Sustained release compositions of endoxifen

Abstract

The present disclosure provides sustained-release compositions of (Z)-endoxifen and its polymorphs and salts, and methods for making sustained-release compositions of (Z)-endoxifen and its polymorphs and salts. The present disclosure also provides methods for treating disorders amenable to (Z)-endoxifen, including hormone-dependent disorders and mood disorders. Non-limiting exemplary sustained-release compositions in the form of sustained-release tablets and enteric-coated delayed-release tablets and capsules are provided in the present disclosure.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 870,656 (Attorney Docket No. 38602-764.101), entitled "SUSTAINED RELEASE COMPOSITIONS OF ENDOXIFEN," filed July 3, 2019; U.S. Provisional Patent Application No. 62 / 989,342 (Attorney Docket No. 38602-764.102), entitled "SUSTAINED RELEASE COMPOSITIONS OF ENDOXIFEN," filed March 13, 2020; and U.S. Provisional Patent Application No. 63 / 021,549 (Attorney Docket No. 38602-764.103), entitled "SUSTAINED RELEASE COMPOSITIONS OF ENDOXIFEN," filed May 7, 2020, each of which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] Background of the Invention Breast cancer is the most common form of cancer in women and the second leading cause of cancer death in humans. In 2019, an estimated 268,600 new cases of invasive breast cancer are expected to be diagnosed in women in the United States, along with 62,930 new cases of non-invasive (invasive) breast cancer. Approximately 2,670 new cases of invasive breast cancer are expected to be diagnosed in men in 2019. Tamoxifen, a selective estrogen receptor modulator, is used to treat women with endocrine-responsive breast cancer, e.g., hormone-dependent or hormone-sensitive breast cancer.

[0003] Adjuvant therapy, primarily with oral delivery of tamoxifen, is known to have severe or troublesome side effects, such as vasomotor symptoms, e.g., hot flashes (reported at frequencies as high as 78% per day of drug administration (Mortimer et al. Breast Cancer Res Treat. 2008 Apr; 108(3): 421-426)), as well as serious side effects, such as coagulation disorders (e.g., stroke, deep vein thrombosis), and reproductive (gynecologic) cancers. As a result, patient compliance with tamoxifen therapy remains a problem. Patients are prescribed selective serotonin reuptake inhibitor (SSRI) antidepressants, such as paroxetine, for the treatment of hot flashes; however, such SSRIs are known to inhibit cytochrome P450 (CYP) enzymes (e.g., CYP2D6 and CYP3A4) that are important for the metabolism of many drugs, including tamoxifen. For example, it is known that coadministration of tamoxifen and paroxetine reduces the plasma concentration of tamoxifen's active metabolite, 4-hydroxy-N-desmethyl-tamoxifen (endoxifen). Moreover, the majority of individuals receiving adjuvant therapy with tamoxifen do not respond to the drug, and 30-50% of patients subsequently die from their disease.

[0004] Therefore, several alternatives to tamoxifen are under development for the treatment of breast cancer, including tamoxifen's active metabolite, afimoxifen (see U.S. Pat. Nos. 7,485,623, 7,507,769, 7,704,516, 7,786,172, 7,968,532, and 8,048,927). , endoxifen (see U.S. Patent No. 9,333,190; U.S. Patent Nos. 9,220,680, 9,090,640, and 9,200,045; U.S. Patent Application Publication Nos. 2009 / 0291134, US20100112041, 20180049999, WO2019051416(A1), and WO2019051370(A1) Atossa Genetics), and their derivatives (see U.S. Patent No. 8,063,249; U.S. Patent Application Publication Nos. 2015 / 0080339 and 2014 / 0193334). It is widely accepted that (Z)-endoxifen is the primary active metabolite of tamoxifen responsible for tamoxifen's clinical efficacy. Endoxifen is mainly produced by CYP2D6-mediated hydrolysis and CYP3A4-mediated N-demethylation of tamoxifen. Any drug that can be a substrate of CYP3A4 or CYP2D6, especially CYP2D6 (e.g., SSRIs), can reduce the level of endoxifen, thereby reducing the therapeutic benefit of tamoxifen. By directly administering endoxifen to such subjects, the effects of such drug interactions can be avoided. Endoxifen hydrochloride and citrate salts (e.g., Fauq et al., Bioorganic & Medicinal Chemistry Letters. 20 (2010) 3036-3038; Stearns et al., J. Natl. Cancer Inst. Vol 95, No. 23, 2003; U.S. Patent Application 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, 579-584) are known in the art and are currently being evaluated for metastatic cancer, but there is an unmet medical need for new compositions and methods for treating and / or preventing hormone-dependent breast and reproductive system (gynecologic) disorders, as well as other disorders amenable to or responsive to endoxifen. There is a strong need for methods for treating and preventing breast disease in men and women, particularly in tamoxifen-resistant patients and in premenopausal female populations, without significant adverse systemic side effects. There is also a strong need for formulations that provide blood levels of endoxifen that avoid rapid release or delivery of endoxifen in subjects that may be associated with side effects or patient tolerance issues. Furthermore, there is a strong need to ensure that a sufficient (Z)-endoxifen dose is available to patients by ensuring that the drug passes through the stomach without being degraded in the stomach's acidic environment. In particular, there is a need for breast cancer treatment and prevention that reduces the effects of compounding effects associated with other administered drugs or their metabolism. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent No. 7,485,623 [Patent Document 2] U.S. Patent No. 7,507,769 [Patent Document 3] U.S. Patent No. 7,704,516 [Patent Document 4] U.S. Patent No. 7,786,172 [Patent Document 5] U.S. Patent No. 7,968,532 [Patent Document 6] U.S. Patent No. 8,048,927 [Patent Document 7] U.S. Patent No. 9,333,190 [Patent Document 8] U.S. Patent No. 9,220,680 [Patent Document 9] U.S. Patent No. 9,090,640 [Patent Document 10] U.S. Patent No. 9,200,045 [Non-patent literature]

[0006] [Non-Patent Document 1] Mortimer et al. Breast Cancer Res Treat. 2008 Apr; 108(3): 421-426 [Non-patent document 2] Fauq et al., Bioorganic & Medicinal Chemistry Letters.20 (2010) 3036-3038 [Non-patent document 3] Stearns et al., J. Natl. Cancer Inst. Vol 95, No. 23, 2003 Summary of the Invention [Means for solving the problem]

[0007] Summary of the Invention Previous publications and prior patents and patent applications have described endoxifen free base and endoxifen salts developed for the treatment of subjects with breast cancer. U.S. Patent No. 9,333,190 describes enteric-coated tablets and capsules made with endoxifen citrate. Patent publications WO2019051416(A1) and WO2019051370(A1) describe methods for making (Z)-endoxifen and compositions using (Z)-endoxifen. WO2019051416(A1) describes enteric-coated (delayed-release) API in capsules, including (Z)-endoxifen free base, its crystalline forms / polymorphs, and salts, and WO2019051370(A1) describes topical compositions containing (Z)-endoxifen free base and its salts. None of these describe a matrix tablet-type sustained-release preparation involving (Z)-endoxifen or a polymorph or salt thereof, in which the active drug (Z)-endoxifen is released over an extended period of time, e.g., 4 to 24 hours or at least 2 hours to at least 72 hours.

[0008] The present disclosure provides novel sustained-release compositions comprising Z-endoxifen and its polymorphs and salts, and methods for making them. Non-limiting exemplary sustained-release compositions in the form of sustained-release tablets and enteric-coated delayed-release tablets and capsules are provided in the present disclosure. The sustained-release compositions of the present disclosure offer certain advantages: novel sustained-release (Z)-endoxifen compositions can be prepared by the methods disclosed herein, and such sustained-release compositions are stable even at low doses. The sustained-release compositions slowly and sustainably release (Z)-endoxifen or its polymorphs or salts, thereby achieving peak drug concentrations (C ) in the subject. max) can be controlled; high blood levels and / or accumulation in the subject can be avoided or controlled, thus reducing the potential for systemic and / or local side effects and toxicity. The sustained-release compositions of the present disclosure can be administered to a subject at lower doses, or as needed, to reduce side effects and ensure patient compliance. Furthermore, the enteric coating of the sustained-release compositions of the present disclosure provides surprisingly greater protection of (Z)-endoxifen by preventing the active (Z)-endoxifen form or reducing interconversion between the active (Z)-endoxifen form and its inactive form, (E)-endoxifen, in the stomach, resulting in greater amounts of (Z)-endoxifen being released in the intestine. The unexpected benefit of inhibiting this interconversion results in greater overall delivery of (Z)-endoxifen and also serves to provide a slower, more consistent release of the therapeutic agent. Targeting the small intestine, e.g., the duodenum and colon, using enteric-coated delayed-release compositions may increase the bioavailability of the drug in a subject, thus improving the drug's efficacy, and increase the likelihood that the composition will withstand the "food effect" (e.g., reducing vulnerability to physical irritation caused by eating). The enteric-coated delayed-release tablets and capsules of the present disclosure are protected from the acidic environment of the stomach and release Z-endoxifen and its polymorphs and salts in the small intestine and large intestine, e.g., at least 2 hours after ingestion of the dose.

[0009] In various aspects, the disclosure provides sustained release compositions comprising a therapeutic agent and a sustained release agent, wherein the therapeutic agent is (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, a salt of (Z)-endoxifen, or a combination thereof, and wherein the therapeutic agent has at least two dissolution percentage parameters selected from less than 20% dissolution percentage at 2 hours, less than 40% dissolution percentage at 7 hours, and at least 30% dissolution percentage at 12 hours, measured at 37°C in simulated gastric fluid at pH 1.2 for 0-2 hours and in simulated intestinal fluid at pH 6.8 after 2 hours.

[0010] In some embodiments, the therapeutic agent has at least three of the dissolution percentage parameters. In some embodiments, the therapeutic agent has a dissolution percentage of less than 35% at 3 hours. In some embodiments, the therapeutic agent has a dissolution percentage in the range of 35% to 55% at 12 hours. In some embodiments, the therapeutic agent has a dissolution percentage of at least 50% at 24 hours. In some embodiments, the therapeutic agent has a dissolution percentage in the range of 65% to 85% at 24 hours. In some embodiments, the sustained-release agent is selected from the group consisting of cellulose ethers, gums, acrylic resins, or combinations thereof.

[0011] In some embodiments, the sustained release agent is hydroxyalkyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or a combination thereof. In some embodiments, the sustained release agent is hypromellose.

[0012] In various aspects, the present disclosure provides sustained release compositions comprising a therapeutic agent and a sustained release agent, wherein the therapeutic agent is (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, a salt of (Z)-endoxifen, or a combination thereof, and the sustained release agent is selected from the group consisting of hydroxyalkyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose.

[0013] In some embodiments, the sustained release composition comprises at least 1% w / w, at least 10% w / w, at least 20% w / w, at least 25% w / w, at least 30% w / w, at least 35% w / w, or at least 40% w / w of the sustained release agent. In some embodiments, the sustained release composition comprises 1%-99% w / w of the sustained release agent. In some embodiments, the sustained release composition comprises 5%-90% w / w of the sustained release agent. In some embodiments, the sustained release composition comprises 5%-70% w / w of the sustained release agent. In some embodiments, the sustained release composition comprises 10%-40% w / w of the sustained release agent. In some embodiments, the sustained release composition comprises 15%-40% w / w of the sustained release agent. In some embodiments, the sustained release agent comprises 0.25%-10% w / w, 0.5%-8% w / w, or 1%-4% w / w of the therapeutic agent.

[0014] In some embodiments, at least 90% w / w, at least 95% w / w, or at least 99% w / w of the therapeutic agent is (Z)-endoxifen Form I, (Z)-endoxifen Form II, (Z)-endoxifen Form III, or a combination thereof.

[0015] In some embodiments, the sustained-release composition further comprises a binder, a lubricant, or a combination thereof. In some embodiments, the binder is a monosaccharide, a disaccharide, a starch, a polyhydric alcohol, mannitol, xylitol, sorbitol, lactose, polyethylene glycol, a gum, alginic acid, polyvinylpyrrolidone, methylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, crystalline cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, calcium carbonate, calcium phosphate, sodium carbonate, sodium phosphate, anhydrous calcium hydrogen phosphate, talc, dextrates, kaolin, mannitol, silicic acid, sorbitol, or a combination thereof. In some embodiments, the binder is microcrystalline cellulose. In some embodiments, the sustained-release composition comprises 1% to 99% w / w of the binder. In some embodiments, the sustained-release composition comprises 1% to 99% w / w of the binder. In some embodiments, the sustained-release composition comprises 30% to 97% w / w of the binder. In some embodiments, the sustained release composition comprises 40%-75% w / w of a binder, hi some embodiments, the sustained release composition comprises 50%-75% w / w of a binder.

[0016] In some embodiments, the lubricant is stearic acid, calcium stearate, magnesium stearate, zinc stearate, potassium stearate, hydrogenated vegetable oil, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycol, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, talc, ethyl oleate, ethyl laureate, agar, wax, or a combination thereof, hi some embodiments, the lubricant is magnesium stearate.

[0017] In some embodiments, the sustained-release composition further comprises an enteric coating encapsulating the tablet comprising the therapeutic agent and the sustained-release agent, the enteric coating comprising a delayed-release agent, a plasticizer, an anti-tack agent, or a combination thereof. In some embodiments, the enteric coating comprises 4% to 40% w / w of the sustained-release composition. In some embodiments, the enteric coating comprises 5% to 30% w / w of the sustained-release composition. In some embodiments, the enteric coating comprises 5% to 25% w / w of the sustained-release composition. In some embodiments, the enteric coating comprises 5% to 20% w / w of the sustained-release composition. In some embodiments, the enteric coating comprises 5% to 15% w / w of the sustained-release composition.

[0018] In some embodiments, the delayed release agent is present at 0.1% to 30% w / w of the enteric coating. In some embodiments, the delayed release agent is present at 5% to 25% w / w of the enteric coating. In some embodiments, the delayed release agent is present at 8% to 14% w / w of the enteric coating. In some embodiments, the delayed release agent is a polymethacrylate.

[0019] In some aspects, the sustained release composition further comprises a pharmaceutically acceptable excipient.

[0020] In various aspects, the present disclosure provides a sustained release composition comprising a tablet and an enteric coating encapsulating the tablet, wherein the tablet comprises a therapeutic agent and a sustained release agent, the enteric coating comprises a delayed release agent, a plasticizer, an anti-adherent agent, or a combination thereof, the therapeutic agent is (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, a salt of (Z)-endoxifen, or a combination thereof, and the sustained release agent is selected from the group consisting of hydroxyalkyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose.

[0021] In various aspects, the present disclosure provides a sustained release composition comprising a tablet and an enteric coating encapsulating the tablet, wherein the tablet comprises a therapeutic agent and hypromellose, the therapeutic agent comprises at least 90% (Z)-endoxifen, and the enteric coating comprises a poly(meth)acrylate polymer and triethyl citrate.

[0022] In some embodiments, the enteric coating further comprises talc. In some embodiments, the tablet comprises at least 20% w / w hypromellose based on the total tablet weight. In some embodiments, the tablet comprises 1% to 40% w / w of a therapeutic agent based on the total tablet weight. In some embodiments, the enteric coating comprises 60% to 80% w / w of a poly(meth)acrylate polymer based on the total enteric coating weight. In some embodiments, the enteric coating comprises 10% w / w or less of triethyl citrate based on the total enteric coating weight. In some embodiments, the enteric coating comprises 10% to 40% w / w of talc based on the total enteric coating weight.

[0023] In various aspects, the present disclosure provides methods for preparing sustained-release compositions, the methods comprising combining and mixing a therapeutic agent selected from (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, a salt of (Z)-endoxifen, and combinations thereof, a sustained-release agent, a binder, and a lubricant; and dry-compressing the therapeutic agent, at least one sustained-release agent, at least one binder, and at least one lubricant to form a core tablet.

[0024] In some embodiments, the method further includes forming a coating solution by combining and mixing at least one delayed-release agent, at least one plasticizer, and at least one anti-stick or anti-adhesion component; and forming a functional coating by substantially coating the core tablet with the coating solution.

[0025] In various aspects, the disclosure provides methods for administering a sustained release composition to a subject in need thereof, comprising orally administering the sustained release composition to a subject in need thereof, wherein the sustained release composition comprises a therapeutic agent and a sustained release agent, wherein the therapeutic agent is (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, a salt of (Z)-endoxifen, or a combination thereof, and wherein the sustained release composition is formulated such that less than 20% of the therapeutic agent dissolves within 2 hours after administration and at least 30% of the therapeutic agent dissolves within 12 hours after administration.

[0026] In some embodiments, the sustained release composition is formulated such that less than 40% of the therapeutic agent is dissolved 7 hours after administration.

[0027] In various aspects, the disclosure provides methods for administering a sustained release composition to a subject in need thereof, the method comprising orally administering the sustained release composition to a subject in need thereof, wherein the sustained release composition comprises a therapeutic agent and a sustained release agent, wherein the therapeutic agent is (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, a salt of (Z)-endoxifen, or a combination thereof, and wherein the sustained release composition is formulated such that less than 20% of the therapeutic agent dissolves in simulated gastric fluid after 2 hours and at least 30% of the therapeutic agent dissolves in simulated gastric fluid after 2 hours, followed by dissolution in simulated intestinal fluid after 10 hours.

[0028] In some embodiments, the sustained release composition is formulated such that less than 40% of the therapeutic agent dissolves in simulated gastric fluid after 2 hours, followed by dissolution in simulated intestinal fluid after 5 hours.

[0029] In various aspects, the disclosure provides methods of administering a sustained release composition to a subject in need thereof, comprising orally administering the sustained release composition to a subject in need thereof, wherein the sustained release composition comprises a therapeutic agent and a sustained release agent, wherein the therapeutic agent is (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, a salt of (Z)-endoxifen, or a combination thereof, and wherein the therapeutic agent exhibits a time to maximum observed concentration in the serum of the subject of at least 8 hours, at least 9 hours, at least 10 hours, at least 15 hours, at least 20 hours, or at least 24 hours.

[0030] In various aspects, the present disclosure provides a method of treating a subject in need thereof, wherein the subject is suffering from or at risk of suffering from a disorder, the method comprising administering to the subject a sustained release composition of the present disclosure.

[0031] In various aspects, the disclosure provides methods of treating a subject in need thereof, wherein the subject is suffering from or at risk of suffering from a disorder, the method comprising administering to the subject a sustained release composition comprising a therapeutic agent and a sustained release agent, wherein the therapeutic agent is (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, a salt of (Z)-endoxifen, or a combination thereof, and the sustained release agent is selected from the group consisting of hydroxyalkyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose.

[0032] In some embodiments, the disorder is a breast disorder. In some embodiments, the breast disorder is benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, dense breast tissue, gynecomastia, ductal carcinoma in situ, lobular carcinoma in situ, breast cancer, precocious puberty, or McCune-Albright syndrome. In some embodiments, the sustained-release composition is orally administered. In some embodiments, the therapeutic agent exhibits a time to peak observed concentration in the serum of a subject of at least 8 hours, at least 9 hours, at least 10 hours, at least 15 hours, at least 20 hours, or at least 24 hours.

[0033] In some embodiments, the sustained release composition is administered in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is a selective serotonin reuptake inhibitor. In some embodiments, the selective serotonin reuptake inhibitor is selected from the group consisting of citalopram, escitalopram, fluoxetine, paroxetine, sertraline, and vilazodone.

[0034] In some embodiments, the subject has a statistically significant change in the biomarker level in the subject's tissue or body fluid compared to the biomarker level in normal subjects. In some embodiments, the biomarker is selected from the group consisting of Ki-67, estrogen receptor, progesterone receptor, proliferating cell nuclear antigen, phosphorylated histone H3, p16, p12, beta-galactosidase, terminal deoxynucleotidyl transferase dUTP nick end labeling, and RNA sequencing, or a combination thereof. In some embodiments, the level of the biomarker in the subject's tissue decreases after administration of the sustained release composition. In some embodiments, the level of the biomarker in the subject's tissue increases after administration of the sustained release composition. In some embodiments, the tissue is a diseased tissue.

[0035] In some embodiments, the sustained release composition is administered to a subject for 14 to 40 days, 10 to 50 days, 10 to 40 days, 10 to 35 days, 10 to 30 days, 10 to 25 days, 12 to 50 days, 12 to 40 days, 12 to 35 days, 12 to 30 days, 12 to 25 days, 12 to 45 days, 12 to 30 days, 14 to 30 days, 14 to 50 days, 14 to 40 days, 14 to 35 days, 14 to 30 days, 14 to 25 days, 16 to 50 days, 16 to 40 days, 16 to 35 days, 16 to 30 days, 16 to 25 days, 18 to 50 days, 18 to 40 days, 18 to 35 days, 18 to 30 days, or 18 to 25 days. In some embodiments, the sustained release composition is administered once a day, twice a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once every seven days. In some embodiments, 1 mg to 4 mg, 2 mg to 4 mg, 2 mg to 6 mg, 2 mg to 8 mg, 1 mg to 10 mg, 1 mg to 12 mg, 1 mg to 16 mg, 2 mg to 10 mg, 2 mg to 12 mg, 2 mg to 16 mg, 3 mg to 10 mg, 3 mg to 12 mg, 3 mg to 16 mg, 4 mg to 10 mg, 4 mg to 12 mg, or 4 mg to 16 mg of the sustained release composition is administered to a subject per dose.

[0036] Incorporation by Reference 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.

[0037] 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 and accompanying drawings that set forth illustrative embodiments, in which the principles of the invention are utilized: [Brief explanation of the drawings]

[0038] [Figure 1]Figure 1 shows the dissolution and release percentage of (Z)-endoxifen from a sustained-release composition in the form of an extended-release tablet (uncoated) containing 4 mg of (Z)-endoxifen free base compared to a control (4 mg of delayed-release pure (Z)-endoxifen free base active pharmaceutical ingredient (API) in a capsule), as measured according to United States Pharmacopeia (USP) Method I. The release of (Z)-endoxifen upon dissolution of the composition was measured using high-performance liquid chromatography with ultraviolet detection (HPLC-UV).

[0039] [Figure 2] Figure 2 shows the dissolution and release percentage of (Z)-endoxifen from exemplary extended-release compositions in the form of extended-release tablets (uncoated) and enteric-coated delayed-release tablets containing 4 mg of (Z)-endoxifen free base, as measured according to USP method I. (Z)-endoxifen release upon dissolution of the compositions was measured using HPLC-UV.

[0040] [Figure 3] Figure 3 shows the dissolution and release percentage of (Z)-endoxifen from exemplary extended-release compositions in the form of low (80 N) and high (120 N) hardness enteric-coated delayed-release tablets containing 4 mg of (Z)-endoxifen free base, and a control (4 mg API in delayed-release (Z)-endoxifen capsules), as measured according to USP I method. (Z)-endoxifen release upon dissolution of the compositions was measured using HPLC-UV.

[0041] [Figure 4] Figure 4 shows the dissolution and release in mg of (Z)-endoxifen from the API in exemplary enteric-coated delayed-release tablets of low hardness (80 N) and high hardness (120 N) containing 4 mg of (Z)-endoxifen free base and control capsules in simulated intestinal fluid according to USP method I. (Z)-endoxifen release upon dissolution of the compositions was measured using HPLC-UV.

[0042] [Figure 5] Figure 5 shows the endoxifen isoform release profiles from an exemplary extended-release composition in the form of an enteric-coated delayed-release tablet containing 4 mg of (Z)-endoxifen free base, as measured according to the USP II (Paddle Apparatus II) method in simulated intestinal fluid. Endoxifen isoform ((Z) and (E)) release upon dissolution of the composition was measured using HPLC-UV.

[0043] [Figure 6] Figure 6 shows the dissolution and release percentage of Z-endoxifen from an exemplary extended-release composition in the form of an enteric-coated delayed-release tablet containing 4 mg of (Z)-endoxifen free base and a control (4 mg API in delayed-release (Z)-endoxifen capsules) as measured according to the USP II (Paddle Apparatus II) method in simulated intestinal fluid. (Z)-endoxifen release upon dissolution of the composition was measured using HPLC-UV.

[0044] [Figure 7] FIG. 7 is an X-ray powder diffraction (XRPD) pattern obtained from a sample of Form I of the compound of formula (III).

[0045] [Figure 8] FIG. 8 is an XRPD pattern obtained from a sample of Form I of the compound of formula (III).

[0046] [Figure 9] FIG. 9 is an XRPD pattern obtained from a sample of Form II of the compound of formula (III).

[0047] [Figure 10] FIG. 10 is an XRPD pattern obtained from a sample of Form II of the compound of formula (III).

[0048] [Figure 11]FIG. 11 is an XRPD pattern obtained from a sample of Form III of the compound of formula (III).

[0049] [Figure 12] Figure 12 shows the dissolution and release percentage of Z-endoxifen from an exemplary extended-release composition in the form of an enteric-coated delayed-release tablet containing 4 mg of (Z)-endoxifen free base (SRT 5Kp) 4 mg with a hardness of 5 Kp, CTM-SRT (used in Example 8), and a reference product / control (4 mg API in delayed-release (Z)-endoxifen capsules) as measured according to the USP II (Paddle Apparatus II) method in simulated intestinal fluid. (Z)-endoxifen release upon dissolution of the compositions was measured using HPLC-UV.

[0050] [Figure 13] Figure 13 shows the dissolution and release percentage of Z-endoxifen from an exemplary extended-release composition in the form of an enteric-coated delayed-release tablet of 12 Kp hardness containing 1 mg of (Z)-endoxifen free base and a reference product (4 mg API in delayed-release (Z)-endoxifen capsules) as measured according to the USP II (Paddle Apparatus II) method in simulated intestinal fluid. (Z)-endoxifen release upon dissolution of the composition was measured using HPLC-UV.

[0051] [Figure 14] Figure 14 shows the dissolution and release percentage of Z-endoxifen from an exemplary extended-release composition in the form of an enteric-coated delayed-release tablet of 11 Kp hardness containing 2 mg of (Z)-endoxifen free base and a reference product (4 mg API in delayed-release (Z)-endoxifen capsules) as measured according to the USP II (Paddle Apparatus II) method in simulated intestinal fluid. (Z)-endoxifen release upon dissolution of the composition was measured using HPLC-UV.

[0052] [Figure 15A]Figure 15A shows the mean plasma concentrations of (Z)-endoxifen on a linear scale from the time of dosing (Time 0) to 336 hours post-dose in fasted subjects who were orally administered a single dose of either 4 mg delayed-release (Z)-endoxifen capsules (Group 1) or 4 mg enteric-coated extended-release tablets with a tablet hardness of 13 Kp (Group 2). The mean plasma concentrations reflect the subjects' uptake of and systemic exposure to (Z)-endoxifen during the single-administered dose phase of the study described in Example 8, as measured in the subjects' plasma using a validated HPLC-MS method.

[0053] [Figure 15B] Figure 15B shows the mean plasma concentrations of (Z)-endoxifen on a semi-logarithmic scale from the time of dosing (Time 0) to 336 hours post-dose in fasted subjects who were orally administered a single dose of either 4 mg delayed-release (Z)-endoxifen capsules (Group 1) or 4 mg enteric-coated extended-release tablets with a tablet hardness of 13 Kp (Group 2). The mean plasma concentrations reflect the subjects' uptake of and systemic exposure to (Z)-endoxifen during the single-administration dose phase of the study described in Example 8, as measured in the subjects' plasma using a validated high-performance liquid chromatography-mass spectrometry (HPLC-MS) method.

[0054] [Figure 16A]Figure 16A shows on a linear scale the mean plasma concentrations of (Z)-endoxifen in fasted subjects who received daily oral doses of either 4 mg delayed-release (Z)-endoxifen capsules (Group 1) or 4 mg enteric-coated extended-release tablets with a tablet hardness of 13 Kp (Group 2) for 14 consecutive days during the multiple administration dose (MAD) phase of the clinical trial described in Example 8. Day 0 is Day 26 of the clinical trial of Example 8. Blood samples were drawn approximately 10 minutes to 1 hour prior to dosing for subjects on Days 26 (Day 0 in Figure 16), 32, and 39 of the study, and 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, and 168 hours after dosing on Day 39 of the study, and plasma (Z)-endoxifen and (E)-endoxifen were measured in the subjects' plasma using a validated HPLC-MS method.

[0055] [Figure 16B] Figure 16B shows the mean plasma levels of (Z)-endoxifen on a semi-logarithmic scale in fasting subjects who received daily oral dosing of either 4 mg delayed-release (Z)-endoxifen capsules (Group 1) or 4 mg enteric-coated extended-release tablets with a tablet hardness of 13 Kp (Group 2) for 14 consecutive days in the multiple administration dose (MAD) phase of the clinical trial described in Example 8.

[0056] [Figure 17] Figure 17 shows the mean plasma trough concentrations of (Z)-endoxifen on a linear scale in fasting subjects who received oral daily dosing of either 4 mg delayed-release (Z)-endoxifen capsules (Group 1) or 4 mg enteric-coated extended-release tablets with a tablet hardness of 13 Kp (Group 2) for 14 consecutive days in the multiple administration dose (MAD) phase of the clinical trial described in Example 8. DETAILED DESCRIPTION OF THE INVENTION

[0057] Detailed Description of the Invention Compounds are described using standard nomenclature. 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.

[0058] As used herein, the terms "a," "an," and "the" include plural referents unless the context dictates otherwise.

[0059] As used herein, the terms "active pharmaceutical ingredient," "active ingredient," "API," "drug," "active substance," "active substances," or "therapeutic agent" are used interchangeably to refer to a pharmaceutically active compound in a pharmaceutical composition. This term is in contrast to other ingredients in the composition, such as excipients, which are substantially or completely pharmaceutically inactive. Suitable active pharmaceutical ingredients (APIs) according to the present disclosure are those for which patient compliance issues with treatment of a particular disease, condition, or disorder exist, or for which such issues may potentially arise. Therapeutic agents, as used herein, include active compounds as well as their salts, prodrugs, and metabolites. As used herein, the term "drug" means a compound intended for use in the diagnosis, cure, mitigation, treatment, and / or prevention of disease in humans or other animals.

[0060] As used herein, "adjuvant therapy" refers to treatment following primary therapy that is administered to a subject at risk of recurrence. In the case of breast cancer or cancers of the reproductive system, adjuvant systemic therapy, such as with tamoxifen, is usually initiated shortly after primary therapy to delay recurrence, prolong survival, or cure the subject.

[0061] As used herein, the term "tamoxifen" refers to (Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine. Tamoxifen can also refer to the E isomer or a combination of the E and Z isomers.

[0062] As used herein, the term "endoxifen" refers to 4-hydroxy-N-desmethyl-tamoxifen. Endoxifen is the secondary active metabolite of tamoxifen.

