HCI-binding compositions for and method of treating acid-base disorders

Abstract

To provide pharmaceutical compositions and methods for treating acid-base disorders, and to provide methods for making the compositions.SOLUTION: Provided is a method for treating an individual afflicted with an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq / l, the method comprising oral administration of a daily dose of a pharmaceutical composition having the capacity to bind at least 5 mEq of HCI as it transits the digestive system to achieve a clinically significant increase in the serum bicarbonate value of at least 1 mEq / l from a baseline within a treatment period within one month.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates generally to methods of treating acid-base disorders that can be used, for example, in the treatment of metabolic acidosis. [Background technology]

[0002] Metabolic acidosis occurs in various disease states when non-volatile acids accumulate in the body and cause the loss of protons (H + ) or hydrogen carbonate (HCO3 - Metabolic acidosis results from metabolic and dietary processes that result in the loss of filtered bicarbonate (HCO3 -Metabolic acidosis is often associated with a decline in the kidney's ability to excrete hydrogen ions, resulting in an inability to reabsorb potassium, synthesize ammonia, and excrete titratable acids. Clinical practice guidelines recommend initiating alkali therapy in patients with nondialysis-dependent chronic kidney disease (CKD) when serum bicarbonate levels are <22 mEq / L to prevent or treat complications of metabolic acidosis. (Clinical practice guidelines for nutrition in chronic renal failure, K / DOQI, National Kidney Foundation, Am. J. Kidney Dis. 2000; 35:S1-140; Raphael, KL, Zhang, Y, Wei, G, et al. 2013, Serum bicarbonate and mortality in adults in NHANES III, Nephrol. Dial. Transplant 28: 1207-1213) These complications include malnutrition and growth retardation in children, exacerbated bone disease, increased muscle breakdown, decreased albumin synthesis, and increased inflammation.(Leman, J, Litzow, JR, Lennon, EJ. 1966. The effects of chronic acid loads in normal man: further evidence for the participation of bone mineral in the defense against chronic metabolic acidosis, J. Clin. Invest. 45: 1608-1614; Franch, WE, Catch WE, 1998, in 1998). uremia: the impact of metabolic acidosis, J. Am. Farwell, WR, Taylor, EN, 2010, Serum anion gap, bicarbonate and biomarkers of inflammation in healthy individuals in a national survey, CMAJ 182:137-141). 2Below this level, the majority of patients develop overt metabolic acidosis. (KDOQI bone guidelines: American Journal of Kidney Diseases (2003) 42:S1-S201. (suppl); Widmer B, Gerhardt RE, Harrington JT, Cohen JJ, Serum electrolyte and acid base composition: The influence of graded degrees of chronic renal failure, Arch Intern Med139:1099-1102, 1979; Dobre M, Yang, W, Chen J, et. al., Association of serum bicarbonate with risk of renal and cardiovascular outcomes in CKD: a report from the chronic renal insufficiency cohort (CRIC) study. Am. J. Kidney Dis. 62: 670-678, 2013; Yaqoob, MM. Acidosis and progression of chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 19: 489-492, 2010).

[0003] Metabolic acidosis, regardless of etiology, decreases extracellular fluid bicarbonate and therefore extracellular pH. The correlation between serum pH and serum bicarbonate is determined by the Henderson-Hasselbalch equation. pH = pK' + log [HCO3 - ] / [(0.03 × PaCO2)] [where 0.03 is the physical solubility coefficient of CO2 and [HCO3 - ] and PaCO2 are the bicarbonate concentration and carbon dioxide partial pressure, respectively] is shown by

[0004] There are several laboratory tests that can be used to determine metabolic acidosis. The tests basically measure the level of bicarbonate (HCO3 - ) or proton (H + ) concentration. These tests measure either bicarbonate (HCO3 - ) or proton (H + ) concentration can be measured by enzymatic methods, ion-selective electrodes, or blood gas analysis. In both enzymatic and ion-selective electrode methods, bicarbonate is "measured." Using blood gas analysis, bicarbonate levels can be calculated using the Henderson-Hasselbalch equation:

[0005] Although arterial blood gas (ABG) analysis is commonly performed for clinical evaluation, it is a painful procedure and can cause complications such as arterial injury, thrombosis with distal ischemia, bleeding, aneurysm formation, median nerve injury, and reflex sympathetic dystrophy, resulting in reduced patient acceptance. Venous blood gas (VBG) analysis is relatively safer because it requires fewer punctures, thereby reducing the risk of needlestick injury for medical personnel. Therefore, as described below, when the present invention requires the evaluation of metabolic acidosis, it is preferable to complete this evaluation using VBG analysis. Any measurement specified herein is preferably achieved by VBG analysis, possibly measuring blood or serum bicarbonate levels, for example.

[0006] The most useful measurements for determining acidosis are venous plasma bicarbonate (or total carbon dioxide [tCO2]) or arterial plasma bicarbonate (or total carbon dioxide [tCO2]), serum electrolytes, and Cl. - , K. + and Na + In the clinical laboratory, measurement of venous plasma or serum electrolytes includes an estimation of tCO2. This measurement is based on the total circulating CO2 [i.e., bicarbonate (HCO3 -), carbonate (HCO3), and dissolved CO2 (0.03 × PCO2) reflects total CO2. tCO2 can also be calculated using the Henderson-Hasselbalch equation: tCO2 = HCO3 - +0.03PCO2 (where PCO2 is the measured CO2 partial pressure) - It can also be related to HCO3 - Venous tCO2 is often greater than venous HCO3 in the blood because its concentration is greater than 90% of tCO2 and there is a small amount of H2CO3 present. - It is used as a reasonable approximation of the concentration of abnormal plasma HCO3, especially in chronic kidney disease. - A value <22 mEq / L generally indicates metabolic acidosis.

[0007] Serum Cl - Changes in concentration, especially serum Na + Changes in concentration and imbalances can raise further considerations for a possible acid-base disorder. When this occurs, serum Cl - Changes in serum Cl concentration are typically related to reciprocal changes in serum bicarbonate. Therefore, in metabolic acidosis with a normal anion gap, serum Cl - increases by >105 mEq / L and serum bicarbonate decreases to <22 mEq / L.

[0008] Arterial blood gases are used to identify the type of acid-base disorder and to determine whether mixed imbalance is present. In general, arterial blood gas results must be reconciled with the medical history, physical examination, and the routine laboratory values ​​listed above. Arterial blood gases are used to measure arterial carbon dioxide tension (P a CO2), acidity (pH) and oxygen tension (P a Measure HCO3 - Concentration is calculated from pH and Paco2. Metabolic acidosis is characterized by a pH < 7.35, P a CO2 < 35 mmHg and HCO3 - <22 mEq / L. aO2 levels (normal 80-95 mmHg) are not used to diagnose metabolic acidosis, but they can help determine the cause. Acid-base imbalances are primarily classified as respiratory or metabolic. Respiratory imbalances are caused by abnormal pulmonary excretion of CO2, resulting in CO2 (carbon dioxide) excess (acidosis) or deficiency (alkalosis) in the extracellular fluid. In respiratory acid-base disorders, serum bicarbonate (HCO3 - ) is the first direct result of the change in Pco2, and further increases in Pco2 lead to HCO3 - (Adrogue HJ, Madias NE, 2003, Respiratory acidosis, respiratory alkalosis, and mixed disorders, in Johnson RJ, Feehally J (eds): Comprehensive Clinical Nephrology. London, CV Mosby, pp. 167-182). Metabolic disorders are caused by excessive uptake or metabolic production or loss of non-volatile acids or bases in the extracellular fluid. These changes result in an increase in the bicarbonate anion (HCO3 - ) and adaptation in this case may involve both buffering (immediate), respiratory (hours to days), and renal (days) mechanisms (DuBose TD, MacDonald GA: Renal tubular acidosis, 2002, in DuBose TD, Hamm LL (eds): Acid-base and electrolyte disorders: A companion to Brenners and Rector's the Kidney, Philadelphia, WB Saunders, pp. 189-206).

[0009] The total hydrogen ion concentration in the blood is determined by the amount of two components: serum HCO3 - It is defined by the ratio of PCO2 content (regulated by the kidney) and PCO2 content (regulated by the lung) and is expressed as follows: [H + ]∝(PCO2 / [HCO3 - ])

[0010] The result of the increase in overall hydrogen ion concentration is a decrease in bicarbonate, the main extracellular buffer. Normal blood pH is 7.38–7.42, with a hydrogen ion (H) concentration of 42–38 nmol / L. + ) concentration (Goldberg M: Approach to Acid-Base Disorders. 2005. In Greenberg A, Cheung AK (eds) Primer on Kidney Diseases, National Kidney Foundation, Philadelphia, Elsevier-Saunders, pp. 104-109). - ) is an anion that acts as a buffer against pH imbalances in the body, and normal plasma bicarbonate levels are in the range of 22-26 mEq / L (Szerlip HM: Metabolic Acidosis, 2005, in Greenberg A, Cheung AK (eds) Primer on Kidney Diseases, National Kidney Foundation, Philadelphia, Elsevier-Saunders, pp. 74-89). Acidosis causes a decrease in blood pH (acidemia) and a loss of hydrogen ions (H + ) reflects the accumulation of bicarbonate ions (HCO3 - The resulting buffering by ATP is the process that causes a decrease in serum bicarbonate. Metabolic acidosis can be described as: [ka] (Clinical practice guidelines for nutrition in chronic renal failure. K / DOQI, National Kidney Foundation. Am. J. Kidney Dis. 2000; 35:S1-140). Using this balanced equation, 1 HCO3 - The loss of one H + is equivalent to the addition of 1 HCO3- The acquisition of 1 H + Therefore, changes in blood pH, especially H + Increased serum HCO3 (lower pH, acidosis) - or equivalently, by an increase in serum H + This can be corrected by a reduction in

[0011] To maintain extracellular pH within normal limits, acid produced daily must be excreted from the body. Acid production in the body is the result of the metabolism of dietary carbohydrates, fats, and amino acids. The complete oxidation of these metabolic substrates produces water and CO2. The carbon dioxide produced by this oxidation (approximately 20,000 mmol / day) is efficiently exhaled through the lungs and represents the volatile acid component of acid-base balance.

[0012] In contrast, nonvolatile acids (approximately 50–100 mEq / day) are produced by the metabolism of sulfate- and phosphate-containing amino acids and nucleic acids. Additional nonvolatile acids (lactic, butyric, acetic, and other organic acids) result from the incomplete oxidation of fats and carbohydrates and from carbohydrate metabolism in the colon, where resident bacteria in the colonic lumen convert substrates into small organic acids, which are absorbed into the bloodstream. The effect of short-chain fatty acids on acidosis is minimized to some extent by their anabolism, e.g., to long-chain fatty acids, or by their catabolism to water and CO2.

[0013] The kidneys filter HCO3 to prevent global bicarbonate depletion. - The pH balance in the blood is maintained by two mechanisms: recycling of ATP and excretion of nonvolatile acids in the urine. Both mechanisms are necessary to prevent bicarbonate depletion and acidosis.

[0014] In the first mechanism, the kidneys convert HCO3 filtered by the glomeruli into - This recycling occurs in the proximal tubule, with approximately 4500 mEq / day of recycled HCO3 - This mechanism consists of HCO3 -In the second mechanism, the kidneys produce enough H to balance the daily production of nonvolatile acids through the metabolism and oxidation of proteins, fats, and carbohydrates. + The excretion of this acid load is + This is accomplished by two distinct pathways within the kidney, involving the active secretion of ions and the synthesis of ammonia. The net result of these two interconnected processes is the excretion of 50-100 mEq / day of nonvolatile acids produced by normal metabolism.

[0015] Therefore, normal renal function is necessary to maintain acid-base balance. During chronic kidney disease, HCO3 - Filtration and recycling of urea is impaired, inhibiting ammonia production and secretion. These defects rapidly lead to chronic metabolic acidosis, which is itself a strong precursor to end-stage renal disease. Decreased acid excretion with continued metabolic acid production leads to H + / HCO3 - This disrupts the balance, causing blood pH to fall below the normal range of pH 7.38 to 7.42.

[0016] Acid-base disorders are common in patients with chronic kidney disease and heart failure. Chronic kidney disease (CKD) gradually impairs renal excretion of approximately 1 mmol / kg body weight of hydrogen ions produced in healthy adults (Yaqoob, MM. 2010, Acidosis and progression of chronic kidney disease, Curr. Opin. Nephrol. Hyperten. 19:489-492). The accumulation of acid (H + ) or base depletion (HCO3 - ) metabolic acidosis is particularly common when the glomerular filtration rate (GFR, an indicator of renal function) is 30 ml / min / 1.73 m 2Metabolic acidosis is a common complication in CKD patients when their blood pressure drops below 100kJ / kg / day. Metabolic acidosis has profound long-term effects on protein and muscle metabolism, bone metabolism, and the development of renal dysplasia. Furthermore, metabolic acidosis affects a variety of paracrine and endocrine functions, with long-term consequences such as increased inflammatory mediators, decreased leptin, insulin resistance, and increased corticosteroid and parathyroid hormone production (Mitch WE, 1997, Influence of metabolic acidosis on nutrition, Am. J. Kidney Dis. 29:46-48). The net effect of persistent metabolic acidosis in CKD patients is bone and muscle loss due to hormonal and cellular abnormalities, negative nitrogen balance, and accelerated chronic renal failure (De Brito-Ashurst I, Varagunam M, Raftery MJ, et al., 2009, Bicarbonate supplementation slows progression of CKD and improves nutritional status, J. Am. Soc. Nephrol. 20: 2075-2084). Conversely, a potential concern with alkaline therapy in CKD patients is the expansion of extracellular fluid volume associated with sodium intake, which can lead to the development or exacerbation of hypertension, accelerated vascular calcification, and decompensation of existing heart failure. Patients with moderate CKD (GFR 20-25% of normal) initially develop hyperchloremic acidosis with a normal anion gap due to the inability to recycle filtered bicarbonate and the excretion of protons and ammonium cations. As CKD progresses to more advanced stages, the anion gap increases, reflecting a continuing decline in the kidney's ability to excrete anions that were previously bound to non-excreted protons. Serum bicarbonate in these patients rarely falls below 15 mmol / L, with a maximum anion gap of approximately 20 mmol / L.The accumulation of non-metabolizable anions in CKD is buffered by alkaline salts from bone (Lemann J Jr, Bushinsky DA, Hamm LL. Bone buffering of acid and base in humans. Am. J. Physiol. Renal Physiol. 2003 Nov, 285(5):F811-32).

[0017] The annual age-related decline in glomerular filtration rate (GFR) after age 40 is 0.75-1.0 ml / min / 1.73 m in normal individuals. 2 In patients with rapidly progressing CKD, >4 ml / min / 1.73 m / year 2 A rapid decline in glomerular filtration rate or estimated glomerular filtration rate is typically used to characterize kidney function and the stage of chronic kidney disease. The five stages of chronic kidney disease and the GFR for each stage are: Stage 1: Normal or high GFR (GFR > 90 mL / min / 1.73 m 2 ) Stage 2: Mild CKD (GFR = 60-89 mL / min / 1.73 m 2 ) Stage 3A: Moderate CKD (GFR = 45-59 mL / min / 1.73 m 2 ) Stage 3B: Moderate CKD (GFR = 30-44 mL / min / 1.73 m 2 ) Stage 4: Severe CKD (GFR = 15-29 mL / min / 1.73 m 2 ) Stage 5: End-stage CKD (GFR < 15 mL / min / 1.73 m 2 )

[0018] In one outcome study, De Brito-Ashurst et al. showed that bicarbonate supplementation preserves renal function in CKD (De Brito-Ashurst I, Varagunam M, Raftery MJ, et al, 2009, Bicarbonate supplementation slows progression of CKD and improves nutritional status, J. Am. Soc. Nephrol. 20: 2075-2084). This study examined patients with CKD (creatinine clearance [CrCl] 15-30 ml / min / 1.73 m 2 One hundred thirty-four adult patients with cerebrospinal fluid (CSF) and serum bicarbonate 16-20 mmol / L were randomly assigned to receive oral sodium bicarbonate supplementation or standard care for 2 years. The mean bicarbonate dose in this study was 1.82 g / day, providing 22 mEq of bicarbonate per day. The primary endpoint was the rate of CrCl decline, i.e., the rapid decline in CrCl (>3 ml / min / 1.73 mEq). 2 / year) and end-stage renal disease ("ESRD") (CrCl < 10 ml / min). Compared with the control group, the decline in CrCl slowed with bicarbonate supplementation (1.88 ml / min / 1.73 m in patients receiving bicarbonate). 2 The decrease was 5.93 ml / min / 1.73 m in the control group 2 (P<0.0001). Patients receiving supplemental bicarbonate were significantly less likely to experience rapid progression (9% vs. 45%; relative risk, 0.15; 95% confidence interval, 0.06 to 0.40; P<0.0001). Similarly, fewer patients receiving supplemental bicarbonate developed ESRD (6.5% vs. 33%; relative risk, 0.13; 95% confidence interval, 0.04 to 0.40; P<0.001).

[0019] Among the various aspects of the present disclosure, the following is a useful guide for one method of treating metabolic acidosis (without being bound by theory): + is pumped into the stomach, HCO3 - enters the systemic circulation and increases serum bicarbonate concentration.+ The initial binding of HCO3 to the non-absorbable composition - enters the systemic circulation, causing an increase in serum bicarbonate concentration. - Binding of luminal Cl to non-absorbable compositions - HCO3 - This prevents the subsequent exchange of HCO3 - The clinical situation analogous to administration of the composition is vomiting. Administration of the composition essentially causes a loss of gastric HCl, as occurs during vomiting. When a person vomits, gastric HCl is lost and serum bicarbonate increases. - HCO3 - and dissipation of increased serum bicarbonate concentration. - The increase in serum bicarbonate persists only if oral administration of . The present disclosure is not limited to these requirements, which are instead explained in detail below.

[0020] Among the various aspects of the present disclosure, mention may be made of a method for treating an individual suffering from a chronic acid-base disorder characterized by a baseline serum bicarbonate level of less than 22 mEq / L, comprising oral administration of a pharmaceutical composition comprising a polymer composition capable of binding HCl as it passes through the digestive system.

[0021] Another aspect of the present disclosure is a method of treating an individual suffering from an acid-base disorder characterized by a baseline serum bicarbonate level of less than 22 mEq / l, the method comprising oral administration of a daily dose of a pharmaceutical composition capable of removing at least 5 meq of HCl as it passes through the digestive system and achieving a clinically significant increase in serum bicarbonate levels of at least 1 mEq / l from baseline within a treatment period of no more than one month.

[0022] Another aspect of the present disclosure is a composition for use in a method for treating metabolic acidosis in an adult patient by increasing the patient's serum bicarbonate level by at least 1 mEq / L over 15 days of treatment (i.e., within 15 days of treatment), wherein the composition is a non-absorbable composition capable of removing HCl from the patient. In this aspect, the composition can be administered orally and is therefore an orally absorbable composition as defined herein.

[0023] Another aspect of the present disclosure is a composition for use in a method for treating metabolic acidosis in an adult patient, wherein the patient has a serum bicarbonate level of less than 20 mEq / L prior to treatment, and the composition is a non-absorbable composition capable of removing HCl from the patient. In this aspect, the composition can be administered orally and is therefore an orally absorbable composition as defined herein.

[0024] In certain embodiments, the orally administered composition contains cations (e.g., Na) that exchange with protons as the composition passes through the gastrointestinal system. + , K. + , Mg 2+ , Ca 2+ Li + , or a combination thereof), and the protons are then excreted from the body along with the non-absorbable composition during bowel movements. The net effect is a decrease in protons in the body in exchange for an increase in one or more cations. In this embodiment, the pharmaceutical composition may also optionally include a pharmaceutically acceptable carrier, diluent, or additive, or a combination thereof, that does not significantly interfere with the proton binding properties of the composition in vivo. Optionally, the pharmaceutical composition may also include an additional therapeutic agent.

[0025] In certain embodiments, the orally administered composition includes an anion that is exchanged with chloride ion, and the anion contained in the orally administered composition is removed by a base (e.g., Cl - , HSO4 - or SO4 2- ) than a stronger base (e.g., OH -), the net effect is the removal of a strong acid (e.g., HCl or H2SO4) from the body in exchange for a weak acid (e.g., HO). In this embodiment, the pharmaceutical composition may also optionally include a pharmaceutically acceptable carrier, diluent, or excipient, or combination thereof, that does not significantly interfere with the chloride-binding properties of the non-absorbable composition in vivo. Optionally, the pharmaceutical composition may also include an additional therapeutic agent.

[0026] In certain embodiments, the orally administered composition is a neutral composition that can bind with strong acids such as HCl or H2SO4 when orally administered and remove them from the body.The composition does not necessarily need to introduce cations or anions to balance the process of removing acid (i.e., by ion exchange).In this embodiment, both ionic species of HCl (H + and Cl - Binding of HCl can occur with deprotonated functional groups, resulting in the hydrochloride salt of the functional group upon administration in an acidic aqueous medium.

[0027] Among the various aspects of the present disclosure, mention may be made of a method of treating an individual suffering from a chronic acid-base disorder, comprising orally administering a pharmaceutical composition comprising a non-absorbable composition capable of binding protons and chloride ions as it passes through the digestive system and removing the bound protons and chloride ions from the individual's digestive system via defecation. In each of these embodiments, the pharmaceutical composition may also optionally include a pharmaceutically acceptable carrier, diluent, or excipient, or combination thereof, that does not significantly interfere with the chloride-binding properties of the non-absorbable composition in vivo. Optionally, the pharmaceutical composition may also include an additional therapeutic agent.

[0028] In those embodiments in which the composition binds chloride ions, it is generally preferred that the composition selectively bind chloride ions over physiologically significant competing anions, such as bicarbonate equivalent anions, phosphate anions, and conjugate bases of bile and fatty acids present in the gastrointestinal tract. Stated another way, it is generally preferred that the non-absorbable composition remove more chloride ions than other competing anions in the gastrointestinal tract.

[0029] It is generally preferred that the pharmaceutical composition bind protons without delivering a physiologically harmful amount of sodium, potassium, calcium, magnesium, and / or other electrolytes in exchange for the protons. As a result, treatment with the pharmaceutical composition does not significantly contribute to edema, hypertension, hyperkalemia, hypercalcemia, or similar disorders associated with increased sodium, potassium, calcium, or other electrolyte loads. Similarly, in those embodiments in which the composition binds protons, it is generally preferred that the composition binds protons without removing a certain amount of sodium, potassium, calcium, magnesium, and / or other electrolytes along with the protons. As a result, treatment with the pharmaceutical composition does not significantly contribute to hypotension, hypokalemia, hypocalcemia, or dental disorders associated with decreased serum concentrations of sodium, potassium, calcium, magnesium, or other electrolytes.

[0030] In certain embodiments, the composition comprises a polymer that has the ability to bind and maintain its ability to bind protons and anions under physiological conditions found along the gastrointestinal (GI) lumen. These conditions can vary depending on food intake (see, for example, Fordtran J, Locklear T. Ionic constituents and osmolality of gastric and small-intestinal fluids after eating. Digest Dis Sci. 1966;11(7):503-21) and location along the GI tract (see, for example, Binder, H et al. Chapters 41-45 in "Medical Physiology", 2nd Edition, Elsevier

[2011] . Boron and Boulpaep [Ed.]). Rapid binding of protons and chloride in the stomach and small intestine is desirable. High binding level and selectivity for chloride in the posterior part of the GI tract (lower small intestine and large intestine) are also desirable. In general, the polymer also preferably has a pKa such that the majority of amines are protonated under the various pH and electrolyte conditions encountered along the digestive tract, thereby allowing the proton, along with an appropriate counterion (preferably chloride), to be eliminated from the body in the feces.

[0031] Because the stomach is a rich source of HCl and the first site (after the mouth) of potential HCl binding, and because the residence time in the stomach is short (gastric half-life of approximately 90 minutes) compared to the rest of the gastrointestinal tract (small intestinal transit time of 4 hours; whole intestinal transit time of 2-3 days; see NW et al. Gastroenterology

[1980] 79:1276), it is desirable for the polymers of the present disclosure to exhibit fast kinetics of proton and chloride binding in the lumen of this organ and in in vitro conditions designed to mimic the gastric lumen (e.g., SGF). Phosphate is a potential interfering anion for chloride binding in the stomach and small intestine, where most phosphate is absorbed (Cross, HS et al. Miner Electrolyte Metab

[1990] 16:115-24). Therefore, rapid and preferential binding of chloride over phosphate is desirable in the small intestine and in in vitro conditions designed to mimic the small intestinal lumen (e.g., SIF). Because colonic transit times are slow (2-3 days) compared to the small intestine, and because orally administered polymers do not encounter colonic conditions until after encountering the stomach and small intestine, the kinetics of chloride binding by the polymers of the present disclosure do not need to be rapid in the colon or in in vitro conditions designed to mimic the lower small intestine / colon. However, it is important that chloride binding and selectivity over other interfering anions is high, e.g., at 24 and / or 48 hours or longer.

[0032] Other aspects and features will be in part apparent and in part pointed out hereinafter. [Brief explanation of the drawings]

[0033] [Figure 1] 1A-1C are flow charts that schematically illustrate the mechanism of action of a polymer as it passes through an individual's digestive tract from the stomach (FIG. 1A), through the upper digestive tract (FIG. 1B), and into the lower digestive tract / colon (FIG. 1C).

[0034] [Figure 2]FIG. 2 is a graph of the effect of TRC101 on serum bicarbonate in a rat model of adenine-induced nephropathy and metabolic acidosis in the Part 1 study described in Example 1.

[0035] [Figure 3] Figures 3A, 3B, and 3C are graphs of the effect of TRC101 on fecal excretion of chloride (Figure 3A), sulfate (Figure 3B), and phosphate (Figure 3C) in a rat model of adenine-induced nephropathy and metabolic acidosis in the Part 1 study described in Example 1.

[0036] [Figure 4] FIG. 4 is a graph of the effect of TRC101 on serum bicarbonate in a rat model of adenine-induced nephropathy and metabolic acidosis in the Part 2 study described in Example 1.

[0037] [Figure 5] Figures 5A, 5B, and 5C are graphs of the effect of TRC101 on fecal excretion of chloride (Figure 5A), sulfate (Figure 5B), and phosphate (Figure 5C) in a rat model of adenine-induced nephropathy and metabolic acidosis in the part 2 study described in Example 1.

[0038] [Figure 6] 6A, 6B, and 6C are graphs of the in vivo chloride (FIG. 6A), sulfate (FIG. 6B), and phosphate (FIG. 6C) binding capacity of the test compound and bixalomer in pigs with normal renal function in the study described in Example 2.

[0039] [Figure 7] FIG. 7 is a line graph showing the mean change and standard error (SE) in serum bicarbonate (SBC) from baseline (BL) by treatment group over time in the human study more fully described in Example 3 (Part 1).

[0040] [Figure 8]8 is a bar graph showing the least squares mean (LSmean) change (CFB) from baseline to end of treatment in serum bicarbonate (SBC) by treatment group in the human study described more fully in Example 3 (Part 1). A single asterisk ("*") indicates a statistically significant difference (p<0.5), and two asterisks ("**") indicate a highly statistically significant difference (p<0.0001).

[0041] [Figure 9] Figure 9 is a bar graph showing the effect of treatment with TRC101 (Tx = treatment) and its discontinuation on serum bicarbonate (SBC) levels and standard error (SE) at days 8 and 15 in a human study described more fully in Example 3 (Part 1).

[0042] [Figure 10] Figure 10 is a line graph showing the mean change in serum bicarbonate (SBC) and standard error (SE) for the four TRC101 active groups and two placebo groups (total) of the study described more fully in Example 3 (Parts 1 and 2).

[0043] [Figure 11] 11 is a bar graph showing the least squares mean (LSmean) change from baseline (CFB) in serum bicarbonate (SBC) by treatment group over time for the four TRC101 active groups and two placebo groups (combined) of the study more fully described in Example 3 (Parts 1 and 2). A single asterisk ("*") indicates a statistically significant difference (p<0.5), and two asterisks ("**") indicate a highly statistically significant difference (p<0.0001).

[0044] [Figure 12] Figure 12 is a bar graph showing the treatment effects of serum bicarbonate (SBC) levels and standard error (SE) at days 8 and 15 resulting from treatment with TRC101 (Tx = treatment) and its discontinuation in a human study more fully described in Example 3 (parts 1 and 2).

[0045] [Figure 13] Figures 13A, 13B, 13C and 13D are graphs showing the change in serum bicarbonate (Figure 13A), serum chloride (Figure 13B), serum sodium (Figure 13C) and serum potassium (Figure 13D) for the four TRC101 active groups (total) versus the two placebo groups (total) over time in a study more fully described in Example 3 (Parts 1 and 2).

[0046] [Figure 14] Figure 14 is a graph showing the change in calculated anion gap for the four TRC101 active groups (total) versus the two placebo groups (total) over time in the study described more fully in Example 3 (parts 1 and 2). DETAILED DESCRIPTION OF THE INVENTION

[0047] Abbreviations and Definitions The following definitions and methods are provided to better define the present invention and to guide those of ordinary skill in the art in the practice of the present invention. Unless otherwise specified, terms should be construed in accordance with conventional usage by those of ordinary skill in the relevant art.

[0048] The term "absorbent capacity" as used herein in connection with a polymer and a swelling agent (or, in the case of a mixture of swelling agents, a mixture of swelling agents) is the amount of swelling agent (or mixture thereof) that is absorbed by immersing a given amount of dry polymer (e.g., in the form of dry beads) in an excess amount of swelling agent (or mixture thereof) for a period of at least 16 hours at room temperature.

[0049] The term "acrylamide" refers to a group of structural formula H2C=CH-C(O)NR-*, where * indicates the point of attachment to the rest of the molecule and R is hydrogen, hydrocarbyl, or substituted hydrocarbyl.

[0050] The term "acrylic" refers to a group of the structural formula H2C=CH-C(O)O-*, where * indicates the point of attachment to the rest of the molecule.

[0051] The term "adult" refers to an individual over the age of 18.

[0052] The terms "alicyclic," "alicyclo," or "alicyclyl" refer to saturated monocyclic groups of 3 to 8 carbon atoms and include cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0053] The term "aliphatic" refers to saturated and non-aromatic unsaturated hydrocarbyl moieties, e.g., having from 1 to about 20 carbon atoms, or in specific embodiments, from 1 to about 12 carbon atoms, from 1 to about 10 carbon atoms, from 1 to about 8 carbon atoms, or from 1 to about 4 carbon atoms. Aliphatic groups include, for example, alkyl moieties such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, etc., and alkenyl moieties of equivalent chain length.

[0054] The term "alkanol" refers to an alkyl moiety substituted with at least one hydroxyl group. In some embodiments, alkanol groups are "lower alkanol" groups containing 1 to 6 carbon atoms, one of which is bonded to an oxygen atom. In other embodiments, lower alkanol groups contain 1 to 3 carbon atoms.

[0055] The term "alkenyl group" encompasses straight- or branched-chain carbon groups having at least one carbon-carbon double bond. The term "alkenyl group" can encompass conjugated and non-conjugated carbon-carbon double bonds, or a combination thereof. Alkenyl groups can include, for example, but are not limited to, from 2 to about 20 carbon atoms, or, in certain embodiments, from 2 to about 12 carbon atoms. In some embodiments, alkenyl groups are "lower alkenyl" groups having from 2 to about 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, vinyl, butenyl, and 4-methylbutenyl. The terms "alkenyl group" and "lower alkenyl group" encompass groups having a "cis" or "trans" orientation, or an "E" or "Z" orientation.

[0056] The term "alkyl group," whether used alone or within other terms such as "haloalkyl group," "aminoalkyl group," and "alkylamino group," includes saturated straight- or branched-chain carbon groups, e.g., having from 1 to about 20 carbon atoms, or in specific embodiments, from 1 to about 12 carbon atoms. In other embodiments, alkyl groups are "lower alkyl" groups having from 1 to about 6 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, and the like. In more specific embodiments, lower alkyl groups have from 1 to 4 carbon atoms.

[0057] The term "alkylamino group" refers to an amino group attached to the rest of the molecule via the nitrogen atom of the amino group, where the nitrogen atom of the alkylamino group is substituted with one or two alkyl groups. In some embodiments, the alkylamino group is a "lower alkylamino" group having one or two alkyl groups of 1 to 6 carbon atoms attached to the nitrogen atom. In other embodiments, the lower alkylamino group is 1 to 3 carbon atoms. Suitable "alkylamino" groups are mono- or dialkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, pentamethyleneamine, and the like.

[0058] The term "aryl" refers to a group having the structural formula H2C=CH-CH2-*, where * indicates the point of attachment to the rest of the molecule, whether it is a heteroatom or an aromatic moiety.

[0059] The term "allylamine" refers to a group having the structural formula HC=CH-CHN(X)(X), where X and X are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, or X and X together form a substituted or unsubstituted alicyclic moiety, an aryl group, or a heterocyclic moiety, each as defined in connection with that term, typically having 3 to 8 atoms in the ring.

[0060] The terms "amine" or "amino" used alone or as part of another group refer to a group of formula -N(X8)(X9), where X8 and X9 are independently hydrogen, hydrocarbyl or substituted hydrocarbyl, heteroaryl or heterocyclo, or X8 and X9 together form a substituted or unsubstituted alicyclic moiety, aryl group, or heterocyclic moiety, each as defined in relation to that term, and typically having 3 to 8 atoms in the ring.

