TW202002955A - Method of treating ACID-BASE DISORDERS - Google Patents

Abstract

The present disclosure provides,inter alia , pharmaceutical compositions for and methods of treating an animal, including a human, and methods of preparing such compositions. In certain embodiments, the pharmaceutical compositions contain nonabsorbable compositions and may be used, for example, to treat diseases or other metabolic conditions in which removal of protons, the conjugate base of a strong acid and/or a strong acid from the gastrointestinal tract would provide physiological benefits such as normalizing serum bicarbonate concentrations and the blood pH in an animal, including a human. In certain embodiments, compositions for and methods of improving the quality of life and/or physical function score of such patients are also provided. In certain embodiments, compositions for and methods of slowing the progression of kidney disease in such patients are also provided.

Description

Treatment of acid-base disorders (ACID-BASE　DISORDERS)

The present invention generally relates to methods of treating acid-base disorders, which can be used, for example, to treat metabolic acidosis.

Metabolic acidosis to produce non-volatile acid which will result in the accumulation of metabolic condition of the body and food processes, resulting in a net increase of protons (H ⁺⁾ or loss of bicarbonate (HCO ₃ ^-) in various disease states. Metabolic acidosis occurs when the body accumulates acids from metabolism and dietary processes and cannot completely remove excess acid from the body by the kidneys. Since the filter can not be recovered bicarbonate (HCO ₃ ^-) secretion ability of the kidney hydrogen ions, ammonia (ammonia-effect) and titratable acid secretion caused by the fall, so chronic kidney disease is usually accompanied by metabolic acidosis. The clinical practice guidelines recommend starting alkaline therapy to prevent or treat complications of metabolic acidosis when the serum bicarbonate content of patients with nondialysis-dependent chronic kidney disease (CKD) is <22 mEq/L. (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, increased bone disease, increased muscle degradation, 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 HA, Mitch WE, 1998, Catabolism in uremia: the impact of metabolic acidosis, J. Am. Soc. Nephrol. 9: S78-81; Ballmer, PE, McNurlan, MA, Hulter, HN et al., 1995 , Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans, J. Clin. Invest. 95: 39-45; Farwell, WR, Taylor, EN, 2010, Serum anion gap, bicarbonate and biomarkers of inflammation in healthy individuals in a national survey, CMAJ 182:137-141). When the glomerular filtration rate is estimated to be less than 30 mL/min/1.73m ² , significant metabolic acidosis is present in a large proportion of patients. (KDOQI Skeleton Guiding Principles: American Journal of Kidney Diseases (2003) 42: S1-S201. (Supplement); 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: from the chronic renal insufficiency group (the chronic renal insufficiency group) insufficiency cohort; CRIC) research report. 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).

Regardless of the cause, metabolic acidosis lowers the extracellular fluid bicarbonate and therefore the extracellular pH. The relationship between serum pH and serum bicarbonate is described by the Henderson-Hasselbalch equation. pH = pK '+ log [HCO 3 -] / [(0.03XP a CO 2)] where 0.03 is the coefficient CO of physical soluble _2, [HCO ₃ ^-] and P _a CO ₂ concentration for each of bicarbonates and The partial pressure of carbon dioxide.

There are several laboratory tests that can be used to define metabolic acidosis. The basis of the test to measure a variety of biological samples (including blood vein or artery) of bicarbonate (HCO ₃ ^-) or a proton (H ⁺⁾ concentration. These tests can be by enzymatic methods, or by ion selective electrode to measure the blood gas analysis by bicarbonate (HCO ₃ ^-) or a proton (H ⁺⁾ concentration. In both enzymatic and ion selective electrode methods, bicarbonate is "measured." Using blood gas analysis, the bicarbonate content can be calculated using the Henderson-Hasselbalch equation.

Arterial blood gas (ABG) analysis is usually performed for clinical evaluation, but this procedure has certain limitations in the reduced form of patient acceptance. This is due to pain procedures and potential causes of complications such as arterial injury, terminal ischemia Thrombosis, bleeding, aneurysm formation, intermediate nerve damage, and reflex sympathetic dystrophy. Venous blood gas (VBG) analysis is a relatively safe procedure because it requires fewer punctures and thus reduces the risk of needle injuries to health care workers. Therefore, as stated below, when the present invention needs to assess metabolic acidosis, it is preferable to complete this assessment using VBG analysis. Where possible, for example, to measure blood or serum bicarbonate content, any measurement specified herein is preferably achieved by VBG analysis.

Acidosis for determining the most effective measure is dependent on the measurement of intravenous plasma bicarbonate (or total carbon dioxide [tCO _2]), or arterial plasma bicarbonate (or total carbon dioxide [tCO _2]), serum electrolytes Cl ^-, K ⁺ and Na ⁺ , and determine the anion gap. In clinical laboratories, measuring venous plasma or serum electrolytes includes estimating tCO ₂ . This measurement reflects the total CO ₂ of the cycle [i.e. by bicarbonate (HCO ₃ ^-) represents the carbonate, (H ₂ CO ₃₎ and dissolved CO ₂ (0.03 × PCO ₂₎ Total CO _2]. By using a simplified and standardized form of the Henderson - Hassell Barr He tCO ₂ and also make the equation HCO ₃ ^{- _{related: tCO 2 = HCO 3 - +0.03}} PCO 2, PCO ₂ which is measured by the amount of CO ₂ Partial pressure. Since HCO ₃ ^- concentration of greater than 90% of tCO _2, a small amount of H ₂ CO _3, thus vein tCO ₂ then typically used as the venous blood and the presence of HCO ₃ ^- concentration reasonable approximation. In particular words, during chronic kidney disease, <22 mEq / L of abnormal plasma HCO ₃ ^- value generally indicates metabolic acidosis.

Changes in serum Cl ^- concentrations can provide additional insights into possible acid-base disorders, especially when they are asymmetric to changes in serum Na ⁺ concentrations. When this occurs, changes in serum Cl ^- concentration are usually associated with reciprocal changes in serum bicarbonate. Therefore, in metabolic acidosis with a standard anion gap, an increase in serum Cl ^- > 105 mEq/L is accompanied by a decrease in serum bicarbonate <22 mEq/L.

Calculation of the anion gap [defined as serum ^{Na + - (Cl - + HCO} 3 -)] is an important aspect poisoning diagnosis of metabolic acidosis. Metabolic acidosis may have a normal or elevated anion gap. However, regardless of changes in serum HCO ₃ ^- , an elevated anion gap usually indicates the presence of metabolic acidosis. Anion gaps greater than 20 mEq/L (standard anion gaps of 8 to 12 mEq/L) are typical characteristics of metabolic acidosis.

Arterial blood gas content is used to identify the type of acid-base disorders and to determine whether there is mixed disorder. In general, the results of arterial blood gas measurement should be combined with medical history, physical tests and routine laboratory data listed above. Arterial blood gas measurement measures arterial carbon dioxide tension (P _a CO ₂ ), acidity (pH) and oxygen tension (P _a O ₂ ). The calculated HCO ₃ pH and P _a CO ₂ ^- concentration. The flag is metabolic acidosis _{pH <7.35, P a CO 2} <35 mm Hg and ^{_{HCO 3 - <22 mEq / L}} . P _a O ₂ value (standard 80-95 mmHg) is not used to make a diagnosis of metabolic acidosis but can help determine the cause. The first category of acid-base disorders is respiration or metabolism. Respiratory disorders are caused by the elimination of abnormal lungs of CO ₂ , the production of extracellular fluid containing excess CO ₂ (carbon dioxide) (acidosis) or lack of CO ₂ (carbon dioxide) (alkaline poisoning). Respiratory acid - alkaline conditions, the serum bicarbonate (HCO ₃ ^-) is the initial change induced HCO ₃ ^- increase in PCO ₂ having the greater the increase in PCO ₂ change in a direct consequence. (Adrogue HJ, Madias NE, 2003, Respiratory acidosis, respiratory alkalosis, and mixed disorders, in Johnson RJ, Feehally J (eds): Comprehensive Clinical Nephrology. London, CV Mosby, pages 167-182). Metabolic disorders are caused by excessive intake of extracellular fluids containing non-volatile acids or bases or metabolic production or loss of extracellular fluids containing non-volatile acids or bases. From the blood of bicarbonate anion (HCO ₃ ^-) concentration of such variations reflect the change, in this case, the adaptation involving buffer (immediately), respiratory (hours to days) and renal (days) two mechanisms By. (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, pages 189-206) .

(PCO₂ /[HCO₃ ^- ])The total hydrogen ion concentration in the blood of the two quantities: Serum HCO ₃ ^- content is limited (regulated by the kidneys) and the content of PCO ₂ (adjusted by the lungs), and the ratio is expressed as follows: [H ^+]

^{_{(PCO 2 / [HCO 3 -}} ])

(Clinical practice guidelines for nutrition in chronic renal failure. K/DOQI, National Kidney Foundation. Am. J. Kidney Dis. 2000; 35:S1-140)。使用此平衡等式，損失一個HCO₃ ^- 等於增加一個H⁺ 且相反地，增加一個HCO₃ ^- 等於損失一個H⁺ 。因此，可藉由增加血清HCO₃ ^- 或等效地藉由減小血清H⁺ 來修正血液pH之變化，特定言之H⁺ 之增加(降低pH，酸中毒)。After the total hydrogen ion concentration increases, the main extracellular buffer is the bicarbonate salt. The standard blood pH is between 7.38 and 7.42, corresponding to a hydrogen ion (H ⁺ ) concentration of 42 to 38 nmol/L (Goldberg M: Approach to Acid-Base Disorders. 2005. In Greenberg A, Cheung AK (ed.) Primer on Kidney Diseases, National Kidney Foundation, Philadelphia, Elsevier-Saunders, pages 104-109). Bicarbonate (HCO ₃ ^-) is the anion for buffering against pH disorder of the body, and a standard range of plasma levels of bicarbonate within 22-26 mEq / L range (Szerlip HM: Metabolic Acidosis, 2005 , in Greenberg A, Cheung AK (ed.) Primer on Kidney Diseases, National Kidney Foundation, Philadelphia, Elsevier-Saunders, pages 74-89). Acidosis resulting in reduced blood pH (acidosis) and reflects the cumulative hydrogen ions (H ⁺⁾ and by the process of the bicarbonate ion (HCO ₃ ^-) so that the subsequent decrease bicarbonate buffered serum. Metabolic acidosis can be expressed as follows:

(Clinical practice guidelines for nutrition in chronic renal failure. K/DOQI, National Kidney Foundation. Am. J. Kidney Dis. 2000; 35:S1-140). Using this equilibrium equation, a loss of HCO ₃ ^- is equal to an increase of H ⁺ and, conversely, an increase of HCO ₃ ^- is equal to a loss of H ⁺ . Therefore, changes in blood pH can be corrected by increasing serum HCO ₃ ^- or equivalently by decreasing serum H ⁺ , specifically the increase in H ⁺ (lowering pH, acidosis).

In order to maintain the extracellular pH within the normal range, the body must secrete daily production of acid. Acid production in the body is produced by the metabolism of dietary carbohydrates, fats and amino acids. The complete oxidation of these metabolic substrates produces water and CO ₂ . The carbon dioxide produced by this oxidation (about 20,000 millimoles per day (mmol/day)) is exhaled efficiently through the lungs and represents the volatile acid component of the acid-base balance.

In contrast, non-volatile acids (about 50-100 meq/day) are produced by the metabolism of amino acids and nucleic acids containing sulfuric acid and phosphoric acid. Additional non-volatile acids (lactic acid, butyric acid, acetic acid, other organic acids) are derived from incomplete oxidation of fats and carbohydrates, and from carbohydrate metabolism in the colon, where bacteria residing in the colon lumen will be affected Converted to smaller organic acids that are subsequently absorbed into the bloodstream. The effect of short-chain fatty acids on acidosis is slightly minimized by assimilation (for example) to long-chain fatty acids, or by metabolism into water and CO ₂ .

The kidneys maintain pH balance in the blood through two mechanisms: recovery of filtered HCO ₃ ^- to prevent total bicarbonate consumption and eliminate non-volatile acids in urine. Two mechanisms are necessary to prevent bicarbonate consumption and acidosis.

In the first mechanism, the kidney recovers HCO ₃ ^- filtered by the glomeruli. This recovery occurs in the proximal tubule and comprises about 4500 meq / day of a recycled HCO ₃ ^-. This mechanism prevents HCO ₃ ^- loss thus prevent metabolic acidosis in the urine. In the second mechanism, the kidney removes enough H ⁺ to equal the daily non-volatile acid produced through the metabolism and oxidation of protein, fat, and carbohydrate. The elimination of this acid load is achieved by two unique pathways in the kidney, including the active secretion of H ⁺ ions and ammonia production. The net result of these two interconnected processes is to offset 50-100 meq/day of non-volatile acids produced by standard metabolism.

Therefore, normal kidney function is required to maintain acid-base balance. During chronic kidney disease, HCO ₃ ^- and recovered by filtration line with the production of ammonia and secretion weakened. These defects quickly cause chronic metabolic acidosis, which itself is a powerful sign of end-stage renal disease. With the continued generation of acid from the metabolism, reduced to eliminate the imbalance of the acid H ⁺ / HCO ₃ ^- equilibrium such that normal blood pH drops below pH = 7.38-7.42.

The treatment of metabolic acidosis by alkaline therapy usually indicates raising and maintaining plasma pH above 7.20. Acidic sodium carbonate (NaHCO ₃ ) is the reagent most commonly used to correct metabolic acidosis. Can be administered intravenously with NaHCO ₃ to properly elevated serum HCO ₃ ^- content will increase the pH to greater than 7.20. Further correction depends on individual circumstances and may not indicate whether the following procedure is treatable or the patient is asymptomatic. This is especially true in certain forms of metabolic acidosis. For example, (AG) in a high anion gap acidosis caused by the accumulation of organic acids, and ketones of the acid, the anionic eventually metabolized to homologous HCO ₃ ^-. When treating the underlying condition, the serum pH is corrected; therefore, care must be taken to prevent an increase in bicarbonate above the normal range (>26 mEq/L) when alkali is provided to these patients to increase the pH significantly above 7.20.

Citrate is alkaline therapy to be given orally or intravenously (IV) as a potassium or sodium salt because it is metabolized by the liver and causes each molar citrate to form trimole bicarbonate. In the presence of kidney damage, intravenously administered potassium citrate should be used carefully and monitored closely to avoid hyperkalemia.

If the metabolic acidosis is severe or if it is unlikely to be corrected without the administration of non-virgin alkali, an acidic sodium carbonate (NaHCO ₃ ) solution may be administered intravenously. In people with chronic metabolic acidosis, oral alkali administration is the preferred treatment route. For oral treatment of the most common forms of the base include lozenges NaHCO _3, 1 g NaHCO ₃ which is equal to 11.9 mEq HCO ₃ ^-. However, the oral form of NaHCO _{3 is} not approved for medical use and the instructions for the intravenous sodium bicarbonate solution include the following contraindications, warnings and precautions (for the Hospira mark of NDC 0409-3486-16): Contraindications : Bicarbonate Sodium injection USP is contraindicated in patients who lose chlorine by vomiting or continuous gastrointestinal aspiration and in patients who receive diuretics known to produce hypochloremic alkalosis. Warning : Patients with congestive heart failure, severe renal insufficiency, and patients in clinical conditions with sodium-retaining edema should be used with caution, if any. In patients with impaired renal function, administration of a solution containing sodium ions can produce sodium retention. Intravenous administration of these solutions can lead to excess fluid and/or solute, resulting in dilution of serum electrolyte concentration, excessive water, congestion, or pulmonary edema. Note : […] Potentially large amounts of sodium given by bicarbonate require the use of sodium bicarbonate in patients with congestive heart failure or edema or sodium retention and in patients with anemia or anuria Must be cautious.

Acid-base disorders are common in patients with chronic kidney disease and heart failure. Chronic kidney disease (CKD) gradually damages the renal secretion with hydrogen ions of about 1 mmol/kg body weight produced in healthy adults (Yaqoob, MM. 2010, Acidosis and progression of chronic kidney disease, Curr. Opin. Nephrol. Hyperten. 19:489-492). By the in vivo accumulation of acid (H ⁺⁾ or base (HCO ₃ ^-) absence of metabolic acidosis caused by poisoning of a patient suffering from a common complication of CKD, the glomerular filtration rate (GFR, renal function of the amount of the measured value of the particular words in ) When it drops below 30 mL/min/1.73m ² . Metabolic acidosis has far-reaching long-term effects on protein and muscle metabolism, bone turnover, and renal bone dystrophy. In addition, metabolic acidosis affects various 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.). Due to hormone and cell abnormalities, the net effects of persistent metabolic acidosis in CKD patients are loss of bone and muscle mass, negative nitrogen balance, and acceleration of 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, potential problems with alkali therapy in patients with CKD include the expansion of extracellular fluid volume associated with sodium uptake, resulting in the generation or worsening of hypertension, the promotion of vascular calcification, and the current decompensation of heart failure. Since filtered bicarbonate cannot be recovered and protons and ammonium cations are secreted, patients with CKD of moderate level (GFR at 20-25% normal) first produce perchloric acid poisoning with a normal anion gap. As it progresses towards late CKD, the anion gap increases, reflecting that the kidney's ability to secrete anions associated with non-secreted protons continues to deteriorate. The serum bicarbonate in these patients rarely changes below 15 mmol/L with a maximum anion gap of approximately 20 mmol/L. The non-metabolizable anions accumulated in CKD are buffered by alkali salts from bones (Lemann J Jr, Bushinsky DA, Hamm LL Bone buffering of acid and base in humans. Am. J. Physiol Renal Physiol. November 2003, 285(5):F811-32).

Most patients with chronic kidney disease suffer from latent diabetes (diabetic nephropathy) and hypertension, which degrades kidney function. In almost all patients with high blood pressure, higher sodium intake will make high blood pressure worse. Therefore, kidney, heart failure, diabetes and hypertension guidelines strictly limit the sodium intake of these patients to less than 1.5 g or 65 mEq/day (HFSA 2010 guidelines, Lindenfeld 2010, J Cardiac Failure V16 No 6 P475). Chronic antihypertensive therapy often induces sodium secretion (diuretics) or regulates the kidney's ability to secrete sodium and water (such as (for example) the renin angiotensin aldosterone system inhibits "RAASi" drugs). However, as renal function deteriorates, diuretics become less effective because the tubules cannot react. RAASi drugs induce life-threatening hyperkalemia when inhibiting renal potassium secretion. In view of the additional sodium load, it is not a reasonable practice to treat patients with metabolic acidosis for a long time by often exceeding the total daily recommended sodium intake of sodium-containing alkali. Therefore, in these patients with diabetic nephropathy, oral sodium bicarbonate is usually not prescribed for a long time. Because patients with CKD cannot easily secrete potassium, potassium bicarbonate is not acceptable and causes severe hyperkalemia.

Despite these shortcomings, the effect of oral sodium bicarbonate has been studied in a smaller subgroup of non-hypertensive CKD patients. As part of the Kidney Research National Dialogue, alkali therapy has been identified as having the potential to slow the progression of CKD and correct metabolic acidosis. The age-related decline in glomerular filtration rate (GFR) after 40 years of age is 0.75-1.0 ml/min/1.73m ^{2 in} normal individuals. In CKD patients with rapid progression, a steeper decline of> 4 ml/min/1.73m ² can be seen each year. Glomerular filtration rate or estimated glomerular filtration rate is usually used to characterize renal function and the stage of chronic kidney disease. The five stages of chronic kidney disease and the GFR of each stage are as follows: Stage 1: with normal or higher 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 ) Phase 5: Final CKD (GFR <15 mL/min/1.73 m ² ).

In a final result study, De Brito-Ashurst et al. demonstrated that bicarbonate supplements maintain 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). The study randomly designated 134 adult patients with CKD (creatinine clearance [CrCl] 15 to 30 ml/min/1.73 m ² ) and serum bicarbonate 16 to 20 mmol/L supplemented with oral sodium bicarbonate or standard care for 2 years. The average dose of bicarbonate in this study was 1.82 g/day, which provided 22 mEq bicarbonate per day. The primary endpoint was the rate of decline in CrCl, with rapid decline in CrCl ^{(> 3ml / min / 1.73m 2} / yr) and end stage renal disease ( "ESRD") (CrCl <10 ml / min ) the proportion of patients. Compared with the control group, CrCl with bicarbonate supplementation decreased more slowly (a decrease of 1.88 ml/min/1.73 m ² in patients receiving bicarbonate compared to a decrease of 5.93 ml/min/1.73 m ^{2 in} the control group ; P <0.0001). Patients who were supplemented with 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 supplemented with bicarbonate produced ESRD (6.5% vs 33%; relative risk 0.13; 95% confidence interval 0.04 to 0.40; P<0.001).

Hyperphosphatemia is a common co-morbidity in patients with CKD, specifically patients with advanced or end stage renal disease. Sevelamer hydrochloride is a commonly used ion exchange resin to reduce serum phosphoric acid concentration. However, the reported disadvantages of this reagent include metabolic acidosis apparently caused by the net absorption of HCl during the binding of phosphoric acid in the small intestine. Several studies in patients with CKD and hyperphosphatemia who have undergone hemodialysis or peritoneal dialysis have found that by using sevelamer hydrochloride, the serum bicarbonate concentration is reduced (Brezina, 2004 Kidney Int. V66 S90 (2004) S39-S45; Fan, 2009 Nephrol Dial Transplant (2009) 24:3794).

Among the various aspects of the invention, the following is an effective guide for a method for treating metabolic acidosis (not wishing to be bound by theory). When the H ⁺ pump is pumped into the stomach, HCO ₃ ^- enters the systemic circulation and raises the serum bicarbonate concentration. The initial combination of gastric H ⁺ with a non-absorbent composition as described herein causes HCO ₃ ^-to enter the systemic circulation and increase the serum bicarbonate concentration. The more H ⁺ combined, the greater the systemic HCO ₃ ^- increase. Cl ^- binding composition of the non-absorbent to prevent lumen in Cl ^- and HCO ₃ ^- The subsequent exchanges, which will counteract HCO ₃ ^- the initial rise. The clinical condition similar to the administration of the composition is vomiting. As with vomiting, administration of the composition substantially causes loss of gastric HCl. If a person vomits, he loses stomach HCl and has an increase in serum bicarbonate. Sustained increase in serum bicarbonate, as long as it does not give a large number of oral Cl ^-, for example, NaCl, which will allow the gut in Cl ^- and HCO ₃ ^- and subsequent exchange of serum bicarbonate concentration increased dissipation. The invention is not limited by these requirements, and instead it is fully described below.

Among the various aspects of the present invention, a method of treating individuals suffering from chronic acid/alkaline disorders characterized by a baseline serum bicarbonate value of less than 22 mEq/l may be noted. The method comprises orally administering a pharmaceutical composition comprising a non-absorbable composition having a target species as it passes through the digestive system and increasing the individual's serum bicarbonate value to at least 24 mEq/l but With a capacity of less than 30 mEq/l, the target species is selected from the group consisting of protons, conjugate bases of strong acids, and strong acids.

Among the various aspects of the present invention, a method of treating individuals suffering from chronic acid/alkaline disorders characterized by a baseline serum bicarbonate value of less than 22 mEq/l may be noted. The method comprises orally administering a pharmaceutical composition comprising a non-absorbable composition having a target species as it passes through the digestive system and increasing the individual's serum bicarbonate value to at least 24 mEq/l but With a capacity not exceeding 29 mEq/l, the target species is selected from the group consisting of protons, conjugate bases of strong acids, and strong acids.

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 value of less than 22 mEq/l, the method comprising orally administering a daily dose of a pharmaceutical composition , The pharmaceutical composition has a removal target of at least 5 meq as it passes through the digestive system within a treatment period of not more than 1 month to increase the individual’s serum bicarbonate value from baseline to at least 24 mEq/l but not more than 29 mEq/l capability. The target species is selected from the group consisting of protons, strong acids and conjugate bases of strong acids.

Another aspect of the present disclosure is a composition for a method for treating metabolic acidosis in an adult patient, which method is by taking the patient's serum within 15 days of treatment (ie, within 15 days of treatment) The bicarbonate value increases by at least 1 mEq/L, and the composition is a non-absorbent composition having the ability to remove protons from the patient. In this aspect, the composition can be administered orally, and thus will be a non-absorbent composition that is orally administered as defined herein.

In certain embodiments, the non-absorbent composition administered orally contains cations (such as Na ⁺ , K ⁺ , Mg ²⁺ , Ca ²⁺ Li ^+, or a combination thereof), and the cations in the non-absorbent composition It exchanges with protons through the digestive system, and then secretes the protons and the non-absorbable composition itself during bowel movements. The net effect is a decrease in protons in the body, adding one or more cations in exchange. In this embodiment, the pharmaceutical composition may optionally include a pharmaceutically acceptable carrier, diluent, or excipient or combination thereof that does not significantly interfere with the proton binding characteristics of the non-absorbent composition in vivo. Optionally, the pharmaceutical composition may also contain additional therapeutic agents.

In certain embodiments, the non-absorbent composition for oral administration contains anions that are interchangeable with chloride ions, and if the non-absorbent composition for oral administration contains anions that are more specific than the removed base (eg, Cl ^-, HSO ₄ ^-, or SO ₄ ^2-) stronger bases (e.g., OH ^-), the net effect of the strong acid is removed from the body (e.g., HCl or H ₂ SO ₄₎ and exchanged for a weak acid (e.g., H ₂ O). In this embodiment, the pharmaceutical composition may optionally include a pharmaceutically acceptable carrier, diluent, or excipient or combination thereof that does not significantly interfere with the chlorine binding characteristics of the non-absorbent composition in vivo. Optionally, the pharmaceutical composition may also contain additional therapeutic agents.

In certain embodiments, the non-absorbent composition for oral administration is a neutral combination with the ability to bind a strong acid (such as HCl or H ₂ SO ₄ ) and remove the strong acid itself upon oral administration Thing. The non-absorbent composition may (but not necessarily) introduce (ie, by ion exchange) counterbalance cations or anions during acid removal. The binding, which may include the hydrogen bonding which interactions and ionic interactions and other ^- in this embodiment, the surface of the host material via advantageously can be realized of two ionic species HCl (H ⁺ and Cl). The recombination of HCl can occur in dehydrated functional groups and occurs when administered in an acidic aqueous medium, producing hydrochloride salts of functional groups.

Among the various aspects of the present invention, a method of treating individuals suffering from chronic acid/alkaline disorders may be additionally noted. The method includes oral administration of a pharmaceutical composition containing a non-absorbable composition, the Its ability to bind protons and chloride ions as it passes through the digestive system and remove the bound protons and chloride ions from the individual's digestive system via defecation. In each of these embodiments, the pharmaceutical composition may optionally include a pharmaceutically acceptable carrier, diluent, or excipient that does not significantly interfere with the chlorine binding characteristics of the non-absorbent composition in vivo Agents or combinations thereof. Optionally, the pharmaceutical composition may also contain additional therapeutic agents.

In one embodiment, any of the methods of treating an individual suffering from an acid-base disorder disclosed in this application includes: i) an individual with a diet regimen, or ii) the method includes, specifies, prescribes or recommends a diet Program. In one embodiment, the meal plan is an alkaline meal plan. In one embodiment, the meal plan is a conventional lower protein meal plan (<0.6 g/kg/day). In one embodiment, the dietary regimen is a very low protein dietary regimen (0.3-0.4 g/kg/day). In one embodiment, the meal plan is a vegetarian meal plan. In one embodiment, the meal plan is a vegetarian plan (keto meal plan) supplemented with essential amino acids or a mixture of essential amino acids and nitrogen-free ketone analogs. In one embodiment, the dietary regimen is a vegetarian very low protein diet supplemented with ketone analogs. In one embodiment, the meal plan is a vegetarian meal plan. In one embodiment, the meal plan is a casein meal plan. In one embodiment, the meal plan is an adenine-containing meal plan. In one embodiment, the dietary regimen includes one or more alkali-producing vegetables (eg, carrots, broccoli, eggplant, lettuce, potatoes, spinach, tomatoes, or zucchini, or combinations thereof). In one embodiment, the dietary regimen includes one or more alkali-producing fruits (eg, apple, apricot, orange, peach, pear, raisin, or strawberry, or a combination thereof). In one embodiment, the meal plan does not include sour-producing meat.

In one embodiment, the meal is started one year before the non-absorbent composition is administered. In another embodiment, the meal begins six months before administration of the non-absorbent composition. In one embodiment, the meal is started one month before the non-absorbent composition is administered. In another embodiment, the meal regimen is started when the non-absorbent composition is started. In one embodiment, the meal is started one month after administration of the non-absorbent composition. In another embodiment, the meal is started six months after administration of the non-absorbent composition. In one embodiment, the meal is started one year after administration of the non-absorbent composition.

In each aspect of the invention, a method of improving the quality of life of patients suffering from chronic kidney disease and acid-base disorders may be noted, which is characterized by a baseline serum bicarbonate value ≤22 mEq/L. The method includes oral administration of a pharmaceutical composition capable of increasing the patient's serum bicarbonate and maintaining above 20 mEq/L for a period of at least twelve weeks, the pharmaceutical composition being capable of combining with a group selected from the group consisting of Target species: protons, strong acids and strong acid conjugate bases.

In another embodiment, a method for improving the quality of life of patients suffering from chronic kidney disease and acid-base disorders is provided. This method includes oral administration of a pharmaceutical composition having: (a) the ability to selectively bind to a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; And (b) target species with a binding capacity of at least 3 mEq/g in the simulated small intestine inorganic buffer (SIB) analysis; where, as assessed by the quality of life (QoL) questionnaire, at least twelve weeks compared to the placebo control group The improvement in quality of life over time is statistically significant.

Another embodiment provides a method of improving the quality of life of patients suffering from chronic kidney disease and acid-base disorders, wherein the patient has a baseline serum bicarbonate value of ≤22 mEq/L. This method involves once daily orally administering an effective amount of TRC101 to the patient for a period of time sufficient to statistically significantly improve the patient's quality of life compared to the placebo control group.

Another embodiment provides a method of improving the quality of life of patients suffering from metabolic acidosis disease. This method involves administering a daily dose of non-absorbable crosslinked amine polymer to the patient, where the daily dose: (a) is sufficient to increase the patient’s serum bicarbonate concentration by at least 1 mEq/L; (b) within at least twelve weeks A maintenance serum bicarbonate increase of at least 1 mEq/L was generated during the period; and (c) during this period, it was sufficient to improve the patient's quality of life compared to the placebo control group, where the improvement in quality of life was statistically significant .

Another embodiment provides a pharmaceutical composition for improving the quality of life of a human patient suffering from chronic kidney disease and acid-base disorders, the patient having a baseline serum bicarbonate content of ≤22 mEq/L before treatment. This composition is a non-absorbable composition, which has the ability to: (a) remove the target species from the patient, the target species is selected from the group consisting of protons, strong acids and conjugate bases of strong acids ; And (b) During a period of at least twelve weeks, compared with the placebo control group, improve the quality of life of the patients in a statistically significant way.

Another embodiment is a pharmaceutical composition for improving the quality of life of a human patient suffering from a disease or condition by increasing the patient's serum bicarbonate value by at least 1 within at least twelve weeks of treatment mEq/L. In this embodiment: the composition: (a) is a non-absorbable composition with the ability to remove the target species from the patient, the target species is selected from the group consisting of protons, strong acids and strong acids Conjugated base; (b) characterized by a binding capacity of at least 3 mEq/g of target species in the simulated small intestine inorganic buffer (SIB) analysis; and (c) compared to the placebo control group, with a period of at least twelve weeks The ability to improve the quality of life of patients in a statistically significant way.

Another embodiment is a pharmaceutical composition for improving the quality of life of a human patient suffering from metabolic acidosis disease, wherein: (a) an effective amount of the pharmaceutical combination is administered to the patient daily for a period of at least twelve weeks (B) The pharmaceutical composition is non-absorbable with the ability to remove the target species from the patient, the target species is selected from the group consisting of protons, strong acids and conjugate bases of strong acids; (c) The pharmaceutical composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in simulated small intestine inorganic buffer (SIB) analysis; and (d) a statistically significant improvement over the twelve-week period compared to the placebo control group quality of life.

Another embodiment is a method of improving the physical function of patients suffering from chronic kidney disease and acid-base disorders characterized by a baseline serum bicarbonate value ≤22 mEq/L. In this embodiment, the method includes oral administration of a pharmaceutical composition capable of increasing the patient's serum bicarbonate and maintaining above 20 mEq/L for a period of at least twelve weeks, the pharmaceutical composition having a binding target The ability of the species. The target species is selected from the group consisting of protons, strong acids and conjugate bases of strong acids.

Another embodiment is a method for improving the physical function of patients suffering from chronic kidney disease and acid-base disorders. This method includes oral administration of a pharmaceutical composition, which has; (a) the ability to selectively bind to a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; And (b) Simultaneous intestinal inorganic buffer (SIB) analysis of at least 3 mEq/g of target species binding capacity, such as by evaluating the answers to patients in question 3 in the Kidney Disease Quality of Life Summary (KDQOL-SF) At least twelve weeks after initiating treatment, the improvement in physical function was statistically significant compared to the placebo control group.

Another embodiment is a method of improving the physical function of patients suffering from chronic kidney disease and acid-base disorders, wherein the patient has a baseline serum bicarbonate value of ≤22 mEq/L. This method consists of orally administering an effective amount of TRC101 to the patient once a day for a period of time sufficient to statistically significantly increase the patient's physical function score, which is based on question 3 of the KDQOL-SF The answer, compared to the patient's baseline physical function score.

Another embodiment is a method to improve the physical function of patients suffering from metabolic acidosis. This method involves administering a daily dose of non-absorbable crosslinked amine polymer to the patient, where the daily dose: (a) is sufficient to increase the patient’s serum bicarbonate concentration by at least 1 mEq/L; (b) within at least twelve weeks Generate a maintenance serum bicarbonate increase of at least 1 mEq/L during the period; and (c) At the end of this period, it is sufficient to increase the patient's body function score compared to the placebo control group, where the increase in body function score is Statistically significant.

Another embodiment is a pharmaceutical composition for increasing the physical function score of a human patient suffering from chronic kidney disease and acid-base disorders whose baseline serum bicarbonate content before treatment is ≤22 mEq/L. In this embodiment, the composition is a non-absorbable composition with the ability to: (a) remove the target species from the patient, the target species selected from the group consisting of protons, strong acids, and strong acids Conjugated base; and (b) Compared to the placebo control group, at the end of at least a twelve-week period, statistically significant increase in the patient's physical function score based on the quality of life for kidney disease (KDQOL-SF) The answer to question 3.

Another embodiment is a pharmaceutical composition for increasing the body function score of a human patient suffering from a disease or condition by increasing the patient's serum bicarbonate value by at least twelve weeks of treatment by at least 1 mEq/L. In this embodiment, the composition: (a) is a non-absorbable composition with the ability to remove the target species from the patient, the target species is selected from the group consisting of protons, strong acids and strong acids Conjugated base; (b) characterized by at least 3 mEq/g of target species binding in simulated small intestine inorganic buffer (SIB) analysis; and (c) compared to placebo control group, with an end of at least twelve week period At the time, the ability of the patient's physical function score based on the answer to question 3 of the Kidney Quality of Life Short Form (KDQOL SF) was statistically significant.

Another embodiment is a pharmaceutical composition for improving the body function score of a human patient suffering from metabolic acidosis disease, wherein: (a) an effective amount of medicine is administered to the patient every day for a period of at least twelve weeks Composition; (b) The pharmaceutical composition is non-absorbable with the ability to remove the target species from the patient, the target species is selected from the group consisting of protons, strong acids and conjugate bases of strong acids; ( c) The pharmaceutical composition is characterized by simulating a small intestine inorganic buffer (SIB) analysis with a chloride ion binding capacity of at least 3 mEq/g; and (d) at the end of the at least twelve week period compared to the placebo control group The increase in body function score is a statistically significant increase over the baseline body function score, which is based on the answer to question 3 of the Kidney Disease Quality of Life Short Form (KDQOL-SF).

Another embodiment is a method of slowing the progression of kidney disease in patients suffering from chronic kidney disease and acid-base disorders characterized by a baseline serum bicarbonate value ≤22 mEq/L. In this embodiment, the method includes oral administration of a pharmaceutical composition capable of increasing the patient's serum bicarbonate and maintaining above 20 mEq/L for a period of at least twelve weeks, the pharmaceutical composition having a binding target The ability of the species. The target species is selected from the group consisting of protons, strong acids and conjugate bases of strong acids.

Another embodiment is a method of slowing the progression of kidney disease in patients suffering from chronic kidney disease and acid-base disorders, wherein the patient has a baseline serum bicarbonate value of ≤22 mEq/L. This method involves once daily administering an effective amount of TRC101 to the patient orally enough to increase the patient's serum bicarbonate by at least 1 mEq/L.

Another embodiment is a method of slowing the progression of kidney disease in patients suffering from chronic kidney disease and metabolic acidosis. This method involves administering to the patient a daily dose of non-absorbable cross-linked amine polymer, where the daily dose: (a) is sufficient to increase the patient's serum bicarbonate concentration by at least 1 mEq/L; (b) produces at least 1 mEq/L Of maintaining serum bicarbonate increases for a period of at least twelve weeks; and (c) sufficient to slow the progression of kidney disease.

Another embodiment is a pharmaceutical composition for slowing the progression of kidney disease in a human patient suffering from chronic kidney disease and acid-base disorders whose baseline serum bicarbonate content before treatment is ≤22 mEq/L. In this embodiment, the composition is a non-absorbable composition with the ability to: (a) remove the target species from the patient, the target species selected from the group consisting of protons, strong acids, and strong acids Conjugated base; and (b) slowing the progression of kidney disease in human patients for a period of at least twelve weeks.

Another embodiment is a pharmaceutical composition for slowing the progression of kidney disease in a human patient suffering from chronic kidney disease and acid-base disorders, the pharmaceutical composition by treating the patient's serum bicarbonate within at least twelve weeks of treatment Increase the value by at least 1 mEq/L. In this embodiment, the composition: (a) is a non-absorbable composition with the ability to remove the target species from the patient, the target species is selected from the group consisting of protons, strong acids and strong acids Conjugated base; (b) is characterized by simulating the binding capacity of the target species of at least 3 mEq/g in the intestinal inorganic buffer (SIB) analysis; and (c) has the ability to slow the progression of kidney disease for a period of at least twelve weeks.

Another embodiment is a pharmaceutical composition for slowing the progression of kidney disease in a human patient who also has a metabolic acidosis disease, wherein: (a) an effective amount of the patient is administered to the patient daily for a period of at least twelve weeks A pharmaceutical composition; (b) the pharmaceutical composition is non-absorbable with the ability to remove the target species from the patient, the target species is selected from the group consisting of protons, strong acids and conjugate bases of strong acids; (c) the pharmaceutical composition is characterized by simulating a small intestine inorganic buffer (SIB) analysis of at least 3 mEq/g of chloride ion binding; and (d) compared to a placebo control that did not receive the pharmaceutical composition Group, slowing the progression of kidney disease in patients within a twelve-week period.

Another embodiment is a pharmaceutical composition for a method of treating an acid-base disorder in a patient, wherein the treatment method improves the quality of life of the patient.

Yet another embodiment is a pharmaceutical composition for a method of treating an acid-base disorder in a patient, wherein the treatment method improves the patient's physical function.

De Brito-Ashurst et al. were one of six published prospective randomized controlled clinical studies on alkali supplementation and dietary intervention, which showed that increasing serum bicarbonate content produced improved renal outcomes associated with chronic metabolic acidosis . The other five studies are: Garneata L, Stancu A, Dragomir D and others, 2016, Ketoanalogue-Supplemented Vegetarian Very Low-Protein Diet and CKD Progression, J. Am. Soc. Nephrol. 27: 2164-2176; Phisitkul S, Khanna A, Simoni J et al., 2010, Amelioration of metabolic acidosis in patients with low GFR reduced kidney endothelin production and kidney injury, and better preserved GFR, Kidney International 77: 617-623; Goraya N, Simoni J, Jo C, Wesson D , 2013, A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate, Clin. J. Am. Soc. Nephrol. 8: 371-381; Goraya N, Simoni J, Jo C, Wesson D, 2014, Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate, Kidney International 86: 1031-1038; and Mahajan A, Simoni J, Sheather S, etc. People, 2010, Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing i ts decline in early hypertensive nephropathy, Kidney International 78: 303-309.

Garneata et al. evaluated the effects of diets containing ketone analogues supplemented with a very low-protein diet (0.3 g/kg/day) following the diet of patients and common mixed-source lower protein diets (0.6 g/kg/day). The baseline serum bicarbonate was similar in both treatment groups (16.7-16.8 mEq/L), however, at the end of the study, the serum bicarbonate value of the very low protein diet group of vegetarians was significantly higher than that of common mixed sources Protein diet group. Among patients with an initial eGFR <20 mL/min.1.73m ² , a very low-protein diet with vegetarian diet has the most significant effect on reducing the incidence of renal events.

In those embodiments where the non-absorbable composition binds chloride ions, it is generally preferred that the non-absorbable composition competes with other physiologically significant anions present in the gastrointestinal tract, such as bicarbonate equivalent anions, phosphoric acid Anions and conjugate bases of bile and fatty acids selectively bind chloride ions. In other words, the non-absorbable composition is generally preferred to remove higher chloride ions in the gastrointestinal tract but not any other competing anions.

In those other embodiments where the non-absorbable composition binds protons, the non-absorbable composition binds protons without delivering sodium, potassium, calcium, magnesium, and/or other electrolytes in exchange for protons in a physiologically unfavorable amount Generally preferred. Therefore, treatment with this non-absorbable composition will not significantly contribute to edema, hypertension, hyperkalemia, hypercalcemia, or similar conditions associated with increased loads of sodium, potassium, calcium, or other electrolytes. Similarly, in those embodiments where the non-absorbent composition binds protons, it is generally preferred that the non-absorbent composition does not remove a certain amount of sodium, potassium, calcium, magnesium and/or other electrolytes and protons In the case of protons. Therefore, treatment with this non-absorbable composition will not significantly contribute to edema, hypertension, hyperkalemia, hypercalcemia, or similar conditions associated with reduced serum concentrations of sodium, potassium, calcium, or other electrolytes.

In certain embodiments, the polymer preferably binds and maintains its ability to bind protons and anions at physiological conditions found along the lumen of the gastrointestinal (GI). These conditions can be based on dietary intake (see, for example, Fordtran J, Locklear T. Ionic constituents and osmolality of gastric and small-intestinal fluids after eating. Digest Dis Sci. 1966; 11(7): 503-21) and along the gastrointestinal tract The position varies (Binder, H et al. Chapters 41-45 in "Medical Physiology", 2nd edition, Elsevier [2011]. Boron and Boulpaep [ed]). A rapid combination of protons and chlorine in the stomach and small intestine is required. There is also a need for higher binding content and selectivity for chlorine in the back of the gastrointestinal tract (lower small intestine and large intestine). In general, the polymer also preferably has pK _a so that most amines are protonated under various pH and electrolyte conditions encountered along the gastrointestinal tract and in turn can proton and suitable counter anions (preferably chloride) themselves Remove into feces.

Because the stomach is a sufficient source of HCl and the stomach is the first site of potential HCl binding (after the mouth), and because compared to the rest of the gastrointestinal tract (small intestine transit time approximately 4 hours; entire intestinal transit time 2- 3 days; Read, NW et al. Gastroenterology [1980] 79:1276), the retention time in the stomach is short (stomach retention half-life is about 90 minutes), so the polymer of the present disclosure is required to show the internal cavity of this organ and the design To mimic the rapid kinetics of the combination of protons and chlorine in the extracorporeal condition of the stomach lumen (eg, SGF). Phosphoric acid is a potentially interfering anion for chlorine binding in the stomach and small intestine, most of which is absorbed (Cross, HS et al., Miner Electrolyte Metab [1990] 16:115-24). Therefore, in the small intestine and in vitro conditions (eg, SIB) that are designed to mimic the lumen of the small intestine, transphosphoric acid is required to rapidly and preferably bind chlorine. Because the transit time of the colon relative to the small intestine is slow (2-3 days), and since the oral administration of the polymer will not encounter the conditions in the colon until the stomach and small intestine have been encountered, so by this disclosure The chlorine binding kinetics of the polymer does not have to be as fast as in the colon or designed to simulate the late intestine/colon in vitro situation. However, the chloride binding and selectivity across other interfering anions is higher, for example, it is important at 24 and/or 48 hours or longer.

Other aspects and features will be partially apparent and partially pointed out below.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned are incorporated by reference in their entirety. In case of conflict, the present specification (including definitions) will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

Cross-reference for related applications

This application requires the benefits of the US provisional patent application serial number 62/748,361 filed on October 19, 2018 and the US provisional patent application serial number 62/680,002 filed on June 4, 2018. The entire application is cited in full Is incorporated into this article. Abbreviations and definitions

The following definitions and methods are provided to better define the present invention and guide those skilled in the art in the practice of the present invention. Unless otherwise noted, the ordinary skilled person will understand the terminology according to the conventional usage.

As used herein, the term "absorptive capacity" in combination with a polymer and a swelling agent (or in the case of a mixture of swelling agents, a mixture of swelling agents) is swelling by immersion in excess during a period of at least 16 hours at room temperature The amount of swelling agent (or such mixture) absorbed by a given amount of dry polymer (eg, in the form of dried beads) in the agent (or such mixture).

The term "acrylamide" indicates a part having the structural formula H ₂ C=CH-C(O)NR-*, where * indicates the attachment point of the part to the rest of the molecule, and R is hydrogen, a hydrocarbon group or a substituted hydrocarbon group.

The term "acrylic acid" indicates a part having the structural formula H ₂ C=CH-C(O)O-*, where * indicates the attachment point of the part to the rest of the molecule.

The term "adult" refers to individuals over 18 years of age.

The term "alicyclic/alicyclo/alicyclyl" means a saturated monocyclic group of 3 to 8 carbon atoms and includes cyclopentyl, cyclohexyl, cycloheptyl and the like.

The term "aliphatic group" refers to saturated and non-aromatic unsaturated hydrocarbon groups having, for example, one to about twenty carbon atoms or, in particular embodiments, one to about twelve carbon atoms, one to about ten Carbon atoms, one to about eight carbon atoms, or even one to about four carbon atoms. Aliphatic groups include, for example, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, third butyl, pentyl, isopentyl, hexyl, etc. The alkyl portion and the alkenyl portion of similar chain length.

The term "alkanol" indicates an alkyl moiety that has been substituted with at least one hydroxyl group. In some embodiments, the alkanol is a "lower alkanol" containing one to six carbon atoms, one of which is attached to an oxygen atom. In other embodiments, the lower alkanol contains one to three carbon atoms.

The term "alkenyl" encompasses linear or branched carbon radicals having at least one carbon-carbon double bond. The term "alkenyl" may encompass conjugated and non-conjugated carbon-carbon double bonds or combinations thereof. An alkenyl group (e.g., but not limited to this) may cover two to about twenty carbon atoms, or in a particular embodiment, two to about twelve carbon atoms. In certain embodiments, the alkenyl group is a "lower alkenyl group" having two to about four carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, vinyl, butenyl, and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl" encompass groups having "cis" or "reverse" orientation or alternatively "E" or "Z" orientation.

The term "alkyl" as used alone or within other terms such as "haloalkyl", "aminoalkyl" and "alkylamino" encompasses, for example, one to about twenty carbon atoms, or in particular In an embodiment, a saturated linear or branched carbon radical of one to about twelve carbon atoms. In other embodiments, the alkyl group is a "lower alkyl group" having one to about six carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, third butyl, pentyl, isopentyl , Hexyl, etc. In a more specific embodiment, the lower alkyl group has one to four carbon atoms.

The term "alkylamino" refers to an amine group directly attached to the rest of the molecule via the nitrogen atom of the amine group, and wherein the nitrogen atom of the alkylamine group is substituted with one or two alkyl groups. In some embodiments, the alkylamine group is a "lower alkylamine group" having one or two alkyl groups attached to one to six carbon atoms of a nitrogen atom. In other embodiments, the lower alkyl amine group has one to three carbon atoms. Suitable "alkylamino" may be mono- or dialkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, penta Methyleneamine group and so on.

The term "allyl" indicates a part having the structural formula H ₂ C=CH-CH2- _* , where * indicates the attachment point of the part to the rest of the molecule and the attachment point is directed to a heteroatom or aromatic part.

The term "allylamine" indicates a portion having the structural formula H ₂ C=CH-CH ₂ N(X ₈ )(X ₉ ), where X ₈ and X _{9 are} independently hydrogen, a hydrocarbon group or a substituted hydrocarbon group, or X ₈ and X ₉ together form a substituted or unsubstituted alicyclic, aryl or heterocyclic moiety, each as defined in connection with such terms, usually having a ring containing 3 to 8 atoms.

If used alone or as part of another group, the term "amine" or "amine group" represents a set of formulas -N(X ₈ )(X ₉ ), where X ₈ and X _{9 are} independently hydrogen, hydrocarbyl or Substituted hydrocarbyl, heteroaryl or heterocyclic, or X ₈ and X _{9 taken} together form a substituted or unsubstituted alicyclic, aryl or heterocyclic moiety, each as defined in connection with such terms, usually has 3 in the ring Up to 8 atoms.

The term "aminoalkyl" encompasses straight or branched chain alkyl groups having one to about ten carbon atoms directly attached to the remainder of the molecule via atoms other than the nitrogen atom in the amine group, such straight chains Or any of the branched chain alkyl groups may be substituted with one or more amine groups. In some embodiments, the aminoalkyl group is a "lower aminoalkyl group" having one to six carbon atoms and one or more amino groups. Examples of such groups include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.

The terms "anion exchange material" and "cation exchange material" have their usual meanings in this technology. For example, the terms "anion exchange material" and "cation exchange material" refer to materials that exchange anions and cations separately. The anion and cation exchange materials are generally water-insoluble substances, which can be exchanged for some of the charged ions or cations contained in the medium they are in contact with, respectively, with some of their cations or anions. The anion exchange material may contain positively charged groups that are fixed to the main chain material and allow anions to pass but reject cations. A non-exhaustive list of such positively charged groups includes: amine groups, alkyl-substituted phosphines, and alkyl-substituted sulfides. A non-exhaustive list of cation or anion exchange materials includes: clay (e.g. bentonite, kaolin and illite), vermiculite, zeolites (e.g. analcite, chabazite) , Sodalite (sodalite) and clinoptilolite (clinoptilolite), synthetic zeolite, polybasic acid salts, hydrated oxides, ferrocyanides (ferrocyanides) and heteropoly acids. The cation exchange material may contain a negatively charged group that is allowed to pass through the cation but rejects the anion and is fixed to the main chain material. A non-exhaustive list of such negatively charged groups includes: sulfate, carboxylate, phosphate and benzoate.

The term "aromatic group" or "aryl" means an aromatic group having one or more rings, wherein such rings may be attached together in a side-by-side manner or may be fused. In certain embodiments, the aromatic group is one, two, or three rings. The monocyclic aryl group may contain a ring containing 5 to 10 carbon atoms, usually 5 to 7 carbon atoms, and more usually 5 to 6 carbon atoms. Typical polycyclic aryl groups have two or three rings. A polycyclic aryl group having two rings usually has a ring containing 8 to 12 carbon atoms, preferably 8 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, dihydroindenyl, biphenyl, phenanthrenyl, anthracenyl, or acenaphthyl.

The term "bead" is used to describe a cross-linked polymer having a substantially spherical shape.

The term "bicarbonate equivalent" is used to describe an organic acid or anion that produces bicarbonate during metabolism. Citrate and succinate are exemplary bicarbonate equivalents.

As used herein in conjunction with a polymer and one or more ions (ie, cations (eg, "proton-bound" polymers) and anions, the term "bound" is an "ionic-bound" polymer and/or When at least a part of the ions remain bound sufficiently in vitro or in vivo, the strength of the correlation is associated with the ions (but usually not necessarily in a non-covalent manner), where the polymer is used to achieve the removal of the ions from the solution or the body Enough time.

The term "ceramic material" has its usual meaning in this technology. In some embodiments, the term "ceramic material" refers to an inorganic, non-metal solid material that contains metal, non-metal, or metalloid atoms predominantly stored in ions and covalent bonds. A non-exhaustive list of examples of ceramic materials includes: barium titanate, bismuth strontium calcium copper oxide, boron trioxide, earthenware, ferrite, lanthanum carbonate, lead zirconate, titanate Salt, magnesium diboride, porcelain, sialon, silicon carbide, silicon nitride, titanium carbide, yttrium barium copper oxide, zinc oxide, zirconium dioxide, and partially stabilized zirconium oxide . In certain embodiments, as used herein in conjunction with therapy, the term "clinically significant improvement" refers to the improvement or provision of a worthy change in returning an individual from an abnormal state to a relatively normal functional state, or will be in normal function The measured value of the other state in the direction or at least the marked improvement moves to the untreated treatment. Various methods can be used to calculate clinical significance. A non-exhaustive list of methods for calculating clinical significance includes: Jacobson-Truax, Gulliksen-Lord-Novick, Edwards-Nunnally, Hageman-Arrindell, and multi-layer linear model (HLM).

The term "crosslink density" indicates the average number of connections of the rest of the amine polymer containing repeating units. The number of connections can be 2, 3, 4 and higher. The repeating units in linear, non-crosslinked polymers are incorporated via 2 connections. To form an insoluble gel, the number of connections should be greater than 2. Lower cross-link density materials such as Sevelamer have an average of about 2.1 connections between repeating units. Higher cross-linking systems such as Pisaromer have an average of about 4.6 connections between repeating units in amine-containing. "Crosslink density" represents a semi-quantitative measurement based on the ratio of the starting materials used. Limitations include the fact that different crosslinking and polymerization methods are not explained. For example, since the cross-linking agent also acts as a monomer to form the polymer backbone, small molecule amine systems require higher amounts of cross-linking agent; however, for free radical polymerization, the polymer chain is formed independently of the cross-linking reaction. This can result in inherently higher crosslink density under this definition for substitute polymerization/small molecule amines compared to free radically polymerized crosslinked materials.

As used alone or within other terms, the term "crosslinking agent" encompasses a hydrocarbyl group or substituted hydrocarbyl group, as described in Formula 1, capable of reacting with any of the described monomers or infinite polymer networks more than once. Chain or branched chain molecule. The reactive groups in the crosslinking agent can include (but are not limited to): halogenated alkyl, epoxide, phosgene, anhydride, carbamate, carbonate, isocyanate, thioisocyanate, ester, active ester , Carboxylic acids and derivatives, sulfonic acid esters and derivatives, acyl halides, aziridine, α,β-unsaturated carboxyl groups, ketones, aldehydes, pentafluoroaryl groups, vinyl groups, allyl groups, acrylates, methyl esters Acrylic acid ester, acrylamide, methacrylamide, styrene, acrylonitrile and combinations thereof. In an exemplary embodiment, the reactive groups of the cross-linking agent will include halogenated alkyl groups, epoxides, anhydrides, isocyanates, allyl groups, vinyl groups, acrylamide, and combinations thereof. In one such embodiment, the reactive group of the cross-linking agent will be a halogenated alkyl, epoxide, or allyl group.

The term "diallylamine" indicates an amine moiety having two allyl groups.

The terms "dry beads" and "dry polymer" refer to beads or polymers containing not more than 5% by weight of non-polymeric swelling agents or solvents. Usually, the swelling agent/solvent remains water at the end of purification. Before storing or otherwise crosslinking the preformed amine polymer, this water is usually removed by freeze drying or drying. The amount of swelling agent/solvent can be measured by heating (eg, heating to 100-200°C) and measuring the resulting weight change. This is called "dry weight loss" or "LOD".

The term "estimated glomerular filtration rate" or eGFR refers to the estimated value of glomerular filtration rate and is based on the serum content of endogenous filtration markers. Creatinine is a commonly used endogenous filtration marker in clinical practice and several equations have been proposed for estimating glomerular filtration rate. As used in this article, all eGFR values can be determined according to the CKD-EPI equation (Levey et al., A New Equation to Estimate Glomerular Filtration Rate. Ann Intern Med. 2009; 150:604-612): GFR = 41 * min( Scr/κ,1) ^α * max(Scr/κ, 1) ^-1.209 * ^{0.993 age} * 1.018 [if female] * 1.159 [if black] where Scr is serum creatinine (mg/dL); for female, κ is 0.7 And for males, κ is 0.9; for females, α is -0.329 and for males, α is -0.411; min indicates the minimum value of Scr/κ or 1; and max indicates the maximum value of Scr/κ or 1.

The term "ether" indicates a part having oxygen bonded to two separate carbon atoms as depicted in the structural formula *-H _x CO-CH _x -*, where * indicates an attachment point attached to the remaining part of the part and x is independently equal to 0, 1, 2 or 3.

The term "gel" is used to describe cross-linked polymers with irregular shapes.

The term "glomerular filtration rate" or GFR is the volume of fluid per unit time that is filtered from the kidney (kidney) glomerular capillaries into Bowman's capsule. GFR has not been measured directly; instead, it uses the endogenous filtration markers as exogenous filtration markers (such as inulin, iodotitanate, iohexol, etc.) indirectly ( mGFR) or estimate (eGFR) measurement.

The term "halo" means halogen, such as fluorine, chlorine, bromine or iodine atom.

The term "haloalkyl" encompasses groups in which any one or more of the alkyl carbon atoms are substituted with a halo group as defined above. It specifically covers monohaloalkyl, dihaloalkyl and polyhaloalkyl groups, including perhaloalkyl groups. For example, the monohaloalkyl group may have iodine, bromine, chlorine, or fluorine atoms in the group. The dihaloalkyl group and the polyhaloalkyl group may have two or more than two identical halogen atoms or a combination of different halogen groups. "Lower haloalkyl" encompasses groups having 1-6 carbon atoms. In some embodiments, the lower haloalkyl has one to three carbon atoms. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, Dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

The term "heteroaliphatic group" describes 1 to 25 carbon atoms, usually 1 to 12 carbon atoms, more usually 1 to 10 carbon atoms and most usually 1 to 8 carbon atoms, and in some embodiments 1 to 4 A chain of carbon atoms, which may be saturated or unsaturated (but not aromatic), contains one or more heteroatoms, such as halogen, oxygen, nitrogen, sulfur, phosphorus, or boron. The heteroatom atom may be a pendant/side group attached to the atom chain (eg -CH(OH)-CH(NH ₂ )-, where the carbon atom is a member of the atom chain) or it may be in the atom chain One (eg -ROR- or -RNHR-, where each R is an aliphatic group). Heteroaliphatic groups encompass heteroalkyl groups and heterocycles do not encompass heteroaryl groups.

The term "heteroalkyl" describes a fully saturated heteroaliphatic moiety.

Unless otherwise stated, the term "heteroaryl" means a monocyclic or bicyclic aryl group of 5 to 10 ring atoms, where one or more (in one embodiment, one, two or three) ring atoms are The hetero atom 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, furyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxyl Oxazolyl, quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl and similar groups. As defined herein, the terms "heteroaryl" and "aryl" are mutually exclusive. "Extended heteroaryl" means a divalent heteroaryl radical.

The term "heteroatom" means atoms other than carbon and 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 can contain different heteroatoms.

The term "heterocyclo/heterocyclic" or "heterocyclic" means a saturated or unsaturated group of 4 to 8 ring atoms, where one or two ring atoms are such as N, O, B, P and S (O) a heteroatom of _n , where n is an integer from 0 to 2, and the remaining ring atoms are carbon. In addition, one or two ring carbon atoms in the heterocyclyl ring may be replaced with a -C(O)- group as the case may be. More specifically, the term heterocyclyl includes, but is not limited to, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, Piperazino, tetrahydropiperanyl, thiomorpholinyl and the like. When the heterocyclyl ring is unsaturated, it may contain one or two ring double bonds, with the restriction that the ring is not aromatic. When the heterocyclic group contains at least one nitrogen atom, it is also referred to herein as a heterocyclic amine group and is a subset of the heterocyclic group.

The term "hydrocarbon group (hydrocarbon group/hydrocarbyl group)" means a chain of 1 to 25 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, and most typically 1 to 8 carbon atoms . The hydrocarbon group may have a linear or branched chain structure. Typical hydrocarbon groups have one or two branches, typically one branch. Typically, the hydrocarbyl group is saturated. The unsaturated hydrocarbon group may have one or more double bonds, one or more parametric bonds, or a combination thereof. Typical unsaturated hydrocarbon groups have one or two double bonds or one parametric bond; more typically unsaturated hydrocarbon groups have one double bond.

"Initiator" is a term used to describe the agent that initiates polymerization.

The term "measured glomerular filtration rate" or "mGFR" refers to the use of any chemical (such as oligosaccharide, iodotitanate, iohexol, etc.) with a stable content in the blood according to standard techniques, and Measurement of glomerular filtration rate that is freely filtered without reabsorption or secretion by the kidney.

The term "Michael acceptor" adopts its usual meaning in this technology. In certain embodiments, the term "Michael acceptor" refers to activated olefins, such as alpha, beta-unsaturated carbonyl compounds. The Michael acceptor may be a conjugated system having an electron-withdrawing group, such as a cyano group, a ketone group, or an ester. A non-exhaustive list of examples of Michael acceptors includes: vinyl ketone, alkyl acrylate, acrylonitrile, and fumarate.

The term "molecular weight/nitrogen" or "MW/N" represents the calculated molecular weight/nitrogen atom in the polymer. It represents the average molecular weight of one amine functional group present in the cross-linked polymer. It is calculated by dividing the mass of the polymer sample by the mole of nitrogen present in the sample. "MW/N" is the reciprocal of theoretical capacity, and the calculation is based on the assumption that the feed rate, crosslinker and monomer fully react. The lower the molecular weight/nitrogen, the higher the theoretical capacity of the cross-linked polymer.

As used herein, the term "non-absorbent" adopts its usual meaning in this technology. Therefore, if something is non-absorbable, it is not absorbed while passing through the human gastrointestinal tract. This non-absorbency can be measured by any suitable method. One option known to those skilled in the art will be to examine the feces to see if the non-absorbent material has been recovered after passing through the gastrointestinal tract. In fact, in this scenario, the amount of recycled non-absorbent material will never be 100% of the administered material. For example, about 90-99% of material can be recovered from feces. Another option known to those skilled in the art would be that lymphatic, blood, interstitial fluid, and various organs will not be produced by oral administration of non-absorbable materials that will not produce increased amounts of other materials in these matrices and tissues ( For example, in the secretions of pancreas, liver, intestine, etc., or in the body of organs (eg, liver, kidney, lung, etc.), look for the presence of materials. The non-absorbable composition may be a particulate composition that is substantially insoluble in the human gastrointestinal tract and has a particle size that is large enough to avoid passive or active absorption through the human gastrointestinal tract. As an example, a non-absorbable composition is intended to imply that the substance does not pass through the main entry point of the human gastrointestinal tract, that is, by the paracellular entry between intestinal epithelial cells, by ingestion via intestinal epithelial cells, or by It enters the lymph, blood, interstitial fluid or organ through the entrance of M cells including intestinal epithelial antigen sampling and immune monitoring system (Jung, 2000), or through active or passive transport processes. There are known size limits for particles to be absorbed in 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), so those skilled in the art will know that when in the gastrointestinal tract, the material will be non-absorbent with a size of at least 1 micron.

The term "optional/optionally" means that the subsequently described event or situation may occur but does not have to occur, and the description includes the occurrence and non-occurrence of the event or situation. For example, "heterocyclic group substituted with an alkyl group as appropriate" means that an alkyl group may (but is not necessary) exist, and the embodiment includes an example in which the heterocyclic group is substituted with an alkyl group and the heterocyclic group is not an alkyl group Alternative examples.

"Granularity" is measured using Mie theory by wetting laser diffraction. The particles are dispersed in a suitable solvent, such as water or methanol, and added to the sample chamber to achieve a 10-20% red channel obscuration. Sonic treatment can be performed, and dispersants such as surfactants (eg, Tween-80) can be added to disturb weaker particle-particle interactions. The refractive index settings of the particles used for size distribution calculations are selected to minimize artifacts in the results and the R parameter value is determined by laser diffraction software. Record the D(0.1), D(0.5) and D(0.9) values that characterize the particle size distribution by volume basis.

"Pharmaceutically acceptable" when used in conjunction with a carrier, diluent or excipient means that the carrier, diluent or excipient is individually suitable for the preparation of generally safe, non-toxic and biologically or otherwise used in animals A pharmaceutical composition for medical use and/or human medical use.

The term "body function" as used herein in connection with patients suffering from chronic kidney disease and acid-base disorders can be used (i) Kidney Disease and Quality of Life (KDQOL) Brief Table-36 as illustrated in Figures 22A and 22B and Example 5 , Question 3 (Body Function Area), or (iii) KDQOL Brief Table-36 Question 3 and standardized repeated sit-and-stand tests (ie, "i" and "ii" in this paragraph) to evaluate.

The term "after polymerization crosslinking" is a term that describes the reaction to the formed beads or gel, where a higher crosslink is introduced into the formed beads or gel to produce beads or coagulum with increased amount of crosslinking glue.

The term "modified after polymerization" is a term that describes a modification to an already formed bead or gel in which additional functional groups are introduced in response or treatment. This functional group can be covalently or non-covalently linked to the formed beads.

為執行QAA分析，在10 mL QAA緩衝液中以2.5 mg/ml(例如，25 mg乾燥質量)濃度製備無胺聚合物。伴隨旋轉混合器上之攪拌，將混合物在37℃下培育約16個小時。在培育且混合，後將600微升上清液移除並使用800微升、0.45微米孔徑、96槽聚丙烯過濾器板過濾。隨著樣品排列於過濾器板中且收集培養盤擬合底部，將單元在1000Xg下離心1分鐘以過濾樣品。在過濾至收集培養盤中後，在量測氯含量前，將相應濾過物適當地稀釋。用於分析濾過物中之氯含量的IC方法(例如，ICS-2100離子層析法，Thermo Fisher Scientific)由以下組成：15 mM KOH移動相、5微升注射體積、以及三分鐘進行時間、1000微升洗滌/沖洗體積及1.25 mL/min之流動速率。為判定結合至聚合物之氯，完成以下計算： 表達為毫莫耳氯/g乾燥聚合物之結合力=

其中Cl開始對應於QAA緩衝液中之氯之初始濃度，Cl eq對應於在暴露於測試聚合物後之經量測濾過物中的氯之均衡值，且2.5為以mg/ml為單位之聚合物濃度。The term "quaternary ammonium amine analysis"("QAA") describes a method of estimating the amount of quaternary amine present in a given cross-linked polymer sample. At a pH of 11.5, this analysis measures the chlorine bound to the cross-linked polymer. At this pH, the primary, secondary, and tertiary amines are not substantially protonated and do not substantially contribute to chlorine binding. Therefore, any combination observed in these cases can be attributed to the presence of permanently charged quaternary amines. The test solution used for QAA analysis was 100 mM sodium chloride with a pH of 11.5. The concentration of chloride ion is similar to that in the SGF analysis, which is used to evaluate the total binding strength of the cross-linked polymer. The quaternary amine content as a percentage of the total amine present is calculated as follows:

To perform QAA analysis, an amine-free polymer was prepared at a concentration of 2.5 mg/ml (eg, 25 mg dry mass) in 10 mL QAA buffer. With stirring on the rotary mixer, the mixture was incubated at 37°C for about 16 hours. After incubation and mixing, 600 microliters of supernatant was removed and filtered using 800 microliters, 0.45 micron pore size, 96-well polypropylene filter plates. With the samples arranged in the filter plate and the collection plate fitted to the bottom, the unit was centrifuged at 1000Xg for 1 minute to filter the samples. After filtering into the collection plate, before measuring the chlorine content, the corresponding filtrate is appropriately diluted. The IC method for analyzing the chlorine content in the filtrate (for example, ICS-2100 ion chromatography, Thermo Fisher Scientific) consists of the following: 15 mM KOH mobile phase, 5 microliter injection volume, and three-minute run time, 1000 Microliter wash/flush volume and 1.25 mL/min flow rate. To determine the chlorine bound to the polymer, complete the following calculation: expressed as millimolar chlorine/g dry polymer binding force =

Where Cl begins to correspond to the initial concentration of chlorine in the QAA buffer, Cl eq corresponds to the equilibrium value of the measured chlorine in the filtrate after exposure to the test polymer, and 2.5 is the polymerization in mg/ml Substance concentration.

