High-dose endoxifen formulations and methods of use thereof

Abstract

Described herein is a pharmaceutical composition comprising high doses of (Z)-endoxifen. The high dose endoxifen composition may be formulated to prevent cross-linking between the endoxifen active pharmaceutical ingredient and a surrounding layer (e.g., capsule). The composition may be further formulated as an enteric-resistant composition for oral administration and delivery to the intestine of a subject. Also described herein is a method of treatment using the high dose endoxifen composition. In various aspects, the disclosure provides a composition comprising a drug formulation comprising 4% by weight or more of (Z)-endoxifen and 1% by weight or more of croscarmellose sodium, and an enteric-resistant delayed release capsule encapsulating the drug formulation.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 334,845, entitled "HIGH DOSE ENDOXIFEN FORMULATIONS AND METHODS OF USE," filed April 26, 2022, and U.S. Provisional Application No. 63 / 437,048, entitled "HIGH DOSE ENDOXIFEN FORMULATIONS AND METHODS OF USE," filed January 4, 2023, which are incorporated by reference in their entireties for all purposes. [Background technology]

[0002] Although cancer survival rates have increased over the past few decades, cancer remains the second leading cause of death in the United States. Despite extensive treatment and prevention research, drug resistance and recurrence remain limiting factors in developing cancer treatments. To combat these and other factors, there is a need for cancer therapies that can effectively kill cancer cells, overcome drug resistance, and prevent recurrence. Summary of the Invention

[0003] In various aspects, the disclosure provides a composition comprising a drug formulation comprising 4% by weight or more of (Z)-endoxifen and 1% by weight or more of croscarmellose sodium, and an enteric-resistant delayed-release capsule encapsulating the drug formulation.

[0004] In some embodiments, the percentage of (Z)-endoxifen to total endoxifen in the drug formulation is 95% or more, 97% or more, or 98% or more, where the total endoxifen consists of (Z)-endoxifen and (E)-endoxifen. In some embodiments, the percentage of (Z)-endoxifen to total endoxifen in the drug formulation is 100% or less. In some embodiments, the drug formulation comprises 5% or more, 7% or more, 10% or more, 12% or more, or 15% or more (Z)-endoxifen by weight. In some embodiments, the drug formulation comprises 20% or less, 22% or less, 25% or less, 30% or less, or 40% or less (Z)-endoxifen by weight. In some embodiments, the drug formulation comprises 5% or more and 40% or less (Z)-endoxifen by weight. In some embodiments, the drug formulation comprises 10% or more and 25% or less (Z)-endoxifen by weight. In some embodiments, the drug formulation comprises between 15% and 20% (Z)-endoxifen by weight, inclusive. In some embodiments, the drug formulation comprises between 17% and 19% (Z)-endoxifen by weight, inclusive.

[0005] In some embodiments, the drug formulation comprises 1 mg to 80 mg of (Z)-endoxifen per enteric-resistant delayed release capsule. In some embodiments, the drug formulation comprises 10 mg to 80 mg of (Z)-endoxifen per enteric-resistant delayed release capsule. In some embodiments, the drug formulation comprises 30 mg to 50 mg of (Z)-endoxifen per enteric-resistant delayed release capsule. In some embodiments, the drug formulation comprises 38 mg to 42 mg of (Z)-endoxifen per enteric-resistant delayed release capsule. In some embodiments, the drug formulation comprises about 1 mg, about 2 mg, about 4 mg, about 10 mg, about 20 mg, about 40 mg, or about 80 mg of (Z)-endoxifen per enteric-resistant delayed release capsule.

[0006] In some embodiments, the drug formulation comprises 1.5% or more, 1.7% or more, 2% or more, 2.2% or more, 2.5% or more, 2.7% or more, or 2.8% or more by weight of croscarmellose sodium. In some embodiments, the drug formulation comprises 3% or less, 3.2% or less, 3.5% or less, 4% or less, 4.5% or less, or 5% or less by weight of croscarmellose sodium. In some embodiments, the drug formulation comprises 1% or more and 5% or less by weight of croscarmellose sodium. In some embodiments, the drug formulation comprises 2% or more and 4% or less by weight of croscarmellose sodium. In some embodiments, the drug formulation comprises 2.5% or more and 3% or less by weight of croscarmellose sodium. In some embodiments, the drug formulation comprises 2.8% or more and 3% or less by weight of croscarmellose sodium.

