Methods of Making and Using Endoxifen

Abstract

The present disclosure provides industrially scalable processes for producing (Z)-endoxifen or its salts, crystalline forms of endoxifen, and compositions containing same. The disclosure further provides methods for treating hormone-dependent breast disorders and hormone-dependent reproductive disorders. [Selected Figure] Figure 1

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 556,799, filed September 11, 2017; U.S. Provisional Patent Application No. 62 / 556,884, filed September 11, 2017; U.S. Provisional Patent Application No. 62 / 624,787, filed January 31, 2018; and U.S. Provisional Patent Application No. 62 / 693,885, filed July 3, 2018, each of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Breast cancer is by far the most common form of cancer in women and the second leading cause of cancer death in humans. Despite advances in breast cancer diagnosis and treatment, the incidence of the disease has steadily increased at a rate of approximately 1% per year since 1940. Today, women living in North America have a 1 in 8 chance of developing breast cancer during their lifetime. In addition to breast cancer, other breast disorders that affect many women include benign, but often precancerous, lesions such as ductal hyperplasia, lobular hyperplasia, atypical ductal hyperplasia, and atypical lobular hyperplasia.

[0003] Current best practices for treating breast cancer involve diagnosing breast cancer with mammography and then treating patients with surgery, radiation therapy, and chemotherapy. The widespread use of modern mammography has resulted in improved breast cancer detection. Although breast cancer is approximately 100 times less common in men than in women, men have a lifetime risk of developing breast cancer that is 1 in 1,000. Approximately 2,470 new cases of invasive breast cancer will be diagnosed in men, and approximately 460 will die from the disease. The American Cancer Society predicts that in 2017, 255,180 new cases of breast cancer will be diagnosed in both men and women, and 41,070 subjects will die from breast cancer. Nevertheless, breast cancer mortality rates remain relatively stable at approximately 21 deaths per 100,000 women and approximately 0.4 deaths per 100,000 men. Most often, breast cancer is discovered at an extremely advanced stage, when treatment options and survival rates are too limited.

[0004] Breast cancer includes any malignant tumor of breast cells. There are several types of breast cancer. Typical breast cancers include, but are not limited to, ductal carcinoma in situ, lobular carcinoma in situ, invasive (or infiltrating) ductal carcinoma, invasive (or infiltrating) lobular carcinoma, inflammatory breast cancer, triple-negative breast cancer, ER+ breast cancer, HER2+ breast cancer, adenoid cystic carcinoma (or adenoid cystic carcinoma), low-grade adenosquamous carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, and micropapillary carcinoma. A single breast tumor may be a combination of these types or may be a mixture of invasive carcinoma and carcinoma in situ.

[0005] Tamoxifen is a selective estrogen receptor modulator used to treat women with endocrine-responsive breast cancer (i.e., hormone-dependent or hormone-sensitive breast cancer). Adjuvant therapy, primarily with oral delivery of tamoxifen, is known to have severe side effects, including vasomotor symptoms, e.g., hot flashes, and reproductive (gynecologic) cancers. Patient compliance remains an issue with tamoxifen treatment. Furthermore, the majority of individuals on adjuvant tamoxifen treatment do not respond to the drug, and 30-50% of patients subsequently die from their disease.

[0006] Several cytochrome P450 (CYP) mutations have been proposed to cause reduced conversion of tamoxifen to its active metabolite, endoxifen, reducing tamoxifen efficacy and increasing drug resistance. To date, over 140 allelic variants of CYP2D6 have been described, a significant portion of which are associated with reduced or absent activity of the encoded enzyme. Based on the combination of alleles possessed, individual subjects can be classified into one of four phenotypic groups: poor metabolizers (PMs), moderate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs), reflecting variations in serum endoxifen levels, with plasma endoxifen levels below 30 nM. However, CYP genotype variation does not fully explain the tamoxifen resistance and reduced endoxifen levels observed in several subjects.

[0007] Therefore, several alternatives to tamoxifen have been developed for the treatment of breast cancer, including low-dose tamoxifen (Lazzeroni M et al. Breast Cancer Res. 2012 Oct 29; 14(5):214) and tamoxifen's active metabolite, affimoxifen (US Patent Nos. 7,485,623) 7,507,769; 7,704,516; 7,786,172; 7,968,532; and 8,048,927; Mansel R et al. Breast Cancer Res Treat. 2007 Dec; 106(3):389-97. PubMed PMID: 17351746; Rouanet P et al. J ClinOncol. 2005 May 1;23(13):2980-7. PubMed PMID: 15860853) endoxifen (see US9333190; US Patent Nos. 9,220,680; 9,090,640; and 9,200,045; US Publication Nos. 2009 / 0291134 and US20100112041) and their derivatives (see US Patent Nos. 8,063,249; US Publication Nos. 2015 / 0080339; and 2014 / 0193334). It is widely accepted that (Z)-endoxifen is the primary active metabolite responsible for the clinical efficacy of tamoxifen.

[0008] Endoxifen hydrochloride and citrate salts (e.g., Fauq et al., Bioorganic & Medicinal Chemistry Letters. 20 (2010) 3036-3038; Stearns et al., J. Natl. Cancer Inst. Vol 95, No. 23, 2003; US Publication Nos. 2009 / 0291134 and 2010 / 0112041; Clinical Trials Gov. Identifier Nos. NCT01273168 and NCT02311933; Goetz et al., 2015, San Antonio Cancer Symposium; Ahmad et al., Clinical Pharmacology & Therapeutics. 88(6) 814-817, 2010; and J Clin. Oncol. 30, 2012 (suppl; abstr 3089); While several novel compositions for treating and / or preventing hormone-dependent breast and reproductive system (gynecologic) diseases (see Ahmad et al. Breast Cancer Research and Treatment 2010, 122, 579-584) are known in the art and are currently under evaluation for metastatic cancer, there remains an unmet medical need for novel compositions and methods for the treatment and / or prevention of hormone-dependent breast and reproductive system (gynecologic) diseases. Summary of the Invention

[0009] The present disclosure addresses this need by providing compositions and methods for the treatment and / or prevention of hormone-dependent breast and reproductive system (gynecology) conditions. In certain embodiments, the present disclosure provides novel, industrially scalable methods for making Z-endoxifen or salts thereof, crystalline forms of endoxifen, and compositions containing same. In certain embodiments, the present disclosure provides novel crystalline forms of endoxifen that may offer advantages, including improved bioavailability and stability, compared to other crystalline or amorphous forms.

[0010] In certain aspects, the present disclosure provides compositions comprising a crystalline form of a compound of formula (III):

[0011] [ka]

[0012] In some embodiments, at least 90% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some embodiments, the crystalline form is Form I of the compound of Formula (III). Crystalline Form I may be characterized by an X-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3°2θ, and optionally at least one peak selected from 16.0±0.3°, 18.8±0.3°, and 26.5±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 12.3±0.3°, 28.0±0.3°, and 29.0±0.3°2θ. The X-ray powder diffraction pattern can further include peaks at 12.3±0.3°, 16.0±0.3°, 18.8±0.3°, 26.5±0.3°, 28.0±0.3°, and 29.0±0.3°2θ. In some embodiments, crystalline Form I is characterized by an X-ray powder diffraction pattern substantially as depicted in FIG. 9 or FIG. 10. 90%, 95%, or 99% by weight of the compound of Formula (III) in the composition can be crystalline Form I. In some embodiments, the composition contains 0.01 mg to 200 mg of the crystalline form, e.g., about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of crystalline Form I.

[0013] In some embodiments, the composition comprises the (E)-isomer and the (Z)-isomer of the compound of Formula (III) in an E / Z ratio between 0.9 and 1.3, e.g., about 1.1. In some embodiments, the crystalline form is Form II of the compound of Formula (III). Crystalline Form II may be characterized by an X-ray powder diffraction pattern comprising major peaks at 7.0±0.3°, 11.9±0.3°, 14.0±0.3°, and 18.4±0.3°2θ, and optionally further comprising a peak at 22.0±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 6.6±0.3°, 13.3±0.3°, and 20.0±0.3°2θ. The X-ray powder diffraction pattern may further include peaks at 6.6±0.3°, 13.3±0.3°, 20.0±0.3°, and 22.0±0.3°2θ. In some embodiments, crystalline Form II is characterized by an X-ray powder diffraction pattern substantially as depicted in FIG. 11 or FIG. 12. 90%, 95%, or 99% by weight of the compound of Formula (III) in the composition may be crystalline Form II. In some embodiments, the composition contains 0.01 mg to 200 mg of crystalline Form II, e.g., about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of crystalline Form II.

[0014] In some embodiments, the composition comprises the (E)-isomer and the (Z)-isomer of the compound of Formula (III) in an E / Z ratio between 0.9 and 1.3, e.g., about 1.1. In some embodiments, the crystalline form is Form III of the compound of Formula (III). Crystalline Form III may be characterized by an X-ray powder diffraction pattern comprising major peaks at 11.9±0.3°, 13.9±0.3°, 17.1±0.3°, and 17.7±0.3°2θ, and optionally further comprising a peak at 25.3±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 18.2±0.3°, 22.5±0.3°, and 26.8±0.3°2θ. The X-ray powder diffraction pattern may further include peaks at 18.2±0.3°, 22.5±0.3°, 25.3±0.3°, and 26.8±0.3°2θ. In some embodiments, crystalline Form III is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 13. 90%, 95%, or 99% by weight of the compound of Formula (III) in the composition may be crystalline Form III. In some embodiments, the composition contains 0.01 mg to 200 mg of crystalline Form III, e.g., about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of crystalline Form III.

[0015] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a composition comprising a crystalline form of the compound of Formula (III). The compositions of the present disclosure can be formulated for oral, parenteral, topical, or intraductal delivery. In some embodiments, the composition is formulated for oral delivery as a tablet, caplet, capsule, or pill. In some embodiments, the mean half-life of endoxifen in a subject treated with the composition is 30 to 60 hours. The composition comprising a crystalline form of the compound of Formula (III) can be formulated for oral delivery as an enteric-coated tablet, enteric-coated caplet, enteric-coated capsule, delayed-release tablet, delayed-release caplet, or delayed-release capsule. In some embodiments, the composition is administered to a subject for the treatment or prevention of a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both in the subject.

[0016] In certain aspects, the present disclosure provides an oral composition comprising 1 mg to 200 mg of a composition per unit dose comprising a crystalline form of the compound of Formula (III) administered to a subject, wherein daily administration of the oral composition achieves the following in the subject: steady-state plasma levels of endoxifen within 7 to 21 days; Endoxifen steady-state plasma levels ranging from 25 nM to 300 nM; steady-state plasma levels of endoxifen greater than 30 nM; The maximum plasma level of endoxifen within 2 to 10 hours after administration; or A combination of these.

[0017] In some embodiments, the mean half-life of endoxifen in subjects treated with a composition comprising a crystalline form of the compound of Formula (III) is 40 to 55 hours. In some embodiments, the composition is formulated as an enteric-coated tablet, enteric-coated caplet, enteric-coated capsule, delayed-release tablet, delayed-release caplet, or delayed-release capsule. In some embodiments, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen in the composition is released in the intestine. In some embodiments, a composition comprising a crystalline form of the compound of Formula (III) has a mean half-life of 20 to 55 hours. * ng / mL~10,000hr * ng / mL, 300hr * ng / mL~8000hr * ng / mL, 400hr * ng / mL~6000hr * ng / mL or 700hr * ng / mL~6000hr * Endoxifen time-infinite (AUC) 0-inf ) are shown.

[0018] In certain aspects, the disclosure provides methods of treating a subject, the methods comprising administering to the subject a composition comprising a crystalline form of the compound of Formula (III). In some embodiments, the subject has or is at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both. The hormone-dependent breast disorder or hormone-dependent reproductive system disorder can be benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer. In some embodiments, the subject has prostate cancer or is at risk of having gynecomastia. The subject can have a tamoxifen-resistant or tamoxifen-resistant hormone-dependent breast disorder or hormone-dependent reproductive system disorder. In some embodiments, the subject is being treated or will be treated with an SSRI drug selected from the group consisting of citalopram, escitalopram, fluoxetine, paroxetine, sertraline, and vilazodone.

[0019] In practicing any of the subject methods, the composition can include 0.01 mg to 200 mg of (Z)-endoxifen. In some embodiments, a subject receives about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of (Z)-endoxifen daily. In some embodiments, the subject's steady-state plasma level of endoxifen is greater than 30 nM. The steady-state plasma level of endoxifen can be achieved within 7 to 21 days of the initial administration of the composition. In some embodiments, the time to maximum plasma level of endoxifen ranges from 2 hours to 10 hours or from 4 hours to 8 hours after administration of the composition.

[0020] In certain aspects, the disclosure provides a method of treating a subject suffering from or at risk of suffering from a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both, the method comprising administering a composition comprising a crystalline form of the compound of formula (III), wherein administering the composition achieves the following: The mean half-life of endoxifen in subjects ranged from 30 to 60 hours after administration; Time to maximum plasma levels of endoxifen ranging from 4 to 8 hours after administration; Steady-state plasma levels of endoxifen greater than 30 nM.

[0021] In some embodiments, the hormone-dependent breast disorder or hormone-dependent reproductive system disorder is selected from the group consisting of benign breast disorders, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer.

[0022] In practicing any of the subject methods, compositions can contain between 0.01 mg and 200 mg of (Z)-endoxifen. In some embodiments, subjects are administered about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of (Z)-endoxifen. The area under 0-inf ) is the average area under the curve extrapolated to 200hr * ng / mL~10,000hr * ng / mL, 300hr * ng / mL~8000hr * ng / mL, 400hr * ng / mL~6000hr * ng / mL or 700hr * ng / mL~6000hr *The concentration of endoxifen in the composition may be ng / mL. In some embodiments, the composition is formulated as an enteric-coated tablet, enteric-coated caplet, enteric-coated capsule, delayed-release tablet, delayed-release caplet, or delayed-release capsule. In some embodiments, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen in the composition is released in the intestine. The composition may be administered once daily, twice daily, three times daily, four times daily, every other day, twice weekly, weekly, every two weeks, twice monthly, monthly, quarterly, every six months, or yearly.

[0023] In one aspect, the present disclosure provides an industrially scalable process for producing (Z)-endoxifen or a salt thereof, comprising: (a) a mixture of (E)-endoxifen and (Z)-endoxifen to form a first crystalline solid and a first crystalline mother liquor;

[0024] [ka] (b) exposing the compound of formula (III) represented by formula (III) to fractional crystallization from a first solvent, wherein the first mother liquor has an E / Z ratio of (Z)-endoxifen that is at least 50% higher than the E / Z ratio of a mixture of (E)-endoxifen and (Z)-endoxifen; (b) exposing the first mother liquor to recrystallization from a second solvent by concentrating the first mother liquor or by replacing the first solvent from the first mother liquor with the second solvent one or more times to form a second crystalline solid and a second mother liquor, wherein the second crystalline solid is ≥ 90% (Z)-endoxifen; and (c) optionally exposing the second crystalline solid to one or more recrystallizations from a third solvent or chromatography treatments to form a third crystalline solid. In some embodiments, any one or more of the first solvent, the second solvent, and the third solvent are preheated to a temperature ranging from 40°C to 80°C.

[0025] In some embodiments, the present disclosure provides an industrially scalable process for producing crystalline Form I of compound of Formula (III), comprising the steps of: (a) mixing a mixture of (E)-endoxifen and (Z)-endoxifen to form a first crystalline solid and a first mother liquor;

[0026] [ka] (b) exposing the compound of formula (III) represented by the formula (III) to fractional crystallization from a first solvent, wherein the first mother liquor has an E / Z ratio of (Z)-endoxifen that is at least 50% higher than the E / Z ratio of a mixture of (E)-endoxifen and (Z)-endoxifen; (b) exposing the first mother liquor to recrystallization from a second solvent by concentrating the first mother liquor or by replacing the first solvent from the first mother liquor with the second solvent one or more times to form a second crystalline solid and a second mother liquor, wherein the second crystalline solid is ≥ 90% (Z)-endoxifen; and (c) exposing the second crystalline solid to one or more recrystallizations or chromatography treatments from a third solvent to form a third crystalline solid, wherein the third crystalline solid is crystalline Form I of the compound of formula (III).

[0027] In certain aspects, the present disclosure provides a crystalline form of the compound of Formula (III) produced according to the methods described herein. In some embodiments, the crystalline form is Form I of the compound of Formula (III). In some embodiments, the crystalline form is Form II of the compound of Formula (III). In some embodiments, the crystalline form is Form III of the compound of Formula (III).

[0028] In another aspect, the present disclosure provides that in step a, the mixture of (E)-endoxifen and (Z)-endoxifen, a compound of formula (III), is pretreated with 6N HCl and neutralized with 8N NaOH.

[0029] In another aspect, the industrially scalable process further comprises preparing a mixture of (E)-endoxifen and (Z)-endoxifen by coupling the compound of formula (II), (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone, to propiophenone mediated by a McMurry reaction with a titanium salt and a reducing agent in an inert organic solvent to form a mixture of (E)-endoxifen and (Z)-endoxifen; wherein the compound of formula (II) is

[0030] [ka] It has a structure represented by the following formula:

[0031] In yet another aspect, the industrially scalable process further comprises the step of preparing a compound of formula (II) by demethylating [4-[2-(dimethylamino)ethoxy]phenyl](4-hydroxyphenyl)methanone, a compound of formula (I), which compound of formula (I) is reacted with a demethylating agent and a proton acceptor in an inert organic solvent to form a compound of formula (II) having the following structure:

[0032] [ka] It has.

[0033] The present disclosure provides an industrially scalable process for producing (Z)-endoxifen and salts thereof, comprising the steps of: (a) mixing a mixture of (E)-endoxifen and (Z)-endoxifen to form a first crystalline solid and a first crystalline mother liquor;

[0034] [ka] (b) subjecting the compound of formula (III) represented by the formula (III) to fractional crystallization from ethyl acetate, wherein the first mother liquor has an E / Z ratio of (Z)-endoxifen that is at least 30% higher than the E / Z ratio of a mixture of (E)-endoxifen and (Z)-endoxifen; (b) subjecting the first mother liquor to recrystallization from IPA or IPA / PPW by concentrating the first mother liquor or by replacing the ethyl acetate from the first mother liquor with IPA or IPA / PPW (1:1 v / v) one or more times to form a second crystalline solid and a second mother liquor, wherein the second crystalline solid is ≥ 90% (Z)-endoxifen; and (c) optionally subjecting the second crystalline solid to one or more recrystallizations from ethanol or column chromatography treatments to form a third crystalline solid.

[0035] In some embodiments, a mixture of (E)-endoxifen and (Z)-endoxifen, a compound of Formula (III), can be prepared by: (a) reacting a compound of Formula (II) with propiophenone (1:0.01-1.5 wt / wt) in an inert organic solvent (1:1-1:20 wt / wt); (b) preparing a titanium salt (1:0.1-1:12 wt / wt) and a reducing agent (1:0.01-1:10 wt / wt) in an inert organic solvent (1:1-1:20 wt / wt); and (c) prepared by coupling the compound of formula (II), (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone, to propiophenone mediated by a McMurry reaction, which comprises reacting the compound of formula (II) in step (a) with a titanium salt and a reducing agent in an inert organic solvent in step (b) to form a mixture of (E)-endoxifen and (Z)-endoxifen; wt / wt is with respect to the compound of formula (II).

[0036] In another embodiment, a mixture of (E)-endoxifen and (Z)-endoxifen, a compound of formula (III), can be prepared by (a) reacting a compound of formula (II) with propiophenone (1:0.01 to 1:5 wt / wt) in THF (1:1 to 1:20 wt / wt); (b) preparing TiCl4 (0.1 to 4 wt / wt) and Zn (0.01 to 1:2 wt / wt) in THF (1:1 to 1:20 wt / wt); and (c) preparing (E)-endoxifen. prepared by coupling the compound of formula (II), (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone, to propiophenone mediated by a McMurry reaction, comprising reacting the compound of formula (II) in step (a) with TiCl and Zn in THF in step (b) to form a mixture of indoxifene and (Z)-endoxifen; wt / wt is with respect to the compound of formula (II).

[0037] In some embodiments, the compound of formula (II) is produced by demethylating a compound of formula (I) with a demethylating agent (1:0.5 to 1:10 wt / wt) and a proton acceptor (1:0.5 to 1:10 wt / wt) in an inert organic solvent (1:1 to 1:20 wt / wt), where wt / wt is relative to the compound of formula (I), to form a compound of formula (II).

[0038] In some embodiments, the compound of formula (II) is prepared by demethylating a compound of formula (I) with 1-chloroethyl chloroformate and DIPEA in THF to form a compound of formula (II), comprising the steps of: (a) reacting a compound of formula (I) with DIPEA (1:0.5 to 1:10 wt / wt) in THF (1:20 wt / wt); (b) adding 1-chloroethyl chloroformate (1:0.5 to 1:10 wt / wt); (c) distilling one or more times with methanol (1:1 to 1:10 wt / wt); (d) reacting with methanol (1:1 to 1:5 wt / wt) / HCl (1:1 to 1:10 wt / wt); and (e) neutralizing with NaOH (1:1 to 1:10 wt / wt); where wt / wt is relative to the compound of formula (I).

[0039] In another aspect, the present disclosure provides a process for making (Z)-endoxifen gluconate by reacting (Z)-endoxifen with D-gluconate or L-gluconate to form (Z)-endoxifen L-gluconate or (Z)-endoxifen D-gluconate.

[0040] In yet another aspect, the present disclosure provides that (Z)-endoxifen, (E)-endoxifen, the compound of Formula (III), the compound of Formula (II), and salts thereof prepared by any of the processes described herein are stable. In particular aspects, the (Z)-endoxifen free base is stable at ambient temperature for at least 9 months.

[0041] In some embodiments, the present disclosure provides an industrially scalable process for producing crystalline Form II or III of compound of Formula (III), comprising: (a) reacting a starting mixture of (E)-endoxifen and (Z)-endoxifen having an E / Z ratio ranging from 99:1 to 40:60 with 6N HCl (1:1 to 1:5 wt / wt) in ethyl acetate (1:1 to 1:20 wt / wt); (b) neutralizing with 8N NaOH (1:1 to 1:20 wt / wt); (c) washing one or more times with ethyl acetate; (d) washing one or more times with a mixture of ethyl acetate and n-heptane; and (e) recovering crystalline Form II or III of compound of Formula (III), wherein wt / wt is relative to the starting mixture of (E)-endoxifen and (Z)-endoxifen.

[0042] In yet another aspect, the present disclosure provides compositions comprising (Z)-endoxifen free base or a salt thereof prepared according to any of the processes described herein. The compositions are formulated for oral, parenteral, topical, and intraductal delivery. The compositions are formulated for oral delivery as tablets, caplets, capsules, or pills. In some embodiments, the compositions are formulated for oral delivery as enteric-coated tablets, enteric-coated caplets, enteric-coated capsules, delayed-release tablets, delayed-release caplets, and delayed-release capsules.

[0043] In certain aspects, the disclosure provides compositions with specific pharmacokinetic profiles. In one aspect, the disclosure provides that at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen in the composition is released in the intestine. In other aspects, the disclosure provides that the endoxifen in the composition has an average half-life in a subject ranging from 30 to 60 hours after administration. In some embodiments, the average half-life of endoxifen in a subject ranges from 40 to 55 hours after administration. In another aspect, the disclosure provides that the endoxifen has an average time-to-infinity (AUC 0-inf ) is the average area under the curve extrapolated to 200hr * ng / mL~10,000hr * ng / mL, 300hr * ng / mL~8000hr * ng / mL, 400hr * ng / mL~6000hr * ng / mL or 700hr * ng / mL~6000hr * The concentration is provided as ng / mL.

[0044] In another aspect, the disclosure provides oral compositions comprising 1 mg to 200 mg of (Z)-endoxifen free base or a salt thereof per unit dose for administration to a subject, wherein daily administration of the oral composition achieves in the subject: (i) a steady-state plasma level of endoxifen within 7 to 21 days; alternatively, (ii) a steady-state plasma level of endoxifen ranging from 25 nM to 300 nM; alternatively, (iii) a steady-state plasma level of endoxifen greater than 30 nM; alternatively, (iv) a maximum plasma level of endoxifen within 2 to 10 hours after administration; or alternatively, (v) any combination thereof. The disclosure further provides that the compositions are administered to a subject in need thereof for the treatment or prevention of a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both in the subject.

[0045] In certain aspects, the disclosure provides methods of treating a subject, the methods comprising administering to the subject an oral composition as disclosed herein. In some embodiments, the subject has or is at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both. In various embodiments, the hormone-dependent breast disorder or hormone-dependent reproductive system disorder is a benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer.

[0046] In some embodiments, the subject has prostate cancer and the subject further has or is at risk of having gynecomastia.

[0047] In certain aspects, the present disclosure provides specific patient populations that would benefit from the above-described treatment methods. In some embodiments, the patient population is a tamoxifen-resistant or tamoxifen-resistant population. In some embodiments, the subjects suffer from a tamoxifen-resistant or tamoxifen-resistant hormone-dependent breast disorder or hormone-dependent reproductive system disorder. In other embodiments, the patient population includes subjects who are being or will be treated with an SSRI drug selected from the group consisting of citalopram, escitalopram, fluoxetine, paroxetine, sertraline, and vilazodone.

[0048] In one aspect, the disclosure provides specific dosages of (Z)-endoxifen administered to a subject in need thereof. In various embodiments, the subject is administered between 0.01 mg and 200 mg of (Z)-endoxifen. In specific embodiments, the subject is administered 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of (Z)-endoxifen daily.

[0049] In other aspects, the disclosure provides treatment of a subject, wherein the subject has a steady-state plasma level of endoxifen greater than 30 nM upon administration of the composition. In some embodiments, such steady-state plasma level of endoxifen is achieved within 7 to 21 days after initial administration of the composition. In some embodiments, the time to maximum plasma level of endoxifen ranges from 2 to 10 hours or from 4 to 8 hours after administration of the composition.

[0050] In another aspect, the disclosure provides a method of treating a subject suffering from or at risk of suffering from a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both, the method comprising administering an oral composition comprising (Z)-endoxifen or a salt thereof, wherein administration of the composition achieves: (i) a mean half-life of endoxifen in the subject ranging from 30 to 60 hours after administration; (ii) a time to maximum plasma level of endoxifen ranging from 4 to 8 hours after administration; and (iii) a steady-state plasma level of endoxifen greater than 30 nM. In certain embodiments, the subject is administered 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of (Z)-endoxifen. In other aspects, the time-to-infinity (AUC) of endoxifen is achieved. 0-inf ) is the average area under the curve extrapolated to 200hr * ng / mL~10,000hr * ng / mL, 300hr * ng / mL~8000hr * ng / mL, 400hr * ng / mL~6000hr * ng / mL or 700hr * ng / mL~6000hr *ng / mL. In some embodiments, the compositions are formulated as enteric-coated tablets, enteric-coated caplets, enteric-coated capsules, delayed-release tablets, delayed-release caplets, or delayed-release capsules. In some embodiments, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen is released in the intestine. In some embodiments, the compositions can be administered once daily, twice daily, three times daily, four times daily, every other day, twice weekly, weekly, every two weeks, twice monthly, monthly, four times a year, every six months, or yearly. In some embodiments, the hormone-dependent breast disorder or hormone-dependent reproductive system disorder is selected from the group consisting of benign breast disorders, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer. INCORPORATION BY REFERENCE

[0051] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief explanation of the drawings]

[0052] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings.

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Figure 12

Figure 13

[0053] Compounds are described using their proper names. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0054] As used herein, the terms "a," "an," and "the" include plural references unless otherwise stated.

[0055] As used herein, the terms "active pharmaceutical ingredient," "active ingredient," "API," "drug," "active," "active," or "therapeutic agent" can be used interchangeably to refer to a pharmaceutically active compound in a pharmaceutical composition. This is in contrast to other components in the composition, such as excipients, which are substantially or completely pharmaceutically inactive. Suitable APIs according to the present disclosure are those for which there are or may be patient compliance issues for treating a particular disease, illness, or disorder. Therapeutic agents as used herein include active compounds and their salts, prodrugs, and metabolites. As used herein, the term "drug" refers to a compound intended for use in the diagnosis, cure, mitigation, treatment, and / or prevention of disease in humans or other animals.

[0056] As used herein, "adjuvant therapy" refers to treatment administered to a subject at risk of recurrence following primary therapy. In the case of breast cancer or reproductive system cancer, adjuvant systemic therapy, for example with tamoxifen, usually begins shortly after primary therapy to delay recurrence, prolong survival, or cure the subject.

[0057] As used herein, the term "tamoxifen" refers to (Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine. Tamoxifen may also refer to the E-isomer or a combination of the E- and Z-isomers.

[0058] As used herein, the terms "4-hydroxytamoxifen," "afimoxifen," and "4-OHT," used interchangeably, refer to 4-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol, which constitutes the active metabolite of tamoxifen. 4-OHT may refer to the Z-isomer, the E-isomer, or a combination thereof.

[0059] As used herein, the term "endoxifen" refers to 4-hydroxy-N-desmethyl-tamoxifen, which is the second active metabolite of tamoxifen.

[0060] Embodiments referring to "compounds," such as compounds of Formula (I), Formula (II), Formula (III), and Formula (IV) throughout the specification, include polymorphs, salts, free bases, co-crystals, and solvate forms of the formulas and / or compounds disclosed herein. Thus, occurrences of "compound," "compound of Formula (I)," "compound of Formula (II)," "compound of Formula (III)," and "compound of Formula (IV)" include Form I of compound of Formula (IV), Forms II-III of compound of Formula (III), the free base of compound of Formula (IV), the free base of compound of Formula (III), and / or the gluconate salt, as described herein.

[0061] The terms "crystalline form," "polymorph," and "form" may be used interchangeably herein and are meant to include all crystalline and amorphous forms of a compound, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, non-solvated polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms, and mixtures thereof, unless a specific crystalline or amorphous form is referenced. Compounds of the present disclosure include crystalline and amorphous forms of such compounds, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, non-solvated polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms, and mixtures thereof.

[0062] All compounds disclosed herein are further understood to include all possible isotopes of atoms occurring in the compounds. Isotopes include atoms having the same atomic number but different mass numbers. By way of example, and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include tetrahydrofuran and tetrahydrofuran. 11 C. 13 C, and 14 Contains C.

[0063] As used in this specification and claims, the terms "comprising," "containing," and "including" are inclusive, open-ended, and do not exclude unrecited elements, components, or method steps. Accordingly, the terms "comprising" and "including" encompass the more restrictive terms "consisting of" and "consisting essentially of."

[0064] As used herein, the term "combination therapy" refers to the use of a composition described herein in combination with one or more additional treatments. The treatment in the combination therapy can be any treatment, such as any prophylactic agent, therapeutic agent (such as chemotherapy), radiation therapy, surgery, etc. A combination can refer to the inclusion of a therapeutic or prophylactic agent in the same composition (e.g., the same capsule, tablet, ointment, etc.) as a composition disclosed herein or in separate compositions (e.g., two separate capsules). The separate compositions can be in different dosage forms. The use of the terms "combination therapy" and "in combination with" does not limit the order in which the compositions described herein and prophylactic and / or therapeutic agents and / or treatments are administered to a subject in need thereof. The compositions of the disclosure may be administered within 1 minute (min), 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour (h), 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 96 hours, 1 week (wk), 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, 6 months (m), 9 months (m), or 12 months (m) prior to administration of one or more prophylactic and / or therapeutic agents and / or treatments to a subject. , or 1 year before), concurrently with, or subsequent to (e.g., 1 minute (min), 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours (h), 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 96 hours, 1 week (wk), 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, 6 months (m), 9 months, or 1 year later). Combination therapy as used herein can also refer to the treatment of a subject with a single disease or multiple diseases, e.g., prostate cancer and gynecomastia in men.

