Peripheral opioid receptor antagonists and uses thereof
The present invention provides a compound of formula I: wherein X − , R 1 , and R 2 are as defined herein, and compositions thereof.
1. A method of treating a gastrointestinal disorder in a subject, comprising administering to the subject a compound of formula III
contained within a packaged composition substantially free of tungsten, wherein A − is a suitable anion;
wherein the packaged composition comprises less than about 190 ppm of a compound of formula II
wherein X − is a suitable anion.
2. The method of claim 1 , wherein the gastrointestinal disorder is constipation.
3. The method of claim 2 , wherein the constipation is opioid-induced.
4. The method of claim 1 , wherein the compound of formula III is provided in a solution.
5. The method of claim 1 , wherein the compound of formula III is of formula III-1
6. The method of claim 5 , wherein the compound of formula III is provided in solution.
7. The method of claim 5 , wherein the gastrointestinal disorder is constipation.
8. The method of claim 7 , wherein the constipation is opioid-induced.
9. The method of claim 1 , wherein the subject is receiving opioids chronically.
10. The method of claim 9 , wherein the subject is a cancer patient.
11. The method of claim 1 , wherein the packaged composition is selected from the group consisting of a syringe, a vial, a sachet and an ampoule.
12. The method of claim 1 , wherein the packaged composition is a syringe.
13. The method of claim 1 , wherein the compound of formula III is in the form of a tablet, a capsule, a powder, a solution, a suspension, an emulsion, a granule, and a suppository.
14. The method of claim 1 , wherein the solution comprises less than about 190 ppm total of the compound of formula II and a compound of formula IV:
wherein R1 and R2 are each independently C1-6 aliphatic; and X is a suitable anion.
15. The method of claim 6 , wherein the compound of formula III is administered by injection or infusion.
16. The method of claim 15 , wherein the compound of formula III is administered by subcutaneous injection.
17. The method of claim 1 , wherein the subject is receiving an opioid at a morphine equivalent dose of between about 30 and about 100 oral mg/day of methadone.
18. The method of claim 1 , wherein the tungsten is present in an amount of less than 50 parts per billion.
19. The method of claim 1 , wherein the tungsten is present in an amount of less than 12 parts per billion.
20. The method of claim 6 , wherein the solution further comprises edetate calcium disodium and glycine hydrochloride.
21. The method of claim 6 , wherein the solution comprises about 8 mg of the compound of formula III in about 0.4 mL water.
22. The method of claim 21 , wherein the compound of formula III is of formula III-1
23. The method of claim 6 , wherein the solution comprises about 12 mg of the compound of formula III in about 0.6 mL water.
24. The method of claim 23 , wherein the compound of formula III is of formula III-1
25. The method of claim 1 , wherein the compound of formula III is stable under ambient storage conditions.
26. The method of claim 25 , wherein the compound of formula III is stable for at least 24 months.
27. A method of treating opioid induced constipation in a subject, comprising administering to the subject a compound of formula III-1
contained within a packaged composition substantially free of tungsten; wherein the packaged composition comprises less than about 190 ppm of a compound of formula II:
wherein X − is a suitable anion.
28. A method of treating constipation in a subject, comprising administering to the subject a unit dosage of a compound of formula III-1
wherein the compound of formula III-1 is administered with a syringe that is substantially free of tungsten; wherein the syringe comprises less than about 190 ppm of a compound of formula II
wherein X − is a suitable anion.
29. A method of treating constipation in a subject, comprising administering to the subject a unit dosage of a compound of formula III
wherein the compound of formula III is administered with a syringe that is substantially free of tungsten, wherein A − is a suitable anion; and
wherein the syringe comprises less than about 190 ppm of a compound of formula II:
wherein X − is a suitable anion.