[0007] In some embodiments, the drug formulation further comprises microcrystalline cellulose. In some embodiments, the drug formulation comprises 60% or more, 65% or more, 70% or more, 75% or more, or 77% or more by weight of microcrystalline cellulose. In some embodiments, the drug formulation comprises 79% or less, 80% or less, 85% or less, 90% or less, or 95% or less by weight of microcrystalline cellulose. In some embodiments, the drug formulation comprises 60% or more and 95% or less by weight of microcrystalline cellulose. In some embodiments, the drug formulation comprises 70% or more and 90% or less by weight of microcrystalline cellulose. In some embodiments, the drug formulation comprises 75% or more and 80% or less by weight of microcrystalline cellulose.

[0008] In some embodiments, the drug formulation further comprises magnesium stearate. In some embodiments, the drug formulation comprises 0.3% or more, 0.5% or more, 0.7% or more, 0.8% or more, or 0.9% or more by weight of magnesium stearate. In some embodiments, the drug formulation comprises 1.1% or less, 1.2% or less, 1.5% or less, 1.8% or less, 2% or less, or 3% or less by weight of magnesium stearate. In some embodiments, the drug formulation comprises 0.5% or more and 3% or less by weight of magnesium stearate. In some embodiments, the drug formulation comprises 0.5% or more and 2% or less by weight of magnesium stearate. In some embodiments, the drug formulation comprises 0.5% or more and 1.5% or less by weight of magnesium stearate.

[0009] In some embodiments, the enteric resistant delayed release capsule comprises hydroxypropyl methylcellulose, gellan gum, gelatin, hydroxypropyl methylcellulose phthalate, coloring agent, opacifier, or any combination thereof. In some embodiments, the enteric resistant delayed release capsule comprises hydroxypropyl methylcellulose. In some embodiments, the enteric resistant delayed release capsule comprises 85% or more by weight and 97% or less by weight of hydroxypropyl methylcellulose. In some embodiments, the enteric resistant delayed release capsule comprises gellan gum, gelatin, or a combination thereof. In some embodiments, the enteric resistant delayed release capsule comprises 3% or more by weight and 10% or less by weight of gellan gum, gelatin, or a combination thereof.

[0010] In some embodiments, (Z)-endoxifen includes a polymorphic form of endoxifen.

[0011] In some embodiments, the polymorphic form of endoxifen is Form I, characterized by an X-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises a) at least one peak selected from 16.0±0.3°, 18.8±0.3°, and 26.5±0.3°2-theta, b) at least one peak selected from 12.3±0.3°, 28.0±0.3°, and 29.0±0.3°2-theta, or c) a combination thereof. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, or at least two peaks, at least three peaks, selected from the group consisting of 16.0±0.3°, 18.8±0.3°, and 26.5±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, or at least two peaks, at least three peaks selected from the group consisting of 12.3±0.3°, 28.0±0.3°, and 29.0±0.3°2-theta.

[0012] In some embodiments, the polymorphic form of endoxifen is Form II, characterized by an X-ray powder diffraction pattern comprising major peaks at 7.0±0.3°, 11.9±0.3°, and 14.0±0.3°. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, or at least two peaks, at least three peaks, or at least four peaks selected from the group consisting of 18.4±0.3°, 22.0±0.3°, 6.6±0.3°, and 13.3±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, or at least two peaks, at least three peaks, at least four peaks, or at least five peaks selected from the group consisting of 20.0±0.3°, 6.6±0.3°, 13.3±0.3°, 20.0±0.3°, and 22.0±0.3°2-theta.

[0013] In some embodiments, the polymorphic form of endoxifen is Form III, characterized by an X-ray powder diffraction pattern comprising major peaks at 11.9±0.3°, 13.9±0.3°, and 17.1±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, or at least two peaks, at least three peaks, or at least four peaks selected from the group consisting of 17.7±0.3°, 25.3±0.3°, 18.2±0.3°, and 22.5±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, or at least two peaks, at least three peaks, at least four peaks, or at least five peaks selected from the group consisting of 26.8±0.3°, 18.2±0.3°, 22.5±0.3°, 25.3±0.3°, and 26.8±0.3°2-theta.

[0014] In some embodiments, the polymorphic form of endoxifen is Form IV, characterized by an X-ray powder diffraction pattern comprising major peaks at 4.7±0.3°2-theta, 23.3±0.3°, and 13.6±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from the group consisting of 23.8±0.3°, 14.2±0.3°, 22.5±0.3°, or 15.7±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from the group consisting of 7.1±0.3°, 20.2±0.3°, or 9.5±0.3°2-theta.