[0061] The term "aminoalkyl group" encompasses straight- or branched-chain alkyl groups having 1 to about 10 carbon atoms, any one of which may be substituted with one or more amino groups, and which are directly attached to the remainder of the molecule through an atom other than the nitrogen atom of the amine group. In some embodiments, the aminoalkyl group is a "lower aminoalkyl" group having 1 to 6 carbon atoms and one or more amino groups. Examples of such groups include aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.

[0062] The terms "anion exchange material" and "cation exchange material" have their usual meanings in the art. For example, the terms "anion exchange material" and "cation exchange material" refer to materials that exchange anions and cations, respectively. Anion and cation exchange materials are typically water-insoluble materials that can exchange some of their cations or anions, respectively, with similarly charged anions or cations contained in the contacting medium. Anion exchange materials may contain positively charged groups, which are fixed to a framework material and allow the passage of anions but reject cations. A non-exhaustive list of such positively charged groups includes amino groups, alkyl-substituted phosphines, and alkyl-substituted sulfides. A non-exhaustive list of cation or anion exchange materials includes clays (e.g., bentonite, kaolinite, and illite), vermiculite, zeolites (e.g., analcite, chabazite, sodalite, and clinoptilolite), synthetic zeolites, polybasic acids, hydrous oxides, metal ferrocyanides, and heteropolyacids. Cation exchange materials may contain negatively charged groups, which are fixed to the framework material and allow the passage of cations but reject anions. A non-exhaustive list of such negatively charged groups includes sulfate, carboxylate, phosphate, and benzoate.

[0063] The terms "aromatic group" or "aryl group" refer to an aromatic group having one or more rings, where such rings may be pendantly attached together or fused. In specific embodiments, the aromatic group is monocyclic, bicyclic, or tricyclic. Monocyclic aromatic groups contain 5 to 10 carbon atoms, typically 5 to 7 carbon atoms, and more typically 5 to 6 carbon atoms, in the ring. Typical polycyclic aromatic groups have two or three rings. Polycyclic aromatic groups having two rings typically have 8 to 12 carbon atoms, preferably 8 to 10 carbon atoms, in the ring. Examples of aromatic groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, or acenaphthyl.

[0064] The term "beads" is used to refer to cross-linked polymers that are substantially spherical.

[0065] The term "bicarbonate equivalent" is used to refer to an organic acid or anion that, when metabolized, yields bicarbonate. Citric acid and succinic acid are exemplary bicarbonate equivalents.

[0066] The term "bound" as used herein in connection with a polymer and one or more ions, i.e., cations (e.g., "proton-bound" polymers) and anions, refers to an "ion-bound" polymer, and / or when it binds with ions, has sufficient binding strength that at least a portion of the ions remain bound under in vitro or in vivo conditions in which the polymer is used for a time sufficient to effect removal of the ions from solution or the body, generally not necessarily in a non-covalent manner.

[0067] The term "ceramic material" has its usual meaning in the art. In certain embodiments, the term "ceramic material" refers to an inorganic, non-metallic solid material containing metal, non-metal, or metalloid atoms held primarily together by ionic and covalent bonds. A non-exhaustive list of examples of ceramic materials includes barium titanate, bismuth strontium calcium copper oxide, boron oxide, porcelain, ferrite, lanthanum carbonate, lead zirconate, titanate, magnesium diboride, porcelain, sialon, silicon carbide, silicon nitride, titanium carbide, yttrium barium copper oxide, zinc oxide, zirconium dioxide, and partially stabilized zirconia. In certain embodiments, the term "clinically significant increase" as used herein in connection with a treatment refers to a treatment that improves or provides a beneficial change in an individual from a dysfunctional state back to a relatively normal functional state, or that moves a measure of that state toward normal function, or at least a significant improvement over untreated treatment. Many methods can be used to assess clinical significance. A non-exhaustive list of methods for calculating clinical significance includes Jacobson-Truax, Gulliksen-Lord-Novick, Edwards-Nunnally, Hageman-Arrindell, and Hierarchical Linear Modeling (HLM).

[0068] The term "crosslinker," used alone or within other terms, encompasses hydrocarbyl or substituted hydrocarbyl, linear or branched, molecules capable of reacting more than once with any of the described monomers or with an infinite polymer network such as that described in Formula 1. The reactive groups in the crosslinker may include, but are not limited to, alkyl halides, epoxides, phosgene, anhydrides, carbamates, carbonates, isocyanates, thioisocyanates, esters, activated esters, carboxylic acids and derivatives, sulfonates and derivatives, acyl halides, aziridines, α,β-unsaturated carbonyls, ketones, aldehydes, pentafluoroaryl groups, vinyls, allyls, acrylates, methacrylates, acrylamides, methacrylamides, styrenes, acrylonitriles, and combinations thereof. In one exemplary embodiment, the reactive groups of the crosslinker include alkyl halides, epoxides, anhydrides, isocyanates, allyls, vinyls, acrylamides, and combinations thereof. In one such embodiment, the reactive groups of the crosslinker are alkyl halides, epoxides, or allyls.

[0069] The term "diallylamine" refers to an amino moiety bearing two allyl groups.

[0070] The terms "dry beads" and "dry polymer" refer to beads or polymers containing 5% by weight or less of a non-polymeric swelling agent or solvent. The other swelling agent / solvent is water remaining at the end of purification. This is typically removed by freeze-drying or oven-drying prior to storage or further crosslinking of the preformed amine polymer. The amount of swelling agent / solvent can be measured by heating (e.g., to 100-200°C) and measuring the resulting weight change. This is referred to as "loss on drying" or "LOD."

[0071] The term "estimated glomerular filtration rate" or eGFR refers to an estimate of glomerular filtration rate, which is estimated from serum levels of endogenous filtration markers. Creatinine is a commonly used endogenous filtration marker in clinical practice, and several equations have been proposed to estimate glomerular filtration rate. All eGFR values ​​used herein are calculated using the CKD-EPI equation (Levey et al., A New Equation to Estimate Glomerular Filtration Rate. Ann Intern Med. 2009; 150:604-612): GFR = 41 × min(Scr / κ,1) α ×Maximum(Scr / κ,1) -1.209 ×0.993 Age × 1.018 [for women] × 1.159 [for black people] [where Scr is serum creatinine (mg / dL), κ is 0.7 for women and 0.9 for men, α is −0.329 for women and −0.411 for men, Min indicates the minimum value of Scr / κ or 1, and Max indicates the maximum value of Scr / κ or 1] can be determined according to

[0072] The term "ether" refers to a compound of the structural formula *-H x CO-CH x - denotes a moiety having oxygen attached to two separate carbon atoms, designated by *, where * denotes the point of attachment to the remainder of the moiety and x is independently 0, 1, 2, or 3.

[0073] The term "gel" is used to refer to a cross-linked polymer having an irregular shape.

[0074] The term "glomerular filtration rate" or GFR is the volume of fluid filtered from the renal glomerular capillaries into Bowman's capsule per unit time. GFR cannot be measured directly; instead, it is measured indirectly as the clearance of exogenous filtration markers (e.g., inulin, iothalamate, iohexol, etc.) (mGFR) or estimated using endogenous filtration markers (eGFR).

[0075] The term "halo" means a halogen such as fluorine, chlorine, bromine or iodine.

[0076] The term "haloalkyl group" encompasses groups in which any one or more of the alkyl carbon atoms is substituted with halo, as defined above. Specifically encompassed are monohaloalkyl, dihaloalkyl, and polyhaloalkyl groups, including perhaloalkyl. Monohaloalkyl groups can have, for example, iodo, bromo, chloro, or fluoro atoms within the group. Dihalo and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups. "Lower haloalkyl groups" encompass groups having 1 to 6 carbon atoms. In some embodiments, lower haloalkyl groups have 1 to 3 carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl.

[0077] The term "heteroaliphatic" refers to a chain of 1 to 25 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, most typically 1 to 8 carbon atoms, and in some embodiments 1 to 4 carbon atoms, that may be saturated or unsaturated (but not aromatic), and that contains one or more heteroatoms such as halogen, oxygen, nitrogen, sulfur, phosphorus, or boron. The heteroatom may be part of a pendant (or side) group attached to the chain of atoms (e.g., -CH(OH)-CH(NH)- in which the carbon atom is a member of the chain of atoms), or may be one of the chain atoms (e.g., -ROR- or -RNHR-, where each R is aliphatic). Heteroaliphatic includes heteroalkyl and heterocyclo, but does not include heteroaryl.

[0078] The term "heteroalkyl" refers to a fully saturated heteroaliphatic moiety.

[0079] The term "heteroaryl," unless otherwise specified, refers to a monocyclic or bicyclic aromatic group having 5 to 10 ring atoms, wherein one or more (in one embodiment, one, two, or three) ring atoms are heteroatoms selected from N, O, or S, and the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. As defined herein, the terms "heteroaryl" and "aryl" are mutually exclusive. "Heteroarylene" refers to a divalent heteroaryl group.

[0080] The term "heteroatom" refers to an atom other than carbon or hydrogen. Typically, but not exclusively, heteroatoms are selected from the group consisting of halogen, sulfur, phosphorus, nitrogen, boron, and oxygen atoms. Groups containing more than one heteroatom may contain different heteroatoms.

[0081] The terms "heterocyclo," "heterocyclic," or "heterocyclyl" refer to saturated or unsaturated groups having 4 to 8 ring atoms, where one or two ring atoms are selected from N, O, B, P, and S(O). n (where n is an integer from 0 to 2), and the remaining ring atoms are carbon. Also, one or two ring carbon atoms of the heterocyclyl ring may be optionally replaced with a —C(O)— group. More specifically, the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, and the like. If the heterocyclyl ring is unsaturated, it may contain one or two ring double bonds, as long as the ring is not aromatic. When a heterocyclyl group contains at least one nitrogen atom, it is also referred to as heterocycloamino, and is a subset of the heterocyclyl group.

[0082] The term "hydrocarbon group" or "hydrocarbyl group" refers to a chain of 1 to 25 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, and most typically 1 to 8 carbon atoms. Hydrocarbon groups can have a straight or branched chain structure. Typical hydrocarbon groups have one or two branches, typically one branch. Typically, hydrocarbon groups are saturated. Unsaturated hydrocarbon groups may have one or more double bonds, one or more triple bonds, or a combination thereof. Typical unsaturated hydrocarbon groups have one or two double bonds or one triple bond, more typically, unsaturated hydrocarbon groups have one double bond.

[0083] "Initiator" is a term used to refer to a reagent that starts polymerization.

[0084] The term "measured glomerular filtration rate" or "mGFR" refers to the measurement of glomerular filtration rate by standard techniques using any chemical that has a stable level in the blood and is freely filtered by the kidney but is neither reabsorbed nor secreted (e.g., inulin, iothalamate, iohexol, etc.).

[0085] The term "Michael acceptor" has its usual meaning in the art. In certain embodiments, the term "Michael acceptor" refers to an activated olefin, such as an α,β-unsaturated carbonyl compound. The Michael acceptor can be a conjugated system with an electron-withdrawing group, such as cyano, keto, or ester. A non-exclusive list of examples of Michael acceptors includes vinyl ketone, alkyl acrylate, acrylonitrile, and fumaric acid.

[0086] The term "molecular weight per nitrogen" or "MW / N" refers to the calculated molecular weight of a polymer per nitrogen atom. It represents the average molecular weight per amine functional group in the crosslinked polymer. It is calculated by dividing the mass of a polymer sample by the moles of nitrogen present in the sample. "MW / N" is the reciprocal of the theoretical capacity, and the calculation is based on the feed ratio, assuming complete reaction of the crosslinker and monomer. The lower the molecular weight per nitrogen, the higher the theoretical capacity of the crosslinked polymer.

[0087] The term "non-absorbable" as used herein takes its usual meaning in the art. Thus, if something is non-absorbable, it is not absorbed during passage through the human gastrointestinal tract. This can be measured by any suitable means. One option known to those skilled in the art is to test feces to see if the non-absorbable substance is recovered after passage through the gastrointestinal tract. As a practical matter, the amount of non-absorbable substance recovered in this scenario will never be 100% of the administered substance. For example, approximately 90-99% of the substance may be recovered from the feces. Another option known to those skilled in the art is to look for the presence of the substance in lymph, blood, interstitial fluid, and secretions from or in body organs (e.g., pancreas, liver, intestine, etc.), since oral administration of a non-absorbable substance does not result in an increase in the amount of the substance in these matrices and tissues. A non-absorbable composition can be a particulate composition that is essentially insoluble in the human gastrointestinal tract and has a particle size large enough to avoid passive or active absorption through the human gastrointestinal tract. For example, a non-absorbable composition means that the substance does not enter lymph, blood, interstitial fluid, or organs through the main entry points of the human gastrointestinal tract: paracellular invasion between intestinal epithelial cells, intracellular uptake through intestinal epithelial cells, invasion by M cells, which comprise the intestinal epithelial antigen sampling and immune surveillance system (Jung, 2000), or through active or passive transport processes. Because there are known size limitations on the particulates absorbed into the human gastrointestinal tract (Jung et al., European Journal of Pharmaceutics and Biopharmaceutics 50 (2000) 147-160; Jani et al., International Journal of Pharmaceutics, 84 (1992) 245-252; and Jani et al., J. Pharm. Pharmacol. 1989, 41:809-812), those skilled in the art know that substances with a size of at least 1 μm when in the gastrointestinal tract are non-absorbable.

[0088] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur; the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that alkyl may, but does not necessarily, be present; the description includes embodiments in which the heterocyclyl group is substituted with an alkyl group and embodiments in which the heterocyclyl group is not substituted with an alkyl group.

[0089] Particle size is measured by wet laser diffraction using a Mie. Particles are dispersed in a suitable solvent, such as water or ethanol, and added to the sample chamber to achieve 10-20% red channel blockage. Sonication or the addition of a dispersing agent, such as a surfactant (e.g., Tween 80), may be performed to disrupt weak interparticle interactions. The refractive index settings for the particles used in particle size distribution calculations are selected to minimize artifacts in the results and R parameter values ​​determined by the laser diffraction software. The D(0.1), D(0.5), and D(0.9) values, which characterize the particle size distribution on a volume basis, are recorded.

[0090] "Pharmaceutically acceptable" when used in connection with a carrier, diluent, or excipient means that the carrier, diluent, or excipient, respectively, is generally safe, non-toxic, and not biologically or otherwise undesirable for veterinary and / or human pharmaceutical use, and is useful in the preparation of pharmaceutical compositions.

[0091] The term "post-polymerization crosslinking" refers to a reaction on already formed beads or gels that introduces additional crosslinks to the already formed beads or gels to create beads or gels with an increased amount of crosslinking.

[0092] The term "post-polymerization modification" refers to a modification to already formed beads or gels in which a reaction or treatment introduces additional functional groups that can be covalently or non-covalently attached to the already formed beads.

[0093] The term "quaternary amine assay" ("QAA") refers to a method for estimating the amount of quaternary amines present in a given crosslinked polymer sample. This assay measures chloride binding of crosslinked polymers at pH 11.5. At this pH, primary, secondary, and tertiary amines are substantially unprotonated and do not contribute substantially to chloride binding. Therefore, any binding seen under these conditions can be attributed to the presence of permanently charged quaternary amines. The test solution used for the QAA assay is 100 mM sodium chloride at pH 11.5. The chloride ion concentration is in accordance with the SGF assay used to assess the total binding capacity of crosslinked polymers. The quaternary amine content as a percentage of the total amines present is calculated as follows:

number

number

[0094] The term " short-chain carboxylic acid " or " short-chain fatty acid " has its usual meaning in the art.In certain embodiments, the term " short-chain carboxylic acid " or " short-chain fatty acid " refers to the carboxylic acid that has a chain length of 0, 1, 2, 3, 4, 5 or 6 carbon atoms.The non-exhaustive list of examples of short-chain carboxylic acid includes formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid and lactic acid.

[0095] The "Simulated Gastric Fluid" or "SGF" assay refers to a test for determining the total chloride binding capacity of a test polymer using a defined buffer that mimics the contents of gastric fluid, as follows: Simulated gastric fluid (SGF) consists of 35 mM NaCl, 63 mM HCl, pH 1.2. To perform this assay, the free amine polymer to be tested is prepared at a concentration of 2.5 mg / ml (25 mg dry weight) in 10 mL of SGF buffer. The mixture is incubated overnight at 37°C with agitation on a rotary mixer for approximately 12-16 hours. Unless otherwise indicated, SGF binding data or binding capacity described herein is determined at this time. After incubation and mixing, the tube containing the polymer is centrifuged at 500-1000 x g for 2 minutes to pellet the test sample. Approximately 750 μL of the supernatant is removed and filtered using an appropriate filter, such as a 0.45 μm pore-size syringe filter or an 800 μL, 1 μm pore-size, 96-well, glass filter plate mounted on a 96-well, 2 mL collection plate. With the latter configuration, multiple samples can be prepared for analysis, including control tubes run through the entire assay process, including free amine sevelamer, free amine bixalomer standard controls, and blank buffer, all tested in SGF buffer. With the samples aligned on the filter plate and the collection plate attached to the bottom, the unit is centrifuged at 1,000 x g for 1 minute to filter the samples. For small sample sets, a syringe filter may be used instead of the filter plate, and approximately 2–4 mL of filtrate is collected in a 15 mL container. After filtration, each filtrate is diluted 4-fold with water, and the chloride content of the filtrate is measured by ion chromatography (IC). The IC method (e.g., Dionex ICS-2100, Thermo Scientific) consists of an AS11 column and a 15 mM KOH mobile phase, with an injection volume of 5 μL, a run time of 3 minutes, a wash / rinse volume of 1000 μL, and a flow rate of 1.25 mL / min. To determine polymer-bound chloride, perform the following calculation:

number

[0096] "Simulated Small Intestinal Inorganic Buffer" or "SIB" is a test for determining the chloride and phosphate binding capacity of free amine test polymers in a selective specific interference buffer assay (SIB). The chloride and phosphate binding capacities of the free amine test polymers, along with the chloride and phosphate binding capacities of the free amine sevelamer and bixalomer control polymers, were determined using a selective specific interference buffer assay (SIB) as follows: The buffer used for the SIB assay contains 36 mM NaCl, 20 mM NaH2PO4, 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5. SIB buffer contains chloride, phosphate, and pH concentrations present in the human duodenum and upper gastrointestinal tract (Stevens T, Conwell DL, Zuccaro G, Van Lente F, Khandwala F, Purich E, et al. Electrolyte composition of endoscopically collected duodenal drainage fluid after synthetic porcine secretin stimulation in healthy subjects. Gastrointestinal endoscopy. 2004;60(3):351-5; Fordtran J, Locklear T. Ionic constituents and osmolality of gastric and small-intestinal fluids after eating. Digest Dis Sci. 1966;11(7):503-21), providing a useful indicator of the selectivity of chloride binding relative to phosphate binding by the polymer. To perform this assay, the free amine polymer to be tested is prepared at a concentration of 2.5 mg / ml (25 mg dry weight) in 10 mL of SIB buffer. The mixture is incubated at 37°C for 1 hour with agitation on a rotary mixer. Unless another time is indicated, the SIB binding data or binding capacity described herein is determined at this time. After incubation and mixing, the tubes containing the polymer are centrifuged at 1000 x g for 2 minutes to pellet the test sample.750 μL of supernatant is removed and filtered using an 800 μL, 1 μm-pore, 96-well, glass filter plate mounted on a 96-well, 2 mL collection plate. This arrangement allows for the preparation of multiple samples for analysis, including control tubes run through the entire assay process, including free amine sevelamer, free amine bixalomer standard controls, and blank buffer, in SIB buffer. With the samples aligned on the filter plate and the collection plate attached to the bottom, the unit is centrifuged at 1,000 x g for 1 minute to filter the samples. For small sample sets, a syringe filter (0.45 μm) may be used instead of the filter plate, and approximately 2–4 mL of filtrate is collected in a 15 mL vial. After filtration into the collection plate, each filtrate is diluted to measure its chloride or phosphate content. For chloride and phosphate measurements, the filtrate under analysis is diluted 4-fold with water. The chloride and phosphate content of the filtrate is measured by ion chromatography (IC). The IC method (e.g., Dionex ICS-2100, Thermo Scientific) consists of an AS24A column, a 45 mM KOH mobile phase, a 5 μL injection volume, a run time of approximately 10 minutes, a 1000 μL wash / rinse volume, and a flow rate of 0.3 mL / min. To determine polymer-bound chloride, perform the following calculation:

number

number

[0097] In certain embodiments, the term "statistically significant" refers to the possibility that the relationship between two or more variables is caused by something other than random probability.More precisely, the significance level α defined for the test is the probability of the test rejecting the null hypothesis if it is true, and the resulting p-value, p, is the probability of obtaining a result that is at least an extreme value if the null hypothesis is true.If p<α, the result is statistically significant according to the criteria of the test.The significance level for the test is selected before data collection and is typically set at 5%.

[0098] As used herein, the terms "substituted hydrocarbyl," "substituted alkyl," "substituted alkenyl," "substituted aryl," "substituted heterocyclo," or "substituted heteroaryl" refer to a hydrocarbyl, alkyl, alkenyl, aryl, heterocyclo, or heteroaryl moiety substituted with at least one atom other than carbon and hydrogen, including moieties in which a carbon chain atom is replaced with a heteroatom such as nitrogen, oxygen, silicon, phosphorus, boron, sulfur, or a halogen atom. These substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketal, acetal, ester, and ether.

[0099] "Swelling ratio" or simply "swelling" refers to the amount of water absorbed by a quantity of polymer divided by the weight of the polymer aliquot. Swelling ratio is expressed as swell = (g swollen polymer - g dry polymer) / g dry polymer. Methods used to determine the swelling ratio of any given polymer include: a. Place 50-100 mg of dry (less than 5% water content by weight) polymer into an 11 mL sealable test tube (with screw cap) of known weight (tube weight = weight A). b. Add deionized water (10 mL) to the polymer-containing tube. Seal the tube and invert it at room temperature for 16 hours (overnight). After incubation, centrifuge the tube at 3000 x g for 3 minutes and carefully remove the supernatant by vacuum aspiration. Polymers that form a very loose pellet should be centrifuged one more time. c. After step (b), record the weight of the swollen polymer plus tubing (Weight B). d. Freeze at -40°C for 30 minutes. Freeze dry for 48 hours. Weigh the dried polymer and test tube (record as weight C). e. Calculate the water absorbed per gram of polymer defined as [(Weight B - Weight A) - (Weight C - Weight A)] / (Weight C - Weight A).

[0100] "Target ion" is the ion to which the polymer binds, typically referring to the primary ion bound by the polymer, or the ion whose binding to the polymer is believed to produce the therapeutic effect of the polymer (e.g., proton and chloride binding resulting in the net removal of HCl).

[0101] The term "theoretical capacity" is the calculated, predicted binding of hydrochloric acid in the "SGF" assay, expressed in mmol / g. Theoretical capacity is based on the assumption that 100% of the amines from the monomer and crosslinker are incorporated into the crosslinked polymer, based on the respective feed ratios. Therefore, the theoretical capacity is equal to the concentration of amine functional groups in the polymer (mmol / g). Theoretical capacity assumes that each amine is available for binding to anions and cations, respectively, and is not adjusted for the type of amine formed (e.g., it does not subtract the capacity of quaternary amines that are not available for proton binding).

[0102] "Therapeutically effective amount" means the amount of proton-linked crosslinked polymer that, when administered to a patient for treating a disease, is sufficient to effect treatment for such disease. What constitutes a "therapeutically effective amount" will vary depending on the polymer, the severity of the disease and the age, weight, etc., of the mammal being treated.

[0103] "Treating" a disease or "treatment" of a disease includes (i) preventing the disease, i.e., arresting or reducing the progression of the disease or its clinical symptoms; or (ii) alleviating the disease, i.e., inducing regression of the disease or its clinical symptoms. Preventing a disease includes, for example, prophylaxis.

[0104] The term "triallylamine" refers to an amino moiety bearing three allyl groups.

[0105] The term "vinyl" refers to a group having the structural formula R x H y denotes a moiety having C=CH-*, where * indicates the point of attachment to the rest of the molecule and is a heteroatom or aryl, X and Y are independently 0, 1 or 2 such that X+Y=2, and R is hydrocarbyl or substituted hydrocarbyl.

[0106] The term "crosslinker weight percent" refers to the percentage, calculated by mass, of a polymer sample that is attributable to the crosslinker. Crosslinker weight percent is calculated using the polymerization feed ratio and assumes complete conversion of monomer and crosslinker. The mass attributed to the crosslinker is equal to the expected increase in molecular weight in an infinite polymer network after the reaction (e.g., 1,3-dichloropropane has 113 amu, but only 42 amu is added to the polymer network after crosslinking with DCP because the chlorine atom as a leaving group is not incorporated into the polymer network).

[0107] When introducing elements of the invention or preferred embodiments thereof, the singular form "a," "an," or "an" is intended to mean that there are one or more elements. The terms "comprise," "include," and "have" are intended to be inclusive and not exclusive (i.e., there may be other elements in addition to the listed elements).

[0108] Implementation According to the present disclosure, acid-base disorders can be treated using a pharmaceutical composition comprising a non-absorbable composition capable of removing clinically significant amounts of protons, one or more conjugate bases of a strong acid, and / or one or more strong acids. Thus, an individual suffering from an acute or chronic acid-base disorder characterized by a baseline serum bicarbonate level of less than 22 mEq / L can be treated by orally administering a pharmaceutical composition comprising the non-absorbable composition, which then passes through the individual's digestive system, binds to target species (protons, one or more conjugate bases of a strong acid, and / or one or more strong acids) as it passes through the digestive system, and removes the bound target species through normal biological functions (e.g., defecation).

[0109] Generally, an individual suffering from an acute or chronic acid-base disorder can be at any stage of chronic kidney disease. For example, in one embodiment, the affected individual has not reached end-stage renal disease ("ESRD") (sometimes also referred to as end-stage chronic kidney disease) and is not on dialysis (i.e., the individual has an ESRD of at least 15 mL / min / 1.73 m 2 In some embodiments, the affected individual has stage 3B CKD (i.e., the individual has a pmGFR (or eGFR) of 30-44 mL / min / 1.73 m for at least 3 months). 2 In some embodiments, the affected individual has stage 3A CKD (i.e., the individual has an mGFR (or eGFR) in the range of 45-59 mL / min / 1.73 m for at least 3 months). 2 Thus, for example, in some embodiments, the affected individual has a mGFR (or eGFR) of 60 mL / min / 1.73 m for at least 3 months. 2 By way of further example, in some embodiments, the affected individual has an mGFR or eGFR of less than 45 mL / min / 1.73 m for at least 3 months. 2 By way of further example, in some embodiments, the affected individual has an mGFR or eGFR of less than 30 mL / min / 1.73 m for at least 3 months. 2By way of further example, in some embodiments, the affected individual has an mGFR or eGFR of less than 15-30, 15-45, 15-60, 30-45, or even 30-60 mL / min / 1.73 m for at least 3 months. 2 have an mGFR or eGFR of

[0110] The baseline serum bicarbonate value may be a serum bicarbonate concentration determined at a single time point, or may be the average or median of two or more serum bicarbonate concentrations determined at two or more time points. For example, in one embodiment, the baseline serum bicarbonate value may be a serum bicarbonate concentration value determined at a single time point, and the baseline serum bicarbonate value is used as the basis for determining an acute acidic condition requiring immediate treatment. In another embodiment, the baseline serum bicarbonate treatment value is the average of serum bicarbonate concentrations for serum samples collected at different time points (e.g., different days). By way of further example, in one such embodiment, the baseline serum bicarbonate treatment value is the average of serum bicarbonate concentrations for serum samples collected on different days (e.g., at least 2, 3, 4, 5, or more days, which may be consecutive or may be separated by one or more days or even weeks). By way of further example, in one such embodiment, the baseline serum bicarbonate treatment value is the average of serum bicarbonate concentrations for serum samples collected on two consecutive days prior to the start of treatment.

[0111] In one embodiment, the acid-base disorder being treated is characterized by a baseline serum bicarbonate level of less than 21 mEq / L. For example, in one such embodiment, the acid-base disorder being treated is characterized by a baseline serum bicarbonate level of less than 20 mEq / L, 19 mEq / L, 18 mEq / L, 17 mEq / L, 16 mEq / L, 15 mEq / L, 14 mEq / L, 13 mEq / L, 12 mEq / L, 11 mEq / L, 10 mEq / L, or even less than 9 mEq / L.

[0112] Generally, however, the acid-base disorder being treated is characterized by a baseline serum bicarbonate level of at least 9 mEq / L. For example, in one such embodiment, the acid-base disorder being treated is characterized by a baseline serum bicarbonate level of at least 10 mEq / L, 11 mEq / L, 12 mEq / L, 13 mEq / L, 14 mEq / L, 15 mEq / L, 16 mEq / L, 17 mEq / L, 18 mEq / L, 19 mEq / L, 20 mEq / L, or even at least 21 mEq / L.

[0113] In certain embodiments, the acid-base disorder being treated is characterized by a baseline serum bicarbonate level in the range of 9-21 mEq / L. For example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate level in the range of 12-20 mEq / L, 12-19 mEq / L, 12-18 mEq / L, 12-17 mEq / L, 12-16 mEq / L, or 12-15 mEq / L. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate level in the range of 9-11 mEq / L, 12-14 mEq / L, 15-17 mEq / L, or even 18-21 mEq / L.

[0114] In certain embodiments, oral administration of a pharmaceutical composition containing a non-absorbable composition increases an individual's serum bicarbonate level from baseline to an increased serum bicarbonate level of at least 1 mEq / L, 1.5 mEq / L, 2 mEq / L, 2.5 mEq / L, 3 mEq / L, 3.5 mEq / L, 4 mEq / L, 5 mEq / L, 6 mEq / L, 7 mEq / L, 8 mEq / L, or even 9 mEq / L above the baseline serum bicarbonate level (provided that the increased serum bicarbonate level does not exceed 29 mEq / L). In each of the exemplary embodiments described in this paragraph, treatment allows the increased serum bicarbonate level to be maintained long-term for at least 1 week, at least 1 month, at least 2 months, at least 3 months, at least 6 months, or even at least 1 year.

[0115] In certain embodiments, treatment with the non-absorbable composition increases an individual's serum bicarbonate level by at least 1 mEq / L from a baseline serum bicarbonate level in the range of 12-20 mEq / L. For example, in one such embodiment, treatment increases an individual's serum bicarbonate level by at least 1.5 mEq / L, 2 mEq / L, 2.5 mEq / L, 3 mEq / L, 3.5 mEq / L, 4 mEq / L, 4.5 mEq / L, 5 mEq / L, 5.5 mEq / L, or even 6 mEq / L from a baseline serum bicarbonate level in the range of 12-20 mEq / L. In each of the exemplary embodiments described in this paragraph, the increased serum bicarbonate level preferably does not exceed 29 mEq / L. Also, in each of the exemplary embodiments described in this paragraph, treatment allows the increased serum bicarbonate levels to be maintained over an extended period of time, such as at least one week, at least one month, at least two months, at least three months, at least six months, or even at least one year.

[0116] In certain embodiments, treatment with the non-absorbable composition increases an individual's serum bicarbonate level by at least 1 mEq / L from a baseline serum bicarbonate level in the range of 9 to 21 mEq / L. For example, in one such embodiment, treatment increases an individual's serum bicarbonate level by at least 1.5 mEq / L, 2 mEq / L, 2.5 mEq / L, 3 mEq / L, 3.5 mEq / L, 4 mEq / L, 4.5 mEq / L, 5 mEq / L, 5.5 mEq / L, or even 6 mEq / L from a baseline serum bicarbonate level in the range of 9 to 21 mEq / L. In each of the exemplary embodiments described in this paragraph, the increased serum bicarbonate level preferably does not exceed 29 mEq / L. Also, in each of the exemplary embodiments described in this paragraph, treatment allows the increased serum bicarbonate levels to be maintained over an extended period of time, such as at least one week, at least one month, at least two months, at least three months, at least six months, or even at least one year.

[0117] In certain embodiments, treatment with the non-absorbable composition increases an individual's serum bicarbonate level by at least 1 mEq / L from a baseline serum bicarbonate level in the range of 12 to 14 mEq / L. For example, in one such embodiment, treatment increases an individual's serum bicarbonate level by at least 1.5 mEq / L, 2 mEq / L, 2.5 mEq / L, 3 mEq / L, 3.5 mEq / L, 4 mEq / L, 4.5 mEq / L, 5 mEq / L, 5.5 mEq / L, 6 mEq / L, 6.5 mEq / L, 7 mEq / L, 7.5 mEq / L, 8 mEq / L, 8.5 mEq / L, or even 9 mEq / L from a baseline serum bicarbonate level in the range of 12 to 14 mEq / L. In each of the exemplary embodiments described in this paragraph, the increased serum bicarbonate preferably does not exceed 29 mEq / L. Also, in each of the exemplary embodiments described in this paragraph, treatment allows the increased serum bicarbonate to be maintained over an extended period of at least one week, at least one month, at least two months, at least three months, at least six months, or even at least one year.

