereof. In particular, the patient does not have type 2 diabetes, or the patient does not have chronic kidney disease (CKD).

[0068] A method of treating hypertension may comprise administering a potassium binder to a patient without Class II or Class III heart failure (HF).

[0069] The method of treating hypertension may also include administering a potassium binder to a patient not being treated with a heart failure therapy, which may be an angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), beta blocker (BB), or a combination thereof.

[0070] Patients receiving the treatment methods of the present invention do not need to be treated with antihypertensive agents including diuretics, calcium channel blockers, alpha blockers, nervous system depressants, vasodilators, angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), beta blockers (BB) or combinations thereof.

[0071] The method of treating hypertension of the present invention can be administered to a patient with normal blood pressure. The serum potassium level of a patient with normal blood pressure is 3.5-5.0 mEq / L.

[0072] The present invention relates to a method for treating hyperkalemia in a chronic kidney disease patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent. The method generally comprises administering to the patient an effective amount of a potassium-binding polymer to increase or stabilize the patient's renal function.

[0073] The present invention relates to a method for treating chronic kidney disease in a patient in need thereof, wherein the patient is optionally treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent. The method generally comprises administering to the patient an effective amount of a potassium binding polymer to increase or stabilize the patient's renal function.

[0074] In methods of treating kidney disease, there are several ways in which the methods can show an increase or stabilization of kidney function in a patient, for example, by reducing the patient's serum creatinine level compared to the patient's serum creatinine level before treatment with a potassium binder; increasing the time to progression to end-stage renal disease compared to chronic kidney disease patients optionally treated with a RAAS agent but not treated with a potassium binder; increasing the survival rate compared to chronic kidney disease patients optionally treated with a RAAS agent but not treated with a potassium binder; and / or increasing or stabilizing the estimated glomerular filtration rate (eGFR) compared to the patient's eGFR before treatment with a potassium binder.

[0075] For all of these treatment methods, including methods for treating hypertension, hyperkalemia, chronic kidney disease, end-stage renal disease, etc., the potassium binder can be a potassium binding polymer.

[0076] For purposes of the treatment methods described herein, the potassium binding polymer can be a cross-linked cation exchange polymer.

[0077] For purposes of the treatment methods described herein, the potassium binding polymer can be an aliphatic cross-linked cation exchange polymer.

[0078] For the treatment methods described herein, the potassium binding polymer can be a cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

[0079] For the treatment methods described herein, the potassium binding agent can be zirconium silicate or zirconium germanate molecular sieves.

[0080] For the treatment methods described herein, the potassium binder may be Na 2.19 ZrSi 3.01 O 9.11 ·2.71H2O.

[0081] As described in detail in Example 2, a Phase II clinical study conducted in patients with type 2 diabetes (T2DM) with stage 3 / 4 chronic kidney disease (CKD) was beneficial. All patients were treated with RAAS inhibitors, and approximately 40% of the patients also had heart failure (HF). In addition, the endpoint measured changes from baseline at different time points. The trial was an 8-week, open-label, randomized, dose-ranging study to determine the optimal starting dose of cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form. In addition, the study consisted of a 44-week long-term safety extension component to collect 1-year safety data that will support long-term use of cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form. With a normal serum K of 4.3–5.0 mEq / L + Patients with serum K levels at baseline were enrolled in a run-in period during which they received the maximum labeled dose of losartan and / or additional spironolactone as needed. + Patients with levels >5.0 mEq / L were enrolled without a run-in period ( Figure 6-9 Data from some of these patients are shown in Figure 2. + >5.0 mEq / L), and two potassium strata were selected according to the definition of hyperkalemia and serum potassium cut-off points for ACEI / ARB dose changes in the National Kidney Foundation Kidney Disease Outcomes Quality Initiative Guidelines 11 (KDOQI, 2004) (Stratum 1 = serum K + >5.0-5.5mEq / L; Tier 2 = serum K + >5.5-<6.0mEq / L).

[0082] The Phase II study enrolled a total of 306 subjects with a mean duration of treatment of 9.5 months. All subjects completed the trial, 266 subjects completed 8 weeks, 226 subjects completed 6 weeks and 197 subjects completed one year.

[0083] Several key observations were made. Looking at the interim data, a statistically significant number of 182 patients had an albumin to creatinine ratio (ACR) ≥ 30 mg / g at baseline, and the rest had an ACR > 300 mg / g and an estimated glomerular filtration rate (eGFR) of 15-44 mL / min / 1.73 m 2 .like Figure 1As shown, for all these patients, the patient's serum potassium concentration decreased from a mean of 5.27 mEq / L at baseline to a mean of 4.57 mEq / L at week 24. For patients with ACR ≥ 30 mg / g, the patient's serum potassium concentration decreased from a mean of 5.28 mEq / L at baseline to a mean of 4.60 mEq / L at week 24. For patients with ACR> 300 mg / g, the patient's serum potassium concentration decreased from a mean of 5.35 mEq / L at baseline to a mean of 4.65 mEq / L at week 24. For patients with eGFR of 15-44 mL / min / 1.73 m 2 For patients treated with PD-1, serum potassium concentrations decreased from a mean of 5.33 mEq / L at baseline to a mean of 4.59 mEq / L at week 24.

[0084] like Figure 2 For all these patients, systolic blood pressure decreased from a baseline mean of 154 to a mean of 137 at week 24; for patients with ACR ≥ 30 mg / g, systolic blood pressure decreased from a baseline mean of 154 to a mean of 138 at week 24; for patients with ACR > 300 mg / g, systolic blood pressure decreased from a baseline mean of 154 to a mean of 137 at week 24; and for patients with eGFR of 15-44 mL / min / 1.73 m 2 For patients treated with the drug, systolic blood pressure dropped from a mean of 152 at baseline to a mean of 135 at week 24.

[0085] like Figure 3 For all these patients, diastolic blood pressure decreased from a baseline mean of 83 to a mean of 74 at week 24; for patients with ACR ≥ 30 mg / g, diastolic blood pressure decreased from a baseline mean of 84 to a mean of 74 at week 24; for patients with ACR > 300 mg / g, diastolic blood pressure decreased from a baseline mean of 86 to a mean of 73 at week 24; and for patients with eGFR of 15-44 mL / min / 1.73 m 2 For patients treated with the drug, diastolic blood pressure dropped from a mean of 82 at baseline to a mean of 73 at week 24.

[0086] like Figure 4 As shown, for all groups and for patients in each group (e.g., ACR ≥ 30 mg / g, ACR > 300 mg / g, eGFR 15-44 mL / min / 1.73 m 2 ), ACR did not change significantly after the 24-week treatment period.

[0087] like Figure 5 For eGFR of 15-44 mL / min / 1.73 m 2For patients with 2 Increased to an average of 38 mL / min / 1.73 m 2 This increase in eGFR was statistically significant for these patients.

[0088] As mentioned above, Figure 6-9 Data from a group of patients with pre-existing hyperkalemia who were taking a stable dose of a RAAS inhibitor and who underwent the trial without a run-in period are shown. Figure 6 As expected in these patients, the mean eGFR at baseline was 46 mL / min / 1.73 m 2 There was no decrease over time. Additional data suggest that in a subgroup of patients, eGFR appears to increase at one year. Figure 7 As shown in the study, the mean serum potassium level of these patients decreased significantly from a baseline of 5.3 mEq / L to the normal range (to 4.6 mEq / L) at 12 months. Figure 8 As shown in Figure 2, the mean urine ACR of these patients at baseline was 853 mg / g, which was not significantly different from the mean urine ACR of the patients at any time point. Fig. 9 As shown, the average systolic blood pressure of these patients dropped from 157 mmHg to 134 mmHg and the average diastolic blood pressure of these patients dropped from 85 mmHg to 77 mmHg.

[0089] Additional observations can be made from the study results. First, initial serum potassium is a factor that determines the efficacy of cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form. An interim analysis of the 8-week treatment initiation period for 304 subjects showed a mean decrease in serum potassium from baseline to week 8, with the highest serum potassium group (stratum group 2: serum K + >5.5 to <6.0 mEq / L) was approximately the same as the average decrease in serum potassium in the lower stratum of subjects (stratum group 1: serum K + >5.0 to 5.5 mEq / L) (-0.90 mEq / L vs. -0.47 mEq / L, respectively). This baseline effect was observed within the first week of treatment. Second, basal RAAS inhibitor therapy did not appear to affect the efficacy of cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form. Third, the efficacy of cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form did not appear to be related to comorbidities.

[0090] The potassium binding polymer may be a cross-linked cation exchange polymer derived from at least one cross-linking agent and at least one monomer containing an acid group, such as a sulfonic acid group, a sulfate group, a carboxylic acid group, a phosphonic acid group, a phosphoric acid group, or an amide sulfonyl group, or a combination thereof, in its protonated or ionized form. Generally, the ionization fraction of the acid groups of the polymers used in the present invention is higher than about 75% at the physiological pH of the colon (e.g., about pH 6.5) and the in vivo potassium binding capacity is higher than about 0.6 mEq / g, more particularly higher than about 0.8 mEq / g and even more particularly higher than about 1.0 mEq / g. Typically, the ionization of the acid groups is higher than about 80%, more particularly higher than about 90%, and most particularly about 100% at the physiological pH of the colon (e.g., about pH 6.5).

[0091] The acid-containing polymer may contain more than one type of acid group. In other cases, the acid-containing polymer is applied in its substantially anhydrous or salt form and produces an ionized form when in contact with physiological fluids. Table 1 shows representative structural units of these potassium-binding polymers, where an asterisk at the end of a bond indicates that the bond is connected to another structural unit or a cross-linking unit.

[0092] Table 1: Examples of cation exchange building blocks - structures and theoretical binding capacities

[0093]

[0094] Other suitable cation exchange polymers contain repeating units having the following structure:

[0095]

[0096] wherein R1 is a bond or nitrogen, R2 is hydrogen or Z, R3 is Z or -CH(Z)2, each Z is independently SO3H or PO3H, x is 2 or 3, and y is 0 or 1, n is about 50 or greater, more particularly n is about 100 or more, even more particularly n is about 200 or greater, and most particularly n is about 500 or greater.

[0097] Sulfonamide (i.e., when Z=SO3H) or phosphoramido (i.e., when Z=PO3H) polymers can be obtained from amine polymers or monomeric precursors treated with sulfonating agents such as sulfur trioxide / amine adducts or phosphonating agents such as P2O5, respectively. Typically, at a pH of about 6 to about 7, the acidic protons of the phosphonic acid group can be exchanged with cations such as sodium or potassium.

[0098] Suitable phosphonate monomers include vinyl phosphonate, vinyl-1,1-bisphosphonate and phosphonocarboxylates, oligo(methylene phosphonates) and vinyl derivatives of hydroxyethane-1,1-diphosphonic acid. Methods for the synthesis of these monomers are well known in the art.

[0099] The acid-containing cation exchange structural units and repeating units described above are cross-linked to form the cross-linked cation exchange polymer of the present invention. Representative cross-linking monomers include the cross-linking monomers shown in Table 2.

[0100] Table 2: Crosslinking agent abbreviations and structures

[0101]

[0102]

[0103] The ratio of repeating units to crosslinking agents can be selected by those skilled in the art based on the desired physical properties of the polymer particles. For example, according to the general understanding of those skilled in the art, when crosslinking increases, the swelling ratio generally decreases, and the swelling ratio can be used to determine the amount of crosslinking.

[0104] The amount of crosslinking agent in the polymerization reaction mixture may be in the range of 3 wt% to 15 wt%, more specifically in the range of 5 wt% to 15 wt% and even more specifically in the range of 8 wt% to 12 wt%, based on the total weight of the monomers and crosslinking agent added to the polymerization reaction. The crosslinking agent may include one of the crosslinking agents in Table 2 or a mixture thereof.

[0105] The cross-linked cation exchange polymer may also include a pKa lowering group, preferably an electron withdrawing substituent located near the acid group, preferably at the α or β position of the acid group. The preferred position of the electron withdrawing group is connected to the α carbon atom of the acid group. Typically, the electron withdrawing substituent is a hydroxyl, ether, ester, acid group or a halogen atom. More preferably, the electron withdrawing substituent is a halogen atom. Most preferably, the electron withdrawing group is fluorine and is connected to the α carbon atom of the acid group. The acid group is a carboxylic acid, a phosphonic acid, a phosphoric acid or a combination thereof.