The term "short-chain carboxylic acid" or "short-chain fatty acid" adopts its usual meaning in this technology. In certain embodiments, the term "short-chain carboxylic acid" or "short-chain fatty acid" refers to a carboxylic acid with a chain length of 0, 1, 2, 3, 4, 5, or 6 carbon atoms. A non-exhaustive list of examples of short-chain carboxylic acids includes: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid and lactic acid.

。 表達為毫莫耳氯/g聚合物之結合力：其中Cl start對應於SGF緩衝液中之氯之初始濃度，Cl eq對應於在暴露於測試聚合物後之稀釋的經量測濾過物中之氯的均衡值，4為稀釋因數且2.5為以為mg/ml單位之聚合物濃度。"Simulated gastric fluid" or "SGF" analysis describes a test that determines the total chlorine binding capacity of the test polymer using a defined buffer that simulates the contents of gastric fluid as follows: Simulated gastric fluid (SGF) consists of: 35 mM NaCl, 63 mM HCl, pH 1.2. To perform this analysis, the tested amine-free polymer was prepared at a concentration of 2.5 mg/ml (25 mg dry mass) in 10 mL SGF buffer. With stirring on the rotary mixer, the mixture was incubated at 37°C overnight for about 12-16 hours. Unless another time period is stated otherwise, the SGF binding data or binding power listed in this article is determined during this time period. After incubation and mixing, the test tube containing the polymer was centrifuged at 500-1000Xg for 2 minutes to pelletize the test sample. Remove approximately 750 μl of supernatant and use a suitable filter, such as a 0.45 μm micropore size syringe filter or 800 μl fitted to a 96-well 2 ml collection culture plate, 1 μm micropore size , 96-slot glass filter plate for filtration. With the latter configuration, multiple samples tested in SGF buffer can be prepared for analysis, including free amine sevelamer, free amine pirate, and standard controls containing blank buffer processed by all analysis steps. Control catheter. Filter the sample by centrifuging the unit at 1000Xg for 1 minute by arranging the sample in the filter plate and fitting the collection plate on the bottom. In the case of smaller sample sets, a syringe filter can be used instead of a filter plate to capture approximately 2-4 mL of filtered material into a 15 mL container. After filtration, the corresponding filtrate was diluted 4X with water and the chlorine content of the filtrate was measured by ion chromatography (IC). The IC method (for example, Dionex ICS-2100, Thermo Scientific) consists of the following: AS11 column and 15 mM KOH mobile phase, 5 microliter injection volume, 3 minutes time, 1000 microliter wash/rinse volume and 1.25 mL/min The flow rate. To determine the chlorine bound to the polymer, complete the following calculations:

. Expressed as millimolar chlorine/g polymer binding force: where Cl start corresponds to the initial concentration of chlorine in the SGF buffer, and Cl eq corresponds to the diluted measured filtrate after exposure to the test polymer The equilibrium value of chlorine, 4 is the dilution factor and 2.5 is the polymer concentration in mg/ml units.

其中Cl_start 對應於SIB緩衝液中之氯之初始濃度，Cl_final 對應於暴露於測試聚合物後之量測的經稀釋濾過物中之氯之最終值，4為稀釋因數且2.5為以mg/ml為單位之聚合物濃度。為判定結合至聚合物之磷酸鹽，完成以下計算： 表達為毫莫耳磷酸/公克聚合物之結合力=

其中P_start 對應於SIB緩衝液中之磷酸鹽之初始濃度，P_final 對應於暴露於測試聚合物後之量測的經稀釋濾過物中之磷酸鹽之最終值，4為稀釋因數且2.5為以mg/ml為單位之聚合物濃度。"Simulated Intestinal Inorganic Buffer" or "SIB" is a test to determine the chlorine and phosphate binding capacity of free amine test polymers in selective specific interference buffer analysis (SIB). Use the following selective specific interference buffer analysis (SIB) to determine the chlorine and phosphate binding capacity of the free amine test polymer and the chlorine and phosphate binding capacity of the free amine sevelamer and pisaromer control polymers: use The buffer for SIB analysis contains 36 mM NaCl, 20 mM NaH ₂ PO ₄ and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5. SIB buffer contains the concentration and pH of chlorine and phosphate present in the human duodenum and upper gastrointestinal tract (Stevens T, Conwell DL, Zuccaro G, Van Lente F, Khandwala F, Purich E, etc. Electrolyte composition of endoscopically collected duodenal drainage fluid after synthetic porcine secretin stimulation in healthy subjects. Gastrointestinal endoscopy. 2004;60(3):351-5, Fordtran J, Locklear T. Ionic constituents and osmolality of gastric and small-intestinal fluids after eating. Digest Dis Sci. 1966; 11(7):503-21), and is an effective measurement of the selectivity of chlorine binding compared to phosphates bound by polymers. To perform this analysis, the tested free amine polymer was prepared at a concentration of 2.5 mg/ml (25 mg dry mass) in 10 mL SIB buffer. With stirring on the rotary mixer, the mixture was incubated at 37°C for 1 hour. Unless another time period is stated otherwise, the SIB binding data or binding power listed in this article is determined during this time period. After incubation and mixing, the test tube containing the polymer was centrifuged at 1000Xg for 2 minutes to pelletize the test sample. Remove 750 microliters of supernatant and use 800 microliters, 1 micron micropore size, 96-slot glass filter plate that has been fitted to a 96-well 2 mL collection culture plate; by this configuration, it can be prepared A number of samples tested in SIB buffer were used for analysis, including free amine sevelamer, free amine pisaromer standard control, and a control catheter containing the blank buffer processed by all analysis steps. Filter the sample by centrifuging the unit at 1000Xg for 1 minute by arranging the sample in the filter plate and fitting the collection plate on the bottom. In the case of smaller sample sets, a syringe filter (0.45 micron) can be used instead of the filter plate to capture approximately 2-4 mL of filtered material into a 15 mL bottle. After filtering into the collection culture plate, before measuring the content of chlorine or phosphate, the corresponding filtrate is diluted. To measure chlorine and phosphate, the filtrate under analysis was diluted 4X with water. The content of chlorine and phosphate in the filtrate is measured by ion chromatography (IC). The IC method (eg, Dionex ICS-2100, Thermo Scientific) consists of the following: AS24A column, 45 mM KOH mobile phase, injection volume of 5 microliters and approximately 10 minutes of time, 1000 microliters wash/flush volume and 0.3 mL /min flow rate. To determine the chlorine bound to the polymer, complete the following calculation: Expressed as millimolar chlorine/g polymer binding force =

Where Cl _start corresponds to the initial concentration of chlorine in the SIB buffer, Cl _final corresponds to the final value of the measured chlorine in the diluted filtrate after exposure to the test polymer, 4 is the dilution factor and 2.5 is in mg/ The polymer concentration in ml. To determine the phosphate bound to the polymer, complete the following calculation: Expressed as millimolar phosphoric acid/gram of polymer binding force =

Where P _start corresponds to the initial concentration of phosphate in the SIB buffer, P _final corresponds to the final value of the measured phosphate in the diluted filtrate after exposure to the test polymer, 4 is the dilution factor and 2.5 is The polymer concentration in mg/ml.

In some embodiments, the term "statistically significant" refers to the possibility that the relationship between two or more variables is caused by something other than random chance. More precisely, the probability, the degree of significant research α defined to reject the null hypothesis that the probability study (in which the condition is correct), and a p value of p is the result obtained as a result of at least the extremum (the null hypothesis is Under the right conditions). According to the research standard, when p<α , the result is statistically significant. The significance of the study is selected before data collection and is typically set at 5%.

As used herein, the terms "substituted hydrocarbyl", "substituted alkyl", "substituted alkenyl", "substituted aryl", "substituted heterocycle" or "substituted "Heteroaryl" refers to a hydrocarbyl, alkyl, alkenyl, aryl, heterocyclic, or heteroaryl moiety substituted with at least one atom other than carbon and hydrogen, including where the carbon chain atoms are passed through such as nitrogen, oxygen, silicon, A part substituted with a heteroatom of phosphorus, boron, sulfur or a halogen atom. Such substituents include halogen, heterocyclic, alkoxy, alkenyloxy, alkynyloxy, aryloxy, hydroxy, keto, acetyl, oxy, nitro, amine, amide, nitro Group, cyano group, thiol, ketal, acetal, ester and ether.

"Expansion ratio" or simply "expansion" describes the amount of water absorbed by a given amount of polymer divided by the weight of the polymer aliquot. The expansion ratio is expressed as: expansion = grams of expanded polymer-grams of dry polymer)/grams of dry polymer. The methods used to determine the expansion ratio for any given polymer include the following: a. Place 50-100 mg of dry (less than 5 wt% water content) polymer in an 11 mL sealable test tube (with screw cap) of known weight (catheter weight = weight A). b. Add deionized water (10 mL) to the catheter containing the polymer. The catheter was sealed and tumbled at room temperature for 16 hours (overnight). After incubation, the catheter was centrifuged at 3000xg for 3 minutes and the supernatant was carefully removed by vacuum suction. For polymers that form extremely loose deposits, another centrifugation step is performed. c. After step (b), record the weight of the expanded polymer plus the catheter (weight B). d. Freeze at -40°C for 30 minutes. Freeze dried for 48h. The dried polymer and test tube were weighed (recorded as weight C). e. Calculate the absorbed water g/polymer g, defined as: [(weight B-weight A)-(weight C-weight A)]/(weight C-weight A).

"Target ion" is an ion bound to a polymer, and generally refers to the main ion bound to the polymer, or the ion bound to the polymer is considered to produce the therapeutic effect of the polymer (e.g., protons and chlorine causing net removal of HCl) Combined).

The term "theoretical capacity" means the calculated and expected combination of hydrochloric acid in the "SGF" analysis, expressed in units of mmol/g. The theoretical capacity is based on the assumption that 100% of the amines from the monomer and crosslinking agent are incorporated into the crosslinked polymer based on the corresponding feed ratio. The theoretical capacity is thus equal to the concentration of amine functional groups in the polymer (mmol/g). The theoretical capacity assumes that each amine can be used to bind the corresponding anion and cation and is not adjusted for the type of amine formed (eg, it does not subtract the ability of a quaternary amine that is not available for binding protons).

"Therapeutically effective amount" means that when administered to a patient for the treatment of a disease, the amount of proton-bound cross-linked polymer is sufficient to affect such treatment of the disease. The amount that constitutes a "therapeutically effective amount" will vary depending on the polymer, the severity of the disease of the mammal to be treated, age, weight, etc.

"Treating/treatment" of a disease includes (i) inhibiting the disease, that is, curbing or reducing the occurrence of the disease or its clinical symptoms; or (ii) relieving the disease, that is, causing the disease or its clinical symptoms to subside. For example, inhibiting disease will include prevention.

The term "triallylamine" indicates an amine moiety having three allyl groups.

The term "vinyl" indicates a part having the structural formula R _x H _y C=CH-*, where * indicates the attachment point of the part to the rest of the molecule, where the attachment point is a heteroatom or an aryl group; X and Y are independently 0 , 1 or 2, such that X+Y=2; and R is a hydrocarbon group or a substituted hydrocarbon group.

The term "wt% crosslinker" means the calculated percentage of polymer samples derived from the crosslinker by mass. The weight percent crosslinking agent was calculated using the feed ratio of the polymerization and assuming a sufficient conversion of monomer and crosslinking agent. The mass attributed to the cross-linking agent is equal to the expected increase in molecular weight in the infinite polymer network after the reaction (for example, 1,3-dichloropropane is 113 amu, but since the chlorine atom (as a leaving group) is not incorporated into In the polymer network, only 42 amu 1,3-dichloropropane was added to the polymer network after crosslinking with DCP).

When introducing elements of the present invention or preferred embodiments thereof, the articles "a/an" and "the/said" are intended to mean that there are one or more elements. The terms "comprising", "including" and "having" are intended to be inclusive and not exclusive (ie, there may be other elements than the listed elements). Examples

According to the invention, a pharmaceutical composition comprising a non-absorbable composition having a clinically significant amount of protons, one or more conjugate bases of strong acids and/or one or The ability to remove a variety of strong acids. Individuals suffering from acute or chronic acid/alkaline disorders, which are characterized by a baseline serum bicarbonate value of less than 22 mEq/l, can therefore be treated by oral administration of a pharmaceutical composition comprising a non-absorbable composition , The pharmaceutical composition then passes through the digestive system of the individual, and as it passes through the digestive system, it binds to the target species (protons, one or more conjugate bases of strong acids and/or one or more strong acids), and through common biological functions (defecation ) Remove the combined target species.

In general, individuals suffering from acute or chronic acid/alkaline disorders 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 referred to as end-stage chronic kidney disease), and it has not undergone dialysis (ie, the individual has at least 15 ml/min/ MGFR (or eGFR) of 1.73 m ² ). In some embodiments, the affected individual will be stage 3B CKD (ie, the individual has an mGFR (or eGFR) in the range of 30-44 mL/min/1.73 m ^{2 for} at least three months). In some embodiments, the affected individual will be stage 3A CKD (ie, the individual has an mGFR (or eGFR) in the range of 45-59 mL/min/1.73 m ^{2 for} at least three months). Thus, for example, in some embodiments, the affected individual has an mGFR or eGFR of less than 60 mL/min/1.73 m ² for at least three months. By way of other examples, in some embodiments, the affected individual has an mGFR or eGFR of less than 45 mL/min/1.73 m ² for at least three months. By way of other examples, in some embodiments, the affected individual has an mGFR or eGFR of less than 30 mL/min/1.73 m ² for at least three months. By way of other examples, in some embodiments, the affected individual has an mGFR or eGFR of 15-30, 15-45, 15-60, 30-45, or even 30-60 mL/min/1.73 m ² for at least three months.

The baseline serum bicarbonate value may be the 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 than two time points . For example, in one embodiment, the baseline serum bicarbonate value may be the value of the serum bicarbonate concentration determined at a single time point and the baseline serum bicarbonate value is used to determine the need for immediate treatment in acute acidic conditions basis. In another embodiment, the baseline serum bicarbonate treatment value is an average of the serum bicarbonate concentrations of serum samples plotted at different time points (eg, different days). By way of other examples, in one such embodiment, the baseline serum bicarbonate treatment value is on different days (eg, at least 2, 3, 4, 5 or more days, which can be continuous or one or more days apart or even several days apart) Week) The average value of the serum bicarbonate concentration of the serum samples plotted. By way of further example, in one such embodiment, the baseline serum bicarbonate treatment value is the average of the serum bicarbonate concentrations of serum samples drawn two consecutive days before initiating treatment.

In one embodiment, the treated acid-base disorder is characterized by a baseline serum bicarbonate value of less than 21 mEq/l. For example, in one such embodiment, the treated acid-base disorder is characterized by a baseline serum bicarbonate value of less than 20 mEq/l. By way of other examples, in one such embodiment, the treated acid-base disorder is characterized by a baseline serum bicarbonate value of less than 19 mEq/l. By way of other examples, in one such embodiment, the treated acid-base disorder is characterized by a baseline serum bicarbonate value of less than 18 mEq/l. By way of other examples, in one such embodiment, the treated acid-base disorder is characterized by a baseline serum bicarbonate value of less than 17 mEq/l. By way of further example, in one such embodiment, the treated acid-base disorder is characterized by a baseline serum bicarbonate value of less than 16 mEq/l. By way of other examples, in one such embodiment, the treated acid-base disorder is characterized by a baseline serum bicarbonate value of less than 15 mEq/l. By way of further example, in one such embodiment, the treated acid-base disorder is characterized by a baseline serum bicarbonate value of less than 14 mEq/l. By way of other examples, in one such embodiment, the treated acid-base disorder is characterized by a baseline serum bicarbonate value of less than 13 mEq/l. By way of other examples, in one such embodiment, the treated acid-base disorder is characterized by a baseline serum bicarbonate value of less than 12 mEq/l. By way of other examples, in one such embodiment, the treated acid-base disorder is characterized by a baseline serum bicarbonate value of less than 11 mEq/l. By way of other examples, in one such embodiment, the treated acid-base disorder is characterized by a baseline serum bicarbonate value of less than 10 mEq/l. By way of other examples, in one such embodiment, the treated acid-base disorder is characterized by a baseline serum bicarbonate value of less than 9 mEq/l.

However, in general, the treated acid-base disorder is characterized by a baseline serum bicarbonate value of at least 9 mEq/l. For example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 10 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 11 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 12 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 13 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 14 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 15 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 16 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 17 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 18 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 19 mEq/l. By way of other examples, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 20 mEq/l. By way of other examples, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 21 mEq/l.

In certain embodiments, the treated acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 9 to 21 mEq/l. For example, in one such embodiment, the treated acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 12 to 20 mEq/l. By way of other examples, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 12 to 19 mEq/l. By way of other examples, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 12 to 18 mEq/l. By way of other examples, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 12 to 17 mEq/l. By way of other examples, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 12 to 16 mEq/l. By way of other examples, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 9 to 11 mEq/l. By way of other examples, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 12-14. By way of other examples, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 15-17. By way of other examples, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 18-21.

In certain embodiments, oral administration of a pharmaceutical composition containing a non-absorbable composition increases the individual's serum bicarbonate value from baseline to an increased serum carbonic acid value of at least 1 mEq/l above the baseline serum bicarbonate value Hydrogen salt value. For example, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 1.5 mEq/l. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 2 mEq/l. By way of further example, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 2.5 mEq/l. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 3 mEq/l. By way of further example, in one such embodiment, the treatment increases the baseline serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 3.5 mEq/l. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 4 mEq/l. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum carbonic acid value that is at least 5 mEq/l above the baseline serum bicarbonate value but does not exceed 29 mEq/l Hydrogen salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 5 mEq/l but does not exceed 28 mEq/l Salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 5 mEq/l but does not exceed 27 mEq/l Salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that is at least 5 mEq/l above the baseline serum bicarbonate value but does not exceed 26 mEq/l Salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 6 mEq/l but does not exceed 29 mEq/l Salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 6 mEq/l but does not exceed 28 mEq/l Salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that is at least 6 mEq/l above the baseline serum bicarbonate value but does not exceed 27 mEq/l Salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 6 mEq/l but does not exceed 26 mEq/l Salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 7 mEq/l but does not exceed 29 mEq/l Salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 7 mEq/l but does not exceed 28 mEq/l Salt value. By way of further example, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 7 mEq/l but does not exceed 27 mEq/l Salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 7 mEq/l but does not exceed 26 mEq/l Salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to at least 8 mEq/l above the baseline serum bicarbonate value but does not exceed an increased serum bicarbonate value of 29 mEq/l Salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 8 mEq/l but does not exceed 28 mEq/l Salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 8 mEq/l but does not exceed 27 mEq/l Salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 8 mEq/l but does not exceed 26 mEq/l Salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 9 mEq/l but does not exceed 29 mEq/l Salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 9 mEq/l but does not exceed 28 mEq/l Salt value. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 9 mEq/l but does not exceed 27 mEq/l Salt value. By way of further example, in one such embodiment, the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that is at least 9 mEq l above the baseline serum bicarbonate value but does not exceed 26 mEq/l value. In each of the foregoing exemplary embodiments listed in this paragraph, the treatment enables the increased serum bicarbonate value to be maintained for at least one week, at least one month, at least two months, at least three months, at least six months, or Even an extension of at least one year.

In certain embodiments, the treatment increases the individual's serum bicarbonate value from a baseline serum bicarbonate value in the range of 12 to 21 mEq/l to an increased value in the range of 24 mEq/l to 29 mEq/l . For example, in one such embodiment, the treatment increases the individual's serum bicarbonate value from a baseline serum bicarbonate value in the range of 12 to 17 mEq/l to a range of 24 mEq/l to 29 mEq/l Increased value within. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value from a baseline serum bicarbonate value in the range of 12 to 14 mEq/l to between 24 mEq/l and 29 mEq/l Increased value within the range. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value from a baseline serum bicarbonate value in the range of 15 to 17 mEq/l to between 24 mEq/l and 29 mEq/l Increased value within the range. By way of other examples, in one such embodiment, the treatment increases the individual's serum bicarbonate value from a baseline serum bicarbonate value in the range of 18 to 21 mEq/l to between 24 mEq/l and 29 mEq/l Increased value within the range. In each of the foregoing embodiments listed in this paragraph, the treatment enables the increased serum bicarbonate value to be maintained for 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 extension.

In some embodiments, a clinically significant increase in treatment is achieved within a treatment period of less than one month. For example, in one such embodiment, treatment achieves a clinically significant increase during the 25-day treatment period. By way of other examples, in one such embodiment, a clinically significant increase in treatment is achieved within a 3 week treatment period. By way of other examples, in one such embodiment, a clinically significant increase in treatment is achieved during the 15-day treatment period. By way of other examples, in one such embodiment, a clinically significant increase in treatment is achieved within a 2 week treatment period. By way of other examples, in one such embodiment, a clinically significant increase in treatment is achieved within a 10-day treatment period. By way of other examples, in one such embodiment, a clinically significant increase in treatment is achieved within a 1-week treatment period. By way of other examples, in one such embodiment, a clinically significant increase in treatment is achieved within a 6-day treatment period. By way of other examples, in one such embodiment, a clinically significant increase in treatment is achieved within a 5-day treatment period. By way of other examples, in one such embodiment, a clinically significant increase in treatment is achieved within a 4-day treatment period. By way of other examples, in one such embodiment, a clinically significant increase in treatment is achieved within a 3-day treatment period. By way of other examples, in one such embodiment, a clinically significant increase in treatment is achieved within a 2 day treatment period. By way of other examples, in one such embodiment, a clinically significant increase in treatment is achieved within a treatment period of 1 day. By way of other examples, in one such embodiment, a clinically significant increase in treatment is achieved within a 12-hour treatment period.

In certain embodiments, a clinically significant increase in treatment is achieved without any change in the individual's diet or dietary habits relative to the time immediately prior to initiating treatment. For example, in one such embodiment, achieving a clinically significant increase is independent of the individual's diet or dietary habits.

In certain embodiments, the individual's serum bicarbonate value returns to a baseline value of ±2.5 mEq/l within 1 month of stopping treatment. For example, in one such embodiment, the individual's serum bicarbonate value returns to a baseline value of ±2.5 mEq/l within 3 weeks of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±2.5 mEq/l within 2 weeks of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returns to a baseline value of ±2.5 mEq/l within 10 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±2.5 mEq/l within 9 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±2.5 mEq/l within 8 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±2.5 mEq/l within 7 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±2.5 mEq/l within 6 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to the baseline value ± 2.5 mEq/l within 5 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±2.5 mEq/l within 4 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returns to a baseline value of ±2.5 mEq/l within 3 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±2.5 mEq/l within 2 days of stopping treatment. For example, in one such embodiment, the individual's serum bicarbonate value returns to a baseline value of ±2.5 mEq/l within 1 day of stopping treatment.

In certain embodiments, the individual's serum bicarbonate value returns to a baseline value of ±2 mEq/l within 1 month of stopping treatment. For example, in one such embodiment, the individual's serum bicarbonate value returns to a baseline value of ±2 mEq/l within 3 weeks of stopping treatment. By way of further example, in one such embodiment, the individual's serum bicarbonate value returned to the baseline value ± 2 mEq/l within 2 weeks of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returns to a baseline value of ±2 mEq/l within 10 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±2 mEq/l within 9 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returns to a baseline value of ±2 mEq/l within 8 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±2 mEq/l within 7 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±2 mEq/l within 6 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to the baseline value ± 2 mEq/l within 5 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to the baseline value ± 2 mEq/l within 4 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±2 mEq/l within 3 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to the baseline value ± 2 mEq/l within 2 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returns to a baseline value of ±2 mEq/l within 1 day of stopping treatment.

In certain embodiments, the individual's serum bicarbonate value returns to a baseline value of ±1.5 mEq/l within 1 month of stopping treatment. For example, in one such embodiment, the individual's serum bicarbonate value returns to a baseline value of ±1.5 mEq/l within 3 weeks of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±1.5 mEq/l within 2 weeks of stopping treatment. By way of further example, in one such embodiment, the individual's serum bicarbonate value returns to the baseline value ± 1.5 mEq/l within 10 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±1.5 mEq/l within 9 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±1.5 mEq/l within 8 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±1.5 mEq/l within 7 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±1.5 mEq/l within 6 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to the baseline value ±1.5 mEq/l within 5 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returns to a baseline value of ±1.5 mEq/l within 4 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±1.5 mEq/l within 3 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to the baseline value ± 1.5 mEq/l within 2 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returns to a baseline value of ±1.5 mEq/l within 1 day of stopping treatment.

In certain embodiments, the individual's serum bicarbonate value returns to a baseline value of ±1 mEq/l within 1 month of stopping treatment. For example, in one such embodiment, the individual's serum bicarbonate value returns to a baseline value of ±1 mEq/l within 3 weeks of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±1 mEq/l within 2 weeks of stopping treatment. By way of further example, in one such embodiment, the individual's serum bicarbonate value returns to the baseline value ± 1 mEq/l within 10 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±1 mEq/l within 9 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±1 mEq/l within 8 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±1 mEq/l within 7 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to a baseline value of ±1 mEq/l within 6 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returns to a baseline value of ±1 mEq/l within 5 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value returns to the baseline value ±1 mEq/l within 4 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returns to a baseline value of ±1 mEq/l within 3 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returned to the baseline value ± 1 mEq/l within 2 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value returns to a baseline value of ±1 mEq/l within 1 day of stopping treatment.

In certain embodiments, the individual's serum bicarbonate value decreases by at least 1 mEq/l within 1 month of stopping treatment when treatment is stopped. For example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 3 weeks of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 2 weeks of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 10 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 9 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 8 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 7 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 6 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 5 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 4 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 3 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 2 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 1 day of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 12 hours of stopping treatment.

In certain embodiments, the individual's serum bicarbonate value decreases by at least 1.5 mEq/l within 1 month of stopping treatment when treatment is stopped. For example, in one such embodiment, the individual's serum bicarbonate value decreases by at least 1.5 mEq/l within 3 weeks of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value decreases by at least 1.5 mEq/l within 2 weeks of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 10 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 9 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 8 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 7 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 6 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 5 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 4 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 3 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 2 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 1 day of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value decreases by at least 1.5 mEq/l within 12 hours of stopping treatment.

In certain embodiments, the individual's serum bicarbonate value decreases by at least 2 mEq/l within 1 month of stopping treatment when treatment is stopped. For example, in one such embodiment, the individual's serum bicarbonate value decreases by at least 2 mEq/l within 3 weeks of stopping treatment. By way of further example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 2 weeks of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 10 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 9 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 8 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 7 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 6 days of stopping treatment. By way of further example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 5 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 4 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 3 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 2 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 1 day of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 12 hours of stopping treatment.

In certain embodiments, the individual's serum bicarbonate value decreases by at least 2.5 mEq/l within 1 month of stopping treatment when treatment is stopped. For example, in one such embodiment, the individual's serum bicarbonate value decreases by at least 2.5 mEq/l within 3 weeks of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 2 weeks of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 10 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 9 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 8 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 7 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 6 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 5 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 4 days of stopping treatment. By way of further example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 3 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 2 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 1 day of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 12 hours of stopping treatment.

In certain embodiments, the individual's serum bicarbonate value decreases by at least 3 mEq/l within 1 month of stopping treatment when treatment is stopped. For example, in one such embodiment, the individual's serum bicarbonate value decreases by at least 3 mEq/l within 3 weeks of stopping treatment. By way of further example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 2 weeks of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 10 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 9 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 8 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 7 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 6 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 5 days of stopping treatment. By way of further example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 4 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 3 days of stopping treatment. By way of further example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 2 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 1 day of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 12 hours of stopping treatment.

In certain embodiments, the individual's serum bicarbonate value decreases by at least 3.5 mEq/l within 1 month of stopping treatment when treatment is stopped. For example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 3 weeks of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 2 weeks of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 10 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 9 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 8 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 7 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 6 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 5 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 4 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 3 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 2 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 1 day of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 12 hours of stopping treatment.

In certain embodiments, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 1 month of stopping treatment when the treatment is stopped. For example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 3 weeks of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 2 weeks of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 10 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 9 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 8 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 7 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 6 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 5 days of stopping treatment. By way of further example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 4 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 3 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 2 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 1 day of stopping treatment. By way of further example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 12 hours of stopping treatment.

In certain embodiments, the individual's serum bicarbonate value decreases by at least 4.5 mEq/l within 1 month of stopping treatment when treatment is stopped. For example, in one such embodiment, the individual's serum bicarbonate value decreases by at least 4.5 mEq/l within 3 weeks of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value decreases by at least 4.5 mEq/l within 2 weeks of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 10 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value decreases by at least 4.5 mEq/l within 9 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 8 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 7 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value decreases by at least 4.5 mEq/l within 6 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 5 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 4 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 3 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 2 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 1 day of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value decreases by at least 4.5 mEq/l within 12 hours of stopping treatment.

In certain embodiments, the individual's serum bicarbonate value decreases by at least 5 mEq/l within 1 month of stopping treatment when treatment is stopped. For example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 3 weeks of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 2 weeks of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 10 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 9 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 8 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 7 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 6 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 5 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 4 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 3 days of stopping treatment. By way of other examples, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 2 days of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 1 day of stopping treatment. By way of other example, in one such embodiment, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 12 hours of stopping treatment.

In one embodiment, the baseline serum bicarbonate value is the value of the serum bicarbonate concentration determined at a single time point. In another embodiment, the baseline serum bicarbonate value is the 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 of serum samples plotted on different days. By way of other examples, the baseline serum bicarbonate value is an average or median value of at least two serum bicarbonate concentrations of serum samples plotted on non-continuous days. By way of other examples, in one such method, discontinuous Japanese are separated by at least two days. By way of other examples, in one such method, non-continuous Japanese are separated by at least one week. By way of other examples, in one such method, non-continuous Japanese are separated by at least two weeks. By way of other examples, in one such method, non-continuous Japanese are separated by at least three weeks.

In certain embodiments, the daily dose is a non-absorbable composition that does not exceed 100 grams per day (g/day). For example, in one such embodiment, the daily dose is a non-absorbent composition that does not exceed 90 g/day. By way of other examples, in one such embodiment, the daily dosage is a non-absorbable composition that does not exceed 75 g/day. By way of other examples, in one such embodiment, the daily dose is a non-absorbable composition that does not exceed 65 g/day. By way of other examples, in one such embodiment, the daily dose is a non-absorbent composition that does not exceed 50 g/day. By way of other examples, in one such embodiment, the daily dose is a non-absorbable composition that does not exceed 40 g/day. By way of other examples, in one such embodiment, the daily dose is a non-absorbent composition that does not exceed 30 g/day. By way of other examples, in one such embodiment, the daily dose is a non-absorbable composition that does not exceed 25 g/day. By way of other examples, in one such embodiment, the daily dosage is a non-absorbable composition that does not exceed 20 g/day. By way of other examples, in one such embodiment, the daily dose is a non-absorbable composition that does not exceed 15 g/day. By way of other examples, in one such embodiment, the daily dose is not more than 10 g/day of a non-absorbable composition. By way of other examples, in one such embodiment, the daily dose is not more than 5 g/day of a non-absorbable composition.

In certain embodiments, the individual is treated with a daily dose for at least one day. For example, in one such embodiment, the individual is treated with a daily dose for at least one week. By way of other examples, in one such embodiment, the individual is treated with a daily dose for at least one month. By way of other examples, in one such embodiment, the individual is treated with a daily dose for at least two months. By way of other examples, in one such embodiment, the individual is treated with a daily dose for at least three months. By way of other examples, in one such embodiment, the individual is treated with a daily dose for at least several months. By way of other examples, in one such embodiment, the individual is treated with a daily dose for at least six months. By way of other examples, in one such embodiment, the individual is treated with a daily dose for at least one year.

In certain embodiments of the disclosed method, the daily dose of the non-absorbent composition has the ability to remove 5 milliequivalents/day of the target species. For example, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 6 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 7 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 8 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 9 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 10 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 11 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 12 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 13 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 14 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dosage of the non-absorbent composition has the ability to remove at least about 15 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 16 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 17 meq/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 18 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 19 meq/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 20 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 21 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dosage of the non-absorbent composition has the ability to remove at least about 22 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 23 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 24 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 25 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 26 meq/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 27 meq/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 28 meq/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 29 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 30 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 31 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dosage of the non-absorbent composition has the ability to remove at least about 32 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 33 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 34 meq/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 35 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 36 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 37 meq/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 38 meq/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 39 meq/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 40 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 41 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 42 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 43 meq/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 44 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 45 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 46 meq/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 47 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 48 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 49 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has the ability to remove at least about 50 milliequivalents/day of the target species.

In certain embodiments of the disclosed method, the daily dose of the non-absorbent composition will remove at least about 5 milliequivalents/day of the target species. For example, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 6 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 7 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 8 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 9 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 10 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 11 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 12 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 13 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 14 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 15 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 16 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 17 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 18 meq/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 19 meq/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 20 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 21 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 22 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 23 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 24 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 25 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 26 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 27 meq/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 28 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 29 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 30 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 31 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 32 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 33 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 34 meq/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 35 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 36 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 37 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 38 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 39 meq/day of target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 40 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 41 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 42 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 43 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 44 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 45 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 46 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 47 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 48 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 49 milliequivalents/day of the target species. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition will remove at least about 50 milliequivalents/day of the target species.

In certain embodiments of the disclosed method, the daily dose of the non-absorbent composition will be less than 60 milliequivalents/day of target species removed. For example, in one such method, the daily dose removes the target species of less than 55 meq/day. By way of other examples, in one such embodiment, the daily dose will remove less than 50 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 45 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 40 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 35 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose will remove less than 34 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 33 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 32 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose will remove less than 31 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 30 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose will remove less than 29 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 28 meq/day. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 27 meq/day. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 26 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 25 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 24 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose will remove less than 23 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 22 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 21 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose will remove less than 20 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 19 meq/day. By way of other examples, in one such embodiment, the daily dose will remove less than 18 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 17 meq/day. By way of other examples, in one such embodiment, the daily dose will remove less than 16 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose will remove less than 15 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 14 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 13 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose will remove less than 12 milliequivalents/day of target species. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 11 meq/day. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 10 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 9 meq/day. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 8 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 7 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose will remove target species of less than 6 milliequivalents/day.

In some embodiments of the disclosed method, the daily dose of the non-absorbent composition does not have the ability to remove target species in excess of 60 milliequivalents/day. For example, in one such method, the daily dose does not have the ability to remove target species in excess of 55 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 50 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 45 mEq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 40 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 35 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 34 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 33 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 32 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 31 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 30 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 29 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 28 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 27 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 26 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 25 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 24 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 23 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 22 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 21 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 20 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 19 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 18 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 17 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 16 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 15 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species exceeding 14 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 13 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 12 milliequivalents/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species exceeding 11 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 10 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species exceeding 9 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species exceeding 8 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species exceeding 7 meq/day. By way of other examples, in one such embodiment, the daily dose does not have the ability to remove target species in excess of 6 milliequivalents/day.

In certain embodiments of the method of the present disclosure, the method comprises orally administering a pharmaceutical composition to increase the serum bicarbonate content of the individual, wherein: (i) the pharmaceutical composition is combined with the individual's digestive system when administered orally The target species in, the target species is selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; and (ii) in placebo-controlled studies, the pharmaceutical composition increases serum bicarbonate content by at least 1 mEq/l, the increase is the difference between the average serum bicarbonate content of the group in the first group at the end of the study and the average serum bicarbonate content of the group in the second group at the end of the study, of which the first group Subjects received the pharmaceutical composition and subjects in the second group received a placebo, wherein the first and second groups each contained at least 25 subjects, each group prescribed the same diet during the study and the study lasted at least two weeks . In one embodiment, the first group receives a daily dose of the pharmaceutical composition that does not exceed 100 g/day. In one embodiment, the first group receives a daily dose of the pharmaceutical composition that does not exceed 50 g/day. In one embodiment, the first group receives a daily dose of the pharmaceutical composition that does not exceed 30 g/day. In one embodiment, the first group receives a daily dose of the pharmaceutical composition that does not exceed 25 g/day. In one embodiment, the first group receives a daily dose of the pharmaceutical composition that does not exceed 20 g/day. In one embodiment, the first group receives a daily dose of the pharmaceutical composition that does not exceed 15 g/day. In one embodiment, the first group receives a daily dose of the pharmaceutical composition that does not exceed 10 g/day. In one embodiment, the first group receives a daily dose of the pharmaceutical composition that does not exceed 5 g/day. In one embodiment, the target species is proton. In one embodiment, the target species is chloride ion. In one embodiment, the target species is a strong acid. In one embodiment, the target species is HCl. In one embodiment, when the pharmaceutical composition is ingested, it is not absorbed.

In one embodiment, the individual or adult patient has chronic kidney disease (CKD3-4 stage; eGFR 20-<60 mL/min/1.73m ² ) and the baseline serum bicarbonate values at the beginning of the study are between 12 and 20 mEq/L between. In one embodiment, in a placebo-controlled study, the pharmaceutical composition increases the serum bicarbonate content of the individual or adult patient by at least 2 mEq/l. In one embodiment, in a placebo-controlled study, the pharmaceutical composition increases the serum bicarbonate content of the individual or adult patient by at least 3 mEq/l. In one embodiment, the individual or adult patient does not yet require kidney replacement therapy (dialysis or transplantation). In one embodiment, the individual or adult patient has not reached end-stage renal disease ("ESRD").

In one embodiment, the individual or adult patient has an mGFR of at least 15 mL/min/1.73 m ² . In one embodiment, the individual or adult patient has an eGFR of at least 15 mL/min/1.73 m ² . In one embodiment, the individual or adult patient has an mGFR of at least 30 mL/min/1.73 m ² . In one embodiment, the individual or adult patient has an eGFR of at least 30 mL/min/1.73 m ² . In one embodiment, the individual or adult patient has an mGFR of less than 45 mL/min/1.73 m ² for at least three months. In one embodiment, the individual or adult patient has an eGFR of less than 45 mL/min/1.73 m ² for at least three months. In one embodiment, the individual or adult patient has an mGFR of less than 60 mL/min/1.73 m ² for at least three months. In one embodiment, the individual or adult patient has an eGFR of less than 60 mL/min/1.73 m ² for at least three months. In one embodiment, the individual or adult patient has stage 3A CKD, stage 3B CKD, or stage 4 CKD.

Although the method described above refers to a daily dose, another aspect of the present disclosure includes the method disclosed herein, in which the dose is administered less than once a day (but still on a regular basis). In any of the present disclosure, instead, a specific daily dose may be administered on a less frequent basis. For example, the disclosed dose can be administered every two or three days. Or, the dose disclosed herein may be administered once, twice, or three times a week.

In addition to (or as a substitute for) serum bicarbonate, other biomarkers of acid-base imbalance can be used as a measure of acid-base status. For example, the concentration of blood (serum or plasma) pH, total CO ₂ , anion gap, and/or other electrolytes (such as sodium, potassium, calcium, magnesium, chlorine, and/or sulfuric acid) can be used as an acid-base imbalance Indicator. Similarly, the concentration of net acid secretion ("NAE"), urine pH, urine ammonium concentration and/or other electrolytes in urine (eg sodium, potassium, calcium, magnesium, chlorine, and/or sulfuric acid) are available Used as an indicator of acid-base imbalance.

In one embodiment, treatment of an individual as described herein can improve the individual's serum anion gap. For example, treatment of acid-base imbalance by a neutral composition with the ability to bind both protons and anions (without the delivery of sodium or potassium ions) can increase serum bicarbonate without accompanying an increase in sodium or potassium (see example 3 and Figures 13A, 13C and 13D). Therefore, the serum anion gap can be increased (decreased) by at least 1 mEq/l or more (for example, at least 2 mEq/l) within a short 2-week period (see Example 3).

The various aspects and embodiments may have a series of advantages, such as improving or successfully treating metabolic acidosis. Such improvements may also include reducing side effects, increasing patient compliance, reducing drug load, increasing the speed of treatment, increasing the degree of treatment, avoiding unnecessary changes in other electrolytes, and/or reducing drug-drug interactions. Another improvement may include reducing the patient's anion gap (as defined above) as part of the methods and other aspects disclosed herein. Other effective features of the disclosed aspects can be found in the examples. Certain specific compositions for treatment

As previously mentioned, one aspect disclosed herein is a composition for a method of treating metabolic acidosis in an adult patient, wherein in the treatment, 0.1-12 g of the composition is administered to the patient every day, The composition is a non-absorbable composition having the ability to remove protons from the patient, wherein the non-absorbable composition is characterized by a chloride ion binding force simulating at least 2.5 mEq/g in the small intestine inorganic ("SIB") analysis . This aspect is based on the data in the examples that demonstrate the absorption and removal of HCl to successfully treat patients, allowing the amount of the composition to be set based on the ability of the composition to bind chlorine in the SIB analysis. As shown in the examples, compositions with this specific chlorine binding content in the "SIB" analysis can be used in specific dosage ranges to successfully treat metabolic acidosis in adult humans. In this aspect, the composition can be administered orally, and thus will be a non-absorbent composition that is orally administered as defined herein.

This aspect is based on the data in the examples that demonstrate the successful treatment of patients using the absorption and removal of HCl from the composition according to this aspect, allowing the setting of the composition based on the ability of the composition to bind chlorine in SIB analysis The amount of the composition. Unexpectedly, the amount required for successful treatment is relatively low.

Another aspect of the present disclosure is a composition for a method for treating metabolic acidosis in an adult patient by increasing the patient's serum bicarbonate value by at least 1 mEq/L within 15 days of treatment, The composition is a non-absorbent composition with the ability to remove protons from the patient. In this aspect, the composition can be administered orally, and thus will be a non-absorbent composition that is orally administered as defined herein.

This aspect is based on the data in the examples that demonstrate the successful treatment of patients using the absorption and removal of HCl from the composition according to this aspect, which provides new information about the reduced likelihood of using the composition of the present disclosure detail. This aspect includes, for example, the patient's serum bicarbonate content increased unexpectedly and the serum bicarbonate content increased unexpectedly in the past few days.

Another aspect of the present disclosure is a composition for a method of treating metabolic acidosis in an adult patient who has a serum bicarbonate content of less than 20 mEq/L before treatment. A non-absorbable composition with the ability to remove protons from the patient. In this aspect, the composition can be administered orally, and thus will be a non-absorbent composition that is orally administered as defined herein.

This aspect is based on the data in the examples that demonstrate for the first time the successful treatment of patients with lower serum bicarbonate content (eg, content that has not previously been shown to be so easy to treat). Patients with reduced serum bicarbonate content respond particularly well to treatment and this improvement of this subgroup is an advantage of this aspect.

Another aspect of the present disclosure is a composition for a method for treating metabolic acidosis in an adult patient by increasing the patient's serum bicarbonate value by at least 1 mEq/L within 15 days of treatment, In this treatment, the patient is administered with> 12-100 g of the polymer daily, the composition is a non-absorbable composition with the ability to remove protons from the patient, wherein the non-absorbable composition is characterized by a simulation Chloride binding capacity of at least 2.5 mEq/g in the analysis of small intestinal inorganic buffer ("SIB"). In this aspect, the composition can be administered orally, and thus will be a non-absorbent composition that is orally administered as defined herein.

Another aspect of the present disclosure is a composition for a method of treating metabolic acidosis in an adult patient, wherein in the treatment, the patient is administered with> 12-100 g of the composition every day, the composition is A non-absorbable composition of the ability of protons to be removed from a patient, wherein the non-absorbable composition is characterized by a chloride ion binding force of less than 2.5 mEq/g in simulated small intestine inorganic buffer ("SIB") analysis. In this aspect, the composition can be administered orally, and thus will be a non-absorbent composition that is orally administered as defined herein.

The chloride ion binding capacity in the SIB analysis is affected by both the selectivity of the composition for binding chlorine and the total space available for chlorine binding. The term "composition" refers to an effective pharmaceutical ingredient, including any counter ion, but without excipients. Therefore, the "amount" of the composition is the amount of the effective pharmaceutical ingredient and does not include any other part of the unit dosage form.

More specifically, in these aspects, the amount of the composition may be any amount disclosed herein in other parts in the range of 0.1 g-12 g. For example, administer 1 to 11 g, 2 to 10 g, 3 to 9 g, 3 to 8 g, 3 to 7 g, 3 to 6 g, 3.5 to 5.5 g, 4 to 5 g, or 4.5 to patients daily -5 g of the polymer, or a 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 composition administered to the patient every day.

More specifically, in these aspects, the chloride ion binding force in the simulated small intestine inorganic buffer ("SIB") analysis can be greater than 3, 3.5, 4, or 4.5 mEq/g. An upper limit for the binding capacity of chloride ions in SIB analysis is 10 mEq/g. Other upper limits may be 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 mEq/g, or no specific upper limit exists.

All combinations of the amount of the composition mentioned herein and the binding capacity of chloride ions are also disclosed. For example, in one embodiment, the composition has a chloride ion binding capacity in a SIB analysis of at least 4.5 mEq/g and only 0.1-6 g of the composition is administered in the method of treating metabolic acidosis.

The compositions in these aspects may additionally have any of the properties or characteristics specified elsewhere herein. For example, the composition may be a non-absorbent composition as described in the following section. In a similar manner, the treatment methods specified in these aspects may include any of the features disclosed in the previous section regarding certain treatment methods. Non-absorbent composition

As previously mentioned, non-absorbent compositions with medical uses described herein possess the ability to remove clinically significant amounts of one or more target species: (i) protons, (ii) one or more strong acids conjugate base (e.g. chlorine, bisulfate (HSO ₄ ^-) and / or sulfate (SO ₄ ^-) ions) and / or (iii) one or more strong acids (e.g. HCl and / or H ₂ SO _4). To bind such target species, the non-absorbent composition can be selected from the group consisting of: cation exchange composition, anion exchange composition, zwitter ion exchange composition, neutral with the ability to bind both protons and anions Compositions, composite materials and mixtures thereof.

In general, the non-absorbable composition has a preferred particle size range, which is (i) large enough to avoid passive or active absorption through the gastrointestinal tract and (ii) small enough to be in powder, sachet and/or Chewable lozenges/dosage forms with an average particle size of at least 3 microns do not cause sandiness or unpleasant taste when ingested. For example, in one such embodiment, the non-absorbent composition includes a population of particles having an average particle size (volume distribution) in the range of 5 to 1,000 microns. By way of other examples, in one such embodiment, the non-absorbent composition contains a population of particles having an average particle size (volume distribution) in the range of 5 to 500 microns. By way of other examples, in one such embodiment, the non-absorbent composition contains a population of particles having an average particle size (volume distribution) in the range of 10 to 400 microns. By way of other examples, in one such embodiment, the non-absorbent composition contains a population of particles having an average particle size (volume distribution) in the range of 10 to 300 microns. By way of other examples, in one such embodiment, the non-absorbent composition contains a population of particles having an average particle size (volume distribution) in the range of 20 to 250 microns. By way of other examples, in one such embodiment, the non-absorbent composition contains a population of particles having an average particle size (volume distribution) in the range of 30 to 250 microns. By way of other examples, in one such embodiment, the non-absorbent composition contains a population of particles having an average particle size (volume distribution) in the range of 40 to 180 microns. In certain embodiments, less than 7% of the particles in the population (volume distribution) have a diameter of less than 10 microns. For example, in such embodiments, less than 5% of the particles in the population (volume distribution) have a diameter of less than 10 microns. By way of other examples, in such embodiments, less than 2.5% of the particles in the population (volume distribution) have a diameter of less than 10 microns. For example, in such embodiments, less than 1% of the particles in the population (volume distribution) have a diameter of less than 10 microns. In all embodiments, the protocol set forth in the abbreviations and definitions section (above) can be used to measure granularity.

To minimize GI side effects in patients who are usually associated with larger volumes of polymer gel moving through the gastrointestinal tract, a non-absorbent composition with a lower swelling ratio is preferred (the weight in water is 0.5 to 0.5% of its own weight) 10 times). For example, in one such embodiment, the non-absorbent composition has an expansion ratio of less than 9. By way of other examples, in one such embodiment, the non-absorbent composition has an expansion ratio of less than 8. By way of other examples, in one such embodiment, the non-absorbent composition has an expansion ratio of less than 7. By way of other examples, in one such embodiment, the non-absorbent composition has an expansion ratio of less than 6. By way of other examples, in one such embodiment, the non-absorbent composition has an expansion ratio of less than 5. By way of other examples, in one such embodiment, the non-absorbent composition has an expansion ratio of less than 4. By way of other examples, in one such embodiment, the non-absorbent composition has an expansion ratio of less than 3. By way of other examples, in one such embodiment, the non-absorbent composition has an expansion ratio of less than 2.

As the non-absorbable composition passes through the gastrointestinal tract, the amount of the target species (proton, strong acid conjugate base and/or strong acid) is mainly the composition of the target species (proton, strong acid conjugate base and/or strong acid) Binding force and a function of the amount of non-absorbable composition administered per day as a daily dose. In general, SGF analysis can be used to determine the amount of species that appears or disappears from the SGF buffer during SGF analysis to determine the theoretical binding force for the target species. For example, the theoretical proton binding capacity of the cation exchange resin can be determined by measuring the increase in the amount of cations (other than protons) in the buffer during SGF analysis. Similarly, the theoretical anion binding capacity of the anion exchange resin (in the form other than the chloride form) can be determined by measuring the increase in the amount of anions (other than chloride ions) in the buffer during the SGF analysis. In addition, the theoretical anion binding capacity of the neutral composition to the conjugate base of protons and strong acids can be determined by measuring the decrease in the concentration of chlorine in the buffer during the SGF analysis.

In general, the non-absorbent composition will have a theoretical binding force of at least about 0.5 mEq/g for the target species (as determined by SGF analysis). For example, in some embodiments, the non-absorbent composition will have a theoretical binding force of at least about 1 mEq/g for the target species. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force of at least about 2 mEq/g for the target species. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force of at least about 3 mEq/g for the target species. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force of at least about 4 mEq/g for the target species. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force of at least about 5 mEq/g for the target species. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force of at least about 7.5 mEq/g for the target species. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force of at least about 10 mEq/g for the target species. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force of at least about 12.5 mEq/g for the target species. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force of at least about 15 mEq/g for the target species. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force of at least about 20 mEq/g for the target species. In general, non-absorbent compositions will generally have a theoretical binding force of no more than about 35 mEq/g for the target species. For example, in some embodiments, the theoretical binding force of the non-absorbent composition to the target species does not exceed 30 mEq/g. Thus, for example, the theoretical binding force of the non-absorbent composition to the target species can be between 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 their embodiments, where the target species includes protons and at least one conjugate base, the binding forces listed in this paragraph are the theoretical binding force for protons and the theoretical binding force for conjugate bases, independently and individually and not For the sum.

In general, the non-absorbent composition will have a theoretical binding force for protons of at least about 0.5 mEq/g (as determined by SGF analysis). For example, in some embodiments, the non-absorbent composition will have a theoretical binding force for protons of at least about 1 mEq/g. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force for protons of at least about 2 mEq/g. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force for protons of at least about 3 mEq/g. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force for protons of at least about 4 mEq/g. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force for protons of at least about 5 mEq/g. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force for protons of at least about 7.5 mEq/g. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force for protons of at least about 10 mEq/g. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force for protons of at least about 12.5 mEq/g. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force for protons of at least about 15 mEq/g. By way of other examples, in some embodiments, the non-absorbent composition will have a theoretical binding force for protons of at least about 20 mEq/g. In general, non-absorbent compositions will generally have a theoretical binding force of no more than about 35 mEq/g for protons. For example, in some embodiments, the theoretical binding force of the non-absorbent composition to protons does not exceed 30 mEq/g. Thus, for example, the theoretical binding force of a non-absorbent composition to protons can be between 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 their embodiments, where the target species includes protons and at least one conjugate base, the binding forces listed in this paragraph are the theoretical binding force for protons and the theoretical binding force for conjugate bases, independently and individually and not For the sum.

Conjugate bases of phosphates, bicarbonates, bicarbonate equivalents, bile fluids and fatty acids are other conjugate bases for chlorine or strong acids in the stomach and small intestine (e.g. HSO ₄ ^- and SO ₄ ^2- ) Potentially interferes with anions. Therefore, there is a need for rapid and better binding of chlorine across phosphate and bicarbonate equivalents in the small intestine and conjugate bases of bile and fatty acids and SIB analysis can be used to determine kinetics and better binding. Because the transit time of the colon relative to the small intestine is slow (2-3 days), and because oral administration and non-absorption will not encounter the situation in the colon until the stomach and small intestine have been encountered, The chlorine binding kinetics of the absorbent composition does not have to be as fast as the colon or in vitro conditions designed to mimic the later small intestine/colon. However, there is a need for higher chloride binding and selectivity across other interfering anions, for example at 24 and/or 48 hours or longer.

In one embodiment, the non-absorbable composition is characterized by at least 1 mEq/g of chloride ion binding force in simulated small intestine inorganic buffer ("SIB") analysis. For example, in one such embodiment, the non-absorbent composition is characterized by a chloride ion binding capacity of at least 1.5 mEq/g in SIB analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a chloride ion binding force of at least 2 mEq/g in SIB analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a chloride ion binding force of at least 2.5 mEq/g in SIB analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a chloride ion binding force of at least 3 mEq/g in SIB analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a chloride ion binding force of at least 3.5 mEq/g in SIB analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a chloride ion binding force of at least 4 mEq/g in SIB analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a chloride ion binding force of at least 4.5 mEq/g in SIB analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a chloride ion binding force of at least 5 mEq/g in SIB analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a chloride ion binding force of at least 5.5 mEq/g in SIB analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a chloride ion binding force of at least 6 mEq/g in SIB analysis.

In one embodiment, as demonstrated in, for example, SIB analysis, the non-absorbent composition binds large amounts of chlorine relative to phosphate. For example, in one embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 0.1:1. By way of other examples, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 0.2:1. By way of further example, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 0.25:1. By way of other examples, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 0.3:1. By way of further example, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 0.35:1. By way of further example, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 0.4:1. By way of other examples, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 0.45:1. By way of other examples, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 0.5:1. By way of other examples, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is respectively at least 2:3. By way of further example, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 0.75:1. By way of further example, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 0.9:1. By way of other examples, in one such embodiment, the ratio of bound chlorine to bound phosphate in the SIB analysis is each at least 1:1. By way of other examples, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 1.25:1. By way of other examples, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 1.5:1. By way of other examples, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 1.75:1. By way of further example, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is respectively at least 2:1. By way of other examples, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 2.25:1. By way of other examples, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 2.5:1. By way of further example, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 2.75:1. By way of other examples, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 3:1. By way of other examples, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 4:1. By way of other examples, in one such embodiment, the ratio of the amount of bound chlorine to bound phosphate in the SIB analysis is each at least 5:1.

In one embodiment, the non-absorbable composition for oral administration is characterized by a proton binding capacity and a chlorine binding capacity in simulated gastric fluid of at least 1 mEq/g in SGF analysis. For example, in one such embodiment, the non-absorbent composition is characterized by a proton binding capacity and a chlorine binding capacity of at least 2 mEq/g in SGF analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton binding capacity and a chlorine binding capacity of at least 3 mEq/g in SGF analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton binding capacity and a chlorine binding capacity of at least 4 mEq/g in SGF analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton binding capacity and a chlorine binding capacity of at least 5 mEq/g in SGF analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton binding capacity and a chlorine binding capacity of at least 6 mEq/g in SGF analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton binding capacity and a chlorine binding capacity of at least 7 mEq/g in SGF analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton binding capacity and a chlorine binding capacity of at least 8 mEq/g in SGF analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton binding capacity and a chlorine binding capacity of at least 9 mEq/g in SGF analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton binding capacity and a chlorine binding capacity of at least 10 mEq/g in SGF analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton binding capacity and a chlorine binding capacity of at least 11 mEq/g in SGF analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton binding capacity and a chlorine binding capacity of at least 12 mEq/g in SGF analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton binding capacity and a chlorine binding capacity of at least 13 mEq/g in SGF analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton binding capacity and a chlorine binding capacity of at least 14 mEq/g in SGF analysis. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton binding force after 1 hour of SGF and a chlorine binding force are respectively the protons of the non-absorbent composition in SGF for 24 hours At least 50% of the binding power and chlorine binding power. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton-binding force and a chlorine-binding force after 1 hour in the SGF are each of the non-absorbent composition in the SGF for 24 hours At least 60% of proton binding capacity and chlorine binding capacity. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton-binding force and a chlorine-binding force after 1 hour in the SGF are each of the non-absorbent composition in the SGF for 24 hours At least 70% of proton binding capacity and chlorine binding capacity. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton-binding capacity and a chlorine-binding capacity after 1 hour in the SGF are each of the non-absorbent composition in the SGF for 24 hours At least 80% of proton binding capacity and chlorine binding capacity. By way of other examples, in one such embodiment, the non-absorbent composition is characterized by a proton-binding capacity and a chlorine-binding capacity after 1 hour in the SGF are each of the non-absorbent composition in the SGF for 24 hours At least 90% of proton binding capacity and chlorine binding capacity.

In one embodiment, the non-absorbable composition is a cation exchange material comprising an insoluble (in the stomach environment) support structure and exchangeable cations. The cation exchange material may be organic (eg, polymer), inorganic (eg, zeolite), or a composite thereof. The exchangeable cation may be selected from, for example, the group consisting of lithium, sodium, potassium, calcium, magnesium, iron, and combinations thereof, and more preferably from the group consisting of: sodium, potassium, calcium , Magnesium and their combinations. In such embodiments, it is generally preferred that the non-absorbent composition contains a combination of exchangeable cations that establish or maintain dynamic quiescence of the electrolyte. For example, in one such embodiment, the non-absorbable composition optionally contains exchangeable sodium ions, but when included, the amount of sodium ions in the daily dose is insufficient to increase the patient's serum sodium ion concentration beyond Values outside the range of 135 to 145 mEq/l. By way of other examples, in one such embodiment, the absorbent composition optionally contains exchangeable potassium ions, but when included, the amount of potassium ions in the daily dose is insufficient to increase the patient's serum potassium ion concentration beyond Values outside the range of 3.7 to 5.2 mEq/L. By way of other examples, in one such embodiment, the absorbent composition optionally contains exchangeable magnesium ions, but when included, the amount of magnesium ions in the daily dose is insufficient to increase the patient's serum magnesium ion concentration beyond Values outside the range of 1.7 to 2.2 mg/dL . By way of other examples, in one such embodiment, the absorbent composition optionally contains exchangeable calcium ions, but when included, the amount of calcium ions in the daily dose is insufficient to increase the patient's serum calcium ion concentration beyond Values outside the range of 8.5 to 10.2 mEq/L. By way of other examples, in one such embodiment, the non-absorbent composition contains a combination of exchangeable cations selected from the group consisting of: sodium, potassium, calcium, magnesium, and combinations thereof, designed to convert serum Na ⁺ The content is maintained in the range of 135 to 145 mEq/l, the serum K ⁺ content is maintained in the range of 3.7 to 5.2 mEq/l, the serum Mg ²⁺ content is maintained in the range of 1.7 to 2.2 mg/dL and the serum Ca ²⁺ content is maintained in In the range of 8.5 to 10.2 mg/dL.

In one embodiment, the non-absorbent composition is a cation exchange material that includes an insoluble (in the stomach environment) support structure, optionally containing exchangeable sodium ion cations. The cation exchange material may be organic (eg, polymer), inorganic (eg, molecular sieve), or a composite thereof. In one such embodiment, the non-absorbent composition contains less than 12% by weight sodium. For example, in one such embodiment, the non-absorbent composition contains less than 9% by weight sodium. By way of other examples, in one such embodiment, the non-absorbent composition contains less than 6% by weight sodium. By way of other examples, in one such embodiment, the non-absorbent composition contains less than 3% by weight sodium. By way of other examples, in one such embodiment, the non-absorbent composition contains less than 1% by weight sodium. By way of other examples, in one such embodiment, the non-absorbent composition contains less than 0.1% by weight sodium. By way of other examples, in one such embodiment, the non-absorbent composition contains less than 0.01% by weight sodium. By way of other examples, in one such embodiment, the non-absorbent composition contains between 0.05 and 3% by weight of sodium.

In an exemplary embodiment, the non-absorbent composition is a resin containing any of a wide range of cross-linked polymeric materials capable of binding protons in an aqueous solution. Exemplary cross-linked polymeric materials include polyanionic cross-linked materials selected from the group consisting of poly (carboxylic acid), poly (acrylic acid), poly (sulfonic acid), poly (maleic acid), poly (phenol), and functionalization Polyols and poly(ethanol), poly(hydroxamic acid), poly(amide) and their copolymers. In one embodiment, the polyanion is coordinated to exchangeable monovalent cations, divalent cations, or a combination thereof. Exemplary monovalent cations include lithium, sodium, and potassium, or any combination thereof. Exemplary divalent cations include magnesium and calcium or combinations thereof.

In an exemplary embodiment, the non-absorbent composition is a cation exchange resin comprising a polyanion backbone that exchanges cations with protons and has an average pKa of at least 4. For example, in one embodiment, the polyanion backbone has an average pKa of 4-5. By way of other examples, in one such embodiment, the polyanion backbone has an average pKa of 5-6. By way of other examples, in one such embodiment, the polyanion backbone has an average pKa of 6-7. By way of other examples, in one such embodiment, the polyanion backbone has an average pKa greater than 7. Exemplary cation exchange resins include poly(carboxylic acid), poly(acrylic acid), poly(sulfonic acid), poly(maleic acid), poly(phenol), functional polyols and poly(ethanol), poly(hydroxime) Acid), poly(acetylenimine) and its copolymers. In one embodiment, these polyanion backbones are further functionalized with functional groups to affect pKa. These functional groups can increase pKa when pushing electrons or decrease pKa when pulling electrons. Exemplary electron donating groups include amine groups, hydroxyl groups, methyl ether, ethers, phenyl groups, and amide groups. Exemplary electron-withdrawing groups include fluoro, chloro, halo, sulfonyl, nitro, trifluoromethyl, and cyano. Other exemplary cation exchange resins include resins modified with protonatable functional groups including carboxylic acids and functionalized ethanol.

A series of chemistries can be used to prepare polymeric cation exchanger resins, including, for example, (i) substituted polymerization of multifunctional reagents, at least one of which contains a basic anion or conjugate acid moiety, and (2) contains at least one containing an acid or conjugate Free radical polymerization of monomers in the acid moiety, and (3) crosslinking of intermediates containing basic anions or conjugated acids with polyfunctional crosslinking agents (containing basic anions or conjugated acid moieties as appropriate). The resulting cross-linked polymer may thus be, for example, a cross-linked homopolymer or a cross-linked copolymer. By way of other examples, the resulting cross-linked polymer will generally possess repeating units containing basic anions or conjugated acids, which are separated by repeating linker (or insertion) units of the same or different lengths. In some embodiments, the polymer includes repeating units that include basic anion or conjugate acid moieties and intervening linker units. In other embodiments, multiple basic anions or conjugate acids containing repeating units are separated by one or more linker units. In addition, the multifunctional cross-linking agent may contain proton-binding functional groups, such as basic anions ("active cross-linking agents"), or may lack proton-binding functional groups, such as acrylates ("passive cross-linking agents").

In some embodiments, the basic anionic or conjugated acid monomer is polymerized and the polymer is crosslinked in parallel in the substitution polymerization reaction. For the polymerization of substituents, the basic anion or conjugate acid reactant (monomer) in the parallel polymerization and crosslinking reaction can be reacted more than once. In one such embodiment, the basic anion or conjugate acid monomer is a branched chain basic anion or conjugate acid having at least two reactive moieties participating in the polymerization of the substituent.

In one embodiment, the non-absorbent composition comprises a cation exchange ceramic material. Porous inorganic binders exhibit a range of properties. Functionally, it can isolate the material based on its size and polarity, as it exhibits a frame charge with a porous structure. It is structurally different and can be crystalline or non-crystalline (amorphous). The porous materials that belong to the category of inorganic binders include hydrated oxides (such as alumina) and metal aluminum silicate compounds, where the metal can be an alkali or alkaline earth metal, such as sodium, potassium, lithium, magnesium, or calcium. Many of these compounds have well-defined crystal structures. This compound class has been used in various biopharmaceutical applications.

The pore size of inorganic microporous and mesoporous materials is measured in units of angstroms (Å) or nanometers (nm). According to IUPAC markings, microporous materials have a pore size of less than 2 nm (20Å) and macroporous materials have a pore size of more than 50 nm (500Å); the mesopore category is therefore with a pore size between 2 and 50 nm (20-500Å) In the middle. The porosity of inorganic porous materials can be tuned or designed by appropriately using pores or "comonomer metals" in the lattice of the porous materials. With proper selection of elements, it has been found that the pore size varies from 3Å to 8Å. These compositions have a porous system that allows solutes, along with other dissolved species, to enter the porous framework of the material so that dissolved species are absorbed. The cavity and pore size of the tuning material can allow molecules of a certain size to be absorbed while rejecting molecules of a larger size. According to the combined perspective view using the size as the selection mechanism, the chloride ion has the advantage of smaller size compared to other species present in the digestive tract (the radius of the chloride anion is 1.8Å and the molecular weight of the chloride anion is 35.5).

Exemplary cation exchange ceramic materials include any of a wide range of microporous or mesoporous ceramic materials. In one embodiment, the non-absorbent composition includes a molecular sieve, such as a molecular sieve selected from the group consisting of: silicon dioxide, titanosilicate, metalloaluminate, aluminum phosphate, and gallogerate ) Molecular sieve. In one embodiment, the non-absorbent composition comprises zeolite, borosilicate, gallosilicate, ferrisilicate, chromosilicate molecular sieve.

Inorganic porous materials exhibit properties that isolate substances from the external environment. The mechanism of binding protons or chlorine or HCl may be an adsorption or absorption mechanism in which ions are bound via a specific porosity of the matrix or ion exchange mechanism. The strong adsorption force in the zeolite molecular sieve is due to the polarity of the surface (hydroxyl metal) and the cations exposed in the crystal lattice. The cations on the surface act as sites for the strong local positive charge of the partial negative charge (such as chlorine of HCl) that electrostatically attracts polar molecules. The basic formula for zeolite can be expressed as M _{2 /n} O.Al ₂ O ₃ .xSiO ₂ .yH ₂ O, where M is an n-valent cation. The basic building block of the molecular sieve structure is a tetrahedron with 4 oxygen anions surrounded by silicon or alumina cations. Sodium ions or other cations (eg, potassium, calcium) constitute a positive charge that lacks alumina tetrahedra to extend the crystal lattice. In multiple molecular sieve types, sodium can be exchanged or sodium can serve as a permanent positive charge within the crystal lattice, thus providing electrostatic interaction. In consideration of these mechanisms, hydrochloric acid can be isolated from the solution via a cation exchange mechanism (sodium exchanged protons), an anion exchange mechanism (hydroxide exchanged chlorine), or through the electrostatic interaction of hydrochloric acid ion species.

Methods for binding HCl are well known in the art and involve contacting the molecular sieve with a solution containing water containing the desired concentration of HCl. The exchange conditions include a temperature of about 25°C to about 100°C and a time of about 20 minutes to about 2 hours. These conditions include conditions encountered in the gastrointestinal tract and exposure time.

In one embodiment, the non-absorbent composition is an anion exchange material comprising an insoluble (in the stomach environment) support structure and exchangeable anions. The anion exchange material may be organic (e.g. polymerizable), inorganic (e.g. hydrated gel of apatite, hydrotalcite or aluminum hydroxide, iron (III) or zirconium) or a composite thereof.