[0118] In certain embodiments, treatment with the non-absorbable composition increases an individual's serum bicarbonate level by at least 1 mEq / L from a baseline serum bicarbonate level in the range of 15 to 17 mEq / L. For example, in one such embodiment, treatment increases an individual's serum bicarbonate level by at least 1.5 mEq / L, 2 mEq / L, 2.5 mEq / L, 3 mEq / L, 3.5 mEq / L, 4 mEq / L, 4.5 mEq / L, 5 mEq / L, 5.5 mEq / L, 6 mEq / L, 6.5 mEq / L, 7 mEq / L, 7.5 mEq / L, 8 mEq / L, 8.5 mEq / L, or even 9 mEq / L from a baseline serum bicarbonate level in the range of 15 to 17 mEq / L. In each of the exemplary embodiments described in this paragraph, the increased serum bicarbonate preferably does not exceed 29 mEq / L. Also, in each of the exemplary embodiments described in this paragraph, treatment allows the increased serum bicarbonate to be maintained over an extended period of at least one week, at least one month, at least two months, at least three months, at least six months, or even at least one year.

[0119] In certain embodiments, treatment with the non-absorbable composition increases an individual's serum bicarbonate level by at least 1 mEq / L from a baseline serum bicarbonate level in the range of 18 to 21 mEq / L. For example, in one such embodiment, treatment increases an individual's serum bicarbonate level by at least 1.5 mEq / L, 2 mEq / L, 2.5 mEq / L, 3 mEq / L, 3.5 mEq / L, 4 mEq / L, 4.5 mEq / L, 5 mEq / L, 5.5 mEq / L, 6 mEq / L, 6.5 mEq / L, 7 mEq / L, 7.5 mEq / L, 8 mEq / L, 8.5 mEq / L, or even 9 mEq / L from a baseline serum bicarbonate level in the range of 18 to 21 mEq / L. In each of the exemplary embodiments described in this paragraph, the increased serum bicarbonate preferably does not exceed 29 mEq / L. Also, in each of the exemplary embodiments described in this paragraph, treatment allows the increased serum bicarbonate to be maintained over an extended period of at least one week, at least one month, at least two months, at least three months, at least six months, or even at least one year.

[0120] In certain embodiments, treatment achieves clinically significant increase within the treatment period of less than 1 month.For example, in one such embodiment, treatment achieves clinically significant increase within the treatment period of 25 days.For further example, in one such embodiment, treatment achieves clinically significant increase within the treatment period of 3 weeks, 15 days, 2 weeks, 10 days, 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day or even 12 hours.

[0121] In certain embodiments, treatment achieves a clinically significant increase without any changes to the individual's diet or eating habits compared to the period immediately prior to the start of treatment. For example, in one such embodiment, the clinically significant increase is achieved independently of the individual's diet or eating habits.

[0122] In certain embodiments, the individual's serum bicarbonate level returns to baseline values ​​of ±2.5 mEq / L, ±2 mEq / L, ±1.5 mEq / L, or even ±1 mEq / L within one month of cessation of treatment. For example, in one such embodiment, the individual's serum bicarbonate level returns to baseline values ​​of ±2.5 mEq / L, ±2 mEq / L, ±1.5 mEq / L, or even ±1 mEq / L within three weeks of cessation of treatment. By way of further example, in one such embodiment, the individual's serum bicarbonate level returns to baseline values ​​of ±2.5 mEq / L, ±2 mEq / L, ±1.5 mEq / L, or even ±1 mEq / L within two weeks of cessation of treatment. By way of further example, in one such embodiment, the individual's serum bicarbonate level returns to baseline values ​​of ±2.5 mEq / L, ±2 mEq / L, ±1.5 mEq / L, or even ±1 mEq / L within 10 days of cessation of treatment. By way of further example, in one such embodiment, the individual's serum bicarbonate level returns to baseline values ​​of ±2.5 mEq / L, ±2 mEq / L, ±1.5 mEq / L, or even ±1 mEq / L within 7 days of cessation of treatment.

[0123] In one embodiment, the baseline serum bicarbonate value is a serum bicarbonate concentration value determined at a single time point. In another embodiment, the baseline serum bicarbonate value is the average of at least two serum bicarbonate concentrations determined at different time points. For example, in one such embodiment, the baseline serum bicarbonate value is the average of at least two serum bicarbonate concentrations for serum samples collected on different days. As a further example, the baseline serum bicarbonate value is the average or median of at least two serum bicarbonate concentrations for serum samples collected on non-consecutive days. As a further example, in one such method, the non-consecutive days are at least two days apart. As a further example, in one such method, the non-consecutive days are at least one week apart. As a further example, in one such method, the non-consecutive days are at least two weeks apart. As a further example, in one such method, the non-consecutive days are at least three weeks apart.

[0124] In certain embodiments, daily dosage is 100g / day or less of the composition.For example, in one such embodiment, daily dosage is 90g / day or less of the non-absorbable composition.For further example, in one such embodiment, daily dosage is 75g / day, 65g / day, 50g / day, 40g / day, 30g / day, 25g / day, 20g / day, 15g / day, 10g / day or less, or even 5g / day or less of the composition.

[0125] In certain embodiments, individuals are treated with daily doses for at least 1 day.For example, in one such embodiment, individuals are treated with daily doses for at least 1 week, 1 month, 2 months, 3 months, 6 months, or even at least 1 year.

[0126] In certain embodiments of the disclosed methods, a daily dose of the non-absorbable composition has the capacity to remove at least about 5 mEq / day of target species. For example, in one such embodiment, a daily dose of the non-absorbable composition has the capacity to remove at least about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or even at least about 50 mEq / day of target species.

[0127] In certain embodiments of the disclosed methods, the daily dose of the non-absorbable composition removes less than 60 mEq / day, 55 mEq / day, 50 mEq / day, 45 mEq / day, 40 mEq / day, 35 mEq / day, 30 mEq / day, 25 mEq / day, 20 mEq / day, 15 mEq / day, or even less than 10 mEq / day of the target species.

[0128] Although the above method refers to a daily dose, further aspects of the present disclosure include the methods described herein in which the dose is administered less frequently than once a day (still administered regularly).In any of the present disclosure, a specific daily dose can instead be administered less frequently.For example, the doses described herein can be administered once every two or three days.Alternatively, the doses described herein can be administered once, twice or three times a week.

[0129] In addition to (or as a substitute for) serum bicarbonate, other biomarkers of acid-base imbalance can be used as measures of acid-base status. For example, blood (serum or plasma) pH, total CO2, anion gap, and / or concentrations of other electrolytes (e.g., sodium, potassium, calcium, magnesium, chloride, and / or sulfate) can be used as indicators of acid-base imbalance. Similarly, total acid excretion ("NAE"), urinary pH, urinary ammonium concentration, and / or concentrations of other electrolytes (e.g., sodium, potassium, calcium, magnesium, chloride, and / or sulfate) in urine can be used as indicators of acid-base imbalance. [Table 1]

[0130] In one embodiment, the treatment of an individual described herein can improve the individual's serum anion gap. For example, treatment of an acid-base imbalance with a neutral composition that has the ability to bind both protons and anions (without delivering sodium or potassium ions) can increase serum bicarbonate without increasing sodium or potassium (see Example 3 and Figures 13A, 13C, and 13D). As a result, the serum anion gap can be improved (reduced) by at least 1 mEq / L or more (e.g., at least 2 mEq / L) within a period as short as two weeks (see Example 3).

[0131] Various aspects and embodiments have various advantages, such as improving or successfully treating metabolic acidosis. Such improvements may also include reduced side effects, increased patient compliance, reduced drug burden, increased treatment rate, increased treatment size, avoidance of unwanted changes to other electrolytes, and / or reduced drug-drug interactions. Further improvements may include reducing the patient's anion gap (as defined above) as part of the methods and other aspects described herein. Further useful features of aspects of the present disclosure can be seen in the examples.

[0132] Compositions for use in certain treatments As noted above, one embodiment described herein is a composition for use in a method for treating metabolic acidosis in an adult patient, the composition comprising a polymer capable of removing HCl from the patient, the polymer characterized by a chloride ion binding capacity of at least 2.5 mEq / g in a simulated small intestine inorganic ("SIB") assay. This embodiment is based on data from the Examples demonstrating that HCl absorption and removal is capable of treating a patient, allowing the amount of composition to be set based on chloride binding capacity in the SIB assay. As shown in the Examples, compositions that bind specific levels of chloride in the "SIB" assay can be used in specific dose ranges to treat metabolic acidosis in adults. In this embodiment, the composition can be administered orally and is therefore an orally absorbable composition as defined herein.

[0133] This embodiment is based on data from the Examples showing that HCl absorption and removal using compositions of this embodiment can be used to treat patients, allowing the amount of composition to be set based on chloride binding capacity in a SIB assay. Surprisingly, relatively small amounts were required for successful treatment.

[0134] Another aspect of the present disclosure is a composition for use in a method for treating metabolic acidosis in an adult patient by increasing the patient's serum bicarbonate level by at least 1 mEq / L over 15 days of treatment, wherein the composition is a non-absorbable composition capable of removing protons from the patient. In this aspect, the composition can be administered orally and is therefore an orally absorbable composition as defined herein.

[0135] This embodiment is based on data from the examples showing that patients can be treated with compositions of this embodiment for HCl absorption and elimination, providing new details regarding the reduction possible with compositions of the present disclosure. This embodiment includes a surprisingly rapid increase in serum bicarbonate levels in patients, e.g., within the first few days, as well as a surprisingly large increase in serum bicarbonate levels.

[0136] Another aspect of the present disclosure is a composition for use in a method of treating metabolic acidosis in an adult patient, wherein the patient has a serum bicarbonate level of less than 20 mEq / L prior to treatment, and the composition is a non-absorbable composition capable of removing protons from the patient. In this aspect, the composition can be administered orally and is therefore an orally absorbable composition as defined herein.

[0137] This embodiment is based on data from the Examples which show for the first time that it is possible to treat patients with low serum bicarbonate levels, such as levels that have not previously been shown to be treated very rapidly. Patients with lower serum bicarbonate levels respond particularly well to treatment, and this improvement in this subgroup is one advantage of this embodiment.

[0138] The chloride ion binding capacity in the SIB assay is affected by both the selectivity of the composition to bind chloride and the total space available for chloride binding. The term "composition" refers to the active pharmaceutical ingredient, including any counterions, but not to any additives. Thus, the "amount" of a composition is the amount of the active pharmaceutical ingredient, not including other portions of any unit dosage form.

[0139] More specifically, in this embodiment, the amount of the composition can be any amount described herein in other sections within the range of 0.1 g to 12 g, e.g., 1-11 g, 2-10 g, 3-9 g, 3-8 g, 3-7 g, 3-6 g, 3.5-5.5 g, 4-5 g, or 4.5-5 g of the polymer is administered to a patient per day, or 0.5 g, 1 g, 1.5 g, 2 g, 2.5 g, 3 g, 3.5 g, 4.0 g, 4.5 g, or 5.0 g of the composition is administered to a patient per day.

[0140] More specifically, in this embodiment, the chloride ion binding capacity in a simulated small intestine inorganic buffer ("SIB") assay can be greater than 3, 3.5, 4, or 4.5 mEq / g. One upper limit for chloride ion binding capacity in a SIB assay is 10 mEq / g. Other upper limits can be 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 mEq / g, or there can be no specific upper limit.

[0141] Also disclosed are all combinations of amounts and chloride ion binding capacities of the compositions described herein. For example, in one embodiment, the composition has a chloride ion binding capacity in the SIB assay of at least 4.5 mEq / g, and only 0.1 to 6 g of the composition is administered in a method for treating metabolic acidosis.

[0142] The compositions in these embodiments may further have any of the properties or characteristics specified elsewhere herein. For example, the compositions may be non-absorbable compositions as described in the section below. Similarly, the methods of treatment specified in these embodiments may include any of the characteristics described in the previous section for certain methods of treatment.

[0143] Non-absorbable compositions As mentioned above, the pharmaceutical compositions having medical uses described herein have the ability to remove clinically significant amounts of HCl. To bind such target species, the pharmaceutical composition can be selected from the group consisting of cation exchange compositions, anion exchange compositions, zwitterion exchange compositions, neutral compositions capable of binding both protons and anions, composites thereof, and mixtures thereof.

[0144] Generally, pharmaceutical compositions comprise a particle population having a preferred particle range: (i) large enough to avoid passive or active absorption through the gastrointestinal tract, and (ii) small enough not to cause a gritty or unpleasant mouthfeel when ingested as a powder, sachet, and / or chewable tablet / dosage form having an average particle size of at least 3 μm. For example, in one such embodiment, the non-absorbable composition comprises a particle population having an average particle size (volume distribution) in the range of 5 to 1,000 μm. As a further example, in one such embodiment, the non-absorbable composition comprises a particle population having an average particle size (volume distribution) in the range of 5 to 500 μm. As a further example, in one such embodiment, the non-absorbable composition comprises a particle population having an average particle size (volume distribution) in the range of 10 to 400 μm. As a further example, in one such embodiment, the non-absorbable composition comprises a particle population having an average particle size (volume distribution) in the range of 10 to 300 μm. As a further example, in one such embodiment, the non-absorbable composition comprises a particle population having an average particle size (volume distribution) in the range of 20-250 μm. As a further example, in one such embodiment, the non-absorbable composition comprises a particle population having an average particle size (volume distribution) in the range of 30-250 μm. As a further example, in one such embodiment, the non-absorbable composition comprises a particle population having an average particle size (volume distribution) in the range of 40-180 μm. In certain embodiments, less than 7% of the particles in the population (volume distribution) have a diameter less than 10 μm. For example, in such embodiments, less than 5% of the particles in the population (volume distribution) have a diameter less than 10 μm. As a further example, in such embodiments, less than 2.5% of the particles in the population (volume distribution) have a diameter less than 10 μm. As a further example, in such embodiments, less than 1% of the particles in the population (volume distribution) have a diameter less than 10 μm. In all embodiments, particle size may be measured using the procedures described in the Abbreviations and Definitions section (above).

[0145] A low swelling ratio of the non-absorbable composition is preferred (0.5 to 10 times its own weight in water) to minimize patient GI side effects often associated with large amounts of polymer gel moving through the gastrointestinal tract. For example, in one such embodiment, the non-absorbable composition has a swelling ratio of less than 9. As a further example, in one such embodiment, the non-absorbable composition has a swelling ratio of less than 8. As a further example, in one such embodiment, the non-absorbable composition has a swelling ratio of less than 7. As a further example, in one such embodiment, the non-absorbable composition has a swelling ratio of less than 6. As a further example, in one such embodiment, the non-absorbable composition has a swelling ratio of less than 5. As a further example, in one such embodiment, the non-absorbable composition has a swelling ratio of less than 4. As a further example, in one such embodiment, the non-absorbable composition has a swelling ratio of less than 3. As a further example, in one such embodiment, the non-absorbable composition has a swelling ratio of less than 2.

[0146] The amount of target species HCl that a non-absorbable composition binds as it passes through the gastrointestinal tract is primarily a function of the composition's binding capacity for the target species and the amount of non-absorbable composition administered per day as a daily dose. Generally, the theoretical HCl binding capacity can be determined using an SGF assay to determine the amount of species that appear or disappear from an SGF buffer during the SGF assay. For example, the theoretical proton binding capacity of a cation exchange resin can be determined by measuring the increase in the amount of cations (other than protons) in the buffer during the SGF assay. Similarly, the theoretical anion binding capacity of an anion exchange resin (in a form other than chloride) can be determined by measuring the increase in the amount of anions (other than chloride ions) in the buffer during the SGF assay. Furthermore, the theoretical anion binding capacity of a neutral composition for protons and a conjugate base of a strong acid can be determined by measuring the decrease in chloride concentration in the buffer during the SGF assay.

[0147] Generally, non-absorbed composition has the theoretical binding capacity of target species (HCl) of at least about 0.5mEq / g (determined in SGF assay).For example, in some embodiments, non-absorbed composition has the theoretical binding capacity of target species of at least about 1mEq / g, 2mEq / g, 3mEq / g, 4mEq / g, 5mEq / g, 7.5mEq / g, 10mEq / g, 12.5mEq / g, 15mEq / g, 20mEq / g, or even at least about 35mEq / g.In certain embodiments, the theoretical binding capacity of non-absorbed composition to target species does not exceed 30mEq / g. Thus, for example, the theoretical binding capacity of the non-absorbable composition for the target species can be in the range of 2-25 mEq / g, 3-25 mEq / g, 5-25 mEq / g, 10-25 mEq / g, 5-20 mEq / g, 6-20 mEq / g, 7.5-20 mEq / g, or even 10-20 mEq / g. In those embodiments in which the target species comprises a proton and at least one conjugate base, the binding capacities described in this paragraph are the theoretical binding capacities for the proton and the conjugate base, independently and individually, and not their sum.

[0148] Generally, non-absorbable compositions have a theoretical proton binding capacity of at least about 0.5 mEq / g (determined in SGF assay).For example, in some embodiments, non-absorbable compositions have a theoretical proton binding capacity of at least about 1 mEq / g, 2 mEq / g, 3 mEq / g, 4 mEq / g, 5 mEq / g, 7.5 mEq / g, 10 mEq / g, 12.5 mEq / g, 15 mEq / g, or even at least about 20 mEq / g.Generally, non-absorbable compositions typically have a theoretical proton binding capacity of no more than about 35 mEq / g.For example, in some embodiments, the theoretical proton binding capacity of non-absorbable compositions does not exceed 30 mEq / g. Thus, for example, the theoretical binding capacity of a non-absorbable composition for protons can range from 2 to 25 mEq / g, 3 to 25 mEq / g, 5 to 25 mEq / g, 10 to 25 mEq / g, 5 to 20 mEq / g, 6 to 20 mEq / g, 7.5 to 20 mEq / g, or even 10 to 20 mEq / g. In those embodiments in which the target species comprises a proton and at least one conjugate base, the binding capacities described in this paragraph are the theoretical binding capacities for the proton and the conjugate base individually and independently, not the sum of them.

[0149] Phosphate, bicarbonate, bicarbonate equivalents, and conjugated bases of bile and fatty acids are converted to chloride or strong acids (e.g., HSO4) in the stomach and small intestine. - and SO4 2-Chloride is a potentially interfering anion relative to other conjugate bases of phosphate, bicarbonate equivalents, and bile and fatty acid conjugate bases in the small intestine. Therefore, rapid and preferential binding of chloride to phosphate, bicarbonate equivalents, and bile and fatty acid conjugate bases in the small intestine is desirable, and the SIB assay can be used to determine the rate and preferential binding. Because colonic transit times are slow (2-3 days) compared to the small intestine, and colonic conditions are not encountered by orally administered nonabsorbable compositions until after stomach and small intestinal conditions have been encountered, the rate of chloride binding by nonabsorbable compositions need not be rapid under in vitro conditions designed to mimic the colon, or the lower small intestine / colon. However, high chloride binding and selectivity relative to other interfering anions is desirable, e.g., over 24 and / or 48 hours or longer.

[0150] In one embodiment, the non-absorbable composition is characterized by a chloride ion binding capacity of at least 1 mEq / g in a simulated small intestine inorganic buffer ("SIB") assay. For example, in one such embodiment, the non-absorbable composition is characterized by a chloride ion binding capacity of at least 1.5 mEq / g, 2 mEq / g, 2.5 mEq / g, 3 mEq / g, 3.5 mEq / g, 4 mEq / g, 4.5 mEq / g, 5 mEq / g, 5.5 mEq / g, or even at least about 6 mEq / g in a SIB assay.

[0151] In one embodiment, the non-absorbable composition binds a significant amount of chloride relative to phosphate, e.g., as shown in a SIB assay. For example, in one embodiment, the ratio of bound chloride to bound phosphate in a SIB assay is at least 0.1:1, respectively. By way of further example, in one such embodiment, the ratio of bound chloride to bound phosphate in a SIB assay is at least 0.2:1, 0.25:1, 0.3:1, 0.35:1, 0.4:1, 0.45:1, 0.5:1, 2:3, 0.75:1, 0.9:1, 1:1, 1.25:1, 1.5:1, 1.75:1, 2:1, 2.25:1, 2.5:1, 2.75:1, 3:1, 4:1, or even at least about 5:1, respectively.

[0152] In one embodiment, the orally administered non-absorbable composition is characterized by a proton-binding capacity and chloride-binding capacity in simulated gastric fluid of at least 1 mEq / g in an SGF assay. For example, in one such embodiment, the non-absorbable composition is characterized by a proton-binding capacity and chloride-binding capacity in an SGF assay of at least 2 mEq / g, 3 mEq / g, 4 mEq / g, 5 mEq / g, 6 mEq / g, 7 mEq / g, 8 mEq / g, 9 mEq / g, 10 mEq / g, 11 mEq / g, 12 mEq / g, 13 mEq / g, or even at least about 14 mEq / g. By way of further example, in one such embodiment, the non-absorbable composition is characterized by a proton-binding capacity and chloride-binding capacity after 1 hour in SGF that are at least 50% of the proton-binding capacity and chloride-binding capacity, respectively, of the non-absorbable composition after 24 hours in SGF. By way of further example, in one such embodiment, the non-absorbable composition is characterized by a proton binding capacity and chloride binding capacity after 1 hour in SGF that is at least 60%, 70%, 80%, or even at least 90%, respectively, of the proton binding capacity and chloride binding capacity of the non-absorbable composition after 24 hours in SGF.

[0153] In one embodiment, the non-absorbable composition comprises a neutral composition capable of binding both protons and anions. Exemplary neutral non-absorbable compositions that bind both protons and anions include propylene oxide-functionalized polymers, Michael acceptor-functionalized polymers, ring-expanded porphyrins, covalently bonded polymeric structures, and polymers containing amine and / or phosphine functional groups.

[0154] In those embodiments in which the non-absorbable composition binds chloride ions, it is generally preferred that the non-absorbable composition selectively bind chloride ions relative to other counterions, such as bicarbonate-equivalent anions, phosphate anions, and bile-fatty acid conjugate bases. Stated differently, in these embodiments, it is generally preferred that the non-absorbable composition (i) remove more chloride ions than bicarbonate-equivalent anions, (ii) remove more chloride ions than phosphate anions, and (iii) remove more chloride ions than bile-fatty acid conjugate bases. Advantageously, therefore, treatment with the non-absorbable composition does not induce or exacerbate hypophosphatemia (i.e., serum phosphorus concentrations less than about 2.4 mg / dL), significantly increase low-density lipoprotein ("LDL"), or negatively affect serum or colonic levels of metabolically relevant anions.

[0155] In some embodiments, the pharmaceutical composition comprises a compound of Formula 1: [ka] wherein R1, R2, and R3 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, provided that at least one of R1, R2, and R3 is other than hydrogen. and R3 is independently hydrogen, hydrocarbyl, or substituted hydrocarbyl. In one embodiment, for example, R1, R2, and R3 are independently hydrogen, aryl, aliphatic, heteroaryl, or heteroaliphatic, with the proviso that R1, R2, and R3 are not each hydrogen. By way of further example, in one such embodiment, R1, R2, and R3 are independently hydrogen, saturated hydrocarbon, unsaturated aliphatic, unsaturated heteroaliphatic, heteroalkyl, heterocyclic, aryl, or heteroaryl, with the proviso that R1, R2, and R3 are not each hydrogen. By way of further example, in one such embodiment, R1, R2, and R3 are independently hydrogen, alkyl, alkenyl, aryl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocycle, with the proviso that each of R1, R2, and R3 is not hydrogen. By way of further example, in one such embodiment, R1, R2, and R3 are independently hydrogen, alkyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocycle, with the proviso that each of R1, R2, and R3 is not hydrogen. By way of further example, in one such embodiment, R1 and R2 (together with the nitrogen atom to which they are attached) together form part of a ring structure, such that the monomer of Formula 1 is a nitrogen-containing heterocycle (e.g., piperidine), and R3 is hydrogen or heteroaliphatic. By way of further example, in one embodiment, R1, R2, and R3 are independently hydrogen, aliphatic, or heteroaliphatic, provided that at least one of R1, R2, and R3 is other than hydrogen. By way of further example, in one embodiment, R1, R2, and R3 are independently hydrogen, allyl, or aminoalkyl.

[0156] In one embodiment, the crosslinked polymer comprises an amine residue corresponding to Formula 1, wherein R1, R2, and R3 are independently hydrogen, heteroaryl, aryl, aliphatic, or heteroaliphatic, provided that at least one of R1, R2, and R3 is aryl or heteroaryl. For example, in this embodiment, R1 and R2, together with the nitrogen atom to which they are attached, can form a saturated or unsaturated nitrogen-containing heterocycle. As a further example, R1 and R2, together with the nitrogen atom to which they are attached, can form part of a pyrrolidino, pyrrole, pyrazolidine, pyrazole, imidazolidine, imidazole, piperidine, pyridine, piperazine, diazine, or triazine ring structure. As a further example, R1 and R2, together with the nitrogen atom to which they are attached, can form part of a piperidine ring structure.

[0157] In one embodiment, the crosslinked polymer comprises an amine residue corresponding to Formula 1, wherein R1, R2, and R3 are independently hydrogen, aliphatic, or heteroaliphatic, provided that at least one of R1, R2, and R3 is other than hydrogen. For example, in this embodiment, R1, R2, and R3 can independently be hydrogen, alkyl, alkenyl, aryl, vinyl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, or heterocycle, provided that at least one of R1, R2, and R3 is other than hydrogen. As a further example, in one such embodiment, R1 and R2, together with the nitrogen atom to which they are attached, can form a saturated or unsaturated nitrogen-containing heterocycle. As a further example, in one such embodiment, R1 and R2, together with the nitrogen atom to which they are attached, can form part of a pyrrolidino, pyrrole, pyrazolidine, pyrazole, imidazolidine, imidazole, piperidine, piperazine, or diazine ring structure. By way of further example, in one such embodiment, R1 and R2, together with the nitrogen atom to which they are attached, can form part of a piperidine ring structure. By way of further example, in one such embodiment, the amine corresponding to Formula 1 is acyclic, and at least one of R1, R2, and R3 is aliphatic or heteroaliphatic. By way of further example, in one such embodiment, R1, R2, and R3 are independently hydrogen, alkyl, allyl, vinyl, alicyclic, aminoalkyl, alkanol, or heterocyclic, provided that at least one of R1, R2, and R3 is other than hydrogen.

[0158] In one embodiment, the crosslinked polymer comprises an amine residue corresponding to Formula 1, and the crosslinked polymer is prepared by substitution polymerization of an amine corresponding to Formula 1 with a multifunctional crosslinker (which may also optionally comprise an amine moiety), wherein R1, R2, and R3 are independently hydrogen, alkyl, aminoalkyl, or alkanol, with the proviso that at least one of R1, R2, and R3 is other than hydrogen.

[0159] In some embodiments, the molecular weight per nitrogen of the polymers of the present disclosure can range from about 40 to about 1000 daltons. In one embodiment, the molecular weight per nitrogen of the polymer is about 40 to about 500 daltons. In another embodiment, the molecular weight per nitrogen of the polymer is about 50 to about 170 daltons. In another embodiment, the molecular weight per nitrogen of the polymer is about 60 to about 110 daltons.

[0160] In some embodiments, an amine-containing monomer is polymerized and the polymer is simultaneously crosslinked in a substitution polymerization reaction in a first reaction step. The amine reactant (monomer) in the simultaneous polymerization and crosslinking reaction can react more than once for substitution polymerization. In one such embodiment, the amine monomer is a linear amine having at least two reactive amine moieties for participating in the substitution polymerization reaction. In another embodiment, the amine monomer is a branched amine having at least two reactive amine moieties for participating in the substitution polymerization reaction. The crosslinking agent for simultaneous substitution polymerization and crosslinking typically has at least two amine-reactive moieties, such as an alkyl chloride and an alkyl epoxide. To be incorporated into the polymer, a primary amine reacts with the crosslinking agent at least once and potentially up to three times; a secondary amine can react with the crosslinking agent up to two times; and a tertiary amine can react with the crosslinking agent only once. However, the formation of a significant number of quaternary nitrogens / amines is generally undesirable because quaternary amines cannot bond with protons.

[0161] Exemplary amines that may be used in the displacement polymerization reactions described herein are 1,3-bis[bis(2-aminoethyl)amino]propane, 3-amino-1-{[2-(bis{2-[bis(3-aminopropyl)amino]ethyl}amino)ethyl](3-aminopropyl)amino}propane, 2-[bis(2-aminoethyl)amino]ethanamine, tris(3-aminopropyl)amine, 1,4-bis[bis(3-aminopropyl)amino]butane, 1,2-ethanediamine, 2-amino-1-(2-aminoethylamino)ethane, 1,2-bis (2-aminoethylamino)ethane, 1,3-propanediamine, 3,3'-diaminodipropylamine, 2,2-dimethyl-1,3-propanediamine, 2-methyl-1,3-propanediamine, N,N'-dimethyl-1,3-propanediamine, N-methyl-1,3-diaminopropane, 3,3'-diamino-N-methyldipropylamine, 1,3-diaminopentane, 1,2-diamino-2-methylpropane, 2-methyl-1,5-diaminopentane, 1,2-diaminopropane, 1,10-diaminodecane, 1,8-diaminooctane, 1,9-Diaminooctane, 1,7-Diaminoheptane, 1,6-Diaminohexane, 1,5-Diaminopentane, 3-Bromopropylamine hydrobromide, N,2-Dimethyl-1,3-propanediamine, N-Isopropyl-1,3-diaminopropane, N,N'-Bis(2-aminoethyl)-1,3-propanediamine, N,N'-Bis(3-aminopropyl)ethylenediamine, N,N'-Bis(3-aminopropyl)-1,4-butanediamine tetrahydrochloride, 1,3-Diamino-2-propanol, N-Ethylethylenediamine Amines, 2,2'-diamino-N-methyldiethylamine, N,N'-diethylethylenediamine, N-isopropylethylenediamine, N-methylethylenediamine, N,N'-di-tert-butylethylenediamine, N,N'-diisopropylethylenediamine, N,N'-dimethylethylenediamine, N-butylethylenediamine, 2-(2-aminoethylamino)ethanol, 1,4,7,10,13,16-hexaazacyclooctadecane, 1,4,7,10-tetraazacyclododecane, 1,4,7-triazacyclononane, N,N'-bis(2-hydroxyethyl)ethylenediamine, piperazine, bis(hexamethylene)triamine, N-(3-hydroxypropyl)ethylenediamine, N-(2-aminoethyl)piperazine, 2-methylpiperazine, homopiperazine, 1,4,8,11-tetraazacyclotetradecane, 1,4,8,12-tetraazacyclopentadecane, 2-(aminomethyl)piperidine, 3-(methylamino)pyrrolidine.

[0162] Exemplary crosslinking agents that may be used in the substitution polymerization reaction and the post-polymerization crosslinking reaction include one or more multifunctional crosslinking agents, such as: dihaloalkanes, haloalkyloxiranes, alkyloxirane sulfonates, di(haloalkyl)amines, tri(haloalkyl)amines, diepoxides, triepoxides, tetraepoxides, bis(halomethyl)benzenes, tri(halomethyl)benzenes, tetra(halomethyl)benzenes, epihalohydrins such as epichlorohydrin and epibromohydrin, poly(epichlorohydrin), (iodomethyl)iodomethyl, and the like. Xylan, glycidyl tosylate, glycidyl 3-nitrobenzenesulfonate, 4-tosyloxy-1,2-epoxybutane, bromo-1,2-epoxybutane, 1,2-dibromoethane, 1,3-dichloropropane, 1,2-dichloroethane, l-bromo-2-chloroethane, 1,3-dibromopropane, bis(2-chloroethyl)amine, tris(2-chloroethyl)amine, and bis(2-chloroethyl)methylamine, 1,3-butadiene diepoxide, 1,5-hexadiene diepoxide, diglycidyl ether, 1,2,7,8-diepoxide Shioctane, 1,2,9,10-diepoxydecane, ethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, 1,2-ethanediol diglycidyl ether, glycerol diglycidyl ether, 1,3-diglycidyl glyceryl ether, N,N-diglycidylaniline, neopentyl glycol diglycidyl ether, diethylene glycol diglycidyl ether, 1,4-bis(glycidyloxy)benzene, resorcinol diglycidyl ether, 1,6-hexa Diglycidyl ether, trimethylolpropane diglycidyl ether, 1,4-cyclohexanedimethanol diglycidyl ether, 1,3-bis-(2,3-epoxypropyloxy)-2-(2,3-dihydroxypropyloxy)propane, 1,2-cyclohexanedicarboxylic acid diglycidyl ester, 2,2'-bis(glycidyloxy)diphenylmethane, bisphenol F diglycidyl ether, 1,4-bis(2',3'epoxypropyl)perfluoro-n-butane, 2,6-di(oxiran-2-ylmethyl)-1,2,3,5,6,7-Hexahydropyrrolo[3,4-f]isoindole-1,3,5,7-tetraone, bisphenol A diglycidyl ether, ethyl 5-hydroxy-6,8-di(oxiran-2-ylmethyl)-4-oxo-4-h-chromene-2-carboxylate, bis[4-(2,3-epoxy-propylthio)phenyl]-sulfide, 1,3-bis(3-glycidoxypropyl)tetramethyldisiloxane, 9,9-bis[4-(glycidyloxy) )phenyl] fluorine, triepoxy isocyanurate, glycerol triglycidyl ether, N,N-diglycidyl-4-glycidyloxyaniline, isocyanuric acid (S,S,S)-triglycidyl ester, isocyanuric acid (R,R,R)-triglycidyl ester, triglycidyl isocyanurate, trimethylolpropane triglycidyl ether, glycerol propoxylate triglycidyl ether, triphenylolmethane triglycidyl ether ether, 3,7,14-tris[[3-(epoxypropoxy)propyl]dimethylsilyloxy]-1,3,5,7,9,11,14-heptacyclopentyltricyclo[7,3,3,15,11]heptasiloxane, 4,4'methylenebis(N,N-diglycidylaniline), bis(halomethyl)benzene, bis(halomethyl)biphenyl and bis(halomethyl)naphthalene, toluene diisocyanate, acrylol chloride, methyl acrylate, Examples of suitable amines include, but are not limited to, ethylene bisacrylamide, pyrometallic dianhydride, succinyl dichloride, dimethyl succinate, 3-chloro-1-(3-chloropropylamino-2-propanol, 1,2-bis(3-chloropropylamino)ethane, bis(3-chloropropyl)amine, 1,3-dichloro-2-propanol, 1,3-dichloropropane, 1-chloro-2,3-epoxypropane, and tris[(2-oxiranyl)methyl]amine.

