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Ep 2671584 A2 (19) TZZ _ T (11) EP 2 671 584 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 11.12.2013 Bulletin 2013/50 A61K 31/4706 (2006.01) A61K 31/675 (2006.01) A61K 38/04 (2006.01) A61P 9/00 (2006.01) (21) Application number: 13171506.2 (22) Date of filing: 23.04.2008 (84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR •Currie,Mark G. HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT Sterling, MA Massachusetts 01564 (US) RO SE SI SK TR • Zimmer, Daniel P. Designated Extension States: Somerville, MA AL BA MK RS Massachusetts 02145 (US) (30) Priority: 04.05.2007 US 916257 P (74) Representative: Simpson, Tobias Rutger et al 17.10.2007 US 980573 P Mathys & Squire LLP 120 Holborn (62) Document number(s) of the earlier application(s) in London EC1N 2SQ (GB) accordance with Art. 76 EPC: 08746595.1 / 2 152 266 Remarks: This application was filed on 11-06-2013 as a (71) Applicant: Ironwood Pharmaceuticals, Inc. divisional application to the application mentioned Cambridge, MA 02141 (US) under INID code 62. (54) Compositions and methods for treating disorders associated with salt or fluid retention (57) Methods for reducing the risk of or treating a that increases anion secretion in the intestine; or c) an disorder associated with fluid and/or salt retention in a agent that both reduces sodium absorption in the intes- patient are described. The methods include administer- tine and increases anion secretion in the intestine. ing to the patient an agent selected from: a) an agent that reduces sodium absorption in the intestine; b) an agent EP 2 671 584 A2 Printed by Jouve, 75001 PARIS (FR) EP 2 671 584 A2 Description BACKGROUND 5 [0001] Excessive retention of fluid or salt is associated with various disorders, including cardiovascular disorders such as congestive heart failure, hypertension, cardiac hypertrophy and stroke. Excessive retention of fluid or salt can also cause or be associated with renal disorders and can lead to acites build up in the abdomen, for example, in the case of liver disease. 10 SUMMARY [0002] Described herein as a method of reducing the risk of or treating a disorder associated with fluid and/or salt retention in a patient, the method comprising administering to the patient an agent selected from: a) an agent that reduces sodium absorption in the intestine; b) an agent that increases anion secretion in the intestine; or c) an agent that both 15 reduces sodium absorption in the intestine and increases anion secretion in the intestine. In certain cases the method comprises administering two or more agents selected from: a) an agent that reduces sodium absorption in the intestine; b) an agent that increases anion secretion in the intestine; or c) an agent that both reduces sodium absorption in the intestine and increases anion secretion in the intestine. In various embodiments: the agent reduces sodium absorption in the intestine; the agent increases anion secretion in the intestine; and the agent both reduces sodium absorption in 20 the intestine and increases anion secretion in the intestine. [0003] In certain embodiments of the method: the agent is selected from: a) a guanylate cyclase receptor C agonist, b) a soluble guanylate cyclase modulator (preferably an agonist of soluble guanylate cyclase), c) a prostanoid, d) a chloride channel activator, e) a 5HT4 agonist, f) a cyclic nucleotide, g) a sodium transport inhibitor, h) a laxative, i) a cystic fibrosis transmembrane conductance regulator (CTFR) modulator, j) an agent that affects cAMP levels (preferably 25 an agent the increases cAMP levels in the body or a tissue), k) a phosphodiesterase inhibitor, 1) a renin inhibitor, m) an aldosterone antagonist, n) potassium, and o) a polymer resin. In sertain embodiments the method comprises adminis- tering two or more agents selected from: a) a guanylate cyclase receptor C agonist, b) a soluble guanylate cyclase modulator (preferably an agonist of soluble guanylate cyclase), c) a prostanoid, d) a chloride channel activator, e) a 5HT4 agonist, f) a cyclic nucleotide, g) a sodium transport inhibitor, h) a laxative, i) a cystic fibrosis transmembrane 30 conductance regulator (CTFR) modulator, j) an agent that affects cAMP levels (preferably an agent the increases cAMP levels in the body or a tissue), k) a phosphodiesterase inhibitor, l) a renin inhibitor, m) an aldosterone antagonist, n) potassium, and o) a polymer resin. [0004] Invarious embodiments: the chloride channel activator islubiprostone; thesodium transport inhibitor is amiloride; the sodium transport inhibitor is an NHE3 inhibitor; the 5HT4 agonist is Zelnorm; the prostanoid is selected from: the 35 compoundrepresented by CASRegistry No. 