In one embodiment, the non-absorbent composition includes an anion exchange material. Exemplary anion exchange materials include strong and weakly basic anion exchange materials. For example, the anion exchange material may include any of a wide range of polymers including quaternary amine moieties, phosphonium salts, N-heteroaromatic salts, or combinations thereof. Other exemplary anion exchange materials include poly(ionic liquids), where the side chain is selected from the group consisting of salts of tetraalkylammonium, imidazolium, pyridinium, pyrrolidinium, guanidinium, piperidinium and Tetraalkylphosphonium cations and combinations thereof. By way of other examples, in one such embodiment, the anion exchange material halogenates the reactive polymer such that when chlorine from about 1 mEq/g to about 35 mEq/g is initially bound to the polymer and then maintained for the duration of the GI passage time A conformational change occurs. In certain embodiments, the halogenation reaction conformation changes when combining 2 mEq/g to about 25 mEq/g chlorine, and in certain more specific embodiments, when combining 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. The polymerization main chain of any of the foregoing polymers may be derived from vinyl, allyl, styrene, acrylamide, methyl (acrylamide) or copolymers thereof. By means of other examples, anion exchange functional groups can be incorporated into the main chain of the polymer. Examples include poly(tetraalkylammonium), poly(imidazolium), poly(pyridine), poly(pyrrolidinium), poly(piperidinium), and poly(tetraalkylphosphonium) cations or combinations thereof. The exchangeable anions can be composed of hydroxide, bicarbonate, acetate, nitrate, or any pharmaceutically and biologically acceptable base or combination thereof.

In one embodiment, the non-absorbent composition is an anion exchange material containing at least 1 mEq/g anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate, etc. Effect anions or combinations thereof. In this embodiment, the non-absorbable composition has a serum that at least partially induces an individual by delivering physiologically large amounts of hydroxide, carbonate, citrate, or other bicarbonate equivalent anions or combinations thereof The ability to increase the bicarbonate value. Exemplary bicarbonate equivalent anions include acetate, lactate and other conjugate bases of short chain carboxylic acids. In one such embodiment, the non-absorbent composition contains an anion of at least 2 mEq/g selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent Substance anion. By way of other examples, in one such embodiment, the non-absorbent composition contains at least 3 mEq/g of anions selected from the group consisting of hydroxide, carbonate, citrate or other Bicarbonate equivalent anion. By way of other examples, in one such embodiment, the non-absorbent composition contains at least 4 mEq/g anions selected from the group consisting of hydroxide, carbonate, citrate or other carbonate Hydrogen salt equivalent anion. By way of other examples, in one such embodiment, the non-absorbent composition contains at least 5 mEq/g of anions selected from the group consisting of hydroxide, carbonate, citrate, or other Bicarbonate equivalent anion.

In one embodiment, the non-absorbent composition is an anion exchange material containing less than 10 mEq/g anions selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate Equivalent anions or combinations thereof. In one such embodiment, the non-absorbent composition contains an anion of less than 7.5 mEq/g selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent Substance anion. By way of other examples, in one such embodiment, the non-absorbent composition contains less than 5 mEq/g of anions selected from the group consisting of hydroxide, carbonate, citrate, or other Bicarbonate equivalent anion. By way of other examples, in one such embodiment, the non-absorbent composition contains an anion of less than 2.5 mEq/g selected from the group consisting of hydroxide, carbonate, citrate or other Bicarbonate equivalent anion. By way of other examples, in one such embodiment, the non-absorbent composition contains less than 1 mEq/g anion selected from the group consisting of hydroxide, carbonate, citrate or other carbonate Hydrogen salt equivalent anion. By way of other examples, in one such embodiment, the non-absorbent composition contains less than 0.1 mEq/g of anions selected from the group consisting of hydroxide, carbonate, citrate or other Bicarbonate equivalent anion.

In one embodiment, the non-absorbent composition comprises amphoteric ion exchange resin. Exemplary amphoteric ion exchange resins include cross-linked polystyrene, polyethylene or the like as a base material and (i) a fourth ammonium group with the same side group (e.g., betaine-containing side group), carboxylic acid group and their Similar groups, such as amphoteric resins sold under the trade name DIAION AMP03 (Mitsubishi Chemical Corporation) or (ii) different pendant groups (eg mixed charged copolymers containing residues of at least two different monomers, one containing ammonium groups and A carboxylic acid group) to provide ion exchange function between cation and negative ion. Exemplary amphoteric ion exchange resins containing exchange sites for mixtures of cations and anions also include resins in which linear polymers reside inside the cross-linked ion exchange resins, such as the amphoteric resins sold under the trade name DOWEX™ Retardion 11A8 (Dow Chemical Company).

In one embodiment, the non-absorbent composition includes a neutral composition having the ability to bind both protons and anions. Exemplary neutral non-absorbent compositions that combine both protons and anions include polymers functionalized with propylene oxide, Michael acceptors, expanded porphyrins, covalently framed functionalized polymers and containing Amine and/or phosphine functional polymer.

In those embodiments where the non-absorbable composition combines chloride ions, it is generally preferred that the non-absorbable composition is relative to other counterions, such as bicarbonate equivalent anions, phosphate anions, and bile and fatty acids. Conjugate base to selectively bind chloride ion. In other words, in these embodiments, it is generally preferred that its non-absorbent composition (i) remove more chloride ions than the bicarbonate equivalent anion; (ii) remove more chloride ions than phosphate anions Chloride ion removal; and (iii) removing more chloride ions than the conjugate base of bile fluid and fatty acids. Advantageously, treatment with a non-absorbable composition does not induce or aggravate hypophosphatemia (ie, a serum phosphorus concentration of less than about 2.4 mg/dL does not significantly increase low-density lipoprotein ("LDL"), or It adversely affects the metabolic-related anion content of serum or colon in other ways.

式1 其中R₁ 、R₂ 及R₃ 獨立地為所提供之氫、烴基或經取代烴基，然而，R₁ 、R₂ 及R₃ 中之至少一者不為氫。換言之，R₁ 、R₂ 及R₃ 中之至少一者為烴基或經取代烴基，且R₁ 、R₂ 及R₃ 之其他獨立地為氫、烴基或經取代烴基。在一個實施例中，例如，R₁ 、R₂ 及R₃ 獨立地為所提供之氫、芳基、脂族基、雜芳基或雜脂族基，然而，R₁ 、R₂ 及R₃ 中無一者為氫。藉助於其他實例，在一個此類實施例中，R₁ 、R₂ 及R₃ 獨立地為所提供之氫、飽和烴、不飽和脂族基、不飽和雜脂族基、雜烷基、雜環、芳基或雜芳基，然而，R₁ 、R₂ 及R₃ 中無一者為氫。藉助於其他實例，在一個此類實施例中，R₁ 、R₂ 及R₃ 獨立地為所提供之氫、烷基、烯基、烯丙基、乙烯基、芳基、胺基烷基、烷醇、鹵烷基、羥基烷基、醚、雜芳基或雜環，然而，R₁ 、R₂ 及R₃ 中無一者為氫。藉助於其他實例，在一個此類實施例中，R₁ 、R₂ 及R₃ 獨立地為所提供之氫、烷基、胺基烷基、烷醇、芳基、鹵烷基、羥基烷基、醚、雜芳基或雜環，然而，R₁ 、R₂ 及R₃ 中無一者為氫。藉助於其他實例，在一個此類實施例中，R₁ 及R₂ (結合其所附接之氮原子)一起構成環結構之部分，使得如藉由式1所描述之單體為含氮雜環(例如哌啶)且R₃ 為氫或雜脂族基。藉助於其他實例，在一個實施例中，R₁ 、R₂ 及R₃ 獨立地為所提供之氫、脂族基或雜脂族基，然而，R₁ 、R₂ 及R₃ 中之至少一者不為氫。藉助於其他實例，在一個實施例中，R₁ 、R₂ 及R₃ 獨立地為氫、烯丙基或胺基烷基。In some embodiments, the pharmaceutical composition comprises a cross-linked polymer containing amine residues, the residues corresponding to formula 1:

Formula 1 wherein R ₁ , R ₂ and R _{3 are} independently hydrogen, hydrocarbon group or substituted hydrocarbon group provided, however, at least one of R ₁ , R ₂ and R ₃ is not hydrogen. In other words, at least one of R ₁ , R ₂ and R ₃ is a hydrocarbon group or a substituted hydrocarbon group, and the others of R ₁ , R ₂ and R _{3 are} independently hydrogen, a hydrocarbon group or a substituted hydrocarbon group. In one embodiment, for example, R ₁ , R ₂ and R _{3 are} independently provided hydrogen, aryl, aliphatic, heteroaryl or heteroaliphatic groups, however, R ₁ , R ₂ and R ₃ None of them is hydrogen. By way of other examples, in one such embodiment, R ₁ , R _2, and R _{3 are} independently provided hydrogen, saturated hydrocarbon, unsaturated aliphatic group, unsaturated heteroaliphatic group, heteroalkyl, hetero Ring, aryl or heteroaryl, however, none of R ₁ , R ₂ and R ₃ is hydrogen. By way of other examples, in one such embodiment, R ₁ , R ₂ and R _{3 are} independently provided hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, Alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl or heterocyclic ring, however, none of R ₁ , R ₂ and R ₃ is hydrogen. By way of other examples, in one such embodiment, R ₁ , R ₂ and R _{3 are} independently provided hydrogen, alkyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl , Ether, heteroaryl or heterocycle, however, none of R ₁ , R ₂ and R ₃ is hydrogen. By way of other examples, in one such embodiment, R ₁ and R ₂ (in combination with the nitrogen atom to which they are attached) together form part of the ring structure so that the monomer as described by Formula 1 is a nitrogen-containing hetero Ring (eg piperidine) and R ₃ is hydrogen or heteroaliphatic. By way of other examples, in one embodiment, R ₁ , R ₂ and R _{3 are} independently hydrogen, aliphatic or heteroaliphatic groups provided, however, at least one of R ₁ , R ₂ and R ₃ Those are not hydrogen. By way of other examples, in one embodiment, R ₁ , R _2, and R _{3 are} independently hydrogen, allyl, or aminoalkyl.

In one embodiment, the cross-linked polymer contains residues corresponding to the amine of Formula 1, wherein R ₁ , R ₂ and R _{3 are} independently hydrogen, heteroaryl, aryl, aliphatic or heterocyclic provided An aliphatic group, however, at least one of R ₁ , R ₂ and R ₃ is an aryl group or a heteroaryl group. For example, in this embodiment, R ₁ and R _{2 in} combination with the nitrogen atom to which they are attached may form a saturated or unsaturated nitrogen-containing heterocyclic ring. By means of other examples, R ₁ and R _{2 in} combination with the nitrogen atom to which they are attached may constitute pyrrolidinyl, pyrrole, pyrazolidine, pyrazole, imidazolidine, imidazole, piperidine, pyridine, piperazine, diazine or triazine Part of the azine ring structure. By way of other examples, R ₁ and R _{2 in} combination with the nitrogen atom to which they are attached may constitute part of the piperidine ring structure.

In one embodiment, the cross-linked polymer contains residues corresponding to the amine of Formula 1, where R ₁ , R ₂ and R _{3 are} independently hydrogen, aliphatic or heteroaliphatic groups provided, however, R ₁ , at least one of R ₂ and R ₃ is not hydrogen. For example, in this embodiment, R ₁ , R ₂ and R ₃ may independently be hydrogen, alkyl, alkenyl, allyl, vinyl, aminoalkyl, alkanol, haloalkane provided Group, hydroxyalkyl group, ether or heterocycle, however, at least one of R ₁ , R ₂ and R ₃ is not hydrogen. By way of other examples, in one such embodiment, R ₁ and R _{2 in} combination with the nitrogen atom to which they are attached may form a saturated or unsaturated nitrogen-containing heterocyclic ring. By way of other examples, in one such embodiment, R ₁ and R _{2 in} combination with the nitrogen atom to which they are attached may constitute pyrrolidinyl, pyrrole, pyrazolidine, pyrazole, imidazolidine, imidazole, piperidine, piper Part of the azine or diazine ring structure. By way of other examples, in one such embodiment, R ₁ and R _{2 in} combination with the nitrogen atom to which they are attached may constitute part of the piperidine ring structure. By way of other examples, in one such embodiment, the amine corresponding to Formula 1 is acyclic and at least one of R ₁ , R _2, and R ₃ is an aliphatic group or a heteroaliphatic group. By way of other examples, in one such embodiment, R ₁ , R ₂ and R _{3 are} independently hydrogen, alkyl, allyl, vinyl, alicyclic, aminoalkyl, alkanol or heterocyclic ring, If at least one of R ₁ , R ₂ and R ₃ is not hydrogen.

In one embodiment, the cross-linked polymer comprises residues corresponding to the amine of formula 1 and the cross-linked polymer is substituted by the amine corresponding to formula 1 and a multifunctional cross-linking agent (and optionally an amine moiety) Preparation by radical polymerization, where R ₁ , R ₂ and R _{3 are} independently hydrogen, alkyl, aminoalkyl or alkanol, provided that at least one of R ₁ , R ₂ and R ₃ is not hydrogen.

In some embodiments, the molecular weight/nitrogen of the polymers of the present disclosure may range from about 40 to about 1000 Daltons. In one embodiment, the molecular weight/nitrogen of the polymer is from about 40 to about 500 Daltons. In another embodiment, the molecular weight/nitrogen of the polymer is from about 50 to about 170 Daltons. In another embodiment, the molecular weight/nitrogen of the polymer is from about 60 to about 110 Daltons.

In some embodiments, the amine-containing monomer is polymerized and the polymer is crosslinked in parallel in the first reaction step in the substituent polymerization reaction. For the polymerization of substituents, the amine reactant (monomer) in the parallel polymerization and crosslinking reaction can be reacted more than once. In one such embodiment, the amine monomer is a linear amine having at least two reactive amine moieties that participate in the polymerization of the substituent. In another embodiment, the amine monomer is a branched amine having at least two reactive amine moieties participating in the polymerization of the substituent. The cross-linking agents used for parallel substituent polymerization and cross-linking typically have at least two amine reaction moieties, such as alkyl chlorides and alkyl epoxides. For incorporation into the polymer, the primary amine can react with the crosslinking agent at least once and potentially react up to three times, the secondary amine can react with the crosslinking agent up to two times, and the tertiary amine can only react once with the crosslinking agent . In general, however, since quaternary amines cannot bind protons, it is generally not preferable to form a significant amount of quaternary nitrogen/amine.

Exemplary amines that can be used in the substituent polymerization described herein include 1,3-bis[bis(2-aminoethyl)amino]propane, 3-amino-1-{[2-(bis{ 2-[bis(3-aminopropyl)amino]ethyl}amino)ethyl](3-aminopropyl)amino}propane, 2-[bis(2-aminoethyl)amine Group] ethylamine, 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-A 1,3-Diaminopropane, 3,3'-diamine-N-methyldipropylamine, 1,3-diaminopentane, 1,2-diamine-2-methylpropane, 2 -Methyl-1,5-diaminopentane, 1,2-diaminopropane, 1,10-diaminodecane, 1,8-diaminooctane, 1,9-diamino Octane, 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-diamine-2- Propanol, N-ethylethylenediamine, 2,2'-diamine-N-methyldiethylamine, N,N'-diethylethylenediamine, N-isopropylethylenediamine, N- Methylethylenediamine, N,N'-di-third-butylethylenediamine, N,N'-diisopropylethylenediamine, N,N'-dimethylethylenediamine, N-butyl Ethylenediamine, 2-(2-aminoethylamino)ethanol, 1,4,7,10,13,16-hexaazacyclooctadecane, 1,4,7,10-tetraazaheterocycle Dodecane, 1,4,7-triazanonane, N,N'-bis(2-hydroxyethyl)ethylenediamine, piperazine, bis(hexyl)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.

Exemplary cross-linking agents that can be used in substituent polymerization and post-polymerization cross-linking reactions include (but are not limited to) one or more multifunctional cross-linking agents, such as: dihaloalkane, haloalkyl ethylene oxide, alkyl ring Alkyloxirane sulfonates, di(haloalkyl)amine, tri(haloalkyl)amine, diepoxide, triepoxide, tetraepoxide, bis(halomethyl)benzene, Tri(halomethyl)benzene, tetra(halomethyl)benzene, epihalohydrin, such as epichlorohydrin and epibromohydrin poly(epichlorohydrin), (iodomethyl)ethylene oxide, toluenesulfonic acid ring Oxypropyl ester, 3-nitrobenzenesulfonic acid glycidyl ester, 4-toluenesulfonyloxy-1,2-butylene oxide, bromine-1,2-butylene oxide, 1,2-dibromo Ethane, 1,3-dichloropropane, 1,2-dichloroethane, l-bromo-2-chloroethane, 1,3-dibromopropane, bis(2-chloroethyl)amine, tri( 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 Ether, 1,2 ethylene glycol diglycidyl ether, glycerol diglycidyl ether, 1,3-diglycidyl glyceryl ether, N,N-diglycidyl aniline, neopentyl glycol diglycidyl ether, di Ethylene glycol diglycidyl ether, 1,4-bis(glycidyloxy)benzene, resorcinol diglycidyl ether, 1,6-hexanediol diglycidyl ether, trimethylolpropane diglycidyl Glycerol ether, 1,4-cyclohexanedimethanol diglycidyl ether, 1,3-bis-(2,3-epoxypropoxy)-2-(2,3-dihydroxypropoxy)propane, 1,2-Cyclohexanedicarboxylic acid diglycidyl ester, 2,2'-bis(glycidoxy)diphenylmethane, bisphenol F diglycidyl ether, 1,4-bis(2',3 'Epoxypropyl) perfluoro-n-butane, 2,6-bis(ethylene oxide-2-ylmethyl, 1,2,3,5,6,7-hexahydropyrrolo[3, 4-f]isoindole-1,3,5,7-tetraone, bisphenol A diglycidyl ether, 5-hydroxy-6,8-di(ethylene oxide-2-ylmethyl)-4 -Ethoxy 4-h-benzopiperan-2-carboxylic acid ethyl ester, bis[4-(2,3-epoxy-propylthio)phenyl]-sulfide, 1,3- Bis(3-glycidoxypropyl)tetramethyldisilaxane, 9,9-bis[4-(glycidoxy)phenyl] fluorine, triepoxyisocyanurate, triglyceride Glycidyl ether, N,N-diglycidyl-4-glycidyl aniline, isocyanuric acid (S,S,S)-triglycidyl ester, isocyanuric acid (R,R,R)-triglycidyl Ester, triglycidyl isocyanurate, trimethylolpropane triglycidyl ether, glycerol propoxy triglycidyl ether, triphenylmethane triglycidyl ether, 3,7,14-tris[[3-(ring Oxypropyloxy)propyl]dimethylsiloxy]-1,3,5, 7,9,11,14-heptylcyclopentyl tricyclo[7,3,3,15,11]heptasiloxane, 4,4' methylene bis(N,N-diglycidylaniline), Bis(halomethyl)benzene, bis(halomethyl)biphenyl and bis(halomethyl)naphthalene, toluene diisocyanate, acryloyl chloride, methyl acrylate, ethylene bisacrylamide, pyrrole metal dianhydride (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, tri[(2 -Epoxyethyl)methyl]amine.

In some embodiments, the carbon to nitrogen ratio of the polymers of the present disclosure may range from about 2:1 to about 6:1, respectively. For example, in one such embodiment, the carbon to nitrogen ratio of the polymers of the present disclosure may be individually in the range of about 2.5:1 to about 5:1. By way of other examples, in one such embodiment, the carbon to nitrogen ratio of the polymers of the present disclosure may be individually in the range of about 3:1 to about 4.5:1. By way of other examples, in one such embodiment, the carbon to nitrogen ratio of the polymers of the present disclosure may individually range from about 3.25:1 to about 4.25:1. By way of other examples, in one such embodiment, the carbon to nitrogen ratio of the polymers of the present disclosure may be individually in the range of about 3.4:1 to about 4:1. In another embodiment, the molecular weight/nitrogen of the polymer is from about 60 to about 110 Daltons.

式1a 其中R₄ 及R₅ 獨立地為氫、烴基或經取代烴基。在一個實施例中，例如，R₄ 及R₅ 獨立地為氫、飽和烴、不飽和脂族基、芳基、雜芳基、不飽和雜脂族基、雜環或雜烷基。藉助於其他實例，在一個此類實施例中，R₄ 及R₅ 獨立地為氫、脂族基、雜脂族基、芳基或雜芳基。藉助於其他實例，在一個此類實施例中，R₄ 及R₅ 獨立地為氫、烷基、烯基、烯丙基、乙烯基、芳基、胺基烷基、烷醇、鹵烷基、羥基烷基、醚、雜芳基或雜環。藉助於其他實例，在一個此類實施例中，R₄ 及R₅ 獨立地為氫、烷基、烯丙基、胺基烷基、烷醇、芳基、鹵烷基、羥基烷基、醚或雜環。藉助於其他實例，在一個此類實施例中，R₄ 及R₅ (結合其所附接之氮原子)一起構成環結構之部分，使得如藉由式1a所描述之單體為含氮雜環(例如哌啶)。藉助於其他實例，在一個實施例中，R₄ 及R₅ 獨立地為氫、脂族基或雜脂族基。藉助於其他實例，在一個實施例中，R₄ 及R₅ 獨立地為氫、烯丙基或胺基烷基。In some embodiments, the cross-linked polymer includes residues corresponding to the amine of Formula 1a, and the cross-linked polymer is prepared by free radical polymerization of the amine corresponding to Formula 1a:

Formula 1a wherein R ₄ and R _{5 are} independently hydrogen, hydrocarbyl or substituted hydrocarbyl. In one embodiment, for example, R ₄ and R _{5 are} independently hydrogen, saturated hydrocarbon, unsaturated aliphatic group, aryl group, heteroaryl group, unsaturated heteroaliphatic group, heterocycle, or heteroalkyl group. By way of other examples, in one such embodiment, R ₄ and R _{5 are} independently hydrogen, aliphatic, heteroaliphatic, aryl, or heteroaryl. By way of other examples, in one such embodiment, R ₄ and R _{5 are} independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl , Hydroxyalkyl, ether, heteroaryl or heterocycle. By way of other examples, in one such embodiment, R ₄ and R _{5 are} independently hydrogen, alkyl, allyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ether Or heterocycle. By way of other examples, in one such embodiment, R ₄ and R ₅ (in combination with the nitrogen atom to which they are attached) together form part of the ring structure so that the monomer as described by formula 1a is a nitrogen-containing hetero Ring (eg piperidine). By way of other examples, in one embodiment, R ₄ and R _{5 are} independently hydrogen, aliphatic, or heteroaliphatic. By way of other examples, in one embodiment, R ₄ and R _{5 are} independently hydrogen, allyl, or aminoalkyl.

式1b 其中R₄ 及R₅ 獨立地為氫、烴基或經取代烴基，R₆ 為脂族基且R₆₁ 及R₆₂ 獨立地為氫、脂族基或雜脂族基。在一個實施例中，例如，R₄ 及R₅ 獨立地為氫、飽和烴、不飽和脂族基、芳基、雜芳基、雜烷基或不飽和雜脂族基。藉助於其他實例，在一個此類實施例中，R₄ 及R₅ 獨立地為氫、脂族基、雜脂族基、芳基或雜芳基。藉助於其他實例，在一個此類實施例中，R₄ 及R₅ 獨立地為氫、烷基、烯基、烯丙基、乙烯基、芳基、胺基烷基、烷醇、鹵烷基、羥基烷基、醚、雜芳基或雜環。藉助於其他實例，在一個此類實施例中，R₄ 及R₅ 獨立地為氫、烷基、烯基、胺基烷基、烷醇、芳基、鹵烷基、羥基烷基、醚、雜芳基或雜環。藉助於其他實例，在一個此類實施例中，R₄ 及R₅ (結合其所附接之氮原子)一起構成環結構之部分，使得如藉由式1a所描述之單體為含氮雜環(例如哌啶)。藉助於其他實例，在一個實施例中，R₄ 及R₅ 獨立地為氫、脂族基或雜脂族基。藉助於其他實例，在一個實施例中，R₄ 及R₅ 獨立地為氫、烯丙基或胺基烷基。藉助於其他實例，在此段落列舉之各實施例中，R₆ 可為亞甲基、乙烯或丙烯，且R₆₁ 及R₆₂ 可獨立地為氫、烯丙基或胺基烷基。In some embodiments, the cross-linked polymer includes residues corresponding to the amine of Formula 1b, and the cross-linked polymer is composed of an amine corresponding to Formula 1b and a multifunctional cross-linking agent (and optionally an amine moiety) Substitution polymerization preparation:

Formula 1b wherein R ₄ and R _{5 are} independently hydrogen, a hydrocarbon group or a substituted hydrocarbon group, R ₆ is an aliphatic group and R ₆₁ and R _{62 are} independently a hydrogen, aliphatic group or heteroaliphatic group. In one embodiment, for example, R ₄ and R _{5 are} independently hydrogen, saturated hydrocarbon, unsaturated aliphatic group, aryl group, heteroaryl group, heteroalkyl group, or unsaturated heteroaliphatic group. By way of other examples, in one such embodiment, R ₄ and R _{5 are} independently hydrogen, aliphatic, heteroaliphatic, aryl, or heteroaryl. By way of other examples, in one such embodiment, R ₄ and R _{5 are} independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl , Hydroxyalkyl, ether, heteroaryl or heterocycle. By way of other examples, in one such embodiment, R ₄ and R _{5 are} independently hydrogen, alkyl, alkenyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ether, Heteroaryl or heterocycle. By way of other examples, in one such embodiment, R ₄ and R ₅ (in combination with the nitrogen atom to which they are attached) together form part of the ring structure so that the monomer as described by formula 1a is a nitrogen-containing hetero Ring (eg piperidine). By way of other examples, in one embodiment, R ₄ and R _{5 are} independently hydrogen, aliphatic, or heteroaliphatic. By way of other examples, in one embodiment, R ₄ and R _{5 are} independently hydrogen, allyl, or aminoalkyl. By way of other examples, in the embodiments listed in this paragraph, R ₆ may be methylene, ethylene, or propylene, and R ₆₁ and R ₆₂ may independently be hydrogen, allyl, or aminoalkyl.

式1c 其中R₇ 為氫、脂族基或雜脂族基且R₈ 為脂族基或雜脂族基。舉例而言，在一個此類實施例中，例如R₇ 為氫且R₈ 為脂族基或雜脂族基。藉助於其他實例，在一個實施例中，R₇ 及R₈ 獨立地脂族基或雜脂族基。藉助於其他實例，在一個此類實施例中，R₇ 及R₈ 中之至少一者包含烯丙基部分。藉助於其他實例，在一個此類實施例中，R₇ 及R₈ 中之至少一者包含胺基烷基部分。藉助於其他實例，在一個此類實施例中，R₇ 及R₈ 各自包含烯丙基部分。藉助於其他實例，在一個此類實施例中，R₇ 及R₈ 各自包含胺基烷基部分。藉助於其他實例，在一個此類實施例中，R₇ 包含烯丙基部分且R₈ 包含胺基烷基部分。In some embodiments, the cross-linked polymer contains residues corresponding to the amine of Formula 1c:

Formula 1c wherein R ₇ is hydrogen, an aliphatic group or a heteroaliphatic group and R ₈ is an aliphatic group or a heteroaliphatic group. For example, in one such embodiment, for example, R ₇ is hydrogen and R ₈ is an aliphatic or heteroaliphatic group. By way of other examples, in one embodiment, R ₇ and R _{8 are} independently aliphatic or heteroaliphatic. By way of other examples, in one such embodiment, at least one of R ₇ and R ₈ includes an allyl moiety. By way of other examples, in one such embodiment, at least one of R ₇ and R ₈ includes an aminoalkyl moiety. By way of other examples, in one such embodiment, R ₇ and R ₈ each include an allyl moiety. By way of other examples, in one such embodiment, R ₇ and R ₈ each include an aminoalkyl moiety. By way of other examples, in one such embodiment, R ₇ includes an allyl moiety and R ₈ includes an aminoalkyl moiety.

式2 其中 m及n獨立地為非負整數； R₁₀ 、R₂₀ 、R₃₀ 及R₄₀ 獨立地為氫、烴基或經取代烴基； X₁ 為

； X₂ 為烴基或經取代烴基； 各X₁₁ 獨立地為氫、烴基、經取代烴基、羥基、胺基、

酸或鹵基；以及 z為非負數。In some embodiments, the cross-linked polymer contains residues corresponding to the amine of Formula 2:

Formula 2 where m and n are independently non-negative integers; R ₁₀ , R ₂₀ , R ₃₀ and R _{40 are} independently hydrogen, hydrocarbyl or substituted hydrocarbyl; X ₁ is

; X ₂ is a hydrocarbon group or a substituted hydrocarbon group; each X _{11 is} independently hydrogen, a hydrocarbon group, a substituted hydrocarbon group, a hydroxyl group, an amine group,

Acid or halo; and z is a non-negative number.

In one embodiment, the cross-linked polymer contains residues corresponding to the amine of formula 2, and the cross-linked polymer is obtained by (1) the amine corresponding to formula 2 and a multifunctional cross-linking agent (optionally including an amine moiety ) Of the substituent polymerization or (2) the radical polymerization of the amine corresponding to formula 2 is prepared, and m and n are independently 0, 1, 2 or 3 and n is 0 or 1.

In one embodiment, the cross-linked polymer includes residues corresponding to the amine of formula 2, the cross-linked polymer is (1) the amine corresponding to formula 2 and a multifunctional cross-linking agent (including an amine moiety as needed ) Substituent polymerization or (2) the radical polymerization corresponding to the amine of formula 2 and R ₁₀ , R ₂₀ , R ₃₀ and R _{40 are} independently hydrogen, aliphatic, aryl, heteroaliphatic or Heteroaryl. By way of other examples, in one such embodiment, R ₁₀ , R ₂₀ , R ₃₀ and R _{40 are} independently hydrogen, aliphatic or heteroaliphatic. By way of other examples, in one such embodiment, R ₁₀ , R ₂₀ , R ₃₀ and R _{40 are} independently hydrogen, alkyl, allyl, vinyl or aminoalkyl. By way of other examples, in one such embodiment, R ₁₀ , R ₂₀ , R ₃₀ and R _{40 are} independently hydrogen, alkyl, allyl, vinyl, -(CH ₂ ) _d NH ₂ , -( CH ₂ ) _d N[(CH ₂ ) _e NH ₂ )] ₂ , where d and e are independently 2-4. In each of the aforementioned exemplary embodiments of this paragraph, m and z may independently be 0, 1, 2, or 3 and n is 0 or 1.

In one embodiment, the cross-linked polymer includes residues corresponding to the amine of formula 2, the cross-linked polymer is (1) the amine corresponding to formula 2 and a multifunctional cross-linking agent (including an amine moiety as needed ) Substituent polymerization or (2) the radical polymerization corresponding to the amine of formula 2 is prepared, and X ₂ is an aliphatic group or a heteroaliphatic group. For example, in one such embodiment, X ₂ is an aliphatic group or a heteroaliphatic group, and R ₁₀ , R ₂₀ , R ₃₀ and R _{40 are} independently hydrogen, an aliphatic group, a heteroaliphatic group. By way of other examples, in one such embodiment, X ₂ is alkyl or aminoalkyl, and R ₁₀ , R ₂₀ , R _30, and R _{40 are} independently hydrogen, aliphatic, or heteroaliphatic. By way of other examples, in one such embodiment, X ₂ is alkyl or aminoalkyl, and R ₁₀ , R ₂₀ , R ₃₀ and R _{40 are} independently hydrogen, alkyl, allyl, vinyl Or aminoalkyl. In each of the aforementioned exemplary embodiments of this paragraph, m and z may independently be 0, 1, 2, or 3 and n is 0 or 1.

In one embodiment, the cross-linked polymer contains residues corresponding to the amine of formula 2, and the cross-linked polymer is obtained by (i) the amine corresponding to formula 2 and a multifunctional cross-linking agent (optionally including an amine moiety ) Of the substituent group polymerization or (2) corresponding to the formula 2 amine radical polymerization prepared, and m is a positive integer. For example, in one such embodiment, m is a positive integer, z is zero, and R ₂₀ is hydrogen, aliphatic or heteroaliphatic. By way of other examples, in one such embodiment, m is a positive integer (eg, 1 to 3), z is a positive integer (eg, 1 to 2), X ₁₁ is hydrogen, an aliphatic group or a heteroaliphatic group, and R ₂₀ is hydrogen, an aliphatic group or a heteroaliphatic group. By way of other examples, in one such embodiment, m is a positive integer, z is zero, one, or two, X ₁₁ is hydrogen, alkyl, alkenyl, or aminoalkyl, and R ₂₀ is hydrogen, alkyl , Alkenyl or aminoalkyl.

In one embodiment, the cross-linked polymer contains residues corresponding to the amine of formula 2, the cross-linked polymer is (i) the amine corresponding to formula 2 and a multifunctional cross-linking agent (including an amine moiety as needed ) Substituent polymerization or (2) the radical polymerization preparation corresponding to the amine of formula 2, and n is a positive integer and R ₃₀ is hydrogen, an aliphatic group or a heteroaliphatic group. By way of other examples, in one such embodiment, n is 0 or 1, and R ₃₀ is hydrogen, alkyl, alkenyl, or aminoalkyl.

In one embodiment, the cross-linked polymer contains residues corresponding to the amine of Formula 2, the cross-linked polymer is substituted by the amine corresponding to Formula 2 and a multifunctional cross-linking agent (and optionally an amine moiety) Radical polymerization or (2) the radical polymerization preparation corresponding to the amine of formula 2, and m and n are independently non-negative integers and X ₂ is an aliphatic group or a heteroaliphatic group. For example, in one such embodiment, m is 0 to 2, n is 0 or 1, X ₂ is an aliphatic or heteroaliphatic group, and R ₁₀ , R ₂₀ , R ₃₀ and R _{40 are} independently It is hydrogen, aliphatic or heteroaliphatic. By way of other examples, in one such embodiment, m is 0 to 2, n is 0 or 1, X ₂ is alkyl or aminoalkyl, and R ₁₀ , R ₂₀ , R ₃₀ and R _{40 are} independently It is hydrogen, aliphatic or heteroaliphatic. By way of other examples, in one such embodiment, m is 0 to 2, n is 0 or 1, X ₂ is alkyl or aminoalkyl, and R ₁₀ , R ₂₀ , R ₃₀ and R _{40 are} independently It is hydrogen, alkyl, alkenyl or aminoalkyl.

式2a 其中 m及n獨立地為非負整數； 各R₁₁ 獨立地為氫、烴基、雜脂族基或雜芳基； R₂₁ 及R₃₁ 獨立地為氫或雜脂族基； R₄₁ 為氫、經取代烴基或烴基； X₁ 為

； X₂ 為烷基或經取代烴基； 各X₁₂ 獨立地為氫、羥基、胺基、胺基烷基、

酸或鹵基；以及 z為非負數。In some embodiments, the cross-linked polymer includes residues corresponding to the amine of Formula 2a, and the cross-linked polymer is composed of an amine corresponding to Formula 2a and a multifunctional cross-linking agent (and optionally an amine moiety) Substitution polymerization preparation:

Formula 2a where m and n are independently non-negative integers; each R _{11 is} independently hydrogen, hydrocarbon, heteroaliphatic or heteroaryl; R ₂₁ and R _{31 are} independently hydrogen or heteroaliphatic; R ₄₁ is hydrogen , Substituted hydrocarbon group or hydrocarbon group; X ₁ is

; X ₂ is an alkyl group or a substituted hydrocarbon group; each X _{12 is} independently hydrogen, hydroxyl, amine group, aminoalkyl group,

Acid or halo; and z is a non-negative number.

In one embodiment, the cross-linked polymer includes residues corresponding to the amine of Formula 2a, and the cross-linked polymer is composed of an amine corresponding to Formula 1 and a multifunctional cross-linking agent (and optionally an amine moiety) Substitution polymerization preparation. For example, in one such embodiment, m and z are independently 0, 1, 2, or 3 and n is 0 or 1.

In one embodiment, the cross-linked polymer comprises residues corresponding to the amine of formula 2a, the cross-linked polymer is substituted by an amine corresponding to formula 2a and a multifunctional cross-linking agent (and optionally an amine moiety) Prepared by radical polymerization, and each R _{11 is} independently hydrogen, aliphatic group, aminoalkyl group, haloalkyl group or heteroaryl group, R ₂₁ and R _{31 are} independently hydrogen or heteroaliphatic group and R ₄₁ is hydrogen, Aliphatic group, aryl group, heteroaliphatic group or heteroaryl group. 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 other examples, in one such embodiment, each R ₁₁ is hydrogen, aliphatic, aminoalkyl, or haloalkyl, R ₂₁ and R ₃₁ are hydrogen or aminoalkyl, and R ₄₁ is hydrogen , Aliphatic or heteroaliphatic. By way of other examples, in one such embodiment, each R ₁₁ and R _{41 are} independently hydrogen, alkyl, or aminoalkyl, and R ₂₁ and R _{31 are} independently hydrogen or heteroaliphatic. By way of other examples, in one such embodiment, each R ₁₁ and R _{41 are} independently hydrogen, alkyl, -(CH ₂ ) _d NH ₂ , -(CH ₂ ) _d N[(CH ₂ ) _e NH ₂ )] ₂ , wherein d and e are independently 2-4, and R ₂₁ and R _{31 are} independently hydrogen or a heteroaliphatic group. In each of the aforementioned exemplary embodiments of this paragraph, m and z may independently be 0, 1, 2, or 3 and n is 0 or 1.

Exemplary amines used to synthesize polymers containing repeating units corresponding to Formula 2a include, but are not limited to the amines presented in Table A. Table A

Exemplary crosslinking agents used to synthesize polymers containing amine residues corresponding to Formula 2a include, but are not limited to, the crosslinking agents presented in Table B. Table B

式2b 其中 m及n獨立地為非負整數； 各R₁₂ 獨立地為氫、經取代烴基或烴基； R₂₂ 及R₃₂ 獨立地為氫、經取代烴基或烴基； R₄₂ 為氫、烴基或經取代烴基； X₁ 為

； X₂ 為烷基、胺基烷基或烷醇； 各X₁₃ 獨立地為氫、羥基、脂環、胺基、胺基烷基、鹵素、烷基、雜芳基、

酸或芳基； z為非負數，且 對應於式2b之胺包含至少一個烯丙基。In some embodiments, the cross-linked polymer includes residues corresponding to the amine of Formula 2b, and the cross-linked polymer is prepared by free radical polymerization of the amine corresponding to Formula 2b:

Formula 2b where m and n are independently non-negative integers; each R _{12 is} independently hydrogen, substituted hydrocarbon group or hydrocarbon group; R ₂₂ and R _{32 are} independently hydrogen, substituted hydrocarbon group or hydrocarbon group; R ₄₂ is hydrogen, hydrocarbon group or hydrocarbon group Substituted hydrocarbon group; X ₁ is

; X ₂ is alkyl, aminoalkyl or alkanol; each X _{13 is} independently hydrogen, hydroxyl, alicyclic, amino, aminoalkyl, halogen, alkyl, heteroaryl,

Acid or aryl; z is a non-negative number and the amine corresponding to formula 2b contains at least one allyl group.

In one embodiment, the cross-linked polymer contains residues corresponding to the amine of formula 2b, the cross-linked polymer is prepared by free radical polymerization of the amine corresponding to formula 2b, and m and z are independently 0, 1 , 2 or 3, and n is 0 or 1.

In one embodiment, the cross-linked polymer contains residues corresponding to the amine of formula 2b, the cross-linked polymer is prepared by free radical polymerization of the amine corresponding to formula 1, and (i) R ₁₂ or R _{42 is} independent Contains 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 alkene Propyl part. 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 comprises at least two allyl or vinyl moieties. By way of other examples, in one such embodiment, m 12 is a positive integer and R ₁₂ , R _22, and R _{42 in combination} comprise at least two allyl or vinyl moieties. By way of other examples, in one such embodiment, n 12 is a positive integer and R ₁₂ , R _32, and R _{42 in combination} comprise at least two allyl or vinyl moieties. By way of other examples, in one such embodiment, m is a positive integer and n is a positive integer, and R ₁₂ , R ₂₂ , R ₃₂ and R _{42 in combination} include at least two allyl or vinyl moieties .

In one embodiment, the cross-linked polymer contains residues corresponding to the amine of formula 2b, the cross-linked polymer is prepared by free radical polymerization of the amine corresponding to formula 2b, and each R _{12 is} independently hydrogen, amine Alkyl, allyl or vinyl, R ₂₂ and R _{32 are} independently hydrogen, alkyl, aminoalkyl, haloalkyl, alkenyl, alkanol, heteroaryl, alicyclic heterocyclic or aryl And R ₄₂ is hydrogen or a substituted hydrocarbon group. 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, and R ₄₂ is hydrogen or substituted hydrocarbon. By way of other examples, in one such embodiment, each R ₁₂ and R _{42 is} independently hydrogen, alkyl, allyl, vinyl, -(CH ₂ ) _d NH ₂ or -(CH ₂ ) _d N [(CH ₂ ) _e NH ₂ ] ₂ , where d and e are independently 2 to 4, and R ₂₂ and R _{32 are} independently hydrogen or a heteroaliphatic group.

Exemplary amines and crosslinking agents (or their salts, such as their hydrochloride, phosphate, sulfate, or hydrobromide salts) used to synthesize the polymers described by Formula 2b include, but are not limited to, those in Table C Others. Table C

式3 其中 R₁₅ 、R₁₆ 及R₁₇ 獨立地為氫、烴基、經取代烴基、羥基、胺基、

酸或鹵基； X₁₅ 為

， X₅ 為烴基、經取代烴基、側氧基(-O-)或胺基，且 z為非負數。In some embodiments, the cross-linked polymer is derived from a resulting polymer that utilizes the monomer described in any one of formulae 1, 1a, 1b, 1c, 2, 2a, and 2b or includes the one described by formula 3 The reaction of the linear polymer of the repeating unit with an external crosslinking agent or a pre-existing polymer functional group that can serve as a crosslinking site. Formula 3 may be a repeating unit of a copolymer or terpolymer, where X ₁₅ is a random copolymer, alternating copolymer, or block copolymer. The repeating unit in Formula 3 may also represent a repeating unit of a branched or hyperbranched polymer, where the main branch point may come from any atom in the main chain of the polymer:

Formula 3 wherein R ₁₅ , R ₁₆ and R _{17 are} independently hydrogen, hydrocarbon group, substituted hydrocarbon group, hydroxyl group, amine group,

Acid or halogen; X ₁₅ is

, X ₅ is a hydrocarbon group, a substituted hydrocarbon group, a pendant (-O-) group, or an amine group, and z is a non-negative number.

酸、鹵基、鹵烷基、烷醇或醚，X₅ 為烴基、經取代烴基、側氧基或胺基，且z為非負整數。在另一實施例中，R₁₅ 、R₁₆ 及R₁₇ 獨立地為氫、烴基、經取代烴基、羥基、胺基、

酸或鹵基，X₅ 為側氧基、胺基、烷胺基、醚、烷醇或鹵烷基，且z為非負整數。In one embodiment, R ₁₅ , R ₁₆ and R _{17 are} independently hydrogen, aryl or heteroaryl, X ₅ is a hydrocarbon group, substituted hydrocarbon group, pendant oxygen group or amine group, and m and z are non-negative integers. In another embodiment, R ₁₅ , R ₁₆ and R _{17 are} independently an aliphatic group or a heteroaliphatic group, X ₅ is a hydrocarbon group, a substituted hydrocarbon group, a pendant (-O-) group or an amine group, and m And z is a non-negative integer. In another embodiment, R ₁₅ , R ₁₆ and R _{17 are} independently unsaturated aliphatic groups or unsaturated heteroaliphatic groups, X ₅ is a hydrocarbon group, a substituted hydrocarbon group, a pendant oxygen group or an amine group, and z is Non-negative integer. In another embodiment, R ₁₅ , R ₁₆ and R _{17 are} independently alkyl or heteroalkyl, X ₅ is a hydrocarbyl group, substituted hydrocarbyl group, pendant oxygen group or amine group, and z is a non-negative integer. In another embodiment, R ₁₅ , R ₁₆ and R _{17 are} independently alkylamino, aminoalkyl, hydroxyl, amine,

Acid, halo, haloalkyl, alkanol or ether, X ₅ is a hydrocarbon group, substituted hydrocarbon group, pendant oxygen group or amine group, and z is a non-negative integer. In another embodiment, R ₁₅ , R ₁₆ and R _{17 are} independently hydrogen, hydrocarbon group, substituted hydrocarbon group, hydroxyl group, amine group,

Acid or halo, X ₅ is pendant, amine, alkylamine, ether, alkanol or haloalkyl, and z is a non-negative integer.

Exemplary crosslinking agents that can be used in free radical polymerization include, but are not limited to, one or more multifunctional crosslinking agents, such as: 1,4-bis(allylamino)butane, 1,2-bis(allyl) Aminoamino)ethane, 2-(allylamino)-1-[2-(allylamino)ethylamino]ethane, 1,3-bis(allylamino)propane, 1,3-bis(allylamino)-2-propanol, triallylamine, diallylamine, divinylbenzene, 1,7-octadiene, 1,6-heptadiene, 1,8- Nonadiene, 1,9-decadiene, 1,4-divinyloxybutane, 1,6-hexamethylenebisacrylamide, ethylidenebisacrylamide, N,N'-bis (Ethylenesulfonylacetoxy) ethylenediamine, 1,3-bis(ethylenesulfonyl)2-propanol, vinyl sulfonamide, N,N'-methylenebisacrylamide vinyl ether, polyether Allyl ether, divinylbenzene, 1,4-divinyloxybutane and combinations thereof.

The cross-linked polymers derived from the monomers and polymers in formulae 1 to 3 can be synthesized in solution or bulk or in a medium dispersion medium. Examples of solvents suitable for synthesizing the polymer of the present invention include, but are not limited to, water, low-boiling alcohols (methanol, ethanol, propanol, butanol), dimethylformamide, dimethylsulfoxide, heptane, chlorobenzene 、Toluene.

Alternative polymer methods may include individual polymerization, stepwise addition of a single starting species monomer through a series of reactions, stepwise addition of monomer blocks, combination, or any other polymerization method such as: living polymerization, direct Polymerization, indirect polymerization, condensation, free radicals, emulsions, precipitation methods, spray dry polymerization or using some bulk crosslinking reaction methods and scale reduction methods such as grinding, compression, extrusion. The method can be implemented as a batch, semi-continuous and continuous method. For the method in the dispersion medium, the continuous phase may be a non-polar solvent such as toluene, benzene, hydrocarbon, halogenated solvent, supercritical carbon dioxide. In the case of direct suspension reaction, water can be used, and salt can be used to adjust the properties of the suspension.

The starting molecules described in Formulae 1 to 3 can be copolymerized with one or more other monomers, oligomers or other polymerizable groups of the present invention. Such copolymer architectures may include, but are not limited to, block or block-based polymers, graft copolymers, and random copolymers. The incorporation of the monomers described by formulas 1 to 3 can range from 1% to 99%. In some embodiments, the incorporation of comonomer is between 20% and 80%.

Non-limiting examples of comonomers that can be used alone or in combination include: styrene, allylamine hydrochloride, substituted allylamine hydrochloride, substituted styrene, alkyl acrylate, substituted alkyl acrylate , Alkyl methacrylate, substituted alkyl methacrylate, acrylonitrile, methacrylonitrile, acrylamide, methacrylamide, N-alkylacrylamide, N-alkylmethacrylamide , N,N-dialkylacrylamide, N,N-dialkylmethacrylamide, isoprene, butadiene, ethylene, vinyl acetate, N-vinylamide, maleimide Acid derivatives, vinyl ethers, allyl, methallyl monomers and combinations thereof. Functionalized versions of these monomers can also be used. Additional specific monomers or comonomers that can be used in the present invention include, but are not limited to: 2-propen-1-ylamine, 1-(allylamino)-2-aminoethane, 1-[N- Allyl (2-aminoethyl)amino]-2-aminoethane, methyl methacrylate, ethyl methacrylate, propyl methacrylate (all isomers) butyl methacrylate (All isomers), 2-ethylhexyl methacrylate, isobornyl methacrylate, methacrylic acid, benzyl methacrylate, phenyl methacrylate, methacrylonitrile, α-methyl Styrene (amethylstyrene), methyl acrylate, ethyl acrylate, propyl acrylate (all isomers), butyl acrylate (all isomers), 2-ethylhexyl acrylate, isobornyl acrylate, acrylic acid, acrylic acid Methyl benzyl, 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 acrylate, N-diethylaminoethyl ester, triethylene glycol acrylate, methacrylamide, N-methacrylamide, N,N-dimethylacrylamide, N-third butylmethacrylamide (butylmethacrylamide), N,N-butylmethacrylamide, N-methylolmethacrylamide, N-hydroxyethylmethacrylamide, N-third butylacrylamide Amine, N,N-butylacrylamide, N-hydroxymethylacrylamide, N-hydroxyethylacrylamide, 4-propenylmorpholine, vinyl benzoic acid (all isomers), diethyl Diethylaminostyrene (all isomers), a-methylvinyl benzoic acid (all isomers), diethylamino a-methylstyrene (all isomers), p-vinyl Benzenesulfonic acid, p-vinylbenzenesulfonic acid sodium salt, trimethoxysilylpropyl methacrylate, triethoxysilylpropyl methacrylate, tributoxysilylpropyl methacrylate (tributoxysilylpropyl) methacrylate), dimethoxymethylsilylpropyl methacrylate, diethoxymethylsilylpropyl methacrylate, dibutoxymethylsilyl methacrylate Propyl ester ylsilylpropyl methacrylate), diisopropoxymethylsilylpropyl methacrylate, dimethoxysilylpropyl methacrylate, diethoxysilylpropyl methacrylate (diethoxysilylpropyl methacrylate), dibutoxysilylpropyl methacrylate, diisopropoxysilylpropyl methacrylate, trimethoxysilylpropyl methacrylate, triethyl acrylate Oxysilyl propyl ester, tributoxysilylpropyl acrylate, trimethoxymethylsilylpropyl acrylate, diethoxymethylsilylpropyl acrylate ), dibutoxymethylsilylpropyl acrylate, diisopropoxymethylsilylpropyl acrylate, dimethoxysilylpropyl acrylate, acrylic acid Diethoxysilylpropyl acrylate, dibutoxysilylpropyl acrylate, diisopropoxysilylpropyl acrylate, maleic anhydride, N- Phenyl maleimide diimide, N-butyl maleimide diimide, N-vinylformamide, N-vinylacetamide, allylamine, methallylamine, allyl alcohol (allylalcohol), methyl-vinyl ether, ethyl vinyl ether, butyl vinyl ether, butadiene, isoprene, chloroprene, ethylene, vinyl acetate, and combinations thereof.

Additional modification of the pre-formed cross-linked polymer can be achieved by adding modifiers, which include but are not limited to amine monomers, additional cross-linking agents and polymers. Modification can be achieved by covalent or non-covalent methods. These modifications can be uniformly or unevenly dispersed throughout the preformed polymer, including modifications biased to the surface of the preformed crosslinked polymer. In addition, modifications can be made to change the physical properties of the pre-formed cross-linked polymer, including but not limited to reactions where residual reactive groups such as haloalkyl and allyl groups appear in the pre-formed polymer. Reactions and modifications to pre-formed cross-linked polymers may include, but are not limited to, acid-base reactions, nucleophilic substitution reactions, Michael reactions, non-covalent electrostatic interactions, hydrophobic interactions, physical interactions (cross-linking) ) And free radical reaction.

式4 其中各R獨立地為氫或交聯胺聚合物(

)之兩個氮原子之間的伸乙基交聯，且a、b、c及m為整數。通常，m為指示伸展聚合物網路之較大整數。在一個此類實施例中，a及b之總和比c的比率(亦即，a+b:c)介於約1:1至5:1之範圍內。舉例而言，在一個此類實施例中，a及b之總和比c的比率(亦即，a+b:c)介於約1.5:1至4:1 之範圍內。藉助於其他實例，在一個此類實施例中，a及b之總和比c的比率(亦即，a+b:c)介於約1.75:1至3:1之範圍內。舉例而言，在一個此類實施例中，a及b之總和為57，c為24，且m為指示伸展聚合物網路的較大整數。在前述實施例中之各者中，a及b之總和比c的比率(亦即，a+b:c)可介於約2:1至2.5:1之範圍內。舉例而言，在此類實施例中，a及b之總和比c的比率(亦即，a+b:c)可介於約2.1:1至2.2:1之範圍內。藉助於其他實例，在此類實施例中，a及b之總和比c之比率(亦即，a+b:c)可介於約2.2:1至2.3:1的範圍內。藉助於其他實例，在此類實施例中，a及b之總和比c之比率(亦即，a+b:c)可介於約2.3:1至2.4:1的範圍內。藉助於其他實例，在此類實施例中，a及b之總和比c之比率(亦即，a+b:c)可介於約2.4:1至2.5:1的範圍內。在前述實施例中之各者中，各R可獨立地為氫或兩個氮原子之間的伸乙基交聯。然而，通常，35-95%之R取代基將為氫，且5-65%將為伸乙基交聯(

)。舉例而言，在一個此類實施例中，50-95%之R取代基將為氫，且5-50%將為伸乙基交聯(

)。舉例而言，在一個此類實施例中，55-90%之R取代基為氫，且10-45%為伸乙基交聯(

)。藉助於其他實例，在一個此類實施例中，60-90%之R取代基為氫，且10-40%為伸乙基交聯。藉助於其他實例，在一個此類實施例中，65-90%之R取代基為氫，且10-35%為伸乙基交聯(

)。藉助於其他實例，在一個此類實施例中，70-90%之R取代基為氫，且10-30%為伸乙基交聯。藉助於其他實例，在一個此類實施例中，75-85%之R取代基為氫，且15-25%為伸乙基交聯。藉助於其他實例，在一個此類實施例中，65-75%之R取代基為氫，且25-35%為伸乙基交聯。藉助於其他實例，在一個此類實施例中，55-65%之R取代基為氫，且35-45%為伸乙基交聯。在一些實施例中，a、b、c及R如上文以使得式4聚合物之碳比氮比率可分別介於約2:1至約6:1的範圍內。舉例而言，在一個此類實施例中，式4聚合物之碳比氮比率可分別介於約2.5:1至約5:1的範圍內。藉助於其他實例，在一個此類實施例中，式4聚合物之碳比氮比率可分別介於約3:1至約4.5:1的範圍內。藉助於其他實例，在一個此類實施例中，式4聚合物之碳比氮比率可分別介於約3.25:1至約4.25:1的範圍內。藉助於其他實例，在一個此類實施例中，式4聚合物之碳比氮比率可分別介於約3.4:1至約4:1的範圍內。藉助於其他實例，在一個此類實施例中，式4聚合物之碳比氮比率可分別介於約3.5:1至約3.9:1的範圍內。藉助於其他實例，在一個此類實施例中，式4聚合物之碳比氮比率可分別介於約3.55:1至約3.85:1的範圍內。在此段中所列舉的前述實施例中之各者中，式4聚合物衍生自單體及交聯劑，其各者包含小於5 wt%氧。In one embodiment, the post-polymerized cross-linked amine polymer is a cross-linked amine polymer containing a structure corresponding to Formula 4:

Formula 4 where each R is independently hydrogen or a crosslinked amine polymer (

), the ethylidene crosslinks between the two nitrogen atoms, and a, b, c and m are integers. Generally, m is a larger integer that indicates the stretched polymer network. In one such embodiment, the ratio of the sum of a and b to the ratio c (ie, 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 (ie, a+b:c) is in the range of about 1.5:1 to 4:1. By way of other examples, in one such embodiment, the ratio of the sum of a and b to c (ie, a+b:c) is in the range of about 1.75:1 to 3:1. For example, in one such embodiment, the sum of a and b is 57, c is 24, and m is a larger integer indicating an extended polymer network. In each of the foregoing embodiments, the ratio of the sum of a and b to the ratio c (that is, a+b:c) may be in the range of about 2:1 to 2.5:1. For example, in such embodiments, the ratio of the sum of a and b to the ratio c (ie, a+b:c) may be in the range of about 2.1:1 to 2.2:1. By way of other examples, in such embodiments, the ratio of the sum of a and b to the ratio c (ie, a+b:c) may range from about 2.2:1 to 2.3:1. By way of other examples, in such embodiments, the ratio of the sum of a and b to c (ie, a+b:c) may be in the range of about 2.3:1 to 2.4:1. By way of other examples, in such embodiments, the ratio of the sum of a and b to the ratio c (ie, a+b:c) may range from about 2.4:1 to 2.5:1. In each of the foregoing embodiments, each R may independently be hydrogen or an ethylidene crosslink between two nitrogen atoms. However, in general, 35-95% of the R substituent will be hydrogen, and 5-65% will be the ethylidene crosslink (

). For example, in one such embodiment, 50-95% of the R substituents will be hydrogen, and 5-50% will be ethylidene crosslinks (

). For example, in one such embodiment, 55-90% of the R substituents are hydrogen, and 10-45% are ethylidene crosslinks (

). By way of other examples, in one such embodiment, 60-90% of the R substituents are hydrogen, and 10-40% are ethylidene crosslinks. By way of other examples, in one such embodiment, 65-90% of the R substituents are hydrogen and 10-35% are ethylidene crosslinks (

). By way of other examples, in one such embodiment, 70-90% of the R substituents are hydrogen, and 10-30% are ethylidene crosslinks. By way of other examples, in one such embodiment, 75-85% of the R substituents are hydrogen, and 15-25% are ethylidene crosslinks. By way of other examples, in one such embodiment, 65-75% of the R substituents are hydrogen and 25-35% are ethylidene crosslinks. By way of other examples, in one such embodiment, 55-65% of the R substituents are hydrogen, and 35-45% are ethylidene crosslinks. In some embodiments, a, b, c, and R are as described above so that the carbon to nitrogen ratio of the polymer of Formula 4 may range from about 2:1 to about 6:1, respectively. For example, in one such embodiment, the carbon to nitrogen ratio of the polymer of Formula 4 may range from about 2.5:1 to about 5:1, respectively. By way of other examples, 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 other examples, 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 other examples, 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 other examples, 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 other examples, 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 listed in this paragraph, the polymer of Formula 4 is derived from a monomer and a cross-linking agent, each of which contains less than 5 wt% oxygen.

In certain embodiments, it is found that polymers that increase cross-linking and/or kinking have lower swelling than other polymers with lower cross-linking and/or kinking, and also have lower cross-linking and/or kinking Polymers are as large or larger as they bind to target ions (eg, chloride ions), while significantly reducing the binding of interfering ions such as phosphate esters. Selective effects can be introduced in two different ways: 1) Sacrificing overall capacity for chloride ion specificity. Crosslinking agents that do not include chloride ion binding sites (e.g., epichlorohydrin) allow for increased crosslinking while reducing the overall capacity in proportion to the amount of crosslinking agent incorporated into the polymer. 2) Retain overall capacity for chloride ion specificity: Cross-linking agents including chloride ion binding sites (eg diallylamine) allow increased cross-linking while the overall capacity remains the same or only a small decrease.

As mentioned previously, a cross-linked polymer having a high capacity for chloride ion binding and a higher selectivity than other competing anions such as phosphate esters can be prepared according to a two-step process according to an embodiment of the present invention. In general, the selectivity of the polymer is a function of its crosslink density, and the polymer's ability is the function of the free amine density of the crosslinked polymer. Advantageously, the two-step method disclosed herein provides a high capacity for chloride ion binding and surpasses other competing ions by mainly relying on carbon-carbon crosslinking in the first step and nitrogen-nitrogen crosslinking in the second step Both have higher selectivity for chloride ion.

In the first step, the cross-linking is preferably capacity-saving, that is, free amine-saving, from carbon to carbon cross-linking. In the second step, the cross-linking is consumed by the amine, and is related to the regulation of selectivity. Based on the desired high capacity, the CN ratio is preferably optimized to maximize the amine functional groups bound by HCl while still maintaining spherical polymer particles of controlled particle size to ensure stable non-absorption and acceptable mouthfeel under GI conditions . The preferred degree of carbon-carbon crosslinking is achieved after the first step is sufficient to permit the resulting beads to swell between 4X and 6X in water (ie, the expansion ratio is 4 to 6).

In one embodiment, a cross-linked polymer having a high ability to bind chloride ions and a higher selectivity than chloride ions of other competitive anions such as phosphate esters can be prepared in a two-step process, and the product of the first polymerization step is better The ground is in the form of beads, and the diameter of the beads is controlled in the range of 5 to 1000 microns, preferably 10 to 500 microns and most preferably 40 to 180 microns.

The product of the first polymerization step is preferably in the form of beads whose expansion ratio in water is between 2 and 10, more preferably from about 3 to about 8, and most preferably from about 4 to about 6.

In addition, if the crosslinked polymer beads produced by the first polymerization step are protonated, this can reduce the amount of nitrogen-nitrogen crosslinking in the second crosslinking step. Therefore, in certain embodiments, the preformed amine polymer is at least partially deprotonated by treatment with a base, preferably a strong base such as a hydroxide base. For example, in one embodiment, the base may be NaOH, KOH, NH ₄ OH, NaHCO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , LiOH, Li ₂ CO ₃ , CsOH, or other metal hydroxide. If the charge is removed from the pre-formed crosslinked amine polymer beads by deprotonation, the beads will tend to break, and unless the beads are prevented from breaking, the crosslinking agent used in the second step may not enter The binding site on the polymer. One method to prevent the breakage of the cross-linked polymer beads is to use a swelling agent such as water to swell the beads, thereby allowing the second step of the cross-linking agent to enter the binding site.

The pre-formed polymer may be cross-linked using any one of a series of cross-linking compounds containing at least two amine-reactive functional groups to form a post-polymerized cross-linked polymer. In one such embodiment, the cross-linking agent is a compound containing at least two amine reactive groups selected from the group consisting of: halide, epoxide, phosgene, acid anhydride, carbamate, Carbonate, isocyanate, thioisocyanate, ester, activated ester, formic acid and its derivatives, sulfonate and its derivatives, acetyl halide, aziridine, α,β-unsaturated carbonyl, ketone , Aldehyde and pentafluoroaryl group For example, the crosslinking agent may be any of the crosslinking agents disclosed herein, including the crosslinking agents selected from Table B. By way of other examples, in one such embodiment, the crosslinking agent is a dihalide such as dichloroalkane.

As mentioned above, in certain embodiments, the preformed amine polymer swelling agent may be included in the second polymerization step reaction mixture along with the crosslinking agent. In general, the swelling agent and the cross-linking agent can be miscible or immiscible, and the swelling agent can be any composition or combination of compositions having the ability to swell preformed amine polymers. Exemplary swelling agents include polar solvents such as water, methanol, ethanol, n-propanol, isopropanol, n-butanol, formic acid, acetic acid, acetonitrile, dimethylformamide, dimethylsulfoxide, nitromethane, carbonic acid Propyl ester or a combination thereof. In addition, the amount of swelling agent contained in the reaction mixture will generally be less than the absorbent capacity of the pre-formed amine polymer of the swelling agent. For example, it is generally preferred that the weight ratio of the expansion agent in the reaction mixture to the preformed polymer is less than 4:1. By way of other examples, in some embodiments, the weight ratio of the expanding agent to the preformed polymer in the reaction mixture will be less than 3:1. By way of other examples, in some embodiments, the weight ratio of the expansion agent in the reaction mixture to the preformed polymer will be less than 2:1. By way of other examples, in some embodiments, the weight ratio of the expanding agent in the reaction mixture to the preformed polymer will be less than 1:1. By way of other examples, in some embodiments, the weight ratio of the expansion agent in the reaction mixture to the preformed polymer will be less than 0.5:1. By way of other examples, in some embodiments, the weight ratio of the expanding agent to the preformed polymer in the reaction mixture will be less than 0.4:1. By way of other examples, in some embodiments, the weight ratio of the expanding agent to the preformed polymer in the reaction mixture will be less than 0.3:1. However, in general, the weight ratio of the expanding agent to the preformed polymer in the reaction mixture will usually be at least 0.05:1, respectively.

In general, the cross-linked polymer may be a cross-linked homopolymer or a cross-linked copolymer containing free amine moieties. The free amine moieties can be separated, for example, by repeating linker (or intervening) units of the same or varying length. In some embodiments, the polymer includes repeating units that contain amine moieties and intervening linker units. In other embodiments, multiple amine-containing repeating units are separated by one or more linking subunits. In addition, the multifunctional crosslinking agent may include HCl binding functional groups, such as amines ("active crosslinking agents"), or may lack HCl binding functional groups such as amines ("passive crosslinking agents").

In a preferred embodiment, the first polymerization (crosslinking) step produces pre-formed amine polymer beads with a target size and chloride ion binding capacity. For example, in one such embodiment, the beads have a chloride ion binding force of at least 10 mmol/g and a swelling ratio ranging from 1 to 6 in Simulated Gastric Fluid ("SGF"). The resulting preformed amine polymer is then preferably (at least partially) deprotonated with a base and combined with a non-protonated swelling agent to swell the free amine polymer without protonating the amine functional group. In addition, the amount of non-protonated swelling agent is selected to adjust the degree of subsequent cross-linking that effectively forms the template, which is then locked in place via an amine depletion cross-linking step. In the second cross-linking step, the pre-formed amine polymer that has undergone expansion and deprotonation is cross-linked with a cross-linking agent containing an amine-reactive portion to form a post-polymerized cross-linked polymer.

In general, the selectivity of chloride ions over other competing ions is achieved with highly cross-linked polymers. For example, a relatively high chloride ion binding force can be obtained by reacting preformed amine polymer beads with a pure crosslinking agent in the presence of a swelling agent (water). Although this "non-dispersed" reaction provides high selectivity for chloride ions over competing ions in SIB analysis, it also produces macroscopic (and microscopic) aggregated polymer beads. Therefore, it is advantageous to include a solvent (such as heptane) in the second cross-linking step to disperse the pre-formed cross-linked polymer beads to avoid inter-bead reaction and cause aggregation. However, using too much solvent (dispersant) can dilute the reaction solution to a point where the resulting beads are not sufficiently cross-linked to have the desired chloride ion selectivity over other competing anions. However, by using a cross-linking agent that also serves as a solvent (dispersant), sufficient solvent (dispersant) can be included in the reaction mixture to avoid inter-bead reaction and aggregation without diluting the mixture until the amine consumes the cross-linking Point of insufficient degree. For example, in an effort to utilize the dispersibility of the solvent (to avoid aggregation during the reaction) while maintaining the reactivity, pure DCE and DCP are used, thereby performing a dual-purpose role as a solvent (dispersant) and crosslinking agent. Interestingly, when compared with similar reactions of DCP and/or heptane, DCE was found to have excellent dispersibility as a solvent. In addition, when the beads were first dispersed in DCE and then water was added in the second operation to swell the beads, less aggregation was observed. If water is added to the preformed amine polymer before the beads are dispersed in DCE, aggregation can occur.

The use of 1,2-dichloroethane ("DCE") as a cross-linking solvent during the second step also produces HCl molecules. The protonation of these HCl molecules blocks some of the free amine sites of the reaction site of the cross-linking reaction and thus limits the number of binding sites available for cross-linking. Therefore, the use of DCE has a self-limiting effect on secondary crosslinking.

In each of the foregoing embodiments, the reaction mixture may contain a wide range of amounts of crosslinking agent. For example, in one embodiment, the crosslinking agent may be used in a large excess relative to the amount of preformed amine polymer in the reaction mixture. In other words, in such embodiments, the cross-linking agent is a cross-linking solvent, that is, it is both the solvent of the reaction mixture and the cross-linking agent that previously formed the amine polymer. In such embodiments, other solvents may optionally be included in the reaction mixture but are not required. Alternatively, the preformed amine polymer, swelling agent and cross-linking agent can be dispersed in a solvent, and the solvent is miscible with the cross-linking agent and not miscible with the swelling agent. For example, in some embodiments, the swelling agent may be a polar solvent; in some such embodiments, for example, the swelling agent may include water, methanol, ethanol, n-propanol, isopropanol, formic acid, acetic acid , Acetonitrile, N, N -dimethylformamide, dimethylsulfoxide, nitromethane, or a combination thereof. By way of other examples, when the expanding agent contains a polar solvent, the solvent system of the reaction mixture will usually contain a non-polar solvent, such as pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane Alkane, chloroform, ether, dichloromethane, dichloroethane, dichloropropane, dichlorobutane, or a combination thereof. In some embodiments, the crosslinking agent and the solvent may be the same; that is, the solvent is a crosslinking solvent, such as 1,2-dichloroethane, 1,3-dichloropropane, 1,4-dichlorobutane or Its combination.

