Mixed metal compounds for treatment of hyperphosphataemia
The present invention relates to mixed metal compounds having pharmaceutical activity, especially as phosphate binders. It also extends to methods of manufacture of those compounds, as well as to pharmaceutical compositions containing such compounds. It further relates to their pharmaceutical use. In particular, the present invention relates to use of compounds of Formula (I): M II 1-a M III a wherein M″ is at least one bivalent metal (i.e. with two positive charges); M1 is at least one trivalent metal (i.e. with three positive charges); and 1>a>0.4.
1. A pharmaceutical composition comprising
(a) a phosphate binding mixed metal compound according to formula (I)
M II 1-a M III a (I)
wherein M II is at least one bivalent metal, and the at least one bivalent metal comprises Mg(II);
M III is at least one trivalent metal; and
0.98>a≥0.7;
the compound contains at least one n-valent anion A n− such that the compound is charge neutral, and the mixed metal compound comprises less than 15% water soluble salts by weight of the mixed metal compound after drying; and
(b) a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.
2. The pharmaceutical composition of claim 1 , wherein the mixed metal compound is of formula (IV)
[M II 1-a M III a O b (OH) d ](A n− ) c .z H 2 O (IV)
0≤b≤2;
the value of c for each anion is determined by the need for charge neutrality as expressed by the formula 2+a−2b−d−cn=0; and
0≤d≤2;
0≤z≤5.
3. The pharmaceutical composition of claim 1 , wherein at least one anion A n− is carbonate.
4. The pharmaceutical composition of claim 1 , wherein M II further comprises a bivalent metal selected from the group consisting of Zn (II), Fe (II), Cu (II), Ca (II), La (II), Ce (II) and Ni(II).
5. The pharmaceutical composition of claim 1 , wherein M III is selected from one or more members of the group consisting of Al (III), Mn(III), Fe(III), La(III), and Ce(III).
6. The pharmaceutical composition of claim 1 , wherein M III is selected from one or more members of the group consisting of Mn(III), Fe(III), La(III), and Ce(III).
7. The pharmaceutical composition of claim 1 , wherein the phosphate binding mixed metal compound is of formula (IV)
[M II 1-a M III a O b (OH) d ](A n− ) c .z H 2 O (IV)
wherein M II is at least one bivalent metal, and the at least one bivalent metal comprises Mg(II);
M III is at least one trivalent metal selected from the group consisting of Mn(III), Fe(III), La(III), and Ce(III); and
A n− is at least one n-valent anion and wherein at least one anion is carbonate;
0.98>a≥0.7;
0≤b≤2;
the value of c for each anion is determined by the need for charge neutrality as expressed by the formula 2+a−2b−d−cn=0;
0≤d≤2;
0<z≤5; and
the mixed metal compound comprises less than 15% water soluble salts by weight of the mixed metal compound after drying.
8. A method of binding phosphate in a subject, comprising administering to a subject a phosphate binding mixed metal compound of formula (I)
M II 1-a M III a (I)
wherein M II is at least one bivalent metal, and the at least one bivalent metal comprises Mg(II);
M III is at least one trivalent metal; and
0.98>a≥0.7;
the compound contains at least one n-valent anion A n− such that the compound is charge neutral, and the mixed metal compound comprises less than 15% water soluble salts by weight of the mixed metal compound after drying.
9. The method of claim 8 , wherein the mixed metal compound is of formula (IV)
[M II 1-a M III a O b (OH) d ](A n− ) c .z H 2 O (IV)
0≤b≤2;
the value of c for each anion is determined by the need for charge neutrality as expressed by the formula 2+a−2b−d−cn=0; and
0≤d≤2;
0≤z≤5.
10. The method of claim 8 , wherein at least one anion A n− is carbonate.
11. The method of claim 8 , wherein M II further comprises a bivalent metal selected from one or more members of the group consisting of Zn (II), Fe (II), Cu (II), Ca (II), La (II), Ce (II), and Ni(II).
12. The method of claim 8 , wherein M III is selected from one or more members of the group consisting of Al (III), Mn(III), Fe(III), La(III), and Ce(III).
13. The method of claim 8 , wherein M III is selected from one or more members of the group consisting of Mn(III), Fe(III), La(III), and Ce(III).