[0163] In some embodiments, the carbon-to-nitrogen ratio of the polymer of the present disclosure may range from about 2:1 to about 6:1, respectively. For example, in one such embodiment, the carbon-to-nitrogen ratio of the polymer of the present disclosure may range from about 2.5:1 to about 5:1, respectively. By way of further example, in one such embodiment, the carbon-to-nitrogen ratio of the polymer of the present disclosure may range from about 3:1 to about 4.5:1, respectively. By way of further example, in one such embodiment, the carbon-to-nitrogen ratio of the polymer of the present disclosure may range from about 3.25:1 to about 4.25:1, respectively. By way of further example, in one such embodiment, the carbon-to-nitrogen ratio of the polymer of the present disclosure may range from about 3.4:1 to about 4:1, respectively. In another embodiment, the molecular weight per nitrogen of the polymer is from about 60 to about 110 daltons.

[0164] In some embodiments, the crosslinked polymer comprises an amine residue corresponding to Formula 1a, wherein the crosslinked polymer is represented by Formula 1a: [ka] wherein 4 and R5 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl. The monomers of formula 1a are prepared by radical polymerization of an amine corresponding to the formula 1a. In one embodiment, for example, R4 and R5 are independently hydrogen, saturated hydrocarbon, unsaturated aliphatic, aryl, heteroaryl, unsaturated heteroaliphatic, heterocyclic, or heteroalkyl. As a further example, in one such embodiment, R4 and R5 are independently hydrogen, aliphatic, heteroaliphatic, aryl, or heteroaryl. As a further example, in one such embodiment, R4 and R5 are independently hydrogen, alkyl, alkenyl, aryl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocyclic. As a further example, in one such embodiment, R4 and R5 are independently hydrogen, alkyl, aryl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ether, or heterocyclic. As a further example, in one such embodiment, R4 and R5 (together with the nitrogen atom to which they are attached) together form part of a ring structure, and thus the monomer of formula 1a is a nitrogen-containing heterocyclic ring (e.g., piperidine). By way of further example, in one embodiment, R4 and R5 are independently hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one embodiment, R4 and R5 are independently hydrogen, allyl, or aminoalkyl.

[0165] In some embodiments, the crosslinked polymer comprises an amine residue corresponding to Formula 1b, wherein the crosslinked polymer is formed by crosslinking with a multifunctional crosslinker (which optionally also comprises an amine moiety) of Formula 1b: [ka] wherein R4 and R5 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl; R6 is aliphatic; and R 61 and R 62 are independently hydrogen, aliphatic, or heteroaliphatic. The monomers of formula 1a are prepared by substitution polymerization of the corresponding amines. In one embodiment, for example, R4 and R5 are independently hydrogen, saturated hydrocarbon, unsaturated aliphatic, aryl, heteroaryl, heteroalkyl, or unsaturated heteroaliphatic. As a further example, in one such embodiment, R4 and R5 are independently hydrogen, aliphatic, heteroaliphatic, aryl, or heteroaryl. As a further example, in one such embodiment, R4 and R5 are independently hydrogen, alkyl, alkenyl, aryl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocycle. As a further example, in one such embodiment, R4 and R5 are independently hydrogen, alkyl, alkenyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocycle. As a further example, in one such embodiment, R4 and R5 (together with the nitrogen atom to which they are attached) together form part of a ring structure, and thus the monomer of formula 1a is a nitrogen-containing heterocycle (e.g., piperidine). By way of further example, in one embodiment, R4 and R5 are independently hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one embodiment, R4 and R5 are independently hydrogen, allyl, or aminoalkyl. By way of further example, in each of the embodiments described in this paragraph, R6 can be methylene, ethylene, or propylene, and R 61 and R 62 can independently be hydrogen, allyl, or aminoalkyl.

[0166] In some embodiments, the crosslinked polymer has Formula 1c: [ka] wherein R7 is hydrogen, aliphatic or heteroaliphatic, and R8 is aliphatic or heteroaliphatic. For example, in one such embodiment, R7 is hydrogen and R8 is aliphatic or heteroaliphatic. As a further example, in one such embodiment, R7 and R8 are independently aliphatic or heteroaliphatic. As a further example, in one such embodiment, at least one of R7 and R8 comprises an allyl moiety. As a further example, in one such embodiment, at least one of R7 and R8 comprises an aminoalkyl moiety. As a further example, in one such embodiment, R7 and R8 each comprise an allyl moiety. As a further example, in one such embodiment, R7 and R8 each comprise an aminoalkyl moiety. As a further example, in one such embodiment, R7 comprises an allyl moiety and R8 comprises an aminoalkyl moiety.

[0167] In some embodiments, the crosslinked polymer has Formula 2: [ka] [In the formula, m and n are independently non-negative integers; R 10 , R 20 , R 30 and R 40 is independently hydrogen, hydrocarbyl, or substituted hydrocarbyl; X1 is [ka] and; X2 is hydrocarbyl or substituted hydrocarbyl; each X 11 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid, or halo; z is a non-negative number] containing an amine residue corresponding to

[0168] In one embodiment, the crosslinked polymer comprises an amine residue corresponding to Formula 2, and the crosslinked polymer is prepared by (i) substitution polymerization of an amine corresponding to Formula 2 with a multifunctional crosslinker (which optionally also comprises an amine moiety) or (2) radical polymerization of an amine corresponding to Formula 2, wherein m and n are independently 0, 1, 2, or 3, and n is 0 or 1.

[0169] In one embodiment, the crosslinked polymer comprises an amine residue corresponding to Formula 2, and the crosslinked polymer is prepared by (i) substitution polymerization of an amine corresponding to Formula 2 with a multifunctional crosslinker (which may optionally also contain an amine moiety), or (2) radical polymerization of an amine corresponding to Formula 2, wherein R 10 , R 20 , R 30 and R 40 is independently hydrogen, aliphatic, aryl, heteroaliphatic, or heteroaryl. By way of further example, in one such embodiment, R 10 , R 20 , R 30 and R 40 are independently hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment, R 10 , R 20 , R 30 and R 40 is independently hydrogen, alkyl, allyl, vinyl, or aminoalkyl. By way of further example, in one such embodiment, R 10 , R 20 , R 30 and R 40 are independently hydrogen, alkyl, aryl, vinyl, -(CH2) d NH2, -(CH2) d N[(CH2) e NH2)]2, and d and e are independently 2 to 4. In each of the exemplary embodiments in this paragraph, m and z can independently be 0, 1, 2, or 3, and n is 0 or 1.

[0170] In one embodiment, the crosslinked polymer comprises an amine residue corresponding to Formula 2, and the crosslinked polymer is prepared by (i) substitution polymerization of an amine corresponding to Formula 2 with a multifunctional crosslinker (which may also optionally contain an amine moiety), or (2) radical polymerization of an amine corresponding to Formula 2, where X2 is aliphatic or heteroaliphatic. For example, in one such embodiment, X2 is aliphatic or heteroaliphatic, and R 10 , R 20 , R 30 and R 40 are independently hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment, X2 is alkyl or aminoalkyl and R 10 , R 20 , R 30 and R 40 are independently hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment, X2 is alkyl or aminoalkyl and R 10 , R 20 , R 30 and R 40 is independently hydrogen, alkyl, allyl, vinyl, or aminoalkyl. In each of the exemplary embodiments in this paragraph, m and z can independently be 0, 1, 2, or 3; and n is 0 or 1.

[0171] In one embodiment, the crosslinked polymer comprises an amine residue corresponding to Formula 2, and the crosslinked polymer is prepared by (i) substitution polymerization of an amine corresponding to Formula 2 with a multifunctional crosslinker (which may also optionally contain an amine moiety), or (2) radical polymerization of an amine corresponding to Formula 2, where m is a positive integer. For example, in one such embodiment, m is a positive integer, z is 0, and R 20 is hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment, m is a positive integer (e.g., 1 to 3), z is a positive integer (e.g., 1 to 2), and X 11 is hydrogen, aliphatic or heteroaliphatic, and R 20is hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment, m is a positive integer, z is 0, 1, or 2, and X 11 is hydrogen, alkyl, alkenyl, or aminoalkyl, and R 20 is hydrogen, alkyl, alkenyl, or aminoalkyl.

[0172] In one embodiment, the crosslinked polymer comprises an amine residue corresponding to Formula 2, and the crosslinked polymer is prepared by (i) substitution polymerization of an amine corresponding to Formula 2 with a multifunctional crosslinker (which may also optionally contain an amine moiety), or (2) radical polymerization of an amine corresponding to Formula 2, where n is a positive integer and R 30 is hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment, n is 0 or 1 and R 30 is hydrogen, alkyl, alkenyl, or aminoalkyl.

[0173] In one embodiment, the crosslinked polymer comprises an amine residue corresponding to Formula 2, and the crosslinked polymer is prepared by (i) substitution polymerization of an amine corresponding to Formula 2 with a multifunctional crosslinker (which may also optionally contain an amine moiety), or (2) radical polymerization of an amine corresponding to Formula 2, where m and n are independently non-negative integers, and X2 is aliphatic or heteroaliphatic. For example, in one such embodiment, m is 0 to 2, n is 0 or 1, X2 is aliphatic or heteroaliphatic, and R 10 , R 20 , R 30 and R 40 are independently hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment, m is 0 to 2, n is 0 or 1, X2 is alkyl or aminoalkyl, and R 10 , R 20 , R 30 and R 40are independently hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment, m is 0 to 2, n is 0 or 1, X2 is alkyl or aminoalkyl, and R 10 , R 20 , R 30 and R 40 is independently hydrogen, alkyl, alkenyl, or aminoalkyl.

[0174] In some embodiments, the crosslinked polymer comprises an amine residue corresponding to formula 2a, wherein the crosslinked polymer is formed by crosslinking with a multifunctional crosslinker (which optionally also comprises an amine moiety) of formula 2a: [ka] [In the formula, m and n are independently non-negative integers; Each R 11 are independently hydrogen, hydrocarbyl, heteroaliphatic, or heteroaryl; R 21 and R 31 are independently hydrogen or heteroaliphatic; R 41 is hydrogen, substituted hydrocarbyl or hydrocarbyl; X1 is [ka] and; X2 is alkyl or substituted hydrocarbyl; each X 12 are independently hydrogen, hydroxy, amino, aminoalkyl, boronic acid, or halo; z is a non-negative number] It is prepared by substitution polymerization of the corresponding amine.

[0175] In one embodiment, the crosslinked polymer comprises an amine residue corresponding to Formula 2a, the crosslinked polymer being prepared by substitution polymerization of an amine corresponding to Formula 1 with a multifunctional crosslinker (which may also optionally comprise an amine moiety). For example, in one such embodiment, m and z are independently 0, 1, 2, or 3, and n is 0 or 1.

[0176] In one embodiment, the crosslinked polymer comprises an amine residue corresponding to Formula 2a, wherein the crosslinked polymer is prepared by substitution polymerization of an amine corresponding to Formula 2a with a multifunctional crosslinker (which may optionally also contain an amine moiety), wherein each R 11 are independently hydrogen, aliphatic, aminoalkyl, haloalkyl, or heteroaryl; R 21 and R 31 are independently hydrogen or heteroaliphatic, and R 41 is hydrogen, aliphatic, aryl, heteroaliphatic, or heteroaryl. For example, in one such embodiment, each R 11 is hydrogen, aliphatic, aminoalkyl, or haloalkyl; R 21 and R 31 are independently hydrogen or heteroaliphatic, and R 41 is hydrogen, alkylamino, aminoalkyl, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment, each R 11 is hydrogen, aliphatic, aminoalkyl, or haloalkyl; R 21 and R 31 is hydrogen or aminoalkyl, and R 41 is hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment, each R 11 and R 41 are independently hydrogen, alkyl, or aminoalkyl; R 21 and R 31 is independently hydrogen or heteroaliphatic. By way of further example, in one such embodiment, each R 11 and R 41 are independently hydrogen, alkyl, -(CH2) d NH2, -(CH2)d N[(CH2) e NH2)]2, d and e are independently 2 to 4, and R 21 and R 31 is independently hydrogen or heteroaliphatic. In each of the exemplary embodiments in this paragraph, m and z can independently be 0, 1, 2, or 3; and n is 0 or 1.

[0177] Exemplary amines for the synthesis of polymers containing repeat units corresponding to Formula 2a include, but are not limited to, those shown in Table A. [Table 2]

[0178] Exemplary crosslinkers for the synthesis of polymers containing amine residues that contain repeat units corresponding to Formula 2a include, but are not limited to, the crosslinkers shown in Table B. [Table 3]

[0179] In some embodiments, the crosslinked polymer comprises an amine residue corresponding to Formula 2b, wherein the crosslinked polymer is represented by Formula 2b: [ka] [In the formula, m and n are independently non-negative integers; Each R 12 is independently hydrogen, substituted hydrocarbyl, or hydrocarbyl; R 22 and R 32 is independently hydrogen, substituted hydrocarbyl, or hydrocarbyl; R 42 is hydrogen, hydrocarbyl or substituted hydrocarbyl; X1 is [ka] and; X2 is alkyl, aminoalkyl or alkanol; each X 13 are independently hydrogen, hydroxy, alicyclic, amino, aminoalkyl, halogen, alkyl, heteroaryl, boronic acid, or aryl; z is a non-negative number] and an amine corresponding to The amine corresponding to formula 2b contains at least one allyl group. It is produced by radical polymerization of

[0180] In one embodiment, the crosslinked polymer comprises an amine residue corresponding to Formula 2b, wherein the crosslinked polymer is prepared by radical polymerization of an amine corresponding to Formula 2b, where m and z are independently 0, 1, 2, or 3, and n is 0 or 1.

[0181] In one embodiment, the crosslinked polymer comprises an amine residue corresponding to Formula 2b, the crosslinked polymer being prepared by radical polymerization of an amine corresponding to Formula 1, wherein (i) R 12 or R 42 independently contain at least one allyl or vinyl moiety; (ii) m is a positive integer; and R 22 contains at least one allyl or vinyl moiety, and / or (iii) n is a positive integer and R 32 contains at least one allyl moiety. For example, in one such embodiment, m and z are independently 0, 1, 2, or 3, and n is 0 or 1. For example, in one such embodiment, R 12 or R 42 In combination, R comprises at least two allyl or vinyl moieties. By way of further example, in one such embodiment, m is a positive integer and R 12 , R 22 and R 42 In combination, n comprises at least two allyl or vinyl moieties. By way of further example, in one such embodiment, n is a positive integer and R 12 , R32 and R 42 In combination, R comprises at least two allyl or vinyl moieties. By way of further example, in one such embodiment, m is a positive integer, n is a positive integer, and R 12 , R 22 , R 32 and R 42 in combination contains at least two allyl or vinyl moieties.

[0182] In one embodiment, the crosslinked polymer comprises an amine residue corresponding to Formula 2b, wherein the crosslinked polymer is prepared by radical polymerization of an amine corresponding to Formula 2b, wherein each R 12 are independently hydrogen, aminoalkyl, allyl, or vinyl, and R 22 and R 32 are independently hydrogen, alkyl, aminoalkyl, haloalkyl, alkenyl, alkanol, heteroaryl, alicyclic, heterocyclic, or aryl; R 42 is hydrogen or substituted hydrocarbyl. For example, in one such embodiment, each R 12 is aminoalkyl, allyl, or vinyl, and R 22 and R 32 are independently hydrogen, alkyl, aminoalkyl, haloalkyl, alkenyl, or alkanol; R 42 is hydrogen or substituted hydrocarbyl. By way of further example, in one such embodiment, each R 12 and R 42 are independently hydrogen, alkyl, aryl, vinyl, -(CH2) d NH2 or -(CH2) d N[(CH2) e NH2]2, d and e are independently 2 to 4, and R 22 and R 32 are independently hydrogen or heteroaliphatic.

[0183] Exemplary amines and crosslinkers (or salts thereof, such as the hydrochloride, phosphoric acid, sulfuric acid, or hydrobromide salts thereof) for the synthesis of polymers of Formula 2b include, but are not limited to, those shown in Table C. [Table 4]

[0184] In some embodiments, the crosslinked polymer is derived from the reaction of a monomer represented by any of Formulas 1, 1a, 1b, 1c, 2, 2a, and 2b, or a linear polymer comprised of repeat units represented by Formula 3 with an external crosslinker or pre-existing polymer functional groups that can act as crosslinking sites, resulting in a polymer. Formula 3 is a crosslinked polymer comprising X 15 may be the repeat unit of a copolymer or terpolymer, which may be either a random, alternating or block copolymer. [ka] [In the formula, R 15 , R 16 and R 17 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid, or halo; X 15 teeth, [ka] and X5 is hydrocarbyl, substituted hydrocarbyl, oxo (—O—) or amino; z is a non-negative number] The repeat unit in also represents a repeat unit of a branched or hyperbranched polymer in which the primary branch point can be from any atom in the backbone of the polymer.

[0185] In one embodiment, R 15 , R 16 and R 17are independently hydrogen, aryl or heteroaryl, X5 is hydrocarbyl, substituted hydrocarbyl, oxo or amino, and m and z are non-negative integers. 15 , R 16 and R 17 is independently aliphatic or heteroaliphatic, X5 is hydrocarbyl, substituted hydrocarbyl, oxo (-O-) or amino, and m and z are non-negative integers. 15 , R 16 and R 17 is independently unsaturated aliphatic or unsaturated heteroaliphatic, X5 is hydrocarbyl, substituted hydrocarbyl, oxo, or amino, and z is a non-negative integer. 15 , R 16 and R 17 is independently alkyl or heteroalkyl, X5 is hydrocarbyl, substituted hydrocarbyl, oxo or amino, and z is a non-negative integer. 15 , R 16 and R 17 is independently alkylamino, aminoalkyl, hydroxyl, amino, boronic acid, halo, haloalkyl, alkanol, or ether; X5 is hydrocarbyl, substituted hydrocarbyl, oxo, or amino; and z is a non-negative integer. 15 , R 16 and R 17 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid, or halo; X5 is oxo, amino, alkylamino, ether, alkanol, or haloalkyl; and z is a non-negative integer.

[0186] Exemplary crosslinkers that may be used in the radical polymerization reaction include one or more multifunctional crosslinkers, such as: 1,4-bis(allylamino)butane, 1,2-bis(allylamino)ethane, 2-(allylamino)-1-[2-(allylamino)ethylamino]ethane, 1,3-bis(allylamino)propane, 1,3-bis(allylamino)-2-propanol, triallylamine, diallylamine, divinylbenzene, 1,7-octadiene, 1,6-heptadiene, 1,8-nonadienylamine, 1,6-octadiene, 1,8-nonadienylamine, 1,6-hexadiene, 1,8 ... The vinyl ethers include, but are not limited to, ethylene, 1,9-decadiene, 1,4-divinyloxybutane, 1,6-hexamethylenebisacrylamide, ethylenebisacrylamide, N,N'-bis(vinylsulfonylacetyl)ethylenediamine, 1,3-bis(vinylsulfonyl)2-propanol, vinyl sulfone, N,N'-methylenebisacrylamide polyvinyl ethers, polyallyl ethers, divinylbenzene, 1,4-divinyloxybutane, and combinations thereof.

[0187] Crosslinked polymers derived from the monomers and polymers in Formulas 1-3 can be synthesized either in solution or in bulk or dispersed media. Examples of solvents suitable for synthesizing the polymers of the present disclosure include, but are not limited to, water, low boiling alcohols (methanol, ethanol, propanol, butanol), dimethylformamide, dimethyl sulfoxide, heptane, chlorobenzene, and toluene.

[0188] Alternative polymer processes can include isolated polymerization reactions, stepwise addition of individual starting monomers through a series of reactions, stepwise addition of blocks of monomers, combinations, or any other polymerization method, such as living polymerization, direct polymerization, indirect polymerization, condensation, radical, emulsion, precipitation, spray-drying polymerization, or certain bulk crosslinking reaction methods, and the use of size reduction processes, such as grinding, compaction, and extrusion. Processing can be carried out as batch, semi-continuous, and continuous processes. For processing in a dispersion medium, the continuous phase can be a non-polar solvent, such as toluene, benzene, hydrocarbons, halogenated solvents, or supercritical carbon dioxide. In direct suspension reactions, water can be used, and salts can be used to adjust the properties of the suspension.

[0189] The starting molecules described in Formulas 1-3 can be polymerized with one or more other monomers, oligomers, or other polymerizable groups of the present invention. Such copolymer structures can include, but are not limited to, block or block-like polymers, graft copolymers, and random copolymers. The incorporation of the monomers described in Formulas 1-3 can range from 1% to 99%. In some embodiments, the incorporation of the comonomer is 20% to 80%.

[0190] Non-limiting examples of copolymers that may be used alone or in combination include styrene, allylamine hydrochloride, substituted allylamine hydrochloride, substituted styrene, alkyl acrylates, substituted alkyl acrylates, alkyl methacrylates, substituted alkyl methacrylates, acrylonitrile, methacrylonitrile, acrylamide, methacrylamide, N-alkyl acrylamide, N-alkyl methacrylamide, N,N-dialkyl acrylamide, N,N-dialkyl methacrylamide, isoprene, butadiene, ethylene, vinyl acetate, N-vinylamide, maleic acid derivatives, vinyl ethers, allyl, methallyl monomers, and combinations thereof. Functionalized versions of these monomers may also be used. Further monomers or comonomers that can be used in the present invention include 2-propen-1-ylamine, 1-(allylamino)-2-aminoethane, 1-[N-allyl(2-aminoethyl)amino]-2-aminoethane, methyl methacrylate, ethyl methacrylate, propyl methacrylate (all isomers), butyl methacrylate (all isomers), 2-ethylhexyl methacrylate, isobornyl methacrylate, methacrylic acid, benzyl methacrylate, phenyl methacrylate, methacrylonitrile, a-methylstyrene, methyl acrylate, ethyl acrylate, propyl acrylate (all isomers), butyl acrylate (all isomers), 2-ethylhexyl acrylate, isobornyl acrylate, acrylic acid, benzyl acrylate, Phenyl acrylate, acrylonitrile, styrene, glycidyl methacrylate, 2-hydroxyethyl methacrylate, hydroxypropyl methacrylate (all isomers), hydroxybutyl methacrylate (all isomers), N,N-dimethylaminoethyl methacrylate, N,N-diethylaminoethyl methacrylate, triethylene glycol methacrylate, itaconic anhydride, itaconic acid, glycidyl acrylate, 2-hydroxyethyl acrylate, hydroxypropyl acrylate (all isomers), hydroxybutyl acrylate (all isomers), N,N-dimethylaminoethyl acrylate, N,N-diethylaminoethyl acrylate, triethylene glycol acrylate, methacrylamide, N-methylacrylamide, N,N-dimethylacrylamide, N-tert-butylmethacrylamide, N-butylmethacrylamide, N-methylolmethacrylamide, N-ethylolmethacrylamide, N-tert-butylacrylamide, N-butylacrylamide, N-methylolacrylamide, N-ethylolacrylamide, 4-acryloylmorpholine, vinylbenzoic acid (all isomers), diethylaminostyrene (all isomers), α-methylvinylbenzoic acid (all isomers), diethylamino α-methylstyrene (all isomers) (body), p-vinylbenzenesulfonic acid, p-vinylbenzenesulfonic acid sodium salt, trimethoxysilylpropyl methacrylate, triethoxysilylpropyl methacrylate, tributoxysilylpropyl methacrylate, dimethoxymethylsilylpropyl methacrylate, diethoxymethylsilylpropyl methacrylate, dibutoxymethylsilylpropyl methacrylate, diisopropoxymethylsilylpropyl methacrylate, dimethoxysilylpropyl methacrylate, diethoxysilylpropyl Examples of suitable silyl acrylates include, but are not limited to, propyl methacrylate, dibutoxysilylpropyl methacrylate, diisopropoxysilylpropyl methacrylate, trimethoxysilylpropyl acrylate, triethoxysilylpropyl acrylate, tributoxysilylpropyl acrylate, dimethoxymethylsilylpropyl acrylate, diethoxymethylsilylpropyl acrylate, dibutoxymethylsilylpropyl acrylate, diisopropoxymethylsilylpropyl acrylate, dimethoxysilylpropyl acrylate, diethoxysilylpropyl acrylate, dibutoxysilylpropyl acrylate, diisopropoxysilylpropyl acrylate, maleic anhydride, N-phenylmaleimide, N-butylmaleimide, N-vinylformamide, N-vinylacetamide, allylamine, methallylamine, allyl alcohol, methyl vinyl ether, ethyl vinyl ether, butyl vinyl ether, butadiene, isoprene, chloroprene, ethylene, vinyl acetate, and combinations thereof.

[0191] Further modification of the preformed crosslinked polymer can be achieved by the addition of modifying agents, including, but not limited to, amine monomers, additional crosslinking agents, and polymers. Modification can be achieved by covalent or non-covalent methods. These modifications, including surface-localized modifications of the preformed crosslinked polymer, can be uniformly or non-uniformly distributed throughout the preformed polymer material. Additionally, modifications can be made to alter the physical properties of the preformed crosslinked polymer, including, but not limited to, reactions with remaining reactive groups in the preformed polymer, such as haloalkyl and allyl groups. Reactions and modifications to the preformed crosslinked polymer include, but are not limited to, acid-base reactions, nucleophilic substitution reactions, Michael reactions, non-covalent electrostatic interactions, hydrophobic interactions, physical interactions (crosslinking), and radical reactions.

[0192] In one embodiment, the post-polymerization crosslinked amine polymer has Formula 4: [ka] wherein each R is independently hydrogen or an ethylene bridge between two nitrogen atoms of the crosslinked amine polymer. [ka] and a, b, c, and m are integers. and m is a large integer indicating an extended polymer network. In one such embodiment, the ratio of the sum of a and b to c (i.e., a + b:c) is in the range of about 1:1 to 5:1. For example, in one such embodiment, the ratio of the sum of a and b to c (i.e., a + b:c) is in the range of about 1.5:1 to 4:1. By way of further example, in one such embodiment, the ratio of the sum of a and b to c (i.e., a + b:c) is in the range of about 1.75:1 to 3:1. For example, in one such embodiment, the ratio of the sum of a and b to c is 57 and c is 24, and m is a large integer indicating an extended polymer network. In each of the foregoing embodiments, the ratio of the sum of a and b to c (i.e., a + b:c) can be in the range of about 2:1 to 2.5:1. For example, in such embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) can be in the range of about 2.1:1 to 2.2:1. By way of further example, in such embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) can be in the range of about 2.2:1 to 2.3:1. By way of further example, in such embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) can be in the range of about 2.3:1 to 2.4:1. By way of further example, in such embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) can be in the range of about 2.4:1 to 2.5:1. In each of the foregoing embodiments, each R can independently be hydrogen or an ethylene bridge between two nitrogen atoms. However, typically, 35 to 95% of the R substituents are hydrogen and 5 to 65% are ethylene bridges. [ka] For example, in one such embodiment, 50-95% of the R substituents are hydrogen and 5-50% are ethylene bridges. [ka] For example, in one such embodiment, 55-90% of the R substituents are hydrogen and 10-45% are ethylene bridges. [ka] By way of further example, in one such embodiment, 60-90% of the R substituents are hydrogen and 10-40% are ethylene bridges. By way of further example, in one such embodiment, 65-90% of the R substituents are hydrogen and 10-35% are ethylene bridges. [ka] As a further example, in one such embodiment, 70-90% of the R substituents are hydrogen and 10-30% are ethylene bridges. As a further example, in one such embodiment, 75-85% of the R substituents are hydrogen and 15-25% are ethylene bridges. As a further example, in one such embodiment, 65-75% of the R substituents are hydrogen and 25-35% are ethylene bridges. As a further example, in one such embodiment, 55-65% of the R substituents are hydrogen and 35-45% are ethylene bridges. In some embodiments, a, b, c, and R are such that the carbon-to-nitrogen ratio of the polymer represented by Formula 4 can each range from about 2:1 to about 6:1. For example, in one such embodiment, the carbon-to-nitrogen ratio of the polymer represented by Formula 4 can each range from about 2.5:1 to about 5:1. By way of further example, in one such embodiment, the carbon-to-nitrogen ratio of the polymer of Formula 4 may range from about 3:1 to about 4.5:1, respectively. By way of further example, in one such embodiment, the carbon-to-nitrogen ratio of the polymer of Formula 4 may range from about 3.25:1 to about 4.25:1, respectively. By way of further example, in one such embodiment, the carbon-to-nitrogen ratio of the polymer of Formula 4 may range from about 3.4:1 to about 4:1, respectively. By way of further example, in one such embodiment, the carbon-to-nitrogen ratio of the polymer of Formula 4 may range from about 3.5:1 to about 3.9:1, respectively. By way of further example, in one such embodiment, the carbon-to-nitrogen ratio of the polymer of Formula 4 may range from about 3.55:1 to about 3.85:1, respectively. In each of the foregoing embodiments described in this paragraph, the polymer of Formula 4 is derived from monomers and crosslinkers each containing less than 5 wt % oxygen.

[0193] In certain embodiments, polymers with increased crosslinking and / or entanglement have been found to have lower swelling than those with less crosslinking and / or entanglement, and also have significantly reduced binding of interfering ions such as phosphate, but also have binding capacities for target ions (e.g., chloride) that are equal to or greater than those with less crosslinking and / or entanglement. Selectivity can be introduced in two different ways: 1) total capacity is sacrificed for chloride specificity. Crosslinkers without binding sites (e.g., epichlorohydrin) allow for increased crosslinking, while total capacity decreases proportionally with the amount of crosslinker incorporated into the polymer. 2) total capacity is maintained for chloride specificity: crosslinkers with binding sites (e.g., diallylamine) allow for increased crosslinking, while total capacity remains the same or only slightly decreases.

[0194] As previously described, crosslinked polymers with high chloride binding capacity and high chloride selectivity over other competing anions, such as phosphate, can be prepared in a two-step process according to one embodiment of the present disclosure. Generally, the selectivity of a polymer is a function of its crosslink density, and the capacity of a polymer is a function of the free amine density of the crosslinked polymer. Advantageously, the two-step process described herein provides both high chloride binding capacity and high chloride selectivity over other competing ions by relying primarily on carbon-carbon crosslinking in the first step and nitrogen-nitrogen crosslinking in the second step.

[0195] In the first step, crosslinking is preferably capacity-saving, i.e., free amine-saving, carbon-to-carbon crosslinking. In the second step, crosslinking is amine-consuming and directed toward selectivity adjustment. Based on the desired high capacity, the C / N ratio is preferably optimized to maximize amine functionality for HCl bonding, while maintaining spherical polymer particles of controlled particle size to ensure non-absorbency and acceptable mouthfeel stability under GI conditions. The preferred range of carbon-carbon crosslinking achieved after the first step is sufficient to allow the resulting beads to swell 4-6 times in water (i.e., a swelling ratio of 4-6).

[0196] In one embodiment, crosslinked polymers with high chloride binding capacity and high chloride selectivity over other competing anions such as phosphate can be produced in a two-step process, with the product of the first polymerization step preferably being in the form of beads with diameters controlled in the range of 5-1000 μm, preferably 10-500 μm, and most preferably 40-180 μm.

[0197] The product of the first polymerization step is preferably in the form of beads having a swelling ratio in water of 2 to 10, more preferably about 3 to about 8, and most preferably about 4 to about 6.

[0198] Also, if the crosslinked polymer beads obtained from the first polymerization step are protonated, this may reduce the amount of nitrogen-nitrogen crosslinks in the second crosslinking step. Also, in certain embodiments, the preformed amine polymer is at least partially deprotonated by treatment with a base, preferably a strong base such as a hydroxide base. For example, in one embodiment, the base can be NaOH, KOH, NH4OH, NaHCO3, Na2CO3, K2CO3, LiOH, Li2CO3, CsOH, or other metal hydroxides. If the charge is removed from the preformed crosslinked amine polymer beads by deprotonation, the beads tend to collapse, and unless the beads are prevented from collapsing, the crosslinking agent used in the second step may not be able to access the binding sites. One way to prevent the collapse of crosslinked polymer beads is to use a swelling agent, such as water, to swell the beads, thereby allowing the crosslinking agent in the second step to access the binding sites.