[0065] As used herein, the term "test sample" refers to a blood sample obtained from a subject. When a blood sample is obtained from a subject, it is understood that the subject's blood is used to determine the subject's endoxifen level and / or other biomarkers that may be measured or tested. As used herein, "plasma endoxifen" refers to the endoxifen level in a subject's test sample, whether the test is performed on whole blood, plasma, or serum.

[0066] As used herein, the term "dosage form" means the form in which a compound or composition of the present disclosure is delivered to a patient.

[0067] As used herein, the terms "pharmaceutically acceptable" or "pharmacologically acceptable" refer to a material, composition, or vehicle that is compatible with other ingredients of a formulation and that, when administered to a subject, produces no significant adverse effects, e.g., a toxic, allergic, or immunological response. They may be approved by a regulatory agency, e.g., of the U.S. Federal or state governments, or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeias, for use in animals, especially humans.

[0068] As used herein, the term "pharmaceutically acceptable carrier" or "carrier" means a pharmaceutically acceptable material, composition, vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting one or more of the compounds of the present disclosure across a tissue, organ, or portion of the body, or across the skin.

[0069] As used herein, the term "pharmaceutically acceptable salt" refers to any salt (e.g., obtained by reaction with an acid or base) of a compound of the present disclosure that is physiologically acceptable in a subject (e.g., a mammal, and / or in a cell, tissue, or organ in vivo, ex vivo, or in vitro). The "salts" of the compounds of the present disclosure can be derived from inorganic or organic acids and bases. Suitable anionic salts include phosphate / diphosphate, arecoline, besylate, bicarbonate, bitartrate, butyl bromide, citrate, camysylate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthanoate, isethionate, malate, mandelate, mesylate, methyl bromide, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, polygalacturonate, salicylate, stearate, sulfate, tanninate, theoclate, fatty acid anions, and triethiodide.

[0070] Suitable cations include benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc.

[0071] For the purposes of this application, salts of the compounds of the disclosure are contemplated as being pharmaceutically acceptable for therapeutic use. However, salts of acids and bases that are non-pharmaceutically acceptable may also be useful, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0072] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent (e.g., an active pharmaceutical compound or ingredient, API) with an inert or active carrier (e.g., a phospholipid) that makes the composition suitable for, inter alia, in vitro, in vivo, or ex vivo diagnostic or therapeutic use.

[0073] As used herein, "primary therapy" refers to the first-line treatment upon initial diagnosis of a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both in a subject. Exemplary primary therapy may include surgery, broad-spectrum chemotherapy, and radiation therapy.

[0074] As used herein, the terms "subject," "patient," and "individual" may be used interchangeably herein and refer to a mammal, such as a human. Mammals also include pet animals, such as dogs and cats, laboratory animals, such as rats and mice, and farm animals, such as cows and horses. Unless otherwise specified, mammals may be of any sex or gender.

[0075] As used herein, the term "tamoxifen resistance" refers to a subject who receives tamoxifen daily for at least two days and has a plasma endoxifen level of less than 30 nM (e.g., less than 20 nM, less than 25 nM, or less than 30 nM). As used herein, the term "tamoxifen resistance" refers to two classes of resistance: (a) de novo resistance, i.e., non-response to tamoxifen treatment from the initiation of treatment, or (b) acquired resistance, i.e., non-response to tamoxifen treatment after an initial response, or tamoxifen-dependent growth / stimulated growth while continuing to exhibit estrogen receptors. Acquired resistance to tamoxifen can occur as early as three months to one year and as late as five to ten years. As used herein, the term "baseline plasma endoxifen level" refers to a value of 30 nM.

[0076] As used herein, the term "unit dosage form" refers to physically discrete units suitable for unitary administration to subjects, each unit containing a predetermined quantity of active material(s) calculated to produce a desired therapeutic effect in a suitable pharmaceutical excipient.

[0077] Any numerical value recited herein includes all values ​​from the low value to the high value, i.e., all possible combinations of numerical values ​​between the lowest and highest values ​​recited are considered to be expressly set forth in this application, and all range endpoints are included within that range and are independently combinable. For example, if a concentration range or useful range is recited as 1% to 50%, values ​​from 2% to 40%, 10% to 30%, 1% to 3%, etc. are intended to be expressly recited herein. Furthermore, when a concentration or dosage is described as a specific value, such as 1 mg or 10 mg, it is intended to include a 10% variation. As another example, a specified concentration of 20% is intended to include values ​​of ±10%. As yet another example, if a ratio of 10:1 to 1:10 is recited, ratios of 1:9 to 9:1, 1:8 to 8:1, 1:7 to 7:1, 1:6 to 6:1, 1:5 to 5:1, 1:4 to 4:1, 1:3 to 3:1, 1:2 to 2:1, 1:1 to 2:1, or 2:5 to 3:5 are specifically contemplated. Examples of what is specifically contemplated are just a few. Unless otherwise specified, values ​​for components or elements of a composition are expressed as weight percent of each component in the element.

[0078] Unless otherwise indicated herein or otherwise clearly contradicted by context, all methods described herein can be performed in any suitable order. The use of any and all examples or exemplary language (e.g., "such as" and "the like") is intended to illustrate the invention only and does not limit the scope of the invention unless otherwise required. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention as used herein.

[0079] As used herein, the terms "hormone-dependent breast disorder," "hormone-dependent reproductive system disorder," and "hormone-dependent breast and reproductive system disorder," individually and collectively, include, but are not limited to, any breast or reproductive system (gynecologic) disorder associated with or hypersensitive to high or normal estrogen levels that need to be reduced, estrogen receptor-positive (ER+) and / or progesterone receptor-positive (PR+) disorders, such as breast disorders, endometriosis, uterine fibroids (also called leiomyomas), and the like. Reproductive system disorders include endometrial, ovarian, cervical, uterine, vaginal, and vulvar cancers. The terms "estrogen-related disorder" and "estrogen receptor-associated disorder" may be used interchangeably to refer to the aforementioned hormone-dependent disorders. Disorders may present primarily or secondarily to an underlying condition, such as prostate cancer or other cancers, such as liver disease. Hormone-dependent disorders of the breast and reproductive system include, for example, McCune-Albright syndrome, a disorder caused by mutations in the GNAS gene that affects bone, skin, and multiple hormone-producing (endocrine) tissues, and often causes abnormal scar-like (fibrous) tissue in bone, a condition called multiple fibrous dysplasia of the bones, hyperthyroidism in individuals who carry such mutations, and precocious puberty in girls.

[0080] As used herein, "breast disorder" refers to any abnormality or set of abnormalities in the breast. Such abnormalities may be proliferative, non-proliferative, benign, or malignant. Breast disorders include benign lesions of the breast (e.g., hyperplasia), increased breast density, gynecomastia, mammary glandular pain, and breast cancer. Benign breast lesions include, but are not limited to, hyperplasia, atypia, ductal hyperplasia, lobular hyperplasia, atypical ductal hyperplasia (ADH), and atypical lobular hyperplasia (ALH). While not cancerous, ADH and ALH may indicate a predisposition to breast cancer.

[0081] Breast density is a breast disorder identified by visual techniques such as mammography. It reflects an increase in fibroglandular tissue within the breast, i.e., an overgrowth of stromal and epithelial cells. Breast density is classified into four classes—Class A, B, C, and D—based on the degree of density severity. It is an independent risk factor for developing breast cancer. At least 23 states in the United States require physicians to notify subjects if they have dense breasts. While subjects are encouraged to make healthy lifestyle choices and undergo regular mammograms to monitor breast changes, there are currently no treatments for dense breasts.

[0082] Gynecomastia is a common male breast condition reflecting increased hyperplasia of breast tissue, including epithelial hyperplasia. The prevalence of asymptomatic gynecomastia is 60%–90% in newborns, 50%–60% in adolescents, and up to 70% in men aged 50–69 years (Therapeutics and Clinical Risk Management 2011:7, 145–148). Gynecomastia in newborns usually resolves within the first four weeks of life, and at least half of adolescent males experience gynecomastia, with typical onset occurring between the ages of 13 and 14 years (Tanner stage 3 or 4). Gynecomastia has been proposed as a risk factor for male breast cancer.

[0083] Furthermore, gynecomastia often occurs secondary to underlying conditions such as prostate cancer, cirrhosis and liver disease, male hypogonadism, hyperthyroidism, and renal failure, and in patients undergoing hemodialysis and type 1 diabetes. Furthermore, medications such as antiandrogen drugs or certain antipsychotics have been reported to cause up to 25% of gynecomastia cases and can be classified by their hormone-like effects. For example, the most common side effects attributed to bicalutamide, a nonsteroidal antiandrogen used to treat prostate cancer, are gynecomastia and breast pain.

[0084] As used herein, "breast cancer" refers to any malignant tumor of breast cells. Breast cancer can be at any stage of breast cancer, including precancerous, early-stage, non-metastatic, pre-metastatic, locally advanced, and metastatic stages. There are several types of breast cancer. Exemplary breast cancers include, but are not limited to, ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), invasive (or infiltrating) lobular carcinoma (ILC), invasive (or infiltrating) ductal carcinoma (IDC), microinvasive breast cancer (MIC), inflammatory breast cancer, ER-positive (ER+) breast cancer, ER-negative (ER-) breast cancer, HER2+ breast cancer, triple-negative breast cancer (TNBC), adenoid cystic (adenocystic) carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary carcinoma, tubular adenocarcinoma, metaplastic carcinoma, or micropapillary carcinoma. A single breast cancer tumor may be a combination of these types, or a mixture of invasive carcinoma in situ.

[0085] DCIS is the most common non-invasive breast cancer. It involves cells lining the milk ducts. In DCIS, the cells have not spread beyond the walls of the ducts into the surrounding breast tissue. Approximately 1 in every 5 new cases of breast cancer is DCIS. LCIS is a precancerous neoplasia. It may indicate a predisposition to invasive cancer. LCIS accounts for only about 15% of in situ (ductal or lobular) breast cancers.

[0086] IDC is the most invasive form of breast cancer. As the name suggests, it is a carcinoma that begins in the milk ducts and then invades the surrounding fatty tissue. Approximately 8 to 10% of invasive breast cancers are infiltrating ductal carcinomas. IDC is often treated with surgery to remove the cancerous tissue and radiation therapy. In addition, chemotherapy combined with immunotherapy (e.g., tamoxifen and trastuzumab) is often used to treat IDC. If the tumor is larger than 4 cm, a radical mastectomy may be performed.

[0087] ILC is a cancer that develops in the breast lobules and invades surrounding tissue. Approximately 1 in 10 cases of invasive breast cancer is ILC. ILC is treated with surgery to remove the cancerous tissue and radiation therapy. In addition, a combination of chemotherapy and immunotherapy (e.g., tamoxifen and trastuzumab) is often used as adjuvant therapy to treat ILC.

[0088] Inflammatory breast cancer accounts for approximately 1% to 3% of all breast cancers. In inflammatory breast cancer, cancer cells block lymphatic vessels in the skin, causing the breast to feel red and warm. Affected breasts may become enlarged or firm, tender, or itchy. Inflammatory breast cancer is treated with chemotherapy, immunotherapy, radiation therapy, and in some cases, surgery.

[0089] Estrogen receptor-positive (ER+) breast cancer is characterized by the presence of estrogen receptors on the surface of cancer cells. The growth of ER+ cancer cells is associated with the availability of estrogen (hormone-dependent or hormone-sensitive breast cancer). Approximately 80% of all breast cancers are ER+ breast cancer. Treatment options for ER+ breast cancer include chemotherapy agents that block estrogen (e.g., tamoxifen).

[0090] This disclosure relates to methods for making and using stable preparations of (Z)-endoxifen free base, mixtures of (E)-endoxifen and (Z)-endoxifen (E / Z-mix), and salts thereof. This disclosure also relates to oral compositions containing (Z)-endoxifen or salts thereof and methods for treating subjects. This disclosure further provides methods for treating a subject suffering from or at risk of suffering from a hormone-dependent breast disorder, a hormone-dependent reproductive system (gynecologic) disorder, or both, by administering to the subject an oral composition containing (Z)-endoxifen, E / Z-mix, or salts thereof.

[0091] In one aspect, the present disclosure relates to oral compositions comprising endoxifen or a salt thereof. The endoxifen comprised in the compositions of the present disclosure can be (Z)-endoxifen, (E)-endoxifen, or a combination thereof. In one aspect, the present disclosure relates to compositions comprising stable (Z)-endoxifen free base.

[0092] In one aspect, the disclosure provides industrially scalable processes for producing (Z)-endoxifen free base, mixtures of (E)-endoxifen and (Z)-endoxifen (E / Z-mix), and salts thereof. In one aspect, the industrially scalable processes are synthetic methods for producing stable (Z)-endoxifen free base, E / Z-mix, and salts thereof. In another aspect, the disclosure provides methods for making compositions comprising stable (Z)-endoxifen free base, E / Z-mix, and salts thereof.

[0093] In certain aspects, the present disclosure provides crystalline forms of (Z)-endoxifen free base and crystalline forms of mixtures of (E)-endoxifen and (Z)-endoxifen, as well as pharmaceutical compositions of endoxifen comprising the crystalline forms described herein.

[0094] Synthesis of (Z)-endoxifen free base Several methods are known in the art for the synthetic preparation of endoxifen. For example, methods for the synthetic preparation of endoxifen and its prodrugs and salts are disclosed in U.S. Patent No. 9,333,190 (Ahmad, Jina Pharmaceuticals); WO 2008 / 070463 (Ahmad, Jina Pharmaceuticals), U.S. Pub. No. 2010 / 0112041 (Ahmad, Jina Pharmaceuticals), WO 2012 / 050263 (Ahmad, Jina Pharmaceuticals), WO 2014 / 141292 (Desai, Intas Pharmaceuticals), WO 2017 / 070651 (USA / Alchem ​​Lab. Corp.); WO 2009 / 120999A2 (Kushner), U.S. Patent No. 8,063,249 (Kushner, Olema Pharmaceuticals), U.S. Patent Nos. 7,531,578 and 8,119,695 (Forman Pharmaceuticals), and U.S. Patent Nos. 6,063,249 (Kushner, Olema Pharmaceuticals), ... and 6,063,249 (Forman Pharmaceuticals). and Yu), and WO 2012 / 050263 (Song, CJ Cheiljedang Corp).

[0095] Methods for the synthetic preparation of endoxifen have been published in the research literature (Gauthier et al., J. Org. Chem, 61, 3890-3893 (1996), Fauq et al., Bioorg Med Chem Lett. 2010 May 15;20(10):3036-3038); Stearns et al., J. Natl. Cancer Inst. Vol 95, No. 23, 2003; Johnson et al., Breast Cancer Research and Treatment. 85:151-159, 2004; Ogawa et al. Chem. Pharm. Bull. 39, 911-916, 1991). However, there remains an unmet need for large-scale scalable manufacturing. Stable (Z)-endoxifen free base can be prepared according to Scheme 1, which is further described below and in Examples 1-9.

[0096] [ka]

[0097] Demethylation In one aspect, the present disclosure relates to an industrially scalable process for making substantially purified (Z)-endoxifen free base, E / Z mix, or a salt thereof, comprising demethylating a compound of Formula (I), [4-[2-(dimethylamino)ethoxy]phenyl](4-hydroxyphenyl)methanone (available from AstaTech Pharmaceuticals, Inc., China), to form a compound of Formula (II). Accordingly, in some embodiments, the industrially scalable process comprises preparing a compound of Formula (II) by demethylating [4-[2-(dimethylamino)ethoxy]phenyl](4-hydroxyphenyl)methanone using a demethylating agent and a proton acceptor in an inert organic solvent to form a compound of Formula (II). The industrially scalable process for producing the compound of Formula (II), (Z)-endoxifen free base, E / Z mix, or a salt thereof comprises demethylating a compound of Formula (I) in an amount ranging from 1 mg to 1000 kg per reaction.

[0098] In some embodiments, the compound of formula (I) can be demethylated by reacting the compound of formula (I) with a demethylating agent. The demethylating agent can be any agent suitable for the purpose. Examples of suitable demethylating agents include N-iodosuccinamide (NIS), ethyl chloroformate (1-chloroethyl chloroformate, dichloroethyl chloroformate, trichloroethyl chloroformate, α-chloroethyl chloroformate (ACE-Cl)), vinyl chloroformate (VO-Cl), cyanogen bromide (BrCN: von Braun reaction), diethyl azodicarboxylate, pyridinium chloride, etc.

[0099] In some embodiments, the demethylating agent is a chloroformate selected from the group consisting of 1-chloroethyl chloroformate, dichloroethyl chloroformate, trichloroethyl chloroformate, α-chloroethyl chloroformate (ACE-Cl), and vinyl chloroformate (VO-Cl). In other embodiments, the demethylating agent is an ethyl chloroformate selected from the group consisting of 1-chloroethyl chloroformate, dichloroethyl chloroformate, trichloroethyl chloroformate, and an ethyl chloroformate such as α-chloroethyl chloroformate (ACE-Cl). In at least one embodiment, the demethylating agent is 1-chloroethyl chloroformate.

[0100] In some embodiments, the demethylating agent is added to the reaction mixture in a wt / wt ratio of compound of Formula (I) to demethylating agent ranging from 1:0.5 to 1:10. In other embodiments, the demethylating agent is present in a ratio (wt / wt) of compound of Formula (I) to demethylating agent ranging from 1:2 to 1:5. In at least one embodiment, the demethylating agent is present in a ratio (wt / wt) of compound of Formula (I) to demethylating agent of 1:2. In at least one embodiment, the demethylating agent is present in a ratio (wt / wt) of compound of Formula (I) to demethylating agent of 1:3.3. In other embodiments, the demethylating agent, 1-chloroethyl chloroformate, is present in a ratio (wt / wt) of compound of Formula (I) to demethylating agent ranging from 1:0.5 to 1:10.

[0101] The demethylation reaction can be carried out in an inert organic solvent suitable for demethylation reactions in the presence of a proton acceptor. Such organic solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, diethyl ether, 1,4-dioxane, tert-butyl methyl ether (TBME), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), diglyme, nitromethane, 1,2-dimethoxyethane (DME), pyridine, acetone, acetonitrile, benzene, o-xylene, m-xylene, p-xylene, xylene, hexane, cyclohexane, heptane, octane, nonane, and decane, or combinations thereof. In one embodiment, the industrially scalable process includes one or more inert organic solvents for demethylation in a ratio (wt / wt) of the compound of Formula (I) to the inert organic solvent ranging from 1:1 to 1:50. In some embodiments, the demethylation solvent is THF in a ratio (wt / wt) of compound of Formula (I) to THF ranging from 1:1 to 1:50, hi other embodiments, the THF is present in a ratio (wt / wt) of compound of Formula (I) to THF ranging from 1:1 to 1:20.

[0102] Suitable proton acceptors for purposes of the present disclosure include, but are not limited to, carbonates, e.g., sodium and potassium carbonate, and bicarbonates, e.g., sodium and potassium bicarbonate, proton sponge, and ethyldiisopropylamine (N',N-diisopropylamine, "DIPEA"). In one aspect, the industrially scalable process includes a proton acceptor added to the reaction mixture in a wt / wt ratio of compound of Formula (I) to proton acceptor ranging from 1:0.5 to 1:10. In some embodiments, the proton acceptor is present in a ratio (wt / wt) of compound of Formula (I) to proton acceptor of 1:1:8.

[0103] Those skilled in the art can readily determine other solvents and proton acceptors known in the art that are suitable for the demethylation reactions of the present disclosure.

[0104] The demethylating agent, the solvent for the demethylation reaction, and the compound of formula (I) can be added in any order. Each reagent can be added in a single bolus or multiple boluses to a suitable reaction apparatus and stirred.

[0105] In some embodiments, a compound of Formula (I) is placed in a suitable reactor, and the inert organic solvent THF and the proton acceptor DIPEA are added to the reactor for the demethylation reaction. The reactor is cooled to 0°C to 20°C, and then one or more demethylating agents are added. THF is added in a wt / wt ratio of 1:1 to 1:20, and the proton acceptor DIPEA is added in a wt / wt ratio of 1:10 to 1:0.5 relative to the demethylation reaction mixture, where wt / wt is relative to the compound of Formula (I). In some embodiments, the reaction mixture is cooled to 15°C or below (NMT), and then one or more demethylating agents are slowly added. The reaction can be carried out under inert conditions, such as under nitrogen or argon.

[0106] A reaction mixture containing a compound of Formula (I), one or more demethylating agents (e.g., 1-chloroethyl chloroformate) in one or more inert organic solvents can be heated at temperatures ranging from 20°C to 250°C, e.g., 40°C to 80°C, 50°C to 230°C, 50°C to 120°C, and 150°C to 200°C. In some embodiments, the reaction mixture is heated under reflux. In other embodiments, the compound of Formula (I) is reacted with the demethylating agent and proton acceptor for 5 hours or more (NLT), 8 hours or more, 12 hours or more, 24 hours or more, 36 hours or more, 48 hours or more, and 72 hours or more. In at least one embodiment, the reaction is heated under reflux for 12 hours or more. The reaction can be held and stored until further use. In some embodiments, the reaction mixture is held under reflux conditions with stirring for 24 hours or less.

[0107] The mixture may be subjected to one or more vacuum distillations. The distillation may be carried out at temperatures below 100°C, below 95°C, below 90°C, below 85°C, below 80°C, or below 70°C using solvents suitable for distillation, such as ethyl acetate, lower alcohols (non-limiting examples include methanol, ethanol, n-propanol, and isopropanol), benzene, acetone, acetonitrile, toluene, dichloromethane, 1,2-dichloroethane, and chloroform. Those skilled in the art can readily determine additional suitable solvents useful for the purpose.

[0108] In at least one embodiment, the solvent used in the distillation is methanol. As a non-limiting example, methanol may be used for solvent exchange for 2 to 5 vacuum distillations.

[0109] A solvent such as methanol may be used in the distillation at a ratio (wt / wt) of compound of formula (I) to solvent ranging from 1:1 to 1:10 per distillation.

[0110] The mixture can then be reacted with a solvent / acid mixture by adding the acid to the solvent (wt / wt ratio of compound of Formula (I) to acid ranging from 1:1 to 1:10) while stirring and heating under reflux. The acid can be any suitable acid. HCl is one example of a suitable acid for purposes of the present disclosure. Non-limiting examples of suitable solvent / acid mixtures include methanol / HCl, ethanol / HCl, propanol / HCl, isopropanol / HCl, methanol / sulfuric acid, methanol / phosphoric acid, ethanol / sulfuric acid, ethanol / phosphoric acid, propanol / sulfuric acid, propanol / phosphoric acid, isopropanol / sulfuric acid, isopropanol / phosphoric acid, methanol / acetic acid, ethanol / acetic acid, propanol / acetic acid, isopropanol / acetic acid, methanol / formic acid, ethanol / formic acid, propanol / formic acid, and isopropanol / formic acid. In at least one embodiment, the solvent / acid mixture is methanol / 6N HCl. As a non-limiting example, the HCl in a methanol / HCl mixture can be added at a wt / wt ratio of the compound of Formula (I) to the methanol in the solvent / acid mixture of 1:3.2, while the methanol in the methanol / HCl mixture can be at a wt / wt ratio of the compound of Formula (I) to the HCl in the solvent / acid mixture of 1:4. In at least one embodiment, the methanol / 6N HCl mixture is added at a wt / wt ratio of the compound of Formula (I) to the methanol / 6N HCl ranging from 1:1 to 1:10, e.g., from 1:1 to 1:5.

[0111] The distillation may be carried out under reduced pressure for 5 hours or more, 8 hours or more, 10 hours or more, 12 hours or more, 14 hours or more. The distillation may be carried out at temperatures below 70°C, below 75°C, below 80°C, below 85°C, below 90°C, and below 90°C.

[0112] The reaction mixture can be held and stored until further use. In some embodiments, the reaction mixture can be held under reflux conditions with stirring for up to 24 hours.

[0113] The reaction mixture may be neutralized with a neutralizing agent such as sodium hydroxide (NaOH), ammonium hydroxide, aminomethylpropanol, etc., and filtered. The resulting wet cake may be washed with water and an organic solvent, such as ethyl acetate (EtOAc), to obtain (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone, a compound of formula (II).

[0114] The neutralizing agent can be in a wt / wt ratio of compound of Formula (I) to neutralizing agent ranging from 1:1 to 1:10. In some embodiments, the neutralizing agent is 8N sodium hydroxide in a ratio ranging from 1:1 to 1:10. In other embodiments, the neutralizing agent is 8N sodium hydroxide in a ratio ranging from 1:2 to 1:8.

[0115] In another aspect, an industrially scalable process for producing (Z)-endoxifen free base, E / Z mix, or a salt thereof includes one or more steps of washing the filtered product (compound of Formula (II)) with purified water (1:1 to 1:5 wt / wt) and an organic solvent, such as ethyl acetate (EtOAc) (1:0.5 to 1:10 wt / wt), where wt / wt is relative to the compound of Formula (I). The wet cake is dried under reduced pressure / vacuum. The temperature can vary from 25°C to 60°C. In some embodiments, drying is performed at a temperature of 50°C or less.

[0116] McMurry reaction In another aspect, the present disclosure relates to an industrially scalable process for producing (Z)-endoxifen free base, E / Z mix, and salts thereof, comprising subjecting a compound of formula (III) to a McMurry reaction to obtain E / Z mix (i.e., a mixture of (E)-endoxifen and (Z)-endoxifen free base), a compound of formula (II).

[0117] The McMurry reaction has been used to prepare tamoxifen (European Patent Application No. 168175). The present disclosure relates to an industrially scalable process in which a compound of formula (II), (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone, is coupled to propiophenone mediated by the McMurry reaction via a titanium salt, e.g., a titanium chloride (e.g., titanium trichloride and titanium tetrachloride (TiCl4)), and a reducing agent in an inert organic solvent to form an E / Z mix of a compound of formula (III).

[0118] Titanium salts useful in the present disclosure include titanium halides (titanium trichloride (TiCl), titanium tetrachloride (TiCl), titanium iodide, titanium bromide, and titanium fluoride), titanium(IV) trichloride isopropoxide, and titanium isopropoxide. In some embodiments, the titanium salt is TiCl. The titanium salt, such as TiCl, is added in a wt / wt ratio of the compound of Formula (II) to the titanium salt ranging from 1:0.1 to 1:12.

[0119] Reducing agents include zinc, zirconium, vanadium, niobium, molybdenum, tungsten, aluminum, magnesium, potassium, copper-zinc couple, alkali and alkaline earth metals, butylium, lithium, and lithium aluminum hydride. In at least one embodiment, the reducing agent is zinc. The McMurry synthesis is conveniently carried out using a reducing agent such as zinc in a wt / wt ratio of compound of Formula (II) to reducing agent ranging from 1:0.1 to 1:10. In some embodiments, the ratio of reducing agent is in excess relative to the titanium salt.

[0120] The McMurry synthesis can be carried out in one or more inert organic solvents. Inert organic solvents useful for the McMurry synthesis include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, diethyl ether, 1,4-dioxane, tert-butyl methyl ether (TBME), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), diglyme, nitromethane, 1,2-dimethoxyethane (DME), pyridine, acetone, acetonitrile, benzene, o-xylene, m-xylene, p-xylene, xylene, hexane, cyclohexane, heptane, octane, nonane, and decane, or combinations thereof. In some embodiments, the inert organic solvent has a wt / wt ratio of the compound of Formula (II) to the solvent ranging from 1:1 to 1:50. In other embodiments, the inert organic solvent has a wt / wt ratio of the compound of Formula (II) to the solvent ranging from 1:1 to 1:20. In some embodiments, the inert organic solvent used in the McMurry reaction is THF. In some embodiments, the THF has a wt / wt ratio of the compound of Formula (II) to the THF ranging from 1:1 to 1:20.

[0121] It is advantageous to combine a titanium salt and a reducing agent in an inert organic solvent to form a premix. The titanium salt is added to the reducing agent and inert organic solvent at the rate described above to maintain an internal temperature of 75°C or less, e.g., 65°C or less, 55°C or less, 45°C or less, 40°C or less, 35°C or less, 30°C or less, 25°C or less, 20°C or less, and 15°C or less. Accordingly, the titanium salt and reducing agent in the inert organic solvent are combined to form a premix. In some embodiments, Zn, TiCl4, and THF are combined to form a Zn / TiCl4 / THF mixture. In at least one embodiment, TiCl4 is added to Zn and THF, mixed, and the internal temperature is maintained at 20°C or less for 10 minutes or more.

[0122] The preparation of the titanium salt and reducing agent in the inert organic solvent can further include heating the titanium salt and reducing agent in the inert organic solvent to a temperature ranging from 20°C to 250°C, e.g., from 40°C to 80°C, from 50°C to 230°C, from 50°C to 120°C, and from 150°C to 200°C. In some embodiments, the titanium salt and reducing agent in the inert organic solvent are heated at 60°C or higher. In some embodiments, the preparation of the titanium salt and reducing agent in the inert organic solvent further includes heating the titanium salt and reducing agent in the inert organic solvent under reflux. The titanium salt and reducing agent in the inert organic solvent are heated under reflux under inert conditions, such as under N or argon, for 30 minutes or more, e.g., 1 hour or more, 2 hours or more, 4 hours or more, 6 hours or more, and 8 hours or more.

[0123] It is also advantageous to premix a compound of Formula (II) with an inert organic solvent, such as THF or propiophenone, and then react the compound of Formula (II) with a premixed reducing agent / titanium salt / solvent mixture, such as a Zn / TiCl4 / THF mixture, to form a mixture of (E)-endoxifen and (Z)-endoxifen, the compound of Formula (III). Propiophenone can be added at a wt / wt ratio of the compound of Formula (II) to propiophenone ranging from 1:0.01 to 1:5. The inert organic solvent can have a wt / wt ratio of the compound of Formula (II) to solvent ranging from 1:1 to 1:20. The compound of Formula (II) in step (a) is reacted with the titanium salt and reducing agent in the organic solvent under reflux for 0.5 hours or more, 1 hour or more, 2 hours or more, 4 hours or more, 6 hours or more, 8 hours or more, 12 hours or more, 24 hours or more, and 48 hours or more. In at least one embodiment, a compound of Formula (II) is mixed with THF and propiophenone, reacted with a premix of Zn, TiCl, and THF, and heated under reflux for at least 2 hours. In another embodiment, a compound of Formula (II) is mixed with THF and propiophenone, reacted with a Zn / THF / TiCl mixture as described above, and heated under reflux for at least 8 hours. The reaction mixture is then cooled to 0°C to 35°C.

[0124] The mixture of (E)-endoxifen and (Z)-endoxifen in the reaction mixture can then be subjected to extractive purification, distillation, and crystallization to obtain a purified mixture of (Z)-endoxifen and (E)-endoxifen. The mixture of (E)-endoxifen and (Z)-endoxifen in the reaction mixture can be subjected to extraction with an inert organic solvent such as THF and MeTHF, or extraction purification by adding a salt such as potassium carbonate, ammonium chloride, sodium chloride, or sodium hydroxide to the reaction mixture, and extraction with an inert organic solvent such as THF or MeTHF.

[0125] In some embodiments, the reaction mixture is extracted one or more times with ammonium chloride, e.g., 25% ammonium chloride (1:1 to 1:30 wt / wt); silica (Celite® bed; (1:0.01 to 1:5 wt / wt) and / or a solvent, e.g., THF (1:1, 1:10 wt / wt). In other embodiments, the reaction mixture is extracted one or more times with potassium carbonate (K2CO3), such as 40% K2CO3 (1:1 to 1:10 wt / wt) and MeTHF (1:1 to 1:10 wt / wt). In some embodiments, the E / Z mixture can be further extracted with NaOH, such as 1 N NaOH (1:1 to 1:20 wt / wt). In at least one embodiment, NaCl (1:0.1 to 1:0.5 wt / wt) can be added to 1 N NaOH for the extraction step.