[0063] As used herein and in the claims, the terms "comprising," "containing," and "including" are inclusive, open-ended, and do not exclude additional, unrecited elements, compositional components, or method steps. Thus, 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 of the present invention described herein in combination with one or more treatments. The treatments in the combination therapy can be any treatment, such as any prophylactic agent, additional therapeutic agent (examples such as chemotherapy and immunotherapy), radiation therapy, surgery, and the like. Combination can refer to the inclusion of a therapeutic or prophylactic agent in the same composition (e.g., in the same capsule, tablet, caplet, etc.) as the compositions of the present invention disclosed herein or in separate compositions (e.g., in two separate tablets). The separate compositions may be in different dosage forms or administered by different routes of administration. The use of the terms "combination therapy" and "in combination with" does not limit the order in which the compositions of the present invention and prophylactic and / or therapeutic agents and / or treatments described herein are administered to a subject in need thereof. The compositions of the present disclosure are administered to a subject in need thereof. or (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 hours, 8 hours, 12 hours, 6 months (m), 9 months, or 1 year prior to administration of one or more prophylactic and / or therapeutic agents or treatments to The combination therapy may be administered before, concurrently with, or after such administration (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 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 6 months (m), 9 months, or 1 year later). Combination therapy as used herein can also refer to the treatment of subjects suffering from a single disease or multiple diseases or conditions, such as prostate cancer and gynecomastia in men, or breast cancer and breast density in women.

[0065] As used herein, the term "test sample" refers to the blood sample taken from a subject.When a blood sample is taken from a subject, it is understood that the subject's blood, such as whole blood, plasma and / or serum, is used to determine the subject's endoxifen level and / or other biomarkers that can be measured or tested.As used herein, "plasma endoxifen" refers to the endoxifen level in a subject's test sample, unless otherwise specified, regardless of whether the test is carried out using whole blood, plasma and / or serum.

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

[0067] As used herein, the terms "pharmaceutically acceptable" or "pharmacologically acceptable" refer to a material, composition, or vehicle that is compatible with the other ingredients of a formulation and that does not produce substantially any adverse reaction, e.g., a toxic, allergic, or immunological reaction, when administered to a subject. They may be approved, for example, by a regulatory agency of the U.S. Federal or state government, or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeia, for use in animals, and more particularly, for use in humans.

[0068] As used herein, the term "pharmaceutically acceptable carrier" or "carrier" means a pharmaceutically acceptable material, composition, or 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 into or out of a tissue, organ, or part of the body or across the skin.

[0069] As used herein, the term "pharmaceutical composition" means a combination of an active agent (e.g., an active pharmaceutical compound or active pharmaceutical ingredient, API) with an inert or active carrier (e.g., a phospholipid) that makes the composition particularly suitable for diagnostic, prophylactic, or therapeutic use in vitro, in vivo, or ex vivo.

[0070] As used herein, "primary therapy" refers to the first line of treatment upon initial diagnosis of an estrogen hormone-dependent disorder or a breast disorder, or both, in a subject. Exemplary primary therapies may include surgery, various chemotherapy regimens, and radiation therapy.

[0071] As used herein, the terms "subject," "patient," "participant," and "individual" may be used interchangeably herein and may refer to a mammal, such as a human. Mammals also include pet animals, such as dogs, cats, laboratory animals, such as rats, mice, and farm animals, such as cows and horses. Unless otherwise specified, mammals may be of any sex or gender.

[0072] As used herein, the term "tamoxifen resistance" refers to a subject who receives daily tamoxifen administration for at least two days and has a plasma endoxifen level of less than 30 nM (e.g., less than 20 nM, less than 25 nM, or less than 30 nM). As used herein, the term "tamoxifen resistance" refers to two classes of resistance: (a) de novo resistance, i.e., non-response to tamoxifen therapy from the start of treatment, and (b) acquired resistance, i.e., non-response to tamoxifen therapy after initial response or after tamoxifen-dependent growth / stimulation growth, which continues to express estrogen receptors (Minsun Chang. Biomol. Ther. 20(3), 256-267 (2012)). Acquired resistance to tamoxifen can occur as early as 3 months to 1 year and as late as 5 to 10 years. As used herein, the term "reference plasma endoxifen level" refers to a value of 30 nM.

[0073] As used herein, the term "unit dosage form" refers to physically discrete units suitable as unitary dosages for subjects, each unit having a predetermined quantity of active material calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0074] Terms such as "include," "including," "contain," "containing," "has," or "having" and the like mean "comprising."

[0075] Pharmacokinetic (PK) parameters as used herein are defined and calculated as follows:

[0076] C max : Maximum observed plasma / serum concentration obtained directly from the data.

[0077] T max : Time to observed peak concentration obtained directly from the data. If peak plasma / serum concentration occurs at more than one time point, the first one is selected.

[0078] AUC 0-tlast or AUC last : Area under the plasma / serum concentration versus time curve, calculated using the linear trapezoidal rule from time 0 to time t (where t is the time of the last quantifiable concentration).

[0079] λz: terminal phase elimination rate constant obtained from the slope of the line fitted by linear least-squares regression through the end points of the logarithmic concentration-time profile.

[0080] AUC inf :(AUC 0-tlast +Ct last / λz)(where, Ct last is the final quantifiable concentration).

[0081] AUCtau : Area under the plasma / serum concentration versus time curve over the period between doses (tau), calculated using the linear trapezoidal rule.

[0082] t 1 / 2 : Apparent terminal half-life, calculated as (ln(2) / λz).

[0083] CL / F:(Dose / AUC inf ) the apparent total plasma / serum clearance of a drug after oral administration, calculated as (F) where F is the fraction of drug absorbed.

[0084] CL / F ss :(Dose / AUC tau ) the apparent total plasma / serum clearance of a drug after multiple oral doses, calculated as (F) where F is the fraction of drug absorbed.

[0085] V z / F: Apparent volume of distribution during the terminal phase after oral administration, calculated as (CL / F / λz).

[0086] C min : The lowest observed plasma / serum concentration over the inter-dose period obtained directly from the data.

[0087] C avg or C average :(AUC tau The mean plasma / serum concentration at steady state calculated as (tau / tau).

[0088] AI:(AUC tau Dose / AUC on day 39 inf The accumulation factor is calculated as the dose on day 1).

[0089] 100×(AUC inf -AUC 0-tlast ) / AUC inf AUC determined by extrapolation, determined as inf %AUC, which is part of extrap .

[0090] The term "bioavailability," as defined in (U.S.) Code of Federal Regulations, Title 21, Section 320, Section 1(a), refers to the rate and extent to which an active ingredient or moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability can be assessed by measurements intended to indicate the rate and extent to which the active ingredient or moiety becomes available at the site of action. For example, bioavailability can be measured as the amount of active ingredient in the blood (serum or plasma) as a function of time. AUC, C max or T max Pharmacokinetic parameters such as can be used to measure and assess bioavailability.

[0091] It is specifically understood that any numerical value recited herein includes every value from the lower value to the upper value, i.e., all possible combinations of numerical values ​​between the lowest and highest values ​​recited are considered to be expressly set forth herein, and all range endpoints are included within the range and independently combinable. For example, if a concentration range or beneficial range is recited as 1% to 50%, it is intended that values ​​such as 2% to 40%, 10% to 30%, 1% to 3%, 1.5% to 2.5%, etc. are also expressly recited herein. It is also understood that when a concentration or dose is recited as a specific value, such as 1 mg or 10 mg, or as "about 1 mg" or "about 10 mg," it is intended to include a variance of 10%. As another example, a concentration recited as 20% or "about 20%" is intended to include the value ±10%. As yet another example, when a ratio of 1:10-10:1 or "about 1:10 to about 10:1" is stated, it is intended that ratios such as 1:9-9:1, 1:8-8:1, 1:7-7:1, 1:6-6:1, 1:5-5:1, 1:4-4:1, 1:3-3:1, 1:2-2:1, 1:1-2:1, 0.9:10.1-10.1 to 0.9, or 2:5-3:5, etc., are specifically contemplated. These are only some examples of what is specifically contemplated. Unless otherwise specified, values ​​for components or ingredients of a composition are expressed as weight percent of each component or ingredient in the core composition.

[0092] All compounds are understood to include all possible isotopes of the atoms present 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 11 C. 13 C and 14 Contains C.

[0093] All methods described herein can be performed in any suitable order unless otherwise indicated or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as" and "the like") is intended to be merely illustrative of the invention and does not impose limitations on the scope of the invention, unless otherwise stated in the claims. As used herein, no language herein should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0094] As used herein, the term "hormone-dependent disorder" refers to any disorder that is related to or sensitive to hormones such as estrogen, estrogen receptor-positive (ER) disorders, including any hormone-dependent reproductive system disorder, breast disorders, endometriosis, uterine fibroids (also called leiomyomas), and hormone-dependent mood disorders. + ) and / or progesterone receptor positive (PR +(Z)-endoxifen or its polymorphs or salts. Reproductive system disorders include endometrial cancer, ovarian cancer, cervical cancer, uterine cancer, vaginal cancer, and vulvar cancer. The terms "estrogen-related disorder" and "estrogen receptor-related disorder" can be used interchangeably to refer to the aforementioned hormone-dependent disorders. Examples of hormone-dependent mood disorders include, but are not limited to, depression, mania, hypomania, bipolar disorder, and schizophrenia. Hormone-dependent disorders can present primarily or secondary to an underlying disease, such as prostate cancer or other disorders, such as liver disease. Hormone-dependent disorders include, for example, McCune-Albright syndrome, a disorder caused by mutations in the GNAS gene that affect bone, skin, and some hormone-producing (endocrine) tissues, often resulting in individuals with such mutations having abnormal scar-like (fibrous) tissue in their bones, a condition called multiple fibrous dysplasia, hyperthyroidism, and often leading to precocious puberty in girls.

[0095] 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 breast lesions (e.g., hyperplasia), dense breast tissue, gynecomastia, breast pain, McCune-Albright syndrome, and breast cancer. Benign breast lesions include, but are not limited to, hyperplasia, atypia, ductal hyperplasia, lobular hyperplasia, atypical ductal hyperplasia (ADH), and atypical lobular hyperplasia (ALH). While not cancerous, ADH and ALH may indicate a predisposition to breast cancer.

[0096] Breast density is a breast disorder identified by visual techniques such as mammography ("mammographic breast density" or "MBD"), magnetic resonance imaging ("MRI"), or X-ray, and represents an increase in fibroglandular tissue within the breast, e.g., an abnormal proliferation of stromal and epithelial cells in the breast. Breast density is classified as Class A (formerly Class I), B (formerly Class II), C (formerly Class III), or D (formerly Class IV) based on the amount or volume of dense tissue or the severity of the density (Wolfe JN. AJR Am J Roentgenol 1976;126:1130-1137). Whitehead et al., using data from the 1970s, demonstrated the existence of a masking effect due to density, but showed that it acts in addition to the differential risk of breast cancer associated with the breast pattern classifications described by Wolfe (Whitehead J, et al. Cancer 1985;56:1280-1286). Therefore, it is considered an independent breast cancer risk factor. At least 35 states in the United States require physicians to inform subjects if they have dense breasts. Subjects are reminded to make healthy lifestyle choices and undergo regular mammograms or other imaging to monitor changes in their breasts, but there are currently no approved treatments for dense breasts.

[0097] Gynecomastia is a common male breast condition characterized by increased breast tissue hyperplasia, 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). Neonatal gynecomastia usually resolves within the first four weeks of life, and at least half of adolescent boys experience gynecomastia, typically occurring between the ages of 13 and 14 years (Tanner stage 3 or 4). Gynecomastia has been proposed as a risk factor for male breast cancer.

[0098] Furthermore, gynecomastia often presents secondary to underlying disorders such as prostate cancer, cirrhosis and liver disease, male hypogonadism, hyperthyroidism, renal failure, and type 1 diabetes in patients undergoing hemodialysis. Furthermore, administered medications, such as antiandrogens or certain antipsychotics, have been reported to cause up to 25% of gynecomastia cases and can be categorized by their hormone-like effects. For example, the most common side effects attributed to bicalutamide, a nonsteroidal antiandrogen used to treat prostate cancer, are gynecomastia and breast pain.

[0099] As used herein, "breast cancer" refers to any malignant tumor of breast cells. Breast cancer may be at any stage of breast cancer, including precancerous, early stage, non-metastatic, pre-metastatic, locally advanced, and metastatic stages. There are several types of breast cancer. Exemplary breast cancers include 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), BRCA1 + Breast cancer, BRCA2 + Breast cancer includes, but is not limited to, adenoid cystic carcinoma, low-grade adenosquamatous carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, or micropapillary carcinoma. A single breast cancer tumor may be a combination of these types, or a mixture of invasive and non-invasive carcinoma. sustained release composition

[0100] The present disclosure relates to novel sustained-release compositions comprising (Z)-endoxifen and its polymorphs and salts as therapeutic agents. The sustained-release compositions of the present disclosure provide controlled release of a therapeutic agent or therapeutic agent over a longer period (e.g., at least 2 hours to about 72 hours, at least 4 hours to 24 hours, at least 6 hours to 48 hours, etc.). Approximately 2 hours after administration or ingestion of a dose, the sustained-release compositions of the present disclosure provide a prolonged release in the intestine after transit of the composition from the stomach, allowing uptake of the therapeutic agent ((Z)-endoxifen or its polymorph or salt) from the subject's intestine and / or colon into the bloodstream. The release rate of (Z)-endoxifen or its polymorph or salt from the sustained-release compositions (e.g., enteric-coated delayed-release tablets) is slower than the release rate observed for the reference product (capsules) described in WO2019051416A1 (Methods for making and using endoxifen). The sustained-release composition provides controlled or prolonged exposure of the subject to the therapeutic agent for a period of at least about 2 hours to about 270 hours per dose after administration. Thus, by reducing the frequency of administration and / or slowing the rate of uptake of the therapeutic agent into the bloodstream, the present disclosure offers the potential for improved or enhanced patient tolerance of the drug and improved patient convenience and compliance. The slow, prolonged release (or sustained release) and slow, prolonged (sustained) uptake of (Z)-endoxifen or its polymorphs or salts into the bloodstream may expose patients to lower peak drug concentrations over time, potentially resulting in reduced local and / or systemic side effects and toxicity, reduced drug accumulation, and / or a reduced total amount of drug for treatment compared to other dosage forms, such as reference products. Targeting the intestine (e.g., duodenum and pleurodendum) and colon by delaying drug release to protect against the acidic stomach environment also potentially improves bioavailability and the ability to withstand the "food effect," improving efficacy.

[0101] The present disclosure provides sustained release compositions and sustained release delivery systems comprising (Z)-endoxifen or a polymorph or salt thereof, the sustained release delivery systems including (i) at least one sustained release (SR) agent or release rate controlling agent ("sustained release agent" or "SR agent" used interchangeably herein), (ii) at least one binder, and (iii) at least one lubricant.

[0102] In one aspect, the present disclosure provides sustained-release compositions comprising stable (Z)-endoxifen free base and polymorphs and salts thereof. In some embodiments, the sustained-release compositions comprising (Z)-endoxifen free base or a polymorph or salt thereof further comprise (E)-endoxifen. In some embodiments, the sustained-release compositions comprise endoxifen primarily as (Z)-endoxifen free base.

[0103] In some embodiments, the sustained-release compositions of the present disclosure are in the form of solid dosage forms, such as tablets, minitablets, beads, microbeads, granules, spheres, particles, multiparticulates and the like.The present disclosure provides that the sustained-release compositions of the present disclosure can be enteric-coated for delayed release targeted to the intestine and colon.Therefore, in some embodiments, the sustained-release compositions are in the form of enteric-coated delayed-release tablets, enteric-coated delayed-release tablets in tablets, enteric-coated delayed-release tablets in capsules, beads in capsules, spheres in capsules and the like.

[0104] (Z)-endoxifen or a polymorph or salt thereof can be uniformly dispersed in the sustained release composition.

[0105] In certain embodiments, the sustained release composition comprises at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, 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%, and 100% (Z)-endoxifen as (Z)-endoxifen free base w / w relative to the total endoxifen in the sustained release composition. In at least one sustained-release composition, the sustained-release composition comprises ≥90% (Z)-endoxifen free base w / w relative to the total endoxifen in the sustained-release composition. In another embodiment, the sustained-release composition comprises ≥95% (Z)-endoxifen free base relative to the total endoxifen in the composition. In yet other embodiments, the sustained-release composition comprises ≥96%, ≥97%, ≥98%, ≥99%, ≥99.5%, or ≥99.9% (Z)-endoxifen free base w / w relative to the total endoxifen in the sustained-release composition.

[0106] In other embodiments, the sustained-release compositions comprise about 0.01% to about 40%, about 0.01% to about 20%, about 0.05% to about 15%, and about 0.1% to about 10% (Z)-endoxifen w / w, based on the sustained-release composition. In at least one embodiment, the sustained-release compositions comprising (Z)-endoxifen comprise 0.01% to 40% (Z)-endoxifen w / w, based on the sustained-release composition. In various other embodiments, the sustained-release compositions comprising (Z)-endoxifen comprise about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 0.1%, about 0.2%, about 0.3%, about 0.4 ... The sustained-release compositions contain 5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, and about 20% (Z)-endoxifen w / w. In some embodiments, the (Z)-endoxifen contained in the sustained-release compositions is substantially pure. Such sustained-release compositions may contain less than 5%, less than 4%, less than 3%, less than 2.5%, less than 2%, less than 1%, less than 0.5%, or less than 0.1% (E)-endoxifen. Such sustained-release compositions may contain less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of other contaminants.

[0107] In some embodiments, the sustained-release compositions of the present disclosure further comprise (E)-endoxifen. In some embodiments, the endoxifen in the sustained-release compositions has an (E)-endoxifen to (Z)-endoxifen ratio (E / Z ratio) of about 1:999, about 5:995, about 1:99, about 5:95, about 10:90, about 15:85, about 20:80, about 25:75, about 30:70, about 40:70, about 45:55, about 50:50, about 55:45, about 60:40, about 65:45, or about 70:30. In other embodiments, the sustained-release compositions comprise endoxifen with an E / Z ratio ranging from about 10:90 to about 70:30. In still other embodiments, the sustained-release compositions comprise endoxifen with an E / Z ratio ranging from about 45:55 to about 55:45.

[0108] Except as specifically referred to by the prefix (Z), (E), or (E / Z), endoxifen, as used generally without a prefix, is used herein to include any or all endoxifen isoforms. A mixture of (E)-endoxifen and (Z)-endoxifen can be represented by formula (III): [ka]

[0109] In one aspect, the present disclosure provides that the sustained release compositions of the present disclosure, in some embodiments, specifically comprise a polymorphic crystalline form of (Z)-endoxifen, e.g., Form I, Form II, or Form III, as described in applicant's patent publication WO2019051416(A1) (incorporated herein by reference).

[0110] In certain embodiments, the present disclosure provides crystalline forms of endoxifen, including crystalline forms of (Z)-endoxifen free base and crystalline forms of mixtures of (E)-endoxifen and (Z)-endoxifen. The present disclosure further provides pharmaceutical compositions of endoxifen comprising the crystalline forms described herein. Crystalline forms of endoxifen can offer bioavailability and stability advantages suitable for use as active ingredients in pharmaceutical compositions. Variability in the crystalline structure of a pharmaceutical drug substance or active ingredient can affect the dissolution rate (which can affect bioavailability, etc.), manufacturability (e.g., ease of handling, 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 variability can affect the preparation or formulation of pharmaceutical compositions in various dosage or delivery forms, such as solid oral dosage forms, including tablets and capsules. Compared with other forms, such as non-crystalline or amorphous forms, crystalline forms may provide desirable or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control. Thus, crystalline forms of endoxifen may provide advantages, such as improving the manufacturing process of the active agent or the stability or storability of the drug product form or active ingredient of the compound, and / or having suitable bioavailability and / or stability as an active agent.

[0111] It has been found that the use of certain solvents and fractional crystallization methods produces various polymorphic forms of endoxifen, including any one or more of polymorphic Forms I, II, and III, which may exhibit one or more of the favorable characteristics described above. In some embodiments, the polymorphic form (e.g., Form I, Form II, or Form III) may affect one or more properties of a composition comprising endoxifen. For example, the polymorphic form (e.g., Form I, Form II, or Form III) of a therapeutic agent (e.g., endoxifen) may affect the dissolution rate, solubility, absorption rate, C of the therapeutic agent in the compositions of the present disclosure. max ,AUC,T max or t1 / 2 In some embodiments, the polymorphic forms of endoxifen may impart one or more properties that favorably contribute to the manufacturability of the compositions of the present disclosure (e.g., sustained-release compositions comprising endoxifen). In some embodiments, the polymorphic forms of endoxifen may impart improved stability to the compositions of the present disclosure. Processes for the preparation of the polymorphs described herein, and characterization of these polymorphs, are described in more detail below. Formula III, Form I

[0112] In certain aspects, the present disclosure provides polymorphic Form I of compound of Formula (III), wherein at least 90% by weight of the compound of Formula (III) in a 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 7 or Figure 8. In some embodiments, polymorphic Form I has an XRPD pattern comprising at least two, at least three, at least four, at least five, or at least six major peaks such as the XRPD pattern substantially as shown in Figure 7 or Figure 8.

[0113] For example, the term "approximately as shown" when referring to an XRPD pattern includes patterns that are not necessarily identical to those depicted herein but that fall within experimental error limits or deviations contemplated by one of ordinary skill in the art. The relative intensities of XRPD peaks can vary depending on particle size, sample preparation method, sample mounting procedure, and the particular instrument used. Furthermore, instrumental variations and other factors can affect 2-theta (2θ) values. Thus, when a specified 2-theta angle is provided, it is understood that the specified 2-theta angle can vary by ±0.5°, e.g., ±0.4°, ±0.3°, ±0.2°, or ±0.1°, from the specified value. As used herein, a "major peak" refers to an XRPD peak having a relative intensity greater than 30%, e.g., greater than 35%. 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.

[0114] In certain embodiments, polymorphic Form I is characterized by an X-ray powder diffraction pattern comprising major peaks at 2-theta 16.8±0.3°, 17.1±0.3°, and 21.8±0.3°. In some embodiments, polymorphic Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 2-theta 16.0±0.3°, 18.8±0.3°, and 26.5±0.3°. In some embodiments, polymorphic Form I is characterized by an X-ray powder diffraction pattern comprising major peaks at 2-theta 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° and at least one peak selected from 2-theta 16.0±0.3°, 18.8±0.3°, and 26.5±0.3°. In some embodiments, polymorph Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 2-theta 12.3±0.3°, 28.0±0.3°, and 29.0±0.3°. In some embodiments, polymorph Form I is characterized by an X-ray powder diffraction pattern comprising major peaks at 2-theta 16.8±0.3°, 17.1±0.3°, and 21.8±0.3°, and at least one peak selected from 2-theta 12.3±0.3°, 28.0±0.3°, and 29.0±0.3°. 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° two-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° two-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° two-theta, and peaks at 12.3±0.3°, 16.0±0.3°, 18.8±0.3°, 26.5±0.3°, 28.0±0.3°, and 29.0±0.3° two-theta.

[0115] In certain embodiments, the present disclosure provides compositions comprising polymorphic Form I. Greater than 90%, 95%, or 99% by weight of the compound of Formula (III) in the composition can be polymorphic Form I. 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. Formula III, Form II

[0116] In certain aspects, the present disclosure provides polymorphic Form II of the compound of Formula (III), wherein the composition comprises the (E)-isomer and the (Z)-isomer of the compound of Formula (III) (i.e., (E)-endoxifen and (Z)-endoxifen) in an E / Z ratio of between 0.9 and 1.3, e.g., about 1.1. In some embodiments, polymorphic Form II exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 9 or Figure 10. In some embodiments, polymorphic Form II has an XRPD pattern comprising at least two, at least three, at least four, at least five, or at least six major peaks such as the XRPD pattern substantially as shown in Figure 9 or Figure 10.

[0117] In certain embodiments, polymorphic Form II is characterized by an X-ray powder diffraction pattern comprising major peaks at 2-theta angles of 7.0±0.3°, 11.9±0.3°, 14.3±0.3°, and 18.4±0.3°. In some embodiments, polymorphic Form II is characterized by an X-ray powder diffraction pattern comprising major peaks at 2-theta angles of 7.0±0.3°, 11.9±0.3°, 14.0±0.3°, and 18.4±0.3°, and a peak at 2-theta angle of 22.0±0.3°. In some embodiments, polymorphic Form II is characterized by an X-ray powder diffraction pattern comprising at least one peak selected from 2-theta angles of 6.6±0.3°, 13.3±0.3°, and 20.0±0.3°. In some embodiments, polymorph Form II is characterized by an X-ray powder diffraction pattern comprising major peaks at 2-theta 7.0±0.3°, 11.9±0.3°, 14.0±0.3°, and 18.4±0.3°, and at least one peak selected from 2-theta 6.6±0.3°, 13.3±0.3°, and 20.0±0.3°. In some embodiments, polymorph Form II is characterized by an X-ray powder diffraction pattern comprising major peaks at 2-theta 7.0±0.3°, 11.9±0.3°, 14.0±0.3°, and 18.4±0.3°, and at least one peak selected from 2-theta 6.6±0.3°, 13.3±0.3°, 20.0±0.3°, and 22.0±0.3°. 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° two-theta, and peaks at 6.6±0.3°, 13.3±0.3°, 20.0±0.3°, and 22.0±0.3° two-theta.

[0118] In certain embodiments, the present disclosure provides a composition comprising polymorphic Form II. More than 90%, 95%, or 99% by weight of the compound of Formula (III) in the composition may be 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. Formula III, Form III

[0119] In certain aspects, the present disclosure provides polymorphic Form III of the compound of Formula (III), wherein the composition comprises the (E)-isomer and the (Z)-isomer of the compound of Formula (III) (i.e., (E)-endoxifen and (Z)-endoxifen) in an E / Z ratio of between 0.9 and 1.3, e.g., about 1.1. In some embodiments, polymorphic Form III exhibits an X-ray powder diffraction (XRPD) pattern approximately like or as shown in Figure 11. In some embodiments, polymorphic Form III has an XRPD pattern comprising at least two, at least three, at least four, at least five, or at least six major peaks, such as an XRPD pattern approximately like or as shown in Figure 11.

[0120] In certain embodiments, polymorphic Form III is characterized by an X-ray powder diffraction pattern comprising major peaks at 2-theta angles of 11.9±0.3°, 13.9±0.3°, 17.1±0.3°, and 17.7±0.3°. In some embodiments, polymorphic Form III is characterized by an X-ray powder diffraction pattern comprising major peaks at 2-theta angles of 11.9±0.3°, 13.9±0.3°, 17.1±0.3°, and 17.7±0.3°, and a peak at 2-theta angle of 25.3±0.3°. In some embodiments, polymorphic Form III is characterized by an X-ray powder diffraction pattern comprising at least one peak selected from 2-theta angles of 18.2±0.3°, 22.5±0.3°, and 26.8±0.3°. In some embodiments, polymorph Form III is characterized by an X-ray powder diffraction pattern comprising major peaks at 2-theta angles of 11.9±0.3°, 13.9±0.3°, 17.1±0.3°, and 17.7±0.3°, and at least one peak selected from 2-theta angles of 18.2±0.3°, 22.5±0.3°, and 26.8±0.3°. In some embodiments, polymorph Form III is characterized by an X-ray powder diffraction pattern comprising major peaks at 2-theta angles of 11.9±0.3°, 13.9±0.3°, 17.1±0.3°, and 17.7±0.3°, and at least one peak selected from 2-theta angles of 18.2±0.3°, 22.5±0.3°, 25.3±0.3°, and 26.8±0.3°. 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° two-theta, and peaks at 18.2±0.3°, 22.5±0.3°, 25.3±0.3°, and 26.8±0.3° two-theta.

[0121] In certain embodiments, the present disclosure provides a composition comprising polymorphic Form III. More than 90%, 95%, or 99% by weight of the compound of Formula (III) in the composition may be 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.

[0122] The terms "crystalline form," "polymorph," and "form" may be used interchangeably herein and are intended to include all crystalline and amorphous forms of a compound, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, nonsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, and mixtures thereof, unless a specific crystalline or amorphous form is referenced. Compounds of the present disclosure include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, nonsolvated polymorphs (including hydrates), conformational polymorphs, and amorphous forms, and mixtures thereof.

[0123] In some embodiments, the sustained-release composition comprises (Z)-endoxifen predominantly as polymorphic Form I. In some embodiments, the sustained-release composition comprises (Z)-endoxifen predominantly as polymorphic Form II. In some embodiments, the sustained-release composition comprises (Z)-endoxifen predominantly as polymorphic Form III. In certain embodiments, the (Z)-endoxifen can be any combination of Forms I, II, and III.

[0124] In certain embodiments, the sustained release composition comprises (Z)-endoxifen w / w of at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.99%, or 100% of a single endoxifen polymorphic form, e.g., Form I, Form II, or Form III, relative to the total endoxifen in the sustained release composition. For example, the sustained release composition can contain (Z)-endoxifen as Form I in an amount of at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.99%, or 100% w / w of total endoxifen in the sustained release composition.In another example, the sustained release composition can contain (Z)-endoxifen as Form II in an amount of at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.99%, or 100% w / w of the total endoxifen in the sustained release composition. In another example, the sustained release composition can contain (Z)-endoxifen as Form III in an amount of at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.99%, or 100% w / w of the total endoxifen in the sustained release composition.

[0125] In at least one sustained-release composition, the composition contains ≥90% w / w of a single polymorphic form of endoxifen, such as Form I, Form II, or Form III, relative to the total endoxifen in the sustained-release composition. For example, the sustained-release composition contains ≥90% w / w of Form I of endoxifen relative to the total endoxifen in the sustained-release composition. In another example, the sustained-release composition contains ≥90% w / w of Form II of endoxifen relative to the total endoxifen in the sustained-release composition. In another example, the sustained-release composition contains ≥90% w / w of Form III of endoxifen relative to the total endoxifen in the sustained-release composition. In another embodiment, the sustained-release composition contains ≥95% w / w of a single polymorphic form of endoxifen, such as Form I, Form II, or Form III, relative to the total endoxifen in the sustained-release composition. In yet another embodiment, the sustained-release composition contains ≥96%, ≥97%, ≥98%, ≥99%, or ≥99.5% w / w of a single polymorphic form of endoxifen, such as Form I, Form II, or Form III, relative to the total endoxifen in the sustained-release composition. For example, the sustained-release composition contains ≥96%, ≥97%, ≥98%, ≥99%, or ≥99.5% w / w of Form I endoxifen relative to the total endoxifen in the sustained-release composition. In another example, the sustained-release composition contains ≥96%, ≥97%, ≥98%, ≥99%, or ≥99.5% w / w of Form II endoxifen relative to the total endoxifen in the sustained-release composition. In another example, the sustained-release composition contains ≥96%, ≥97%, ≥98%, ≥99%, or ≥99.5% w / w of Form III endoxifen relative to the total endoxifen in the sustained-release composition. When a specified weight percentage of endoxifen is a single polymorphic form, the remainder of the endoxifen in the sustained-release composition is some combination of amorphous endoxifen and / or one or more polymorphic forms of endoxifen, not including that single polymorphic form. When polymorphic endoxifen is defined as one particular form of endoxifen, the remainder is made up of amorphous endoxifen and / or one or more polymorphic forms other than the specified particular form.Examples of single polymorphic forms include endoxifen Forms I, II, and III, as well as descriptions of single polymorphic forms characterized by one or more properties as described in applicant's patent publication WO2019051416(A1).