[0106] Other particularly preferred polymers are produced by polymerization of α-fluoroacrylic acid, difluoromaleic acid or their anhydrides. Monomers useful herein include α-fluoroacrylates and difluoromaleic acid, with α-fluoroacrylate being most preferred. Such monomers can be prepared by a variety of routes, see, for example, Gassen et al., J. Fluorine Chemistry, 55, (1991) 149-162, KF Pittman, CU, M. Ueda et al. (1980) Macromolecules 13 (5): 1031-1036. Difluoromaleic acid is prepared by oxidation of fluorinated aromatic compounds (Bogachev et al., Zhurnal Organisheskoi Khimii, 1986, 22 (12), 2578-83 or fluorinated furan derivatives (see U.S. Pat. No. 5,112,993). A synthesis pattern for α-fluoroacrylates is given in EP 415214.

[0107] In addition, the potassium binding polymer can be a cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form. In particular, the cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form is in salt form. The salt form contains sodium, calcium, magnesium, ammonium or a combination thereof; preferably, the salt form contains a calcium salt form.

[0108] In addition, the cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt form can be stabilized with a linear polyol. In particular, the cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt form can be stabilized with 10 wt % to about 40 wt % of the linear polyol based on the total weight of the composition.

[0109] A linear polyol is added to a composition containing a potassium binding polymer (e.g., crosslinked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt form) in an amount effective to stabilize the polymer salt, and typically from about 10 wt % to about 40 wt % of the linear polyol based on the total weight of the composition.

[0110] The linear polyol is preferably a linear sugar (i.e., a linear sugar alcohol). The linear sugar alcohol is preferably selected from D-(+) arabitol, erythritol, glycerol, maltitol, D-mannitol, ribitol, D-sorbitol, xylitol, threitol, dulcitol, isomalt, iditol, lactitol, and combinations thereof, more preferably selected from D-(+) arabitol, erythritol, glycerol, maltitol, D-mannitol, ribitol, D-sorbitol, xylitol, and combinations thereof, and most preferably selected from xylitol, sorbitol, and combinations thereof.

[0111] Preferably, the pharmaceutical composition comprises from about 15% to about 35% by weight of the stabilizing polyol, based on the total weight of the composition. The concentration of the linear polyol can be sufficient to reduce the release of fluoride ions from the cation exchange polymer during storage, compared to an otherwise identical composition without the stabilizing polyol, at the same temperature and storage time.

[0112] Additionally, the potassium binding polymer may be a cross-linked cation exchange polymer comprising units having Formulas 1, 2, and 3 as represented by the following structures:

[0113]

[0114] wherein R1 and R2 are independently selected from hydrogen, alkyl, cycloalkyl or aryl; A1 is a carboxylic acid group, a phosphonic acid group or a phosphoric acid group in the form of its salt or acid; X1 is an arylene group; X2 is an alkylene group, an ether moiety or an amide moiety, m is in the range of about 85 to about 93 mol %, n is in the range of about 1 to about 10 mol %, and p is in the range of about 1 to about 10 mol %, calculated based on the ratio of the monomer and the crosslinker added to the polymerization mixture.

[0115] When X2 is an ether moiety, the ether moiety may be -(CH2) d -O-(CH2) e -or-(CH2) d -O-(CH2) e -O-(CH2) d -, wherein d and e are independently integers from 1 to 5.

[0116] Preferably, d is an integer from 1 to 2, and e is an integer from 1 to 3.

[0117] When X2 is an amide moiety, the amide moiety may be -C(O)-NH-(CH2) p -NH-C(O)-, wherein p is an integer from 1 to 8. Preferably, p is an integer from 4 to 6.

[0118] The unit corresponding to Formula 2 may be derived from a bifunctional crosslinking monomer having the formula CH2=CH-X1-CH=CH2, wherein X1 is the same as defined with respect to Formula 2.

[0119] The unit corresponding to Formula 3 may be derived from a bifunctional crosslinking monomer having the formula CH2=CH-X2-CH=CH2, wherein X2 is the same as defined with respect to Formula 3.

[0120] With respect to Formula 1, R1 and R2 are hydrogen and A1 is a carboxylic acid.

[0121] Regarding Formula 2, X1 is an optionally substituted phenylene group, and is preferably a phenylene group.

[0122] With respect to Formula 3, X2 is an optionally substituted ethylene, propylene, butylene, pentylene or hexylene; more specifically, X2 is ethylene, propylene, butylene, pentylene or hexylene; and preferably, X2 is butylene. Specifically, R1 and R2 are hydrogen, A1 is a carboxylic acid, X1 is a phenylene group and X2 is a butylene group.

[0123] Typically, the structural units of formulae 1, 2 and 3 of the terpolymer have a specific ratio, for example, wherein the structural unit corresponding to formula 1 constitutes at least about 80 wt%, specifically at least about 85 wt%, and more specifically at least about 90 wt%, or about 80 wt% to about 95 wt%, about 85 wt% to about 95 wt%, about 85 wt% to about 93 wt%, or about 88 wt% to about 92 wt%, based on the total weight of the structural units of formulae 1, 2 and 3 in the polymer, calculated based on the monomers of formulae 11, 22 and 33 used in the polymerization reaction, and the weight ratio of the structural unit corresponding to formula 2 and the structural unit corresponding to formula 3 is about 4:1 to about 1:4, or about 1:1.

[0124] In addition, the ratio of the structural units, expressed as the mole fraction of the structural unit of Formula 1 in the polymer, is at least about 0.87, or about 0.87 to about 0.94, or about 0.9 to about 0.92, based on the total number of structural units of Formulas 1, 2, and 3, and the molar ratio of the structural unit of Formula 2 to the structural unit of Formula 3 is about 0.2:1 to about 7:1, about 0.2:1 to about 3.5:1, about 0.5:1 to about 1.3:1, about 0.8 to about 0.9, or about 0.85:1; these calculations are also made using the amounts of monomers of Formulas 11, 22, and 33 used in the polymerization reaction. No conversion needs to be calculated.

[0125] In some aspects, the crosslinked cation exchange polymer comprises units corresponding to Formulas 1A, 2A, and 3A, wherein Formulas 1A, 2A, and 3A correspond to the following structures.

[0126]

[0127] In Formula 1 or 1A, the carboxylic acid may be in acid form (i.e., balanced by hydrogen), in salt form (i.e., balanced by a counterion, such as Ca 2+ Mg 2+ 、Na + NH4 + etc.) or in ester form (ie, balanced by an alkyl group such as a methyl group). Preferably, the carboxylic acid is in salt form and is reacted with Ca 2+ Counter ion balance.

[0128] When the carboxylic acid in the cross-linked cation exchange form is balanced with a divalent counterion, two carboxylic acid groups can associate with one divalent cation.

[0129] The polymers described herein are generally random polymers in which the exact order of the structural units of Formula 1, 2 or 3 (derived from monomers of Formula 11, 22 or 33) or 1A, 2A or 3A (derived from monomers of Formula 11A, 22A or 33A) is not predetermined.

[0130] The cation exchange polymer derived from the monomer of Formula 11, 22 or 33 after hydrolysis may have the following structure:

[0131]

[0132] wherein R1, R2, A1, X1 and X2 are the same as defined with respect to Formulas 1, 2 and 3 and are calculated based on the ratio of monomers and crosslinkers added to the polymerization mixture, m is in the range of about 85 to about 93 mol%, n is in the range of about 1 to about 10 mol%, and p is in the range of about 1 to about 10 mol%. The wavy bonds in the polymer structure of Formula 40 are included to represent the random connection of the structural units to each other, wherein the structural unit of Formula 1 can be connected to another structural unit of Formula 1, a structural unit of Formula 2 or a structural unit of Formula 3; the structural units of Formula 2 and Formula 3 have the same range of connection possibilities.

[0133] Using the polymerization process described herein, with monomers of formula 11A, 22A and 33A, after hydrolysis and calcium ion exchange, polymers having the general structure shown below are obtained:

[0134]

[0135] Wherein m is in the range of about 85 to about 93 mol%, n is in the range of about 1 to about 10 mol%, and p is in the range of about 1 to about 10 mol%, calculated based on the ratio of monomers and crosslinking agents added to the polymerization mixture. The wavy bonds in the polymer structure of Formula 40A are included to represent the random connection of the structural units to each other, wherein the structural unit of Formula 1A can be connected to another structural unit of Formula 1A, a structural unit of Formula 2A, or a structural unit of Formula 3A; the structural units of Formula 2A and Formula 3A have the same range of connection possibilities.

[0136] The crosslinked cation exchange polymer is typically the reaction product of a polymerization mixture subjected to polymerization conditions. The polymerization mixture also contains components that are not chemically incorporated into the polymer. The crosslinked cation exchange polymer typically comprises a fluoro group and an acid group that is a polymerization product of three different monomer units, wherein one monomer comprises a fluoro group and an acid group, another monomer is a difunctional arylene monomer and the third monomer is a difunctional alkylene, ether or amide containing monomer. More specifically, the crosslinked cation exchange polymer may be the reaction product of a polymerization mixture comprising monomers of formulas 11, 22, and 33. The monomer of formula 11, the monomer of formula 22, and the monomer of formula 33 have the general formula:

[0137]

[0138] R1 and R2 are the same as defined with respect to Formula 1, X1 is the same as defined with respect to Formula 2, X2 is the same as defined with respect to Formula 3, and A 11 is an optionally protected carboxylic acid group, phosphonic acid group or phosphoric acid group.

[0139] Preferably, A 11 is a protected carboxylic acid group, phosphonic acid group or phosphoric acid group.

[0140] The polymerization mixture also typically contains a polymerization initiator.

[0141] The reaction product of the polymerization mixture comprising Formula 11, 22, 33 comprises a polymer having protected acid groups and comprising units corresponding to Formula 10 and units corresponding to Formulas 2 and 3. The polymer product having protected acid groups can be hydrolyzed to form a polymer having unprotected acid groups and comprising units corresponding to Formulas 1, 2, and 3. The structural unit corresponding to Formula 10 has the structure:

[0142]

[0143] R1, R2 and A 11 is the same as defined with respect to Formula 11 and m is the same as defined with respect to Formula 1.

[0144] In any of the methods of the present invention, wherein the crosslinked cation exchange polymer is the reaction product of a polymerization mixture of monomers, A 11 The protected carboxylic acid group, phosphonic acid group or phosphate group may be a protected carboxylic acid group, phosphonic acid group or phosphate group. The polymer formed in the polymerization reaction contains protected carboxylic acid groups, phosphonic acid groups or phosphate groups. A hydrolyzing agent may be added to the polymer formed in the polymerization reaction to hydrolyze these protected groups and convert them into carboxylic acid groups, phosphonic acid groups or phosphate groups, or other deprotection methods well known in the art may be used. Preferably, the hydrolyzed polymer is subjected to ion exchange to obtain a preferred polymer salt for treatment.

[0145] Typically, the polymerization reaction mixture contains at least about 85 wt % or about 80 wt % to about 95 wt % of the monomer corresponding to Formula 11, based on the total weight of the monomers corresponding to Formulas 11, 22 and 33; and the weight ratio of the monomer corresponding to Formula 22 and the monomer corresponding to Formula 33 of the mixture is about 4:1 to about 1:4, about 2:1 to 1:2, or about 1:1.

[0146] The polymerization reaction mixture may contain a mole fraction of at least about 0.87 or about 0.87 to about 0.94 of the monomer corresponding to Formula 11, based on the moles of the monomers corresponding to Formulas 11, 22, and 33, and the molar ratio of the monomer corresponding to Formula 22 to the monomer corresponding to Formula 33 of the mixture is about 0.2:1 to about 7:1, about 0.2:1 to about 3.5:1, about 0.5:1 to about 1.3:1, about 0.8 to about 0.9, or about 0.85:1.

[0147] The specific crosslinked cation exchange polymer is the reaction product of a monomer corresponding to Formula 11A, a monomer corresponding to Formula 22A, a monomer corresponding to Formula 33A, and a polymerization initiator. The monomers corresponding to Formulas 11A, 22A, and 33A have the structure:

[0148]

[0149] Wherein alkyl is preferably selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl or tert-pentyl. Most preferably, alkyl is methyl or tert-butyl. The -O-alkyl moiety protects the carboxyl moiety from reacting with other reactive moieties during the polymerization reaction and can be removed by hydrolysis or other deprotection methods described in more detail below.