14. The method of claim 8 , wherein the phosphate binding mixed metal compound is of formula (IV)
[M II 1-a M III a O b (OH) d ](A n− ) c .z H 2 O (IV)
wherein M II is at least one bivalent metal, and the at least one bivalent metal comprises Mg(II);
M III is at least one trivalent metal selected from the group consisting of Mn(III), Fe(III), La(III), and Ce(III); and
A n− is at least one n-valent anion and wherein at least one anion is carbonate;
0.98>a≥0.7;
0≤b≤2;
the value of c for each anion is determined by the need for charge neutrality as expressed by the formula 2+a−2b−d−cn=0;
0≤d≤2;
0<z≤5; and
the mixed metal compound comprises less than 15% water soluble salts by weight of the mixed metal compound after drying.
15. A method for the treatment in a subject of any one of hyperphosphataemia, renal insufficiency, hypoparathyroidism, pseudohypoparathyroidism, acute untreated acromegaly, chronic kidney disease and over medication of phosphate salts, comprising administering to the subject a phosphate binding mixed metal compound of formula (I)
M II 1-a M III a (I)
wherein M II is at least one bivalent metal, and the at least one bivalent metal comprises Mg(II); M III is at least one trivalent metal; and
0.98>a≥0.7;
the compound contains at least one n-valent anion A n− such that the compound is charge neutral, and the mixed metal compound comprises less than 15% water soluble salts by weight of the mixed metal compound after drying.
16. The method of claim 15 , wherein the mixed metal compound is of formula (IV)
[M II 1-a M III a O b (OH) d ](A n− ) c .z H 2 O (IV)
0≤b≤2;
the value of c for each anion is determined by the need for charge neutrality as expressed by the formula 2+a−2b−d−cn=0; and
0≤d≤2;
0≤z≤5.
17. The method of claim 15 , wherein at least one anion A n− is carbonate.
18. The method of claim 15 , wherein M II further comprises a bivalent metal selected from one or more members of the group consisting of Zn (II), Fe (II), Cu (II), Ca (II), La (II), Ce (II), and Ni(II).
19. The method of claim 15 , wherein M III is selected from one or more members of the group consisting of Al (III), Mn(III), Fe(III), La(III), and Ce(III).
20. The method of claim 15 , wherein M III is selected from one or more members of the group consisting of Mn(III), Fe(III), La(III), and Ce(III).
21. The method of claim 15 , wherein the phosphate binding mixed metal compound is of formula (IV)
[M II 1-a M III a O b (OH) d ](A n− ) c .z H 2 O (IV)
wherein M II is at least one bivalent metal, and the at least one bivalent metal comprises Mg(II);
M III is at least one trivalent metal selected from the group consisting of Mn(III), Fe(III), La(III), and Ce(III); and
A n− is at least one n-valent anion and wherein at least one anion is carbonate;
0.98>a≥0.7;
0≤d≤2;
the value of c for each anion is determined by the need for charge neutrality as expressed by the formula 2+a−2b−d−cn=0;
0≤d≤2;
0<z≤5; and
the mixed metal compound comprises less than 15% water soluble salts by weight of the mixed metal compound after drying.
22. The method of claim 15 comprising administering to the patient the mixed metal compound of formula (I) for the treatment of hyperphosphataemia.
23. A phosphate binding mixed metal compound comprising formula (IV)
[M II 1-a M III a O b (OH) d ](A n− ) c .z H 2 O (IV)
wherein M II is at least one bivalent metal, and the at least one bivalent metal comprises Mg (II);
M III is at least one trivalent metal selected from the group consisting of Mn(III), Fe(III), La(III), and Ce(III); and
A n− is at least one n-valent anion and wherein at least one anion is carbonate;
0.98>a≥0.7;
0≤d≤2;
the value of c for each anion is determined by the need for charge neutrality as expressed by the formula 2+a−2b−d−cn=0;
0≤d≤2;
0<z≤5; and
the mixed metal compound comprises less than 15% water soluble salts by weight of the mixed metal compound after drying.