[0199] The preformed polymer can be crosslinked to form a crosslinked polymer after polymerization using any of a range of crosslinking compounds containing at least two amine-reactive functional groups. In one such embodiment, the crosslinking agent is a compound containing at least two amine-reactive groups selected from the group consisting of halides, epoxides, phosgene, anhydrides, carbamates, carbonates, isocyanates, thioisocyanates, esters, activated esters, carboxylic acids and their derivatives, sulfonates and their derivatives, acyl halides, aziridines, α,β-unsaturated carbonyls, ketones, aldehydes, and pentafluoroaryl groups. For example, the crosslinking agent can be any of the crosslinking agents described herein, including those selected from Table B. As a further example, in one such embodiment, the crosslinking agent is a dihalide, such as a dichloroalkane.

[0200] As described above, in certain embodiments, a swelling agent for the preformed amine polymer can be included in the reaction mixture for the second polymerization step along with the crosslinker. Generally, the swelling agent and crosslinker can be miscible or immiscible, and the swelling agent can be any composition or combination of compositions capable of swelling the preformed amine polymer. Exemplary swelling agents include polar solvents such as water, methanol, ethanol, n-propanol, isopropanol, n-butanol, formic acid, acetic acid, acetonitrile, dimethylformamide, dimethyl sulfoxide, nitromethane, propylene carbonate, or combinations thereof. Furthermore, the amount of swelling agent included in the reaction mixture is typically less than the absorption capacity of the preformed amine polymer. For example, it is generally preferred that the weight ratio of swelling agent to preformed polymer in the reaction mixture is less than 4:1. As a further example, in some embodiments, the weight ratio of swelling agent to preformed polymer in the reaction mixture is less than 3:1. By way of further example, in some embodiments, the weight ratio of swelling agent to preformed polymer in the reaction mixture is less than 2:1. By way of further example, in some embodiments, the weight ratio of swelling agent to preformed polymer in the reaction mixture is less than 1:1. By way of further example, in some embodiments, the weight ratio of swelling agent to preformed polymer in the reaction mixture is less than 0.5:1. By way of further example, in some embodiments, the weight ratio of swelling agent to preformed polymer in the reaction mixture is less than 0.4:1. By way of further example, in some embodiments, the weight ratio of swelling agent to preformed polymer in the reaction mixture is less than 0.3:1. Generally, however, the weight ratio of swelling agent to preformed polymer in the reaction mixture is typically at least 0.05:1, respectively.

[0201] Generally, the crosslinked polymer can be a crosslinked homopolymer or a crosslinked copolymer containing amine moieties. The free amine moieties can be separated, for example, by repeating linker (or intervening) units of the same or varying lengths. In some embodiments, the polymer contains repeating units containing amine moieties and intervening linker units. In other embodiments, multiple amine-containing repeating units are separated by one or more linker units. Additionally, the multifunctional crosslinker can contain HCl-binding functional groups, e.g., amines ("active crosslinkers"), or can lack HCl-binding functional groups, e.g., amines ("passive crosslinkers").

[0202] In a preferred embodiment, the first polymerization (crosslinking) step produces preformed amine polymer beads having a target size and chloride binding capacity. For example, in one such embodiment, the beads have a chloride binding capacity of at least 10 mmol / g in simulated gastric fluid ("SGF") and a swelling ratio in the range of 1 to 6. The resulting preformed amine polymer is then preferably (at least partially) deprotonated with the beads and combined with an unprotonated swelling agent to swell the free amine polymer without protonating the amine functional groups. Furthermore, the amount of unprotonated swelling agent is selected to adjust the degree of subsequent crosslinking to effectively form a template that is incorporated into place by the amine-consuming crosslinking step. In a second crosslinking step, the swollen, deprotonated preformed amine polymer is crosslinked with a crosslinker containing an amine-reactive moiety to form a post-polymerization crosslinked polymer.

[0203] Generally, chloride selectivity over other competing ions is achieved with highly crosslinked polymers. For example, relatively high chloride binding capacity can be achieved by reacting preformed amine polymer beads with a neat crosslinker in the presence of a swelling agent (water). This "non-dispersive" reaction provides access to high chloride selectivity over competing ions in SIB assays, but also results in macroscopically (and microscopically) aggregated polymer beads. It is also advantageous to include a solvent (e.g., heptane) in the second crosslinking step to disperse the preformed crosslinked polymer beads to avoid inter-bead reaction and subsequent aggregation. However, using too much solvent (dispersant) can dilute the reaction solution to the point where the resulting beads are not sufficiently crosslinked to have the desired chloride selectivity over other competing ions. However, by using a crosslinker that also functions as a solvent (dispersant), enough solvent (dispersant) can be included in the reaction mixture to avoid inter-bead reaction and aggregation without diluting to the point where the amine consumption crosslinking degree is insufficient. For example, DCE and DCP were used directly to take advantage of the solvent's dispersing properties while maintaining reactivity (avoiding agglomeration during the reaction), thus serving a dual purpose as both a solvent (dispersant) and a crosslinker. Interestingly, DCE was found to have superior dispersing properties as a solvent compared to similar reactions with DCP and / or heptane. Also, less agglomeration was observed when beads were first dispersed in DCE and then, in a second run, water was added to swell the beads. Agglomeration can occur if water is added to the preformed amine polymer before dispersing the beads in DCE.

[0204] The use of 1,2-dichloroethane ("DCE") as a cross-linking solvent can also generate HCl molecules during the second step. These HCl molecules protonate some of the free amine sites, blocking reactive sites for the cross-linking reaction, thereby limiting the number of binding sites available for cross-linking. As a result, the use of DCE has a self-limiting effect on the second cross-linking.

[0205] In each of the above embodiments, the reaction mixture can contain a wide range of amounts of crosslinker. For example, in one embodiment, the crosslinker can be used in large excess compared to the amount of preformed amine polymer in the reaction mixture. In other words, in such embodiments, the crosslinker is a crosslinking solvent, i.e., both a solvent for the reaction mixture and a crosslinker for the preformed amine polymer. In such embodiments, other solvents can be included in the reaction mixture if desired, but are not required. Also, the preformed amine polymer, swelling agent, and crosslinker can be dispersed in a solvent that is miscible with the crosslinker and immiscible with the swelling agent. For example, in some embodiments, the swelling agent can be a polar solvent; in some such embodiments, the swelling agent can include water, methanol, ethanol, n-propanol, isopropanol, formic acid, acetic acid, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, nitromethane, or a combination thereof. For further example, when the swelling agent comprises a polar solvent, the solvent system for the reaction mixture typically comprises a non-polar solvent, such as pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, dichloromethane, dichloroethane, dichloropropane, dichlorobutane, or a combination thereof. In certain embodiments, the crosslinker and the solvent can be the same; that is, the solvent is a crosslinking solvent, such as 1,2-dichloroethane, 1,3-dichloropropane, 1,4-dichlorobutane, or a combination thereof.

[0206] It is noteworthy that in crosslinking solvent (e.g., DCE dispersion reactions), regardless of the amount of crosslinking solvent (e.g., DCE) used to disperse the beads, there is a large excess of crosslinker (e.g., 1 g:3 mL beads:DCE and 1 g:10 mL beads:DCE are both large excesses of crosslinker, most of which is not consumed in the reaction). Nevertheless, the relative degree of crosslinking and performance in the SIB assay are not affected by changes in the ratio of reactive crosslinker to polymer beads. This is possible because the reaction is limited by the acid-neutralizing capacity of the polymer beads rather than the amount of crosslinker (e.g., DCE).

[0207] The amines of the preformed polymer beads preferably have a free electron pair (neutral, deprotonated) to react more efficiently with DCE or other crosslinkers. When the free amines of the preformed polymer beads react with a crosslinker (e.g., DCE), the HCl is deprotonated and the amine is protonated, limiting the reaction. For this reason, the preformed amine polymer beads preferably start as free amines in the second crosslinking step. If the preformed amine polymer beads are deprotonated after the first step of carbon-carbon crosslinking, amine-consuming crosslinking in the second step is limited, thereby reducing the desired chloride selectivity over other competing ions. This is demonstrated by adding a known amount of HCl to the preformed amine polymer beads immediately after the second-step crosslinking with DCE (Table 7). When less than 3 mol % HCl (relative to the amine in the preformed polymer amine beads) is added before the second-step crosslinking, the total chloride capacity (SGF) and chloride selectivity in the SIB are similar to beads not treated with HCl in the second step. When less than 5 mol% HCl (relative to the amine in the preformed polymeric amine beads) is added prior to the second step crosslinking, the total chloride capacity (SGF) increases and the chloride selectivity in the SIB decreases, indicating lower uptake of crosslinker.

[0208] The benefit of deprotonated preformed polymer beads in the second-step crosslinking highlights the benefit of using two steps to obtain the final product. In the first step, to form the amine polymer beads, all monomers (e.g., allylamine and DAPDA) are deprotonated and remain in the aqueous phase, avoiding radical transfer reactions that severely limit the polymerization of unprotonated allylamine (and derivatives). Once the beads are formed by carbon-carbon crosslinking, they can then be deprotonated and further crosslinked with an amine-reactive crosslinker in the second step.

[0209] Providing a large excess of the two crosslinkers / solvents can result in incorporation of one of these reagents, resulting in inherently hydrophobic alkyl chloride functional groups on the crosslinked polymer beads, which can increase nonspecific interactions with undesired solutes other than HCl, which is inherently more hydrophobic. Washing with ammonium hydroxide solution converts the alkyl chloride to an alkyl amine, which is hydrophilic and minimizes nonspecific interactions with undesired solutes. Other modifications, such as -OH, that result in more hydrophilic groups than alkyl chloride are suitable for quenching one incorporated crosslinker / solvent.

[0210] Any range of polymerization chemistries can be used in the first reaction step, provided the crosslinking mechanism is primarily carbon-carbon crosslinking. Thus, in one exemplary embodiment, the first reaction step involves radical polymerization. In such reactions, the amine monomer is typically a monofunctional vinyl, allyl, or acrylamide (e.g., allylamine) and a crosslinker with two or more vinyl, allyl, or acrylamide functional groups (e.g., diallylamine). Simultaneous polymerization and crosslinking occur via radical-initiated polymerization of a mixture of monofunctional and polyfunctional allylamines. The resulting polymer network is thus crosslinked through the carbon backbone. Each crosslinking reaction forms a carbon-carbon bond (as opposed to a substitution reaction, in which a carbon-heteroatom bond is formed during crosslinking). During simultaneous polymerization and crosslinking, the amine functionality of the monomers does not undergo crosslinking reactions and is maintained in the final polymer (i.e., primary amines remain primary, secondary amines remain secondary, and tertiary amines remain tertiary).

[0211] In those embodiments in which the first reaction step involves radical polymerization, a wide range of initiators may be used, including cationic and radical initiators. Some examples of suitable initiators that can be used are free radical peroxy and azo type compounds such as azodiisobutyronitrile, azodiisovaleronitrile, dimethyl azodiisobutyrate, 2,2' azobis(isobutyronitrile), 2,2'-azobis(N,N'-dimethyl-eneisobutyramidine) dihydrochloride, 2,2'-azobis(2-amidinopropane) dihydrochloride, 2,2'-azobis(N,N'-dimethyleneisobutyramidine), 1,1'-azobis(1-cyclohexanecarbonitrile), 4,4'-azobis(4-cyanopentanoic acid), 2,2'-azobis(isobutyramide) dihydrate, 2,2'-azobis(2-methylpropane), 2,2'-azobis(2-methylbutyronitrile), VAZO 67, including cyanopentanoic acid, peroxypivalate, dodecylbenzene peroxide, benzoyl peroxide, di-t-butyl hydroperoxide, t-butyl peracetate, acetyl peroxide, dicumyl peroxide, cumyl hydroperoxide, and dimethylbis(butylperoxy)hexane.

[0212] The above exemplary amine-containing polymers are more fully disclosed and exemplified in WO2016 / 094685 and WO2014 / 197725, the entire contents of which are incorporated herein by reference.

[0213] In one embodiment, the pharmaceutical composition comprises a mixture of any of the non-absorbable materials identified above. For example, in one embodiment, the pharmaceutical composition comprises a mixture of at least one anion exchange composition, zwitterion exchange composition, or neutral composition capable of binding both protons and anions, and a cation exchange composition. In another embodiment, the pharmaceutical composition comprises a mixture of at least one cation exchange composition, zwitterion exchange composition, or neutral composition capable of binding both protons and anions, and an anion exchange composition. In yet another embodiment, the pharmaceutical composition comprises a mixture of at least one cation exchange composition, zwitterion exchange composition, or anion exchange composition, and a neutral composition capable of binding both protons and anions.

[0214] As shown schematically in Figures 1A-1C and according to one embodiment, the non-absorbable free amine polymers of the present disclosure are taken orally and used to treat metabolic acidosis in mammals (including by increasing serum bicarbonate and normalizing blood pH) by binding HCl in the gastrointestinal ("GI") tract and eliminating the HCl through the feces. The free amine polymers are administered orally at a compliance-enhancing dose targeted to chronically bind sufficient HCl to enable a clinically significant increase in serum bicarbonate of 3 mEq / L (Figure 1A). In the stomach (Figure 1B), the free amine polymers are converted to HCl by the H + The polymer is then protonated by binding to Cl. - and other larger organic anions (e.g., X) by controlling access to the binding site through cross-linking and hydrophilic / hydrophobic properties. - and Y - Other HCl-containing compounds (e.g., acetate, propionate, butyrate, etc., expressed as HCl) bind to a lesser extent, if at all. Thus, the net effect is the binding of HCl. In the lower gastrointestinal tract / colon (Figure 1C), Cl - is not completely released, and HCl is removed from the body through normal intestinal motility and fecal excretion, resulting in a net alkylation in serum. - The bond is Cl- / HCO3 - It is not available for exchange by antiporters.

[0215] In one embodiment, the polymer is designed to maximize efficacy (net HCl binding and excretion) while simultaneously minimizing GI side effects (through low swelling particle design and particle size distribution). Optimized HCl binding is achieved through capacity (number of amine binding sites), selectivity (preferential binding of chloride over other anions, especially organic anions, in the colon), and retention (retention of Cl in the colon and gastrointestinal tract without releasing significant amounts of chloride in the lower GI tract). - / HCO3 - avoiding the activity of exchangers; if chloride is not tightly bound to the polymer, Cl - / HCO3 - The exchanger mediates the uptake of chloride ions from the gastrointestinal lumen and the reciprocal exchange of bicarbonate from the serum, and can therefore effectively reduce serum bicarbonate, which can be achieved by a careful balance of

[0216] Competing anions that displace chloride result in a net decrease in bicarbonate through the following mechanisms: First, displacement of chloride from the polymer in the GI lumen, particularly the colonic lumen, provides a ready exchange for bicarbonate in serum. The colon possesses an anion exchanger (chloride / bicarbonate antiporter) that moves chloride from the luminal side in exchange for secreted bicarbonate. When free chloride is released from the polymer in the GI tract, it is exchanged for bicarbonate, which is subsequently lost in the stool, causing a decrease in total extracellular bicarbonate (Davis, 1983; D'Agostino, 1953). Binding of short-chain fatty acids (SCFAs) in exchange for bound chloride on the polymer results in the loss of extracellular HCO3 -Short-chain fatty acids are bacterial metabolites of complex carbohydrates that are not catabolized by normal digestive processes (Chemlarova, 2007). Short-chain fatty acids that reach the colon are absorbed and distributed to various tissues, with a common metabolic pathway being the production of HO and CO, which are converted to bicarbonate equivalents. Therefore, conjugating SCFAs to polymers to neutralize the proton charge is detrimental to overall bicarbonate storage and buffering capacity, necessitating the design of chemical and physical features in the polymer that limit SCFA exchange. Finally, because phosphate is an additional source of buffering capacity in situations where ammonia synthesis and / or hydrogen ion secretion are impaired in chronic kidney disease, phosphate conjugation to polymers should be similarly limited.

[0217] For each proton binding, an anion is preferably bound, so that a positive charge is released from the human body as a neutral polymer. The "binding" of ions exceeds the minimum binding, i.e., at least about 0.2 mmol ions / g polymer, in some embodiments at least about 1 mmol ions / g polymer, in some embodiments at least about 1.5 mmol ions / g polymer, in some embodiments at least about 3 mmol ions / g polymer, in some embodiments at least about 5 mmol ions / g polymer, in some embodiments at least about 10 mmol ions / g polymer, in some embodiments at least about 12 mmol ions / g polymer, in some embodiments at least about 13 mmol ions / g polymer, and even in some embodiments at least about 14 mmol ions / g polymer. In one embodiment, the polymer is characterized by a high proton binding capacity and simultaneously provides anion selectivity; chloride selectivity is achieved by reducing binding with interfering anions, including, but not limited to, phosphate, citrate, acetate, bile acids, and fatty acids. For example, in some embodiments, the polymers of the present disclosure bind phosphate with a binding capacity of less than about 5 mmol / g, less than about 4 mmol / g, less than about 3 mmol / g, less than about 2 mmol / g, or even less than about 1 mmol / g. In some embodiments, the polymers of the present disclosure bind bile and fatty acids with a binding capacity of less than about 5 mmol / g, less than about 4 mmol / g, less than about 3 mmol / g, less than about 2 mmol / g, in some embodiments less than about 1 mmol / g, in some embodiments less than about 0.5 mmol / g, in some embodiments less than about 0.3 mmol / g, and in some embodiments less than about 0.1 mmol / g.

[0218] Pharmaceutical Compositions and Administration Generally, dosage levels of non-absorbable compositions for therapeutic and / or prophylactic use can range from about 0.5 g / day to about 100 g / day. To facilitate patient compliance, dosages ranging from about 1 g / day to about 50 g / day are generally preferred. For example, in one such embodiment, the dosage is from about 2 g / day to about 25 g / day. As a further example, in one such embodiment, the dosage is from about 3 g / day to about 25 g / day. As a further example, in one such embodiment, the dosage is from about 4 g / day to about 25 g / day. As a further example, in one such embodiment, the dosage is from about 5 g / day to about 25 g / day. As a further example, in one such embodiment, the dosage is from about 2.5 g / day to about 20 g / day. As a further example, in one such embodiment, the dosage is from about 2.5 g / day to about 15 g / day. By way of further example, in one such embodiment, the dosage is about 1 g / day to about 10 g / day. If desired, the daily dosage may be administered as a single dose (i.e., once daily) or divided into multiple doses (e.g., two, three, or more doses) throughout the day. Generally, the non-absorbable composition may be administered as a fixed daily dose or titrated based on the patient's serum bicarbonate level or other indicator of acidosis in need of treatment. Titration may occur as needed at the initiation of treatment or throughout, with initial and maintenance dosage levels varying from patient to patient based on the severity of the underlying disease.

[0219] The effectiveness of non-absorbable compositions can be established in animal models or human volunteers and patients. In addition, in vitro, ex vivo, and in vivo methods are useful for establishing HCl binding. In vitro binding solutions can be used to measure the binding capacity for protons, chloride, and other ions at various pH levels. Ex vivo extracts, such as the contents of the gastrointestinal tract lumen from human volunteers or model animals, can be used for similar purposes. The selectivity of binding and / or retaining certain ions preferentially over others can also be demonstrated in such in vitro and ex vivo solutions. In vivo models of metabolic acidosis can be used to test the effectiveness of nonabsorbable compositions in normalizing acid-base balance—for example, 5 / 6 nephrectomized rats fed a casein-containing diet (reviewed in Phisitkul S, Hacker C, Simoni J, Tran RM, Wesson DE. Dietary protein causes a decline in the glomerular filtration rate of the remnant kidney mediated by metabolic acidosis and endothelin receptors. Kidney International. 2008;73(2):192-9) or adenine-fed rats (Terai K, K Mizukami and M Okada. 2008. Comparison of chronic renal failure rats and modification of the preparation protocol as a hyperphosphatemia model. Nephrol. 13: 139-146).

[0220] In one embodiment, the non-absorbable composition is provided to animals, including humans (by oral administration) in a regimen of one, two, or even multiple (i.e., at least three) doses per day to treat acid-base disorders (e.g., metabolic acidosis) and achieve the clinically significant and sustained increases described above. For example, in one embodiment, a daily dose of the non-absorbable composition (whether administered orally in a single dose or multiple doses per day) has a sufficient capacity to remove at least 5 mmol of protons, chloride ions, or each per day. By way of further example, in one such embodiment, a daily dose of the non-absorbable composition has a sufficient capacity to remove at least 10 mmol of protons, chloride ions, or each per day. By way of further example, in one such embodiment, a daily dose of the non-absorbable composition has a sufficient capacity to remove at least 20 mmol of protons, chloride ions, or each of strong acids (e.g., Cl), per day. - , HSO4 - and SO4 2- ) and / or strong acid (e.g., HCl or H2SO4), respectively. By way of further example, in one such embodiment, a daily dose of the non-absorbable composition has a sufficient capacity to remove at least 30 mmol of protons, conjugate bases of the strong acid, and / or strong acid, respectively, per day. By way of further example, in one such embodiment, a daily dose of the non-absorbable composition has a sufficient capacity to remove at least 40 mmol of protons, conjugate bases of the strong acid, and / or strong acid, respectively, per day. By way of further example, in one such embodiment, a daily dose of the non-absorbable composition has a sufficient capacity to remove at least 50 mmol of protons, conjugate bases of the strong acid, and / or strong acid, respectively, per day.

[0221] Pharmaceutical dosage unit forms containing non-absorbable compositions can be in any form suitable for oral administration. Such dosage unit forms include powders, tablets, pills, lozenges, sachets, cachets, elixirs, suspensions, syrups, soft or hard gelatin capsules, etc. In one embodiment, the pharmaceutical composition contains only the non-absorbable composition. Alternatively, the pharmaceutical composition may contain carriers, diluents, or additives in addition to the non-absorbable composition. Examples of carriers, additives, and diluents that can be used in these formulations and other foods and beverages include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, alginic acid, tragacanth, gelatin, calcium silicate, crystalline cellulose, polyvinylpyrrolidone, cellulose, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, propyl hydroxybenzoate, and talc. Pharmaceutical additives useful in pharmaceutical compositions include binders such as microcrystalline cellulose, colloidal silica, and combinations thereof (Prosolv 90), carbopol, povidone, and xanthan gum; flavoring agents such as sucrose, mannitol, xylitol, maltodextrin, fructose, or sorbitol; lubricants such as magnesium stearate, stearic acid, sodium stearyl fumarate, and vegetable fatty acids; and, optionally, disintegrants such as croscarmellose sodium, gellan gum, low-substituted hydroxypropyl ether of cellulose, and sodium starch glycolate. Other additives may include plasticizers, pigments, talc, and the like. Such additives and other suitable ingredients are well known in the art; see, for example, Gennaro AR (ed.), Remington's Pharmaceutical Sciences, 20th Edition.

[0222] In one embodiment, non-absorbable compositions can be co-administered with other active pharmaceuticals depending on the condition to be treated.This co-administration can include simultaneous administration of the two drugs in the same dosage form, simultaneous administration in separate dosage forms, and separate administration.For example, for the treatment of metabolic acidosis, non-absorbable compositions can be co-administered with the general treatments required to treat the underlying comorbidities, including but not limited to edema, hypertension, diabetes, obesity, heart failure, and chronic kidney disease complications.These pharmaceuticals and non-absorbable compositions can be formulated together in the same dosage form and administered simultaneously, unless they show any clinically significant drug-drug interactions.Alternatively, these treatments and non-absorbable compositions can be administered separately and sequentially, with one being administered after the other.

[0223] In one embodiment, daily doses for the treatment of chronic metabolic acidosis improve compliance (approximately 15 g or less per day) and achieve clinically significant and sustained increases in serum bicarbonate of approximately 3 mEq / L at these daily doses. The non-absorbable nature of the polymer and the lack of sodium loading and / or other harmful ion introduction with such oral medications allow for safe, long-term treatment for the first time without worsening blood pressure / hypertension and / or causing increased fluid retention and fluid overload. Another benefit is further delaying the progression of kidney disease and the need for lifelong renal replacement therapy (end-stage renal disease, "ESRD," including three times weekly dialysis) or kidney transplantation. Both are associated with significant mortality, reduced quality of life, and a significant burden on healthcare systems worldwide. In the United States alone, approximately 20% of the 400,000 ESRD patients die each year, and 100,000 new patients begin dialysis.

[0224] A further aspect of the present invention is a pharmaceutical product comprising a sealed package and the non-absorbable composition of the present disclosure therein. The sealed package is preferably substantially impermeable to moisture and oxygen to enhance the stability of the pharmaceutical composition. For example, a dosage unit form may include a sealed container (e.g., a sealed sachet) that prevents or reduces moisture and oxygen ingress when the non-absorbable composition is packaged within the container. The container size may be optimized to reduce headspace in the container after packaging, and any headspace may be filled with an inert gas such as nitrogen. Furthermore, the packaging material of the structure may be selected to minimize moisture and oxygen ingress within the container after packaging. For example, the non-absorbable composition may be packaged in a multi-layer sachet that includes at least one or more layers that act as a barrier layer against moisture and oxygen ingress. In another example, the non-absorbable composition may be packaged in a single- or multi-layer plastic, metal, or glass container with at least one or more layers incorporated into the structure that limits oxygen and / or moisture ingress after packaging. For example, in one such embodiment, the sachet (or other container or packaging) may comprise a multi-layer laminate of a contacting inner layer, an outer layer, and a barrier layer disposed between the contacting layer and the outer layer. In one exemplary embodiment, the container comprises one or more oxygen scavenging layers.

[0225] The present disclosure includes further embodiments, including the following embodiments 1-849:

[0226] Embodiment 1. A method of treating an individual suffering from an acid-base disorder characterized by a baseline serum bicarbonate level of less than 22 mEq / l, the method comprising oral administration of a daily dose of a pharmaceutical composition capable of binding at least 5 mEq of protons and chloride ions as it passes through the digestive system and achieving a clinically significant increase in serum bicarbonate levels of at least 1 mEq / l from baseline within a treatment period of no more than one month.

[0227] Embodiment 2. A method of treating an individual suffering from an acid-base disorder characterized by a baseline serum bicarbonate level of less than 22 mEq / l, the method comprising oral administration of a pharmaceutical composition, wherein the orally administered pharmaceutical composition binds an average of at least 5 mEq / day of protons and chloride ions in the gastrointestinal system, and wherein the oral administration achieves a clinically significant increase in serum bicarbonate level of at least 1 mEq / l from baseline within a treatment period of not more than one month.

[0228] Embodiment 3: The method of embodiment 2, wherein oral administration is at least once a week within the treatment period.

[0229] Embodiment 4: The method of embodiment 2, wherein oral administration is at least twice a week within the treatment period.

[0230] Embodiment 5: The method of embodiment 2, wherein oral administration is at least once daily within the treatment period.

[0231] Embodiment 6. The method of embodiment 1, 2, 3 or 5, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of less than 21 mEq / l.

[0232] Embodiment 7. The method of embodiment 1, 2, 3 or 5, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of less than 20 mEq / l.

[0233] Embodiment 8. The method of embodiment 1, 2, 3 or 5, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of less than 19 mEq / l.

[0234] Embodiment 9. The method of embodiment 1, 2, 3 or 5, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of less than 18 mEq / l.

[0235] Embodiment 10. The method of embodiment 1, 2, 3 or 5, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of less than 17 mEq / l.

[0236] Embodiment 11. The method of embodiment 1, 2, 3 or 5, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of less than 16 mEq / l.

[0237] Embodiment 12. The method of embodiment 1, 2, 3 or 5, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of less than 15 mEq / l.

[0238] Embodiment 13. The method of embodiment 1, 2, 3 or 5, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of less than 14 mEq / l.

[0239] Embodiment 14. The method of embodiment 1, 2, 3, or 5, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of less than 13 mEq / l.

[0240] Embodiment 15. The method of embodiment 1, 2, 3 or 5, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of less than 12 mEq / l.

[0241] Embodiment 16. The method of embodiment 1, 2, 3, or 5, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of less than 11 mEq / l.

[0242] Embodiment 17. The method of embodiment 1, 2, 3 or 5, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of less than 10 mEq / l.

[0243] Embodiment 18. The method of any of the above-listed embodiments, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of at least 9 mEq / l.

[0244] Embodiment 19. The method of any of embodiments 1 to 16, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of at least 10 mEq / l.

[0245] Embodiment 20. The method of any of embodiments 1 to 15, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of at least 11 mEq / l.

[0246] Embodiment 21. The method of any of embodiments 1 to 14, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of at least 12 mEq / l.

[0247] Embodiment 22. The method of any of embodiments 1 to 13, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of at least 13 mEq / l.

[0248] Embodiment 23. The method of any of embodiments 1 to 12, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of at least 14 mEq / l.

[0249] Embodiment 24. The method of any of embodiments 1 to 11, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of at least 15 mEq / l.

[0250] Embodiment 25. The method of any of embodiments 1 to 10, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of at least 16 mEq / l.

[0251] Embodiment 26. The method of any of embodiments 1 to 9, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of at least 17 mEq / l.

[0252] Embodiment 27. The method of any of embodiments 1 to 8, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of at least 18 mEq / l.

[0253] Embodiment 28. The method of any of embodiments 1 to 7, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of at least 19 mEq / l.

[0254] Embodiment 29. The method of any of embodiments 1 to 6, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of at least 20 mEq / l.

[0255] Embodiment 30. The method of embodiment 1, 2, 3 or 5, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of at least 21 mEq / l.

[0256] Embodiment 31. The method of any of the above-listed embodiments, wherein the method increases serum bicarbonate levels from a baseline serum bicarbonate level to an increased serum bicarbonate level of at least 22 mEq / l.

[0257] Embodiment 32. The method of any of the above-listed embodiments, wherein the method increases serum bicarbonate levels from a baseline serum bicarbonate level to an increased serum bicarbonate level of at least 23 mEq / l.

[0258] Embodiment 33. The method of any of the above-listed embodiments, wherein the method increases serum bicarbonate levels from a baseline serum bicarbonate level to an increased serum bicarbonate level of at least 24 mEq / l.

[0259] Embodiment 34. The method of any of the above-listed embodiments, wherein the method increases serum bicarbonate levels from a baseline serum bicarbonate level to an increased serum bicarbonate level of at least 25 mEq / l.

[0260] Embodiment 35. The method of any of the above-listed embodiments, wherein the method increases serum bicarbonate levels from a baseline serum bicarbonate level to an increased serum bicarbonate level of at least 26 mEq / l.

[0261] Embodiment 36. The method of any of the above-listed embodiments, wherein the method increases serum bicarbonate levels from a baseline serum bicarbonate level to an increased serum bicarbonate level of at least 27 mEq / l.

[0262] Embodiment 37. The method of any of the above-listed embodiments, wherein the method increases serum bicarbonate levels from a baseline serum bicarbonate level to an increased serum bicarbonate level of at least 28 mEq / l.

[0263] Embodiment 38. A method according to any of the above-listed embodiments, wherein the method increases the baseline serum bicarbonate level to a serum bicarbonate level not exceeding 29 mEq / l.

[0264] Embodiment 39. The method of any of embodiments 1 to 36, wherein the method increases the baseline serum bicarbonate level to a serum bicarbonate level not exceeding 28 mEq / l.

[0265] Embodiment 40. The method of any of embodiments 1 to 35, wherein the method increases the baseline serum bicarbonate level to a serum bicarbonate level not exceeding 27 mEq / l.

[0266] Embodiment 41. A method according to any of embodiments 1 to 34, wherein the method increases the baseline serum bicarbonate level to a serum bicarbonate level not exceeding 26 mEq / l.

[0267] Embodiment 42. A method according to any of embodiments 1 to 33, wherein the method increases the baseline serum bicarbonate level to a serum bicarbonate level not exceeding 25 mEq / l.

[0268] Embodiment 43. A method according to any of the above-listed embodiments, wherein the method increases the baseline serum bicarbonate level to a serum bicarbonate level not exceeding 24 mEq / l.

[0269] Embodiment 44. A method according to any of the above-listed embodiments, wherein the method increases the baseline serum bicarbonate level to a serum bicarbonate level not exceeding 23 mEq / l.

[0270] Embodiment 45. A method according to any of the above-listed embodiments, wherein the clinically significant increase is at least 1 mEq / l.

[0271] Embodiment 46. A method according to any of the above-listed embodiments, wherein the clinically significant increase is at least 1.5 mEq / l.

[0272] Embodiment 47 A method according to any of the above-listed embodiments, wherein the clinically significant increase is at least 2 mEq / l.

[0273] Embodiment 48. A method according to any of the above-listed embodiments, wherein the clinically significant increase is at least 2.5 mEq / l.

[0274] Embodiment 49. A method according to any of the above-listed embodiments, wherein the clinically significant increase is at least 3 mEq / l.

[0275] Embodiment 50. A method according to any of the above-listed embodiments, wherein the clinically significant increase is at least 3.5 mEq / l.

[0276] Embodiment 51 A method according to any of the above-listed embodiments, wherein the clinically significant increase is at least 4 mEq / l.