[0126] In some embodiments, the reaction mixture can be further extracted one or more times with THF or MeTHF. In at least one embodiment, the reaction mixture is extracted three or more times with MeTHF. Applicants have discovered that MeTHF is surprisingly suitable for the extraction of a mixture of (E)-endoxifen and (Z)-endoxifen to obtain a purified mixture of (E)-endoxifen and (Z)-endoxifen in high yields. In at least one embodiment, the mixture can still be further extracted with 20% sodium chloride (1:1 to 1:10 wt / wt).

[0127] The reaction mixture may then be subjected to 2 to 5 solvent exchanges and distillations using suitable solvents, such as ethyl acetate, IPA, and IPA / PPW (1:1 to 1:10 wt / wt relative to the compound of Formula (III)). The distillation may be carried out under reduced pressure / vacuum at temperatures ranging from 30°C to 90°C. In some embodiments, the distillation may be carried out at temperatures below 30°C, below 35°C, below 40°C, below 45°C, below 50°C, below 55°C, below 60°C, below 65°C, below 70°C, below 75°C, below 80°C, and below 90°C, and filtered. The filtered product can be washed with a solvent such as EtOAc, IPA, IPA / PPW, or n-heptane, and then crystallized using a crystallization system such as EtOAc / n-heptane (1:2 v / v) or IPA / n-heptane (1:2.7 v / v) with a wt / wt ratio of compound of Formula (III) to EtOAc / n-heptane or IPA / n-heptane ranging from 1:1 to 1:20, and dried, for example, at 60°C or below, to obtain a crystalline solid mixture of (E)-endoxifen and (Z)-endoxifen free base, the compound of Formula (III).

[0128] In yet another aspect, the present disclosure relates to an industrially scalable method for producing or re-equilibrating an E / Z mix having an E / Z ratio of approximately 1:1 (45:55 to 55:45). A suitable reactor may contain a compound of Formula (III) prepared by the McMurry reaction described above, dissolved in an inert organic solvent such as ethyl acetate. The compound of Formula (III) may have an E / Z ratio of 99:1 to 60:40. The mixture may be concentrated at a temperature ranging from 40°C to 85°C. In some embodiments, the mixture is concentrated at a temperature of 75°C or less until the volume reaches 5 vol. The mixture is heated to reflux and then cooled to a temperature ranging from 40°C to 60°C. In some embodiments, the temperature of the mixture is cooled to 50±5°C. n-Heptane may be slowly added to the mixture in a ratio of compound of Formula (III) to n-heptane ranging from 1:1 to 1:20, and the mixture may be cooled to 0±5°C. The mixture can be stirred at 0±5°C for 0.5 hours or more, e.g., 1 hour or more, 2 hours or more, 4 hours or more, 8 hours or more, 12 hours or more, or 24 hours or more. The mixture can be filtered and washed with ethyl acetate / n-heptane (1:2 v / v) at a wt / wt ratio of the compound of Formula (III) to ethyl acetate / n-heptane ranging from 1:1 to 1:10. The wet cake can be dried under reduced pressure to obtain an E / Z endoxifen mixture having an E / Z ratio of approximately 1:1. Drying can be performed at a temperature ranging from 30°C to 70°C. In some embodiments, the wet cake is dried under reduced pressure or vacuum at 60°C or below to obtain an E / Z endoxifen mixture having an E / Z ratio of approximately 1:1 (45:55 to 55:45).

[0129] In yet another embodiment, the compound of formula (III) can be further purified, enriched, or re-equilibrated to obtain substantially pure (Z)-endoxifen as described below.

[0130] Concentration and purification of (Z)-endoxifen free base In yet another aspect, the present disclosure relates to an industrially scalable method for the enrichment and purification of (Z)-endoxifen free base. Industrially scalable enrichment and purification of (Z)-endoxifen can be carried out using the method of Step 3 of Exemplary Schematic 1, as described herein and as further described in Examples 1, 2, 4, and 9. The starting mixture of (E)-endoxifen and (Z)-endoxifen used for fractional crystallization can have any E / Z ratio, for example, an E / Z ratio ranging from 99:1 to 1:10. In some embodiments, the E / Z ratio of the starting (Z) / (E)-endoxifen mixture ranges from 30:70 to 70:30. In some embodiments, the E / Z ratio of the starting (Z) / (E)-endoxifen mixture ranges from 99:1 to 1:99. In some embodiments, the E / Z ratio of the starting (Z) / (E)-endoxifen mixture is 51:1, 1:1.8, or 1:5.6.

[0131] The E / Z mixture can be a compound of Formula (III) obtained as described above or can be commercially available (e.g., from Sigma-Aldrich). A mixture of (E)-endoxifen and (Z)-endoxifen (the E / Z mixture) is fractionally crystallized to obtain a first crystalline solid enriched with (Z)-endoxifen free base and a first mother liquor (Example 1). Fractional crystallization is performed using a first solvent capable of disintegrating endoxifen and its derivatives, such that (Z)-endoxifen tends to remain in the filtrate. Suitable first solvents specifically solubilize endoxifen isomers and include, but are not limited to, ethyl acetate, isopropanol, isopropanol / PPW, acetonitrile, acetonitrile / PPW, and dichloromethane. In some embodiments, the first solvent is ethyl acetate. The first solvent, e.g., ethyl acetate, is added at a wt / wt ratio of the compound of Formula (III) to the first solvent ranging from 1:1 to 1:20. In some embodiments, the compound of Formula (III) is dissolved in a first solvent and heated to a temperature ranging from 50°C to 80°C and cooled to 35°C or below.

[0132] It was a surprising discovery that acidifying the mixture enhances the conversion of (E)-endoxifen to (Z)-endoxifen. Thus, in some embodiments, the compound of formula (III) is pretreated with an acid and then neutralized with a base.

[0133] As a non-limiting example, a suitable reaction apparatus is charged with the compound of Formula (III), a first solvent is added thereto, and the mixture is cooled to 0°C to 5°C. An acid, such as HCl or TFA, can then be added slowly. In some embodiments, the acid is added to the E / Z-endoxifen mixture in a wt / wt ratio of the compound of Formula (III) to the acid ranging from 1:1 to 1:5. The reaction mixture may then be heated to a temperature ranging from 50°C to 70°C while stirring. In some embodiments, the reaction is carried out under reflux. The reaction can be carried out for 4 hours or more, e.g., 6 hours or more, 12 hours or more, 24 hours or more, and 48 hours or more. The reaction mixture is cooled to 0°C to 5°C and neutralized with a neutralizing agent.

[0134] In some embodiments, the neutralizing agent is added to the reaction mixture in a wt / wt ratio of the compound of Formula (III) to the neutralizing agent ranging from 1:1 to 1:5. Suitable neutralizing agents include sodium hydroxide, potassium hydroxide, ammonium hydroxide, aminomethylpropanol, and the like. In some embodiments, the neutralizing agent is 8N sodium hydroxide. The pH of the reaction mixture is preferably alkaline. In some embodiments, the pH is ≧10, e.g., ≧11 or ≧12.

[0135] In some embodiments, (Z)-endoxifen is extracted into an organic layer and collected, and the aqueous phase is washed one or more times with a first solvent, such as ethyl acetate (added at a wt / wt ratio of the compound of Formula (III) to the first solvent ranging from 1:1 to 1:10). The organic layers are pooled and washed one or more times with brine (20% NaCl; added at a wt / wt ratio of the compound of Formula (III) to NaCl ranging from 1:1 to 1:10). The organic layer is treated with activated carbon and filtered over a silicon dioxide (Celite®) bed (added at a wt / wt ratio of the compound of Formula (III) to silica ranging from 1.01 to 1:0.1). The product is further washed one or more times with the first solvent (added at a wt / wt ratio of the compound of Formula (III) to the first solvent ranging from 1:1 to 1:10) and distilled. The distillation may be carried out at a temperature ranging from 50° C. to 80° C. In some embodiments, the temperature may be 75° C. or less.

[0136] The first mother liquor is enriched in (Z)-endoxifen, as seen in Example 1, Tables 2 and 3. In some embodiments, the first mother liquor is enriched by at least 50% compared to the E / Z ratio of the mixture of E-endoxifen and Z-endoxifen. In other embodiments, the first mother liquor is enriched by at least 70% in (Z)-endoxifen compared to the E / Z ratio of the mixture of E-endoxifen and Z-endoxifen.

[0137] The first mother liquor can be subjected to recrystallization by concentrating the first mother liquor or by exchanging the first solvent from the first mother liquor one or more times to obtain a second crystalline solid and a second mother liquor (Table 5). The recrystallization is carried out using an exchanging second solvent. The second solvent is added to form a slurry in a wt / wt ratio of the compound of Formula (III) to the second solvent ranging from 1:1 to 1:10. Suitable second solvents include IPA, IPA / PPW, acetone, acetone / MTBE, ethanol, EtOAc, and EtOAc / n-heptane. In some embodiments, the second solvent is IPA. Surprisingly, IPA has been found to break down (Z)-endoxifen into solids at a higher level than EtOAc. Thus, in some embodiments, when the first solvent is EtOAc, the second solvent is IPA or IPA / PPW. This is useful for directing (Z)-endoxifen first from EtOAc to the filtrate (first mother liquor) and then from IPA or IPA / PPW to the solids. In at least one embodiment, the second solvent is IPA / PPW (Table 7). In yet another embodiment, the second solvent is acetone / MTBE. The second crystalline solid is (Z)-endoxifen, (Z)-4-(1-(4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut-1-enyl)phenol, a compound of formula (IV). Molecular weight 373.49; molecular formula: C 25 H 27 NO2; melting point 139°C-143°C. The second crystalline solid is ≧70% (Z)-endoxifen, e.g., ≧75% (Z)-endoxifen, ≧80% (Z)-endoxifen, or ≧90% (Z)-endoxifen. In some embodiments, the second crystalline solid is ≧90% (Z)-endoxifen.

[0138] The second crystalline solid can be optionally subjected to recrystallization to obtain a third crystalline solid, (Z)-endoxifen (Table 5). The third crystalline solid can be ≧90% (Z)-endoxifen, e.g., ≧91% (Z)-endoxifen, ≧92% (Z)-endoxifen, ≧93% (Z)-endoxifen, ≧94% (Z)-endoxifen, ≧95% (Z)-endoxifen, ≧96% (Z)-endoxifen, ≧97% (Z)-endoxifen, ≧98% (Z)-endoxifen, or ≧99% (Z)-endoxifen. In some embodiments, the third crystalline solid is ≧90% (Z)-endoxifen. In some embodiments, the third crystalline solid is ≧95% (Z)-endoxifen. This optional recrystallization is carried out using a third solvent. The third solvent is selected from the group consisting of ethanol, methanol, ethyl acetate, IPA, IPA / PPW, acetone, acetone / MTBE, and EtOAc / n-heptane.

[0139] In one aspect, the present disclosure relates to preheating the first solvent, second solvent, and third solvent prior to use (Table 2). In some embodiments, one or more of the first solvent, second solvent, and third solvent may each independently be preheated to a temperature ranging from 40°C to 80°C. The fractional crystallization and recrystallization steps may also include distilling at 60°C to 80°C and / or cooling the resulting solution to a temperature ranging from 0°C to 35°C.

[0140] It should be understood that in some embodiments, the first, second, and third crystalline solids and the second mother liquor obtained as described above can be subjected to one or more further fractional crystallizations and recrystallizations as described above to obtain purified (Z)-endoxifen. It should also be understood that the first, second, and / or third crystalline solids can be optionally reprocessed using column chromatography techniques to obtain more (Z)-endoxifen.

[0141] In certain embodiments, the industrially scalable processes described herein independently include additional steps or treatments (e.g., removing reaction by-products or working up, isolating, or purifying reaction products) described in the examples herein. In some embodiments, the (Z)-endoxifen free base has <2%, <1%, and <0.5% impurities. In other embodiments, the compound of Formula (III) has <2%, <1%, and <0.5% impurities.

[0142] Those skilled in the art will recognize several parameters of the foregoing processes that can be varied to achieve desired results. These parameters include, for example, the method and means of purification of the reactants and solvent; the order of addition of the reactants and solvent to the reaction mixture; the duration of the reaction of the reactants and solvent; and the temperature and rate of stirring, mixing, or agitation of the reactants and solvent during the reaction.

[0143] The process (including specific process steps) embodied by the methods herein has been found to meet one or more of the following criteria: greater stability, safety, simplicity, higher yield, and greater economics when compared to known processes for producing compounds of Formulas (II), (III), and (IV). (Z)-endoxifen prepared by the process disclosed below is stable at 5°C and 25°C and 60% relative humidity (25°C / 60% RH) for at least 9 months and at 40°C / 75% RH for at least 3 months (Example 9). Stability at elevated temperatures indicates long-term stability. Thus, (Z)-endoxifen free base prepared by the disclosed process is stable for at least 6 months, e.g., at least 9 months, at least 12 months, or at least 18 months. Furthermore, the process described herein is considered scalable for multi-kilogram operations and suitable for commercial production.

[0144] Endoxifen salts In yet another aspect, the present application provides endoxifen salts and methods for making endoxifen salts. Endoxifen salts known in the art include the hydrochloride salt (Fauq et al., Bioorg Med Chem Lett. 2010 May 15;20(10):3036-3038) and the citrate salt of endoxifen (U.S. Patent No. 9,333,190; U.S. Patent Application Publication No. 2010 / 0112041) and have been evaluated for oral administration to subjects.

[0145] In certain embodiments, the present disclosure provides a compound selected from the group consisting of arecoline, besylate, bicarbonate, bitartrate, butyl bromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methyl bromide, methyl bromine ... An anionic salt of endoxifen selected from the group consisting of amide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamaoate (embonate), pantothenate, phosphate / diphosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, teoclate, and triethiodide is provided.

[0146] In other embodiments, the present disclosure provides a cationic salt of endoxifen selected from the group consisting of benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc.

[0147] The endoxifen salts of the present disclosure can be made using any of the compounds of formulas (I), (II), (III), and (IV) prepared as described above.

[0148] Endoxifen Gluconate In some embodiments, the present disclosure provides a gluconate salt of endoxifen or its chemical equivalent.Thus, in at least one embodiment, the endoxifen contained in the composition of the present disclosure is endoxifen gluconate or its chemical equivalent.Unless otherwise specified, it will be understood that when referring to endoxifen gluconate herein, its chemical equivalent will also be included.

[0149] For purposes of this disclosure, chemical equivalents of endoxifen gluconate include all anionic, cationic, and nonionic reaction complexes between the endoxifen molecule and the gluconate moiety. Such complexes typically react with the hydroxyl groups of the endoxifen molecule. The gluconate moiety includes D-gluconic acid, gluconic acid, glycogenic acid, glycan-Δ-lactone, and the like. In some embodiments, the gluconate moiety is a pharmaceutically acceptable gluconate salt. Such salts include calcium gluconate, sodium gluconate, and alkali metal and alkaline earth metal salts, such as potassium gluconate, magnesium gluconate, and lithium gluconate.

[0150] Both stereoisomers of glucarate, D- and L-, are encompassed by the present disclosure. In some embodiments, the endoxifen gluconate included in the compositions of the present disclosure is selected from the group consisting of (Z)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, (E)-endoxifen D-gluconate, (E)-endoxifen L-gluconate, and combinations thereof. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen L-gluconate. In certain embodiments, the pharmaceutical composition comprises (Z)-endoxifen D-gluconate. Unless otherwise specified, compositions may exist as racemic mixtures, pure stereoisomers (e.g., enantiomers and diastereomers), stereoenriched mixtures, etc. Where a particular stereoisomer is shown or specified herein, it will be understood by those skilled in the art that minor amounts of other stereoisomers may be present in the compositions of the present disclosure, provided that the usefulness of the composition as a whole is not precluded by the presence of such other isomers. The individual isomers can be obtained by a number of methods well known in the art, including chiral chromatography using a suitable chiral stationary phase or support, or by chemically converting them into diastereoisomers, separating the diastereoisomers by conventional means such as chromatography or recrystallization, and then regenerating the original stereoisomers.

[0151] The present disclosure also includes a method for producing endoxifen gluconate or a chemical equivalent thereof, the method comprising mixing endoxifen with a glucolate moiety to obtain endoxifen gluconate. Methods for producing gluconate salts of therapeutic agents are known in the art (e.g., U.S. Patent Application Publication No. 2002 / 0127665).

[0152] In some embodiments, endoxifen D-glucarate (e.g., (Z)-endoxifen D-glucarate) salts can be obtained by mixing an ethanolic slurry of endoxifen as free base (e.g., (Z)-endoxifen prepared by the methods described above) with an aqueous solution of D-gluconate obtained by hydrolysis of a 20% w / v solution of D-gluconolactone in water by heating at 70°C for 15-30 minutes. In some embodiments, a minimal amount of ethanol is used, and 5 ml of aqueous D-gluconic acid solution is added per gram of endoxifen free base. Stirring is then continued until a clear solution is obtained. The required amount of this solution is then added to one or more other excipients to produce a formulation in which the "active ingredient" is (Z)-endoxifen D-gluconate or (Z)-endoxifen L-gluconate. The salts can be purified by any of the art-known methods disclosed herein.

[0153] Both purified (Z)-endoxifen free base or a mixture of (E) / (Z)-endoxifen are useful for preparing endoxifen gluconate. Solutions of (Z)-endoxifen D-glucarate or (Z)-endoxifen L-glucarate can also be purified from the (E) / (Z)-endoxifen gluconate mixtures described herein by fractional crystallization or recrystallization (Examples 1-3) to obtain solid purified (Z)-endoxifen salts. The solid salts are stored at -5°C under N until further use.

[0154] It will be understood by those skilled in the art that other endoxifen salts having a glycolate moiety or gluconate salt can be used as starting materials to obtain endoxifen gluconate or its chemical equivalents.

[0155] Endoxifen gluconate or its chemical equivalent can be prepared using (Z)-endoxifen prepared as described above, or using readily available starting reactants. For example, crude endoxifen HCl (≥98%) and sodium gluconate are readily available from Sigma-Aldrich, USA.

[0156] In some embodiments, endoxifen HCl and sodium gluconate are dissolved in a suitable solvent to obtain endoxifen gluconate or its chemical equivalent. In at least one embodiment, a composition comprising endoxifen gluconate also comprises endoxifen HCl. In other embodiments, an (E) / (Z)-endoxifen mixture (a compound of Formula (III)) and sodium gluconate are dissolved in a suitable solvent to obtain endoxifen gluconate or its chemical equivalent.

[0157] Suitable solvents for preparing endoxifen gluconate or its chemical equivalents include, but are not limited to, organic solvents such as alcohols, acetone, DMSO, polyethylene glycol, fatty acids and aliphatic alcohols and their derivatives, hydroxyl acids, pyrrolidone, urea, vegetable oils, animal oils such as fish oils, aromatic oils, etc., or mixtures thereof, and water-miscible solvents such as water-miscible alcohols, dimethyl sulfoxide, dimethylformamide, water-miscible ethers such as tetrahydrofuran, water-miscible nitriles such as acrylonitrile, water-miscible ketones such as acetone or methyl ethyl ketone, amides such as dimethylacetamide, propylene glycol, glycerin, polyethylene glycol 400, glycofurol, tetraglycol, etc., or mixtures thereof.

[0158] Water-miscible solvents useful for preparing endoxifen gluconate include glycerin, ethanol, propanol, isopropanol, propylene glycol, polyethylene glycol, or a mixture thereof. Additional useful solvents include diglycol monoethyl ether (transcutol); alkylene glycols such as dipropylene glycol, propylene glycol, polyethylene glycols such as PEG 300, 400, 3395, 4450, etc.; dimethyl isosorbide; and absolute alcohol. In some embodiments, the solvent is dehydrated alcohol, such as absolute alcohol. In certain embodiments, the solvent is in an amount sufficient to dissolve endoxifen (free base, salt) and gluconate. The concentration of the solvent can also be adjusted as needed. The reaction can be carried out at room temperature and atmospheric pressure.

[0159] The amounts of endoxifen free base or endoxifen salt (e.g., endoxifen HCl) and gluconate (e.g., sodium gluconate) that can be used to make endoxifen gluconate or its chemical equivalents can vary depending on the amounts of reactants used. The resulting endoxifen gluconate has a 1:1 ratio of endoxifen:glucarate moieties.

[0160] In some embodiments, the amount of endoxifen or endoxifen salt used to prepare endoxifen gluconate is 0.01 to 40 (e.g., 1% to 10%, or 3% to 5%) weight percent (wt / wt) of the total composition. In some embodiments, the amount of gluconate used to prepare endoxifen gluconate is 0.01 to 40% (wt / wt) (e.g., 1% to 10% (wt / wt), or 3% to 5% (wt / wt)). Those of ordinary skill in the art will be guided by their skill and knowledge in the art and this disclosure, including, but not limited to, amounts of reactants effective to achieve the desired yield.

[0161] Crystalline morphology In certain embodiments, the present disclosure provides crystalline forms, including crystalline forms of (Z)-endoxifen free base and mixtures of (E)-endoxifen and (Z)-endoxifen. The present disclosure further provides pharmaceutical compositions of endoxifen comprising the crystalline forms described herein. Crystalline forms of endoxifen can offer bioavailability and stability advantages suitable for use as active ingredients in pharmaceutical compositions. Changes in the crystalline structure of a drug substance or active ingredient can affect the dissolution rate (which can affect bioavailability, etc.), manufacturability (e.g., ease of handling and the ability to consistently prepare doses of known strengths), and stability (e.g., thermal stability, shelf life, etc.) of the pharmaceutical drug product or active ingredient. Such changes may also affect the preparation or formulation of pharmaceutical compositions at different doses or in delivery forms such as solid oral dosage forms, including tablets and capsules. Compared with other forms, such as amorphous or non-crystalline forms, crystalline forms can provide desirable or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control. Thus, crystalline forms of endoxifen can provide advantages such as improving the manufacturing process of the active agent or the stability or storage of pharmaceutical forms of the compound or active ingredient, and / or having suitable bioavailability and / or stability as an active agent.

[0162] The use of certain solvents and fractional crystallization methods has been found to produce different polymorphic forms of endoxifen, including any one or more of polymorphic Forms I, II, and II, which may exhibit one or more of the favorable characteristics described above. The processes for the preparation of the polymorphs described herein, and the characterization of these polymorphs, are described in further detail below.

[0163] Formula III, Form I In certain aspects, the present disclosure provides polymorphic Form I of the compound of Formula (III), wherein at least 90% by weight of the compound of Formula (III) in the composition is the (Z)-isomer (i.e., (Z)-endoxifen). In some embodiments, polymorphic Form I exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 9 or Figure 10. In some embodiments, polymorphic Form I comprises an XRPD pattern comprising at least two, at least three, at least four, at least five, or at least six major peaks in an XRPD pattern substantially as shown in Figure 9 or Figure 10.

[0164] For example, the term "substantially as shown" when referring to an XRPD pattern does not necessarily have to be identical to that depicted herein, but includes patterns that are within experimental error or variation as considered by one of ordinary skill in the art. The relative intensities of XRPD peaks can vary depending on particle size, sample preparation technique, sample mounting procedure, and the particular instrument utilized. Furthermore, instrument variations and other factors may affect two theta (2θ) values. Thus, when a specific two theta angle is provided, it is understood that the specific two theta angle may vary by ±0.5°, e.g., ±0.4°, ±0.3°, ±0.2°, or ±0.1°, from the specified value. As used herein, a "major peak" refers to an XRPD peak having a relative intensity greater than 30%, e.g., greater than 35%. Relative intensity is calculated as the ratio of the peak intensity of the peak of interest to the peak intensity of the largest peak in the XRPD pattern.

[0165] In certain embodiments, polymorph Form I is characterized by an X-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° 2-theta. In some embodiments, polymorph Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 16.0±0.3°, 18.8±0.3°, and 26.5±0.3° 2-theta. In some embodiments, polymorph Form I is characterized by an X-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° 2-theta, and at least one peak selected from 16.0±0.3°, 18.8±0.3°, and 26.5±0.3° 2-theta. In some embodiments, polymorph Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 12.3±0.3°, 28.0±0.3°, and 29.0±0.3° 2-theta. In some embodiments, polymorph Form I is characterized by an X-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° 2-theta, and at least one peak selected from 12.3±0.3°, 28.0±0.3°, and 29.0±0.3° 2-theta. In some embodiments, polymorph Form I is characterized by an X-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° 2-theta, and at least one peak selected from 12.3±0.3°, 16.0±0.3°, 18.8±0.3°, 26.5±0.3°, 28.0±0.3°, and 29.0±0.3° 2-theta. In some embodiments, polymorph Form I is characterized by an X-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° 2-theta, and peaks at 12.3±0.3°, 16.0±0.3°, 18.8±0.3°, 26.5±0.3°, 28.0±0.3°, and 29.0±0.3° 2-theta.

[0166] In certain embodiments, the present disclosure provides compositions comprising polymorphic Form I. The composition may comprise 90%, 95%, or 99% or more by weight of the compound of Formula (III) in the polymorphic form. In some embodiments, the composition comprises 0.01 mg to 200 mg of polymorphic Form I. In some embodiments, the composition comprises about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of polymorphic Form I.

[0167] Formula III, Form II In certain aspects, the present disclosure provides polymorphic Form II of the compound of Formula (III), wherein the composition comprises the (E)-isomer and the (Z)-isomer of the compound of Formula (III) (i.e., (E)-endoxifen and (Z)-endoxifen) in an E / Z ratio of between 0.9 and 1.3, e.g., about 1.1. In some embodiments, polymorphic Form II exhibits an X-ray powder diffraction (XRPD) pattern substantially as depicted in Figure 11 or Figure 12. In some embodiments, polymorphic Form II has an XRPD pattern substantially as depicted in Figure 11 or Figure 12, comprising at least two, at least three, at least four, at least five, or at least six major peaks.

[0168] In certain embodiments, polymorph Form II is characterized by an X-ray powder diffraction pattern comprising major peaks at 7.0±0.3°, 11.9±0.3°, 14.0±0.3°, and 18.4±0.3° 2-theta. In some embodiments, polymorph Form II is characterized by an X-ray powder diffraction pattern comprising a peak at 22.0±0.3° 2-theta. In some embodiments, polymorph Form II is characterized by an X-ray powder diffraction pattern comprising major peaks at 7.0±0.3°, 11.9±0.3°, 14.0±0.3°, and 18.4±0.3° 2-theta, as well as a peak at 22.0±0.3° 2-theta. In some embodiments, polymorph Form II is characterized by an X-ray powder diffraction pattern comprising at least one peak selected from 6.6±0.3°, 13.3±0.3°, and 20.0±0.3° 2-theta. In some embodiments, polymorph Form II is characterized by an X-ray powder diffraction pattern comprising major peaks at 7.0±0.3°, 11.9±0.3°, 14.0±0.3°, and 18.4±0.3° 2-theta, and at least one peak selected from 6.6±0.3°, 13.3±0.3°, and 20.0±0.3° 2-theta. In some embodiments, polymorph Form II is characterized by an X-ray powder diffraction pattern comprising major peaks at 7.0±0.3°, 11.9±0.3°, 14.0±0.3°, and 18.4±0.3° 2-theta, and at least one peak selected from 6.6±0.3°, 13.3±0.3°, 20.0±0.3°, and 22.0±0.3° 2-theta. In some embodiments, polymorph Form II is characterized by an X-ray powder diffraction pattern comprising major peaks at 7.0±0.3°, 11.9±0.3°, 14.0±0.3°, and 18.4±0.3° 2-theta, and peaks at 6.6±0.3°, 13.3±0.3°, 20.0±0.3°, and 22.0±0.3° 2-theta.

[0169] In certain embodiments, the present disclosure provides a composition comprising polymorphic Form II. The composition of the compound of Formula (III) may comprise 90%, 95%, or 99% or more by weight of polymorphic Form II. In some embodiments, the composition comprises 0.01 mg to 200 mg of polymorphic Form II. In some embodiments, the composition comprises about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of polymorphic Form II.

[0170] Formula III, Form III In certain aspects, the present disclosure provides polymorphic Form III of the compound of Formula (III), wherein the composition comprises the (E)-isomer and the (Z)-isomer of the compound of Formula III (i.e., (E)-endoxifen and (Z)-endoxifen) in an E / Z ratio of between 0.9 and 1.3, e.g., about 1.1. In some embodiments, polymorphic Form III exhibits an X-ray powder diffraction (XRPD) pattern substantially as depicted in Figure 13. In some embodiments, polymorphic Form III has an XRPD pattern substantially as depicted in Figure 13, comprising at least two, at least three, at least four, at least five, or at least six major peaks.

[0171] In certain embodiments, polymorphic Form III is characterized by an X-ray powder diffraction pattern comprising major peaks at 11.9±0.3°, 13.9±0.3°, 17.1±0.3°, and 17.7±0.3° 2-theta. In some embodiments, polymorphic Form III is characterized by an X-ray powder diffraction pattern comprising a peak at 25.3±0.3° 2-theta. In some embodiments, polymorphic Form III is characterized by an X-ray powder diffraction pattern comprising major peaks at 11.9±0.3°, 13.9±0.3°, 17.1±0.3°, and 17.7±0.3° 2-theta, as well as a peak at 25.3±0.3° 2-theta. In some embodiments, polymorph Form III is characterized by an X-ray powder diffraction pattern comprising at least one peak selected from 18.2±0.3°, 22.5±0.3°, and 26.8±0.3° 2-theta. In some embodiments, polymorph Form III is characterized by an X-ray powder diffraction pattern comprising major peaks at 11.9±0.3°, 13.9±0.3°, 17.1±0.3°, and 17.7±0.3° 2-theta, and at least one peak selected from 18.2±0.3°, 22.5±0.3°, and 26.8±0.3° 2-theta. In some embodiments, polymorph Form III is characterized by an X-ray powder diffraction pattern comprising major peaks at 11.9±0.3°, 13.9±0.3°, 17.1±0.3°, and 17.7±0.3° 2-theta, and at least one peak selected from 18.2±0.3°, 22.5±0.3°, 25.3±0.3°, and 26.8±0.3° 2-theta. In some embodiments, polymorph Form III is characterized by an X-ray powder diffraction pattern comprising major peaks at 11.9±0.3°, 13.9±0.3°, 17.1±0.3°, and 17.7±0.3° 2-theta, and peaks at 18.2±0.3°, 22.5±0.3°, 25.3±0.3°, and 26.8±0.3° 2-theta.

[0172] In certain embodiments, the present disclosure provides a composition comprising polymorphic Form III. The composition of the compound of Formula (III) may comprise 90%, 95%, or 99% or more by weight of polymorphic Form III. In some embodiments, the composition comprises 0.01 mg to 200 mg of polymorphic Form III. In some embodiments, the composition comprises about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of polymorphic Form III.

[0173] Endoxifen Free Base Compositions In one aspect, the present disclosure provides a stable (Z)-endoxifen free base or a salt thereof, and a composition comprising the (Z)-endoxifen free base or a salt thereof. In some embodiments, the pharmaceutical composition comprises predominantly endoxifen as the (Z)-endoxifen free base.

[0174] In certain embodiments, the composition comprises endoxifen as at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.99%, or 100% wt / wt (Z)-endoxifen free base of the total endoxifen in the composition. In at least one composition, the composition comprises ≧90% wt / wt (Z)-endoxifen free base of the total endoxifen in the composition. In another embodiment, the composition comprises ≧95% wt / wt of (Z)-endoxifen free base of the total endoxifen in the composition. In yet other embodiments, the composition comprises ≧96%, ≧97%, ≧98%, ≧99%, or ≧99.5% wt / wt of (Z)-endoxifen free base of the total endoxifen in the composition.