Notably, in the cross-linking solvent (for example, DCE dispersion reaction), regardless of the amount of cross-linking solvent (for example, DCE) used to disperse the beads, there is a large excess of cross-linking agent (for example, 1 g:3 mL:: Beads: DCE and 1 g: 10 mL:: Beads: DCE are all large amounts of cross-linking agent, most of which are not consumed during the reaction). Regardless of this situation, the relative degree of crosslinking and the performance in the SIB analysis 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 ability of the polymer beads rather than the amount of cross-linking agent (eg DCE).

In order to more effectively react with DCE or other cross-linking agents, the amines preformed into polymer beads preferably have free electron pairs (neutral, deprotonated). Since the free amine that previously formed the polymer beads reacted with a cross-linking agent (eg, DCE), HCl is generated and the amine is protonated, thereby limiting the reaction. For this reason, the preformed amine polymer beads preferably start as free amine in the second crosslinking step. If the preformed amine polymer beads are protonated after the first carbon-carbon crosslinking step, the amine consumption crosslinking in the second step will be limited, thereby reducing the required selectivity of chloride ions over other competing ions. This has been demonstrated by adding a known amount of HCl to the preformed amine polymer beads just before the second step is crosslinked with DCE. When less than 3 mol% HCl (to the amine in the preformed polymer amine beads) is added before crosslinking in the second step, the total chloride ion capacity (SGF) and the chloride ion selectivity in the SIB are similar to those in the second step Beads not treated with HCl. When more than 5 mole% HCl (to the amine in the preformed polymer amine beads) is added before the second step crosslinking, the total chloride ion capacity (SGF) increases and the chloride ion selectivity in the SIB decreases, indicating crosslinking The lower of the combined agent is incorporated.

The benefit of deprotonated preformed polymer beads in the second step crosslinking emphasizes the advantages of using two steps to achieve the final product. In the first step, to form amine polymer beads, all monomers (eg, allylamine and DAPDA) are protonated to remain in the aqueous phase and to avoid severe restrictions on non-protonated allylamine (and derivatives) ) Polymerization of free radical transfer reaction. Once the beads are formed by carbon-carbon crosslinking, the beads can then be deprotonated and further crosslinked with an amine-reactive crosslinking agent in the second step.

Given a large excess of double cross-linking agent/solvent, a single incorporation of this agent can occur, producing alkyl chloride ion functional groups on the cross-linked polymer beads that are hydrophobic in nature and can increase and differ in nature Non-specific interaction of undesired solutes of more hydrophobic HCl. Washing with ammonium hydroxide solution converts the alkyl-chloride ions into alkyl-amine functional groups, which are hydrophilic and minimize non-specific interactions with undesired solutes. Other modifications that produce more hydrophilic groups than alkyl chloride ions such as -OH are suitable for quenching the crosslinker/solvent that is mono-incorporated.

Any one of a series of polymerization chemical reactions can be used in the first reaction step, with the limitation that the cross-linking mechanism is mainly carbon-carbon cross-linking. Therefore, in an exemplary embodiment, the first reaction step includes free radical polymerization. In such reactions, the amine monomer will usually be a monofunctional vinyl, allyl, or acrylamide (eg, allylamine), and the crosslinker will have two or more vinyl, allyl, or Acrylamide functional groups (for example, diallylamine). Synergistic polymerization and crosslinking occur by fundamentally starting to polymerize a mixture of monofunctional and polyfunctional allylamines. The resulting polymer network is therefore cross-linked through the carbon backbone. Each crosslinking reaction forms a carbon-carbon bond (compared to a substitution reaction that forms a carbon-heteroatom bond during crosslinking). During the co-acting polymerization and crosslinking, the amine functional group of the monomer does not undergo crosslinking reaction and remains in the final polymer (that is, the primary amine is still primary, the secondary amine is secondary, and the tertiary amine (Still at level 3).

In those embodiments where the first reaction step involves free radical polymerization, a wide range of initiators including cationic and free radical initiators can be used. Some examples of suitable initiators that can be used include: free radical peroxy and azo-based compounds, such as azobisisobutyronitrile, azodiisovaleronitrile, dimethylazobisisobutyric acid (dimethylazodiisobutyrate), 2,2'azobis (isobutyronitrile), 2,2'-azobis (N,N'-dimethylene-isobutylformamidine (N,N'-dimethy1-eneisobutyramidine) di Hydrochloride, 2,2'-azobis(2-carboxamidinepropane) dihydrochloride, 2,2'-azobis(N,N'-dimethylmethylene isobutylformamidine), 1, 1'-azobis(l-cyclohexane-nitrile), 4,4'-azobis(4-cyanovaleric acid), 2,2'-azobis(isobutylamide) dihydrate , 2,2'-azobis (2-methylpropane), 2,2'-azobis (2-methylbutanenitrile), VAZO 67, cyanovaleric acid, peroxypivalate ), dodecylbenzene peroxide, benzoyl peroxide, di-tert-butyl hydroperoxide, tert-butyl peracetate, acetyl peroxide, dicumyl peroxide, isoperoxide Cumene hydroperoxide, dimethyl bis (butyl peroxy) hexane.

Exemplary amine-containing polymers as described above are more fully disclosed and exemplified in WO2016/094685 A1 and WO2014/197725 A1, the entire contents of which are incorporated herein by reference.

In one embodiment, the pharmaceutical composition comprises a mixture of any of the previously identified non-absorbent substances. For example, in one embodiment, the pharmaceutical composition comprises a mixture of a cation exchange composition and at least one anion exchange composition, amphoteric ion exchange composition, or a neutral composition having the ability to bind both protons and anions. In another embodiment, the pharmaceutical composition comprises a mixture of an anion exchange composition and at least one cation exchange composition, amphoteric ion exchange composition, or a neutral composition having the ability to bind both protons and anions. In yet another embodiment, the pharmaceutical composition comprises a mixture of a neutral composition having the ability to bind both protons and anions and at least one cation exchange composition, zwitter ion exchange composition, or anion exchange composition.

As schematically depicted in FIGS. 1A-1C and according to one embodiment, the non-absorbable free amine polymer of the present invention is orally ingested and used to migrate through feces by binding HCl in the gastrointestinal ("GI") tract Excluding HCl to treat metabolic acidosis in mammals (including by increasing serum bicarbonate and normalizing blood pH). The free amine polymer is administered orally with a compliance-increasing dose that targets a sufficient amount of HCl for long-term binding (Figure 1A) to enable a clinically meaningful increase of 3 mEq/L serum bicarbonate. In the stomach (Figure IB), the free amine is protonated by binding H ⁺ . The positive charge on the polymer can then be used to bind Cl ^-; by the control proceeds to the binding site by cross-linking and hydrophilic / hydrophobic properties, if any, other large organic anions (e.g., acetic acid, propionic acetate, butyrate, depicted as X ^- and Y ^-) bonded to a lesser extent. The net effect is therefore a combination of HCI. In the lower part of the gastrointestinal tract / colon (FIG. 1C) in, Cl ^- not completely released, and the physical laws of HCI from intestinal motility and removed by the fecal excretion, causing net basified serum. The bonding in this manner Cl ^- not available via a Cl ^- exchange antiporter (of Antiporter) systems ^- / HCO _3.

In one embodiment, the polymer is designed to simultaneously maximize efficacy (net HCl binding and excretion) and minimize GI side effects (through low swelling particle design and particle size distribution). Optimized HCl binding capacity (number of amine binding sites), selectivity (better binding of chloride ions to other anions, which are specifically organic anions in the colon), and colon and intestine the retentate (large amount of chlorine ions are not released in the lower part of the gastrointestinal tract to avoid Cl ^- / HCO ₃ ^- exchanger [antiporter] the active; if chloride ions are not tightly bonded to the polymer, the Cl ^- / HCO ₃ ^- exchanger The agent can mediate the absorption of chloride ions from the intestinal lumen and the reciprocal exchange of bicarbonate from the serum, thereby effectively reducing the careful balance of serum bicarbonate).

Competing anions that replace chloride ions cause a reduction in net bicarbonate through the following mechanism. First, the replacement of chloride ions from the polymer in the GI lumen, especially the lumen of the colon, provides a convenient exchange with bicarbonate in the serum. The colon has an anion exchanger (chloride ion/bicarbonate reverse transporter) that moves chloride ions from the cavity side when exchanging secreted bicarbonate. When free chloride ions are released from the polymer in the gastrointestinal tract, it will exchange bicarbonate, which will subsequently be lost to the stool and reduce the total extracellular bicarbonate (Davis, 1983; D'Agostino, 1953) . When a key on the switching junction chloride binding polymer short chain fatty acids (of SCFA) causes the extracellular HCO ₃ ^- storage was consumed. Short-chain fatty acids are the products of bacterial metabolism of complex carbohydrates that are not catabolized by normal digestion methods (Chemlarova, 2007). The short-chain fatty acids that reach the colon are absorbed and distributed to various tissues, where the common metabolic fate is the production of H ₂ O and CO ₂ , which are converted into bicarbonate equivalents. Therefore, the incorporation of SCFA into the polymer to neutralize the proton charge will be detrimental to the overall bicarbonate storage and buffer capacity, forcing a design that limits the chemical and physical characteristics of the SCFA-exchanged polymer. Finally, phosphate esters bound to polymers should also be limited, since phosphate esters represent an additional source of buffering capacity in situations where ammonia production and/or hydrogen ion secretion is impaired in chronic kidney disease.

For each proton binding, anions are preferably bonded as the positive charge attempts to leave the human body as a neutral polymer. The "binding" of ions is more than that of very little binding, that is, in some embodiments, at least about 0.2 mmol ions/g polymer, at least about 1 mmol ions/g polymer, and in some embodiments, at least about 1.5 mmol ions/g 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, or in some embodiments, even at least about 14 mmol ions/g polymer Thing. In one embodiment, the polymer is characterized by its high proton binding capacity while providing anionic selectivity; chloride ion selectivity includes, but is not limited to, phosphates, citrates, acetic acid, cholic acid, and fatty acids by reducing To interfere with the combination of anions. For example, in some embodiments, the polymers of the present invention are 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 The binding force of g binds phosphate ester. In some embodiments, the polymers of the present invention are less than about less than about 5 mmol/g, less than about 4 mmol/g, less than about 3 mmol/g, less than about 2 mmol/g, and in some embodiments less than about 1 The binding force of mmol/g, less than about 0.5 mmol/g in some embodiments, less than about 0.3 mmol/g in some embodiments, and less than about 0.1 mmol/g in some embodiments binds bile and fatty acids. Pharmaceutical composition and administration

In general, the dosage concentration of the therapeutic agent and/or the non-absorbable composition for prophylactic use may range from about 0.5 g/day to about 100 g/day. To facilitate patient compliance, it is generally preferred that the dosage should be in the range of about 1 g/day to about 50 g/day. For example, in one such embodiment, the dosage will be from about 2 g/day to about 25 g/day. By way of other examples, in one such embodiment, the dosage will be from about 3 g/day to about 25 g/day. By way of other examples, in one such embodiment, the dosage will be from about 4 g/day to about 25 g/day. By way of other examples, in one such embodiment, the dosage will be from about 5 g/day to about 25 g/day. By way of other examples, in one such embodiment, the dosage will be from about 2.5 g/day to about 20 g/day. By way of other examples, in one such embodiment, the dosage will be from about 2.5 g/day to about 15 g/day. By way of other examples, in one such embodiment, the dosage will be from about 1 g/day to about 10 g/day. Optionally, the daily dose can be administered as a single dose (ie, once a day) or divided into multiple doses (eg, two, three, or more than three doses) during the course of a day. In general, non-absorbable compositions can be administered as a fixed daily dose or titrated based on the serum bicarbonate value or other indicator of acidosis in patients in need of treatment. Titration may occur at the beginning or during treatment as needed, and the initial and maintenance dose concentrations may vary from patient to patient based on the severity of the underlying disease.

The effectiveness of non-absorbable compositions can be established in animal models, or in human volunteers and patients. In addition, in vitro, in vitro, and in vivo methods can be used to establish HCl binding. The in vitro binding solution can be used to measure the binding power of protons, chloride ions and other ions at different pH. In vitro extracts such as gastrointestinal lumen contents from human volunteers or from model animals can be used for similar purposes. The selectivity that preferably exceeds the binding of other ions and/or holds certain ions can also be demonstrated in such test tubes and in vitro solutions. An in vivo model of metabolic acidosis can be used to test the effectiveness of non-absorbable compositions in normalizing acid/base balance--for example, feeding 5/6 nephrectomy rats with casein-containing foods (e.g. Phistitkul 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 feeding glands Purine 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).

In one embodiment, the non-absorbable composition is provided (by oral administration) to animals including humans in one, two or even multiple (ie, at least three) doses per day dosing regimen, To treat acid-base disorders (eg, metabolic acidosis) and achieve a clinically significant and continuous increase in serum bicarbonate as previously described. For example, in one embodiment, the daily dose of the non-absorbable composition (whether administered in a single dose or multiple doses during the course of the day) has sufficient capacity to remove at least 5 mmol protons, Chloride ion or each of them every day. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has sufficient capacity to remove at least 10 mmol of proton chloride ion or each day. Other means of example, in one such embodiment, the daily dose of a non-absorbent composition having sufficient capacity to remove at least 20 mmol proton, a conjugate base of a strong acid (e.g., Cl ^-, HSO ₄ ^- and SO ₄ ^2- ) and/or strong acids (for example, HCl or H ₂ SO ₄ ) each day. By way of other examples, in one such embodiment, the daily dosage of the non-absorbent composition has sufficient capacity to remove at least 30 mmol of protons, strong acid conjugate bases, and/or strong acids each day. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has sufficient capacity to remove at least 40 mmol of protons, conjugate bases of strong acids, and/or strong acids each day. By way of other examples, in one such embodiment, the daily dose of the non-absorbent composition has sufficient capacity to remove at least 50 mmol of protons, strong acid conjugate bases, and/or strong acids each day.

The unit dosage form of the medicine containing the non-absorbable composition may be any form suitable for oral administration. Such unit dosage forms include powders, lozenges, pills, lozenges, sachets, cachets, elixirs, suspensions, syrups, soft or hard gelatin capsules, and the like. In one embodiment, the pharmaceutical composition comprises only non-absorbent compositions. Alternatively, the pharmaceutical composition may contain a carrier, diluent or excipient unless the absorbent composition. Examples of carriers, excipients and diluents that can be used in these formulations and others include foods, beverages, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, alginate , Tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate and talc. Pharmaceutical excipients suitable for pharmaceutical compositions further include: binding agents, such as microcrystalline cellulose, colloidal silica and combinations thereof (Prosolv 90), carbopol, carbopol, povidone, and sanxian gum; Flavoring agents, such as sucrose, mannitol, xylitol, maltodextrin, fructose, or sorbitol; lubricants, such as magnesium stearate, stearic acid, sodium stearyl fumarate, and based Fatty acid plants; and, as appropriate, disintegrants, such as croscarmellose sodium, gellan gum, low-substituted hydroxypropyl ether of cellulose, sodium starch glycolate. Other additives may include plasticizers, pigments, talc, and the like. Such additives and other suitable ingredients are well known in the art; see, for example, Gennaro AR (ed.), Remington's Pharmaceutical Sciences, 20th edition.

In one embodiment, the non-absorbable composition may be co-administered with other active pharmaceutical agents depending on the condition being treated. This co-administration may include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. For example, for the treatment of metabolic acidosis, the non-absorbable composition can be co-administered with the co-treatment required for the treatment of potential complications including but not limited to: edema, hypertension, diabetes, obesity, Heart failure and complications of chronic kidney disease. These drugs and non-absorbable compositions can be formulated together and administered at the same time as long as they do not show any clinically significant drug-drug interactions. Alternatively, these therapeutic and non-absorbent compositions can be administered separately and sequentially with one administration followed by another.

In one embodiment, the daily dose compliance of chronic metabolic acidosis treatment is increased (approximately 15 g or less per day) and at these daily doses clinically approximately 3 mEq/L of serum bicarbonate is achieved clinically Significant and continuous increase. The non-absorbable nature of the polymer of this oral drug and the lack of sodium loading and/or the introduction of other harmful ions make it possible for the first time without worsening blood pressure/hypertension and/or without causing increased fluid retention and fluid overload Safe and chronic treatment of metabolic acidosis under conditions. Another benefit is to further slow down the development of kidney disease and the start of lifelong renal replacement therapy (end-stage renal disease "ESRD" includes 3 dialysis sessions a week) or the need for kidney transplantation. All of the above are associated with significant mortality, low quality of life and a significant burden on health systems around the world. In the United States alone, approximately 20% of the 400,000 ESRD patients die each year, and 100,000 new patients begin dialysis.

Another aspect of the invention is a pharmaceutical product comprising a sealed package and the non-absorbent composition of the invention in a sealed package. The sealed package is preferably substantially impermeable to moisture and oxygen to increase the stability of the pharmaceutical composition. For example, a unit dosage form may include a sealed container (eg, a sealed sachet) that prevents or reduces the ingress of moisture and oxygen when the non-absorbent composition is enclosed in the container. The size of the container can be optimized to reduce the head space in the container after packaging, and any head space can be filled with an inert gas such as nitrogen. In addition, the container construction material can be selected to minimize the amount of moisture and oxygen entering inside the container after packaging. For example, the non-absorbent composition may be encapsulated in a multilayer sachet containing at least one or more layers that serve as a barrier to moisture and oxygen ingress. In another example, the non-absorbent composition can be encapsulated in a single-layer or multi-layer plastic, metal, or glass container with at least one or more barrier layers that are incorporated after the encapsulation is restricted Oxygen and/or moisture enter the volume structure. For example, in one such embodiment, the sachet (or other container or package) may include a multi-layer laminate having: an inner contact layer, an outer layer; and a barrier layer disposed on the contact layer and the outer layer between. In an exemplary embodiment, the container includes one or more oxygen scavenging layers.

In other embodiments, listed as Examples 1-849 below, the present invention includes:

Example 1. A method of treating an individual suffering from an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l, the method comprising orally administering a daily dose of the pharmaceutical composition, This daily dose has the ability to bind at least 5 mEq target species as it passes through the digestive system to increase the serum bicarbonate value to a value in the range of 24 to 29 mEq/l within a treatment period not exceeding 1 month The target species is selected from the group consisting of protons, strong acids and conjugate bases of strong acids.

Example 2. A method of treating an individual suffering from an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l, the method comprising orally administering a pharmaceutical composition, wherein the oral administration The medicinal composition is combined with a target species in the digestive system with an average of at least 5 mEq per day to maintain the serum bicarbonate value at a value in the range of 24 to 29 mEq/l. The target species is selected from the group consisting of: Protons, strong acids and strong acid conjugate bases. .

Example 3. The method as in Example 2, wherein oral administration is at least once a week during the treatment period.

Example 4. The method as in Example 2, wherein oral administration is at least once every half week during the treatment period.

Embodiment 5. The method of embodiment 2, wherein oral administration is at least once daily during the treatment period.

Example 6. The method as in Example 1, 2, 3 or 5, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 21 mEq/l.

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

Example 8. The method as in Example 1, 2, 3, or 5, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 19 mEq/l.

Example 9. The method as in Example 1, 2, 3, or 5, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 18 mEq/l.

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

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

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

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

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

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

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

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

Embodiment 18. The method of any of the foregoing enumerated embodiments, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 9 mEq/l.

Embodiment 19. The method as in any one of embodiments 1 to 16, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 10 mEq/l.

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

Embodiment 21. The method as in any one of embodiments 1 to 14, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 12 mEq/l.

Embodiment 22. The method as in any one of embodiments 1 to 13, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 13 mEq/l.

Embodiment 23. The method as in any one of embodiments 1 to 12, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 14 mEq/l.

Embodiment 24. The method as in any one of embodiments 1 to 11, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 15 mEq/l.

Embodiment 25. The method as in any one of embodiments 1 to 10, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 16 mEq/l.

Embodiment 26. The method as in any one of embodiments 1 to 9, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 17 mEq/l.

Embodiment 27. The method as in any one of embodiments 1 to 8, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 18 mEq/l.

Embodiment 28. The method as in any one of embodiments 1 to 7, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 19 mEq/l.

Embodiment 29. The method as in any one of embodiments 1 to 6, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 20 mEq/l.

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

Embodiment 34. The method of any of the foregoing enumerated embodiments, wherein the method increases the serum bicarbonate value from the baseline serum bicarbonate value to an increased serum bicarbonate value of at least 25 mEq/l.

Embodiment 35. The method of any of the foregoing enumerated embodiments, wherein the method increases the serum bicarbonate value from the baseline serum bicarbonate value to an increased serum bicarbonate value of at least 26 mEq/l.

Embodiment 36. The method of any of the foregoing enumerated embodiments, wherein the method increases the serum bicarbonate value from the baseline serum bicarbonate value to an increased serum bicarbonate value of at least 27 mEq/l.

Embodiment 37. The method as in any of the previously listed embodiments, wherein the method increases the serum bicarbonate value from the baseline serum bicarbonate value to an increased serum bicarbonate value of at least 28 mEq/l.

Embodiment 38. The method of any of the foregoing enumerated embodiments, wherein the method sets the baseline serum bicarbonate value to an increased serum bicarbonate value of no more than 29 mEq/l.

Embodiment 39. The method as in any one of embodiments 1 to 36, wherein the method increases the baseline serum bicarbonate value to an increased serum bicarbonate value that does not exceed 28 mEq/l.

Embodiment 40. The method of any one of embodiments 1 to 35, wherein the method increases the baseline serum bicarbonate value to an increased serum bicarbonate value of no more than 27 mEq/l.

Embodiment 41. The method as in any one of embodiments 1 to 34, wherein the method increases the baseline serum bicarbonate value to an increased serum bicarbonate value that does not exceed 26 mEq/l.

Embodiment 42. The method of any one of embodiments 1 to 33, wherein the method increases the baseline serum bicarbonate value to an increased serum bicarbonate value of no more than 25 mEq/l.

Embodiment 45. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value by at least 1 mEq/l.

Embodiment 46. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value by at least 1.5 mEq/l.

Embodiment 47. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value by at least 2 mEq/l.

Embodiment 48. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value by at least 2.5 mEq/l.

Embodiment 49. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value by at least 3 mEq/l.

Embodiment 50. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value by at least 3.5 mEq/l.

Embodiment 51. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value by at least 4 mEq/l.

Embodiment 52. The method as in any of the previously listed embodiments, wherein the method increases the baseline serum bicarbonate value by at least 4.5 mEq/l.

Embodiment 53. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value by at least 5 mEq/l.

Embodiment 54. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value by at least 5.5 mEq/l.

Embodiment 55. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value by at least 6 mEq/l.

Embodiment 56. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value by at least 6.5 mEq/l.

Embodiment 57. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value by at least 7 mEq/l.

Embodiment 58. The method as in any of the previously listed embodiments, wherein the method increases the baseline serum bicarbonate value by at least 7.5 mEq/l.

Embodiment 59. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value by at least 8 mEq/l.

Embodiment 60. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value by at least 8.5 mEq/l.

Embodiment 61. The method as in any of the previously listed embodiments, wherein the method increases the baseline serum bicarbonate value by at least 9 mEq/l.

Embodiment 62. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value to a value in the range of 24 to 29 mEq/l during a treatment period of less than one month.

Embodiment 63. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value to a value in the range of 24 to 29 mEq/l during the 25-day treatment period.

Embodiment 64. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value to a value in the range of 24 to 29 mEq/l during the 3-week treatment period.

Example 65. The method as in any of the previously listed examples, wherein the method increases the baseline serum bicarbonate value to a value in the range of 24 to 29 mEq/l during the 15-day treatment period.

Embodiment 66. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value to a value in the range of 24 to 29 mEq/l during the 2-week treatment period.

Embodiment 67. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value to a value in the range of 24 to 29 mEq/l during the 10-day treatment period.

Embodiment 68. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value to a value in the range of 24 to 29 mEq/l during a 1-week treatment period.

Embodiment 69. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value to a value in the range of 24 to 29 mEq/l within 6 days of starting treatment.

Embodiment 70. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value to a value in the range of 24 to 29 mEq/l during the 5-day treatment period.

Example 71. The method of any of the foregoing enumerated examples, wherein the method increases the baseline serum bicarbonate value to a value in the range of 24 to 29 mEq/l during the 4-day treatment period.

Embodiment 72. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value to a value in the range of 24 to 29 mEq/l during the 3-day treatment period.

Example 73. The method as in any of the previously listed examples, wherein the method increases the baseline serum bicarbonate value to a value in the range of 24 to 29 mEq/l during the 2-day treatment period.

Embodiment 74. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value to a value in the range of 24 to 29 mEq/l during the 1-day treatment period.

Embodiment 75. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value to a value in the range of 24 to 29 mEq/l during the 12-hour treatment period.

Embodiment 76. The method of any of the foregoing enumerated embodiments, wherein the method increases the baseline serum bicarbonate value to 24 without any change in the individual's diet or eating habits relative to the period immediately before the start of treatment Values in the range to 29 mEq/l.

Example 77. The method as in any of the previously listed examples, wherein the method does not depend on the individual's diet or dietary habits to increase the baseline serum bicarbonate value to a value in the range of 24 to 29 mEq/l.

Embodiment 78. The method as in any of the foregoing embodiments, wherein the individual's serum bicarbonate value returns to the baseline value ± 2.5 mEq/l within 1 month of stopping treatment.

Embodiment 79. The method as in any of the previously listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2.5 mEq/l within 3 weeks of stopping treatment.

Embodiment 80. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to the baseline value ± 2.5 mEq/l within 2 weeks of stopping treatment.

Embodiment 81. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to the baseline value ± 2.5 mEq/l within 10 days of stopping treatment.

Example 82. The method as in any of the aforementioned examples, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2.5 mEq/l within 9 days of stopping treatment.

Example 83. The method as in any of the aforementioned examples, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2.5 mEq/l within 8 days of stopping treatment.

Embodiment 84. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2.5 mEq/l within 7 days of stopping treatment.

Embodiment 85. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to the baseline value ± 2.5 mEq/l within 6 days of stopping treatment.

Embodiment 86. The method as in any of the foregoing enumerated embodiments, wherein the individual's serum bicarbonate value returns to the baseline value ± 2.5 mEq/l within 5 days of stopping treatment.

Example 87. The method as in any of the previously listed examples, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2.5 mEq/l within 4 days of stopping treatment.

Embodiment 88. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2.5 mEq/l within 3 days of stopping treatment.

Embodiment 89. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2.5 mEq/l within 2 days of stopping treatment.

Embodiment 90. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2.5 mEq/l within 1 day of stopping treatment.

Embodiment 91. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2 mEq/l within 1 month of stopping treatment.

Example 92. The method as in any of the previously listed examples, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2 mEq/l within 3 weeks of stopping treatment.

Example 93. The method as in any of the previously listed examples, wherein the individual's serum bicarbonate value returns to the baseline value ± 2 mEq/l within 2 weeks of stopping treatment.

Example 94. The method as in any of the previously listed examples, wherein the individual's serum bicarbonate value returns to the baseline value ± 2 mEq/l within 10 days of stopping treatment.

Embodiment 95. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2 mEq/l within 9 days of stopping treatment.

Example 96. The method as in any of the previously listed examples, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2 mEq/l within 8 days of stopping treatment.

Embodiment 97. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2 mEq/l within 7 days of stopping treatment.

Embodiment 98. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2 mEq/l within 6 days of stopping treatment.

Embodiment 99. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2 mEq/l within 5 days of stopping treatment.

Embodiment 100. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2 mEq/l within 4 days of stopping treatment.

Embodiment 101. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2 mEq/l within 3 days of stopping treatment.

Embodiment 102. The method as in any of the aforementioned embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2 mEq/l within 2 days of stopping treatment.

Embodiment 103. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 2 mEq/l within 1 day of stopping treatment.

Embodiment 104. The method of any of the foregoing enumerated embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 1.5 mEq/l within 1 month of stopping treatment.

Embodiment 105. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 1.5 mEq/l within 3 weeks of stopping treatment.

Embodiment 106. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to the baseline value ± 1.5 mEq/l within 2 weeks of stopping treatment.

Embodiment 107. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to the baseline value ± 1.5 mEq/l within 10 days of stopping treatment.

Embodiment 108. The method of any of the foregoing enumerated embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 1.5 mEq/l within 9 days of stopping treatment.

Embodiment 109. The method as in any of the aforementioned embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 1.5 mEq/l within 8 days of stopping treatment.

Embodiment 110. The method of any of the foregoing enumerated embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 1.5 mEq/l within 7 days of stopping treatment.

Embodiment 111. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to the baseline value ± 1.5 mEq/l within 6 days of stopping treatment.

Embodiment 112. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to the baseline value ± 1.5 mEq/l within 5 days of stopping treatment.

Embodiment 113. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 1.5 mEq/l within 4 days of stopping treatment.

Embodiment 114. The method of any of the foregoing enumerated embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 1.5 mEq/l within 3 days of stopping treatment.

Embodiment 115. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to the baseline value ± 1.5 mEq/l within 2 days of stopping treatment.

Embodiment 116. The method of any of the foregoing enumerated embodiments, wherein the individual's serum bicarbonate value returns to the baseline value ± 1.5 mEq/l within 1 day of stopping treatment.

Embodiment 117. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to the baseline value within 1 month of stopping treatment ± 1 mEq/l.

Embodiment 118. The method of any of the foregoing enumerated embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 1 mEq/l within 3 weeks of stopping treatment.

Embodiment 119. The method as in any of the foregoing enumerated embodiments, wherein the individual's serum bicarbonate value returns to the baseline value ± 1 mEq/l within 2 weeks of stopping treatment.

Embodiment 120. The method of any of the foregoing enumerated embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 1 mEq/l within 10 days of stopping treatment.

Embodiment 121. The method of any of the foregoing enumerated embodiments, wherein the individual's serum bicarbonate value returns to the baseline value ± 1 mEq/l within 9 days of stopping treatment.

Embodiment 122. The method of any of the foregoing enumerated embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 1 mEq/l within 8 days of stopping treatment.

Embodiment 123. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 1 mEq/l within 7 days of stopping treatment.

Embodiment 124. The method of any of the foregoing enumerated embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 1 mEq/l within 6 days of stopping treatment.

Embodiment 125. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to the baseline value ± 1 mEq/l within 5 days of stopping treatment.

Embodiment 126. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 1 mEq/l within 4 days of stopping treatment.

Embodiment 127. The method as in any of the foregoing listed embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 1 mEq/l within 3 days of stopping treatment.

Embodiment 128. The method of any of the foregoing enumerated embodiments, wherein the individual's serum bicarbonate value returns to the baseline value ± 1 mEq/l within 2 days of stopping treatment.

Embodiment 129. The method of any of the foregoing enumerated embodiments, wherein the individual's serum bicarbonate value returns to a baseline value of ± 1 mEq/l within 1 day of stopping treatment.

Embodiment 130. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 1 month of stopping the treatment.

Embodiment 131. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 3 weeks of stopping the treatment.

Embodiment 132. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 2 weeks of stopping the treatment.

Embodiment 133. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 10 days of stopping the treatment.

Embodiment 134. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 9 days of stopping the treatment.

Embodiment 135. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 8 days of stopping the treatment.

Embodiment 136. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 7 days of stopping the treatment.

Embodiment 137. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 6 days of stopping the treatment.

Embodiment 138. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 5 days of stopping the treatment.

Embodiment 139. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 4 days of stopping the treatment.

Embodiment 140. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 3 days of stopping the treatment.

Embodiment 141. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 2 days of stopping the treatment.

Embodiment 142. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1 mEq/l within 1 day of stopping the treatment.

Embodiment 143. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 1 month of stopping the treatment.

Embodiment 144. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value decreases by at least 1.5 mEq/l within 3 weeks of stopping the treatment.

Embodiment 145. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 2 weeks of stopping the treatment.

Embodiment 146. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 10 days of stopping the treatment.

Embodiment 147. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 9 days of stopping the treatment.

Embodiment 148. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 8 days of stopping the treatment.

Embodiment 149. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 7 days of stopping the treatment.

Embodiment 150. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value decreases by at least 1.5 mEq/l within 6 days of stopping the treatment.

Embodiment 151. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 5 days of stopping the treatment.

Embodiment 152. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 4 days of stopping the treatment.

Embodiment 153. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 3 days of stopping the treatment.

Embodiment 154. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 2 days of stopping the treatment.

Embodiment 155. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 1.5 mEq/l within 1 day of stopping the treatment.

Embodiment 156. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 1 month of stopping the treatment.

Embodiment 157. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 3 weeks of stopping the treatment.

Embodiment 158. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 2 weeks of stopping the treatment.

Embodiment 159. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 10 days of stopping the treatment.

Embodiment 160. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 9 days of stopping the treatment.

Embodiment 161. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 8 days of stopping the treatment.

Embodiment 162. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 7 days of stopping the treatment.

Embodiment 163. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 6 days of stopping the treatment.

Embodiment 164. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 5 days of stopping the treatment.

Embodiment 165. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 4 days of stopping the treatment.

Embodiment 166. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 3 days of stopping the treatment.

Embodiment 167. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 2 days of stopping the treatment.

Embodiment 168. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2 mEq/l within 1 day of stopping the treatment.

Embodiment 169. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 1 month of stopping the treatment.

Embodiment 170. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 3 weeks of stopping the treatment.

Embodiment 171. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value decreases by at least 2.5 mEq/l within 2 weeks of stopping the treatment.

Embodiment 172. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 10 days of stopping the treatment.

Embodiment 173. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 9 days of stopping the treatment.

Embodiment 174. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 8 days of stopping the treatment.

Embodiment 175. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 7 days of stopping the treatment.

Embodiment 176. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 6 days of stopping the treatment.

Embodiment 177. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 5 days of stopping the treatment.

Embodiment 178. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 4 days of stopping the treatment.

Embodiment 179. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 3 days of stopping the treatment.

Embodiment 180. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 2 days of stopping the treatment.

Embodiment 181. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 2.5 mEq/l within 1 day of stopping the treatment.

Embodiment 182. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 1 month of stopping the treatment.

Embodiment 183. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 3 weeks of stopping the treatment.

Embodiment 184. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 2 weeks of stopping the treatment.

Embodiment 185. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 10 days of stopping the treatment.

Embodiment 186. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 9 days of stopping the treatment.

Embodiment 187. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 8 days of stopping the treatment.

Embodiment 188. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 7 days of stopping the treatment.

Embodiment 189. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 6 days of stopping the treatment.

Embodiment 190. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 5 days of stopping the treatment.

Embodiment 191. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 4 days of stopping the treatment.

Embodiment 192. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 3 days of stopping the treatment.

Embodiment 193. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 2 days of stopping the treatment.

Embodiment 194. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3 mEq/l within 1 day of stopping the treatment.

Embodiment 195. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 1 month of stopping the treatment.

Embodiment 196. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value decreases by at least 3.5 mEq/l within 3 weeks of stopping the treatment.

Embodiment 197. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value decreases by at least 3.5 mEq/l within 2 weeks of stopping the treatment.

Embodiment 198. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 10 days of stopping the treatment.

Embodiment 199. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 9 days of stopping the treatment.

Embodiment 200. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 8 days of stopping the treatment.

Embodiment 201. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 7 days of stopping the treatment.

Embodiment 202. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value decreases by at least 3.5 mEq/l within 6 days of stopping the treatment.

Embodiment 203. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 5 days of stopping the treatment.

Embodiment 204. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 4 days of stopping the treatment.

Embodiment 205. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 3 days of stopping the treatment.

Embodiment 206. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 2 days of stopping the treatment.

Embodiment 207. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 3.5 mEq/l within 1 day of stopping the treatment.

Embodiment 208. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 1 month of stopping the treatment.

Embodiment 209. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 3 weeks of stopping the treatment.

Embodiment 210. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value decreases by at least 4 mEq/l within 2 weeks of stopping the treatment.

Embodiment 211. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 10 days of stopping the treatment.

Embodiment 212. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 9 days of stopping the treatment.

Embodiment 213. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 8 days of stopping the treatment.

Embodiment 214. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 7 days of stopping the treatment.

Embodiment 215. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 6 days of stopping the treatment.

Embodiment 216. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 5 days of stopping the treatment.

Embodiment 217. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 4 days of stopping the treatment.

Embodiment 218. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 3 days of stopping the treatment.

Embodiment 219. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 2 days of stopping the treatment.

Embodiment 220. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4 mEq/l within 1 day of stopping the treatment.

Embodiment 221. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 1 month of stopping the treatment.

Embodiment 222. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 3 weeks of stopping the treatment.

Embodiment 223. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value decreases by at least 4.5 mEq/l within 2 weeks of stopping the treatment.

Embodiment 224. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 10 days of stopping the treatment.

Embodiment 225. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 9 days of stopping the treatment.

Embodiment 226. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 8 days of stopping the treatment.

Embodiment 227. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value decreases by at least 4.5 mEq/l within 7 days of stopping the treatment.

Embodiment 228. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value decreases by at least 4.5 mEq/l within 6 days of stopping the treatment.

Embodiment 229. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 5 days of stopping the treatment.

Embodiment 230. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 4 days of stopping the treatment.

Embodiment 231. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 3 days of stopping the treatment.

Embodiment 232. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value decreases by at least 4.5 mEq/l within 2 days of stopping the treatment.

Embodiment 233. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 4.5 mEq/l within 1 day of stopping the treatment.

Embodiment 234. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 1 month of stopping the treatment.

Embodiment 235. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 3 weeks of stopping the treatment.

Embodiment 236. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 2 weeks of stopping the treatment.

Embodiment 237. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 10 days of stopping the treatment.

Embodiment 238. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 9 days of stopping the treatment.

Embodiment 239. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 8 days of stopping the treatment.

Embodiment 240. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 7 days of stopping the treatment.

Embodiment 241. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 6 days of stopping the treatment.

Embodiment 242. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 5 days of stopping the treatment.

Embodiment 243. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 4 days of stopping the treatment.

Embodiment 244. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 3 days of stopping the treatment.

Embodiment 245. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 2 days of stopping the treatment.

Embodiment 246. The method of any of the foregoing enumerated embodiments, wherein when the treatment is stopped, the individual's serum bicarbonate value is reduced by at least 5 mEq/l within 1 day of stopping the treatment.

Embodiment 247. The method of any of the foregoing enumerated embodiments, wherein the baseline serum bicarbonate value is the value of the serum bicarbonate concentration determined at a single time point.

Embodiment 248. The method of any one of embodiments 1 to 246, wherein the baseline serum bicarbonate value is the average of at least two serum bicarbonate concentrations determined at different time points.

Embodiment 249. The method as in any one of embodiments 1 to 246, wherein the baseline serum bicarbonate value is the average of at least two serum bicarbonate concentrations of serum samples taken on different days.

Embodiment 250. The method as in embodiment 249, wherein the baseline serum bicarbonate value is the average of at least two serum bicarbonate concentrations of serum samples taken on consecutive days.

Embodiment 251. The method as in embodiment 249, wherein the baseline serum bicarbonate value is the average of at least two serum bicarbonate concentrations in serum samples taken on two consecutive days and before starting treatment.

Embodiment 252. The method as in embodiment 249, wherein the baseline serum bicarbonate value is the average or median of at least two serum bicarbonate concentrations of serum samples taken on non-consecutive days.

Embodiment 253. The method of embodiment 252, wherein the discrete days are separated by at least two days.

Embodiment 254. The method of embodiment 252, wherein the discrete days are separated by at least one week.

Embodiment 255. The method of embodiment 252, wherein the discrete days are separated by at least two weeks.

Embodiment 256. The method of embodiment 252, wherein the discrete days are separated by at least three weeks.

Embodiment 257. The method of any of the foregoing enumerated embodiments, wherein the individual is treated for acute metabolic acidosis.

Embodiment 258. The method of any of the foregoing enumerated embodiments, wherein the individual is treated for chronic metabolic acidosis.

Embodiment 259. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 7.5 mEq target species as it passes through the digestive system.

Embodiment 260. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 10 mEq target species as it passes through the digestive system.

Embodiment 261. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 15 mEq target species as it passes through the digestive system.

Embodiment 262. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 20 mEq target species as it passes through the digestive system.

Embodiment 263. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 25 mEq target species as it passes through the digestive system.

Embodiment 264. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 30 mEq target species as it passes through the digestive system.

Embodiment 265. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 35 mEq target species as it passes through the digestive system.

Embodiment 266. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 40 mEq target species as it passes through the digestive system.

Embodiment 267. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 45 mEq target species as it passes through the digestive system.

Embodiment 268. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 50 mEq target species as it passes through the digestive system.

Embodiment 269. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 55 mEq target species as it passes through the digestive system.

Embodiment 270. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 60 mEq target species as it passes through the digestive system.

Embodiment 271. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 65 mEq target species as it passes through the digestive system.

Embodiment 272. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 70 mEq target species as it passes through the digestive system.

Embodiment 273. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 75 mEq target species as it passes through the digestive system.

Embodiment 274. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 80 mEq target species as it passes through the digestive system.

Embodiment 275. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 85 mEq target species as it passes through the digestive system.

Embodiment 276. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 90 mEq target species as it passes through the digestive system.

Embodiment 277. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 95 mEq target species as it passes through the digestive system.

Embodiment 278. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 100 mEq target species as it passes through the digestive system.

Embodiment 279. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 105 mEq target species as it passes through the digestive system.

Embodiment 280. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove at least 110 mEq target species as it passes through the digestive system.

Embodiment 281. The method of any of the foregoing enumerated embodiments, wherein the daily dose does not exceed 100 g/day.

Embodiment 282. The method of any of the foregoing enumerated embodiments, wherein the daily dose does not exceed 90 g/day.

Embodiment 283. The method of any of the foregoing enumerated embodiments, wherein the daily dose is less than 75 g/day.

Embodiment 284. The method of any of the foregoing enumerated embodiments, wherein the daily dose is less than 65 g/day.

Embodiment 285. The method of any of the foregoing enumerated embodiments, wherein the daily dose is less than 50 g/day.

Embodiment 286. The method of any of the foregoing enumerated embodiments, wherein the daily dose is less than 40 g/day.

Embodiment 287. The method of any of the foregoing enumerated embodiments, wherein the daily dose is less than 30 g/day.

Embodiment 288. The method of any of the foregoing enumerated embodiments, wherein the daily dose is less than 25 g/day.

Embodiment 289. The method of any of the foregoing enumerated embodiments, wherein the daily dose is less than 20 g/day.

Embodiment 290. The method of any of the foregoing enumerated embodiments, wherein the daily dose is less than 15 g/day.

Embodiment 291. The method of any of the foregoing enumerated embodiments, wherein the daily dose is less than 10 g/day.

Embodiment 292. The method of any of the foregoing enumerated embodiments, wherein the daily dose is less than 5 g/day.

Embodiment 293. The method of any of the foregoing enumerated embodiments, wherein the individual is treated for at least one day.

Embodiment 294. The method of any of the foregoing enumerated embodiments, wherein the individual is treated for at least one week.

Embodiment 295. The method of any of the foregoing enumerated embodiments, wherein the individual is treated for at least one month.

Embodiment 296. The method of any of the foregoing enumerated embodiments, wherein the individual is treated for at least several months.

Embodiment 297. The method of any of the foregoing enumerated embodiments, wherein the individual is treated for at least six months.

Embodiment 298. The method of any of the foregoing enumerated embodiments, wherein the individual is treated for at least one year.

Embodiment 299. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles having an equal particle size (volume distribution) of at least 3 microns.

Embodiment 300. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles having a medium particle size (volume distribution) in the range of 5 to 1,000 microns.

Embodiment 301. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles having a medium particle size (volume distribution) in the range of 5 to 500 microns.

Embodiment 302. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles having a medium particle size (volume distribution) in the range of 10 to 400 microns.

Embodiment 303. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles having a medium particle size (volume distribution) in the range of 10 to 300 microns.

Embodiment 304. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles having a medium particle size (volume distribution) in the range of 20 to 250 microns.

Embodiment 305. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles having a medium particle size (volume distribution) in the range of 30 to 250 microns.

Embodiment 306. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles having a medium particle size (volume distribution) in the range of 40 to 180 microns.

Embodiment 307. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles with less than 7% of particles in the group (volume distribution) having a diameter of less than 10 microns.

Embodiment 308. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles with less than 5% of the particles in the group (volume distribution) having a diameter of less than 10 microns .

Embodiment 309. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles with less than 2.5% of the particles in the group (volume distribution) having a diameter of less than 10 microns .

Embodiment 310. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles, and less than 1% of the particles in the group (volume distribution) have a diameter of less than 10 microns .

Embodiment 311. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a group of particles having the following particle size range: (i) large enough to avoid passive or active absorption through the gastrointestinal tract and ( ii) As small as not ingesting in the form of powders, suspensions, gels and/or lozenges without sandiness or unpleasant taste.

Embodiment 312. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles having an expansion ratio of less than 9.

Embodiment 313. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles having an expansion ratio of less than 8.

Embodiment 314. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles having an expansion ratio of less than 7.

Embodiment 315. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles having an expansion ratio of less than 6.

Embodiment 316. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles having an expansion ratio of less than 5.

Embodiment 317. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles having an expansion ratio of less than 4.

Embodiment 318. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles having an expansion ratio of less than 3.

Embodiment 319. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a group of particles having an expansion ratio of less than 2.

Embodiment 320. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species of at least about 0.5 mEq/g.

Embodiment 321. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species of at least about 1 mEq/g.

Embodiment 322. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species of at least about 2 mEq/g.

Embodiment 323. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species of at least about 3 mEq/g.

Embodiment 324. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species of at least about 4 mEq/g.

Embodiment 325. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species of at least about 5 mEq/g.

Embodiment 326. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species of at least about 7.5 mEq/g.

Embodiment 327. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species of at least about 10 mEq/g.

Embodiment 328. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species of at least about 12.5 mEq/g.

Embodiment 329. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species of at least about 15 mEq/g.

Embodiment 330. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species of at least about 20 mEq/g.

Embodiment 331. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species of at least about 25 mEq/g.

Embodiment 332. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species of at least about 30 mEq/g.

Embodiment 333. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species of at least about 35 mEq/g.

Embodiment 334. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species in the range of 2 to 25 mEq/g.

Embodiment 335. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species in the range of 3 to 25 mEq/g.

Embodiment 336. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species in the range of 5 to 25 mEq/g.

Embodiment 337. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species in the range of 10 to 25 mEq/g.

Embodiment 338. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species in the range of 5 to 20 mEq/g.

Embodiment 339. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species in the range of 6 to 20 mEq/g.

Embodiment 340. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species in the range of 7.5 to 20 mEq/g.

Embodiment 341. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition has a theoretical binding force to the target species in the range of 10 to 20 mEq/g.

Embodiment 342. The method of any of the foregoing enumerated embodiments, wherein the theoretical binding force for the target species is the theoretical binding force as determined in the SGF analysis.

Embodiment 343. The method of any of the foregoing enumerated embodiments, wherein the target species contains protons.

Embodiment 344. The method of any of the foregoing enumerated embodiments, wherein the target species comprises a strong acid conjugate base.

Embodiment 345. The method of any of the foregoing enumerated embodiments, wherein the target species comprises a conjugate base of a strong acid selected from the group consisting of chloride ion, hydrogen sulfate ion, and sulfate ion.

Embodiment 346. The method of any of the foregoing enumerated embodiments, wherein the target species includes chloride ions.

Embodiment 347. The method of any of the foregoing enumerated embodiments, wherein the target species includes a strong acid.

Embodiment 348. The method of any of the foregoing enumerated embodiments, wherein the target species includes hydrochloric acid.

Embodiment 349. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is characterized by a chloride ion binding capacity of at least 1 mEq/g in SIB analysis.

Embodiment 350. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is characterized by a chloride ion binding capacity of at least 1.5 mEq/g in SIB analysis.

Embodiment 351. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is characterized by a chloride ion binding capacity of at least 2 mEq/g in SIB analysis.

Embodiment 352. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is characterized by a chloride ion binding capacity of at least 2.5 mEq/g in SIB analysis.

Embodiment 353. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in SIB analysis.

Embodiment 354. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is characterized by a chloride ion binding capacity of at least 3.5 mEq/g in SIB analysis.

Embodiment 355. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is characterized by a chloride ion binding capacity of at least 4 mEq/g in SIB analysis.

Embodiment 356. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is characterized by a chloride ion binding capacity of at least 4.5 mEq/g in SIB analysis.

Embodiment 357. The method of any of the foregoing listed embodiments, wherein the non-absorbent composition is characterized by a chloride ion binding capacity of at least 5 mEq/g in SIB analysis.

Embodiment 358. The method of any of the foregoing listed embodiments, wherein the non-absorbent composition is characterized by a chloride ion binding capacity of at least 5.5 mEq/g in SIB analysis.

Embodiment 359. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is characterized by a chloride ion binding capacity of at least 6 mEq/g in SIB analysis.

Embodiment 360. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 0.1:1.

Embodiment 361. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 0.2:1.

Embodiment 362. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 0.25:1.

Embodiment 363. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 0.3:1.

Embodiment 364. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 0.35:1, respectively.

Embodiment 365. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 0.4:1.

Embodiment 366. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 0.45:1.

Embodiment 367. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 0.5:1.

Embodiment 368. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 2:3, respectively.

Embodiment 369. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 0.75:1, respectively.

Embodiment 370. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 0.9:1.

Embodiment 371. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is respectively at least 1:1.

Embodiment 372. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 1.25:1, respectively.

Embodiment 373. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 1.5:1.

Embodiment 374. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 1.75:1, respectively.

Embodiment 375. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 2:1.

Embodiment 376. The method of any of the foregoing listed embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 2.25:1, respectively.

Embodiment 377. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 2.5:1.

Embodiment 378. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 2.75:1, respectively.

Embodiment 379. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 3:1, respectively.

Embodiment 380. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 4:1.

Embodiment 381. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 5:1.

Embodiment 382. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 6:1.

Embodiment 383. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 7:1.

Embodiment 384. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 8:1.

Embodiment 385. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 9:1.

Embodiment 386. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 10:1.

Embodiment 387. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 12.5:1, respectively.

Embodiment 388. The method of any of the foregoing enumerated embodiments, wherein the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis is at least 15:1.

Embodiment 389. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 5 mEq/day. .

Embodiment 390. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 6 mEq/day.

Embodiment 391. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 7 mEq/day.

Embodiment 392. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 8 mEq/day.

Embodiment 393. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 9 mEq/day.

Embodiment 394. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 10 mEq/day.

Embodiment 395. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 11 mEq/day.

Embodiment 396. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 12 mEq/day.

Embodiment 397. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 13 mEq/day.

Embodiment 398. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 14 mEq/day. .

Embodiment 399. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 15 mEq/day.

Embodiment 400. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 16 mEq/day.

Embodiment 401. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 17 mEq/day.

Embodiment 402. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 18 mEq/day.

Embodiment 403. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 19 mEq/day.

Embodiment 404. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 20 mEq/day.

Embodiment 405. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 21 mEq/day.

Embodiment 406. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 22 mEq/day.

Embodiment 407. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 23 mEq/day.

Embodiment 408. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 24 mEq/day.

Embodiment 409. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 25 mEq/day.

Embodiment 410. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 26 mEq/day.

Embodiment 411. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 27 mEq/day.

Embodiment 412. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 28 mEq/day.

Embodiment 413. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 29 mEq/day.

Embodiment 414. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 30 mEq/day.

Embodiment 415. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 31 mEq/day.

Embodiment 416. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 32 mEq/day.

Embodiment 417. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 33 mEq/day.

Embodiment 418. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 34 mEq/day.

Embodiment 419. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 35 mEq/day.

Embodiment 420. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 36 mEq/day.

Embodiment 421. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 37 mEq/day.

Embodiment 422. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 38 mEq/day.

Embodiment 423. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 39 mEq/day.

Embodiment 424. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 40 mEq/day.

Embodiment 425. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 41 mEq/day.

Embodiment 426. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 42 mEq/day.

Embodiment 427. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 43 mEq/day.

Embodiment 428. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 44 mEq/day.

Embodiment 429. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 45 mEq/day.

Embodiment 430. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 46 mEq/day.

Embodiment 431. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 47 mEq/day.

Embodiment 432. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 48 mEq/day.

Embodiment 433. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 49 mEq/day.

Embodiment 434. The method of any of the foregoing enumerated embodiments, wherein the daily dose has the ability to remove target species of at least about 50 mEq/day.

Embodiment 435. The method of any of the foregoing enumerated embodiments, wherein the daily dose removes less than 60 mEq/day of target species.

Embodiment 436. The method of any of the foregoing enumerated embodiments, wherein the daily dose removes less than 55 mEq/day of the target species.

Embodiment 437. The method of any one of embodiments 1 to 433, wherein the daily dose removes less than 50 mEq/day of the target species.

Embodiment 438. The method of any one of embodiments 1 to 428, wherein the daily dose removes less than 45 mEq/day of the target species.

Embodiment 439. The method of any one of embodiments 1 to 423, wherein the daily dose removes less than 40 mEq/day of the target species.

Embodiment 440. The method of any one of embodiments 1 to 418, wherein the daily dose removes less than 35 mEq/day of the target species.

Embodiment 441. The method of any one of Embodiments 1 to 417, wherein the daily dose removes less than 34 mEq/day of the target species.

Embodiment 442. The method of any one of embodiments 1 to 416, wherein the daily dose removes less than 33 mEq/day of the target species.

Embodiment 443. The method of any one of embodiments 1 to 415, wherein the daily dose removes less than 32 mEq/day of the target species.

Embodiment 444. The method of any one of embodiments 1 to 414, wherein the daily dose removes less than 31 mEq/day of the target species.

Embodiment 445. The method of any one of embodiments 1 to 413, wherein the daily dose removes less than 30 mEq/day of the target species.

Embodiment 446. The method of any one of Embodiments 1 to 412, wherein the daily dose removes less than 29 mEq/day of the target species.

Embodiment 447. The method of any one of Embodiments 1 to 411, wherein the daily dose removes less than 28 mEq/day of the target species.

Embodiment 448. The method of any one of embodiments 1 to 410, wherein the daily dose removes less than 27 mEq/day of the target species.

Embodiment 449. The method of any one of embodiments 1 to 409, wherein the daily dose removes less than 26 mEq/day of the target species.

Embodiment 450. The method of any one of embodiments 1 to 408, wherein the daily dose removes less than 25 mEq/day of the target species.

Embodiment 451. The method of any one of embodiments 1 to 407, wherein the daily dose removes less than 24 mEq/day of the target species.

Embodiment 452. The method of any one of embodiments 1 to 406, wherein the daily dose removes less than 23 mEq/day of the target species.

Embodiment 453. The method of any one of embodiments 1 to 405, wherein the daily dose removes less than 22 mEq/day of the target species.

Embodiment 454. The method of any one of embodiments 1 to 404, wherein the daily dose removes less than 21 mEq/day of the target species.

Embodiment 455. The method of any one of embodiments 1 to 403, wherein the daily dose removes less than 20 mEq/day of the target species.

Embodiment 456. The method of any one of embodiments 1 to 402, wherein the daily dose removes less than 19 mEq/day of the target species.

Embodiment 457. The method of any one of embodiments 1 to 401, wherein the daily dose removes less than 18 mEq/day of the target species.

Embodiment 458. The method of any one of Embodiments 1 to 400, wherein the daily dose removes less than 17 mEq/day of the target species.

Embodiment 459. The method of any one of embodiments 1 to 399, wherein the daily dose removes less than 16 mEq/day of the target species.

Embodiment 460. The method of any one of embodiments 1 to 398, wherein the daily dose removes less than 15 mEq/day of the target species.

Embodiment 461. The method of any one of embodiments 1 to 397, wherein the daily dose removes less than 14 mEq/day of the target species.

Embodiment 462. The method of any one of embodiments 1 to 396, wherein the daily dose removes less than 13 mEq/day of the target species.

Embodiment 463. The method of any one of embodiments 1 to 395, wherein the daily dose removes less than 12 mEq/day of the target species.

Embodiment 464. The method of any one of embodiments 1 to 394, wherein the daily dose removes less than 11 mEq/day of the target species.

Embodiment 465. The method of any one of embodiments 1 to 393, wherein the daily dose removes less than 10 mEq/day of the target species.

Embodiment 466. The method of any one of embodiments 1 to 392, wherein the daily dose removes less than 9 mEq/day of the target species.

Embodiment 467. The method of any one of embodiments 1 to 391, wherein the daily dose removes less than 8 mEq/day of the target species.

Embodiment 468. The method of any one of embodiments 1 to 390, wherein the daily dose removes less than 7 mEq/day of the target species.

Embodiment 469. The method of any one of embodiments 1 to 389, wherein the daily dose removes less than 6 mEq/day of the target species.

Embodiment 470. The method of any of the foregoing enumerated embodiments, wherein the non-absorbable composition is a cation exchange substance comprising an insoluble (in the stomach environment) support structure and exchangeable cations.

Embodiment 471. The method as in any of the foregoing listed embodiments, wherein the non-absorbable composition is a cation exchange substance comprising an insoluble (in stomach environment) support structure and exchangeable cations, wherein the cation exchange substance is organic or inorganic Or its complex.

Embodiment 472. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange substance comprising exchangeable cations selected from the group consisting of: lithium, sodium, potassium, calcium, magnesium , Iron and combinations.

Embodiment 473. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange substance comprising exchangeable cations selected from the group consisting of: sodium, potassium, calcium, magnesium, and combination.

Embodiment 474. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange substance comprising exchangeable cations selected from the group consisting of: sodium, potassium, and combinations thereof.

Embodiment 475. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange substance comprising a combination of exchangeable cations that establish or maintain a steady state of the electrolyte.

Embodiment 476. The method as in any of the foregoing listed embodiments, wherein the non-absorbent composition is a cation exchange substance containing optionally exchangeable sodium ions, however, the limitation is that the amount of sodium ions in the daily dose is insufficient To increase the patient's serum sodium ion concentration to a value outside the range of 135 to 145 mEq/l.

Embodiment 477. The method as in any of the foregoing listed embodiments, wherein the non-absorbent composition is a cation exchange substance containing optionally exchangeable potassium ions, however, the limitation is that the amount of sodium ions in the daily dose is insufficient To increase the patient's serum potassium ion concentration to a value outside the range of 3.7 to 5.2 mEq/L.

Embodiment 478. The method as in any of the foregoing listed embodiments, wherein the non-absorbent composition is a cation exchange substance containing optionally exchangeable magnesium ions, however, the limitation is that the amount of magnesium ions in the daily dose is insufficient To increase the patient's serum magnesium ion concentration to a value outside the range of 1.7 to 2.2 mg /dL.

Embodiment 479. The method as in any of the foregoing listed embodiments, wherein the non-absorbent composition is a cation exchange substance containing optionally exchangeable calcium ions, however, the limitation is that the amount of calcium ions in the daily dose is insufficient To increase the patient's serum calcium ion concentration to a value outside the range of 8.5 to 10.2 mg/dL.

Embodiment 480. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange substance that optionally contains a combination of exchangeable cations selected from the group consisting of: sodium, potassium, calcium , Magnesium, and combinations designed to maintain serum Na ⁺ levels in the range of 135 to 145 mEq/l, maintain serum K ⁺ levels in the range of 3.7 to 5.2 mEq/L, and maintain serum Mg ²⁺ levels In the range of 1.7 to 2.2 mg /dL, and maintain the serum Ca ²⁺ content in the range of 8.5 to 10.2 mg/dL.

Embodiment 481. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange material containing exchangeable sodium ions, and the composition contains less than 12% by weight sodium.

Embodiment 482. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange material containing exchangeable sodium ions, and the composition contains less than 9% by weight sodium.

Embodiment 483. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange material containing exchangeable sodium ions, and the composition contains less than 6% by weight sodium.

Embodiment 484. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange material containing exchangeable sodium ions, and the composition contains less than 3% by weight sodium.

Embodiment 485. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange material containing exchangeable sodium ions, and the composition contains less than 1% by weight sodium.

Embodiment 486. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange material containing exchangeable sodium ions, and the composition contains less than 0.1% by weight sodium.

Embodiment 487. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange material containing exchangeable sodium ions, and the composition contains less than 0.01% by weight sodium.

Embodiment 488. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange material containing exchangeable sodium ions, and the composition contains between 0.05 and 3% by weight of sodium.

Embodiment 489. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a polymeric substance having the ability to bind protons in an aqueous solution.

Embodiment 490. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a polymeric substance having the ability to bind protons in an aqueous solution and the non-absorbent composition is selected from the group consisting of cross-linked polymers containing a polyanion backbone Group of substances.

Embodiment 491. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a polymeric substance having the ability to bind protons in an aqueous solution, and the non-absorbent composition is selected from cross-links containing a polyanion backbone A group consisting of polymeric substances, wherein the polyanion main chain is selected from the group consisting of poly(formic acid), poly(acrylic acid), poly(sulfonic acid), poly(maleic acid), poly(phenol), Functionalized polyols and poly(alcohol), poly(hydroxamic acid), poly(amide) and their copolymers.

Embodiment 492. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a polymeric substance having the ability to bind protons in an aqueous solution, and the non-absorbent composition is selected from the group consisting of cross-linked polymers containing polyanion backbone A group consisting of substances, and the polyanion main chain is coordinated to exchange monovalent cations, divalent cations, or a combination thereof.

Embodiment 493. The method as in any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange resin comprising a polyanion backbone of proton-exchanging cations and having an average pKa of at least 4.

Embodiment 494. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange resin comprising a polyanion backbone with proton exchange cations and an average pKa of 4-5.

Embodiment 495. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange resin comprising a polyanion backbone with proton exchange cations and an average pKa of 5-6.

Embodiment 496. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange resin comprising a polyanion backbone of proton-exchanging cations and having an average pKa of 6-7.

Embodiment 497. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange resin comprising a polyanion backbone of proton-exchanging cations and having an average pKa of at least 7.

Embodiment 498. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange resin selected from the group consisting of: poly(formic acid), poly(acrylic acid), poly(sulfonic acid ), poly(maleic acid), poly(phenol), functionalized polyols and poly(alcohols), poly(hydroxamic acid), poly(amide) and their copolymers.

Embodiment 499. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange resin selected from the group consisting of: poly(formic acid), poly(acrylic acid), poly(sulfonic acid ), poly(maleic acid), poly(phenol), functionalized polyols and poly(alcohols), poly(hydroxamic acid), poly(amideimine) and their copolymers, in which the polyanion main chain It is further functionalized with functional groups to affect pKa.

Embodiment 500. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange resin selected from the group consisting of: poly(formic acid), poly(acrylic acid), poly(sulfonic acid ), poly(maleic acid), poly(phenol), functionalized polyols and poly(alcohols), poly(hydroxamic acid), poly(amideimine) and their copolymers, in which the polyanion main chain The functional group is further functionalized to affect pKa, and the functional group is an electron-withdrawing functional group or an electron-donating functional group.

Embodiment 501. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a cation exchange resin selected from the group consisting of: poly(formic acid), poly(acrylic acid), poly(sulfonic acid ), poly(maleic acid), poly(phenol), functionalized polyols and poly(alcohols), poly(hydroxamic acid), poly(amideimine) and their copolymers, in which the polyanion main chain Further functionalized by functional groups to affect pKa, functional groups are electron-withdrawing functional groups or electron-donating functional groups selected from the group consisting of fluorine, chlorine, amine, hydroxyl, alkoxy, phenyl, subphyla , Nitryl and cyano.

Embodiment 502. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a ceramic substance.

Embodiment 503. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a ceramic substance, and the ceramic substance is microporous or mesoporous.

Embodiment 504. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a ceramic substance, and the ceramic substance is microporous.

Embodiment 505. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a ceramic substance, and the ceramic substance is mesoporous.

Embodiment 506. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a ceramic substance, and the ceramic substance is a cation exchange ceramic composition.

Embodiment 507. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a ceramic substance, and the ceramic substance comprises a molecular sieve.

Embodiment 508. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a ceramic substance, and the ceramic substance comprises a molecular sieve selected from the group consisting of: silicon dioxide, Metalloaluminate, aluminum phosphate, and gallium germanate (gallogerminate).

Embodiment 509. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a ceramic substance, and the ceramic substance comprises a silica molecular sieve.

Embodiment 510. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a ceramic substance, and the ceramic substance comprises a titanoslicate molecular sieve.

Embodiment 511. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a ceramic substance, and the ceramic substance comprises a metallosilicate molecular sieve.

Embodiment 512. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a ceramic substance, and the ceramic substance comprises zeolite, borosilicate, gallosilicate, iron Ferrosilicate or chromosilicate molecular sieve.

Embodiment 513. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a ceramic substance, and the ceramic substance comprises a molecular sieve.

Embodiment 514. The method of any of the foregoing enumerated embodiments, wherein the non-absorbable composition is an anion exchange substance comprising an insoluble (in stomach environment) support structure and exchangeable anions.

Embodiment 515. The method of any of the foregoing enumerated embodiments, wherein the non-absorbable composition is an anion exchange substance comprising an insoluble (in stomach environment) support structure and exchangeable anions, wherein the anion exchange substance is organic or inorganic Or its complex.

Embodiment 516. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a strongly basic anion exchange material.

Embodiment 517. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a weakly basic anion exchange material.

Embodiment 518. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is an anion exchange material comprising a quaternary amine moiety, a phosphonium salt, an N-heteroaromatic salt, or a combination thereof.

Embodiment 519. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is an anion exchange material comprising poly(ionic liquid), wherein the side chain is selected from the group consisting of: tetraalkylammonium , Imidazolium, pyridinium, pyrrolidonium (pyrrolidonium), guanidinium (guanidinium), piperidinium, and tetraalkylphosphonium cations and combinations thereof.

Embodiment 520. The method of any of the foregoing enumerated embodiments, wherein the non-absorbable composition is an equivalent anion having at least partly a physiologically significant amount of hydroxide, carbonate, citrate, or other bicarbonate or Anion exchange substances that combine their ability to induce an increase in an individual's serum bicarbonate value.

Embodiment 521. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is an anion exchange material comprising at least 1 mEq/g anion selected from the group consisting of: hydroxide, Carbonate, citrate or other bicarbonate equivalent anions or combinations thereof.

Embodiment 522. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is an anion exchange material comprising at least 2 mEq/g anions selected from the group consisting of: hydroxide, Carbonate, citrate or other bicarbonate equivalent anions.

Embodiment 523. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is an anion exchange material comprising at least 5 mEq/g anions selected from the group consisting of: hydroxide, Carbonate, citrate or other bicarbonate equivalent anions.

Embodiment 524. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is an anion exchange material comprising at least 10 mEq/g anions selected from the group consisting of: hydroxide, Carbonate, citrate or other bicarbonate equivalent anions.

Embodiment 525. The method of any one of Embodiments 1 to 523, wherein the non-absorbent composition is an anion exchange material containing less than 10 mEq/g anions selected from the group consisting of: hydrogen Oxygen, carbonate, citrate or other bicarbonate equivalent anions or combinations thereof.

Embodiment 526. The method of any one of Embodiments 1 to 522, wherein the non-absorbent composition is an anion exchange material containing less than 5 mEq/g anions selected from the group consisting of: hydrogen Oxygen, carbonate, citrate or other bicarbonate equivalent anions.

Embodiment 527. The method of any one of embodiments 1 to 522, wherein the non-absorbent composition is an anion exchange material comprising less than 2.5 mEq/g anions selected from the group consisting of: hydrogen Oxygen, carbonate, citrate or other bicarbonate equivalent anions.

Embodiment 528. The method of any one of embodiments 1 to 520, wherein the non-absorbent composition is an anion exchange material containing less than 1 mEq/g anion selected from the group consisting of: hydrogen Oxygen, carbonate, citrate or other bicarbonate equivalent anions.