[0015] In some embodiments, the polymorphic form of endoxifen is Form V, characterized by an X-ray powder diffraction pattern comprising major peaks at 12.5±0.3°, 19.6±0.3°, and 8.9±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from the group consisting of 21.7±0.3°, 20.8±0.3°, 19.8±0.3°, or 16.0±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from the group consisting of 21.7±0.3°, 20.8±0.3°, 19.8±0.3°, 16.0±0.3°, 22.0±0.3°, 13.5±0.3°, and 14.4±0.3°2-theta.

[0016] In some embodiments, the polymorphic form of endoxifen is Form VI, characterized by an X-ray powder diffraction pattern comprising major peaks at 9.9±0.3°, 13.4±0.3°, and 13.7±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from the group consisting of 17.6±0.3°, 18.6±0.3°, 17.3±0.3°, or 21.8±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from the group consisting of 10.2±0.3°, 19.5±0.3°, or 14.2±0.3°2-theta.

[0017] In some embodiments, the polymorphic form of endoxifen is Form VII, characterized by an X-ray powder diffraction pattern comprising major peaks at 20.0±0.3°, 22.6±0.3°, and 10.6±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from the group consisting of 11.4±0.3°, 16.4±0.3°, 9.6±0.3°, or 13.3±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from the group consisting of 18.2±0.3°, 13.1±0.3°, or 27.0±0.3°2-theta.

[0018] In some embodiments, the polymorphic form of endoxifen is Form VIII, characterized by an X-ray powder diffraction pattern comprising major peaks at 4.8±0.3°, 18.9±0.3°, and 9.5±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from the group consisting of 23.7±0.3°, 21.9±0.3°, 21.2±0.3°, or 12.9±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from the group consisting of 25.0±0.3°, 21.5±0.3°, or 16.4±0.3°2-theta.

[0019] In some embodiments, the polymorphic form of endoxifen is Form IX, characterized by an X-ray powder diffraction pattern comprising major peaks at 19.0±0.3°, 12.9±0.3°, and 15.9±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least two peaks, at least three peaks, or at least four peaks selected from the group consisting of 21.7±0.3°, 20.8±0.3°, 21.1±0.3°, or 8.9±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from the group consisting of 16.4±0.3°, 4.2±0.3°, or 12.7±0.3°2-theta.

[0020] In some embodiments, the polymorphic form of endoxifen is Form X, characterized by an X-ray powder diffraction pattern comprising major peaks at 7.2±0.3°, 14.3±0.3°, and 18.7±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from the group consisting of 21.5±0.3°, 22.7±0.3°, and 17.1±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from the group consisting of 21.8±0.3°, 27.3±0.3°, or 29.4±0.3°2-theta.

[0021] In some embodiments, the polymorphic form of endoxifen is Form XI, characterized by an X-ray powder diffraction pattern comprising major peaks at 14.0±0.3°, 17.7±0.3°, and 11.9±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from the group consisting of 18.4±0.3°, 23.9±0.3°, or 17.3±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from the group consisting of 21.8±0.3°, 20.8±0.3°, and 23.0±0.3°, or 22.2±0.3°2-theta.

[0022] In some embodiments, the polymorphic form of endoxifen is Form XII, characterized by an X-ray powder diffraction pattern comprising major peaks at 12.5±0.3°, 15.6±0.3°, and 19.0±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from the group consisting of 21.9±0.3°, 20.2±0.3°, 16.0±0.3°, or 21.6±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from the group consisting of 22.4±0.3°, 16.8±0.3°, or 12.8±0.3°2-theta.

[0023] In some embodiments, the polymorphic form of endoxifen is Form XIV, characterized by an X-ray powder diffraction pattern comprising major peaks at 11.6±0.3°, 21.3±0.3°, and 19.3±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from the group consisting of 17.5±0.3°, 15.4±0.3°, 21.6±0.3°, or 5.8±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from the group consisting of 16.3±0.3°, 21.9±0.3°, or 23.9±0.3°2-theta.

[0024] In some embodiments, the polymorphic form of endoxifen is Form XV, characterized by an X-ray powder diffraction pattern comprising major peaks at 9.8±0.3°, 4.7±0.3°, and 14.0±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from the group consisting of 20.2±0.3°, 7.1±0.3°, 23.4±0.3°, or 22.4±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from the group consisting of 21.7±0.3°, 22.7±0.3°, or 18.8±0.3°2-theta.

[0025] In some embodiments, the polymorphic form of endoxifen is Form XIX, characterized by an X-ray powder diffraction pattern comprising major peaks at 4.7±0.3°, 23.6±0.3°, and 18.9±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from the group consisting of 9.4±0.3°, 23.3±0.3°, 22.3±0.3°, or 20.1±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from the group consisting of 19.6±0.3°, 7.1±0.3°, or 15.7±0.3°2-theta.