[0175] In other embodiments, the compositions comprising endoxifen comprise between 0.01% and 20%, between 0.05% and 15%, or between 0.1% and 10% (Z)-endoxifen wt / wt or w / v of the composition. In at least one embodiment, the compositions comprising endoxifen comprise between 0.01% and 20% (Z)-endoxifen wt / wt or w / v of the composition. In various other embodiments, the compositions comprising endoxifen comprise 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 10%, or 20% wt / wt of (Z)-endoxifen of the composition.

[0176] In one aspect, a composition comprising (Z)-endoxifen further comprises (E)-endoxifen. In some embodiments, the endoxifen in the composition has an (E)-endoxifen to (Z)-endoxifen ratio (E / Z ratio) of 1:99; 5:95; 10:90, 15:85; 20:80, 25:75; 30:70; 40:70, 45:55; 50:50; 55:45; 60:40; 65:45; and 70:30. In other embodiments, the composition comprises endoxifen with an E / Z ratio ranging from 10:90 to 70:30. In yet another embodiment, the composition comprises endoxifen with an E / Z ratio ranging from 45:55 to 55:45.

[0177] Unless otherwise indicated by the prefix (Z), (E), or (E / Z), endoxifen, as used generally without a prefix, is used herein to include any or all endoxifen isoforms.

[0178] Endoxifen Salt Compositions In some embodiments, the present disclosure provides compositions comprising a salt of endoxifen. In some embodiments, the present disclosure provides compositions comprising a pharmaceutically acceptable salt of endoxifen. In certain embodiments, provided herein are compositions comprising 1%, 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.99%, or 100% of an endoxifen salt.

[0179] In some embodiments, the salt is selected from the group consisting of arecoline, besylate, bicarbonate, bitartrate, butyl bromide, citrate, camsylate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinol, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, isethionate, malate, mandelate, mesylate, methyl bromide, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, papain, methyl methacrylate ... The salt is selected from the group consisting of oate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, tannate, teoclate, and liethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc. In some embodiments, the salt is endoxifen gluconate. The endoxifen gluconate may be selected from the group consisting of (Z)-endoxifen D-gluconate, (E)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, (E)-endoxifen L-gluconate, or a combination thereof.

[0180] In some embodiments, the compositions comprising endoxifen gluconate comprise 10% to 100% (Z)-endoxifen D-gluconate on a wt / wt basis of the total endoxifen gluconate in the composition. In some embodiments, the compositions comprising endoxifen gluconate comprise 10% to 100% (Z)-endoxifen L-gluconate on a wt / wt basis of the total endoxifen in the composition.

[0181] In other embodiments, compositions containing endoxifen gluconate contain 10%, 20%, 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75%, 99.99%, or 100% (Z)-endoxifen D-gluconate or (Z)-endoxifen L-gluconate relative to the total endoxifen gluconate. In some embodiments, the composition comprises at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.99% (Z)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, or a combination thereof.

[0182] In some embodiments, provided herein are compositions comprising (Z)-endoxifen D-gluconate and (E)-endoxifen D-gluconate. The (Z)-endoxifen D-gluconate and (E)-endoxifen D-gluconate may be present in the composition in a wt / wt or v / v ratio of 10:90 to 99:1. In some embodiments, the ratio of (Z)-endoxifen D-gluconate to (E)-endoxifen D-gluconate (wt / wt or v / v) is 10:90 to 99:1 (e.g., 45:55, 50:50, 60:40, 70:30, 80:20, 90:10; 91:9; 92:8; 93:7; 94:8; 95:5, 96:4, 97:3, 98:2, 99:1, 99.5:0.5, or 99.99:0.01), respectively. In some embodiments, the ratio of (Z)-endoxifen D-gluconate to (E)-endoxifen D-gluconate (wt / wt or v / v) is 90:10; 91:9; 92:8; 93:7; 94:8; 95:5, 96:4, 97:3, 98:2, 99:1, 99.5:0.5, or 99.99:0.01. Those skilled in the art will recognize that other combinations of endoxifen gluconate isomers are encompassed by the present disclosure.

[0183] In some embodiments, compositions comprising endoxifen gluconate comprise 0.01%, 0.05%, 0.01%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% endoxifen gluconate (wt / wt) or (w / v) of the composition. In some embodiments, compositions comprising endoxifen gluconate comprise 0.01%, 0.05%, 0.01%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% (Z)-endoxifen gluconate (wt / wt) or (w / v) of the composition.

[0184] The compounds and compositions of the present disclosure can be administered to a subject in need thereof by any route known in the art, including, but not limited to, oral, parenteral, topical, and intraductal delivery. Accordingly, the compositions disclosed herein are formulated to be compatible with the intended route of administration.

[0185] In some embodiments, a composition comprising endoxifen further comprises an excipient, such excipient being compatible with the intended route of administration.

[0186] Endoxifen Polymorphic Compositions In one aspect, the disclosure provides compositions comprising one or more polymorphic forms, such as Form I, Form II, or Form III of endoxifen as described herein. In some embodiments, the pharmaceutical composition comprises endoxifen predominantly as polymorphic Form I. In some embodiments, the pharmaceutical composition comprises endoxifen predominantly as polymorphic Form II. In some embodiments, the pharmaceutical composition comprises endoxifen predominantly as polymorphic Form III.

[0187] In certain embodiments, the composition comprises endoxifen as a single polymorphic form of endoxifen, e.g., Form I, Form II, or Form III wt / wt of at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.99%, or 100% of the total endoxifen in the composition. In at least one composition, the composition comprises ≥90% wt / wt of a single polymorphic form of endoxifen, e.g., Form I, Form II, or Form III, of the total endoxifen in the composition. In another embodiment, the composition comprises ≥95% wt / wt of a single polymorphic form of endoxifen, e.g., Form I, Form II, or Form III, of the total endoxifen in the composition. In yet other embodiments, the composition comprises ≥96%, ≥97%, ≥98%, ≥99%, or ≥99.5% wt / wt of a single polymorphic form of endoxifen, e.g., Form I, Form II, or Form III, of the total endoxifen in the composition. When a particular weight percent of endoxifen is a single polymorphic form, the remainder of the endoxifen in the composition is amorphous endoxifen and / or some combination of one or more polymorphic forms of endoxifen excluding the single polymorphic form. When a polymorphic form of endoxifen is defined as one particular form of endoxifen, the remainder consists of amorphous endoxifen and / or one or more polymorphic forms other than the identified particular form. Examples of single polymorphic forms include endoxifen Forms I, II, and III, as well as single polymorphic forms characterized by one or more properties described herein.

[0188] In other embodiments, a composition comprising endoxifen comprises 0.01% to 20%, 0.05% to 15%, or 0.1% to 10% wt / wt or w / v of a single polymorphic form of endoxifen, e.g., Form I, Form II, or Form III, of the composition. In at least one embodiment, a composition comprising endoxifen comprises 0.01% to 20% wt / wt or w / v of a single polymorphic form of endoxifen, e.g., Form I, Form II, or Form III, of the composition. In various other embodiments, a composition comprising endoxifen comprises 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 10%, or 20% wt / wt of a single polymorphic form of endoxifen, e.g., Form I, Form II, or Form III. In one aspect, a composition comprising a single polymorphic form of endoxifen, e.g., Form I, Form II, or Form III, further comprises a second polymorphic form of endoxifen.

[0189] Oral formulation In some embodiments, the pharmaceutical composition of the present disclosure is formulated for oral delivery.The composition intended for oral use can be prepared in solid or fluid unit dosage form.In at least some embodiments, the composition is formulated for oral delivery as tablets, caplets, capsules, pills, powder, troches, elixirs, suspensions, syrups, wafers, chewing gum, dragees, lozenges, etc.

[0190] In some embodiments, the oral dosage form is a solid oral dosage form such as a tablet, caplet, or capsule. In some embodiments, the capsule is a hard capsule or a soft capsule. In other embodiments, the capsule is a gelatin capsule, a gelatin-free capsule, a "cap-in-cap" capsule, an alginate capsule, a hydroxypropylmethylcellulose (HPMC) capsule, a polyvinyl alcohol (PVA) capsule, a hypromellose capsule, or a starch capsule.

[0191] excipients In some embodiments, oral compositions comprising (Z)-endoxifen or a salt thereof further comprise one or more excipients. In some embodiments, oral compositions comprising endoxifen or a polymorphic form thereof further comprise one or more excipients. Thus, compositions designed for oral administration can be prepared using the inert or active excipients or edible carriers disclosed herein.

[0192] In various embodiments, the compositions provided herein comprise about 1 to about 99.99%, about 5 to about 95%, about 5 to about 90%, about 10 to about 80%, about 15 to about 70%, about 20 to about 60%, about 30 to about 95%, about 50 to about 90%, about 60 to about 90%, about 60 to about 80%, or about 70 to about 80% by weight of one or more excipients. In certain embodiments, the compositions provided herein comprise about 99.99%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% by weight of one or more excipients. In certain embodiments, the compositions provided herein comprise about 99.99%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 89%, about 88%, about 87%, about 86%, or about 85% by weight of one or more excipients. In certain embodiments, the compositions provided herein comprise about 85%, about 84%, about 83%, about 82%, about 80%, about 79%, about 78%, about 77%, about 76%, about 75%, about 74%, about 73%, about 72%, about 71%, about 70%, about 69%, about 68%, about 67%, about 66%, or about 65% by weight of one or more excipients. In certain embodiments, the compositions provided herein comprise about 55%, about 54%, about 53%, about 52%, about 51%, about 50%, about 49%, about 48%, about 47%, about 46%, or about 45% by weight of one or more excipients. In certain embodiments, the compositions provided herein comprise about 30%, about 29%, about 28%, about 27%, about 26%, about 25%, about 24%, about 23%, about 22%, about 21%, or about 20% by weight of one or more excipients.

[0193] Examples of excipients that may be used in compositions formulated for oral administration are provided herein and include, but are not limited to, one or more of fillers, binders, filling agents, disintegrants, lubricants, glidants, controlled-release agents, enteric coatings, film-forming agents, plasticizers, colorants, sweeteners, flavoring agents, and the like, or any combination thereof.

[0194] Binders suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, sucrose, starches such as corn starch, potato starch, or starch paste, pregelatinized starch, and starch 1500, PEG 6000, methocel, walocel HM, Luvitec, Luvicaparolactam, Avicel, SMCC, UNIPURE, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL PH 101, AVICEL pH 103, AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. In some embodiments, the binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose. Suitable anhydrous or low-moisture excipients or additives include AVICEL PH 103 and starch 1500 LM.

[0195] Examples of fillers suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), sugars such as dextrose, sucrose, lactose, salts such as calcium carbonate, calcium phosphate, sodium carbonate, sodium phosphate, starch, microcrystalline cellulose, powdered cellulose, cellulose bases such as methylcellulose, carboxymethylcellulose dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0196] The one or more binders or fillers in the composition are typically present in about 10% to about 99% (wt / wt) of the composition or dosage form. In some embodiments, the binder and / or filler in the composition comprises about 15% to 99%, about 20% to 60%, about 25% to 55%, about 30% to 50%, about 35% to 60%, or about 50% to 99% (wt / wt) of the composition.

[0197] Disintegrants can be used in compositions to provide tablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate during storage, and tablets that contain too little disintegrant may not disintegrate at the desired speed or under the desired conditions.Therefore, a sufficient amount of disintegrant must be used to form a solid oral dosage form, but not too much or too little to adversely change the release of active ingredients.In some embodiments, disintegrants are located deep within the oral solid dosage form to slow disintegration.The amount of disintegrant used varies based on the type of formulation and can be easily identified by those skilled in the art.

[0198] Typical compositions contain 0.5% to 15% (wt / wt) of disintegrant. In some embodiments, the composition contains 1% to 5% (wt / wt) of the disintegrant in the composition. In other embodiments, the disintegrant is 1% to 25%, 2% to 20%, 5% to 15%, 8% to 12%, or about 10% (wt / wt) of the composition.

[0199] Disintegrants that can be used in the pharmaceutical compositions provided herein include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0200] Lubricants that may be used in the pharmaceutical compositions provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, magnesium stearate, or potassium stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Additional lubricants include, for example, syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, Md.), coagulated aerosol of synthetic silica (sold by Degussa Co. of Plano, Tex.), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), Q7-9120 (Dow Corning), and mixtures thereof. If used at all, lubricants are typically used in amounts of less than 1% (wt / wt) of the composition or dosage form into which they are incorporated. In yet other embodiments, the lubricant is 0.1% to 3%, e.g., 0.5% to 1% (wt / wt) of the composition.

[0201] Plasticizers can be added to control the softness or flexibility of oral dosage forms such as capsule shells, caplets or tablets, and thus improve the mechanical properties of the pH-sensitive material of the coating of oral dosage forms.Suitable plasticizers include, but are not limited to, petroleum oils (e.g., paraffinic processing oil, naphthenic processing oil, and aromatic processing oil), squalene, squalane, vegetable oils (e.g., olive oil, camellia oil, castor oil, tall oil, and peanut oil), silicone oil, dibasic acid esters (e.g., dibutyl phthalate and dioctyl phthalate), liquid rubbers (e.g., polybutene and liquid isoprene rubber), liquid fatty acid esters (e.g., isopropyl myristate ISM), isopropyl myristate, diethyl sebacate, and diisopropyl sebacate, triethyl citrate, triacetin, diethylene glycol, polyethylene glycol, polypropylene glycol, phthalate, sorbitol, glycol salicylate, crotamiton, and glycerin or mixtures thereof. The amount of plasticizer can vary based on the chemical composition of the formulation. In one embodiment, at least one plasticizer is sorbitol, dimethyl isosorbide, or glycerol. In another embodiment, the plasticizer is 1% to 10%, e.g., 3% to 5% (wt / wt) of the composition.

[0202] Examples of lubricants include, but are not limited to, colloidal silicon dioxide, cellulose, calcium phosphate, di- or tri-basic, and the like.

[0203] Examples of sweeteners or sweetening agents include sucrose, saccharin, dextrose, maltose, sugar substitutes, aspartame, xylitol, mannitol, cyclamate, sucralose, maltitol, sorbitol, acesulfame K, and the like.

[0204] Examples of flavorings include peppermint, methyl salicylate, peppermint, spearment, methyl salicylate, raspberry, red berry, strawberry, pineapple, orange, cherry, and the like.

[0205] The compositions formulated for oral delivery described herein, such as tablets, caplets, and capsules, can be coated with one or more enteric coatings, controlled-release agents, or film-forming agents to control or delay the disintegration and absorption of the compositions containing endoxifen or a salt thereof in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. Thus, in some embodiments, the tablets can be enteric-coated tablets, the caplets can be enteric-coated caplets, or the capsules can be enteric-coated capsules. The enteric-coated tablets, caplets, or capsules of the present disclosure can be prepared by techniques known in the art.

[0206] The formulations disclosed herein may include a controlled-release agent. Examples of controlled-release agents suitable for use include, but are not limited to, pH-dependent polymers and acid-insoluble polymers, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, shellac, cellulose acetate trimellitate, sodium alginate), sodium alginate, zein, synthetic waxes, microcrystalline wax, paraffin wax, carnauba wax, and beeswax; polyethoxylated castor oil derivatives, hydrogenated oils, glyceryl monobenate, dibenate, tribenate, glyceryl monostearate, glyceryl distearate, long-chain alcohols such as stearyl alcohol, cetyl alcohol, and polyethylene glycol; and mixtures thereof. In some embodiments, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. In other embodiments, the controlled-release agent is a digestible waxy material such as solid paraffin wax.

[0207] In some embodiments, the composition includes one or more pH-dependent polymers, such as acid-insoluble polymers. pH-dependent polymers become increasingly permeable above pH 5.0 but impermeable below pH 5.0, while acid-insoluble polymers become soluble under neutral to slightly alkaline conditions. Such controlled-release polymers target the upper small intestine and colon. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate, alginic acid, such as sodium alginate or potassium alginate, shellac, pectin, and acrylic acid-methacrylic acid copolymer (available under the tradenames EUDRAGIT® L and EUDRAGIT® S from Rohm America Inc., Piscataway, NJ, as a powder or a 30% aqueous dispersion; or EASTACRYL® from Eastman Chemical Co., Kingsport, TN, as a 30% dispersion). Additional examples include EUDRAGIT® L100-55, EUDRAGIT® L30D-55, EUDRAGIT® L100, EUDRAGIT® L100 12.5, EUDRAGIT® S100, EUDRAGIT® S12.5, EUDRAGIT® FS 30D, EUDRAGIT® E100, EUDRAGIT® E 12.5, and EUDRAGIT® PO. In at least one embodiment, the composition comprises EUDRAGIT® L100-55. EUDRAGIT® RS and RL, and EUDRAGIT® NE and NM are useful polymers for purposes of the present disclosure. In some embodiments, the composition comprises EUDRAGIT® L30D 55. In another embodiment, the preparation comprises EUDRAGIT® FS 30D. Those skilled in the art will also recognize that at least some of the acid-insoluble polymers described herein are biodegradable.

[0208] For time-delay or delayed-release formulations of oral dosage forms, glyceryl monostearate, glyceryl distearate, and acid-insoluble polymers, such as polymethacrylate pH-sensitive polymer-based coatings, may be used (e.g., as coating materials, i.e., enteric coating agents for capsules, caplets, and tablets). Delayed-release oral dosage forms, such as DRCaps made of hypromellose (HPMC), are available from commercial sources, such as Capsugel, USA. Such delayed-release oral dosage forms are acid-resistant and can withstand acidity such as that found in the stomach for at least 30 minutes, e.g., at least 1 hour, at least 1.5 hours, or at least 2 hours. Such delayed-release oral dosage forms can release at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of endoxifen or its salt in the intestine (e.g., small intestine, large intestine / colon).

[0209] In one embodiment of the present disclosure, enteric-coated tablets, enteric-coated caplets, and enteric-coated capsules may be uncoated. Non-hard-coated capsules with enteric capabilities that essentially use enteric capsule technology (e.g., EnTrinsic drug delivery available from Capsugel) are suitable for purposes of the present disclosure.

[0210] In various embodiments, the enteric-coated tablet is a hard tablet made with a free-flowing powder of (Z)-endoxifen or a salt thereof. In various embodiments, the enteric-coated capsule is a capsule made with a free-flowing powder of (Z)-endoxifen or a salt thereof. In various embodiments, the enteric-coated tablet is a hard tablet made with a free-flowing powder of endoxifen or a polymorph thereof. In various embodiments, the enteric-coated capsule is a capsule made with a free-flowing powder of endoxifen or a polymorph thereof.

[0211] In some embodiments, the enteric-coated capsule is a non-animal-based capsule such as a hypromellose capsule (e.g., commercially available self-gelling Vcaps, VCaps Plus, enteric-coated VCaps, Xcellodose from Capsugel, ENCODE's colonic delivery technology, and other enteric-coated capsules manufactured using EnTrinsic™ drug delivery technology). Other technologies known in the art and commercially available for formulating enteric-coated oral solid dosage forms (e.g., Qualicaps, USA, Nutrascience, USA, etc.) can also be utilized. In at least one embodiment, the capsule is an API-in-capsule, meaning that (Z)-endoxifen free base or a salt thereof is tightly packed into the capsule. In such an API-in-capsule oral dosage form, the active ingredient, (Z)-endoxifen or a salt thereof, can be a free-flowing powder or a micronized powder. When the dosage form is a capsule, in at least one embodiment, the capsule can be a seamless capsule or a banded capsule.

[0212] Rapid absorption and bioavailability of anti-cancer therapeutics such as endoxifen, which can further reduce the rate of cancer growth, is highly desirable. In one aspect, the present disclosure provides compositions formulated for specific pharmacokinetic (PK) properties.

[0213] In one aspect, rapid achievement of maximum and steady-state plasma levels of endoxifen is a particular aspect of the present disclosure. The present disclosure provides compositions that achieve maximum plasma levels of endoxifen within 2 to 30 hours, 3 to 20 hours, 2 to 10 hours, or 4 to 8 hours after administration of the composition. Thus, in some embodiments, the time to maximum (peak) plasma levels of endoxifen is within 2 to 10 hours after administration of the composition. In some embodiments, the time to maximum plasma levels of endoxifen is within 4 to 8 hours after administration of a composition disclosed herein.

[0214] Rapid attainment of steady-state plasma levels of endoxifen is also highly desirable, and the compositions of the present disclosure can provide plasma levels of endoxifen in subjects administered compositions containing a polymorphic form of endoxifen, (Z)-endoxifen, or a salt thereof that rapidly attain steady state. Steady-state plasma levels can be achieved between days 7 and 21. In some embodiments, steady-state plasma levels can be achieved by day 7 upon daily administration of the compositions disclosed herein (Figure 5).

[0215] In one aspect, the present disclosure provides that circulating endoxifen released from the compositions disclosed herein may be cleared more rapidly than tamoxifen. Tamoxifen's terminal elimination half-life is said to be 5-7 days (Jordan C. Steroids. 2007 Nov; 72(13): 829-842), with tamoxifen's peak concentration time being approximately 5 hours after administration. Endoxifen released from the compositions disclosed herein may have a terminal elimination half-life in the range of 30-60 hours, significantly shorter than tamoxifen. In some embodiments, the mean half-life is in the range of 40-53 hours. For compositions containing 1 mg to 4 mg of (Z)-endoxifen or a salt thereof, the AUC 24hr (Day 21) / AUC 0-inf The mean ratio (on Day 1) typically ranges from 0.7 to 1.2. Thus, the accumulation of endoxifen released from the compositions disclosed herein does not change significantly over continued treatment.

[0216] In other aspects, the compositions described herein achieve therapeutically effective absorption of endoxifen.

[0217] Area under the curve AUC( 0-24hr )("AUC 24hr") describes a subject's total exposure to a drug over a 24-hour period from the time of administration (0 hr). Compositions containing (Z)-endoxifen or a salt thereof typically provide a 150-hour (24-hour) dose on Day 1 for an initial (first) dose of 1 mg to 4 mg of a composition containing (Z)-endoxifen. * ng / mL~600 hours * ng / mL mean (AUC 24hr Compositions containing (Z)-endoxifen or a salt thereof typically achieve a 400-hour response on day 21 of an initial (first) dose of a composition containing 1 mg to 4 mg of (Z)-endoxifen. * ng / mL~2500 hours * Mean AUC in ng / mL 24hr Achieve this.

[0218] AUC 0-inf ("AUC 0-inf "), i.e., the time-averaged concentration of drug circulating in the analyzed body fluid (usually plasma, blood, or serum), describes the subject's total exposure to the drug. In this disclosure, exposure to endoxifen (AUC 0-inf ) can be dose-proportional. In some embodiments, AUC 0-inf is 200 hours * ng / mL~10000 hours * In another embodiment, the AUC 0-inf is 300 hours * ng / mL~8000 hours * In certain embodiments, the AUC 0-inf over a dose range of 1 mg to 4 mg of (Z)-endoxifen for 400 hours. * ng / mL~6000 hours * ng / mL range (see, for example, Table 17).

[0219] Dissolution of the oral dosage forms disclosed herein is tested by dissolution testing according to the current method of USP 711. In some embodiments, the oral dosage forms disclosed herein are protected from the acidic environment of the stomach and do not dissolve for at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, 6 hours, at least 7 hours, or at least 8 hours. In at least one embodiment, the oral dosage form does not release endoxifen for at least 6 hours. In another embodiment, the oral dosage form does not release endoxifen or a salt thereof for at least 2 hours.

[0220] In other embodiments, less than 10% of (Z)-endoxifen in a composition comprising endoxifen or a salt thereof disclosed herein is released in the stomach 2 hours after administration; or wherein less than 40% of (Z)-endoxifen is released in the stomach 4 hours after administration; or wherein less than 50% of (Z)-endoxifen is released in the stomach 6 hours after administration as tested by the method of USP 711.

[0221] In another embodiment, the compositions disclosed herein release less than 40% of (Z)-endoxifen after 4 hours of administration, less than 10% of (Z)-endoxifen after 2 hours of administration; and less than 50% of (Z)-endoxifen after 6 hours of administration in the stomach as tested by the method of USP 711.

[0222] In still other embodiments, the composition is formulated to release in the small intestine such that at least 10% of the endoxifen is released 4 hours after administration; or at least 30% of the endoxifen is released 6 hours after administration; or at least 40% of the endoxifen is released 7 hours after administration; or at least 50% of the endoxifen is released 8 hours after administration, as tested by the method of USP 711.

[0223] In a further embodiment, the composition is formulated to release at least 50% of the endoxifen in the colon 8 hours after administration as determined by the method of USP 711.

[0224] In further embodiments, the composition is formulated to release at least 20% of endoxifen in the colon 4 hours after administration; at least 40% of endoxifen after 6 hours after administration; at least 60% of endoxifen after 7 hours after administration; or at least 80% of endoxifen after 8 hours after administration.

[0225] The oral dosage form may be of any shape suitable for oral administration, e.g., spherical (0.05-5 mL), oval (0.05-7 mL), ellipsoid, pear-shaped (0.3-5 mL), cylindrical, cubic, regular and / or irregular shapes. The oral dosage form may be of any size suitable for oral administration, e.g., size 0, size 2.

[0226] Those skilled in the art will further recognize that the compositions disclosed herein can contain one or more of the excipients known in the art and disclosed herein in any combination appropriate to the desired formulation or preparation. Additional excipients are generally found in Remington's "The Science and Practice of Pharmacy," Meade Publishing Co., United States Pharmacopeia / National Formulary. Those skilled in the art will be able to select appropriate excipients necessary for the preparation of a formulation compatible with the route of administration and an appropriate dosage form based on their skill and knowledge of the art and the disclosure herein. In all cases, the final dosage form must be sterile and stable under the conditions of manufacture and use.

[0227] With respect to the formulation of the solid dosage compositions disclosed herein, water activity (A w) is less than 0.75, there is typically no need to test for total plate count (TAC) and USP indicator organisms. The publication "Microbial Bioburden on Oral Solid Dosage Form, by Jose E. Martinez, Pharmaceutical Technology, February 2002, pages 58 to 70" is incorporated herein by reference in its entirety.

[0228] Additionally, formulations of the compositions disclosed herein also have a water activity of less than 0.75 and therefore typically do not require extensive microbial testing. The TAC is an estimate of all viable aerobic bacteria present in a sample of raw material, intermediate material, or final product. Samples are tested according to the latest USP 39 <61> , analyzed in accordance with "Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests."

[0229] Acceptable TACs for oral solid dosage forms (OSDF) are established for formulations of the original composition in terms of warning and action levels, which may be 1000 cfu g / mL and 10,000 cfu g / mL, respectively. A TAC of 20,000 cfu g / mL may be considered unacceptable.

[0230] For other preparations, such as liquid or fluid preparations with a water activity of less than 0.75, testing for certain microorganisms (Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella, C. albicans, Clostridium, Escherichia coli, and bile acid-resistant Gram-negative bacteria) may not need to be performed according to Chapter 62 of the USP guidelines.

[0231] How to use The compounds of formulas (I), (II), (III), and (IV), the endoxifen salts disclosed herein, the polymorphic forms of endoxifen disclosed herein, and compositions comprising them, can be used in the manufacture of a medicament for use in treating a subject in need thereof, for example, a subject suffering from or at risk of suffering from a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both.

[0232] When intended to ameliorate or cure a subject suffering from or at risk of suffering from a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both, the compositions of the present disclosure can be used as a primary therapy, as part of a neoadjuvant therapy (to a primary therapy), or as part of an adjuvant therapy regimen.

[0233] In certain embodiments, the disorder is a hormone-dependent breast disorder. In other embodiments, the disorder is a hormone-dependent reproductive system disorder. In yet another embodiment, the subject suffers from both a hormone-dependent breast disorder and a hormone-dependent reproductive system disorder. In some embodiments, the hormone-dependent disorder is benign breast disorder, hyperplasia, atypical, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer.

[0234] In some embodiments, the breast disorder is increased breast density, for example, the breast disorder is Class B (formerly Class II), Class C (formerly Class III), or Class D (formerly Class IV) breast density.

[0235] In some embodiments, the hormone-dependent breast disorder or hormone-dependent reproductive system disorder is precocious puberty. In other embodiments, the hormone-dependent breast disorder or hormone-dependent reproductive system disorder is McCune-Albright syndrome.

[0236] In some embodiments, the breast disorder is gynecomastia. In some embodiments, gynecomastia occurs secondary to an underlying disease. Thus, in some embodiments, the subject also suffers from an underlying disease selected from the group consisting of prostate cancer, cirrhosis and liver disease, male hypogonadism, hyperthyroidism, renal failure, patients undergoing hemodialysis, or type I diabetes. In certain embodiments, the subject suffers from prostate cancer as the underlying disease, wherein the subject has or is at risk of having gynecomastia.

[0237] In certain embodiments, the breast cancer is DCIS, LCIS, ILC, IDC, MIC, inflammatory breast cancer, ER-positive (ER+) breast cancer, HER2+ breast cancer, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma (or colloid carcinoma), papillary carcinoma, tubular carcinoma, metaplastic carcinoma, or micropapillary carcinoma. In at least one embodiment, a single breast cancer tumor may be a combination of the foregoing or may be a mixture of invasive carcinoma and carcinoma in situ.

[0238] The present disclosure contemplates the use of the compounds and compositions disclosed herein in various stages of tumor development and progression, including the treatment of progressive and / or invasive tumors, i.e., overt disease in subjects that are not amenable to localized treatment such as surgery or radiation therapy, metastatic disease, or locally advanced disease. Thus, in some embodiments, the breast cancer is pre-cancer, early-stage cancer, non-metastatic cancer, pre-metastatic cancer, or locally advanced cancer. In at least one embodiment, the breast disorder is metastatic cancer. In some embodiments, the subject also suffers from prostate cancer.

[0239] Despite the serious side effects, poor patient compliance, and drug resistance due to low plasma endoxifen levels observed in subjects, tamoxifen remains the current treatment of choice for such disorders. Such subjects may have low endoxifen levels when administered tamoxifen for several reasons, such as having CYP gene mutations in CYP2D6, CYP3A4, or CYP2C9, which prevent tamoxifen from being metabolized to its active metabolite, endoxifen, or low-functioning or dysfunctional estrogen receptors, preventing (or reducing) sufficient tamoxifen uptake, and other reasons that have not yet been identified. The reported therapeutic level of plasma tamoxifen in subjects administered 20 mg oral tamoxifen is ≧30 nM ((Lyon et al. Genet Med. 2012 Dec;14(12):990-1000). Regardless of the mechanism underlying low plasma endoxifen in a subject, the compositions of the present disclosure are useful for any disease where the subject has low endoxifen or where the subject suffers from or is at risk of suffering from a hormone-dependent breast disorder or a hormone-dependent reproductive system disorder. Thus, the compositions of the present disclosure may be particularly important in treating tamoxifen-resistant, hormone-dependent breast disorders or hormone-dependent reproductive system disorders.

[0240] In certain embodiments, patient populations for which the pharmaceutical compositions are particularly useful are provided herein.The compositions of the present disclosure are also particularly important in treating tamoxifen-resistant subjects suffering from hormone-dependent breast disorders or hormone-dependent reproductive system disorders.Thus, in some embodiments, the compositions disclosed herein are useful for treating tamoxifen-resistant or tamoxifen-resistant subjects suffering from or at risk of suffering from hormone-dependent breast disorders, hormone-dependent reproductive system disorders, or both.In some embodiments, compositions comprising endoxifen salts, such as endoxifen gluconate, administered to such subjects at dosages disclosed herein would be advantageous.