[0150] In addition, based on the total weight of monomers of Formulae 11A, 22A and 33A, the reaction mixture contains at least about 80 wt%, specifically at least about 85 wt%, and more specifically at least about 90 wt%, or about 80 wt% to about 95 wt%, about 85 wt% to about 95 wt%, about 85 wt% to about 93 wt%, or about 88 wt% to about 92 wt% of the monomer corresponding to Formula 11A, and the weight ratio of the monomer corresponding to Formula 22A to the monomer corresponding to Formula 33A is from about 4:1 to about 1:4 or about 1:1. Additionally, the reaction mixture can have a mole fraction of at least about 0.87 or about 0.87 to about 0.94 of monomer of formula 11A based on the total moles of monomers of formulae 11A, 22A, and 33A and a molar ratio of monomer of formula 22A to monomer of formula 33A of the mixture of about 0.2:1 to about 7:1, about 0.2:1 to about 3.5:1, about 0.5:1 to about 1.3:1, about 0.8 to about 0.9, or about 0.85:1.

[0151] Typically, the reaction mixture contains about 80% to about 95% by weight of the monomer corresponding to Formula 11A, based on the total weight of the monomers corresponding to Formula 11A, 22A, and 33A. In addition, the weight ratio of the monomer corresponding to Formula 22A to the monomer corresponding to Formula 33A is about 4:1 to about 1:4 or about 1:1. In addition, based on the total moles of the monomers of Formulas 11A, 22A, and 33A, the reaction mixture may have a mole fraction of the monomer of Formula 11A of about 0.9 to about 0.92. Similarly, the molar ratio of the monomer of Formula 22A to the monomer of Formula 33A of the mixture is about 0.2:1 to about 7:1, about 0.2:1 to about 3.5:1, about 0.5:1 to about 1.3:1, about 0.8 to about 0.9, or about 0.85:1.

[0152] An initiated polymerization reaction is employed, wherein a polymerization initiator is used in the polymerization mixture to assist in initiating the polymerization reaction. When preparing poly(methyl fluoroacrylate) or (poly-MeFA) or any other crosslinked cation exchange polymer of the present invention in a suspension polymerization reaction, the nature of the free radical initiator plays a role in the quality of the suspension in terms of polymer particle stability, polymer particle yield and polymer particle shape. The use of water-insoluble free radical initiators, such as lauroyl peroxide, can produce high yields of polymer particles. Without being bound by any particular theory, it is believed that water-insoluble free radical initiators initiate polymerization primarily in the dispersed phase containing monomers of formulas 11, 22 and 33. Such reaction schemes provide polymer particles rather than bulk polymer gels. Therefore, the process uses a free radical initiator with a water solubility of less than 0.1 g / L, particularly less than 0.01 g / L. Polymethyl fluoroacrylate particles can be produced with a low water-soluble free radical initiator in the presence of a salt such as sodium chloride in the aqueous phase.

[0153] The polymerization initiator can be selected from a variety of classes of initiators. For example, initiators that generate polymer initiating groups upon heat exposure include peroxides, persulfates, or azo-type initiators (e.g., 2,2′-azobis(2-methylpropionitrile), lauroyl peroxide (LPO), tert-butyl hydroperoxide, 2,2′-azobis(dimethyl 2-methylpropionate), 2,2′-azobis[2-methyl-N-(2-hydroxyethylpropionamide], 2,2′-azobis[2-(2-imidazolin-2-yl)propane], (2,2″-azobis(2,4-dimethylvaleronitrile), azobisisobutyronitrile (AIBN), or a combination thereof. Another class of polymer initiating groups are groups generated by redox reactions, such as persulfates and amines. Groups can also be generated by exposing certain initiators to ultraviolet light or to air.

[0154] For polymerization reactions containing additional components in the polymerization mixture that are not intentionally incorporated into the polymer, such additional components typically include surfactants, solvents, salts, buffers, aqueous polymerization initiators, and / or other components known to those skilled in the art.

[0155] When the polymerization is carried out in suspension mode, the aqueous phase may contain additional components, while the organic phase may contain monomers and initiators. When an aqueous phase is present, it may consist of water, surfactants, stabilizers, buffers, salts and polymerization initiators.

[0156] Surfactant can be selected from anionic surfactant, cationic surfactant, nonionic surfactant, amphoteric surfactant, zwitterionic surfactant or its combination. Anionic surfactant is usually based on sulfate, sulfonate or carboxylate anion. These surfactants include sodium dodecyl sulfate (SDS), ammonium dodecyl sulfate, other alkyl sulfates, sodium lauryl ether sulfate (or sodium lauryl ether sulfate (SLES)), N-dodecyl sarcosine sodium salt, lauryl dimethylamine oxide (LDAO), ethyl trimethyl ammonium bromide (CTAB), di (2-ethylhexyl) sulfosuccinic acid sodium salt, alkyl benzene sulfonate, soap, fatty acid salt or its combination.

[0157] For example, cationic surfactants contain quaternary ammonium salt cations. These surfactants are cetyl trimethyl ammonium bromide (CTAB or cetyl trimethyl ammonium bromide), cetyl pyridinium chloride (CPC), polyethoxylated tallow amine (POEA), benzalkonium chloride (BAC), benzethonium chloride (BZT) or a combination thereof.

[0158] Zwitterionic or amphoteric surfactants include lauryl betaine, lauryl dimethyl amine oxide, cocamidopropyl betaine, cocoampholyglycinate, or combinations thereof.

[0159] Nonionic surfactants include alkyl poly (ethylene oxide), copolymers of poly (ethylene oxide) and poly (propylene oxide) (commercially known as polyhydroxyalkylenes or poloxamines), alkyl polyglucosides (including octyl glucoside, decyl maltoside) fatty alcohols, cetyl alcohol, oleyl alcohol, cocamide MEA, cocamide DEA or combinations thereof. Other pharmaceutically acceptable surfactants are well known in the art and are described in McCutcheon's Emulsifiers and Detergents, N. American Edition (2007).

[0160] The polymeric stabilizer may be selected from organic polymers and inorganic particulate stabilizers. Examples include polyvinyl alcohol-co-vinyl acetate and a series of hydrolyzates thereof, polyvinyl acetate, polyvinyl pyrrolidone, polyacrylates, cellulose ethers, natural gums or combinations thereof.

[0161] The buffer may be selected from, for example, 4-2-hydroxyethyl-1-piperazineethanesulfonic acid, 2-{[tris(hydroxymethyl)methyl]amino}ethanesulfonic acid, 3-(N-morpholino)propanesulfonic acid, piperazine-N,N′-di(2-ethanesulfonic acid), disodium hydrogen phosphate heptahydrate, sodium dihydrogen phosphate monohydrate, or a combination thereof.

[0162] The polymerization salt may be selected from potassium chloride, calcium chloride, potassium bromide, sodium bromide, sodium bicarbonate, ammonium persulfate, or a combination thereof.

[0163] Polymerization inhibitors may be used as known in the art and are selected from 1,1,3-tris(2-methyl-4-hydroxy-5-tert-butylphenyl)butane, 1,3,5-trimethyl-2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl)benzene, 1-aza-3,7-dioxabicyclo[3.3.0]octane-5-methanol, 2,2′-ethylene-bis(4,6-di-tert-butylphenol), 2,2′-ethylenebis(4,6-di-tert-butylphenyl)phosphite, 2, 2′-methylenebis(6-tert-butyl-4-ethylphenol), 2,2′-methylenebis(6-tert-butyl-4-methylphenol), 2,5-di-tert-butyl-4-methoxyphenol, 2,6-di-tert-butyl-4-(dimethylaminomethyl)phenol, 2-heptanone oxime, 3,3′,5,5′-tetramethylbiphenyl-4,4′-diol, 3,9-bis(2,4-diisopropylphenylphenoxy)-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane, 4,4-dimethyloxazolidine, 4-methyl-2-pentanone oxime, 5-ethyl-1-aza-3,7-dioxabicyclo[3.3.0]octane, 6,6′-dihydroxy-5,5′-dimethoxy-[1,1′-diphenyl]-3,3′-dicarbaldehyde, 3,3′-dioctadecyl thiodipropionate, 3,3′-ditetradecyl thiodipropionate, 3,3′-ditridecyl thiodipropionate, 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid Octadecyl ester, pentaerythritol tetrakis(3,5-di-tert-butyl-4-hydroxyphenyl)propionate]hydroxyhydrocinnamic acid ester, poly(1,2-dihydro-2,2,4-trimethylquinoline), sodium D-isoascorbate monohydrate, tetrakis(2,4-di-tert-butylphenyl)-4,4′-biphenyl diphosphite, tris(3,5-di-tert-butyl-4-hydroxybenzyl) isocyanurate, tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl) isocyanurate, sodium nitrite or a combination thereof.

[0164] Typically, the polymerization mixture is subjected to polymerization conditions. As discussed herein, although suspension polymerization is preferred, the polymers of the present invention may also be prepared in bulk, solution or emulsion polymerization processes. The details of such processes are within the skill of one of ordinary skill in the art, in light of the present disclosure. Polymerization conditions typically include polymerization reaction temperature, pressure, mixing and reactor geometry, order and rate of addition of the polymerization mixture, and the like.

[0165] The polymerization temperature is typically in the range of about 50 to 100° C. The polymerization pressure is typically run at atmospheric pressure, but may be run at elevated pressure (e.g., 130 PSI nitrogen). The polymerization depends on the scale of the polymerization and the equipment used, and is within the skill of one of ordinary skill in the art. Various α-fluoroacrylate polymers and the synthesis of these polymers are described in U.S. Application Publication No. 2005 / 0220752, incorporated herein by reference.

[0166] As described in more detail herein with examples, crosslinked cation exchange polymers can be synthesized by preparing an organic phase and an aqueous phase in a polymerization suspension polymerization reaction. The organic phase typically contains a monomer of formula 11, a monomer of formula 22, a monomer of formula 33, and a polymerization initiator. The aqueous phase contains a suspension stabilizer, a water-soluble salt, water, and an optional buffer. The organic phase and the aqueous phase are then combined and stirred under nitrogen. The mixture is typically heated for about 2.5 to about 3.5 hours to about 60° C. to about 80° C., raised to 95° C. after initiation of polymerization, and then cooled to room temperature. After cooling, the aqueous phase is removed. Water is added to the mixture, the mixture is stirred, and the resulting solid is filtered. The solid is washed with water, alcohol, or an alcohol / water mixture.

[0167] As mentioned above, polymeric suspension stabilizers, such as polyvinyl alcohol, are used to prevent particle agglomeration during the polymerization process. In addition, it has been observed that the addition of sodium chloride in the aqueous phase reduces agglomeration and particle aggregation. Other salts suitable for this purpose include salts that are soluble in the aqueous phase. Water-soluble salts are added at a concentration of about 0.1% to about 10% by weight, particularly about 2% to about 5% by weight, and even more particularly about 3% to about 4% by weight.

[0168] Preferably, an organic phase of methyl 2-fluoroacrylate (90 wt %), 1,7-octadiene (5 wt %) and divinylbenzene (5 wt %) is prepared and 0.5 wt % of lauroyl peroxide is added to initiate polymerization. Additionally, an aqueous phase of water, polyvinyl alcohol, phosphate, sodium chloride and sodium nitrite is prepared. The aqueous and organic phases are mixed together under nitrogen and while maintaining the temperature below about 30° C. Once fully mixed, the reaction mixture is gradually heated while stirring continuously. After initiation of polymerization, the temperature of the reaction mixture is raised to about 95° C. Once polymerization is complete, the reaction mixture is cooled to room temperature and the aqueous phase is removed. After adding water to the mixture, the solids can be separated by filtration. The resulting product is a crosslinked (methyl 2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer.

[0169] As discussed herein, after polymerization, the product can be hydrolyzed or otherwise deprotected using methods known in the art. In order to hydrolyze a polymer having an ester group to form a polymer having a carboxylic acid group, preferably, the polymer is hydrolyzed with a strong base (e.g., NaOH, KOH, Mg(OH)2 or Ca(OH)2) to remove the alkyl group (e.g., methyl) and form a carboxylate. Depending on the pH of the hydrolysis mixture, a proton form of the (2-fluoroacrylic acid)-divinylbenzene-1,7-octadiene terpolymer is formed. Alternatively, the polymer can be hydrolyzed with a strong acid (e.g., HCl) to form a carboxylate. Preferably, the (2-fluoroacrylic acid)-divinylbenzene-1,7-octadiene terpolymer is hydrolyzed with an excess of aqueous sodium hydroxide at a temperature of about 30°C to about 100°C to produce a (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer. Typically, the hydrolysis reaction is carried out for about 15-25 hours. After hydrolysis, the solid is filtered and washed with water and / or alcohol.