[0026] In some embodiments, at least 90% by weight of the (Z)-endoxifen is a polymorphic form of endoxifen.

[0027] In some embodiments, the composition comprises an in vitro dissolution profile in which: a) 20% or less of (Z)-endoxifen is released within 2 hours after the composition is introduced into the acidic stage of an in vitro dissolution assay; b) 70% or less of (Z)-endoxifen is released within 1.5 hours after the composition is introduced into the buffer stage of an in vitro dissolution assay; or c) a combination thereof. In some embodiments, 5% or less, 10% or less, or 15% or less of (Z)-endoxifen is released within 2 hours after the composition is introduced into the acidic stage of an in vitro dissolution assay. In some embodiments, 75% or more, 80% or more, or 85% or more of (Z)-endoxifen is released within 1.5 hours after the composition is introduced into the buffer stage of an in vitro dissolution assay. In some embodiments, the buffer stage comprises a pH of less than 2. In some embodiments, the buffer stage comprises a pH of about 6.8. In some embodiments, the buffer stage comprises 0.75% polysorbate 80. In some embodiments, when the composition is orally administered to a subject, 5% or less, 10% or less, 15% or less, or 20% or less of the (Z)-endoxifen is released in the subject's stomach and 70% or more, 75% or more, 80% or more, or 85% or more of the (Z)-endoxifen is released in the subject's intestine.

[0028] In various aspects, the disclosure provides a composition comprising a drug formulation comprising 15% to 20% by weight of (Z)-endoxifen, 2% to 4% by weight of croscarmellose sodium, 0.5% to 2% by weight of magnesium stearate, and 70% to 80% by weight of microcrystalline cellulose, and an enteric resistant delayed release capsule encapsulating the drug formulation, wherein the enteric resistant delayed release capsule comprises 85% to 97% by weight of hydroxypropyl methylcellulose and 3% to 7% by weight of gellan gum.

[0029] In some embodiments, the drug formulation comprises 17% to 19% (Z)-endoxifen by weight. In some embodiments, the drug formulation comprises 2.8% to 3% croscarmellose sodium by weight. In some embodiments, the drug formulation comprises 0.7% to 1.2% magnesium stearate by weight. In some embodiments, the drug formulation comprises 75% to 80% microcrystalline cellulose by weight.

[0030] In various aspects, the disclosure provides a method of treating a disorder in a subject comprising orally administering to the subject a composition comprising a drug formulation comprising 4% by weight or less of (Z)-endoxifen and 1% by weight or less of croscarmellose sodium, and an enteric resistant delayed-release capsule encapsulating the drug formulation, thereby treating cancer.

[0031] In various aspects, the disclosure provides a method of treating a disorder in a subject, comprising orally administering to the subject a composition described herein, thereby treating the disorder.

[0032] In some embodiments, the disorder is cancer, hormone-dependent breast disorder, or hormone-dependent reproductive tract disorder. In some embodiments, the cancer is breast cancer, cervical cancer, ovarian cancer, endometrial cancer, uterine cancer, vaginal cancer, vulvar cancer, melanoma, colon cancer, gastric cancer, neuroblastoma, pancreatic cancer, esophageal cancer, rectal cancer, or bile duct cancer. In some embodiments, the breast cancer is triple-negative breast cancer, in situ ductal carcinoma, in situ lobular carcinoma, invasive ductal carcinoma, or invasive lobular carcinoma. In some embodiments, the hormone-dependent breast disorder or hormone-dependent reproductive tract disorder is benign breast disorder, hyperplasia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, precocious puberty, or McCune-Albright syndrome. In some embodiments, the disorder is tamoxifen-resistant or tamoxifen-refractory.

[0033] In some embodiments, the method further comprises, after oral administration of the composition, releasing 5% or less, 10% or less, 15% or less, or 20% or less of the (Z)-endoxifen into the stomach of the subject and releasing 70% or more, 75% or more, 80% or more, or 85% or more of the (Z)-endoxifen into the intestine of the subject. In some embodiments, the method further comprises producing a plasma concentration of endoxifen in the subject that is 70% or more, 75% or more, 80% or more, or 85% or more in the (Z)-isoform. Incorporation by Reference

[0034] 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.

