Methods for making and using endoxifen

Abstract

To provide methods for treating diseases.SOLUTION: The present disclosure provides industrially scalable methods of making (Z)-endoxifen or a salt thereof, crystalline forms of endoxifen, and compositions comprising them. The present disclosure also provides methods for treating hormone-dependent breast and hormone-dependent reproductive tract disorders. The present disclosure provides compositions and methods for the treatment and / or prevention of hormone-dependent breast and reproductive tract (gynecologic) disorders to meet the need.SELECTED DRAWING: 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 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] The current best practice for the treatment of breast cancer is to diagnose breast cancer by mammography and then treat the patient with surgery, radiation therapy, and chemotherapy. The current widespread use of mammography has resulted in improved detection of breast cancer. Although breast cancer is about 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 about 460 will die from breast cancer. 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 remains relatively unchanged at about 21 deaths per 100,000 women and about 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. Exemplary breast cancer includes, but is not limited to, ductal carcinoma in situ, lobular carcinoma in situ, invasive (or invasive) ductal carcinoma, invasive (or invasive) 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 gelatinous) 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 system (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 a decrease in the conversion of tamoxifen to its active metabolite, endoxifen, and to reduce the efficacy of tamoxifen and increase resistance to the drug. More than 140 allelic variants of P2D6 have been described, and a significant proportion of these are associated with reduced or absent activity of the encoded enzyme. Based on the combination of alleles carried, individual subjects can each be classified into one of four phenotypic groups: poor metabolizers (PM) with plasma endoxifen levels below 30 nM, moderate metabolizers (IM), extensive metabolizers (EM), and ultrarapid metabolizers (UM), reflecting variability in serum endoxifen levels. However, CYP genotype variation does not fully explain the tamoxifen resistance and reduced endoxifen levels observed in several subjects.

[0007] Thus, 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] The hydrochloride and citrate salts of endoxifen (see, 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); Ahmad et al. Breast Cancer Research and Treatment 2010, 122, Although novel compositions for treating and / or preventing hormone-dependent breast and reproductive system (gynecologic) diseases (see, for example, 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 new 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) disorders. In certain embodiments, the present disclosure provides novel, industrially scalable methods for making Z-endoxifen or salts thereof, crystalline forms of endoxifen, and compositions comprising same. 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 a composition 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 comprises major peaks at 16.8 ± 0.3°, 17.1 ± 0.3°, and 21.8 ± 0.3° 2θ, and optionally, at 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 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. 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 may be crystalline Form I. In some embodiments, the composition comprises between 0.01 mg and 200 mg of the crystalline form, for example, 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, for example about 1.1. In some embodiments, the crystalline form is Form II of the compound of formula (III). The 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 set forth 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 comprises 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) with an E / Z ratio between 0.9 and 1.3, for example about 1.1. In some embodiments, the crystalline form is Form III of the compound of formula (III). The 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 set forth in FIG. 13. 90%, 95%, or even 99% by weight of the compound of Formula (III) in the composition may be crystalline Form III. In some embodiments, the composition comprises 0.01 mg to 200 mg of crystalline Form III, e.g., about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or even 20 mg of crystalline Form III.

[0015] In an aspect, the present disclosure provides a pharmaceutical composition comprising a pharma- ceutically acceptable carrier or diluent and a composition comprising a crystalline form of the compound of formula (III). The composition of the present disclosure may 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) may 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 hormone-dependent breast disorders, hormone-dependent reproductive system disorders, or both in the subject.

[0016] In an embodiment, the present disclosure provides an oral composition comprising 1 mg to 200 mg of a composition per unit dose comprising a crystalline form of a compound of formula (III) administered to a subject, wherein daily administration of the oral composition achieves in the 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; 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 between 40 and 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, the composition comprising a crystalline form of the compound of Formula (III) is released in the intestine for 200 hours. * ng / mL~10000hr * 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 some aspects, the disclosure provides a method of treating a subject, the method comprising administering to the subject a composition comprising a crystalline form of the compound of formula (III). In some embodiments, the subject suffers from or is at risk of suffering from 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 suffers from prostate cancer or is at risk of suffering from gynecomastia. The subject can suffer from a tamoxifen-resistant or tamoxifen-resistant hormone-dependent breast disorder or hormone-dependent reproductive system disorder. In some embodiments, the subject is being 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, the subject is administered about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of (Z)-endoxifen daily. In some embodiments, the subject has a steady state plasma level of endoxifen greater than 30 nM. The steady state plasma level of endoxifen can be achieved within 7 to 21 days of the first administration of the composition. In some embodiments, the time to maximum plasma level of endoxifen ranges from 2 hours to 10 hours, or 4 hours to 8 hours after administration of the composition.

[0020] In an 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, comprising administering a composition comprising a crystalline form of a compound of formula (III), wherein administration of 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 ranged 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 include 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. 0-inf ) is the average area under the curve extrapolated to 200hr * ng / mL~10000hr * ng / mL, 300hr * ng / mL~8000hr * ng / mL, 400hr * ng / mL~6000hr * ng / mL or 700hr * ng / mL~6000hr *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 a day, twice a day, three times a day, four times a day, every other day, twice a week, weekly, every two weeks, twice a month, monthly, quarterly, once every six months, or annually.

[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 the formula: 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 chromatographic 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 first mother liquor to fractional crystallization 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 chromatographic processes 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 disclosure provides a crystalline form of a compound of formula (III) produced according to the methods described herein. In some embodiments, the crystalline form is of formula (III): 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, a 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 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 embodiment, 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 is reacted with a demethylating agent and a proton acceptor in an inert organic solvent to form a compound of formula (II), the compound of formula (I) having the following structure:

[0032] [ka] 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) exposing the compound of formula (III), represented by the formula: to fractional crystallization from ethyl acetate, wherein a 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) exposing 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 one or more times with IPA or IPA / PPW (1:1 v / v) 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 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 the steps of: (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 comprising 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), is prepared by the steps of: (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) reacting TiCl in THF (1:1 to 1:20 wt / wt); 4 (c) preparing a mixture of (E)-endoxifen and (Z)-endoxifen in THF with the compound of formula (II) in step (a) and TiCl in THF in step (b) to form a mixture of (E)-endoxifen and (Z)-endoxifen. 4 and Zn; wt / wt is for compound of formula (II).

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

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

[0039] In another aspect, the 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 as described herein are stable. In a particular aspect, 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 in the range of 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 the wt / wt is relative to the starting mixture of (E)-endoxifen and (Z)-endoxifen.

[0042] In yet another aspect, the present disclosure provides a composition comprising (Z)-endoxifen free base or a salt thereof prepared according to any of the processes described herein. The composition is formulated for oral, parenteral, topical, and intraductal delivery. The composition is formulated for oral delivery as a tablet, caplet, capsule, or pill. In some embodiments, the composition is formulated for oral delivery tablets 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 having a particular pharmacokinetic profile. 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 time-infinity (AUC 0-inf ) is the average area under the curve extrapolated to 200hr* ng / mL~10000hr * ng / mL, 300hr * ng / mL~8000hr * ng / mL, 400hr * ng / mL~6000hr * ng / mL or 700hr * ng / mL~6000hr * The amount is provided as ng / mL.

[0044] In another aspect, the disclosure provides an oral composition 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; alternatively, (v) any combination thereof. The disclosure further provides that the composition is administered to a subject in need thereof for treatment or prevention of a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both in the subject.

[0045] In some aspects, the disclosure provides a method of treating a subject, the method comprising administering to the subject an oral composition as disclosed herein. In some embodiments, the subject suffers from or is at risk of suffering from 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 some aspects, the present disclosure provides specific patient populations that will benefit from the above treatment methods. In some embodiments, the patient population is a tamoxifen-resistant or resistant population. In some embodiments, the subject suffers from a tamoxifen-resistant or 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 7-21 days of the first administration of the composition. In some embodiments, the time to maximum plasma level of endoxifen ranges from 2 hours to 10 hours or 4 hours 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, comprising administering an oral composition comprising (Z)-endoxifen or a salt thereof, wherein administration of the composition achieves: (i) an average 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 0-inf ) is the average area under the curve extrapolated to 200hr * ng / mL~10000hr * 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 may be administered once daily, twice daily, three times daily, four times daily, every other day, twice weekly, weekly, biweekly, twice monthly, monthly, four times a year, once every six months, or annually. 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.

[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 description 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 in which: [Figure 1]FIG. 1 is a scheme depicting the metabolic pathway of tamoxifen to endoxifen and other metabolites. Plasma concentrations of 4-hydroxytamoxifen are low compared to those of N-desmethyltamoxifen, suggesting that the primary pathway for metabolism of the parent drug is via N-demethylation to N-desmethyltamoxifen by cytochrome P450 3A4 (CYP3A4) followed by hydroxylation to endoxifen by cytochrome P450 2D6 (CYP2D6). [Diagram 2] 1 is a representative infrared spectrum of (Z)-endoxifen free base prepared using the methods disclosed herein. [Diagram 3] Time to maximum plasma concentrations of endoxifen (nM) following treatment with placebo or 1 mg, 2 mg, or 4 mg endoxifen capsules is shown. [Figure 4] Figure 1 shows time to maximum blood concentrations of endoxifen following treatment with placebo or 1 mg, 2 mg, or 4 mg endoxifen capsules on days 1 and 21. Time after administration (hours) is plotted on the X-axis and mean serum concentrations (ng / mL) are plotted on the Y-axis. [Diagram 5] FIG. 5 shows the time to achieve steady state blood concentrations of endoxifen capsules following treatment with placebo or 1 mg, 2 mg, or 4 mg endoxifen capsules from day 0 (day 0 refers to day 8 on the x-axis) through day 21. The x-axis is time in days (days 8 through 21) and the y-axis is the mean serum concentration in ng / mL. Blood was drawn daily from day 0 through the end of the clinical trial period. Subjects were dosed on day 1 and plasma endoxifen levels were measured as shown in Table 17. Subjects were then dosed daily beginning on day 8 (labeled as day 8 in FIG. 5) through the end of the study period. [Figure 6] Mean serum concentrations (ng / mL) over time following treatment with placebo or 1 mg, 2 mg, or 4 mg endoxifen capsules on days 1 and 21 are shown (linear). [Figure 7]Mean serum concentrations (ng / mL) over time after treatment with placebo or 1 mg, 2 mg, or 4 mg endoxifen capsules on days 1 and 21 are shown (semi-logarithmic). [Figure 8] Mean serum concentrations (nM) over time following treatment with placebo or 1 mg, 2 mg, or 4 mg endoxifen capsules on days 1 and 21 are shown (linear). [Figure 9] FIG. 1 is an XRPD pattern obtained from a sample of Form I of compound of formula (III). [Figure 10] FIG. 1 is an XRPD pattern obtained from a sample of Form I of compound of formula (III). [Figure 11] FIG. 1 is an XRPD pattern obtained from a sample of Form II of compound of formula (III). [Figure 12] FIG. 1 is an XRPD pattern obtained from a sample of Form II of compound of formula (III). [Figure 13] FIG. 1 is an XRPD pattern obtained from a sample of Form III of compound of formula (III). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0053] Compounds are described using formal 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", "actives", or "therapeutic agent" may be used interchangeably to refer to a pharma- ceutical active compound in a pharmaceutical composition. This is in contrast to other components in the composition, such as excipients, which are substantially or completely pharma- ceutically 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 a treatment administered to a subject at risk of recurrence following primary therapy. In the case of breast cancer or reproductive system cancer, for example, adjuvant systemic therapy using tamoxifen is usually initiated immediately 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, nonsolvated polymorphs (including anhydrous), conformational polymorphs, and amorphous forms, and mixtures thereof, unless a specific crystalline or amorphous form is referred to. Compounds of the present disclosure include crystalline and amorphous forms of such compounds, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, nonsolvated polymorphs (including anhydrous), 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 tritium and deuterium. 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 the compositions 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. The 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 the 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. Compositions of the disclosure can be administered prior to administration of one or more prophylactic and / or therapeutic agents and / or treatments to a subject (e.g., 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). , or 1 year prior to said administration, concomitantly with said administration, or subsequent to said administration (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 may further refer to the treatment of a subject with a single disease or multiple diseases, for example, prostate cancer and gynecomastia in men.