Embodiment 529. The method of any one of embodiments 1 to 519, wherein the non-absorbent composition is an anion exchange material containing less than 0.1 mEq/g anion selected from the group consisting of: hydrogen Oxygen, carbonate, citrate or other bicarbonate equivalent anions.

Embodiment 530. The method of any one of embodiments 521 to 529, wherein the equivalent anion of bicarbonate is selected from the group consisting of conjugate bases of acetate, lactate, and other short-chain formic acid.

Embodiment 531. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is an amphoteric ion exchange resin.

Embodiment 532. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a neutral composition having the ability to bind both protons and anions.

Embodiment 533. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition is a neutral composition having the ability to bind both protons and anions, the non-absorbent composition is selected from the group consisting of Group: Polymers functionalized with propylene oxide, polymers functionalized with Michael acceptors, expanded porphyrin, covalently structured, and polymers containing amine and/or phosphine functional groups.

Embodiment 534. The method of any of the foregoing enumerated embodiments, wherein the non-absorbent composition (i) removes more chloride ions than bicarbonate equivalent anions, (ii) removes more than phosphate anions Chloride ion, and (iii) remove more chloride ion than the conjugate base of bile and fatty acid.

Embodiment 535. The method of any of the foregoing enumerated embodiments, wherein treatment with a non-absorbable composition does not have a clinically significant effect on the serum or colon content of metabolically related species.

Embodiment 536. The method of any of the foregoing enumerated embodiments, wherein treatment with a non-absorbable composition does not have a clinically significant effect on the serum or colon content of metabolically relevant cationic species.

Embodiment 537. The method of any of the foregoing listed embodiments, wherein treatment with a non-absorbable composition does not have a clinically significant effect on the serum or colon content of metabolically related anionic species.

Embodiment 538. The method of any of the foregoing listed embodiments, wherein treatment with a non-absorbable composition does not have a clinically significant effect on the serum potassium content of a statistically large number of individuals.

Embodiment 539. The method of any of the foregoing listed embodiments, wherein treatment with a non-absorbable composition does not have a clinically significant effect on the serum phosphate content of a statistically large number of individuals.

Embodiment 540. The method of any of the foregoing enumerated embodiments, wherein treatment with a non-absorbable composition does not have clinically significant serum low density lipoprotein (LDL) levels in a statistically large number of individuals Impact.

式1 其中R₁ 、R₂ 及R₃ 獨立地為所提供之氫、烴基或經取代烴基，然而，R₁ 、R₂ 及R₃ 中之至少一者不為氫。Embodiment 541. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a proton-bound cross-linked amine polymer, the proton-bound cross-linked amine polymer comprising Amine residues:

Formula 1 wherein R ₁ , R ₂ and R _{3 are} independently hydrogen, hydrocarbon group or substituted hydrocarbon group provided, however, at least one of R ₁ , R ₂ and R ₃ is not hydrogen.

式1 其中R₁ 、R₂ 及R₃ 獨立地為所提供之氫、烴基或經取代烴基，然而，R₁ 、R₂ 及R₃ 中之至少一者不為氫，且交聯胺聚合物具有(i)在含有35 mM NaCl及63 mM HCl的pH 1.2及37℃之水性模擬胃液緩衝液(「SGF」)中至少5 mmol/g的均衡質子結合力及至少5 mmol/g之氯離子結合力及(ii)在去離子水中約2或更小之均衡膨脹比率。Embodiment 542. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a proton-bound cross-linked amine polymer, the proton-bound cross-linked amine polymer comprising Amine residues:

Formula 1 where R ₁ , R ₂ and R _{3 are} independently provided hydrogen, hydrocarbon group or substituted hydrocarbon group, however, at least one of R ₁ , R ₂ and R ₃ is not hydrogen and the cross-linked amine polymer Has (i) a balanced proton binding capacity of at least 5 mmol/g and chloride ions of at least 5 mmol/g in an aqueous simulated gastric fluid buffer ("SGF") containing pH 1.2 and 37 ℃ of 35 mM NaCl and 63 mM HCl The binding force and (ii) a balanced expansion ratio of about 2 or less in deionized water.

式1 其中R₁ 、R₂ 及R₃ 獨立地為所提供之氫、烴基、經取代烴基，然而，R₁ 、R₂ 及R₃ 中之至少一者不為氫，交聯胺聚合物在去離子水中具有約5或更小的均衡膨脹比率，且交聯胺聚合物在干擾離子緩衝液中在37℃下分別結合至少0.35:1的氯離子比干擾離子之莫耳比，其中干擾離子為磷酸根離子，且干擾離子緩衝液為36 mM氯離子及20 mM磷酸根之pH 5.5的緩衝溶液。Embodiment 543. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising residues corresponding to the amine of Formula 1:

Formula 1 where R ₁ , R ₂ and R _{3 are} independently provided hydrogen, hydrocarbon group, substituted hydrocarbon group, however, at least one of R ₁ , R ₂ and R ₃ is not hydrogen, the cross-linked amine polymer is Deionized water has a balanced expansion ratio of about 5 or less, and the cross-linked amine polymer binds at least 0.35:1 molar ratio of chloride ion to interference ion at 37°C in the interference ion buffer, where the interference ions It is phosphate ion, and the interfering ion buffer is a buffer solution of 36 mM chloride ion and 20 mM phosphate pH 5.5.

Embodiment 544. The method of any of the foregoing enumerated embodiments, wherein the non-absorbable composition has at least at least 35 in an aqueous simulated gastric fluid buffer ("SGF") containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37°C Balanced chloride ion binding capacity of 7.5 mmol/g.

Embodiment 545. The method of any of the foregoing enumerated embodiments, wherein the non-absorbable composition has at least at least 35 in an aqueous simulated gastric fluid buffer ("SGF") containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37°C 10 mmol/g equilibrium chloride ion binding capacity.

Embodiment 546. The method of any one of embodiments 541 to 545, wherein R ₁ , R ₂ and R _{3 are} independently provided hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, Aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl or heterocyclic ring, however, each of R ₁ , R ₂ and R ₃ is not hydrogen.

Embodiment 547. The method of any one of embodiments 541 to 545, wherein R ₁ , R ₂ and R _{3 are} independently hydrogen, aliphatic or heteroaliphatic provided, however, R ₁ , R ₂ And at least one of R ₃ is not hydrogen.

Embodiment 548. The method as in any one of embodiments 541 to 547, wherein the cross-linked amine polymer is prepared by substitution polymerization of an amine and a multifunctional cross-linking agent that optionally also includes an amine moiety.

式1a 其中R₄ 及R₅ 獨立地為氫、烴基或經取代烴基。Embodiment 549. The method as in any one of embodiments 541 to 548, wherein the cross-linked amine polymer comprises residues corresponding to the amine of formula 1a, and the cross-linked amine polymer is free by the amine corresponding to formula 1a Base polymer preparation:

Formula 1a wherein R ₄ and R _{5 are} independently hydrogen, hydrocarbyl or substituted hydrocarbyl.

Embodiment 550. The method of embodiment 549, wherein R ₄ and R _{5 are} independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, Hydroxyalkyl, ether, heteroaryl or heterocycle.

Embodiment 551. The method as in embodiment 549, wherein R ₄ and R _{5 are} independently hydrogen, aliphatic or heteroaliphatic.

式1b 其中R₄ 及R₅ 獨立地為氫、烴基或經取代烴基，R₆ 為脂族基且R₆₁ 及R₆₂ 獨立地為氫、脂族基或雜脂族基。Embodiment 552. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a cross-linked amine polymer containing a residue corresponding to the amine of Formula 1b, And the cross-linked amine polymer is prepared by substitution polymerization corresponding to the amine of Formula 1b and multifunctional cross-linking agent:

Formula 1b wherein R ₄ and R _{5 are} independently hydrogen, a hydrocarbon group or a substituted hydrocarbon group, R ₆ is an aliphatic group and R ₆₁ and R _{62 are} independently a hydrogen, aliphatic group or heteroaliphatic group.

Embodiment 553. The method of embodiment 552, wherein R ₄ and R _{5 are} independently hydrogen, saturated hydrocarbon, unsaturated aliphatic group, aryl group, heteroaryl group, heteroalkyl group, or unsaturated heteroaliphatic group.

Embodiment 554. The method of embodiment 552, wherein R ₄ and R _{5 are} independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, Hydroxyalkyl, ether, heteroaryl or heterocycle.

Embodiment 555. The method of embodiment 552, wherein R ₄ and R _{5 are} independently hydrogen, allyl, or aminoalkyl.

Embodiment 556. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is in unit dosage form.

Embodiment 557. The method of embodiment 556, wherein the unit dosage form is a capsule, lozenge, or sachet dosage form.

Embodiment 558. The method of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier, excipient, or diluent.

Embodiment 559. The method of any of the foregoing enumerated embodiments, wherein the daily dose is administered once a day (QD).

Embodiment 560. The method of any of the foregoing enumerated embodiments, wherein the daily dose is administered twice daily (BID).

Embodiment 561. The method of any of the foregoing enumerated embodiments, wherein the daily dose is administered three times a day.

Embodiment 562. The method of any of the foregoing enumerated embodiments, wherein the daily dose is obtained from the pharmaceutical product comprising the sealed container and the non-absorbent composition in the sealed container.

Embodiment 563. The method of Embodiment 562, wherein the sealed container includes a moisture-proof layer.

Embodiment 564. The method of embodiment 562 or 563, wherein the sealed container includes an oxygen barrier layer.

Embodiment 565. The method of any one of embodiments 562 to 564, wherein the sealed container is a sealed sachet.

Embodiment 566. The method of any one of Embodiments 562 to 564, wherein the sealed container includes a multilayer laminate having the following: an inner contact layer, an outer layer; and a barrier layer disposed between the contact layer and the outer layer.

Embodiment 567. The method of any one of embodiments 562 to 564, wherein the sealed container includes a multilayer laminate having: an inner contact layer, an outer layer; and an oxygen barrier layer disposed between the contact layer and the outer layer .

Embodiment 568. The method of any one of embodiments 562 to 564, wherein the sealed container includes a multilayer laminate having: an inner contact layer, an outer layer; and a moisture-proof layer disposed between the contact layer and the outer layer .

Embodiment 569. The method of any one of Embodiments 562 to 564, wherein the sealed container includes a multilayer laminate having: an inner contact layer, an outer layer; and an oxygen barrier layer disposed between the contact layer and the outer layer And moisture barrier.

Embodiment 570. The method of any one of Embodiments 562 to 564, wherein the sealed container includes a multilayer laminate having: an inner contact layer, an outer layer; and an oxygen scavenging layer disposed between the contact layer and the outer layer .

Embodiment 571. A composition for a method of treating metabolic acidosis in an adult patient, wherein in the treatment, 0.1-12 g of the composition is administered to the patient every day, the composition is removed from the patient A proton-capable non-absorbable composition, wherein the non-absorbable composition is characterized by at least 2.5 mEq/g of chloride ion binding force in the analysis of the small intestine inorganic buffer ("SIB") analysis.

Embodiment 572. A composition for a method of treating metabolic acidosis in an adult patient who has a serum bicarbonate content of less than 20 mEq/L prior to treatment, the composition having proton removal from the patient Non-absorbent composition.

Embodiment 573. The composition as used in Embodiment 572, wherein the patient's serum bicarbonate content is less than 19 mEq/L before treatment.

Embodiment 574. The composition as used in Embodiment 572, wherein the patient's serum bicarbonate content is less than 18 mEq/L before treatment.

Embodiment 575. The composition as used in Embodiment 572, wherein the patient's serum bicarbonate content is less than 17 mEq/L before treatment.

Embodiment 576. The composition as used in Embodiment 572, wherein the patient's serum bicarbonate content is less than 16 mEq/L before treatment.

Embodiment 577. The composition as used in Embodiment 572, wherein the patient's serum bicarbonate content is less than 15 mEq/L before treatment.

Embodiment 578. The composition as used in Embodiment 572, wherein the patient's serum bicarbonate content is less than 14 mEq/L before treatment.

Example 579. The composition as used in Example 572, wherein the patient's serum bicarbonate content is less than 13 mEq/L before treatment.

Embodiment 580. The composition as used in Embodiment 572, wherein the patient's serum bicarbonate content is less than 12 mEq/L before treatment.

Embodiment 581. The composition as used in Embodiment 572, wherein the patient's serum bicarbonate content is less than 11 mEq/L before treatment.

Embodiment 582. The composition as used in Embodiment 572, wherein the patient's serum bicarbonate content is less than 10 mEq/L before treatment.

Embodiment 583. The composition as used in Embodiments 572 to 582, wherein the patient's serum bicarbonate value is increased by at least 1 mEq/L over 15 days of treatment.

Embodiment 584. The composition of embodiments 572 to 583, wherein in the treatment, 0.1-12 g of the polymer is administered to the patient daily.

Embodiment 585. The composition of any one of embodiments 572 to 584, wherein the non-absorbable composition is characterized by a chloride ion binding force of at least 2.5 mEq/g in the simulated small intestine inorganic buffer ("SIB") analysis .

Embodiment 586. A composition for a method for treating metabolic acidosis in an adult patient by increasing the patient's serum bicarbonate value by at least 1 mEq/L over 15 days of treatment, the composition A non-absorbable composition of the patient's ability to remove protons.

Embodiment 587. The composition of embodiments 571 to 586, wherein in the treatment, 0.1-12 g of the polymer is administered to the patient daily.

Embodiment 588. The composition of any one of embodiments 572 to 587, wherein the non-absorbable composition is characterized by a chloride ion binding force of at least 2.5 mEq/g in the simulated small intestine inorganic buffer ("SIB") analysis .

Embodiment 589. The composition of any one of embodiments 586 to 588, wherein the patient's serum bicarbonate content value is increased by at least 1 mEq/L over 15 days of treatment.

Embodiment 590. The composition as used in any one of embodiments 586 to 589, wherein the increase in serum bicarbonate content is at least 1.5 mEq/L.

Embodiment 591. The composition as used in any one of Embodiments 586 to 590, wherein the increase in serum bicarbonate content is at least 2 mEq/L.

Embodiment 592. The composition as used in any one of embodiments 586 to 591, wherein the increase in serum bicarbonate content is at least 2.5 mEq/L.

Embodiment 593. The composition as used in any one of Embodiments 586 to 592, wherein the increase in serum bicarbonate content is at least 3 mEq/L.

Embodiment 594. The composition as used in any one of Embodiments 586 to 593, wherein the increase in serum bicarbonate content is at least 3.5 mEq/L.

Embodiment 595. The composition as used in any one of Embodiments 586 to 594, wherein the increase in serum bicarbonate content is at least 4 mEq/L.

Embodiment 596. The composition as used in any one of embodiments 586 to 595, wherein the increase in serum bicarbonate content is at least 4.5 mEq/L.

Embodiment 597. The composition as used in any one of embodiments 586 to 596, wherein the increase in serum bicarbonate content is at least 5 mEq/L.

Embodiment 598. The composition as used in any one of embodiments 586 to 597, wherein an increase is observed during the 14-day treatment.

Example 599. The composition as used in any one of Examples 586 to 598, wherein an increase is observed during the 13 days of treatment.

Embodiment 600. The composition as used in any one of embodiments 586 to 599, wherein an increase is observed during the 12-day treatment period.

Example 601. The composition as used in any one of Examples 586 to 600, wherein an increase is observed during the 11 days of treatment.

Embodiment 602. The composition as used in any one of embodiments 586 to 601, wherein an increase is observed during the 10-day treatment period.

Embodiment 603. The composition as used in any one of embodiments 586 to 602, wherein an increase is observed during a 9-day treatment period.

Embodiment 604. The composition as used in any one of embodiments 586 to 603, wherein an increase is observed during the 8 days of treatment.

Embodiment 605. The composition as used in any one of embodiments 586 to 604, wherein an increase is observed during the 7 days of treatment.

Embodiment 606. The composition as used in any one of embodiments 586 to 605, wherein an increase is observed during the 6 days of treatment.

Embodiment 607. The composition as used in any one of embodiments 586 to 606, wherein an increase is observed during the 5 days of treatment.

Embodiment 608. The composition as used in any one of embodiments 586 to 607, wherein an increase is observed during the 4 days of treatment.

Embodiment 609. The composition as used in any one of embodiments 586 to 608, wherein an increase is observed during the 3 days of treatment.

Embodiment 610. The composition as used in any one of embodiments 586 to 609, wherein an increase is observed during 2 days of treatment.

Example 611. The composition as used in any one of Examples 586 to 610, wherein an increase is observed during 1 day of treatment.

Embodiment 612. The composition as used in any one of embodiments 571 to 611, wherein the specified number of treatment days is the first day of treatment with the composition.

Embodiment 613. The composition as used in embodiments 572 to 601, wherein in the treatment, 0.1-12 g of the polymer is administered to the patient every day.

Embodiment 614. The composition as used in Embodiment 613, wherein in the treatment, 1-11 g of the polymer is administered to the patient daily.

Embodiment 615. The composition as used in Embodiment 613, wherein in the treatment, 2-10 g of the polymer is administered to the patient daily.

Embodiment 616. The composition as used in Embodiment 613, wherein in the treatment, 3-9 g of the polymer is administered to the patient daily.

Embodiment 617. The composition as used in Embodiment 613, wherein in the treatment, 3-8 g of the polymer is administered to the patient daily.

Example 618. The composition as used in Example 613, wherein in the treatment, 3-7 g of the polymer is administered to the patient daily.

Example 619. The composition as used in Example 613, wherein in this treatment, 3-6 g of the polymer is administered to the patient daily.

Example 620. The composition as used in Example 613, wherein in this treatment, 3.5-5.5 g of the polymer is administered to the patient daily.

Example 621. The composition as used in Example 613, wherein in this treatment, 4-5 g of the polymer is administered to the patient daily.

Example 622. The composition as used in Example 613, wherein in this treatment, 1-3 g of the polymer is administered to the patient daily.

Embodiment 623. The composition as used in Embodiment 571 or 572, wherein about 0.5 g of the composition is administered to the patient daily.

Embodiment 624. The composition as used in Embodiment 571 or 572, wherein about 1 g of the composition is administered to the patient daily.

Embodiment 625. The composition as used in Embodiment 571 or 572, wherein about 1.5 g of the composition is administered to the patient daily.

Embodiment 626. The composition as used in Embodiment 571 or 572, wherein about 2 g of the composition is administered to the patient daily.

Embodiment 627. The composition as used in Embodiment 571 or 572, wherein about 2.5 g of the composition is administered to the patient daily.

Embodiment 628. The composition as used in Embodiment 571 or 572, wherein about 3 g of the composition is administered to the patient daily.

Embodiment 629. The composition as used in Embodiment 571 or 572, wherein about 3.5 g of the composition is administered to the patient daily.

Embodiment 630. The composition as used in Embodiment 571 or 572, wherein about 4.0 g of the composition is administered to the patient daily.

Embodiment 631. The composition as used in embodiment 571 or 572, wherein about 4.5 g of the composition is administered to the patient daily.

Embodiment 632. The composition as used in Embodiment 571 or 572, wherein about 5.0 g of the composition is administered to the patient daily.

Example 633. The composition as used in any one of Examples 571 to 632, wherein the chloride ion binding force in the analysis of the simulated small intestine inorganic buffer ("SIB") is at least 3 mEq/g.

Example 634. The composition as used in any one of Examples 571 to 633, wherein the chloride ion binding force in the analysis of the simulated small intestine inorganic buffer ("SIB") is at least 3.5 mEq/g.

Example 635. The composition as used in any one of Examples 571 to 634, wherein the chloride ion binding force in the analysis of the simulated small intestine inorganic buffer ("SIB") is at least 4 mEq/g.

Embodiment 636. The composition as used in any one of Embodiments 571 to 635, wherein the chloride ion binding force in the simulated small intestine inorganic buffer ("SIB") analysis is at least 4.5 mEq/g.

Embodiment 637. The composition as used in any one of Embodiments 571 to 636, wherein the chloride ion binding force in the analysis of simulated small intestine inorganic buffer ("SIB") is at least 5 mEq/g.

Embodiment 638. The composition as used in any one of Embodiments 571 to 637, wherein the chloride ion binding force in the SIB analysis is less than 10 mEq/g.

Embodiment 639. The composition as used in any one of Embodiments 571 to 638, wherein the chloride ion binding force in the SIB analysis is less than 9 mEq/g.

Embodiment 640. The composition as used in any one of Embodiments 571 to 639, wherein the chloride ion binding force in the SIB analysis is less than 8 mEq/g.

Embodiment 641. The composition as used in any one of Embodiments 571 to 640, wherein the chloride ion binding force in the SIB analysis is less than 7 mEq/g.

Embodiment 642. The composition as used in any one of Embodiments 571 to 641, wherein the chloride ion binding force in the SIB analysis is less than 6 mEq/g.

Embodiment 643. The composition as used in any one of Embodiments 571 to 642, wherein the chloride ion binding force in the SIB analysis is less than 5 mEq/g.

Embodiment 644. A composition for a method of treating metabolic acidosis in an adult patient, wherein in the treatment, more than 12-100 g of the composition is administered to the patient every day, the composition is A non-absorbable composition with the ability to remove protons, wherein the non-absorbable composition is characterized by a chloride ion binding force of less than 2.5 mEq/g in the analysis of the small intestine inorganic buffer ("SIB") analysis.

Embodiment 645. The composition of embodiment 644, wherein the patient's serum bicarbonate value is increased by at least 1 mEq/L over 15 days of treatment.

Embodiment 646. A composition for a method of treating metabolic acidosis in an adult patient by increasing the patient's serum bicarbonate value by at least 1 mEq/L over 15 days of treatment, wherein in the treatment, daily Administer greater than 12-100 g of the polymer to the patient, the composition is a non-absorbable composition with the ability to remove protons from the patient, wherein the non-absorbable composition is characterized by simulating an intestinal inorganic buffer ("SIB" ) At least 2.5 mEq/g of chloride ion binding in the analysis.

Embodiment 647. The composition as used in Embodiment 645 or 646, wherein the increase in serum bicarbonate content is at least 1 mEq/L.

Embodiment 648. The composition as used in Embodiment 645 or 646, wherein the increase in serum bicarbonate content is at least 1.5 mEq/L.

Embodiment 649. The composition as used in Embodiment 645 or 646, wherein the increase in serum bicarbonate content is at least 2 mEq/L.

Embodiment 650. The composition as used in Embodiment 645 or 646, wherein the increase in serum bicarbonate content is at least 2.5 mEq/L.

Embodiment 651. The composition as used in Embodiment 645 or 646, wherein the increase in serum bicarbonate content is at least 3 mEq/L.

Embodiment 652. The composition as used in Embodiment 645 or 646, wherein the increase in serum bicarbonate content is at least 3.5 mEq/L.

Embodiment 653. The composition as used in Embodiment 645 or 646, wherein the increase in serum bicarbonate content is at least 4 mEq/L.

Embodiment 654. The composition as used in Embodiment 645 or 646, wherein the increase in serum bicarbonate content is at least 4.5 mEq/L.

Embodiment 655. The composition as used in Embodiment 645 or 646, wherein the increase in serum bicarbonate content is at least 5 mEq/L.

Embodiment 656. The composition as used in embodiment 645 or 646, wherein an increase is observed during the 14-day treatment.

Example 657. The composition as used in Example 645 or 646, wherein an increase is observed during the 13-day treatment.

Example 658. The composition as used in Example 645 or 646, wherein an increase is observed during the 12-day treatment period.

Embodiment 659. The composition as used in Embodiment 645 or 646, wherein an increase is observed during the 11 days of treatment.

Example 660. The composition as used in Example 645 or 646, wherein an increase is observed during the 10-day treatment period.

Example 661. The composition as used in Example 645 or 646, wherein an increase is observed during the 9-day treatment period.

Embodiment 662. The composition as used in embodiment 645 or 646, wherein an increase is observed during the 8 days of treatment.

Example 663. The composition as used in Example 645 or 646, wherein an increase is observed during the 7-day treatment period.

Embodiment 664. The composition as used in embodiment 645 or 646, wherein an increase is observed during the 6 days of treatment.

Embodiment 665. The composition as used in embodiment 645 or 646, wherein an increase is observed during the 5 days of treatment.

Embodiment 666. The composition as used in Embodiment 645 or 646, wherein an increase is observed during the 4 days of treatment.

Embodiment 667. The composition as used in embodiment 645 or 646, wherein an increase is observed during the 3 days of treatment.

Example 668. The composition as used in Example 645 or 646, wherein an increase is observed during the 2 days of treatment.

Example 669. The composition as used in Example 645 or 646, wherein an increase is observed during 1 day of treatment.

Embodiment 670. The composition as used in any one of embodiments 644 to 654, wherein the specified number of treatment days is the first day of treatment with the composition.

Embodiment 671. A composition as used in Embodiments 644 to 670, wherein 12-100 g is administered to the patient daily.

Embodiment 672. A composition as used in Embodiments 644 to 671, wherein 20-90 g is administered to the patient daily.

Embodiment 673. A composition as used in Embodiments 644 to 672, wherein 20-80 g is administered to the patient daily.

Embodiment 674. A composition as used in Embodiments 644 to 673, wherein 20-70 g is administered to the patient daily.

Embodiment 675. A composition as used in Embodiments 644 to 674, wherein 20-60 g is administered to the patient daily.

Embodiment 676. A composition as used in Embodiments 644 to 675, wherein 20-50 g is administered to the patient daily.

Embodiment 677. A composition as used in Embodiments 644 to 676, wherein 20-40 g is administered to the patient daily.

Embodiment 678. A composition as used in Embodiments 644 to 677 wherein 20-35 g is administered to the patient daily.

Embodiment 679. A composition as used in Embodiments 644 to 678, wherein 20-30 g is administered to the patient daily.

Embodiment 680. A composition as used in Embodiments 644 to 679, wherein 20-25 g is administered to the patient daily.

Embodiment 681. The composition as used in any one of Embodiments 644 to 680, wherein the chloride ion binding force in the analysis of the simulated small intestine inorganic buffer ("SIB") is less than 2 mEq/g.

Example 682. The composition as used in any one of Examples 644 to 681, wherein the chloride ion binding force in the analysis of simulated small intestine inorganic buffer ("SIB") is less than 1.5 mEq/g.

Example 683. The composition as used in any one of Examples 644 to 682, wherein the chloride ion binding force in the analysis of the simulated small intestine inorganic buffer ("SIB") is less than 1 mEq/g.

Embodiment 684. The composition as used in any one of Embodiments 644 to 683, wherein the chloride ion binding force in the analysis of simulated small intestine inorganic buffer ("SIB") is less than 0.75 mEq/g.

Embodiment 685. The composition as used in any one of Embodiments 644 to 684, wherein the chloride ion binding force in the analysis of the simulated small intestine inorganic buffer ("SIB") is greater than 0.5 mEq/g.

Embodiment 686. The composition as used in any one of Embodiments 644 to 685, wherein the chloride ion binding force in the analysis of simulated small intestine inorganic buffer ("SIB") is greater than 1 mEq/g.

Embodiment 687. The composition as used in any one of Embodiments 644 to 686, wherein the chloride ion binding force in the analysis of simulated small intestine inorganic buffer ("SIB") is greater than 1.5 mEq/g.

Embodiment 688. The composition as used in any one of embodiments 644 to 687, wherein the chloride ion binding force in the analysis of simulated small intestine inorganic buffer ("SIB") is greater than 2 mEq/g.

Embodiment 689. The composition as used in any of the preceding embodiments, wherein the composition is administered once a day to provide a total specified daily dose.

Embodiment 690. The composition as used in any of the preceding embodiments, wherein the composition is administered twice a day to provide a total specified daily dose.

Embodiment 691. The composition as used in any of the preceding embodiments, wherein the composition is administered three times a day to provide a total specified daily dose.

Embodiment 692. The composition as used in any of the foregoing listed embodiments, wherein the composition is administered orally.

式1 其中R₁ 、R₂ 及R₃ 獨立地為所提供之氫、烴基或經取代烴基，然而，R₁ 、R₂ 及R₃ 中之至少一者不為氫，且交聯胺聚合物具有(i)在含有35 mM NaCl及63 mM HCl的pH 1.2及37℃之水性模擬胃液緩衝液(「SGF」)中至少5 mmol/g的均衡質子結合力及至少5 mmol/g之氯離子結合力及(ii)在去離子水中約2或更小之均衡膨脹比率。Embodiment 693. The composition as used in any one of embodiments 571 to 692, wherein the composition is a pharmaceutical composition comprising a proton-bound cross-linked amine polymer, the proton-bound cross-linked amine polymer comprising Residues of the amine of formula 1:

Formula 1 where R ₁ , R ₂ and R _{3 are} independently provided hydrogen, hydrocarbon group or substituted hydrocarbon group, however, at least one of R ₁ , R ₂ and R ₃ is not hydrogen and the cross-linked amine polymer Has (i) a balanced proton binding capacity of at least 5 mmol/g and chloride ions of at least 5 mmol/g in an aqueous simulated gastric fluid buffer ("SGF") containing pH 1.2 and 37 ℃ of 35 mM NaCl and 63 mM HCl The binding force and (ii) a balanced expansion ratio of about 2 or less in deionized water.

式1 其中R₁ 、R₂ 及R₃ 獨立地為所提供之氫、烴基、經取代烴基，然而，R₁ 、R₂ 及R₃ 中之至少一者不為氫，交聯胺聚合物在去離子水中具有約5或更小的均衡膨脹比率，且交聯胺聚合物在干擾離子緩衝液中在37℃下分別結合至少0.35:1的氯離子比干擾離子之莫耳比，其中干擾離子為磷酸根離子，且干擾離子緩衝液為36 mM氯離子及20 mM磷酸根之pH 5.5的緩衝溶液。Embodiment 694. The composition as used in any one of embodiments 571 to 692, wherein the composition is a pharmaceutical composition comprising a proton-bound cross-linked amine polymer, the proton-bound cross-linked amine polymer comprising Residues of the amine of formula 1:

Formula 1 where R ₁ , R ₂ and R _{3 are} independently provided hydrogen, hydrocarbon group, substituted hydrocarbon group, however, at least one of R ₁ , R ₂ and R ₃ is not hydrogen, the cross-linked amine polymer is Deionized water has a balanced expansion ratio of about 5 or less, and the cross-linked amine polymer binds at least 0.35:1 molar ratio of chloride ion to interference ion at 37°C in the interference ion buffer, where the interference ions It is phosphate ion, and the interfering ion buffer is a buffer solution of 36 mM chloride ion and 20 mM phosphate pH 5.5.

Embodiment 695. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 682, wherein the cross-linked amine polymer is at a pH containing 35 mM NaCl and 63 mM HCl Aqueous simulated gastric fluid buffer ("SGF") at 1.2 and 37°C has a balanced chloride ion binding capacity of at least 7.5 mmol/g.

Embodiment 696. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 682, wherein the cross-linked amine polymer is at a pH containing 35 mM NaCl and 63 mM HCl 1.2 and 37°C aqueous simulated gastric buffer ("SGF") has a balanced chloride ion binding capacity of at least 10 mmol/g.

Embodiment 697. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 683, wherein the crosslinked amine polymer has about 4 or less in deionized water Balanced expansion ratio.

Embodiment 698. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 683, wherein the crosslinked amine polymer has about 3 or less in deionized water Balanced expansion ratio.

Embodiment 699. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 683, wherein the crosslinked amine polymer has about 2 or less in deionized water Balanced expansion ratio.

Embodiment 700. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the previously listed embodiments, wherein R ₁ , R ₂ and R _{3 are} independently Provided hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl or heterocyclic ring, however, R ₁ , Each of R ₂ and R ₃ is not hydrogen.

Embodiment 701. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the previously listed embodiments, wherein R ₁ , R ₂ and R _{3 are} independently Provided hydrogen, aliphatic group or heteroaliphatic group, however, at least one of R ₁ , R ₂ and R ₃ is not hydrogen.

Embodiment 702. The composition as used in any one of embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the previously listed embodiments, wherein the cross-linked amine polymer It is prepared by substitution polymerization of multifunctional crosslinking agents containing amine moieties.

式1a 其中R₄ 及R₅ 獨立地為氫、烴基或經取代烴基。Embodiment 703. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of any one of Embodiments 693 to 701, wherein the cross-linked amine polymer comprises a compound corresponding to Formula 1a Amine residues, and cross-linked amine polymers are prepared by free radical polymerization corresponding to amines of formula 1a:

Formula 1a wherein R ₄ and R _{5 are} independently hydrogen, hydrocarbyl or substituted hydrocarbyl.

Embodiment 704. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 703, wherein R ₄ and R _{5 are} independently hydrogen, alkyl, alkenyl, Allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl or heterocyclic ring.

Embodiment 705. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 703, wherein R ₄ and R _{5 are} independently hydrogen, an aliphatic group, or a heterolipid Family base.

式1b 其中R₄ 及R₅ 獨立地為氫、烴基或經取代烴基，R₆ 為脂族基且R₆₁ 及R₆₂ 獨立地為氫、脂族基或雜脂族基。Embodiment 706. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of any one of Embodiments 693 to 701, wherein the cross-linked amine polymer comprises corresponding to Formula 1b Amine residues, and crosslinked amine polymers are prepared by substitution polymerization of amines corresponding to Formula 1b and multifunctional crosslinking agents:

Formula 1b wherein R ₄ and R _{5 are} independently hydrogen, a hydrocarbon group or a substituted hydrocarbon group, R ₆ is an aliphatic group and R ₆₁ and R _{62 are} independently a hydrogen, aliphatic group or heteroaliphatic group.

Embodiment 707. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 706, wherein R ₄ and R _{5 are} independently hydrogen, saturated hydrocarbon, unsaturated fat Group, aryl, heteroaryl, heteroalkyl or unsaturated heteroaliphatic group.

Embodiment 708. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 706, wherein R ₄ and R _{5 are} independently hydrogen, alkyl, alkenyl, Allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl or heterocyclic ring.

Embodiment 709. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 706, wherein R ₄ and R _{5 are} independently hydrogen, allyl, or amine alkyl.

式1c 其中R₇ 為氫、脂族基或雜脂族基且R₈ 為脂族基或雜脂族基。Embodiment 710. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the previously listed embodiments, wherein the cross-linked amine polymer comprises an amine corresponding to Formula 1c Of residues:

Formula 1c wherein R ₇ is hydrogen, an aliphatic group or a heteroaliphatic group and R ₈ is an aliphatic group or a heteroaliphatic group.

式2 其中 m及n獨立地為非負整數； R₁₀ 、R₂₀ 、R₃₀ 及R₄₀ 獨立地為氫、烴基或經取代烴基； X₁ 為

； X₂ 為烴基或經取代烴基； 各X₁₁ 獨立地為氫、烴基、經取代烴基、羥基或胺基；且 z為非負數。Embodiment 711. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of any one of Embodiments 693 to 701, wherein the cross-linked amine polymer comprises a compound corresponding to Formula 2 Of amine residues:

Formula 2 where m and n are independently non-negative integers; R ₁₀ , R ₂₀ , R ₃₀ and R _{40 are} independently hydrogen, hydrocarbyl or substituted hydrocarbyl; X ₁ is

; X ₂ is a hydrocarbon group or a substituted hydrocarbon group; each X _{11 is} independently hydrogen, a hydrocarbon group, a substituted hydrocarbon group, a hydroxyl group, or an amine group; and z is a non-negative number.

Embodiment 712. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition as in Embodiment 711, wherein R ₁₀ , R ₂₀ , R ₃₀ and R _{40 are} independently hydrogen, An aliphatic group, an aryl group, a heteroaliphatic group or a heteroaryl group, m and z are independently 0-3, and n is 0 or 1.

Embodiment 713. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in Embodiment 711 or 712, wherein X ₂ is an aliphatic group or a heteroaliphatic group.

Embodiment 714. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in Embodiments 711, 712, or 713, wherein m is 1-3, and X ₁₁ is hydrogen, Aliphatic group or heteroaliphatic group.

式2a 其中 m及n獨立地為非負整數； 各R₁₁ 獨立地為氫、烴基、雜脂族基或雜芳基； R₂₁ 及R₃₁ 獨立地為氫或雜脂族基； R₄₁ 為氫、經取代烴基或烴基； X₁ 為

； X₂ 為烷基或經取代烴基； 各X₁₂ 獨立地為氫、羥基、胺基、胺基烷基、

酸或鹵基；且 z為非負數。Embodiment 715. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of any one of Embodiments 693 to 701, wherein the cross-linked amine polymer comprises a compound corresponding to Formula 2a Of amine residues:

Formula 2a where m and n are independently non-negative integers; each R _{11 is} independently hydrogen, hydrocarbon, heteroaliphatic or heteroaryl; R ₂₁ and R _{31 are} independently hydrogen or heteroaliphatic; R ₄₁ is hydrogen , Substituted hydrocarbon group or hydrocarbon group; X ₁ is

; X ₂ is an alkyl group or a substituted hydrocarbon group; each X _{12 is} independently hydrogen, hydroxyl, amine group, aminoalkyl group,

Acid or halo; and z is a non-negative number.

Embodiment 716. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 715, wherein m and z are independently 0-3, and n is 0 or 1 .

Embodiment 717. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in Embodiment 715 or 716, wherein R _{11 is} independently hydrogen, an aliphatic group, an aminoalkane Group, haloalkyl or heteroaryl, R ₂₁ and R _{31 are} independently hydrogen or heteroaliphatic, and R ₄₁ is hydrogen, aliphatic, aryl, heteroaliphatic or heteroaryl.

Embodiment 718. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in Embodiment 715 or 716, wherein each R ₁₁ is hydrogen, an aliphatic group, an aminoalkyl group Or haloalkyl, R ₂₁ and R ₃₁ are hydrogen or aminoalkyl, and R ₄₁ is hydrogen, aliphatic or heteroaliphatic.

式2b 其中 m及n獨立地為非負整數； 各R₁₂ 獨立地為氫、經取代烴基或烴基； R₂₂ 及R₃₂ 獨立地為氫、經取代烴基或烴基； R₄₂ 為氫、烴基或經取代烴基； X₁ 為

； X₂ 為烷基、胺基烷基或烷醇； 各X₁₃ 獨立地為氫、羥基、脂環、胺基、胺基烷基、鹵素、烷基、雜芳基、

酸或芳基； z為非負數；且 對應於式2b之胺包含至少一個烯丙基。Embodiment 719. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of any one of Embodiments 693 to 701, wherein the crosslinked amine polymer comprises a compound corresponding to Formula 2b Of amine residues:

Formula 2b where m and n are independently non-negative integers; each R _{12 is} independently hydrogen, substituted hydrocarbon group or hydrocarbon group; R ₂₂ and R _{32 are} independently hydrogen, substituted hydrocarbon group or hydrocarbon group; R ₄₂ is hydrogen, hydrocarbon group or hydrocarbon group Substituted hydrocarbon group; X ₁ is

; X ₂ is alkyl, aminoalkyl or alkanol; each X _{13 is} independently hydrogen, hydroxyl, alicyclic, amino, aminoalkyl, halogen, alkyl, heteroaryl,

Acid or aryl; z is a non-negative number; and the amine corresponding to formula 2b contains at least one allyl group.

Embodiment 720. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 719, wherein m and z are independently 0-3, and n is 0 or 1 .

Embodiment 721. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in Embodiment 719 or 720, wherein R ₁₂ or R ₄₂ independently comprises at least one allyl group or Vinyl part.

Embodiment 722. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in Embodiment 719 or 720, wherein (i) m is a positive integer and R ₁₂ , R ₂₂ and R ₄₂ comprises at least two allyl or vinyl moieties in combination, or (ii) n is a positive integer and R ₁₂ , R ₃₂ and R ₄₂ comprise at least two allyl or vinyl moieties in combination.

Embodiment 723. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in Embodiment 719 or 720, wherein the crosslinked amine polymer comprises the amines presented in Table A Residues.

Embodiment 724. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition as in Embodiments 719, 720, or 723, wherein the crosslinked amine polymer is as presented in Table B Crosslinking agent crosslinking.

式3 其中 R₁₅ 、R₁₆ 及R₁₇ 獨立地為氫、烴基、經取代烴基、羥基、胺基、

酸或鹵基； X₁₅ 為

； X₅ 為烴基、經取代烴基、側氧基(-O-)或胺基；且 z為非負數。Embodiment 725. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the previously listed embodiments, wherein the cross-linked amine polymer comprises a repeat corresponding to Formula 3 unit:

Formula 3 wherein R ₁₅ , R ₁₆ and R _{17 are} independently hydrogen, hydrocarbon group, substituted hydrocarbon group, hydroxyl group, amine group,

Acid or halogen; X ₁₅ is

; X ₅ is a hydrocarbon group, a substituted hydrocarbon group, a pendant (-O-) group, or an amine group; and z is a non-negative number.

Embodiment 726. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition as in Embodiment 725, wherein R ₁₅ , R ₁₆ and R _{17 are} independently aliphatic or hetero Aliphatic group.

Embodiment 727. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition as in Embodiment 725 or 726, wherein X ₅ is pendant, amine, alkylamino, Ether, alkanol or haloalkyl.

Embodiment 728. The composition as used in any one of embodiments 571 to 692, wherein the composition is the pharmaceutical composition of any one of embodiments 693 to 701, wherein the cross-linked amine polymer is prepared by : (I) substitution polymerization of polyfunctional reagents, at least one of which contains amine moieties, (2) free radical polymerization of monomers containing at least one amine moiety or nitrogen-containing moiety, or (3) Crosslinking of the amine intermediate product with a crosslinking agent that optionally contains amine moieties.

Embodiment 729. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 728, wherein the cross-linked amine polymer is a cross-linked homopolymer or cross-linked copolymer .

Embodiment 730. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 728, wherein the crosslinked amine polymer comprises repeating linking subunits of the same or varying length Separated free amine part.

Embodiment 731. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 728, wherein the crosslinked amine polymer is composed of an amine-containing monomer and a crosslinking agent in It is prepared instead of the polymerization in the polymerization reaction.

Embodiment 732. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 731, wherein the amine-containing monomer has at least two reactive amine moieties to participate in the substitution Linear amine for polymerization.

Embodiment 733. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in 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]ethylamine, ginseng (3-aminopropyl)amine, 1,4-bis[bis(3-aminopropyl) Radical)amino]butane, 1,2-ethanediamine, 2-amino-1-(2-aminoethylamino)ethane, 1,2-bis(2-aminoethylamino) Ethane, 1,3-propanediamine, 3,3'-diaminodipropylamine, 2,2-dimethyl-1,3-propanediamine, 2-methyl-1,3-propanediamine , N,N'-dimethyl-1,3-propanediamine, N-methyl-1,3-diaminopropane, 3,3'-diamino-N-methyldipropylamine, 1, 3-diaminopentane, 1,2-diamino-2-methylpropane, 2-methyl-1,5-diaminopentane, 1,2-diaminopropane, 1,10- Diaminodecane, 1,8-diaminooctane, 1,9-diaminooctane, 1,7-diaminoheptane, 1,6-diaminohexane, 1,5- Diaminopentane, 3-bromopropylamine hydrobromide, N,2-dimethyl-1,3-propanediamine, N-isopropyl-1,3-diaminopropane, N,N' -Bis(2-aminoethyl)-1,3-propanediamine, N,N'-bis(3-aminopropyl) ethylenediamine, N,N'-bis(3-aminopropyl)- 1,4-butanediamine tetrahydrochloride, 1,3-diamino-2-propanol, N-ethylethylenediamine, 2,2'-diamino-N-methyldiamine Ethylamine, N,N'-diethylethylenediamine (diethylethylenediamine), N-isopropylethylenediamine (isopropylethylenediamine), N-methylethylenediamine, N,N'-di-third-butyl Ethylenediamine (butylethylenediamine), N,N'-diisopropylethylenediamine, N,N'-dimethylethylenediamine, N-butylethylenediamine, 2-(2-amino (Ethylamino) 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 (Tetra azacyclopentadecane), 2-(aminomethyl)piperidine or 3-(methylamino)pyrrolidine.

Embodiment 734. The composition as used in any one of embodiments 571 to 692, wherein the composition is the pharmaceutical composition of any one of embodiments 728, 730, 732, and 733, wherein the crosslinking agent is selected from the group consisting of Group consisting of: dihaloalkane, haloalkyloxirane, alkyloxirane sulfonate, di(haloalkyl)amine, tri(haloalkyl)amine, bicyclic Oxides, triepoxides, tetraepoxides, bis(halomethyl)benzene, tri(halomethyl)benzene, tetra(halomethyl)benzene, such as epichlorohydrin and epibromohydrin poly(epichlorohydrin ) Of epihalohydrin, (iodomethyl) ethylene oxide, glycidyl tosylate, glycidyl 3-nitrobenzenesulfonate, 4-toluenesulfonyloxy-1,2-ring Oxybutane, bromo-1,2-epoxybutane, 1,2-dibromoethane, 1,3-dichloropropane, 1,2-dichloroethane, l-bromo-2-chloro Ethane, 1,3-dibromopropane, bis(2-chloroethyl)amine, ginseng(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-diepoxide Decane (diepoxydecane), ethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, 1, 2, ethylene glycol diglycidyl ether, glycerol diglycidyl ether , 1,3-diglycidyl glyceryl ether, N, N-diglycidyl aniline, neopentyl glycol diglycidyl ether, diethylene glycol diglycidyl ether, 1,4-bis (glycidyl) Oxy)benzene, resorcinol ether, 1,6-hexanediol diglycidyl ether, trimethylolpropane diglycidyl ether, 1,4-cyclohexane dimethanol diglycidyl ether, 1,3 -Bis-(2,3-epoxypropoxy)-2-(2,3-dihydroxypropoxy)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-bis( Oxirane-2-ylmethyl)-1,2,3,5,6,7-hexahydropyrrolo[3,4-f]isoindole-1,3,5,7-tetraone, bis Phenol A diglycidyl ether, 5-hydroxy-6,8-bis(oxiran-2-ylmethyl)-4-oxo-4-h-benzopiperan-2-carboxylic acid ethyl ester, bis [4-(2,3-epoxy-propylthio)phenyl]-sulfide, 1,3-bis(3-glycidoxypropyl)tetramethyldisilaxane, 9,9 -Bis[4-(glycidyloxy)phenyl]fluoro, triepoxyisocyanurate, glycerol triglycidyl ether, N, N-diglycidyl-4-glycidyl Oxyaniline (glycidyloxyaniline), isocyanuric acid (S,S,S)-tris Glycidyl ester, isocyanuric acid (R,R,R)-triglycidyl ester, isocyanuric acid triglycidyl ester, trimethylolpropane triglycidyl ether, glycerol propoxylated triglycidyl ether, Triphenylolmethane triglycidyl ether, 3,7,14-ginseng[[3-(glycidoxypropyl)propyl]dimethylsilyloxy]-1,3,5 ,7,9,11,14-heptylcyclopentyl tricyclo[7,3,3,15,11]heptasiloxane, 4,4'methylene bis(N, N-diglycidylaniline) , Bis(halomethyl)benzene, bis(halomethyl)biphenyl and bis(halomethyl)naphthalene, toluene diisocyanate, acrylol chloride, methyl acrylate, ethylidene bis Acrylamide, 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- Propylene oxide, ginseng [(2-epoxyethyl) methyl] amine and combinations thereof.

Embodiment 735. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 728, wherein the preparation of the cross-linked amine polymer comprises at least one amine moiety or nitrogen-containing Free radical polymerization of some amine monomers.

Embodiment 736. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the foregoing listed embodiments, wherein the cross-linked amine polymer has about 1.5 in deionized water Or a smaller equilibrium expansion ratio.

Embodiment 737. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the foregoing listed embodiments, wherein the cross-linked amine polymer has about 1 in deionized water Or a smaller equilibrium expansion ratio.

Embodiment 738. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the previously listed embodiments, wherein the cross-linked amine polymer contains 36 mM NaCl, 20 mM NaH ₂ PO ₄ and 50 mM 2-(N-morpholinyl)ethanesulfonic acid (MES) are buffered to pH 5.5 and have an aqueous simulated small intestine inorganic buffer (``SIB'') at 37°C with at least Chloride ion ratio of 0.5:1 is combined with phosphate ion and molar ratio.

Embodiment 739. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the previously listed embodiments, wherein the cross-linked amine polymer contains 36 mM NaCl, 20 mM NaH ₂ PO ₄ and 50 mM 2-(N-morpholinyl)ethanesulfonic acid (MES) are buffered to pH 5.5 and have an aqueous simulated small intestine inorganic buffer (``SIB'') at 37°C with at least Chloride ions are more than phosphate ions combined with molar ratio of 1:1.

Embodiment 740. The composition as used in any one of embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the previously listed embodiments, wherein the cross-linked amine polymer contains 36 mM NaCl, 20 mM NaH ₂ PO ₄ and 50 mM 2-(N-morpholinyl)ethanesulfonic acid (MES) are buffered to pH 5.5 and have an aqueous simulated small intestine inorganic buffer (``SIB'') at 37°C with The chloride ion of 2:1 is combined with the phosphate ion and the molar ratio.

Embodiment 741. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the previously listed embodiments, wherein the cross-linked amine polymer contains 35 mM NaCl and 63 mM HCl pH 1.2 and 37°C aqueous simulated gastric buffer (“SGF”) have a proton binding capacity of at least 10 mmol/g and a chloride binding capacity of at least 10 mmol/g.

Embodiment 742. The composition as used in any one of embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the previously listed embodiments, wherein the cross-linked amine polymer contains 35 mM NaCl and 63 mM HCl has a balanced 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 buffer ("SGF") at pH 1.2 and 37°C.

Embodiment 743. The composition as used in any one of embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the previously listed embodiments, wherein the cross-linked amine polymer contains 35 mM NaCl and 63 mM HCl has a balanced proton binding capacity of at least 14 mmol/g and a chloride binding capacity of at least 14 mmol/g in an aqueous simulated gastric juice buffer ("SGF") at pH 1.2 and 37°C.

Embodiment 744. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the foregoing listed embodiments, wherein the percentage of quaternized amines is less than 40%.

Embodiment 745. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the foregoing listed embodiments, wherein the percentage of quaternized amines is less than 30%.

Embodiment 746. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the foregoing listed embodiments, wherein the percentage of quaternized amines is less than 20%.

Embodiment 747. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the previously listed embodiments, wherein the percentage of quaternized amines is less than 10%.

Embodiment 748. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the previously listed embodiments, wherein the percentage of quaternized amines is less than 5%.

Embodiment 749. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the foregoing listed embodiments, wherein the cross-linked amine polymer is a gel or has 40 to Beads with an average particle size of 180 microns.

Embodiment 750. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the previously listed embodiments, wherein the cross-linked amine polymer is a gel or has from 60 to Beads with an average particle size of 160 microns.

Embodiment 751. The composition as used in any one of embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the previously listed embodiments, wherein the cross-linked amine polymer is a gel or has 80 to Beads with an average particle size of 140 microns.

Embodiment 752. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of any one of Embodiments 749 to 751, wherein the diameter of particles less than about 0.5 volume percent is less than about 10 microns.

Embodiment 753. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of any one of Embodiments 749 to 751, wherein the diameter of particles less than about 5 volume percent is less than about 20 microns.

Embodiment 754. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of any one of Embodiments 749 to 751, wherein the diameter of particles less than about 0.5 volume percent is less than about 20 microns.

Embodiment 755. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of any one of Embodiments 749 to 751, wherein the diameter of particles less than about 5 volume percent is less than about 30 microns.

Embodiment 756. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as any of the foregoing listed embodiments in unit dosage form.

Embodiment 757. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the pharmaceutical composition of Embodiment 756, wherein the unit dosage form is a capsule, lozenge, or sachet dosage form.

Embodiment 758. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a pharmaceutical composition as in any of the previously listed embodiments, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier , Excipients or diluents.

Embodiment 759. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a composition that is transferred by oral administration of the pharmaceutical composition of any of the foregoing listed embodiments A method of treating acid/alkali disorders in animals including humans in addition to HCl.

Embodiment 760. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the treatment method of Embodiment 759, wherein the acid/alkaline disorder is metabolic acidosis.

Embodiment 761. The composition as used in any one of embodiments 571 to 692, wherein the composition is the treatment method of embodiment 759, wherein the pH is controlled or standardized.

Embodiment 762. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the treatment method of Embodiment 759, wherein the serum bicarbonate is controlled or standardized.

Embodiment 763. The composition as used in any one of embodiments 571 to 692, wherein the composition is the treatment method of embodiment 759, wherein less than 1 g of sodium or potassium is administered daily.

Embodiment 764. The composition as used in any one of embodiments 571 to 692, wherein the composition is the treatment method of embodiment 759, wherein less than 0.5 g of sodium or potassium is administered daily.

Embodiment 765. The composition as used in any one of embodiments 571 to 692, wherein the composition is the treatment method of embodiment 759, wherein less than 0.1 g of sodium or potassium is administered daily.

Embodiment 766. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the treatment method of Embodiment 759, wherein sodium or potassium is not administered.

Embodiment 767. The composition as used in any one of embodiments 571 to 692, wherein the composition is the pharmaceutical composition of any one of embodiments 682 to 755, based on the serum bicarbonate of the patient in need of treatment Value or other indicators of acidosis to titrate the dose of the pharmaceutical composition.

式4 其中各R獨立地為氫或交聯胺聚合物(

)之兩個氮原子之間的伸乙基交聯，且a、b、c及m為整數。Embodiment 768. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a polymer comprising a structure corresponding to Formula 4:

Formula 4 where each R is independently hydrogen or a crosslinked amine polymer (

), the ethylidene crosslinks between the two nitrogen atoms, and a, b, c and m are integers.

Embodiment 769. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the polymer of Embodiment 768, where m is a larger integer indicating an extended polymer network.

Embodiment 770. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a polymer as in Embodiment 768 or 769, wherein the sum of a and b is a ratio of c (ie, a+ b:c) in the range of about 1:1 to 5:1.

Embodiment 771. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the polymer of Embodiment 768 or 769, wherein the ratio of the sum of a and b to the ratio of c (ie, a+b :c) in the range of about 1.5:1 to 4:1.

Embodiment 772. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a polymer as in Embodiment 768 or 769, wherein the sum of a and b is a ratio of c (ie, a+ b:c) in the range of about 1.75:1 to 3:1.

Embodiment 773. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a polymer as in Embodiment 768 or 769, and the ratio of the sum of a and b to c (ie, a+b :c) in the range of about 2:1 to 2.5:1.

Embodiment 774. The composition as used in any one of Embodiments 571 to 692, wherein the composition is a polymer as in Embodiment 768 or 769, wherein the sum of a and b is 57 and c is 24.

Embodiment 775. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the polymer of any one of Embodiments 768 or 774, wherein 50-95% of the R substituents are hydrogen, And 5-50% is the ethylidene crosslink between the two nitrogens of the crosslinked amine polymer.

Embodiment 776. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the polymer of any one of Embodiments 768 or 774, wherein 55-90% of the R substituents are hydrogen, And 10-45% is the ethylidene crosslink between the two nitrogens of the crosslinked amine polymer.

Embodiment 777. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the polymer of any one of Embodiments 768 or 774, wherein 60-90% of the R substituents are hydrogen, And 10-40% is the ethylidene crosslink between the two nitrogens of the crosslinked amine polymer.

Embodiment 778. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the polymer of any one of Embodiments 768 or 774, wherein 65-90% of the R substituents are hydrogen, And 10-35% is an ethylene crosslink between two nitrogens of the crosslinked amine polymer.

Embodiment 779. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the polymer of any one of Embodiments 768 or 774, wherein 70-90% of the R substituents are hydrogen, And 10-30% is the ethylidene crosslink between the two nitrogens of the crosslinked amine polymer.

Embodiment 780. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the polymer of any one of Embodiments 768 or 774, wherein 75-85% of the R substituents are hydrogen, And 15-25% is the ethylidene crosslink between the two nitrogens of the crosslinked amine polymer.

Embodiment 781. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the polymer of any one of Embodiments 768 or 774, wherein 80-85% of the R substituents are hydrogen, And 15-20% is the ethylidene crosslink between the two nitrogens of the crosslinked amine polymer.

Embodiment 782. The composition as used in any one of Embodiments 571 to 692, wherein the composition is the polymer of any one of Embodiments 768 to 774, wherein about 81% of the R substituents are hydrogen, and Approximately 19% are ethylidene crosslinks.

Embodiment 783. The composition as used in any one of Embodiments 571 to 592, wherein the method of treatment further comprises one or more features or portions thereof as recited in any one of Embodiments 1 to 570.

Embodiment 784. A composition for a method of treating metabolic acidosis in an adult patient, wherein the treatment is administered to the patient less than once a day, the composition being non-absorbent with the ability to remove protons from the patient性组合物。 Sexual composition.

Embodiment 785. The composition of embodiment 784, wherein the composition is administered on a regular schedule.

Embodiment 786. The composition of embodiment 784, wherein the regular schedule is once every two days.

Embodiment 787. The composition of embodiment 785, wherein the regular schedule is once every three days.

Embodiment 788. The composition of embodiment 785, wherein the regular schedule is twice a week.

Embodiment 789. The composition of embodiment 785, wherein the regular schedule is three times a week.

Embodiment 790. The composition of embodiment 785, wherein the regular schedule is four times a week.

Embodiment 791. The composition of any one of embodiments 784 to 790, wherein the composition is as defined in any of the foregoing listed embodiments.

Embodiment 792. The composition of any one of embodiments 784 to 791, wherein the method of treatment is as defined in any of the foregoing listed embodiments.

Embodiment 793. A method of increasing the serum bicarbonate content in an individual suffering from an acid-base disorder, the method comprising orally administering a pharmaceutical composition to increase the serum bicarbonate content of the individual, wherein: (i) The pharmaceutical composition, when administered orally, binds to the target species in the individual's digestive system, the target species is selected from the group consisting of protons, strong acids and conjugate bases of strong acids, and (ii) The pharmaceutical composition increased the serum bicarbonate content in the placebo-controlled study by at least 1 mEq/l, which is the average serum bicarbonate content of the group in the first group at the end of the study relative to that at the end of the study The difference between the mean serum bicarbonate content of the groups in the second group, where the subjects in the first group received the pharmaceutical composition and the subjects in the second group received the placebo, in which the first and second groups At least 25 subjects were included, each group prescribed the same diet during the study and the study continued for at least two weeks.

Embodiment 794. The method as in embodiment 793, wherein the first group receives a daily dose of the pharmaceutical composition that does not exceed 100 g/day.

Embodiment 795. The method as in Embodiment 793, wherein the first group receives a daily dose of the pharmaceutical composition that does not exceed 50 g/day.

Embodiment 796. The method as in embodiment 793, wherein the first group receives a daily dose of the pharmaceutical composition that does not exceed 30 g/day.

Embodiment 797. The method as in Embodiment 793, wherein the first group receives a daily dose of the pharmaceutical composition that does not exceed 25 g/day.

Embodiment 798. The method as in embodiment 793, wherein the first group receives a daily dose of the pharmaceutical composition that does not exceed 20 g/day.

Embodiment 799. The method as in embodiment 793, wherein the first group receives a daily dose of the pharmaceutical composition that does not exceed 15 g/day.

Embodiment 800. The method as in embodiment 793, wherein the first group receives a daily dose of the pharmaceutical composition that does not exceed 10 g/day.

Embodiment 801. The method as in Embodiment 793, wherein the first group receives a daily dose of the pharmaceutical composition that does not exceed 5 g/day.

Embodiment 802. The method of any one of embodiments 793 to 801, wherein the target species is a proton.

Embodiment 803. The method of any one of Embodiments 793 to 801, wherein the target species is chloride ion.

Embodiment 804. The method of any one of embodiments 793 to 801, wherein the target species is a strong acid.

Embodiment 805. The method of any one of embodiments 793 to 801, wherein the target species is HCl.

Embodiment 806. The method of any one of embodiments 793 to 805, wherein the pharmaceutical composition is not absorbed when ingested.

式1 其中R₁ 、R₂ 及R₃ 獨立地為所提供之氫、烴基或經取代烴基，然而，R₁ 、R₂ 及R₃ 中之至少一者不為氫，且交聯胺聚合物具有(i)在含有35 mM NaCl及63 mM HCl的pH 1.2及37℃之水性模擬胃液緩衝液(「SGF」)中至少5 mmol/g的均衡質子結合力及至少5 mmol/g之氯離子結合力及(ii)在去離子水中約2或更小之均衡膨脹比率。Embodiment 807. The method of any one of embodiments 793 to 806, wherein the composition is a pharmaceutical composition comprising a proton-bound cross-linked amine polymer, the proton-bound cross-linked amine polymer comprising Amine residues:

Formula 1 where R ₁ , R ₂ and R _{3 are} independently provided hydrogen, hydrocarbon group or substituted hydrocarbon group, however, at least one of R ₁ , R ₂ and R ₃ is not hydrogen and the cross-linked amine polymer Has (i) a balanced proton binding capacity of at least 5 mmol/g and chloride ions of at least 5 mmol/g in an aqueous simulated gastric fluid buffer ("SGF") containing pH 1.2 and 37 ℃ of 35 mM NaCl and 63 mM HCl The binding force and (ii) a balanced expansion ratio of about 2 or less in deionized water.

式1 其中R₁ 、R₂ 及R₃ 獨立地為所提供之氫、烴基、經取代烴基，然而，R₁ 、R₂ 及R₃ 中之至少一者不為氫，交聯胺聚合物在去離子水中具有約5或更小的均衡膨脹比率，且交聯胺聚合物在干擾離子緩衝液中在37℃下分別結合至少0.35:1的氯離子比干擾離子之莫耳比，其中干擾離子為磷酸根離子，且干擾離子緩衝液為36 mM氯離子及20 mM磷酸根之pH 5.5的緩衝溶液。Embodiment 808. The method of any one of embodiments 793 to 806, wherein the composition is a pharmaceutical composition comprising a proton-bound cross-linked amine polymer, the proton-bound cross-linked amine polymer comprising Amine residues:

Formula 1 where R ₁ , R ₂ and R _{3 are} independently provided hydrogen, hydrocarbon group, substituted hydrocarbon group, however, at least one of R ₁ , R ₂ and R ₃ is not hydrogen, the cross-linked amine polymer is Deionized water has a balanced expansion ratio of about 5 or less, and the cross-linked amine polymer binds at least 0.35:1 molar ratio of chloride ion to interference ion at 37°C in the interference ion buffer, where the interference ions It is phosphate ion, and the interfering ion buffer is a buffer solution of 36 mM chloride ion and 20 mM phosphate pH 5.5.

Embodiment 809. The method as in Embodiment 807 or 808, wherein the cross-linked amine polymer has at least 7.5 mmol in an aqueous simulated gastric fluid buffer ("SGF") containing pH 35 and 35 mM NaCl and 63 mM HCl at pH 1.2 and 37°C /g Balanced chloride ion binding.

Embodiment 810. The method as in embodiment 807 or 808, wherein the cross-linked amine polymer has at least 10 mmol in an aqueous simulated gastric fluid buffer ("SGF") containing pH 35 at 35 mM NaCl and 63 mM HCl and 37°C /g Balanced chloride ion binding.

Embodiment 811. The method as in Embodiment 807 or 808, wherein the crosslinked amine polymer has a balanced expansion ratio of about 4 or less in deionized water.

Embodiment 812. The method as in Embodiment 807 or 808, wherein the cross-linked amine polymer has a balanced expansion ratio of about 3 or less in deionized water.

Embodiment 813. The method as in Embodiment 807 or 808, wherein the crosslinked amine polymer has a balanced expansion ratio of about 2 or less in deionized water.

Embodiment 814. The method of any one of embodiments 807 to 813, wherein R ₁ , R ₂ and R _{3 are} independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, Aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl or heterocyclic ring, however, each of R ₁ , R ₂ and R ₃ is not hydrogen.

Embodiment 815. The method of any one of embodiments 807 to 813, wherein R ₁ , R _2, and R _{3 are} independently hydrogen, aliphatic, or heteroaliphatic groups provided, however, R ₁ , R ₂ And at least one of R ₃ is not hydrogen.

Embodiment 816. The method as in any one of Embodiments 807 to 813, wherein the crosslinked amine polymer is prepared by substitution polymerization of an amine and a multifunctional crosslinking agent that optionally also includes an amine moiety.

Embodiment 817. The method as in any one of embodiments 807 to 816, wherein the possible renal acid load (PRAL value) of the diet averages 0.82 mEq/d.

Embodiment 818. The method as in any one of embodiments 807 to 817, wherein the eligible subjects of the study have chronic kidney disease (chronic kidney disease, CKD stage 3-4; eGFR 20-<60 mL/min /1.73 m ² ) and had a baseline serum bicarbonate value between 12 and 20 mEq/L at the beginning of the study.

Embodiment 819. The method of any one of embodiments 807 to 818, wherein the pharmaceutical composition increases the degree of serum bicarbonate in the placebo-controlled study by at least 2 mEq/l.

Embodiment 820. The method of any one of embodiments 807 to 818, wherein the pharmaceutical composition increases the degree of serum bicarbonate in the placebo-controlled study by at least 3 mEq/l.

Embodiment 821. The method or composition of any of the foregoing listed embodiments wherein the individual or adult patient has chronic kidney disease.

Embodiment 822. The method or composition of any of the foregoing enumerated embodiments, wherein the individual or adult patient does not yet require renal replacement therapy (dialysis or transplantation).

Embodiment 823. The method or composition of any of the foregoing listed embodiments, wherein the individual or adult patient has not yet reached end stage renal disease ("ESRD").

Embodiment 824. The method or composition of any of the foregoing listed embodiments, wherein the individual or adult patient has an mGFR of at least 15 mL/min/1.73 m ² .

Embodiment 825. The method or composition of any preceding enumerated embodiment, wherein the individual or adult patient has an eGFR of at least 15 mL/min/1.73 m ² .

Embodiment 826. The method or composition of any of the foregoing enumerated embodiments, wherein the individual or adult patient has an mGFR of at least 30 mL/min/1.73 m ² .

Embodiment 827. The method or composition of any of the foregoing enumerated embodiments, wherein the individual or adult patient has an eGFR of at least 30 mL/min/1.73 m ² .

Embodiment 828. The method or composition of any of the foregoing listed embodiments, wherein the individual or adult patient has an mGFR of less than 45 mL/min/1.73 m ² for at least three months.

Embodiment 829. The method or composition of any of the foregoing enumerated embodiments, wherein the individual or adult patient has an eGFR of less than 45 mL/min/1.73 m ² for at least three months.

Embodiment 830. The method or composition of any preceding enumerated embodiment, wherein the individual or adult patient has an mGFR of less than 60 mL/min/1.73 m ² for at least three months.

Embodiment 831. The method or composition of any of the foregoing enumerated embodiments, wherein the individual or adult patient has an eGFR of less than 60 mL/min/1.73 m ² for at least three months.

Embodiment 832. The method or composition of any of the foregoing enumerated embodiments, wherein the individual or adult patient has stage 3A CKD, stage 3B CKD, or stage 4 CKD.

Embodiment 833. A method of treating an individual suffering from an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l, the method comprising orally administering a daily dose containing non-absorbable Pharmaceutical composition of the composition; Wherein the oral administration increases the individual's serum bicarbonate value from baseline to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 1 mEq/l; and The treatment allows the increased serum bicarbonate value to last for 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 at least one year.

Embodiment 834. The method or pharmaceutical composition of embodiment 833, wherein the method or pharmaceutical composition is one of any of the foregoing listed embodiments.

Embodiment 835. The method of any of the foregoing enumerated embodiments, wherein the treatment reduces the individual's anion gap by at least 1 mEq/L.

Embodiment 836. The method of any of the foregoing enumerated embodiments, wherein the treatment reduces the individual's anion gap by at least 2 mEq/L.

Embodiment 837. The method of any of the foregoing enumerated embodiments, wherein the treatment reduces the individual's anion gap by at least 3 mEq/L.

Embodiment 838. The method of any of the foregoing enumerated embodiments, wherein the treatment reduces the individual's anion gap by at least 4 mEq/L.

Embodiment 839. The method of any of the foregoing enumerated embodiments, wherein the treatment reduces the individual's anion gap by at least 5 mEq/L.