[0126] In other embodiments, sustained release compositions comprising (Z)-endoxifen comprise, by weight of the sustained release composition, about 0.01% to about 20%, about 0.05% to about 15%, or about 0.1% to about 10% of a single polymorphic form of endoxifen, such as Form I, Form II, or Form III. In at least one embodiment, sustained release compositions comprising (Z)-endoxifen comprise, by weight of the composition, about 0.01% to about 20% of a single polymorphic form of endoxifen, such as Form I, Form II, or Form III. In various other embodiments, sustained release compositions comprising endoxifen comprise about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, or about 20% of a single polymorphic form of endoxifen, such as Form I, Form II, or Form III, w / w of the sustained release composition. In some aspects, sustained release compositions comprising a single polymorphic form of (Z)-endoxifen, such as Form I, Form II, or Form III, further comprise a second polymorphic form of endoxifen.

[0127] In one aspect, a sustained-release composition comprises a polymorphic form of (Z)-endoxifen in an amount ranging from about 0.1 mg to about 200 mg per unit dose. In various embodiments, the sustained-release composition comprises 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, and 40 mg of a polymorphic form of (Z)-endoxifen, such as Form I, Form II, or Form III, or a combination thereof. For example, the sustained-release composition can comprise 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, and 40 mg of Form I of (Z)-endoxifen. In another example, a sustained release composition can contain 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, and 40 mg of Form II (Z)-endoxifen. In another example, a sustained release composition can contain 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, and 40 mg of Form III (Z)-endoxifen. In some embodiments, the sustained release composition may contain 0.1 mg to 1 mg, 0.1 mg to 2 mg, 0.1 mg to 3 mg, 0.1 mg to 4 mg, 0.1 mg to 5 mg, 1 mg to 2 mg, 1 mg to 3 mg, 1 mg to 4 mg, 1 mg to 5 mg, 1 mg to 6 mg, 1 mg to 7 mg, 1 mg to 8 mg, 1 mg to 9 mg, 1 mg to 10 mg, 5 mg to 6 mg, 5 mg to 7 mg, 5 mg to 8 mg, 5 mg to 9 mg, 5 mg to 10 mg, 5 mg to 15 mg, 5 mg to 20 mg, 5 mg to 40 mg, 10 mg to 15 mg, 10 mg to 20 mg, or 10 mg to 40 mg of (Z)-endoxifen in a polymorphic form such as Form I, Form II, or Form III, or a combination thereof.

[0128] Examples of (Z)-endoxifen salts suitable for the sustained-release compositions of the present disclosure include pharmacologically acceptable salts, such as salts with inorganic acids, salts with organic acids, salts with amino acids, and the like. Examples of (Z)-endoxifen salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. In some embodiments, the present disclosure provides (Z)-endoxifen salts with inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.

[0129] Examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.

[0130] Examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, citric acid, and the like. In some embodiments, the present disclosure provides (Z)-endoxifen salts with aspartic acid, citric acid, or glutamic acid.

[0131] Examples of anionic salts of (Z)-endoxifen include arecoline, besylate, bicarbonate, bitartarate, butyl bromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaptanoate, isethionate, malate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, teoclate, and triethiodide.

[0132] Examples of cationic salts of (Z)-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, and the like.

[0133] In some embodiments, the present disclosure provides that the embodiments include salts made with non-pharmaceutically acceptable acids.

[0134] The present disclosure provides that in some embodiments, the sustained release composition is selected from the group consisting of acetate, arecoline, benzathine, benzoate, besylate, benzosulfonate, bicarbonate, bitartrate, butyl bromide, citrate, camsylate, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, formate, fumarate, glucolate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaptanoate, isethionate, malate, maleate, mandelate, meglumine, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, mucate, naphthyl benzoate ... The present invention provides a method for treating endoxifen comprising administering to a subject therapies ...

[0135] In some embodiments, the present disclosure provides sustained-release compositions comprising a pharmaceutically acceptable salt of (Z)-endoxifen. In certain embodiments, sustained-release compositions are provided herein that comprise 1%, 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or 100% (Z)-endoxifen salt w / w relative to total endoxifen. In some embodiments, the sustained-release compositions comprise ≧90%, ≧95%, ≧96%, ≧97%, ≧98%, ≧99%, ≧99.5%, ≧99.9%, ≧99.99%, or 100% (Z)-endoxifen salt w / w relative to total endoxifen. In certain embodiments, provided herein are sustained release compositions comprising 1%, 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99% or 100% of the composition an (Z)-endoxifen salt. In some embodiments, the sustained release composition comprises between 1% and 50%, 5% and 50%, 10% and 50%, 15% and 50%, 20% and 50%, 25% and 50%, 30% and 50%, 35% and 50%, 40% and 50%, 45% and 50%, 20% and 80%, 25% and 80%, 30% and 80%, 35% and 80%, 40% and 80%, 45% and 80%, 50% and 80%, 55% and 80%, 60% and 80%, 65% and 80%, 70% and 80%, 50% and 90%, 55% and 90%, 60% and 90%, 65% and 90%, 70% and 90%, 75% and 90%, or 80% and 90% of the (Z)-endoxifen salt by weight of the composition.

[0136] In some embodiments, the salt is (Z)-endoxifen gluconate. The endoxifen gluconate may be selected from the group consisting of (Z)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, or a combination thereof.

[0137] In some embodiments, the sustained-release composition comprising endoxifen gluconate is comprised of 10% to 100% (Z)-endoxifen D-gluconate on a w / w basis relative to the total endoxifen gluconate in the sustained-release composition. In some embodiments, the sustained-release composition comprising (Z)-endoxifen gluconate is comprised of 10% to 100% (Z)-endoxifen L-gluconate on a w / w basis relative to the total endoxifen in the sustained-release composition.

[0138] In other embodiments, the sustained release compositions comprising endoxifen gluconate are comprised of 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% and 100% (Z)-endoxifen D-gluconate or (Z)-endoxifen L-gluconate relative to the total endoxifen gluconate. In some embodiments, the sustained release 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%, and at least 99.99% (Z)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, or a combination thereof.

[0139] In some embodiments, provided herein are sustained-release compositions comprising (Z)-endoxifen D-gluconate and (E)-endoxifen D-gluconate, which may be present in the sustained-release composition in a ratio ranging from 10:90 to 99:1 w / w, respectively. In some embodiments, the ratio of (Z)-endoxifen D-gluconate to (E)-endoxifen D-gluconate is 10:90 to 99:1 (w / w), respectively (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). In certain embodiments, the ratio (w / w) of (Z)-endoxifen D-gluconate to (E)-endoxifen D-gluconate is 90:10, 91:9, 92:8, 93:7, 94:8, 95:5, 96:4, 97:3, 98:2, and 99:1, 99.5:0.5, or 99.99:0.01, respectively. Those of skill in the art will recognize that other combinations of endoxifen gluconate isomers are encompassed by the present disclosure.

[0140] In some embodiments, the sustained release compositions comprising endoxifen gluconate include 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% and 20% (Z)-endoxifen D-gluconate (w / w) of the sustained release composition. In some embodiments, the sustained release compositions comprising endoxifen gluconate include 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% and 20% (Z)-endoxifen L-gluconate (w / w) of the sustained release composition.

[0141] The amount of (Z)-endoxifen or a polymorph or salt thereof in the sustained-release compositions of the present disclosure will vary depending on the sustained-release composition's dosage form, the target disease, the severity of the disease, and the like, but will generally be an amount corresponding to or equivalent to about 0.01 mg to about 200 mg of (Z)-endoxifen. Those skilled in the art will understand that when the sustained-release composition includes a salt of (Z)-endoxifen, the endoxifen salt will be present in an equivalent amount based on the released (Z)-endoxifen.

[0142] In some embodiments, (Z)-endoxifen or a polymorph or salt thereof is present in the sustained-release compositions of the present disclosure in an amount ranging from about 0.01 mg to about 200 mg, about 0.1 mg to about 150 mg, about 0.5 mg to about 100 mg, about 0.5 mg to about 40 mg, about 0.5 mg to about 20 mg, about 1 mg to about 10 mg, or about 20 mg to about 100 mg per unit dose. In some embodiments, (Z)-endoxifen or a polymorph or salt thereof is present in the sustained-release compositions of the present disclosure in an amount ranging from about 0.1 mg to about 40 mg or about 0.5 mg to about 20 mg per unit dose. In some embodiments, (Z)-endoxifen or a polymorph or salt thereof is present in the sustained release compositions of the present disclosure in an amount of about 0.1 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg per unit dose.

[0143] (Z)-Endoxifen and its polymorphs and salts can be diluted with diluents commonly used in the medical field, food field and the like.

[0144] It will be understood by those skilled in the art that the amount of (Z)-endoxifen polymorphs and salts will be present in the sustained release compositions in an amount equivalent on a molar basis to the pharmacologically active (Z)-endoxifen free form.

[0145] In certain aspects, the present disclosure provides that the sustained-release compositions of the present disclosure exhibit sustained release of the drug (Z)-endoxifen or a polymorph or salt thereof from the sustained-release compositions over a period of about 2 hours to about 72 hours. In some embodiments, the sustained-release compositions of the present disclosure exhibit sustained release of the drug (Z)-endoxifen or a polymorph or salt thereof from the sustained-release compositions over a period of about 4 hours to about 24 hours or more. In some embodiments, the sustained-release compositions of the present disclosure sustainably release (Z)-endoxifen or a polymorph or salt thereof over a period of at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 24 hours, at least 48 hours, and at least 72 hours. In some embodiments, the sustained-release (Z)-endoxifen or a polymorph or salt thereof is released over a period of 6 hours to 48 hours. In some embodiments, (Z)-endoxifen or a polymorph or salt thereof is released from the sustained-release composition about 2 hours after administration for a period ranging from about 2 hours to about 72 hours. In some embodiments, about 2 hours after administration, (Z)-endoxifen or a polymorph or salt thereof is released from the sustained-release composition for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, and about 24 hours. In some embodiments, the release rate of the therapeutic agent ((Z)-endoxifen or a polymorph or salt thereof) is slower, more sustained, or more prolonged than the release rate of a reference product, which is an enterically resistant delayed-release (Z)-endoxifen capsule as set forth herein of the present disclosure ("capsule" or "control," used interchangeably herein).

[0146] In dissolution testing of certain sustained release compositions of the present disclosure performed according to USP I method, the sustained release compositions exhibit percentage dissolution ranging from about 0% to 35% at 3 hours, from about 35% to about 55% at 12 hours, and from about 65% to 85% at 24 hours in a dissolution test according to 75 RPM USP I method using simulated gastric fluid at pH 1.2 at 37°C for 2 hours and simulated intestinal fluid at pH 6.8 at 37°C for 24 hours as test media.

[0147] A method for measuring the dissolution of a composition (e.g., a sustained-release composition) can include measuring dissolution in an acidic phase (e.g., simulated gastric fluid) followed by a buffer phase (e.g., simulated intestinal fluid). The acidic phase can include placing 750 mL of 0.1 N hydrochloric acid in a container and assembling an apparatus (e.g., a paddle or basket apparatus). The medium can be allowed to equilibrate to a temperature of 37±0.5°C. One dosage unit can be placed in the apparatus, the container can be capped, and the apparatus can be run at a specified speed. After two hours of operation in 0.1 N hydrochloric acid, an aliquot of the fluid can be withdrawn. The method can then proceed immediately according to the instructions under the buffer stage. Analysis of the aliquot can be performed using a suitable assay method. While the apparatus is running at a specified speed, 250 mL of 0.20 M tribasic sodium phosphate equilibrated to 37±0.5°C can be added to the fluid in the container. The fluid can be adjusted to a pH of 6.8±0.05 with 2N hydrochloric acid or 2N sodium hydroxide, as needed. The device can be allowed to run for 45 minutes or a specified time period. At the end of that time period, an aliquot of the fluid can be withdrawn and analyzed using a suitable assay method.

[0148] In some embodiments, dissolution percentages are measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 for 0-2 hours at 37°C and in simulated gastric fluid at pH 6.8 after 2 hours at 37°C. Dissolution percentages refer to the percentage by weight of the composition dissolved. Dissolution percentages refer to the weight percent dissolved (Z)-endoxifen or a polymorph or salt thereof during a dissolution study. As a non-limiting example, if a tablet contains 4 mg of (Z)-endoxifen and 1 mg of (Z)-endoxifen is dissolved in solution at the 3-hour time point during a dissolution study, the dissolution percentage at 3 hours is 25%. Dissolution percentages can be determined, for example, by high-pressure liquid chromatography.

[0149] In some embodiments, the sustained release composition has a dissolution percentage in the range of about 5% to about 35%, about 10% to about 15%, about 20% to about 25%, about 30% to about 35%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, or about 30% to about 35% at 3 hours as measured by the 75 rpm USP paddle method at 37°C for 0-2 hours in simulated gastric fluid, pH 1.2, and after 2 hours in simulated intestinal fluid, pH 6.8, at 37°C.

[0150] In some embodiments, the sustained release composition has a dissolution percentage at 2 hours of about 5% or less, about 10% or less, about 15% or less, about 20% or less, about 25% or less, about 30% or less, about 35% or less, about 40% or less, about 45% or less, or about 50% or less, as measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 for 0-2 hours at 37° C. and after 2 hours in simulated intestinal fluid at pH 6.8 at 37° C. In some embodiments, the sustained release composition has a dissolution percentage at 3 hours of at most (NMT) about 30%, NMT about 25%, NMT about 20%, NMT about 15%, NMT about 10%, or NMT about 5%.

[0151] In some embodiments, the sustained release composition has a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of less than about 5% at 2 hours and in the range of about 5% to about 80%, about 10% to about 75%, about 20% to about 70%, about 30% to about 65%, about 5% to about 75%, about 5% to about 70%, about 5% to about 60%, about 5% to about 65%, about 5% to about 60%, about 10% to about 55%, about 5% to about 50%, about 30% to about 80%, about 25% to about 75%, about 35% to about 80%, or at least about 70% at 3 hours, as measured by the 75 rpm USP paddle method at 37°C for 0-2 hours in simulated gastric fluid, pH 1.2, and after 2 hours in simulated intestinal fluid, pH 6.8, at 37°C.

[0152] In some embodiments, the sustained release composition has a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 31%, less than about 32%, less than about 33%, less than about 34%, less than about 35%, less than about 36%, less than about 37%, less than about 38%, less than about 39%, or less than about 40% at 7 hours as measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 at 37°C for 0-2 hours and in simulated intestinal fluid at pH 6.8 at 37°C after 2 hours.

[0153] In some embodiments, the sustained release composition has a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of less than about 5% at 2 hours and in the range of about 70% to about 99%, about 75% to about 95%, about 85% to about 95%, about 90% to about 95%, about 75% to about 90%, about 85% to about 90%, about 75% to about 85%, about 80% to about 99%, about 85% to about 99%, about 90% to about 99%, about 95% to about 99%, about 95% to about 99%, or at least about 95% at 6 hours, as measured by the 75 rpm USP paddle method at 37°C for 0-2 hours in simulated gastric fluid at pH 1.2 and after 2 hours in simulated intestinal fluid at 37°C at pH 6.8.

[0154] In some embodiments, the sustained release composition has a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of less than about 5% at 2 hours and at least (NLT) about 20%, about 25%, about 30%, about 35% or about 40% at 6 hours.

[0155] In some embodiments, the sustained release composition has a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of less than about 5% at 2 hours and NLT about 40%, about 45%, about 50%, about 55% or about 60% at 9 hours.

[0156] In some embodiments, the sustained release composition has a dissolution percentage in the range of about 35% to about 55%, about 40% to about 55%, about 45% to about 55%, about 50% to about 55%, about 35% to about 50%, about 35% to about 45%, about 35% to about 40%, about 35% to about 40%, about 40% to about 45%, about 45% to about 50%, or about 50% to about 55% at 12 hours as measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 at 37°C for 0-2 hours and in simulated intestinal fluid at pH 6.8 at 37°C after 2 hours.

[0157] In some embodiments, the sustained release composition has a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of less than 20% at 2 hours and a dissolution percentage of at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% at 12 hours, as measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 at 37°C for 0-2 hours and in simulated intestinal fluid at pH 6.8 at 37°C after 2 hours.

[0158] In some embodiments, the sustained release composition has a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of less than about 20% at 2 hours and a dissolution percentage of at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% at 24 hours, as measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 at 37°C for 0-2 hours and in simulated intestinal fluid at pH 6.8 at 37°C after 2 hours.

[0159] In some embodiments, the sustained release composition has a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of less than about 5% at 2 hours and about 70% to about 99%, about 75% to about 95%, about 85% to about 95%, about 90% to about 95%, about 75% to about 90%, about 85% to about 90%, about 75% to about 85%, about 80% to about 99%, about 85% to about 99%, about 90% to about 99%, about 95% to about 99%, or about 100% at 12 hours, as measured by the 75 rpm USP paddle method at 37°C for 0-2 hours in simulated gastric fluid at pH 1.2 and after 2 hours in simulated intestinal fluid at 37°C at pH 6.8.

[0160] In some embodiments, the sustained-release composition has a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of less than about 5% at 2 hours and about 55% to about 90%, about 60% to about 85%, or about 70% to about 80% at 14 hours, as measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 for 0-2 hours at 37° C. and in simulated intestinal fluid at pH 6.8 after 2 hours at 37° C. In some embodiments, the sustained-release composition has a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of less than about 5% at 2 hours and NLT about 70%, about 75%, about 80%, about 85%, or about 90% at 14 hours.

[0161] In some embodiments, the sustained release composition has a dissolution percentage in the range of about 65% to about 85%, about 70% to about 85%, about 75% to about 85%, about 80% to about 85%, about 65% to about 80%, about 65% to about 75%, about 65% to about 70%, about 65% to about 70%, about 70% to about 75%, about 75% to about 80%, or about 80% to about 85% at 24 hours as measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 at 37°C for 0-2 hours and in simulated intestinal fluid at pH 6.8 at 37°C after 2 hours.

[0162] In some embodiments, the sustained release composition has a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of less than about 5% at 2 hours and about 55% to about 100%, about 60% to about 99%, about 75% to about 90%, about 80% to about 85%, about 55% to about 99%, about 65% to about 99%, about 70% to about 99%, about 75% to about 99%, about 80% to about 99%, about 90% to about 99%, about 80% to about 95%, or about 75% to about 95% at 72 hours, as measured by the 75 rpm USP paddle method at 37°C for 0-2 hours in simulated gastric fluid at pH 1.2 and after 2 hours in simulated intestinal fluid at pH 6.8 at 37°C.

[0163] In dissolution testing of certain sustained release compositions of the present disclosure performed according to the USP II paddle method, the sustained release compositions exhibit percentage dissolution ranging from about 0% to 35% at 3 hours, from about 35% to about 55% at 12 hours, and from about 65% to 85% at 24 hours in a dissolution test according to the 75 RPM USP paddle method using simulated gastric fluid at pH 1.2 at 37°C for 2 hours and simulated intestinal fluid at pH 6.8 at 37°C for 24 hours as test media.

[0164] In some embodiments, the sustained release compositions of the present disclosure exhibit a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of about 0% to 30% at 3 hours, about 40% to about 50% at 12 hours, and about 70% to 80% at 24 hours in a dissolution test according to the USP paddle method at 75 rpm using simulated gastric fluid at pH 1.2 at 37°C for 2 hours and simulated intestinal fluid at pH 6.8 at 37°C for 24 hours.

[0165] In some embodiments, the sustained release compositions of the present disclosure exhibit a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of NMT 30% at 3 hours, NMT 50% at 12 hours, and NLT 80% at 24 hours in a dissolution test according to the USP paddle method at 75 rpm using simulated gastric fluid at pH 1.2 at 37°C for 2 hours and simulated intestinal fluid at pH 6.8 at 37°C for 24 hours.

[0166] In some embodiments, the sustained release compositions exhibit a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of at most about 5% (NMT) at 2 hours, at least (NLT) 70% at 3 hours, at least NLT 90% at 6 hours, and at most about 100% at 12 hours in a dissolution test conforming to the 75 RPM USP II method using simulated gastric fluid at pH 1.2 at 37°C for 2 hours and simulated intestinal fluid at pH 6.8 at 37°C for 24 hours.

[0167] In some embodiments, the sustained release compositions exhibit a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of about NMT 5% at 2 hours, about NLT 10% at 3 hours, about NLT 30% at 6 hours, about NLT 50% at 9 hours, and about 80% at 14 hours in a dissolution test conforming to the 75 RPM USP II method using simulated gastric fluid at pH 1.2 for 2 hours at 37°C and simulated intestinal fluid at pH 6.8 for 24 hours at 37°C.

[0168] In some embodiments, the sustained release compositions of the present disclosure exhibit a percentage dissolution of (Z)-endoxifen or a polymorph or salt thereof of at least 10%, at least 20%, at least 30%, or at least 40% after 24 hours in a dissolution test according to the USP paddle method at 75 rpm using simulated gastric fluid at pH 1.2 at 37°C for 2 hours and simulated intestinal fluid at pH 6.8 at 37°C for 24 hours.

[0169] Such specific solubility properties allow for the preparation and use of sustained release compositions for use in the treatment of breast disorders, such as estrogen hormone-dependent disorders, including breast cancer, dense breast tissue, gynecomastia, and the like, and mood disorders.

[0170] In certain aspects, the sustained-release compositions of the present disclosure are formulated or prepared as solid dosage forms, including, but not limited to, tablets, minitablets, caplets, beads, microbeads, spheres, pellets, microspheres, granules, pills, tablets in tablets, tablets in capsules, granules in capsules, and the like. The sustained-release compositions of the present disclosure in the form of solid dosage forms provide slow, controlled release of the drug, the active ingredient (Z)-endoxifen or a polymorph or salt thereof, over a surprisingly extended period (e.g., at least about 4 hours to about 24 hours, at least 2 hours to about 72 hours) than that observed in other compositions containing (Z)-endoxifen. In at least one embodiment, the sustained-release composition in the form of a solid dosage form is a tablet.

[0171] Such sustained release compositions may be coated or uncoated.

[0172] In certain aspects, the present disclosure provides that the solid dosage forms of the present disclosure can be delivered orally.

[0173] In some embodiments, the present disclosure provides that the active ingredient ((Z)-endoxifen or a polymorph or salt thereof) is dispersed within a sustained-release delivery system. The (Z)-endoxifen or a salt or polymorph thereof can be dispersed evenly or uniformly. The sustained-release delivery system includes, but is not limited to, at least one release-controlling agent, such as a sustained-release agent that controls the release rate of the drug (Z)-endoxifen or a salt or polymorph thereof, at least one binder, and at least one lubricant.

[0174] In some embodiments, the sustained release delivery system is present in the sustained release compositions of the present disclosure in an amount ranging from about 60% to about 99.99%.

[0175] In some embodiments, the sustained release delivery system is present in the sustained release compositions of the present disclosure in an amount ranging from about 10 mg to about 499.5 mg, about 25 mg to about 450 mg, about 50 mg to about 400 mg, or about 100 mg to about 300 mg. In at least one embodiment, the sustained release delivery system is present in the sustained release composition in an amount ranging from about 50 mg to about 199.5 mg. In another embodiment, the sustained release delivery system is present in the sustained release composition in an amount of about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 95 mg, or about 100 mg. In yet another embodiment, the sustained release delivery system is present in the sustained release composition in an amount of about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 145 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 195 mg, about 200 mg, about 210 mg, about 225 mg, about 300 mg, about 400 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 495 mg, or about 499.5 mg. In some embodiments, the sustained release delivery system is present in the sustained release composition in an amount of about 50 mg to about 99.5 mg. In at least one embodiment, the sustained release delivery system is present in the sustained release composition in an amount of about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, or about 99.5 mg.

[0176] In some embodiments of the sustained release compositions of the present disclosure, the ratio of (Z)-endoxifen or a polymorph or salt thereof to the sustained release delivery system is generally from about 4:1 to about 0.1:100. In some embodiments, the ratio of (Z)-endoxifen or a polymorph or salt thereof to the sustained release delivery system is from 2.5:1 to about 1:20.

[0177] The sustained release agent present in the sustained release compositions of the present disclosure can be any sustained release agent known in the art to slow the release of hydrophobic drugs, such as (Z)-endoxifen or a polymorph or salt thereof.

[0178] Examples of sustained-release agents include cellulose ethers, rubbers, acrylic resins, such as polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, methyl methyl acrylate, and combinations thereof, polyvinylpyrrolidone, and protein-derived compounds. Examples of cellulose ethers include hydroxyalkyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (HPMC or hypromellose, for example, Nos. 2208, 2906, 2910), carboxyalkyl cellulose, and carboxymethyl cellulose. In some embodiments, at least one sustained-release agent is a pH-sustained-release agent, such as an acid-insoluble polymer that becomes increasingly soluble and permeable above pH 5.0 but remains impermeable below pH 5.0. Such controlled-release polymers target the upper small intestine and / or colon. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate, algenic acid salts such as sodium or potassium alginate, shellac, pectin, acrylic acid-methacrylic acid copolymers, including those commercially available from Evonik or Rohm (Eudragit® sustained-release polymers Eudragit® RL (high permeability), Eudragit® RS (low permeability), and Eudragit® NM 30D (low permeability)—alone or in any combination to achieve the desired permeability for sustained release). The viscosity of the sustained-release agent can be any viscosity suitable for the sustained release of (Z)-endoxifen or its polymorphs or salts. In certain embodiments, the viscosity of at least the sustained-release agent ranges from about 1,000 mPa·s to about 150,000 mPa·s. In some embodiments, the sustained release delivery system comprises one or more SR / release rate controlling agents having a viscosity in the range of about 1000 mPa·s to about 10,000 mPa·s, about 10,000 mPa·s to about 70,000 mPa·s, about 70,000 mPa·s to about 150,000 mPa·s, or a combination thereof.In some embodiments, the present disclosure provides a sustained release delivery system comprising two or more sustained release agents, each of which may have the same or different viscosity, e.g., one sustained release agent may have a viscosity ranging from about 1000 mPa·s to about 10,000 mPa·s, while another sustained release agent may have a viscosity ranging from about 10,000 mPa·s to about 70,000 mPa·s or from about 70,000 mPa·s to about 150,000 mPa·s.

[0179] In some embodiments, the sustained release agent is HPMC / hypromellose (e.g., Nos. 2208, 2906, 2910). Hypromellose used in this disclosure has a weight average molecular weight of about 20,000 to 500,000. In some embodiments, hypromellose generally has a molecular weight average of 20,000 to 250,000. Hypromellose is commercially available from Dow Chemicals under the trade name Methocell™, e.g., Methocell™ K100 (average molecular weight 26,000, 2% viscosity; 75,000-140,000 mPa s), Methocell™ K15M (average molecular weight 120,000, 2% viscosity; 15,000 cP, 13275-24,780 mPa s), and Methocell™ K4M (average molecular weight 86,000, 2% viscosity; 4,000 cP, 75,000-140,000 mPa s). One grade of hypromellose may be used alone or in combination with another.

[0180] In some embodiments, the sustained release agent, such as hypromellose, generally has an average molecular weight in the range of 15,000 to 140,000 daltons, and in at least one embodiment, an average molecular weight of about 15,000 daltons, providing sustained release compositions exhibiting sustained release of (Z)-endoxifen or a polymorph or salt thereof for at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 24 hours, at least 48 hours, and at least 72 hours.

[0181] The amount of sustained-release agent in the composition can be any amount effective to delay the release of the therapeutic agent (Z)-endoxifen or a polymorph or salt thereof for about 2 hours after administration to protect the therapeutic agent from the acidic environment of the stomach and to allow the therapeutic agent to transit through the stomach into the intestine, and to prolong such release from about 2 hours to about 72 hours. The amount of sustained-release agent in the composition can be any amount effective to provide a slower release rate of the therapeutic agent (Z)-endoxifen or a polymorph or salt thereof compared to a reference product. In some embodiments, the amount of sustained release agent in the composition can be any amount effective to delay the release of the therapeutic agent (Z)-endoxifen or a polymorph or salt thereof by at least about 1 hour, at least about 1.1 hours, at least about 1.2 hours, at least about 1.3 hours, at least about 1.4 hours, at least about 1.5 hours, at least about 1.6 hours, at least about 1.7 hours, at least about 1.8 hours, at least about 1.9 hours, at least about 2 hours, at least about 2.1 hours, at least about 2.2 hours, at least about 2.3 hours, at least about 2.4 hours, or at least about 2.5 hours after administration compared to a reference product.

[0182] At least one sustained release agent, such as hypromellose (HPMC), may generally be present in the sustained release compositions of the present disclosure in an amount of about 0.1 to about 99%, about 0.1% to about 90%, about 5% to about 90%, about 5% to about 80%, about 5% to about 70%, and about 5% to about 60%, w / w of the sustained release composition, provided that the sustained release composition exhibits a dissolution percentage range of about 0% to 35% at 3 hours, about 35% to about 55% at 12 hours, and about 65% to 85% at 24 hours in a dissolution test according to the 75 RPM USP paddle method using simulated gastric fluid at pH 1.2 at 37°C for 2 hours and simulated intestinal fluid at pH 6.8 at 37°C for 24 hours as the test media. In some embodiments, the sustained-release agent (e.g., gum, acrylic resin, methacrylic acid, methyl acrylate, methyl methyl acrylate, polyvinylpyrrolidone, a protein-derived compound, hydroxyalkyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxyalkyl cellulose, or carboxymethyl cellulose) may be present in an amount of about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 20% to about 40%, about 20% to about 50%, or about 20% to about 60%. In some embodiments, the sustained-release agent may be present in an amount of at least about 10%, at least about 20%, at least about 30%, or at least about 40%. As disclosed herein, such sustained-release compositions of the present disclosure release (Z)-endoxifen or a polymorph or salt thereof in a sustained manner for at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 24 hours, at least 48 hours, and at least 72 hours. See Examples 1-8 and Figures 1-6 and 12-17. In some embodiments, the therapeutic agent in the sustained-release composition is released over a period of 6 to 48 hours.In some embodiments, the therapeutic agent (e.g., (Z)-endoxifen or a polymorph or salt thereof) is released over a period of 2 hours to 72 hours when tested by USP II method using simulated gastric fluid for 2 hours at pH 1.2 at 37°C and simulated intestinal fluid for 24 hours at pH 6.8 at 37°C.

