Gallium Complexes, Pharmaceutical Compositions and Methods of Use
The present invention provides complexes of gallium with a ligand, methods of making the complexes, methods of using the complexes and pharmaceutical gallium compositions comprising the complexes, in particular those compositions suitable for therapeutic oral administration.
1 . A compound comprising ionic gallium in a complex with a ligand selected from the group consisting of histidine, carnosine, kojic acid, picolinic acid, mandelic acid, hydroxymethyl-protected kojic acid, isomaltol, methionine, and 2,3-Dihydro-3,5-dihydroxy-6-methyl-4h-pyran-4-one, and wherein the ratio of ligand to ionic gallium in the complex is 3:1
2 . The compound of claim 1 which is gallium picolinate, gallium kojate, gallium (+)-mandalate, gallium (−)-mandalate, gallium histidinate or gallium carnosinate.
3 . The compound of claim 2 which is a neutral complex.
4 . The compound of claim 2 which is ionic gallium histidinate, gallium (−)-mandalate, gallium (+)-mandalate or gallium carnosinate.
5 . The compound of claim 4 which further comprises a counterion selected from the group consisting of nitrate, chloride, bromide, iodide, and sulfate.
6 . The compound of claim 2 which is gallium (S)-(+)-mandalate or gallium (R)-(−)-mandalate.
7 . The compound of claim 1 which is hydroxymethyl-protected kojic acid, wherein the hydroxymethyl group is protected by an amino acid acyl group, a hydroxy acid acyl group, a GRAS reagent, or a hydroxyl protecting group such as an ester or an ether.
8 . The compound of claim 1 which comprises residual counter ion of no more than about 5%
9 . The compound of claim 8 , which comprises residual counter ion of 0.3 to 2%.
10 . A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable excipient.
11 . The pharmaceutical composition of claim 10 which is formulated for oral administration.
12 . The pharmaceutical composition of claim 11 which is in the form of a tablet, capsule or caplet, powder, solution or suspension.
13 . The pharmaceutical composition of claim 12 , wherein the tablet contains up to about 300 mg gallium.
14 . A method for treating a patient suffering from a condition or disease which is treatable with gallium, the method comprising administering to the patient a therapeutically effective amount of the compound or pharmaceutical composition of claim 1 to treat the disease or condition.
15 . The method of claim 14 wherein the compound or pharmaceutical composition is administered to a patient with a bacterial infection, cancer, hypercalcemia, osteoporosis, osteopenia, arthritis, autoimmune disease, or Paget's disease.
16 . The method of claim 15 wherein the compound or pharmaceutical composition is administered to a subject with a bacterial infection, wherein the method further comprises administering an antibiotic or antibacterial compound.
17 . The method of claim 14 wherein the compound or pharmaceutical composition is administered orally.
18 . A method of making the compound of claim 1 comprising preparing a solution of a sodium salt of the ligand in alcohol using a minimum volume of water at 20-100° C., adding a gallium salt to the solution in portions and recovering the compound.
19 . The method of claim 18 wherein the gallium salt is added as a solid.
20 . The method of claim 19 wherein the gallium salt is a chloride, nitrate, bromide, iodide or sulfate salt and the alcohol is ethanol or methanol.