Embodiment 840. The method of any of the foregoing enumerated embodiments, wherein the treatment reduces the individual's anion gap by 1-2 mEq/L.

Embodiment 841. The method of any of the foregoing enumerated embodiments, wherein the treatment reduces the individual's anion gap by 1-3 mEq/L.

Embodiment 842. The method of any of the foregoing enumerated embodiments, wherein the treatment reduces the individual's anion gap by 1-4 mEq/L.

Embodiment 843. The method of any of the foregoing enumerated embodiments, wherein the treatment reduces the individual's anion gap by 1-5 mEq/L.

Embodiment 844. The method of any of the foregoing enumerated embodiments, wherein the treatment reduces the individual's anion gap by 2-3 mEq/L.

Embodiment 845. The method of any of the foregoing enumerated embodiments, wherein the treatment reduces the individual's anion gap by 2-4 mEq/L.

Embodiment 846. The method of any of the foregoing enumerated embodiments, wherein the treatment reduces the individual's anion gap by 2-5 mEq/L.

Embodiment 846. The method of any of the foregoing enumerated embodiments, wherein the treatment reduces the individual's anion gap by 3-4 mEq/L.

Embodiment 847. The method of any of the foregoing enumerated embodiments, wherein the treatment reduces the individual's anion gap by 3-5 mEq/L.

Embodiment 848. The method of any of the foregoing enumerated embodiments, wherein the treatment reduces the individual's anion gap by 4-5 mEq/L.

Embodiment 849. The method of any of the foregoing enumerated embodiments, wherein the treatment reduces the individual's anion gap by less than 1 mEq/L (eg, 0.5 mEq/L or 0.75 mEq/L).

Embodiment 850. A method of improving the quality of life of a patient suffering from chronic kidney disease and an acid-base disorder, wherein the patient has a baseline serum bicarbonate value ≤ 22 mEq/L, the method comprising continuous oral administration for at least twelve weeks A pharmaceutical composition that increases and maintains the patient's serum bicarbonate above 20 mEq/L. The pharmaceutical composition has the ability to bind a target species selected from the group consisting of protons, strong acids and conjugate bases of strong acids .

Embodiment 851. A method of improving the quality of life of patients suffering from chronic kidney disease and acid-base disorders, the method comprising orally administering a pharmaceutical composition having the following: (a) selective binding selected from the group consisting of The ability of the target species: protons, strong acids and conjugate bases of strong acids; and (b) at least 3 mEq/g of target species binding capacity in the analysis of simulated small intestine inorganic buffer (SIB), where the improvement in quality of life is due to The Quality of Life (QoL) questionnaire evaluated lasts at least twelve weeks and is statistically significant compared to the placebo control group.

Embodiment 852. A method of improving the quality of life of a patient suffering from chronic kidney disease and an acid-base disorder, wherein the patient has a baseline serum bicarbonate value of ≤ 22 mEq/L, the method comprising once daily oral administration to the patient An effective amount of TRC101 is a period of time sufficient to statistically significantly enhance the patient's quality of life compared to the placebo control group.

Embodiment 853. A method of improving the quality of life of a patient suffering from a metabolic acidosis disease, the method comprising administering to the patient a daily dose of unabsorbed crosslinked amine polymer, the daily dose: (a) sufficient to treat the patient Increase in serum bicarbonate concentration by at least 1 mEq/L; (b) produce a continuous increase in serum bicarbonate of at least 1 mEq/L over a period of at least twelve weeks; and (c) compare with the placebo control group The time period is sufficient to improve the patient's quality of life, of which the improvement in quality of life is statistically significant.

Embodiment 854. A pharmaceutical composition for improving the quality of life of a human patient suffering from chronic kidney disease and acid-base disorders, the patient having a baseline serum bicarbonate level of ≤ 22 mEq/L before treatment, the composition is having A non-absorbable composition with the following capabilities: (a) remove the target species selected from the group consisting of protons, strong acids, and strong acid conjugate bases from the patient; and (b) compared to the placebo control group Improve the patient's quality of life in a statistically significant way over a period of at least twelve weeks.

Embodiment 855. A pharmaceutical composition for improving the quality of life of a human patient suffering from a disease or disorder by increasing the patient's serum bicarbonate value by at least 1 mEq/L during at least twelve weeks of treatment, composition : (A) is a non-absorbable composition with a target species selected from the group consisting of protons, strong acids, and strong acid conjugate bases removed from the patient; (b) is characterized by simulating an intestinal inorganic buffer (SIB) At least 3 mEq/g of target species binding in the analysis; and (c) has the ability to improve the quality of life of the patient in a statistically significant way over a period of at least twelve weeks compared to the placebo control group.

Embodiment 856. A pharmaceutical composition for improving the quality of life of a human patient suffering from metabolic acidosis disease, wherein: (a) an effective amount of the pharmaceutical composition is administered to the patient daily for a period of at least twelve weeks ; (B) The pharmaceutical composition is a non-absorbable substance capable of removing the target species from the patient. The target species is selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (c) pharmaceutical combinations The substance is characterized by a binding capacity of at least 3 mEq/g of chloride ion in the simulated small intestine inorganic buffer (SIB) analysis; and (d) a statistically significant improvement in quality of life over a twelve-week period compared to the placebo control group .

Embodiment 857. A method of improving the physical function of a patient suffering from chronic kidney disease and an acid-base disorder characterized by a baseline serum bicarbonate value ≤ 22 mEq/L, the method comprising continuing for at least twelve weeks Oral administration of a pharmaceutical composition capable of increasing and maintaining the patient's serum bicarbonate above 20 mEq/L. The pharmaceutical composition has the ability to bind target species selected from the group consisting of protons, strong acids and strong acids Of the conjugate base.

Embodiment 858. A method of improving the physical function of a patient suffering from chronic kidney disease and acid-base disorders, the method comprising orally administering a pharmaceutical composition having the following: (a) selective binding selected from the group consisting of The ability of the target species: protons, strong acids and conjugate bases of strong acids; and (b) at least 3 mEq/g of target species binding capacity in the simulated small intestine inorganic buffer (SIB) analysis, including improvement and comfort in body function The agent control group was statistically significant at least twelve weeks after initiation of treatment as compared to the answers to patients from question 3 of the Kidney Disease Quality of Life Short Form (KDQOL-SF).

Embodiment 859. A method of improving the physical function of a patient suffering from chronic kidney disease and acid-base disorders, wherein the patient has a baseline serum bicarbonate value of ≤ 22 mEq/L, the method comprising once daily oral administration to the patient The effective amount of TRC101 lasts for a period of time that is sufficient for the statistically significant increase in the patient's physical function score based on the answer to question 3 of the Kidney Disease Quality of Life (KDQOL-SF) compared to the patient's baseline physical function score .

Embodiment 860. A method of improving the physical function of a patient suffering from a metabolic acidosis disease, the method comprising administering to the patient a daily dose of unabsorbed crosslinked amine polymer, the daily dose: (a) sufficient to treat the patient Increase in serum bicarbonate concentration by at least 1 mEq/L; (b) produce a continuous increase in serum bicarbonate of at least 1 mEq/L over a period of at least twelve weeks; and (c) compared with the placebo control group At the end of the period it is sufficient to increase the person's body function score, where the increase in body function score is statistically significant.

Embodiment 861. A pharmaceutical composition for increasing the body function score of a human patient suffering from chronic kidney disease and acid-base disorders, the patient has a baseline serum bicarbonate content of ≤ 22 mEq/L before treatment, the composition is A non-absorbable composition with the following capabilities: (a) remove the target species selected from the group consisting of protons, strong acids, and strong acid conjugate bases from the patient; and (b) compared to the placebo control group Based on the answer to question 3 of the Kidney Quality of Life Short Form (KDQOL-SF), at the end of at least a twelve-week period, the patient's physical function score is statistically significant.

Embodiment 862. A pharmaceutical composition for improving the physical function score of a human patient suffering from a disease or condition by increasing the patient's serum bicarbonate value by at least 1 mEq/L within at least twelve weeks of treatment, Composition: (a) is a non-absorbable composition with the ability to remove target species selected from the group consisting of protons, strong acids, and strong acid conjugate bases from the patient; (b) is characterized by Intestinal Inorganic Buffer (SIB) analysis of at least 3 mEq/g of target species binding capacity; and (c) having the answer to question 3 based on the Kidney Disease Quality of Life Summary (KDQOL-SF) compared to the placebo control group. The ability to increase the patient's physical function score in a statistically significant manner at the end of at least a twelve-week period.

Embodiment 863. A pharmaceutical composition for improving the physical function score of a human patient suffering from metabolic acidosis disease, wherein: (a) an effective amount of the pharmaceutical composition is administered to the patient daily for a period of at least twelve weeks ; (B) The pharmaceutical composition is a non-absorbable substance capable of removing the target species from the patient. The target species is selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (c) pharmaceutical combinations The substance is characterized by a binding capacity of at least 3 mEq/g of chloride ions in the simulated small intestine inorganic buffer (SIB) analysis; and (d) at the end of the at least twelve-week period, compared with the placebo control group, the body function score The improvement is a statistically significant improvement over the baseline physical function score, which is based on the answer to question 3 of the Kidney Disease Quality of Life Short Form (KDQOL-SF).

Embodiment 864. A method of slowing the progression of kidney disease in a patient suffering from chronic kidney disease and an acid-base disorder characterized by a baseline serum bicarbonate value ≤ 22 mEq/L, the method comprising continuing for at least twelve Oral administration of a medicinal composition capable of increasing and maintaining the patient's serum bicarbonate above 20 mEq/L. The medicinal composition has the ability to bind target species selected from the group consisting of protons, strong acids And strong acid conjugate base.

Embodiment 865. A method of slowing the progression of kidney disease in a patient suffering from chronic kidney disease and acid-base disorders, wherein the patient has a baseline serum bicarbonate value of ≤ 22 mEq/L, the method comprising once-daily oral administration to the patient Administration of an effective amount of TRC101 for a period of time sufficient to increase the patient's serum bicarbonate by at least 1 mEq/L.

Embodiment 866. A method of slowing the progression of kidney disease in a patient suffering from chronic kidney disease and metabolic acidosis disease, the method comprising administering to the patient a daily dose of unabsorbed cross-linked amine polymer, the daily dose: ( a) sufficient to increase the patient's serum bicarbonate concentration by at least 1 mEq/L; (b) produce a continuous increase in serum bicarbonate of at least 1 mEq/L over a period of at least twelve weeks; and (c) sufficient to alleviate kidney disease Progress.

Example 867. A pharmaceutical composition for slowing the progression of kidney disease in a human patient suffering from chronic kidney disease and acid-base disorders, the patient has a baseline serum bicarbonate content of ≤ 22 mEq/L prior to treatment, the composition Is a non-absorbable composition with the ability to: (a) remove the target species selected from the group consisting of protons, strong acids, and strong acid conjugate bases from the patient; and (b) at least twelve weeks Slows the progression of kidney disease in human patients during a period of time.

Embodiment 868. A medicine for slowing the progression of kidney disease in human patients suffering from chronic kidney disease and acid-base disorders by increasing the patient's serum bicarbonate value by at least 1 mEq/L within at least twelve weeks of treatment Composition, composition: (a) is a non-absorbable composition with the ability to remove a target species selected from the group consisting of protons, strong acids and conjugate bases of strong acids from the patient; (b) characteristics It is a target species binding force of at least 3 mEq/g in Simulated Small Intestine Inorganic Buffer (SIB) analysis; and (c) has the ability to slow the progression of kidney disease for a period of at least twelve weeks.

Embodiment 869. A pharmaceutical composition for slowing the progression of kidney disease in a human patient who also has a metabolic acidosis disease, wherein: (a) an effective amount of medicine is administered to the patient daily for a period of at least twelve weeks The composition; (b) The pharmaceutical composition is a non-absorbable substance capable of removing the target species from the patient. The target species is selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (c) The pharmaceutical composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in the simulated small intestine inorganic buffer (SIB) analysis; and (d) compared with the placebo control group not receiving the pharmaceutical composition, at twelve weeks Slow down the progression of kidney disease in the patient during this period.

Embodiment 870. A pharmaceutical composition for a method of treating an acid-base disorder in a patient, wherein the method of treatment improves the quality of life of the patient.

Embodiment 871. A pharmaceutical composition for a method of treating an acid-base disorder in a patient, wherein the method of treatment improves the patient's physical function.

式1Embodiment 872. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a proton-bound cross-linked amine polymer, the proton-bound cross-linked amine polymer comprising a corresponding Residues of the amine in formula 1:

Formula 1

Where R ₁ , R ₂ and R _{3 are} independently provided hydrogen, hydrocarbon group or substituted hydrocarbon group, however, at least one of R ₁ , R ₂ and R ₃ is not hydrogen.

Embodiment 872. The method/composition as in Embodiment 871, wherein R ₁ , R ₂ and R _{3 are} independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkane provided Group, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl or heterocyclic ring, however, each of R ₁ , R ₂ and R ₃ is not hydrogen.

Embodiment 873. The method/composition of any one of embodiments 871 to 872, wherein R ₁ , R ₂ and R _{3 are} independently hydrogen, aliphatic or heteroaliphatic provided, however, R ₁ , At least one of R ₂ and R ₃ is not hydrogen.

Embodiment 874. The method/composition of any one of embodiments 871 to 873, wherein the cross-linked amine polymer is prepared by substitution polymerization of an amine and a multifunctional cross-linking agent that also optionally includes an amine moiety.

式1a 其中R₄ 及R₅ 獨立地為氫、烴基或經取代烴基。Embodiment 875. The method/composition of any one of Embodiments 871 to 874, wherein the cross-linked amine polymer comprises residues corresponding to the amine of Formula 1a, and the cross-linked amine polymer by corresponding to Formula 1a Free radical polymerization of amines:

Formula 1a wherein R ₄ and R _{5 are} independently hydrogen, hydrocarbyl or substituted hydrocarbyl.

Embodiment 876. The method/composition of embodiment 875 wherein R ₄ and R _{5 are} independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, halogen Alkyl, hydroxyalkyl, ether, heteroaryl or heterocyclic.

Embodiment 877. The method/composition of embodiment 875 wherein R ₄ and R _{5 are} independently hydrogen, aliphatic or heteroaliphatic.

式1b 其中R₄ 及R₅ 獨立地為氫、烴基或經取代烴基，R₆ 為脂族基且R₆₁ 及R₆₂ 獨立地為氫、脂族基或雜脂族基。Embodiment 878. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbent composition comprising a cross-linked amine polymer containing a amine corresponding to the amine of Formula 1b Residues, and crosslinked amine polymers are prepared by substitution polymerization of amines corresponding to Formula 1b and multifunctional crosslinking agents:

Formula 1b wherein R ₄ and R _{5 are} independently hydrogen, a hydrocarbon group or a substituted hydrocarbon group, R ₆ is an aliphatic group and R ₆₁ and R _{62 are} independently a hydrogen, aliphatic group or heteroaliphatic group.

Embodiment 879. The method/composition of embodiment 878 wherein R ₄ and R _{5 are} independently hydrogen, saturated hydrocarbon, unsaturated aliphatic, aryl, heteroaryl, heteroalkyl, or unsaturated heteroaliphatic base.

Embodiment 880. The method/composition of embodiment 878, wherein R ₄ and R _{5 are} independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, halogen Alkyl, hydroxyalkyl, ether, heteroaryl or heterocyclic.

Embodiment 881. The method/composition of embodiment 878, wherein R ₄ and R _{5 are} independently hydrogen, allyl, or aminoalkyl.

式1c 其中R₇ 為氫、脂族基或雜脂族基且R₈ 為脂族基或雜脂族基。Embodiment 882. The method/composition of any one of embodiments 871 to 881, wherein the cross-linked amine polymer comprises residues corresponding to the amine of formula 1c:

Formula 1c wherein R ₇ is hydrogen, an aliphatic group or a heteroaliphatic group and R ₈ is an aliphatic group or a heteroaliphatic group.

式2 其中 m及n獨立地為非負整數； R₁₀ 、R₂₀ 、R₃₀ 及R₄₀ 獨立地為氫、烴基或經取代烴基； X₁ 為

； X₂ 為烴基或經取代烴基； 各X₁₁ 獨立地為氫、烴基、經取代烴基、羥基或胺基；且 z為非負數。Embodiment 883. The method/composition of any of the preceding listed embodiments, wherein the cross-linked amine polymer comprises residues corresponding to the amine of Formula 2:

Formula 2 where m and n are independently non-negative integers; R ₁₀ , R ₂₀ , R ₃₀ and R _{40 are} independently hydrogen, hydrocarbyl or substituted hydrocarbyl; X ₁ is

; X ₂ is a hydrocarbon group or a substituted hydrocarbon group; each X _{11 is} independently hydrogen, a hydrocarbon group, a substituted hydrocarbon group, a hydroxyl group, or an amine group; and z is a non-negative number.

Embodiment 884. The method/composition of embodiment 883, wherein R ₁₀ , R ₂₀ , R ₃₀ and R _{40 are} independently hydrogen, aliphatic, aryl, heteroaliphatic or heteroaryl, m and z Independently 0-3, and n is 0 or 1.

Embodiment 885. The method/composition as in Embodiment 883, wherein X ₂ is an aliphatic group or a heteroaliphatic group.

Embodiment 886. The method/composition of embodiment 883, wherein m is 1-3, and X ₁₁ is hydrogen, an aliphatic group, or a heteroaliphatic group.

式2a 其中 m及n獨立地為非負整數； 各R₁₁ 獨立地為氫、烴基、雜脂族基或雜芳基； R₂₁ 及R₃₁ 獨立地為氫或雜脂族基； R₄₁ 為氫、經取代烴基或烴基； X₁ 為

； X₂ 為烷基或經取代烴基； 各X₁₂ 獨立地為氫、羥基、胺基、胺基烷基、

酸或鹵基；且 z為非負數。Embodiment 887. The method/composition of embodiment 883, wherein the crosslinked amine polymer comprises residues corresponding to the amine of formula 2a:

Formula 2a where m and n are independently non-negative integers; each R _{11 is} independently hydrogen, hydrocarbon, heteroaliphatic or heteroaryl; R ₂₁ and R _{31 are} independently hydrogen or heteroaliphatic; R ₄₁ is hydrogen , Substituted hydrocarbon group or hydrocarbon group; X ₁ is

; X ₂ is an alkyl group or a substituted hydrocarbon group; each X _{12 is} independently hydrogen, hydroxyl, amine group, aminoalkyl group,

Acid or halo; and z is a non-negative number.

Embodiment 888. The method/composition of embodiment 887, wherein m and z are independently 0-3, and n is 0 or 1.

Embodiment 889. The method/composition of any one of embodiments 887 to 888, wherein R _{11 is} independently hydrogen, aliphatic, aminoalkyl, haloalkyl, or heteroaryl, R ₂₁ and R _{31 is} independently hydrogen or a heteroaliphatic group, and R ₄₁ is hydrogen, an aliphatic group, an aryl group, a heteroaliphatic group, or a heteroaryl group.

Embodiment 890. The method/composition of any one of Embodiments 887 to 889 wherein each R ₁₁ is hydrogen, aliphatic, aminoalkyl or haloalkyl, and R ₂₁ and R ₃₁ are hydrogen or aminoalkyl Group, and R ₄₁ is hydrogen, an aliphatic group or a heteroaliphatic group.

式2b 其中 m及n獨立地為非負整數； 各R₁₂ 獨立地為氫、經取代烴基或烴基； R₂₂ 及R₃₂ 獨立地為氫、經取代烴基或烴基； R₄₂ 為氫、烴基或經取代烴基； X₁ 為

； X₂ 為烷基、胺基烷基或烷醇； 各X₁₃ 獨立地為氫、羥基、脂環、胺基、胺基烷基、鹵素、烷基、雜芳基、

酸或芳基； z為非負數；且 對應於式2b之胺包含至少一個烯丙基。Embodiment 891. The method/composition of any one of embodiments 887 to 890, wherein the crosslinked amine polymer comprises residues corresponding to the amine of formula 2b:

Formula 2b where m and n are independently non-negative integers; each R _{12 is} independently hydrogen, substituted hydrocarbon group or hydrocarbon group; R ₂₂ and R _{32 are} independently hydrogen, substituted hydrocarbon group or hydrocarbon group; R ₄₂ is hydrogen, hydrocarbon group or hydrocarbon group Substituted hydrocarbon group; X ₁ is

; X ₂ is alkyl, aminoalkyl or alkanol; each X _{13 is} independently hydrogen, hydroxyl, alicyclic, amino, aminoalkyl, halogen, alkyl, heteroaryl,

Acid or aryl; z is a non-negative number; and the amine corresponding to formula 2b contains at least one allyl group.

Embodiment 892. The method/composition of embodiment 891, wherein m and z are independently 0-3, and n is 0 or 1.

Embodiment 893. The method/composition of any one of embodiments 891 to 892, wherein R ₁₂ or R ₄₂ independently comprise at least one allyl or vinyl moiety.

Embodiment 894. The method/composition of any one of embodiments 891 to 893, wherein (i) m is a positive integer, and R ₁₂ , R ₂₂ and R ₄₂ comprise at least two allyl or ethylene in combination The base moiety, or (ii) n is a positive integer, and R ₁₂ , R ₃₂ and R ₄₂ comprise at least two allyl or vinyl moieties in combination.

Embodiment 895. The method/composition of any of the foregoing enumerated embodiments, wherein the crosslinked amine polymer comprises the residues of the amines presented in Table A.

Embodiment 896. The method/composition of any of the foregoing enumerated embodiments wherein the cross-linked amine polymer is cross-linked with the cross-linking agent presented in Table B.

式3 其中 R₁₅ 、R₁₆ 及R₁₇ 獨立地為氫、烴基、經取代烴基、羥基、胺基、

酸或鹵基； X₁₅ 為

； X₅ 為烴基、經取代烴基、側氧基(-O-)或胺基；且 z為非負數。Embodiment 897. The method/composition of any of the foregoing listed embodiments, wherein the cross-linked amine polymer comprises repeating units corresponding to Formula 3:

Formula 3 wherein R ₁₅ , R ₁₆ and R _{17 are} independently hydrogen, hydrocarbon group, substituted hydrocarbon group, hydroxyl group, amine group,

Acid or halogen; X ₁₅ is

; X ₅ is a hydrocarbon group, a substituted hydrocarbon group, a pendant (-O-) group, or an amine group; and z is a non-negative number.

Embodiment 898. The method/composition of embodiment 897, wherein R ₁₅ , R ₁₆ and R _{17 are} independently an aliphatic group or a heteroaliphatic group.

Embodiment 899. The method/composition of any one of embodiments 897 to 898, wherein X ₅ is pendant, amine, alkylamino, ether, alkanol, or haloalkyl.

Embodiment 900. The method/composition of any one of embodiments 897 to 899, wherein the crosslinked amine polymer is prepared by: (i) substitution polymerization of a multifunctional reagent, at least one of these reagents It contains amine moieties, (2) free radical polymerization of monomers containing at least one amine moiety or nitrogen-containing moieties, or (3) crosslinking of amine-containing intermediates and optionally crosslinkers containing amine moieties.

Embodiment 901. The method/composition of any of the foregoing listed embodiments, wherein the cross-linked amine polymer is a cross-linked homopolymer or cross-linked copolymer.

Embodiment 902. The method/composition of any of the foregoing enumerated embodiments, wherein the cross-linked amine polymer comprises a free amine moiety, separated by repeating linking subunits of the same or varying length.

Embodiment 903. The method/composition of any of the foregoing enumerated embodiments, wherein the cross-linked amine polymer is prepared by polymerizing an amine-containing monomer and a cross-linking agent in a substitution polymerization reaction.

Embodiment 904. The method/composition of any of the foregoing listed embodiments, wherein the amine-containing monomer is a linear amine having at least two reactive amine moieties that participate in the substitution polymerization reaction.

Embodiment 905. The method/composition of any of the foregoing embodiments, 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]ethylamine, ginseng (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'-di Aminodipropylamine, 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-propanedi Amine, N,N'-bis(3-aminopropyl) ethylenediamine, N,N'-bis(3-aminopropyl)-1,4-butanediamine tetrahydrochloride, 1,3-di Amino-2-propanol, N-ethylethylenediamine, 2,2'-diamino-N-methyldiethylamine, N,N'-diethylethylenediamine, N-isopropyl Ethylenediamine, N-methylethylenediamine, N,N'-di-tert-butylethylenediamine, N,N'-diisopropylethylenediamine, N,N'-dimethylethylene Diamine, 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-tetrazole Heterocyclotetradecane, 1,4,8,12-tetraazacyclopentadecane, 2-(aminomethyl)piperidine or 3-(methylamino)pyrrolidinyl.

Embodiment 906. The method/composition of any of the foregoing listed embodiments, wherein the cross-linking agent is selected from the group consisting of dihaloalkanes, haloalkyl ethylene oxides, alkyl ethylene oxides Sulfonate, di(haloalkyl)amine, tri(haloalkyl)amine, diepoxide, triepoxide, tetraepoxide, bis(halomethyl)benzene, tri(halomethyl)benzene , Tetra (halomethyl) benzene, epihalohydrin such as epichlorohydrin and epibromohydrin poly (epichlorohydrin), (iodomethyl) ethylene oxide, propyl tosylate, 3-nitrate Glycidyl benzenesulfonate glycidyl ester, 4-toluenesulfonyloxy-1,2-butylene oxide, bromo-1,2-butylene oxide, 1,2-dibromoethane, 1,3 -Dichloropropane, 1,2-dichloroethane, l-bromo-2-chloroethane, 1,3-dibromopropane, bis(2-chloroethyl)amine, ginseng (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 Ethylene glycol diglycidyl ether, glycerol diglycidyl ether, 1,3-diglycidyl glyceryl ether, N, N-diglycidyl aniline, neopentyl glycol diglycidyl ether, diethyl Glycol diglycidyl ether, 1,4-bis(glycidyloxy)benzene, resorcinol ether, 1,6-hexanediol diglycidyl ether, trimethylolpropane diglycidyl ether, 1 ,4-cyclohexanedimethanol diglycidyl ether, 1,3-bis-(2,3-epoxypropoxy)-2-(2,3-dihydroxypropoxy)propane, 1,2- Cyclohexanedicarboxylic acid diglycidyl ester, 2,2'-bis(glycidyloxy)diphenylmethane, bisphenol F diglycidyl ether, 1,4-bis(2',3'epoxy Propyl) perfluoro-n-butane, 2,6-bis(oxiran-2-ylmethyl)-1,2,3,5,6,7-hexahydropyrrolo[3,4-f] Isoindole-1,3,5,7-tetraone, bisphenol A diglycidyl ether, 5-hydroxy-6,8-bis(oxiran-2-ylmethyl)-4-pentoxy- 4-h-Benzopran-2-carboxylic acid ethyl ester, bis[4-(2,3-epoxy-propylthio)phenyl]-sulfide, 1,3-bis(3-glycidyl) Oxypropyl) tetramethyldisilaxane, 9,9-bis[4-(glycidyloxy)phenyl] fluorine, triepoxy isocyanurate, glycerol triglycidyl ether, N, N-diglycidyl-4-glycidoxyaniline, isocyanuric acid (S,S,S)-triglycidyl ester, isocyanuric acid (R,R,R)-triglycidyl ester, iso Triglycidyl cyanurate, trimethylolpropane triglycidyl ether, glycerol propoxylated triglycidyl ether, trihydroxyphenylmethane triglycidyl ether, 3,7,14-ginseng[[3- (Glyoxypropyloxy)propyl]dimethylsiloxy]-1,3,5,7,9,11,14-heptylcyclopentyl tricyclo[ 7,3,3,15,11]heptasiloxane, 4,4' methylene bis (N, N-diglycidyl aniline), bis (halomethyl) benzene, bis (halomethyl) Diphenyl and bis(halomethyl)naphthalene, tolyl diisocyanate, acrylic chloride, methyl acrylate, ethyl bisacrylamide, heat-resistant metal dianhydride, succinyl dichloride, dimethyl succinate Ester, 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, ginseng[(2-epoxyethyl)methyl]amine and combinations thereof.

Embodiment 907. The method/composition of any of the foregoing enumerated embodiments, wherein the preparation of the cross-linked amine polymer comprises free radical polymerization of an amine monomer comprising at least one amine moiety or nitrogen-containing moiety.

Embodiment 908. The method/composition of any of the foregoing enumerated embodiments, wherein the cross-linked amine polymer has a balanced expansion ratio of about 1.5 or less in deionized water.

Embodiment 909. The method/composition of any of the foregoing enumerated embodiments, wherein the crosslinked amine polymer has a balanced expansion ratio of about 1 or less in deionized water.

Embodiment 910. The method/composition of any of the foregoing listed embodiments, wherein the cross-linked amine polymer contains 36 mM NaCl, 20 mM NaH2PO4, and 50 mM 2-(N-morpholinyl)ethanesulfonic acid (MES ) Buffered to pH 5.5 and at least 0.5:1 chloride ion to phosphate ion combined molar ratio in an aqueous simulated small intestine inorganic buffer ("SIB") at 37°C, respectively.

式4 其中各R獨立地為氫或交聯胺聚合物(

)之兩個氮原子之間的伸乙基交聯，且a、b、c及m為整數。Embodiment 911. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition comprises a polymer comprising a structure corresponding to Formula 4:

Formula 4 where each R is independently hydrogen or a crosslinked amine polymer (

), the ethylidene crosslinks between the two nitrogen atoms, and a, b, c and m are integers.

Embodiment 912. The method/composition as in Embodiment 911, where m is a larger integer indicating an extended polymer network.

Embodiment 913. The method/composition of embodiment 911 or 912, wherein the ratio of the sum of a and b to c (ie, a+b:c) is in the range of about 1:1 to 5:1.

Embodiment 914. The method/composition of any one of embodiments 911 to 913, wherein the ratio of the sum of a and b to c (ie, a+b:c) is between about 1.5:1 to 4:1 Within.

Embodiment 915. The method/composition according to any one of embodiments 911 to 914, wherein the ratio of the sum of a and b to c (ie, a+b:c) is between about 1.75:1 to 3: 1 range.

Embodiment 916. The method/composition according to any one of embodiments 911 to 915, wherein the ratio of the sum of a and b to c (ie, a+b:c) is from about 2:1 to 2.5: 1 range.

Embodiment 917. The method/composition according to any one of embodiments 911 to 916, wherein the sum of a and b is 57 and c is 24.

Embodiment 918. The method/composition according to any of the preceding enumerated embodiments, wherein 50% to 95% of the R substituents are hydrogen and 5% to 50% is ethylene between two nitrogens of the crosslinked amine polymer Crosslink.

Embodiment 919. The method/composition according to any of the preceding enumerated embodiments, wherein 55% to 90% of the R substituents are hydrogen and 10% to 45% are ethylene between two nitrogens of the crosslinked amine polymer Crosslink.

Embodiment 920. The method/composition according to any of the preceding enumerated embodiments, wherein 60% to 90% of the R substituents are hydrogen and 10% to 40% is ethylene between two nitrogens of the crosslinked amine polymer Crosslink.

Embodiment 921. The method/composition according to any of the preceding enumerated embodiments, wherein 65% to 90% of the R substituents are hydrogen and 10% to 35% are ethylene between two nitrogens of the crosslinked amine polymer Crosslink.

Embodiment 922. The method/composition according to any one of embodiments 911 to 921, wherein the R substituent is hydrogen and 10% to 30% is ethylene crosslinking between two nitrogens of the crosslinked amine polymer .

Embodiment 923. The method/composition according to any of the preceding enumerated embodiments, wherein the composition is the polymer of any one of Embodiment 768 to Embodiment 774, wherein 75% to 85% of the R substituents are hydrogen and 15% to 25% are cross-linked ethylene between two nitrogens of the cross-linked amine polymer.

Embodiment 924. The method/composition according to any of the foregoing enumerated embodiments, wherein the R substituent is hydrogen and 15% to 20% is an ethylene crosslink between the two nitrogens of the crosslinked amine polymer.

Embodiment 925. The method/composition according to any of the preceding enumerated embodiments, wherein the R substituent is hydrogen and about 19% is ethylene cross-linked.

Embodiment 926. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding force of at least 1 mEq/g in SIB analysis.

Embodiment 927. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding force of at least 1.5 mEq/g in SIB analysis.

Embodiment 928. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 2 mEq/g in SIB analysis.

Embodiment 929. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding force of at least 2.5 mEq/g in SIB analysis.

Embodiment 930. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding force of at least 3 mEq/g in SIB analysis.

Embodiment 931. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 3.5 mEq/g in SIB analysis.

Embodiment 932. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 4 mEq/g in SIB analysis.

Embodiment 933. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding force of at least 4.5 mEq/g in SIB analysis.

Embodiment 934. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding force of at least 5 mEq/g in SIB analysis.

Embodiment 935. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding force of at least 5.5 mEq/g in SIB analysis.

Embodiment 936. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 6 mEq/g in SIB analysis.

Embodiment 937. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 0.1:1, respectively.

Example 938. The method/composition of any of the foregoing enumerated examples, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis of at least 0.2:1, respectively.

Embodiment 939. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 0.25:1, respectively.

Embodiment 940. The method/composition of any of the preceding enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 0.3:1, respectively.

Embodiment 941. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 0.35:1, respectively.

Embodiment 942. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 0.4:1, respectively.

Embodiment 943. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 0.45:1, respectively.

Embodiment 944. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to the bound phosphate in SIB analysis of at least 0.5:1, respectively.

Embodiment 945. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 2:3, respectively.

Embodiment 946. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 0.75:1, respectively.

Embodiment 947. The method/composition of any of the foregoing enumerated embodiments, wherein the binding force of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis of at least 0.9:1, respectively.

Embodiment 948. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 1:1, respectively.

Embodiment 949. The method/composition of any of the aforementioned enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 1.25:1, respectively.

Embodiment 950. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 1.5:1, respectively.

Embodiment 951. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 1.75:1, respectively.

Embodiment 952. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 2:1, respectively.

Embodiment 953. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to the bound phosphate in the SIB analysis of at least 2.25:1, respectively.

Embodiment 954. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 2.5:1, respectively.

Embodiment 955. The method/composition of any of the aforementioned enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 2.75:1, respectively.

Embodiment 956. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 3:1, respectively.

Embodiment 957. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 4:1, respectively.

Embodiment 958. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized in that the ratio of the amount of bound chloride ion to the bound phosphate group is at least 5:1 in SIB analysis, respectively.

Embodiment 959. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 6:1, respectively.

Embodiment 960. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 7:1, respectively.

Embodiment 961. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 8:1, respectively.

Embodiment 962. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 9:1, respectively.

Embodiment 963. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 10:1, respectively.

Embodiment 964. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 12.5:1, respectively.

Embodiment 965. The method/composition of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate in the SIB analysis of at least 15:1, respectively.

Embodiment 966. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is in an aqueous simulated gastric fluid buffer ("SGF") containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37°C It has a balanced chloride ion binding capacity of at least 5 mmol/g.

Embodiment 967. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is in an aqueous simulated gastric fluid buffer ("SGF") containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37°C Have a balance of at least 7.5 mmol/g chloride ion binding.

Embodiment 968. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is in an aqueous simulated gastric fluid buffer ("SGF") containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37°C It has a balanced chloride ion binding capacity of at least 10 mmol/g.

Example 969. The method/composition of any of the foregoing enumerated examples, wherein the pharmaceutical composition increased the serum bicarbonate content by at least 1 mEq/L in the placebo-controlled study, the increase being the first group at the end of the study The difference between the average serum bicarbonate content in the middle group and the average serum bicarbonate content in the second group at the end of the study, where subjects in the first group received the pharmaceutical composition and subjects in the second group received Participants received a placebo, where the first and second groups each included a patient population of sufficient size to estimate a statistically significant difference in serum bicarbonate content between the groups during the cycle.

Example 970. The method/composition of any of the foregoing enumerated examples, wherein the pharmaceutical composition increases serum bicarbonate content by at least 2 mEq/L in the placebo-controlled study, the increase being the first group at the end of the study The difference between the average serum bicarbonate content in the middle group and the average serum bicarbonate content in the second group at the end of the study, where subjects in the first group received the pharmaceutical composition and subjects in the second group received Participants received a placebo, where the first and second groups each included a patient population of sufficient size to estimate a statistically significant difference in serum bicarbonate content between the groups during the cycle.

Example 971. The method/composition of any of the foregoing enumerated examples, wherein the pharmaceutical composition increased the serum bicarbonate content by at least 2.5 mEq/L in the placebo-controlled study, the increase being the first group at the end of the study The difference between the average serum bicarbonate content in the middle group and the average serum bicarbonate content in the second group at the end of the study, where subjects in the first group received the pharmaceutical composition and subjects in the second group received Participants received a placebo, where the first and second groups each included a patient population of sufficient size to estimate a statistically significant difference in serum bicarbonate content between the groups during the cycle.

Embodiment 972. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition has the ability to change the patient’s baseline serum bicarbonate content by at least 2 mEq/L at the end of the placebo-controlled study for at least twelve weeks .

Embodiment 973. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition has the ability to change the patient's baseline serum bicarbonate content by at least 3 mEq/L at the end of the placebo-controlled study for at least twelve weeks .

Embodiment 974. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition has the ability to change the patient’s baseline serum bicarbonate content by at least 4 mEq/L at the end of the placebo-controlled study for at least twelve weeks .

Embodiment 975. The method/composition of any of the foregoing enumerated embodiments, wherein the patient population of each group is at least 25 patients.

Embodiment 976. The method/composition of any preceding enumerated embodiment, wherein the patient population of each group is at least 50 patients.

Embodiment 977. The method/composition of any of the foregoing enumerated embodiments, wherein the patient population of each group is at least 100 patients.

Embodiment 978. The method/composition of any preceding enumerated embodiment, wherein the patient population of each group is at least 150 patients.

Embodiment 979. The method/composition of any of the foregoing enumerated embodiments, wherein the patient population of each group is at least 200 patients.

Embodiment 980. The method/composition of any of the aforementioned enumerated embodiments, wherein the quality of life or the quality of life is assessed by the same questionnaire answered by the first group at the end of the cycle relative to the same questionnaire answered by the second group at the end of the cycle Improvements in physical function, where subjects in the first group receive the pharmaceutical composition and subjects in the second group receive the placebo.

Embodiment 981. The method/composition of any of the foregoing enumerated embodiments, wherein the improvement in quality of life or physical function is assessed by questionnaire, which is a clinically validated assessment used to assess the physical and mental health of the patient.

Embodiment 982. The method/composition of any of the foregoing enumerated embodiments, wherein the questionnaire contains questions about parameters selected from the group consisting of: symptoms/problems related to diseases/pathologies, diseases/pathologies Impact, burden of disease/pathology, work status, cognitive function, quality of social interaction, sleep, social support, physical function, pain, general health, emotional well-being, social function, energy/fatigue and combinations thereof.

Embodiment 983. The method/composition of any of the foregoing enumerated embodiments, wherein the questionnaire contains questions about how the patient's health limits the patient's ability to participate in physical activities selected from the group consisting of: intense activity; moderate activity; lifting or Carrying groceries; climbing several stairs; climbing one stairs; bending, kneeling or bending; walking more than a mile; walking several blocks; walking one block; and bathing or dressing.

Embodiment 984. The method/composition of any preceding enumerated embodiment wherein the patient achieves at least about a 10% improvement in the quality of life rating relative to the placebo control group.

Embodiment 985. The method/composition of any of the aforementioned enumerated embodiments, wherein the patient achieves at least about 25% improvement in the quality of life rating relative to the placebo control group.

Embodiment 986. The method/composition of any preceding enumerated embodiment wherein the patient achieves at least about a 50% improvement in the quality of life rating relative to the placebo control group.

Embodiment 987. The method/composition of any preceding enumerated embodiment wherein the patient achieves at least about 75% improvement in the quality of life rating relative to the placebo control group.

Embodiment 988. The method/composition of any of the foregoing enumerated embodiments, wherein the improvement in physical function comprises: (a) the patient's baseline based on the patient's answer to question 3 of the Kidney Disease Quality of Life Short Form (KDQOL-SF) A physical function score improvement of at least 1.5 points; (b) a patient’s baseline repeat sitting time improvement of at least -1.5 seconds; or (c) a patient’s baseline physical function score improvement of at least 1.5 points based on the patient’s answer to KDQOL-SF question 3 And the patient's baseline repeat sitting time improved by at least -1.5 seconds. In one aspect of this embodiment and other embodiments, after a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks of treatment, an improvement in the patient's baseline repeated sitting time is seen . In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients. In another aspect of this and other embodiments, the patient's baseline repeat sitting time is improved by at least about 0.5 seconds, 0.75 seconds, 1.0 seconds, 1.1 seconds, 1.2 seconds, 1.3 seconds, or 1.4 seconds. In another aspect of this embodiment and other embodiments, the improvement of the patient's baseline body function score is based on the patient's performance in single sitting and/or repeated sitting as depicted in FIG. 22. In another aspect of this embodiment and other embodiments, the KDQOL-SF score of the patient is calculated as follows: 1 (very limited) = 0; 2 (smallly limited) = 50; 3 (unrestricted) = 100 . Overall score = the sum of all 10 divided by 10.

Embodiment 989. The method/composition of any of the foregoing enumerated embodiments, wherein the improvement in the quality of life of the patient includes a reduction or prevention of further bone loss and/or a reduction or prevention of further muscle loss in the patient.

Embodiment 990. The method as in any of the foregoing enumerated embodiments, wherein the improvement in body function score further comprises an improvement in the patient’s baseline repeated sitting time compared to the placebo control group by at least -1.5 seconds during the period. In one aspect of this and other embodiments, after a period of treatment of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks, an improvement in the patient's baseline repeated sitting position is seen . In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients. In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients. In another aspect of this and other embodiments, the patient's baseline repeat sitting time is improved by at least about 0.5 seconds, 0.75 seconds, 1.0 seconds, 1.1 seconds, 1.2 seconds, 1.3 seconds, or 1.4 seconds. In another aspect of this embodiment and other embodiments, the improvement of the patient's baseline body function score is based on the patient's performance in single sitting and/or repeated sitting as depicted in FIG. 22. In another aspect of this embodiment and other embodiments, the patient's KDQOL-SF score is calculated as follows: 1 (very restricted) = 0; 2 (rarely restricted) = 50; 3 (unrestricted) = 100. Overall score = the sum of all 10 divided by 10.

Example 991. The method/composition of any of the foregoing enumerated examples, wherein the patient achieves an improvement of at least about 1.5 points on the KDQOL-SF rating relative to the placebo control group.

Embodiment 992. The method/composition of any preceding enumerated embodiment wherein the patient achieves an improvement of at least about 3.0 points on the KDQOL-SF rating relative to the placebo control group.

Embodiment 993. The method/composition of any preceding enumerated embodiment wherein the patient achieves an improvement of at least about 4.5 points on the KDQOL-SF rating relative to the placebo control group.

Embodiment 994. The method/composition of any preceding enumerated embodiment wherein the patient achieves an improvement of at least about 6.0 points on the KDQOL-SF grade relative to the placebo control group.

Embodiment 995. The method/composition of any preceding enumerated embodiment wherein the disease or disorder is characterized by a baseline serum bicarbonate value of less than 18 mEq/L.

Embodiment 996. The method/composition of any preceding enumerated embodiment wherein the disease or disorder is characterized by a baseline serum bicarbonate value of at least 12 mEq/L.

Embodiment 997. The method/composition of any preceding enumerated embodiment wherein the disease or disorder is characterized by a baseline serum bicarbonate value of at least 15 mEq/L.

Embodiment 998. The method/composition of any preceding enumerated embodiment wherein the patient's baseline serum bicarbonate value increases by at least 1 mEq/L during the cycle.

Embodiment 999. The method/composition of any preceding enumerated embodiment wherein the patient's baseline serum bicarbonate value increases by at least 2 mEq/L during the cycle.

Embodiment 1000. The method/composition of any preceding enumerated embodiment, wherein the patient's baseline serum bicarbonate value increases by at least 3 mEq/L during the cycle.

Embodiment 1001. The method/composition of any of the foregoing enumerated embodiments, wherein the patient is administered a daily dose of the pharmaceutical composition, and the daily dose has a target species removal of at least about 10 milliequivalents/day, at least about 15 A capacity of milliequivalents/day, at least about 20 milliequivalents/day, at least about 25 milliequivalents/day, or at least about 30 milliequivalents/day.

Embodiment 1002. The method/composition of any of the foregoing enumerated embodiments, wherein a daily dose of the pharmaceutical composition is administered to the patient, and the daily dose has a target species removal of less than 50 milliequivalents/day or less than 35 Million equivalent/day capacity.

Embodiment 1003. The method/composition of any of the foregoing enumerated embodiments, wherein the period is at least three weeks, at least one month, at least two months, at least six months, at least 12 months, at least 18 months, or at least 24 Months.

Embodiment 1004. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition has the ability to bind a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids.

Embodiment 1005. The method/composition of any of the foregoing enumerated embodiments, wherein the conjugate base of a strong acid is selected from the group consisting of chloride ion, bisulfate ion, and sulfate ion.

Embodiment 1006. The method/composition of any of the foregoing enumerated embodiments, wherein the target species includes chloride ions.

Embodiment 1007. The method/composition of any of the foregoing enumerated embodiments, wherein the target species comprises hydrochloric acid.

Embodiment 62A. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding force of at least 1 mEq/g in SIB analysis.

Embodiment 1008. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding force of at least 1.5 mEq/g in SIB analysis.

Embodiment 1009. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding force of at least 2 mEq/g in SIB analysis.

Embodiment 1010. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition has the ability to bind chloride and phosphate ions in a SIB analysis at a ratio of at least 0.25:1, respectively.

Example 1011. The method/composition of any of the foregoing enumerated examples, wherein the pharmaceutical composition has the ability to bind chloride and phosphate ions in a SIB analysis at a ratio of at least 0.5:1, respectively.

Embodiment 1012. The method/composition of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition has the ability to bind chloride and phosphate ions in a SIB analysis at a ratio of at least 1:1, respectively.

Embodiment 1013. The method/composition of any of the foregoing enumerated embodiments, wherein the effective amount of the pharmaceutical composition or TRC101 comprises at least about 1 g/day.

Embodiment 1014. The method/composition of any of the foregoing enumerated embodiments, wherein the effective amount of the pharmaceutical composition or TRC101 comprises about 1 g/day to 9 g/day.

Embodiment 1015. The method/composition of any of the foregoing enumerated embodiments, wherein the effective amount of the pharmaceutical composition or TRC101 comprises about 4 g/day to 6 g/day.

Embodiment 1016. The method/composition of any of the foregoing enumerated embodiments, wherein the effective amount of the pharmaceutical composition or TRC101 comprises about 6 grams/day.

Embodiment 1017. The method/composition of any of the foregoing enumerated embodiments, wherein the patient is administered an effective amount of the pharmaceutical composition or TRC101 in an oral dosage form once a day.

Example 1018. The method/composition of any of the foregoing enumerated examples, wherein the effective amount of the pharmaceutical composition or TRC101 is adjusted to maintain the patient's serum bicarbonate content between 22 mEq/L and 29 mEq/L Within range.

Example 1019. The method/composition of any of the foregoing enumerated examples, wherein the improvement in the patient's baseline repeat sitting time represents an improvement in at least one repeat.

Example 1020. The method/composition of any of the foregoing enumerated examples, wherein the improvement in the patient's baseline repeat sitting time represents an improvement in at least two repeats.

Example 1021. The method/composition of any of the foregoing enumerated examples, wherein the improvement in the patient's baseline repeat sitting time represents an improvement in at least three repeats.

Example 1022. The method/composition of any of the foregoing enumerated examples, wherein the improvement in the patient's baseline repeat sitting time represents an improvement in at least four repeats.

Example 1023. The method/composition of any of the foregoing enumerated examples, wherein the improvement in the patient's baseline repeat sitting time represents an improvement in at least five repeats.

Embodiment 1024. The method/composition of any of the foregoing enumerated embodiments, wherein the improvement of the patient's baseline physical function score is based on the patient's answer to at least one question of question 3 of KDQOL-SF as depicted in FIG. 21.

Example 1025. The method/composition of any of the foregoing enumerated examples, wherein the improvement of the patient's baseline body function score is based on the patient's answers to at least five questions of question 3 of KDQOL-SF as depicted in Figure 21 .

Example 1026. The method/composition of any of the foregoing enumerated examples, wherein the improvement of the patient's baseline body function score is based on the patient's answers to at least seven questions of question 3 of KDQOL-SF as depicted in Figure 21 .

Example 1027. The method/composition of any of the aforementioned enumerated examples, wherein the improvement of the patient's baseline body function score is based on the patient's answers to all questions of KDQOL-SF question 3 as depicted in FIG. 21.

Embodiment 1028. A pharmaceutical composition for use in a method of treating an acid-base disorder in a patient, wherein the treatment method improves the quality of life of the patient.

Embodiment 1029. A pharmaceutical composition for use in a method of treating an acid-base disorder in a patient, wherein the method of treatment improves the patient's physical function.

式1 其中R₁ 、R₂ 及R₃ 獨立地為所提供之氫、烴基或經取代烴基，然而，R₁ 、R₂ 及R₃ 中之至少一者不為氫。Embodiment 1030. A pharmaceutical composition for use in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-absorbable composition comprising a proton conjugate and a cross-linked amine polymer. The hydrazine polymer contains residues corresponding to the amine of formula 1:

Formula 1 wherein R ₁ , R ₂ and R _{3 are} independently hydrogen, hydrocarbon group or substituted hydrocarbon group provided, however, at least one of R ₁ , R ₂ and R ₃ is not hydrogen.

Embodiment 1031. The pharmaceutical composition as used in the method of treating the acid-base disorder of Embodiment 1030, wherein R ₁ , R ₂ and R _{3 are} independently provided hydrogen, alkyl, alkenyl, allyl, Vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocyclic ring, however, each of R ₁ , R _2, and R ₃ is not hydrogen.

Embodiment 1032. The pharmaceutical composition as used in the method for treating the acid-base disorder of any one of Embodiments 1030 to 1031, wherein R ₁ , R ₂ and R _{3 are} independently hydrogen, aliphatic provided Group or heteroaliphatic group, however, at least one of R ₁ , R ₂ and R ₃ is not hydrogen.

Embodiment 1033. The pharmaceutical composition as used in the method for treating the acid-base disorder of any one of Embodiments 1030 to 1032, wherein the amine is carried out by using a multifunctional cross-linking agent that optionally also includes an amine moiety Substitute polymerization to prepare crosslinked amine polymers.

式1a 其中R₄ 及R₅ 獨立地為氫、烴基或經取代烴基。Embodiment 1034. The pharmaceutical composition as used in the method of treating the acid-base disorder of any one of Embodiments 1030 to 1033, wherein the cross-linked amine polymer comprises residues corresponding to the amine of Formula 1a, and Cross-linked amine polymers are prepared by free radical polymerization of amines corresponding to formula 1a:

Formula 1a wherein R ₄ and R _{5 are} independently hydrogen, hydrocarbyl or substituted hydrocarbyl.

Embodiment 1035. The pharmaceutical composition as used in the method of treating the acid-base disorder of Embodiment 1034, wherein R ₄ and R _{5 are} independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, Aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl or heterocycle.

Embodiment 1036. The pharmaceutical composition as used in the method of treating the acid-base disorder of Embodiment 1034, wherein R ₄ and R _{5 are} independently hydrogen, aliphatic, or heteroaliphatic.

式1b 其中R₄ 及R₅ 獨立地為氫、烴基或經取代烴基，R₆ 為脂族基且R₆₁ 及R₆₂ 獨立地為氫、脂族基或雜脂族基。Embodiment 1037. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is a non-containing cross-linked amine polymer containing a residue corresponding to the amine of formula 1b An absorbent composition, and a cross-linked amine polymer is prepared by subjecting the amine corresponding to Formula 1b to substitution polymerization using a multifunctional cross-linking agent:

Formula 1b wherein R ₄ and R _{5 are} independently hydrogen, a hydrocarbon group or a substituted hydrocarbon group, R ₆ is an aliphatic group and R ₆₁ and R _{62 are} independently a hydrogen, aliphatic group or heteroaliphatic group.

Embodiment 1038. The pharmaceutical composition as used in the method of treating the acid-base disorder of Embodiment 1037, wherein R ₄ and R _{5 are} independently hydrogen, saturated hydrocarbon, unsaturated aliphatic group, aryl group, heteroaryl group, Heteroalkyl or unsaturated heteroaliphatic group.

Embodiment 1039. The pharmaceutical composition as used in the method of treating the acid-base disorder of Embodiment 1037, wherein R ₄ and R _{5 are} independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, Aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl or heterocycle.

Example 1040. The pharmaceutical composition as used in the method of treating the acid-base disorder of Example 1037, wherein R ₄ and R _{5 are} independently hydrogen, allyl, or aminoalkyl.

式1c 其中R₇ 為氫、脂族基或雜脂族基且R₈ 為脂族基或雜脂族基。Embodiment 1041. The pharmaceutical composition as used in the method for treating the acid-base disorder according to any one of embodiments 2E1 to 1040, wherein the crosslinked amine polymer comprises residues corresponding to the amine of formula 1c:

Formula 1c wherein R ₇ is hydrogen, an aliphatic group or a heteroaliphatic group and R ₈ is an aliphatic group or a heteroaliphatic group.

式2 其中 m及n獨立地為非負整數； R₁₀ 、R₂₀ 、R₃₀ 及R₄₀ 獨立地為氫、烴基或經取代烴基； X₁ 為

； X₂ 為烴基或經取代烴基； 各X₁₁ 獨立地為氫、烴基、經取代烴基、羥基或胺基；且 z為非負數。Embodiment 1042. A pharmaceutical composition for use in a method of treating an acid-base disorder according to any one of the enumerated embodiments above, wherein the cross-linked amine polymer comprises residues corresponding to the amine of formula 2:

Formula 2 where m and n are independently non-negative integers; R ₁₀ , R ₂₀ , R ₃₀ and R _{40 are} independently hydrogen, hydrocarbyl or substituted hydrocarbyl; X ₁ is

; X ₂ is a hydrocarbon group or a substituted hydrocarbon group; each X _{11 is} independently hydrogen, a hydrocarbon group, a substituted hydrocarbon group, a hydroxyl group, or an amine group; and z is a non-negative number.

Embodiment 1043. A pharmaceutical composition as used in a method of treating an acid-base disorder according to embodiment 1042, wherein R ₁₀ , R ₂₀ , R ₃₀ and R _{40 are} independently hydrogen, aliphatic, aryl, heterolipid Group or heteroaryl, m and z are independently 0 to 3 and n is 0 or 1.

Embodiment 1044. The pharmaceutical composition as used in the method for treating the acid-base disorder according to the embodiment, wherein X ₂ is an aliphatic group or a heteroaliphatic group.

Embodiment 1045. A pharmaceutical composition as used in a method for treating the acid-base disorder according to embodiment 1042, wherein m is 1 to 3 and X ₁₁ is hydrogen, aliphatic or heteroaliphatic.

式2a 其中 m及n獨立地為非負整數； 各R₁₁ 獨立地為氫、烴基、雜脂族基或雜芳基； R₂₁ 及R₃₁ 獨立地為氫或雜脂族基； R₄₁ 為氫、經取代烴基或烴基； X₁ 為

； X₂ 為烷基或經取代烴基； 各X₁₂ 獨立地為氫、羥基、胺基、胺基烷基、□酸或鹵基；且 z為非負數。Embodiment 1046. The pharmaceutical composition as used in the method for treating the acid-base disorder according to embodiment 1042, wherein the cross-linked amine polymer comprises residues corresponding to the amine of formula 2a:

Formula 2a where m and n are independently non-negative integers; each R _{11 is} independently hydrogen, hydrocarbon, heteroaliphatic or heteroaryl; R ₂₁ and R _{31 are} independently hydrogen or heteroaliphatic; R ₄₁ is hydrogen , Substituted hydrocarbon group or hydrocarbon group; X ₁ is

; X ₂ is an alkyl group or a substituted hydrocarbon group; each X _{12 is} independently hydrogen, a hydroxyl group, an amino group, an amino alkyl group, an acid, or a halogen group; and z is a non-negative number.

Embodiment 1047. The pharmaceutical composition as used in the method for treating the acid-base disorder according to embodiment 1046, wherein m and z are independently 0 to 3 and n is 0 or 1.

Embodiment 1048. A pharmaceutical composition for use in a method of treating an acid-base disorder according to any one of embodiments 1046 to 1047, wherein R _{11 is} independently hydrogen, aliphatic, aminoalkyl, halogen Alkyl or heteroaryl, R ₂₁ and R _{31 are} independently hydrogen or heteroaliphatic, and R ₄₁ is hydrogen, aliphatic, aryl, heteroaliphatic or heteroaryl.

Embodiment 1049. The pharmaceutical composition for use in the method of treating an acid-base disorder according to any one of Embodiments 1046 to 1048, each R ₁₁ is hydrogen, aliphatic, aminoalkyl, or haloalkyl , R ₂₁ and R ₃₁ are hydrogen or aminoalkyl, and R ₄₁ is hydrogen, aliphatic or heteroaliphatic.

式2b 其中 m及n獨立地為非負整數； 各R₁₂ 獨立地為氫、經取代烴基或烴基； R₂₂ 及R₃₂ 獨立地為氫、經取代烴基或烴基； R₄₂ 為氫、烴基或經取代烴基； X₁ 為

； X₂ 為烷基、胺基烷基或烷醇； 各X₁₃ 獨立地為氫、羥基、脂環、胺基、胺基烷基、鹵素、烷基、雜芳基、

酸或芳基； z為非負數；且 對應於式2b之胺包含至少一個烯丙基。Embodiment 1050. The pharmaceutical composition as used in the method for treating the acid-base disorder according to any one of embodiments 1046 to 1049, wherein the cross-linked amine polymer comprises residues corresponding to the amine of formula 2b:

Formula 2b where m and n are independently non-negative integers; each R _{12 is} independently hydrogen, substituted hydrocarbon group or hydrocarbon group; R ₂₂ and R _{32 are} independently hydrogen, substituted hydrocarbon group or hydrocarbon group; R ₄₂ is hydrogen, hydrocarbon group or hydrocarbon group Substituted hydrocarbon group; X ₁ is

; X ₂ is alkyl, aminoalkyl or alkanol; each X _{13 is} independently hydrogen, hydroxyl, alicyclic, amino, aminoalkyl, halogen, alkyl, heteroaryl,

Acid or aryl; z is a non-negative number; and the amine corresponding to formula 2b contains at least one allyl group.

Embodiment 1051. A pharmaceutical composition as used in the method of treating an acid-base disorder according to embodiment 1050, wherein m and z are independently 0 to 3 and n is 0 or 1.

Embodiment 1052. The pharmaceutical composition as used in the method of treating an acid-base disorder according to any one of Embodiment 1050 to Embodiment 1051, wherein R ₁₂ or R ₄₂ independently comprises at least one allyl or vinyl moiety .

Embodiment 1053. A pharmaceutical composition for use in a method of treating an acid-base disorder according to any one of Embodiment 1050 to Embodiment 1052, wherein (i) m is a positive integer and R ₁₂ , R ₂₂ and R ₄₂ are The combined form contains at least two allyl or vinyl moieties, or (ii) n is a positive integer and R ₁₂ , R ₃₂ and R ₄₂ in combined form contain at least two allyl or vinyl moieties.

Embodiment 1054. A pharmaceutical composition as used in a method of treating an acid-base disorder according to the foregoing enumerated embodiments, wherein the cross-linked amine polymer comprises residues of amines appearing in Table A.

Embodiment 1055. A pharmaceutical composition as used in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, wherein the cross-linked amine polymer is cross-linked via the cross-linking agent appearing in Table B.

式3 其中 R₁₅ 、R₁₆ 及R₁₇ 獨立地為氫、烴基、經取代烴基、羥基、胺基、

酸或鹵基； X₁₅ 為

； X₅ 為烴基、經取代烴基、側氧基(-O-)或胺基，且 z為非負數。Embodiment 1056. A pharmaceutical composition as used in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, wherein the cross-linked amine polymer comprises repeating units corresponding to formula 3:

Formula 3 wherein R ₁₅ , R ₁₆ and R _{17 are} independently hydrogen, hydrocarbon group, substituted hydrocarbon group, hydroxyl group, amine group,

Acid or halogen; X ₁₅ is

; X ₅ is a hydrocarbon group, a substituted hydrocarbon group, a pendant oxygen group (-O-) or an amine group, and z is a non-negative number.

Embodiment 1057. A pharmaceutical composition as used in a method for treating the acid-base disorder according to embodiment 1056, wherein R ₁₅ , R ₁₆ and R _{17 are} independently hydrogen, aliphatic or heteroaliphatic.

Embodiment 1058. A pharmaceutical composition for use in a method of treating an acid-base disorder according to any one of Embodiments 1056 to 1057, wherein X ₅ is pendant, amine, alkylamino, ether, alkyl Alcohol or haloalkyl.

Embodiment 1059. The pharmaceutical composition as used in the method for treating the acid-base disorder according to any one of embodiments 1056 to 1058, wherein the cross-linked amine polymer is prepared by: (i) at least one of Substitution polymerization of multifunctional reagents containing amine moieties, (2) free radical polymerization of monomers containing at least one amine moiety or nitrogen-containing moieties, or (3) crosslinkers containing amine intermediates and optionally amine moieties Crosslink.

Embodiment 1060. A pharmaceutical composition as used in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, wherein the cross-linked amine polymer is a cross-linked homopolymer or cross-linked copolymer.

Embodiment 1061. A pharmaceutical composition as used in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, wherein the cross-linked amine polymer comprises free amine moieties separated by repeating linker units of the same or varying length.

Embodiment 1062. A pharmaceutical composition as used in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, wherein a cross-linked amine polymerization is prepared by polymerizing an amine-containing monomer in a substitution polymerization reaction using a cross-linking agent Thing.

Embodiment 1063. A pharmaceutical composition as used in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, wherein the amine-containing monomer is a straight chain possessing at least two reactive amine moieties participating in the substitution polymerization reaction amine.

Embodiment 1064. A pharmaceutical composition as used in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, 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} Acetamide, 2-[bis(2-aminoethyl)amino]ethylamine, 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-propane Diamine, 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'-diamine-N-methyldipropylamine, 1,3-diaminopentane, 1 ,2-diamine-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 Salt, 1,3-diamine-2-propanol, N-ethylethylenediamine, 2,2'-diamine-N-methyldiethylamine, N,N'-diethylethylenediamine, N-isopropylethylethylenediamine, N-methylethylenediamine, N,N'-di-third-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 or 3-(methylamino)pyrrolidine.

Embodiment 1065. A pharmaceutical composition for use in a method of treating acid-base disorders according to any of the foregoing enumerated embodiments, wherein the crosslinking agent is selected from the group consisting of dihaloalkane, haloalkylethylene oxide Alkane, sulfonic acid alkyl ethylene oxide, di(haloalkyl)amine, ginseng(haloalkyl)amine, diepoxide, triepoxide, tetraepoxide, bis(halomethyl)benzene, Ginseng (halomethyl)benzene, tetra(halomethyl)benzene, epihalohydrin such as epichlorohydrin and epibromohydrin poly(epichlorohydrin), (iodomethyl)ethylene oxide, epoxypropyl Tosylate, epoxypropyl 3-nitrobenzenesulfonate, 4-toluenesulfonyloxy-1,2-epoxybutane, bromine-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, propylene oxide ether , 1,2,7,8-diepoxyoctane, 1,2,9,10-decane, ethylene glycol propylene oxide ether, propylene glycol propylene oxide ether, 1,4-butanediol dioxide Allyl ether, 1,2 ethylene glycol diglycidyl ether, glycerin dioxypropylene ether, 1,3-diglycidyl glyceryl ether, N,N-diglycidyl aniline, neopentyl glycol dioxypropylene ether, Diethylene glycol propylene oxide ether, 1,4-bis(glycidyloxy)benzene, resorcinol diglycidyl ether, 1,6-hexanediol propylene oxide ether, trimethylolpropane dioxide Propylene ether, 1,4-cyclohexane dimethanol propylene oxide 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 propylene oxide ether, 1,4-bis(2', 3'epoxypropyl) perfluoro-n-butane, 2,6-bis(ethylene oxide-2-ylmethyl)-1,2,3,5,6,7-hexahydropyrrolo[ 3,4-f]isoindole-1,3,5,7-tetraone, bisphenol A propylene oxide ether, ethyl 5-hydroxy-6,8-di(ethylene oxide-2-ylmethyl Group)-4-oxo-4-h-benzopiperan-2-carboxylate, bis[4-(2,3-epoxy-propylthio)phenyl]-sulfide, 1 ,3-bis(3-glycidoxypropyl)tetramethyldisilaxane, 9,9-bis[4-(glycidyloxy)phenyl]fluoro, triepoxyisocyanurate , Glycerol triglycidyl ether, N,N-diglycidyl-4-glycidoxyaniline, isocyanuric acid (S,S,S)-triglycidyl ester, isocyanuric acid (R,R,R) -Triglycidyl isocyanurate triglycidyl ester, trimethylolpropane triglycidyl ether, glycerol propoxylated triglycidyl ether, trihydroxyphenylmethane triglycidyl ether, 3,7,14-tri [[ 3-(glycidoxy)propyl]dimethylsilyloxy]-1,3,5,7,9,11, 14-heptylcyclopentyl tricyclo[7,3,3,15,11]heptasiloxane, 4,4' methylene bis(N,N-diglycidyl aniline), bis(halomethyl) Benzene, bis(halomethyl)biphenyl and bis(halomethyl)naphthalene, tolyl diisocyanate, acryloyl chloride, methyl acrylate, ethylene bisacrylamide, heat-resistant metal 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, tri[(2-epoxyethyl)methyl Radical] amines and combinations thereof.

Embodiment 1066. A pharmaceutical composition for use in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, wherein the preparation of the cross-linked amine polymer comprises free radical polymerization of an amine monomer, the amine monomer comprising at least An amine moiety or nitrogen-containing moiety.

Embodiment 1067. A pharmaceutical composition as used in a method of treating acid-base disorders according to any of the foregoing enumerated embodiments, wherein the cross-linked amine polymer has a balanced expansion ratio of about 1.5 or less in deionized water.

Embodiment 1068. A pharmaceutical composition as used in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, wherein the cross-linked amine polymer has an equilibrium expansion ratio of about 1 or less in deionized water.

Example 1069. A pharmaceutical composition as used in a method for treating an acid-base disorder according to any of the foregoing enumerated examples, which contains 36 mM NaCl, 20 mM NaH2PO4, and 50 mM buffered to pH 5.5 and at 37°C 2-(N-Morpholinyl)ethanesulfonic acid (MES) in an aqueous simulated small intestine inorganic buffer ("SIB"), the cross-linked amine polymers have at least 0.5:1 chloride ion and phosphate ion combined Moore ratio.

式4 其中各R獨立地為氫或交聯胺聚合物(

)之兩個氮原子之間的乙烯交聯，且a、b、c及m為整數。Embodiment 1070. A pharmaceutical composition for use in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, wherein the pharmaceutical composition comprises a structure corresponding to Formula 4:

Formula 4 where each R is independently hydrogen or a crosslinked amine polymer (

) Crosslinks ethylene between two nitrogen atoms, and a, b, c, and m are integers.

Embodiment 1071. A pharmaceutical composition as used in a method of treating an acid-base disorder according to embodiment 1070, where m is a larger integer indicating an extended polymer network.

Embodiment 1072. A pharmaceutical composition for use in a method of treating an acid-base disorder according to embodiment 1070 or embodiment 1071, wherein the ratio of the sum of a and b to c (ie, a+b:c) is about 1 : 1 to 5:1.

Embodiment 1073. A pharmaceutical composition for use in a method of treating an acid-base disorder according to any one of embodiments 1070 to 1072, wherein the ratio of the sum of a and b to c (ie a+b:c ) In the range of about 1.5:1 to 4:1.

Embodiment 1074. A pharmaceutical composition for use in a method of treating an acid-base disorder according to any one of embodiments 1070 to 1073, wherein the ratio of the sum of a and b to c (ie a+b:c ) In the range of about 1.75:1 to 3:1.

