PROCESSES FOR THE PREPARATION OF SOLUBLE SALTS OF INOSITOL PHOSPHATES
The present invention provides processes for preparing soluble salts of inositol phosphate characterized by a low level of impurities. Processes for preparing soluble salts (e.g., alkali-metal or ammonium) of inositol phosphates (e.g., hexasodium or dodecasodium salts), and of inositol hexaphosphate in particular (e.g., Na 6 IP 6 and Na 12 IP 6 ), are described. Also provided are pharmaceutical compositions, methods of use, combination treatments, kits, and articles of manufacture comprising soluble salts of inositol phosphates prepared according to the method of the invention.
1 - 59 . (canceled)
60 . A soluble inositol hexaphosphate (Na 6 IP 6 ) composition comprising Na 6 IP 6 and
(i) DL-Inositol 1,2,3,4,6-pentaphosphate≤2.0% (w/w);
(ii) DL-Inositol 1,2,3,5,6-pentaphosphate≤4.0% (w/w);
(iii) DL-Inositol 1,2,4,5,6-pentaphosphate≤5.0% (w/w); and,
(iv) DL-Inositol 1,3,4,5,6-pentaphosphate≤3.0% (w/w),
wherein the soluble Na 6 IP 6 composition has
(a) a decrease in Na 6 IP 6 of ≤2% after storage a 5° C. or −20° C. at 60% relative humidity for 12 months, and/or,
(b) a decrease in Na 6 IP 6 of ≤4% after storage at 25° C. at 60% relative humidity for 6 months.
61 . The soluble Na 6 IP 6 composition of claim 60 , wherein DL-Inositol 1,2,3,4,6-pentaphosphate≤1.4% (w/w).
62 . The soluble Na 6 IP 6 composition of claim 60 , wherein DL-Inositol 1,2,3,5,6-pentaphosphate≤2.1% (w/w).
63 . The soluble Na 6 IP 6 composition of claim 60 , wherein DL-Inositol 1,2,4,5,6-pentaphosphate≤2.6% (w/w).
64 . The soluble Na 6 IP 6 composition of claim 60 , wherein DL-Inositol 1,3,4,5,6-pentaphosphate≤0.52% (w/w).
65 . The soluble Na 6 IP 6 composition of claim 60 , wherein at least 70% (w/w), at least 75% (w/w), at least 80% (w/w), at least 85% (w/w), at least 90% (w/w), or at least 95 (w/w/) is pure Na 6 IP 6 .
66 . The soluble Na 6 IP 6 composition of claim 60 , comprising about 20 mg/mL, about 30 mg/mL or about 90 mg/mL of Na 6 IP 6 .
67 . A dosage form comprising the soluble Na 6 IP 6 composition of claim 60 .
68 . A composition formulated for intravenous infusion comprising the soluble Na 6 IP 6 composition of claim 60 .
69 . A pharmaceutical composition comprising the soluble Na 6 IP 6 composition of claim 60 .
70 . The pharmaceutical composition of claim 69 , comprising between about 0.001 mg/mL to about 100 mg/mL of the soluble Na 6 IP 6 composition.
71 . The pharmaceutical composition of claim 70 , comprising between about 20 mg/mL to about 90 mg/mL of the soluble Na 6 IP 6 composition.
72 . The pharmaceutical composition of claim 71 , comprising about 20 mg/mL, about 30 mg/mL or about 90 mg/mL of the soluble Na 6 IP 6 composition.
73 . The pharmaceutical composition of claim 69 , comprising at least one tonicity agent.
74 . The pharmaceutical composition of claim 71 , wherein the tonicity agent is selected from the group consisting of dextrose, glycerin, sodium chloride, and a combination thereof.
75 . The pharmaceutical composition of claim 71 , wherein the tonicity agent is at a concentration between about 0.001 mg/mL to 50 mg/mL.
76 . The pharmaceutical composition of claim 71 , wherein the tonicity agent comprises an aqueous solution of about 0.01 mg/mL to about 10 mg/mL of sodium chloride.
77 . The pharmaceutical composition of claim 71 , wherein the tonicity agent comprises an aqueous solution of about 9 mg/mL of sodium chloride.
78 . A combination treatment comprising the soluble Na 6 IP 6 composition of claim 60 , and at least a second therapeutic agent or treatment or a combination thereof.
79 . The combination treatment of claim 78 , wherein the therapeutic agent is selected from the group consisting of osteoprotegerin, a corticosteroid, fetuin-alpha, a vitamin, protein C, protein S, matrix Gla protein, a calcimimetic, a phosphate binder, a bisphosphonate, sodium thiosulfate, an ectopic calcification inhibitor, a gram positive antibiotic, an anaerobic germ antibiotic, an analgesic, an opioid, a GBA analog, a central pain modulator, lidocaine, a morphine infusion gel, and a combination thereof.
80 . The combination treatment of claim 78 , wherein the treatment is hyperbaric medicine.
81 . A method of treating or preventing a disease or condition comprising pathological crystallization of calcium or a consequence thereof wherein the method comprises administering the soluble Na 6 IP 6 composition of claim 60 to a subject in need thereof.
82 . The method of claim 81 , wherein the pathological crystallization is an ectopic calcification or a consequence thereof.
83 . The method of claim 82 , wherein the ectopic calcification is selected from the group consisting of dystrophic calcification, metastatic calcification, idiopathic calcification, iatrogenic calcification, and calciphylaxis
84 . The method of claim 82 , wherein the consequence of the ectopic calcification is (i) a functional or trophic complication, (ii) pain, (iii) an infection or (iv) a combination thereof.
85 . The method of claim 84 , wherein the functional or trophic complication is a limitation of range of motion, a limitation of joint function, ischemia, an ischemic lesion, necrosis, or combination thereof.
86 . The method of claim 81 , wherein the disease or condition is peripheral arterial disease, critical limb ischemia, pyrophosphate arthropathy, or general arterial calcification of infancy.
87 . The method of claim 81 , wherein the subject is undergoing hemodialysis.
88 . The method of claim 81 , wherein the subject has endstage renal disease.
89 . The method of claim 81 , wherein the soluble Na 6 IP 6 composition is administered
90 . A dosage form comprising a 9 mg/kg amount of a soluble Na 6 IP 6 composition comprising at least 80% of pure Na 6 IP 6 and DL-Inositol 1,2,3,4,6-pentaphosphate≤1.4% (w/w), DL-Inositol 1,2,3,5,6-pentaphosphate≤2.1% (w/w), DL-Inositol 1,2,4,5,6-pentaphosphate≤2.6% (w/w), DL-Inositol 1,3,4,5,6-pentaphosphate≤0.52% (w/w), wherein the soluble Na 6 IP 6 composition has (a) a decrease in Na 6 IP 6 of ≤2% after storage a 5° C. or −20° C. at 60% relative humidity for 12 months, and/or, (b) a decrease in Na 6 IP 6 of ≤4% after storage at 25° C. at 60% relative humidity for 6 months.