[0277] Embodiment 52. A method according to any of the above-listed embodiments, wherein the clinically significant increase is at least 4.5 mEq / l.

[0278] Embodiment 53. A method according to any of the above-listed embodiments, wherein the clinically significant increase is at least 5 mEq / l.

[0279] Embodiment 54 A method according to any of the above-listed embodiments, wherein the clinically significant increase is at least 5.5 mEq / l.

[0280] Embodiment 55. A method according to any of the above-listed embodiments, wherein the clinically significant increase is at least 6 mEq / l.

[0281] Embodiment 56. A method according to any of the above-listed embodiments, wherein the clinically significant increase is at least 6.5 mEq / l.

[0282] Embodiment 57 A method according to any of the above-listed embodiments, wherein the clinically significant increase is at least 7 mEq / l.

[0283] Embodiment 58. A method according to any of the above-listed embodiments, wherein the clinically significant increase is at least 7.5 mEq / l.

[0284] Embodiment 59. A method according to any of the above-listed embodiments, wherein the clinically significant increase is at least 8 mEq / l.

[0285] Embodiment 60. A method according to any of the above-listed embodiments, wherein the clinically significant increase is at least 8.5 mEq / l.

[0286] Embodiment 61 A method described in any of the above-listed embodiments, wherein the clinically significant increase is at least 9 mEq / l.

[0287] Embodiment 62 A method according to any of the above-listed embodiments, wherein a clinically significant increase is achieved within a treatment period of less than one month.

[0288] Embodiment 63. A method according to any of the above-listed embodiments, wherein a clinically significant increase is achieved within a 25-day treatment period.

[0289] Embodiment 64 A method according to any of the above-listed embodiments, wherein a clinically significant increase is achieved within a 3-week treatment period.

[0290] Embodiment 65 A method according to any of the above-listed embodiments, wherein a clinically significant increase is achieved within a 15-day treatment period.

[0291] Embodiment 66. A method according to any of the above-listed embodiments, wherein a clinically significant increase is achieved within a 2-week treatment period.

[0292] Embodiment 67 A method according to any of the above-listed embodiments, wherein a clinically significant increase is achieved within a 10-day treatment period.

[0293] Embodiment 68. A method according to any of the above-listed embodiments, wherein a clinically significant increase is achieved within a one-week treatment period.

[0294] Embodiment 69. A method according to any of the above-listed embodiments, wherein a clinically significant increase is achieved within 6 days of initiating treatment.

[0295] Embodiment 70. A method according to any of the above-listed embodiments, wherein a clinically significant increase is achieved within a 5-day treatment period.

[0296] Embodiment 71 A method according to any of the above-listed embodiments, wherein a clinically significant increase is achieved within a treatment period of 4 days.

[0297] Embodiment 72 A method according to any of the above-listed embodiments, wherein a clinically significant increase is achieved within a 3-day treatment period.

[0298] Embodiment 73. A method according to any of the above-listed embodiments, wherein a clinically significant increase is achieved within a treatment period of 2 days.

[0299] Embodiment 74 A method according to any of the above-listed embodiments, wherein a clinically significant increase is achieved within a 1-day treatment period.

[0300] Embodiment 75. A method according to any of the above-listed embodiments, wherein a clinically significant increase is achieved within a 12-hour treatment period.

[0301] Embodiment 76. A method according to any of the above-listed embodiments, wherein the clinically significant increase is achieved without any change in the individual's diet or eating habits compared to the period immediately prior to the start of treatment.

[0302] Embodiment 77. A method according to any of the above-listed embodiments, wherein the clinically significant increase is achieved independently of the individual's diet or eating habits.

[0303] Embodiment 78. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level returns to baseline value ± 2.5 mEq / l within one month of cessation of treatment.

[0304] Embodiment 79. The method of any of the above-listed embodiments, wherein the individual's serum bicarbonate level returns to baseline value ± 2.5 mEq / l within 3 weeks of cessation of treatment.

[0305] Embodiment 80. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level returns to baseline value ± 2.5 mEq / l within 2 weeks of cessation of treatment.

[0306] Embodiment 81 A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level returns to baseline value ± 2 mEq / l within one month of cessation of treatment.

[0307] Embodiment 82. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level returns to baseline value ± 2 mEq / l within 3 weeks of cessation of treatment.

[0308] Embodiment 83. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level returns to baseline value ± 2 mEq / l within 2 weeks of cessation of treatment.

[0309] Embodiment 84. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level returns to baseline value ± 1.5 mEq / l within one month of cessation of treatment.

[0310] Embodiment 85. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level returns to baseline value ± 1.5 mEq / l within 3 weeks of cessation of treatment.

[0311] Embodiment 86. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level returns to baseline value ± 1.5 mEq / l within 2 weeks of cessation of treatment.

[0312] Embodiment 87. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level returns to baseline value ±1 mEq / l within one month of cessation of treatment.

[0313] Embodiment 88. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level returns to baseline value ± 1 mEq / l within 3 weeks of cessation of treatment.

[0314] Embodiment 89. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level returns to baseline value ± 1 mEq / l within 2 weeks of cessation of treatment.

[0315] Embodiment 90. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 1 mEq / l within one month of cessation of treatment.

[0316] Embodiment 91 A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 1 mEq / l within 3 weeks of cessation of treatment.

[0317] Embodiment 92. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 1 mEq / l within two weeks of cessation of treatment.

[0318] Embodiment 93. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 1.5 mEq / l within one month of cessation of treatment.

[0319] Embodiment 94. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 1.5 mEq / l within 3 weeks of cessation of treatment.

[0320] Embodiment 95. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 1.5 mEq / l within two weeks of cessation of treatment.

[0321] Embodiment 96. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 2 mEq / l within one month of cessation of treatment.

[0322] Embodiment 97. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 2 mEq / l within 3 weeks of cessation of treatment.

[0323] Embodiment 98. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 2 mEq / l within two weeks of cessation of treatment.

[0324] Embodiment 99. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 2.5 mEq / l within one month of cessation of treatment.

[0325] Embodiment 100. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 2.5 mEq / l within 3 weeks of cessation of treatment.

[0326] Embodiment 101 A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 2.5 mEq / l within two weeks of cessation of treatment.

[0327] Embodiment 102 A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 3 mEq / l within one month of cessation of treatment.

[0328] Embodiment 103. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 3 mEq / l within 3 weeks of cessation of treatment.

[0329] Embodiment 104 A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 3 mEq / l within two weeks of cessation of treatment.

[0330] Embodiment 105. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 3.5 mEq / l within one month of cessation of treatment.

[0331] Embodiment 106. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 3.5 mEq / l within 3 weeks of cessation of treatment.

[0332] Embodiment 107. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 3.5 mEq / l within two weeks of cessation of treatment.

[0333] Embodiment 108. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 4 mEq / l within one month of cessation of treatment.

[0334] Embodiment 109. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 4 mEq / l within 3 weeks of cessation of treatment.

[0335] Embodiment 110. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 4 mEq / l within two weeks of cessation of treatment.

[0336] Embodiment 111 A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 4.5 mEq / l within one month of cessation of treatment.

[0337] Embodiment 112 A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 4.5 mEq / l within 3 weeks of cessation of treatment.

[0338] Embodiment 113 A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 4.5 mEq / l within two weeks of cessation of treatment.

[0339] Embodiment 114 A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 5 mEq / l within one month of cessation of treatment.

[0340] Embodiment 115 A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 5 mEq / l within 3 weeks of cessation of treatment.

[0341] Embodiment 116. A method according to any of the above-listed embodiments, wherein the individual's serum bicarbonate level at the time of cessation of treatment is reduced by at least 5 mEq / l within two weeks of cessation of treatment.

[0342] Embodiment 117. The method of any of the above-listed embodiments, wherein the baseline serum bicarbonate value is a serum bicarbonate concentration value determined at a single point in time.

[0343] Embodiment 118. A method according to any of embodiments 1 to 116, wherein the baseline serum bicarbonate value is the average value of at least two serum bicarbonate concentrations determined at different time points.

[0344] Embodiment 119. A method according to any of embodiments 1 to 116, wherein the baseline serum bicarbonate value is the average value of at least two serum bicarbonate concentrations for serum samples taken on different days.

[0345] Embodiment 120. The method of embodiment 119, wherein the baseline serum bicarbonate value is the average value of at least two serum bicarbonate concentrations for serum samples collected on consecutive days.

[0346] Embodiment 121 The method described in embodiment 119, wherein the baseline serum bicarbonate value is the average value of at least two serum bicarbonate concentrations for serum samples taken on two consecutive days and before the start of treatment.

[0347] Embodiment 122. The method of embodiment 119, wherein the baseline serum bicarbonate value is the mean or median of at least two serum bicarbonate concentrations for serum samples collected on non-consecutive days.

[0348] Embodiment 123 The method described in embodiment 122, wherein the non-consecutive days are at least two days apart.

[0349] Embodiment 124 The method described in embodiment 122, wherein the non-consecutive days are at least one week apart.

[0350] Embodiment 125 The method described in embodiment 122, wherein the non-consecutive days are at least two weeks apart.

[0351] Embodiment 126 The method described in embodiment 122, wherein the non-consecutive days are at least 3 weeks apart.

[0352] Embodiment 127 A method according to any of the above-listed embodiments, wherein the individual is being treated for acute metabolic acidosis.

[0353] Embodiment 128. A method according to any of the above-listed embodiments, wherein the individual is being treated for chronic metabolic acidosis.

[0354] Embodiment 129 A method according to any of the above-listed embodiments, wherein the daily dose has the capacity to remove at least 7.5 mEq each of protons and chloride ions when passing through the digestive system.

[0355] Embodiment 130 A method according to any of the above-listed embodiments, wherein the daily dose has the capacity to remove at least 10 mEq each of protons and chloride ions when passing through the digestive system.

[0356] Embodiment 131 A method described in any of the above-listed embodiments, wherein the daily dose has the capacity to remove at least 15 mEq of protons and chloride ions each when passing through the digestive system.

[0357] Embodiment 132 A method according to any of the above-listed embodiments, wherein the daily dose has the capacity to remove at least 20 mEq each of protons and chloride ions when passing through the digestive system.

[0358] Embodiment 133 A method described in any of the above-listed embodiments, wherein the daily dose has the capacity to remove at least 25 mEq each of protons and chloride ions when passing through the digestive system.

[0359] Embodiment 134 A method according to any of the above-listed embodiments, wherein the daily dose has the capacity to remove at least 30 mEq each of protons and chloride ions when passing through the digestive system.

[0360] Embodiment 135 A method described in any of the above-listed embodiments, wherein the daily dose has the capacity to remove at least 35 mEq of protons and chloride ions each when passing through the digestive system.

[0361] Embodiment 136 A method according to any of the above-listed embodiments, wherein the daily dose has the capacity to remove at least 40 mEq each of protons and chloride ions when passing through the digestive system.

[0362] Embodiment 137 A method described in any of the above-listed embodiments, wherein the daily dose has the capacity to remove at least 45 mEq of protons and chloride ions each when passing through the digestive system.

[0363] Embodiment 138 A method described in any of the above-listed embodiments, wherein the daily dose has the capacity to remove at least 50 mEq each of protons and chloride ions when passing through the digestive system.

[0364] Embodiment 139 A method described in any of the above-listed embodiments, wherein the daily dose is 100 g / day or less.

[0365] Embodiment 140 A method described in any of the above-listed embodiments, wherein the daily dose is less than 50 g / day.

[0366] Embodiment 141 A method described in any of the above-listed embodiments, wherein the daily dose is less than 40 g / day.

[0367] Embodiment 142 A method described in any of the above-listed embodiments, wherein the daily dose is less than 30 g / day.

[0368] Embodiment 143 A method described in any of the above listed embodiments, wherein the daily dose is less than 25 g / day.

[0369] Embodiment 144 A method described in any of the above-listed embodiments, wherein the daily dose is less than 20 g / day.

[0370] Embodiment 145 A method described in any of the above-listed embodiments, wherein the daily dose is less than 15 g / day.

[0371] Embodiment 146 A method described in any of the above-listed embodiments, wherein the daily dose is less than 10 g / day.

[0372] Embodiment 147 A method described in any of the above listed embodiments, wherein the daily dose is less than 5 g / day.

[0373] Embodiment 148 A method described in any of the above-listed embodiments, wherein the individual is treated for at least one day.

[0374] Embodiment 149 A method described in any of the above-listed embodiments, wherein the individual is treated for at least one week.

[0375] Embodiment 150 A method described in any of the above-listed embodiments, wherein the individual is treated for at least one month.

[0376] Embodiment 151 A method described in any of the above-listed embodiments, wherein the individual is treated for at least several months.

[0377] Embodiment 152 A method according to any of the above-listed embodiments, wherein the individual is treated for at least 6 months.

[0378] Embodiment 153 A method described in any of the above-listed embodiments, wherein the individual is treated for at least one year.

[0379] Embodiment 154 A method described in any of the above-listed embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a particle population having a median particle size (volume distribution) of at least 3 μm.

[0380] Embodiment 155 A method described in any of the above-listed embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a particle population having a median particle size (volume distribution) in the range of 5 to 1,000 μm.

[0381] Embodiment 156 A method described in any of the above-listed embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a particle population having a median particle size (volume distribution) in the range of 5 to 500 μm.

[0382] Embodiment 157 A method described in any of the above-listed embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a particle population having a median particle size (volume distribution) in the range of 10 to 400 μm.

[0383] Embodiment 158 ​​A method described in any of the above-listed embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a particle population having a median particle size (volume distribution) in the range of 10 to 300 μm.

[0384] Embodiment 159 A method described in any of the above-listed embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a particle population having a median particle size (volume distribution) in the range of 20 to 250 μm.

[0385] Embodiment 160 A method described in any of the above-listed embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a particle population having a median particle size (volume distribution) in the range of 30 to 250 μm.

[0386] Embodiment 161 A method described in any of the above-listed embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a particle population having a median particle size (volume distribution) in the range of 40 to 180 μm.

[0387] Embodiment 162 A method described in any of the above-listed embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a particle population in which less than 7% of the particles in the population (volume distribution) have a diameter of less than 10 μm.

[0388] Embodiment 163 A method described in any of the above-listed embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a particle population in which less than 5% of the particles in the population (volume distribution) have a diameter of less than 10 μm.

[0389] Embodiment 164 A method described in any of the above-listed embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a particle population in which less than 2.5% of the particles in the population (volume distribution) have a diameter of less than 10 μm.

[0390] Embodiment 165 A method described in any of the above-listed embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a particle population in which less than 1% of the particles in the population (volume distribution) have a diameter of less than 10 μm.

[0391] Embodiment 166: The method of any of the above-listed embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a population of particles having a particle size range that is (i) large enough to avoid passive or active absorption through the digestive tract and (ii) small enough so as not to cause a gritty or unpleasant mouthfeel when ingested as a powder, suspension, gel and / or tablet.

[0392] Embodiment 167 A method described in any of the above-listed embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a particle population having a swelling ratio of less than 9.

[0393] Embodiment 168 The method of any of the above-listed embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a particle population having a swelling ratio of less than 5.

[0394] Embodiment 169 The method described in any of the above-listed embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a particle population having a swelling ratio of less than 2.

[0395] Embodiment 170. The method of any of the above-listed embodiments, wherein the non-absorbable composition has a binding capacity for protons and chloride ions of at least about 0.5 mEq / g.

[0396] Embodiment 171 The method of any of the above-listed embodiments, wherein the non-absorbable composition has a binding capacity for protons and chloride ions of at least about 1 mEq / g.

[0397] Embodiment 172 The method of any of the above-listed embodiments, wherein the non-absorbable composition has a binding capacity for protons and chloride ions of at least about 2 mEq / g.

[0398] Embodiment 173. The method of any of the above-listed embodiments, wherein the non-absorbable composition has a binding capacity for protons and chloride ions of at least about 3 mEq / g.

[0399] Embodiment 174 The method of any of the above-listed embodiments, wherein the non-absorbable composition has a binding capacity for protons and chloride ions of at least about 5 mEq / g.

[0400] Embodiment 175 The method of any of the above-listed embodiments, wherein the non-absorbable composition has a binding capacity for protons and chloride ions of at least about 7.5 mEq / g.

[0401] Embodiment 176. The method of any of the above-listed embodiments, wherein the non-absorbable composition has a binding capacity for protons and chloride ions of at least about 10 mEq / g.

[0402] Embodiment 177 The method of any of the above-listed embodiments, wherein the non-absorbable composition has a binding capacity for protons and chloride ions of at least about 15 mEq / g.

[0403] Embodiment 178. The method of any of the above-listed embodiments, wherein the non-absorbable composition has a binding capacity for protons and chloride ions of at least about 20 mEq / g.

[0404] Embodiment 179 The method of any of the above-listed embodiments, wherein the non-absorbable composition has a binding capacity for protons and chloride ions of at least about 25 mEq / g.

[0405] Embodiment 180 The method of any of the above-listed embodiments, wherein the non-absorbable composition has a theoretical binding capacity for protons and chloride ions in the range of 2 to 25 mEq / g.

[0406] Embodiment 181 The method of any of the above-listed embodiments, wherein the non-absorbable composition has a theoretical binding capacity for protons and chloride ions in the range of 5 to 25 mEq / g.

[0407] Embodiment 182 The method of any of the above-listed embodiments, wherein the non-absorbable composition has a theoretical binding capacity for protons and chloride ions in the range of 10 to 25 mEq / g.

[0408] Embodiment 183 The method of any of the above-listed embodiments, wherein the non-absorbable composition has a theoretical binding capacity for protons and chloride ions in the range of 5 to 20 mEq / g.

[0409] Embodiment 184 The method of any of the above-listed embodiments, wherein the non-absorbable composition has a theoretical binding capacity for protons and chloride ions in the range of 7.5 to 20 mEq / g.

[0410] Embodiment 185 The method of any of the above-listed embodiments, wherein the non-absorbable composition has a theoretical binding capacity for protons and chloride ions in the range of 10 to 20 mEq / g.

[0411] Embodiment 186 A method described in any of the above-listed embodiments, wherein the theoretical binding capacity for protons and chloride ions is the theoretical binding capacity determined in an SGF assay.

[0412] Embodiment 187. A method according to any of the above-listed embodiments, wherein the non-absorbable composition is characterized by a chloride ion binding capacity in the SIB assay of at least 1 mEq / g.

[0413] Embodiment 188. A method according to any of the above-listed embodiments, wherein the non-absorbable composition is characterized by a chloride ion binding capacity of at least 1.5 mEq / g in a SIB assay.

[0414] Embodiment 189. A method according to any of the above-listed embodiments, wherein the non-absorbable composition is characterized by a chloride ion binding capacity in the SIB assay of at least 2 mEq / g.

[0415] Embodiment 190. A method according to any of the above-listed embodiments, wherein the non-absorbable composition is characterized by a chloride ion binding capacity of at least 2.5 mEq / g in a SIB assay.

[0416] Embodiment 191 A method described in any of the above-listed embodiments, wherein the non-absorbable composition is characterized by a chloride ion binding capacity of at least 3 mEq / g in the SIB assay.

[0417] Embodiment 192. A method according to any of the above-listed embodiments, wherein the non-absorbable composition is characterized by a chloride ion binding capacity in the SIB assay of at least 3.5 mEq / g.

[0418] Embodiment 193. A method according to any of the above-listed embodiments, wherein the non-absorbable composition is characterized by a chloride ion binding capacity of at least 4 mEq / g in a SIB assay.

[0419] Embodiment 194 A method described in any of the above-listed embodiments, wherein the non-absorbable composition is characterized by a chloride ion binding capacity of at least 4.5 mEq / g in a SIB assay.

[0420] Embodiment 195. A method according to any of the above-listed embodiments, wherein the non-absorbable composition is characterized by a chloride ion binding capacity in the SIB assay of at least 5 mEq / g.

[0421] Embodiment 196. A method described in any of the above-listed embodiments, wherein the ratio of bound chloride to bound phosphate in the SIB assay is at least 0.1:1, respectively.

[0422] Embodiment 197 A method described in any of the above-listed embodiments, wherein the ratio of bound chloride to bound phosphate in the SIB assay is at least 0.3:1, respectively.

[0423] Embodiment 198. A method according to any of the above-listed embodiments, wherein the ratio of bound chloride to bound phosphate in the SIB assay is at least 0.35:1, respectively.

[0424] Embodiment 199 A method described in any of the above-listed embodiments, wherein the ratio of bound chloride to bound phosphate in the SIB assay is at least 0.4:1, respectively.

[0425] Embodiment 200 A method described in any of the above-listed embodiments, wherein the ratio of bound chloride to bound phosphate in the SIB assay is at least 0.45:1, respectively.

[0426] Embodiment 201 A method described in any of the above-listed embodiments, wherein the ratio of bound chloride to bound phosphate in the SIB assay is at least 0.5:1, respectively.

[0427] Embodiment 202 A method described in any of the above-listed embodiments, wherein the ratio of bound chloride to bound phosphate in the SIB assay is at least 0.75:1, respectively.

[0428] Embodiment 203 A method described in any of the above-listed embodiments, wherein the ratio of bound chloride to bound phosphate in the SIB assay is at least 1:1, respectively.

[0429] Embodiment 204 A method described in any of the above-listed embodiments, wherein the ratio of bound chloride to bound phosphate in the SIB assay is at least 1.25:1, respectively.

[0430] Embodiment 205 A method described in any of the above-listed embodiments, wherein the ratio of bound chloride to bound phosphate in the SIB assay is at least 1.5:1, respectively.

[0431] Embodiment 206. A method according to any of the above-listed embodiments, wherein the ratio of bound chloride to bound phosphate in the SIB assay is at least 1.75:1, respectively.

[0432] Embodiment 207 A method described in any of the above-listed embodiments, wherein the ratio of bound chloride to bound phosphate in the SIB assay is at least 2:1, respectively.

[0433] Embodiment 208 A method described in any of the above-listed embodiments, wherein the ratio of bound chloride to bound phosphate in the SIB assay is at least 2.5:1, respectively.

[0434] Embodiment 209 A method described in any of the above listed embodiments, wherein the ratio of bound chloride to bound phosphate in the SIB assay is at least 3:1, respectively.

[0435] Embodiment 210 A method described in any of the above-listed embodiments, wherein the ratio of bound chloride to bound phosphate in the SIB assay is at least 4:1, respectively.

[0436] Embodiment 211 A method described in any of the above-listed embodiments, wherein the ratio of bound chloride to bound phosphate in the SIB assay is at least 5:1, respectively.

[0437] Embodiment 212 A method according to any of the above-listed embodiments, wherein the daily dose has the capacity to remove protons and chloride ions of at least about 5 mEq / day each.

[0438] Embodiment 213 A method described in any of the above-listed embodiments, wherein the daily dose has a capacity to remove protons and chloride ions of at least about 7 mEq / day each.

[0439] Embodiment 214 A method according to any of the above-listed embodiments, wherein the daily dose has a capacity to remove protons and chloride ions of at least about 10 mEq / day each.

[0440] Embodiment 215 A method according to any of the above-listed embodiments, wherein the daily dose has a capacity to remove protons and chloride ions of at least about 15 mEq / day each.

[0441] Embodiment 216 A method described in any of the above-listed embodiments, wherein the daily dose has a capacity to remove protons and chloride ions of at least about 20 mEq / day each.

[0442] Embodiment 217 A method described in any of the above-listed embodiments, wherein the daily dose has a capacity to remove protons and chloride ions of at least about 25 mEq / day each.

[0443] Embodiment 218 A method according to any of the above-listed embodiments, wherein the daily dose has the capacity to remove protons and chloride ions of at least about 30 mEq / day each.

[0444] Embodiment 219 A method according to any of the above-listed embodiments, wherein the daily dose has a capacity to remove protons and chloride ions of at least about 35 mEq / day each.

[0445] Embodiment 220 A method described in any of the above-listed embodiments, wherein the daily dose has a capacity to remove protons and chloride ions of at least about 40 mEq / day each.

[0446] Embodiment 221 A method described in any of the above-listed embodiments, wherein the daily dose has the capacity to remove protons and chloride ions of at least about 45 mEq / day each.

[0447] Embodiment 222 A method described in any of the above-listed embodiments, wherein the daily dose has the capacity to remove protons and chloride ions of at least about 50 mEq / day each.

[0448] Embodiment 223 A method described in any of the above-listed embodiments, wherein the daily dose removes less than 60 mEq / day of protons and chloride ions each.

[0449] Embodiment 224 A method according to any of the above-listed embodiments, wherein the daily dose removes less than 55 mEq / day of protons and chloride ions each.

[0450] Embodiment 225 A method described in any of embodiments 1 to 221, wherein the daily dose removes less than 50 mEq / day of the target species.

[0451] Embodiment 226 A method described in any of embodiments 1 to 220, wherein the daily dose removes less than 45 mEq / day of protons and chloride ions each.

[0452] Embodiment 227 A method described in any of embodiments 1 to 219, wherein the daily dose removes less than 40 mEq / day of the target species.

[0453] Embodiment 228 A method described in any of embodiments 1 to 218, wherein the daily dose removes less than 35 mEq / day of the target species.

[0454] Embodiment 229 A method described in any of embodiments 1 to 217, wherein the daily dose removes less than 30 mEq / day of the target species.

[0455] Embodiment 230 A method described in any of embodiments 1 to 216, wherein the daily dose removes less than 25 mEq / day of the target species.

[0456] Embodiment 231 A method described in any of embodiments 1 to 215, wherein the daily dose removes less than 20 mEq / day of the target species.

[0457] Embodiment 232 A method described in any of embodiments 1 to 214, wherein the daily dose removes less than 15 mEq / day of protons and chloride ions each.

[0458] Embodiment 233. A method according to any of embodiments 1 to 213, wherein the daily dose removes less than 10 mEq / day of protons and chloride ions each.

[0459] Embodiment 234 A method described in any of the above-listed embodiments, wherein the pharmaceutical composition contains exchangeable sodium ions and the composition contains less than 0.1% by weight of sodium.

[0460] Embodiment 235 A method described in any of the above-listed embodiments, wherein the pharmaceutical composition contains exchangeable sodium ions and the composition contains less than 0.01% by weight of sodium.

[0461] Embodiment 236. The method of any of the above-listed embodiments, wherein the pharmaceutical composition is an anion exchange material comprising an insoluble (in the gastric environment) supporting structure and exchangeable anions.

[0462] Embodiment 237 A method described in any of the above-listed embodiments, wherein the pharmaceutical composition is an anion exchange material comprising an insoluble (in the gastric environment) supporting structure and exchangeable anions, and the anion exchange material is organic, inorganic, or a composite thereof.

[0463] Embodiment 238. The method of any of the above-listed embodiments, wherein the pharmaceutical composition is a strongly basic anion exchange material.

[0464] Embodiment 239 The method of any of the above-listed embodiments, wherein the pharmaceutical composition is a weakly basic anion exchange material.

[0465] Embodiment 240 The method described in any of the above-listed embodiments, wherein the pharmaceutical composition is an anion exchange material containing at least 1 mEq / g of anions selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anions, or combinations thereof.

[0466] Embodiment 241 The method described in any of the above-listed embodiments, wherein the pharmaceutical composition is an anion exchange material containing at least 2 mEq / g of anions selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anions.

[0467] Embodiment 242 The method of any of the above-listed embodiments, wherein the pharmaceutical composition is an anion exchange material containing at least 5 mEq / g of anions selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anions.

[0468] Embodiment 243 The method of any of the above-listed embodiments, wherein the pharmaceutical composition is an anion exchange material containing at least 10 mEq / g of anions selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anions.

[0469] Embodiment 244 A method described in any of embodiments 1 to 242, wherein the pharmaceutical composition is an anion exchange material containing less than 10 mEq / g of anions selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anions, or combinations thereof.

[0470] Embodiment 245 The method of any of the above-listed embodiments, wherein the pharmaceutical composition is an anion exchange material containing less than 5 mEq / g of anions selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anions.

[0471] Embodiment 246. A method described in any one of embodiments 1 to 241, wherein the pharmaceutical composition is an anion exchange material containing less than 2.5 mEq / g of anions selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anions.

[0472] Embodiment 247 A method described in any of embodiments 1 to 239, wherein the pharmaceutical composition is an anion exchange material containing less than 1 mEq / g of anions selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anions.

[0473] Embodiment 248. A method according to any one of embodiments 240 to 247, wherein the bicarbonate equivalent anion is selected from the group consisting of conjugate bases of acetic acid, lactic acid and other short-chain carboxylic acids.

[0474] Embodiment 249 The method described in any of the above-listed embodiments, wherein the pharmaceutical composition is a zwitterion exchange resin.

[0475] Embodiment 250 The method of any of the above-listed embodiments, wherein the pharmaceutical composition is a neutral composition capable of binding both protons and chloride ions selected from the group consisting of polymers functionalized with propylene oxide, polymers functionalized with Michael acceptors, ring-expanded porphyrins, covalently bonded structures, and polymers containing amine and / or phosphine functional groups.

[0476] Embodiment 251 A method described in any of the above-listed embodiments, wherein the pharmaceutical composition (i) removes more chloride ions than bicarbonate equivalent anions, (ii) removes more chloride ions than phosphate anion ions, and (iii) removes more chloride ions than the conjugate base of bile and fatty acid ions.

[0477] Embodiment 252 A method described in any of the above-listed embodiments, wherein treatment with the pharmaceutical composition does not have a clinically significant effect on serum or colonic levels of metabolically related species.

[0478] Embodiment 253 A method according to any of the above-listed embodiments, wherein treatment with the pharmaceutical composition does not have a clinically significant effect on serum or colonic levels of metabolically relevant cationic species.

[0479] Embodiment 254 A method according to any of the above-listed embodiments, wherein treatment with the pharmaceutical composition does not have a clinically significant effect on serum or colonic levels of metabolically-related anionic species.

[0480] Embodiment 255 A method described in any of the above-listed embodiments, wherein treatment with the pharmaceutical composition does not have a clinically significant effect on serum potassium levels in a statistically significant number of individuals.

[0481] Embodiment 256 A method described in any of the above-listed embodiments, wherein treatment with the pharmaceutical composition does not have a clinically significant effect on serum phosphate levels in a statistically significant number of individuals.

[0482] Embodiment 257 A method described in any of the above-listed embodiments, wherein treatment with the pharmaceutical composition does not have a clinically significant effect on serum low-density lipoprotein (LDL) levels in a statistically significant number of individuals.

[0483] Embodiment 258. The pharmaceutical composition comprises a compound of Formula 1: [ka] wherein R1, R2, and R3 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, provided that at least one of R1, R2, and R3 is other than hydrogen. 10. The method of any of the preceding embodiments, wherein the non-absorbable composition comprises a proton-binding crosslinked amine polymer comprising an amine residue corresponding to

[0484] Embodiment 259. The pharmaceutical composition comprises a compound of Formula 1: [ka] wherein R1, R2, and R3 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, provided that at least one of R1, R2, and R3 is other than hydrogen. wherein the crosslinked amine polymer has (i) an equilibrium proton binding capacity of at least 5 mmol / g and a chloride ion binding capacity of at least 5 mmol / g in aqueous simulated gastric fluid buffer ("SGF") containing 35 mM NaCl and 63 mM HCl at pH 1.2, 37° C., and (ii) an equilibrium swelling ratio of about 2 or less in deionized water.

[0485] Embodiment 260. The pharmaceutical composition comprises a compound of Formula 1: [ka] wherein R1, R2, and R3 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, provided that at least one of R1, R2, and R3 is other than hydrogen. wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 5 or less, and the crosslinked amine polymer binds in an interfering ion buffer at 37° C. a molar ratio of chloride ions to interfering ions of at least 0.35:1, respectively, wherein the interfering ions are phosphate ions, and the interfering ion buffer is a buffered solution of 36 mM chloride and 20 mM phosphate at pH 5.5.

[0486] Embodiment 261 The method described in any of the above-listed embodiments, wherein the pharmaceutical composition has an equilibrium chloride binding capacity of at least 7.5 mmol / g in aqueous simulated gastric fluid buffer ("SGF") containing 35 mM NaCl and 63 mM HCl at pH 1.2, 37°C.

[0487] Embodiment 262 The method described in any of the above-listed embodiments, wherein the pharmaceutical composition has an equilibrium chloride binding capacity of at least 10 mmol / g in aqueous simulated gastric fluid buffer ("SGF") containing 35 mM NaCl and 63 mM HCl at pH 1.2, 37°C.

[0488] Embodiment 263: A method described in any one of embodiments 258 to 262, wherein R1, R2, and R3 are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocycle, provided that each of R1, R2, and R3 is not hydrogen.

[0489] Embodiment 264 A method described in any of embodiments 258 to 262, wherein R1, R2 and R3 are independently hydrogen, aliphatic or heteroaliphatic, provided that at least one of R1, R2 and R3 is other than hydrogen.

[0490]

[0072] Embodiment 247. The method of any one of embodiments 258 to 264, wherein the crosslinked amine polymer is produced by substitution polymerization of an amine with a multifunctional crosslinker, which optionally contains an amine moiety.

[0491] Embodiment 248. A crosslinked amine polymer comprising an amine residue corresponding to Formula 1a: [ka] wherein R4 and R5 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl. 248. The method of any one of embodiments 258 to 247, wherein the compound is prepared by radical polymerization of an amine corresponding to

[0492] Embodiment 249. The method of embodiment 248, wherein R4 and R5 are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocycle.