[0183] As non-limiting examples, the ratio of (Z)-endoxifen or a polymorph or salt thereof to sustained-release agent ranges from about 1:20 to about 20:1, from about 1:10 to about 10:1, or from about 1:5 to about 2:5 to prepare sustained-release compositions of the present disclosure. To prepare sustained-release tablets containing about 0.1 mg to about 200 mg of (Z)-endoxifen or a salt thereof, the ratio of drug to sustained-release agent ranges from about 20:1 to about 1:20. In some embodiments, the ratio of drug to sustained-release agent ranges from about 10:1 to about 1:10 in sustained-release tablets containing about 0.1 mg to about 200 mg of (Z)-endoxifen or a salt thereof. In certain embodiments, the ratio of therapeutic agent (Z)-endoxifen or a polymorph or salt thereof to sustained-release agent is about 1:5. It will be understood by those skilled in the art that the release rate of (Z)-endoxifen or a polymorph or salt thereof can be adjusted for sustained release as desired by varying the viscosity grade of the sustained release composition of the present disclosure and the amount of sustained release agent as disclosed herein.

[0184] The binder present in the sustained release composition of the present disclosure can be any binder known in the art that can hold together the components or ingredients in the sustained release composition of the present disclosure.Binders suitable for use in the sustained release compositions provided herein include monosaccharides (e.g., sucrose, dextrose, fructose), disaccharides, starch, such as corn starch, potato starch, or starch, such as starch paste, pregelatinized starch and starch 1500, polyhydric alcohols, mannitol, xylitol, sorbitol, lactose, polyethylene glycol, such as PEG6000, natural and synthetic gums, such as gum arabic, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose (e.g., powdered cellulose and pregelatinized starch) and its derivatives (e.g., ethyl cellulose). Suitable celluloses include, but are not limited to, cellulose acetate, methylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium), polyvinylpyrrolidone, methylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose (e.g., Nos. 2208, 2906, 2910), crystalline cellulose, microcrystalline cellulose (MCC), silicified microcrystalline cellulose, calcium carbonate and its salts, calcium phosphate, precipitated calcium phosphate, sodium carbonate, sodium phosphate, anhydrous calcium hydrogen phosphate, talc, dextrates, kaolin, mannitol, silicic acid, sorbitol, and combinations or mixtures thereof. Suitable forms of crystalline and microcrystalline cellulose include, but are not limited to, materials commercially 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 Pharmacel 101. Anhydrous or low moisture excipients are preferred.Suitable anhydrous or low moisture excipients or additives include microcrystalline cellulose, commercially available as AVICEL® PH 101, AVICEL® PH 103, and Pharmacel 101. In at least one embodiment, the binder is microcrystalline cellulose (e.g., AVICEL® PH 101) or silicified microcrystalline cellulose.

[0185] The sustained-release compositions of the present disclosure may typically contain at least one binder in an amount ranging from about 1% to about 99%, about 5% to about 95%, about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, or about 20% to about 85% w / w of the sustained-release composition. In certain embodiments, the sustained-release compositions of the present disclosure typically contain microcrystalline cellulose in an amount ranging from about 1% to about 99%, about 5% to about 95%, about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, or about 20% to about 85% w / w of the sustained-release composition.

[0186] Exemplary lubricants that may be used in the sustained-release compositions provided herein include, but are not limited to, stearic acid, calcium stearate, magnesium stearate, zinc stearate, potassium stearate, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycol, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, talc, ethyl oleate, ethyl laurate, agar, wax, and combinations thereof. Additional lubricants include, for example, syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co., Baltimore, Md.), coagulated aerosol of synthetic silica (commercially available from Degussa Co., Plano, Texas), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co., Boston, Mass.), Q7-9120 (Dow Corning), and combinations thereof. In some embodiments, the lubricant is magnesium stearate. Magnesium stearate reduces friction between the die wall and tablet mix during tablet compression and ejection. Magnesium stearate prevents tablets from sticking to the punches and die. Magnesium stearate also aids in powder flow in the hopper and into the die. Magnesium stearate has a particle size range of 450 to 550 micrometers and a density range of 1.00 to 1.80 g / mL. Magnesium stearate is stable in the tableting mix and does not polymerize. One lubricant, magnesium stearate, may also be used in the formulation.

[0187] Typically, the sustained release compositions of the present disclosure may include at least one lubricant in an amount ranging from about 0.01% to about 5%, about 0.2% to about 2%, or about 0.5% to about 1.5% w / w based on the weight of the sustained release composition. In certain embodiments, the sustained release compositions of the present disclosure include magnesium stearate in an amount ranging from about 0.01% to about 5%, about 0.2% to about 2%, or about 0.5% to about 1.5% w / w based on the weight of the sustained release composition.

[0188] Certain exemplary embodiments of the sustained release compositions of the present disclosure include, but are not limited to, the following embodiments.

[0189] In some embodiments, at least one sustained release agent (e.g., HPMC, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, sodium alginate, potassium alginate, shellac, pectin, or acrylic acid-methylacrylic acid copolymer) is present in the sustained release composition in an amount ranging from about 0.1% to about 99%, at least one binder is present in the sustained release composition in an amount ranging from about 1% to about 99%, and at least one lubricant is present in the sustained release delivery system in an amount ranging from about 0.01% to about 5%, wherein these percentages are percentages on a w / w basis relative to the weight of the sustained release composition.

[0190] In some embodiments, the at least one sustained release agent is present in the sustained release composition in an amount ranging from about 0.1% to about 90%, the at least one binder is present in the sustained release composition in an amount ranging from about 1% to about 99%, and the at least one lubricant is present in the sustained release delivery system in an amount ranging from about 0.01% to about 5%, these percentages being percentages on a w / w basis relative to the weight of the sustained release composition.

[0191] In at least one embodiment, the sustained release composition comprises at least one sustained release agent in an amount ranging from about 5% to 60%, at least one binder in an amount ranging from about 10% to about 90%, and at least one lubricant in an amount ranging from about 0.01% to about 5%, these percentages being percentages on a w / w basis relative to the weight of the sustained release composition.

[0192] In some embodiments, the at least one sustained release agent is present in the sustained release composition in an amount ranging from about 0.1% to about 10%, the at least one binder is present in the sustained release composition in an amount ranging from about 80% to about 99%, and the at least one lubricant is present in the sustained release delivery system in an amount ranging from about 0.02% to about 2%, these percentages being percentages on a w / w basis relative to the weight of the sustained release composition.

[0193] In at least one embodiment, the sustained release composition comprises at least one sustained release agent in an amount ranging from about 10% to about 45%, at least one binder in an amount ranging from about 50% to about 80%, and at least one lubricant in an amount ranging from about 0.02% to about 2%, these percentages being percentages on a w / w basis relative to the weight of the sustained release composition.

[0194] In certain embodiments, the at least one sustained release agent is present in the sustained release composition in an amount of about 8%, about 9%, about 10%, about 12%, about 15%, about 18%, about 20%, about 22%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%; the at least one binder is present in the sustained release composition in an amount of about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80%; and about 0.02%, about 0.05%, about 0.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2% of at least one lubricant, wherein the percentages are percentages on a w / w basis relative to the weight of the sustained release composition.

[0195] In certain embodiments, the at least one sustained release agent is present in the sustained release composition in an amount of about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25%, and the at least one binder is present in the sustained release composition in an amount of about 29%, about 25%, about 30%, about 35%, about 39%, about The at least one lubricant is present in the sustained release composition in an amount of about 40%, about 45%, about 49%, about 50%, about 55%, about 60%, about 64%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79% or about 80%, and the at least one lubricant is present in the sustained release composition in an amount of about 0.8%, about 0.9%, about 1%, about 1.2%, about 1.3%, about 1.4%, or about 1.5%.

[0196] In at least one embodiment, the at least one sustained release agent is present in the sustained release composition in an amount of about 10%, about 20%, or about 40%, the at least one binder is present in the sustained release composition in an amount of about 55%, about 75%, about 80%, about 85%, or about 87%, and the at least one lubricant is present in the sustained release composition in an amount of about 0.9% to about 1.1%, where the percentages are on a w / w basis relative to the weight of the sustained release composition.

[0197] In certain embodiments, the sustained release compositions of the present disclosure comprise an additional sustained release agent, binder, lubricant, or any combination thereof.

[0198] The compositions and sustained release delivery systems of the present disclosure can further comprise pharmaceutically acceptable excipients.The pharmaceutically acceptable excipients can be any additives commonly used in the pharmaceutical technology field, such as fillers, stabilizers, glidants, surfactants, light-blocking agents, sweeteners, colorants, flavorings, antioxidants, preservatives, reducing agents, chelating agents and the like.The pharmaceutically acceptable excipients are used in the amounts commonly used in the pharmaceutical technology field.In addition, two or more kinds of additives can be mixed and used in appropriate ratios.

[0199] Examples of fillers suitable for use in the sustained release compositions of the present disclosure 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, cellulosic substrates such as methylcellulose, carboxymethylcellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0200] Examples of stabilizers include sodium ascorbate, tocopherol, tertrasodium edetate, cyclodextrin, nicotinamide, alkaline earth metal salts (e.g., calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium silicate, magnesium aluminate), and butylhydroxyanisole.

[0201] Examples of glidants include, but are not limited to, colloidal silicon dioxide, cellulose, calcium phosphate, di- or tribasic, and the like.

[0202] Examples of surfactants include sodium lauryl sulfate, polysorbate 80, and the like.

[0203] Examples of sunscreens include titanium dioxide. Sunscreens are desirable for light-sensitive active ingredients, such as (Z)-endoxifen, and its polymorphs and salts.

[0204] Examples of antioxidants include butylhydroxytoluene (BHT), butylhydrozyanysole (BHA), tocopherol, tocopherol esters (e.g., tocopherol acetate), ascorbic acid or its alkali or alkaline earth metal salts, lycopene, and beta-carotene.

[0205] Examples of reducing agents include cystine and cysteine.

[0206] Examples of chelating agents include EDTA or its alkali metal or alkaline earth metal salts.

[0207] Examples of coloring agents include food colorings, such as Food Color Yellow No. 5, US Food Color No. 6, Swedish Orange, Food Color Blue No. 2, Food Color Red No. 2, and the like, food lake colorings, yellow iron oxide (yellow iron oxide pigment), red iron oxide (red iron oxide pigment), black iron oxide (black iron oxide pigment), riboflavin, riboflavin organic acid esters, riboflavin phosphate ester or alkali metal or alkaline earth metal salts thereof, phenolphthalein, titanium oxide, lycopene, and beta-carotene.

[0208] Examples of sweeteners include aspartame, acesulfame, potassium, thaumatin, sodium saccharin, and dipotassium glycyrrhizinate.

[0209] Examples of flavorings include menthol, peppermint oil, lemon oil, vanillin, and strawberry.

[0210] The shape of the sustained-release composition in the form of a solid dosage form such as a tablet is not particularly limited and may be any shape suitable for administration, for example, oral administration, such as a spherical, oval, elliptical, pear-shaped, cylindrical, cubic, regular, and / or irregular shape. The tablet may have one of a variety of different shapes. For example, the tablet may be shaped as a polyhedron such as a cube, pyramid, prism, or the like, or may have a spatial geometric shape with several uneven surfaces, such as a cone, truncated cone, cylinder, sphere, torus, or the like. In certain embodiments, the tablet has one or more major surfaces. For example, the tablet surface typically has opposing upper and lower surfaces formed by contact with the upper and lower punch surfaces of a compression machine. In such embodiments, the tablet surface typically further includes a "belly band" located between the upper and lower surfaces, which is formed by contact with the die wall in the compression machine.

[0211] In one aspect, the present disclosure provides a sustained-release composition in the form of a sustained-release tablet having a tablet weight of about 60 to about 500 mg. In some embodiments, the sustained-release composition in the form of a sustained-release tablet has a tablet weight of about 90 to about 110 mg. The sustained-release composition in the form of a sustained-release tablet has a tablet thickness of about 2.75 to about 3.75 mm. In some embodiments, the sustained-release composition in the form of a sustained-release tablet has a tablet thickness of about 3 to about 3.5 mm.

[0212] The hardness of tablets of the present disclosure can vary depending on various factors, including, for example, the relative amounts and specific types of ingredients used, the tableting equipment employed, and the processing parameters selected. The compression and pressure used to prepare the tablets can affect the release profile of the therapeutic agent (Z)-endoxifen or its polymorph or salt in a subject. The compression and pressure used to prepare tablets of the present invention can vary depending on their surface area and the amount and particle size of the therapeutic agent (Z)-endoxifen or its polymorph or salt, sustained-release agent, binder, lubricant, and other excipients included in the tablet. The degree of hydration and solvation of the components in the composition also play an important role in determining tablet hardness. In some embodiments, the sustained-release composition in the form of a sustained-release tablet has a tablet hardness of about 4 kiloponds (Kp) to about 16 Kp. In some embodiments, the sustained-release composition in the form of a sustained-release tablet has a tablet hardness of about 10 to about 16 Kp. In some embodiments, the sustained-release composition in the form of a sustained-release tablet has a tablet hardness of about 4Kp, about 4.5Kp, about 5Kp, about 5.5Kp, about 6Kp, about 6.5Kp, about 7Kp, about 7.5Kp, about 8Kp, about 8.5Kp, about 9Kp, about 9.5Kp, about 10Kp, about 10.5Kp, about 11Kp, about 11.5Kp, about 12Kp, about 12.5Kp, about 13Kp, about 13.5Kp, about 14Kp, about 14.5Kp, about 15Kp, about 15.5Kp, and about 16Kp. In some embodiments, the sustained-release composition in the form of a sustained-release tablet has a tablet hardness of about 13Kp. In at least one embodiment, the sustained-release composition in the form of a sustained-release tablet has a tablet hardness of 5Kp.

[0213] The friability of sustained-release tablets is typically at most 1.0% (NMT). In some embodiments, the sustained-release composition in the form of a sustained-release tablet contains a light-blocking agent such as titanium oxide. The sustained-release composition in the form of a sustained-release tablet can be any color known in the art, such as Food Color Yellow No. 5, US Food Color No. 6, Swedish orange, Food Color Blue No. 2, Food Color Red No. 2, and the like, food lake coloring, yellow iron oxide (yellow iron oxide pigment), red iron oxide (red iron oxide pigment), black iron oxide (black iron oxide pigment), riboflavin, riboflavin organic acid ester, riboflavin phosphate or its alkali metal or alkaline earth metal salt, phenolphthalein, titanium oxide, lycopene, and beta-carotene. In some embodiments, the sustained-release composition in the form of a sustained-release tablet is white or off-white in color.

[0214] The sustained release compositions, such as the sustained release tablets described herein, can be coated or uncoated.

[0215] In another aspect, the present disclosure provides that the sustained-release compositions of the present disclosure are used to prepare enteric-coated delayed-release solid dosage forms, such as enteric-coated delayed-release tablets.An advantageous aspect of such enteric-coated compositions is that these sustained-release compositions, including enteric-coated delayed-release tablets, are formulated to minimize the release of (Z)-endoxifen or its polymorphs or salts in the stomach to avoid the degradation of (Z)-endoxifen or its polymorphs or salts, and to target the release of the active agent (Z)-endoxifen or its polymorphs or salts to the small intestine or colon or both.Targeting the small intestine and colon increases the bioavailability of (Z)-endoxifen or its polymorphs or salts.In some embodiments, the sustained-release compositions of the present disclosure deliver (Z)-endoxifen or its polymorphs or salts to the duodenum or jejunum.

[0216] Those skilled in the art will understand that the sustained-release compositions of the present disclosure can themselves function as sustained-release compositions (see Example 5 and Tables 6 and 7), and can also serve as "cores" (e.g., core tablets) used in the preparation of enteric-coated dosage forms (e.g., enteric-coated delayed-release tablets or enteric-coated delayed-release capsules) that provide delayed release of (Z)-endoxifen or a polymorph or salt thereof targeted to the small intestine or colon or both.

[0217] Thus, in some embodiments, the sustained-release composition of the present disclosure in solid dosage form (e.g., as a tablet) serves as a "core" composition (e.g., core tablet) for preparing an enterically coated delayed-release composition. Such sustained-release compositions can protect the acid-sensitive active ingredient (Z)-endoxifen or a polymorph or salt thereof from the acidic environment of the stomach and dissolve at a pH greater than 5.5, generally in the intestine, e.g., in the duodenum, jejunum, and / or ileum of the small intestine, and / or in the colon. The enteric coating protects the active (Z)-endoxifen from interconversion with (E)-endoxifen in the stomach, and the drug (Z)-endoxifen is then released at a slower rate in the intestine, e.g., after 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, etc., after administration. The surprisingly reduced interconversion of (Z)-endoxifen based on the formulations disclosed herein provides an unexpected benefit of administering (Z)-endoxifen, or a polymorph or salt thereof.

[0218] As a non-limiting example, the present disclosure provides a sustained-release composition of the present disclosure in the form of a solid dosage form, such as an enteric-coated delayed-release tablet. Such a sustained-release composition in the form of a tablet serves as a core (hereinafter referred to as a "core," "core tablet," or "tablet core," and used interchangeably) that is substantially covered by at least one functional coating layer. In other words, the enteric-coated delayed-release tablet of the present disclosure has a core comprising (i) (Z)-endoxifen or a salt or polymorph thereof, (ii) at least one sustained-release agent, and (iii) at least one lubricant, the core being substantially covered by at least one functional coating layer.

[0219] In some embodiments, the functional coating includes at least one release-controlling agent, such as a delayed-release agent that targets the intestine (e.g., the duodenum) or the colon, or both. The present disclosure provides that the functional coating can further include additional excipients, such as plasticizers, anti-adherents, and the like. The addition of a delayed-release agent to the functional coating provided a surprisingly advantageous result: the conversion of (Z)-endoxifen to (E)-endoxifen was significantly reduced. This surprising advantage of coating a composition (e.g., a tablet) with a coating containing a delayed-release agent demonstrates that such a coating can facilitate more efficient delivery of (Z)-endoxifen. Furthermore, it has surprisingly been found that a coating containing a delayed-release agent provides a more consistent and slower release.

[0220] In certain embodiments, the functional coating of the present disclosure comprises at least one release-controlling agent, such as a delayed-release agent, at least one plasticizer, and at least one anti-sticking / anti-adherent agent. In some embodiments, the enteric-coated delayed-release tablet can be coated with at least two coatings, where at least one coating is a functional coating comprising a delayed-release agent, at least one plasticizer, and at least one anti-sticking / anti-adherent agent.

[0221] Thus, in some embodiments, the sustained-release compositions comprising (Z)-endoxifen or its polymorphs or salts disclosed herein include a core (e.g., a core tablet) that is substantially coated with at least one functional coating layer using a coating solution. The coating solution includes at least one release-controlling agent, such as a delayed-release agent, at least one plasticizer, and at least one anti-tack / anti-adherent agent. Those skilled in the art will understand that the core tablets disclosed herein can be enclosed in tablets, caplets, or capsules, and the like, and further coated with the coating solutions disclosed herein to prepare other solid dosage forms, such as tablets within tablets, tablets within caplets, tablets within capsules, and the like. In such cases, the sustained-release compositions, such as tablets within tablets, tablets within caplets, tablets within capsules, and the like, will be substantially coated with at least one functional coating layer as described herein. As a result, the coated tablets contained within other coated tablets, caplets, and capsules can provide a pulsatile release of (Z)-endoxifen or its polymorphs or salts.

[0222] Those skilled in the art will also understand that, like the core tablets described herein, other solid dosage forms of sustained-release compositions, such as minitablets, spheres, beads, granules, pellets, pills, and the like, can also be used as cores for preparing enteric-coated delayed-release tablets, caplets, and capsules. Examples of such sustained-release compositions include, but are not limited to, sustained-release enteric-coated tablets, enteric-coated minitablets, enteric-coated capsules, enteric-coated beads, enteric-coated microspheres, enteric-coated granules, enteric-coated pellets, enteric-coated pills, enteric-coated tablets in tablets, enteric-coated tablets in capsules, and the like, and such sustained-release compositions are used for the delayed release of (Z)-endoxifen or its polymorphs or salts into the small intestine or colon, or both. Commercially available delayed-release capsules, such as those available from Capsugel (e.g., VCaps® Plus enteric-coated capsules), can be used to prepare enteric-coated delayed-release capsules, and are therefore encompassed by the present disclosure. In some embodiments, the enteric-coated delayed-release capsule can be a non-animal capsule, such as a hypromellose capsule (e.g., commercially available self-gelling Vcaps, VCaps Plus, VCaps enteric, Xcellodose from Capsugel, ENCODE colonic delivery technology, and other enteric-coated capsules made using EnTrinsic™ drug delivery technology).Other technologies known in the art and commercially available for formulating enteric-coated oral solid dosage forms (e.g., Qualicaps, USA, Nutrascience, USA, etc.) can also be utilized.

[0223] The present disclosure provides that the core can be functionally coated using a coating solution containing, but not limited to, at least one release-controlling agent, such as a delayed-release agent. In some embodiments, the functional coating solution can include a plasticizer, an anti-blocking agent, and the like. In some embodiments, the core can be functionally coated using a coating solution containing, but not limited to, at least one release-controlling agent, such as a delayed-release agent, at least one plasticizer, and at least one anti-blocking / anti-adhesion agent. To prepare enteric-coated delayed-release solid dosage forms using the sustained-release compositions described herein, the coating solutions provided herein can be applied as a coating, such as a thin film, onto a wide range of solid dosage forms, including particles, beads, spheres, granules, pellets, tablets, minitablets, pills, multiparticulates, and capsules (with hard and soft shells) encapsulating the core (e.g., immediate-release capsules).

[0224] When a sustained-release composition, such as an enteric-coated delayed-release tablet, exhibits a dissolution percentage range of about 0% to about 35% at 3 hours, about 35% to about 55% at 12 hours, and about 65% to about 85% at 24 hours in a dissolution test according to the 75 RPM USP paddle method using simulated gastric fluid at pH 1.2 at 37°C for 2 hours and simulated intestinal fluid at pH 6.8 at 37°C for 24 hours as the test media, the at least one functional coating layer provides a weight gain of about 1% to about 60%, about 2% to about 40%, about 5% to about 30%, and about 6% to about 20% relative to the weight of the core (e.g., tablet core).

[0225] When a sustained release composition, such as an enteric-coated delayed-release tablet, exhibits a dissolution percentage of about NMT 5% at 2 hours, about NLT 60% at 3 hours, about NLT 95% at 6 hours, and about 100% at 12 hours in a dissolution test according to the 75 RPM USP paddle method using simulated gastric fluid at pH 1.2 at 37°C for 2 hours and simulated intestinal fluid at pH 6.8 at 37°C for 24 hours as the test media, the at least one functional coating layer provides a weight gain of about 1% to about 60%, about 2% to about 40%, about 5% to about 30%, and about 6% to about 20% relative to the weight of the core (e.g., tablet core).

[0226] The at least one functional coating layer provides a weight gain of about 1% to about 60%, about 2% to about 40%, about 5% to about 30%, and about 6% to about 20% relative to the weight of the core (e.g., tablet core) when the extended release composition, such as an enteric-coated delayed-release tablet, exhibits a dissolution percentage of about NMT 10% at 3 hours, about NLT 30% at 6 hours, about NLT 50% at 9 hours, and about NLT 80% at 14 hours in a dissolution test according to the 75 RPM USP paddle method using simulated gastric fluid at pH 1.2 for 2 hours at 37°C and simulated intestinal fluid at pH 6.8 for 24 hours at 37°C as the test media.

[0227] Tablet weight will also vary depending on, among other factors, the dosage of the therapeutic agent (Z)-endoxifen or its polymorph or salt, the type and amount of sustained-release agent used, and the presence, type, and amount of additional materials. Tablet weights for dosages of about 0.5 mg to about 200 mg of therapeutic agent can range from about 10 mg to about 2000 mg per tablet. In some embodiments, tablet weights range from 50 mg to 500 mg. In some embodiments, enteric-coated delayed-release tablets have tablet weights ranging from about 101 mg to 160 mg, 90 mg to 110 mg, or about 105 mg to about 120 mg. For time-delayed or delayed-release pharmaceutical preparations of the sustained-release compositions of the present disclosure in oral dosage forms, acid-insoluble polymers (e.g., polymethacrylates) can be used as the delayed-release agent in the coating solution.

[0228] For enteric coated delayed-release preparations, cellulosic polymers such as glyceryl monostearate, glyceryl distearate, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, and sodium carboxymethyl cellulose; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate, and those available under the trade name EUDRAGIT® (Evoniks, Rohm Other methacrylic resins commercially available from EUDRAGIT Pharma; Westerstadt, Germany, include methacrylic acid-ethyl acrylate copolymers (1:1) (EUDRAGIT® L30D-55) and L100-55 (soluble at pH 5.5 and above), EUDRAGIT® 1,100D (soluble at pH 6.0 and above), EUDRAGIT® S (soluble at pH 7.0 and above as a result of a higher degree of esterification), and EUDRAGIT® NE, RL, and RS (water-insoluble polymers with different degrees of permeability and foaming properties); vinyl polymers and copolymers, such as polyvinylpyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate-crotonic acid copolymer, and ethylene-vinyl acetate copolymer; enzymatically degradable polymers, such as azopolymers, pectin, chitosan, amylase, and guar gum; zein and shellac.

[0229] In certain embodiments, the delayed release agent is a pH-sensitive polymer, such as polymethacrylate. In some embodiments, the delayed release agent is methacrylic acid-ethyl acrylate copolymer (1:1) USP-NF (EUDRAGIT® L30D-55). In some embodiments, the delayed release agent is methacrylic acid-ethyl acrylate copolymer (1:2).

[0230] The present disclosure provides that a combination or mixture of different delayed release agents can be used in a single functional coating layer. In some embodiments, a multi-layer (e.g., two or more layers) coating using different delayed release agents or polymers can also be applied to the core.

[0231] When a sustained release composition in the form of an enteric-coated delayed-release dosage form (e.g., an enteric-coated delayed-release tablet) that releases (Z)-endoxifen or a polymorph / salt thereof continuously for at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 24 hours, at least 48 hours, or at least 72 hours is obtained, the delayed-release agent, such as methacrylic acid-ethyl acrylate copolymer (1:1) USP-NF (EUDRAGIT® L30D-55), is present in at least one functional coating layer in an amount ranging from about 0.1% to about 35%, from about 5% to about 35%, or from about 8% to about 20%, w / w based on the weight of the core (e.g., core tablet).

[0232] The delayed-release agent is present in at least one coating layer in an amount ranging from about 0.1% to about 30%, about 5% to about 25%, or about 8% to about 14% w / w of the core tablet weight when the sustained-release composition of the present disclosure, such as a delayed-release tablet, exhibits a dissolution percentage range of about 0% to 35% at 3 hours, about 35% to about 55% at 12 hours, and about 65% to 85% at 24 hours in a dissolution test according to the 75 RPM USP paddle method using simulated gastric fluid at pH 1.2 at 37° C. for 2 hours and simulated intestinal fluid at pH 6.8 at 37° C. for 24 hours as the test media. In some embodiments, the delayed-release agent is present in at least one coating layer in an amount ranging from about 0.1% to about 20% w / w of the core tablet weight.

[0233] When a sustained release composition of the present disclosure, such as a delayed-release tablet, exhibits a dissolution percentage of about 5% NMT at 2 hours, about 70% NLT at 3 hours, and about 95% and about 100% NLT at 12 hours in a dissolution test according to the 75 RPM USP paddle method using simulated gastric fluid at pH 1.2 at 37° C. for 2 hours and simulated intestinal fluid at pH 6.8 at 37° C. for 24 hours as the test media, the delayed-release agent is present in at least one coating layer in an amount ranging from about 0.1% to about 30%, about 5% to about 25%, or about 8% to about 14% w / w of the core tablet weight. In some embodiments, the delayed-release agent is present in at least one coating layer in an amount ranging from about 0.1% to about 20% w / w of the core tablet weight.

[0234] Such release of (Z)-endoxifen or a polymorph / salt thereof from the sustained release compositions of the present disclosure generally begins in the intestine about 2 hours after administration.

[0235] At least one plasticizer is added to control the softness or flexibility of the sustained release composition prepared as a solid dosage form, such as an enteric-coated delayed-release tablet, or capsule or caplet shell, and can thus improve the mechanical properties of the pH-sensitive material of the coating on the solid dosage form.

[0236] Suitable plasticizers include petroleum oils (e.g., for paraffinic, naphthenic, and aromatic process oils), squalene, squalane, vegetable oils (e.g., olive oil, camellia oil, castor oil, tall oil, and peanut oil), mineral oil, silicone oil, dibasic acid or phthalate esters (e.g., dibutyl phthalate, diethyl phthalate, dimethyl phthalate, and dioctyl phthalate), liquid rubbers (e.g., polybutylene and liquid isoprene rubber), liquid fatty acid esters (e.g., isopropyl myristate), and the like. ISM), hexyl laurate, diethyl and diisopropyl sebacate, citrate esters such as triethyl citrate, tributyl citrate, acetyl tributyl citrate and acetyl triethyl citrate, triacetin, propylene glycol, diethylene glycol, polyethylene glycol, polypropylene glycol, other polyethylene oxide sorbitan esters, phthalates, sorbitol, glycol salicylate, crotamington, glycerin, PLASACRYL™ T20, or mixtures thereof.

[0237] In some embodiments, at least one plasticizer in the functional coating is triethyl citrate. In some embodiments, the at least one plasticizer (e.g., a citrate ester such as triethyl citrate) is present in an amount ranging from about 0.01% to about 5%, about 0.1% to about 4%, about 0.2% to about 2%, or about 0.5% to about 1.5%, w / w of the core tablet weight.

[0238] The present disclosure provides that at least one functional coating layer comprises at least one anti-blocking / anti-adherent agent. The anti-blocking / anti-adherent agent is included in the coating solution for coating to prevent tablet sticking to punch faces and to machine dosators, filler pins, etc. Exemplary anti-blocking agents include talc, glyceryl monostearate, colloidal silicon dioxide, kaolin, or any combination thereof.

[0239] The addition of talc as an anti-adherent agent to the functional coating provided the surprisingly advantageous result of significantly reducing the conversion of (Z)-endoxifen to (E)-endoxifen. This surprising benefit of coating a composition (e.g., a tablet) with a coating containing talc demonstrates that such a coating can facilitate more efficient delivery of (Z)-endoxifen. Furthermore, it was surprisingly found that a coating containing a delayed-release agent provided a more consistent, slower release.

[0240] The sustained release composition (e.g., enteric-coated delayed-release tablet) comprises at least one anti-adherent agent present in an amount ranging from about 0.1% to about 10%, about 1% to about 8%, or about 2% to about 6% w / w of the core.

[0241] Exemplary enteric coated delayed release tablets are provided in Examples 2 and 3 herein.

[0242] An exemplary sustained-release composition in the form of an enteric-coated delayed-release tablet comprises a core tablet comprising about 0.01% to about 40% or about 0.5 mg to about 200 mg of (Z)-endoxifen or a polymorph or salt thereof, hypromellose, microcrystalline cellulose, and magnesium stearate, substantially encased in at least one functional coating layer, wherein the at least one functional coating layer comprises methacrylic acid-ethyl acrylate copolymer (ranging from 2:1 to 1:2), triethyl citrate, and talc.