Embodiment 1075. The pharmaceutical composition as used in the method for treating the acid-base disorder according to any one of Embodiment 1070 to Embodiment 1074, wherein the ratio of the sum of a and b to c (ie a+b:c ) In the range of about 2:1 to 2.5:1.

Embodiment 1076. The pharmaceutical composition as used in the method for treating the acid-base disorder according to any one of embodiments 1070 to 1075, wherein the sum of a and b is 57 and c is 24.

Embodiment 1077. A pharmaceutical composition as used in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, wherein 50% to 95% of the R substituents are hydrogen and 5% to 50% are cross-linked amines Ethylene crosslinks between the two nitrogens of the polymer.

Embodiment 1078. A pharmaceutical composition as used in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, wherein 55% to 90% of the R substituents are hydrogen and 10% to 45% are cross-linked amines Ethylene crosslinks between the two nitrogens of the polymer.

Embodiment 1079. A pharmaceutical composition as used in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, wherein 60% to 90% of the R substituents are hydrogen and 10% to 40% are cross-linked amines Ethylene crosslinks between the two nitrogens of the polymer.

Embodiment 1080. A pharmaceutical composition as used in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, wherein 65% to 90% of the R substituents are hydrogen and 10% to 35% are cross-linked amines Ethylene crosslinks between the two nitrogens of the polymer.

Embodiment 1081. A pharmaceutical composition for use in a method of treating an acid-base disorder according to any one of embodiments 1070 to 1082, wherein the R substituent is hydrogen and 10% to 30% is a cross-linked amine polymerization Ethylene crosslinks between two nitrogens.

Embodiment 1082. A pharmaceutical composition for use in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, wherein the composition is the polymer of any one of embodiments 768 to 774, wherein the R substituent Among them, 75% to 85% are hydrogen and 15% to 25% are ethylene crosslinks between two nitrogens of the crosslinked amine polymer.

Embodiment 1083. A pharmaceutical composition for use in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, wherein the R substituent is hydrogen and 15% to 20% of the two nitrogens of the crosslinked amine polymer Cross-linking of ethylene.

Embodiment 1084. A pharmaceutical composition as used in a method of treating an acid-base disorder according to any of the foregoing enumerated embodiments, wherein the R substituent is hydrogen and about 19% is ethylene cross-linked.

Embodiment 1085. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 1 mEq/g in SIB analysis.

Embodiment 1086. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 1.5 mEq/g in SIB analysis.

Embodiment 1087. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 2 mEq/g in SIB analysis.

Embodiment 1088. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 2.5 mEq/g in SIB analysis.

Embodiment 1089. A pharmaceutical composition as used in the method of treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in SIB analysis.

Embodiment 1090. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 3.5 mEq/g in SIB analysis.

Embodiment 1091. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 4 mEq/g in SIB analysis.

Embodiment 1092. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 4.5 mEq/g in SIB analysis.

Embodiment 1093. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 5 mEq/g in SIB analysis.

Embodiment 1094. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 5.5 mEq/g in SIB analysis.

Embodiment 1095. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 6 mEq/g in SIB analysis.

Embodiment 1096. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate group in the SIB At least 0.1:1 in the analysis.

Embodiment 1097. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized in that the ratio of the amount of bound chloride ion to the bound phosphate is in the SIB At least 0.2:1 in the analysis.

Embodiment 1098. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized in that the ratio of the amount of bound chloride ion to bound phosphate is in the SIB At least 0.25:1 in the analysis.

Embodiment 1099. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate group in the SIB At least 0.3:1 in the analysis.

Embodiment 1100. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate group in the SIB At least 0.35:1 in the analysis.

Embodiment 1101. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate group in the SIB In the analysis, they were at least 0.4:1.

Embodiment 1102. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate group in the SIB At least 0.45:1 in the analysis.

Embodiment 1103. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized in that the ratio of the amount of bound chloride ion to bound phosphate is in the SIB At least 0.5:1 in the analysis.

Embodiment 1104. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized in that the ratio of the amount of bound chloride ion to bound phosphate is in the SIB At least 2:3 in the analysis.

Embodiment 1105. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized in that the ratio of the amount of bound chloride ion to bound phosphate is in the SIB At least 0.75:1 in the analysis.

Embodiment 1106. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate group in the SIB In the analysis, they were at least 0.9:1.

Embodiment 1107. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the aforementioned enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate group in the SIB At least 1:1 in the analysis.

Embodiment 1108. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized in that the ratio of the amount of bound chloride ion to bound phosphate is in the SIB At least 1.25:1 in the analysis.

Embodiment 1109. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate group in the SIB At least 1.5:1 in the analysis.

Embodiment 1110. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized in that the ratio of the amount of bound chloride ion to the bound phosphate is in the SIB At least 1.75:1 in the analysis.

Embodiment 1111. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized in that the ratio of the amount of bound chloride ion to bound phosphate is in the SIB At least 2:1 in the analysis.

Embodiment 1112. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized in that the ratio of the amount of bound chloride ion to bound phosphate is in the SIB At least 2.25:1 in the analysis.

Embodiment 1113. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized in that the ratio of the amount of bound chloride ion to bound phosphate is in the SIB At least 2.5:1 in the analysis.

Embodiment 1114. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized in that the ratio of the amount of bound chloride ion to the bound phosphate is in the SIB At least 2.75:1 in the analysis.

Embodiment 1115. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized in that the ratio of the amount of bound chloride ion to the bound phosphate is in the SIB At least 3:1 in the analysis.

Embodiment 1116. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate group in the SIB At least 4:1 in the analysis.

Example 1117. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the binding force of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate group in the SIB At least 5:1 in the analysis.

Embodiment 1118. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized in that the ratio of the amount of bound chloride ion to bound phosphate is in the SIB At least 6:1 in the analysis.

Embodiment 1119. A pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate group in the SIB At least 7:1 in the analysis.

Embodiment 1120. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the aforementioned enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate group in the SIB At least 8:1 in the analysis.

Example 1121. A pharmaceutical composition for use in the method of treating any acid-base disorder of the foregoing enumerated examples, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to the bound phosphate group in the SIB At least 9:1 in the analysis.

Embodiment 1122. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized in that the ratio of the amount of bound chloride ion to bound phosphate is in the SIB At least 10:1 in the analysis.

Embodiment 1123. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized in that the ratio of the amount of bound chloride ion to the bound phosphate is in the SIB At least 12.5:1 in the analysis.

Embodiment 1124. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the binding power of the pharmaceutical composition is characterized by the ratio of the amount of bound chloride ion to bound phosphate group in the SIB At least 15:1 in the analysis.

Example 1125. A pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated examples, in which an aqueous simulated gastric buffer containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37°C ( "SGF"), the pharmaceutical composition has a balanced chloride ion binding capacity of at least 5 mmol/g.

Example 1126. A pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein an aqueous simulated gastric fluid buffer containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37°C ( "SGF"), the pharmaceutical composition has a balanced chloride ion binding capacity of at least 7.5 mmol/g.

Example 1127. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein an aqueous simulated gastric juice buffer containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37°C ( "SGF"), the pharmaceutical composition has a balanced chloride ion binding capacity of at least 10 mmol/g.

Embodiment 1128. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the acid-base disorder is metabolic acidosis.

Embodiment 1129. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient suffers from chronic kidney disease.

Embodiment 1130. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition comprises a polymer as defined at any location in the description.

Example 1131. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than about 21 mEq/l.

Example 1132. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than about 20 mEq/l.

Example 1133. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than about 19 mEq/l.

Embodiment 1134. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than about 18 mEq/l.

Embodiment 1135. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than about 17 mEq/l.

Embodiment 1136. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than about 16 mEq/l.

Embodiment 1137. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than about 15 mEq/l.

Embodiment 1138. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than about 14 mEq/l.

Embodiment 1139. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than about 13 mEq/l.

Embodiment 1140. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than about 12 mEq/l.

Embodiment 1141. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than about 11 mEq/l.

Embodiment 1142. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than about 10 mEq/l.

Embodiment 1143. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least about 10 mEq/l.

Embodiment 1144. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least about 11 mEq/l.

Embodiment 1145. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least about 12 mEq/l.

Embodiment 1146. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least about 13 mEq/l.

Embodiment 1147. The pharmaceutical composition as used in the method of treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least about 14 mEq/l.

Embodiment 1148. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least about 15 mEq/l.

Embodiment 1149. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least about 16 mEq/l.

Embodiment 1150. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least about 17 mEq/l.

Embodiment 1151. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least about 18 mEq/l.

Embodiment 1152. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least about 19 mEq/l.

Embodiment 1153. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least about 20 mEq/l.

Embodiment 1154. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least about 21 mEq/l.

Embodiment 1155. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the serum bicarbonate value from a baseline serum bicarbonate value to at least about 22 mEg/l Increased serum bicarbonate value.

Embodiment 1156. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the serum bicarbonate value from a baseline serum bicarbonate value to at least about 23 mEg/l Increased serum bicarbonate value.

Example 1157. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the method increases the serum bicarbonate value from a baseline serum bicarbonate value to at least about 24 mEg/l Increased serum bicarbonate value.

Embodiment 1158. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the serum bicarbonate value from a baseline serum bicarbonate value to at least about 25 mEg/l Increased serum bicarbonate value.

Embodiment 1159. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the serum bicarbonate value from a baseline serum bicarbonate value to at least about 26 mEg/l Increased serum bicarbonate value.

Embodiment 1160. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the serum bicarbonate value from a baseline serum bicarbonate value to at least about 27 mEg/l Increased serum bicarbonate value.

Embodiment 1161. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the serum bicarbonate value from a baseline serum bicarbonate value to at least about 28 mEg/l Increased serum bicarbonate value.

Embodiment 1162. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the serum bicarbonate value from the baseline serum bicarbonate value to no more than about 29 mEg/ l Increased serum bicarbonate value.

Embodiment 1163. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the serum bicarbonate value from the baseline serum bicarbonate value to no more than about 28 mEg/ l Increased serum bicarbonate value.

Embodiment 1164. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the serum bicarbonate value from the baseline serum bicarbonate value to no more than about 27 mEg/ l Increased serum bicarbonate value.

Embodiment 1165. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the serum bicarbonate value from the baseline serum bicarbonate value to no more than about 26 mEg/ l Increased serum bicarbonate value.

Example 1166. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the method increases the serum bicarbonate value from the baseline serum bicarbonate value to no more than about 25 mEg/ l Increased serum bicarbonate value.

Embodiment 1167. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the serum bicarbonate value from the baseline serum bicarbonate value to no more than about 24 mEg/ l Increased serum bicarbonate value.

Embodiment 1168. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the serum bicarbonate value from the baseline serum bicarbonate value to no more than about 23 mEg/ l Increased serum bicarbonate value.

Embodiment 1169. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method maintains the patient's serum bicarbonate in the range of 22 mEq/l to 29 mEq/l .

Embodiment 1170. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method maintains the patient's serum bicarbonate within the range of 22 mEq/l to 28 mEq/l .

Embodiment 1171. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method maintains the patient's serum bicarbonate in the range of 22 mEq/l to 27 mEq/l .

Embodiment 1172. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method maintains the patient's serum bicarbonate in the range of 22 mEq/l to 26 mEq/l .

Embodiment 1173. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method maintains the patient's serum bicarbonate in the range of 22 mEq/l to 25 mEq/l .

Embodiment 1174. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method maintains the patient's serum bicarbonate in the range of 22 mEq/l to 24 mEq/l .

Embodiment 1175. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method maintains the patient's serum bicarbonate in the range of 22 mEq/l to 23 mEq/l .

Embodiment 1176. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value relative to the patient's baseline serum bicarbonate value by at least about 1 mEq/l.

Embodiment 1177. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value relative to the patient's baseline serum bicarbonate value by at least about 1.5 mEq/l.

Embodiment 1178. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value relative to the patient's baseline serum bicarbonate value by at least about 2 mEq/l.

Embodiment 1179. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value relative to the patient's baseline serum bicarbonate value by at least about 2.5 mEq/l.

Embodiment 1180. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value relative to the patient's baseline serum bicarbonate value by at least about 3 mEq/l.

Embodiment 1181. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value relative to the patient's baseline serum bicarbonate value by at least about 3.5 mEq/l.

Embodiment 1182. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value relative to the patient's baseline serum bicarbonate value by at least about 4 mEq/l.

Embodiment 1183. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value relative to the patient's baseline serum bicarbonate value by at least about 4.5 mEq/l.

Embodiment 1184. A pharmaceutical composition for use in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value by at least about 5 relative to the patient's baseline serum bicarbonate value mEq/l.

Embodiment 1185. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value relative to the patient's baseline serum bicarbonate value by at least about 5.5 mEq/l.

Embodiment 1186. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value relative to the patient's baseline serum bicarbonate value by at least about 6 mEq/l.

Embodiment 1187. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value relative to the patient's baseline serum bicarbonate value by at least about 6.5 mEq/l.

Embodiment 1188. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value relative to the patient's baseline serum bicarbonate value by at least about 7 mEq/l.

Embodiment 1189. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value relative to the patient's baseline serum bicarbonate value by at least about 7.5 mEq/l.

Embodiment 1190. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value relative to the patient's baseline serum bicarbonate value by at least about 8 mEq/l.

Embodiment 1191. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value relative to the patient's baseline serum bicarbonate value by at least about 8.5 mEq/l.

Embodiment 1192. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the method increases the patient's serum bicarbonate value relative to the patient's baseline serum bicarbonate value by at least about 9 mEq/l.

Embodiment 1193. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of at least about one week.

Embodiment 1194. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of about one week.

Embodiment 1195. The pharmaceutical composition as used in the method of treating any of the foregoing acid-base disorders of the enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of at least about two weeks.

Example 1196. The pharmaceutical composition as used in the method of treating any of the foregoing acid-base disorders of the enumerated examples, wherein the patient's increased serum bicarbonate value is maintained for a period of about two weeks.

Embodiment 1197. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of at least about three weeks.

Embodiment 1198. The pharmaceutical composition as used in the method of treating any of the foregoing acid-base disorders of the enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of about three weeks.

Embodiment 1199. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of at least about four weeks.

Embodiment 1200. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of about four weeks.

Embodiment 1201. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of at least about five weeks.

Embodiment 1202. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of about five weeks.

Embodiment 1203. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of at least about six weeks.

Embodiment 1204. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of about six weeks.

Embodiment 1205. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of at least about seven weeks.

Embodiment 1206. The pharmaceutical composition as used in the method of treating any of the foregoing acid-base disorders of the enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of about seven weeks.

Embodiment 1207. The pharmaceutical composition as used in the method of treating any acid-base disorder of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of at least about eight weeks.

Embodiment 1208. The pharmaceutical composition as used in the method of treating any acid-base disorder of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of about eight weeks.

Embodiment 1209. The pharmaceutical composition as used in the method of treating any of the foregoing acid-base disorders of the enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of at least about nine weeks.

Embodiment 1210. The pharmaceutical composition as used in the method of treating any acid-base disorder of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of about nine weeks.

Embodiment 1211. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of at least about ten weeks.

Embodiment 1212. The pharmaceutical composition as used in the method of treating any acid-base disorder of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of about ten weeks.

Embodiment 1213. The pharmaceutical composition as used in the method of treating any acid-base disorder of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of at least about 11 weeks.

Embodiment 1214. The pharmaceutical composition as used in the method of treating any acid-base disorder of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of about 11 weeks.

Embodiment 1215. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of at least about 12 weeks.

Embodiment 1216. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of about 12 weeks.

Embodiment 1217. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of at least about 13 weeks.

Embodiment 1218. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of about 13 weeks.

Embodiment 1219. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for at least about 14 weeks, 15 weeks, 16 weeks, 17 Weekly, 18-week, 19-week, or 20-week cycles.

Embodiment 1220. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for about 14 weeks, 15 weeks, 16 weeks, and 17 weeks , 18 weeks, 19 weeks or 20 weeks.

Example 1221. A pharmaceutical composition as used in the method of treating any acid-base disorder of the foregoing enumerated examples, wherein the patient's increased serum bicarbonate value is maintained for a period of at least about six months.

Embodiment 1222. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's increased serum bicarbonate value is maintained for a period of about six months.

Embodiment 1223. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of active ingredient of the pharmaceutical composition is about 1 g/day.

Embodiment 1224. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 1.5 g/day.

Embodiment 1225. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 2 g/day.

Embodiment 1226. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 2.5 g/day.

Embodiment 1227. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 3 g/day.

Embodiment 1228. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 3.5 g/day.

Embodiment 1229. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 4 g/day.

Embodiment 1230. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 4.5 g/day.

Embodiment 1231. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of active ingredient of the pharmaceutical composition is about 5 g/day.

Embodiment 1232. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 5.5 g/day.

Embodiment 1233. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 6 g/day.

Embodiment 1234. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 6.5 g/day.

Embodiment 1235. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 7 g/day.

Embodiment 1236. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of active ingredient of the pharmaceutical composition is about 7.5 g/day.

Embodiment 1237. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 8 g/day.

Embodiment 1238. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 8.5 g/day.

Embodiment 1239. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 9 g/day.

Embodiment 1240. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of active ingredient of the pharmaceutical composition is about 9.5 g/day.

Embodiment 1241. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 10 g/day.

Embodiment 1242. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 15 g/day.

Embodiment 1243. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 20 g/day.

Embodiment 1244. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the amount of the active ingredient of the pharmaceutical composition is about 25 g/day.

Embodiment 1245. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the pharmaceutical composition is administered to the patient in an oral dosage form once a day.

Embodiment 1246. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the active ingredient is a composition as defined in any of the numbered embodiments in the description.

Example 1247. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the quality of life of the patient improves after a period of treatment of at least about one week.

Embodiment 1248. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of about one week of treatment.

Embodiment 1249. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of treatment of at least about two weeks.

Embodiment 1250. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the aforementioned enumerated embodiments, wherein the quality of life of the patient improves after a period of about two weeks of treatment.

Embodiment 1251. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of treatment of at least about three weeks.

Embodiment 1252. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of about three weeks of treatment.

Embodiment 1253. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of treatment of at least about four weeks.

Embodiment 1254. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of about four weeks of treatment.

Embodiment 1255. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of treatment of at least about five weeks.

Embodiment 1256. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of about five weeks of treatment.

Embodiment 1257. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of treatment of at least about six weeks.

Embodiment 1258. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of about six weeks of treatment.

Embodiment 1259. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of treatment of at least about seven weeks.

Embodiment 1260. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of about seven weeks of treatment.

Embodiment 1261. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of treatment of at least about eight weeks.

Embodiment 1262. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of about eight weeks of treatment.

Embodiment 1263. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of treatment of at least about nine weeks.

Embodiment 1264. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's quality of life improves after a period of about nine weeks of treatment.

Embodiment 1265. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of treatment of at least about ten weeks.

Example 1266. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the patient's quality of life improves after a period of about ten weeks of treatment.

Embodiment 1267. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of at least about 11 weeks of treatment.

Embodiment 1268. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of about 11 weeks of treatment.

Embodiment 1269. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of treatment of at least about 52 weeks. In other aspects of this embodiment, the patient's quality of life improves after a period of treatment of at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks.

Embodiment 1270. The pharmaceutical composition as used in the method of treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of approximately 52 weeks of treatment. In other aspects of this embodiment, the patient's quality of life improves after a period of treatment of at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks.

Embodiment 1271. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of at least about 13 weeks of treatment.

Embodiment 1272. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of about 13 weeks of treatment.

Embodiment 1273. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the aforementioned enumerated embodiments, wherein the quality of life of the patient is at least about 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, Improve after 19 or 20 weeks.

Embodiment 1274. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient is treated for about 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 Improve after a weekly or 20-week cycle.

Embodiment 1275. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the quality of life of the patient improves after a period of treatment of at least about six months.

Example 1276. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the quality of life of the patient improves after a period of about six months of treatment.

Embodiment 1277. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of treatment of at least about one week.

Embodiment 1278. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of about one week of treatment.

Embodiment 1279. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of at least about two weeks of treatment.

Embodiment 1280. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of about two weeks of treatment.

Embodiment 1281. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of about at least three weeks of treatment.

Embodiment 1282. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of about three weeks of treatment.

Embodiment 1283. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of treatment of at least about four weeks.

Embodiment 1284. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of about four weeks of treatment.

Embodiment 1285. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of treatment of at least about five weeks.

Embodiment 1286. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of about five weeks of treatment.

Embodiment 1287. The pharmaceutical composition as used in the method of treating any acid-base disorder of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of at least about six weeks of treatment.

Embodiment 1289. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of about six weeks of treatment.

Embodiment 1290. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of treatment of at least about seven weeks.

Embodiment 1291. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of about seven weeks of treatment.

Embodiment 1292. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of treatment of at least about eight weeks.

Embodiment 1293. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of about eight weeks of treatment.

Embodiment 1294. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of treatment of at least about nine weeks.

Embodiment 1295. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of about nine weeks of treatment.

Embodiment 1296. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of treatment of at least about ten weeks.

Embodiment 1297. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of about ten weeks of treatment.

Embodiment 1298. The pharmaceutical composition as used in the method of treating any acid-base disorder of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of treatment of at least about 11 weeks.

Embodiment 1299. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of about 11 weeks of treatment.

Embodiment 1300. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of at least about 52 weeks of treatment. In other aspects of this embodiment, the patient's quality of life improves after a period of treatment of at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks.

Embodiment 1301. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of about 52 weeks of treatment. In other aspects of this embodiment, the patient's quality of life improves after a period of treatment of at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks.

Embodiment 1302. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of at least about 13 weeks of treatment.

Embodiment 1303. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of about 13 weeks of treatment.

Embodiment 1304. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's body function is treated for at least about 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, Improve after 19 or 20 weeks.

Embodiment 1305. A pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's body function is treated for approximately 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 Improve after a weekly or 20-week cycle.

Embodiment 1306. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of treatment of at least about six months.

Embodiment 1307. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the patient's physical function improves after a period of about six months of treatment.

Embodiment 1308. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the patient's quality of life can be determined by the quality of life questionnaire.

Example 1309. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the improvement in the patient's quality of life can be compared by comparing the scores of the quality of life questionnaire obtained before and after treatment determine.

Example 1310. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the aforementioned enumerated examples, wherein the improvement in the patient's quality of life can be determined by a kidney disease quality of life (KDQOL) physical function assessment.

Example 1311. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the improvement of the patient's physical function can be achieved by according to Goldfarb DS et al., Kidney International (2009) 75, 15 Kidney disease quality of life (KDQOL) physical function assessment to 24 was determined.

Example 1312. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the aforementioned enumerated examples, wherein the improvement of the patient's physical function can be solved by a problem based on the quality of life for kidney disease (KDQOL SF) The answer to 3 is determined by the increase in the patient's physical function score compared to the patient's baseline physical function score.

Embodiment 1313. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement of the patient's physical function can be determined by the improvement of the patient's ability to perform vigorous activity, the violent activity For example, one or more of running, lifting heavy objects, or participating in strenuous sports.

Embodiment 1314. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement of the patient's physical function can be determined by the improvement of the patient's ability to perform gentle activities, the mild activity For example, one or more of moving a table, pushing a vacuum cleaner, bowling or playing golf.

Embodiment 1315. A pharmaceutical composition for use in the method of treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement of the patient's physical function can be determined by the improvement of the patient's ability to lift or carry groceries, Examples of such groceries are 1 kg, 2 kg, 3 kg, 4 kg or 5 kg groceries.

Embodiment 1316. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the aforementioned enumerated embodiments, wherein the improvement of the patient's physical function can be improved by the patient's ability to climb several stairs, such as 100 steps to make sure.

Embodiment 1317. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement of the patient's physical function can be achieved by the improvement of the patient's ability to climb, for example, 20 steps determine.

Embodiment 1318. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement of the patient's physical function can be determined by the improvement of the patient's ability to bend, kneel, or bend over.

Embodiment 1319. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the patient's physical function can be determined by the improvement in the patient's ability to walk more than a mile.

Embodiment 1320. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the patient's physical function can be determined by the improvement in the patient's ability to walk, for example, a block of 500 feet .

Example 1321. A pharmaceutical composition as used in a method for treating the acid-base disorders of any of the foregoing enumerated examples, wherein the improvement of the patient's physical function can be determined by the improvement of the patient's ability to walk several blocks, such as 2000 feet .

Embodiment 1322. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement of the patient's physical function can be determined by the improvement of the patient's ability to bathe or dress independently.

Embodiment 1323. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer of 3 improves the patient's physical function score by at least about 1.

Example 1324. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer to 3 is that the patient's physical function score improves by at least about 1.5.

Example 1325. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer to 3 is that the patient's physical function score improves by at least about 2.

Example 1326. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer to 3 is that the patient's physical function score improves by at least about 2.5.

Example 1327. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer to 3 is that the patient's physical function score improves by at least about 3.

Example 1328. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer to 3 is that the patient's physical function score improves by at least about 3.5.

Example 1329. A pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer of 3 improves the patient's physical function score by at least about 4.

Example 1330. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer to 3 is that the patient's physical function score improves by at least about 4.5.

Example 1331. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer of 3 improves the patient's physical function score by at least about 5.

Example 1332. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer to 3 is that the patient's physical function score improves by at least about 5.5.

Example 1333. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the aforementioned enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer of 3 improves the patient's physical function score by at least about 6.

Example 1334. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) In response to 3, the patient's physical function score improved by at least about 6.5.

Example 1335. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer of 3 improves the patient's physical function score by at least about 7.

Example 1336. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the aforementioned enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) In response to 3, the patient's physical function score improved by at least about 7.5.

Example 1337. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the aforementioned enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer of 3 improves the patient's physical function score by at least about 8.

Example 1338. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the aforementioned enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) In answer to 3, the patient's physical function score improved by at least about 8.5.

Example 1339. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the aforementioned enumerated examples, wherein the baseline physical function score relative to the patient is based on the question of the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer of 3 improves the patient's physical function score by at least about 9.

Example 1340. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the aforementioned enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer of 3 improves the patient's physical function score by at least about 10.

Embodiment 1341. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the aforementioned enumerated embodiments, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer to 3 is that the patient's physical function score improves by at least about 11.

Embodiment 1342. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) In response to 3, the patient's physical function score improved by at least about 12.

Embodiment 1343. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer to 3 is that the patient's physical function score improves by at least about 13.

Example 1344. A pharmaceutical composition as used in the method of treating any of the foregoing enumerated examples of acid-base disorders, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) In response to 3, the patient's physical function score improved by at least about 14.

Example 1345. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) The answer to 3 is that the patient's physical function score improves by at least about 15.

Example 1346. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the aforementioned enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) In response to 3, the patient's physical function score improved by at least about 20.

Example 1347. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) In response to 3, the patient's physical function score improved by at least about 25.

Example 1348. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the baseline physical function score relative to the patient is based on a question about the Kidney Disease Quality of Life Short Form (KDQOL SF) In response to 3, the patient's physical function score improved by at least about 30.

Embodiment 1349. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the patient's physical function score is achieved at the end of the time period stated in any of the foregoing enumerated embodiments .

Embodiment 1350. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the patient's physical function can be determined by repeated sit-and-stand tests.

Embodiment 1351. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the patient's physical function is determined by repeating a sit-and-stand test, in which the patient completes 5 chair sit-downs The time to repetition of standing improved by at least about 1 second relative to the baseline. In one aspect of this embodiment and other embodiments, after a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks of treatment, an improvement in the patient's baseline repeated sitting time is seen . In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients.

Embodiment 1352. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the patient's physical function is determined by repeating a sit-and-stand test, in which the patient completes 5 chair sittings The time until the repetition of standing improved by at least about 1.1 seconds relative to the baseline. In one aspect of this embodiment and other embodiments, after a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks of treatment, an improvement in the patient's baseline repeated sitting time is seen . In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients.

Embodiment 1353. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the patient's physical function is determined by repeating a sit-and-stand test, in which the patient completes 5 chair sit-downs The time until the repetition of standing improved by at least about 1.2 seconds relative to the baseline. In one aspect of this embodiment and other embodiments, after a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks of treatment, an improvement in the patient's baseline repeated sitting time is seen . In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients.

Embodiment 1354. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the patient's physical function is determined by repeating a sit-and-stand test, in which the patient completes 5 chair seats The time until the repetition of standing improved by at least about 1.3 seconds relative to the baseline. In one aspect of this embodiment and other embodiments, after a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks of treatment, an improvement in the patient's baseline repeated sitting time is seen . In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients.

Embodiment 1355. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the patient's physical function is determined by repeating a sit-and-stand test, in which the patient completes 5 chair sit-downs The time until the repetition of standing improved by at least about 1.4 seconds relative to the baseline. In one aspect of this embodiment and other embodiments, after a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks of treatment, an improvement in the patient's baseline repeated sitting time is seen . In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients.

Embodiment 1356. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the patient's physical function is determined by repeating the sit-and-stand test, in which the patient completes 5 chair sit-downs The time until the repetition of standing improved by at least about 1.5 seconds relative to the baseline. In one aspect of this embodiment and other embodiments, after a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks of treatment, an improvement in the patient's baseline repeated sitting time is seen . In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients.

Embodiment 1357. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement of the patient's physical function is determined by repeating the sit-and-stand test, in which the patient completes 5 chair sit-downs The time until the repetition of standing improved by at least about 1.6 seconds relative to the baseline. In one aspect of this embodiment and other embodiments, after a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks of treatment, an improvement in the patient's baseline repeated sitting time is seen . In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients.

Example 1358. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the improvement of the patient's physical function is determined by repeating a sit-and-stand test, in which the patient completes 5 chair sittings The time until the repetition of standing improved by at least about 1.7 seconds relative to the baseline. In one aspect of this embodiment and other embodiments, after a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks of treatment, an improvement in the patient's baseline repeated sitting time is seen . In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients.

Example 1359. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated examples, wherein the improvement in the patient's physical function is determined by repeating a sit-and-stand test, in which the patient completes 5 chair sit-downs The time until the repetition of standing improved by at least about 1.8 seconds relative to the baseline. In one aspect of this embodiment and other embodiments, after a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks of treatment, an improvement in the patient's baseline repeated sitting time is seen . In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients.

Embodiment 1360. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the patient's physical function is determined by repeating a sit-and-stand test, in which the patient completes 5 chair seats The time until the repetition of standing improved by at least about 1.9 seconds relative to the baseline. In one aspect of this embodiment and other embodiments, after a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks of treatment, an improvement in the patient's baseline repeated sitting time is seen . In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients.

Embodiment 1361. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the patient's physical function is determined by repeating a sit-and-stand test, in which the patient completes 5 chair sit-downs The time until the repetition of standing improved by at least about 2 seconds relative to the baseline. In one aspect of this embodiment and other embodiments, after a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks of treatment, an improvement in the patient's baseline repeated sitting time is seen . In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients.

Embodiment 1362. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the patient's physical function is determined by repeating the sit-and-stand test, in which the patient completes 5 chair sit-downs The time until the repetition of standing improved by at least about 3 seconds relative to the baseline. In one aspect of this embodiment and other embodiments, after a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks of treatment, an improvement in the patient's baseline repeated sitting time is seen . In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients.

Embodiment 1363. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the patient's physical function is determined by repeating a sit-and-stand test, in which the patient completes 5 chair sit-downs The time until the repetition of standing improved by at least about 4 seconds relative to the baseline. In one aspect of this embodiment and other embodiments, after a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks of treatment, an improvement in the patient's baseline repeated sitting time is seen . In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients.

Embodiment 1364. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the patient's physical function is determined by repeating the sit-and-stand test, in which the patient completes 5 chair sit-downs The time until the repetition of standing improved by at least about 5 seconds relative to the baseline. In one aspect of this embodiment and other embodiments, after a period of at least about 52 weeks, at least about 40 weeks, at least about 26 weeks, or at least about 12 weeks of treatment, an improvement in the patient's baseline repeated sitting time is seen . In another aspect of this embodiment and other embodiments, in the repeated sit-and-stand test, after about twelve weeks of treatment, there is a trend toward a significant difference between treated and placebo-treated patients.

Embodiment 1365. The pharmaceutical composition as used in the method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein the improvement in the time taken for the patient to complete 5 times of chair sitting to standing and repeating the collection is implemented in any of the foregoing enumerations Reached at the end of the time period stated in the example.

Embodiment 1366. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein in the treatment method, the quality of life of the patient is by one of the routes stated in the technical solution or Multiple to determine.

Embodiment 1367. A pharmaceutical composition as used in a method for treating the acid-base disorder of any of the foregoing enumerated embodiments, wherein in the treatment method, the patient's physical function is by one of the routes stated in the technical solution or Multiple to determine.

Having described the present invention in detail, it will be apparent that modifications and variations are possible without departing from the scope of the present invention defined in the scope of the accompanying patent application. Indeed, as part of the present invention, each enumerated embodiment is expected to be combined with one or more other enumerated embodiments in any chemical and/or clinically relevant manner. In addition, it should be understood that all examples in this disclosure are provided as non-limiting examples. Exemplary synthetic routes for the preparation of example for the treatment of acid-base imbalance embodiment of the polymer without absorption (reproduced from WO2016 / 094685A1) Exemplary Synthesis A

Step 1: Two aqueous stock solutions (50% w/w) of monomers were prepared by dissolving 43.83 g allylamine hydrochloride and 45.60 g diallyl propylene diamine ("DAPDA") in water, respectively. A 3-neck 2L round bottom flask with a four-side baffle equipped with an overhead stirrer (stirring at 180 rpm), a Dean-Stark apparatus and condenser, and a nitrogen inlet were charged with heptane/chlorobenzene dissolved in 1,200 g 12 g of surfactant (Stepan Sulfonic 100) in the solution (26/74 v/v), followed by an aqueous stock solution and an additional portion of water (59.14 g). In a separate container, prepare a 15 wt% solution of 2,2'-azobis(2-methylpropionamidine)-dihydrochloride ("V-50") (9.08 g) in water. When the reaction vessel was brought to 67°C in an oil bath, the two mixtures were respectively aerated with nitrogen (approximately 30 min). Under an inert atmosphere, the starter solution was added to the reaction mixture, and then heated at 67°C for 16 hours. The second aliquot of the starter solution (equal to the first aliquot) and the reaction mixture were aerated with nitrogen for 30 minutes, and were combined for the final dehydration step (Dean-Stark) before increasing the temperature to 115°C ). The reaction was kept at 115°C until the collection of water in the Dean-Stark trap was stopped (6 h, 235 mL was removed, total water >90%, T _internal >99°C). The reaction was cooled to room temperature, and stirring was stopped to allow the beads to settle. The organic phase was removed from the bead filter cake by decantation. The beads were purified by washing (MeOH twice, H ₂ O once, 1N HCl twice, H ₂ O once, 1N NaOH three times, and then H ₂ O until the pH of the solution was 7 after washing) and Dry it by lyophilization.

*來自預成多胺珠粒之4個批次的平均資料例示性合成 B 至 例示性合成 E Step 2: Add the dried preformed amine polymer beads (15.00 g) prepared according to Step 1 to a 250 mL round bottom flask equipped with a stirring blade and nitrogen inlet. 1,2-Dichloroethane (DCE) (90 mL was added to the beads to obtain a 1:6 ratio of beads to DCE (g/mL)). Mechanical agitation (about 150 rpm stirring) was used to disperse the beads in the DCE. Water (3.75 mL, resulting in a water-to-bead mass ratio of 0.25:1) was directly added to the dispersion, and stirring was continued for 30 minutes. After 30 minutes, the flask was submerged into an oil bath maintained at 70°C. The reaction was kept in an oil bath and stirred for 16 hours under a nitrogen atmosphere using mechanical stirring. Methanol (100 ml) was added to the reaction and the solvent was removed by decantation. The beads were then filtered and then washed by (MeOH twice, H ₂ O once, 1N HCl twice, H ₂ O once, 1N NaOH three times, and then H ₂ O until the pH of the solution was 7 after washing So far) to purify it. The purified beads were then dried by lyophilization for 48 hours. The swelling ratio, particle size, chloride ion binding force in SGF, and chloride ion binding force (SIB-Cl) and phosphate binding force (SIB-P) in SIB are shown in Table S-1. Table S-1

*Average data from 4 batches of preformed polyamine beads Exemplary Synthesis B to Exemplary Synthesis E

Step 1 Exemplary Synthesis B: To a 500 mL round bottom flask was added polyallylamine (14 g, 15 kDa) and water (28 mL). The solution was purged with nitrogen and stirred overhead at 220 rpm for 1 hour to completely dissolve the polymer. Subsequently, 30 wt% aqueous NaOH (7 mL) was added and stirred for 5 minutes. A pre-made solution of DCE (175 mL), n-heptane (105 mL) and Span 80 (2.8 g) was added to the aqueous solution. The solution was heated to 70°C and stirred for 16 hours. The Dean-Stark step was started by adding cyclohexane (100 ml) and heating the reaction to 95 °C to remove water (>90%) from the beads. The expansion ratio, chloride ion binding force in SGF, chloride ion binding force (SIB-Cl) and phosphate binding force (SIB-P) in SIB are shown in Table S-2 (item 018013) In A1 FA and item 015026-A1 FA), the SGF, SIB-Cl and SIB-P values are expressed in mmol/g dry beads.

Step 1 Exemplary Synthesis C: To a 100 mL round bottom flask, add DCP (31 mL), n-heptane (19 mL), and Span 80 (0.5 g). Prepare separated aqueous stock solution of polyallylamine (2.3 g, 900 kDa), aqueous NaOH solution (1 mL, 30 wt%) and water (4 mL). Add the aqueous stock solution to the organic solution in the round bottom flask. The solution was purged with nitrogen for 15 minutes, heated to 70°C and stirred for 16 hours. Methanol (30 mL) was added to the reaction mixture and the organic solvent was removed by decantation. The resulting beads were purified and isolated by washing the beads with MeOH, HCl, aqueous sodium hydroxide, and water. The lyophilization technique is used to dry the beads. The expansion ratio, chloride ion binding force in SGF, chloride ion binding force (SIB-Cl) and phosphate binding force (SIB-P) in SIB are shown in Table S-2 (018001-A2b In FA), the SGF, SIB-Cl and SIB-P values are expressed in mmol/g dry beads.

Step 1 Exemplary synthesis D: Polyallylamine 15 kDa (3.0 g) and water (9.05 g) were dissolved in a conical flask. Sodium hydroxide (0.71 g) was added to the solution and the mixture was stirred for 30 minutes. To a 100 mL round bottom flask equipped with a side arm and an overhead stirrer, add 0.38 g of sorbitan sesquioleate and 37.9 g of toluene. The overhead stirrer was turned on to provide agitation to the reaction solution. Dichloropropanol (0.41 g) was added directly to the polyallylamine solution while stirring. The resulting aqueous polyallylamine solution was added to the toluene solution in the 100 mL flask. The reaction was heated to 50°C for 16 hours. Thereafter, the reaction was heated to 80°C for 1 hour and then cooled to room temperature. The resulting beads were purified and isolated by washing the beads with MeOH, HCl, aqueous sodium hydroxide, and water. The lyophilization technique is used to dry the beads. The expansion ratio, chloride ion binding force in SGF, chloride ion binding force (SIB-Cl) and phosphate binding force (SIB-P) in SIB are shown in Table S-2 (item 002054- In A3 FA and items 011021-A6 FA), the SGF, SIB-Cl and SIB-P values are expressed in mmol/g dry beads.

Step 1 Exemplary synthesis E: Polyallylamine 15 kDa (3.1 g) and water (9.35 g) were dissolved in a conical flask. Sodium hydroxide (0.73 g) was added to the solution and the mixture was stirred for 30 minutes. To a 100 mL round bottom flask equipped with a side arm and an overhead stirrer, 0.31 g of sorbitan trioleate and 39.25 g of toluene were added. The overhead stirrer was turned on to provide agitation to the reaction solution. The aqueous polyallylamine solution was added to the toluene solution in the 100 mL flask. Epichlorohydrin (0.30 g) was added directly to the reaction mixture using a syringe. The reaction was heated to 50°C for 16 hours. Thereafter, the reaction was heated to 80°C for 1 hour and then cooled to room temperature. The resulting beads were purified and isolated by washing the beads with MeOH, HCl, aqueous sodium hydroxide, and water. The lyophilization technique is used to dry the beads. The expansion ratio, chloride ion binding force in SGF, and chloride ion binding force (SIB-Cl) and phosphate binding force (SIB-P) in SIB are shown in Table S-2 (item 002050- In A1 FA and item 002050-A2 FA), the SGF, SIB-Cl and SIB-P values are expressed in mmol/g dry beads. Table S-2

例示性合成 F Step 1 A polymer selected from Exemplary Synthesis B and Exemplary Synthesis D undergoes cross-linking Step 2 according to the following general procedure. The dried preformed amine polymer beads were added to a reactor vessel equipped with agitating blades and nitrogen inlet. Add 1,2-dichloroethane (DCE) to the beads. Mechanical agitation was used to disperse the beads in the DCE. Add water directly to the dispersion and continue stirring. Immerse the flask in an oil bath maintained at the selected temperature. The reactants were kept in an oil bath and agitated under a nitrogen atmosphere using mechanical stirring for a selected amount of time. Methanol was added to the reaction and the solvent was removed by decantation. The beads are then filtered, and then purified by washing. The expansion ratio, the chloride ion binding force in SGF, and the chloride ion binding force (SIB-Cl) and phosphate binding force (SIB-P) in SIB are shown in Table S-3. Table S-3

Exemplary synthetic F

例示性合成G:Step 2 Exemplary Synthesis F: Add dried preformed amine polymer beads (3.00 g) (prepared as described in Step 1 of Exemplary Synthesis A) to a 100 mL round bottom equipped with a stirring blade and nitrogen inlet Flask. DCP (4.30 mL) and DCE (13.70 mL) were added to the beads to obtain a mass/volume ratio of beads to DCE of 1:6). Mechanical agitation (about 150 rpm stirring) was used to disperse the beads in the DCE. Water (3.00 mL, giving a water-to-bead mass ratio of 1:1) was directly added to the dispersion, and stirring was continued for 30 minutes. After 30 minutes, the flask was submerged into an oil bath maintained at 70°C. The reaction was kept in an oil bath and stirred under a nitrogen atmosphere for 16 hours using mechanical stirring. Methanol (60 ml) was added to the reaction and the solvent was removed by decantation. The beads were then filtered and then washed by (MeOH twice, H ₂ O once, 1N HCl twice, H ₂ O once, 1N NaOH three times, and then H ₂ O until the pH of the solution was 7 after washing So far) to purify it. The purified beads were then dried by lyophilization for 48 hours. The expansion ratio, the chloride ion binding force in SGF, and the chloride ion binding force (SIB-Cl) and phosphate binding force (SIB-P) in SIB are shown in Table S-4. Table S-4

Exemplary synthetic G:

The polyallylamine hydrochloride was dissolved in water. Sodium hydroxide is added to partially deprotonate the polyallylamine hydrochloride (preferably 50 mol%). The resulting water phase has a water content (by weight) of 2.42 times the weight of polyallylamine hydrochloride. A blocked 3-neck flask equipped with an overhead mechanical stirrer, a nitrogen inlet, and a Dean Stark device with a condenser were installed for the suspension reaction. A dichloroethane heptane mixture was prepared so that dichloroethane was 3 times heptane by weight. This mixed solvent of dichloroethane and heptane was added to the blocked 3-neck flask. The aqueous solution was added to the flask so that the ratio by volume was 6.4 dichloroethane to 1 water. The reaction mixture was stirred and heated to 70 °C for 16 hours. At this time, beads formed. The Dean Stark step was started to remove all water from the beads, while returning dichloromethane and heptane to the reaction mixture. Once no more water is removed, the reaction mixture is cooled. Water and sodium hydroxide were added back to the reaction mixture with a ratio of water to polyallylamine of 0.25, and 1 equivalent of sodium hydroxide per chloride ion was added to the added allylamine (both counted from the beginning of the reaction Polyallylamine hydrochloride). The reaction was heated at 70°C for another 16 hours. The reaction was cooled to room temperature. The filter glass frit was used to purify the beads with the following washing solvents: methanol, water, an aqueous solution of HCl, water, an aqueous solution of sodium hydroxide, and a 3-water washing solution, or until the filtrate was measured for pH 7. Example 1 Efficacy of TRC101 in acidosis in an adenine-induced model of treatment of nephropathy in rats

The drug substance TRC101 is an unabsorbed free-flowing powder composed of low-expansion spherical beads with a diameter of approximately 100 microns; each bead is a high-molecular-weight molecule that has undergone a single crosslink. TRC101 is a highly crosslinked aliphatic amine polymer synthesized by the following operations: first, two monomers allylamine hydrochloride and N,N'-diallyl-1,3-diaminopropane The dihydrochloride is copolymerized, and then the polymer is crosslinked with 1,2-dichloroethane as described in Exemplary Synthesis A and WO2016/094685 A1. TRC101 is a polymer with unique ID 019070-A3 FA in Table S-1 of Exemplary Synthesis A.

TRC101 is administered as a free amine polymer and contains no relative ions. TRC101 is insoluble in aqueous and non-aqueous solvents. TRC101 has high proton binding capacity, chloride ion binding capacity and chloride ion binding selectivity. The high amine content of the polymer causes TRC101's high proton binding and chloride binding; compared to other potentially interfering anions such as phosphate, citrate, cholic acid, and short-chain fatty acids and long-chain fatty acids, the polymer has a wide range of interactions Union provides size exclusion characteristics and selectivity.

TRC101 was evaluated in vivo in an adenine-induced rat model of chronic kidney disease (CKD) and metabolic acidosis. The study was designed in two parts. In two parts, male Sprague-Dawley rats weighing 260 g to 280 g (10 per group) were first administered to adenine (0.75 wt% in casein diet) for 2 weeks to induce nephropathy. Research Part 1 explored the effect of early treatment with TRC101 administered in a casein diet with 0.25 wt% adenine after a 2-week nephropathy induction cycle for 4 weeks. In contrast, Study Part 2 evaluated the effect of TRC101 administered before the start of the 4-week TRC101 treatment cycle and after the induction cycle, after the animal had maintained a casein diet with 0.25 wt% adenine for 5 weeks. The dosage of TRC101 is 0 wt%, 1.5wt%, 3.0wt% and 4.5wt% in the diet. Two study sections evaluated the effect of withdrawing TRC101 after the end of the treatment phase with a 2-week withdrawal phase, in which TRC101 was discontinued in the low (1.5 wt%) TRC101 dose group and high (4.5 wt%) TRC101 dose group, while in the middle Continue to administer TRC101 in the dose group (3.0 wt%). All animals received a casein diet with 0.25 wt% adenine during the withdrawal phase.

In both study parts, before the start of treatment and weekly during the treatment and withdrawal cycle, blood samples were collected from the tail vein of the animal for the amount of blood bicarbonate (SBC) using the HESKA element POC™ blood gas analyzer Measurement. The animals were randomized based on the SBC content at baseline (ie, after adenine induction of nephropathy and before the start of the dosing cycle) so that the average baseline SBC content in all dose groups was comparable. In addition, 24-hour stool collection was performed on the untreated and 4.5 wt% TRC101 group. Before being dried in the lyophilizer for 3 days, the collected stool samples were stored at -20°C, and then homogenized with mortar and pestle. Anions (Cl, SO ₄ and PO ₄ ) were extracted from the freeze-dried, homogenized stool samples by incubating the samples with NaOH for 18 hours. The samples were analyzed by ion chromatography (IC).

In Part 1, relative to the untreated control group (Figure 2; statistical analysis: two-way ANOVA using Dunnett's multiple comparison test to compare the untreated group; horizontal dotted lines mark normal SBC of male Sprague-Dawley rats of the same age Scope), early treatment with TRC101 resulted in a significant dose-dependent increase in SBC in all treated groups. Compared with the control group with a progressive decrease in mean SBC due to adenine-induced renal failure during the 4-week treatment cycle, the mean SBC content increased and remained within the normal range of the low-treatment group, the intermediate treatment group, and the high-treatment group Inside. At the time of withdrawal of TRC101, the average SBC content fell below the normal range in the low treatment group and the high treatment group, and was similar to the untreated control group at the end of the withdrawal cycle; however, TRC101 (3.0 wt%) continued treatment The SBC content was maintained within a normal range, where the average value was significantly higher than that of the untreated control group.

Consistent with the results observed for SBC, in Part 1 of the study, fecal samples recovered from animals treated with 4.5 wt% TRC101 showed a significant 15-fold increase in fecal Cl relative to the untreated control group ( image 3). TRC101 also significantly increased fecal SO ₄ and PO ₄ excretion, but the effect was much smaller than that observed for Cl (compared to a 3-fold increase and 2-fold increase in the untreated control group, respectively).

In Part 2 of the study, maintaining the adenine-containing diet for a total of 7 weeks before the start of the treatment phase resulted in a mean baseline SBC value of approximately 20 mEq/L to 21 mEq/L which was lower than that in all treatment groups normal range. Compared to the untreated control group, treatment with TRC101 resulted in a significant dose-dependent increase in SBC in all treated groups. At the end of the 4-week treatment cycle, the average SBC content in the control animals remained below the normal range. The average SBC content at low dose (1.5 wt% TRC101) is only slightly lower than the normal range. At the intermediate (3.0 wt%) and high (4.5wt%) doses of TRC101, the average SBC value remained within the normal range (Figure 4; two-way ANOVA using Dunnett's multiple comparison test compared to the untreated group; horizontal dotted line marks The normal SBC range of male Sprague-Dawley rats of the same age). Similar to the results observed in Part 1 of the study, the withdrawal of TRC101 administration in Part 2 resulted in a reduction in the average SBC to the normal range in the low-dose and high-dose treatment groups; however, the use of 3.0 wt% TRC101 continued The treatment maintained the average SBC content within the normal range (Figure 5). The average SBC content in the 3.0 wt% TRC101 group remained significantly higher than the average SBC content of the untreated control group throughout the study.

Consistent with the results observed for SBC, in Part 2 of the study, the stool samples recovered from animals treated with 4.5 wt% TRC101 showed a significant 10-fold increase in stool Cl compared to the control group, but stool SO ₄ and PO ₄ excretion increased only 2 times (Figure 5). Example 2 In vivo anion binding of polymers in pigs with normal kidney function

The anionic binding capacity of TRC101 (as described in Example 1) of female Yorkshire pigs with normal renal function was evaluated in vivo. Comparative experiments were performed using the free amine form of bixalomer (approved in Japan), which is an anion-binding resin designed to bind phosphate and commercially available to treat hyperphosphatemia. The free amine forms of TRC101 and Pisa Romer were individually sealed in nylon sachets (with a 64-micron mesh size and each polymer is distinguished by a sachet), and each polymer was given a total dose of 2 g (that is, each 10 sachets) were fed to a single-headed pig, and then polymer was recovered from the sachets collected in the feces within a 10-day period (seven and six sachets were recovered from the feces for Pisa Romer and TRC101, respectively). The bound anions were extracted from the polymer by incubation with NaOH for 18 hours. Determine the anion concentration in the sample by IC in Shangcheng solution.

Analysis of the anions bound to the polymer after recovery from feces revealed that TRC101 and Pisa Romer per gram combined an average of 2.62 mEq and 0.50 mEq of chloride ion, 0.46 mmol and 0.11 mmol of sulfate and 0.37 mmol in vivo, respectively And 0.95 mmol of phosphate (Figure 6l statistical analysis unpaired T test; mean ± standard deviation; for Pisa Romer and TRC101, N = 7 sachets and 6 sachets, respectively). Therefore, TRC101 removes chloride ions and sulfates greater than 5 times and 4 times, respectively, compared to pizza romer removed from the gastrointestinal tract of pigs. On the other hand, compared to TRC101 which was removed from the gastrointestinal tract of pigs, the phosphate binder pisaromer removed phosphate more than 2.5 times. Example 3 TRC101 effect in a subject suffering from chronic kidney disease and low serum bicarbonate salt content of the body portion 1

A double-blind placebo-controlled parallel design of four fixed-dose studies to study TRC101 (as described in Example 1) to estimate TRC101 control of serum bicarbonate (SBC) in human subjects with marked metabolic acidosis ) Ability. A total of 101 subjects with chronic kidney disease (CKD) and low SBC values were randomly divided into one of four groups at a ratio of approximately 1:1:1:1 (total daily dose of 3 g/day , 6 g/day or 9 g/day TRC101 or 3 g/day placebo [microcrystalline cellulose], administered twice daily [BID]).

If the subject is 18 to 80 years old, both have stage 3 or stage 4 CKD on the first day of screening and study (estimated glomerular filtration rate [eGFR], 20 to <60 mL/min/1.73 m ² body surface area) and the SBC content of 12 mEq/L to 20 mEq/L (including the end point), the systolic blood pressure (SBP) of <170 mmHg at the time of screening, and ≤9.0% of hemoglobin A1c ( HbA1c) value and fasting serum glucose (FSG) value of ≤250 mg/dL (13.9 mmol/L) are suitable for inclusion in the study. The key exclusion criteria are history of anuria, dialysis, acute kidney injury, acute renal failure in the past 3 months or serum creatinine >30% increase or eGFR 30% decrease, such as having the largest New York Heart Association (NYHA ) Severe concomitant symptoms of congestive heart failure (except CKD) of category III or category IV symptoms, unstable colic or acute coronary syndrome, dementia, hypertension emergency or emergency, temporary ischemic attack, Stroke, or residential oxygen use during the 6 months prior to screening. Other exclusion criteria are <3.8 mEq/L or >5.9 mEq/L at screening, type 1 diabetes or chronic obstructive pulmonary disease, history or current diagnosis of heart or kidney transplantation, clinically significant diabetic gastroparesis, obesity Surgery, intestinal obstruction, swallowing disorders, severe gastrointestinal disorders, severe recurrent diarrhea, or severe recurrent constipation.

Ca =鈣；K =鉀；Mg =鎂；Na =納；P =磷At the time of screening, subjects meeting all project guidelines were approved to the Clinical Research Unit (CRU) on Day 1, and according to dietary recommendations for patients with CKD (KDOQI, 2003), control proteins, calorie content, anions, Cationic and fiber fed to study diet. Calculate the potential renal acid load (ie PRAL value) for the daily meal plan (Scialla, 2013) to ensure that the study diet is neither acidic nor alkaline; the PRAL value range for the four daily meal plans is -1.71 To +1.92 and an average of 0.82. The PRAL calculation is as follows: PRAL(mEq/d) = (0.49 * protein [g/d]) + (0.037 * phosphorus [mg/d])-(0.21 * potassium [mg/d])-(0.26 * magnesium [mg /d])-0.013 * (Calcium [mg/d]) Developed four detailed meal plans designated for daily breakfast, lunch, dinner and two kinds of snacks (including measured quantities) (Table S- 5). Take care to ensure that the diet closely approximates the subject's typical diet, so that disturbances in serum bicarbonate associated with sudden changes in diet will be minimized. The source of dietary protein is mainly plant-based. On two of the four meal plans, meat (ie pork, fish) is served once a day. During the course of the treatment cycle, the site rotates through four daily meal plans. The mean (±standard deviation) serum bicarbonate content in the placebo group was 17.6 (±1.43) mEq/L at baseline and remained constant during the 14-day treatment cycle (17.5 [±1.87] mEq/ on day 15 L), showing that the diet did not change the content of serum bicarbonate. Table S-5: Composition of study treatment cycle diet

Ca = calcium; K = potassium; Mg = magnesium; Na = sodium; P = phosphorus

On day 1, the selected subjects were randomly assigned to one of three TRC101 doses or placebo, and they were administered on the morning of day 1 (next day) according to randomization. At a ratio of roughly 1: 1: 1: 1 to 101 patients were randomized to one of the group groups: Group 1 in equal divided doses BID (twice daily) administered to 3 g / day of comfort agents for 14 days (n = 25);. group 2 in equal divided doses BID administered 3 g / day of TRC101 for 14 days (n = 25);. group 3 in equal divided doses BID administered 6 g / day for 14 days of TRC101 (n = 25);. group 4 in equal divided doses administered BID to 9 g / day for 14 days of TRC101 (n = 26). Oral administration of TRC101 or placebo in the form of an aqueous suspension BID with breakfast and dinner. Acquire the first dose of study drug with breakfast. One hour before administration of study drug, venous blood was drawn for pre-administration SBC (contributing to baseline SBC value) and safety laboratory measurements. Subjects were kept in the CRU and continued to use the study drug for BID administration (at breakfast and dinner) for 14 days. On day 15, the subjects were discharged from the CRU. All subjects who completed the study were discharged for assessment on Day 15 and returned to CRU on Days 17 and 21 for AE collection, blood extraction, and safety assessment. A subset of patients (n=41) also returned to CRU on day 28 for AE collection, blood extraction, and safety assessment.

No target withdrew from the study early for any reason. The majority of subjects were male (65%), all subjects were white, and the median age was 61 years (range: 30 to 79 years).

Subjects in the study had stage 3 to stage 4 CKD (39% had stage 4), with an average baseline eGFR of 36.4 mL/min/1.73m ² (range 19.0 mL/min/1.73m ² to 66.0 mL/ min/1.73m ² ) and the metabolic acidosis is characterized by an average SBC content of 17.6 mEq/L (range 14.1 mEq/L to 20.4 mEq/L). At baseline, 60% of subjects had SBC values of 12 mEq/L to 18 mEq/L, and 40% had SBC values >18 mEq/L to 20 mEq/L.

The subjects had baseline comorbidities commonly seen in CKD patients including hypertension (93%), diabetes (73%), left ventricular hypertrophy (30%), and congestive heart failure (21%). As expected in the phase 3 to 4 CKD population, almost all study subjects have indications of sodium limitation: hypertension (93%), congestive heart failure (21%), peripheral edema (15%) and Use of diuretics (41%).

TRC101 significantly increased the content of SBC in the study population of CKD patients with a baseline SBC content ranging from 14 mEq/L to 20 mEq/L during the 2-week treatment cycle. On day 15, all three doses tested (3 g/day, 6 g/day, and 9 g/day TRC101 BID) significantly (p<0.0001) increased the average SBC content from baseline and compared to placebo Each dose increased the SBC content to a significant (p<0.0001) range.

Figure 7 illustrates the steady increase in average SBC observed in all three TRC101 dose groups during the 14-day treatment cycle, where at the end of treatment, the average increase in all three active dose groups was approximately 3 mEq/L to 4 mEq/L. The serum bicarbonate content in the placebo group remained essentially unchanged throughout the study, indicating that the diet administered with the control protein and cation/anion content in the clinical research unit matched well with the subject’s consumption at home, so There is no significant effect on its SBC value.

After the start of treatment in all three TRC101 dose groups that were combined, TRC101 had a rapid onset of action within the first 24 hours to 48 hours (that is, a statistically significant average increase in SBC from baseline group changes; p <0.0001). The time to onset of the difference between the groups (active vs. placebo) appears to appear between 48 hours and 72 hours after the start of treatment with TRC101. On day 4 (72 hours after the first administration of TRC101), the average increase of SBC from the baseline of each TRC101 group was 1 mEq/L to 2 mEq/L: 3 g/day (p=0.0011); 6 g /Day (p=0.0001); 9 g/day (p<0.0001).

注意：基線血清碳酸氫鹽(SBC)經限定為來自於第1天及投藥前第1天所收集到的樣本中之兩個SBC值之平均值。自基線之改變(CFB)經限定為後基線值減基線值。注意：最小平方(LS)平均值、LS平均值之標準誤差(SEM)、LS平均值之95% CI及P值係基於混合效果重複量測模型，其中SBC值之CFB作為因變數；治療(安慰劑，3 g/d BID、6 g/d BID及9 g/d BID)、時間點(第2天至第15天)且治療乘以時間點作為固定影響；受試者作為隨機因素；且經基線估計之腎小球濾過率(eGFR)及基線SBC作為連續共變數。受試者內相關性經模型化為假設一級自回歸共變數結構。Each of the TRC101 dose groups showed that after 2 weeks of treatment, the statistically significant (p<0.0001) increase in SBC from baseline was approximately 3 mEq/L to 4 mEq/L (see Table 1). Table 1: SBC change from baseline on day 15

Note: Baseline serum bicarbonate (SBC) is defined as the average of the two SBC values from the samples collected on Day 1 and Day 1 before dosing. The change from baseline (CFB) is defined as the posterior baseline value minus the baseline value. Note: The least squares (LS) mean, the standard error of the LS mean (SEM), the 95% CI and P values of the LS mean are based on the mixed effect repeated measurement model, where the CFB of the SBC value is used as the dependent variable; treatment ( Placebo, 3 g/d BID, 6 g/d BID and 9 g/d BID), time point (Day 2 to Day 15) and treatment multiplied by time point as a fixed effect; subjects as random factors; The estimated glomerular filtration rate (eGFR) and baseline SBC at baseline were used as continuous covariates. The intra-subject correlation was modeled as a hypothetical first-order autoregressive covariate structure.

There appears to be a small difference in efficacy between the 3 g/day and 6 g/day TRC101 doses; however, subjects in the 9 g/day TRC101 dose group exhibited a faster and larger increase in SBC. For example, the average increase of SBC in the TRC101 dose groups of 3 g/day, 6 g/day and 9 g/day on the 8th day was 1.82 mEq/L, 2.00 mEq/L and 2.79 mEq/L (i.e. The difference between the 9 g/day dose group and the other two TRC101 dose groups was about 0.8 mEq/L to 1.0 mEq/L). On day 15, comparable SBC increases were 3.21 mEq/L, 3.04 mEq/L, and 3.74 mEq/L (that is, about 0.5 mEq/L between the 9 g/day dose group and the other two TRC101 dose groups to 0.7 mEq/L difference) (Figure 8)).

Within the TRC101 treatment group, the statistically significant SBC change from baseline to day 15 (active agent versus placebo) ranged from 3.14 mEq/L to 3.84 mEq/L, with a combined mean difference from TRC101 Between placebo and 3.43 mEq/L (p<0.0001) (see Table 1).

As shown in Table 2, after 2 weeks of treatment, compared with 8.0% of the subjects in the placebo group, in more than half of the subjects (52.6%) in the combined TRC101 group, the SBC content increased by ≥ 3 mEq/L (p<0.0001). In addition, compared to 0 subjects in the placebo group, 22.4% of all TRC101-treated subjects had an increase in SBC of ≥5 mEq/L. Table 2: SBC changes over time by classification

In the combined TRC101 treatment group, after 2 weeks of treatment, the SBC of 35.5% of the subjects was corrected to the normal range (22 mEq/L to 29 mEq/L), and at the end of the treatment cycle, 64.5% of the Subjects treated with TRC101 had SBC levels above the upper limit of the baseline range (>20 mEq/L) (Table 3). The proportion of subjects achieving SBC> 22 mEq/L was similar in the TRC101 dose groups of 3 g/day, 6 g/day, and 9 g/day (40.0%, 28.0%, and 38.5%, respectively). On the 8th day of the treatment period, only about half of the treatment effect was seen, again indicating that at the end of the 2-week treatment cycle, the increase in SBC was not yet stable. Table 3: SBC changes over time by classification

The 2-week treatment cycle in the study was followed by a 2-week follow-up cycle in which subjects were off treatment. At the end of the 2-week tracking period, a withdrawal effect of approximately 3 mEq/L was observed in the combined TRC101 group, where the SBC content almost returned to baseline (Figure 9). These results emphasize the chronic nature of the potential metabolic acidosis in these CKD patients and indicate the need for continued treatment with TRC101 to maintain higher SBC levels.

No average changes in serum parameters (sodium, calcium, potassium, phosphate, magnesium, low-density lipoprotein) observed in the study will indicate the off-target effect of TRC101; there is no average change in serum chloride ion. Part 2

Expand the double-blind placebo-controlled parallel design fixed-dose study of Part 1 with the introduction of two additional groups: a total of 34 subjects with chronic (CKD) and low SBC values were randomly divided into two additional groups One of the groups: total daily dose of 6 g/day TRC101 (28 subjects) or 3 g/day placebo (6 subjects) [microcrystalline cellulose], once daily [QD ]). All subjects who completed Part 2 of the study underwent discharge assessment on Day 15 and returned to CRU on Days 17, 21, and 28 for AE collection, blood extraction, and safety assessment. Part 2 and Part 1 of the study are otherwise unchanged. Discussion on the research results of Part 1 and Part 2

In terms of demographics, baseline EGFR or serum bicarbonate or comorbidities, there was no significant difference between TRC101 and placebo treatment groups (Table 4). The patient had an average baseline eGFR of 34.8 mL/min/1.73 m2 and an average baseline serum bicarbonate content of 17.7 mEq/L. Study participants had the same conditions as patients with CKD, including hypertension (93.3%), diabetes (69.6%), left ventricular hypertrophy (28.9%), congestive heart failure (21.5%), and peripheral edema ( 14.1%) and stable diuretic use (42.2%).

Analysis of the mean serum bicarbonate content in the placebo group during the treatment period of the unit treatment cycle and the outpatient follow-up cycle revealed that the diet did not change the serum bicarbonate content. The mean (±standard deviation) serum bicarbonate content in the placebo group was 17.6 (±1.43) mEq/L at baseline and remained constant during the 14-day treatment cycle (17.5 [±1.87] mEq/ on day 15) L).

Compared to placebo, there was a significant increase in mean serum bicarbonate in all groups treated with TRC101 within the first 24 to 48 hours (Figure 10 and Figure 11). Within 72 hours after the first administration of TRC101, the average increase in serum bicarbonate from the baseline of each TRC101 group was 1 mEq/L to 2 mEq/L.

Compared with the 2-week treatment cycle, TRC101 increased serum bicarbonate values above the respective baseline values of each group, while patients treated with analgesia did not have changes in serum bicarbonate (Figures 10 and 11). On day 15, the difference between serum bicarbonate versus placebo was 3.31 mEq/L (95% of LS mean CI 2.15 to 4.46; p<0.0001), 3.14 mEq/L (95% of LS mean CI was 1.99 to 4.29; p<0.0001), 3.84 mEq/L (LS average 95% CI 2.70 to 4.98; p<0.0001) and 3.72 mEq/L (LS average 95% CI 2.70 to 4.74; p<0.0001) , TRC101 dose group were 1.5 g, 3.0 g, 4.5 g BID and 6 g QD. By comparison, the change from baseline to day 15 in the placebo group was -0.21 mEq/L (LS mean 95% CI was -0.91 to 0.49; p=0.56). The average increase in the combined TRC101 dose group was 3.57 mEq/L, which was higher than the average increase at the end of the 14-day treatment period in the placebo group (LS average 95% CI 2.75 to 4.38; p<0.0001). On Day 15, when TRC101 was provided at a dose of 6.0 g once daily versus 3.0 g twice daily, there was no significant difference in average serum bicarbonate increase (-0.53 mEq/L; the average 95% CI of LS was -1.61 to 0.56; p=0.34).

Treatment with TRC101 resulted in a steady increase in mean serum bicarbonate over the entire TRC101 dose group during the 14-day treatment cycle. The slope of the increase in serum bicarbonate remained constant, with no signs of a flat line at the end of treatment, indicating that the maximum increase in serum bicarbonate was not established with the study dose of TRC101. At the end of the treatment cycle, changes in serum bicarbonate were similar in all groups treated with TRC101 (Figure 10 and Figure 11).

After 2 weeks of treatment with TRC101, more than half of the patients in the combined TRC101 dose group (51.9%) had an increase in serum bicarbonate ≥3 mEq/L compared to 6.5% of patients in the placebo group (Table 5) . In addition, compared with 3.2% and 0% of patients treated with placebo, the increase in 38.5% and 22.1% of all patients treated with TRC101 was ≥4 mEq/L and ≥5 mEq/ L.

At the end of TRC101 treatment, 34.6% of patients in the combined TRC101 group had serum bicarbonate in the normal range (22 mEq/L to 29 mEq/L) compared to no patients in the placebo group. At the end of TRC101 administration, the proportion of patients with normal serum bicarbonate was similar in the four TRC101 dose groups (40.0%, 28.0% and 1.5% for 1.5 g BID, 3.0 g BID, 4.5 g BID and 6.0 g QD, respectively. 38.5%, 32.1%), and none of the patients in the placebo group had normal serum bicarbonate (Table 6).