24. The mixed metal compound of claim 23 , wherein d is 0.
25. The mixed metal compound of claim 23 , wherein 0<d≤2.
26. The mixed metal compound of claim 23 , wherein b is 0.
27. The mixed metal compound of claim 23 , wherein 0<b≤2.
28. The mixed metal compound of claim 23 , wherein b is 1.5 or less.
29. The mixed metal compound of claim 23 , wherein b is 1.2 or less.
30. The mixed metal compound of claim 23 , wherein d is 1 or less.
31. The mixed metal compound of claim 23 , wherein 0≤z≤2.
32. The mixed metal compound of claim 23 , wherein z≤1.5.
33. The mixed metal compound of claim 23 , wherein 0.95>a≥0.7.
34. The mixed metal compound of claim 23 , wherein 0.9>a≥0.7.
35. The mixed metal compound of claim 23 , wherein 0.85>a≥0.7.
36. The mixed metal compound of claim 23 , wherein a has the value 0.7.
37. The mixed metal compound of claim 23 , wherein M III is at least Fe(III).
38. The mixed metal compound of claim 23 , wherein M III is Fe(III).
39. The mixed metal compound of claim 23 , wherein M II is at least Mg(II).
40. The mixed metal compound of claim 23 , wherein M II is Mg(II).
41. The mixed metal compound of claim 23 , wherein M II is Mg(II) and M II is Fe(III).
42. The mixed metal compound of claim 23 , wherein A n− is selected from one or more members of the group consisting of carbonate, hydrogencarbonate, sulphate, nitrate, halide, and hydroxide, wherein at least one A n− is carbonate.
43. The mixed metal compound of claim 23 , wherein A n− is carbonate.
44. The mixed metal compound of claim 23 , obtained by treatment with an acid, a chelating agent or a mixture thereof of a starting material compound according to formula (IV)
[M II 1-a M III a O b (OH) d ](A n− ) c .z H 2 O (IV)
wherein M II is at least one bivalent metal, and the at least one bivalent metal comprises Mg (II);
M III is at least one trivalent metal selected from the group consisting of Mn(III), Fe(III), La(III), and Ce(III); and
A n− is at least one n-valent anion and wherein at least one anion is carbonate;
0<a≤0.4;
0≤d≤2;
the value of c for each anion is determined by the need for charge neutrality as expressed by the formula 2+a−2b−d−cn=0; and
0≤d≤2;
0<0≤z≤5.
45. The mixed metal compound of claim 44 , wherein the compound obtained by the treatment of the starting material compound is further subjected to heat treatment.
46. The mixed metal compound of claim 45 , wherein the heat treatment is calcination.
47. The mixed metal compound of claim 44 , wherein the acid or chelating agent is hydrochloric acid.
48. The mixed metal compound of claim 44 , wherein the acid or chelating agent is hydrochloric acid at a concentration in a range of 2 M to 0.1 M.
49. The mixed metal compound of claim 44 , wherein the acid or chelating agent is hydrochloric acid at a concentration in a range of 1.5 to 0.5 M.
50. The mixed metal compound of claim 44 , wherein the acid or chelating agent is hydrochloric acid at a concentration of 1M.
51. The mixed metal compound of claim 44 , wherein the starting material compound is treated with the acid, chelating agent or mixture thereof of for a period of 5 minutes or longer.
52. The mixed metal compound of claim 44 wherein the starting material compound is treated with the acid, chelating agent or mixture thereof of for a period of 15 minutes or longer.
53. The mixed metal compound of claim 44 , wherein the starting material compound is treated with the acid, chelating agent or mixture thereof of for a period of 1 hour or longer.
54. The mixed metal compound of claim 44 , wherein the starting material compound is treated with the acid, chelating agent or mixture thereof of for a period of 1 hour or less.
55. The mixed metal compound of claim 44 , wherein the starting material compound is treated with the acid, chelating agent or mixture thereof of for a period of 30 minutes or less.
56. The mixed metal compound of claim 44 , wherein the starting material compound is treated with the acid, chelating agent or mixture thereof of for a period of 15 minutes or less.
57. A process for the production of a phosphate binding bivalent metal-depleted mixed metal compound of formula (IV)
[M II 1-a M III a O b (OH) d ](A n− ) c .z H 2 O (IV)
wherein 0.98>a≥0.7;
the process comprising the steps of:
a) contacting a starting material compound of formula (IV)
[M II 1-a M III a O b (OH) d ](A n− ) c .z H 2 O (IV)
wherein 0<a≤0.4;
with an acid, a chelating agent, or a mixture thereof;
b) washing the contacted starting material until the mixed metal compound comprises less than 15% water soluble salts by weight of the mixed metal compound after drying; and
c) optionally subjecting the resulting compound to heat treatment;
wherein M II is at least one bivalent metal selected from the group consisting of Mg (II), Zn (II), Fe (II), Cu (II), Ca (II), La (II), Ce (II), and Ni(II);
M III is at least one trivalent metal selected from the group consisting of Mn(III), Fe(III), La(III), and Ce(III);
A n− is at least one n-valent anion and wherein at least one anion is carbonate;
0≤d≤2;
the value of c for each anion is determined by the need for charge neutrality as expressed by the formula 2+a−2b−d−cn=0;
0≤d≤2;
0<0≤z≤5.