[0065] As used herein, the term "test sample" refers to a blood sample obtained from a subject. It will be understood that when a blood sample is obtained from a subject, the subject's blood is used to determine the subject's endoxifen levels and / or other biomarkers that may be measured or tested. As used herein, "plasma endoxifen" is used to refer to the endoxifen levels 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" refers to the form in which a compound or composition of the disclosure is delivered to a patient.

[0067] As used herein, the terms "pharmacologically 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 side effects, e.g., a toxic, allergic, or immune response. They may be approved by a regulatory agency, e.g., of the U.S. Federal or state government, or as 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" refers to a pharma- ceutically 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 "pharmaceutical 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, the salts of the compounds of the disclosure are contemplated as being pharma- ceutically acceptable for therapeutic use. However, salts of acids and bases that are non-pharma- ceutically acceptable may also be useful, for example, in the preparation or purification of a pharma- ceutical 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., phospholipids) 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 further 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 is dosed with 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-responsiveness to tamoxifen treatment from the start of treatment, or (b) acquired resistance, i.e., non-responsiveness 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 3 months to 1 year, or as late as 5-10 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 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 recited in this application, and all range endpoints are included within the range and are independently combinable. For example, if a concentration range or useful range is recited as 1% to 50%, values ​​such as 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 stated 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. To name just a few, the values ​​for components or elements of a composition are expressed as the weight percent of each component in the element unless otherwise specified.

[0078] Unless otherwise indicated herein or otherwise clearly contrary to context, all methods described herein may 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 be illustrative of 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. It won't be.

[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, etc. (also called leiomyomas), etc. Reproductive system disorders include endometrial, ovarian, cervical, uterine, vaginal, and vulvar cancers. The terms "estrogen-related disorder" and "estrogen receptor-related 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 leads to abnormal scar-like (fibrous) tissue in bone, a disease called multiple fibrous dysplasia, 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 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). Although not cancer, ADH and ALH may indicate a predisposition to breast cancer.

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

[0082] Gynecomastia is a common male breast disorder 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 4 weeks of life, and at least half of adolescent males experience gynecomastia, with typical onset at age 13-14 years (Tanner stage 3 or 4). Gynecomastia has been proposed to be a risk factor for male breast cancer.

[0083] Furthermore, gynecomastia often appears secondary to underlying conditions such as prostate cancer, cirrhosis and liver disease, male hypogonadism, hyperthyroidism, renal failure, and in patients undergoing hemodialysis, type I diabetes. Furthermore, drugs such as antiandrogen drugs or certain antipsychotics have been reported to cause up to 25% of gynecomastia cases and can be classified according to their hormone-like effects. For example, the most common side effects due 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 any stage of breast cancer, including pre-cancer, early stage cancer, non-metastatic cancer, pre-metastatic cancer, locally advanced cancer, and metastatic cancer 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 invasive) lobular carcinoma (ILC), invasive (or invasive) 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 the 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 aggressive 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 percent 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 the surrounding tissue. Approximately 1 in 10 cases of invasive breast cancer is ILC. ILC is treated by 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 an 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, making the breast red and feel warm. Affected breasts may become enlarged or hard, tender, or itchy. Inflammatory breast cancer is treated with chemotherapy, immunotherapy, radiation therapy, and sometimes 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] The present disclosure relates to methods of making and using stable preparations of (Z)-endoxifen free base, mixtures of (E)-endoxifen and (Z)-endoxifen (E / Z-mix), and salts thereof. The present disclosure further relates to oral compositions comprising (Z)-endoxifen or salts thereof, and methods of treating a subject. The present disclosure further 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 (gynecologic) disorder, or both, by administering to the subject an oral composition comprising (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 an industrially scalable process 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 process is a synthetic process for producing stable (Z)-endoxifen free base, E / Z mix, and salts thereof. In another aspect, the disclosure provides a method for making compositions comprising stable (Z)-endoxifen free base, E / Z mix, and salts thereof.

[0093] In certain aspects, the 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 for the synthetic preparation of endoxifen are known in the art. For example, methods for the synthetic preparation of endoxifen and its prodrugs and salts are disclosed in US Patent No. 9,333,190 (Ahmad, Jina Pharmaceuticals); WO 2008 / 070463 (Ahmad, Jina Pharmaceuticals), US 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), US Patent No. 8,063,249 (Kushner, Olema Pharmaceuticals), US Patent Nos. 7,531,578 and 8,119,695 (Forman 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., 2003). 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 salts 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 a compound of formula (II), (Z)-endoxifen free base, E / Z mix, or salts 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 is 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 a demethylating agent in a range of 1:0.5 to 1:10. The demethylating agent is added to the reaction mixture in a wt / wt ratio of compound of formula (I) to demethylating agent ranging from 1:2 to 1:5. In at least one embodiment, the demethylating agent is present in a ratio 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 of compound of formula (I) to demethylating agent ranging from 1:2 to 1:3.3. In another embodiment, the demethylating agent, 1-chloroethyl chloroformate, is present in a ratio 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 the demethylation reaction in the presence of a proton acceptor. Such inorganic 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 aspect, 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 with a ratio (wt / wt) of compound of formula (I) to THF ranging from 1:1 to 1:50. In 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] One of skill 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) may be added in any order. Each reagent may be added in a single bolus or multiple boluses to a suitable reaction apparatus and stirred.

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

[0106] Compounds of formula (I) in one or more inert organic solvents, one or more demethylating agents (e.g. The reaction mixture containing the demethylating agent (1-chloroethyl chloroformate) may be heated at a temperature 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 may 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 100° C. or less, 95° C. or less, 90° C. or less, 85° C. or less, 80° C. or less, or 70° C. or less, using a solvent 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 that serve 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 2-5 vacuum distillations.

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

[0110] The mixture can then be reacted with a solvent / acid mixture by addition of 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 the purposes of this 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 methanol / HCl mixture can be added at a wt / wt ratio of compound of formula (I) to 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 compound of formula (I) to 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 compound of formula (I) to methanol / 6N HCl ranging from 1:1 to 1:10, e.g., 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 or below 70°C, 75°C or less, 80°C or less, 85°C or less, 90°C or less, and below 90°C.

[0112] The reaction mixture may be held and stored until further use, hi some embodiments, the reaction mixture may 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 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 salts thereof, comprises 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, e.g., ethyl acetate (EtOAc) (1:0.5 to 1:10 wt / wt), where wt / wt is with respect to 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 below 50° C.

[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 reacted with a titanium salt, e.g., a chloride of titanium (e.g., titanium trichloride and titanium tetrachloride (TiCl), in an inert organic solvent to form an E / Z mix of a compound of formula (III). 4 )) and coupled to propiophenone mediated by a reducing agent-mediated McMurry reaction.

[0118] Salts of titanium useful in this disclosure include titanium halides (titanium trichloride (TiCl 3 ), titanium tetrachloride (TiCl 4 ), titanium iodide, titanium bromide, and titanium fluoride), titanium(IV) trichloride isopropoxide, and titanium isopropoxide. In some embodiments, the titanium salt is TiCl 4 TiCl 4 are added in a wt / wt ratio of compound of formula (II) to 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 compared 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, ... The inert organic solvent may be 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 a combination thereof. In some embodiments, the inert organic solvent is 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 is 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 is 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 the titanium salt and the reducing agent in an inert organic solvent to make a premix. The titanium salt is added to the reducing agent and the 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 the reducing agent in the inert organic solvent are combined to make a premix. In some embodiments, Zn, TiCl 4 , and THF is Zn / TiCl 4 In at least one embodiment, TiCl is combined to produce a TiCl / THF mixture. 4 is added to the Zn and THF and mixed, maintaining the internal temperature below 20°C for not less than 10 minutes.

[0122] The preparation of the titanium salt and reducing agent in the inert organic solvent may 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 present 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 may be N 2 or heated under reflux under inert conditions, such as under argon, for 30 minutes or more, such as 1 hour or more, 2 hours or more, 4 hours or more, 6 hours or more, and 8 hours or more.

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

[0124] Thereafter, the mixture of (E)-endoxifen and (Z)-endoxifen in the reaction mixture was The product may 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 may be subjected to extractive purification by extraction with an inert organic solvent such as THF and MeTHF, or by addition of a salt such as potassium carbonate, ammonium chloride, sodium chloride, sodium hydroxide, etc. 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 40% K 2 CO 3 (1:1 to 1:10 wt / wt) and MeTHF (1:1 to 1:10 wt / wt) 2 CO 3 ) one or more times. In some embodiments, the E / Z mixture may 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) may be added to the 1 N NaOH for the extraction step.

[0126] In some embodiments, the reaction mixture may 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 found MeTHF to be surprisingly suitable for the process of 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 may still be further extracted with 20% sodium chloride (1:1 to 1:10 wt / wt).