333963-40-9, the compound represented by CASRegistry No. 136790-76-6, (-)-7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl]heptanoic acid; and the 13, 14-dihydro-15-keto prostaglandins E disclosed in US5284858 including 13,14- dihydro-15-keto-PGE2 alkyl ester, 13,14-dihydro-15-keto-PGE2 cycloalkyl ester; 13,14-dihydro-15-keto-PGE2 hydroxy alkyl ester, 13,14-dihydro-15-keto- PGE2 benzyl ester, 13,14- dihydro-15-keto-PGE1 alkyl ester, 13,14- dihydro-6,15-diketo-PGE1 alkyl ester, 13,14- dihydro- 40 15-keto-18-methoxy-19, 20-dinor-PGE2 or an alkyl ester thereof, 13,14-dihydro-15-keto-18-methoxy-PGE2 or an alkyl 2 2 ester thereof, 13,14-dihydro-15-keto-Δ -PGE2 or an alkyl ester thereof, 13,14-dihydro-15-keto-20-methoxy-Δ -PGE2 or an alkyl ester thereof, 13,14- dihydro-15-keto-3R,S-methyl-PGE2 or an alkyl ester thereof, 13,14-dihydro-15-keto-3R,S- methyl-20-methoxy-PGE2 or an alkyl ester thereof, 13, 14-dihydro-15-keto-11-dehydroxy-11R-methyl-PGE2 or an alkyl ester thereof, 13,14-dihydro-15-keto-16R,S-fluoro-11-dehydroxy-11R-methyl-PGE2 or an alkyl ester thereof, 13,14-di- 45 hydro-15-keto-16R,S-hydroxy-PGE2 or an alkyl ester thereof, 13,14- dihydro-15-keto-16R,S-fluoro-PGE2 or an alkyl ester thereof, 13,14-dihydro-15-keto-16R,S-methyl-PGE2 or an alkyl ester thereof, 13,14-dihydro-15-keto-16,16-dimethyl- PGE2 or an alkyl ester thereof, 13,14- dihydro-15-keto-16,16-dimethyl-20-methoxy-PGE2 or an alkyl ester thereof, 13,14- dihydro-15-keto-17S-methyl-PGE2 or an alkyl ester thereof, 13,14-dihydro-15-keto-19-methy-PGE2 or an alkyl ester thereof, 13,14-dihydro-15-keto-20-isopropropylidene PGE2 or an alkyl ester thereof, 13,14-dihydro-15-keto-20-ethyl- 50 PGE2 or an alkyl ester thereof, 13,14- dihydro-15-keto-20-ethyl-11-dehydroxy-11R-methyl-PGE2 or an alkyl ester thereof, 13,14-dihydro-15 -keto-20-n-propyl-PGE2 or an alkyl ester thereof, 13,14-dihydro-15-keto-20-ethyl-PGE1 or an alkyl ester thereof, 13,14-dihydro-6,15-diketo-16R,S-fluoro-PGE1 or an alkyl ester thereof, 13,14- dihydro-6,15-diketo-16R,S- fluoro-11-dehydroxy-11R-methyl-PGE1 or an alkyl ester thereof, 13,14-dihydro-6,15-diketo-16R,S-methyl-PGE1 or an alkyl ester thereof, 13,14- dihydro-6,15-diketo-16,16-dimethyl-PGE1 or an alkyl ester thereof, 13,14- dihydro-6,15-diketo- 55 19-methyl-PGE1 or an alkyl ester thereof, 13,14-dihydro-6,15-diketo-20-methyl-PGE1 or an alkyl ester thereof, 13,14- dihydro-6,15-diketo-11-dehydroxy-11R-methyl-PGE1or analkyl esterthereof, 13,14- dihydro-6,15-diketo-11-dehydroxy- 11R-hydroxymethyl PGE1 alkyl ester, 13,14-dihydro-15-keto-20-methyl-PGE1 or an alkyl ester thereof, 13,14-dihydro- 2 15-keto-Δ -PGE1 or an alkyl ester thereof, 13,14- dihydro-15-keto-16R,S-fluoro-20-methyl-PGE2 or an alkyl ester thereof, 2 EP 2 671 584 A2 13,14-dihydro-15-keto-16,16-difluoro-PGE2 or an alkyl ester thereof, 13,14-dihydro-15-keto-5,6-dehydro-20-methoxy- PGE2 or an alkyl ester thereof, and 13,14- dihydro-6,15-diketo-16R,S-fluoro-PGE1 or an alkyl ester thereof; the prostanoid is misoprostol; the prostanoid is the free acid of the compound associated with CAS registry NO. 59122-49-5; the prostanoid comprises a mixture of steroisomers; only a single isomer of a prostanoid is administered; the laxative is 5 selected from: a CCK-1 antagonist, a stimulant, a bulk-producing agent and a stool softener; the laxative is selected from dexloxiglumide, psyllium husk, docusate sodium, bisacodyl, and phenolphthalein; the polymer resin is selected from psyllium, lipid lowering polymers, nonabsorbed polymer resins, and sodium binding polymers; the lipid lowering polymer is selected from: Colesevelam, Sevalmer, Cholestyramine; the nonabsorbed polymer resin is selected from: hyaluronic acid, polycarbophil calcium, polyvinyl acetate, polyvinyl pyrrolidone, polystyrene sulfate; the sodium- binding 10 polymer is selected from: crosslinked polyvinylsulfamate polymer, N-(bis-phosphonic-ethyl) polyvinylamine polymer, poly-α-acrylic acid polymer, poly- α-fluoroacrylic acid polymer, polyvinylphosphoramidic polymer, polyvinylsulfamate pol- ymer,polyvinylsulfamate/ vinylsulfatecopolymer, polyvinylsulfatepolymer, polyvinylsulfonate polymer, polyvinylsulfonate polymer, vinylphosphonate/α-fluoroacrylic acid copolymer, vinylphosphonate/α-fluoroacrylic acid copolymer, or vinyl- phosphonate/acrylic acid copolymer; the sodium- binding polymer is administered as core- shell composition which further 15 comprises a semi- permeable shell; the semi- permeable shell comprises at least one of a poly- 11 trimethylammoniounde- cylmethacrylate polymer, a styrene-vinylpyridine polymer, 11-dimethyl-aminodecylmethacrylate/laurylmethacrylate co- polymer, or a polyallylamine/polystyrene sulfonate polymer.
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