[0035] The novel features of the invention are set forth with particularity in the appended claims. The features and advantages of the present invention will be better understood by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [Brief description of the drawings]

[0036] [Figure 1A] HPLC chromatogram of 40 mg of (Z)-endoxifen containing 40 mg of (Z)-endoxifen, 173.78 mg of microcrystalline cellulose, 6.50 mg of croscarmellose sodium, and 2.23 mg of magnesium stearate, encapsulated in an enteric-resistant delayed-release capsule and dissolved in diluent to give a concentration of 0.5 mg / mL of (Z)-endoxifen. [Figure 1B] HPLC chromatogram of a 0.5 mg / mL (Z)-endoxifen reference sample in an enteric-resistant delayed release capsule and dissolved in diluent. [Figure 1C] FIG. 1 shows HPLC chromatograms of the diluents used to dissolve the samples assayed in FIG. 1A and FIG. 1B. [Figure 2A] 1 shows the X-ray powder diffraction pattern obtained from a sample of endoxifen Form I. [Figure 2B] 1 shows an X-ray powder diffraction (XRPD) pattern obtained from a sample of endoxifen Form I. [Figure 2C] 1 shows the XRPD pattern obtained from a sample of endoxifen Form I. [Diagram 3] 1 shows the XRPD pattern obtained from a sample of endoxifen Form II. [Figure 4] 1 shows the XRPD pattern obtained from a sample of endoxifen Form III. [Diagram 5] 1 shows the XRPD pattern obtained from a sample of endoxifen Form IV. [Figure 6] 1 shows the XRPD pattern obtained from a sample of endoxifen form V. [Figure 7] 1 shows the XRPD pattern obtained from a sample of endoxifen Form VI. [Figure 8] 1 shows the XRPD pattern obtained from a sample of endoxifen Form VII. [Figure 9] 1 shows the XRPD pattern obtained from a sample of endoxifen Form VIII. [Figure 10] 1 shows the XRPD pattern obtained from a sample of endoxifen Form IX. [Figure 11] 1 shows the XRPD pattern obtained from a sample of endoxifen form X. [Figure 12] 1 shows the XRPD pattern obtained from a sample of endoxifen form XI. [Figure 13] 1 shows the XRPD pattern obtained from a sample of endoxifen Form XII. [Figure 14] 1 shows the XRPD patterns obtained from samples of endoxifen Forms XII and XIII. [Figure 15]1 shows the XRPD pattern obtained from a sample of endoxifen form XIV. [Figure 16] 1 shows the XRPD pattern obtained from a sample of endoxifen form XV. [Figure 17] 1 shows the XRPD pattern obtained from a sample of endoxifen form XVII. [Figure 18] 1 shows the XRPD pattern obtained from a sample of endoxifen form XVIII. [Figure 19] 1 shows the XRPD pattern obtained from a sample of endoxifen form XIX. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] The present disclosure provides high-dose oral endoxifen formulations and methods of using such formulations. Endoxifen, also known as 4-hydroxy-N-desmethyl-tamoxifen, is the secondary active metabolite of tamoxifen and can be used to treat a variety of hormone-dependent disorders and cancers. Oral drug formulations can be easily self-administered, providing a simple and convenient means of drug delivery. However, oral delivery of endoxifen, especially at high doses, has proven difficult due to the observed tendency of endoxifen to interconvert between the pharmacologic active (Z) form and the less active (E) form under acidic conditions. Furthermore, cross-linking between endoxifen and enteric-resistant delayed-release capsules has been observed in high-dose endoxifen preformulations, resulting in poor dissolution and drug delivery. High-dose endoxifen formulations can be advantageous for treatment regimens requiring high doses of endoxifen, which may otherwise be administered as numerous low-dose pills.

[0038] Described herein are high-dose oral endoxifen compositions that exhibit low solubility in the acidic environment of the stomach and high solubility in the intestinal environment. Such high-dose oral endoxifen compositions can be used to effectively deliver (Z)-endoxifen to a subject to provide bioavailable endoxifen in its pharmacologic active (Z)-form. The (Z)-isoform of endoxifen can serve as the more pharmacologic active isoform of the two isoforms. However, under acidic conditions such as in the stomach, endoxifen can readily interconvert between (Z)-endoxifen and (E)-endoxifen, resulting in an equilibrium of the two isoforms, as shown in Example 1. To protect against the acidic environment of the stomach, the endoxifen composition can be encapsulated in an enteric-resistant delayed-release capsule. This capsule, also referred to as an "enteric capsule", "enteric-resistant capsule", "delayed-release capsule" or "DR capsule", exhibits limited dissolution in the stomach and high dissolution in the intestine when administered orally. The endoxifen compositions of the present disclosure may be formulated to prevent cross-linking between the endoxifen and the enteric resistant delayed release capsule.