[0243] An exemplary sustained-release composition in the form of an enteric-coated delayed-release tablet comprises a core tablet comprising (i) about 0.01% to about 40% (Z)-endoxifen or a polymorph or salt thereof, (ii) about 0.1% to about 99% hypromellose, (iii) about 1% to about 99% microcrystalline cellulose, and (iv) about 0.01% to about 5% magnesium stearate, substantially encased in at least one functional coating layer, the at least one functional coating layer comprising (i) about 5% to about 40% methacrylic acid-ethyl acrylate copolymer (1:1) (polymethacrylate-methacrylic acid copolymer dispersion, 30% solids), the at least one functional coating layer contributing about 2% to about 20% weight gain relative to the average core tablet weight. These amounts are expressed as weight percentages based on the weight of the core tablet. In some embodiments, the sustained release composition has a ratio of drug ((Z)-endoxifen or a polymorph or salt thereof) to sustained release agent of 1:5.

[0244] An exemplary sustained-release composition in the form of an enteric-coated delayed-release tablet comprises a core tablet comprising (i) about 0.01% to about 40% (Z)-endoxifen or a polymorph or salt thereof, (ii) about 5% to about 60% hypromellose, (iii) about 10% to about 90% microcrystalline cellulose, and (iv) about 0.01% to about 5% magnesium stearate, substantially encased in at least one functional coating layer, the at least one functional coating layer comprising (i) about 5% to about 40% methacrylic acid-ethyl acrylate copolymer (1:1) (polymethacrylate-methacrylic acid copolymer dispersion, 30% solids), the at least one functional coating layer contributing about 2% to about 20% weight gain relative to the average core tablet weight. These amounts are expressed as weight percentages based on the weight of the core tablet.

[0245] An exemplary sustained-release composition in the form of an enteric-coated delayed-release tablet comprises a core tablet comprising: (i) about 0.01% to about 40% (Z)-endoxifen or a polymorph or salt thereof; (ii) about 5% to about 60% hypromellose; (iii) about 10% to about 90% microcrystalline cellulose; and (iv) about 0.01% to about 5% magnesium stearate; the core tablet is substantially encapsulated in at least one functional coating layer, the at least one functional coating layer comprising: (i) about 0.1% to about 20% methacrylic acid-ethyl acrylate copolymer (1:1) (polymethacrylate-methacrylic acid copolymer dispersion, 30% solids); (ii) about 0.01% to about 5% triethyl citrate; and (iii) about 1% to about 10% talc; and the at least one functional coating layer contributes about 2% to about 20% weight gain relative to the average core tablet weight. These amounts are expressed as weight percentages based on the weight of the core tablet.

[0246] An exemplary sustained-release composition in the form of an enteric-coated delayed-release tablet is a core tablet comprising: (i) 0.5 mg, 1 mg, 2 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 20 mg, or 40 mg of (Z)-endoxifen or a polymorph or salt thereof; (ii) about 0.1% to about 99% or about 5% to about 60% hypromellose; (iii) about 1% to about 99% or about 10% to about 90% microcrystalline cellulose; and (iv) about 0.01% to about 5% magnesium stearate, wherein at least and (c) about 1% to about 10% talc, wherein the at least one functional coating layer contributes about 2% to about 20% weight gain relative to the average core tablet weight. The amounts of all components (ii) to (iv) and (a) to (c) are expressed as weight percentages based on the weight of the core tablet. Such enteric-coated delayed-release tablets (i) provide sustained release of (Z)-endoxifen or a polymorph or salt thereof over a period of at least 2 hours, at least 3 hours, at least 4 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 24 hours, at least 48 hours, or at least 72 hours in a dissolution test according to the 75 RPM USP paddle method using simulated gastric fluid at pH 1.2 at 37°C for 2 hours and simulated intestinal fluid at pH 6.8 at 37°C for 24 hours as test media.

[0247] In some embodiments, such enteric-coated delayed-release tablets exhibit a dissolution percentage of about 0% to about 30% at 3 hours, about 30% to about 50% at 12 hours, and about 65% to about 85% after 12 hours in a dissolution test according to the 75 RPM USP paddle method using simulated gastric fluid at pH 1.2 for 2 hours at 37°C and simulated intestinal fluid at pH 6.8 for 24 hours at 37°C as the test media.

[0248] In some embodiments, such enteric-coated delayed-release tablets exhibit, in a dissolution test according to the 75 RPM USP paddle method using simulated gastric fluid at pH 1.2 at 37° C. for 2 hours and simulated intestinal fluid at pH 6.8 at 37° C. for 24 hours as the test media, (i) a dissolution percentage ranging from about 0% to 35% at 3 hours, from about 35% to about 55% at 12 hours, and from about 65% to 85% at 24 hours; (ii) a dissolution percentage of NMT 30% at 3 hours, NMT 50% at 12 hours, and NLT 80% at 24 hours; or (iii) a dissolution percentage of at least 20% to 30% after 24 hours.

[0249] In some embodiments, such enteric coated delayed-release tablets exhibit a dissolution percentage of NMT about 5% at 2 hours, NLT about 70% at 3 hours, NLT about 95% at 6 hours, and about 100% at 12 hours in a dissolution test according to the 75 RPM USP paddle method using simulated gastric fluid at pH 1.2 for 2 hours at 37°C and simulated intestinal fluid at pH 6.8 for 24 hours at 37°C as the test media.

[0250] In some embodiments, such enteric coated delayed-release tablets exhibit a dissolution percentage of NMT about 5% at 2 hours, NMT about 10% at 3 hours, NLT about 30% at 6 hours, NLT about 50% at 9 hours, and NLT about 80% at 14 hours in a dissolution test according to the 75 RPM USP paddle method using simulated gastric fluid at pH 1.2 for 2 hours at 37°C and simulated intestinal fluid at pH 6.8 for 24 hours at 37°C as the test media.

[0251] In some embodiments, such enteric coated delayed-release tablets exhibit a dissolution percentage of NMT about 10% at 3 hours, NLT about 30% at 6 hours, NLT about 50% at 9 hours, and NLT about 80% at 14 hours in a dissolution test according to the 75 RPM USP paddle method using simulated gastric fluid at pH 1.2 for 2 hours at 37°C and simulated intestinal fluid at pH 6.8 for 24 hours at 37°C as the test media.

[0252] The functional coating of the sustained-release composition of the present disclosure, including enteric-coated delayed-release tablets, may further comprise a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be any additive commonly used in the pharmaceutical arts, such as fillers, stabilizers, glidants, surfactants, light-blocking agents, sweeteners, colorants, flavorings, antioxidants, preservatives, reducing agents, chelating agents, and the like, as described herein. The pharmaceutically acceptable excipients are used in amounts commonly used in the pharmaceutical arts. In addition, two or more of these pharmaceutically acceptable excipients may be mixed and used in appropriate ratios. In one embodiment, the present disclosure provides a sustained-release composition that, upon oral administration, releases the therapeutic agent (Z)-endoxifen or a polymorph or salt thereof, providing a subject with sustained exposure to the therapeutic agent for about 2 to about 270 hours per dose. In some embodiments, the sustained release compositions provide a subject with sustained exposure to the released therapeutic agent (Z)-endoxifen or a polymorph or salt thereof for at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 18 hours, at least 20 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 160 hours, at least 180 hours, at least 200 hours, at least 220 hours, at least 250 hours, and at least 270 hours. Pharmacokinetic properties

[0253] In certain aspects, the sustained release compositions of the present disclosure comprising the therapeutic agent (Z)-endoxifen or a polymorph or salt thereof can provide improved pharmacokinetics in a subject upon oral administration compared to a reference product capsule.

[0254] Exemplary pharmacokinetic parameters for a single dose of extended-release tablets in the form of enteric-coated delayed-release tablets of the present disclosure are provided herein. The PK parameters disclosed herein are generally mean plasma parameters, but the present disclosure provides that PK parameters for serum are typically 1.1 to 1 times higher than plasma PK parameters. As a non-limiting example, for certain embodiments, a single oral dose of an extended-release composition (e.g., in the form of an enteric-coated delayed-release tablet) ingested by a subject may be measured at an AUC of an equivalent single oral dose of a capsule. last at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, and at least about 90% of the mean plasma AUC last (time × ng / mL) or such mean plasma AUC last In certain embodiments, a single dose of an enteric-coated delayed-release tablet of the present disclosure taken orally by a subject in the fasted state can achieve a mean plasma AUC of an equivalent single oral dose of the capsule in the fasted state. last At least 70% of the mean plasma AUC last or such a mean plasma AUC last can be achieved.

[0255] Similarly, in certain embodiments, a single oral dose of a sustained release composition (e.g., in the form of an enteric-coated delayed-release tablet) ingested by a subject has a C of less than that of an equivalent single oral dose of a capsule. maxat least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, and at least about 90% of the mean plasma C max (ng / mL) or such mean plasma C max In certain embodiments, a single dose of an orally ingested enteric coated delayed-release tablet of the present disclosure has a hardness that is less than or equal to the C of an orally ingested equivalent single dose of a capsule. max At least about 45% of the mean plasma C max (ng / mL) or such mean plasma C max can be achieved.

[0256] The present disclosure provides a method for determining whether a single oral dose of a sustained release composition, such as an enteric coated delayed release tablet of the present disclosure, taken by a subject reduces the mean plasma T max (hours) longer mean plasma T max (hours) or such mean plasma T max As a non-limiting example, it is proposed that the mean plasma T of a single oral dose of an enteric-coated delayed-release tablet taken by a subject in the fasted state can be achieved. max (hours) is the mean plasma T max Similarly, in certain embodiments, a single oral dose of a sustained release composition of the present disclosure, e.g., in the form of an enteric-coated delayed-release tablet, has a mean plasma T that is at least 0.1, at least 0.5, at least 1, at least 1.5, at least 2, at least 2.5, at least about 3, at least about 3.5, at least about 4, at least about 4.5, at least 5, at least about 5.5, at least about 6, at least about 6.5, at least about 7, at least about 7.5, at least about 8, at least 8.5, at least 9-fold, at least 9.5, and at least 10-fold longer than that of an equivalent single oral dose of a capsule reference product.max Thus, the sustained release compositions of the present disclosure exhibit significantly slower mean plasma C max (See Table 15.) The mean plasma concentrations over time after a single dose of the sustained release composition and the reference product capsule are provided in Table 14. In certain embodiments, the sustained release composition of the present disclosure in the form of a hard enteric coated delayed release tablet achieves a mean plasma T of at least about 6 to about 10 times longer than the reference product capsule. max You can have (time).

[0257] In some embodiments, the sustained release compositions (e.g., enteric coated delayed release tablets) of the present disclosure have a sustained release effect in the plasma or serum of a subject to which the sustained release composition is orally administered, the sustained release composition lasting for at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, or at least about 24 hours. a mean T of a therapeutic agent (e.g., (Z)-endoxifen) for at least about 22 hours, at least about 23 hours, at least about 24 hours, at least about 26 hours, at least about 28 hours, at least about 30 hours, at least about 32 hours, at least about 34 hours, at least about 36 hours, at least about 38 hours, at least about 40 hours, at least about 42 hours, at least about 44 hours, at least about 46 hours, at least about 48 hours, at least about 50 hours, at least about 55 hours, at least about 60 hours, at least about 65 hours, at least about 70 hours, at least about 75 hours, or at least about 80 hours maxIn some embodiments, the sustained release composition can produce a sustained release effect in the plasma or serum of a subject to which the sustained release composition is orally administered, for 4 hours to 80 hours, 5 hours to 80 hours, 6 hours to 80 hours, 7 hours to 80 hours, 8 hours to 80 hours, 9 hours to 80 hours, 10 hours to 80 hours, 15 hours to 80 hours, 24 hours to 80 hours, 36 hours to 80 hours, 48 ​​hours to 80 hours, 4 hours to 70 hours, 5 hours to 70 hours, 6 hours to 70 hours, 7 hours to 70 hours, 8 hours to 70 hours, 9 hours to 70 hours, 10 hours to 70 hours, 15 hours to 70 hours, 24 hours to 70 hours, 36 hours to 80 hours, 48 ​​hours to 80 hours, Mean T of the therapeutic agent for hours to 70 hours, 48 ​​hours to 70 hours, 4 hours to 60 hours, 5 hours to 60 hours, 6 hours to 60 hours, 7 hours to 60 hours, 8 hours to 60 hours, 9 hours to 60 hours, 10 hours to 60 hours, 15 hours to 60 hours, 24 hours to 60 hours, 36 hours to 60 hours, 48 ​​hours to 60 hours, 4 hours to 55 hours, 5 hours to 55 hours, 6 hours to 55 hours, 7 hours to 55 hours, 8 hours to 55 hours, 9 hours to 55 hours, 10 hours to 55 hours, 15 hours to 55 hours, 24 hours to 55 hours, 36 hours to 55 hours, or 48 hours to 55 hours max can be generated.

[0258] Furthermore, the longer T for sustained release compositions such as the gastroenterically coated delayed release tablets described above compared to capsules. max The advanced drug release profile also suggests that the release and absorption or uptake rates (used interchangeably in this disclosure) of the therapeutic agent ((Z)-endoxifen or a polymorph or salt thereof) into the subject's blood from an orally administered sustained release composition are slow compared to the release and absorption rates of the therapeutic agent from a capsule. In certain embodiments, the present disclosure provides that a sustained release composition, for example, in the form of a sustained release tablet, such as an enteric-coated delayed release tablet, can achieve one or more of the pharmacokinetic parameters and mean plasma concentrations as disclosed in Tables 14, 15, and 17 after oral administration of a single dose of the sustained release composition to a subject. In some embodiments, the T of the sustained release composition of the present disclosure after a single dose maxThe median T is about 65-75 hours. In at least one embodiment, the T of the sustained release composition of the present disclosure after administration of a single dose is max The median time is approximately 73 hours.

[0259] Exemplary pharmacokinetic parameters for multiple doses (eg, 14 once-daily doses) of extended-release tablets in the form of enteric-coated delayed-release tablets of the present disclosure are provided herein.

[0260] As a non-limiting example, for certain embodiments, a sustained release composition (e.g., in the form of a sustained release tablet, such as an enteric-coated delayed release tablet) may be administered orally in multiple equivalent doses (e.g., 1 mg once daily for 14 days) to a subject, such that the AUC last at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, and at least about 90% of the mean plasma AUC last (time × ng / mL) or such mean plasma AUC last In certain embodiments, the sustained release composition in the form of an enteric-coated delayed-release tablet of the disclosed hardness can achieve a mean plasma AUC of the capsule when the sustained release composition and capsule are orally administered in multiple equivalent doses (e.g., 4 mg once daily for 14 days) to subjects in a fasted state. last At least 60% of the mean plasma AUC last or such a mean plasma AUC last can be achieved.

[0261] As a non-limiting example, for certain embodiments, a sustained release composition (e.g., in the form of a sustained release tablet, such as an enteric-coated delayed release tablet) may be administered orally in multiple equivalent doses (e.g., 1 mg once daily for 14 days) to a subject, such that the AUC tauat least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 70%, at least about 75%, and at least about 80%, at least about 85%, and at least about 90% of the mean plasma AUC tau (time × ng / mL) or such mean plasma AUC tau In certain embodiments, the sustained release composition of the present disclosure in the form of an enteric coated delayed release tablet of the present disclosure can achieve an AUC of the capsule when the sustained release composition and capsule are orally administered in multiple equivalent doses (as a non-limiting example, 4 mg once daily for 14 days) to a subject in a fasted state. tau At least about 50% of the mean plasma AUC tau (time × ng / mL) or such mean plasma AUC tau can be achieved.

[0262] Similarly, in certain embodiments, the sustained release compositions of the present disclosure (e.g., in the form of sustained release tablets, such as enteric coated delayed release tablets) exhibit a C of the capsule when the sustained release composition and capsule are orally administered to a subject in multiple equivalent doses (as a non-limiting example, 1 mg once daily for 14 days). max at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, and at least about 90% of the mean plasma C max (ng / mL) or such mean plasma C max In certain embodiments, the sustained release composition of the present disclosure, for example in the form of an enteric coated delayed release tablet of the present disclosure, can achieve a C of the capsule when the sustained release composition and capsule are orally administered in multiple equivalent doses (as a non-limiting example, 4 mg once daily for 14 days) to a subject in a fasted state. max At least about 45% of the mean plasma C max(ng / mL) or such mean plasma C max can be achieved.

[0263] Similarly, in certain embodiments, the sustained release compositions of the present disclosure (e.g., in the form of sustained release tablets, such as enteric-coated delayed-release tablets) exhibit a C of 1 mg / dose of the capsule when the sustained release composition and capsule are orally administered to a subject in multiple equivalent doses (as a non-limiting example, 1 mg once daily for 14 days). min at least about 40%, at least about 45%, at least about 50%, at least about 55%, and at least about 60% of the mean plasma C min (ng / mL) or such mean plasma C min can be achieved. In certain embodiments, the sustained release composition of the present disclosure in the form of an enteric coated delayed release tablet of the present disclosure exhibits a C of the capsule when the sustained release composition and capsule are orally administered in multiple equivalent doses (as a non-limiting example, 4 mg once daily for 14 days) to a subject in a fasted state. min At least 45% of the mean plasma C min (ng / mL) or such mean plasma C min can be achieved.

[0264] The present disclosure provides a method for determining whether a sustained release composition of the present disclosure (e.g., a delayed release tablet, such as an enteric-coated delayed release tablet) reduces the mean plasma C of a reference product capsule when the sustained release composition and capsule are orally administered to subjects at multiple equivalent doses (as a non-limiting example, 1 mg once daily for 14 days). average Mean plasma C that is substantially equal to or less than (ng / mL) average (ng / mL) or such mean plasma C average As a non-limiting example, the mean plasma C of delayed-release tablets in the form of enteric-coated delayed-release tablets can be achieved. average(ng / mL) is the mean plasma C of the reference product capsule when the sustained-release compositions and capsules are orally administered at multiple equivalent doses (as a non-limiting example, 4 mg once daily for 14 days) to subjects in a fasted state. average (ng / mL) (see FIG. 16). In certain embodiments, the sustained release compositions of the present disclosure have a C of the capsule when the sustained release composition and capsule are orally administered to a subject in multiple equivalent doses (for example, 1 mg once daily for 14 days). average at least about 40%, at least about 45%, at least about 50%, at least about 55%, and at least about 60% of the mean plasma C average (ng / mL) or such mean plasma C average In certain embodiments, the sustained release composition of the present disclosure in the form of an enteric coated delayed release tablet of the present disclosure can achieve a C of the capsule when the sustained release composition and capsule are orally administered in multiple doses (as a non-limiting example, 4 mg once daily for 14 days) to a subject in a fasted state. average At least 45% of the mean plasma C average (ng / mL) or such mean plasma C average can be achieved.

[0265] The mean time to reach steady-state levels of (Z)-endoxifen or a polymorph or salt thereof with multiple doses of the sustained-release compositions of the present disclosure is about 14 days. At steady state, the sustained-release compositions of the present disclosure show less variability over the period between doses compared to the reference product capsules.

[0266] Compositions of the present disclosure (e.g., compositions comprising (Z)-endoxifen) can produce a steady-state average concentration (Css) of endoxifen in a subject. In some embodiments, the composition can produce a steady-state average concentration (Css) of endoxifen in a subject of 1 ng / mL to 10 ng / mL, 5 ng / mL to 15 ng / mL, 10 ng / mL to 20 ng / mL, 15 ng / mL to 25 ng / mL, 20 ng / mL to 30 ng / mL, 25 ng / mL to 35 ng / mL, 30 ng / mL to 40 ng / mL, 35 ng / mL to 45 ng / mL, 40 ng / mL to 50 ng / mL, 45 ng / mL to 60 ng / mL, 50 ng / mL to 65 ng / mL, 60 ng / mL to 70 ng / mL, 75 ng / mL to 80 ng / mL, 85 ng / mL to 90 ng / mL, 90 ng / mL to 100 ng / mL, 100 ng / mL to 120 ng / mL, 125 ng / mL to 140 ng / mL, 145 ng / mL to 150 ng / mL, 150 ng / mL to 160 ng / mL, 165 ng / mL to 180 ng / mL, 185 ng / mL to 200 ng / mL, 185 ng / mL to 220 ng / mL, 185 ng / mL to 240 ng / mL, 185 ng / mL to 260 ng / mL, 185 ng / mL to 280 ng / mL, 185 ng / mL to 290 ng / mL, A steady-state mean concentration (Css) of 100ng / mL to 70ng / mL, 60ng / mL to 80ng / mL, 70ng / mL to 90ng / mL, 80ng / mL to 100ng / mL, 90ng / mL to 110ng / mL, 100ng / mL to 120ng / mL, 110ng / mL to 130ng / mL, 120ng / mL to 140ng / mL, or 130ng / mL to 150ng / mL can be produced. In some embodiments, the composition can produce a steady state average concentration (Css) in a subject of 1 ng / mL to 10 ng / mL, 5 ng / mL to 15 ng / mL, 10 ng / mL to 20 ng / mL, 15 ng / mL to 25 ng / mL, 20 ng / mL to 30 ng / mL, 25 ng / mL to 35 ng / mL, or 30 ng / mL to 40 ng / mL per milligram of endoxifen administered to the subject.

[0267] In certain embodiments, the present disclosure provides that a sustained release composition, e.g., in the form of a sustained release tablet, such as an enteric-coated delayed release tablet, can achieve one or more of the pharmacokinetic parameters set forth in Table 16 or Table 17 after multiple doses of oral administration to a subject or at steady state. In other embodiments, the T of a sustained release composition of the present disclosure after multiple doses or at steady state can be max The median T is in the range of about 3 to 5 hours. In at least one embodiment, the T of the sustained release compositions of the present disclosure after multiple doses or at steady state is max The median time is 4 hours.

[0268] The present disclosure provides, in some embodiments, the relative bioavailability of a therapeutic agent from a sustained-release composition of the present disclosure, such as an enteric-coated delayed-release tablet, when orally administered in single and / or multiple doses, ranges from at least about 40% to at least about 90% compared to an equivalent single or multiple dose of a reference product, capsule, administered orally to a subject. In certain embodiments, single and / or multiple doses of an enteric-coated delayed-release tablet of the present disclosure taken orally by a subject can provide or achieve a relative bioavailability of at least about 60% to at least about 90% compared to an equivalent single or multiple oral dose of capsule. Improved pharmacokinetic parameters (e.g., plasma and serum T) of a therapeutic agent ((Z)-endoxifen or a polymorph or salt thereof) as disclosed herein can be achieved. max Sustained release compositions in the form of enteric coated delayed-release tablets having a bioavailability of the therapeutic agent that is longer and less variable, and has a lower frequency and / or intensity of vasomotor side effects (see Example 8)), may be desirable for long-term use for breast disorders, e.g., treatment and prevention of breast disorders, e.g., treatment and prevention of breast cancer, prevention of breast density, reduction of breast density and for reducing breast density to reveal breast cancer, and for continued use and compliance by the subject.

[0269] Thus, the present disclosure provides that the therapeutic agent ((Z)-endoxifen or a polymorph or salt thereof) is absorbed and systemically available in a controlled, sustained manner after 2 hours. The present disclosure also provides that the sustained-release composition provides a consistent and consistent profile of peak drug concentrations in plasma and serum, as well as of the AUC curve, e.g., AUC 1000 over the dose range of 0.1 mg to 8 mg. inf It is suggested that the dose is proportional to the dose.

[0270] In certain aspects, the present disclosure provides that the sustained-release compositions of the present disclosure and their pharmacokinetics advantageously produce fewer side effects, such as vasomotor symptoms (hot flashes, night sweats, feeling of "hot" heat, sleep disturbances, and the like), compared to tamoxifen. The present disclosure provides that while 78% of subjects taking tamoxifen reportedly experienced hot flashes (Mortimer et al. Breast Cancer Res Treat. 2008 Apr;108(3):421-426), less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, and less than 25% of subjects orally administered the sustained-release compositions of the present disclosure experience side effects, such as vasomotor symptoms, such as hot flashes, night sweats, feeling of hot heat, sleep disturbances, and the like. In some embodiments, less than 50% of subjects taking sustained-release tablets experience vasomotor symptoms, such as hot flashes, night sweats, and the like. In some embodiments, less than 30% of the subjects who take sustained-release tablets experience vasomotor symptoms, such as hot flashes, night sweats and the like.In certain embodiments, the sustained-release compositions of the present disclosure that are orally administered cause such vasomotor symptoms in subjects at a frequency of less than about 25% of the days on which the drug is administered, less than about 20%, less than about 15%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, and less than about 1% of the days on which the drug is administered.In at least one embodiment, as a result of oral administration of the sustained-release compositions of the present disclosure, subjects will experience such vasomotor symptoms at a frequency of less than about 25% of the days on which the drug is administered.

[0271] In another aspect, the present disclosure provides that the sustained release compositions of the present disclosure provide a subject with a longer, controlled exposure to (Z)-endoxifen or a polymorph or salt thereof. In some embodiments, a subject is exposed to the therapeutic agent (Z)-endoxifen or a polymorph or salt thereof for a period ranging from about 2 hours to about 270 hours per dose after release of the therapeutic agent from the sustained release composition.

[0272] In another aspect, the present disclosure relates to methods of making the sustained-release compositions of the present disclosure. Solid dosage forms of the sustained-release compositions of the present disclosure can be prepared by dry compression, dry granulation, or wet granulation. Direct dry compression or dry granulation is preferred to reduce the possibility of interconversion of (Z)-endoxifen and the inactive (E)-endoxifen isomer in the solution phase.

[0273] In one embodiment of the present invention, (Z)-endoxifen or a polymorph or salt thereof and a sustained-release agent are mixed with a binder, also referred to herein as a tablet matrix. In one embodiment, the binder has an average particle size of about 10 μm to about 500 μm, e.g., between 25 μm and 150 μm. Particles in this size range are particularly useful for direct compression processes. In one embodiment, the components are blended together, e.g., as dry powders, and fed into a die cavity of a device that applies pressure to form a tablet. Any suitable compression molding device can be used, including, but not limited to, a conventional single-punch or rotary tablet press. In one embodiment, tablets can be formed by compression using a rotary tablet press (e.g., one commercially available from Fette America Inc., Rockaway, NJ, or Manesty Machines LTD, Liverpool, UK). Typically, a metered volume of the blended mixture is filled into the die cavity of a rotary tablet press (the blended mixture is gravity-fed from a feeder or mechanically fed), and the cavity rotates from the fill position to the compression position as part of a "die table." At the compression position, the blended mixture is compressed between an upper and lower punch, and the resulting tablet is then pushed out of the die cavity by the lower punch and then guided by a fixed "ejector" bar into an injection chute.

[0274] In one embodiment, tablet can be a direct compression tablet core made from powder that is substantially free of water-soluble polymer binder and hydrated polymer.As used herein, "substantially free" means less than 5%, for example, less than 1%, for example, less than 0.1%, for example, completely free (for example, 0%).This composition is advantageous for minimizing tablet processing and material costs and providing optimal physical and chemical stability.

[0275] Example 1 provides further details regarding methods for making extended-release tablets (cores) containing (Z)-endoxifen free base. Non-limiting exemplary tablet cores containing 4% (4 mg) (Z)-endoxifen free base produced by the disclosed methods are provided in Table 2. Properties of certain exemplary extended-release tablets (core tablets) produced by such methods are provided in Table 3.

[0276] As a non-limiting example, extended release tablets, including 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, and 40 mg (Z)-endoxifen tablets, as provided in Tables 1 and 5, can be prepared using the methods disclosed herein. Those skilled in the art will understand that additional extended release tablets, including 0.5 mg to 200 mg extended release solid dosage forms (cores), can be prepared based on the present disclosure. Table 1. Exemplary extended-release tablets (cores) [Table 1]

[0277] In at least one embodiment, a method for preparing a sustained release composition in the form of an enteric coated delayed-release tablet for the sustained release of (Z)-endoxifen or a polymorph or salt thereof, comprising preparing a solid dosage form such as a tablet, wherein preparing the solid dosage form such as a core tablet comprises: a. combining (i) (Z)-endoxifen or a polymorph or salt thereof, (ii) at least one sustained-release agent (e.g., hypromellose), (iii) at least one binder (e.g., microcrystalline cellulose), and (iv) at least one lubricant (e.g., magnesium stearate) to obtain a component blend; b. blending the component mixture of step (a) so that (Z)-endoxifen or a polymorph or salt thereof is uniformly dispersed in the component mixture to obtain a blended mixture; and c. Dry compressing the blended mixture to form a solid dosage form, such as a tablet (e.g., a core tablet). A method is provided herein, comprising:

[0278] In some embodiments, the method includes the steps of: (a) combining and blending (i) (Z)-endoxifen or a polymorph or salt thereof, (ii) at least one sustained-release agent (e.g., hypromellose), and (iii) at least one binder (e.g., microcrystalline cellulose) to form a component mixture; (b) adding at least one lubricant, such as magnesium stearate, to the component mixture and further blending to obtain a blended mixture; and (c) dry-compressing the blended mixture to form a solid dosage form, such as a tablet (e.g., a core tablet).

[0279] In certain embodiments, the sustained release composition in the form of a solid dosage form is substantially encapsulated in at least one functional coating layer by coating a functional coating solution onto the solid dosage form, where the coating solution is prepared by combining at least one release-controlling agent, e.g., a delayed-release agent (a non-limiting example is a poly(methacrylate) polymer, e.g., methacrylic acid-ethyl acrylate copolymer (1:1) (polymethacrylate-methacrylic acid copolymer dispersion, 30% solids)) with a diluent or solvent to form the coating solution.

[0280] In certain embodiments, the ratio of (Z)-endoxifen or a polymorph or salt thereof to sustained-release agent ranges from 1:10 to 10:1. In some embodiments, the ratio of (Z)-endoxifen or a polymorph or salt thereof to sustained-release agent ranges from 2:6 to 6:2. In certain embodiments, the ratio of (Z)-endoxifen or a polymorph or salt thereof to sustained-release agent is 1:5.

[0281] In certain embodiments, the sustained release composition in the form of a solid dosage form is substantially encapsulated in at least one functional coating layer by coating a functional coating solution onto the solid dosage form, where the coating solution is prepared by combining at least one release-controlling agent, e.g., a delayed-release agent (non-limiting example is a poly(methacrylate) polymer, e.g., methacrylic acid-ethyl acrylate copolymer (1:1) (polymethacrylate-methacrylic acid copolymer dispersion, 30% solids)), at least one plasticizer (e.g., triethyl citrate), and at least one anti-blocking / anti-adherent agent (e.g., talc) to form the coating solution.

