# US 10,245,249 B2 · Pharmaceutical compositions comprising nitroxyl donors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,245,249 B2 - Document ID: US10245249B2 - Status: Granted - Kind: B2 - Application number: 14/761,934 - Filed: 2014-01-17 - Published: 2015-12-24 - Granted: 2019-04-02 - Earliest claimed: 2013-01-18 - Assignees: Cardioxyl Pharmaceuticals, Inc. - Applicants: Cardioxyl Pharmaceuticals, Inc. - Inventors: Vincent Jacob Kalish; John Reardon; Frederick Arthur Brookfield; Stephen Martin Courtney; Lisa Marie Frost; John P. Toscano - Web page: https://patentgrep.com/patent/US10245249B2 ## CPC - A61K 31/341: not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine - A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)} - A61K 9/08: Solutions {(composition of solutions A61K47/00)} - A61K 31/18: Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) - A61K 31/222: with compounds having aromatic groups, e.g. dipivefrine, ibopamine - A61K 31/24: having an amino or nitro group - A61K 31/255: of sulfoxy acids or sulfur analogues thereof - A61K 31/343: condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone - A61K 31/381: having five-membered rings - A61K 31/404: Indoles, e.g. pindolol - A61K 31/42: Oxazoles - A61K 31/433: Thidiazoles - A61K 31/4436: containing a heterocyclic ring having sulfur as a ring hetero atom - A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol - A61K 31/538: ortho- or peri-condensed with carbocyclic ring systems - A61K 47/12: Carboxylic acids; Salts or anhydrides thereof - A61K 47/40: Cyclodextrins; Derivatives thereof - A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure - C07C 317/14: having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings - C07D 307/64: Sulfur atoms - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract The present disclosure provides nitroxyl donating pharmaceutical compositions comprising N-substituted hydroxylamine derivatives. The compositions are highly efficacious in treating cardiovascular diseases (e.g., heart failure), have a suitable toxicological profile, and are sufficiently stable for intravenous or oral administration. ## Claims ### Claim 1 A pharmaceutical composition comprising a N-hydroxysulfonamide type nitroxyl donor and an aqueous buffer, wherein the N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (1) and wherein the composition has a pH of from about 5 to about 6.5. ### Claim 2 (depends on 1) The pharmaceutical composition of claim 1, wherein the aqueous buffer provides a pH to the composition of from about 5.5 to about 6.2. ### Claim 3 (depends on 1) The pharmaceutical composition of claim 1, wherein the aqueous buffer provides a pH to the composition of about 6. ### Claim 4 (depends on 1) The pharmaceutical composition of claim 1, wherein the buffer is a phosphate or acetate buffer. ### Claim 5 (depends on 1) The pharmaceutical composition of claim 1, further comprising a stabilizing agent. ### Claim 6 (depends on 5) The pharmaceutical composition of claim 5, wherein the stabilizing agent is a cyclodextrin. ### Claim 7 (depends on 6) The pharmaceutical composition of claim 6, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having six or seven sulfo-n-butyl ether groups per cyclodextrin molecule. ### Claim 8 (depends on 4) The pharmaceutical composition of claim 4, wherein the aqueous buffer is a potassium phosphate buffer. ### Claim 9 (depends on 4) The pharmaceutical composition of claim 4, wherein the aqueous buffer is a potassium acetate buffer. ### Claim 10 (depends on 6) The pharmaceutical composition of claim 6, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin, which is a β-cyclodextrin having at least one —OH group that is derivatized by replacing the hydrogen atom thereof with (CH2)4—S(O)2—O−Z+, wherein each Z is a Na+. ### Claim 11 (depends on 6) The pharmaceutical composition of claim 6, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.02:1 to about 2:1. ### Claim 12 (depends on 6) The pharmaceutical composition of claim 6, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.05:1 to about 1.5:1. ### Claim 13 (depends on 6) The pharmaceutical composition of claim 6, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.5:1 to about 1:1. ### Claim 14 A pharmaceutical composition comprising a N-hydroxysulfonamide type nitroxyl donor and a cyclodextrin, wherein the N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (1): ### Claim 15 (depends on 14) The pharmaceutical composition of claim 14, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having six or seven sulfo-n-butyl ether groups per cyclodextrin molecule. ### Claim 16 (depends on 14) The pharmaceutical composition of claim 14, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin, which is a β-cyclodextrin having at least one —OH group that is derivatized by replacing the hydrogen atom thereof with (CH2)4—S(O)2—O−Z+, wherein each Z is a Na+. ### Claim 17 (depends on 14) The pharmaceutical composition of claim 14, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.02:1 to about 2:1. ### Claim 18 (depends on 14) The pharmaceutical composition of claim 14, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.05:1 to about 1.5:1. ### Claim 19 (depends on 14) The pharmaceutical composition of claim 14, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.1:1 to about 1:1. ### Claim 20 (depends on 14) The pharmaceutical composition of claim 14, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.5:1 to about 1:1. ### Claim 21 (depends on 17) The pharmaceutical composition of claim 17, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having six or seven sulfo-n-butyl ether groups per cyclodextrin molecule. ### Claim 22 (depends on 17) The pharmaceutical composition of claim 17, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin, which is a β-cyclodextrin having at least one —OH group that is derivatized by replacing the hydrogen atom thereof with —(CH2)4—S(O)2—O−Z+, wherein each Z is a Na+. ### Claim 23 (depends on 18) The pharmaceutical composition of claim 18, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having six or seven sulfo-n-butyl ether groups per cyclodextrin molecule. ### Claim 24 (depends on 18) The pharmaceutical composition of claim 18, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin, which is a β-cyclodextrin having at least one —OH group that is derivatized by replacing the hydrogen atom thereof with —(CH2)4—S(O)2—O−Z+, wherein each Z is a Na+. ### Claim 25 (depends on 19) The pharmaceutical composition of claim 19, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having six or seven sulfo-n-butyl ether groups per cyclodextrin molecule. ### Claim 26 (depends on 19) The pharmaceutical composition of claim 19, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin, which is a 3-cyclodextrin having at least one —OH group that is derivatized by replacing the hydrogen atom thereof with —(CH2)4—S(O)2—O−Z+, wherein each Z is a Na+. ### Claim 27 (depends on 20) The pharmaceutical composition of claim 20, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having six or seven sulfo-n-butyl ether groups per cyclodextrin molecule. ### Claim 28 (depends on 20) The pharmaceutical composition of claim 20, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin, which is a β-cyclodextrin having at least one —OH group that is derivatized by replacing the hydrogen atom thereof with —(CH2)4—S(O)2—O−Z+, wherein each Z is a Na+. ### Claim 29 An admixture comprising a N-hydroxysulfonamide type nitroxyl donor and a cyclodextrin, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.02:1 to about 2:1; and wherein the N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (1): ### Claim 30 (depends on 29) The admixture of claim 29, which is formed by lyophilization. ### Claim 31 (depends on 29) The admixture of claim 29, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.05:1 to about 1.5:1. ### Claim 32 (depends on 29) The admixture of claim 29, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.5:1 to about 1:1. ### Claim 33 (depends on 29) The admixture of claim 29, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.1:1 to about 1:1. ### Claim 34 (depends on 29) The admixture of claim 29, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having six or seven sulfo-n-butyl ether groups per cyclodextrin molecule. ### Claim 35 (depends on 29) The admixture of claim 29, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin, which is a β-cyclodextrin having at least one —OH group that is derivatized by replacing the hydrogen atom thereof with —(CH2)4—S(O)2—O−Z+, wherein each Z is a Na+. ### Claim 36 (depends on 29) The admixture of claim 29, further comprising a buffering agent. ### Claim 37 (depends on 36) The admixture of claim 36, wherein the buffering agent is potassium acetate. ### Claim 38 (depends on 37) The admixture of claim 37, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having six or seven sulfo-n-butyl ether groups per cyclodextrin molecule. ### Claim 39 (depends on 37) The admixture of claim 37, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin, which is a β-cyclodextrin having at least one —OH group that is derivatized by replacing the hydrogen atom thereof with —(CH2)4—S(O)2—O−Z+, wherein each Z is a Na+. ### Claim 40 (depends on 1) The pharmaceutical composition of claim 1 for use in the treatment of heart failure. ### Claim 41 (depends on 1) The pharmaceutical composition of claim 1 for use in the treatment of acute decompensated heart failure. ### Claim 42 (depends on 14) The pharmaceutical composition of claim 14 for use in the treatment of heart failure. ### Claim 43 (depends on 14) The pharmaceutical composition of claim 14 for use in the treatment of acute decompensated heart failure. ### Claim 44 (depends on 1) The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is suitable for parenteral administration. ### Claim 45 (depends on 1) The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is suitable for intravenous administration. ### Claim 46 (depends on 14) The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is suitable for parenteral administration. ### Claim 47 (depends on 14) The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is suitable for intravenous administration. ### Claim 48 A pharmaceutical composition comprising a N-hydroxysulfonamide type nitroxyl donor and an aqueous buffer, wherein the N-hydroxysulfonamide type nitroxyl donor is a pharmaceutically acceptable salt of a compound of the formula (1) and wherein the composition has a pH of from about 5 to about 6. ### Claim 49 A pharmaceutical composition comprising a N-hydroxysulfonamide type nitroxyl donor and a cyclodextrin, wherein the N-hydroxysulfonamide type nitroxyl donor is a pharmaceutically acceptable salt of a compound of the formula (1):