[0039] Endoxifen Compositions As used herein, "endoxifen" may refer to a composition comprising the (Z)-isoform designated "(Z)-endoxifen," the (E)-isoform designated "(E)-endoxifen," or a mixture of the (Z)-isoform and the (E)-isoform designated "(E / Z)-endoxifen." The present disclosure provides compositions comprising (Z)-endoxifen, e.g., high-dose oral endoxifen formulations. In some embodiments, (Z)-endoxifen may comprise a stable (Z)-endoxifen free base, or a polymorph or salt thereof. In some embodiments, the composition may further comprise (E)-endoxifen. In some embodiments, the composition may comprise endoxifen primarily in the form of the (Z)-endoxifen free base. Unless otherwise noted by the prefixes (Z), (E), or (E / Z), endoxifen as generally used herein without a prefix is ​​used to include any or all endoxifen isoforms.

[0040] A mixture of (E)-endoxifen and (Z)-endoxifen, also referred to as (E / Z)-endoxifen, may be represented by formula (I): [ka]

[0041] (Z)-Endoxifen may be represented by formula (II): [ka]

[0042] (E)-Endoxifen can be represented by formula (III): [ka]

[0043] In some embodiments, the endoxifen compositions of the present disclosure may comprise at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 91% by weight, at least about 92% by weight, at least about 93% by weight, at least about 94% by weight, at least about 95% by weight, at least about 96% by weight, at least about 97% by weight, at least about 98% by weight, at least about 99% by weight, at least about 99.5% by weight, at least about 99.99% by weight, or about 100% by weight of (Z)-endoxifen in the composition. In some embodiments, the compositions comprise at least 90% by weight of (Z)-endoxifen relative to the total endoxifen in the composition. In some embodiments, the compositions comprise at least 95% by weight of (Z)-endoxifen relative to the total endoxifen in the composition. In some embodiments, the composition comprises at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, or at least about 99.9% by weight of (Z)-endoxifen relative to the total endoxifen in the composition. In some embodiments, the endoxifen compositions of the present disclosure may comprise (E)-endoxifen as about 10% or less by weight, about 8% or less by weight, about 6% or less by weight, about 7% or less by weight, about 8% or less by weight, about 9% or less by weight, about 2% or less by weight, or about 1% or less by weight of total endoxifen (e.g., (Z)-endoxifen and (E)-endoxifen) in the composition.

[0044] In some embodiments, the endoxifen compositions of the present disclosure may comprise a ratio of (Z)-endoxifen:(E)-endoxifen (Z:E ratio) that is at least about 50:50, at least about 60:40, at least about 64:36, at least about 70:30, at least about 80:30, at least about 82:18, at least about 85:15, at least about 90:10, at least about 94:6, at least about 95:5, at least about 96:4, at least about 97:3, at least about 98:2, at least about 99:1, or about 100:0. In some embodiments, the endoxifen compositions of the present disclosure may comprise a ratio of (Z)-endoxifen:(E)-endoxifen (Z:E ratio) that is about 50:50 to about 100:0, about 60:40 to about 100:0, about 64:36 to about 100:0, about 70:30 to about 100:0, about 80:30 to about 100:0, about 82:18 to about 100:0, about 85:15 to about 100:0, about 90:10 to about 100:0, about 94:6 to about 100:0, about 95:5 to about 100:0, about 96:4 to about 100:0, about 97:3 to about 100:0, about 98:2 to about 100:0, or about 99:1 to about 100:0.

[0045] A composition comprising (Z)-endoxifen may comprise at least about 4% by weight of (Z)-endoxifen based on the total fill weight of the composition (e.g., excluding the capsule or coating that encapsulates the composition, if present). A composition comprising (Z)-endoxifen may comprise at least about 10% by weight of (Z)-endoxifen based on the total fill weight of the composition. In some embodiments, a composition comprising (Z)-endoxifen may comprise at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, or at least about 20% by weight of (Z)-endoxifen based on the total fill weight of the composition. In some embodiments, a composition comprising (Z)-endoxifen comprises about 4% to about 50% by weight, about 5% to about 50% by weight, about 7% to about 50% by weight, about 10% to about 50% by weight, about 12% to about 50% by weight, about 15% to about 50% by weight, about 4% to about 40% by weight, about 5% to about 40% by weight, about 7% to about 40% by weight, about 10% to about 40% by weight, about 12% to about 40% by weight, about The composition may contain 15% to about 40% by weight, about 4% to about 30% by weight, about 5% to about 30% by weight, about 7% to about 30% by weight, about 10% to about 30% by weight, about 12% to about 30% by weight, about 15% to about 30% by weight, about 4% to about 20% by weight, about 5% to about 20% by weight, about 7% to about 20% by weight, about 10% to about 20% by weight, about 12% to about 20% by weight, or about 15% to about 20% by weight of (Z)-endoxifen.