[0282] In at least one embodiment, there is provided a method for preparing an enteric coated delayed-release tablet for extended release of (Z)-endoxifen, or a salt or polymorph thereof, comprising: a. preparing a solid dosage form such as a tablet, the preparation of the solid dosage form such as a core tablet comprising: (1) combining (i) (Z)-endoxifen or a polymorph or salt thereof, (ii) at least one release rate controlling agent (e.g., hypromellose), (iii) at least one binder (e.g., microcrystalline cellulose), and (iv) at least one lubricant (e.g., magnesium stearate) to obtain a combined mixture; (2) blending the combined mixture of step (a) such that the (Z)-endoxifen or a polymorph or salt thereof is uniformly dispersed in the combined mixture; and (3) dry-compressing the combined mixture to obtain a core tablet; and b. combining at least one delayed-release controlling agent (non-limiting example is a poly(methacrylate) polymer, e.g., methacrylic acid-ethyl acrylate copolymer (1:1) (polymethacrylate-methacrylic acid copolymer dispersion, 30% solids)), at least one plasticizer (e.g., triethyl citrate), and at least one anti-blocking / anti-adherent agent (e.g., talc) to form a coating solution; and c. Substantially coating the core tablet of step (a) with a coating solution to form at least one functional coating layer. A method is provided herein, comprising:

[0283] Examples 2 and 3 provide further details regarding methods for preparing enteric-coated delayed-release tablets using the cores prepared in Example 1 and disclosed in Tables 1 and 2. The coating solutions used to prepare at least one functional coating layer are provided in Table 4. Similarly, enteric-coated delayed-release tablets containing 0.5 mg to 200 mg of (Z)-endoxifen or a polymorph or salt thereof can be prepared.

[0284] It will be further understood by those skilled in the art that the sustained-release compositions disclosed herein can contain one or more of the excipients known in the art and disclosed herein in any combination suitable for desired formulation or preparation. Additional excipients can generally be found in Remington's The Science and Practice of Pharmacy, Meade Publishing Co., United States Pharmacopeia / National Formulary, and Handbook of Pharmaceutical Excipients, 3rd edition, Edited by AH Kibbe, Published by: American Pharmaceutical Association, Washington DC, ISBN: 0-917330-96-X, or Handbook of Pharmaceutical Excipients (4th edition), Edited by Raymond C Rowe--Publisher: Science and Practice. Those skilled in the art will be able to select the appropriate excipients required for the preparation of a formulation and the appropriate dosage form compatible with the administration route based on their own skills, knowledge in the art, and the disclosure made herein. In all cases, the final dosage form must not exceed microbial purity and quality standards and must be stable under the conditions of manufacture and storage.

[0285] The methods and compositions disclosed herein are industrially scalable and meet the standards required for administering such sustained release compositions to subjects. <905> would meet the criteria.

[0286] For tablet formulations disclosed herein, testing for total antimicrobial count (TAC) and USP indicator microorganisms is not required if the water activity (Aw) is less than 0.75. The publication, "Microbial Bioburden on Oral Solid Dosage Form," by Jose E. Martinez, Pharmaceutical Technology, February 2002, pages 58 to 70, is hereby incorporated by reference in its entirety.

[0287] Additionally, formulations of the compositions disclosed herein also have a water activity of less than 0.75, so that no extensive microbial testing must be performed. The TAC is an estimate of the total viable aerobic microorganisms present in a sample of raw materials, intermediate materials, or finished products. Samples are tested according to the latest USP 42 <61> The test is analyzed in accordance with "Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests."

[0288] Acceptable TACs for oral solid dosage forms are 10 and 15 for formulations of the compositions of the present invention, respectively. 3 cfu g / mL and 1 × 10 4 The alert and action levels are established by the cfu g / mL. 4 A TAC of cfu g / mL is considered unacceptable. An acceptable combined yeast and mold count (TYMC) is NMT 10 2 CFU / g. The absence of E. coli in 1 g is (USP <1111> (according to the ) is considered acceptable.

[0289] The present disclosure provides that the sustained-release compositions of the present disclosure are stable at ambient temperatures for at least 1 month, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 2 years, at least 3 years, at least 4 years, and at least 5 years. The present disclosure also provides that (Z)-endoxifen and its polymorphs and salts in the sustained-release compositions of the present disclosure are stable at ambient temperatures for at least 1 month, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 2 years, at least 3 years, at least 4 years, and at least 5 years. In at least one embodiment, the sustained-release compositions in the form of sustained-release tablets and enteric-coated delayed-release tablets are stable at ambient temperatures for at least 1 year. In at least one embodiment, the (Z)-endoxifen or its polymorphs or salts in the sustained-release compositions in the form of sustained-release tablets and enteric-coated delayed-release tablets are stable at ambient temperatures for at least 1 year. The present disclosure provides that the sustained-release compositions of the present disclosure are stable at 25°C / 60%RH (relative humidity) and 40°C / 75%RH (relative humidity) for at least 1 month, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 2 years, at least 3 years, at least 4 years, and at least 5 years. The present disclosure also provides that (Z)-endoxifen and its polymorphs and salts in the sustained-release compositions of the present disclosure are stable at 25°C / 60%RH and 40°C / 75%RH for at least 1 month, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 2 years, at least 3 years, at least 4 years, and at least 5 years.

[0290] The sustained release compositions comprising (Z)-endoxifen and its polymorphs and salts disclosed herein can be used in the manufacture of a medicament for use in treating a subject in need thereof.

[0291] In some aspects, the present disclosure provides that, without regard to mechanism of action or any other theory, subjects suffering from or at risk of suffering from a disorder susceptible to (Z)-endoxifen and its polymorphs and salts can be treated with the sustained-release compositions of the present disclosure. In some embodiments, the disorder is a hormone-dependent disorder. In some embodiments, the disorder is a mental or mood disorder, such as depression, mania, hypomania, or bipolar disorder. Such mental or mood disorders may or may not have psychotic features. Such mental or mood disorders may be hormone-independent or hormone-dependent.

[0292] The sustained-release composition of the present disclosure can be used by orally administering it to a subject in need thereof.In a specific embodiment, the subject is orally administered the sustained-release composition of the present disclosure in the form of a sustained-release tablet.In other embodiments, the subject is orally administered the sustained-release composition of the present disclosure in the form of an enteric-coated delayed-release tablet as disclosed herein.

[0293] The sustained release compositions of the present disclosure can be used as a primary treatment, as part of neoadjuvant therapy (towards primary therapy), or as part of an adjuvant therapy regimen, with the goal of improving or curing subjects suffering from or at risk of suffering from disorders such as hormone-dependent disorders or mental or mood disorders. In some embodiments, the sustained release compositions can be used during the "window of opportunity," where patients newly diagnosed with such disorders are administered the composition from the time of diagnosis until the date of surgery. Non-limiting examples include those for ER, requiring mastectomy or lumpectomy. + and HER2 negative (HER2 -) Patients newly diagnosed with stage 1 or 2 invasive breast cancer can be administered the sustained-release composition of the present disclosure for at least 14 days from the time of diagnosis until the date of surgery. In some embodiments, the treatment window can be after a patient is diagnosed with cancer or before the patient undergoes surgery to remove the cancer. Even if the patient never undergoes surgery, treatment can be administered during the treatment window between diagnosis and surgery. For example, a composition of the present disclosure can be administered to a patient after a cancer diagnosis but before the patient is predicted, scheduled, or recommended to undergo surgery to remove the cancer. In some embodiments, the treatment window can begin when a breast condition (e.g., cancer, lesion, or dense breast) is identified on a mammogram. Administration of the composition can extend the treatment window by delaying surgery or by reducing or eliminating necessary surgery. In some embodiments, administration of a composition comprising endoxifen can extend the treatment window after a cancer diagnosis. The extended therapeutic window allows more time to perform imaging studies, obtain tumor specimens, and obtain blood samples.

[0294] In some embodiments, the therapeutic window (e.g., the time between cancer diagnosis and surgery to remove the cancer) can be extended by at least 5 days, at least 10 days, at least 15 days, at least 20 days, at least 25 days, at least 30 days, at least 60 days, at least 90 days, at least 120 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 1 year, at least 1.2 years, at least 1.4 years, at least 1.6 years, at least 1.8 years, at least 2 years, at least 2.5 years, at least 3 years, at least 3.5 years, at least 4 years, at least 4.5 years, or at least 5 years. In some embodiments, the therapeutic window can be extended indefinitely after administration of a composition of the present disclosure (e.g., a composition comprising endoxifen).

[0295] In certain embodiments, the disorder is a breast disorder. In some embodiments, the disorder is a hormone-dependent breast disorder. In other embodiments, the disorder is a hormone-dependent reproductive system disorder. In still other embodiments, 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, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, dense breast tissue, gynecomastia, DCIS, LCIS, breast cancer, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer.

[0296] In some embodiments, the breast disorder is hyperdense breast tissue. For example, the breast disorder is BI-RAD class B (formerly class II), class C (formerly class III), or class D (formerly class IV) breast tissue density. Administration of the sustained release composition of the present disclosure to a subject with hyperdense breast tissue (class B, C, or D) reduces the amount and severity of the hyperdense breast tissue observed in the subject. The reduction in the subject's hyperdense breast tissue induced by the sustained release composition is advantageous not only in reducing the independent risk factor for breast cancer caused by hyperdense breast tissue, but also in revealing previously undetectable breast disorders such as breast cancer. Thus, in some embodiments, treating a subject suffering from breast cancer hidden by hyperdense breast tissue with the sustained release composition of the present disclosure can reduce the subject's hyperdense breast tissue and reveal breast cancer.

[0297] 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.

[0298] In some embodiments, the breast disorder is gynecomastia. In some embodiments, gynecomastia is secondary to an underlying disease or is the result of certain medication use (such as exogenous estrogens, antiandrogens (e.g., bicalutamide, flutamide, finasteride, dutasteride), antihypertensive drugs (e.g., spironolactone, 5-alpha reductase inhibitors), antiretroviral agents (e.g., protease inhibitors (e.g., saquinavir, indinavir, nelfinavir, ritonavir, lopinavir), reverse transcriptase inhibitors (stavudine, zidovudine, lamivudine) and gastrointestinal drugs (e.g., H2 histamine receptor blockers (e.g., cimetidine)). Thus, in some embodiments, the subject also has 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 has prostate cancer as the underlying disease, and the subject suffers from or is at risk of suffering from gynecomastia.Administering the sustained-release composition of the present disclosure to the subject suffers from or is at risk of suffering from gynecomastia can alleviate gynecomastia or reduce the risk of developing gynecomastia.The alleviation induced by the sustained-release composition of gynecomastia can result in the reduction of at least one symptom of the disorder, such as breast swelling (breast tissue volume), discomfort or pain.Such sustained-release composition can also improve the physical health and mental health of the subject, including depression.

[0299] In certain embodiments, the breast cancer is DCIS, LCIS, ILC, IDC, MIC, inflammatory breast cancer, ER-positive (ER + ) Breast cancer, HER2 + Breast cancer, BRCA1 + Breast cancer, BRCA2 + Breast cancer, adenoid cystic (adenocystic) carcinoma, low-grade squamous cell carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, or micropapillary carcinoma. In at least one embodiment, the single breast cancer tumor may be a combination of the above, or may be a mixture of invasive and non-invasive carcinoma.

[0300] The present disclosure contemplates the use of the sustained release compositions disclosed herein in various stages of tumor development and progression, including the treatment of advanced and / or high-grade neoplasms, for example, overt disease, metastatic disease, or locally advanced disease in subjects who are unable to be cured by local methods such as surgery or radiotherapy.Therefore, in some embodiments, breast cancer is precancerous, early cancer, non-metastatic cancer, pre-metastatic cancer, or locally advanced cancer.In at least one embodiment, breast disorder is metastatic cancer.In some embodiments, the subject is further affected by prostate cancer.

[0301] The administration of the sustained release composition of the present disclosure can reduce the occurrence of any hormone-dependent disorder.In the case of a subject suffering from breast cancer, the administration, for example, oral administration, of the sustained release composition of the present disclosure to a subject suffering from breast cancer can alleviate or improve the symptoms of the disease, can reduce the disease burden, can slow the growth rate of cancer, can reduce the volume or size of tumors, can reduce or prevent tumor angiogenesis, tumor escape and metastasis, and can reduce disease biomarkers, such as BRCA-1, BRCA-2, ER, PR, Her2, uPA, PAI, Tf, p53, Ki-67, cytokines, cancer tumor antigens, and other biomarkers measured by Mammaprint, OncotypeDx, PAM50, EndoxPredict, MammoStrat, and other diagnostic and predictive tests known in the art. For example, administration of a composition of the present disclosure (e.g., a composition comprising (Z)-endoxifen) can reduce the level of the Ki-67 biomarker in a tumor after endoxifen administration by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% compared to the level before endoxifen administration. In some embodiments, the level of a biomarker (e.g., BRCA-1, BRCA-2, ER, PR, Her2, uPA, PAI, Tf, p53, Ki-67, cytokeratin, or cancer tumor antigen) can be measured in tissue (e.g., breast tissue, cancer tissue, non-cancerous tissue, or biopsy tissue) obtained from a subject. In some embodiments, the level of the biomarker can be measured in a bodily fluid (eg, blood, plasma, intraductal fluid, breast milk, urine, or saliva) taken from the subject.In some embodiments, the level of a biomarker in a tissue or fluid taken from a subject after treatment with endoxifen can be compared to the level of the biomarker in a tissue or fluid taken from the subject before administering endoxifen. In some embodiments, the level of a biomarker in a tissue or fluid taken from a subject after treatment with endoxifen can be compared to the average or expected level of the biomarker in a similar tissue or fluid from a normal subject (e.g., an unaffected individual). In some embodiments, the level of a biomarker in a tissue or fluid taken from a subject before administering endoxifen can be compared to the average or expected level of the biomarker in a similar tissue or fluid from an unaffected individual. In some embodiments, the average or expected level of the biomarker can be from a database of biomarker levels.

[0302] By administering the sustained-release composition of the present disclosure to subjects suffering from breast disorders such as breast cancer or dense breast tissue, compared with anti-cancer drugs such as tamoxifen or immediate-release endoxifen, subjects may experience fewer side effects, such as vasomotor effects, such as hot flashes, night sweats, headaches, dry mouth, and the like. Tamoxifen is effective in treating breast cancer or reduced breast tissue, but it causes vasomotor symptoms of mild, moderate, or severe intensity, which may occur more than 25 times a day, or as frequently as every day. As many as 78% of subjects taking tamoxifen endure hot flashes (Mortimer et al.). The number of hot flash events multiplied by the severity of each event (using a scale of 1 for mild, 2 for moderate, and 3 for severe) is used to derive a score for perseverance ("perseverance score"). For example, a woman who has five mild hot flashes and two severe hot flashes in two days will have a score of 11 (1 x 5 + 2 x 3). The higher this number, the lower the tolerance to the drug. As a result, although tamoxifen can prevent more than 50% of breast cancers, fewer than 5% of women who could benefit from tamoxifen or endoxifen actually take the drug due to poor tolerability, which leads to low adherence to treatment regimens. This represents a huge unmet medical need for drugs with improved tolerance. For some time, SSRIs were administered to women receiving tamoxifen to relieve vasomotor symptoms, but SSRIs alleviated symptoms by simply inhibiting the formation of tamoxifen's active metabolite, endoxifen, which is required for treatment, and / or breast cancer recurrence.

[0303] In one aspect, the present disclosure provides that subjects orally administered a sustained-release (Z)-endoxifen composition of the present disclosure, such as a sustained-release tablet, experience fewer vasomotor symptoms (e.g., fewer days or fewer events) over the course of a drug administration period, such as hot flashes, night sweats, cold sweats, or a feeling of heat, compared to subjects orally administered a capsule that is tamoxifen. In another aspect, the present disclosure provides that fewer subjects administered such sustained-release compositions experience vasomotor symptoms compared to subjects administered tamoxifen. In another aspect, the present disclosure provides that subjects orally administered a sustained-release composition experience vasomotor symptoms that are less intense than those experienced by subjects administered tamoxifen.

[0304] The present disclosure provides that lower, i.e., improved, tolerability scores are observed for subjects taking the sustained release composition compared to tolerability scores for those taking tamoxifen.

[0305] Based on the in vitro release profiles and pharmacokinetic profiles of the sustained-release compositions disclosed herein, subjects taking sustained-release tablets, e.g., in the form of enteric-coated delayed-release tablets, absorb the therapeutic agent (Z)-endoxifen and its polymorphs and salts into their blood at a slow rate. While not wishing to be bound by any mechanism of action or any other theory, the present disclosure proposes that the improved tolerance scores and / or reduced vasomotor symptoms experienced by subjects taking the sustained-release compositions of the present disclosure (e.g., in the form of sustained-release tablets) are attributable to the novel sustained-release compositions and the desirable pharmacokinetic profiles of the enteric-coated delayed-release tablets.

[0306] Provided herein are methods of treating a subject suffering from a disorder by orally administering a sustained release composition of the present disclosure, wherein the composition is capable of achieving one or more pharmacokinetic parameters disclosed in Tables 14-17.

[0307] The present disclosure provides that subjects orally administered a sustained-release composition of the present disclosure experience vasomotor effects (e.g., hot flashes, night sweats, or a feeling of heat) less than 25%, less than 20%, less than 15%, less than 10%, and less than 5% of the days on which the drug is administered. In certain embodiments, subjects orally administered a sustained-release composition of the present disclosure experience vasomotor effects less than 25% of the days on which the drug is administered. In at least one embodiment, subjects orally administered a sustained-release composition of the present disclosure experience vasomotor effects less than 5% of the days on which the drug is administered. Thus, provided herein is a method for treating a subject suffering from a disorder by orally administering a sustained-release composition of the present disclosure, wherein the subject experiences vasomotor effects (e.g., hot flashes, night sweats, or a feeling of heat) less than 25% of the days on which the drug is administered upon ingesting the sustained-release composition. For example, if a subject is administered a sustained release composition of the present disclosure once daily for 100 days, the subject will experience vasomotor symptoms (e.g., hot flashes) on 25 of the days that the subject takes the composition.

[0308] The percentage of subjects administered or taking extended-release (Z)-endoxifen tablets who experience vasomotor symptoms (such as hot flashes, burning sensations, and night sweats) (approximately 25%) is also lower compared to the reported percentage of subjects administered tamoxifen who experience hot flashes (approximately 78%). Those skilled in the art will readily appreciate that improved tolerability to extended-release compositions (e.g., extended-release (Z)-endoxifen tablets of the present disclosure) due to reduced or fewer vasomotor symptoms will advantageously promote greater compliance with treatment regimens in subjects suffering from disorders such as breast disorders.

[0309] Administration of the sustained-release composition of the present disclosure to a subject at risk of breast cancer or at risk of breast cancer recurrence can prevent the occurrence or recurrence of breast cancer, for example, delay (or prolong) the time to recurrence.Therefore, the sustained-release composition can be used for disease prevention or treatment.The current treatment option for such breast cancer disorders remains tamoxifen, despite the serious adverse effects, poor patient compliance, and drug resistance caused by low plasma endoxifen levels found in subjects.Such subjects may have low endoxifen levels when administered tamoxifen for several reasons, such as having CYP gene mutations, such as CYP2D6, CYP3A4, or CYP2C9 mutations, which prevent them from metabolizing tamoxifen to its active metabolite, endoxifen, or may have few or dysfunctional estrogen receptors, which prevent (or reduce) sufficient tamoxifen uptake for other reasons that have not yet been identified. The reported therapeutic level of plasma tamoxifen in subjects receiving 20 mg of oral tamoxifen is ≧30 nM (Lyon et al. Genet Med. 2012 Dec;14(12):990-1000). Regardless of the mechanism underlying low plasma endoxifen levels in subjects, the sustained-release compositions of the present disclosure are useful for any condition in which a subject has low endoxifen or in which the subject suffers from or is at risk for a hormone-dependent disorder. Therefore, the compositions of the present disclosure are particularly important for the treatment of tamoxifen-resistant, hormone-dependent disorders, including hormone-dependent breast disorders or hormone-dependent reproductive disorders.

[0310] In certain embodiments, patient populations for which the pharmaceutical composition is particularly useful are presented. The sustained-release compositions of the present disclosure are also particularly important for treating tamoxifen-resistant subjects with hormone-dependent disorders, including hormone-dependent breast disorders and hormone-dependent reproductive system disorders. Thus, in some embodiments, the sustained-release compositions disclosed herein are useful for treating tamoxifen-resistant or tamoxifen-resistant subjects suffering from or at risk of suffering from hormone-dependent disorders. In some embodiments, sustained-release compositions comprising endoxifen salts, such as (Z)-endoxifen gluconate, (Z)-endoxifen citrate, or (Z)-endoxifen hydrochloride, administered to such subjects at the doses disclosed herein are advantageous. In some embodiments, the sustained-release compositions are orally administered to subjects.

[0311] Furthermore, Donneyong et al. demonstrated that drug interactions exist between tamoxifen and selective serotonin reuptake inhibitor (SSRI) drugs such as fluoxetine (Prozac) and paroxetine (Paxil), which are harmful to breast cancer subjects (Donneyong et al. BMJ 2016;354:i5014). SSRI drugs SSRI's are antidepressants that reduce or stop the hepatic metabolism of tamoxifen to endoxifen in subjects using SSRI drugs. Thus, in certain embodiments, presented herein are patient populations being or will be treated with SSRI drugs (such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil, Pexeva), sertraline (Zoloft), vilazodone (Viibryd), and the like) that would benefit from treatment with the compositions of the present disclosure.

[0312] The sustained-release compositions disclosed herein are also suitable for treating the subject who suffers from or is at risk of suffering from disorders, such as mental or mood disorders, for example, depression, mania, hypomania, bipolar disorder and schizophrenia, whether or not the subject is treated with SSRI drugs.Such mental disorders may or may not have psychotic features. Research has shown that female reproductive events and hormonal treatments can affect the course of bipolar disorder and schizophrenia in women (Gogos A, Sbisa AM, Sun J, Gibbons A, Udawela M, Dean B. A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings. Int J Endocrinol. 2015;2015:615356. doi: 10.1155 / 2015 / 615356. Epub 2015 Sep 27. PubMed PMID: 26491441; PubMed Central PMCID: PMC4600562). Furthermore, research has shown that the risk of postpartum psychiatric disorders among primiparous women increases in the months following delivery (Munk-Olsen, T et al. JAMA. 2006 Dec 6;296(21):2582-9). In particular, childbirth is known to be associated with the onset of affective episodes in women with bipolar disorder (Meinhard N. et al. Nord J Psychiatry. 2014 Feb;68(2):81-7). Preliminary studies by Ahmad et al. and others suggest that tamoxifen and its metabolite endoxifen may have antimanic activity. Accordingly, the present disclosure provides that the sustained-release compositions of the present disclosure can be orally administered to subjects suffering from mental or mood disorders such as depression, mania, hypomania, bipolar disorder, and schizophrenia. Orally administered sustained-release compositions disclosed herein maintain a 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, plasma steady-state endoxifen levels are maintained at >40 nM.

[0313] Such maintenance of plasma endoxifen at steady-state levels greater than 30 nM is advantageous because the likelihood of recurrence (relapse) of hormone-dependent disorders, particularly breast cancer, is reduced at plasma endoxifen levels less than 30 nM, which is particularly advantageous for subjects receiving the compositions disclosed herein who are poor metabolizers of tamoxifen (having plasma endoxifen levels less than 16 nM) or intermediate metabolizers of tamoxifen (having plasma endoxifen levels less than 27 nM). It is also advantageous for subjects suffering from a mental or mood disorder (e.g., depression, mania, hypomania, bipolar disorder, and schizophrenia) and for subjects receiving or who are receiving treatment with an antidepressant, e.g., an SSRI drug, such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil, Pexeva), sertraline (Zoloft), vilazodone (Viibryd), and the like, e.g., for subjects suffering from or likely to suffer from a mental or mood disorder such as depression.

[0314] Although plasma endoxifen levels of ≥30 nM are desirable for the treatment and prevention of hormone-dependent disorders, such as breast cancer, in subjects suffering from or at risk of developing such disorders, lower plasma (Z)-endoxifen levels in a subject may be desirable under certain circumstances, for example, for the treatment and prevention of the development and progression of dense breast tissue (i.e., breast density). Although dense breast tissue (i.e., increased breast density or high breast density) is a common breast disorder, affecting 40-50 percent of women aged 40-74 in the United States alone (which is itself an independent risk factor for breast cancer in addition to masking the presence and preventing detection of existing breast tumors and cancers), and although approximately 34 states in the United States have laws requiring physicians to provide subjects with a handwritten letter informing them of their dense breast tissue status, no drugs are approved for the treatment or prevention (of the development or progression) of dense breast tissue. In one aspect, the present disclosure provides that a sustained release composition of the present disclosure can be administered to a subject with dense breasts (BIRAD classes B-D) in an amount effective to reduce breast density. In another aspect, the sustained release composition can be administered to prevent the development of dense breasts or the progression of breast density to a higher breast density class. In another aspect, the present disclosure provides that a sustained release composition of the present disclosure can be administered to a subject at risk for breast cancer hidden by breast density to reduce breast density and reveal breast cancer. Thus, provided herein is a method for reducing breast density in a subject, the method comprising the steps of: (a) determining whether the subject has breast density by (i) performing or having performed a mammogram on the subject's breasts; (ii) quantifying or having quantified the volume of dense tissue in the subject's breasts and classifying the subject's breast density into Class A, Class B, Class C, or Class D (wherein if the subject has Class C or Class D dense breasts, the subject is determined to have breast density and be at risk for breast cancer); and (b) administering to the subject an amount of a sustained release composition of the present disclosure, thereby reducing breast density in the subject.In some embodiments, administration of the sustained release composition reveals the presence of breast cancer in the subject.

[0315] The amount administered may be any amount effective to reduce breast density and / or to reveal breast cancer. In some embodiments, such amount may be any amount that maintains a subject's plasma (Z)-endoxifen level in the range of 2 nM to 300 nM for the treatment or prevention of breast density increase or the progression of dense breast tissue to a higher breast density class. In some embodiments, the plasma level of (Z)-endoxifen or a polymorph or salt thereof in a subject orally administered a sustained-release composition of the present disclosure may be maintained in the range of 2 nM to 25 nM, 10 nM to 30 nM, 5 to 15 nM, or 10 nM to 20 nM. In some embodiments, the plasma level of (Z)-endoxifen or a polymorph or salt thereof in a subject orally administered a sustained-release composition may be maintained in the range of ≥ 30 nM to 300 nM. A composition orally administered to such a subject can reduce breast density, prevent its occurrence or inhibit its progression to a higher breast density class, uncover underlying breast cancer, and / or reduce the independent risk of developing breast cancer. In some embodiments, the sustained-release composition administered to the subject is an enteric-coated delayed-release tablet capable of achieving one or more parameters of any one or more of Tables 14, 15, 16, and 17.

[0316] In certain embodiments, the subject's response to treatment can be monitored. For example, breast density or tumor size (if detectable at all) can be determined by performing or completing a mammogram on the subject's breast and comparing the breast density and / or tumor size in the subject's breast before and after treatment. Thus, the treatment method further includes performing or completing a mammogram on the subject's breast and determining whether the subject's breast density or breast tumor size shows a decrease, an increase, or no change compared to the breast density or breast tumor size of the subject quantified before treatment with the sustained-release composition. The healthcare professional can adjust the treatment regimen based on the observed changes. As a non-limiting example, the healthcare professional can administer a higher dose of the sustained-release composition if the concentration or tumor size increases, or can reduce the dose if the subject's breast density or tumor size decreases. In some embodiments, the healthcare professional can initiate treatment to maintain a lower plasma level of (Z)-endoxifen in the subject. In another aspect, provided herein is a method for treating a subject suffering from or at risk of suffering from a disorder susceptible to (Z)-endoxifen, who experiences vasomotor symptoms when administered tamoxifen at a frequency of ≥ 50% on the subject's drug administration days. Such a subject can benefit from oral administration of a sustained-release composition of the present disclosure, for example, by experiencing a reduction in the frequency of vasomotor symptoms to less than 50% on the subject's drug administration days. For example, if a subject receives a once-daily administration of a sustained-release composition for 14 days, the subject may experience vasomotor symptoms less than 7 days (i.e., 6 days or less) on the subject's drug administration days. In some embodiments, the frequency of vasomotor symptoms experienced by a subject who takes a sustained-release composition of the present disclosure can be reduced to less than 25% on the subject's drug administration days.Thus, provided herein are methods for treating a subject suffering from or at risk of suffering from a disease susceptible to (Z)-endoxifen, who experiences vasomotor symptoms when taking tamoxifen more than 50% of the subject's drug-administered days, the method comprising administering a sustained-release composition of the present disclosure, thereby reducing the frequency of vasomotor symptoms experienced by the subject to less than 50% of the subject's drug-administered days. In some embodiments, a subject taking a sustained-release composition of the present disclosure may experience vasomotor symptoms less than 25% of the drug-administered days. In some embodiments, a sustained-release composition of the present disclosure taken by a subject can achieve one or more parameters of any one or more of Tables 14, 15, 16, and 17. In some embodiments, the subject's individual pharmacokinetic parameters for (Z)-endoxifen or a polymorph or salt thereof released from the sustained-release composition are monitored to determine one or more of the pharmacokinetic parameters, for example, the absorption rate, T, of the therapeutic agent (Z)-endoxifen or a polymorph or salt thereof from the sustained-release composition in the subject. max The attending healthcare professional can determine the pharmacokinetic parameters of the drug in the subject and determine the rate of absorption, bioavailability, T max By using the method of the present invention to determine the optimal sustained release composition suitable for administration to a subject, a sustained release composition can be formulated having a drug release profile that is tailored to the subject.

[0317] In another aspect, provided herein is a method of treating a subject suffering from or at risk of suffering from a breast disorder, comprising: (a) orally administering to the subject a sustained-release composition of the present disclosure; (b) collecting or completing the collection of a biological sample, e.g., whole blood, plasma, and / or serum, from the subject; (c) measuring or completing the measurement of (Z)-endoxifen in the subject's whole blood, plasma, and / or serum over a period of time, e.g., at least 6 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 120 hours, at least 7 days, or at least 14 days; and (d) if the subject experiences vasomotor symptoms more than 50% of the days of administration, orally administering to the subject a different sustained-release composition of the present disclosure, wherein the sustained-release composition is capable of achieving one or more parameters in any one or more of Tables 14, 15, 16, and 17.

[0318] Whether a subject is tamoxifen refractory can be determined by administering the first dose of tamoxifen to the subject and determining the subject's plasma endoxifen steady-state level.The plasma endoxifen steady-state level in the subject who has received tamoxifen serves as a biomarker for tamoxifen refractory subjects.The plasma endoxifen level (acute and / or steady-state) can be determined by obtaining a test sample from the subject, and the test sample can be a blood sample taken from the subject after the subject is administered tamoxifen.Plasma or serum can be obtained from the blood sample to test the biomarker endoxifen level.The first dose can include 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.