[0170] The cation of the polymer salt formed in the hydrolysis reaction or other deprotection step depends on the base used in the step. For example, when sodium hydroxide is used as the base, the sodium salt of the polymer is formed. This sodium ion can be exchanged with another cation by contacting the sodium salt with an excess of an aqueous metal salt to produce an insoluble solid of the desired polymer salt. After the desired ion exchange, the product is washed with alcohol and / or water and dried directly or after dehydration treatment with denatured alcohol; preferably, the product is washed with water and dried directly. For example, by washing with a solution that replaces sodium with calcium, such as washing with calcium chloride, calcium acetate, calcium lactate gluconate or a combination thereof, the sodium salt of the cation exchange polymer is converted to a calcium salt. And, more specifically, to exchange sodium ions for calcium ions, the (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer is contacted with an excess of an aqueous solution of calcium chloride to produce an insoluble solid of a crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer. If the pH of the hydrolysis mixture is low enough, the proton form of the (2-fluoroacrylic acid)-divinylbenzene-1,7-octadiene terpolymer is formed.

[0171] Using this suspension polymerization process, cross-linked poly-MeFA polymers are isolated in high yields, typically greater than about 85%, more particularly greater than about 90%, and even more particularly greater than about 93%. The yield of the second step (i.e., hydrolysis) is preferably present at 100%, thereby providing an overall yield after hydrolysis greater than about 85%, more particularly greater than about 90%, and even more particularly greater than about 93%.

[0172] To add a linear polyol to the composition, the salt of the polymer is slurried with an aqueous solution of a polyol (e.g., sorbitol), typically with an excess of the polyol by weight of the polymer. This step can be performed to reduce the inorganic fluoride in the composition. The slurry is maintained under conditions known to those skilled in the art, such as for at least 3 hours and at ambient temperature and pressure. The solid is then filtered out and dried to the desired moisture content.

[0173] Treatment methods for hypertension, hyperkalemia, and chronic kidney disease may use multiple treatment periods, including 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 weeks or more. The treatment period may also be 2 years, 3 years, 4 years, 5 years or longer.

[0174] When treating hyperkalemia or chronic kidney disease in a patient using the methods of the present invention, the patient's estimated glomerular filtration rate (eGFR) may be about 15 mL / min / 1.73 m 2 to about 44mL / min / 1.73m 2 .

[0175] Methods for treating hyperkalemia, methods for treating hypertension in patients with chronic kidney disease, type 2 diabetes, heart failure, or a combination thereof, and methods for treating chronic kidney disease of the present invention can produce several improvements, such as a decrease in the patient's serum potassium level after 48 hours or more of treatment compared to the patient's serum potassium level before treatment with a potassium binder; an increase in the patient's eGFR after 2, 3, 4, 5, 6 months or more of treatment compared to the patient's eGFR before treatment with a potassium binder; a decrease in the patient's urine albumin:creatinine ratio (ACR) after 2, 3, 4, 5, 6 months or more of treatment compared to the patient's urine ACR before treatment with a potassium binder; a decrease in the patient's systolic and diastolic blood pressure after 1, 2, 3, 4, 5, 6, 7 days or more of treatment compared to the patient's systolic and diastolic blood pressure before treatment with a potassium binder; a decrease in the patient's serum aldosterone level after 6, 12, 24, 48, 72 hours or more of treatment compared to the patient's serum aldosterone level before treatment with a potassium binder, or a combination thereof.

[0176] With respect to changes in serum potassium levels, eGFR, blood pressure, and ACR, it is understood that even when the methods are described involving administration of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form, the potassium binder may be any of the agents described herein.

[0177] A method of treating hyperkalemia in a chronic kidney disease patient in need thereof who is optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent comprises administering to the patient an effective amount of a potassium binder and observing (i) a decrease in the patient's serum creatinine level compared to the patient's serum creatinine level prior to treatment with the potassium binder, (ii) an increase in the time to progression to end-stage renal disease compared to chronic kidney disease patients who are optionally treated with the RAAS agent but not treated with the potassium binder, (iii) an increase in survival compared to chronic kidney disease patients who are optionally treated with the RAAS agent but not treated with the potassium binder, or (iv) an increase or stabilization in estimated glomerular filtration rate (eGFR) compared to the patient's eGFR prior to treatment with the potassium binder, all of which indicate that the patient's renal function has improved or stabilized.

[0178] The potassium binder may be a cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

[0179] Methods for treating hyperkalemia, methods for treating hypertension in patients with chronic kidney disease, type 2 diabetes, heart failure, or a combination thereof, and methods for treating chronic kidney disease can result in an increase in the patient's eGFR after treatment with a potassium binder by at least 4, 5, or 6 mL / min / 1.73 m compared to the patient's eGFR before treatment with the potassium binder 2 or more.

[0180] In the treatment of hypertension, hyperkalemia or chronic kidney disease in a patient in need thereof, an effective amount of a potassium binder comprises a maximum daily dose of up to 60 g. An effective amount of a potassium binder may be a daily dose of about 3 g to about 60 g, about 5 g to about 60 g, about 7 g to about 60 g, about 10 g to about 60 g, about 12 g to about 60 g, or about 15 g to about 60 g.

[0181] An effective amount of the potassium binder may be a daily dose of about 3 g to about 40 g, about 5 g to about 40 g, about 10 g to about 40 g, or about 15 g to about 40 g.

[0182] In particular, the effective amount of the potassium binder may be a daily dose of about 18 g to about 60 g or about 18 g to about 40 g.

[0183] When the potassium binder is cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form, the dose in grams is calculated by determining the amount of cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt form plus calcium counterion. Thus, the dose does not include water and sorbitol that may be contained in the powder administered to the patient.

[0184] Administration may be once daily, twice daily or three times daily, however, once daily or twice daily is preferred, and once daily is most preferred.

[0185] The method for treating hypertension, hyperkalemia or chronic kidney disease of the present invention may further include administering an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent to a patient; measuring the serum potassium level in the patient; and, based on the serum potassium level, if it is higher than or equal to 5.1 mEq / L, increasing the amount of potassium binder subsequently administered to the patient. The method for treating hypertension, hyperkalemia or chronic kidney disease may further include a step in which the amount of potassium binder is increased by 5 g or 10 g per day.

[0186] The method for treating hypertension, hyperkalemia or chronic kidney disease of the present invention may further include administering an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent to a patient; measuring the serum potassium level in the patient; and, based on the serum potassium level, if it is below 4.0 mEq / L, reducing the amount of potassium binder subsequently administered to the patient. The method for treating hypertension, hyperkalemia or chronic kidney disease may further include a step in which the amount of potassium binder is reduced by 5 g or 10 g per day.

[0187] The method of treating hypertension, hyperkalemia or chronic kidney disease of the present invention may further include treating proteinuria.

[0188] In addition, the method of treating hypertension, hyperkalemia, proteinuria or chronic kidney disease may include treating the patient with an effective amount of a RAAS agent, which is an angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), an aldosterone antagonist (AA), an aldosterone synthase inhibitor, or a combination thereof. In particular, the patient may be treated with an effective amount of a RAAS agent, which is an ACE inhibitor, an ARB, or a combination thereof.

[0189] For methods of treating a patient with an effective amount of a RAAS agent, the effective amount of the RAAS agent comprises the maximum daily tolerated dose.

[0190] RAAS agents include fosinopril, ramipril, captopril, lisinopril, trandolapril, moexipril, quinapril, enalapril, benazepril, perindopril, eprosartan, olmesartan, losartan, telmisartan, valsartan, candesartan, irbesartan, azilsartan medoxomil, spironolactone, eplerenone, or a combination thereof.

[0191] The maximum tolerated daily dose of specific RAAS agents is 4 mg / day (trandolapril), 8 mg / day (perindopril), 20 mg / day (ramipril), 30 mg / day (moexipril), 32 mg / day (candesartan), 40 mg / day (fosinopril, lisinopril, enalapril, benazepril, olmesartan), 80 mg / day (quinapril, telmisartan, azilsartan medoxomil), 100 mg / day (losartan), 300 mg / day (captopril, irbesartan), 320 mg / day (valsartan), or 800 mg / day (eprosartan).

[0192] When the RAAS agent includes spironolactone, the maximum tolerated daily dose is 200 mg / day.

[0193] When the RAAS agent includes eplerenone, the maximum tolerated daily dose is 50 mg / day.

[0194] Patients treated with the method of the present invention for treating hypertension, hyperkalemia or chronic kidney disease may be further treated with an effective amount of a beta-adrenergic blocking agent. The beta-adrenergic blocking agent may include betaxolol, bisoprolol, atenolol, metoprolol, nebivolol, metoprolol, esmolol, acebutolol, propranolol, nadolol, carvedilol, labetalol, sotalol, timolol, carteolol, penbutolol, pindolol or a combination thereof.

[0195] In all of the above methods, the potassium binder may be a cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

[0196] As used herein, the term "treating" includes achieving a therapeutic benefit. By therapeutic benefit is meant eradication, amelioration, or prevention of the underlying condition being treated. For example, in a patient with hyperkalemia, a therapeutic benefit includes eradication or amelioration of the underlying hyperkalemia. Likewise, a therapeutic benefit is achieved by eradication, amelioration, or prevention of one or more physiological symptoms associated with the underlying condition, such that improvement is observed in the patient despite the patient still suffering from the underlying condition. For example, administration of a potassium-binding polymer to a patient experiencing hyperkalemia provides a therapeutic benefit not only when the patient's serum potassium level is reduced, but also when improvement is observed in the patient relative to other conditions associated with hyperkalemia, such as renal failure. In some treatment regimens, a cross-linked cation exchange polymer or composition of the present invention may be administered to a patient at risk of developing hyperkalemia or to a patient reporting one or more physiological symptoms of hyperkalemia, even though a diagnosis of hyperkalemia may not yet have been made.

[0197] End-stage renal disease is characterized by patients who are on dialysis or have undergone a kidney transplant.

[0198] Proteinuria, also called proteinuria or albuminuria, is a condition in which the urine contains abnormal amounts of protein. Albumin is the main protein in the blood. Protein is a component of all body parts, including muscles, bones, hair, and nails. Protein in the blood also performs many important functions. It protects the body from infection, helps the blood clot, and keeps the right amount of fluid circulating throughout the body.

[0199] When blood passes through healthy kidneys, it filters out waste products and leaves behind substances the body needs, such as albumin and other proteins. Most proteins are too large to pass through the kidneys' filters and enter the urine. However, when the kidney filters, called glomeruli, become damaged, proteins from the blood can seep into the urine.

[0200] Proteinuria is a sign of chronic kidney disease (CKD), which can be caused by diabetes, high blood pressure, and diseases that cause inflammation in the kidneys. For this reason, testing for albumin in the urine is part of everyone's routine medical evaluation. Kidney disease is sometimes called nephropathy. If CKD progresses, when the kidneys fail completely, it can lead to end-stage renal disease (ESRD). Patients with ESRD must receive a kidney transplant or regular blood-cleansing treatment called dialysis.

[0201] The potassium-binding polymers used in the methods of the present invention can be administered as a pharmaceutical composition containing an effective amount, i.e., an amount effective to achieve a therapeutic or preventive benefit, of the potassium-binding polymer and a pharmaceutically acceptable carrier. The actual amount effective for a particular application will depend on the patient (e.g., age, weight, etc.), the condition being treated, and the route of administration. Determination of an effective amount is well within the capabilities of those skilled in the art, especially in light of the disclosure herein. Effective amounts for use in humans will be determined by animal models. For example, a dose for use in humans can be formulated to achieve a gastrointestinal concentration that has been found to be effective in animals.

[0202] The polymers and compositions described herein can be used as food and / or food additives. They can be added to food before consumption or while packaging.

[0203] Various routes or modes of administration can be used to deliver the polymers described herein, or pharmaceutically acceptable salts thereof, or compositions thereof, to a patient. The most preferred routes of administration are oral, enteral, or rectal. Rectal routes of administration are known to those skilled in the art. Enteral routes of administration generally refer to administration directly to a section of the gastrointestinal tract, such as through a gastrointestinal tube or through an anastomosis. The most preferred route of administration is oral.