At the end of the 2-week off-treatment tracking period, a reduction in serum bicarbonate from the end of the treatment value was observed in all TRC101 dose groups from approximately 3.0 mEq/L to 3.5 mEq/L, with serum bicarbonate content in each Almost all groups returned to baseline values (Figure 10 and Figure 11).

Compared with serum bicarbonate, the contents of serum potassium, serum sodium, and serum chloride did not change significantly during the course of the study (Figures 13A to 13D). The serum anion gap exceeded 2 mEq/L during the course of the study. Change (Figure 14).

All 135 randomized patients received TRC101 or placebo daily for 14 consecutive days and were included in the safety analysis population. No patients died during the study period, or any adverse events caused treatment interruption, and no patients suffered major or serious adverse events. Gastrointestinal adverse events were the most frequently reported events in patients treated with TRC101, and the severity of all events was mild or moderate (Table 7). Diarrhea is the most common adverse event; all diarrhea events are mild, self-limited, short-term, and require no treatment. No trend indicates the off-target effect of TRC101 on the electrolyte (ie, sodium, potassium, magnesium, calcium, or phosphate). There is no trend to indicate the effect of TRC101 on vital signs or ECG interval. No subject experienced an increase in serum bicarbonate that caused metabolic alkalosis (ie, serum bicarbonate> 29 mEq/L).

表5：於第15天按血清碳酸氫鹽增加分類之患者的比例

表6：按血清碳酸氫鹽分類之患者的比例(第8天及第15天)

表 7 ： 治療引發不良事件出現於任何治療組中之 ＞5%的患者中 (安全性分析組 )

BID =每日兩次；GFR =腎小球濾過率；QD =一日一次；TEAE =治療引發不良事件。實例 4 較高血清碳酸氫鹽含量之益處的回溯性分析 This two-part double-blind placebo-controlled parallel design 6-group fixed-dose clinical study showed that TRC101 uptake was very significant as assessed by both baseline changes within the group and by comparison between the active agent and placebo groups Increase serum bicarbonate levels in patients with stage 3 or 4 CKD and patients with low SBC. The rapid onset of action (within 24 hours to 72 hours) and efficacy (increased in SBC>3.0 mEq/L) in the study indicate that TRC101 is an effective agent to control the SBC content in the target patient population. Unlike sodium bicarbonate, TRC101 does not introduce cations such as sodium or potassium, which are harmful to sodium-sensitive patients with common CKD comorbidities (such as hypertension, edema, and heart failure). TRC101 is expected to provide safe treatment for the control of SBC in CKD patients with low SBC, including those patients who are sodium-sensitive. Table 4: Baseline demographics, dietary intake, renal function, serum bicarbonate and total complications ^(a median value)

Table 5: Proportion of patients classified by serum bicarbonate increase on day 15

Table 6: Proportion of patients classified by serum bicarbonate (Day 8 and Day 15)

Table 7 : Treatment-induced adverse events occurred in >5% of patients in any treatment group ( safety analysis group )

BID = twice a day; GFR = glomerular filtration rate; QD = once a day; TEAE = treatment-induced adverse events. Example 4 Retrospective analysis of the benefits of higher serum bicarbonate content

The relationship between reducing serum bicarbonate levels and worsening clinical outcomes is continuous (i.e., as bicarbonate levels decrease from normal levels, there is a disadvantage associated with metabolic acidosis such as death or the progression of CKD The resulting risk gradually increases). To develop a quantitative predictive model of this relationship and to assess the impact of various CKD comorbidities, the implementation of the use includes the use of serum bicarbonate content of 12 mEq/L to 29 mEq/L and EGFR 15 mL/min/1.73m ² to 45 mL Longitudinal analysis of the population of Optum, Inc. database of CKD patients within the range of /min/1.73m ² . The key advantage of the large longitudinal data set is the ability to determine the presence (or absence) of metabolic acidosis and evaluate the baseline period of significant duration (1 year to 2 years) of kidney disease progression at that time. See for example Figure 25.

Because the use of retrospective database analysis to distinguish causality can be difficult (that is, a reduction in eGFR can lead to a reduction in serum bicarbonate and metabolic acidosis can in turn lead to a reduction in renal function), the requirements include All patients in the analysis data set have at least two eGFR and serum bicarbonate measurements within a 1- to 2-year baseline period. Any kidney progression events during this cycle are not counted and will be excluded from patients who died or progressed to dialysis/kidney transplantation during the baseline cycle. Only after the end of the baseline period did we count the leading outcome events (ie, death, progression to dialysis or kidney transplantation or eGFR reduction ≥40% from baseline; "DD40" below). In addition, I equate to specifying at least one additional confirmed serum bicarbonate value (that is, the last reliable value in the patient's medical history) during the observation period.

To understand the quantitative relationship between the increase in serum bicarbonate and the result of interest (ie DD40), three independent analyses were performed. These analyses assess: 1) the risk ratio of DD40 in patients with metabolic acidosis (12 mEq/L to <22 mEq/L); 2) compared with the normal serum bicarbonate content (22 mEq/ L to 29 mEq/L) of their patients, the risk ratio of DD40 in patients with metabolic acidosis; and 3) the population of patients with serum bicarbonate from 12 mEq/L to 20 mEq/L ( That is, we intend to be enrolled in the TRCA-301 and TRCA-303 studies) for the benefit associated with different magnitudes of the increase in serum bicarbonate (ie, the reduction in the hazard ratio of DD40). These analyses are described in more detail below. Analysis 1 : In the subgroup of acidosis with a serum bicarbonate value between 12 mEq/L and <22 mEq/L (N=646), we used baseline serum bicarbonate as a covariate to evaluate Cox Proportional risk model to determine the effect of incremental changes in bicarbonate on the risk ratio of DD40. Analysis 2 : A subgroup of acidosis patients with a serum bicarbonate value between 12 mEq/L and <22 mEq/L (N=646) and normal serum bicarbonate (22 mEq/L to 29 mEq /L; N=6,535) subgroups of patients were compared to quantify the risk associated with having low serum bicarbonate. Analysis 3 : The subgroup of patients with serum bicarbonate from 12 mEq/L to 20 mEq/L (ie, the population to be selected in the TRCA-301 and TRCA-303 studies; N=351) was used as a reference group to It is estimated that the risk of DD40 clinical outcomes associated with an increase in the average serum bicarbonate value of 3 mEq/L or 5 mEq/L is reduced. This analysis was performed to quantify the benefit of increased serum bicarbonate from 2 mEq/L to <4 mEq/L or ≥4 mEq/L in the populations enrolled in the TRCA-301 and TRCA-303 studies.

The data set used for this analysis was an extraction of the Optum de-identified electronic health record data set (2007 to 2013), which contains longitudinal electronic health records for the lives of >22 million unique patients. The source of information in the database is approximately 36 US health systems covering approximately 200 hospitals and 1,800 outpatient clinics in 43 continents. The extraction includes the diagnostic signs or clinical signs of stage 3, 4 or 5 CKD recorded at the beginning of the data cycle (based on the ninth revision, international classification of diseases [ICD-9] codes 585.4, 585.5) or Patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m ² and having at least one serum bicarbonate (HCO ₃ ) test result. The data cycle of electronic health records is from January 2007 to July 2013. To exclude false values, only serum bicarbonate values in the range of 10 mEq/L to 40 mEq/L and serum creatinine values in the range of 0 mg/dL to 20 mg/dL will be included in the analysis data set.

To assess the quantitative relationship between at least 40% of death, dialysis, or eGFR decline ("DD40" endpoint) and serum bicarbonate content, the analysis population was first limited to include only those with a range of 15 mL/min/1.73m ² to < CKD patients with eGFR values in the range of 45 mL/min/1.73m ² and serum bicarbonate levels in the range of 12 mEq/L to 29 mEq/L. Signs of a baseline period of 1 year to 2 years of duration with stable serum bicarbonate and eGFR values before the patient reached the 6.5-year observation period during which renal results were evaluated.

To be included in the analysis group, patients are required to maintain the same serum bicarbonate layer at the following three time points (that is, low [12 mEq/L to 20 mEq/L], and the boundary [>20 mEq/L to < 22 mEq/L] or normal [22 mEq/L to 29 mEq/L]) with consistent signs of acidosis (where the second and third values allow a slightly wider range to be measured Variability): 1. The baseline serum bicarbonate value, which is defined as the average value of the serum bicarbonate results collected within 30 days from the first date of the recorded collection, with the serum bicarbonate results at 10 mEq/L Between 40 mEq/L; 2. After the baseline HCO3 date, the first recorded serum bicarbonate value appears for at least 1 year but not more than 2 years; and 3. Record the serum bicarbonate value at the end.

At the end of the 1-year to 2-year baseline period and at the end of the observation period, patients are required to maintain the same serum bicarbonate layer they were assigned at the beginning of the baseline period. This approach was chosen to ensure that the DD40 endpoint recorded during the observation period can be reliably associated with a specific serum bicarbonate layer. A drawback of this approach is that the analysis group may be slightly healthier than the group selected for post-marketing research TRCA-303. This approach is considered reasonable because it is not expected to magnify the observed difference in DD40 event rates between layers.

The needs included in the analysis group also specify that the patient's eGFR must have been kept within the target range of 15 mL/min/1.73m ² to <45 mL/min/1.73m ² at the beginning, and the target range is from 1 year to 2 At the end of the annual baseline cycle is 10 mL/min/1.73m ² to <50 mL/min/1.73m ² . At the end of the baseline period, eGFR was used as the baseline value of eGFR from which eGFR reduction was calculated for the purpose of DD40 endpoint evaluation. For the reduction of eGFR to be counted towards the end point of DD40 from the baseline value of eGFR, it must have been supported by confirmed eGFR values that also appear during the observation period that also represents a reduction of at least 40% from the baseline.

The requirements included in the analysis group and the resulting size of the analysis group after implementing each requirement are summarized in 15 and 16, respectively. Analyze the baseline characteristics of groups

The analysis population consisted of 7,181 CKD patients, which were divided into three layers based on their baseline serum bicarbonate content: 351 patients with low bicarbonate content (12 mEq/L to 20 mEq/L), 295 patients with Boundary acidosis (>20 mEq/L to <22 mEq/L) and 6,535 patients with normal serum bicarbonate (22 mEq/L to 29 mEq/L). The demographic and baseline information of the analyzed groups by serum bicarbonate layer is provided in Table 400.

Approximately 60% of the analysis group is female, with an average age of approximately 74 years. Two thirds (67%) of patients were diagnosed with hypertension and 32% were diagnosed with diabetes. A small percentage of patients (12%) have a history of cerebrovascular disease. The use of renin angiotensin aldosterone system (RAAS) inhibitors before the start of the observation period is common in the analysis population (approximately 42% of patients).

Demographic and baseline characteristics are similar among the three serum bicarbonate layers, with the following exceptions: compared to patients in normal serum bicarbonate layers (22 mEq/L to 29 mEq/L), in low serum bicarbonate Patients in the salt layer (12 mEq/L to 20 mEq/L) are younger, have lower baseline eGFR, and are more male.

ACEi=血管收縮素轉化酶抑制劑；ARB=血管緊張素受體阻斷劑；CKD=慢性腎臟疾病；eGFR=所估計腎小球濾過率；HCO3=血清碳酸氫鹽；SD=標準差 注意：因為分別有＞95%及＞85%之患者未記錄有此資訊，因此不包括人種及尿白蛋白與肌酐比。^a 年齡按出生日期與基線碳酸氫鹽日期之間的差以年來計算。將全部患者之出生月及日設定為6月1日。無可靠出生日期(亦即無出生年)之患者將其出生年設定為與基線血清碳酸氫鹽量測收集年(亦即年齡=0歲)相同的年。將具有1928之出生年或更早的患者之出生年設定為1928 (亦即年齡=85歲)。^b 按第一HCO₃ 值之30天內的全部HCO₃ 值之平均值所計算之基線血清碳酸氫鹽。 分析群體之限定血清碳酸氫鹽及eGFR值At the first defined eGFR value (ie, at the beginning of the baseline cycle), the majority (79%) of the patients in the analysis population had stage 3b CKD, with the remainder suffering from more severe disease (stage 4 CKD). Compared with border acidosis and normal serum bicarbonate layers (26% and 20%, respectively), the lowest serum bicarbonate layer had a larger proportion of patients with stage 4 CKD (44%). Table 4 00 Demographic data and baseline characteristics of the analysis group

ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; HCO3 = serum bicarbonate; SD = standard deviation Note: Since this information was not recorded in patients with >95% and >85%, respectively, race and urinary albumin to creatinine ratio were not included. ^a Age is calculated in years based on the difference between the date of birth and the baseline bicarbonate date. Set the birth month and day of all patients to June 1. Patients without a reliable birth date (ie no birth year) set their birth year to the same year as the baseline serum bicarbonate measurement collection year (ie age = 0 years). The birth year of a patient with a birth year of 1928 or earlier is set to 1928 (that is, age=85 years). ^b Baseline serum bicarbonate calculated from the average of all HCO ₃ values within 30 days of the first HCO ₃ value. Analysis of the defined serum bicarbonate and eGFR values

Because patients are required to remain in the same serum bicarbonate layer they were assigned at the beginning of the baseline period, there is a small difference in the average serum bicarbonate value in a particular layer during the baseline treatment period and observation period. For example, patients in the low serum bicarbonate layer have an average serum bicarbonate content of 18.3 mEq/L at the beginning of the baseline cycle and 18.5 mEq/ at the end of the baseline cycle (which is also the beginning of the observation cycle) L, and at the end of the observation period is 18.5 mEq/L. Similarly, patients in the border and normal serum bicarbonate layers had no significant changes in serum bicarbonate values during the analysis period (Table 500). Because it was determined by the appearance of the first serum bicarbonate record of at least 1 year but not more than 2 years after the patient's first recorded serum bicarbonate value, the length of the baseline period varied among patients. The average duration of the baseline period determined by the second defined serum bicarbonate value was 15.2 months in the total analysis population and was similar among the three serum bicarbonate layers (Table 500).

To ensure that we assess the impact of various levels of acidosis on CKD patients representing our established TRCA-303 population, the patients in the analysis population are required to have at least 1 year but not more than 10 mL/min/1.73m ² and The eGFR value 2 years after the first recorded serum bicarbonate value of the patient in the range between 50 mL/min/1.73m ² . The patient's baseline eGFR value was calculated based on the average of the serum creatinine values recorded 90 days before this second defined eGFR value. The average baseline eGFR values were 29.6 mL/min/1.73m ² , 32.8 mL/min/1.73m ² and 35.4 mL/min in the low serum bicarbonate group, border serum bicarbonate group and normal serum bicarbonate group, respectively /1.73m ² . As defined by the time between the first defined eGFR value and the second defined eGFR value, the duration of the baseline cycle was 15.06 months in the total analysis population, and it was similar among the three serum bicarbonate layers (Table 500). The patient's baseline eGFR value is used to evaluate all DD40 endpoint events that occurred during the observation period. The eGFR is large enough to contribute to the reduction in the DD40 event rate (ie, ≥40%) is calculated as the reduction in eGFR value since then, not the eGFR at the beginning of the baseline period. The overall reduction in eGFR that contributed to the DD40 event rate was also confirmed by the second eGFR value that was confirmed to have reduced amplitude.

eGFR=所估計腎小球濾過率；HCO₃ =血清碳酸氫鹽；SD=標準差 分析 藉由血清碳酸氫鹽層之終點事件的頻率As defined by the time from the baseline eGFR date to the last recorded patient contact, the average duration of the observation period was 34.9 months in the total analysis population and 32.9 months among the three serum bicarbonate layers To 35.0 months. Table 500 Serum bicarbonate and eGFR values of analyzed groups

eGFR=estimated glomerular filtration rate; HCO ₃ =serum bicarbonate; SD=standard deviation analysis of the frequency of endpoint events by serum bicarbonate layer

數目(%)之患者經報導。 DD40=死亡之複合、透析或腎臟移植及eGFR自基線≥40%之下降；eGFR=所估計腎小球濾過率 Cox回歸分析During the almost 6.5-year follow-up period of 7,181 patients in the analysis population, 572 patients experienced the DD40 endpoint (Table 600). Of these patients, 50 died, 60 started dialysis or received kidney transplants, and 462 had eGFR decreased by ≥40% from baseline. Compared to patients with normal serum bicarbonate, the incidence of each of the single endpoint events and the DD40 composite endpoint was 2.4 to 6.7 times higher in the group of patients with low baseline serum bicarbonate. Table 600 Frequency and incidence of end events by serum bicarbonate layer

The number (%) of patients has been reported. DD40 = death compound, dialysis or kidney transplantation and eGFR ≥40% decrease from baseline; eGFR = estimated glomerular filtration rate Cox regression analysis

To understand the effect of every 1 mEq/L increase in serum bicarbonate on the reduced risk of DD40, three independent analyses were performed (17). These analyses assess: 1) the risk ratio of DD40 in patients with metabolic acidosis (12 mEq/L to 22 mEq/L); 2) compared with the normal serum bicarbonate content (22 mEq/L To 29 mEq/L) of these patients, the risk ratio of DD40 in patients with metabolic acidosis; and 3) compared with the population of patients with serum bicarbonate from 12 mEq/L to 20 mEq/L Ratio, the benefits associated with different magnitudes of increased serum bicarbonate (ie, the reduction in the risk ratio of DD40) (Figure 17). Analysis 1: The effect of incremental changes in serum bicarbonate on the risk of DD40

For a subpopulation of patients with subnormal serum bicarbonate, we evaluated the Cox proportional hazards model adjusted for the hazard ratio of the DD40 clinical endpoint of the following covariates: baseline bicarbonate, age, gender, hypertension , Cerebrovascular disease, diabetes, baseline, angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) use and initiation of eGFR. Apply stepwise model selection using the reverse forward method. Before it can enter the model, the variable must be significant at the 0.3 level, and the variable must be significant at the 0.21 level to remain in the final Cox proportional hazards regression model. Significantly enter and stay in the significance content of the model so that the variables are included in the final model even if all are not significant at the 0.05 content.

ACEi=血管收縮素轉化酶抑制劑；ARB=血管緊張素受體阻斷劑；CI=置信區間；eGFR=所估計腎小球濾過率；HCO₃ =血清碳酸氫鹽^a Cox比例風險模型使用對以下各者之逐步選擇：基線HCO₃ 值、年齡(＜65或≥65)、性別(男性或女性)、高血壓(有、無)、腦血管疾病(有、無)、糖尿病(有、無)、起始限定eGFR值及基線ACEi/ARB使用(有、無)。^b 基線血清碳酸氫鹽按HCO₃ 之第一量測值的30天內之量測值的平均值來計算。 分析2：低血清碳酸氫鹽對DD40之影響As shown in Table 401, every 1 mEq/L increase in baseline serum bicarbonate is associated with a roughly 12% decrease in DD40 risk. Table 401 Cox regression model of DD40 (patients with serum bicarbonate from 12 mEq/L to 22 mEq/L)

ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; CI = confidence interval; eGFR = estimated glomerular filtration rate; HCO ₃ = serum bicarbonate ^a Cox proportional hazard model Step by step selection of the following: baseline HCO ₃ value, age (<65 or ≥65), gender (male or female), hypertension (yes, no), cerebrovascular disease (yes, no), diabetes (yes, no ), initial limit eGFR value and baseline ACei/ARB use (yes, no). ^{b The} baseline serum bicarbonate is calculated as the average of the first 30 days of HCO ₃ measurements. Analysis 2: Effect of low serum bicarbonate on DD40

Use two serum bicarbonate layers to perform Cox regression adjusted for multiple covariates (i.e. age, gender, hypertension, cerebrovascular disease, diabetes, baseline ACE inhibitor or ARB use, and initial eGFR) Analysis: Patients with baseline serum bicarbonate in the range of 12 mEq/L to <22 mEq/L and 22 mEq/L to 29 mEq/L.

The results showed that the risk of the DD40 endpoint was higher in the group of patients with low serum bicarbonate compared to their patients with normal serum bicarbonate. The adjusted risk ratio is 1.79 (95% confidence interval [CI]: 1.31, 2.43; p=0.0002; Table 501; Figure 26).

ACEi=血管收縮素轉化酶抑制劑；ARB=血管緊張素受體阻斷劑；CI=置信區間；eGFR=所估計腎小球濾過率；SD=標準差^a 未針對共變數調整之Cox比例風險模型。^b 針對以下各者逐步選擇之Cox比例風險模型：年齡(＜65或≥65)、性別(男性或女性)、高血壓(有、無)、腦血管疾病(有、無)、糖尿病(有、無)、起始限定eGFR值及基線ACEi/ARB使用(有、無)。此等共變數之p值必須＜0.3以包括於模型中。 分析3：遞增較高之血清碳酸氫鹽含量對DD40之影響We also explored the potential impact of factors other than serum bicarbonate content on the DD40 hazard ratio in our analysis group. The factors explored included demographic factors (age, gender), comorbidities (hypertension, diabetes, cerebrovascular disease) commonly found in the CKD population, use of ACE inhibitors or ARB at baseline, and the severity of their kidney disease The degree of measurement of the patient's initial eGFR value. When adjusting other factors, the risk ratio (95% CI) of each factor is provided in Table 501. Table 501 Cox model hazard ratio (95% CI) of DD40 by serum bicarbonate layer

ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; CI = confidence interval; eGFR = estimated glomerular filtration rate; SD = standard deviation ^a Cox proportional risk not adjusted for covariates model. ^b Cox proportional hazards model selected gradually for each of the following: age (<65 or ≥65), gender (male or female), hypertension (yes, no), cerebrovascular disease (yes, no), diabetes (yes, None), initial limited eGFR value and baseline ACEi/ARB use (yes, no). The p-value of these covariates must be <0.3 to be included in the model. Analysis 3: The effect of increasing serum bicarbonate content on DD40

結論As shown in Table 700, the hazard ratio of the DD40 endpoint decreases with both moderate and large increases in serum bicarbonate. This analysis used low serum bicarbonate (12 mEq/L to 20 mEq/L) layers as a reference for comparison with two layers with higher mean serum bicarbonate content. The average baseline serum bicarbonate content in the reference layer was 18.3 mEq/L. The test layer had an average baseline serum bicarbonate content of 21.0 mEq/L and 23.1 mEq/L, indicating that the increase in serum bicarbonate was approximately 3 mEq/L and 5 mEq/L. A higher average serum bicarbonate content of 3 mEq/L resulted in an adjusted hazard ratio of 0.60 (95% CI: 0.40, 0.91; p=0.0153), indicating that moderately higher serum bicarbonate content significantly reduced the risk of DD40 endpoint . A higher mean serum bicarbonate content of 5 mEq/L resulted in an adjusted hazard ratio of 0.39 (95% CI: 0.29, 0.53; p<0.0001).

in conclusion

Subgroups of patients with an increase in serum bicarbonate from 2 mEq/L to <4 mEq/L or ≥4 mEq/L in acidosis (serum bicarbonate 12 mEq/L to 20 mEq/L) population had 40 % And 61% of the reduced risk of DD40. This result indicates that every 1 mEq/L increase in serum bicarbonate reduces the risk of DD40 by about 12% to 13%. Example 5 Description and analysis of results from clinical trials

Enrolled with stage 3b or stage 4 CKD (estimated glomerular filtration rate [eGFR] 20 mL/min/1.73m ² to 40 mL/min/1.73m ² ) and have low blood bicarbonate content (at 12 mEq/L and 20 mEq/L) 217 subjects in a double-blind randomized placebo-controlled study. At the beginning of the 12-week treatment cycle, subjects were randomized into a ratio of 4:3 to receive the pharmaceutical composition according to the invention, such as TRC101 or placebo, once daily or QD. Subjects in the active group initially received a 6-gram QD dose of TRC101 (2 sachets). After 4 weeks, a double-blind dose adjustment to 3 g/day (1 sachet) or 9 g/day (3 sachets) was allowed to maintain blood bicarbonate within the normal range. Subjects in the placebo group initially received 2 sachets of placebo with the same capacity for two-way dose adjustment after 4 weeks. The dose titration algorithm requires a downward titration at a blood bicarbonate value of 27 mEq/L to 30 mEq/L. Subjects with a blood bicarbonate content greater than 30 experienced an interruption of study drug according to the titration algorithm. Subjects were allowed to continue their existing oral alkaline supplements during the trial, with the restriction that the administration remained stable. The test was conducted at 47 sites in the United States and Europe.

Suitable patients are 18 to 85 years old and have a systolic blood pressure of <170 mmHg and ≤9% of hemoglobin A1c. During the 2-week screening cycle, three defined fasting serum bicarbonate values over 14 days are needed to establish applicability; the average of the first two values and all three is required to be between 12 mmol/L and 20 mmol/L Within. During screening, two defined eGFR values with a difference >20% and ranging from 20 mL/min/1.73m ² to 40 mL/min/1.73m ² are required. If its serum bicarbonate content is low enough to require emergency intervention or assessment of the process of acute acidosis, or if it has anuria, dialysis, or acute or chronic worsening renal function (eg, decreased eGFR) within 3 months before the first screening visit ≥30%), the patient is excluded. Patients with the following recent medical history were also excluded: chronic obstructive pulmonary disease, heart failure with New York Heart Association classification IV symptoms, stroke, transient ischemic attack, cancer, myocardial event, diabetic gastroparesis, obesity treatment surgery, obstruction , Swallowing disorders, severe gastrointestinal disorders or hospitalizations that do not target pre-planned diagnostic or minimally invasive surgery, those patients with heart or kidney transplants, and those planning to start kidney replacement therapy within 12 weeks. Suitable patients do not have liver enzyme content> 3 times the upper limit of normal, serum calcium content ≤ 2 mmol/L or serum potassium content <3.8 mmol/L or> 5.9 mmol/L. The concomitant drug demand for research participation excludes the use of any other research drugs and other binder drugs (except for the short-term use of potassium binders for the treatment of hyperkalemia), and in the case of using them, stability is required Dosage (as much as possible) of the following preparations: calcium-containing supplements; antacids; H2 blockers; proton pump inhibitors; oral bases; diuretics; renin-angiotensin-aldosterone system inhibitors; and non-transocular Carbonic anhydrase inhibitor. Oral concomitant drug and research drug administration separation ≥ 4 hours.

*藉由根據獨立血液抽取之重複量測所確認之血清碳酸氫鹽值＜12 mmol/L或＞30 mmol/L。The initial study drug dose was 6 g/day of TRC101 (2 packets/day) or placebo (2 packets/day) administered orally as a suspension in water with lunch. The first dose was administered in the clinic on the day of randomization, after which, the patient was administered the study drug for 12 weeks and the dose was recorded in the diary, which was used with the unused study drug returned at each consultation Review together. Beginning in the 4th week, at each consultation, the study drug will be studied based on bicarbonate measurement values through the interactive response technology system in the range of 0 g/day to 9 g/day (or equivalent number of placebo packets) The dose is titrated algorithmically to a target bicarbonate of 22 mmol/L to 29 mmol/L. If the bicarbonate is high normal (27 mmol/L to 30 mmol/L), the dose is titrated downward, and if it is >30 mmol/L, it is discontinued (Table 800). Table 800 Dose Titration Algorithm

*Serum bicarbonate value <12 mmol/L or >30 mmol/L confirmed by repeated measurements based on independent blood draws.

The co-morbidities between the treated and placebo subjects entering the trial were equally balanced and included: 97% with hypertension, 65% with type 2 diabetes, 44% with left ventricular hypertrophy and 31% with Congestive heart failure; during the three months before baseline, 12% of the subjects suffered from shortness of breath while exercising and 9% had repeated or continuous signs/symptoms of edema or fluid overload. Percentage of the total patient population in the trial, Nine Meridians, reported the use of oral alkali therapy at baseline.

The blood bicarbonate content of the subject is measured on day 1, week 1, week 2 and every two weeks thereafter (and including) week 14 ( see, for example, Figure 18). The leading efficacy endpoint of the trial was an increase in blood bicarbonate content of at least 4 mEq/L, or a blood bicarbonate content within the normal range of 22 mEq/L to 29 mEq/L at the end of the 12-week treatment cycle. The secondary efficacy endpoint of the trial was the change from baseline in blood bicarbonate at the end of treatment.

The study was conducted in accordance with the principles of Helsinki's statement and in accordance with the principles of good clinical practice standards. The research protocol is approved by the relevant institutional review committee or ethics committee of each site and the appropriate competent authority in accordance with applicable laws and regulations. Before enrollment, all patients provided written informed consent. The non-blind independent data monitoring committee conducts scheduled review of safety data during the study period. program

During the screening cycle, Screening 1 and Screening 2 were separated by > 5 days and Screening 1 and Baseline were separated by ≤ 14 days. After randomization, patients participated in scheduled consultations at Week 1, Week 2, Week 4, Week 8, Week 8, Week 10, and Week 12, during which time i-STAT ^Ò hand-held blood was used Analyzer (Abbott Point of Care) to measure serum bicarbonate and conduct safety assessment (Figure 18: eGFR, estimated glomerular filtration rate; n, number of patients in each treatment group; QD, daily Once; R, random grouping; W, week).

Before the measurement of bicarbonate content, the patient's fasting ≥ 4 hours (except water) to reduce the indirect effect of food-induced bicarbonate to the secretion of blood flow. The venous blood measured by bicarbonate was drawn into a 2 ml lithium heparin tube, and transferred to the i-STAT G3+ cartridge using a mini dropper as soon as possible (within 10 minutes) for the bicarbonate using the i-STAT device Assessment. The tube was capped until the blood was transferred into the filter cartridge, and strict requirements for blood extraction and transfer techniques were followed. Before and during the study, calibrate the i-STAT device according to the manufacturer's recommendations. Kidney disease and quality of life (KDQOL) profile-36, question 3 (body function domain) (Figure 21), and standardized repeated sitting and standing tests (Figure 22A and 22B) were administered at baseline and Week 12. Forward and reverse translation of KDQOL in CKD patients, verbal verification, cultural adaptation, review by clinicians and report on cognition. After the completion of the 12th week of study treatment, the patient was transferred to the 40-week extended study or experienced two follow-up visits after the last dose of study drug (Week 13 and Week 14). Serum bicarbonate

A total of 71 of 120 (59%) TRC101-treated patients and 20 of 89 (22%) placebo-treated patients met the lead endpoint response limit (for comparison, p<0.0001), where treatment differences (TRC101-placebo) was 37% (95% CI, 23% to 49%). For each of the two components of the leading end point, similar treatment differences minus placebo were observed. Compared with the placebo group, a higher percentage of patients in the TRC101 group had an increase in serum bicarbonate at all predefined thresholds (≥2 mmol/L to ≥7 mmol/L).

The serum bicarbonate curves of the TRC101 and placebo groups began to separate at time 1 week of treatment and maintained separation until the end of treatment (Figure 19C). At week 12, the average change from baseline in the TRC101 and placebo groups was 4.5 (95% CI, 3.9 to 5.1) mmol/L and 1.7 (95% CI, 1.0 to 2.3) mmol/L (p<0.0001), respectively. The LS mean (SEM) change from baseline to the 12th week secondary endpoint was 4.4 (3.5) mmol/L and 1.8 (3.1) mmol/L in the TRC101 and placebo groups (p<0.0001), respectively. (Figures 19A to 19C: Changes in serum bicarbonate-Figure 19A: Compound lead endpoint: percentage of patients minus placebo to achieve an increase in serum bicarbonate from baseline of ≥4 mmol/L or serum bicarbonate during treatment The normal range (22 mmol/L to 29 mmol/L) at 12 weeks (37%, 95% CI: 23%, 49%) is depicted as the top line. The two lower lines depict the components of the leading end point. The analysis of a single leading endpoint component was pre-specified but not adjusted for multiple comparisons. The P value was the difference in the ratio between TRC101 and placebo (Fisher's exact test). Figure 19B: TRC101 (round) and placebo (square) The percentage of patients in the group whose serum bicarbonate content increased from baseline to Week 12 with a pre-specified threshold. Achieving a ≥4 mmol/L increase was the leading end point component. Figure 19C: Baseline bicarbonate (treatment 0 Week), Screening 1, Screening 2 mean and baseline day 1 values were 17.3 mmol/L in the two treatment groups. The depicted value is the change in serum bicarbonate mean (±95% CI) from baseline ( mmol/L). At week 12, the mean increase in serum bicarbonate was 4.5 (95% CI, 3.9 to 5.1) mmol/L in the TRC101 group (circles) compared to 1.7 in the placebo group (squares) (95% CI, 1.0 to 2.3) mmol/L.

The results from the post-mortem analysis using the grade-based model are consistent with those from the pre-specified MMRM model (p<0.0001 for treatment effect).

Except in the subgroup with <8 patients, the lower 95% confidence interval of the treatment difference was combined in all pre-specified subgroups including age, gender, geographic area, baseline bicarbonate, screening eGFR, and baseline alkali use More than 0 in the group. Except in subgroups with <8 patients, the lower 95% confidence interval for treatment differences was combined in all pre-specified subgroups including age, gender, geographic area, baseline alkali use, baseline bicarbonate, and eGFR screening More than 0 in the group. The p-value of the interaction between treatment and each subgroup was obtained from a logistic regression model, in which the interaction of treatment, subgroup, and treatment×subgroup was included as a predictor. However, these should be explained together with the points that give the post-mortem nature of analysis and multiple comparisons. Body function

Metabolic acidosis has been shown to be an important factor contributing to the reduction of muscle mass, the reduction of lean body mass and muscle strength, and the increase of protein metabolic rate. Before the measurable decrease in blood bicarbonate, the body was partially adapted to increase the acid load (mainly protein and organophosphates) by using intracellular buffers in the muscles.

Two exploratory endpoints were included in this study to assess whether improvements in muscle function and patient quality of life can be demonstrated in the patient population through treatment of metabolic acidosis. The first exploratory endpoint tested the effect of TRC101 treatment on the self-reported response or KDQOL-SF survey of the body function subsection of kidney disease and quality of life profiles. The KDQOL-SF survey is a validated questionnaire designed to assess health-related quality of life or HRQOL in patients with kidney disease. Participants in the trial responded to 10 questions related to physical function during the daily activity or KDQOL-SF physical function survey (Question 3) (see, for example, Figure 21). The conversion of the survey scores is as follows: 1 (very limited) = 0; 2 (a few limited) = 50; 3 (unrestricted) = 100 Overall score = the sum of all 10 divided by 10. The second exploratory endpoint objectively measures the body functions derived from the repeated chair stand test/Repeated Chair Stand Test. In the repeated sit-and-stand test, the subject was required to hold his chest with his hands and stand up once from the sitting position; if he successfully got up from the chair, he was asked to stand up and sit down five times as quickly as possible, and record this The time for five repetitions (see, for example, Figure 22). The KDQOL-SF body function survey and repeated sit-and-stand test were administered and scored in a blinded manner, and the change from baseline in the body function survey score and repeated sit-and-stand test time at week 12 was pre-defined as an exploratory endpoint.

At the end of 12 weeks of treatment, compared to placebo-treated patients, as measured by the KDQOL body function domain, the patient’s restrictions on performing daily activities such as climbing stairs and walking (Figure 21) Physical function, quantified from the degree of reporting, increased significantly in patients treated with TRC101 (p=0.0122) (Figure 20A). Such as literature (Clement, FM et al., 2009, The Impact of Selecting a High Hemoglobin Target Level on Health-Related Quality of Life for Patients with Chronic Kidney Disease: A Systematic Review and Meta-Analysis, Arch. Intern. Med. 169 ( 12): 1104 to 1112; Collister, D et al., 2016, The Effect of Erythropoietin-Stimulating Agents on Health-Related Quality of Lide in Anemia of Chronic Kidney Disease: A Systematic Review and Meta-Analysis, Ann. Intern. Med. 164(7): 472 to 478; Leaf, DE et al., 2009, Interpretation and Review of Health-Related Quality of Life Data in CKD Patients Receiving Treatment for Anemia, KidneyInt. 75(1): 15 to 24; Samsa, G Et al., Determining Clinically Important Differences in Health Status Measures: A General Approach with Illustration to the Health Utilities Index Mark II, Pharmacoeconomics, 15(2): 141 to 155), the average LS in the TRC101 group (95% CI ) Both changes (6.3 [3.7, 8.9]) and placebo-less treatment effects (5.2 [1.1, 9.2]) both exceeded the minimum clinically significant difference in the KDQOL subscale. If the physical function is measured by repeated sitting and standing tests, the numerical improvement in the TRC101 group (p=0.0249) and the numerical deterioration in the placebo group (p=0.5727): average (LS average [95% CI]) and In other words, sitting time increased by 0.35 (-0.9, 1.6) seconds in the placebo group and decreased by 1.17 (0.2, 2.2) seconds in the TRC101 group (Figure 20B). The difference between the groups was not statistically significant (p=0.0630). (Figures 20A to 20B-Changes in body function.) (Figure 20A: The patient reported how he was limited in 10 items in the body function domain of kidney disease and quality of life (KDQOL) at baseline and at week 12 of treatment (see Figure 21). The least squared mean and 95% CI of the total change score from baseline to week 12 are presented for each group. The smallest clinically significant difference reported for the KDQOL subscale ranged from 3 to 5 points.) ( Figure 20B: Timing the patient at a speed that can be repeated five times from the chair at baseline and the 12th week of treatment at this speed. The change from baseline to the 12th week during the time the repeated sit-stand test is performed for each group The least squares mean and 95% CI. Not all patients are able to perform the test. Present the data of the patients who performed the test at baseline and week 12. (TRC101, n=109; placebo, n=76).)

Post-mortem analysis of physical function shows a strong correlation between the consistent results of the patient's reported physical function (p=0.0117) and the time between completion of the repeated sitting and standing test (p=0.0027), both of which contribute to TRC101 . safety

TRC101 is well tolerated. Overall, more than 95% of the subjects in each group completed the trial. The overall treatment-related adverse events occurred in 9.7% of the placebo group and 13.7% of the TRC101-treated subjects. The most common treatment-related adverse events were mild to moderate GI disorders, which occurred in 5.4% of subjects in the placebo group and 12.9% of subjects treated with TRC101. Adverse GI events that occurred in more than one subject in the trial included diarrhea, flatulence, nausea, and constipation. The only other treatment-related adverse event that occurred in more than one subject was paresthesia (1.1% of subjects in the placebo group and 0.8% of subjects treated with TRC101). TRC101 has no significant effect on serum parameters such as sodium, calcium, potassium, phosphate, magnesium, or low-density lipoprotein that would be observed in experiments that would indicate off-target effects of TRC101. A high blood bicarbonate content was temporarily observed in 2 individuals, defined as greater than 30 mEq/L, or 0.9%. The interruption of the TRC101, a defined dosing algorithm per protocol, resulted in the standardization of blood bicarbonate in these subjects.

TRC101 had no significant effect on vital signs, ECG interval, renal function, blood disease parameters, liver function tests, lipid or urine analysis (Table 806). Table 806 Changes in laboratory parameters and blood pressure from baseline after 12 weeks of treatment

論述 High (>30 mmol/L) serum bicarbonate content was temporarily observed in two patients but the interruption of the study drug according to the titration algorithm per protocol was standardized. The absence of serum electrolytes will indicate a significant effect of the off-target effect of TRC101 (Table 806). The incidence of serum potassium ≥5.0 mmol/L or ≥6.0 mmol/L (Table 807) and the mean serum potassium over time were similar in both groups. Table 807 Proportion of patients whose serum potassium exceeds the predefined threshold

Discourse

In non-dialysis dependent patients with CKD and chronic metabolic acidosis (mean serum bicarbonate 17.3 mmol/L), 12 weeks of treatment with TRC101 significantly increased serum bicarbonate, of which 50% of patients achieved standardization , 56% achieved an increase of ≥4 mmol/L, and 59% met the composite lead endpoint limit. The average increase in serum bicarbonate in the TRC101 group at week 12 was 4.5 mmol/L, and 39% and 26% of patients treated with TRC101 had an increase in serum bicarbonate ≥6 mmol/L and ≥7 mmol/L, respectively . In these outpatients whose dietary protein intake was not controlled by the study protocol, the effect of TRC101 on serum bicarbonate was rapid and sustained within 12 weeks.

Accumulated acid-stimulated accumulation increases renal production of endothelin, angiotensin II and aldosterone, provides short-term benefits that promote renal tubular acid excretion but contributes to renal interstitium in the long-term by promoting progressive decline in renal function Inflammatory and fibrotic and harmful substances. In a similar manner, in response to acid maintenance, the kidneys increase the production of amines per functional nephron to facilitate acid excretion; however, the increased levels of amines also contribute to the activity of inflammation and supplementation of renal fibrosis.

Metabolic acidosis in patients with CKD has traditionally been treated with sodium base supplements (sodium bicarbonate, sodium citrate) that enter the systemic circulation and neutralize the accumulated acid. Because of the risk of life-threatening hyperkalemia, potassium-based therapies (such as potassium bicarbonate) are rarely used in patients with CKD. Alternative treatments for metabolic acidosis include vegetarian diets, but these diets restrict patient choice and have low long-term compliance. In the absence of sodium or potassium loading, replacement therapy will remove rather than neutralize the acid. The removal of acid by binding to a non-absorbed polymer that is subsequently excreted is a potentially novel mechanism for treating metabolic acidosis in patients with CKD.

The studies described in this example indicate that the unabsorbed relatively ion-free polymer drug TRC101, which selectively binds and removes hydrochloric acid from the gastrointestinal tract and thus increases the systemic bicarbonate concentration, is effective in the treatment of metabolic acidosis. These findings indicate that the effect of TRC101 on serum bicarbonate reached a flat line after 4 to 8 weeks of treatment, and that the effect was maintained in the CKD population of outpatients who took a free choice of diet for 12 weeks.

The embodiments described in this disclosure may be combined in various ways. Any aspect or feature described for one embodiment may be incorporated into any other embodiment mentioned in this disclosure. Although various novel features of the principles of the present invention as applied to its specific embodiments have been shown, described, and pointed out, it should be understood that those skilled in the art can make various omissions and substitutions without departing from the spirit of the present disclosure And change. Those skilled in the art will understand that the principles of the present invention may be practiced in addition to the described embodiments, which are presented for illustrative purposes and are not limiting.

The patent or application file contains at least one color drawing. After applying and paying the necessary fees, the Patent Office will provide a copy of the patent or patent application publication in color.

The following drawings form part of this specification and are included here to further demonstrate certain aspects of the invention. The invention can be better understood with reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

Figures 1A-1C schematically depict the passage of the polymer from the oral intake/stomach (Figure 1A) through the individual's gastrointestinal tract to the upper gastrointestinal tract (GI tract) (Figure 1B) to the lower gastrointestinal tract/colon (Figure 1C) Flow chart of the mechanism of time.

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

Figures 3A, 3B and 3C are the chlorine (Figure 3A), sulfuric acid (Figure 3B) and phosphoric acid in the rat model of TRC101 in Part 1 of the study described in Example 1 for adenine-induced nephropathy and metabolic acidosis Figure 3C) A graph of the effect of fecal secretion.

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

5A, 5B, and 5C are the chlorine (Figure 5A), sulfuric acid (Figure 5B), and phosphoric acid in the rat model of TRC101 in Part 2 of the study described in Example 1 for adenine-induced nephropathy and metabolic acidosis. Figure 5C) A graph of the effect of fecal secretion.

6A, 6B and 6C are in vivo chlorine (FIG. 6A), sulfuric acid (FIG. 6B) and phosphoric acid (TRC101 and bixalomer) in vivo in pigs with normal kidney function in the study described in Example 2. Figure 6C) The graph of the binding force.

7 is a graph showing the mean change and standard error (SE) of the serum bicarbonate (SBC) from the baseline (BL) of the treatment group over time in the human study as described more fully in Example 3 (Part 1) Line graph.

Figure 8 is a graph showing the least squared mean (LS mean) baseline change (CFB) from the treatment group's serum bicarbonate (SBC) to the end of treatment in a human study as described more fully in Example 3 (Part 1) ) Bar chart. A single asterisk ("*") indicates a statistically significant difference (p<0.5) and a double asterisk ("**") indicates a statistically significant difference in height (p<0.0001).

Figure 9 is a graph showing the effects of treatment (Tx=treatment) in human studies as described more fully in Example 3 (Part 1) and the treatment of serum bicarbonate on days 8 and 15 caused by withdrawal of TRC101 ( SBC) A bar graph of the effects of content and standard error.

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

11 is a graph showing the least squared mean of serum bicarbonate (SBC) over time in four TRC101 active groups and two placebo groups used in the study more fully described in Example 3 (Parts 1 and 2) (LS mean) histogram of baseline change (CFB). A single asterisk ("*") indicates a statistically significant difference (p<0.5) and a double asterisk ("**") indicates a statistically significant difference in height (p<0.0001).

Figure 12 is a graph showing the serum carbonic acid on day 8 and day 15 caused by treatment with TRC101 (Tx=treatment) and withdrawal in human studies as described more fully in Example 3 (Parts 1 and 2) Bar graph of the therapeutic effect of hydrogen salt (SBC) content and standard error (SE).

Figures 13A, 13B, 13C and 13D show the serum bicarbonate over time for the four TRC101 active groups (combination) versus the two placebo groups (combined) used in the study more fully described in Example 3 (Parts 1 and 2) Curves of changes in salt (Figure 13A), serum chlorine (Figure 13B), serum sodium (Figure 13C), and serum potassium (Figure 13D).

Figure 14 is a graph showing the change in the calculated anion gap over time for the four TRC101 active groups for the study more fully described in Example 3 (Parts 1 and 2) versus the two placebo groups (combined).

Figure 15 is a data set analysis diagram and timetable, as described in more detail in Example 4.

Figure 16 is a flow chart for population analysis, as described in more detail in Example 4.

Figure 17 is a graphical representation of the subgroups used for Cox regression analysis, as described in more detail in Example 4.

18 is an analysis diagram and timeline for clinical trials as described in more detail in Example 5. FIG.

19A is a graph showing the composite primary endpoint at the end of the treatment period used in the clinical study described in more detail in Example 5. FIG.

19B is a graph showing the achievement of serum bicarbonate thresholds at various time points for the clinical study described in more detail in Example 5. FIG.

19C is a graph showing the change from baseline in serum bicarbonate over time at various time points used in the clinical study described in more detail in Example 5. FIG.

FIGS. 20A-20B show the statistically significant improvement in the physical function of specific subjects of TRC101-treated individuals experiencing quality of life based on the results from question #3 in the KDQOL-SF survey for the clinical study described in more detail in Example 5. Schema.

Figure 21 is a copy of Question #3 for the KDQOL-SF survey described in the clinical study described in Example 5. The score conversion is as follows: 1 (many limits) = 0; 2 (minimum limit) = 50; 3 (unlimited) = 100. Total score = the sum of all 10, divided by 10.

FIG. 22A is a single sitting and repeated sitting method, including a copy of the scoring criteria (FIG. 22B), as described in Example 5 in more detail.

23 is a table showing the analysis of the baseline total score based on kidney disease and quality of life (question 3) at Week 12 as described in Example 5 in more detail.

FIG. 24 is a table showing the analysis based on the baseline time (seconds) at which the repeated sitting at the end of the 12th week, as described in Example 5 in more detail.

25 is a diagram showing the overall design of the retrospective model, as described in Example 4 in more detail.

FIG. 26 is a graph showing the time when the DD40 end point first appeared, as described in more detail in Example 4.

Claims (84)

A method for improving the quality of life of patients suffering from chronic kidney disease and acid-base disorders characterized by a baseline serum bicarbonate value ≤22 mEq/L. The method includes oral administration for at least twelve weeks The patient's serum bicarbonate increased and maintained a pharmaceutical composition above 20 mEq/L, which has the ability to bind the target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids. A method for improving the quality of life of patients suffering from chronic kidney disease and acid-base disorders, the method comprising orally administering a pharmaceutical composition having the following: (a) the ability to selectively bind a target species selected from the group consisting of: protons , Strong acids, and strong acid conjugate bases; and (b) at least 3 mEq/g of target species binding capacity in simulated small intestine inorganic buffer (SIB) analysis, where the improvement in quality of life is at least 3% compared to placebo Twelve weeks are statistically significant, as assessed by a quality of life (QoL) questionnaire. A method for improving the quality of life of a patient suffering from chronic kidney disease and acid-base disorders, wherein the patient has a baseline serum bicarbonate value of ≤22 mEq/L, the method comprises once daily administering an effective amount of TRC101 to the patient A period of time sufficient to statistically significantly increase the patient's quality of life compared to the placebo control group. A method for improving the quality of life of a patient suffering from a metabolic acidosis disease, the method comprising administering to the patient a daily dose of non-absorbable cross-linked amine polymer, wherein the daily dose: (a) is sufficient to carbonate the patient's serum An increase in hydrogen salt concentration of at least 1 mEq/L; (b) produces an increase in serum bicarbonate that lasts at least 1 mEq/L over a period of at least twelve weeks; and (c) is sufficient during this period compared to placebo control The group improved the quality of life of the patient, where the improvement in quality of life was statistically significant. A pharmaceutical composition for improving the quality of life of human patients suffering from chronic kidney disease and acid-base disorders, the patient having a baseline serum bicarbonate content of ≤22 mEq/L before treatment, the composition is a non- Absorbent composition: (a) remove target species selected from the group consisting of protons, strong acids, and strong acid conjugate bases; and (b) statistically significant for a period of at least twelve weeks The method improved the patient's quality of life compared to the placebo control group. A pharmaceutical composition for improving the quality of life of a human patient suffering from a disease or condition by increasing the patient's serum bicarbonate value by at least 1 mEq/L within at least twelve weeks of treatment, the composition is: (a) Non-absorbable composition with the ability to remove target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (b) characterized by simulating small intestine inorganic buffer (SIB) At least 3 mEq/g of the target species binding capacity in the analysis; and (c) the ability to improve the patient's quality of life in a statistically significant manner compared to the placebo control group over a period of at least twelve weeks. A pharmaceutical composition for improving the quality of life of a human patient suffering from metabolic acidosis, wherein; (a) an effective amount of the pharmaceutical composition is administered to the patient every day for a period of at least twelve weeks; (b ) The pharmaceutical composition is non-absorbable and has the ability to remove target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (c) the pharmaceutical composition is characterized by Chloride ion binding capacity of at least 3 mEq/g in the simulated small intestine inorganic buffer (SIB) analysis; and (d) the improvement in quality of life during the twelve-week period is statistically significant compared to the placebo control group . A method for improving the physical function of patients suffering from chronic kidney disease and acid-base disorders characterized by a baseline serum bicarbonate value ≤22 mEq/L, which includes a period of at least twelve weeks Oral administration of a pharmaceutical composition capable of increasing and maintaining the patient's serum bicarbonate above 20 mEq/L, the pharmaceutical composition having the ability to bind target species selected from the group consisting of protons, strong acids, and strong acids Conjugate base. A method for improving the physical function of patients suffering from chronic kidney disease and acid-base disorders, the method comprising orally administering a pharmaceutical composition having the following: (a) the ability to selectively bind a target species selected from the group consisting of: Protons, strong acids, and strong acid conjugate bases; and (b) at least 3 mEq/g of target species binding capacity in simulated small intestine inorganic buffer (SIB) analysis, where, for example, the patient’s quality of life for kidney disease KDQOL-SF)'s answer to question 3 assesses that, at least twelve weeks after starting treatment, the improvement in physical function is statistically significant compared to the placebo control group. A method for improving the physical function of a patient suffering from chronic kidney disease and acid-base disorders, wherein the patient has a baseline serum bicarbonate value of ≤22 mEq/L, the method comprising orally administering an effective amount to the patient once a day TRC101 is a period of time sufficient to statistically significantly increase the patient’s physical function score compared to the patient’s baseline physical function score based on question 3 of the KDQOL-SF Reply. A method for improving the physical function of a patient suffering from a metabolic acidosis disease, the method comprising administering to the patient a daily dose of a non-absorbable cross-linked amine polymer whose daily dose is: (a) sufficient to treat the patient's serum An increase in bicarbonate concentration of at least 1 mEq/L; (b) an increase in serum bicarbonate that lasts at least 1 mEq/L over a period of at least twelve weeks; and (c) sufficient at the end of the period compared to comfort The agent control group improved the patient's physical function score, wherein the improvement of the physical function score was statistically significant. A pharmaceutical composition for improving the physical function score of a human patient suffering from chronic kidney disease and acid-base disorders, the patient has a baseline serum bicarbonate content of ≤22 mEq/L before treatment, the composition is capable of Non-absorbable composition: (a) remove the target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; and (b) at the end of at least a twelve week period, Compared with the placebo control group, the patient's physical function score was improved in a statistically significant manner based on the answer to question 3 in the Kidney Disease Quality of Life Summary (KDQOL-SF). A pharmaceutical composition for improving the body function score of a human patient suffering from a disease or condition by increasing the patient's serum bicarbonate value by at least 1 mEq/L within at least twelve weeks of treatment, the composition It is: (a) a non-absorbable composition with the ability to remove target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (b) characterized by an inorganic buffer in the simulated small intestine Fluid (SIB) analysis of at least 3 mEq/g of target species binding capacity; and (c) the ability to improve the patient’s performance in a statistically significant manner compared to the placebo control group at the end of at least the twelve-week period Body function score, which is based on the answer to question 3 in the Kidney Disease Quality of Life Short Form (KDQOL-SF). A pharmaceutical composition for improving the physical function score of a human patient suffering from a metabolic acidosis disease, wherein: (a) an effective amount of the pharmaceutical composition is administered to the patient daily for a period of at least twelve weeks; ( b) The pharmaceutical composition is non-absorbable and has the ability to remove target species selected from the group consisting of protons, strong acids, and strong acid conjugate bases; (c) characteristics of the pharmaceutical composition Lies in the chloride ion binding capacity of at least 3 mEq/g in the simulated small intestine inorganic buffer (SIB) analysis; and (d) at the end of the at least twelve-week period, the physical function score is compared to the placebo control group The improvement is statistically significantly improved from the baseline physical function score, which is based on the answer to question 3 in the Kidney Disease Quality of Life Short Form (KDQOL-SF). A method for slowing the progression of nephropathy in patients suffering from chronic kidney disease and acid-base disorders characterized by a baseline serum bicarbonate value ≤22 mEq/L, the method comprising oral administration capable of increasing and maintaining the The pharmaceutical composition of the patient whose serum bicarbonate is higher than 20 mEq/L for a period of at least twelve weeks, the pharmaceutical composition has the ability to bind the target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids . A method for slowing the progression of nephropathy in patients suffering from chronic kidney disease and acid-base disorders, wherein the patient has a baseline serum bicarbonate value of ≤22 mEq/L, the method comprises orally administering an effective amount to the patient once a day TRC101 is a period of time sufficient to increase the patient's serum bicarbonate by at least 1 mEq/L. A method of slowing the progression of kidney disease in a patient suffering from chronic kidney disease and metabolic acidosis disease, the method comprising administering to the patient a daily dose of a non-absorbable cross-linked amine polymer whose daily dose: (a) is sufficient to treat The patient's serum bicarbonate concentration increases by at least 1 mEq/L; (b) produces an increase in serum bicarbonate lasting at least 1 mEq/L over a period of at least twelve weeks; and (c) is sufficient to slow the progression of the kidney disease. A pharmaceutical composition for slowing the progression of kidney disease in human patients suffering from chronic kidney disease and acid-base disorders, the patient having a baseline serum bicarbonate content of ≤22 mEq/L before treatment, the composition is capable of Non-absorbable composition: (a) remove target species selected from the group consisting of protons, strong acids, and strong acid conjugate bases; and (b) slow down human patients for a period of at least twelve weeks The progress of kidney disease. A pharmaceutical composition for slowing the progression of kidney disease in human patients suffering from chronic kidney disease and acid-base disorders by increasing the patient's serum bicarbonate value by at least 1 mEq/L within at least twelve weeks of treatment, the combination The substance is: (a) a non-absorbable composition with the ability to remove target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; (b) characterized by simulating the small intestine inorganic At least 3 mEq/g of target species binding capacity in buffer (SIB) analysis; and (c) the ability to slow the progression of the kidney disease for at least the twelve-week period. A pharmaceutical composition for slowing the progression of kidney disease in human patients also suffering from metabolic acidosis, wherein: (a) an effective amount of the pharmaceutical composition is administered to the patient daily for a period of at least twelve weeks; ( b) The pharmaceutical composition is non-absorbable and has the ability to remove target species selected from the group consisting of protons, strong acids, and strong acid conjugate bases; (c) characteristics of the pharmaceutical composition Lies in the chloride ion binding capacity of at least 3 mEq/g in the simulated small intestine inorganic buffer (SIB) analysis; and (d) compared to the placebo control group that did not receive the pharmaceutical composition, slowed down during the twelve-week period The kidney disease progressed in this patient. A pharmaceutical composition for a method of treating an acid-base disorder of a patient, wherein the treatment method improves the quality of life of the patient. A pharmaceutical composition for a method of treating an acid-base disorder in a patient, wherein the treatment method improves the patient's physical function. The method/composition of any one of the preceding claims, wherein the pharmaceutical composition increases the serum bicarbonate content in the placebo-controlled study by at least 1 mEq/L, the increase being that in the first group at the end of the study The difference between the average serum bicarbonate content of the group and the average serum bicarbonate content of the group in the second group at the end of the study, wherein the individuals in the first group received the pharmaceutical composition and the individuals in the second group A placebo was received, where the first and second groups each contained a patient population of sufficient size to estimate the statistically significant difference in serum bicarbonate content between the groups during the period. The method/composition of any of the preceding claims, wherein the pharmaceutical composition increases the serum bicarbonate content by at least 2 mEq/L in a placebo-controlled study, the increase being in the first group at the end of the study The difference between the average serum bicarbonate content of the group and the average serum bicarbonate content of the group in the second group at the end of the study, wherein the individuals in the first group received the pharmaceutical composition and the second group Individuals received a placebo, where the first and second groups each included a patient population of sufficient size to estimate a statistically significant difference in serum bicarbonate content between the groups during the period. The method/composition of any one of the preceding claims, wherein the pharmaceutical composition increases the serum bicarbonate content in the placebo-controlled study by at least 2.5 mEq/L, the increase being that in the first group at the end of the study The difference between the average serum bicarbonate content of the group and the average serum bicarbonate content of the group in the second group at the end of the study, wherein the individuals in the first group received the pharmaceutical composition and the individuals in the second group A placebo was received, where the first and second groups each contained a patient population of sufficient size to estimate the statistically significant difference in serum bicarbonate content between the groups during the period. The method/composition of any of the preceding claims, wherein the pharmaceutical composition has the ability to change the baseline serum bicarbonate content of the patient by at least 2 mEq/L at the end of the placebo-controlled study for at least twelve weeks. The method/composition of any of the preceding claims, wherein the pharmaceutical composition has the ability to change the baseline serum bicarbonate content of the patient by at least 3 mEq/L at the end of the placebo-controlled study for at least twelve weeks. The method/composition of any of the preceding claims, wherein the pharmaceutical composition has the ability to change the baseline serum bicarbonate content of the patient by at least 4 mEq/L at the end of the placebo-controlled study for at least twelve weeks. The method/composition of any one of the preceding claims, wherein the patient population of each group is at least 25 patients. The method/composition of any of the preceding claims, wherein the patient population of each group is at least 50 patients. The method/composition of any of the preceding claims, wherein the patient population of each group is at least 100 patients. The method/composition of any one of the preceding claims, wherein the patient population of each group is at least 150 patients. The method/composition of any of the preceding claims, wherein the patient population of each group is at least 200 patients. A method/composition as claimed in any one of the preceding claims, wherein the quality of life or body is assessed by the same questionnaire answered by the first group at the end of the period relative to the same questionnaire answered by the second group at the end of the period Functional improvement, wherein the individuals in the first group receive the pharmaceutical composition and the individuals in the second group receive a placebo. The method/composition of any one of the preceding claims, wherein the improvement in quality of life or physical function is assessed by questionnaire, which is a clinically validated assessment used to assess the physical and mental health of the patient. The method/composition of any of the preceding claims, wherein the questionnaire contains questions about parameters selected from the group consisting of: symptoms/problems related to diseases/pathologies, effects of diseases/pathologies, diseases/ The burden of pathology, work status, cognitive function, quality of social interaction, sleep, social support, physical function, pain, general health, emotional well-being, social function, energy/fatigue, and combinations thereof. The method/composition of any one of the preceding claims, wherein the questionnaire contains questions about how the patient's health limits the patient's ability to participate in physical activities selected from the group consisting of: vigorous activities; moderate activities ; Lifting or carrying groceries; climbing a number of stairs; climbing a floor of stairs; leaning over, kneeling or bending; walking more than a mile; walking a few blocks; walking a block; and bathing or dressing. The method/composition of any of the preceding claims, wherein the patient achieves at least about a 10% improvement in the quality of life rating relative to the placebo control group. The method/composition of any one of the preceding claims, wherein the patient achieves at least about 25% improvement in the quality of life rating relative to the placebo control group. The method/composition of any one of the preceding claims, wherein the patient achieves at least about 50% improvement in the quality of life rating relative to the placebo control group. The method/composition of any one of the preceding claims, wherein the patient achieves at least about 75% improvement in the quality of life rating relative to the placebo control group. The method/composition of any one of the preceding claims, wherein the improvement in physical function comprises: (a) based on the patient’s answer to question 3 in the Kidney Disease Quality of Life Summary (KDQOL-SF), the patient’s baseline A physical function score improvement of at least 1.5 points; (b) the patient’s baseline repeat sitting time is improved by at least -1.5 seconds; or (c) the patient’s baseline physical function score based on the patient’s answer to question 3 in KDQOL-SF Improve by at least 1.5 minutes, and the patient's baseline repeat sitting time improves by at least -1.5 seconds. The method/composition of any one of the preceding claims, wherein the improvement of the patient's baseline physical function score is based on the patient's Single Chair Stand and/or repeated sitting as depicted in Figure 22 Stand (Repeated Chair Stand) performance. The method/composition of any one of the preceding claims, wherein the improvement in the patient's baseline repeat sitting time represents an improvement in at least one repeat. The method/composition of any one of the preceding claims, wherein the improvement in the patient's baseline repeat sitting time represents an improvement in at least two repeats. The method/composition of any one of the preceding claims, wherein the improvement in the patient's baseline repeat sitting time represents an improvement in at least three repeats. The method/composition of any one of the preceding claims, wherein the improvement in the patient's baseline repeat sitting time represents an improvement in at least four repeats. The method/composition of any one of the preceding claims, wherein the improvement in the patient's baseline repeat sitting time represents an improvement in at least five repeats. The method/composition of any of the preceding claims, wherein the improvement in the patient's baseline physical function score is based on the patient's answer to at least one question of question 3 in the KDQOL-SF as depicted in FIG. 21. The method/composition of any of the preceding claims, wherein the improvement in the patient's baseline physical function score is based on the patient's answers to at least five questions of question 3 in the KDQOL-SF as depicted in FIG. 21 . The method/composition of any of the preceding claims, wherein the improvement of the patient's baseline physical function score is based on the patient's answers to at least seven questions of question 3 in the KDQOL-SF as depicted in FIG. 21 . The method/composition of any of the preceding claims, wherein the improvement in the patient's baseline physical function score is based on the patient's answers to all questions in question 3 of the KDQOL-SF as depicted in FIG. 21. The method/composition of any one of the preceding claims, wherein the improvement in the patient's quality of life includes the reduction or prevention of further bone loss and/or the reduction or prevention of further muscle loss in the patient. The method/composition of any one of the preceding claims, wherein the improvement in the physical function score further comprises that the patient's baseline repeated sitting time is improved by at least -1.5 seconds during the period compared to the placebo control group. The method/composition of any of the preceding claims, wherein the patient achieves an improvement of at least about 1.5 points in the KDQOL-SF grade relative to the placebo control group. The method/composition of any of the preceding claims, wherein the patient achieves an improvement of at least about 3.0 points in the KDQOL-SF grade relative to the placebo control group. The method/composition of any of the preceding claims, wherein the patient achieves an improvement of at least about 4.5 points on the KDQOL-SF grade relative to the placebo control group. The method/composition of any of the preceding claims, wherein the patient achieves an improvement of at least about 6.0 points in the KDQOL-SF grade relative to the placebo control group. The method/composition of any one of the preceding claims, wherein the KDQOL-SF score of the patient is calculated as follows: 1 (many limits) = 0; 2 (minimum limit) = 50; 3 (unlimited) = 100 ; Total score = the sum of all 10, divided by 10. The method/composition of any of the preceding claims, wherein the disease or condition is characterized by a baseline serum bicarbonate value of less than 18 mEq/L. The method/composition of any of the preceding claims, wherein the disease or condition is characterized by a baseline serum bicarbonate value of at least 12 mEq/L. The method/composition of any of the preceding claims, wherein the disease or condition is characterized by a baseline serum bicarbonate value of at least 15 mEq/L. The method/composition of any of the preceding claims, wherein the patient's baseline serum bicarbonate value increases by at least 1 mEq/L during this period. The method/composition of any of the preceding claims, wherein the patient's baseline serum bicarbonate value increases by at least 2 mEq/L during this period. The method/composition of any of the preceding claims, wherein the patient's baseline serum bicarbonate value increases by at least 3 mEq/L during this period. The method/composition of any one of the preceding claims, wherein the patient is administered a daily dose of the pharmaceutical composition, and the daily dose has the ability to be at least about 10 milliequivalents (mEq)/day, at least about The target species of 15 meq/day, at least about 20 meq/day, at least about 25 meq/day, or at least about 30 meq/day is removed. The method/composition of any one of the preceding claims, wherein the patient is administered a daily dose of the pharmaceutical composition and the daily dose has the ability to be less than 50 milliequivalents/day or less than 35 milliequivalents/day The target species is removed. The method/composition of any one of the preceding claims, wherein the period of time is at least three weeks, at least one month, at least two months, at least six months, at least 12 months, at least 18 months, or at least 24 month. The method/composition of any one of the preceding claims, wherein the pharmaceutical composition has the ability to bind a target species selected from the group consisting of protons, strong acids, and conjugate bases of strong acids. The method/composition of any of the preceding claims, wherein the conjugate base of the strong acid is selected from the group consisting of chloride ion, bisulfate ion and sulfate ion. The method/composition of any of the preceding claims, wherein the target species contains chloride ions. The method/composition of any of the preceding claims, wherein the target species includes hydrochloric acid. The method/composition of any one of the preceding claims, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 1 mEq/g in SIB analysis. The method/composition of any of the preceding claims, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 1.5 mEq/g in SIB analysis. The method/composition of any of the preceding claims, wherein the pharmaceutical composition is characterized by a chloride ion binding capacity of at least 2 mEq/g in SIB analysis. The method/composition of any of the preceding claims, wherein the pharmaceutical composition has the ability to bind chloride and phosphate ions in a SIB analysis at a ratio of at least 0.25:1, respectively. The method/composition of any one of the preceding claims, wherein the pharmaceutical composition has the ability to bind chloride and phosphate ions in a SIB analysis at a ratio of at least 0.5:1. The method/composition of any one of the preceding claims, wherein the pharmaceutical composition has the ability to bind chloride and phosphate ions in a SIB analysis at a ratio of at least 1:1, respectively. The method/composition of any one of the preceding claims, wherein the effective amount of the pharmaceutical composition or TRC101 comprises at least about 1 g/day. The method/composition of any one of the preceding claims, wherein the effective amount of the pharmaceutical composition or TRC101 comprises about 1 to 9 g/day. The method/composition of any one of the preceding claims, wherein the effective amount of the pharmaceutical composition or TRC101 comprises about 4 to 6 g/day. The method/composition of any one of the preceding claims, wherein the effective amount of the pharmaceutical composition or TRC101 comprises about 6 g/day. The method/composition of any of the preceding claims, wherein the patient is administered an effective amount of the pharmaceutical composition or TRC101 in an oral dosage form once a day. The method/composition of any one of the preceding claims, wherein the effective amount of the pharmaceutical composition or TRC101 is adjusted to maintain the patient's serum bicarbonate content in the range between 22 and 29 mEq/L.

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