58. A process for the production of a phosphate binding bivalent metal-depleted mixed metal compound of formula (IV)
[M II 1-a M III a O b (OH) d ](A n− ) c .z H 2 O (IV)
wherein 0.98>a≥0.7;
the process comprising the steps of:
a) contacting a starting material compound of formula (IV)
[M II 1-a M III a O b (OH) d ](A n− ) c .z H 2 O (IV)
wherein 0<a≤0.4;
with an acid, a chelating agent, or a mixture thereof; and
b) washing the contacted starting material until the mixed metal compound comprises less than 15% water soluble salts by weight of the mixed metal compound after drying; and
c) optionally subjecting the resulting compound to heat treatment;
wherein M II comprises Mg (II);
M III is at least one trivalent metal selected from the group consisting of Mn(III), Fe(III), La(III), and Ce(III);
A n− is at least one n-valent anion and wherein at least one anion is carbonate;
0≤d≤2;
the value of c for each anion is determined by the need for charge neutrality as expressed by the formula 2+a−2b−d−cn=0;
0≤d≤2; and
0<0≤z≤5.
59. The process of claim 58 wherein, the acid or chelating agent is selected from one or more members of the group consisting of HCl, H 2 SO 4 , Citric Acid, EDTA, HNO 3 , and Acetic Acid.
60. The process of claim 58 , wherein the acid or chelating agent is hydrochloric acid.
61. The process of claim 60 , wherein the hydrochloric acid is at a concentration of in a range of 0.01 M to 5M.
62. The process of claim 60 , wherein the hydrochloric acid is at a concentration of in a range of 0.1 M to 2 M.
63. The process of claim 60 , wherein the hydrochloric acid is at a concentration of in a range of 0.5 M to 1.5 M.
64. The process of claim 60 , wherein the hydrochloric acid is at a concentration of 1 M.
65. The process of claim 58 , comprising contacting the starting material compound with the acid or the chelating agent for a period of 5 minutes or longer.
66. The process of claim 58 , comprising contacting the starting material compound with the acid or the chelating agent for a period of 15 minutes or longer.
67. The process of claim 58 , comprising contacting the starting material compound with the acid or the chelating agent for a period of a period of 1 hour or longer.
68. The process of claim 58 , comprising subjecting the resulting compound to a heat treatment, wherein the heat treatment results in calcination.
69. A mixed metal compound prepared by a process as defined in claim 58 .
70. A pharmaceutical composition comprising
(a) a compound as defined in claim 23 , and
(b) a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.
71. A method of binding phosphate in a subject, comprising administering to the subject a mixed metal compound as defined in claim 23 .
72. A method for the treatment in a subject of any one of hyperphosphataemia, metabolic bone disease, metabolic syndrome, renal insufficiency, hypoparathyroidism, pseudohypoparathyroidism, acute untreated acromegaly, chronic kidney disease (CKD), severe hone problems, soft tissue calcification, secondary hyperparathyroidism, over medication of phosphate salts and other conditions requiring control of phosphate absorption, comprising administering a mixed metal compound as defined in claim 23 .
73. The method of claim 72 , comprising administering the mixed metal compound of claim 23 for the treatment of hyperphosphataemia.
74. The pharmaceutical composition of claim 1 , wherein 0.98>a≥0.8.
75. The pharmaceutical composition of claim 1 , wherein M II is Mg(II).
76. A pharmaceutical composition comprising a phosphate binding mixed metal compound according to formula (I)
M II 1-a M III a (I)
wherein M II is at least one bivalent metal, and the at least one bivalent metal comprises Mg(II);
M III is at least one trivalent metal; and
0.98>a≥0.7;
the compound contains at least one n-valent anion A n− such that the compound is charge neutral, and the mixed metal compound comprises less than 15% water soluble salts by weight of the mixed metal compound after drying.