[0319] A 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 with a reference plasma endoxifen level. For purposes of the present disclosure, the reference plasma level is 30 nM. If a subject's plasma endoxifen level is determined to be lower than 30 nM, the subject is defined as tamoxifen-refractory. Such tamoxifen-refractory subjects who may be suffering from or at risk of suffering from hormone-dependent disorders are treated by administering to the subject a sustained-release composition comprising (Z)-endoxifen or a polymorph or salt thereof disclosed herein. In some embodiments, the sustained-release composition orally administered to such subjects comprises (Z)-endoxifen free base. In some embodiments, the sustained-release composition orally administered to such subjects comprises a polymorphic form, such as endoxifen Form I, Form II, or Form III. In other embodiments, the sustained-release composition orally administered to such a subject comprises an endoxifen gluconate selected from the group consisting of (Z)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, (E)-endoxifen D-gluconate, (E)-endoxifen L-gluconate, or a combination thereof. In other embodiments, the sustained-release composition comprising a (Z)-endoxifen salt is (Z)-endoxifen hydrochloride or (Z)-endoxifen citrate. The present disclosure also contemplates determining or monitoring a subject's plasma endoxifen levels periodically or as needed. If necessary, a subject receiving an initial dosage of tamoxifen can undergo adjustment of their plasma endoxifen steady-state levels based on test results by continuing to orally administer a sustained-release composition comprising (Z)-endoxifen or a polymorph or salt thereof.

[0320] In some embodiments, the tamoxifen-refractory status of a subject can be determined by determining the tamoxifen metabolite profile of the subject and comparing it with the reference tamoxifen metabolite profile found in control or normal subjects.Compared with the reference tamoxifen metabolite profile of the subject's tamoxifen metabolite profile, the subject's plasma endoxifen level is low, and a sustained-release composition comprising (Z)-endoxifen or its polymorph or salt is administered.Such a composition can comprise synthetically prepared endoxifen.

[0321] Plasma endoxifen can be measured by any method known in the art.The plasma endoxifen level in test samples can be determined based on the subject's gene, DNA, RNA, protein, tamoxifen metabolite profile, or a combination thereof.The tamoxifen metabolite profile can include at least tamoxifen, 4-OHT, N-desmethyltamoxifen, and / or endoxifen.In some embodiments, the plasma endoxifen level and / or tamoxifen metabolite profile in test samples are measured by high-performance liquid chromatography (HPLC), high-performance liquid chromatography mass spectrometry (HPLC-MS), 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), etc.In some embodiments, the tamoxifen metabolite profile is predicted based on the subject's genetic composition. In some embodiments, the subject's CYP genotyping includes, but is not limited to, analysis of the CYP2D6 gene, the CYP3A4 gene, and the CYP2C9 gene. In some embodiments, the subject's estrogen receptor levels can be analyzed. In other embodiments, plasma endoxifen determination can be performed at a third-party laboratory.

[0322] Thus, provided herein are methods for maintaining plasma endoxifen levels above 30 nM in a subject in need thereof by orally administering to the subject a sustained-release composition comprising (Z)-endoxifen or a polymorph or salt thereof. In some embodiments, the subject's plasma endoxifen levels are maintained at a steady-state level above 30 nM. In some embodiments, the subject's plasma endoxifen levels are maintained at a steady-state level in the range of 30 nM to 5000 nM (e.g., 40 nM to 4000 nM, 50 nM to 3000 nM, 60 nM to 2000 nM, 30 nM to 300 nM, or 30 nM to 80 nM). In some embodiments, the subject's plasma endoxifen levels are maintained at a steady-state level of >40 nM.

[0323] In another embodiment, a subject can be tested for a biomarker profile of the subject's test sample that can indicate or monitor a hormone-dependent disorder. 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, Ki-67, cytokeratin, cancer tumor antigen, and other biomarkers measured by Mammaprint, OncotypeDx, PAM50, EndoxPredict, MammoStrat, and other diagnostic and predictive tests. A sustained-release composition disclosed herein can be orally administered to a subject whose biomarker profile indicates that the subject is suffering from or at risk of suffering from a hormone-dependent disorder. In one aspect, the present disclosure provides a method of treating a subject suffering from or at risk of suffering from a hormone-dependent disorder, comprising determining the subject's tamoxifen-refractory or tamoxifen-resistant status and administering to the subject a sustained release composition described herein.

[0324] The level of a biomarker in a subject can be measured. For example, the level of one or more of Ki-67, estrogen receptor, progesterone receptor, proliferating cell nuclear antigen, phosphorylated histone H3, p16, p12, beta-galactosidase, terminal deoxynucleotidyl transferase dUTP nick end labeling, RNA sequence, or a combination thereof can be measured in a subject. In some embodiments, the level can be measured before administering a composition of the present disclosure. In some embodiments, the level can be measured after administering a composition of the present disclosure. The level of the biomarker after administration of the composition can be compared to the level of the biomarker before administration of the composition. The level of the biomarker can be measured by any method known in the art. For example, the level of the biomarker can be measured by immunohistochemistry, fluorescence in situ hybridization (FISH), Western blot, quantitative PCR, quantitative PCR with reverse transcription, mass spectrometry, or chromatography.

[0325] In some aspects, provided herein are methods for treating a tamoxifen-refractory or tamoxifen-resistant subject, comprising orally administering to the subject a sustained-release composition comprising (Z)-endoxifen, or a polymorph or salt thereof.

[0326] In some embodiments, disclosed herein are methods for treating a tamoxifen-refractory subject suffering from or at risk of suffering from a hormone-dependent disorder, comprising administering to the subject a sustained-release composition comprising (Z)-endoxifen, or a polymorph or salt thereof, wherein the subject's plasma endoxifen level is 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 sustained-release composition comprising a (Z)-endoxifen salt is (Z)-endoxifen gluconate, (Z)-endoxifen hydrochloride, or (Z)-endoxifen citrate. In other embodiments, a sustained-release solid dosage form comprising at least 90% (Z)-endoxifen or a salt thereof is orally administered. In other embodiments, a sustained-release solid dosage form comprising at least 90% of endoxifen polymorph Form I, Form II, or Form III is orally administered.

[0327] Also provided herein are methods for treating a tamoxifen-refractory or tamoxifen-resistant subject, comprising: (a) determining or having determined a plasma endoxifen level in a test sample obtained from the subject; (b) comparing or having determined a plasma endoxifen level in the test sample with a reference plasma endoxifen level; (c) determining or having determined a decrease in the plasma endoxifen level in the test sample compared to the reference plasma endoxifen level; and (d) administering to the subject a sustained-release composition comprising (Z)-endoxifen, or a polymorph or salt thereof. Oral administration of a sustained-release composition comprising (Z)-endoxifen, or a polymorph or salt thereof, maintains plasma endoxifen levels 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 about 300 nM. The present invention provides a method for treating a subject suffering from or at risk of suffering from a hormone-dependent disorder, comprising: (a) administering to the subject a first composition comprising tamoxifen; (b) determining or having determined the plasma endoxifen level in a test sample obtained from the subject; (c) determining or having determined the decrease in the plasma endoxifen level in the test sample compared to a reference plasma endoxifen level; and (d) orally administering to the subject a sustained-release composition as disclosed herein. The subject can 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, oral administration of a sustained-release composition comprising (Z)-endoxifen or its polymorph or salt maintains the subject's plasma endoxifen at a level greater than 30 nM.In other embodiments, oral administration of a sustained-release composition comprising (Z)-endoxifen, or a polymorph or salt thereof, maintains the subject's plasma endoxifen at a level ranging from 30 nM to 5000 nM (e.g., 40 nM to 4000 nM, 50 nM to 3000 nM, 60 nM to 2000 nM, 30 nM to 300 nM, or 30 nM to 80 nM). In some embodiments, the subject is orally administered a sustained-release composition comprising (Z)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, (E)-endoxifen D-gluconate, (E)-endoxifen L-gluconate, or a combination thereof. In other embodiments, the sustained-release composition comprising a (Z)-endoxifen salt is (Z)-endoxifen hydrochloride or (Z)-endoxifen citrate. In some embodiments, a subject is orally administered a sustained release composition comprising polymorphic Form I, Form II, or Form III of endoxifen disclosed herein.

[0328] The present invention provides a method for treating a subject suffering from or at risk of suffering from hormone-dependent disorders, mood disorders, or any disorders susceptible to (Z)-endoxifen or its polymorphs or salts, comprising the steps of: a) administering to the subject a first composition comprising tamoxifen; (b) determining or having determined the subject's tamoxifen metabolite profile in a test sample obtained from the subject; (c) determining a decrease in the subject's plasma endoxifen level based on the subject's tamoxifen metabolite profile compared with a reference plasma endoxifen level in a reference tamoxifen metabolite profile; and (d) orally administering to the subject a sustained-release composition comprising (Z)-endoxifen or its polymorphs or salts.In certain embodiments, the sustained-release composition comprising (Z)-endoxifen is (Z)-endoxifen gluconate, (Z)-endoxifen hydrochloride, or (Z)-endoxifen citrate.In some embodiments, the sustained-release composition comprises endoxifen polymorph Form I, Form II, or Form III.

[0329] Provided herein is a method for adjusting plasma endoxifen levels in a subject undergoing treatment for a hormone-dependent disorder, the subject having one or more CYP2D6 or CYP3A4 mutations or who has previously received an initial dose of tamoxifen, and whose plasma endoxifen level is lower than a reference plasma endoxifen level, the method comprising: (a) measuring the subject's plasma endoxifen level after the initial dose of tamoxifen; (b) comparing the subject's plasma endoxifen level with a reference plasma endoxifen level; and (c) orally administering to the subject a sustained-release composition comprising (Z)-endoxifen or a polymorph or salt thereof such that the subject's plasma endoxifen level is maintained at a level greater than 30 nM. In some embodiments, oral administration of a sustained-release composition comprising (Z)-endoxifen or a polymorph or salt thereof maintains the subject's plasma endoxifen at a level ranging from 30 nM to 5000 nM (e.g., 40 nM to 4000 nM, 50 nM to 3000 nM, 60 nM to 2000 nM, 30 nM to 300 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 can be administered an initial dosage 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.

[0330] In one aspect, the present disclosure contemplates a method of treating a subject suffering from or at risk of suffering from a hormone-dependent disorder, comprising removing breast tissue from the subject or administering radiation therapy to the subject, and orally administering a sustained-release composition comprising (Z)-endoxifen or a polymorph or salt thereof disclosed herein. In another aspect, the present disclosure contemplates a method of treating a subject suffering from or at risk of suffering from a hormone-dependent disorder, comprising orally administering a sustained-release composition disclosed herein, followed by removing breast tissue from the subject or administering radiation therapy to the subject.

[0331] Dosages administered to a subject are typically in unit dosage form. An example range of endoxifen in each dosage unit form is 0.01 mg to 200 mg. The dosage should generally be effective and correspond, on a molar basis, to the pharmacologically active (Z)-endoxifen free form that, upon metabolic release of the active free drug, is produced by the dosage formulation to achieve the desired pharmacological and physiological effects. In some embodiments, sustained-release compositions comprising (Z)-endoxifen, or a polymorph or salt thereof, are orally administered to a subject at a dose of 0.01 mg to 200.0 mg. In other embodiments, sustained-release compositions comprising (Z)-endoxifen, or a polymorph or salt thereof, are orally administered to a subject at a dose of 1 mg to 200.0 mg. In some embodiments, sustained-release compositions containing (Z)-endoxifen or a polymorph or salt thereof are orally administered 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 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg, or 200 mg per unit dose. In certain embodiments, sustained-release compositions containing at least 90% (Z)-endoxifen (w / w) endoxifen are orally administered at a dose of 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg, or 200 mg per unit dose. In some embodiments, sustained-release compositions containing endoxifen gluconate are orally administered at a dose ranging from 0.01 to 20 mg. In some embodiments, sustained-release compositions containing (Z)-endoxifen D-gluconate are orally administered in unit doses of 0.5 mg, 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg, and 200 mg. In some embodiments, sustained-release compositions containing 1 mg of (Z)-endoxifen D-gluconate are orally administered. In other embodiments, sustained-release compositions containing 1 mg of (Z)-endoxifen L-gluconate are orally administered.In yet another embodiment, a sustained-release composition containing 2 mg of (Z)-endoxifen D-gluconate and (E)-endoxifen D-gluconate is orally administered. In certain embodiments, a sustained-release composition containing at least 90% polymorphic form (w / w) of endoxifen, such as polymorphic Form I, Form II, or Form III, is orally administered at a dose of 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg, or 200 mg per unit dose. In some embodiments, a sustained-release composition containing a polymorphic form, such as Form I, Form II, or Form III of endoxifen, is orally administered at a dose ranging from 0.01 to 20 mg.

[0332] Compositions containing endoxifen can be administered to a subject at a daily dose of 0.5 mg to 2 mg, 1 mg to 3 mg, 2 mg to 4 mg, 3 mg to 5 mg, 4 mg to 5 mg, 5 mg to 8 mg, 5 mg to 10 mg, 8 mg to 12 mg, 10 mg to 14 mg, 12 mg to 15 mg, 14 mg to 16 mg, 15 mg to 18 mg, 16 mg to 20 mg, 18 mg to 25 mg, 20 mg to 30 mg, 25 mg to 40 mg, 30 mg to 50 mg, 40 mg to 60 mg, 50 mg to 70 mg, 60 mg to 80 mg, 70 mg to 90 mg, 80 mg to 100 mg, 90 mg to 125 mg, 100 mg to 150 mg, 125 mg to 175 mg, or 150 mg to 200 mg of endoxifen. A composition containing endoxifen can be administered to a subject for 1 to 14 days, 7 to 14 days, 7 to 21 days, 7 to 28 days, 7 to 35 days, 7 to 40 days, 7 to 42 days, 7 to 49 days, 7 to 50 days, 14 to 21 days, 14 to 28 days, 14 to 35 days, 14 to 40 days, 14 to 42 days, 14 to 49 days, 14 to 50 days, 21 to 28 days, 21 to 35 days, 21 to 40 days, 21 to 42 days, 21 to 49 days, 21 to 50 days, 40 to 50 days, 40 to 60 days, 40 to 70 days, 40 to 80 days, 40 to 90 days, or 40 to 100 days. In some embodiments, a composition comprising endoxifen can be administered to a subject once, twice, or three times per day. In some embodiments, a composition comprising endoxifen can be administered to a subject every 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.

[0333] A breast cancer growth rate study, using mammographic screening of subjects with breast cancer, showed that breast cancer growth rates at the 25th percentile in women aged 50-59 years indicated an unmet need to expose subjects to rapidly acting treatments (Weeden-Fekjaer et al. Breast Cancer Research 200810: R41). Increased bioavailability and sustained absorption of anticancer therapeutics such as (Z)-endoxifen, which can further reduce cancer growth rate, tumor volume or size, disease burden, etc., are highly desirable.

[0334] In one aspect, the disclosure provides a method of treating a subject suffering from or at risk of suffering from a hormone-dependent disorder, comprising orally administering a sustained-release composition comprising (Z)-endoxifen or a polymorph or salt thereof, wherein the sustained-release composition comprising (Z)-endoxifen or a polymorph or salt thereof exhibits sustained release of the drug (Z)-endoxifen or a polymorph or salt thereof from the sustained-release composition over a period of about 4 hours to about 24 hours or longer in the subject. In some embodiments, the sustained-release compositions of the disclosure release (Z)-endoxifen or a polymorph or salt thereof in a sustained manner over a period of about 2 hours to about 72 hours. In some embodiments, the sustained release compositions of the present disclosure release (Z)-endoxifen or a polymorph or salt thereof in a sustained manner over a period of at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 24 hours, at least 48 hours, and at least 72 hours. In these methods, the present disclosure provides (Z)-endoxifen or a polymorph or salt thereof that is released into the intestine about 2 hours after administration (e.g., ingestion by a subject).

[0335] In one aspect, the disclosure provides a method of treating a subject suffering from or at risk of suffering from a hormone-dependent disorder, comprising orally administering a sustained-release composition comprising (Z)-endoxifen or a polymorph or salt thereof, wherein the sustained-release composition comprising (Z)-endoxifen or a polymorph or salt thereof exhibits a dissolution percentage of about 0% to 30% at 3 hours, about 30% to 50% at 12 hours, and about 65% to 85% at 12 hours in a dissolution test conducted according to the USP II paddle method at 75 rpm using a test sample from the subject (e.g., the subject's blood, serum, plasma, etc.) in simulated gastric fluid at pH 1.2 at 37°C for 2 hours and in simulated intestinal fluid at pH 6.8 at 37°C for 24 hours. In some embodiments, the sustained-release composition exhibits the following dissolution percentages in a dissolution test conducted according to the USP II paddle method: a. Ranges of about 0% to about 35% at 3 hours, about 35% to about 55% at 12 hours, and about 65% to about 85% at 24 hours; b. Approximately 0% to approximately 30% at 3 hours, approximately 40% to approximately 50% at 12 hours, and approximately 70% to approximately 80% at 24 hours; c. Dissolution percentage of NMT of approximately 30% at 3 hours, dissolution percentage of NMT of approximately 50% at 12 hours, and dissolution percentage of NLT of approximately 80% at 24 hours; d.NMT dissolution percentage of about 5% at 2 hours, NMT dissolution percentage of about 10% at 3 hours, NLT dissolution percentage of about 30% at 6 hours, NLT dissolution percentage of 50% at 9 hours, and NLT dissolution percentage of about 80% at 14 hours; e. A dissolution percentage of NMT of about 5% at 2 hours, a dissolution percentage of NLT of about 60% at 3 hours, a dissolution percentage of NLT of about 90% at 6 hours, and a dissolution percentage of NLT of about 100% at 12 hours; or f. at least 10%, at least 20%, at least 30%, or at least 40% after 24 hours.

[0336] In some embodiments, the sustained-release composition comprises a therapeutic agent, the therapeutic agent being (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, a salt of (Z)-endoxifen, or a combination thereof, wherein the therapeutic agent has at least one dissolution percentage parameter selected from a dissolution percentage in the range of about 0% to about 35% at 3 hours; a dissolution percentage in the range of about 35% to about 55% at 12 hours; or a dissolution percentage in the range of about 65% to about 85% at 24 hours, where the dissolution percentage is measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and 37°C for 0-2 hours and in simulated intestinal fluid at pH 6.8 and 37°C for more than 2 hours. In some embodiments, the composition comprises at least two of the dissolution percentage parameters. In some embodiments, the composition comprises all three of the dissolution percentage parameters.

[0337] In some embodiments, the extended release composition in the form of an extended release tablet or an enteric coated delayed release tablet exhibits the following dissolution percentages in a dissolution test conducted according to the USP II paddle method: a. Ranges of about 0% to about 35% at 3 hours, about 35% to about 55% at 12 hours, and about 65% to about 85% at 24 hours; b. Approximately 0% to approximately 30% at 3 hours, approximately 40% to approximately 50% at 12 hours, and approximately 70% to approximately 80% at 24 hours; c.NMT dissolution percentage of 30% at 3 hours, NMT dissolution percentage of approximately 50% at 12 hours, and NLT dissolution percentage of approximately 80% at 24 hours; d.NMT dissolution percentage of about 5% at 2 hours, NMT dissolution percentage of about 10% at 3 hours, NLT dissolution percentage of about 30% at 6 hours, NLT dissolution percentage of about 50% at 9 hours, and NLT dissolution percentage of about 80% at 14 hours; e. A dissolution percentage of NMT of about 5% at 2 hours, a dissolution percentage of NLT of about 60% at 3 hours, a dissolution percentage of NLT of about 90% at 6 hours, and a dissolution percentage of NLT of about 100% at 12 hours; or f. at least 10%, at least 20%, at least 30%, or at least 40% after 24 hours.

[0338] A medical professional, such as an attending physician, can adjust the dosing regimen based on the pharmacokinetic profile of the sustained release composition in the subject.

[0339] In yet another aspect, the disclosure provides a method of treating a subject in need thereof, comprising orally administering a sustained release composition comprising (Z)-endoxifen or a polymorph or salt thereof once daily, twice daily, once every two days, once every three days, once every four days, once every five days, once every six days, or once every seven days, twice weekly, or once weekly.

[0340] In one aspect, the sustained-release compositions of the present disclosure can be used alone or as a combination therapy. For example, the sustained-release compositions disclosed herein can be used in combination with one or more "additional therapeutic agents" as part of primary, neoadjuvant, or adjuvant therapy. For example, a composition comprising endoxifen can be administered as neoadjuvant therapy to reduce tumor cell proliferation. It is an aspect of the present disclosure that the sustained-release compositions of the present disclosure can be used in combination with other treatments, such as surgery and radiation, as neoadjuvant or adjuvant therapy. In some embodiments, the compositions of the present disclosure can be administered as neoadjuvant therapy to reduce tumor size or tumor cell activity before surgery. In some embodiments, treatment methods involving other treatments can be modified based on the outcome of the neoadjuvant therapy (e.g., including endoxifen). In some embodiments, after a favorable outcome is achieved with treatment using a composition of the present disclosure (e.g., including endoxifen), adjuvant therapy can be reduced or eliminated. For example, a patient awaiting surgery for cancer (e.g., breast cancer) may no longer need surgery after treatment with a composition comprising endoxifen. In some embodiments, the composition (e.g., a composition comprising endoxifen) can be used as an adjunct to mammography. For example, a patient can be treated with oral administration of an endoxifen composition after or simultaneously with a mammogram to identify a breast disorder or potential breast disorder (e.g., BIRADS 3, BIRADS 4, BIRADS 5, or BIRADS 6 classification, or BIRADS B, BIRADS C, or BIRADS D classification). In some embodiments, a mammogram can be performed after or simultaneously with endoxifen treatment to monitor the status of a breast disorder or potential breast disorder.

[0341] The combination of sustained-release compositions can improve the effectiveness of additional therapeutic agents and can therefore be used to improve standard cancer treatments.For example, if a subject has prostate cancer and is undergoing treatment with bicalutamide or enzalutamide to treat prostate cancer, the subject is likely to develop gynecomastia as a result of the treatment.To prevent and / or treat gynecomastia, the compositions disclosed herein can be administered to a subject with prostate cancer as a combination therapy.As another example, a subject with ER+ / Her2+ positive breast cancer may be undergoing combination therapy with other oncological drugs or immunotherapy, such as trastuzumab or antineoplastic agents, and the sustained-release compositions disclosed herein can be used to treat such a subject with ER+ / Her2+ positive breast cancer. Thus, in some embodiments, the composition contains, as an additional therapeutic agent, bicalutamide, enzalutamide, or an anticancer drug, e.g., trastuzumab, atezolizumab (Tecentriq), alpelisib (Piqray), olaparib (Lynparza), talazoparib (Talzenna), ribociclib (Kisqali), neratinib (Nerlynx), an anti-neoplastic drug, e.g., capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinol), cyclophosphamide (Neosar), docetaxel (Docefrez, Taxotere), doxorubicin (Adriamycin), or the like. cin), pegylated liposomal doxorubicin (Doxil), epirubicin (Ellence), fluorouracil (5-FU, Adrucil), gemcitabine (Gemzar), methotrexate (numerous trade names), paclitaxel (Taxol), protein-bound paclitaxel (nab-paclitaxel or Abraxane), vinorelbine (Navelbine), eribulin (Halaven), ixabepilone (Ixempra), immune checkpoint inhibitors (such as inhibitors of PD1, inhibitors of PD-L1 and inhibitors of CTLA4), and ATP cassette binding protein inhibitors.

[0342] In another aspect, the sustained-release compositions disclosed herein may contain a therapeutic agent that increases the bioavailability of (Z)-endoxifen in a subject. P-glycoprotein (P-gp, ABCB1) is a highly efficient drug efflux pump expressed in the brain, liver, and small intestine, but is also expressed in cancer cells, where it affects the pharmacokinetics of many anticancer drugs and confers therapeutic resistance to them. Therefore, in some embodiments, the composition further contains an inhibitor of an ATP-binding cassette (ABC family) transporter, such as an inhibitor of breast cancer resistance protein (BCRP protein) and an inhibitor of P-gp. Several inhibitors of BCRP protein and P-Gp are known in the art. For example, inhibitors of BCRP protein include cyclosporine, omeprazole, pantoprazole, saquinavir, and tacrolimus.

[0343] 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 cyclopropyldibenzosuberanzosquidar (LY335979), laniquidar (R101933), mitotane (NSC-38721), biricodar (VX-710), elacridar (GF120918 / GG918), ONT-093, tariquidar (XR9576), and HM30181; and anti-P-gp monoclonal antibodies such as MRK-16.

[0344] The present disclosure further provides a therapeutic kit containing one or more of the sustained release compositions disclosed herein for use in treating a subject suffering from or at risk of suffering from a hormone-dependent disorder. The kit of the present disclosure may include a sustained release composition disclosed herein, a sealed container for containing the composition, and instructions for use of the sustained release composition. In some embodiments, the kit of the present disclosure may include a second or additional therapeutic agent. Such a second or additional therapeutic agent may be bicalutamide, enzalutamide, or an anti-cancer drug such as trastuzumab, an anti-neoplastic drug such as capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinol), cyclophosphamide (Neosar), docetaxel (Docefrez, Taxotere), doxorubicin (Adriamycin), pegylated liposomal doxorubicin (Doxil), epirubicin (Ellence), fluorouracil ( ATP-binding cassette (ABC transporter) inhibitors such as 5-FU, Adrucil), gemcitabine (Gemzar), methotrexate (numerous trade names), paclitaxel (Taxol), protein-bound paclitaxel (Abraxane), vinorelbine (Navelbine), eribulin (Halaven), ixabepilone (Ixempra), immune checkpoint inhibitors (such as inhibitors of PD1, inhibitors of PD-L1 and inhibitors of CTLA4), and P-gp inhibitors.

[0345] In yet another aspect, the present disclosure relates to a kit for treating a subject in need thereof, having or at risk of having an estrogen-dependent disorder, the kit comprising: (a) a sustained release composition disclosed herein; and (b) a sealed container for housing the sustained release composition; and c) instructions for use of the sustained release composition.

[0346] In yet another aspect, the present disclosure provides a kit for treating an estrogen-dependent disorder or a subject at risk of developing an estrogen-dependent disorder in a subject in need thereof, the kit comprising: (a) a sustained-release composition disclosed herein; and (b) a sealed container for housing the sustained-release composition; and c) instructions for use of the sustained-release composition, the kit comprising: bicalutamide, enzalutamide, and an anti-cancer drug, e.g., trastuzumab, atezolizumab (Tecentriq), alpelisib (Piqray), olaparib (Lynparza), talazoparib (Talzenna), ribociclib (Kisqali), neratinib (Nerlynx), an anti-neoplastic agent, e.g., capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinol), or the like. , cyclophosphamide (Neosar), docetaxel (Docefrez, Taxotere), doxorubicin (Adriamycin), PEGylated liposomal doxorubicin (Doxil), epirubicin (Ellence), fluorouracil (5-FU, Adrucil), gemcitabine (Gemzar), methotrexate (numerous trade names), paclitaxel (Taxol), protein-bound paclitaxel (Abraxane), vinorelbine (Navelbine), eribulin (Halaven), ixabepilone (Ixempra), checkpoint inhibitors such as inhibitors of PD1, inhibitors of PD-L1, inhibitors of CTLA4, and ATP cassette binding protein transport inhibitors.

[0347] In yet another aspect, the present disclosure relates to a method of administering a composition prepared according to any of the processes described herein to a subject in need thereof according to instructions included in a kit containing the composition.

