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EP-3703706-B1 - COMPOSITIONS FOR AND METHOD OF TREATING ACID-BASE DISORDERS

EP3703706B1EP 3703706 B1EP3703706 B1EP 3703706B1EP-3703706-B1

Inventors

  • KLAERNER, GERRIT
  • BUYSSE, JERRY M.
  • SHAO, JUN
  • OTTO, Dawn Parsell

Dates

Publication Date
20260506
Application Date
20181103

Claims (14)

  1. A nonabsorbable pharmaceutical composition that binds a target species comprising HCl and/or H 2 SO 4 for use in a method of treating or preventing eubicarbonatemic metabolic acidosis in a patient wherein the method comprises oral administration of the nonabsorbable pharmaceutical composition, the nonabsorbable pharmaceutical composition is a proton-binding, crosslinked amine polymer comprising the residue of an amine, or salt thereof, selected from 1,4-bis(allylamino)butane, 1,2-bis(allylamino)ethane, 2-(allylamino)-1-[2-(allylamino)ethylamino]ethane, 1,3-bis(allylamino)propane, 1,3-bis(allylamino)-2-propanol, 2-propen-1-ylamine, 1-(allylamino)-2-aminoethane, 1-[N-allyl(2-aminoethyl)amino]-2-aminoethane, and N,N,N- triallylamine, and the crosslinked amine polymer is crosslinked with a crosslinking agent that may be used in substitution polymerization reactions and post-polymerization crosslinking reactions selected from 1,2-dibromoethane, 1,3-dichloropropane, 1,2-dichloroethane, 1-bromo-2-chloroethane, and 1,3-dibromopropane.
  2. The nonabsorbable pharmaceutical composition for use according to claim 1, wherein the patient has chronic kidney disease.
  3. The nonabsorbable pharmaceutical composition for use according to claim 1 or claim 2, wherein the nonabsorbable pharmaceutical composition binds HCl.
  4. The nonabsorbable pharmaceutical composition for use according to any preceding claim wherein the treatment enables the patient's serum bicarbonate value to be sustained at a value greater than 24 mEq/I but not greater than 29 mEq/I for a period of at least: (a) one week, (b) one month, (c) three months, (d) six months, or (e) one year.
  5. The nonabsorbable pharmaceutical composition for use according to any preceding claim, wherein the crosslinked amine polymer has a chloride ion to phosphate ion binding molar ratio of at least 2:1, respectively, in an aqueous simulated small intestine inorganic buffer ("SIB") containing 36 mM NaCl, 20 mM NaH 2 PO 4 , and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5 and at 37 °C
  6. The nonabsorbable pharmaceutical composition for use according to any preceding claim, wherein the residue of the amine, or salt thereof, is selected from 1,3-bis(allylamino)propane, and 2-propen-1-ylamine.
  7. The nonabsorbable pharmaceutical composition for use according to any preceding claim, wherein the crosslinking agent is selected from 1,2-dibromoethane, 1,2-dichloroethane and 1-bromo-2-chloroethane.
  8. The nonabsorbable pharmaceutical composition for use according to any preceding claim, wherein the crosslinking agent is 1,2-dichloroethane.
  9. The nonabsorbable pharmaceutical composition for use according to any one of claims 1-4, wherein the crosslinked amine polymer is obtainable by first copolymerizing two monomers, allylamine hydrochloride and N,N'-diallyl-1,3-diaminopropane dihydrochloride followed by crosslinking the polymer with 1,2-dichloroethane.
  10. The nonabsorbable pharmaceutical composition for use according to any preceding claim, wherein the crosslinked amine polymer comprises a structure corresponding to Formula 4: wherein each R is indendently hydrogen or an ethylene crosslink between two nitrogen atoms of the crosslinked amine polymer and a, b, c, and m are integers.
  11. The nonabsorbable pharmaceutical composition for use according to any preceding claim wherein the patient has an mGFR and/or eGFR of: (a) at least 15 mL/min/1.73 m 2 , (b) at least 30 mL/min/1.73 m 2 , (c) less than 45 mL/min/1.73 m 2 , or (d) less than 60 mL/min/1.73 m 2 .
  12. The nonabsorbable pharmaceutical composition for use according to any preceding claim wherein the patient or the eubicarbonatemic metabolic acidosis is (A) characterized by baseline urine citrate excretion values below about: (a) 640 mg/day, (b) 400 mg/day, or (c) 180 - 370 mg/day; and/or (B) characterized by a baseline urine ammonium excretion above about: (a) 40 mEq/day, (b) 100 mEq/day, or (c) 200 mEq/day.
  13. The nonabsorbable pharmaceutical composition for use according to any preceding claim wherein the patient or the eubicarbonatemic metabolic acidosis is characterized by baseline net acid excretion (NAE) values below about: (a) 60 mEq/day, (b) 50 mEq/day, (c) 40 mEq/day, (d) 30 mEq/day, or (e) 20 mEq/day.
  14. The nonabsorbable pharmaceutical composition for use according to any preceding claim wherein the patient or the eubicarbonatemic metabolic acidosis is (A) characterized by baseline plasma Endothelin 1 (ET-1) levels: (a) above about 2.0 pg/mL, (b) above about 3.0 pg/mL, (c) above about 4.0 pg/mL, (d) in the range of 2.0-5.0 pg/mL, or (e) in the range of 2.0-4.0 pg/mL; and/or (B) characterized by baseline urine Endothelin 1 (ET-1) levels as a ratio of creatinine (ET-1 / creatinine) of greater than: (a) 4.0, (b) 4.2, (c) 4.5, (d) 4.7, or (e) 5; and/or (C) characterized by baseline plasma aldosterone values above about: (a) 16 ng/dL when measured lying down, (b) 30 ng/dL when measured lying down, or (c) 40 - 64 ng/gL when measured lying down.