[0046] The compositions of the present disclosure (e.g., enteric resistant delayed release high dose endoxifen formulations) may include an amount of (Z)-endoxifen formulated as a dosage form such as a tablet or capsule. In some embodiments, a single high dose endoxifen dosage form (e.g., a single capsule or a single tablet) may include about 10 mg, about 12 mg, about 15 mg, about 16 mg, about 20 mg, about 22 mg, about 24 mg, about 25 mg, about 28 mg, about 30 mg, about 32 mg, about 35 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg of (Z)-endoxifen. In some embodiments, a single high dose endoxifen dosage form may contain about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 50 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, or about 10 mg to about 30 mg of (Z)-endoxifen.

[0047] Endoxifen is also referred to as 4-hydroxy-N-desmethyl-tamoxifen and may include polymorphs, salts, free bases, co-crystals, or solvates of endoxifen. Examples of (Z)-endoxifen salts suitable for the endoxifen compositions (e.g., enteric-resistant delayed release high-dose endoxifen formulations) of the present disclosure include pharmacologically acceptable salts such as salts with inorganic acids, salts with organic acids, and salts with amino acids. Examples of (Z)-endoxifen salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. 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, etc. Examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, citric acid, etc.

[0048] Examples of anionic salts of (Z)-endoxifen include arecoline, besylate, bicarbonate, bitartrate, butyl bromide, citrate, camsylate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methyl bromide, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacronate, salicylate, stearate, sulfate, tannate, teoclate, and triethiodide. Examples of cationic salts of (Z)-endoxifen are selected from the group consisting of benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc, etc. In some embodiments, the present disclosure provides that the embodiments include salts made with non-pharmaceutical acceptable acids.

[0049] In some embodiments, the endoxifen compositions of the present disclosure may be administered in the form of acetate, arecoline, benzathine, benzoate, besylate, benzosulfonate, bicarbonate, bitartrate, butyl bromide, citrate, camsylate, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, formate, fumarate, glycolate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaptanoate, isethionate, malate, maleate, mandelate, meglumine, mesylate, methyl bromide, methyl bromide, methyl nitrate, methyl sulfate, methyl methacrylate ... The salts of (Z)-endoxifen include salts selected from the group consisting of tansulfonate, mucate, napsylate, nitrate, nitrate, oxalate, pamoate (embonate), pantothenate, perchlorate, phosphate, diphosphate, piperazine, procaine, polygalacronate, 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. 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.

[0050] The amount of (Z)-endoxifen or a polymorph or salt thereof in the endoxifen compositions of the present disclosure will vary depending on the formulation of the composition, the target disease, the severity of the disease, etc., but will generally correspond or be equivalent to about 0.01 mg to about 200 mg of (Z)-endoxifen. One of skill in the art will recognize that when the composition includes a salt of (Z)-endoxifen, the endoxifen salt may be in an equivalent amount based on the released (Z)-endoxifen.

[0051] In some embodiments, endoxifen can include one or more polymorphic forms of endoxifen (e.g., Form I). Polymorphic forms can be distinguished by X-ray powder diffraction patterns. In some embodiments, methods of treating cancer can include administering a pharmaceutical composition that includes endoxifen predominantly as polymorphic Form I. In some embodiments, polymorphic Form I is characterized by an X-ray powder diffraction pattern that includes major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° 2-theta.

[0052] Endoxifen in the compositions of the present disclosure may be present in one or more polymorphic forms (e.g., Form I). For example, the compositions of the present disclosure may contain at least about 90% by weight of the total endoxifen as polymorphic Form I. In another example, the compositions of the present disclosure may contain at least about 95% by weight of the total endoxifen as polymorphic Form I. When a certain percentage by weight of endoxifen is in a single polymorphic form (e.g., Form I), the remaining endoxifen in the composition may be amorphous endoxifen or some combination of one or more polymorphic forms of endoxifen other than the single polymorphic form. In some embodiments, the endoxifen composition contains (Z)-endoxifen predominantly as polymorphic Form I.