[0127] The reaction mixture may then be subjected to 2-5 solvent exchanges and distillation using a suitable solvent, 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 a temperature ranging from 30°C to 90°C. In some embodiments, the distillation may be carried out and filtered 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. The filtered product may 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 or below 60° C., 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 be charged with a compound of formula (III) prepared by the McMurry reaction as described above, dissolved in an inert organic solvent such as ethyl acetate. The compound of formula (III) can 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 is slowly added to the mixture with a ratio of compound of formula (III) to n-heptane ranging from 1:1 to 1:20. A 1:1 ratio of the compound of formula (III) to the ethyl acetate / n-heptane may be added and the mixture may be cooled to 0±5°C. The mixture may 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 may be filtered and washed with ethyl acetate / n-heptane (1:2 v / v) with a wt / wt ratio of the compound of formula (III) to the ethyl acetate / n-heptane ranging from 1:1 to 1:10. The wet cake may be dried under reduced pressure to obtain an E / Z endoxifen mixture having an E / Z ratio of approximately 1:1. Drying may 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 or below 60°C 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 preparation of (Z)-endoxifen free base by concentration and purification. The industrially scalable concentration 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 supplied (e.g., from Sigma-Aldrich). The mixture of (E)-endoxifen and (Z)-endoxifen (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). The fractional crystallization is performed using a first solvent that can disintegrate endoxifen and its derivatives so that (Z)-endoxifen tends to remain in the filtrate. Suitable first solvents are those that 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, a 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 below 35°C.

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

[0133] As a non-limiting example, a suitable reactor is charged with the compound of formula (III), a first solvent is added thereto, and 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 at a wt / wt ratio of the compound of formula (III) to 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 with stirring. In some embodiments, the reaction is carried out under reflux. The reaction may be carried out for 4 hours or more, such as 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 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, for example, ≧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 in 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 in 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 on a silicon dioxide (Celite®) bed (added in 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 a first solvent (added in 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 lower.

[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 in (Z)-endoxifen, as compared to the E / Z ratio of the mixture of E-endoxifen and Z-endoxifen. In other embodiments, the first mother liquor is enriched in (Z)-endoxifen, as compared to the E / Z ratio of the mixture of E-endoxifen and Z-endoxifen, by at least 70%.

[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, EtOAc / n-heptane. In some embodiments, the second solvent is IPA. Surprisingly, IPA has been found to grind (Z)-endoxifen to a solid 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 other embodiments, 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 NO 2 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, for example, ≧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 disclosure relates to preheating the first solvent, the second solvent, and the third solvent prior to use (Table 2). In some embodiments, one or more of the first solvent, the second solvent, and the 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 obtained as above, and the second mother liquor can be subjected to one or more further fractional crystallization and recrystallization 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 procedures described in the examples herein (e.g., removing reaction by-products or working up, isolating, or purifying the reaction product). 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 may be varied to obtain desired results, including, for example, the method and means of purification of the reactants and solvents, the order of addition of the reactants and solvents to the reaction mixture, the duration of the reaction of the reactants and solvents, and the temperature and rate of stirring, mixing, or agitation of the reactants and solvents during the reaction.

[0143] The process (including the specific process steps) embodied by the methods herein have been found to meet one or more of the following criteria: greater stability, safer, simpler, higher yielding, more economical when compared to known processes for producing compounds of formula (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 high temperatures indicates long-term stability. Thus, (Z)-endoxifen free base prepared by the process disclosed herein is stable for at least 6 months, for example, at least 9 months, at least 12 months, or at least 2 months. Both are stable for 18 months. Furthermore, the processes described herein are 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 of 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. 9333190; 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 arecoline, besylate, bicarbonate, bitartrate, butyl bromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methyl bromide, methyl bromine ... The present invention provides an anionic salt of endoxifen selected from the group consisting of: mide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamaoate (embonate), pantothenate, phosphate / diphosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, teoclate, and triethiodide.

[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 may 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 the gluconate salt of endoxifen or its chemical equivalent.Therefore, 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 in this specification, its chemical equivalent will also be included.

[0149] For the 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 group 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 pharma-ceutically acceptable gluconate salt. Such salts include calcium gluconate, sodium gluconate, and salts of alkali metals and alkaline earth metals, such as potassium gluconate, magnesium gluconate, lithium gluconate, and the like.

[0150] Both stereoisomers of glucarate, D- and L-, are encompassed by the present disclosure. In some embodiments, the endoxifen gluconate included in the composition 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 includes (Z)-endoxifen L-gluconate. In certain embodiments, the pharmaceutical composition includes (Z)-endoxifen D-gluconate. Unless otherwise specified, the composition may exist as a racemic mixture, a pure stereoisomer (e.g., enantiomers and diastereoisomers), a stereoenriched mixture, and the like. 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 composition 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 appropriate chiral stationary phases or supports, 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 its chemical equivalent, 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 a 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 minimum 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 methods known in the art as disclosed herein.

[0153] Both purified (Z)-endoxifen free base or mixtures of (E) / (Z)-endoxifen are useful for the purpose of preparing endoxifen gluconate. Solutions of (Z)-endoxifen D-glucarate or (Z)-endoxifen L-glucarate can also be purified from mixtures of (E) / (Z)-endoxifen gluconate as described herein by fractional crystallization or recrystallization (Examples 1-3) to obtain a solid purified (Z)-endoxifen salt. The solid salt can be stored in a cool, dark place for 24 hours until further use. 2 Store at -5°C under low temperature.

[0154] It will be understood by those skilled in the art that other endoxifen salts having a glycolate moiety or a 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, such as crude endoxifen HCl (>=98%) and sodium gluconate. The ammonium salt is 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, the composition comprising endoxifen gluconate also comprises endoxifen HCl.In other embodiments, the (E) / (Z)-endoxifen mixture (compound of formula (III)) and sodium gluconate are dissolved in a suitable solvent to obtain endoxifen gluconate or its chemical equivalent.

[0157] Solvents suitable 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, dimethylsulfoxide, 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 are glycerin, ethanol, propanol, isopropanol, propylene glycol, polyethylene glycol, or mixtures 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, and the like; dimethyl isosorbide; and absolute alcohol. In some embodiments, the solvent is dehydrated alcohol, such as absolute alcohol. In certain embodiments, the solvent is sufficient to dissolve endoxifen (free base, salt) and gluconate. The concentration of the solvent can also be adjusted as necessary. The reaction can be carried out at room temperature and at atmospheric pressure.

[0159] The amount of endoxifen free base or endoxifen salt (such as endoxifen HCl) and gluconate (such as 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 0.01-40 (e.g., 1%-10%, or 3%-5%) weight percent (wt / wt) of the total composition. In some embodiments, the amount of gluconate used to prepare endoxifen gluconate is 0.01%-40% (wt / wt) (e.g., 1%-10% (wt / wt), or 3%-5% (wt / wt)). One of skill in the art will be guided by skill and knowledge in the art and this disclosure, including, but not limited to, amounts of reactants effective to achieve the desired yield.

[0161] Crystal morphology In certain embodiments, the present disclosure provides a crystalline form of (Z)-endoxifen free base, The present disclosure further provides crystalline forms, including those of mixtures of (E)-endoxifen and (Z)-endoxifen. The present disclosure further provides pharmaceutical compositions of endoxifen comprising the crystalline forms described herein. The crystalline forms of endoxifen can provide bioavailability and stability advantages suitable for use as an active ingredient in pharmaceutical compositions. Changes in the crystalline structure of a pharmaceutical substance or active ingredient can affect the dissolution rate (which can affect bioavailability, etc.), manufacturability (e.g., ease of handling and 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 can also affect the preparation or formulation of pharmaceutical compositions in different doses or delivery forms such as solid oral dosage forms, including tablets and capsules. Compared to other forms, such as amorphous or noncrystalline forms, crystalline forms can provide desired or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control. Thus, the crystalline forms of endoxifen may provide advantages such as improving the manufacturing process of the active agent or the stability or storage of a pharmaceutical form 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 process 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 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 as 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 includes a pattern that is not necessarily identical to that depicted herein, but is within experimental error or deviation as considered by one of ordinary skill in the art. The relative intensity of XRPD peaks can vary depending on particle size, sample preparation technique, sample mounting procedure, and the particular instrument utilized. Furthermore, instrumental variations and other factors may affect the two theta (2θ) values. Thus, when a particular two theta angle is provided, it is understood that the particular two theta angle may vary by ±0.5°, e.g., ±0.4°, ±0.3°, ±0.2°, or ±0.1°, from the particular value. As used herein, a "major peak" refers to an XRPD peak having a relative intensity greater than 30%, e.g., greater than 35%. The 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, polymorphic Form I is characterized by an X-ray powder diffraction pattern including major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° 2-theta. In some embodiments, polymorphic Form I is characterized by an X-ray powder diffraction pattern including peaks at 16.0±0.3°, 18.8±0.3°, and 26.5±0.3° 2-theta. In some embodiments, polymorphic Form I is characterized by an X-ray powder diffraction pattern including major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° 2-theta, and minor peaks at 16.0±0.3°, 18.8±0.3°, and 26.5±0.3° 2-theta. In some embodiments, polymorphic form I is characterized by an X-ray powder diffraction pattern comprising at least one peak selected from 12.3±0.3°, 28.0±0.3°, and 29.0±0.3° 2-theta. In some embodiments, polymorphic form I is characterized by an X-ray powder diffraction pattern comprising a major peak 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 including major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° 2-theta, as well as 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 disclosure provides a composition comprising polymorphic Form I. More than 90%, 95%, or 99% by weight of the compound of formula (III) in the composition may be in 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 disclosure provides polymorphic Form II of the compound of formula (III), wherein the composition comprises the (E)- and (Z)-isomers of the compound of formula (III) (i.e., (E)-endoxifen and (Z)-endoxifen) with an E / Z ratio 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 FIG. 11 or FIG. 12. In some embodiments, polymorphic Form II has an XRPD pattern substantially as depicted in FIG. 11 or FIG. 12, comprising at least two, at least three, at least four, at least five, or at least six major peaks.

[0168] In certain embodiments, polymorphic Form II is characterized by an X-ray powder diffraction pattern that includes 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, polymorphic Form II is characterized by an X-ray powder diffraction pattern that includes a peak at 22.0±0.3° 2-theta. In some embodiments, polymorphic Form II is characterized by an X-ray powder diffraction pattern that includes 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, polymorphic 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, polymorphic 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, polymorphic 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 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 be 90%, 95%, or 99% by weight or more 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 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 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 FIG. 13. In some embodiments, polymorphic Form III has an XRPD pattern substantially as depicted in FIG. 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 that includes 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 that includes a peak at 25.3±0.3° 2-theta. In some embodiments, polymorphic form III is characterized by an X-ray powder diffraction pattern that includes 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, 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, 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, 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, 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 compositions comprising polymorphic Form III. The composition of the compound of formula (III) may be 90%, 95%, or 99% by weight or more 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 (Z)-endoxifen free base or a salt thereof. In some embodiments, the pharmaceutical composition comprises predominantly endoxifen as (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% (Z)-endoxifen free base wt / wt of the total endoxifen in the composition. In at least one composition, the composition comprises > 90% (Z)-endoxifen free base wt / wt of the total endoxifen in the composition. In another embodiment, the composition comprises ≧95% (Z)-endoxifen free base wt / wt of the total endoxifen in the composition. In yet other embodiments, the composition comprises ≧96%, ≧97%, ≧98%, ≧99%, or ≧99.5% (Z)-endoxifen free base wt / wt 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, the composition comprising (Z)-endoxifen further comprises (E)-endoxifen. In some embodiments, the endoxifen in the composition has a ratio of (E)-endoxifen to (Z)-endoxifen (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 having an E / Z ratio in the range of 10:90 to 70:30. In yet another embodiment, the composition comprises endoxifen having an E / Z ratio in the range of 45:55 to 55:45.