[0493] Embodiment 250 The method of embodiment 248, wherein R4 and R5 are independently hydrogen, aliphatic, or heteroaliphatic.

[0494] Embodiment 251. A pharmaceutical composition is a non-absorbable composition comprising a crosslinked amine polymer comprising an amine residue corresponding to Formula 1b, wherein the crosslinked amine polymer is a crosslinked amine polymer of Formula 1b: [ka] wherein R4 and R5 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl; R6 is aliphatic; and R 61 and R 62 are independently hydrogen, aliphatic, or heteroaliphatic. The method of any of the above listed embodiments, wherein the compound is prepared by substitution polymerization of an amine corresponding to

[0495] Embodiment 252. The method of embodiment 251, wherein R4 and R5 are independently hydrogen, saturated hydrocarbon, unsaturated aliphatic, aryl, heteroaryl, heteroalkyl, or unsaturated heteroaliphatic.

[0496] Embodiment 253. The method of embodiment 251, wherein R4 and R5 are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocycle.

[0497] Embodiment 254 The method of embodiment 251, wherein R4 and R5 are independently hydrogen, allyl, or aminoalkyl.

[0498] Embodiment 255. The pharmaceutical composition comprises a compound of Formula 4: [ka] wherein each R is independently hydrogen or an ethylene bridge between two nitrogen atoms of the crosslinked amine polymer; [ka] and a, b, and c are integers. 3. The method of claim 1, wherein the polymer comprises a structure corresponding to:

[0499] Embodiment 256 The method described in embodiment 255, wherein the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 5:1.

[0500] Embodiment 257 The method described in embodiment 255, wherein the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1.5:1 to 4:1.

[0501] Embodiment 258 The method described in embodiment 255, wherein the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1.75:1 to 3:1.

[0502] Embodiment 259 The method described in embodiment 255, wherein the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 2:1 to 2.5:1.

[0503] Embodiment 260. The method of any one of embodiments 255 to 259, wherein the polymer has a carbon to nitrogen ratio of from 2.5:1 to 5:1.

[0504] Embodiment 261. The method of any one of embodiments 255 to 259, wherein the polymer has a carbon to nitrogen ratio of 3:1 to 4:1.

[0505] Embodiment 262. The method of any one of embodiments 255 to 259, wherein the polymer has a carbon to nitrogen ratio of from 3:5:1 to 3.9:1.

[0506] Embodiment 263. The method of any one of embodiments 255 to 259, wherein the polymer has a carbon to nitrogen ratio of from 3:7:1 to 3.9:1.

[0507] Embodiment 264. The method of any of embodiments 255-263, wherein 35-95% of the R substituents are hydrogen and 5-65% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

[0508] Embodiment 265. The method of any of embodiments 255-263, wherein 50-95% of the R substituents are hydrogen and 5-50% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

[0509] Embodiment 266. The method of any of embodiments 255-263, wherein 55-85% of the R substituents are hydrogen and 15-45% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

[0510] Embodiment 267. The method of any of embodiments 255-263, wherein 55-90% of the R substituents are hydrogen and 10-45% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

[0511] Embodiment 268. The method of any of embodiments 255-263, wherein 60-90% of the R substituents are hydrogen and 10-40% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

[0512] Embodiment 269. The method of any of embodiments 255-263, wherein 65-90% of the R substituents are hydrogen and 10-35% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

[0513] Embodiment 270. The method of any of embodiments 255-263, wherein 70-90% of the R substituents are hydrogen and 10-30% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

[0514] Embodiment 271. The method of any of embodiments 255-263, wherein 75-85% of the R substituents are hydrogen and 15-25% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

[0515] Embodiment 272. The method of any of embodiments 255-263, wherein 80-85% of the R substituents are hydrogen and 15-20% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

[0516] Embodiment 273 The method described in any of the above-listed embodiments, wherein the pharmaceutical composition is in dosage unit form.

[0517] Embodiment 274 The method described in embodiment 273, wherein the dosage unit form is a capsule, tablet or sachet dosage form.

[0518] Embodiment 275 The method described in any of the above-listed embodiments, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier, excipient, or diluent.

[0519] Embodiment 276 A method described in any of the above-listed embodiments, wherein the daily dose is administered once a day (QD).

[0520] Embodiment 277 A method described in any of the above-listed embodiments, wherein the daily dose is administered twice a day (BID).

[0521] Embodiment 278 A method described in any of the above-listed embodiments, wherein the daily dose is administered three times a day.

[0522] Embodiment 279 A method described in any of the above-listed embodiments, wherein the daily dose is obtained from a pharmaceutical product comprising a sealed container and a non-absorbable composition within the sealed container.

[0523] Embodiment 280 The method of embodiment 279, wherein the sealed container comprises a moisture barrier.

[0524] Embodiment 281 The method of embodiment 279 or 280, wherein the sealed container comprises an oxygen barrier.

[0525] Embodiment 282 A method described in any of embodiments 279 to 281, wherein the sealed container is a sealed sachet.

[0526] Embodiment 283 The method of any of embodiments 279 to 281, wherein the sealed container comprises a multilayer laminate of a contacting inner layer, an outer layer, and a barrier layer disposed between the contacting layer and the outer layer.

[0527] Embodiment 284 The method of any of embodiments 279 to 281, wherein the sealed container comprises a multilayer laminate of a contacting inner layer, an outer layer, and an oxygen barrier layer disposed between the contacting layer and the outer layer.

[0528] Embodiment 285: The method of any of embodiments 279 to 281, wherein the sealed container comprises a multilayer laminate of a contacting inner layer, an outer layer, and a moisture barrier layer disposed between the contacting layer and the outer layer.

[0529] Embodiment 286: The method of any of embodiments 279 to 281, wherein the sealed container comprises a multilayer laminate of a contacting inner layer, an outer layer, and an oxygen barrier layer and a moisture barrier layer disposed between the contacting layer and the outer layer.

[0530] Embodiment 287 The method of any of embodiments 279 to 281, wherein the sealed container comprises a multilayer laminate of a contacting inner layer, an outer layer, and an oxygen scavenging layer disposed between the contacting layer and the outer layer.

[0531] Embodiments 288 to 570 have been intentionally omitted.

[0532] Embodiment 571 A composition for use in a method for treating metabolic acidosis in an adult patient, wherein 0.1 to 12 g of the composition is administered to the patient per day in the treatment, and the composition is a non-absorbable composition having the ability to remove protons from the patient, and the non-absorbable composition is characterized by a chloride ion binding capacity of at least 2.5 mEq / g in a simulated small intestine inorganic buffer ("SIB") assay.

[0533] Embodiment 572 A composition for use in a method for treating metabolic acidosis in an adult patient, wherein the patient has a serum bicarbonate level of less than 20 mEq / L before treatment, and the composition is a non-absorbable composition capable of removing protons from the patient.

[0534] Embodiment 573 A composition for the method described in embodiment 571 or 572, wherein the patient's serum bicarbonate level is less than 19 mEq / L before treatment.

[0535] Embodiment 574 A composition for the method described in embodiment 571 or 572, wherein the patient's serum bicarbonate level is less than 18 mEq / L before treatment.

[0536] Embodiment 575 A composition for the method described in embodiment 571 or 572, wherein the patient's serum bicarbonate level is less than 17 mEq / L before treatment.

[0537] Embodiment 576. A composition for the method described in embodiment 571 or 572, wherein the patient's serum bicarbonate level is less than 16 mEq / L before treatment.

[0538] Embodiment 577 A composition for the method described in embodiment 571 or 572, wherein the patient's serum bicarbonate level is less than 15 mEq / L before treatment.

[0539] Embodiment 578. A composition for the method described in embodiment 571 or 572, wherein the patient's serum bicarbonate level is less than 14 mEq / L before treatment.

[0540] Embodiment 579 A composition for the method described in embodiment 571 or 572, wherein the patient's serum bicarbonate level is less than 13 mEq / L before treatment.

[0541] Embodiment 580 A composition for the method described in embodiment 571 or 572, wherein the patient's serum bicarbonate level is less than 12 mEq / L before treatment.

[0542] Embodiment 581 A composition for the method described in embodiment 571 or 572, wherein the patient's serum bicarbonate level is less than 11 mEq / L before treatment.

[0543] Embodiment 582 A composition for the method described in embodiment 571 or 572, wherein the patient's serum bicarbonate level is less than 10 mEq / L before treatment.

[0544] Embodiment 583 A composition for the methods described in embodiments 571 to 582, wherein the patient's serum bicarbonate level increases by at least 1 mEq / L over 15 days of treatment.

[0545] Embodiment 584. The composition described in embodiments 571 to 583, wherein in the treatment 0.1 to 12 g of the polymer is administered to the patient per day.

[0546] Embodiment 585. A composition described in any of embodiments 571 to 584, wherein the non-absorbable composition is characterized by a chloride ion binding capacity of at least 2.5 mEq / g in a simulated small intestine inorganic buffer ("SIB") assay.

[0547] Embodiment 586 A composition for use in a method for treating metabolic acidosis in an adult patient by increasing the patient's serum bicarbonate level by at least 1 mEq / L over 15 days of treatment, wherein the composition is a non-absorbable composition capable of removing protons from the patient.

[0548] Embodiment 587 The composition described in embodiments 571 to 586, wherein in the treatment 0.1 to 12 g of the polymer is administered to the patient per day.

[0549] Embodiment 588. A composition described in any of embodiments 572 to 587, wherein the non-absorbable composition is characterized by a chloride ion binding capacity of at least 2.5 mEq / g in a simulated small intestine inorganic buffer ("SIB") assay.

[0550] Embodiment 589. The composition of any of embodiments 586 to 588, wherein the patient's serum bicarbonate level value increases by at least 1 mEq / L over 15 days of treatment.

[0551] Embodiment 590 A composition for use according to any of embodiments 586 to 589, wherein the increase in serum bicarbonate level is at least 1.5 mEq / L.

[0552] Embodiment 591 A composition for use according to any of embodiments 586 to 590, wherein the increase in serum bicarbonate level is at least 2 mEq / L.

[0553] Embodiment 592 A composition for use described in any of embodiments 586 to 591, wherein the increase in serum bicarbonate level is at least 2.5 mEq / L.

[0554] Embodiment 593 A composition for use described in any of embodiments 586 to 592, wherein the increase in serum bicarbonate level is at least 3 mEq / L.

[0555] Embodiment 594 A composition for use described in any of embodiments 586 to 593, wherein the increase in serum bicarbonate level is at least 3.5 mEq / L.

[0556] Embodiment 595 A composition for use described in any of embodiments 586 to 594, wherein the increase in serum bicarbonate level is at least 4 mEq / L.

[0557] Embodiment 596. A composition for use according to any of embodiments 586 to 595, wherein the increase in serum bicarbonate level is at least 4.5 mEq / L.

[0558] Embodiment 597 A composition for use described in any of embodiments 586 to 596, wherein the increase in serum bicarbonate level is at least 5 mEq / L.

[0559] Embodiment 598. A composition for use described in any of embodiments 586 to 597, wherein the increase is observed during 14 days of treatment.

[0560] Embodiment 599 A composition for use described in any of embodiments 586 to 598, wherein the increase is observed during 13 days of treatment.

[0561] Embodiment 600 A composition for use described in any of embodiments 586 to 599, wherein the increase is observed within 12 days of treatment.

[0562] Embodiment 601 A composition for use described in any of embodiments 586 to 600, wherein the increase is observed during 11 days of treatment.

[0563] Embodiment 602 A composition for use described in any of embodiments 586 to 601, wherein the increase is observed within 10 days of treatment.

[0564] Embodiment 603 A composition for use described in any of embodiments 586 to 602, wherein the increase is observed within 9 days of treatment.

[0565] Embodiment 604 A composition for use described in any of embodiments 586 to 603, wherein the increase is observed within 8 days of treatment.

[0566] Embodiment 605 A composition for use described in any of embodiments 586 to 604, wherein the increase is observed within 7 days of treatment.

[0567] Embodiment 606 A composition for use described in any of embodiments 586 to 605, wherein the increase is observed within 6 days of treatment.

[0568] Embodiment 607 A composition for use described in any of embodiments 586 to 606, wherein the increase is observed within 5 days of treatment.

[0569] Embodiment 608 A composition for use described in any of embodiments 586 to 607, wherein the increase is observed within 4 days of treatment.

[0570] Embodiment 609 A composition for use described in any of embodiments 586 to 608, wherein the increase is observed within 3 days of treatment.

[0571] Embodiment 610 A composition for use described in any of embodiments 586 to 609, wherein the increase is observed within 2 days of treatment.

[0572] Embodiment 611 A composition for use described in any of embodiments 586 to 610, wherein the increase is observed within one day of treatment.

[0573] Embodiment 612 A composition for use described in any of embodiments 571 to 611, wherein the specified treatment day is the first day of treatment with the composition.

[0574] Embodiment 613 A composition for the methods described in embodiments 572 to 601, wherein in the treatment 0.1 to 12 g of the polymer is administered to the patient per day.

[0575] Embodiment 614 A composition for the method described in embodiment 613, wherein in the treatment 1 to 11 g of the polymer is administered to the patient per day.

[0576] Embodiment 615. A composition for the method described in embodiment 613, wherein in the treatment 2 to 10 g of the polymer is administered to the patient per day.

[0577] Embodiment 616 A composition for the method described in embodiment 613, wherein 3 to 9 g of the polymer is administered to the patient per day in the treatment.

[0578] Embodiment 617 A composition for the method described in embodiment 613, wherein 3 to 8 g of the polymer is administered to the patient per day in the treatment.

[0579] Embodiment 618 A composition for the method described in embodiment 613, wherein in the treatment 3 to 7 g of the polymer is administered to the patient per day.

[0580] Embodiment 619 A composition for the method described in embodiment 613, wherein in the treatment 3 to 6 g of the polymer is administered to the patient per day.

[0581] Embodiment 620 A composition for the method described in embodiment 613, wherein in the treatment 3.5 to 5.5 g of the polymer is administered to the patient per day.

[0582] Embodiment 621 A composition for the method described in embodiment 613, wherein 4 to 5 g of the polymer is administered to the patient per day in the treatment.

[0583] Embodiment 622 A composition for the method described in embodiment 613, wherein 1 to 3 g of the polymer is administered to the patient per day in the treatment.

[0584] Embodiment 623 A composition for the method described in embodiment 571 or 572, wherein about 0.5 g of the composition is administered to the patient per day.

[0585] Embodiment 624 A composition for the method described in embodiment 571 or 572, wherein about 1 g of the composition is administered to the patient per day.

[0586] Embodiment 625 A composition for the method described in embodiment 571 or 572, wherein about 1.5 g of the composition is administered to the patient per day.

[0587] Embodiment 626 A composition for the method described in embodiment 571 or 572, wherein about 2 g of the composition is administered to the patient per day.

[0588] Embodiment 627 A composition for the method described in embodiment 571 or 572, wherein about 2.5 g of the composition is administered to the patient per day.

[0589] Embodiment 628 A composition for the method described in embodiment 571 or 572, wherein about 3 g of the composition is administered to the patient per day.

[0590] Embodiment 629 A composition for the method described in embodiment 571 or 572, wherein about 3.5 g of the composition is administered to the patient per day.

[0591] Embodiment 630 A composition for the method described in embodiment 571 or 572, wherein about 4.0 g of the composition is administered to the patient per day.

[0592] Embodiment 631 A composition for the method described in embodiment 571 or 572, wherein about 4.5 g of the composition is administered to the patient per day.

[0593] Embodiment 632 A composition for the method described in embodiment 571 or 572, wherein about 5.0 g of the composition is administered to the patient per day.

[0594] Embodiment 633. A composition for use described in any of embodiments 571 to 632, having a chloride ion binding capacity in an artificial small intestine inorganic buffer ("SIB") assay of at least 3 mEq / g.

[0595] Embodiment 634 A composition for use described in any of embodiments 571 to 633, having a chloride ion binding capacity in an artificial small intestine inorganic buffer ("SIB") assay of at least 3.5 mEq / g.

[0596] Embodiment 635. A composition for use described in any of embodiments 571 to 634, having a chloride ion binding capacity in an artificial small intestine inorganic buffer ("SIB") assay of at least 4 mEq / g.

[0597] Embodiment 636 A composition for use described in any of embodiments 571 to 635, having a chloride ion binding capacity in a simulated small intestine inorganic buffer ("SIB") assay of at least 4.5 mEq / g.

[0598] Embodiment 637 A composition for use described in any of embodiments 571 to 636, having a chloride ion binding capacity in an artificial small intestine inorganic buffer ("SIB") assay of at least 5 mEq / g.

[0599] Embodiment 638. A composition for use according to any of embodiments 571 to 637, having a chloride ion binding capacity in a SIB assay of less than 10 mEq / g.

[0600] Embodiment 639 A composition for use according to any of embodiments 571 to 638, having a chloride ion binding capacity in a SIB assay of less than 9 mEq / g.

[0601] Embodiment 640 A composition for use described in any of embodiments 571 to 639, having a chloride ion binding capacity in a SIB assay of less than 8 mEq / g.

[0602] Embodiment 641 A composition for use according to any of embodiments 571 to 640, having a chloride ion binding capacity in a SIB assay of less than 7 mEq / g.

[0603] Embodiment 642. A composition for use according to any of embodiments 571 to 641, having a chloride ion binding capacity in a SIB assay of less than 6 mEq / g.

[0604] Embodiment 643. A composition for use according to any of embodiments 571 to 642, having a chloride ion binding capacity in a SIB assay of less than 5 mEq / g.

[0605] Embodiment 644 A composition for use in a method for treating metabolic acidosis in an adult patient, wherein >12 to 100 g of the composition is administered to the patient per day in the treatment, and the composition is a non-absorbable composition having the ability to remove protons from the patient, and the non-absorbable composition is characterized by a chloride ion binding capacity of less than 2.5 mEq / g in a simulated small intestine inorganic buffer ("SIB") assay.

[0606] Embodiment 645. The composition described in embodiment 644, wherein the patient's serum bicarbonate level increases by at least 1 mEq / L over 15 days of treatment.

[0607] Embodiment 646 A composition for use in a method for treating metabolic acidosis in an adult patient by increasing the patient's serum bicarbonate level by at least 1 mEq / L over a 15-day period, wherein >12 to 100 g of the polymer are administered to the patient per day, and the composition is a non-absorbable composition capable of removing protons from the patient, wherein the non-absorbable composition is characterized by a chloride ion binding capacity of at least 2.5 mEq / g in a simulated small intestine inorganic buffer ("SIB") assay.

[0608] Embodiment 647 A composition for the method described in embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 1 mEq / L.

[0609] Embodiment 648. A composition for the method described in embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 1.5 mEq / L.

[0610] Embodiment 649 A composition for the method described in embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 2 mEq / L.

[0611] Embodiment 650 A composition for the method described in embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 2.5 mEq / L.

[0612] Embodiment 651 A composition for the method described in embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 3 mEq / L.

[0613] Embodiment 652 A composition for the method described in embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 3.5 mEq / L.

[0614] Embodiment 653 A composition for the method described in embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 4 mEq / L.

[0615] Embodiment 654 A composition for the method described in embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 4.5 mEq / L.

[0616] Embodiment 655 A composition for the method described in embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 5 mEq / L.

[0617] Embodiment 656 A composition for the method described in embodiment 645 or 646, wherein the increase is observed within 14 days of treatment.

[0618] Embodiment 657 A composition for the method described in embodiment 645 or 646, wherein the increase is observed within 13 days of treatment.

[0619] Embodiment 658 A composition for the method described in embodiment 645 or 646, wherein the increase is observed during 12 days of treatment.

[0620] Embodiment 659 A composition for the method described in embodiment 645 or 646, wherein the increase is observed during 11 days of treatment.

[0621] Embodiment 660 A composition for the method described in embodiment 645 or 646, wherein the increase is observed within 10 days of treatment.

[0622] Embodiment 661 A composition for the method described in embodiment 645 or 646, wherein the increase is observed within 9 days of treatment.

[0623] Embodiment 662 A composition for the method described in embodiment 645 or 646, wherein the increase is observed within 8 days of treatment.

[0624] Embodiment 663 A composition for the method described in embodiment 645 or 646, wherein the increase is observed within 7 days of treatment.

[0625] Embodiment 664 A composition for the method described in embodiment 645 or 646, wherein the increase is observed within 6 days of treatment.

[0626] Embodiment 665 A composition for the method described in embodiment 645 or 646, wherein the increase is observed within 5 days of treatment.

[0627] Embodiment 666 A composition for the method described in embodiment 645 or 646, wherein the increase is observed within 4 days of treatment.

[0628] Embodiment 667 A composition for the method described in embodiment 645 or 646, wherein the increase is observed within 3 days of treatment.

[0629] Embodiment 668 A composition for the method described in embodiment 645 or 646, wherein the increase is observed within two days of treatment.

[0630] Embodiment 669 A composition for the method described in embodiment 645 or 646, wherein the increase is observed within one day of treatment.

[0631] Embodiment 670. A composition for use described in any of embodiments 644 to 654, wherein the specified treatment day is the first day of treatment with the composition.

[0632] Embodiment 671 A composition for use according to embodiments 644 to 670, wherein 12 to 100 g is administered to the patient per day.

[0633] Embodiment 672 A composition for use according to embodiments 644 to 671, wherein 20 to 90 g is administered to the patient per day.

[0634] Embodiment 673: A composition for use according to embodiments 644 to 672, wherein 20 to 80 g is administered to the patient per day.

[0635] Embodiment 674 A composition for use according to embodiments 644 to 673, wherein 20 to 70 g is administered to the patient per day.

[0636] Embodiment 675 A composition for use according to embodiments 644 to 674, wherein 20 to 60 g is administered to the patient per day.

[0637] Embodiment 676: A composition for use according to embodiments 644 to 675, wherein 20 to 50 g is administered to the patient per day.

[0638] Embodiment 677 A composition for use according to embodiments 644 to 676, wherein 20 to 40 g is administered to the patient per day.

[0639] Embodiment 678: A composition for use according to embodiments 644 to 677, wherein 20 to 35 g is administered to the patient per day.

[0640] Embodiment 679 A composition for use according to embodiments 644 to 678, wherein 20 to 30 g is administered to the patient per day.

[0641] Embodiment 680 A composition for use according to embodiments 644 to 679, wherein 20 to 25 g is administered to the patient per day.

[0642] Embodiment 681 A composition for use described in any of embodiments 644 to 680, having a chloride ion binding capacity in an artificial small intestine inorganic buffer ("SIB") assay of less than 2 mEq / g.

[0643] Embodiment 682 A composition for use described in any of embodiments 644 to 681, having a chloride ion binding capacity in an artificial small intestine inorganic buffer ("SIB") assay of less than 1.5 mEq / g.

[0644] Embodiment 683. A composition for use described in any of embodiments 644 to 682, having a chloride ion binding capacity in an artificial small intestine inorganic buffer ("SIB") assay of less than 1 mEq / g.

[0645] Embodiment 684 A composition for use described in any of embodiments 644 to 683, having a chloride ion binding capacity in an artificial small intestine inorganic buffer ("SIB") assay of less than 0.75 mEq / g.

[0646] Embodiment 685. A composition for use described in any of embodiments 644 to 684, having a chloride ion binding capacity in an artificial small intestine inorganic buffer ("SIB") assay of more than 0.5 mEq / g.

[0647] Embodiment 686 A composition for use described in any of embodiments 644 to 685, having a chloride ion binding capacity in an artificial small intestine inorganic buffer ("SIB") assay of more than 1 mEq / g.

[0648] Embodiment 687 A composition for use described in any of embodiments 644 to 686, having a chloride ion binding capacity in an artificial small intestine inorganic buffer ("SIB") assay of more than 1.5 mEq / g.

[0649] Embodiment 688. A composition for use described in any of embodiments 644 to 687, having a chloride ion binding capacity in an artificial small intestine inorganic buffer ("SIB") assay of more than 2 mEq / g.

[0650] Embodiment 689 A composition for use according to any of the preceding embodiments, wherein the composition is administered once daily to provide a total specified daily dose.

[0651] Embodiment 690 A composition for use according to any of the preceding embodiments, wherein the composition is administered twice a day to provide a total specified daily dose.

[0652] Embodiment 691 A composition for use according to any of the preceding embodiments, wherein the composition is administered three times a day to provide a total specified daily dose.

[0653] Embodiment 692 A composition for use described in any of the above listed embodiments, wherein the composition is administered orally.

[0654] Embodiment 693. The composition of claim 1, wherein the compound is a compound of Formula 1: [ka] wherein R1, R2, and R3 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, provided that at least one of R1, R2, and R3 is other than hydrogen. wherein the crosslinked amine polymer has (i) an equilibrium proton binding capacity of at least 5 mmol / g and a chloride ion binding capacity of at least 5 mmol / g in aqueous simulated gastric fluid buffer ("SGF") containing 35 mM NaCl and 63 mM HCl at pH 1.2, 37°C, and (ii) an equilibrium swelling ratio in deionized water of about 2 or less.

[0655] Embodiment 694 The composition comprises a compound represented by Formula 1: [ka] wherein R1, R2, and R3 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, provided that at least one of R1, R2, and R3 is other than hydrogen. wherein the crosslinked amine polymer has an equilibrium swelling ratio of about 5 or less in deionized water, and the crosslinked amine polymer binds in an interfering ion buffer at 37°C at a molar ratio of chloride ions to interfering ions of at least 0.35:1, respectively, wherein the interfering ions are phosphate ions, and the interfering ion buffer is a buffered solution of 36 mM chloride and 20 mM phosphate at pH 5.5.

[0656] Embodiment 695 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 682, and the crosslinked amine polymer has an equilibrium chloride binding capacity of at least 7.5 mmol / g in aqueous simulated gastric fluid buffer ("SGF") containing 35 mM NaCl and 63 mM HCl at pH 1.2, 37°C.

[0657] Embodiment 696 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 682, and the crosslinked amine polymer has an equilibrium chloride binding capacity of at least 10 mmol / g in aqueous simulated gastric fluid buffer ("SGF") containing 35 mM NaCl and 63 mM HCl at pH 1.2, 37°C.

[0658] Embodiment 697 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 683 and the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 4 or less.

[0659] Embodiment 698 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 683 and the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 3 or less.

[0660] Embodiment 699 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 683 and the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 2 or less.

[0661] Embodiment 700 A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the embodiments listed above, and R1, R2, and R3 are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocycle, provided that each of R1, R2, and R3 is not hydrogen.

[0662] Embodiment 701 A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments, and R1, R2 and R3 are independently hydrogen, aliphatic or heteroaliphatic, provided that at least one of R1, R2 and R3 is other than hydrogen.

[0663] Embodiment 702. A composition for use according to any of embodiments 571 to 692, wherein the composition is a composition according to any of the above listed embodiments and the crosslinked amine polymer is prepared by substitution polymerization of an amine with a multifunctional crosslinker, which may optionally contain an amine moiety.

[0664] Embodiment 703. The composition is the pharmaceutical composition of any of embodiments 693 to 701, wherein the crosslinked amine polymer comprises an amine residue corresponding to formula 1a, wherein the crosslinked amine polymer is a compound of formula 1a: [ka] wherein R4 and R5 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl. 693. The composition for use according to any one of embodiments 571 to 692, which is prepared by radical polymerization of an amine corresponding to

[0665] Embodiment 704 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 703, and R4 and R5 are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl or heterocycle.

[0666] Embodiment 705 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 703, and R4 and R5 are independently hydrogen, aliphatic or heteroaliphatic.

[0667] Embodiment 706. The composition is the pharmaceutical composition of any of embodiments 693 to 701, wherein the crosslinked amine polymer comprises an amine residue corresponding to formula 1b, and the crosslinked amine polymer is crosslinked with a multifunctional crosslinker according to formula 1b: [ka] wherein R4 and R5 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl; R6 is aliphatic; and R 61 and R 62 are independently hydrogen, aliphatic, or heteroaliphatic. 693. The composition for use according to any one of embodiments 571 to 692, wherein the composition is prepared by substitution polymerization of an amine corresponding to:

[0668] Embodiment 707 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 706, and R4 and R5 are independently hydrogen, saturated hydrocarbon, unsaturated aliphatic, aryl, heteroaryl, heteroalkyl or unsaturated heteroaliphatic.

[0669] Embodiment 708 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 706, and R4 and R5 are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl or heterocycle.

[0670] Embodiment 709 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 706, and R4 and R5 are independently hydrogen, allyl or aminoalkyl.

[0671] Embodiment 710. The composition of any of the above-listed embodiments, wherein the crosslinked amine polymer is a compound represented by Formula 1c: [ka] wherein R7 is hydrogen, aliphatic or heteroaliphatic, and R8 is aliphatic or heteroaliphatic. 693. The composition for use according to any of embodiments 571 to 692, comprising an amine residue corresponding to:

[0672] Embodiment 711. The composition is a pharmaceutical composition according to any of embodiments 693 to 701, wherein the crosslinked amine polymer is a compound of Formula 2: [ka] [In the formula, m and n are independently non-negative integers; R 10 , R 20 , R 30 and R 40 is independently hydrogen, hydrocarbyl, or substituted hydrocarbyl; X1, [ka] and; X2 is hydrocarbyl or substituted hydrocarbyl; each X 11 is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxy, or amino; z is a non-negative number] 693. The composition for use according to any of embodiments 571 to 692, comprising an amine residue corresponding to:

[0673] Embodiment 712. The composition is a pharmaceutical composition according to embodiment 711, wherein R 10 , R 20 , R 30 and R 40 is independently hydrogen, aliphatic, aryl, heteroaliphatic, or heteroaryl; m and z are independently 0 to 3; and n is 0 or 1.

[0674] Embodiment 713 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 711 or 712, and X2 is aliphatic or heteroaliphatic.

[0675] Embodiment 714. The composition is a pharmaceutical composition according to embodiment 711, 712 or 713, wherein m is 1 to 3 and X 11 The composition for use according to any of embodiments 571-692, wherein is hydrogen, aliphatic or heteroaliphatic.

[0676] Embodiment 715. The composition is a pharmaceutical composition according to any of embodiments 693 to 701, wherein the crosslinked amine polymer is a compound of formula 2a: [ka] [In the formula, m and n are independently non-negative integers; Each R 11 is independently hydrogen, hydrocarbyl, heteroaliphatic, or heteroaryl; R 21 and R 31 are independently hydrogen or heteroaliphatic; R 41 is hydrogen, substituted hydrocarbyl or hydrocarbyl; X1, [ka] and; X2 is alkyl or substituted hydrocarbyl; each X 12 is independently hydrogen, hydroxy, amino, aminoalkyl, boronic acid, or halo; z is a non-negative number] 693. The composition for use according to any of embodiments 571 to 692, comprising an amine residue corresponding to:

[0677] Embodiment 716 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 715, wherein m and z are independently 0 to 3 and n is 0 or 1.

[0678] Embodiment 717. The composition is a pharmaceutical composition according to embodiment 715 or 716, wherein R 11 are independently hydrogen, aliphatic, aminoalkyl, haloalkyl, or heteroaryl; R 21 and R 31 are independently hydrogen or heteroaliphatic, and R 41 The composition for use according to any of embodiments 571-692, wherein is hydrogen, aliphatic, aryl, heteroaliphatic, or heteroaryl.

[0679] Embodiment 718. The composition is a pharmaceutical composition according to embodiment 715 or 716, wherein each R 11 is hydrogen, aliphatic, aminoalkyl, or haloalkyl, and R 21 and R 31 is hydrogen or aminoalkyl, and R 41 The composition for use according to any of embodiments 571-692, wherein is hydrogen, aliphatic or heteroaliphatic.

[0680] Embodiment 719. The composition is a pharmaceutical composition according to any of embodiments 693 to 701, wherein the crosslinked amine polymer is a compound of formula 2b: [ka] [In the formula, m and n are independently non-negative integers; Each R 12 is independently hydrogen, substituted hydrocarbyl, or hydrocarbyl; R 22 and R 32 is independently hydrogen, substituted hydrocarbyl, or hydrocarbyl; R 42 is hydrogen, hydrocarbyl or substituted hydrocarbyl; X1, [ka] and; X2 is alkyl, aminoalkyl or alkanol; each X 13 are independently hydrogen, hydroxy, alicyclic, amino, aminoalkyl, halogen, alkyl, heteroaryl, boronic acid, or aryl; z is a non-negative number] containing an amine residue corresponding to The amine corresponding to formula 2b contains at least one allyl group. A composition for use according to any one of embodiments 571 to 692.

[0681] Embodiment 720 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 719, wherein m and z are independently 0 to 3 and n is 0 or 1.

[0682] Embodiment 721. The composition is a pharmaceutical composition according to embodiment 719 or 720, wherein R 12 or R 42independently comprise at least one allyl or vinyl moiety.

[0683] Embodiment 722. The composition is the pharmaceutical composition of embodiment 719 or 720, wherein (i) m is a positive integer and R 12 , R 22 and R 42 in combination contain at least two allyl or vinyl moieties, or (ii) n is a positive integer and R 12 , R 32 and R 42 In combination, the composition for use of any of embodiments 571-692 comprises at least two allyl or vinyl moieties.

