Crystallization method and bioavailability
Preparation, in-vitro and in vivo characterization of novel forms of (1-hydroxy-2-imidazol-1-yl-1-phosphono-ethyl) phosphonic acid, suitable for pharmaceutical compositions in drug delivery systems for humans.
1. A crystalline molecular complex comprising zoledronic acid, DL-lysine, and water characterized by a Fourier transform infrared spectroscopy pattern corresponding to FIG. 20 .
2. A pharmaceutical composition comprising the crystalline molecular complex of claim 1 and a pharmaceutically acceptable excipient.
3. The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition is an oral dosage form.
4. The pharmaceutical composition of claim 3 , wherein the oral dosage form is selected from a tablet, a capsule, and a liquid suspension of the crystalline molecular complex.
5. The pharmaceutical composition of claim 3 , wherein the oral dosage form is an enteric coated tablet.
6. The pharmaceutical composition of claim 3 , wherein the pharmaceutical composition is in the form of an injectable, a suppository, a topical, or transdermal.
7. A composition comprising a physical mixture of the crystalline molecular complex of claim 1 and an excess amount of lysine or glycine.
8. The composition of claim 7 , comprising an excess amount of lysine.
9. The composition of claim 8 , wherein the excess amount of lysine is DL-lysine monohydrate.
10. The crystalline molecular complex of claim 1 , wherein the bioavailability of the zoledronic acid from the crystalline molecular complex is greater than the bioavailability of the zoledronic acid without DL-lysine.
11. The crystalline molecular complex of claim 1 , wherein the zoledronic acid in the crystalline molecular complex has improved aqueous solubility compared to zoledronic acid without DL-lysine.
12. A method for the treatment of disease states associated with osteoporosis, hypercalcemia, cancer induced bone metastasis, Paget's disease or adjuvant or neoadjuvant cancer therapies comprising the step of administering to a patient in need thereof a therapeutically effective amount of the crystalline molecular complex of claim 1 .
13. The method of claim 12 , wherein said hypercalcemia is tumor induced hypercalcemia (TIH).
14. The method of claim 12 , wherein said disease is cancer induced bone metastasis.
15. A method for the treatment of disease states associated with osteoporosis, hypercalcemia, cancer induced bone metastasis, Paget's disease or adjuvant or neoadjuvant cancer therapies comprising the step of administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 2 .
16. A method for the treatment of disease states associated with osteoporosis, hypercalcemia, cancer induced bone metastasis, Paget's disease or adjuvant or neoadjuvant cancer therapies comprising the step of administering to a patient in need thereof a therapeutically effective amount of the composition of claim 7 .
17. A method for the treatment of disease states associated with osteoporosis, hypercalcemia, cancer induced bone metastasis, Paget's disease or adjuvant or neoadjuvant cancer therapies comprising the step of administering to a patient in need thereof a therapeutically effective amount of the composition of claim 8 .
18. A method for the treatment of disease states associated with osteoporosis, hypercalcemia, cancer induced bone metastasis, Paget's disease or adjuvant or neoadjuvant cancer therapies comprising the step of administering to a patient in need thereof a therapeutically effective amount of the composition of claim 9 .
19. A method for enhancing the bioavailability or permeability of zoledronic acid comprising the step of administering to a patient in need thereof a therapeutically effective amount of zoledronic acid in the form of the crystalline molecular complex of claim 1 .
20. A method for making the crystalline molecular complex of claim 1 , comprising:
slurrying zoledronic acid with DL-lysine in tetrahydrofuran and water to form a crystalline molecular complex; and
separating the crystalline molecular complex from the slurry.