[0204] The polymer (or its pharmaceutically acceptable salt) can be administered per se or in the form of a pharmaceutical composition in which the active compound is admixed or mixed with one or more pharmaceutically acceptable excipients. The pharmaceutical composition used according to the present invention can be formulated into a physiologically usable formulation using one or more pharmaceutically acceptable excipients in a conventional manner, including carriers, diluents and adjuvants that are conducive to handling the active compound. The appropriate composition will depend on the selected route of administration.

[0205] For oral administration, the polymers and compositions of the invention can be readily formulated by combining the polymer or composition with pharmaceutically acceptable excipients well known in the art. Such excipients enable the compositions of the invention to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, pastes, suspensions, wafers, and the like for oral ingestion by a patient to be treated.

[0206] Oral compositions may not be enteric-coated.

[0207] Pharmaceutical preparations for oral administration can be obtained as solid excipients, optionally grinding the resulting mixture and, if desired, processing the granular mixture after adding suitable auxiliary agents to obtain tablets or dragee cores. In particular, suitable excipients are fillers such as sugars, including lactose or sucrose; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP); and various flavoring agents known in the art. If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salts such as sodium alginate can be added.

[0208] The active ingredient (e.g., polymer) constitutes about 20% or more, more particularly about 40% or more, even more particularly about 50% or more, and most particularly about 60% or more of the oral dosage form by weight, with the remainder comprising suitable excipients. In compositions containing water and linear polyols, the polymer constitutes preferably about 20% or more, more particularly about 40% or more, and even more particularly about 50% or more of the oral dosage form by weight.

[0209] The polymers of the invention can be provided as a pharmaceutical composition in the form of a liquid composition. The pharmaceutical composition can contain the polymer dispersed in a suitable liquid excipient. Suitable liquid excipients are known in the art; see, for example, Remington's Pharmaceutical Sciences.

[0210] Unless otherwise indicated, an alkyl group as described herein alone or as part of another group is an optionally substituted straight chain saturated monovalent hydrocarbon group containing 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, or an optionally substituted branched chain saturated monovalent hydrocarbon group containing 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms. Examples of unsubstituted alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, etc.

[0211] Where R A and R B are independently hydrogen or alkyl and R CFor example, the amide portion may be -C(O)-NH-(CH2) p -NH-C(O)-, wherein p is an integer of 1 to 8.

[0212] The term "aryl" as used herein alone or as part of another group refers to an optionally substituted monovalent aromatic hydrocarbon radical, preferably a monovalent monocyclic or bicyclic radical containing 6-12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the most preferred aryl radicals. The term "aryl" also includes heteroaryl radicals.

[0213] The term "carboxylic acid", "carboxylic acid" or "carboxyl" refers to the monovalent group -C(O)OH. Depending on the pH conditions, the monovalent group may be -C(O)O - Q + form, where Q + is a cation (e.g., sodium), or two monovalent groups in close proximity can react with a divalent cation Q 2+ (e.g., calcium, magnesium) bonding, or a combination of these divalent groups and -C(O)OH is present.

[0214] As used herein, the term "cycloalkyl" refers to an optionally substituted cyclic saturated monovalent bridged or non-bridged hydrocarbon radical containing 3-8 carbon atoms in one ring and up to 20 carbon atoms in a polycyclic group. Exemplary unsubstituted cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, norbornyl, and the like.

[0215] The term "alkylene" used as a prefix as part of another group refers to a divalent group in which one hydrogen is removed from each of the two terminal carbons of the group, or if the group is cyclic, from each of two different carbon atoms in the ring. For example, alkylene refers to a divalent alkyl group such as methylene (-CH2-) or vinyl (-CH2CH2-), and arylene refers to a divalent aryl group such as o-phenylene, m-phenylene or p-phenylene.

[0216] As used herein, the term "ether moiety" refers to a divalent (ie, bifunctional) group including at least one ether bond (ie, -O-). For example, in Formula 3 or 33 as defined herein, the ether moiety may be -R A OR B -or-R A OR C OR B , where R A , R B and R C are independently alkylene.

[0217] The term "heteroaryl" as used herein alone or as part of another group refers to an optionally substituted monovalent monocyclic or bicyclic aromatic group of 5-10 ring atoms, wherein one or more, preferably 1, 2 or 3, of the ring atoms are heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon. Exemplary heteroaryl moieties include benzofuranyl, benzo[d]thiazolyl, isoquinolyl, quinolyl, thiazolyl, imidazolyl, oxazolyl, quinolyl, furanyl, thiazolyl, pyridinyl, furanyl, thienyl, pyridinyl, oxazolyl, pyrrolyl, indolyl, quinolyl, isoquinolyl, and the like.

[0218] The term "heterocycle" as used herein alone or as part of another group refers to a saturated or unsaturated monovalent monocyclic group of 4-8 ring atoms, wherein one or two atoms are heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms. In addition, the heterocycle may be fused to a phenyl or heteroaryl ring, provided that the entire heterocycle is not completely aromatic. Exemplary heterocyclic groups include the above-mentioned heteroaryls, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, etc.

[0219] The term "hydrocarbon" as used herein describes a compound or group consisting only of the elements carbon and hydrogen.

[0220] The term "phosphonate" or "phosphono" refers to a monovalent group

[0221] The term "phosphate" or "phosphoryl" refers to a monovalent group

[0222] The term "protected" as used herein alone or as part of another group refers to a group that blocks reactions on the protected portion of the compound but is easily removed under conditions mild enough not to disturb other substituents of the compound. For example, a protected carboxylic acid group -C(O)OP g or protected phosphate OP(O)(OH)OP g or protected phosphonic acid group -P(O)(OH)OP g Each has a protecting group P associated with the oxygen of the acid group g , where P gCan be alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, etc.), benzyl, silyl (for example, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), triphenylsilyl (TPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) etc.). Various protecting groups and their synthesis can be found in "Protective Groups in Organic Synthesis", TW Greene and PGM Wuts, John Wiley & Sons, 1999. When the term "protected" introduces a series of potentially protected groups, it is intended that the term is applicable to each member of the group. That is, the phrase "protected carboxylic acid group, phosphonic acid group or phosphoric acid group" should be interpreted as "protected carboxylic acid group, protected phosphonic acid group or protected phosphoric acid group". Likewise, the phrase "optionally protected carboxylic acid, phosphonic acid or phosphoric acid" should be interpreted as "optionally protected carboxylic acid, optionally protected phosphonic acid or optionally protected phosphoric acid".

[0223] The term "substituted" as in "substituted aryl", "substituted alkyl", etc. means that in the group in question (i.e., the alkyl, aryl or other group following the term), at least one hydrogen atom bonded to a carbon atom is replaced by one or more substituents, such as hydroxyl (-OH), alkylthio, phosphino, amido (-CON (R A )(R B ) where R A and R B are independently hydrogen, alkyl or aryl), amino (-N(R A )(R B ) where R A and R B independently hydrogen, alkyl or aryl), halo (fluoro, chloro, bromo or iodo), silyl, nitro (-NO2), ether (-OR A Where R A is an alkyl or aryl group), an ester group (-OC(O)R A Where R A is an alkyl or aryl group), a keto group (-C(O)R A Where R A alkyl or aryl), heterocyclyl, etc. When the term "substituted" introduces a list of possible substituted groups, it means that the term applies to each member of the group. That is, the phrase "optionally substituted alkyl or aryl" should be interpreted as "optionally substituted alkyl or optionally substituted aryl".

[0224] Having described the invention in detail, it will be apparent that modifications and variations are possible without departing from the scope of the invention as defined in the appended claims. Example

[0225] The following non-limiting examples are provided to further illustrate the present invention.

[0226] Example 1 :Sorbitol-loaded cross-linked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer

[0227] Methyl 2-fluoroacrylate (MeFA) was purchased and vacuum distilled before use. Divinylbenzene (DVB) (technical grade, 80%, isomer mixture) was purchased from Aldrich and used as received. 1,7-Octadiene (ODE), lauroyl peroxide (LPO), polyvinyl alcohol (PVA) (typically molecular weight 85,000-146,000, 87-89% hydrolyzed), sodium chloride (NaCl), disodium hydrogen phosphate heptahydrate (Na2HPO4·7H2O) and sodium dihydrogen phosphate monohydrate (NaH2PO4·H2O) were purchased from commercial sources and used as received.

[0228] In a reactor of suitable size with suitable stirring and other equipment, prepare a 90:5:5 weight ratio mixture of monomer organic phase by mixing methyl 2-fluoroacrylate, 1,7-octadiene and divinylbenzene. Add half part of lauroyl peroxide as initiator for polymerization. Prepare a stable aqueous phase from water, polyvinyl alcohol, phosphate, sodium chloride and sodium nitrite. Mix the aqueous phase and the monomer phase together under nitrogen at atmospheric pressure while maintaining the temperature below 30°C. Gradually heat the reaction mixture while stirring continuously. Once the polymerization reaction starts, raise the temperature of the reaction mixture to a maximum of 95°C.

[0229] After the polymerization reaction is completed, the reaction mixture is cooled and the aqueous phase is removed. Water is added, the mixture is stirred, and the solid matter is separated by filtration. The solid is then washed with water to obtain a crosslinked (2-fluoro methyl acrylate)-divinylbenzene-1,7-octadiene copolymer. (2-fluoro methyl acrylate)-divinylbenzene-1,7-octadiene copolymer is hydrolyzed with an excess of sodium hydroxide aqueous solution at 90 ° C for 24 h to obtain (2-fluoro acrylate sodium)-divinylbenzene-1,7-octadiene copolymer. After hydrolysis, the solid is filtered and washed with water. (2-fluoro acrylate sodium)-divinylbenzene-1,7-octadiene copolymer is exposed to an excess of calcium chloride aqueous solution at room temperature to obtain an insoluble crosslinked (2-fluoro acrylate calcium)-divinylbenzene-1,7-octadiene copolymer.

[0230] After calcium ion exchange, the wet polymer was slurried with a 25-30% w / w sorbitol aqueous solution at ambient temperature to obtain a sorbitol-loaded polymer. Excess sorbitol was removed by filtration. The resulting polymer was dried at 20-30°C until the desired moisture content (10-25 w / w / %) was reached. This provided a sorbitol-loaded crosslinked (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer (5016CaS).

[0231] Example 2 :Phase II clinical study

[0232] Study Design Overview. The study had two 5016CaS treatment periods: an 8-week treatment induction period followed by an additional 44-week long-term maintenance period, thus allowing a total of up to one year (i.e., 52 weeks) of treatment with 5016CaS. Eligible non-hyperkalemic patients began a 1-4 week run-in period during the continuation period (Cohorts 1 and 2). Eligible hyperkalemic patients immediately began treatment with 5016CaS (Cohort 3). The first occurrence of serum potassium (K + )>5.0–<6.0 mEq / L, eligible patients from all 3 groups were assigned to one of two strata according to baseline serum potassium and received 5016CaS treatment at a randomized starting dose ranging from 10 to 40 g / day. The dose was calculated as the amount of polymer anion plus calcium (e.g., as water and sorbitol free radicals). A 10 g dose of polymer anion plus calcium was equivalent to an 8.4 g dose of polymer anion. The study duration for each patient was up to 62 weeks (including screening and follow-up processes) and the study population was approximately 306 patients. Study variables included changes in serum potassium, blood pressure, estimated GFR, and ACR.

[0233] Eligible patients were assigned to one of two 5016CaS treatment strata, with stratum 1 consisting of serum K + Patients with serum K >5.0–5.5 mEq / L were randomized in a 1:1:1 ratio within each cohort to receive 10 g / day, 20 g / day, or 30 g / day of 5016CaS starting dose. + Patients with >5.5–<6.0 mEq / L were randomized in a 1:1:1 ratio within each cohort to receive a starting dose of 20 g / day, 30 g / day, or 40 g / day 5016CaS.

[0234] Patients started 5016CaS treatment at their assigned dose level on the evening of Day 1. They continued to take losartan 100 mg / d (with or without spironolactone 25-50 mg / d) or pre-study ACEI and / or ARB with spironolactone 25-50 mg / d (according to their Cohort 1 or 2 assignment), as well as any other protocol-permitted antihypertensive therapy. Patients in Cohort 3 continued their pre-study ACEI and / or ARB.

[0235] 5016CaS administration dose and route. 5016CaS was taken orally twice daily in equal doses starting from day 1 for 52 weeks (only in the evening). Patients took 5016CaS twice daily and had regular meals (breakfast and dinner). From day 3, the 5016CaS dose was adjusted as needed according to the appropriate titration algorithm (treatment start or long-term maintenance) and the visit was made to week 51. The minimum allowed dose was 0 g / d (5016CaS was not dispersed) and the maximum dose was 60 g / d.