[0241] Furthermore, Donneyong et al. have shown that pharmacological interactions exist between tamoxifen and selective serotonin reuptake inhibitor (SSRI) drugs, such as Prozac and Paxil (paroxetine), which are harmful to breast cancer subjects (Donneyong et al. BMJ 2016;354:i5014). SSRI drugs reduce or stop the hepatic metabolism of tamoxifen to endoxifen in subjects taking SSRI drugs. Therefore, in certain embodiments, provided herein are patient populations currently being treated with or to be treated with SSRI drugs that would benefit from treatment with the compositions of the present disclosure.

[0242] Orally administered compositions disclosed herein maintain a subject's plasma endoxifen at a steady-state level greater than 30 nM, e.g., a level in the range of 30 nM to 80 nM, or a level in the range of 30 nM to 300 nM. In some embodiments, the plasma steady-state endoxifen level is maintained at >40 nM. Such maintenance of plasma endoxifen at a steady-state level greater than 30 nM is effective in reducing the likelihood of recurrence of hormone-dependent breast disorders or hormone-dependent reproductive system disorders, particularly breast cancer, at plasma endoxifen levels less than 30 nM. Administering the compositions disclosed herein is particularly advantageous for subjects who are deficient in metabolic activity of tamoxifen (having plasma endoxifen levels less than 16 nM) or its intermediate metabolite (having plasma endoxifen levels less than 27 nM). This is advantageous for subjects who are being treated or will be treated with antidepressants such as SSRI drugs, e.g., citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil, Pexeva), sertraline (Zoloft), vilazodone (Viibryd), etc., e.g., subjects who have or are likely to have depression.

[0243] By administering an initial dose of tamoxifen to a subject and determining the steady-state plasma endoxifen level of the subject, it can be determined whether the subject is tamoxifen resistant.The steady-state plasma endoxifen level in a subject administered with tamoxifen serves as a biomarker for the subject being tamoxifen resistant.Plasma endoxifen level (acute and / or steady-state) can be determined by obtaining a test sample (which can be a blood sample) collected from the subject after administering tamoxifen.Plasma or serum can be obtained from the blood sample to test the biomarker endoxifen level.The initial dose includes daily administration of tamoxifen for at least 1 day, 2 days, 3 days, 15 days, 1 week, 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. The subject may also be administered a first composition comprising tamoxifen daily for at least 1 day, 2 days, 3 days, 15 days, 1 week, 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, or 10 years.

[0244] The steady-state plasma endoxifen level of a subject can be determined by measuring endoxifen in a test sample. The steady-state plasma endoxifen level of a subject is compared to a reference plasma endoxifen level. For purposes of this disclosure, the reference plasma level is 30 nM. If the subject's plasma endoxifen level is determined to be less than 30 nM, the subject is defined as tamoxifen-resistant. Such tamoxifen-resistant subjects suffering from or at risk of suffering from hormone-dependent breast disorders or hormone-dependent reproductive system disorders are treated by administering to the subject an oral composition comprising (Z)-endoxifen or a salt thereof disclosed herein, or a polymorphic form of endoxifen disclosed herein. In some embodiments, the composition administered to such subjects comprises (Z)-endoxifen free base. In some embodiments, the composition administered to such subjects comprises a polymorphic form, such as endoxifen Form I, Form II, or Form III. In other embodiments, the composition administered to such a subject comprises an endoxifen gluconate selected from the group consisting of (Z)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, (E)-endoxifen D-gluconate, (E)-endoxifen L-gluconate, or a combination thereof. In other embodiments, the composition comprising endoxifen is endoxifen HCl or endoxifen citrate. The present disclosure also contemplates that a subject's plasma endoxifen levels may be tracked or monitored periodically or as needed. If necessary, a subject administered an initial dose of tamoxifen can adjust their plasma endoxifen steady-state levels based on test results by continuing to administer a composition comprising endoxifen.

[0245] In some embodiments, the tamoxifen-resistant status of a subject can be determined by determining the subject's tamoxifen metabolite profile, which is compared with a reference tamoxifen metabolite profile found in a control or normal subject.A subject with a low plasma endoxifen level in the subject's tamoxifen metabolite profile compared with the reference tamoxifen metabolite profile is treated with an oral composition comprising endoxifen or a salt thereof.Such a composition may comprise synthetically prepared endoxifen.

[0246] Plasma endoxifen may be measured by any method known in the art. The plasma endoxifen level in a test sample can be determined based on the subject's genetic, DNA, RNA, protein, tamoxifen metabolite profile, or a combination thereof. The tamoxifen metabolite profile may include at least tamoxifen, 4-OHT, N-desmethyltamoxifen, and / or endoxifen. In some embodiments, the plasma endoxifen and / or tamoxifen metabolite profile levels in a test sample are measured by high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-tandem mass spectrometry (LC-MS / MS), immunohistochemistry (IHC), polymerase chain reaction (PCR), quantitative PCR (qPCR), or the like. In some embodiments, the tamoxifen metabolite profile is predicted based on the subject's genetic composition. In some embodiments, the subject's CYP genotype may include, but is not limited to, analysis of the CYP2D6, CYP3A4, and CYP2C9 genes. In some embodiments, the subject's estrogen receptor levels may be analyzed. In other embodiments, plasma endoxifen determination may be performed by a third-party laboratory.

[0247] Thus, provided herein are methods for maintaining plasma endoxifen at levels greater than 30 nM in a subject by administering to the subject a composition comprising endoxifen or a salt thereof. In some embodiments, the subject's plasma endoxifen level is maintained at a steady-state level greater than 30 nM. In some embodiments, the subject's plasma endoxifen level is maintained at a steady-state level in the range of 30 nM to 300 nM (e.g., 30 nM to 200 nM, or 30 nM to 80 nM). In some embodiments, the subject's plasma endoxifen level is maintained at a steady-state level of >40 nM.

[0248] In other embodiments, subjects can have their test samples tested for their own biomarker profile, which indicates or can monitor hormone-dependent breast disorders, hormone-dependent reproductive system disorders, or both. Such biomarkers are known in the art, and non-limiting examples include biomarkers such as CYP2D6, BRCA-1, BRCA-2, ER, PR, Her2, uPA, PAI, Tf, p53, Ki67, cytokeratin, cancer tumor antigens, and other biomarkers measured by Mammaprint, OncotypeDx, PAM50, EndoxPredict, MammoStrat, and other diagnostic and predictive tests. Subjects with a biomarker profile indicating that they are suffering from or at risk of suffering from hormone-dependent breast disorders, hormone-dependent reproductive system disorders, or both can be administered the compositions disclosed herein. In one aspect, the present disclosure provides a method of treating a subject suffering from or at risk of suffering from a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both, comprising determining the subject's tamoxifen-resistant or tamoxifen-tolerant status and administering to the subject a composition described herein.

[0249] In some aspects, provided herein are methods of treating a tamoxifen-resistant or tamoxifen-tolerant subject, the methods comprising administering to the subject a composition comprising endoxifen, or a salt or polymorphic form thereof.

[0250] In some embodiments, disclosed herein are methods for treating a tamoxifen-resistant subject suffering from or at risk of suffering from a hormone-sensitive breast disorder, a hormone-sensitive reproductive system disorder, or both, comprising administering to the subject an oral composition comprising endoxifen or a salt thereof, wherein the subject has a plasma endoxifen level of less than 30 nM, less than 25 nM, less than 20 nM, less than 15 nM, less than 10 nM, less than 5 nM, or less than 1 nM. In certain embodiments, the composition comprising an endoxifen salt is endoxifen gluconate, endoxifen HCl, or endoxifen citrate. In other embodiments, an oral solid dosage form comprising at least 90% (Z)-endoxifen or a salt thereof is administered. In other embodiments, an oral solid dosage form comprising at least 90% of endoxifen polymorphic Form I, Form II, or Form III is administered.

[0251] Further provided herein are methods for treating a tamoxifen-resistant subject, the methods comprising: (a) determining or being determined a plasma endoxifen level in a test sample obtained from the subject; (b) comparing or being determined a plasma endoxifen level in the test sample with a reference plasma endoxifen level; (c) determining a decrease in the plasma endoxifen level in the test sample compared to the reference plasma endoxifen level; and (d) administering to the subject a composition comprising endoxifen, or a salt or polymorphic form thereof. Administration of the composition comprising endoxifen, or a salt or polymorphic form thereof, maintains the plasma endoxifen level in the subject at a steady-state level greater than 30 nM. In some embodiments, the plasma endoxifen level in the subject is maintained at a steady-state level in the range of 30 nM to 80 nM.

[0252] Provided herein are methods for treating a subject suffering from or at risk of suffering from a hormone-dependent breast disorder or a hormone-dependent reproductive system disorder, the methods comprising: (a) administering to the subject a first composition comprising endoxifen; (b) determining or being determined the plasma endoxifen level in a test sample obtained from the subject; (c) determining or being determined a decrease in the plasma endoxifen level in the test sample compared to a baseline plasma endoxifen level; and (d) administering to the subject an oral composition disclosed herein. The subject may be administered the first composition comprising tamoxifen daily for at least 1 day, 2 days, 3 days, 15 days, 1 week, 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, or 10 years. In some embodiments, administration of an oral composition comprising endoxifen or a salt or polymorphic form thereof maintains the subject's plasma endoxifen at a level of 30 nM or greater. In other embodiments, administration of an oral composition comprising endoxifen, or a salt or polymorphic form thereof, maintains the subject's plasma endoxifen at levels ranging from 30 nM to 300 nM (e.g., 30 nM to 200 nM, or 30 nM to 80 nM). In some embodiments, the subject is administered an oral composition comprising (Z)-endoxifen gluconate, (Z)-endoxifen L-gluconate, (E)-endoxifen D-gluconate, (E)-endoxifen L-gluconate, or a combination thereof. In other embodiments, the oral composition comprising an endoxifen salt is endoxifen HCl or endoxifen citrate. In some embodiments, the subject is administered an oral composition comprising polymorphic Form I, Form II, or Form III of endoxifen disclosed herein.

[0253] Provided herein is a method for treating a subject suffering from hormone-dependent breast disorders or hormone-dependent reproductive system disorders, the method comprising: (a) administering a first composition comprising tamoxifen to the subject; (b) determining or being determining the tamoxifen metabolite profile of the subject in a test sample obtained from the subject; (c) determining a decrease in the subject's plasma endoxifen level based on the subject's tamoxifen metabolite profile to compare the reference plasma endoxifen level with the reference tamoxifen metabolite profile; (d) administering an oral composition comprising endoxifen or its salt or polymorphic form to the subject.In certain embodiments, the composition comprising endoxifen is endoxifen gluconate, endoxifen HCl, or endoxifen citrate.In some embodiments, the composition comprises polymorphic Form I, Form II, or Form III of endoxifen.

[0254] Provided herein are methods for regulating plasma endoxifen levels in a subject being treated for a hormone-dependent breast disorder or a hormone-dependent reproductive system disorder, the subject having one or more CYP2D6 or CYP3A4 mutations or having previously received an initial dose of tamoxifen and having a plasma endoxifen level below a baseline plasma endoxifen level, the method comprising: (a) measuring the subject's plasma endoxifen level after administration of the initial dose of tamoxifen; (b) comparing the subject's plasma endoxifen level with a baseline plasma endoxifen level; and (c) administering to the subject an oral composition containing endoxifen, or a salt or polymorphic form thereof, to maintain the subject's plasma endoxifen level at a level greater than 30 nM. In some embodiments, administration of the oral composition containing endoxifen, or a salt or polymorphic form thereof, maintains the subject's plasma endoxifen at a level ranging from 30 nM to 300 nM (e.g., from 30 nM to 200 nM, or from 30 nM to 80 nM). In some embodiments, the subject's plasma endoxifen level is maintained at a steady-state level. The subject may receive an initial dose of tamoxifen daily for at least 1 day, 2 days, 3 days, 15 days, 1 week, 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months.

[0255] Provided herein is a method for adjusting plasma endoxifen levels in a subject being treated for a hormone-dependent breast disorder or a hormonal reproductive system disorder who has previously received an initial dose of tamoxifen and has a plasma endoxifen level of less than 30 nM, the method comprising: (a) measuring the subject's plasma tamoxifen metabolite endoxifen level after administration of an initial dose of tamoxifen; (b) comparing the plasma level of tamoxifen metabolite endoxifen with a reference level of normal tamoxifen metabolite endoxifen level; and (c) administering an adjustment dose of a composition comprising synthetically prepared endoxifen, wherein the adjustment dose of synthetically prepared endoxifen is sufficient to maintain the subject's plasma endoxifen at a level greater than 30 nM. In some embodiments, administration of the second composition containing synthetically prepared endoxifen maintains the subject's plasma endoxifen at levels ranging from 30 nM to 300 nM (e.g., 30 nM to 200 nM, 30 nM to 80 nM). In some embodiments, steps (a) through (c) can be repeated until the subject exhibits the desired plasma level of endoxifen.

[0256] In one aspect, the present disclosure contemplates a method of treating a subject suffering from or at risk of suffering from a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both, comprising removing breast tissue from the subject, subjecting the subject to radiation therapy, or administering an oral composition comprising endoxifen, or a salt or polymorphic form thereof, as disclosed herein. In another aspect, the present disclosure contemplates a method of treating a subject suffering from or at risk of suffering from a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both, comprising administering an oral composition disclosed herein before removing breast tissue from the subject or before administering radiation therapy to the subject.

[0257] The dose administered to a subject may typically be in unit dosage form. An example range of endoxifen in each dosage unit form is 0.01 mg to 200 mg. The dose generally will be an effective amount and equivalent amount, on a molar basis, of the pharmacologically active (Z)-free form produced by the dosage formulation upon metabolic release of the active free drug to achieve the desired pharmacological and physiological effect. In some embodiments, a composition comprising endoxifen or an endoxifen salt or polymorphic form is administered to a subject at a dose of 0.01 mg to 200.0 mg. In other embodiments, an oral composition comprising endoxifen or an endoxifen salt or polymorphic form is administered to a subject at a dose of 1 mg to 200.0 mg. In some embodiments, oral compositions containing endoxifen or an endoxifen salt or polymorphic form are administered to a subject at a dose of 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, 2.0 mg, 4.0 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg, or 200 mg per unit dose. In certain embodiments, oral compositions containing at least 90% (Z)-endoxifen (wt / wt) of endoxifen are administered at a dose of 1 mg, 2.0 mg, 4.0 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg, or 200 mg per unit dose. In some embodiments, compositions containing endoxifen gluconate are administered at a dose ranging from 0.01 to 20 mg. In some embodiments, compositions containing (Z)-endoxifen D-gluconate are administered at 0.5 mg, 1 mg, 2 mg, 4.0 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg, and 200 mg per unit dose. In some embodiments, a composition containing 1 mg of (Z)-endoxifen D-gluconate is administered. In other embodiments, a composition containing 1 mg of (Z)-endoxifen L-gluconate is administered. In yet other embodiments, a composition containing 2 mg of (Z)-endoxifen D-gluconate and (E)-endoxifen D-gluconate is administered.In certain embodiments, oral compositions comprising at least 90% of a polymorph, e.g., polymorphic Form I, Form II, or Form III of endoxifen (wt / wt), are administered at doses of 1 mg, 2.0 mg, 4.0 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg, or 200 mg per unit dose. In some embodiments, compositions comprising a polymorphic form, e.g., Form I, Form II, or Form III of endoxifen, are administered at doses ranging from 0.01 to 20 mg.

[0258] A breast cancer growth rate study using mammography screening of subjects with breast cancer revealed that breast cancer growth rates in the 25th percentile of women aged 50-59 indicate an unmet need for rapid exposure of subjects to therapeutics (Weeden-Fekjaer et al. Breast Cancer Research 2008 10:R41). Rapid absorption and bioavailability of anti-cancer therapeutics such as endoxifen, which can further reduce cancer growth rates, are highly desirable.

[0259] In one aspect, rapid achievement of maximum and steady-state plasma levels of endoxifen is a particular aspect of the present disclosure. The present disclosure provides that administration of a composition disclosed herein to a subject achieves maximum plasma levels of endoxifen within 2 to 30 hours, 3 to 20 hours, 2 to 10 hours, or 4 to 8 hours after administration of the composition. Thus, in some embodiments, the time to maximum (peak) plasma levels of endoxifen ranges from 2 to 10 hours after administration of the composition. In some embodiments, the time to maximum plasma levels of endoxifen ranges from 4 to 8 hours after administration of a composition disclosed herein.

[0260] Rapid achievement of steady-state plasma levels of endoxifen is also highly desirable. Endoxifen plasma levels rapidly reach steady state in subjects administered a composition disclosed herein comprising (Z)-endoxifen, or a salt or polymorphic form thereof. Steady-state plasma levels can be achieved between days 7 and 21. In some embodiments, steady-state plasma levels can be achieved by day 7 following daily administration of a composition disclosed herein ( FIG. 5 ).

[0261] In one aspect, the present disclosure provides that circulating endoxifen released from the compositions disclosed herein can be cleared more rapidly than tamoxifen. Tamoxifen's terminal elimination half-life is said to be 5-7 days (Jordan C. Steroids. 2007 Nov; 72(13): 829-842), with tamoxifen's peak concentration time being approximately 5 hours after administration. Endoxifen released from the compositions disclosed herein can have a terminal elimination half-life in the range of 30-60 hours, significantly shorter than tamoxifen. In some embodiments, the mean half-life is in the range of 40-53 hours. For compositions containing 1 mg to 4 mg of (Z)-endoxifen, or a salt or polymorphic form thereof, the AUC 24hr (Day 21) / AUC 0-inf The mean ratio (on Day 1) typically ranges from 0.7 to 1.2. Thus, the accumulation of endoxifen released from the compositions disclosed herein does not change significantly over time.

[0262] In other aspects, the present disclosure provides that administration of the compositions disclosed herein achieves therapeutically effective absorption of endoxifen.

[0263] Area under the curve AUC( 0-24hr )("AUC 24hr") describes a subject's total exposure to a drug over a 24-hour period from the time of administration (hour 0). Compositions containing (Z)-endoxifen or a salt thereof typically provide a 150-hour dose on Day 1 of an initial (first) dose of a composition containing 1 mg to 4 mg of (Z)-endoxifen. * ng / mL~600 hours * ng / mL mean (AUC 24hr Compositions containing (Z)-endoxifen or a salt thereof typically achieve a 400-hour response on day 21 of an initial (first) dose of a composition containing 1 mg to 4 mg of (Z)-endoxifen. * ng / mL~2500 hours * Mean AUC in ng / mL 24hr Achieve this.

[0264] AUC( 0-inf )("AUC 0-inf "), i.e., the time-averaged concentration of drug circulating in the analyzed body fluid (usually plasma, blood, or serum), describes the subject's total exposure to the drug. In this disclosure, the exposure of a subject to endoxifen (AUC 0-inf ) can be dose-proportional. In some embodiments, AUC 0-inf is 200 hours * ng / mL~10000 hours * In another embodiment, the AUC 0-inf is 300 hours * ng / mL~8000 hours * In certain embodiments, the AUC 0-inf over a dose range of 1 mg to 4 mg of (Z)-endoxifen for 400 hours. * ng / mL~6000 hours * ng / mL range (see, for example, Table 17).

[0265] A healthcare professional, such as an attending physician, may adjust the dosing regimen based on the pharmacokinetic profile of the composition in the subject.

[0266] In one embodiment, the compositions of the present disclosure can be used alone or in combination therapy. For example, the compositions disclosed herein can be used in combination with one or more therapeutic agents as part of primary therapy, neoadjuvant therapy, or adjuvant therapy. An embodiment of the present disclosure discloses that the compositions of the present disclosure can be used in combination with other treatments, such as surgery and radiation as neoadjuvant or adjuvant therapy. The combination of compositions can act to improve the effectiveness of therapeutic agents and thus can be used to improve standard cancer treatments. For example, if a subject has prostate cancer and is receiving bicalutamide or enzalutamide treatment for the treatment of prostate cancer, the subject is likely to develop gynecomastia as a result of the treatment. The compositions disclosed herein can be administered as combination therapy to a subject with prostate cancer to treat and / or prevent gynecomastia. As another example, a subject suffering from ER+ / Her2+ positive breast cancer is receiving combination therapy with other tumor drugs, such as trastuzumab or anti-tumor or immunotherapy, and the compositions disclosed herein can be used to treat such a subject suffering from ER+ / Her2+ positive breast cancer. Thus, in some embodiments, the composition comprises bicalutamide, enzalutamide or an anticancer drug, e.g., trastuzumab, antineoplastic drugs, e.g., capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinol), cyclophosphamide (Neosar), docetaxel (Docefrez, Taxotere), doxorubicin (Adriamycin), pegylated liposomal doxorubicin (Doxil), epirubicin (Ellence), fluorouracil (5-FU, Adrucil), gemcitabine (Gemzar), methotrexate (several trade names), paclitaxel (Taxol), protein-bound paclitaxel (Abraxane), vinorelbine (Navelbine), eribulin (Halaven), ixabepilone (Ixempra), and ATP cassette binding protein inhibitors.

[0267] In other aspects, the compositions disclosed herein may contain a therapeutic agent that increases the bioavailability of endoxifen in a subject. P-glycoprotein (P-gp, ABCB1) is a highly efficient drug efflux pump expressed not only in the brain, liver, and small intestine but also in cancer cells, which affects pharmacokinetics and confers therapeutic resistance to many anticancer drugs. Therefore, in some embodiments, the compositions further contain an inhibitor of an ATP-binding cassette (ABC family) transporter, such as an inhibitor of breast cancer resistance protein (BCRP protein) and P-gp. Several inhibitors of BCRP protein and P-Gp are known in the art. For example, inhibitors of BCRP protein include cyclosporine, omeprazole, pantoprazole, saquinavir, and tacrolimus.

[0268] Non-limiting examples of P-gp inhibitors include first generation inhibitors such as verapamil, cyclosporin A, reserpine, quinidine, yohimbine, tamoxifen, and toremifene, second generation inhibitors such as dexverapamil, dexniguldipine, valspodar (PSC 833), and dofequidar fumarate (MS-209), third generation P-gp inhibitors such as cyclopropyldibenzosuberane zosuquidar, zosuquidar (LY335979), laniquidar (R101933), mitotein (NSC-38721), biricodar (VX-710), elacridar (GF120918 / GG918), ONT-093, tariquidar (XR9576), and HM30181 and anti-P-gp monoclonal antibodies, such as MRK-16.

[0269] The present disclosure further provides a therapeutic kit containing one or more compositions for use in treating a subject suffering from or at risk of suffering from a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both. The kit of the present disclosure may include an oral composition disclosed herein, a sealed container for containing the oral composition, and instructions for use of the composition to be orally administered. In one embodiment, the kit of the present disclosure may include a second therapeutic agent. Such a second therapeutic agent may be bicalutamide, enzalutamide, or an anti-cancer drug such as trastuzumab, an anti-neoplastic drug such as capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinol), cyclophosphamide (Neosar), docetaxel (Docefrez, Taxotere), doxorubicin (Adriamycin), pegylated liposomal doxorubicin (Doxil), Epirubicin, or the like. (Ellence), fluorouracil (5-FU, Adrucil), gemcitabine (Gemzar), methotrexate (several trade names), paclitaxel (Taxol), protein-bound paclitaxel (Abraxane), vinorelbine (Navelbine), eribulin (Halaven), ixabepilone (Ixempra), and ATP-binding cassette (ABC transporter) inhibitors, e.g., P-gp inhibitors.

[0270] Exemplary Compositions Exemplary, non-limiting compositions are provided below. As noted above, percentages (%) refer to amounts by weight based on the total weight (wt / wt) of the composition. The sum of the different components of the composition may total up to 100% (wt / wt) of the total composition. At least 90% (≧90%) of (Z)-endoxifen free base refers to the percent weight of the (Z)-endoxifen isomer compared to the total weight of endoxifen in any composition.

[0271] In one aspect, the present disclosure relates to an industrially scalable process for producing (Z)-endoxifen, the compound of formula (I), the compound of formula (II), and salts and polymorphic forms thereof.

[0272] In one aspect, the present disclosure relates to an industrially scalable process for producing (Z)-endoxifen, the process comprising: (a) reacting a mixture of (E)-endoxifen and (Z)-endoxifen, a compound of formula (III), with 6N HCl (1:1, 1:5 wt / wt) in EtOAc (1:1, 1:20 wt / wt); (b) neutralizing with 8N NaOH (1:1, 1:20 wt / wt); (c) neutralizing with EtOAc (1:1 to 1:10 wt (d) washing one or more times with 20% NaCl (1:1 to 1:5 wt / wt); (e) reacting with activated carbon (1:0.01 to 1:1); (f) washing one or more times with IPA (1:1 = 1:10 wt / wt) and extracting with MeOH / PPW (1:1 to 1:10 wt / wt), where wt / wt is relative to a mixture of (E)-endoxifen and (Z)-endoxifen, e.g., the compound of formula (III).

[0273] In one aspect, the present disclosure relates to an industrially scalable process for producing a mixture of (E)-endoxifen and (Z)-endoxifen (compound of formula (III)), comprising: (a) reacting a compound of formula (II) with propiophenone in THF (4.4 wt / wt); (b) preparing a solution of TiCl4 (1.4 wt / wt) and Zn (0.9 wt / wt) in THF (8.9 wt / wt); and (c) reacting the compound of formula (II) of step (a) with TiCl4 and Zn in THF from step (b) to form a mixture of (E)-endoxifen and (Z)-endoxifen, where wt / wt is relative to the compound of formula (II).

[0274] In one aspect, the present disclosure relates to an industrially scalable process for producing a mixture of (E)-endoxifen and (Z)-endoxifen, a compound of formula (III), comprising one or more of the following steps: (a) extraction with 25% ammonium chloride (1:20 wt / wt) and silica (celite) (1:1 wt / wt); (b) washing one or more times with THF (1:1 to 1:5 wt / wt); (c) washing one or more times with 20% sodium chloride (1:3 wt / wt); (c) distillation with EtOAc (1:4.5 wt / wt); and (d) crystallization with (1:2 v / v) EtOAc / n-heptane (1:3.8 wt / wt), where wt / wt is relative to the compound of formula (II).

[0275] In one aspect, the present disclosure relates to an industrially scalable process for producing a mixture of (E)-endoxifen and (Z)-endoxifen, a compound of formula (III), comprising: (a) one or more extractions with 40% K2CO3 (1:2 wt / wt); (b) 1N (c) extracting with NaOH (1:10 wt / wt) and MeTHF (1:1 to 1:10 wt / wt); (d) extracting with 20% sodium chloride (1:5 wt / wt); (e) distilling with IPA (1:4.5 wt / wt); and (f) crystallizing with (1:2.7 v / v) IPA / n-heptane (1:3.4 wt / wt), where wt / wt is relative to the compound of formula (II).

[0276] In one aspect, the present disclosure relates to an industrially scalable process for producing a compound of formula (II) comprising: (a) reacting a compound of formula (I) (1 equivalent) with DIPEA (3 wt / wt) in THF (4.9 wt / wt); (b) adding 1-chloroethyl chloroformate (3.3 wt / wt); (c) distilling 1 to 5 times with methanol (4.0 wt / wt); (d) distilling with methanol (3.2 wt / wt); (e) reacting with methanol (3.2 wt / wt) in 6N HCl (4 wt / wt); and (f) neutralizing with 8N NaOH (5 wt / wt), and wherein wt / wt is relative to the compound of formula (I).

[0277] In one aspect, the present disclosure relates to (Z)-endoxifen, (E)-endoxifen, the compound of Formula (III), the compound of Formula (II), and salts thereof, prepared according to the processes described herein. In one aspect, the present disclosure relates to (Z)-endoxifen prepared according to the processes disclosed herein, wherein the (Z)-endoxifen is stable at ambient temperature for at least 6 months, at least 9 months, at least 12 months, or at least 18 months.

[0278] The (Z)-endoxifen free base prepared according to the processes disclosed herein has <1% impurities. In yet other embodiments, the (E) / (Z)-endoxifen free base prepared according to the processes disclosed herein has <1% impurities.

[0279] In one aspect, the present disclosure relates to a composition comprising (Z)-endoxifen free base or a salt thereof prepared according to any of the methods disclosed herein.

[0280] In another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen free base or a salt thereof prepared according to any of the methods disclosed herein, wherein the (Z)-endoxifen is at least 90% (Z)-endoxifen free base wt / wt of the total endoxifen in the composition.

[0281] In still other embodiments, the composition further comprises (E)-endoxifen, wherein the ratio of (E)-endoxifen to (Z)-endoxifen (E / Z ratio) is 1:99; 5:95; 10:90, 15:85; 20:80, 25:75; 30:70; 40:70, 45:55; 50:50; 55:45; 60:40; 65:45; or 70:30.

[0282] In a further embodiment, the composition comprises (E)-endoxifen, wherein the E / Z ratio ranges from 45:55 to 55:45, or is approximately 1:1.

[0283] In one aspect, the composition comprises (Z)-endoxifen or a salt or polymorphic form thereof prepared according to any of the methods disclosed herein, wherein the (Z)-endoxifen is stable at ambient temperature for at least 6 months, at least 9 months, at least 12 months, or at least 18 months.

[0284] In other embodiments, a composition comprises (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein: a. the composition has a plate count of 20,000 g / mL or less; b. The moisture content of the composition is 1.0% or less as tested by USP 921, Method Ic; c. the composition has a water activity (Aw) of less than 0.9; d. Residue on ignition is 0.1% or less as tested by the method of USP 281; e. Heavy metals are 20 ppm or less as tested by USP 231, Method II; or f. Methanol is less than or equal to 3000 ppm, tetrahydrofuran is less than or equal to 720 ppm, isopropanol is less than or equal to 5000 ppm, ethyl acetate is less than or equal to 5000 ppm; n-heptane is less than or equal to 5000 ppm, and ethanol is less than or equal to 5000 ppm as tested by a validated HPLC method.

[0285] In yet other embodiments, compositions containing (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein contain between 0.01 mg and 200 mg of (Z)-endoxifen or a salt or polymorphic form thereof per unit dose.

[0286] In yet other embodiments, a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein contains between 1 mg and 20 mg of (Z)-endoxifen or a salt or polymorphic form thereof per unit dose.

[0287] In a further embodiment, a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein contains 0.01% to 20% (wt / wt) endoxifen or a salt or polymorphic form thereof.

[0288] In a further aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition comprises 0.1% to 10% (wt / wt) of (Z)-endoxifen or a salt or polymorphic form thereof.

[0289] In another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition further comprises one or more excipients.

[0290] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition further comprises one or more excipients, wherein the excipients are binders, fillers, disintegrants, lubricants, glidants, controlled-release agents, enteric coating agents, film-forming agents, plasticizers, sweeteners, flavoring agents, or combinations thereof.

[0291] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition further comprises one or more excipients, wherein the excipients are from about 0.1% to about 99% wt / wt of the composition.

[0292] In a further aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is selected from the group consisting of an acid-insoluble polymer, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, shellac, cellulose acetate trimellitate, sodium alginate), sodium alginate, zein, waxes including synthetic waxes, microcrystalline wax, paraffin wax, carnauba wax and beeswax, polyethoxylated castor oil derivatives, hydrogenated oils, glyceryl monobenate, dibenate, tribenate, glyceryl monostearate, glyceryl distearate, long chain alcohols such as stearyl alcohol, cetyl alcohol, and polyethylene glycol, and mixtures thereof.

[0293] In one aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral, parenteral, topical, and intraductal delivery.

[0294] In another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery as a tablet, caplet, capsule, pill, powder, troche, elixir, suspension, syrup, wafer, chewing gum, dragee, and lozenge.

[0295] In yet other aspects, the present disclosure relates to compositions comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the compositions formulated for oral delivery are tablets formulated as enteric-coated tablets, caplets formulated as enteric-coated caplets, and capsules formulated as enteric-coated capsules.

