Methods for making and using endoxifen
The present disclosure provides industrially scalable methods of making (Z)-endoxifen or a salt thereof, crystalline forms of endoxifin, and compositions comprising them. The present disclosure also provides methods for treating hormone-dependent breast and hormone-dependent reproductive tract disorders.
1. An oral formulation comprising an enterically encapsulated endoxifen composition formulated as a suspension, wherein the enterically encapsulated endoxifen composition comprises a compound of Formula (III):
wherein at least 90% by weight of the compound of Formula (III) is (Z)-endoxifen.
2. The oral formulation of claim 1 , wherein the suspension comprises a syrup or an elixir.
3. The oral formulation of claim 1 , wherein the suspension comprises a fluid.
4. The oral formulation of claim 3 , wherein the fluid comprises an alcohol.
5. The oral formulation of claim 4 , wherein the alcohol comprises ethanol.
6. The oral formulation of claim 1 , wherein the compound of Formula (III) is stable in the suspension for at least 10 days at about 25° C.
7. The oral formulation of claim 1 , wherein the suspension comprises an alcohol, a plant oil, a mineral oil, a glycol, an agar, or a mixture thereof.
8. The oral formulation of claim 1 , wherein the suspension comprises ethanol, mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, vegetable oil, stearic acid, sodium lauryl sulfate, or a mixture thereof.
9. The oral formulation of claim 1 , wherein the suspension further comprises a sweetener.
10. The oral formulation of claim 9 , wherein the sweetener comprises sucrose, saccharin, dextrose, maltose, a sugar substitute, aspartame, xylitol, mannitol, cyclamate, sucralose, maltitol, sorbitol, acesulfame K, or a mixture thereof.
11. The oral formulation of claim 1 , wherein the suspension further comprises a flavoring agent.
12. The oral formulation of claim 11 , wherein the flavoring agent comprises peppermint, methyl salicylate, peppermint, spearmint, methyl salicylate, raspberry, red berry, strawberry, pineapple, orange, cherry, or a mixture thereof.
13. A method of making an oral formulation, the method comprising suspending an enterically encapsulated endoxifen composition in a fluid, wherein the enterically encapsulated endoxifen composition comprises a compound of Formula (III):
wherein at least 90% by weight of the compound of Formula (III) is (Z)-endoxifen.
14. The method of claim 13 , wherein the fluid comprises an alcohol, ethanol, a plant oil, a mineral oil, a glycol, an agar, glycerin, sorbitol, mannitol, polyethylene glycol, vegetable oil, stearic acid, sodium lauryl sulfate, or a mixture thereof.
15. A method of delivering (Z)-endoxifen to a subject, the method comprising administering to the subject an oral formulation comprising an enterically encapsulated endoxifen composition formulated as a suspension, wherein the enterically encapsulated endoxifen composition comprises a compound of Formula (III):
wherein at least 90% by weight of the compound of Formula (III) is (Z)-endoxifen.
16. The method of claim 15 , the method further comprising treating a condition in the subject.
17. The method of claim 15 , wherein the subject has prostate cancer, a hormone-dependent breast disorder, or a hormone-dependent reproductive tract disorder.
18. The method of claim 17 , wherein the hormone-dependent breast disorder or the hormone-dependent reproductive tract disorder is a benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, ductal carcinoma in situ, lobular carcinoma in situ, breast cancer, precocious puberty, McCune-Albright Syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer.
19. The method of claim 18 , wherein the breast cancer is ductal carcinoma in situ, lobular carcinoma in situ, invasive lobular carcinoma, invasive ductal carcinoma, microinvasive ductal carcinoma, inflammatory breast cancer, ER-positive (ER+) breast cancer, HER2+ breast cancer, adenoid cystic (adenocystic) carcinoma, low-grade adenosquamatous carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, or micropapillary carcinoma.
20. The method of claim 18 , wherein the breast cancer is a pre-cancer, an early-stage cancer, a non-metastatic cancer, a pre-metastatic cancer, or a locally advanced cancer.
21. The method of claim 17 , wherein the hormone-dependent breast disorder or the hormone-dependent reproductive tract disorder is tamoxifen-refractory or tamoxifen resistant.
22. The method of claim 17 , wherein the hormone-dependent breast disorder is metastatic cancer.