[0177] Unless specifically noted by the prefix (Z), (E), or (E / Z), endoxifen, as used generically 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 pharma- ceutically 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 salts are 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, pama The salt is selected from the group consisting of oates (embonates), pantothenates, phosphates / diphosphates, polygalacturonates, salicylates, stearates, sulfates, tannates, theoclates, and liethiodides, 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 combinations thereof.

[0180] In some embodiments, a composition comprising endoxifen gluconate comprises 10%-100% (Z)-endoxifen D-gluconate on a wt / wt basis of total endoxifen gluconate in the composition. In some embodiments, a composition comprising endoxifen gluconate comprises 10%-100% (Z)-endoxifen L-gluconate on a wt / wt basis of 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 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 (wt / wt or v / v) of (Z)-endoxifen D-gluconate to (E)-endoxifen D-gluconate 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. The ratio of 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. One of skill in the art will recognize that other combinations of endoxifen gluconate isomers are included in 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. Thus, 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 contains 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 of the total endoxifen in the composition as a single polymorphic form of endoxifen, e.g., Form I, Form II, or Form III. 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 percentage of endoxifen is a single polymorphic form, the remainder of the endoxifen in the composition may be amorphous endoxifen and / or a single polymorphic form. The polymorphic form of endoxifen is a combination of one or more polymorphic forms of endoxifen, excluding the polymorphic form. If polymorphic endoxifen is defined as one specific form of endoxifen, the remainder is composed of amorphous endoxifen and / or one or more polymorphic forms other than the specific form specified. Examples of single polymorphic forms include endoxifen forms I, II, and III, and single polymorphic forms characterized by one or more properties described herein.

[0188] In other embodiments, a composition comprising endoxifen comprises 0.01%-20%, 0.05%-15%, or 0.1%-10% wt / wt or w / v of a single polymorphic form of endoxifen, such as Form I, Form II, or Form III, of the composition. In at least one embodiment, a composition comprising endoxifen comprises 0.01%-20% wt / wt or w / v of a single polymorphic form of endoxifen, such as Form I, Form II, or Form III, of the composition. In various other embodiments, the 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, the 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 Formulations 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, powders, troches, elixirs, suspensions, syrups, wafers, chewing gums, dragees, lozenges, etc.

[0190] In some embodiments, the oral dosage form is a solid oral dosage form such as a tablet, a caplet, and a 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 inert or active excipients or edible carriers disclosed herein.

[0192] In various embodiments, the compositions provided herein comprise about 1 to about 99.99% by weight, about 5 to about 95% by weight, about 5 to about 90% by weight, about 10 to about 80% by weight, about 15 to about 70% by weight, about 20 to about 60% by weight, about 30 to about 95% by weight, about 50 to about 90% by weight, about 60 to about 90% by weight, about 60 to about 80% by weight, or about 70 to about 80% by weight of one or more excipients. In certain embodiments, the compositions provided herein comprise about 99.99% by weight, about 95% by weight, about 90% by weight, about 85% by weight, about 80% by weight, about 75% by weight, about 70% by weight, about 65% by weight, about 60% by weight, about 55% by weight, or about 5 ... 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 a filler, binder, injection agent, disintegrant, lubricant, glidant, controlled release agent, enteric coating, film-forming agent, plasticizer, colorant, sweetener, flavoring agent, 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, for example, 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 carboxylmethylcellulose), 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. The agents and / or fillers comprise about 15%-99%, about 20%-60%, about 25%-55%, about 30%-50%, about 35%-60%, about 50%-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 rate 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, the disintegrant is deep in the oral solid dosage form to slow down disintegration. The amount of disintegrant used varies based on the type of formulation and can be easily discerned by those skilled in the art.

[0198] Typical compositions contain 0.5%-15% (wt / wt) of disintegrant. In some embodiments, the composition contains 1%-5% (wt / wt) of the disintegrant in the composition. In other embodiments, the disintegrant is 1%-25%, 2%-20%, 5%-15%, 8%-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 or potassium stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Additional lubricants include, for example, syloid silica gel (AEROSIL 200, WR Grace Co. of Baltimore, Md.), coagulated aerosol of synthetic silica (sold by Degussa Co. of Plano, Tex.), CAB O SIL (Cabot Co. of Boston, Examples of suitable lubricants include pyrogenic silicon dioxide products sold by Mass., Q7-9120 (Dow Corning), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than 1% (wt / wt) of the composition or dosage form into which it is incorporated. In yet other embodiments, the lubricant is 0.1%-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 the oral dosage form. Suitable plasticizers include, but are not limited to, petroleum-based 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 oils, 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. Examples of plasticizers include sorbitol, triethyl citrate, triacetin, diethylene glycol, polyethylene glycol, polypropylene glycol, phthalate, sorbitol, glycol salicylate, crotamiton, and glycerin or mixtures thereof. The amount of plasticizer may 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 coating agents, controlled release agents, or film-coating agents to control or delay the disintegration and absorption of the compositions comprising endoxifen or its salt in the gastrointestinal tract, thereby providing a sustained action over a longer period of time.Thus, in some embodiments, the tablet can be an enteric-coated tablet, the caplet can be an enteric-coated caplet, or the capsule can be an enteric-coated capsule.The enteric-coated tablet, enteric-coated caplet, or enteric-coated capsule 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 acidic acid-insoluble polymers, methyl acrylate-methacrylic acid copolymers, 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 copolymers, 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 monostearate, dibenzyl esters, tribenates, 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 at 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, ... Examples of suitable additives include butyrate, hydroxypropyl methylcellulose phthalate, alginic acid, such as sodium 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 available under the tradename 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-delayed 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 enteric coatings of tablets). Commercial sources of delayed release oral dosage forms, such as DRCaps made of hypromellose (HPMC), are available from 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 (such as 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.Hard uncoated capsules with enteric capabilities using essentially enteric capsule technology (e.g., EnTrinsic drug delivery available from Capsugel) are suitable for the 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 techniques known in the art and commercially available (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 the (Z)-endoxifen free base or a salt thereof is tightly filled 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 or micronized powder. When the dosage form is a capsule, in at least one embodiment, the capsule is a seamless capsule or a banded capsule. It may also be a 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 embodiment, in the present disclosure, the compositions are 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 2-30 hours, 3-20 hours, 2-10 hours, or 4-8 hours after administration of the composition. Thus, in some embodiments, the time to maximum (peak) plasma levels of endoxifen ranges from 2-10 hours after administration of the composition. In some embodiments, the time to maximum plasma levels of endoxifen ranges from 4-8 hours after administration of the compositions disclosed herein.

[0214] Rapid achievement 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 comprising a polymorphic form of endoxifen, (Z)-endoxifen or a salt thereof that rapidly achieve 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 (FIG. 5).

[0215] In one aspect, the present disclosure provides that circulating endoxifen released from the compositions disclosed herein may be cleared faster 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, which is significantly shorter than tamoxifen. In some embodiments, the average 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-infThe average ratios (on day 1) typically range 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). A composition containing (Z)-endoxifen or a salt thereof typically has an initial (first) dose of 1 mg to 4 mg of (Z)-endoxifen on Day 1, followed by a 150 hour dose of 1 mg to 4 mg of (Z)-endoxifen. * ng / mL~600 hours * Mean ng / mL (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 "), that is, the time-averaged concentration of drug circulating in the analyzed bodily fluid (usually plasma, blood, or serum), describes the subject's total exposure to the drug. In this disclosure, exposure to endoxifen (AUC 0-inf ) may be dose proportional. In some embodiments, the 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-infwere administered over a dose range of 1 mg to 4 mg of (Z)-endoxifen for 400 h. * ng / mL~6000 hours * ng / mL range (see, for example, Table 17).

[0219] The 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 yet other embodiments, the composition is formulated for 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 USP 711 method.

[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), elliptical (0.05-7 mL), ellipsoidal, 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 may contain one or more of the excipients known in the art and disclosed herein in any combination appropriate for 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 appropriate dosage form based on their own skill and knowledge of the art and the disclosures 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 Since the total organism count (TAC) and USP indicator organisms are typically not required to be tested, the total organism count (TAC) and USP indicator organisms are typically not required to be tested, since the total organism count (TAC) and USP indicator organisms are typically not required to be tested, since the total organism count (TAC) and USP indicator organisms are typically not required to be tested, since the total organism count (TAC) and USP indicator organisms are typically not required

[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 a raw material, intermediate material, or final product. Samples are tested according to the most recent USP 39 <61> , and are analyzed in accordance with "Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests."

[0229] Acceptable TACs for oral solid dosage forms (OSDFs) are established for formulations of the inventive 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 USP Guidelines Chapter 62.

[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 containing them, can be used in the manufacture of a medicament for use in treating a subject in need thereof, such as a subject suffering from or at risk of suffering from a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both.

[0232] Have a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, or both Where the intent is to ameliorate or cure a subject at risk of or suffering from a cancer, 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 a 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 appears 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 an 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 (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 a mixture of invasive and in situ carcinoma.

[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 treatment by localized modes of 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 further suffers from prostate cancer.

[0239] Despite severe side effects, poor patient compliance, and resistance to the drug due to low plasma endoxifen levels found in subjects, the current choice of treatment for such disorders remains tamoxifen. Such subjects may have low endoxifen levels when administered tamoxifen for any number of reasons, such as having CYP gene mutations in, for example, CYP2D6, CYP3A4, or CYP2C9, which render them unable to metabolize tamoxifen to its active metabolite, endoxifen, or low-functioning or dysfunctional estrogen receptors, preventing (or reducing) sufficient tamoxifen uptake, and other reasons yet to be identified. The reported therapeutic levels of plasma tamoxifen in subjects administered 20 mg oral tamoxifen are > 30 nM (Lyon et al. Ge Net 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 in which the subject has low endoxifen or where the subject suffers from or is at risk for suffering from a hormone-dependent breast disorder or a hormone-dependent reproductive system disorder. Thus, the compositions of the present disclosure may be of particular importance in the treatment of tamoxifen-resistant, hormone-dependent breast disorder or a hormone-dependent reproductive system disorder.