[0236] Figure 1-5 , potassium reduction, hematological control, changes in eGFR, and changes in proteinuria were examined by the following patient subtypes: (1) patients with any amount of protein in the urine, (2) patients with microalbuminuria, (3) patients with macroalbuminuria, and (4) patients with stage 4 chronic kidney disease (CKD). Figure 1 It was shown that these patient types all experienced a decrease in serum potassium. Figure 2 and 3 Blood pressure was shown to be lowered and 5016CaS was equally effective in lowering blood in all patient types. Figure 4 It showed that the proteinuria level was not significantly increased in any patient type, so 5016CaS effectively stabilized the protein excretion of patients. Figure 5 Renal function appeared to be stable in all patients, with improvement possible in patients with stage 4 CKD.

[0237] 182 patients completed the study protocol and were analyzed as per this Example 2. A statistically significant number of these patients had an albumin creatinine ratio (ACR) ≥ 30 mg / g at baseline while the rest had an ACR > 300 mg / g and an estimated glomerular filtration rate (eGFR) of 15-44 mL / min / 1.73 m 2For all these patients, serum potassium concentrations decreased from a mean of 5.27 mEq / L at baseline to a mean of 4.57 mEq / L at week 24. For patients with ACR ≥ 30 mg / g, serum potassium concentrations decreased from a mean of 5.28 mEq / L at baseline to a mean of 4.60 mEq / L at week 24. For patients with ACR > 300 mg / g, serum potassium concentrations decreased from a mean of 5.35 mEq / L at baseline to a mean of 4.65 mEq / L at week 24. For patients with eGFR 15-44 mL / min / 1.73 m 2 For patients treated with PD-1, serum potassium concentrations decreased from a mean of 5.33 mEq / L at baseline to a mean of 4.59 mEq / L at week 24.

[0238] For eGFR of 15-44 mL / min / 1.73 m 2 For patients with 2 Increased to an average of 38 mL / min / 1.73 m 2 This increase in eGFR was statistically significant for these patients.

[0239] For all groups and for patients in each group (e.g., ACR ≥ 30 mg / g, ACR > 300 mg / g, eGFR 15-44 mL / min / 1.73 m 2 ), ACR did not change significantly after the 24-week treatment period.

[0240] For all these patients, systolic blood pressure decreased from a mean of 154 at baseline to a mean of 137 at week 24 and diastolic blood pressure decreased from a mean of 83 at baseline to a mean of 74 at week 24. For patients with ACR ≥ 30 mg / g, systolic blood pressure decreased from a mean of 154 at baseline to a mean of 138 at week 24 and diastolic blood pressure decreased from a mean of 84 at baseline to a mean of 74 at week 24. For patients with ACR > 300 mg / g, systolic blood pressure decreased from a mean of 154 at baseline to a mean of 137 at week 24 and diastolic blood pressure decreased from a mean of 86 at baseline to a mean of 73 at week 24. For patients with eGFR 15-44 mL / min / 1.73 m 2 For patients treated with the drug, systolic blood pressure decreased from a mean of 152 at baseline to a mean of 135 at week 24, and diastolic blood pressure decreased from a mean of 82 at baseline to a mean of 73 at week 24.

[0241] Figure 6-9 One-year data from a group of 90 patients with pre-existing hyperkalemia who were taking a stable dose of a RAAS inhibitor without a run-in period are presented. The figures show renal function ( Figure 6 ) and urinary protein excretion ( Figure 8 ) appears stable, serum potassium ( Figure 7 ) and blood pressure ( Fig. 9 When analyzing the 12-month data for these patients, the mean eGFR at baseline (BL) was 46 mL / min / 1.73 m 2 , at 1 month (M1) it was 49 mL / min / 1.73 m 2 , 51 mL / min / 1.73 m at 2 months (M2) 2 , 49 mL / min / 1.73 m at 6 months (M6) 2 and 48 mL / min / 1.73 m at 12 months (M12) 2 ( Figure 6 There was no significant change in eGFR in these patients during the 12-month treatment period. These patients also experienced a significant reduction in serum potassium levels. Figure 7 ) For example, the mean serum potassium level was 5.3 mEq / L at baseline (BL), 4.5 mEq / L at 1 month (M1), 4.5 mEq / L at 2 months (M2), 4.6 mEq / L at 6 months (M6) and 4.6 mEq / L at 12 months (M12). Also the mean urine ACR for these patients was 853 mg / g at baseline (BL), 900 mg / g at 1 month (M1), 971 mg / g at 2 months (M2), 930 mg / g at 6 months (M6) and 802 mg / g at 12 months (M12). The mean systolic blood pressure of these patients was 157 mmHg at baseline (BL), 138 mmHg at 1 month (M1), 139 mmHg at 2 months (M2), 138 mmHg at 6 months (M6) and 134 mmHg at 12 months (M12). The mean diastolic blood pressure was 85 mmHg at baseline (BL), 74 mmHg at 1 month (M1), 73 mmHg at 2 months (M2), 73 mmHg at 6 months (M6) and 77 mmHg at 12 months (M12).

[0242] The mean change in serum potassium from baseline to Week 4 or first dose titration, whichever occurred first, is presented by stratum group in Table 1. To be consistent with the study protocol, the most recent nonmissing measurement of serum potassium was used for patients who were not titrated before the 4-week visit (last observation carried forward, or LOCF). 5016CaS reduced serum potassium in all dose groups in both strata; the p value indicated that the reduction was statistically significantly different from zero. The reference group for both strata was the randomized starting dose selected for the Phase III study.

[0243]

[0244] 5016CaS reduced serum potassium in all dose groups in both strata, regardless of dose titration starting as early as day 3 and stabilizing approximately after week 2. Most patients in all dose groups in both strata were able to maintain serum potassium within the range of 4.0 mEq / L-5.0 mEq / L before and after dose titration.

[0245] The primary outcome, mean change from baseline in serum potassium at week 4 or first 5016CaS dose titration, analyzed using a parallel lines ANCOVA model, was 0.47 ± 0.038 (p < 0.001) in S1 and -0.90 ± 0.076 (p < 0.001) in S2. The mean K reduction after a median of 2 days of treatment was -0.29 ± 0.03 (S1) and -0.55 ± 0.05 mEq / L (S2). Table 2 summarizes the means and changes from baseline, allowing for titration.

[0246] Table 2.

[0247]

[0248] 5016CaS reduced serum K within the first few days of treatment, and the effect lasted for 12 months without obvious side effects.

[0249] Example 3 : Analysis of systolic blood pressure from a phase II clinical study

[0250] The following section contains the results of repeated measures analysis of mean systolic blood pressure during the 8-week treatment initiation period of the Phase II clinical study disclosed in Example 2. Tables 3 to 6 present an analysis of mean changes from baseline. Tables 3 and 4 present the results for all patients; Tables 5 and 6 present the subgroups analyzed according to hyperkalemia status at screening (Cohort 3). In general, patients in stratum group 2 (serum K + >5.5–<6.0 mEq / L) compared with patients in stratum 1 (serum K + >5.0–5.5 mEq / L) experienced smaller mean changes in BP. Patients in Cohort 3 who participated in the hyperkalemia study but not in the run-in period resulted in a decrease in mean systolic BP (Tables 5 and 6).

[0251] For Tables 3-6, the header counts include all randomized patients who received RLY5016 at each randomized starting dose within the stratum group (intention-to-treat population). Data were obtained from mixed models for repeated measures, where the outcome variable was change from baseline in systolic blood pressure (SBP). Each stratum group was analyzed separately. Each model contained a visit-by-visit interaction for fixed effects of group, randomized starting dose, time (visit), continuous baseline SBP, and randomized starting dose. Within-patient correlations were modeled using a heterogeneous Toeplitz structure. Estimates, standard errors (SEs), and confidence intervals for each randomized starting dose were generated using linear contrasts of the observed values ​​for the covariates. Overall estimates, standard errors (SEs), and confidence intervals for the randomized treatment groups were evenly distributed across treatment groups. The total number of patients analyzed, N, was determined by the number of randomized patients who received RLY5016, had a baseline measurement, and contributed at least one post-baseline measurement to the analysis. Not all patients contributed a measurement at every visit.

[0252] Table 3. Mean change from baseline in systolic blood pressure for all patients in stratum 1, estimated by randomized starting dose

[0253]

[0254] 4. Mean change from baseline in systolic blood pressure for all patients in stratum 2 estimated by randomized starting dose

[0255]

[0256] Table 5. Mean Change from Baseline in Systolic Blood Pressure in Patients with Hyperkalemia at Screening in Stratum 1 Estimated by Randomized Starting Dose

[0257]

[0258] 6. Mean change from baseline in systolic blood pressure in patients with hyperkalemia at screening in stratum 2 estimated by randomized starting dose

[0259]

[0260] Example 4 : Analysis of diastolic blood pressure from a phase II clinical study

[0261] This section contains the results of repeated measures analysis of mean diastolic blood pressure during the 8-week treatment initiation period of the Phase II clinical study disclosed in Example 2. Tables 7 to 10 present an analysis of the mean change in diastolic blood pressure from baseline. Tables 7 and 8 present the results for all patients; Tables 9 and 10 present the subgroups analyzed according to hyperkalemia status at screening (Cohort 3). Patients in both the cohort and stratum groups experienced a mean modest reduction in diastolic blood pressure.

[0262] For Tables 7-10, the header counts include all randomized patients who received RLY5016 at each randomized starting dose within the stratum group (intention-to-treat population). Data were obtained from mixed models for repeated measures, where the outcome variable was change from baseline in diastolic blood pressure (DBP). Each stratum group was analyzed separately. Each model contained a visit-by-visit interaction for fixed effects of group, randomized starting dose, time (visit), continuous baseline DBP, and randomized starting dose. Within-patient correlations were modeled using a heterogeneous Toeplitz structure. Estimates, standard errors (SEs), and confidence intervals for each randomized starting dose were generated using linear contrasts of the observed values ​​for the covariates. Overall estimates, standard errors (SEs), and confidence intervals for the randomized treatment groups were evenly distributed across treatment groups. The total number of patients analyzed, N, was determined by the number of randomized patients who received RLY5016, had a baseline measurement, and contributed at least one post-baseline measurement to the analysis. Not all patients contributed a measurement at every visit.

[0263] Table 7. Mean Change from Baseline in Diastolic Blood Pressure for All Patients in Stratum 1 Estimated by Randomized Starting Dose

[0264]

[0265] 8. Mean change from baseline in diastolic blood pressure for all patients in stratum 2 estimated by randomized starting dose

[0266]

[0267] 9. Mean change from baseline in diastolic blood pressure in patients with hyperkalemia at screening in stratum 1 estimated by randomized starting dose

[0268]

[0269] 10. Mean change from baseline in diastolic blood pressure in patients with hyperkalemia at screening in stratum 2 estimated by randomized starting dose

[0270]

[0271] Embodiment 5: Study on the relationship between serum potassium and serum aldosterone levels

[0272] Male, uninephrectomized, spontaneously hypertensive rats (SHR) (N=32) were used in the experimental groups of this study. Non-manipulated SHR (N=6) were used as the control group. Animals were adapted to low Ca 2+ and Mg 2+The diet of the experimental group was then switched to a diet supplemented with spironolactone (0.4% w / w, TD120436) and the drinking water was supplemented with amiloride (0.05 mM) and quinapril (30 mg / L) for the duration of the study.

[0273] Animals in the control group were maintained on the TD04498 diet and unsupplemented water for the duration of the study.

[0274] All animals had baseline blood draws after day 16. Animals were randomized into 4 groups based on baseline serum potassium levels and received potassium binder treatment regimens as described in the table below.

[0275] Group treat N 1 TD120436 (untreated) 8 2 TD120436+2% potassium binder 8 3 TD120436+4% potassium binder 8 4 TD120436+6% potassium binder 8 5 Comparison 6

[0276] Blood, feces, and urine were collected 9 and 15 days after the start of the treatment regimen. Proximal and distal gastrointestinal segments were harvested at the end of the study. Serum, fecal, and urine potassium levels and serum aldosterone levels were determined at each time point.

