Compositions for oral administration of zoledronic acid or related compounds for treating disease
View Patent ↗Oral dosage forms of bisphosphonate compounds, such as zoledronic acid, can be used to treat or alleviate pain or related conditions. The oral bioavailability of zoledronic acid can be enhanced by administering the zoledronic acid in the disodium salt form.
1. A method of preparing an oral dosage form having enhanced oral bioavailability of zoledronic acid comprising: mixing a disodium salt form of zoledronic acid with an excipient; wherein the method results in a disodium salt form of zoledronic acid in the dosage form that has an enhanced oral bioavailability in a mammal as compared to a diacid form of zoledronic acid.
2. The method of claim 1 , wherein the dosage form has an oral bioavailability that results in an area under the plasma concentration curve of zoledronic acid of about 4 ng·h/mL to about 2000 ng·h/mL if the dosage form is administered to the mammal.
3. The method of claim 2 , wherein the dosage form has an oral bioavailability that results in an area under the plasma concentration curve of zoledronic acid of about 100 ng·h/mL to about 2000 ng·h/mL if the dosage form is administered to the mammal.
4. The method of claim 2 , wherein the dosage form has an oral bioavailability that results in an area under the plasma concentration curve of zoledronic acid of about 20 ng·h/mL to about 700 ng·h/mL if the dosage form is administered to the mammal.
5. The method of claim 2 , wherein the dosage form is produced as a solid comprising at least about 50% (w/w) of zoledronic acid.
6. The method of claim 2 , wherein the dosage form is suitable for administration at an interval of about 3 to about 4 weeks.
7. The method of claim 1 , wherein the dosage form is prepared in a form that is suitable to be administered weekly, or 3 to 5 times in a month, wherein the dosage form has an oral bioavailability that results in an area under the plasma concentration curve of zoledronic acid of about 20 ng·h/mL to about 700 ng·h/mL if the dosage form is administered to the mammal.
8. The method of claim 1 , wherein the dosage form is prepared in a form that is suitable to be administered daily, wherein the dosage form has an oral bioavailability that results in an area under the plasma concentration curve of zoledronic acid of about 4 ng·h/mL to about 100 ng·h/mL if the dosage form is administered to the mammal.
9. The method of claim 1 , wherein the dosage form is a solid.
10. The method of claim 1 , wherein the oral bioavailability of dosage form in the mammal is improved by at least about 20% as compared to administration of zoledronic acid in the diacid form.
11. The method of claim 1 , wherein the dosage form comprises, on a molar basis, less of the zoledronic acid in the disodium salt form than would be present of zoledronic acid in the diacid form in order to achieve the same plasma levels of zoledronic acid.
12. The method of claim 1 , wherein the dosage form comprises at least about 10 mole % less of the disodium salt form as compared to the amount of zoledronic acid in the diacid form that would be administered in order to achieve the same plasma levels of zoledronic acid in the mammal.
13. The method of claim 1 , wherein the dosage form comprises the disodium salt form in an amount, on a molar basis, that has a value of about 0.8n d to about 1.2n d , wherein:
n d =( b a /b d )( n a )
wherein b a is the oral bioavailability of the diacid form, b d is the oral bioavailability of the disodium salt form, and n a is the number of moles of zoledronic acid in the diacid form that would be administered in order to achieve the same plasma levels of zoledronic acid in the mammal.