[0240] In certain embodiments, the present disclosure provides a patient population for which the pharmaceutical composition is particularly useful.The compositions of the present disclosure are also particularly important in the treatment of tamoxifen-resistant subjects suffering from hormone-dependent breast disorder or hormone-dependent reproductive system disorder.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 disorder, hormone-dependent reproductive system disorder, or both.In some embodiments, compositions comprising endoxifen salts, such as endoxifen gluconate, administered to such subjects in dosages disclosed herein will 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. Thus, in certain embodiments, provided herein are patient populations that are or will be treated with SSRI drugs that would benefit from treatment with the compositions of the present disclosure.

[0242] The compositions disclosed herein administered orally maintain the subject's plasma endoxifen at a steady-state level greater than 30 nM, for example, at a level in the range of 30 nM to 80 nM, or at 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), an intermediate metabolite of tamoxifen (having plasma endoxifen levels less than 27 nM). This is advantageous for subjects who are being 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] Whether a subject is tamoxifen resistant can be determined by administering an initial dose of tamoxifen to the subject and determining the subject's steady-state plasma endoxifen level. The steady-state plasma endoxifen level in a subject administered tamoxifen serves as a biomarker for subjects that are tamoxifen resistant. Plasma endoxifen levels (acute and / or steady-state) can be determined from the subject by obtaining a test sample (which can be a blood sample) collected from the subject after administration of tamoxifen. The plasma or serum can be analyzed for the biomarker endoxifen levels. The blood sample for testing the bell can be obtained. The initial dose comprises administering 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. The subject can 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 subject's plasma endoxifen steady state level can be determined by measuring endoxifen in a test sample. The subject's plasma endoxifen steady state level is compared to a reference plasma endoxifen level. For the 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, for example, Form I, Form II, or Form III of endoxifen. In other embodiments, the composition administered to such subjects 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 the subject's plasma endoxifen level is tracked or monitored periodically or as needed. If necessary, the subject who has been administered an initial dose of tamoxifen can adjust their plasma endoxifen steady-state level based on the test results by continuing to administer a composition comprising endoxifen.

[0245] In some embodiments, the tamoxifen resistance status of a subject can be determined by determining the tamoxifen metabolite profile of the subject, which is compared to a reference tamoxifen metabolite profile as seen in a control or normal subject.Compared to the reference tamoxifen metabolite profile, subjects with low plasma endoxifen levels in the tamoxifen metabolite profile of the subject are treated with an oral composition comprising endoxifen or a salt thereof.Such compositions may comprise synthetically prepared endoxifen.

[0246] Plasma endoxifen may be measured by any of the methods known in the art. The level of plasma endoxifen in the 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 level of plasma endoxifen and / or tamoxifen metabolite profile in the test sample is 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), and the like. In some embodiments, the tamoxifen metabolite profile is determined by the following methods: The risk of developing leukemia is predicted based on the genetic makeup of the subject. In some embodiments, the subject's CYP genotype includes, but is not limited to, analysis of the CYP2D6, CYP3A4, CYP2C9 genes. In some embodiments, the subject's estrogen receptor levels may be analyzed. In other embodiments, the determination of plasma endoxifen may be performed by a third-party laboratory.

[0247] Thus, provided herein is a method of maintaining plasma endoxifen at 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, the subject can test the test sample tested for their own biomarker profile that can indicate or monitor hormone-dependent breast disorder, hormone-dependent reproductive system disorder, 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 antigen, and other biomarkers measured by Mammaprint, OncotypeDx, PAM50, EndoxPredict, MammoStrat, and other diagnostic and predictive tests. Subjects with a biomarker profile that indicates that the subject suffers from or is at risk of suffering from hormone-dependent breast disorder, hormone-dependent reproductive system disorder, or both can be administered the compositions disclosed herein. In one 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, comprising determining the subject's tamoxifen-resistant or tamoxifen-resistant 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-resistant 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 is a method for treating a tamoxifen-resistant subject suffering from or at risk of suffering from hormone-sensitive breast disorder, 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 polymorphic Form I, Form II, or Form III of endoxifen is administered.

[0251] Further provided herein is a method of treating a tamoxifen-resistant subject, the method comprising: (a) determining or having determined a plasma endoxifen level in a test sample obtained from the subject; and (b) determining a baseline plasma endoxifen level. (c) determining a decrease in plasma endoxifen level in the test sample relative to a 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 is a method for treating a subject suffering from or at risk of suffering from a hormone-dependent breast disorder or a hormone-dependent reproductive system disorder, comprising: (a) administering to the subject a first composition comprising endoxifen; (b) determining or determining a plasma endoxifen level in a test sample obtained from the subject; (c) determining or determining a decrease in plasma endoxifen level in the test sample compared to a baseline level of plasma endoxifen; 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 higher. 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 combinations 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 disorder or hormone-dependent reproductive system disorder, the method includes: (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 the reduction of the plasma endoxifen level of the subject based on the tamoxifen metabolite profile of the subject to compare the reference plasma endoxifen level with the reference tamoxifen metabolite profile; (d) administering an oral composition comprising endoxifen or a salt or polymorphic form thereof 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 modulating 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 been administered an initial dose of tamoxifen and having a plasma endoxifen level that is less than 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 to a baseline plasma endoxifen level; and (c) measuring the plasma endoxifen level of the subject over a 30-day period. and administering to the subject an oral composition comprising endoxifen or a salt or polymorphic form thereof to maintain the subject's plasma endoxifen level at a level greater than nM. 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 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. The subject may be administered 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 to 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 comprising 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)-(c) may be repeated until the subject exhibits the desired plasma level of endoxifen.

[0256] In one aspect, the 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 the step of removing breast tissue from the subject, administering radiation therapy to the subject, or administering an oral composition comprising endoxifen or a salt or polymorphic form thereof disclosed herein. In another aspect, the 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 the step of administering an oral composition disclosed herein prior to removing breast tissue from the subject or administering radiation therapy to the subject.

[0257] The dose administered to the 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 is generally intended to 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, the composition comprising endoxifen or an endoxifen salt or polymorphic form is administered to the subject in a dose of 0.01 mg to 200.0 mg. In other embodiments, the oral composition comprising endoxifen or an endoxifen salt or polymorphic form is administered to the subject in a dose of 1 mg to 200.0 mg. In some embodiments, oral compositions comprising 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 comprising 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. g, 40 mg, 50 mg, 100 mg, or 200 mg. In some embodiments, the compositions comprising endoxifen gluconate are administered in a dose range of 0.01-20 mg. In some embodiments, the compositions comprising (Z)-endoxifen D-gluconate are administered in 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 comprising 1 mg of (Z)-endoxifen D-gluconate is administered. In other embodiments, a composition comprising 1 mg of (Z)-endoxifen L-gluconate is administered. In yet other embodiments, a composition comprising 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 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 comprising a polymorphic form, e.g., Form I, Form II, or Form III of endoxifen, are administered at a dose ranging from 0.01 to 20 mg.

[0258] A breast cancer growth rate study using mammography screening of subjects with breast cancer revealed that the breast cancer growth rate in the 25th percentile of women aged 50-59 years indicates an unmet need for rapid exposure of subjects to therapeutics (Weeden-Fekjaer et al. Breast Cancer Research 200810:R41). Rapid absorption and bioavailability of anti-cancer therapeutics such as endoxifen that can further reduce cancer growth rate is 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 2-30 hours, within 3-20 hours, within 2-10 hours, or within 4-8 hours after administration of the composition. Thus, in some embodiments, the time to maximum (peak) plasma levels of endoxifen ranges from 2-10 hours after administration of the composition. In some embodiments, the time to maximum plasma levels of endoxifen ranges from 4-8 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 in subjects administered compositions disclosed herein, including (Z)-endoxifen or a salt or polymorphic form thereof, rapidly achieve 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 following daily administration of a composition disclosed herein (FIG. 5).

[0261] In one aspect, the present disclosure provides that circulating endoxifen released from compositions disclosed herein may be cleared faster 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 compositions disclosed herein may have a terminal elimination half-life in the range of 30-60 hours, which is significantly shorter than tamoxifen. In some embodiments, the average 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 average ratio (on day 1) is typically in the range of 0.7 to 1.2. Thus, the amount of glycerol released from the compositions disclosed herein is Accumulation of endoxifen in the rats does not change significantly over continued treatment.

[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). A composition containing (Z)-endoxifen or a salt thereof typically is administered on day 1 with an initial (first) dose of 1 mg to 4 mg of a composition containing (Z)-endoxifen for 150 hours. * ng / mL~600 hours * Mean ng / mL (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 "), that is, the time-averaged concentration of drug circulating in the analyzed bodily 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 ) may be dose proportional. In some embodiments, the 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 were administered over a dose range of 1 mg to 4 mg of (Z)-endoxifen for 400 h. *ng / mL~6000 hours * ng / mL range (see, for example, Table 17).

[0265] A medical 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 may be used in combination with one or more therapeutic agents as part of a 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 effect of therapeutic agents, and thus can be used to improve standard cancer therapeutics. For example, if a subject suffers from 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 suffering from 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 trastuzumab or other tumor drugs, such as 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 includes an anti-cancer drug, such as bicalutamide, enzalutamide, or an anti-cancer drug, such as trastuzumab, antineoplastic drugs, such as 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. Includes ribozyme-binding protein inhibitors.

[0267] In other aspects, the compositions disclosed herein may include 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 in cancer cells as well as in the brain, liver, and small intestine, which affects pharmacokinetics and confers therapeutic resistance to many anticancer drugs. Thus, in some embodiments, the compositions further include an inhibitor of an ATP-binding cassette (ABC family) transporter, such as an inhibitor of breast cancer resistance protein (BCRP protein) and P-gp. Some 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, cyclosporine 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), as well as HM30181 and anti-P-gp monoclonal antibodies, such as MRK-16.

[0269] The present disclosure further provides a therapeutic kit containing one or more of the 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, antineoplastic 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, such as P-gp inhibitors.

[0270] Exemplary Compositions Exemplary non-limiting compositions are provided below. As stated 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 can be up to 100% (wt / wt) of the total composition. At least 90% (≧90%) of (Z)-endoxifen free base refers to the percent weight of (Z)-endoxifen isomer compared to the total weight of endoxifen in any composition.

[0271] In one aspect, the present disclosure provides a compound of formula (I), a compound of formula (II), The present invention relates to an industrially scalable process for producing the compounds of the formula (I) and their salts and polymorphic forms.