[0277] Serum potassium levels (mmol / L) were analyzed for control, untreated, and experimental groups at baseline, day 9, and day 15. Mean serum potassium reduction levels compared to the untreated group were -9.1% (2% potassium binders), -18.2% (4% potassium binders), and -20.3% (6% potassium binders) at day 9, and -6.9% (2% potassium binders), -13.2% (4% potassium binders), and -17.4% (6% potassium binders) at day 15. Significant reductions in serum potassium levels were observed in all groups treated with potassium binders on day 9 and at the two higher doses on day 15 compared to the untreated group. Two-way ANOVA with Bonferroni post hoc test was used for analysis (**P<0.01; ***P<0.001 compared to the untreated group).

[0278] Serum aldosterone levels (pg / mL) of the control, untreated, and experimental groups at baseline, day 9, and day 15 were also analyzed. Mean serum aldosterone reduction levels compared to the untreated group were -22.7% (2% potassium binders), -53.0% (4% potassium binders), and -57.6% (6% potassium binders) at day 9, and -16.6% (2% potassium binders), -37.9% (4% potassium binders), and -50.3% (6% potassium binders) at day 15. Significant reductions in serum aldosterone levels were observed in all groups treated with potassium binders at day 9 and at the two higher doses at day 15 compared to the untreated group. Two-way ANOVA with Bonferroni post hoc test was used for analysis (*P<0.05; **P<0.01; ***P<0.001 compared to the untreated group).

[0279] There were no differences in urinary potassium excretion levels among all treatment groups.

[0280] Studies have shown that a decrease in serum aldosterone was observed with a decrease in serum potassium.

[0281] When introducing elements of the present invention or the preferred embodiments thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements besides the listed elements.

[0282] In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

[0283] As various changes could be made in the above method without departing from the scope of the invention, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.

Claims

1. A method of treating hypertension (HTN) in a patient in need thereof, the method comprising administering to a patient suffering from hyperkalemia or proteinuria an effective amount of a potassium binder, wherein when the potassium binder is a polymer, the polymer comprises an aliphatic cross-linked cation exchange polymer, 5 mol% to 15 mol% of the cross-linker of the polymer.

2. A method of treating hypertension in a patient in need thereof, the method comprising administering to a patient suffering from hyperkalemia or proteinuria an effective amount of a potassium binder, wherein when the potassium binder is a polymer, the polymer comprises a cross-linked cation exchange polymer other than a polystyrene cation exchange polymer and comprises 5 mol % to 12 mol % of a cross-linking agent.

3. The method of claim 1 or 2, wherein the patient suffers from hyperkalemia.

4. The method of any one of claims 1-3, wherein the patient suffers from proteinuria.

5. The method of any one of claims 1-4, wherein the patient suffers from chronic kidney disease.

6. The method of any one of claims 1-5, wherein the patient is receiving dialysis.

7. The method of any one of claims 1-6, wherein the patient is being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent.

8. The method of any one of claims 1 to 7, wherein the crosslinked cation exchange polymer is in its salt or acid form and is the reaction product of a polymerization mixture comprising monomers of (i) Formula 11 and 22, (ii) Formula 11 and 33, or (iii) Formula 11, 22, and 33, wherein Equation 11, Equation 22, and Equation 33 are represented by the following structure: And among them R1 and R2 are each independently hydrogen, alkyl, cycloalkyl or aryl; A 11 is an optionally protected carboxylic acid group, phosphonic acid group or phosphoric acid group; X1 is an arylene group; and X2 is an alkylene group, an ether moiety or an amide moiety.

9. The method according to claim 8, wherein A 11 is a protected carboxylic acid group, phosphonic acid group or phosphoric acid group.

10. The method according to claim 8 or 9, wherein the polymerization mixture further comprises a polymerization initiator.

11. The method according to any one of claims 1 to 7, wherein the cross-linked cation exchange polymer comprises structural units corresponding to Formulas 1, 2 and 3, wherein (i) based on the total weight of the structural units of formulae 1, 2 and 3 in the polymer, calculated from the amount of monomers used in the polymerization reaction, the structural unit corresponding to formula 1 constitutes at least about 85 weight percent, and the weight ratio of the structural unit corresponding to formula 2 to the structural unit corresponding to formula 3 is from about 4:1 to about 1:4, or (ii) the mole fraction of the structural unit of formula 1 in the polymer is at least about 0.87, and the molar ratio of the structural unit of formula 2 to the structural unit of formula 3 is from about 0.2:1 to about 7:1, based on the total moles of the structural units of formulas 1, 2 and 3, calculated from the amount of monomers used in the polymerization reaction, and Formula 1, Formula 2 and Formula 3 correspond to the following structures: in R1 and R2 are each independently hydrogen, alkyl, cycloalkyl or aryl; A 11 is a carboxylic acid group, a phosphonic acid group or a phosphoric acid group in the form of its salt or acid; X1 is an arylene group; X2 is an alkylene group, an ether moiety or an amide moiety.

12. The method according to claim 11, wherein Formula 1, Formula 2 and Formula 3 correspond to the following structures:

13. The method according to any one of claims 8 or 11, wherein X2 of Formula 3 or 33 is (a) selected from -(CH2) d -O-(CH2) e -or-(CH2) d -O-(CH2) e -O-(CH2) d- The ether portion of the formula -C(O)-NH-(CH2) p -NH-C(O)-, wherein p is an integer from 1 to 8, or (c) Formula 3 or 33 is a mixture of structural units having an ether portion and an amide portion.

14. The method according to claim 13, wherein X2 is an ether moiety, d is an integer from 1 to 2, and e is an integer from 1 to 3.

15. The method of any one of claims 1-7, wherein the potassium binding agent is a zeolite.

16. The method of any one of claims 1-14, wherein the crosslinked cation exchange polymer is in the form of generally spherical particles having an average diameter of about 20 μm to about 200 μm and less than about 4% by volume of the particles have a diameter less than about 10 μm, and the crosslinked cation exchange polymer has a sedimentation yield stress of less than about 4000 Pa and a swelling ratio of less than 10 grams of water / gram of polymer.

17. The method of any one of claims 1 to 14, wherein the crosslinked cation exchange polymer is in the form of generally spherical particles having an average diameter of less than about 250 μm and less than about 4% by volume of the particles have a diameter of less than about 10 μm, and wherein the crosslinked cation exchange polymer has a swelling ratio of less than 10 grams of water per gram of polymer, and wherein the viscosity of the hydrated and deposited mass of polymer particles is less than about 1,000,000 Pa·s, wherein the viscosity is less than about 0.01 sec·s. -1 Measured at a shear rate of .

18. The method of claim 16 or 17, wherein the average diameter is from about 25 μm to about 150 μm.

19. The method of claim 16 or 17, wherein the average diameter is from about 50 μm to about 125 μm.

20. The method of any one of claims 16-19, wherein less than about 0.5% by volume of the particles have a diameter less than about 10 μm.

21. The method of any one of claims 16-19, wherein less than about 4% by volume of the particles have a diameter less than about 20 μm.

22. The method of any one of claims 16-19, wherein less than about 0.5% by volume of the particles have a diameter less than about 20 μm.

23. The method of any one of claims 16-19, wherein less than about 4% by volume of the particles have a diameter less than about 30 μm.

24. The method of any one of claims 16-23, wherein the polymer has a swelling ratio of about 1 to about 5.

25. The method of any one of claims 16-23, wherein the polymer has a swelling ratio of about 1 to about 3.

26. The method of any one of claims 17-25, wherein the deposited yield stress is less than 4000 Pa.

27. The method of any one of claims 16-25, wherein the deposited yield stress is less than 3000 Pa.

28. The method of any one of claims 16-25, wherein the deposited yield stress is less than 2500 Pa.

29. The method of any one of claims 16 and 18-28, wherein the mass of polymer particles formed by hydration and deposition of the polymer has a viscosity of less than about 1,000,000 Pa·s at 0.01 sec. -1 Measured at a shear rate of .

30. The method of claim 29, wherein the viscosity of the deposited mass of particles is less than 800,000 Pa·s.

31. The method of claim 29, wherein the viscosity of the deposited mass of particles is less than 500,000 Pa·s.

32. The method of any one of claims 16-31, wherein the polymer particles in dry form have a compressibility index of less than about 14, wherein the compressibility index is defined as 100*(TD-BD) / TD, and BD and TD are bulk density and tap density, respectively.

33. The method of claim 32, wherein the compression index is less than about 10.

34. The method of any one of claims 16-33, wherein the average distance from peak to valley of the surface features of the particles is less than about 2 μm.

35. The method of any one of claims 1-34, wherein the potassium binding agent comprises a cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

36. A method of treating hypertension in a patient in need thereof, the method comprising administering to the patient an effective amount of a cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

37. The method of claim 36, wherein the cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form is administered chronically.

38. The method of any one of claims 1-37, wherein the patient's systolic blood pressure is reduced by 5, 6, 7, 8 mm Hg or more after 4 weeks of treatment with the potassium binder or the cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form compared to the patient's systolic blood pressure prior to treatment with the potassium binder or the cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

39. The method of any one of claims 1-37, wherein the patient's systolic blood pressure is reduced by 9, 10, 11, 12, 13, 14, 15, 16, 17 mm Hg or more after 4 weeks of treatment with the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form compared to the patient's systolic blood pressure prior to treatment with the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

40. The method of any one of claims 1-39, wherein the patient's diastolic blood pressure is reduced by 2, 3, 4, 5, 6 mm Hg compared to the patient's diastolic blood pressure prior to treatment with the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

41. The method of any one of claims 1-39, wherein the patient's diastolic blood pressure is reduced by 7, 8, 9, 10, 11, 12, 13 mm Hg or more compared to the patient's diastolic blood pressure prior to treatment with the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

42. The method of any one of claims 1-41, wherein the patient's systolic blood pressure is reduced by at least 6, 7, 8, 9, 10, 11, 12 or more percent compared to the patient's systolic blood pressure prior to treatment with the potassium binder or the cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

43. The method of any one of claims 1-42, wherein the patient's diastolic blood pressure is reduced by at least 8, 9, 10, 11, 12, 13, 14, 15 or more percent compared to the patient's diastolic blood pressure prior to treatment with the potassium binder or the cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

44. The method of any one of claims 1-43, wherein the patient has a systolic blood pressure of 130 to 200 mm Hg prior to treatment with the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

45. The method of any one of claims 1-43, wherein the patient has a systolic blood pressure of 135 mmHg to 200 mmHg prior to treatment with the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

46. ​​The method of any one of claims 1-43, wherein the patient has a systolic blood pressure of 140 to 200 mm Hg prior to treatment with the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

47. The method of any one of claims 1-43, wherein the patient's systolic blood pressure is between 143 mmHg and 200 mmHg prior to treatment with the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

48. The method of any one of claims 1-43, wherein the patient has a systolic blood pressure of 145 to 180 mm Hg prior to treatment with the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

49. The method of any one of claims 1-43, wherein the patient's systolic blood pressure is between 148 mmHg and 180 mmHg prior to treatment with the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

50. The method of any one of claims 1-49, wherein the patient's systolic blood pressure is maintained below 130 mm Hg after at least 90% of the cycles of treatment with the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

51. The method of any one of claims 1-50, wherein the patient's diastolic blood pressure is maintained below 80 mm Hg after at least 90% of the cycles of treatment with the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

52. The method of any one of claims 1-50, wherein the patient is not treated with an aldosterone antagonist.

53. The method of any one of claims 1-52, wherein the patient has no other conditions causing hypertension.

54. The method of claim 53, wherein the patient does not have type 2 diabetes.

55. The method of claim 53, wherein the patient does not have Class II or Class III heart failure (HF).

56. The method of any one of claims 1-55, wherein the patient is not treated with heart failure therapy.

57. The method of claim 56, wherein the heart failure therapy is an angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), beta blocker (BB), or a combination thereof.

58. The method of any one of claims 1-57, wherein the patient is not treated with an antihypertensive agent comprising a diuretic, a calcium channel blocker, an alpha blocker, a nervous system depressant, a vasodilator, an angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), a beta blocker (BB), or a combination thereof.

59. The method of any one of claims 1, 2, and 4-58, wherein the patient has normokalemia.

60. A method of treating hypertension in a chronic kidney disease patient in need thereof, said patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, said method comprising administering to said patient an effective amount of a potassium binder.

61. A method of treating hypertension in a heart failure patient in need thereof, said patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, said method comprising administering to said patient an effective amount of a potassium binder.

62. A method of treating hypertension in a type 2 diabetic patient in need thereof, said patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, said method comprising administering to said patient an effective amount of a potassium binder.