[0348] Advantageous aspects of sustained release compositions, including sustained release compositions comprising (Z)-endoxifen or a salt or polymorph thereof, having the desirable pharmacokinetic parameters disclosed in this disclosure will be apparent to those skilled in the art in that the sustained release compositions disclosed herein maintain therapeutic concentrations over an extended period of time, their use is likely to avoid high blood levels as desired, slows drug release thereby allowing for slower and more consistent absorption over time, reducing side effects such as vasomotor symptoms (e.g., hot flushes) and / or toxicity, avoids or minimizes trough blood levels between once-daily doses, minimizes drug accumulation commonly observed with prolonged dosing, minimizes total drug usage, minimizes local and systemic side effects, improves tolerability and patient compliance, and improves (Z)-endoxifen bioavailability and efficacy of treatment. Numbered Embodiments

[0349] The following embodiments list non-limiting permutations of the combinations of features disclosed herein. Other permutations of the combinations of features are also contemplated. In particular, each of these numbered embodiments is intended to be dependent on or related to every preceding or following numbered embodiment, regardless of the order in which they are listed. 1. A sustained-release composition comprising a therapeutic agent, wherein the therapeutic agent is (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, a salt of (Z)-endoxifen, or a combination thereof, and wherein the therapeutic agent has at least two dissolution percentage parameters selected from a dissolution percentage of 35% or less at 3 hours, a dissolution percentage in the range of 35% to 55% at 12 hours, or a dissolution percentage in the range of 65% to 85% at 24 hours, as measured by the USP paddle method at 75 rpm in simulated gastric fluid at pH 1.2 and 37°C from time 0 to time 2, and in simulated intestinal fluid at pH 6.8 and 37°C after time 2. 2. The sustained-release composition of embodiment 1, wherein the therapeutic agent has at least three of the dissolution percentage parameters. 3. The sustained-release composition of any one of embodiments 1 to 2, comprising 0.01 mg to 200 mg of the therapeutic agent. 4. The sustained-release composition of any one of embodiments 1 to 3, comprising 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 20 mg, or 40 mg of the therapeutic agent. 5. The sustained-release composition of any one of embodiments 1 to 4, wherein the therapeutic agent is (Z)-endoxifen free base. 6. The sustained-release composition of any one of embodiments 1 to 5, wherein greater than 90%, greater than 95%, or greater than 99% by weight of the therapeutic agent is (Z)-endoxifen Form I, (Z)-endoxifen Form II, (Z)-endoxifen Form III, or a combination thereof. 7. The sustained-release composition of any one of embodiments 1 to 6, further comprising at least one sustained-release agent, at least one binder, and at least one lubricant.8. A sustained release composition comprising a therapeutic agent selected from the group consisting of (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, a salt of (Z)-endoxifen, and combinations thereof, at least one sustained release agent, at least one binder, and at least one lubricant. 9. The sustained release composition of any one of embodiments 1 to 8, comprising 0.5 mg, 1 mg, 2 mg, 4 mg, 5 mg, 6 mg, 10 mg, 20 mg, or 40 mg of either (Z)-endoxifen Form I, (Z)-endoxifen Form II, (Z)-endoxifen Form III, or combinations thereof. 10. (Z)-Endoxifen salts include acetate, arecoline, benzathine, benzoate, besylate, benzosulfonate, bicarbonate, bitartrate, butyl bromide, citrate, camsylate, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, formate, fumarate, glycolate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaptanoate, isethionate, malate, maleate, mandelate, meglumine, mesylate, methyl bromide, methyl nitrate, methyl sulfate, metathesis. 10. The sustained-release composition of any one of embodiments 1 to 9, wherein the at least one sustained-release agent is selected from the group consisting of: toluenesulfonate, mucate, napsylate, nitric, nitrate, oxalate, pamoate, pantothenate, perchlorate, phosphate, diphosphate, piperazine, procaine, polygalacturonate, p-toluenesulfonate, salicylate, stearate, succinate, sulfate, sulfonate, sulfuric, tannate, tartrate, teoclate, triethiodide, trifluoroacetate, aluminum, barium, bismuth, lithium, magnesium, potassium, zinc, and any combination thereof. 11. The sustained-release composition of any one of embodiments 7 to 10, wherein the at least one sustained-release agent has a viscosity in the range of 1000 mPa·s to 150,000 mPa·s.12. The sustained release composition of any one of embodiments 7 to 11, wherein the at least one sustained release agent has a viscosity at 25° C. in the range of 1000 mPa·s to 10,000 mPa·s, 10,000 mPa·s to 70,000 mPa·s, 70,000 mPa·s to 150,000 mPa·s, or any combination thereof. 13. The sustained release composition of any one of embodiments 7 to 12, comprising 0.1% to 99% w / w, 1% to 95% w / w, 5% to 90% w / w, 5% to 80% w / w, 5% to 70% w / w, or 5% to 60% w / w of the at least one sustained release agent. 14. The sustained release composition of any one of embodiments 7 to 13, wherein the at least one sustained release agent is hypromellose. 15. The sustained release composition of any one of embodiments 7 to 14, comprising 1% to 99% w / w, 5% to 95% w / w, 10% to 90% w / w, 15% to 85% w / w, 20% to 80% w / w, or 20% to 85% w / w of at least one binder. 16. The sustained release composition of any one of embodiments 7 to 15, wherein the at least one binder is microcrystalline cellulose. 17. The sustained release composition of any one of embodiments 7 to 16, comprising 0.01% to 5% w / w, 0.2% to 2% w / w, or 0.5% to 1.5% w / w of at least one lubricant. 18. The sustained release composition of any one of embodiments 7 to 17, wherein the at least one lubricant is magnesium stearate. 19. The extended release composition of any one of embodiments 1 to 18, which is a sustained release tablet or an enteric coated delayed release tablet. 20. The extended release composition of embodiment 19, wherein the sustained release tablet is coated with a coating solution comprising at least one delayed release agent, and the sustained release tablet serves as a core tablet substantially encased in at least one layer of the coating solution, thereby forming a functional coating and providing an enteric coated delayed release tablet.21. The extended-release composition of embodiment 19, wherein the extended-release tablet is coated with a coating solution comprising at least one delayed-release agent, at least one plasticizer, and at least one anti-adherent agent, and the extended-release tablet serves as a core tablet substantially encased in at least one layer of the coating solution, thereby forming a functional coating to provide an enteric-coated delayed-release tablet. 22. The extended-release composition of any one of embodiments 20 to 21, wherein the at least one delayed-release agent is present in at least one layer of the functional coating in an amount of 0.1% to 30% w / w, 5% to 25% w / w, or 8% to 14% w / w of the functional coating. 23. The extended-release composition of any one of embodiments 20 to 21, wherein the delayed-release agent is present in at least one layer of the functional coating in an amount of 0.1% to 30% w / w, 5% to 25% w / w, or 8% to 14% w / w of the core tablet weight. 24. The sustained release composition of any one of embodiments 20 to 23, wherein at least one delayed release agent is a poly(meth)acrylate. 25. The sustained release composition of any one of embodiments 20 to 24, wherein at least one delayed release agent comprises a copolymer of methacrylic acid and ethyl acrylate in a ratio of about 1:1 w / w. 26. The sustained release composition of any one of embodiments 20 to 24, wherein at least one delayed release agent comprises a copolymer of methacrylic acid and ethyl acrylate in a ratio of 2:1 to 1:2. 27. The sustained release composition of any one of embodiments 21 to 26, wherein at least one plasticizer is present in an amount of 0.01% to 5% w / w, 0.1% to 4% w / w, 0.2% to 2% w / w, or 0.5% to 1.5% w / w of the core tablet weight. 28. The sustained release composition of any of embodiments 21 to 26, wherein the at least one plasticizer is present in an amount of 0.01% to 5% w / w, 0.1% to 4% w / w, 0.2% to 2% w / w, or 0.5% to 1.5% w / w of the functional coating. 29. The sustained release composition of any of embodiments 21 to 28, wherein the at least one plasticizer is triethyl citrate. 30. The sustained release composition of any of embodiments 21 to 29, wherein the at least one anti-adherent agent is present in an amount of 0.1% to 10% w / w, 1% to 8% w / w, or 2% to 6% w / w of the core tablet weight.31. The sustained release composition of any of embodiments 21 to 29, wherein the at least one anti-adherent agent is present in an amount of 0.1% to 10% w / w, 1% to 8% w / w, or 2% to 6% w / w of the functional coating. 32. The sustained release composition of any of embodiments 21 to 31, wherein the anti-adherent agent is talc. 33. The sustained release composition of any of embodiments 21 to 32, wherein at least one layer of the functional coating provides a weight gain of 1% to 60%, 2% to 40%, 5% to 30%, or 6% to 20% relative to the core tablet weight. 34. The sustained release composition of any of embodiments 21 to 33, wherein the functional coating comprises a weight gain of 1% to 60% w / w, 2% to 40% w / w, 5% to 30% w / w, or 6% to 20% w / w relative to the core tablet weight. 35. The sustained release composition of any one of embodiments 21 to 34, wherein the core tablet has a weight of 60 mg to 500 mg. 36. The sustained release composition of any one of embodiments 21 to 35, wherein the core tablet has a weight of 100 mg to 160 mg, 90 mg to 110 mg, or 100 mg to 120 mg. 37. The sustained release composition of any one of embodiments 21 to 36, wherein the core tablet has a thickness of 2.75 mm to 3.75 mm. 38. The sustained release composition of any one of embodiments 21 to 37, wherein the core tablet has a thickness of 3 mm to 3.5 mm. 39. The sustained release composition of any one of embodiments 21 to 38, wherein the core tablet has a hardness of 4 Kp to 16 Kp or 10 Kp to 16 Kp. 40. The sustained release composition of any one of embodiments 21 to 39, wherein the core tablet has a hardness of about 13 Kp.41. The sustained-release composition of any of embodiments 1 to 40, in the form of an enteric-coated delayed-release tablet, comprising a core tablet encased in at least one layer of a functional coating, the core tablet comprising 0.01 mg to 200 mg of a therapeutic agent, 0.1% to 99% w / w of hypromellose, 1% to 99% w / w of microcrystalline cellulose, and 0.01% to 5% w / w of magnesium stearate, and a functional coating comprising 0.1% to 20% w / w of a copolymer of methacrylic acid and ethyl acrylate having a ratio of about 1:1, 0.01% to 5% w / w of triethyl citrate, and 1% to 10% w / w of talc, wherein at least one layer of the functional coating contributes to a weight gain of 2% to 20% relative to the average core tablet weight. 42. The sustained-release composition of embodiment 41, wherein the core tablet comprises 5% to 60% w / w of hypromellose. 43. The sustained release composition of embodiment 41 or embodiment 42, wherein the core tablet comprises 10% to 90% w / w microcrystalline cellulose. 44. The sustained release composition of any one of embodiments 41 to 43, comprising 0.5 mg, 1 mg, 2 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 20 mg, or 40 mg of a therapeutic agent. 45. The sustained release composition of any one of embodiments 41 to 43, comprising 0.5 mg to 1 mg, 1 mg to 2 mg, 2 mg to 3 mg, 3 mg to 4 mg, 4 mg to 5 mg, 5 mg to 6 mg, 6 mg to 7 mg, 7 mg to 8 mg, 8 mg to 9 mg, 9 mg to 10 mg, 10 mg to 20 mg, or 20 mg to 40 mg of a therapeutic agent. 46. ​​At least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, or less after administration of the medication. 46. ​​The sustained release composition of any one of embodiments 41 to 45, which provides sustained release of the therapeutic agent over a period of at least 14 hours, at least 16 hours, at least 18 hours, at least 24 hours, at least 48 hours, or at least 72 hours. 47. The sustained release composition of any one of embodiments 41 to 46, which provides sustained release of the therapeutic agent over a period of at least 3 hours to 72 hours or at least 6 hours to 48 hours. 48. The sustained release composition of any one of embodiments 41 to 47, which exhibits a dissolution percentage of 30% or less at 3 hours, 30% to 50% at 12 hours, and 65% to 85% at 12 hours, as measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and 37°C for 0 to 2 hours, and in simulated intestinal fluid at pH 6.8 and 37°C after 2 hours. 49. The sustained release composition of any one of embodiments 41 to 48, having a dissolution percentage of: no more than 35% at 3 hours, 35% to 55% at 12 hours, and 65% to 85% at 24 hours; no more than 30% at 3 hours, no more than 50% at 12 hours, and not less than 80% at 24 hours; no more than 5% at 2 hours, no more than 10% at 3 hours, no more than 30% at 6 hours, no more than 50% at 9 hours, and not less than 80% at 14 hours; no more than 5% at 2 hours, no more than 60% at 3 hours, no more than 90% at 6 hours, and 100% at 12 hours, or at least 10%, at least 20%, at least 30%, or at least 40% after 24 hours, as measured by the USP paddle method at 75 rpm in simulated gastric fluid at pH 1.2 and 37°C for 0 to 2 hours and in simulated intestinal fluid at pH 6.8 and 37°C after 2 hours. 50. The sustained release composition of any one of embodiments 19 to 49, wherein the enteric coated delayed-release tablet has a weight of 101 mg to 160 mg, or 105 mg to 120 mg. 51. The sustained release composition of any one of embodiments 1 to 50, further comprising a pharmaceutically acceptable excipient. 52. The sustained release composition of any of embodiments 1 to 51, which is stable at ambient temperature, 25°C / 65% RH, or 40°C / 75% RH for at least 1 month, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 2 years, at least 3 years, at least 4 years, or at least 5 years.53. The sustained release composition of any one of embodiments 1 to 52, wherein the therapeutic agent in the sustained release composition is stable at ambient temperature, 25°C / 65%RH, or 40°C / 75%RH for at least 1 month, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 2 years, at least 3 years, at least 4 years, or at least 5 years. 54. The sustained release composition of any one of embodiments 19 to 53, wherein the total level of impurities is less than 5% w / w of the enteric coated delayed-release tablet weight or the core tablet weight. 55. The sustained release composition disclosed in Table 1, Table 2, Table 5, Table 6, or Table 7. 56. A sustained-release composition comprising a core tablet encased in at least one layer of a functional coating, the core tablet comprising 0.01 mg to 200 mg of a therapeutic agent selected from the group consisting of (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, and a salt of (Z)-endoxifen, or a combination thereof, 0.1% to 99% w / w of hypromellose, 1% to 99% w / w of microcrystalline cellulose, and 0.01% to 5% w / w of magnesium stearate. 57. The sustained-release composition of embodiment 56, wherein the core tablet comprises 5% to 60% w / w of hypromellose. 58. The sustained-release composition of embodiment 56 or 57, wherein the core tablet comprises 10% to 90% w / w of microcrystalline cellulose. 59. The sustained release composition of any one of embodiments 56 to 58, wherein the functional coating comprises 0.1% to 20% w / w of a copolymer of methacrylic acid and ethyl acrylate having a ratio of 2:1 to 1:2, 0.01% to 5% w / w of triethyl citrate, and 1% to 10% w / w of talc. 60. The sustained release composition of embodiment 59, wherein the ratio of the copolymer of methacrylic acid and ethyl acrylate is about 1:1. 61. The sustained release composition of any one of embodiments 56 to 60, wherein at least one layer of the functional coating contributes to a weight gain of 2% to 20% relative to the average core tablet weight.62. The sustained release composition of any one of embodiments 1 to 61, having a dissolution percentage in the range of 5% to 35%, 10% to 15%, 20% to 25%, 30% to 35%, 5% to 30%, 5% to 25%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, or 30% to 35% at 3 hours, as measured by the USP paddle method at 75 rpm for 0 to 2 hours in simulated gastric fluid at pH 1.2 and 37°C, and after 2 hours in simulated intestinal fluid at pH 6.8 and 37°C. 63. The sustained release composition of any one of embodiments 1 to 62, having a dissolution percentage in the range of 35% to 55%, 40% to 55%, 45% to 55%, 50% to 55%, 35% to 50%, 35% to 45%, 35% to 40%, 35% to 40%, 40% to 45%, 45% to 50%, or 50% to 55% at 12 hours, as measured by the USP paddle method at 75 rpm for 0 to 2 hours in simulated gastric fluid at pH 1.2 and 37°C, and after 2 hours in simulated intestinal fluid at pH 6.8 and 37°C. 64. The sustained release composition of any one of embodiments 1 to 63, having a dissolution percentage in the range of 65% to 85%, 70% to 85%, 75% to 85%, 80% to 85%, 65% to 80%, 65% to 75%, 65% to 70%, 65% to 70%, 70% to 75%, 75% to 80%, or 80% to 85% at 24 hours, as measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and 37°C for 0 to 2 hours, and in simulated intestinal fluid at pH 6.8 and 37°C for more than 2 hours. 65. The sustained release composition of any one of embodiments 1 to 64, having a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of less than 5% at 2 hours and not less than 5% to 80%, 10% to 75%, 20% to 70%, 30% to 65%, 5% to 75%, 5% to 70%, 5% to 60%, 5% to 65%, 5% to 60%, 10% to 55%, 5% to 50%, 30% to 80%, 25% to 75%, 35% to 80%, or 70% at 3 hours, as measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and 37°C for 0 to 2 hours and in simulated intestinal fluid at pH 6.8 and 37°C for more than 2 hours.66. The sustained release composition of any one of embodiments 1 to 65, having a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of less than 5% at 2 hours and not less than 70% to 99%, 75% to 95%, 85% to 95%, 90% to 95%, 75% to 90%, 85% to 90%, 75% to 85%, 80% to 99%, 85% to 99%, 90% to 99%, 95% to 99%, or 95% at 6 hours, as measured by the USP paddle method at 75 rpm in simulated gastric fluid at pH 1.2 and 37°C for 0 to 2 hours and in simulated intestinal fluid at pH 6.8 and 37°C for more than 2 hours. 67. The sustained release composition of any one of embodiments 1 to 66, having a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of less than 5% at 2 hours and in the range of 70% to 99%, 75% to 95%, 85% to 95%, 90% to 95%, 75% to 90%, 85% to 90%, 75% to 85%, 80% to 99%, 85% to 99%, 90% to 99%, 95% to 99%, or 100% at 12 hours, as measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and 37°C for 0 to 2 hours and in simulated intestinal fluid at pH 6.8 and 37°C for more than 2 hours. 68. The sustained release composition of any one of the preceding embodiments, having a dissolution percentage of (Z)-endoxifen or a polymorph or salt thereof of less than 5% at 2 hours and in the range of 55% to 100%, 60% to 99%, 75% to 90%, 80% to 85%, 55% to 99%, 65% to 99%, 70% to 99%, 75% to 99%, 80% to 99%, 90% to 99%, 80% to 95%, or 75% to 95% at 72 hours, as measured by the USP paddle method at 75 rpm in simulated gastric fluid at pH 1.2 and 37°C for 0 to 2 hours and in simulated intestinal fluid at pH 6.8 and 37°C for more than 2 hours. 69. The sustained release composition of any one of the preceding embodiments, having a dissolution percentage of NMT of about 10% at 3 hours, a dissolution percentage of NLT of about 30% at 6 hours, a dissolution percentage of NLT of about 50% at 9 hours, and a dissolution percentage of NLT of about 80% at 14 hours, as measured by the USP paddle method at 75 rpm in simulated gastric fluid at pH 1.2 and 37°C for 0 to 2 hours, and in simulated intestinal fluid at pH 6.8 and 37°C after 2 hours.70. The sustained release composition of any one of embodiments 1 to 69, having a dissolution percentage of NMT of about 5% at 2 hours. 71. The sustained release composition of any one of embodiments 1 to 70, which, after oral administration, provides sustained exposure of a subject to a therapeutic agent for a period of at least 3 hours to 270 hours per dose. 72. The sustained release composition of any one of embodiments 1 to 71, which is capable of achieving one or more pharmacokinetic parameters in Table 15 after oral administration to a subject in a single dose. 73. The sustained release composition of any one of embodiments 1 to 72, which is capable of achieving one or more pharmacokinetic parameters in Table 16 after oral administration to a subject in multiple doses or at steady state. 74. The sustained release composition of any one of embodiments 1 to 73, wherein a single dose provides an oral bioavailability of at least 70 percent as measured by a decrease in AUC compared to a reference product, or wherein multiple doses provide an oral bioavailability of at least 40 percent as measured by a decrease in AUC compared to a reference product.75. A core tablet substantially encased in at least one layer of a functional coating, the core tablet comprising a therapeutic agent selected from the group consisting of (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, a salt of (Z)-endoxifen, and combinations thereof, at least one sustained-release agent, at least one binder, and at least one lubricant, wherein the core tablet is capable of achieving one or more pharmacokinetic parameters in Table 15 after oral administration to a subject in a single dose, and one or more pharmacokinetic parameters in Table 16 after oral administration to a subject in multiple doses or at steady state. and wherein, after oral administration, the sustained release composition provides a sustained exposure of the subject to a therapeutic agent for a period of at least 4 hours to 270 hours per dose, wherein a single dose provides at least 70 percent oral bioavailability as measured by a reduction in AUC compared to a reference product, and wherein multiple doses provide at least 40 percent oral bioavailability as measured by a reduction in AUC compared to a reference product, or wherein, when orally administered to a subject, the sustained release composition causes vasomotor symptoms in the subject less than 25% of the days on which the drug is administered. 76. The sustained-release composition of any of embodiments 1 to 75, wherein the core tablet comprises 0.01 mg to 200 mg of (Z)-endoxifen free base as the therapeutic agent, 0.1% to 99% w / w of hypromellose as at least one sustained-release agent, 1% to 99% w / w of microcrystalline cellulose as at least one binder, and 0.01% to 5% w / w of magnesium stearate as at least one lubricant, and the functional coating comprises 0.1% to 20% w / w of a copolymer of methacrylic acid and ethyl acrylate having a ratio of 2:1 to 1:2, 0.01% to 5% w / w of triethyl citrate, and 1% to 10% w / w of talc. 77. When administered to a subject, the subject experiences vasomotor symptoms (e.g., hot flashes, drowsiness) with a frequency of less than 5% of drug dosing days. 77. The sustained release composition of any of embodiments 1-76, wherein the sustained release composition causes symptoms such as sweating, dry mouth, hot feeling, cold sweat, etc. 78. The sustained release composition of any of embodiments 1-77, further comprising an additional therapeutic agent. 79. The additional therapeutic agent is bicalutamide, enzalutamide, or an anticancer drug, e.g., trastuzumab, atezolizumab (Tecentriq), alpelisib (Piqray), olaparib (Lynparza), talazoparib (Talzenna), ribociclib (Kisqali), neratinib (Nerlynx), an anti-cancer drug, e.g., capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinol), cyclophosphamide (Neosar), docetaxel (Docefrez, Taxotere), doxorubicin (Adriamycin), pegylated liposomal doxorubicin 79. The sustained-release composition of embodiment 78, wherein the active ingredient is selected from the group consisting of rifabutin (Doxil), epirubicin (Ellence), fluorouracil (5-FU, Adrucil), gemcitabine (Gemzar), methotrexate (numerous trade names), paclitaxel (Taxol), protein-bound paclitaxel (nab-paclitaxel or Abraxane), vinorelbine (Navelbine), eribulin (Halaven), ixabepilone (Ixempra), immune checkpoint inhibitors (such as inhibitors of PD1, inhibitors of PD-L1, and inhibitors of CTLA4), and ATP cassette binding protein inhibitors, etc. 80. A method for preparing a sustained-release composition in the form of an enteric-coated delayed-release tablet for the sustained release of (Z)-endoxifen or a polymorph or salt thereof, comprising: (a) combining, blending, and dry-compressing (Z)-endoxifen or a polymorph or salt thereof, at least one sustained-release agent, at least one binder, and at least one lubricant to form a core tablet; (b) combining at least one delayed-release agent, at least one plasticizer, and at least one anti-stick / anti-adherent agent to form a coating solution; and (c) subsequently coating the core tablet of step (a) with the coating solution of step (b) to form at least one layer of a functional coating.81. The method of embodiment 80, wherein the coating is performed by spraying the coating solution onto the core tablet. 82. A method for preparing a sustained-release composition for releasing a therapeutic agent, comprising the steps of combining and mixing a therapeutic agent selected from (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, a salt of (Z)-endoxifen, and combinations thereof, at least one sustained-release agent, at least one binder, and at least one lubricant; and dry-compressing the therapeutic agent, the at least one sustained-release agent, the at least one binder, and the at least one lubricant to form a core tablet. 83. The method of any one of embodiments 80 to 82, wherein the percentage of (E)-endoxifen in the sustained-release composition is less than 5% w / w, less than 4% w / w, less than 3% w / w, less than 2.5% w / w, or less than 2% w / w of the average core tablet weight. 84. The method of any one of embodiments 80 to 83, wherein the total level of impurities in the enteric coated delayed-release tablet is less than 5% w / w. 85. The method of any one of embodiments 80 to 84, wherein the total level of impurities in the core tablet is less than 5% w / w. 86. The enteric coated delayed-release tablet is <1111> 87. The method of any one of embodiments 80 to 86, wherein the at least one sustained-release agent is hypromellose. 88. The method of any one of embodiments 80 to 87, wherein the at least one binder is microcrystalline cellulose. 89. The method of any one of embodiments 80 to 88, wherein the at least one lubricant is magnesium stearate. 90. The method of any one of embodiments 81 to 89, further comprising the steps of: combining and mixing at least one delayed-release agent, at least one plasticizer, and at least one anti-stick or anti-adhesion component to form a coating solution; and subsequently coating the core tablet with the coating solution to form at least one layer of the functional coating.91. The method of embodiment 90, wherein at least one delayed-release agent is a poly(methacrylic acid) polymer. 92. The method of any one of embodiments 90 to 91, wherein at least one delayed-release agent is a copolymer of methacrylic acid and ethyl acrylate having a ratio of 1:2 to 2:1. 93. The method of embodiment 92, wherein the ratio of the copolymer of methacrylic acid and ethyl acrylate is about 1:1. 94. The method of any one of embodiments 90 to 93, wherein at least one plasticizer is triethyl citrate. 95. The method of any one of embodiments 90 to 94, wherein at least one anti-stick component is talc. 96. A method of treating a disorder in a subject in need thereof, comprising orally administering to a subject in need thereof a sustained-release composition of any one of embodiments 1 to 79. 97. A method of treating a subject suffering from or at risk of suffering from a disorder, comprising orally administering to the subject the sustained release composition of any one of embodiments 1 to 79. 98. The method of any one of embodiments 96 to 97, wherein the sustained release composition is in the form of an enteric-coated delayed-release tablet or sustained-release tablet. 99. The method of any one of embodiments 96 to 98, wherein the disorder is a hormone-dependent disorder. 100. The method of embodiment 99, wherein the hormone-dependent disorder is a breast disorder. 101. The method of any one of embodiments 96 to 100, wherein the disorder is a breast disorder. 102. The method of any one of embodiments 100 to 101, wherein the breast disorder is a benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, dense breast tissue, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, or McCune-Albright syndrome. 103. The method of any one of embodiments 96 to 99, wherein the disorder is depression, mania, hypomania, bipolar disorder, or schizophrenia. 104. The method of any one of embodiments 96 to 103, wherein the subject is tamoxifen-refractory or tamoxifen-resistant.105. The method of any one of embodiments 96 to 104, wherein the subject is undergoing or will undergo treatment with an SSRI drug selected from the group consisting of citalopram, escitalopram, fluoxetine, paroxetine, sertraline, and vilazodone. 106. The method of any one of embodiments 96 to 105, wherein the subject is administered the sustained-release compositi...

Claims

1. 1. A sustained release composition comprising a core tablet coated with an enteric coating, the core tablet comprising: A therapeutic agent comprising (Z)-endoxifen; A sustained release agent comprising no less than 16% and no more than 60% by weight of hydroxypropyl methylcellulose based on the total core tablet weight; Hardness not less than 10 kilopounds (Kp) and not more than 16 Kp wherein the enteric coating comprises a delayed release agent.

2. 2. The sustained release composition of claim 1, wherein the therapeutic agent comprises at least 90% by weight of (Z)-endoxifen based on the total therapeutic agent weight.

3. 3. The sustained release composition of claim 1 or claim 2, wherein the core tablet comprises not less than 1% by weight and not more than 40% by weight of a therapeutic agent based on the total core tablet weight.

4. 4. The sustained release composition of claim 1, wherein the sustained release agent further comprises a hydroxyalkyl cellulose, a cellulose ether, a gum, an acrylic resin, or a combination thereof.

5. 5. The sustained release composition of claim 4, wherein the hydroxyalkyl cellulose comprises hydroxymethyl cellulose, hydroxyethyl cellulose, or hydroxypropyl cellulose.

6. 6. The sustained release composition of claim 1, wherein the core tablet comprises not less than 20% by weight and not more than 60% by weight of the sustained release agent based on the total core tablet weight.

7. 7. The sustained release composition of claim 1, wherein the core tablet further comprises a binder.

8. 8. The sustained release composition of claim 7, wherein the core tablet comprises not less than 30% by weight and not more than 97% by weight of binder based on the total core tablet weight.

9. 9. The sustained release composition of claim 7 or claim 8, wherein the binder comprises a monosaccharide, a disaccharide, a starch, a polyhydric alcohol, mannitol, xylitol, sorbitol, lactose, polyethylene glycol, a gum, an alginic acid, a polyvinylpyrrolidone, a methylcellulose, a hydroxypropylmethylcellulose, a crystalline cellulose, a microcrystalline cellulose, a silicified microcrystalline cellulose, a calcium carbonate, a calcium phosphate, a sodium carbonate, a sodium phosphate, anhydrous calcium hydrogen phosphate, a talc, a dextrate, a kaolin, a silicic acid, or a combination thereof.

10. 10. The sustained release composition of claim 9, wherein the core tablet comprises not less than 10% by weight and not more than 90% by weight of microcrystalline cellulose based on the total core tablet weight.

11. 11. The sustained release composition of claim 1, wherein the core tablet further comprises a lubricant.

12. 12. The sustained release composition of claim 11, wherein the lubricant comprises stearic acid, calcium stearate, magnesium stearate, zinc stearate, potassium stearate, hydrogenated vegetable oil, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycerol, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, talc, ethyl oleate, ethyl laurate, agar, wax, or a combination thereof.

13. 13. The sustained release composition of claim 12, wherein the core tablet comprises not less than 0.01% by weight and not more than 5% by weight of magnesium stearate based on the total core tablet weight.

14. 14. The sustained release composition of claim 1, wherein the release retarding agent comprises a poly(meth)acrylate polymer.

15. 15. The sustained release composition of claim 14, wherein the enteric coating comprises no less than 60% and no more than 80% by weight of poly(meth)acrylate polymer based on the total enteric coating weight.

16. 16. The sustained release composition of claim 1, wherein the enteric coating further comprises a plasticizer.

17. 17. The sustained release composition of claim 16, wherein the plasticizer comprises triethyl citrate.

18. 18. The sustained release composition of claim 17, wherein the enteric coating comprises not less than 0.01% by weight and not more than 5% by weight of triethyl citrate based on the total enteric coating weight.

19. 19. The sustained release composition of claim 1, wherein the enteric coating further comprises an anti-adherent agent.

20. 20. The sustained release composition of claim 19, wherein the anti-adherent agent comprises talc.

21. 21. The sustained release composition of claim 20, wherein the enteric coating comprises no less than 1% and no more than 40% by weight of talc based on the total enteric coating weight.

22. 22. The sustained release composition of any one of claims 1 to 21, wherein the enteric coating comprises no less than 5% by weight and no more than 30% by weight of the total sustained release composition weight.

23. 23. The sustained release composition of any one of claims 1 to 22, wherein the (Z)-endoxifen comprises (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, a salt of (Z)-endoxifen, or a combination thereof.

24. The (Z)-endoxifen salt may be acetate, arecoline, benzathine, benzoate, besylate, benzosulfonate, bicarbonate, bitartrate, butyl bromide, citrate, camsylate, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, formate, fumarate, glycolate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaptanoate, isethionate, malate, maleate, mandelate, meglumine, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, methyl nitr ...

24. The sustained release composition of claim 23, comprising an acid salt selected from the group consisting of sulfonate, mucate, napsylate, nitrate, nitrate, oxalate, pamoate (embonate), pantothenate, perchlorate, phosphate, diphosphate, piperazine, procaine, polygalacturonate, p-toluenesulfonate, salicylate, stearate, succinate, sulfate, sulfonate, sulfate, tannate, tartrate, theoclate, triethiodide, trifluoroacetate, aluminum, barium, bismuth, lithium, magnesium, potassium and zinc, aluminum, barium, bismuth, lithium, magnesium, potassium and zinc, or any combination thereof.

25. The sustained release composition of any one of claims 1 to 24, wherein the sustained release agent comprises not less than 20% and not more than 60% by weight of hydroxypropyl methylcellulose based on the total core tablet weight, and the therapeutic agent has a dissolution percentage of less than 20% at 2 hours, less than 40% at 7 hours, at least 30% at 12 hours, or a combination thereof, measured at 37°C for 0-2 hours in simulated gastric fluid of pH 1.2 and after 2 hours in simulated intestinal fluid of pH 6.

8.

26. 26. The sustained release composition of any one of claims 1 to 25, wherein the therapeutic agent has a dissolution percentage of less than 35% at 3 hours, at least 50% at 24 hours, or both.

27. 27. The sustained release composition of any one of claims 1 to 26, wherein at least 90% by weight of the therapeutic agent is polymorphic Form I of (Z)-endoxifen, said polymorphic Form I being 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.

28. 28. The sustained release composition of claim 27, wherein the polymorphic Form I is characterized by an X-ray powder diffraction pattern further comprising 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.

29. 1. A sustained release composition comprising a therapeutic agent and a sustained release agent, wherein the therapeutic agent is (Z)-endoxifen free base, a polymorph of (Z)-endoxifen, a salt of (Z)-endoxifen, or a combination thereof, the sustained release agent comprises not less than 20% and not more than 60% by weight of hydroxypropyl methylcellulose based on the total weight of the sustained release composition, and wherein the therapeutic agent exhibits a hydroxypropyl methylcellulose concentration of 0.01% or more at 0.05% relative to the total weight of the sustained release composition, as measured at 37° C. in simulated gastric fluid at pH 1.2 for 0-2 hours and in simulated intestinal fluid at pH 6.8 after 2 hours. Percentage of dissolution less than 20% in 2 hours; Percentage of dissolution less than 40% at 7 hours, and At least 30% dissolution percentage in 12 hours 13. A sustained release composition having at least two dissolution percentage parameters selected from:

30. 30. The sustained release composition of any one of claims 1 to 29, characterized in that it is orally administered to a subject in need thereof.

31. 30. The sustained release composition of any one of claims 1 to 29 for treating a disorder in a subject in need thereof, wherein the subject is afflicted with or at risk of being afflicted with the disorder, and wherein the sustained release composition is orally administered to the subject.

32. 32. The sustained release composition of claim 31, wherein the disorder is a breast disorder, a benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, dense breast, gynecomastia, ductal carcinoma in situ, lobular carcinoma in situ, breast cancer, precocious puberty, or McCune-Albright syndrome.

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