[0272] In one aspect, the present disclosure relates to an industrially scalable process for producing (Z)-endoxifen, 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 / wt); (d) washing one or more times with 20% NaCl (1:1 to 1:5 wt / wt); (e) reacting with activated charcoal (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 for 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 (a compound of formula (III)) comprising: (a) reacting a compound of formula (II) with propiophenone in THF (4.4 wt / wt); (b) reacting TiCl in THF (8.9 wt / wt); 4 (c) preparing a solution of TiCl (1.4 wt / wt) and Zn (0.9 wt / wt) in THF to form a mixture of (E)-endoxifen and (Z)-endoxifen; 4 and Zn, where wt / wt is with respect 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 steps of: (a) extracting 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) distilling using EtOAc (1:4.5 wt / wt); and (d) crystallizing using (1:2 v / v) EtOAc / n-heptane (1:3.8 wt / wt), where wt / wt is with respect 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) a K 2 CO 3 (b) extracting one or more times with 1N NaOH (1:10 wt / wt) and MeTHF (1:1 to 1:10 wt / wt); (c) extracting two more times with MeTHF (1:1 to 1:20 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 1-5 times with methanol (4.0 wt / wt); (d) distilling 1-5 times with methanol (3.2 wt / wt); (e) reacting with methanol (3.2 wt / wt) / 6N HCl (4 wt / wt); and (f) neutralizing with 8N NaOH (5 wt / wt), where wt / wt is with respect to the compound of formula (I).

[0277] In one aspect, the present disclosure relates to (Z)-endoxifen, (E)-endoxifen, compounds of formula (III), compounds 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] (Z)-endoxifen free base prepared according to the processes disclosed herein has <1% impurities. In yet other embodiments, (E) / (Z)-endoxifen free base prepared according to the processes disclosed herein has <1% impurities.

[0279] In one aspect, the 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, a 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 aspects, a composition comprises (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein: a. the composition has a bacterial count of 20,000 g / mL or less; b. the composition has a moisture content of 1.0% or less when 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 when tested by the method of USP 281; e. Heavy metals are 20 ppm or less when 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 when tested by a validated HPLC method.

[0285] In yet other embodiments, a composition containing (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein contains 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 containing (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 per unit dose.

[0287] In a further aspect, a composition containing (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein contains 0.01% to 20% (wt / wt) of 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 said composition contains 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, said composition further comprising 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, flavorings, 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, said composition further comprising one or more excipients, wherein said 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 said 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. nothing.

[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 said 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 said composition formulated for oral delivery is a tablet, caplet, capsule, pill, powder, troche, elixir, suspension, syrup, wafer, chewing gum, dragees, and lozenges.

[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 said 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 said 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 has: 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 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 methods of USP 711 or 701, said composition has: a. Less than 10% of (Z)endoxifen at 2 hours after administration; b. Less than 20% of (Z) endoxifen at 2 hours post-dose; 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 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 contains at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of endoxifen as tested by the methods of USP 711 or 701. is released in the intestine.

[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 methods 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 methods 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 methods of USP 711 or 701.

[0303] In other aspects, the 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 has: a. at least 10% of endoxifen 4 hours after administration; b. at least 30% of endoxifen 6 hours after administration; c. at least 40% of endoxifen 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 2 hours after administration; h. at least 80% of endoxifen at 2 hours post-dose; or i. At least 90% of endoxifen is lost 2 hours after administration is released in the small intestine.

[0304] In other aspects, the 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 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 endoxifen is at least 90% (Z)-endoxifen free base; and where: The composition has a total viable count of 20,000 g / ml or less; The moisture content of (Z)-endoxifen is less than or equal to 1% as determined by USP 921, Method Ic; (Z)-endoxifen has a residue on ignition of 0.10% or less when tested by the method of USP 281; or Heavy metals are less than 20 ppm when 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 said 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 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 for release 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, the 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 total viable count of 20,000 g / ml or less; The moisture content of (Z)-endoxifen is less than or equal to 1% as determined by USP 921, Method Ic; (Z)-endoxifen has a residue on ignition of 0.10% or less when tested by the method of USP 281; or Heavy metals are less than or equal to 20 ppm when 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 an enteric capsule comprising (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 total viable count of 20,000 g / ml or less; The moisture content of (Z)-endoxifen is less than or equal to 1% as determined by USP 921, Method Ic; (Z)-endoxifen has a residue on ignition of 0.10% or less when tested by the method of USP 281; and Heavy metals are less than 20 ppm when tested by USP 231, Method II.

[0311] In 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 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, pamaoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, tannate, theoclate, 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) of (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 provides a method for the treatment and prevention of any of the processes described herein for the treatment and prevention of hormone-dependent breast disorders, hormone-dependent reproductive system disorders, or both. The present invention also relates to compositions comprising (Z)-endoxifen or a salt or polymorphic form thereof prepared thereby.

[0317] In yet 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 for the treatment and prevention of a hormone-dependent breast disorder, a hormone-dependent reproductive system disorder, 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-resistant.

[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 said 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, said composition being administered to a subject in need thereof, said subject having breast cancer, said breast cancer being pre-cancer, early stage cancer, non-metastatic cancer, pre-metastatic cancer, locally advanced cancer, or metastatic cancer. It's 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 wherein the subject is undergoing or will be beginning 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 wherein 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-resistant.

[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 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, 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 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, 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, biweekly, 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, said composition being administered to a subject as a priming therapy, neoadjuvant therapy, or adjuvant therapy. It is administered as a bunt therapy drug.

[0334] 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 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, the composition being 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 (Delphi), cyclosporine (Cyclosporin ... cetamol (Docefrez, Taxotere), doxorubicin (Adriamycin), pegylated liposomal doxorubicin (Doxil), epirubicin (Ellence), fluorouracil (5-FU, Adrsil), gemcitabine (Gemzar), methotrexate (several brands), 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 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 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 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 for having a hormone-dependent breast disorder, a hormone-dependent reproductive disorder, or both, 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.

[0340] 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.

[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 is afflicted with 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, 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 a tamoxifen-resistant or tamoxifen-resistant hormone-dependent breast disorder or a hormone-dependent reproductive disorder.

[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, biweekly, 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 of 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 a first dose (day 1).

[0349] In yet another aspect, the present disclosure relates to a method of treating a subject 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 level 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 following 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 following 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 steady state plasma levels 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, 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 steady state plasma levels 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 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, 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 steady state plasma levels 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 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, 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 Here, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen is released to 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 disorder or a 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, 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 Here, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen is released to 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 disorder or a 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, 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 steady state plasma levels 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 disorder or hormone-dependent reproductive disorder selected from the group consisting of benign breast disorder, hyperplasia, atypical, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, 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 Here, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen is released to 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 disorder or a 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, 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 0-inf ) is 200hr * ng / mL~10000hr * ng / mL, 300hr * ng / mL~8000hr * ng / mL, 400hr * ng / mL~6000hr * ng / mL or 700hr * ng / mL~6000hr * ng / mL; and Here, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen is released to 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, the method being a first-line treatment, a neoadjuvant treatment, or an adjuvant treatment.

[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, antineoplastic agents, e.g., capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinol), cyclophosphamide (Neosar), docetaxel (Docefrez, Taxotere), doxorubicin (Adriamycin), and the like. In some embodiments, the medicament is selected from the group consisting of ribavirin (ribavirin), pegylated liposomal doxorubicin (Doxil), epirubicin (Ellence), fluorouracil (5-FU, Adrsil), gemcitabine (Gemzar), methotrexate (several 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, 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 reduction in the subject's plasma level of endoxifen based on the subject's tamoxifen metabolite profile as compared to the plasma level of endoxifen in the reference tamoxifen metabolite profile; and Administering a composition of the present disclosure to the subject.

[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, 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 reduction in the subject's plasma level of endoxifen based on the subject's tamoxifen metabolite profile as compared to the plasma level of endoxifen in the 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 plasma endoxifen in the subject at a steady state level of 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, the 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 disclosure provides a kit for treating a subject having or at risk for a hormone-dependent breast disorder, a hormone-dependent reproductive disorder, or both. and (c) instructions for using the composition to be orally administered, wherein the kit includes a second therapeutic agent, the second therapeutic agent being selected from the group consisting of bicalutamide, enzalutamide, and anti-cancer drugs, e.g., trastuzumab, antineoplastic agents, 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 (several brands), 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 said composition. EXAMPLES

[0370] Abbreviations used herein ACN / PPW = acetonitrile / process purified water NaHCO 3 = Sodium bicarbonate HCl = Hydrochloric Acid THF = tetrahydrofuran MeTHF = 2-methyltetrahydrofuran CH 2 Cl 2 = 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 ratios (E / Z ratios) of 51 / 1, 1 / 1.8, and 1 / 5.8, respectively, in 10 volumes of the solvent, isopropanol (IPA). A second set of solutions was prepared by suspending 1 g of each endoxifen in E / Z ratios of 51 / 1, 1 / 1.8, and 1 / 5.8 in 10 volumes of the solvent, EtOAc. The solutions were heated to a first temperature of 50° C. to create hot slurries and stirred at 50° C. overnight. The hot slurry samples were The mixture was filtered using a 0.5 μm pore size cellulose filter. The mixture was then stirred for 12 hours while cooling to a second temperature, i.e., room temperature, 23°C, to achieve crystallization. An aliquot of the cooled sample was filtered using a 0.5 μm pore size cellulose filter. Aliquots of solids and filtrate were obtained at each temperature of 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 added back to their respective mother liquors.

[0373] HPLC-UV analysis of the samples was carried out using a Luna phenyl-hexyl column (particle size 4.6 mm x 150 mm x 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 of sample in methanol as sample buffer. The samples were then injected into the column with an injection volume of 20 μl. Similarly, a mildly acidic (pH 4.3) ammonium formate buffer / methanol in the mobile phase with gradient elution was used. The mobile phase system consisted of the following: Mobile Phase A (MPA) buffer was 10 mM HCOOH with 0.03% HCOOH buffer in water. 4 and mobile phase B (MBP) buffer is 10 mM HCOONH in methanol with the gradient program used. 4 It was.

[0374] [Table 1]

[0375] The run time was 30 min, the flow rate was 1.0 mL / m, and the delay time was 5 min. Samples were detected by UV detection at 243 nm. Retention times were typically 12.95-13.20 min for (E)-endoxifen and 14.0-14.33 min 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) show that Z-endoxifen can be enriched using commercially available crude E / Z endoxifen starting material from a hot slurry of endoxifen mixture made with IPA and EtOAc. Z-endoxifen can be purified from E / Z-endoxifen mixtures with 1:1 E / Z, 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 of EtOAc compared to IPA. Both the solid and the filtrate are useful for the preparation of (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 having high E-endoxifen levels in the E / Z mixture.