[0684] Embodiment 723. A composition for use according to any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition according to embodiment 719 or 720, and the crosslinked amine polymer comprises an amine residue as shown in Table A.

[0685] Embodiment 724. A composition for use according to any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition according to embodiment 719, 720 or 723, and the crosslinked amine polymer is crosslinked with a crosslinker shown in Table B.

[0686] Embodiment 725. The composition of any of the above-listed embodiments, wherein the crosslinked amine polymer is a compound represented by Formula 3: [ka] [In the formula, R 15 , R 16 and R 17 is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid, or halo; X 15 but, [ka] and; X5 is hydrocarbyl, substituted hydrocarbyl, oxo (—O—) or amino; z is a non-negative number] 693. The composition for use according to any of embodiments 571 to 692, comprising a repeating unit corresponding to:

[0687] Embodiment 726. The composition is a pharmaceutical composition according to embodiment 725, wherein R 15 , R 16 and R 17 is independently aliphatic or heteroaliphatic.

[0688] Embodiment 727 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 725 or 726, and X5 is oxo, amino, alkylamino, ether, alkanol or haloalkyl.

[0689] Embodiment 728 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in any of embodiments 693 to 701, and the crosslinked amine polymer is prepared by (i) substitution polymerization of multifunctional reagents, at least one of which contains an amine moiety, (2) radical polymerization of monomers containing at least one amine moiety or nitrogen-containing moiety, or (3) crosslinking of an amine-containing intermediate with a crosslinker, which may optionally contain an amine moiety.

[0690] Embodiment 729 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 728 and the crosslinked amine polymer is a crosslinked homopolymer or crosslinked copolymer.

[0691] Embodiment 730. A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 728, and the crosslinked amine polymer comprises free amine moieties separated by repeating linker units of the same or varying lengths.

[0692] Embodiment 731 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 728 and the crosslinked amine polymer is produced by polymerizing a crosslinker and an amine-containing monomer in a substitution polymerization reaction.

[0693] Embodiment 732. A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 731 and the amine-containing monomer is a linear amine having at least two reactive amine moieties for participating in a substitution polymerization reaction.

[0694] Embodiment 733. The composition is the pharmaceutical composition of embodiment 731 or 732, wherein the amine-containing monomer is 1,3-bis[bis(2-aminoethyl)amino]propane, 3-amino-1-{[2-(bis{2-[bis(3-aminopropyl)amino]ethyl}amino)ethyl](3-aminopropyl)amino}propane, 2-[bis(2-aminoethyl)amino]ethanamine, tris(3-aminopropyl)amine, 1,4-bis[bis(3-aminopropyl)amino]butane, 1,2-ethanediamine, 2-amino-1-(2-aminoethylamino)ethane , 1,2-bis(2-aminoethylamino)ethane, 1,3-propanediamine, 3,3'-diaminodipropylamine, 2,2-dimethyl-1,3-propanediamine, 2-methyl-1,3-propanediamine, N,N'-dimethyl-1,3-propanediamine, N-methyl-1,3-diaminopropane, 3,3'-diamino-N-methyldipropylamine, 1,3-diaminopentane, 1,2-diamino-2-methylpropane, 2-methyl-1,5-diaminopentane, 1,2-diaminopropane, 1,10-diaminodecane, 1,8-diamino Octane, 1,9-diaminooctane, 1,7-diaminoheptane, 1,6-diaminohexane, 1,5-diaminopentane, 3-bromopropylamine hydrobromide, N,2-dimethyl-1,3-propanediamine, N-isopropyl-1,3-diaminopropane, N,N'-bis(2-aminoethyl)-1,3-propanediamine, N,N'-bis(3-aminopropyl)ethylenediamine, N,N'-bis(3-aminopropyl)-1,4-butanediamine tetrahydrochloride, 1,3-diamino-2-propanol, N-ethylethylenediamine diamine, 2,2'-diamino-N-methyldiethylamine, N,N'-diethylethylenediamine, N-isopropylethylenediamine, N-methylethylenediamine, N,N'-di-tert-butylethylenediamine, N,N'-diisopropylethylenediamine, N,N'-dimethylethylenediamine, N-butylethylenediamine, 2-(2-aminoethylamino)ethanol, 1,4,7,10,13,16-hexaazacyclooctadecane, 1,4,7,10-tetraazacyclododecane, 1,4,7-triazacyclononane, N,The composition for use according to any of embodiments 571 to 692, wherein the hydroxybenzoate is N'-bis(2-hydroxyethyl)ethylenediamine, piperazine, bis(hexamethylene)triamine, N-(3-hydroxypropyl)ethylenediamine, N-(2-aminoethyl)piperazine, 2-methylpiperazine, homopiperazine, 1,4,8,11-tetraazacyclotetradecane, 1,4,8,12-tetraazacyclopentadecane, 2-(aminomethyl)piperidine, or 3-(methylamino)pyrrolidino.

[0695] Embodiment 734. The composition is the pharmaceutical composition of any of embodiments 728, 730, 732, and 733, wherein the crosslinker is selected from the group consisting of dihaloalkanes, haloalkyloxiranes, alkyloxirane sulfonates, di(haloalkyl)amines, tri(haloalkyl)amines, diepoxides, triepoxides, tetraepoxides, bis(halomethyl)benzenes, tri(halomethyl)benzenes, tetra(halomethyl)benzenes, epihalohydrins such as epichlorohydrin and epibromohydrin, poly(epichlorohydrin), (iodomethane), methyl ... tyl)oxirane, glycidyl tosylate, glycidyl 3-nitrobenzenesulfonate, 4-tosyloxy-1,2-epoxybutane, bromo-1,2-epoxybutane, 1,2-dibromoethane, 1,3-dichloropropane, 1,2-dichloroethane, l-bromo-2-chloroethane, 1,3-dibromopropane, bis(2-chloroethyl)amine, tris(2-chloroethyl)amine, and bis(2-chloroethyl)methylamine, 1,3-butadiene diepoxide, 1,5-hexadiene diepoxide, diglycidyl ether, 1 ,2,7,8-diepoxyoctane, 1,2,9,10-diepoxydecane, ethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, 1,2-ethanediol diglycidyl ether, glycerol diglycidyl ether, 1,3-diglycidyl glyceryl ether, N,N-diglycidylaniline, neopentyl glycol diglycidyl ether, diethylene glycol diglycidyl ether, 1,4-bis(glycidyloxy)benzene, resorcinol Diglycidyl ether, 1,6-hexanediol diglycidyl ether, trimethylolpropane diglycidyl ether, 1,4-cyclohexanedimethanol diglycidyl ether, 1,3-bis-(2,3-epoxypropyloxy)-2-(2,3-dihydroxypropyloxy)propane, 1,2-cyclohexanedicarboxylic acid diglycidyl ester, 2,2'-bis(glycidyloxy)diphenylmethane, bisphenol F diglycidyl ether, 1,4-bis(2',3'epoxypropyl)perfluoro-n-butane, 2,6-Di(oxiran-2-ylmethyl)-1,2,3,5,6,7-hexahydropyrrolo[3,4-f]isoindole-1,3,5,7-tetraone, Bisphenol A diglycidyl ether, Ethyl 5-hydroxy-6,8-di(oxiran-2-ylmethyl)-4-oxo-4-h-chromene-2-carboxylate, Bis[4-(2,3-epoxy-propylthio)phenyl]-sulfide, 1,3-bis(3-glycidoxypropyl)tetramethyldisiloxane, 9,9-bis[4- (Glycidyloxy)phenyl] fluorine, triepoxy isocyanurate, glycerol triglycidyl ether, N,N-diglycidyl-4-glycidyloxyaniline, isocyanuric acid (S,S,S)-triglycidyl ester, isocyanuric acid (R,R,R)-triglycidyl ester, triglycidyl isocyanurate, trimethylolpropane triglycidyl ether, glycerol propoxylate triglycidyl ether, triphenylolmethane triglycidyl ether, 3, 7,14-tris[[3-(epoxypropoxy)propyl]dimethylsilyloxy]-1,3,5,7,9,11,14-heptacyclopentyltricyclo[7,3,3,15,11]heptasiloxane, 4,4'methylenebis(N,N-diglycidylaniline), bis(halomethyl)benzene, bis(halomethyl)biphenyl and bis(halomethyl)naphthalene, toluene diisocyanate, acrylol chloride, methyl acrylate, ethylene bisacrylamide, dihydropyrrolidone The composition for use according to any of embodiments 571 to 692, wherein the hydroxybenzoate is selected from the group consisting of hydrate, succinyl dichloride, dimethylsuccinate, 3-chloro-1-(3-chloropropylamino-2-propanol, 1,2-bis(3-chloropropylamino)ethane, bis(3-chloropropyl)amine, 1,3-dichloro-2-propanol, 1,3-dichloropropane, 1-chloro-2,3-epoxypropane, tris[(2-oxiranyl)methyl]amine, and combinations thereof.

[0696] Embodiment 735. A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 728 and the preparation of the crosslinked amine polymer comprises radical polymerization of an amine monomer comprising at least one amine moiety or nitrogen-containing moiety.

[0697] Embodiment 736: A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments, and the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 1.5 or less.

[0698] Embodiment 737 A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments and the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 1 or less.

[0699] Embodiment 738. A composition for use according to any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments, and the crosslinked amine polymer has chloride ions to phosphate ions bound in a molar ratio of at least 0.5:1, respectively, in an aqueous simulated small intestinal inorganic buffer ("SIB") at 37°C, buffered to pH 5.5, containing 36 mM NaCl, 20 mM NaH2PO4 and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES).

[0700] Embodiment 739 A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments, and the crosslinked amine polymer has chloride ions to phosphate ions bound in a molar ratio of at least 1:1, respectively, in an aqueous simulated small intestinal inorganic buffer ("SIB") containing 36 mM NaCl, 20 mM NaH2PO4 and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) at 37°C and buffered to pH 5.5.

[0701] Embodiment 740. A composition for use according to any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments, and the crosslinked amine polymer has chloride ions to phosphate ions bound in a molar ratio of at least 2:1, respectively, in an aqueous simulated small intestinal inorganic buffer ("SIB") at 37°C, buffered to pH 5.5, containing 36 mM NaCl, 20 mM NaH2PO4 and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES).

[0702] Embodiment 741 A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments, and the crosslinked amine polymer has a proton binding capacity of at least 10 mmol / g and a chloride ion binding capacity of at least 10 mmol / g in an aqueous simulated gastric fluid buffer ("SGF") containing 35 mM NaCl and 63 mM HCl at pH 1.2, 37°C.

[0703] Embodiment 742 A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments, and the crosslinked amine polymer has an equilibrium proton binding capacity of at least 12 mmol / g and a chloride ion binding capacity of at least 12 mmol / g in an aqueous simulated gastric fluid buffer ("SGF") containing 35 mM NaCl and 63 mM HCl at pH 1.2, 37°C.

[0704] Embodiment 743. A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments, and the crosslinked amine polymer has an equilibrium proton binding capacity of at least 14 mmol / g and a chloride ion binding capacity of at least 14 mmol / g in an aqueous simulated gastric fluid buffer ("SGF") containing 35 mM NaCl and 63 mM HCl at pH 1.2, 37°C.

[0705] Embodiment 744 A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments and the proportion of quaternized amines is less than 40%.

[0706] Embodiment 745 A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments and the proportion of quaternized amines is less than 30%.

[0707] Embodiment 746 A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments and the proportion of quaternized amines is less than 20%.

[0708] Embodiment 747 A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments and the proportion of quaternized amines is less than 10%.

[0709] Embodiment 748. A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments and the proportion of quaternized amines is less than 5%.

[0710] Embodiment 749 A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments and the crosslinked amine polymer is a gel or beads having an average particle size of 40 to 180 μm.

[0711] Embodiment 750 A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments and the crosslinked amine polymer is a gel or beads having an average particle size of 60 to 160 μm.

[0712] Embodiment 751 A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments and the crosslinked amine polymer is a gel or beads having an average particle size of 80 to 140 μm.

[0713] Embodiment 752 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in any of embodiments 749 to 751, and less than about 0.5% by volume of the particles have a diameter of less than about 10 μm.

[0714] Embodiment 753 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in any of embodiments 749 to 751, and less than about 5% by volume of the particles have a diameter of less than about 20 μm.

[0715] Embodiment 754 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in any of embodiments 749 to 751, and less than about 0.5% by volume of the particles have a diameter of less than about 20 μm.

[0716] Embodiment 755 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in any of embodiments 749 to 751, and less than about 5% by volume of the particles have a diameter of less than about 30 μm.

[0717] Embodiment 756 A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments in dosage unit form.

[0718] Embodiment 757 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in embodiment 756 and the dosage unit form is a capsule, tablet or sachet dosage form.

[0719] Embodiment 758 A composition for use described in any of embodiments 571 to 692, wherein the composition is a composition described in any of the above listed embodiments and the pharmaceutical composition comprises a pharmaceutically acceptable carrier, excipient or diluent.

[0720] Embodiment 759. A composition for use according to any of embodiments 571 to 692, which is a method for treating acid-base disorders in animals, including humans, by removing HCl by oral administration of a pharmaceutical composition according to any of the above-listed embodiments.

[0721] Embodiment 760 A composition for use described in any of embodiments 571 to 692, wherein the composition is a treatment method described in embodiment 759 and the acid-base disorder is metabolic acidosis.

[0722] Embodiment 761 A composition for use described in any of embodiments 571 to 692, wherein the composition is a treatment method described in embodiment 759, and the pH is controlled or normalized.

[0723] Embodiment 762 A composition for use described in any of embodiments 571 to 692, wherein the composition is a treatment method described in embodiment 759, and serum bicarbonate is controlled or normalized.

[0724] Embodiment 763 A composition for use described in any of embodiments 571 to 692, wherein the composition is a treatment method described in embodiment 759 and less than 1 g of sodium or potassium is administered per day.

[0725] Embodiment 764 A composition for use described in any of embodiments 571 to 692, wherein the composition is a treatment method described in embodiment 759, and less than 0.5 g of sodium or potassium is administered per day.

[0726] Embodiment 765. A composition for use described in any of embodiments 571 to 692, wherein the composition is a treatment method described in embodiment 759 and less than 0.1 g of sodium or potassium is administered per day.

[0727] Embodiment 766 A composition for use described in any of embodiments 571 to 692, wherein the composition is a treatment method described in embodiment 759 and sodium or potassium is not administered.

[0728] Embodiment 767 A composition for use described in any of embodiments 571 to 692, wherein the composition is a pharmaceutical composition described in any of embodiments 682 to 755, and the dose of the ph...

Claims

1. 1. A method of treating an individual suffering from an acid-base disorder characterized by a baseline serum bicarbonate level of less than 22 mEq / L, the method comprising oral administration of a daily dose of a pharmaceutical composition capable of binding at least 5 mEq of HCl as it passes through the digestive system and achieving a clinically significant increase in serum bicarbonate levels of at least 1 mEq / L from baseline within a treatment period of no more than one month.

2. 1. A method of treating an individual suffering from an acid-base disorder characterized by a baseline serum bicarbonate level of less than 22 mEq / L, the method comprising oral administration of a pharmaceutical composition, wherein the orally administered pharmaceutical composition binds an average of at least 5 mEq / day of HCl in the gastrointestinal system, and wherein the oral administration achieves a clinically significant increase in serum bicarbonate level of at least 1 mEq / L from baseline within a treatment period of not more than one month.

3. 1. A method of increasing serum bicarbonate levels in an individual suffering from an acid-base disorder, the method comprising oral administration of a pharmaceutical composition that increases serum bicarbonate levels in the individual, wherein: (i) the pharmaceutical composition, when orally administered, binds HCl in the digestive system of an individual; and (ii) the pharmaceutical composition increases serum bicarbonate levels by at least 3 mEq / l in a placebo-controlled study, wherein the increase is the difference between the cohort mean serum bicarbonate level in a first cohort at the end of the study compared to the cohort mean serum bicarbonate level in a second cohort at the end of the study, wherein subjects in the first cohort are administered the pharmaceutical composition and subjects in the second cohort are administered a placebo, wherein each of the first and second cohorts includes at least 25 subjects, each cohort is prescribed the same diet throughout the study, and the study lasts at least 2 weeks; method.

4. The method according to any one of claims 1 to 3, wherein the acid-base disorder is metabolic acidosis.

5. The method of any one of claims 1 to 4, wherein the individual has chronic kidney disease.

6. 6. The method of any one of claims 1 to 5, wherein the individual does not already require renal replacement therapy (dialysis or transplant).

7. Individuals should be able to achieve a blood flow rate of at least 15 mL / min / 1.73 m 2 The method of any one of claims 1 to 6, wherein the patient has an mGFR or eGFR of

8. Individuals should be able to achieve a blood flow rate of at least 30 mL / min / 1.73 m 2 The method of any one of claims 1 to 7, wherein the patient has an mGFR or eGFR of

9. If the individual has a blood pressure of 45 mL / min / 1.73 m for at least 3 months 2 The method of any one of claims 1 to 8, wherein the patient has an mGFR or eGFR of less than 100 mg / kg.

10. If the individual has a blood pressure of 60 mL / min / 1.73 m for at least 3 months 2 The method of any one of claims 1 to 9, wherein the patient has an mGFR or eGFR of less than 100 mg / kg.

11. 11. The method or composition of any one of claims 1 to 10, wherein the individual or adult patient has stage 3A CKD, stage 3B CKD or stage 4 CKD.

12. 12. The method of any one of claims 1 to 11, wherein oral administration is at least once a week, at least twice a week, or at least once a day within the treatment period.

13. 13. The method of any one of claims 1 to 12, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of less than 18 mEq / l.

14. 14. The method of any one of claims 1 to 13, wherein the method increases serum bicarbonate levels from a baseline serum bicarbonate level to an increased serum bicarbonate level of at least 22 mEq / l.

15. 15. The method of any one of claims 1 to 14, wherein the clinically significant increase is at least 3 mEq / l.

16. 16. The method of any one of claims 1 to 15, wherein a clinically significant increase is achieved within a treatment period of less than 1 month, 25 days, 3 weeks, 2 weeks, 1 week, or 3 days.

17. 17. The method of any one of claims 1 to 16, wherein the individual's serum bicarbonate level returns to baseline value ±2 mEq / l within 1 month, 3 weeks or 2 weeks of cessation of treatment.

18. 18. The method of any one of claims 1 to 17, wherein the baseline serum bicarbonate value is the average value of at least two serum bicarbonate concentrations for serum samples taken on different days.

19. 19. The method of any one of claims 1 to 18, wherein the daily dose has a capacity to remove at least 7.5 mEq of the target species when passing through the digestive system.

20. 20. The method of any one of claims 1 to 19, wherein the daily dose is less than 100g / day, 30g / day or 10g / day.

21. 21. The method of any one of claims 1 to 20, wherein the individual is treated for at least several months.

22. 22. The method of any one of claims 1 to 21, wherein the pharmaceutical composition comprises a population of crosslinked amine polymer particles having a median particle size (volume distribution) in the range of 10 to 400 μm.

23. 23. The method of any one of claims 1 to 22, wherein the pharmaceutical composition comprises a population of crosslinked amine polymer particles having a swelling ratio of less than 5 or less than 2.

24. 24. The method of any one of claims 1 to 23, wherein the pharmaceutical composition comprises a crosslinked amine polymer having a theoretical binding capacity for HCl in the range of 2 to 25 mEq / g.

25. 25. The method of any one of claims 1 to 24, wherein the pharmaceutical composition comprises a crosslinked amine polymer characterized by a chloride ion binding capacity in a SIB assay of at least 1 mEq / g, 1.5 mEq / g, 2 mEq / g, 2.5 mEq / g, 3 mEq / g, 3.5 mEq / g, 4 mEq / g, 4.5 mEq / g, 5 mEq / g, 5.5 mEq / g or 6 mEq / g.

26. 26. The method of any one of claims 1 to 25, wherein the pharmaceutical composition comprises a crosslinked amine polymer having an amount of bound chloride to bound phosphate ratio in a SIB assay of at least 0.3:1, 0.5:1, or at least 1:1, respectively.

27. 1. The pharmaceutical composition according to claim 1, wherein the compound is a compound of Formula 1: 【Chemical 1】 [In the formula, R 1 , R 2 and R 3 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, with the proviso that R 1 , R 2 and R 3 at least one of which is other than hydrogen.

27. The method of any one of claims 1 to 26, comprising crosslinking an amine polymer comprising an amine residue corresponding to

28. 1. The pharmaceutical composition according to claim 1, wherein the compound is a compound of formula 1a: 【Chemistry 2】 [In the formula, R 4 and R 5 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl.

28. The method of any one of claims 1 to 27, comprising a crosslinked amine polymer comprising an amine residue corresponding to

29. 29. The method of any one of claims 1 to 28, wherein the pharmaceutical composition comprises a crosslinked amine polymer made in two steps, the first step comprising a simultaneous polymerization and crosslinking reaction to produce a preformed crosslinked amine polymer, the crosslinks being predominantly carbon-carbon crosslinks, and in the second step the preformed amine polymer is further crosslinked in a substitution reaction to form a carbon-nitrogen bond.

30. 30. The method of any one of claims 1 to 29, wherein the pharmaceutical composition comprises a crosslinked amine polymer prepared in two steps, (i) the first step comprises a simultaneous polymerization and crosslinking reaction between a monofunctional vinyl, allyl, or acrylamide monomer and a crosslinker having two or more vinyl, allyl, or acrylamide functional groups to produce a preformed crosslinked amine polymer, wherein the crosslinks are predominantly carbon-carbon crosslinks, and (ii) in the second step, the preformed amine polymer is further crosslinked in a substitution reaction to form a carbon-nitrogen bond.

31. 31. The method of any one of claims 1 to 30, wherein the pharmaceutical composition comprises a crosslinked amine polymer prepared in two steps, (i) a first step comprising a simultaneous polymerization and crosslinking reaction between allylamine and diallylpropyldiamine to produce a preformed amine polymer, and (ii) in a second step, the preformed amine polymer is further crosslinked in a substitution reaction with dichloroethane.

32. 1. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a compound of Formula 4: 【Chemistry 3】 wherein each R is independently hydrogen or an ethylene bridge between two nitrogen atoms of the crosslinked amine polymer. 【Chemistry 4】 and a, b, and c are integers.

32. The method of any one of claims 1 to 31, comprising a crosslinked amine polymer comprising a repeat unit corresponding to

33. 1. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a compound of Formula 4: 【Chemistry 5】 wherein each R is independently hydrogen or an ethylene bridge between two nitrogen atoms of the crosslinked amine polymer. 【Chemistry 6】 and the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 5:

1.

33. The method of any one of claims 1 to 32, comprising a crosslinked amine polymer comprising a repeat unit corresponding to

34. 1. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a compound of Formula 4: 【Chemistry 7】 wherein each R is independently hydrogen or an ethylene bridge between two nitrogen atoms of the crosslinked amine polymer. 【Chemistry 8】 and the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 2.1:1 to 2.5:

1.

34. The method of any one of claims 1 to 33, comprising a crosslinked amine polymer comprising a repeat unit corresponding to

35. 1. A composition for use in a method of treating an individual suffering from an acid-base disorder characterized by a baseline serum bicarbonate level of less than 22 mEq / L, the method comprising oral administration of a daily dose of a pharmaceutical composition having the ability to bind at least 5 mEq of HCl as it passes through the digestive system and achieve a clinically significant increase in serum bicarbonate levels of at least 1 mEq / L from baseline within a treatment period of not more than one month.

36. 1. A composition for use in a method of treating an individual suffering from an acid-base disorder characterized by a baseline serum bicarbonate level of less than 22 mEq / L, the method comprising oral administration of a pharmaceutical composition, wherein the orally administered pharmaceutical composition binds an average of at least 5 mEq / day of HCl in the gastrointestinal system, and wherein the oral administration achieves a clinically significant increase in serum bicarbonate level of at least 1 mEq / L from baseline within a treatment period of not more than one month.

37. 1. A composition for use in a method for increasing serum bicarbonate levels in an individual suffering from an acid-base disorder, the method comprising oral administration of a pharmaceutical composition that increases serum bicarbonate levels in the individual, wherein: (i) the pharmaceutical composition, when orally administered, binds HCl in the digestive system of an individual; and (ii) the pharmaceutical composition increases serum bicarbonate levels by at least 3 mEq / l in a placebo-controlled study, wherein the increase is the difference between the cohort mean serum bicarbonate level in a first cohort at the end of the study compared to the cohort mean serum bicarbonate level in a second cohort at the end of the study, wherein subjects in the first cohort are administered the pharmaceutical composition and subjects in the second cohort are administered a placebo, wherein each of the first and second cohorts includes at least 25 subjects, each cohort is prescribed the same diet throughout the study, and the study lasts at least 2 weeks; composition.

38. The composition of any one of claims 35 to 37, wherein the acid-base disorder is metabolic acidosis.

39. The composition of any one of claims 35 to 38, wherein the individual has chronic kidney disease.

40. 40. The composition of any one of claims 35 to 39, wherein the individual does not already require renal replacement therapy (dialysis or transplant).

41. Individuals should be able to achieve a blood flow rate of at least 15 mL / min / 1.73 m 2 The composition of any one of claims 35 to 40, having an mGFR or eGFR of

42. Individuals should be able to achieve a blood flow rate of at least 30 mL / min / 1.73 m 2 The composition of any one of claims 35 to 41, having an mGFR or eGFR of

43. If the individual has a blood pressure of 45 mL / min / 1.73 m for at least 3 months 2 The composition of any one of claims 35 to 42, having an mGFR or eGFR of less than 100 mg / kg.

44. If the individual has a blood pressure of 60 mL / min / 1.73 m for at least 3 months 2 The composition of any one of claims 35 to 43, having an mGFR or eGFR of less than 100 mg / kg.

45. 10. The method or composition of any one of the preceding claims, wherein the individual or adult patient has stage 3A CKD, stage 3B CKD or stage 4 CKD.

46. 46. ​​The composition of any one of claims 35 to 45, wherein oral administration is at least once a week, at least twice a week, or at least once a day within the treatment period.

47. 47. The composition of any one of claims 35 to 46, wherein the acid-base disorder is characterized by a baseline serum bicarbonate level of less than 18 mEq / l.

48. 48. The composition of any one of claims 35 to 47, wherein the method increases serum bicarbonate levels from a baseline serum bicarbonate level to an increased serum bicarbonate level of at least 22 mEq / l.

49. 49. The composition of any one of claims 35 to 48, wherein the clinically significant increase is at least 3 mEq / l.

50. 50. The composition of any one of claims 35-49, wherein a clinically significant increase is achieved within a treatment period of less than 1 month, 25 days, 3 weeks, 2 weeks, 1 week, or 3 days.

51. 51. The composition of any one of claims 35 to 50, wherein the individual's serum bicarbonate level returns to baseline value ±2 mEq / l within one month, three weeks, or two weeks of cessation of treatment.

52. 52. The composition of any one of claims 35 to 51, wherein the baseline serum bicarbonate value is the average value of at least two serum bicarbonate concentrations for serum samples taken on different days.

53. 53. The composition of any one of claims 35 to 52, wherein a daily dose has the capacity to remove at least 7.5 mEq of the target species as it passes through the digestive system.

54. 54. The composition of any one of claims 35 to 53, wherein the daily dose is less than 100g / day, 30g / day or 10g / day.

55. The composition of any one of claims 35 to 54, wherein the individual is treated for at least several months.

56. 56. The composition of any one of claims 35 to 55, wherein the pharmaceutical composition comprises a population of crosslinked amine polymer particles having a median particle size (volume distribution) in the range of 10 to 400 μm.

57. 57. The composition of any one of claims 35 to 56, wherein the pharmaceutical composition comprises a population of crosslinked amine polymer particles having a swelling ratio of less than 5 or less than 2.

58. 58. The composition of any one of claims 35 to 57, wherein the pharmaceutical composition comprises a crosslinked amine polymer having a theoretical binding capacity for HCl in the range of 2 to 25 mEq / g.

59. 59. The composition of any one of claims 35-58, wherein the pharmaceutical composition comprises a crosslinked amine polymer characterized by a chloride ion binding capacity in a SIB assay of at least 1 mEq / g, 1.5 mEq / g, 2 mEq / g, 2.5 mEq / g, 3 mEq / g, 3.5 mEq / g, 4 mEq / g, 4.5 mEq / g, 5 mEq / g, 5.5 mEq / g or 6 mEq / g.

60. 60. The composition of any one of claims 35-59, wherein the pharmaceutical composition comprises a crosslinked amine polymer having an amount of bound chloride to bound phosphate ratio in a SIB assay of at least 0.3:1, 0.5:1, or at least 1:1, respectively.

61. 1. The pharmaceutical composition according to claim 1, wherein the compound is a compound of Formula 1: 【Chemistry 9】 [In the formula, R 1 , R 2 and R 3 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, with the proviso that R 1 , R 2 and R 3 at least one of which is other than hydrogen.

61. The composition of any one of claims 35 to 60, comprising a crosslinked amine polymer comprising an amine residue corresponding to:

62. 1. The pharmaceutical composition according to claim 1, wherein the compound is a compound of formula 1a: 【Chemistry 10】 [In the formula, R 4 and R 5 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl.

62. The composition of any one of claims 35 to 61, comprising a crosslinked amine polymer comprising an amine residue corresponding to:

63. 63. The pharmaceutical composition of any one of claims 35-62, wherein the pharmaceutical composition comprises a crosslinked amine polymer made in two steps, the first step comprising a simultaneous polymerization and crosslinking reaction to produce a preformed crosslinked amine polymer, the crosslinks being predominantly carbon-carbon crosslinks, and in the second step the preformed amine polymer is further crosslinked in a substitution reaction to form carbon-nitrogen bonds.

64. 64. The pharmaceutical composition of any one of claims 35-63, wherein the pharmaceutical composition comprises a crosslinked amine polymer prepared in two steps, (i) the first step comprises a simultaneous polymerization and crosslinking reaction between a monofunctional vinyl, allyl, or acrylamide monomer and a crosslinker having two or more vinyl, allyl, or acrylamide functional groups to produce a preformed crosslinked amine polymer, wherein the crosslinks are predominantly carbon-carbon crosslinks, and (ii) in the second step, the preformed amine polymer is further crosslinked in a substitution reaction to form a carbon-nitrogen bond.

65. 65. The composition of any one of claims 35-64, wherein the pharmaceutical composition comprises a crosslinked amine polymer made in two steps, (i) the first step comprises a simultaneous polymerization and crosslinking reaction between allylamine and diallylpropyldiamine to produce a preformed amine polymer, and (ii) in the second step, the preformed amine polymer is further crosslinked in a substitution reaction with dichloroethane.

66. 1. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a compound of Formula 4: 【Chemistry 11】 wherein each R is independently hydrogen or an ethylene bridge between two nitrogen atoms of the crosslinked amine polymer. 【Chemistry 12】 and a, b, and c are integers.

66. The composition of any one of claims 35 to 65, comprising a crosslinked amine polymer comprising a repeat unit corresponding to:

67. 1. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a compound of Formula 4: 【Chemistry 13】 wherein each R is independently hydrogen or an ethylene bridge between two nitrogen atoms of the crosslinked amine polymer. 【Chemistry 14】 and the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 5:

1.

67. The composition of any one of claims 35 to 66, comprising a crosslinked amine polymer comprising a repeat unit corresponding to:

68. 67. The composition of claim 65 or 66, wherein the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1.5:1 to 4:

1.

69. 67. The composition of claim 65 or 66, wherein the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1.75:1 to 3:

1.

70. 67. The composition of claim 65 or 66, wherein the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 2:1 to 2.5:

1.

71. 70. The composition of any one of claims 65 to 69, wherein the polymer has a carbon to nitrogen ratio of from 2.5:1 to 5:

1.

72. 70. The composition of any one of claims 65 to 69, wherein the polymer has a carbon to nitrogen ratio of from 3:1 to 4:

1.

73. 70. The composition of any one of claims 65 to 69, wherein the polymer has a carbon to nitrogen ratio of from 3:5:1 to 3.9:

1.

74. 70. The composition of any one of claims 65 to 69, wherein the polymer has a carbon to nitrogen ratio of from 3:7:1 to 3.9:

1.

75. 74. The composition of any one of claims 65-73, wherein 35-95% of the R substituents are hydrogen and 5-65% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

76. 74. The composition of any one of claims 65-73, wherein 50-95% of the R substituents are hydrogen and 5-50% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

77. 74. The composition of any one of claims 65-73, wherein 55-85% of the R substituents are hydrogen and 15-45% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

78. 74. The composition of any one of claims 65-73, wherein 55-90% of the R substituents are hydrogen and 10-45% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

79. 74. The composition of any one of claims 65-73, wherein 60-90% of the R substituents are hydrogen and 10-40% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

80. 74. The composition of any one of claims 65-73, wherein 65-90% of the R substituents are hydrogen and 10-35% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

81. 74. The composition of any one of claims 65-73, wherein 70-90% of the R substituents are hydrogen and 10-30% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

82. 74. The composition of any one of claims 65-73, wherein 75-85% of the R substituents are hydrogen and 15-25% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

83. 74. The composition of any one of claims 65-73, wherein 80-85% of the R substituents are hydrogen and 15-20% are ethylene bridges between two nitrogens of the crosslinked amine polymer.

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