Description

The present invention is as defined in the appended claims. The following description and examples serve to illustrate the claimed invention. The present invention relates to nonabsorbable pharmaceutical compositions for use in methods of treating or preventing eubicarbonatemic metabolic acidosis as defined in appended claim 1. The nonabsorbable pharmaceutical compositions of the present invention may be used, for example, in the treatment of patients with chronic kidney disease (CKD) who have a serum bicarbonate value of at least 22 mEq/l. The nonabsorbable pharmaceutical compositions of the present invention are used in the treatment of eubicarbonatemic metabolic acidosis. Any references to methods of treatment by therapy or surgery in this description are to be interpreted as references to polymers, nonabsorbable compositions, pharmaceutical compositions or nonabsorbable pharmaceutical compositions for use in those methods. Acid-base disorders are common in chronic kidney disease and heart failure patients. Chronic kidney disease (CKD) progressively impairs renal excretion of the approximately 1 mmol/kg body weight of hydrogen ions generated in healthy adults (Yaqoob, MM. 2010, Acidosis and progression of chronic kidney disease, Curr. Opin. Nephrol. Hyperten. 19:489-492.). Metabolic acidosis, resulting from the accumulation of acid (H+) or depletion of base (HCO3-) in the body, is a common complication of patients with CKD, particularly when the glomerular filtration rate (GFR, a measure of renal function) falls below 30 ml/min/1.73m2. Metabolic acidosis has profound long-term effects on protein and muscle metabolism, bone turnover and the development of renal osteodystrophy. In addition, metabolic acidosis influences a variety of paracrine and endocrine functions, again with long term consequences such as increased inflammatory mediators, reduced leptin, insulin resistance, and increased corticosteroid and parathyroid hormone production (Mitch WE, 1997, Influence of metabolic acidosis on nutrition, Am. J. Kidney Dis. 29:46-48.). The net effect of sustained metabolic acidosis in the CKD patient is loss of bone and muscle mass, a negative nitrogen balance, and the acceleration of chronic renal failure due to hormonal and cellular abnormalities (De Brito-Ashurst I, Varagunam M, Raftery MJ, et al, 2009, Bicarbonate supplementation slows progression of CKD and improves nutritional status, J. Am. Soc. Nephrol. 20: 2075-2084). Conversely, the potential concerns with alkali therapy in CKD patients include expansion of extracellular fluid volume associated with sodium ingestion, resulting in the development or aggravation of hypertension, facilitation of vascular calcification, and the decompensation of existing heart failure. CKD patients of moderate degree (GFR at 20-25% of normal) first develop hyperchloremic acidosis with a normal anion gap due to the inability to reclaim filtered bicarbonate and excrete proton and ammonium cations. As they progress toward the advanced stages of CKD the anion gap typically increases, reflective of the continuing degradation of the kidney's ability to excrete the anions that were associated with the unexcreted protons. Serum bicarbonate in these patients rarely goes below 15 mmol/L with a maximum elevated anion gap of approximately 20 mmol/L. The non-metabolizable anions that accumulate in CKD are buffered by alkaline salts from bone (Lemann J Jr, Bushinsky DA, Hamm LL Bone buffering of acid and base in humans. Am. J. Physiol Renal Physiol. 2003 Nov, 285(5):F811-32). The majority of patients with chronic kidney disease have underlying diabetes (diabetic nephropathy) and hypertension, leading to deterioration of renal function. In almost all patients with hypertension a high sodium intake will worsen the hypertension. Accordingly, kidney, heart failure, diabetes and hypertensive guidelines strictly limit sodium intake in these patients to less than 1.5 g or 65 mEq per day (HFSA 2010 guidelines, Lindenfeld 2010, J Cardiac Failure V16 No 6 P475). Chronic antihypertensive therapies often induce sodium excretion (diuretics) or modify the kidney's ability to excrete sodium and water (such as, for example, Renin Angiotensin Aldosterone System inhibiting "RAASi" drugs). However, as kidney function deteriorates, diuretics become less effective due to an inability of the tubule to respond. The RAASi drugs induce life-threatening hyperkalemia as they inhibit renal potassium excretion. Given the additional sodium load, chronically treating metabolic acidosis patients with amounts of sodium-containing base that often exceed the total daily recommended sodium intake is not a reasonable practice. As a consequence, oral sodium bicarbonate is not commonly prescribed chronically in these diabetic nephropathy patients. Potassium bicarbonate is also not acceptable as patients with CKD are unable to readily excrete potassium, leading to severe hyperkalemia. Despite these shortcomings, the role of