[0296] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt prepared according to any of the methods disclosed herein, wherein the composition formulated for oral delivery is a tablet formulated as a delayed-release tablet, a caplet formulated as a delayed-release caplet, or a capsule formulated as a delayed-release capsule.

[0297] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein said composition is formulated for oral delivery, and wherein, as tested by the methods of USP 711 or 701, said composition exhibits: a. Less than 10% of endoxifen at 2 hours after administration; b. Less than 20% of endoxifen at 2 hours after administration; c. Less than 30% of endoxifen at 2 hours after administration; d. Less than 40% of endoxifen at 4 hours after administration; or e. Less than 50% of endoxifen levels at 6 hours after administration is released in the stomach.

[0298] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein said composition is formulated for oral delivery, and wherein, as tested by the method of USP 711 or 701, said composition: a. Less than 10% of (Z) endoxifen at 2 hours after administration; b. Less than 20% of (Z) endoxifen at 2 hours after administration; c. Less than 40% of (Z) endoxifen at 4 hours after administration; or d. Less than 50% of (Z)endoxifen at 6 hours after administration is released in the stomach.

[0299] In other aspects, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery, and wherein the composition releases at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen in the intestine as tested by the method of USP 711 or 701.

[0300] In other aspects, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery, and wherein the composition releases at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen in the intestine 2 hours after administration as tested by the method of USP 711 or 701.

[0301] In other aspects, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery, and wherein the composition releases at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen in the intestine 3 hours after administration as tested by the method of USP 711 or 701.

[0302] In other aspects, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery, and wherein the composition releases at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen in the intestine 4 hours after administration as tested by the method of USP 711 or 701.

[0303] In other aspects, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein said composition is formulated for oral delivery, and wherein, as tested by the methods of USP 711 or 701, said composition: a. at least 10% of endoxifen at 4 hours after administration; b. at least 30% of endoxifen at 6 hours after administration; c. at least 40% of endoxifen at 7 hours after administration; d. at least 50% of endoxifen 8 hours after administration; e. at least 50% of endoxifen at 2 hours after administration; f. at least 60% of endoxifen at 2 hours after administration; g. At least 70% of endoxifen at 2 hours after administration; h. At least 80% of endoxifen at 2 hours after administration; or i. At least 90% of endoxifen is lost 2 hours after administration is released in the small intestine.

[0304] In other aspects, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery, and wherein the composition is formulated to release at least 50% of the endoxifen in the colon 8 hours after administration, as tested by the method of USP 711.

[0305] In another aspect, the present disclosure relates to a composition formulated for oral administration, said composition comprising: 1 mg to 200 mg of endoxifen per unit dose; and wherein said composition is stable for at least 6 months.

[0306] In other aspects, the present disclosure relates to compositions formulated for oral administration, said compositions comprising: 1 mg to 200 mg of endoxifen per unit dose; wherein the endoxifen is at least 90% (Z)-endoxifen free base; and where: The composition has a viable count of 20,000 g / ml or less; The water content of (Z)-endoxifen is less than or equal to 1% as determined by USP 921 Method Ic; The (Z)-endoxifen has a residue on ignition of 0.10% or less as tested by the method of USP 281; or Heavy metals are less than 20 ppm as tested by USP 231 Method II.

[0307] In another aspect, the present disclosure relates to a composition formulated for oral administration, said composition comprising: 1 mg to 200 mg of endoxifen per unit dose; wherein the compositions are formulated as enteric-coated tablets, enteric-coated caplets, and enteric-coated capsules; wherein, as determined by the method of USP 711, the composition comprises: at least 25% of endoxifen at 4 hours after administration; at least 30% of endoxifen 6 hours after administration; At least 40% of endoxifen at 7 hours after administration; or at least 50% of endoxifen 8 hours after administration; is formulated to be released in the small intestine, or wherein the composition is formulated to release at least 50% of the endoxifen in the colon as determined by the method of USP 711.

[0308] In another aspect, the present disclosure relates to an oral solid dosage form composition, said composition comprising: 1 mg to 200 mg of endoxifen per unit dose; wherein the endoxifen has at least 90% (Z)-endoxifen free base; and The composition has a viable count of 20,000 g / ml or less; The water content of (Z)-endoxifen is less than or equal to 1% as determined by USP 921 Method Ic; The (Z)-endoxifen has a residue on ignition of 0.10% or less as tested by the method of USP 281; or Heavy metals are 20 ppm or less as tested by USP 231, Method II; and The compositions are formulated as enteric-coated tablets, enteric-coated caplets, and enteric-coated capsules; and The endoxifen is neat; or The composition comprises an excipient selected from the group consisting of a binder, a filler, a disintegrant, a lubricant, a glidant, a controlled release agent, an enteric coating agent, a film-forming agent, a plasticizer, a colorant, a sweetener, and a flavoring agent, or a combination thereof.

[0309] In another aspect, the present disclosure relates to enteric coated capsules containing (Z)-endoxifen free base prepared by the processes described herein.

[0310] In another aspect, the present disclosure relates to an enteric coated capsule containing 1 mg to 200 mg of neat endoxifen per unit dose: wherein the endoxifen has at least 90% (Z)-endoxifen free base; and The composition has a viable count of 20,000 g / ml or less; The water content of (Z)-endoxifen is less than or equal to 1% as determined by USP 921 Method Ic; The residue on ignition of (Z)-endoxifen is 0.10% or less as tested by the method of USP 281; and Heavy metals are less than 20 ppm as tested by USP 231 Method II.

[0311] In another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorphic form thereof prepared by any of the processes described herein, wherein the endoxifen salt is selected from the group consisting of arecoline, besylate, bicarbonate, bitartrate, butyl bromide, citrate, camsylate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinol, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, isethionate, malate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl methacrylate ... Selected from the group consisting of methyl sulfate, mucate, napsylate, nitrate, permaoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, tannate, teoclate, and liethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc.

[0312] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorphic form thereof prepared by any of the processes described herein, wherein the endoxifen salt is endoxifen gluconate.

[0313] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorphic form thereof prepared by any of the processes described herein, wherein the endoxifen salt is an endoxifen gluconate selected from the group consisting of (Z)-endoxifen D-gluconate, (E)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, and (E)-endoxifen L-gluconate, or a combination thereof.

[0314] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorphic form thereof prepared by any of the processes described herein, wherein the endoxifen salt is endoxifen gluconate, and the endoxifen gluconate comprises 1%, 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.99%, or 100% (wt / wt) (Z)-endoxifen D-gluconate or (Z)-endoxifen L-gluconate.

[0315] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorphic form thereof prepared by any of the processes described herein, wherein the endoxifen salt is endoxifen gluconate and the endoxifen gluconate comprises (Z)-endoxifen D-gluconate and (E)-endoxifen D-gluconate (wt / wt) in a Z / E-ratio of 10:90, 20:80, 30:70; 40:60; 50:50, 60:40, 70:30, 80:20, 90:10; 91:9; 92:8; 93:7; 94:8; 95:5, 96:4, 97:3, 98:2, 99:1; 99.5:0.5; or 99.99:0.01.

[0316] In yet another aspect, the present disclosure relates to compositions comprising (Z)-endoxifen or a salt or polymorphic form thereof prepared by any of the processes described herein for the treatment and prevention of hormone-dependent breast disorders, hormone-dependent reproductive system disorders, or both.

[0317] In yet another aspect, the disclosure relates to compositions comprising (Z)-endoxifen or a salt or polymorphic form thereof prepared by any of the processes described herein for the treatment and prevention of hormone-dependent breast disorders, hormone-dependent reproductive system disorders, or both, wherein the hormone-dependent breast disorder or hormone-dependent reproductive system disorder is benign breast disorder, hyperplasia, atypical, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer.

[0318] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorphic form thereof prepared by any of the processes described herein for the treatment and prevention of hormone-dependent breast disorders, hormone-dependent reproductive system disorders, or both, wherein the hormone-dependent breast disorder is breast cancer.

[0319] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorphic form thereof prepared by any of the processes described herein for the treatment and prevention of hormone-dependent breast disorders, hormone-dependent reproductive system disorders, or both, wherein the hormone-dependent breast disorder is breast cancer, and wherein the breast cancer is precancer, early stage cancer, non-metastatic cancer, pre-metastatic cancer, locally advanced cancer, or metastatic cancer.

[0320] In yet another aspect, the present disclosure relates to compositions comprising (Z)-endoxifen or a salt or polymorphic form thereof prepared by any of the processes described herein for the treatment and prevention of hormone-dependent breast disorders, hormone-dependent reproductive system disorders, or both, wherein the hormone-dependent breast disorders or hormone-dependent reproductive system disorders are tamoxifen-resistant or tamoxifen-refractory.

[0321] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject in need thereof.

[0322] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject in need thereof, the subject having or at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive disorder, or both.

[0323] In yet another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject in need thereof, wherein the subject's hormone-dependent breast disorder or hormone-dependent reproductive disorder is benign breast disorder, hyperplasia, atypical, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer.

[0324] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject in need thereof, the subject having breast cancer, wherein the breast cancer is pre-cancer, early stage cancer, non-metastatic cancer, pre-metastatic cancer, locally advanced cancer, or metastatic cancer.

[0325] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject in need thereof, wherein the subject has prostate cancer, and the subject is undergoing or will begin treatment for prostate cancer.

[0326] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject in need thereof, wherein the subject has prostate cancer and the subject has or is at risk of having gynecomastia.

[0327] In yet another aspect, the disclosure relates to a composition comprising (Z) endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject having or at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive disorder, or both, wherein the subject's hormone-dependent breast disorder or hormone-dependent reproductive disorder is tamoxifen-resistant or tamoxifen-refractory.

[0328] In yet another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject in a unit dose of 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, 2.0 mg, 4 mg, 5 mg, 10 mg, 20 mg, 25 mg, 50 mg, or 200 mg of (Z)-endoxifen.

[0329] In yet another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject at a dose of 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, 2.0 mg, 4 mg, 5 mg, 10 mg, 20 mg, 25 mg, 50 mg, or 200 mg of (Z)-endoxifen.

[0330] The present invention relates to a composition comprising (Z)endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject once daily, twice daily, three times daily, four times daily, every other day, twice weekly, weekly, every other week, twice monthly, once every four months, once every six months, or yearly.

[0331] In yet another aspect, the present disclosure relates to a composition comprising (Z) endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein oral administration of the composition maintains plasma endoxifen in a subject at a level greater than 30 nM.

[0332] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof, prepared by any of the processes described herein, wherein the composition is administered to a subject as a combination therapy.

[0333] In yet another aspect, the present disclosure relates to a composition comprising (Z) endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject as a prima facie, neoadjuvant, or adjuvant therapy.

[0334] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject alone or in combination with a second therapeutic agent.

[0335] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject alone or in combination with a second therapeutic agent, the second therapeutic agent being selected from the group consisting of bicalutamide, enzalutamide, or an anti-cancer drug, e.g., trastuzumab, an anti-neoplastic agent, e.g., capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinol), cyclophosphamide (Neosar), doxorubicin (Denkistrodin), cyclosphamide ... cetacel (Docefrez, Taxotere), doxorubicin (Adriamycin), pegylated liposomal doxorubicin (Doxil), epirubicin (Ellence), fluorouracil (5-FU, Adrsil), gemcitabine (Gemzar), methotrexate (trademarks), paclitaxel (Taxol), protein-bound paclitaxel (Abraxane), vinorelbine (Navelbine), eribulin (Halaven), ixabepilone (Ixempra), or inhibitors of ATP-binding cassette transporters.

[0336] In yet another aspect, the present disclosure relates to a method of treating a subject, the method comprising administering a composition prepared according to any one of the processes disclosed herein.

[0337] In yet another aspect, the present disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen, or a salt or polymorph thereof, prepared according to any one of the processes disclosed herein.

[0338] In yet another aspect, the present disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof, prepared according to any one of the processes disclosed herein, wherein the subject has or is at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive disorder, or both.

[0339] In yet another aspect, the disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof, prepared according to any one of the processes disclosed herein, wherein the subject has or is at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive disorder, or both, where the hormone-dependent breast disorder or hormone-dependent reproductive disorder is benign breast disorder, hyperplasia, atypical, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer.

[0340] In yet another aspect, the present disclosure relates to a method of treating a subject having breast cancer, the method comprising administering a composition comprising (Z)-endoxifen, or a salt or polymorph thereof, prepared according to any one of the processes disclosed herein.

[0341] In yet another aspect, the present disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof, prepared according to any one of the processes disclosed herein, wherein the subject has breast cancer, and the breast cancer is pre-cancer, early stage cancer, non-metastatic cancer, pre-metastatic cancer, locally advanced cancer, or metastatic cancer.

[0342] In yet another aspect, the present disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof, prepared according to any one of the processes disclosed herein, wherein the subject has prostate cancer, and the subject further has or is at risk of having gynecomastia.

[0343] In yet another aspect, the present disclosure relates to a method of treating a subject having a tamoxifen-resistant or tamoxifen-resistant hormone-dependent breast disorder or a hormone-dependent reproductive disorder, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof, prepared according to any one of the processes disclosed herein.

[0344] In yet another aspect, the present disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the composition is administered to the subject in a unit dosage of 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, 2.0 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, or 200 mg.

[0345] In yet another aspect, the present disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof, prepared according to any one of the processes disclosed herein, wherein the composition is administered to the subject once daily, twice daily, three times daily, four times daily, every other day, twice weekly, weekly, every other week, twice monthly, once every four months, once every six months, or yearly.

[0346] In yet another aspect, the present disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof, prepared according to any one of the processes disclosed herein, wherein oral administration of the composition maintains plasma endoxifen in the subject at a steady-state level greater than 30 nM.

[0347] In yet another aspect, the present disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof, prepared according to any one of the processes disclosed herein, wherein oral administration of the composition achieves a steady-state level of plasma endoxifen in the subject of greater than 30 nM by 14 days after administration of the first dose (Day 1).

[0348] In yet another aspect, the disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof, wherein oral administration of the composition achieves a steady-state level of plasma endoxifen in the subject of greater than 30 nM by 14 days after administration of the first dose (Day 1).

[0349] In yet another aspect, the present disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof, prepared according to any one of the processes disclosed herein, wherein oral administration of the composition achieves a time to maximum plasma levels of endoxifen in the subject from 2 to 10 hours post-dose.

[0350] In yet another aspect, the disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof, wherein oral administration of the composition achieves a time to maximum plasma levels of endoxifen in the subject from 2 to 10 hours post-dose.

[0351] In yet another aspect, the disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen, or a salt or polymorph thereof, wherein the mean terminal elimination half-life of endoxifen in the subject ranges from 30 to 60 hours after administration.

[0352] In yet another aspect, the disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof, wherein the mean terminal elimination half-life of endoxifen in the subject ranges from 40 to 55 hours after administration.

[0353] In another aspect, the disclosure relates to a method of treating a subject having or at risk for a hormone-dependent breast disorder, a hormone-dependent reproductive disorder, or both, comprising administering an oral composition comprising (Z)-endoxifen or a salt or polymorph thereof, wherein administering the composition comprises: a. The mean half-life of endoxifen in subjects ranging from 30 to 60 hours after administration; b. Time to maximum plasma levels of endoxifen ranging from 2 hours to 10 hours after administration; and c. Achieve a steady-state plasma level of endoxifen greater than 30 nM.

[0354] In another aspect, the disclosure relates to a method of treating a subject having or at risk for a hormone-dependent breast disorder or hormone-dependent reproductive disorder selected from the group consisting of benign breast disorders, hyperplasia, atypical, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering an oral composition comprising (Z)-endoxifen or a salt or polymorph thereof, wherein administering the composition comprises: a. The mean half-life of endoxifen in subjects ranging from 30 to 60 hours after administration; b. Time to maximum plasma levels of endoxifen ranging from 2 hours to 10 hours after administration; and c. Achieve a steady-state plasma level of endoxifen greater than 30 nM.

[0355] In another aspect, the disclosure relates to a method of treating a subject having or at risk for a hormone-dependent breast or reproductive disorder selected from the group consisting of benign breast disorders, hyperplasia, atypical, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering an oral composition comprising (Z)-endoxifen or a salt or polymorph thereof formulated as an enteric-coated tablet, enteric-coated caplet, enteric-coated capsule, delayed-release tablet, delayed-release caplet, or delayed-release capsule, wherein administering the composition comprises: a. The mean half-life of endoxifen in subjects ranging from 30 to 60 hours after administration; b. Time to maximum plasma levels of endoxifen ranging from 2 hours to 10 hours after administration; and c. Achieve a steady-state plasma level of endoxifen greater than 30 nM.

[0356] In another aspect, the disclosure relates to a method of treating a subject having or at risk for a hormone-dependent breast or reproductive disorder selected from the group consisting of benign breast disorders, hyperplasia, atypical, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering an oral composition comprising (Z)-endoxifen or a salt or polymorph thereof formulated as an enteric-coated tablet, enteric-coated caplet, enteric-coated capsule, delayed-release tablet, delayed-release caplet, or delayed-release capsule, wherein administering the composition comprises: a. The mean half-life of endoxifen in subjects ranging from 30 to 60 hours after administration; b. Time to maximum plasma levels of endoxifen ranging from 2 hours to 10 hours after administration; and c. Achieving a steady-state plasma level of endoxifen greater than 30 nM; and wherein at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen is released into the intestine.

[0357] In another aspect, the disclosure relates to a method of treating a subject having or at risk for a hormone-dependent breast or reproductive disorder selected from the group consisting of benign breast disorders, hyperplasia, atypical, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering an oral composition comprising 0.01 mg to 200 mg of (Z)-endoxifen or a salt or polymorph thereof formulated as an enteric-coated tablet, enteric-coated caplet, enteric-coated capsule, delayed-release tablet, delayed-release caplet, or delayed-release capsule, wherein administering the composition comprises: a. The mean half-life of endoxifen in subjects ranging from 30 to 60 hours after administration; b. Time to maximum plasma levels of endoxifen ranging from 2 hours to 10 hours after administration; and c. Achieving a steady-state plasma level of endoxifen greater than 30 nM; and wherein at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen is released into the intestine.

[0358] In another aspect, the disclosure relates to a method of treating a subject having or at risk for a hormone-dependent breast or reproductive disorder selected from the group consisting of benign breast disorders, hyperplasia, atypical, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering an oral composition comprising 0.01 mg to 200 mg of (Z)-endoxifen or a salt or polymorph thereof formulated as an enteric-coated tablet, enteric-coated caplet, enteric-coated capsule, delayed-release tablet, delayed-release caplet, or delayed-release capsule, wherein administering the composition comprises: a. The mean half-life of endoxifen in subjects ranging from 30 to 60 hours after administration; b. Time to maximum plasma levels of endoxifen ranging from 2 hours to 10 hours after administration; and c. Achieve a steady-state plasma level of endoxifen greater than 30 nM.

[0359] In another aspect, the disclosure relates to a method of treating a subject having or at risk for a hormone-dependent breast or reproductive disorder selected from the group consisting of benign breast disorders, hyperplasia, atypical, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McKune-Albright, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering an oral composition comprising 0.01 mg to 200 mg of (Z)-endoxifen or a salt or polymorph thereof formulated as an enteric-coated tablet, enteric-coated caplet, enteric-coated capsule, delayed-release tablet, delayed-release caplet, or delayed-release capsule, wherein administration of the composition achieves the following: a. The mean half-life of endoxifen in subjects ranging from 30 to 60 hours after administration; b. Time to maximum plasma levels of endoxifen ranging from 2 hours to 10 hours after administration; and c. Achieving a steady-state plasma level of endoxifen greater than 30 nM; and wherein at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen is released into the intestine.

[0360] In another aspect, the disclosure relates to a method of treating a subject having or at risk for a hormone-dependent breast or reproductive disorder selected from the group consisting of benign breast disorders, hyperplasia, atypical, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McKune-Albright, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering an oral composition comprising 0.01 mg to 200 mg of (Z)-endoxifen or a salt or polymorph thereof formulated as an enteric-coated tablet, enteric-coated caplet, enteric-coated capsule, delayed-release tablet, delayed-release caplet, or delayed-release capsule, wherein administering the composition comprises: a. The mean half-life of endoxifen in subjects ranging from 30 to 60 hours after administration; b. Time to maximum plasma levels of endoxifen ranging from 2 hours to 10 hours after administration; and c. Achieving a steady-state plasma level of endoxifen greater than 30 nM; where the average area under the curve (AUC) extrapolated to infinite time 0-inf ) is 200hr * ng / mL~10,000hr * ng / mL, 300hr * ng / mL~8000hr * ng / mL, 400hr * ng / mL~6000hr * ng / mL, or 700hr * ng / mL~6000hr * ng / mL; and wherein at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen is released into the intestine.

[0361] In yet another aspect, the present disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof, prepared according to any one of the processes disclosed herein, wherein the method is a primary treatment, a neoadjuvant therapy, or an adjuvant therapy.

[0362] In yet another aspect, the present disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen, or a salt or polymorph thereof, prepared according to any one of the processes disclosed herein, wherein the composition is administered to the subject as a combination therapy.

[0363] In yet another aspect, the present disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof, prepared according to any one of the processes disclosed herein, wherein the composition is administered to the subject alone or in combination with a second therapeutic agent.

[0364] In yet another aspect, the present disclosure relates to a method of treating a subject, the method comprising administering a composition comprising (Z)-endoxifen, or a salt or polymorph thereof, prepared according to any one of the processes disclosed herein, wherein the composition is administered to the subject in combination with a second therapeutic agent, the second therapeutic agent being selected from the group consisting of bicalutamide, enzalutamide, or an anti-cancer drug, e.g., trastuzumab, an anti-neoplastic agent, e.g., capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinol), cyclophosphamide (Neosar), docetaxel, or the like. and selected from the group consisting of cefotaxime (Docefrez, Taxotere), doxorubicin (Adriamycin), pegylated liposomal doxorubicin (Doxil), epirubicin (Ellence), fluorouracil (5-FU, Adrsil), gemcitabine (Gemzar), methotrexate (trademarks), paclitaxel (Taxol), protein-bound paclitaxel (Abraxane), vinorelbine (Navelbine), eribulin (Halaven), ixabepilone (Ixempra), and ATP cassette-binding protein transporter inhibitors.

[0365] In yet another aspect, the disclosure relates to a use for the treatment and prevention of a hormone-dependent breast disorder, a hormone-dependent reproductive disorder, or both, in a subject, said use comprising: administering to the subject a first composition comprising tamoxifen; determining a tamoxifen metabolite profile of the subject in a test sample obtained from the subject; Determining a decrease in the subject's plasma endoxifen level based on the subject's tamoxifen metabolite profile compared to the plasma endoxifen level in a reference tamoxifen metabolite profile; and administering to the subject a composition of the present disclosure.

[0366] In yet another aspect, the disclosure relates to a use for the treatment and prevention of a hormone-dependent breast disorder, a hormone-dependent reproductive disorder, or both, in a subject, said use comprising: administering to the subject a first composition comprising tamoxifen; determining a tamoxifen metabolite profile of the subject in a test sample obtained from the subject; Determining a decrease in the subject's plasma endoxifen level based on the subject's tamoxifen metabolite profile compared to the plasma endoxifen level in a reference tamoxifen metabolite profile; and administering to the subject a composition of the present disclosure; wherein the composition is orally administered at a dosage sufficient to maintain a steady-state level of plasma endoxifen in the subject at greater than 30 nM; wherein the tamoxifen metabolite profile comprises a panel of at least tamoxifen, 4-hydroxytamoxifen, n-desmethyltamoxifen, or endoxifen; wherein the hormone-dependent breast disorder or hormone-dependent reproductive disorder is benign breast disorder, hyperplasia, atypical, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer; wherein the hormone-dependent breast disorder is precancer, early stage cancer, non-metastatic cancer, pre-metastatic cancer, locally advanced cancer, or metastatic cancer; wherein the hormone-dependent breast disorder is a non-metastatic cancer; wherein the subject has prostate cancer and said subject further has or is at risk of having gynecomastia; or Here, the hormone-dependent breast disorder or hormone-dependent reproductive disorder is tamoxifen-resistant or tamoxifen-resistant.

[0367] In yet another aspect, the present disclosure relates to a kit for treating a subject having or at risk for a hormone-dependent breast disorder, a hormone-dependent reproductive disorder, or both, said kit comprising: (a) a composition of the present disclosure; (b) a sealed container for containing the composition; and (c) instructions for using the composition to be orally administered.

[0368] In yet another aspect, the present disclosure relates to a kit for treating a subject having or at risk for a hormone-dependent breast disorder, a hormone-dependent reproductive disorder, or both, said kit comprising: (a) a composition of the present disclosure; (b) a sealed container for housing the composition; and (c) instructions for use of the composition to be orally administered, wherein the kit also comprises a second therapeutic agent, said second therapeutic agent being selected from the group consisting of bicalutamide, enzalutamide, and an anti-cancer drug, e.g., trastuzumab, an anti-neoplastic agent, e.g., capecitabine (Xeloda), carboplatin (Paraplatin), Selected from the group consisting of cisplatin (Platinol), cyclophosphamide (Neosar), docetaxel (Docefrez, Taxotere), doxorubicin (Adriamycin), pegylated liposomal doxorubicin (Doxil), epirubicin (Ellence), fluorouracil (5-FU, Adrsil), gemcitabine (Gemzar), methotrexate (trademarks), paclitaxel (Taxol), protein-bound paclitaxel (Abraxane), vinorelbine (Navelbine), eribulin (Halaven), ixabepilone (Ixempra), and ATP cassette-binding protein transporter inhibitors.

[0369] In yet another aspect, the present disclosure relates to a method of administering a composition prepared according to any of the processes described herein to a subject in need thereof according to instructions included in a kit containing the composition. [Example]

[0370] Abbreviations used herein ACN / PPW = acetonitrile / process purified water NaHCO3 = sodium bicarbonate HCl = Hydrochloric acid THF = tetrahydrofuran MeTHF = 2-methyltetrahydrofuran CH2Cl2 = dichloromethane EtOH = ethanol MeOH = methanol EtOAc = ethyl acetate IPA = isopropyl alcohol; isopropanol TFA = trifluoroacetic acid TCA = trichloroacetic acid PPW = Process Purified Water IPA / PPW = Isopropyl alcohol / Process Purified Water

[0371] Example 1: Enrichment and Preparation of (Z)-Endoxifen Free Base A. Fractionated crystals (Z)-endoxifen free base (drug substance) can be prepared from a mixture of (E)-endoxifen and (Z)-endoxifen by fractional crystallization as described herein. Briefly, (Z)-endoxifen was prepared as free base by using a commercially available crude endoxifen mixture of (E)-endoxifen and (Z)-endoxifen isoforms (Astatech Ltd. China) as the starting material.

[0372] iE / Z-endoxifen solutions were prepared by suspending 1 g of endoxifen, including (E)-endoxifen and (Z)-endoxifen, in 10 volumes of solvent, isopropanol (IPA), at E / Z ratios of 51 / 1, 1 / 1.8, and 1 / 5.8. A second set of solutions was prepared by suspending 1 g of each endoxifen in 10 volumes of solvent, EtOAc, at E / Z ratios of 51 / 1, 1 / 1.8, and 1 / 5.8. The solutions were heated to a first temperature of 50°C to form hot slurries, which were then stirred overnight at 50°C. The hot slurry samples were filtered using a 0.5 μm pore size cellulose filter. The mixtures were then cooled to a second temperature, room temperature, 23°C, while stirring for 12 hours to achieve crystallization. Aliquots of the cooled samples were filtered using a 0.5 μm pore size cellulose filter. Aliquots of the solids and filtrate were obtained at 50°C and 23°C and monitored by HPLC-UV to determine their E / Z-endoxifen ratios. The (Z)-endoxifen-rich filtrate and the (E)-endoxifen-rich filtrate were returned to their respective mother liquors.

[0373] HPLC-UV analysis of the samples was performed using a Luna phenyl-hexyl column (particle size 4.6 mm × 150 mm × 3 μm). The column temperature was 40 °C, and the sample compartment temperature was maintained at ambient temperature. Samples were prepared by dissolving the solids and filtrate at 0.2 mg / ml in methanol as the sample buffer. The sample was then injected onto the column with an injection volume of 20 μl. Similarly, a mildly acidic (pH 4.3) ammonium formate buffer / methanol was used as the mobile phase with gradient elution. The mobile phase system consisted of the following: Mobile Phase A (MPA) buffer was 10 mM HCOOH with 0.03% HCOOH buffer in water, and Mobile Phase B (MBP) buffer was 10 mM HCOOH in methanol using a gradient program.

[0374] [Table 1]

[0375] The run time was 30 minutes, the flow rate was 1.0 mL / m, and the delay time was 5 minutes. Samples were detected by UV at 243 nm. Retention times were typically 12.95-13.20 minutes for (E)-endoxifen and 14.0-14.33 minutes for (Z)-endoxifen. The relative retention times (RRT) for (E)-endoxifen were 0.4-0.9 and 1.0 for (Z)-endoxifen.

[0376] [Table 2]

[0377] The results (Table 2) demonstrate that Z-endoxifen can be enriched using commercially available crude E / Z endoxifen starting material from a hot slurry of an endoxifen mixture made with IPA and EtOAc. Z-endoxifen can be purified from E / Z-endoxifen mixtures with a 1:1 E / Z ratio, with higher levels of Z-endoxifen in the mixture, e.g., 1:8 and 1:5.8. Substantial Z-endoxifen enrichment was achieved using fractional crystallization methods in a single step, e.g., the E / Z ratio was 1:90 in Example 1A described herein. (Z)-endoxifen was found to be more soluble than (E)-endoxifen in EtOAc. (Z)-endoxifen also tended to remain in greater amounts in the filtrate from EtOAc compared to IPA. Both the solid and the filtrate are useful for preparing (Z)-endoxifen free base. Continuous enrichment of Z-endoxifen by returning the filtrate to the first filtrate (first mother liquor) is also feasible.

[0378] Similarly, E-endoxifen can be purified from an E / Z-endoxifen mixture with high E-endoxifen levels in the E / Z mixture.

[0379] ii. Similar results were obtained in experiments in which the E / Z endoxifen mixture was suspended in a hot slurry prepared with a mixture of IPA / PPW (1:1 v / v), extracted, and washed with pre-chilled IPA / PPW (1:1) to form a crystalline solid and filtrate containing enriched (Z)-endoxifen.

[0380] B. Recrystallization from the solid fraction Successive enrichment of (Z)-endoxifen can be performed by subjecting endoxifen mixtures with E / Z-endoxifen ratios of 51:1, 1:1.8, and 1:5.6, as well as the solids and mother liquor obtained from fractional crystallization, to one or more recrystallizations.

[0381] (Z)-endoxifen can be enriched in substantially purified form from the crude E / Z-endoxifen mixture, the (Z)-enriched crystalline solid, and the (Z)-enriched mother liquor by recrystallization from solvents such as ethanol, ethyl acetate / n-heptane, acetone / MTBE, IPA, IPA / PPW, etc. under conditions as described herein.

[0382] Ethanol. The crystalline solid obtained from the hot IPA slurry mixture of E / Z-endoxifen described above was used to further refine Z-endoxifen. After cooling to 23°C, the solid fractions of Sample 2 (80 g) and Sample 3 (79 g) in Table 2 above were combined and recrystallized using 1000 mL (1 L) of EtOH. The ethanol mixture was heated to reflux. The melting point was 75°C. The heated solution was filtered using a cellulose filter (pore size 0.5 μm), and external impurities such as cotton fibers were removed by polish filtration. The filtrate solution was then initially stirred at 70°C for 30 minutes. The solution was then cooled to 0°C–5°C and intermittently stirred at 0°C–5°C for 5 hours. The solution was then filtered again. The crystals on the filter were washed with 200 mL of EtOH.