63. The method of any one of claims 60-62, wherein the potassium binding agent is a cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

64. The method of claims 60 and 63, wherein the patient also suffers from heart failure and type 2 diabetes.

65. The method of any one of claims 61-63, wherein the patient also has chronic kidney disease.

66. The method of claim 62 or 63, wherein the patient also suffers from heart failure.

67. The method of any one of claims 60-66, wherein the patient's systolic blood pressure is reduced by 5, 6, 7, 8 mm Hg compared to the patient's systolic blood pressure prior to treatment with the potassium binder.

68. The method of any one of claims 60-66, wherein the patient's systolic blood pressure is reduced by more than 9, 10, 11, 12, 13, 14, 15, 16, 17 mm Hg compared to the patient's systolic blood pressure prior to treatment with the potassium binder.

69. The method of any one of claims 60-68, wherein the patient's diastolic blood pressure is reduced by 2, 3, 4, 5, 6 mm Hg compared to the patient's diastolic blood pressure prior to treatment with the potassium binder.

70. The method of any one of claims 60-68, wherein the patient's diastolic blood pressure is reduced by 7, 8, 9, 10, 11, 12, 13 mm Hg or more compared to the patient's diastolic blood pressure prior to treatment with cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

71. The method of any one of claims 60-66 and 68-70, wherein the patient's systolic blood pressure is reduced by at least 6, 7, 8, 9, 10, 11, 12, or more percent compared to the patient's systolic blood pressure prior to treatment with the potassium binder.

72. The method of any one of claims 60-68, 70, and 71, wherein the patient's diastolic blood pressure is reduced by at least 8, 9, 10, 11, 12, 13, 14, 15, or more percent compared to the patient's diastolic blood pressure prior to treatment with the cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

73. A method of treating hyperkalemia in a chronic kidney disease patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising: Administering an effective amount of a potassium binder to the patient and observing a decrease in the patient's serum creatinine level compared to the patient's serum creatinine level before treatment with the potassium binder indicates that the patient's renal function has improved or stabilized.

74. A method of treating hyperkalemia in a chronic kidney disease patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising: Administering an effective amount of a potassium binder to the patient and observing an increased time to progression of end-stage renal disease compared to a chronic kidney disease patient optionally treated with a RAAS agent but not treated with the potassium binder indicates that the patient's renal function is improving or stabilizing.

75. A method of treating hyperkalemia in a chronic kidney disease patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising: Administering an effective amount of a potassium binder to the patient and observing an increased survival rate compared to chronic kidney disease patients optionally treated with a RAAS agent but not treated with the potassium binder indicates that the patient's renal function has improved or stabilized.

76. A method of treating hyperkalemia in a chronic kidney disease patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising: Administering an effective amount of a potassium binder to the patient and observing an increase or stabilization in estimated glomerular filtration rate (eGFR) compared to the patient's eGFR prior to treatment with the potassium binder indicates that the patient's renal function has improved or stabilized.

77. A method of treating chronic kidney disease in a patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising: An effective amount of a potassium binder is administered to the patient to enhance or stabilize the patient's renal function by reducing the patient's serum creatinine level as compared to the patient's serum creatinine level prior to treatment with the potassium binder.

78. A method of treating chronic kidney disease in a patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising: An effective amount of a potassium binder is administered to the patient to enhance or stabilize the patient's renal function by increasing the time to progression of end stage renal disease compared to a chronic kidney disease patient optionally treated with a RAAS agent but not treated with the potassium binder.

79. A method of treating chronic kidney disease in a patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising: An effective amount of a potassium binder is administered to the patient to enhance or stabilize the patient's renal function by increasing survival compared to chronic kidney disease patients optionally treated with a RAAS agent but not treated with the potassium binder.

80. A method of treating chronic kidney disease in a patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising: An effective amount of a potassium binder is administered to the patient to enhance or stabilize the patient's renal function by increasing or stabilizing the patient's estimated glomerular filtration rate (eGFR) as compared to the patient's eGFR prior to treatment with the potassium binder.

81. The method of any one of claims 73-80, wherein the potassium binding agent is a cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form.

82. The method of any one of claims 77-80, further comprising treating hyperkalemia in a patient in need thereof.

83. The method of any one of claims 1-82, wherein the treatment period is 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 weeks or more.

84. The method of any one of claims 1-83, wherein the patient has a baseline estimated glomerular filtration rate (eGFR) of about 15 mL / min / 1.73 m 2 to about 44mL / min / 1.73m 2 .

85. The method of any one of claims 1-84, wherein the patient's eGFR after treatment with the potassium binder is not significantly different from the patient's eGFR before treatment with the potassium binder.

86. The method of any one of claims 1-85, wherein after 2, 3, 4, 5, 6 months or longer of treatment, the patient's eGFR is increased compared to the patient's eGFR prior to treatment with the potassium binder.

87. The method of claim 86, wherein the patient's eGFR after treatment with the potassium binder is increased by at least 4, 5, 6 mL / min / 1.73 m2 compared to the patient's eGFR before treatment with the potassium binder. 2 .

88. The method of any one of claims 1-87, wherein after 1, 2, 3, 4, 5, 6, 7 days or more of treatment, the patient's serum potassium level is reduced compared to the patient's serum potassium level prior to treatment with the potassium binding agent.

89. The method of any one of claims 1-88, wherein after 2, 3, 4, 5, 6 months or longer of treatment, the patient's urine albumin:creatinine ratio (ACR) is not significantly different compared to the patient's urine ACR prior to treatment with the potassium binder.

90. The method of any one of claims 60-89, wherein after 1, 2, 3, 4, 5, 6, 7 days or more of treatment, the patient's systolic and diastolic blood pressure are reduced compared to the patient's systolic and diastolic blood pressure prior to treatment with the potassium binder.

91. The method of claim 90, wherein the patient's systolic blood pressure is reduced by 5, 6, 7, 8 mm Hg or more compared to the patient's systolic blood pressure prior to treatment with the potassium binder.

92. The method of claim 90, wherein the patient's systolic blood pressure is reduced by 9, 10, 11, 12, 13, 14, 15, 16, 17 mm Hg or more compared to the patient's systolic blood pressure prior to treatment with the potassium binder.

93. The method of any one of claims 90-92, wherein the patient's diastolic blood pressure is reduced by 2, 3, 4, 5, 6 mm Hg compared to the patient's diastolic blood pressure prior to treatment with the potassium binder.

94. The method of any one of claims 90-92, wherein the patient's diastolic blood pressure is reduced by 7, 8, 9, 10, 11, 12, 13 mm Hg or more compared to the patient's diastolic blood pressure prior to treatment with the potassium binder.

95. The method of any one of claims 90 and 92-94, wherein the patient's systolic blood pressure is reduced by at least 6, 7, 8, 9, 10, 11, 12 or more percent compared to the patient's systolic blood pressure prior to treatment with the potassium binder.

96. The method of any one of claims 90-92, 94, and 95, wherein the patient's diastolic blood pressure is reduced by at least 8, 9, 10, 11, 12, 13, 14, 15, or more percent compared to the patient's diastolic blood pressure prior to treatment with the potassium binder.

97. The method of any one of claims 1-96, wherein after 4 weeks or more of treatment, the patient's serum aldosterone level is reduced compared to the patient's serum aldosterone level prior to treatment with the potassium binder.

98. The method of any one of claims 1-97, wherein the effective amount of the potassium binder comprises a maximum daily dose of up to 60 g.

99. The method of claim 98, wherein the effective amount of the potassium binder comprises a daily dose of 10 g to 60 g.

100. The method of claim 98, wherein the effective amount of the potassium binder comprises a daily dose of 18 g-40 g.

101. The method of any one of claims 1-100, wherein the dosage is adjusted to maintain the patient's serum potassium level within a normal range.

102. The method of any one of claims 35-59, 63-72, and 81-101, wherein the crosslinked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form is in salt form.

103. The method of claim 102, wherein the salt form comprises sodium, calcium, magnesium, ammonium, or a combination thereof.

104. The method of claim 103, wherein the salt form comprises a calcium salt form.

105. The method of any one of claims 102-104, wherein the crosslinked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt form is stabilized with a linear polyol.

106. The method of claim 105, wherein the cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt form is stabilized with sorbitol.

107. The method of any one of claims 1-106, wherein the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form exhibits long-term tolerability in the patient.

108. The method of any one of claims 1-107, wherein the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form exhibits long-term safety in the patient.

109. The method of any one of claims 1-108, wherein the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form exhibits long-term efficacy in the patient.

110. The method of any one of claims 1-109, wherein the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form is administered daily to the patient for more than 8 weeks.

111. The method of any one of claims 1-109, wherein the potassium binder or cross-linked 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer in salt or acid form is administered daily to the patient for more than one year.

112. The method of any one of claims 1-51, 53-55, and 59-111, wherein the patient is being treated or is further being treated with an effective amount of a RAAS agent, which is an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), an aldosterone antagonist (AA), an aldosterone synthase inhibitor, or a combination thereof.

113. The method of claim 112, wherein the RAAS agent is an ACE inhibitor, an ARB, or a combination thereof.

114. The method of claim 112 or 113, wherein the effective amount of the RAAS agent comprises the maximum daily tolerated dose.

115. The method of any one of claims 112-114, wherein the RAAS agent comprises fosinopril, ramipril, captopril, lisinopril, trandolapril, moexipril, quinapril, enalapril, benazepril, perindopril, eprosartan, olmesartan, losartan, telmisartan, valsartan, candesartan, irbesartan, azilsartan medoxomil, spironolactone, eplerenone, or a combination thereof.

116. The method of claim 115, wherein the RAAS agent comprises fosinopril and the maximum tolerated daily dose is 40 mg / day.

117. The method of claim 115, wherein the RAAS agent comprises ramipril and the maximum tolerated daily dose is 20 mg / day.

118. The method of claim 115, wherein the RAAS agent comprises captopril and the maximum tolerated daily dose is 300 mg / day.

119. The method of claim 115, wherein the RAAS agent comprises lisinopril and the maximum tolerated daily dose is 40 mg / day.

120. The method of claim 115, wherein the RAAS agent comprises trandolapril and the maximum tolerated daily dose is 4 mg.

121. The method of claim 115, wherein the RAAS agent comprises moexipril and the maximum tolerated daily dose is 30 mg / day.

122. The method of claim 115, wherein the RAAS agent comprises quinapril and the maximum tolerated daily dose is 80 mg / day.

123. The method of claim 115, wherein the RAAS agent comprises enalapril and the maximum tolerated daily dose is 40 mg / day.

124. The method of claim 115, wherein the RAAS agent comprises benazepril and the maximum tolerated daily dose is 40 mg / day.

125. The method of claim 115, wherein the RAAS agent comprises perindopril and the maximum tolerated daily dose is 8 mg / day.

126. The method of claim 115, wherein the RAAS agent comprises eprosartan and the maximum tolerated daily dose is 800 mg / day.

127. The method of claim 115, wherein the RAAS agent comprises Olmesartan and the maximum tolerated daily dose is 40 mg / day.

128. The method of claim 115, wherein the RAAS agent comprises losartan and the maximum tolerated daily dose is 100 mg / day.

129. The method of claim 115, wherein the RAAS agent comprises telmisartan and the maximum tolerated daily dose is 80 mg / day.

130. The method of claim 115, wherein the RAAS agent comprises valsartan and the maximum tolerated daily dose is 320 mg / day.

131. The method of claim 115, wherein the RAAS agent comprises candesartan and the maximum tolerated daily dose is 32 mg / day.

132. The method of claim 115, wherein the RAAS agent comprises irbesartan and the maximum tolerated daily dose is 300 mg / day.

133. The method of claim 115, wherein the RAAS agent comprises azilsartan medoxomil and the maximum tolerated daily dose is 80 mg / day.

134. The method of claim 115, wherein the RAAS agent comprises spironolactone and the maximum tolerated daily dose is 200 mg / day.

135. The method of claim 115, wherein the RAAS agent comprises eplerenone and the maximum tolerated daily dose is 50 mg / day.

136. The method of any one of claims 1-55 and 59-135, wherein the patient is further treated with an effective amount of a beta-adrenergic blocking agent.

137. The method of claim 136, wherein the beta-adrenergic blocking agent comprises betaxolol, bisoprolol, atenolol, metoprolol, nebivolol, metoprolol, esmolol, acebutolol, propranolol, nadolol, carvedilol, labetalol, sotalol, timolol, carteolol, penbutolol, pindolol, or a combination thereof.

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