[0379] ii. Similar results were obtained in experiments where 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 a filtrate containing enriched (Z)-endoxifen.

[0380] B. Recrystallization from the solid fraction Successive enrichment of (Z)-endoxifen is feasible 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 above E / Z-endoxifen hot IPA slurry mixture was used to obtain further purified Z-endoxifen. After cooling to 23°C, the solid fraction of sample 2 (80 g) and the solid fraction of 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 filtered again. The crystals on the filter were washed with 200 mL of EtOH.

[0383] The results indicate that the solid crystals of endoxifen had an E / Z ratio of ≥ 1 / 100 (0.22% / 99.48%) and that 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 different experiments performed by this method showed that the retention time of (Z)-endoxifen was 14.00 min and that of (E)-endoxifen was 13.14 min. The levels of (Z)-endoxifen ranged from 97% to 99.48%, while the levels of (E)-endoxifen 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 studied as described below.

[0385] 5 g of endoxifen (E / Z ratio 1 / 5.8) was added to EtOAc / n-heptane (140 mL, 1 / 1 v / v) and stirred overnight with heating to 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 and filtered. After isolation as described above, the solid product 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 similar ratios as 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 (10v; 5 mL) solvent, and anti-solvent MTBE (9 mL) was added to the solution and stirred overnight under heating at reflux (~82°C) 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 and filtered. 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 is useful for separating E-endoxifen from (Z)-endoxifen in the filtrate to a solid.

[0388] C. Recrystallization from mother liquor Purified (Z)-endoxifen can be recovered from the mother liquor enriched with (Z)-endoxifen 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 including: a first step of dissolving the E / Z-endoxifen mixture in a first solvent, ethyl acetate, to enrich (Z)-endoxifen into a first mother liquor; a second step of adding IPA to obtain crystalline (Z)- a second step of forming endoxifen and a second mother liquor; and adding a third solvent, 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 EtOAc, respectively, and heated (~70 °C) until dissolved. The mixture was then cooled to 25 °C while stirring overnight for precipitation. The suspension was filtered and the E / Z ratio of the solid and filtrate were determined by HPLC.

[0393] The filtrate was then concentrated to dryness and 230 mL and 900 mL IPA, respectively, were added 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 h, respectively, and filtered. Z-endoxifen in the solids and filtrate was again determined.

[0394] The solids of each sample (14.8 g and 21.6 g) were further recrystallized from 148 mL and 220 mL of EtOH by heating to below 70°C and cooling to 25°C over 0.5 h and 1 h, respectively. The samples were further cooled to 0°C-5°C over 1 h and filtered. The E / Z ratios of the solids and filtrate 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 show that greater than 90% purified crystalline (Z)-endoxifen can be obtained by subjecting the 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 HPLC method as 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 The (E)-endoxifen enriched E / Z endoxifen mixture is 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 notion that re-equilibration can be performed with a starting E / Z-endoxifen mixture having any E / Z ratio, e.g., 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 is 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, then cooling to 0 °C-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 E / Z endoxifen mixture, a compound of formula (III) at an E / Z ratio of 1 / 5.8, was carried out 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 in 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 >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] In a suitable 10 L reactor, the starting materials [4-[2-(dimethylamino)ethoxy]phenyl](4-hydroxyphenyl)methanone, the compound of formula (I) (0.5 kg, 1.0 equiv.), DIPEA (1.5 kg, 6.65 equiv., 3.0 wt. / wt.), and tetrahydrofuran (5 L, 10 vol. / wt., 8.9 wt. / wt.) were added with N 2 Charged under atmosphere. 1-Chloroethyl chloroformate (1.7 kg, 6.65 equiv., 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 above 75°C until the volume reached the minimum stirrable volume. Methanol (2.5 L, 5 vol. / wt, 4.0 wt. / wt.) was added slowly 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 again and the mixture was further distilled under reduced pressure above 75°C until the volume again reached the lowest 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 added slowly until the pH of the mixture was 11-12. The mixture was stirred at 0-5°C for not less than 2 hours. The mixture was filtered and eluted with H 2The wet cake was dried under reduced pressure below 50°C to obtain the compound of formula (II), which is (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone. Yield: 297gm, 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] In a suitable 2 L reactor, 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.) were added with N 2 Charged under atmosphere. The mixture was heated to above 60°C and 1-chloroethyl chloroformate (140 gm, 4.0 eq, 2.0 wt.). 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 added slowly and the mixture was concentrated until the volume reached 3 vol. (210 mL). Methanol (350 mL, 5.0 vol., 4.0 wt.) was then 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 .about.4 vol. (280 mL). The mixture was cooled to ambient temperature and the mixture was concentrated. 8N NaOH (350 mL or more, 5.0 vol., 5.0 wt.) was slowly added until the pH was 13 or higher. Ethyl acetate (280 mL, 4.0 vol., 3.6 wt.) was added to the mixture for extraction. After phase separation, 6N NaOH was added to the aqueous layer until the pH was 8-10. HCl (not less than 42 mL, 0.6 vol., 0.6 wt.) was added. The mixture was cooled to 0±5°C and stirred for not less than 2 hours. The mixture was filtered and washed with purified water (not less than 140 mL, 2.0 vol., 2.0 wt.) and ethyl acetate (not less than 140 mL, 2 vol., 1.8 wt.). The wet cake was dried under reduced pressure at not less than 60°C to obtain the compound of formula (II), which is (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone. Yield: 55.2 gm, 83%; Purity: 100% (expected yield - not less than 70%)

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

[0411] [ka]

[0412] In a suitable 10 L reactor, Zn powder (0.27 kg, 4.0 equiv., 0.9 wt. / wt.) and tetrahydrofuran (1.5 L, 5 vol. / wt., 4.4 wt. / wt.) were added to a 10 L reactor with N 2 Filling was carried out under atmospheric conditions. 4(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 not less than 2 hours. A suspension of (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone, compound of formula (II) from step 1 (0.297 kg, 1.0 equiv.), and propiophenone (0.21 kg, 1.5 equiv., 0.7 wt. / wt.) in tetrahydrofuran (3.0 L, 10 vol. / wt., 8.9 wt. / wt.) was added and reflux was continued for not less than 8 hours. 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; trade name Celite® S) available from Sigma Aldrich mixture (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% K 2 CO 3 (1.2 L, 4 vol. / wt., 5.6 wt. / wt.). The organic layer was concentrated under reduced pressure at >75°C until the volume reached the lowest 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 until the volume reached the lowest 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 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 >2 hours. The mixture was filtered, and the residue was diluted with ethyl acetate / n-heptane = 1 / 2 (v / v, 1.5 L, 5 vol. / wt., 3 The residue wet cake was dried under reduced pressure at up to 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: 176g, 42%; Purity: 81.96%. E / Z ratio: 3.1:1 (expected yield - 40-60%).

[0414] A suitable 10 L reactor was charged with (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 not less than 2 hours. The mixture was cooled to 0±5°C and stirred at 0-5°C for not less than 2 hours. The mixture was filtered and washed with pre-chilled isopropanol / purified water=1 / 1 (0.5 L, 2 vol. / wt., 3.6 wt. / wt.). The residual wet cake was dried at up to 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 added slowly 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, 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 at 65±5°C for not less than 8 hours. Cool the mixture to below 30°C and add 40% K 2 CO 3 (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 diluted with 40% K 2 CO 3 (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 until the volume reached 3 vol. (30 mL). The mixture was extracted with 1N 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 and then extracted four times with Me-THF (50 mL, 5.0 vol., 4.3 wt.). The four organic layers were combined and concentrated until the volume reached 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 until the volume reached 3 vol. mL, 5.0 vol., 4.5 wt.) was added and the mixture was concentrated until the volume reached 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 not less than 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 below 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, compound of formula (III). Yield: 6.7 g, 45%; purity: 96.79%. E / Z ratio: 48.6:1 (expected yield -30% or more).

[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 not less than 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 was ≥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 (charcoal) (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 the volume reached 10 vol. (1.1 L). The mixture was cooled to 0-5° C. and stirred at 0-5° C. for not less than 2 h. The mixture was filtered and the filtrate was collected. The filtrate was concentrated at not less than 75° C. 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 volume reached the lowest stirrable volume. Isopropanol (1.1 L, 10 vol. / wt, 7.9 wt. / wt.) was added again and the mixture was concentrated above 75°C until the volume reached the lowest stirrable volume. 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 not less than 6 hours. The mixture was cooled to 20±5°C and stirred at 20±5°C for not less than 4 hours. The mixture was filtered and washed with isopropanol (0.2 L, 2 vol. / wt., 1.6 wt. / wt.). The wet cake was cooled to below 60°C. Upon drying, purified (Z-endoxifen) solid compound of formula (IV) was obtained 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) above and a third solvent, isopropanol (390 mL, 10 vol. / wt.). The suspension was stirred at 50±5°C for not less than 6 hours. The mixture was cooled to 20±5°C and stirred at 20±5°C for not less than 4 hours. 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 the 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: Industrial Success of a 1:1 E-Endoxifen / Z-Endoxifen Mixture Scalable Enrichment 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 (charcoal) (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 the volume reached 5 vol. (2.0 L). 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 not less than 2 hours. The mixture was filtered and washed with EtOAc / n-heptane=1 / 2 (v / v). The wet cake was dried under reduced pressure below 60°C to give essentially pure ∼1:1 E / Z-endoxifen. [Yield: 106g, 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 the 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. provide 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 presumed to be more rapid in a solution environment. In aqueous media, Elkins et al. provide t90 values ​​for (Z)-endoxifen HCl of 149 days at room temperature and 9 days at 45°C. A need remains for (Z)-endoxifen free base formulations that are well suited for the preparation of pharmaceutical compositions suitable for administration to a subject, e.g., at ambient temperature, as well as at higher temperatures and humidity.

[0432] Provided in the present disclosure 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 is defined as the continuous presence of at least 90% (Z)-endoxifen in the composition for at least six 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 upon storage in solid form and in ethanol (EtOH) solution at various temperatures. The levels of (E)-endoxifen and (Z)-endoxifen were measured in dry N 2The pH of purified (Z)-endoxifen free base was measured 2, 7, and 10 days after placement of 1 g aliquots of purified (Z)-endoxifen free base in 180 mL HDPE bottles under 50° C. and then the aliquots were placed in double LDPE bags. The double bagged HDPE bottles containing each sample were individually packaged in aluminum foil bags and heat sealed until opened for testing of sample stability. The (E)- and (Z)-isomers of endoxifen were monitored by HPLC as disclosed above. The purity of (Z)-endoxifen in solid form remained about 97% for up to 10 days at 40° C., 60° C., and 80° C. The results of the 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 a 10-day period. 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, .about.1 g aliquots of (Z)-endoxifen free base were individually placed inside double LDPE bags tied with nylon cable ties. The LDPE bags were then placed into 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 day 0, day 10, 1 m, and 3 m. Table 13 below provides bulk drug substance stability data at 9m for endoxifen free base at various storage conditions.