[0383] The results indicate that the endoxifen solid crystals had an E / Z ratio of ≥ 1 / 100 (0.22% / 99.48%), and that the endoxifen in the filtrate had an E / Z ratio of 1 / 5.9 (13.93% / 82.48%) upon recrystallization with EtOH. HPLC analysis of at least three separate experiments performed by this method showed that the retention time for (Z)-endoxifen was 14.00 min and the retention time for (E)-endoxifen was 13.14 min. The (Z)-endoxifen levels ranged from 97% to 99.48%, while the (E)-endoxifen levels ranged from 0.22% to 2.14%. Other impurities were <1%.

[0384] Ethyl acetate / n-heptane. The feasibility of recrystallization with EtOAc / n-heptane was investigated as described below.

[0385] Five grams of endoxifen (E / Z ratio 1:5.8) was added to 140 mL of 1 / 1 v / v EtOAc / n-heptane and stirred overnight at reflux (~82°C) to obtain a clear solution. The cloud point of the mixture was 30°C. The mixture was then cooled to room temperature to precipitate the product, which was then filtered. After isolation as described above, the solid endoxifen was determined by HPLC to have an E / Z ratio of 1:8.1 (10.9%:88.60%) with a product yield of 66% (3.3 g). (Z)-endoxifen in the filtrate was enriched with an E / Z ratio of 1:3 (23.94%:74.47%). Recrystallization using EtOAc / n-heptane can also provide purified Z-endoxifen in a similar ratio to the hot IPA slurry, as shown in Table 3.

[0386] [Table 3]

[0387] Acetone / MTBE. 0.5 g of endoxifen (E / Z ratio 1:1.8) was added to acetone (10 v; 5 mL) solvent, and the anti-solvent MTBE (9 mL) was added to the solution. The solution was heated to reflux (~82°C) and stirred overnight to obtain a clear solution. The cloud point of the mixture was ~22°C. The mixture was then cooled to room temperature to precipitate the product, which was then filtered. The endoxifen in the solid product was determined by HPLC to have an E / Z ratio of 39:1, while the filtrate was enriched with (Z)-endoxifen, with an E / Z ratio of 1:2.6. The acetone / MTBE solvent system was useful for separating E-endoxifen from (Z)-endoxifen in the filtrate to form a solid.

[0388] C. Recrystallization from mother liquor Purified (Z)-endoxifen can be recovered from the (Z)-endoxifen enriched mother liquor as shown in Tables 4 and 5 below.

[0389] i. The crude E / Z-endoxifen mixture starting material can be dissolved in a first solvent, ethyl acetate, to form a first mother liquor, from which (Z)-endoxifen can be recovered by a second step of adding a second solvent, such as n-heptane or ethanol, as shown in Table 4.

[0390] [Table 4]

[0391] ii. (Z)-endoxifen was prepared by a process comprising: a first step of dissolving an E / Z-endoxifen mixture in a first solvent, ethyl acetate, to enrich (Z)-endoxifen into a first mother liquor; a second step of adding a second solvent, IPA, to form crystalline (Z)-endoxifen and a second mother liquor; and a third step of adding ethanol to recrystallize and recover (Z)-endoxifen from the second mother liquor.

[0392] Briefly, endoxifen (E / Z = 1 / 1.8, 30 g) and (E / Z = 1.2 / 1, 50 g non-GMP) were dissolved in 300 mL and 500 mL of EtOAc, respectively, and heated (~70 °C) until dissolved. The mixture was then cooled to 25 °C and stirred overnight for precipitation. The suspension was filtered, and the E / Z ratios of the solid and filtrate were determined by HPLC.

[0393] The filtrate was then concentrated to dryness, and 230 mL and 900 mL of IPA were added, respectively, with stirring to form a hot slurry (50°C). The hot slurry was continuously stirred at 50°C overnight. The slurry was then cooled to 25°C over 0.5 and 1 hours, respectively, and filtered. The amount of Z-endoxifen in the solids and filtrate was again determined.

[0394] The solids from each sample (14.8 g and 21.6 g) were further recrystallized from 148 mL and 220 mL of EtOH by heating below 70°C and cooling to 25°C over 0.5 and 1 hour, respectively. The samples were further cooled to 0-5°C over 1 hour and filtered. The E / Z ratios of the solids and filtrates were again determined by HPLC. The E / Z ratios and purity of each sample are provided in Table 5 below.

[0395] [Table 5]

[0396] The results demonstrate that greater than 90% purified crystalline (Z)-endoxifen can be obtained by subjecting an E / Z-endoxifen mixture to fractional crystallization with a first solvent, ethyl acetate, to form a crystalline solid and a first mother liquor; subjecting the first mother liquor to crystallization with a second solvent, such as hot IPA, to form a second crystalline solid and a second mother liquor; and then recrystallizing the solid from a third solvent, such as ethanol. Yields of greater than 95% (Z)-endoxifen are also achievable. The (E) / (Z)-endoxifen ratio can be improved from ~1.2:1 and 1:1.8 to 1:51 to greater than 1:118. The impurity profile of (Z)-endoxifen was analyzed by the HPLC method described above and found to be less than 2%. The retention times of (Z)-endoxifen and (E)-endoxifen were 14.19 and 13.2 minutes, respectively.

[0397] Example 2: Reequilibrium of (E)-Endoxifen Enriched E / Z Mixture (E)-endoxifen-enriched E / Z endoxifen mixtures are also useful for preparing Z-endoxifen free base (as well as for preparing purified (E)-endoxifen). The (E)-endoxifen-enriched E / Z-endoxifen mixture is re-equilibrated from an E / Z ratio of ≥ 1.5:1 (e.g., an E / Z ratio of 51:1) to a mixture of about ∼1:1. The present disclosure encompasses the concept that re-equilibration can be performed with a starting E / Z-endoxifen mixture having any E / Z ratio, for example, from 99:1 to 1:99. Such re-equilibration is useful for preparing a stable ∼1:1 mixture of (E) / (Z)-endoxifen, as well as for further enrichment and purification of Z-endoxifen free base, as described in Example 1 above.

[0398] Briefly, (E)-endoxifen was converted to (Z)-endoxifen by dissolving crude E / Z-endoxifen in an inert solvent, such as acetonitrile / water (8:1) or dichloromethane, in the presence of an acid, such as hydrochloric acid, trichloroacetic acid, or trifluoroacetic acid. The reaction mixture with ACN / PPW was stirred at 60°C for 1 hour, while the reaction mixture with dichloromethane and TFA was stirred at room temperature for 1 hour. After workup as described in Table 6, the E / Z ratio of the product was determined to be E / Z-endoxifen (approximately 1:1 ratio) with a purity of greater than 90%.

[0399] [Table 6]

[0400] Example 3: Purification of (E)-Endoxifen (E)-Endoxifen was similarly purified by recrystallization in EtOH (500 mL) by heating the reaction mixture to below 70°C to obtain a clear solution, and then cooling to 0-5°C to precipitate the product. After purification by the methods described herein, 38.1 g of (E)-endoxifen was obtained in 76% yield with a purity of 97.6%.

[0401] Example 4: Scale-up The synthesis and purification methods disclosed herein are also useful for scaling up the preparation of (Z)-endoxifen to produce industrial drug product dosage forms, such as oral, transdermal / topical, nasal, and intraductal parenteral dosage forms, for clinical use in subjects. A crystallization feasibility study using 5 g, 100 g, and 110 g of an E / Z endoxifen mixture, a compound of Formula (III) at an E / Z ratio of 1 / 5.8, was performed by suspending the E / Z endoxifen mixture in 10 volumes of IPA, heating to 50°C, and stirring at 50°C for 4 hours. The samples were filtered using a cellulose filter with a pore size of 0.5 μm, and the E / Z ratio was determined on the solids. After filtration, the samples were cooled to 23°C and continuously stirred at 23°C for 4 hours. The samples were filtered again. The solids and filtrate were monitored for (E)-endoxifen and (Z)-endoxifen levels by HPLC as described above, and the results are provided in Table 7 below.

[0402] [Table 7]

[0403] The results show that Z-endoxifen can be obtained from ≥65% (Z)-endoxifen in the filtrate, as well as E / Z-endoxifen from IPA solvent at concentrations greater than ≥90% as crystalline solids. IPA is therefore useful as a first solvent, a second solvent, or both.

[0404] Example 5: Industrially Scalable Preparation of [4-[2-(methylamino)ethoxy]phenyl](4-hydroxyphenyl)methanone

[0405] [ka]

[0406] A suitable 10 L reactor was charged with the starting materials [4-[2-(dimethylamino)ethoxy]phenyl](4-hydroxyphenyl)methanone, the compound of Formula (I) (0.5 kg, 1.0 equivalent), DIPEA (1.5 kg, 6.65 equivalents, 3.0 wt. / wt.), and tetrahydrofuran (5 L, 10 vol. / wt., 8.9 wt. / wt.) under a N atmosphere. 1-Chloroethyl chloroformate (1.7 kg, 6.65 equivalents, 3.3 wt. / wt.) was added slowly while maintaining the internal temperature below 20 °C. The mixture was heated to reflux and stirred at reflux for not less than 12 hours. The mixture was evaporated under reduced pressure at not less than 75 °C until the volume reached the minimum stirrable volume. Methanol (2.5 L, 5 vol. / wt, 4.0 wt. / wt.) was slowly added, and the mixture was allowed to distill under reduced pressure above 75°C until the volume reached the minimum stirrable volume. Methanol (2.5 L, 5 vol. / wt, 4.0 wt. / wt.) was added, and the mixture was allowed to distill under reduced pressure above 75°C until the volume reached the minimum stirrable volume. Methanol (2.5 L, 5 vol. / wt, 4.0 wt. / wt.) was added once more, and the mixture was allowed to distill under reduced pressure above 75°C until the volume again reached the minimum stirrable volume. Methanol (2 L, 4 vol. / wt., 3.2 wt. / wt.) and 6N HCl (2 L, 4 vol. / wt., 4.0 wt. / wt.) were added to the mixture, and the mixture was heated to reflux. The mixture was stirred at reflux for not less than 12 hours. After completion of the reaction, the mixture was evaporated under reduced pressure above 75°C until most of the MeOH was removed. The mixture was cooled to 25±5°C, and 8N NaOH (2.5 L, 5 vol. / wt., 5.0 wt. / wt.) was slowly added until the pH of the mixture reached 11-12. The mixture was stirred at 0-5°C for 2 hours or more. The mixture was filtered and washed with HO (1 L, 2 vol. / wt.) and ethyl acetate (1 L, 2 vol. / wt., 1.8 wt. / wt.). The wet cake was dried under reduced pressure below 50°C to give (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone, a compound of formula (II). Yield: 297 gm, 63%; Purity: 100% (expected yield - 60-90%).

[0407] Example 6: Industrially scalable preparation of [4-[2-(methylamino)ethoxy]phenyl](4-hydroxyphenyl)methanone

[0408] [ka]

[0409] A suitable 2 L reactor was charged with the starting materials [4-[2-(dimethylamino)ethoxy]phenyl](4-hydroxyphenyl)methanone, compound of Formula (I) (70 gm, 1.0 equiv.), N-ethyldiisopropylamine (126 gm, 4.0 equiv., 1.8 wt.), and tetrahydrofuran (700 mL, 10.0 vol., 8.9 wt.) under a N atmosphere. The mixture was heated to above 60°C and 1-chloroethyl chloroformate (140 gm, 4.0 equiv., 2.0 wt.) was added. The mixture was heated to reflux and stirred for not less than 12 hours. The mixture was concentrated until the volume reached 3 vol. Methanol (350 mL, 5.0 vol., 4.0 wt.) was slowly added, and the mixture was concentrated until the volume reached 3 vol. (210 mL). Next, methanol (350 mL, 5.0 vol., 4.0 wt.) was added, and the mixture was concentrated until the volume reached 4 vol. (280 mL). 6N HCl (280 mL, 4.0 vol., 4.0 wt.) was added, and the mixture was heated to reflux. The mixture was stirred at reflux for 12 hours or more. After completion of the reaction, the mixture was concentrated until the volume reached ~4 vol. (280 mL). The mixture was cooled to ambient temperature, and 8N NaOH (350 mL or more, 5.0 vol., 5.0 wt.) was slowly added until the pH of the mixture reached 13 or higher. Ethyl acetate (280 mL, 4.0 vol., 3.6 wt.) was added to the mixture for extraction. After phase separation, 6N HCl (42 mL or more, 0.6 vol., 0.6 wt.) was added to the aqueous layer until the pH reached 8-10. The mixture was cooled to 0±5°C and stirred for 2 hours or more. The mixture was filtered and washed with purified water (≥140 mL, 2.0 vol., 2.0 wt.) and ethyl acetate (≥140 mL, 2 vol., 1.8 wt.). The wet cake was dried under reduced pressure at ≥60°C to give the compound of formula (II), (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone. Yield: 55.2 gm, 83%; Purity: 100% (≥70% of expected yield).

[0410] Example 7: Industrially scalable preparation of E / Z-endoxifen mixtures in the McMurry reaction

[0411] [ka]

[0412] A suitable 10 L reactor was charged with Zn powder (0.27 kg, 4.0 equiv., 0.9 wt. / wt.) and tetrahydrofuran (1.5 L, 5 vol. / wt., 4.4 wt. / wt.) under a N atmosphere. TiCl (0.42 kg, 2.0 equiv., 1.4 wt. / wt.) was added slowly while maintaining the internal temperature below 15°C. The reaction was heated to reflux and stirred at reflux for 2 more hours. A suspension of (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone, the compound of formula (II) from step 1 (0.297 kg, 1.0 equivalent), and propiophenone (0.21 kg, 1.5 equivalent, 0.7 wt. / wt.) in tetrahydrofuran (3.0 L, 10 vol. / wt., 8.9 wt. / wt.) was added and refluxing was continued for 8 hours or more. The mixture was cooled to 20-30°C and added to a 25% ammonium chloride (5.9 L, 20 vol. / wt., 20 wt. / wt.) / silica (diatomaceous earth / silicon dioxide; trademark Celite® S) mixture available from Sigma Aldrich (0.3 kg, 1.0 wt. / wt.). The mixture was filtered and washed with tetrahydrofuran (0.9 L, 3 vol. / wt., 2.7 wt. / wt.).

[0413] The mixture was allowed to settle for phase separation. The organic layer was collected, and the aqueous layer was washed with tetrahydrofuran (0.9 L, 3 vol. / wt., 2.7 wt. / wt.). The organic layer was collected again and combined with the first organic layer. The combined organic layers were washed with 40% K2CO3 (1.2 L, 4 vol. / wt., 5.6 wt. / wt.). The organic layer was concentrated under reduced pressure at 75°C or higher until the volume reached the minimum stirrable volume. Ethyl acetate (1.5 L, 5 vol. / wt., 4.5 wt. / wt.) was added, and the mixture was allowed to distill under reduced pressure at 75°C or higher until the volume reached the minimum stirrable volume. Ethyl acetate (1.5 L, 5 vol. / wt., 4.5 wt. / wt.) was added, and the mixture was allowed to distill under reduced pressure at 75°C or higher until the volume reached 5 vol. (1.5 L). The mixture was heated to dissolve, and n-heptane (3.0 L, 10 vol. / wt., 6.8 wt. / wt.) was added. The mixture was cooled to 0±5°C and stirred at 0±5°C for at least 2 hours. The mixture was filtered, and the residue was washed with ethyl acetate / n-heptane = 1 / 2 (v / v, 1.5 L, 5 vol. / wt., 3.7 wt. / wt.). The residual wet cake was dried under reduced pressure at ≤60°C to give a mixture of (Z)-endoxifen and (E)-endoxifen, (E / Z)-4-[1-[4-[2-(methylamino)ethoxy]phenyl]-2-phenyl-1-buten-1-yl]-phenol, compound of formula (III). Yield: 176 g, 42%; Purity: 81.96%. E / Z ratio: 3.1:1 (expected yield - 40-60%)

[0414] A suitable 10 L reactor was charged with the above (E / Z)-endoxifen (0.250 kg, 1.0 wt.), isopropanol (1.25 L, 5 vol. / wt., 3.9 wt. / wt.), and purified water (1.25 L, 5 vol. / wt., 5.0 wt. / wt.). The mixture was heated to 70 ± 5°C and stirred at 70 ± 5°C for ≥ 2 hours. The mixture was cooled to 0 ± 5°C and stirred at 0-5°C for ≥ 2 hours. The mixture was filtered and washed with pre-chilled 1 / 1 isopropanol / purified water (0.5 L, 2 vol. / wt., 3.6 wt. / wt.). The residual wet cake was dried at ≤60°C to give a mixture of (Z)-endoxifen and (E)-endoxifen, (E / Z)-4-[1-[4-[2-(methylamino)ethoxy]phenyl]-2-phenyl-1-buten-1-yl]-phenol, compound of formula (III). Yield: 105 g, 41%; Purity: 96.79%. E / Z ratio: 48.61 (expected yield - 40-60%).

[0415] Example 8: Industrially scalable preparation of E / Z-endoxifen mixtures in the McMurry reaction

[0416] [ka]

[0417] A suitable reactor was charged with zinc powder (10 gm, 4.0 equiv., 1.0 wt.) and tetrahydrofuran (50 mL, 5.0 vol., 4.3 wt.). Titanium(IV) chloride (14 gm, 2.0 equiv., 1.4 wt.) was slowly added while maintaining the internal temperature below 45°C. The reaction was heated to 65±5°C and stirred for not less than 2 hours. A suspension of (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone, the compound of formula (II) from Example 5 (10 gm, 1.0 equiv.), and propiophenone (5 gm, 1.0 equiv., 0.5 wt.) in tetrahydrofuran (100 mL, 10.0 vol., 8.5 wt.) was added to the above mixture and stirred for not less than 8 hours at 65±5°C. The mixture was cooled to below 30°C and 40% K2CO3 (20 mL, 2.0 vol., 2.0 wt.) was added. The mixture was stirred for 1 h or more. The mixture was filtered and washed with Me-THF (40 mL, 4.0 vol., 3.5 wt.). The filtrate was added to 40% K2CO3 (30 mL, 3.0 vol., 3.0 wt.) and stirred for 30 min or more. The mixture was filtered and washed with Me-THF (20 mL, 2.0 vol., 1.7 wt.). The filtrate was set aside for phase separation and the organic layer was concentrated to a volume of 3 vol. (30 mL). The mixture was extracted with 1 N NaOH (100 mL, 10.0 vol., 10.0 wt.), and the organic layer was discarded. Sodium chloride (1 gm, 0.10 wt.) was added to the aqueous layer, followed by four extractions with Me-THF (50 mL, 5.0 vol., 4.3 wt.). The four organic layers were combined and concentrated to a volume of 5 vol. The mixture was extracted with 20% NaCl (50 mL, 5.0 vol., 5.0 wt.). Isopropanol (50 mL, 5.0 vol., 3.9 wt.) was added to the organic layer, and the mixture was concentrated to a volume of 3 vol. Isopropanol (50 mL, 5.0 vol., 4.5 wt.) was added, and the mixture was concentrated to a volume of 3 vol. (30 mL). The mixture was heated to 65 ± 5 °C, and n-heptane (120 mL, 12.0 vol., 8.2 wt.) was added. The mixture was cooled to below 5 °C and stirred at below 5 °C for at least 2 hours.The mixture was filtered and washed with n-heptane (50 mL, 5 vol., 3.4 wt.). The wet cake was dried under reduced pressure at ≤70°C to give a mixture of (Z)-endoxifen and (E)-endoxifen, (E / Z)-4-[1-[4-[2-(methylamino)ethoxy]phenyl]-2-phenyl-1-buten-1-yl]-phenol, the compound of formula (III). Yield: 6.7 g, 45%; Purity: 96.79%. E / Z ratio: 48.6:1 (over 30% of expected yield).

[0418] Example 9: Industrially scalable enrichment of Z-endoxifen

[0419] [ka]

[0420] A suitable reactor was charged with a mixture of (Z)-endoxifen and (E)-endoxifen, the compound of Formula (III) (0.105 kg, 1.0 wt.), and a first solvent, ethyl acetate (1.1 L, 10 vol. / wt., 9.0 wt. / wt.). The mixture was cooled to 0-5°C, and 6N HCl (0.3 L, 3 vol. / wt., 3.0 wt. / wt.) was slowly added to the mixture. The mixture was heated to 60±5°C and stirred at 60±5°C for ≥6 hours. The mixture was cooled to 0±5°C, and 8N NaOH (0.3 L, 3.0 vol. / wt., 3.0 wt. / wt.) was slowly added until the pH of the mixture reached ≥12.

[0421] The mixture was allowed to settle for phase separation, the organic layer was collected, and the aqueous layer was washed with the first solvent, ethyl acetate (0.5 L, 5 vol. / wt., 4.5 wt. / wt.). The organic layer was collected. The combined organic layers were washed with 20% NaCl (0.3 L, 3 vol. / wt., 3.0 wt. / wt.). The organic layer was treated with activated carbon (0.005 kg, 0.05 wt.) and stirred at 50±5°C for ≥1 h. The mixture was filtered through a bed of diatomaceous earth / silica (Celite® S) and washed with ethyl acetate (0.5 L, 5 vol. / wt., 4.5 wt. / wt.). The filtrate was concentrated at ≥75°C until a volume of 10 vol. (1.1 L) was reached. The mixture was cooled to 0-5°C and stirred at 0-5°C for 2 hours or more. The mixture was filtered and the filtrate was collected. The filtrate was concentrated at 75°C or more until the volume reached the lowest stirrable volume.

[0422] A second solvent, isopropanol (1.1 L, 10 vol. / wt, 7.9 wt. / wt.), was added, and the mixture was concentrated above 75 °C until the minimum stirrable volume was reached. Isopropanol (1.1 L, 10 vol. / wt, 7.9 wt. / wt.) was added again, and the mixture was concentrated above 75 °C until the minimum stirrable volume was reached. Isopropanol (1.1 L, 10 vol. / wt, 7.9 wt. / wt.) was added, and the mixture was concentrated above 75 °C until the volume reached 5 vol. (0.5 L). The suspension was stirred at 50 ± 5 °C for ≥ 6 h. The mixture was cooled to 20 ± 5 °C and stirred at 20 ± 5 °C for ≥ 4 h. The mixture was filtered and washed with isopropanol (0.2 L, 2 vol. / wt., 1.6 wt. / wt.). The wet cake was dried at ≤60°C to obtain purified (Z-endoxifen) solid compound of formula (IV) as an off-white solid. Yield: 39.5 g, 36%, (E) / (Z) ratio: 1 / 12.2; Purity (Z): 89.59% by HPLC, expected yield (20-40%).

[0423] A suitable 1 L reactor was charged with Z-endoxifen (39 g) solid compound of formula (IV) and a third solvent, isopropanol (390 mL, 10 vol. / wt.). The suspension was stirred at 50 ± 5°C for 6 hours or more. The mixture was cooled to 20 ± 5°C and stirred at 20 ± 5°C for 4 hours or more. The mixture was filtered and washed with isopropanol (78 mL, 2 vol / wt.). The wet cake was dried below 60°C to obtain purified (Z-endoxifen) solid compound of formula (IV) as an off-white solid. Yield: 25 g, 61%, (E) / (Z) ratio: 1 / 55.1; purity (Z): 95.81%, expected yield (50-70%).

[0424] In this manner, endoxifen polymorphic Form I was prepared. The XRPD patterns for two batches of the resulting polymorph are provided in Figures 9 and 10. The XRPD peaks for Figures 9 and 10 are provided in Table 8.

[0425] [Table 8]

[0426] Example 10: Industrially Scalable Enrichment of a ∼1:1 E-Endoxifen / Z-Endoxifen Mixture A suitable reactor was charged with a mixture of (Z)-endoxifen and (E)-endoxifen, the compound of Formula (III) (0.420 kg, 1.0 wt.), and ethyl acetate (4.2 L, 10 vol. / wt., 9.0 wt. / wt.). The mixture was cooled to 0-5°C, and 6N HCl (1.3 L, 3 vol. / wt., 3.0 wt. / wt.) was slowly added. The mixture was heated to 60±5°C and stirred at 60±5°C for not less than 6 hours. The mixture was cooled to 0±5°C, and 8N NaOH (1.3 L, 3.0 vol. / wt., 3.0 wt. / wt.) was slowly added until the pH of the mixture was ≥12.

[0427] The mixture was allowed to settle for phase separation, the organic layer was collected, and the aqueous layer was washed with ethyl acetate (2.0 L, 5 vol. / wt., 4.5 wt. / wt.). The organic layer was collected. The combined organic layers were washed with 20% NaCl (1.3 L, 3 vol. / wt., 3.0 wt. / wt.). The organic layer was treated with activated carbon (0.02 kg, 0.05 wt.) and stirred at 50±5°C for ≥1 h. The mixture was filtered through a bed of diatomaceous earth / silica (Celite® S) and washed with ethyl acetate (2.0 L, 5 vol. / wt., 4.5 wt. / wt.). The filtrate was concentrated at ≥75°C until a volume of 5 vol. (2.0 L) was reached. The mixture was heated to reflux and then cooled to 50±5°C. n-Heptane was added slowly at 50±5°C. The mixture was cooled to 0±5°C and stirred at 0±5°C for ≥2 hours. The mixture was filtered and washed with 1 / 2 (v / v) EtOAc / n-heptane. The wet cake was dried under reduced pressure below 60°C to give essentially pure ∼1:1 E / Z-endoxifen. [Yield: 106 g, 25%; (E) / (Z) ratio: 1.1 / 1; Purity (E / Z): 97.94%, expected yield (20-40%)].

[0428] In this manner, polymorphic Forms II and III of endoxifen were prepared. Detailed parameters for the preparation of polymorphic Forms II and III are provided in Table 9, and XRPD patterns are provided in Figures 11-13. The XRPD peaks in Figures 11-13 are provided in Table 10.

[0429] [Table 9]

[0430] [Table 10]

[0431] Example 11: Stability of Z-endoxifen free base Commercially, endoxifen is available as ≥98% (Z)-endoxifen HCl and (Z)-endoxifen citrate salts, as well as the E / Z isomer free base mixture. The stability of the Z-endoxifen HCl salt in aqueous and solid forms has been previously published (Elkins et al. J Pharm Biomed Anal. 2014 January; 88: 174-179). Elkins et al. provided predicted t90 values ​​for 10% conversion of (Z)-endoxifen HCl to (E)-endoxifen in the solid state of 53 months at 25°C / 60% RH and 4.3 months at 40°C / 75% RH. Conversion is expected to be more rapid in a solution environment. In aqueous media, Elkins et al. provided t90 values ​​for (Z)-endoxifen HCl of 149 days at room temperature and 9 days at 45°C. There remains a need for (Z)-endoxifen free base formulations that are well suited for the preparation of pharmaceutical compositions suitable for administration to a subject, for example, at ambient temperature as well as at higher temperatures and humidity.

[0432] Provided herein are preparations of endoxifen free base that are substantially pure, i.e., at least 90% (Z)-endoxifen free base, and that are suitable for at least 9 months under ambient and elevated temperature and humidity conditions. Stability, for purposes of this disclosure, is defined as the continuous presence of at least 90% (Z)-endoxifen in the composition for at least 6 months, and is measurable by the conversion of (Z)-endoxifen to (E)-endoxifen starting from the date of synthesis.

[0433] A. Accelerated 10-Day Stability Study of (Z)-Endoxifen Free Base The stability of (Z)-endoxifen free base, Sample 1 in Table 11, was investigated during storage in solid form and in ethanol (EtOH) solution at various temperatures. (E)-endoxifen and (Z)-endoxifen levels were measured 2, 7, and 10 days after placing 1 g aliquots of purified (Z)-endoxifen free base in 180 mL HDPE bottles under dry N2, after which the aliquots were placed in double-bag LDPE bags. The double-bag HDPE bottles containing each sample were individually packaged in aluminum foil bags and heat-sealed until opened for sample stability testing. The (E)- and (Z)-isomers of endoxifen were monitored by HPLC as disclosed above. The purity of (Z)-endoxifen in solid form remained approximately 97% for up to 10 days at 40°C, 60°C, and 80°C. Results of an accelerated 10-day study indicate that (Z)-endoxifen in solid form does not interconvert to (E)-endoxifen for up to 10 days at the test temperatures.

[0434] [Table 11]

[0435] [Table 12]

[0436] The results show that (Z)-endoxifen free base is surprisingly stable in alcoholic (e.g., ethanol and isopropanol (not shown)) solutions at elevated temperatures (40°C) and higher concentrations over 10 days. Accelerated stability at higher temperatures is generally considered predictive of long-term (at least 18 min) stability at ambient temperatures.

[0437] B. Bulk Drug Substance Stability Testing The disclosed (Z)-endoxifen free base prepared by the methods disclosed herein is surprisingly stable in bulk form. For bulk stability testing, ~1 g aliquots of (Z)-endoxifen free base were individually placed inside double-layered LDPE bags tied with nylon cable ties. The LDPE bags were then placed inside aluminum foil bags and heat-sealed. Stability samples were placed in tightly capped 180 mL HDPE bottles under inert conditions (dry nitrogen) at 5°C and 25°C / 60% RH for 12 months and at 40°C / 75% RH for 3 months. Samples were tested for (E)-endoxifen and (Z)-endoxifen concentration and impurities, moisture or water content by Karl Fischer titration, aerobic bacterial colony-forming units, and appearance at days 0, 10, 1 m, and 3 m. Table 13 below provides bulk drug substance stability data at 9m for endoxifen free base under various storage conditions.

[0438] [Table 13]

[0439] Results indicate that solid Z-endoxifen free base is stable for at least 9 months at 5°C and 25°C / 60% RH. Accelerated stability at elevated temperatures is considered predictive of long-term (at least 18 min) stability at ambient temperatures. Endoxifen interconversion from (Z) to (E) was minimal at the storage conditions studied, with moisture content below 1% and aerobic bacterial plate count TAC (cfu) below 20,000 cfu g / mL. Maximum individual impurities were determined at each time point and ranged from 0.10% to 0.11%.

[0440] Example 12: Characterization of Purified Solid Z-Endoxifen Free Base The (Z)-endoxifen free base produced by the methods disclosed herein was a white to off-white powder. The water content of such powder was 1% or less as determined using USP 921, Method 1c (Karl Fischer titration). Residual solvents were measured: methanol was 3000 ppm or less (NMT), tetrahydrofuran was 720 ppm or less, and isopropanol, ethyl acetate, n-heptane, and ethanol were each 5000 ppm.

[0441] The residue on ignition of (Z)-endoxifen was 0.1% or less as determined by USP 281, Method II. The residue on ignition of (Z)-endoxifen ranged from 0.02% to 0.099%. In some embodiments, the residue on ignition is 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, and 0.1% or less. In another embodiment, heavy metals were 20 ppm or less as tested by USP 231, Method II.

[0442] The levels of elements in solid (Z)-endoxifen free base are tested using the test methods of USP 232 and USP 40.

[0443] Thus, the processes described herein, and endoxifen prepared using these processes, are suitable for the manufacture of clinical and commercial grade (Z)-endoxifen.

[0444] FTIR spectrum of Z-endoxifen

[0445] (Z)-Endoxifen was analyzed by Fourier transform infrared spectroscopy with a standard light source and a TGS detector (instrument type: FT / IR4600 Type A; Jasco: S / N ratio 25,000:1, maximum resolution 0.7 cm). -1) was used for analysis. Infrared spectra were recorded on an FTIR spectrometer (model FT / IR4600 Type A; manufacturer Jasco) equipped with a triglycine sulfate (TGS) detector and a KBr beam splitter using an AgBr window. Approximately 10 mg of (Z)-endoxifen free base was placed on the ATR crystal and pressure was applied to the tip to collect the sample spectrum. Spectra were collected using a hydration film at scan speeds up to 2 mm / sec. Interferograms were recorded at 0.4 cm -1 and the spectral region 4000–650 cm with a nominal resolution of 32 scans. -1 Figure 2 shows a representative IR spectrum of (Z)-endoxifen free base.

[0446] Figure 2 shows that purified (Z)-endoxifen exhibits the following wavelengths cm: 702.0, 730.9, 794.5, 825.4, 907.3, 1027.9, 1167.7, 1238.1, 1278.6, 1508.1, 1575.6, 1607.4, and 3310.2 cm -1 + / -0.4cm -1 A previously published FT / IR spectrum of free endoxifen shows peaks at wavelengths of 706, 831, 1053, 1171, 1240, 1465, 1507, and 1604 cm. -1 (Agudelo et al. PLoS ONE 8(3): e60250. doi:10.1371 / journal.pone.0060250).

[0447] [Table 14]

[0448] Example 13: Oral composition of Z-entry API-in-Capsule. ≥90% Z-endoxifen free base was prepared as disclosed above. The dry, white to off-white powder was formulated as a stable, free-flowing powder and suitably filled into capsules as an oral solid dosage form of drug-in-capsule (DIC, also known as API-in-capsule, AIC). 1 mg, 2 mg, and 4 mg endoxifen were at least 90% (Z)-endoxifen and suitably filled into VCaps® Plus enteric-coated capsules using Xcellodose technology (Capsugel). The AIC was size 0 and Swedish orange in color.

[0449] VCaps® Plus enteric capsules (Capsugel) are manufactured with hypromellose (a mixed methyl and hydroxypropyl ether of cellulose), a gluten-free, non-animal, self-gelling product with low moisture content suitable for moisture-sensitive ingredients such as (Z)-endoxifen. The capsules are coated with an enteric coating designed to achieve intestinal targeting (upper GI and colon) by the method of Cole et al. (Cole et al., Int. Journal of Pharmaceutics Vol. 231 83-95, 2002). Eudragit FS D30 is used as the enteric coating for colon-targeted release, and Eudragit L30 D55 is used as the enteric coating for upper gastrointestinal tract-targeted release.

[0450] (Z)-endoxifen free base in the AIC is released significantly in the intestine (upper GI and colon) and is protected from the acidic environment in the stomach for at least 6 hours. As tested by the USP 711 method, the enteric coating of the capsule prevents release of (Z)-endoxifen in the stomach for at least 6 hours.

[0451] The enteric coated AIC disclosed herein is stable for at least six months.

[0452] Standards and Tests for Microbial Contamination of Oral Solid Dosage Forms of the Present Disclosure. For formulations of the solid dosage compositions disclosed herein, testing for TAC and USP indicator organisms is not required if the moisture content is 1% or less and the water activity (Aw) is less than 0.75. Jose E. Martinez, Pharmaceutical Technology, February 2002, publication "Microbial Bioburden on Oral Solid Dosage Form," pages 58-70, is incorporated herein by reference in its entirety.

[0453] Additionally, formulations of the compositions disclosed herein have a water activity of less than 0.75, eliminating the need for extensive microbial testing. Total aerobic plate count (TAC) is an estimate of the total viable aerobic bacteria present in a sample of raw material, intermediate material, or final product. Samples are analyzed according to the latest USP Guidelines Chapter 61 (Microbial Limits Tests).

[0454] Acceptable TACs for oral solid dosage forms (OSDF) are established for formulations of the compositions of the present invention in terms of alert and action levels, which can be 1000 cfu g / ml and 10,000 cfu g / mL, respectively. A TAC of 20,000 cfu g / mL is considered unacceptable.

[0455] Example 14: Preparation of (Z)-endoxifen salts (Z)-Endoxifen D-gluconate is prepared by mixing an ethanolic slurry of (Z)-endoxifen as the free base with an aqueous solution of D-gluconic acid, followed by hydrolysis of a 20% w / v solution of D-gluconolactone in water and heating at 70°C for 15-30 minutes. Using a minimum amount of ethanol, 5 ml of aqueous D-gluconic acid solution is added for every 1 g of endoxifen free base. Stirring is then continued until a clear solution is obtained. (Z)-Endoxifen D-gluconate is crystallized using the methods disclosed in Examples 1-4 above to obtain (Z)-endoxifen D-gluconate.

[0456] AIC enteric-coated capsules of 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, and 40 mg are prepared as described above. Similarly, 1 mg to 50 mg tablets are prepared using (Z)-endoxifen D-gluconate with the enteric coatings EUDRAGIT® FS D30 and EUDRAGIT® L30D 55 to target the small intestine and colon.

[0457] [Table 15]

[0458] Example 15: Placebo-Controlled Dose-Escalation Safety Pharmacokinetic Study of Oral (Z)-Endoxifen The objective of the study was to evaluate the safety and tolerability of oral (Z)-endoxifen when administered as a topical application to the breast or as an oral capsule to healthy female volunteers. A secondary objective was to evaluate the pharmacokinetics of multiple doses of oral (Z)-endoxifen in subjects.

[0459] Generally, healthy female volunteers aged ≥18 to ≤65 years were enrolled. Twenty-four participants were enrolled in three cohorts and administered the study drug orally. Three dose levels of oral (Z)-endoxifen were examined in the three cohorts. In each cohort, participants were randomized to receive oral (Z)-endoxifen or placebo in a blinded manner. The enteric-resistant capsules used in the study were designed as delayed-release capsules, resistant to rupture under gastric conditions for at least 30 minutes, but typically approximately 2 hours, before fully opening in intestinal fluids (DRCaps; Capsugel, a Lonza Company, USA). Enteric-resistant (Swedish Orange size Zero (0); Capsugel, USA) DRCaps capsules were manually filled with the appropriate 1, 2, or 4 mg (Z)-endoxifen dose in compliance with GMP requirements. The placebo capsules contained microcrystalline cellulose, an inert common capsule and tablet excipient.

[0460] Of the eight participants enrolled in each cohort, six participants will receive oral (Z)-endoxifen 1 mg capsules at doses of 1 mg (Cohort 1), 2 mg (Cohort 2), or 4 mg (Cohort 3), and two participants will receive matching placebo capsules. In Cohort 1 (dose level = 1 mg), two participants (sentinels) were dosed 24 hours before the remaining participants. One sentinel received (Z)-endoxifen and the other a placebo. Once no safety concerns were identified in the sentinel participants, the remaining six participants in Cohort 1 were dosed. Non-sentinel participants in Cohort 1 were admitted to the clinical investigation site at least one day later than the sentinel patients. There were no sentinel participants in Cohorts 2 and 3.

[0461] Participants' engagement in this study was for 56 days. This period included a 28-day screening period and a 7-day post-treatment period for pharmacokinetic (PK) sampling. Two restriction periods were present: one at the beginning of the dosing period and one at the end of the dosing period. Participants were confined to the clinical site on days -1-2, 21, and 22. Participants were required to remain at the clinical site for further observation at the discretion of the principal investigator (PI) if they experienced any clinically significant adverse events during the study.

[0462] Healthy female volunteers were screened within 28 days prior to starting dosing. Participants were admitted to the clinical site on Day -1 for up to 3 days. The first dose of (Z)-endoxifen or placebo capsules was administered on Day 1. After completing all safety assessments and sampling for pharmacokinetic analysis, participants were released from the clinical site on Day 2. Following the first dose on Day 1, a 6-day treatment-free period (Days 2-7) was observed. Each participant returned to the clinical site and underwent pharmacokinetic blood sampling and safety assessments during the treatment-free period on Study Days 4 and 6. On Day 8, participants began daily administration of (Z)-endoxifen or placebo capsules for 14 consecutive days (Days 8-21). Participants were provided with study drug capsules and asked to self-administer them daily. Participants returned to the clinical site on Days 11, 14, and 17 for pharmacokinetic blood sampling and safety assessments prior to dosing. On the morning of Day 21, each participant received their dose after returning to the clinical site and remained confined to the site until Day 22 to allow for PK blood draws and collection of safety assessments. The Day 21 dose was the last dose of study drug. Participants were released from the clinical site on Day 22 and returned to the site for PK blood draws and safety assessments on Study Days 24, 26, and 28.

[0463] Study assessments included obtaining subject medical history, including any study-related adverse events and concomitant medications; height and weight; physical examination; periodic vital signs (temperature, heart rate, respiratory rate, blood pressure); and periodic 12-lead electrocardiogram assessment. Laboratory tests included hematology, coagulation, urinalysis, serum chemistry, and biomarker analysis (e.g., CYP2D6, BRCA1 / 2, Ki67, tamoxifen metabolites, etc.). Specific assessments to assess treatment safety included the frequency and type of adverse events, clinical laboratory tests, 12-lead electrocardiogram, and vital signs. Symptoms were assessed using a modified FACT-ESR scoring questionnaire.

[0464] Blood samples for PK analysis were collected on Days 1 and 21 pre-dose (within 10 minutes) and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after study drug administration. PK samples on all other study days were collected within 10 minutes pre-dose. PK samples were obtained on Days 4 and 6 during the off-treatment period. Additional PK samples were collected during the daily dosing period (within 10 minutes pre-dose) on Days 8, 11, 14, and 17. PK samples after completion of treatment were collected on Days 24, 26, and 28. AUC(inf) was measured for the blood samples collected on Day 1. Steady-state plasma level determinations began on Day 8 or later (which served as Day 0 for this determination).

[0465] Safety and tolerability Safety endpoints were summarized by dose cohort and placebo were pooled across cohorts. Treatment-emergent AEs were coded using the latest version of MedDRA by system organ class (SOC) and preferred term, categorized from verbatim terms. The occurrence and frequency of AEs and SAEs were summarized by cohort according to SOC and preferred term, and by severity and relatedness. AE duration was determined and listed along with the resulting effect and outcome. Vital signs, ECG, and safety laboratory parameters were summarized at each scheduled time point using descriptive statistics. Post-dose assessments were compared with baseline measurements. The occurrence of laboratory abnormalities was summarized. Physical examination findings were presented in a listing.

[0466] Treatment-emergent AEs considered to be (probably or potentially) related to the study drug were reported in 15 of 18 subjects receiving (Z)-endoxifen (83%, 41 AEs) and in 4 of 6 subjects receiving placebo (67%, 20 AEs). Most treatment-related AEs were mild in severity, and treatment-related AEs of moderate severity were reported in 5 of 18 subjects receiving (Z)-endoxifen (28%, 6 AEs) and 2 of 6 subjects receiving placebo (33%, 2 AEs).

[0467] All AEs were classified as mild (75 of 84 AEs) or moderate (9 of 84 AEs) in severity; none were classified as severe. Common adverse events of tension headache, headache, abdominal pain, nausea, dysmenorrhea, and fatigue were reported in both subjects receiving oral (Z)-endoxifen and those receiving placebo. Upper respiratory tract infection, hot flushes, abdominal distension, xerostomia, and delayed menstruation were reported only in subjects receiving (Z)-endoxifen.

[0468] Safety as assessed by clinical laboratory tests, vital signs, ECG assessments, and FACT-ES responses were not significantly different in subjects receiving topical or oral (Z)-endoxifen compared with subjects receiving placebo, and there were no dose-related trends in these safety assessments in subjects receiving (Z)-endoxifen.

[0469] Pharmacokinetics Mean and individual (Z)-endoxifen serum concentration-time curves were tabulated for each dose cohort and presented graphically, with concentrations displayed on linear and logarithmic scales. Pharmacokinetic parameters were determined for each participant and summarized by cohort using descriptive statistics (arithmetic mean, standard deviation, coefficient of variation, sample size, minimum, maximum, and median). Additionally, geometric means were calculated for AUC and Cmax. Analyses using linear models were performed to assess dose proportionality (after both single and multiple doses), time dependence and accumulation (oral multiple doses), and attainment of steady state (multiple doses).

[0470] Parameters determined for the first and last dose (Days 1 and 21) were time to maximum concentration (Tmax), maximum concentration (Cmax), and area under the concentration-time curve (AUC) from 0 to 24 hours after drug administration. 0-24h ), terminal elimination rate constant (kel), terminal half-life (t1 / 2), terminal clearance (CL / F), and volume of distribution (Vd / F). Area under the concentration-time curve from time 0 to infinity (AUC 0-inf ) was also determined for the first dose on day 1.

[0471] Pharmacokinetic parameters were determined using non-compartmental methods. Descriptive statistics for pharmacokinetic parameters included mean, standard deviation (SD), and coefficient of variation (CV), minimum (min), and maximum (max). Dose-related trends in pharmacokinetic parameters were assessed.

[0472] Mean and individual endoxifen serum concentration-time curves were tabulated for each dose cohort. Pharmacokinetic parameters were determined for each participant and summarized by cohort using descriptive statistics (arithmetic mean, SD, CV, sample size [N], min, max, and median). Additionally, geometric means were calculated for AUC and Cmax. Analysis using linear models was performed to assess dose proportionality (after both single (oral) and multiple (topical and oral) doses). Statistical analysis was performed on pharmacokinetic parameters using SAS v9.3 and Phoenix WinNonLin version 7.0 or higher.

[0473] Abbreviations used: CV coefficient of variation Tmax Time to maximum concentration Cmax maximum concentration AUC 0-24h ("AUC24hr") Area under the concentration-time curve from 0 to 24 hours after drug administration kel terminal loss rate constant, and its capacity t1 / 2 terminal half-life CL / F Terminal clearance Vd / F distribution AUC 0-inf ("AUC 0-inf The area under the concentration-time curve from time 0 to infinity is also determined for the first dose on Day 1.

[0474] A summary of the pharmacokinetic parameters for (Z)-endoxifen, including terminal half-life, terminal elimination half-life, Tmax, Cmax, and AUC, is provided below in Table 16.

[0475] [Table 16]

[0476] Oral administration of once-daily delayed-release (acid-resistant) (Z)-endoxifen capsules demonstrated significant differences in Cmax and AUC of endoxifen across the three dose levels used in the study. 24hrThere was dose proportionality (linear dose response) between doses of 1 mg and 4 mg. Cmax increased from 9.6 ng / mL to 32.5 ng / mL on Day 1 and from 24.6 ng / mL to 115.0 ng / mL on Day 21. The median Tmax by dose level on Days 1 and 21 ranged from 4 to 8 hours. The apparent terminal half-life (t1 / 2) by dose ranged from 42 to 53 hours, with steady state appearing to be reached after approximately 7 days (Figures 5-8 for dosing and Css on Day 14). The time to reach maximum plasma concentrations ranged from 4 to 8 hours (Figure 4).

[0477] [Table 17]

[0478] [Table 18A]

[0479] [Table 18B]

[0480] [Table 18C]

[0481] [Table 19A]

[0482] [Table 19B]

[0483] [Table 19C]

[0484] [Table 19D]

[0485] [Table 19E]

[0486] [Table 19F]

[0487] [Table 20]

[0488] Comparing the ratios of parameters on Day 21 and Day 1, the mean accumulation ratios ranged from 2.74 to 3.56 for Cmax and AUC 24hr The mean values ​​ranged from 3.04 to 3.47. There were no significant trends in clearance (Cl / F) and volume of distribution (Vd / F) by dose level on days 1 and 21.

[0489] Time to maximum serum endoxifen levels was achieved by approximately 10 hours, and there was a dose-related increase in serum endoxifen levels (Figures 3 and 4). Serum endoxifen levels ranged from approximately 25 nM to approximately 80 nM.

[0490] Pharmacokinetic assessment of predose trough concentrations from days 8 to 21 (Figure 4) showed linearity achieved after day 14. Steady-state serum endoxifen levels appear to be achieved by day 7 with daily dosing. Predose serum concentrations show little accumulation after 17 days with 4 mg (Z)-endoxifen.

[0491] [Table 21]

[0492] [Table 22]

[0493] Published literature 1. Wu X et al. Cancer Res. 2009 Mar 1; 69(5):1722-7. PubMed PMID: 19244106 2. Ahmad A et al. Breast Cancer Res Treat. 2010 Jul; 122(2):579-84. PubMed PMID:20052538 3. Ahmad A et al. J Clin Oncol 30, 2012 (suppl; abstr 3089) 4. Goetz MP et al. San Antonio Breast Conference 2013 [PD3-4] 5. Goetz MP et al. San Antonio Breast Conference 2015. [PD203] 6. Ahmad A et al. Clin Transl Sci. 2016 Jun 27. doi:10.1111 / cts.12407. PubMed PMID: 27346789 7. Lee O et al. Cancer Chemother Pharmacol. 2015 Dec; 76(6):1235-46

[0494] Thus, data from this study suggest that the safety and tolerability of oral endoxifen is overall comparable to oral tamoxifen, and that subjects receiving the (Z)-endoxifen composition had plasma endoxifen levels that were within the range shown to be therapeutically effective in the adjuvant setting in women with breast cancer. (Z)-Endoxifen is rapidly absorbed and systemically available, with peak drug concentrations in serum (C(max)) and areas under the concentration-time curve (AUC) extrapolated from 0 to infinity over the dose range 1 mg-4.0 mg. 0-inf ) shows the dose proportionality.

[0495] Example 16: Therapeutic Treatment of Tamoxifen-Resistant Breast Cancer with Oral Administration of Z-Endoxifen Free Base The objective of the study is to demonstrate that stable and therapeutic (Z)-endoxifen levels can be achieved in tamoxifen-resistant patients by supplementing tamoxifen with (Z)-endoxifen. Plasma endoxifen levels will be used as a surrogate endpoint to predict clinical benefit as well as recurrence rates in this population, and to confirm the safety and tolerability of (Z)-endoxifen administration compared with tamoxifen.

[0496] Overall healthy subjects with early-stage estrogen receptor-positive breast cancer will receive at least 30 days of adjuvant tamoxifen treatment and be enrolled in the study for up to 6 months. At least 75 tamoxifen-resistant breast cancer subjects will be enrolled in the study to ensure an evaluable population of at least 25 tamoxifen and 25 (Z)-endoxifen subjects will be achieved. Additional subjects will be enrolled to achieve the desired population of tamoxifen-resistant subjects. These subjects will be diagnosed with breast cancer and undergo mastectomy or lumpectomy.

[0497] After at least 30 days of oral tamoxifen administration, endoxifen plasma levels are measured. If endoxifen levels are below 30 or 40 nM, 1 mg of oral (Z)-endoxifen is added to the oral tamoxifen adjuvant regimen. Additional (Z)-endoxifen doses are added until a stable endoxifen level of at least 40 nM but less than 80 nM is achieved. The endpoint is to establish therapeutically stable endoxifen levels in the tamoxifen + endoxifen group for at least 6 months.

[0498] Example 17: Pre-operative treatment of estrogen receptor-positive breast cancer with oral administration of Z-endoxifen-D-gluconate The objective was to determine whether Z-endoxifen-D-gluconate reduces tumor activity in patients with estrogen receptor-positive breast cancer before surgery. Upon initial diagnosis of ER+ breast cancer, eight patients were assigned to one of three groups, in which each patient received 1, 2, or 4 mg of (Z)-endoxifen-D-gluconate for 21 days before surgery.

[0499] Tumor biomarker KI-67 levels will be compared from the time of initial biopsy and surgical samples to determine whether one of the three doses results in a reduction in tumor activity.

[0500] Example 18: Therapeutic Treatment of Breast Cancer with Oral Administration of (Z)-Endoxifen D-Gluconate The objectives of the study are to demonstrate that therapeutic (Z)-endoxifen levels in subject plasma are achievable in tamoxifen-resistant patients initiating adjuvant breast cancer treatment, to use plasma endoxifen levels as a surrogate endpoint to predict clinical benefit as well as recurrence rates in this population, and to confirm the safety and tolerability of oral (Z)-endoxifen D-gluconate compared with tamoxifen.

[0501] Overall healthy subjects with estrogen receptor-positive breast cancer will be enrolled in the study for up to six months, with tamoxifen indicated as part of the complete treatment regimen. At least 75 tamoxifen-resistant breast cancer subjects will be enrolled in the study to ensure an evaluable population of at least 25 tamoxifen and 25 (Z)-endoxifen subjects will be achieved. Additional subjects will be enrolled to achieve the desired population of tamoxifen-resistant subjects. These subjects will be diagnosed with breast cancer and undergo mastectomy or lumpectomy.

[0502] Immediately after mastectomy or lumpectomy, 25 subjects were assigned to the tamoxifen group and received 20 mg of oral tamoxifen daily for a period of three months. An additional 25 subjects were assigned to the (Z)-endoxifen group and received 10 mg of oral (Z)-endoxifen D-gluconate tablets daily for a period of three months. Blood samples were collected from each subject on days 0 (baseline), 7, 14, 21, 28, 60, and 90. Plasma (Z)-endoxifen levels, hematology, chemistry, and coagulation parameters were collected for both treatment sets on days 0 (baseline measurement), 7, 14, 21, 28, 60, and 90.

[0503] The plasma (Z)-endoxifen levels of the two treatment sets will be compared. If the plasma endoxifen level of a subject treated with tamoxifen is less than 30 nM, the subject will be transferred to the (Z)-endoxifen treatment group and treatment will continue for an additional 6 months. If the plasma endoxifen level of a subject treated with tamoxifen is greater than 30 nM, the subject will continue treatment with tamoxifen. Blood samples will continue to be collected weekly until the end of the study to monitor the subject's plasma (Z)-endoxifen levels, hematology, chemistry, and coagulation parameters. Cancer recurrence in subjects will be monitored and compared between treatment groups. Safety and efficacy will be assessed every 3 months until the end of the study.

[0504] While preferred embodiments of the present invention have been shown and described herein, such embodiments may It will be apparent to those skilled in the art that the embodiments are provided by way of example only. Variations, modifications, and substitutions of the present invention may be made by those skilled in the art without departing from the present invention. Various alternatives to the embodiments of the invention described herein are intended to be included within the scope of the invention. It is understood that the following claims are within the scope of the present invention. The scope of the present invention is defined by the claims and equivalents thereof. and structures are intended to be encompassed thereby. According to a preferred embodiment of the present invention, for example, the following is provided. (Item 1) A composition comprising a crystalline form of the compound of formula (III). [ka] (Item 2) At least 90% by weight of the compound of formula (III) in the composition is the (Z)-isomer, The composition according to Item 1 above. (Item 3) The composition according to Item 2 above, wherein the crystalline form is Form I of the compound of formula (III). (Item 4) The crystalline form is characterized by an X-ray powder diffraction pattern comprising main peaks at 16.8 ± 0.3°, 17.1 ± 0.3°, and 21.8 ± 0.3° 2 θ, the composition according to Item 3 above 。 (Item 5) The X-ray powder diffraction pattern further comprises at least one peak selected from 16.0 ± 0.3°, 18.8 ± 0.3°, and 2 6.5 ± 0.3° 2θ, the composition according to Item 4 above composition. (Item 6) The X-ray powder diffraction pattern further comprises at least one peak selected from 12.3 ± 0.3°, 28.0 ± 0.3°, and 2 9.0 ± 0.3° 2θ, the composition according to Item 4 or 5 above. (Item 7) The X-ray powder diffraction pattern further comprises peaks at 12.3 ± 0.3°, 16.0 ± 0.3°, 18.8 ± 0.3°, 26.5 ± 0.3°, 28.0 ± 0.3°, and 29.0 ± 0.3° 2θ the composition according to Item 4 above. (Item 8) The crystalline form is characterized by an X-ray powder diffraction pattern substantially described in Figure 9 or Figure 10 the composition according to any one of Items 3-7 above. (Item 9) 90% by weight, 95% by weight, or 99% by weight of the compound of formula (III) in the composition is Form I, the composition according to any one of Items 3-8 above. (Item 10) The composition contains 0.01 mg to 200 mg of Form I, any one of Items 3-9 above the composition described in. (Item 11) The composition contains about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of crystalline Form I, the composition according to Item ​ ​ ​ ​ ​ ​ ​ ​ ​ The crystal morphologies were 7.0±0.3°, 11.9±0.3°, 14.0±0.3°, and 1 characterized by an X-ray powder diffraction pattern containing a major peak at 8.4±0.3° 2θ. Item 15. The composition according to item 14. (Section 16) Item 16. The composition according to item 15, wherein the X-ray powder diffraction pattern further comprises a peak at 22.0±0.3° 2θ. (Section 17) The X-ray powder diffraction pattern further showed 6.6±0.3°, 13.3±0.3°, and 20 Item 15 or 1 above, which contains at least one peak selected from the range of 0.0±0.3° 2θ 6. The composition according to claim 6. (Section 18) The X-ray powder diffraction pattern further shows the following: 6.6±0.3°, 13.3±0.3°, 20.0± 16. The composition according to item 15, comprising peaks at 0.3° and 22.0±0.3° 2θ. Finished product. (Section 19) The crystalline form is characterized by an X-ray powder diffraction pattern substantially as depicted in FIG. 11 or FIG. 12. 19. The composition according to any one of items 14 to 18. (Section 20) 90%, 95%, or 99% by weight of the compound of formula (III) in the composition 20. The composition according to any one of the above items 14-19, which is in crystalline form II. (Section 21) The composition according to any one of items 14 to 20, wherein the composition contains 0.01 mg to 200 mg of crystalline form II. The composition according to any one of the preceding claims. (Section 22) The composition may contain about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of crystalline form. 22. The composition according to claim 21, comprising Form II. (Section 23) 14. The compound according to claim 12 or 13, wherein the crystalline form is Form III of the compound of formula (III). composition. (Section 24) The crystalline forms were 11.9±0.3°, 13.9±0.3°, 17.1±0.3°, and 24. The composition according to item 23, characterized by an X-ray powder diffraction pattern containing a major peak at 17.7±0.3° 2θ. (Section 25) The X-ray powder diffraction pattern further includes a peak at 25.3±0.3° 2θ. Item 25. The composition according to item 24. (Section 26) The X-ray powder diffraction pattern further showed the following: 18.2±0.3°, 22.5±0.3°, and 2 Item 24 above, or 25. The composition described in 25. (Section 27) The X-ray powder diffraction pattern further shows the following: 18.2±0.3°, 22.5±0.3°, 25.3 25. The method according to claim 24, comprising peaks at 26.8±0.3° 2θ and 26.8±0.3° 2θ. composition. (Section 28) The crystalline form is characterized by an X-ray powder diffraction pattern substantially as set forth in FIG. 23-27. A composition according to any one of claims 23-27. (Section 29) 90%, 95%, or 99% by weight of the compound of formula (III) in the composition 29. The composition according to any one of the above paragraphs 23-28, which is in crystalline form III. (Section 30) The composition according to any one of the above items 23 to 29, wherein the composition contains 0.01 mg to 200 mg of crystalline form III. The composition described in any one of the above. (Section 31) The composition may contain about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of crystalline form. 31. The composition according to item 30, comprising Form III. (Section 32) A pharmaceutically acceptable carrier or diluent and a combination of any one of items 1-31 above. A pharmaceutical composition comprising the composition. (Section 33) The composition is formulated for oral, parenteral, topical, or intraductal delivery. -32. The composition according to any one of claims 1 to 32. (Section 34) The compositions are formulated for oral delivery as tablets, caplets, capsules, or pills. The composition according to any one of items 1 to 33 above, (Section 35) The mean half-life of endoxifen in subjects treated with the composition ranged from 30 hours to 6 hours. 35. The composition according to any one of the above items 1-34, wherein the time is 0 hours. (Section 36) The compositions include enteric coated tablets, enteric coated caplets, enteric coated capsules, delayed release tablets, delayed release caplets, or delayed-rele...

Claims

1. A composition comprising a crystal of a compound of formula (III), 【Chemistry 1】 wherein at least 90% by weight of said compound of Formula (III) in said composition is the (Z)-isomer, and wherein the crystals of said compound of Formula (III) have a crystalline form of Form I and are characterized by an X-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3°2θ, and additional peaks at 18.2±0.3°, 20.9±0.3°, 24.3±0.3°, 14.2±0.3°, 21.3±0.3°, 9.3±0.3°, and 26.9±0.3°2θ. composition.

2. The crystalline form is shown in FIG. 9 or FIG. 10 【Chemistry 9】 【Chemistry 10】 10. The composition of claim 1, characterized by an X-ray powder diffraction pattern according to

3. 3. The composition of claim 1 or claim 2, wherein greater than 90%, 95%, or 99% by weight of the compound of formula (III) in the composition is crystalline form I.

4. 4. The composition of claim 1, wherein the composition is stable at 5°C and 60% relative humidity or at 25°C and 60% relative humidity for at least 9 months.

5. A pharmaceutical composition comprising the composition of any one of claims 1-4 and a pharmaceutically acceptable carrier or diluent.

6. 6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is formulated for oral, parenteral, topical, or intraductal delivery.

7. 7. The pharmaceutical composition of claim 5 or claim 6, wherein the pharmaceutical composition is formulated for oral delivery as a tablet, caplet, capsule, or pill.

8. 8. The pharmaceutical composition of any one of claims 5-7, wherein the pharmaceutical composition is formulated as an enteric-coated tablet, enteric-coated caplet, enteric-coated capsule, delayed-release tablet, delayed-release caplet, or delayed-release capsule.

9. 9. The pharmaceutical composition of any one of claims 5-8, comprising a gelatin capsule, a gelatin-free capsule, a cap-in-cap capsule, an alginate capsule, a hydroxypropylmethyl cellulose capsule, a polyvinyl alcohol capsule, a hypromellose capsule, or a starch capsule.

10. A composition for use in a method of treating a subject, the method comprising administering to the subject a composition according to any one of claims 1-4 or a pharmaceutical composition according to any one of claims 5-9.

11. 11. The composition of claim 10, wherein the subject has or is at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both.

12. 12. The composition of claim 10 or claim 11, wherein the subject has prostate cancer and the subject further has or is at risk of having gynecomastia.

13. The composition of any one of claims 10-12, wherein the subject is suffering from a tamoxifen-resistant or tamoxifen-refractory hormone-dependent breast disorder or hormone-dependent reproductive system disorder.

14. The composition of any one of claims 10-13, wherein the method comprises administering to the subject 0.01 mg to 200 mg of (Z)-endoxifen per day.

15. The composition of any one of claims 10-14, wherein the method comprises administering to the subject daily about 1 mg, about 2 mg, about 4 mg, about 6 mg, about 10 mg, or about 20 mg of (Z)-endoxifen.

16. The composition of any one of claims 10-15, wherein the composition or pharmaceutical composition is administered orally.

17. The composition of any one of claims 10-16, wherein the mean half-life of endoxifen in the subject is at least 30 hours and not more than 60 hours.

18. The composition of any one of claims 10-17, wherein the mean half-life of endoxifen in the subject is at least 40 hours and not more than 55 hours.

19. The daily administration of the composition or pharmaceutical composition results in the following in a subject: Steady-state plasma levels of endoxifen within 7 to 21 days; Steady-state plasma levels of endoxifen ranging from 25 nM to 300 nM, a steady-state plasma level of endoxifen greater than 30 nM, or Maximum plasma levels of endoxifen within 2 to 10 hours after administration; 19. The composition of any one of claims 10-18, which achieves one or more of the following:

20. 20. The composition of any one of claims 10-19, wherein at least 80% of the endoxifen in the composition and pharmaceutical composition is released in the intestine of the subject.

21. After administration to the subject, the mean area under the curve (AUC) extrapolated to infinity for endoxifen was measured in the subject. ０－ｉｎｆ 21. The composition according to claim 10, wherein

22. 22. The composition of any one of claims 10-21, wherein a steady-state plasma level of endoxifen is achieved within 7 to 21 days of initial administration of the composition or pharmaceutical composition, and wherein the steady-state plasma level of endoxifen in the subject is greater than 30 nM.

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