[0438] [Table 13]

[0439] Results indicate that solid Z-endoxifen free base is stable at 5°C and 25°C / 60% RH for at least 9 months. 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 moisture content of such powder was 1% or less as determined using USP921 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 less than or equal to 0.1% as determined by Method II of USP 281. The residue on ignition of (Z)-endoxifen ranged from 0.02% to 0.099%. In some embodiments, the residue on ignition is less than or equal to 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, and 0.1%. In another embodiment, the heavy metals were less than or equal to 20 ppm as tested by Method II of USP 231.

[0442] The levels of elements in solid (Z)-endoxifen free base are tested using the test methods of USP232 and USP40.

[0443] Thus, the processes described herein, and endoxifen prepared using these processes, are suitable for the manufacture of clinical and commercial grades of (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: signal-to-noise ratio 25,000:1, maximum resolution 0.7 cm). -1) 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 AgBr windows. Approximately 10 mg of (Z)-endoxifen free base was placed onto the ATR crystal and pressure was applied to the tip to collect the sample spectrum. Spectra were collected using a hydrated film with scan speeds up to 2 mm / sec. Interferograms were recorded using a 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 chromatin dynamics at wavelengths of 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). Endoxifen at 1 mg, 2 mg, and 4 mg contained at least 90% (Z)-endoxifen. The AIC was formulated as a medicament for the preparation of a medicament for use in the preparation of a pharmaceutical composition for use in ...

[0449] VCaps®Plus enteric capsules (Capsugel) are manufactured with hypromellose (mixed methyl and hydroxypropyl ethers 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. The enteric coating of the capsule prevents release of (Z)-endoxifen in the stomach for at least 6 hours as tested by the USP 711 method.

[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 the formulations of the solid dosage compositions disclosed herein, with moisture content of 1% or less and water activity (Aw) less than 0.75, TAC and USP indicator organism testing are not required. 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 overall viable aerobic bacteria present in a sample of a 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 may 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 gram 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 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-escalating 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 received the study drug orally. Three dose levels of orally administered (Z)-endoxifen were examined in the three cohorts. In each cohort, participants were randomized to receive oral (Z)-endoxifen or placebo in a blinded fashion. 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 for approximately 2 hours, and then fully opened in intestinal fluids (DRCaps; Capsugel, a Lonza Company, USA). Enteric-resistant (Swedish Orange size Zero (0); Capsugel, USA) DRCaps capsules were used, manually filled with the appropriate 1, 2, or 4 mg (Z)-endoxifen 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 dosed at least one day later than the sentinel patients. Cohorts 2 and 3 had no sentinel participants.

[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. There were two restriction periods, one at the beginning of the dosing period and the other 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 had 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 PK analysis, participants were released from the clinical site on day 2. The first dose on day 1 was followed by a 6-day treatment-free period (days 2-7). Each participant returned to the clinical site and underwent PK blood sampling and safety assessments during the treatment-free period on study days 4 and 6. On day 8, participants began daily dosing 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 visited the clinical site on days 11, 14, and 17 for PK 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 at the site until day 22 to allow for collection of PK blood draws and 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 adverse events and concomitant medication use; 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: 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 draws 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 are collected on Days 24, 26, and 28. AUC(inf) was measured for blood samples drawn on Day 1. Steady-state plasma level determinations began from Day 8 onwards (which served as Day 0 for this determination).

[0465] Safety and Tolerability Safety endpoints were summarized by dose cohort and placebo 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 with the effect and outcome obtained. Vital signs, ECGs, 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 list.

[0466] Treatment-emergent AEs deemed 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, with none 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, facial flushing, 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 trends toward a dose-related relationship 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). In addition, 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 (multiple oral doses), and attainment of steady state (multiple doses).

[0470] Parameters determined for the first and last doses (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 noncompartmental 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 evaluated.

[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). In addition, geometric means were calculated for AUC and Cmax. Analysis using linear models was performed to determine dose proportionality (single dose (oral) and multiple dose (topical and Statistical analyses were 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 elimination 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, are provided below in Table 16.

[0475] [Table 16]

[0476] With oral administration of once-daily delayed-release (acid-resistant) (Z)-endoxifen capsules, the Cmax and AUC of endoxifen were significantly higher across the three dose levels used in the study. 24hrThere was dose proportionality (linear dose response) between the doses. Cmax increased from 9.6 ng / mL to 32.5 ng / mL for doses of 1 mg to 4 mg 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, and steady state appeared to be reached after approximately 7 days (Figures 5-8 for dosing and Css on day 14). The time to reach maximum blood concentration 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 ​​for clearance (Cl / F) and volume of distribution (Vd / F) on days 1 and 21 ranged from 3.04 to 3.47. There were no significant trends among dose levels in clearance (Cl / F) and volume of distribution (Vd / F) 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 levels of serum endoxifen 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 to tamoxifen.

[0496] Overall healthy subjects with early stage estrogen receptor positive breast cancer will receive adjuvant tamoxifen treatment for at least 30 days and will 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 that an evaluable population consisting 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] Endoxifen plasma levels are measured after at least 30 days of oral tamoxifen. 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 of at least 40 nM but not greater 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: Preoperative 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 prior to 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 prior to 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 by 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 determine the safety and tolerability of oral (Z)-endoxifen D-gluconate administration compared to tamoxifen.

[0501] Overall healthy subjects with estrogen receptor positive breast cancer are 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 are enrolled in the study to ensure that an evaluable population consisting of at least 25 tamoxifen and 25 (Z)-endoxifen subjects is achieved. Additional subjects are enrolled to achieve the desired population of tamoxifen-resistant subjects. These subjects are diagnosed with breast cancer and undergo mastectomy or lumpectomy.

[0502] Immediately following mastectomy or lumpectomy, 25 subjects were assigned to the tamoxifen group to receive 20 mg of oral tamoxifen daily for a period of 3 months. An additional 25 subjects were assigned to the (Z)-endoxifen group to receive a 10 mg oral tablet of (Z)-endoxifen D-gluconate daily for a period of 3 months. Blood was drawn from each subject on day 0 (baseline), and on days 7, 14, 21, 28, 60, and 14. Plasma (Z)-endoxifen levels, hematology, chemistry, and coagulation parameters will be collected on day 0 (baseline measurement), as well as days 7, 14, 21, 28, 60, and 90 for both treatment sets.

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

[0504] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be utilized in practicing the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents are covered thereby.

[0505] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) A composition comprising a crystalline form of the compound of formula (III). [ka] (Section 2) Item 3. The composition according to item 1, wherein at least 90% by weight of the compound of formula (III) in the composition is the (Z)-isomer. (Section 3) 3. The composition according to item 2, wherein the crystalline form is Form I of the compound of formula (III). (Section 4) 4. The composition of claim 3, wherein the crystalline form is characterized by an X-ray powder diffraction pattern containing major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° 2θ. (Section 5) The composition according to item 4, wherein the X-ray powder diffraction pattern further comprises at least one peak selected from 16.0±0.3°, 18.8±0.3°, and 26.5±0.3°2θ. (Section 6) The X-ray powder diffraction pattern further includes at least one peak selected from 12.3±0.3°, 28.0±0.3°, and 29.0±0.3° 2θ, as described in paragraph 4 or 5 above. The composition described in (Section 7) The composition of claim 4, wherein 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. (Section 8) The composition according to any one of paragraphs 3-7, wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 9 or FIG. 10. (Section 9) 9. The composition according to any one of the above items 3-8, wherein 90%, 95% or 99% by weight of the compound of formula (III) in the composition is crystalline form I. (Section 10) The composition according to any one of the above items 3-9, wherein the composition contains 0.01 mg to 200 mg of crystalline form I. (Section 11) 11. The composition of claim 10, wherein the composition comprises about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of crystalline form I. (Section 12) Item 1. The composition according to item 1, wherein 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. (Section 13) Item 13. The composition according to item 12, wherein the E / Z ratio is about 1.1. (Section 14) 14. The composition according to claim 12 or 13, wherein the crystalline form is Form II of the compound of formula (III). (Section 15) 15. The composition of claim 14, wherein the crystalline form 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° 2θ. (Section 16) 16. The composition of claim 15, wherein the X-ray powder diffraction pattern further comprises a peak at 22.0±0.3° 2θ. (Section 17) Item 17. The composition according to item 15 or 16, wherein 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. (Section 18) 16. The composition of claim 15, wherein the X-ray powder diffraction pattern further comprises peaks at 6.6±0.3°, 13.3±0.3°, 20.0±0.3°, and 22.0±0.3° 2θ. (Section 19) 19. The composition according to any one of paragraphs 14-18, wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially as depicted in FIG. 11 or FIG. 12. (Section 20) 20. The composition according to any one of paragraphs 14-19, wherein 90%, 95% or 99% by weight of the compound of formula (III) in the composition is crystalline form II. (Section 21) 21. The composition according to any one of items 14-20, wherein the composition comprises 0.01 mg to 200 mg of crystalline form II. (Section 22) 22. The composition of claim 21, wherein the composition comprises about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of crystalline Form II. (Section 23) 14. The composition according to claim 12 or 13, wherein the crystalline form is Form III of the compound of formula (III). (Section 24) 24. The composition of claim 23, wherein the crystalline form 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° 2θ. (Section 25) 25. The composition according to claim 24, wherein the X-ray powder diffraction pattern further comprises a peak at 25.3±0.3°2θ. (Section 26) 26. The composition according to claim 24 or 25, wherein 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. (Section 27) 25. The composition of claim 24, wherein the X-ray powder diffraction pattern further comprises peaks at 18.2±0.3°, 22.5±0.3°, 25.3±0.3°, and 26.8±0.3° 2θ. (Section 28) 28. The composition according to any one of paragraphs 23-27, wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially as depicted in FIG. 13. (Section 29) 29. The composition according to any one of paragraphs 23-28, wherein 90%, 95% or 99% by weight of the compound of formula (III) in the composition is crystalline form III. (Section 30) 30. The composition according to any one of the above items 23-29, wherein the composition comprises 0.01 mg to 200 mg of crystalline form III. (Section 31) 31. The composition of claim 30, wherein the composition comprises about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, or 20 mg of crystalline Form III. (Section 32) A pharmaceutical composition comprising a pharma- ceutically acceptable carrier or diluent and the composition of any one of paragraphs 1-31 above. (Section 33) 33. The composition of a...

Claims

[Claim 1] The invention as depicted in the drawings.

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