[0053] 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, including the crystalline forms described herein. The crystalline forms of endoxifen may provide advantages of bioavailability and stability, making them suitable for use as active ingredients in pharmaceutical compositions. Variations in the crystal structure of a pharmaceutical drug substance or active ingredient may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ability to consistently prepare doses of known strength), and stability (e.g., thermal stability, shelf life, etc.) of the pharmaceutical drug substance or active ingredient. Such variations may affect the preparation or formulation of pharmaceutical compositions in different dosage or delivery forms, such as solid oral dosage forms (including tablets and capsules). Compared to other forms (e.g., 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, process control, or combinations thereof. Thus, crystalline forms of endoxifen may provide advantages such as improved manufacturing processes for active agents, or improved stability or shelf life of drug product forms of the compound or active ingredient, and / or having suitable bioavailability and / or stability as an active agent.

[0054] The use of certain solvents and fractional crystallization methods can result in different polymorphs of endoxifen that can exhibit one or more advantageous properties described above. In some embodiments, the polymorphic form (e.g., Form I) can affect one or more properties of a composition comprising endoxifen. For example, a polymorphic form (e.g., Form I) of a therapeutic agent (e.g., endoxifen) can affect the dissolution rate, solubility, absorption rate, C, of ​​the therapeutic agent in a composition of the present disclosure. max ,A.U.C.,T. max , or t 1 / 2In 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., enteric resistant delayed release high dose endoxifen formulations). In some embodiments, the polymorphic forms of endoxifen may impart improved stability to the compositions of the present disclosure. The processes in the preparation of the polymorphs described herein, and the characterization of these polymorphs, are described in more detail below.

[0055] Polymorphic forms of endoxifen The compositions of the present disclosure may include polymorphic forms of endoxifen (e.g., (Z)-endoxifen). In some embodiments, endoxifen may include one or more polymorphic forms (e.g., Form I, Form II, Form III, Form IV, Form V, Form VI, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVII, Form XVIII, or Form XIX of endoxifen). In some embodiments, the polymorphic forms may be crystalline forms. The polymorphic forms may be distinguished by X-ray powder diffraction patterns. In some embodiments, the compositions may include endoxifen predominantly as polymorphic Form I. In some embodiments, the compositions may include endoxifen predominantly as polymorphic Form II. In some embodiments, the compositions may include endoxifen predominantly as polymorphic Form III. In some embodiments, the compositions may include endoxifen predominantly as polymorphic Form IV. In some embodiments, the compositions may include endoxifen predominantly as polymorphic Form V. In some embodiments, the composition may contain endoxifen predominantly as polymorphic form VI. In some embodiments, the composition may contain endoxifen predominantly as polymorphic form VII. In some embodiments, the composition may contain endoxifen predominantly as polymorphic form VIII. In some embodiments, the composition may contain endoxifen predominantly as polymorphic form IX. In some embodiments, the composition may contain endoxifen predominantly as polymorphic form X. In some embodiments, the composition may contain endoxifen predominantly as polymorphic form XI. In some embodiments, the composition may contain endoxifen predominantly as polymorphic form XII. In some embodiments, the composition may contain endoxifen predominantly as polymorphic form XIII. In some embodiments, the composition may contain endoxifen predominantly as polymorphic form XIV. In some embodiments, the composition may contain endoxifen predominantly as polymorphic form XV. In some embodiments, the composition may contain endoxifen predominantly as polymorphic form XVII.In some embodiments, the compositions may contain endoxifen predominantly as polymorphic Form XVIII. In some embodiments, the compositions may contain endoxifen predominantly as polymorphic Form XIX.

[0056] In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form I. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form II. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form III. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form IV. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form V. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form VI. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form VII. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form VIII. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form IX. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form X. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form XI. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form XII. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form XII. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form XIV. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form XV. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form XVII. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form XVIII. In some embodiments, at least 90% of the endoxifen in the composition may be polymorphic form XIX.

[0057] In certain aspects, the present disclosure provides a composition comprising polymorphic Form I of endoxifen. In some embodiments, at least 90% by weight of the endoxifen in the composition is the (Z)-isomer (i.e., (Z)-endoxifen). In some embodiments, polymorphic Form I of endoxifen exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 2A, FIG. 2B, or FIG. 2C. In some embodiments, polymorphic Form I has an XRPD pattern substantially as shown in FIG. 2A, FIG. 2B, or FIG. 2C, comprising at least two, at least three, at least four, at least five, or at least six major peaks. The crystalline form of Form I of the compound of formula (III) may be characterized by an XRPD pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° 2-theta. In some cases, the XRPD pattern further comprises at least one peak, or at least two peaks, or at least three peaks selected from 16.0±0.3°, 18.8±0.3°, and 26.5±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, or at least two peaks, or at least three peaks selected from 12.3±0.3°, 28.0±0.3°, and 29.0±0.3°2-theta.

[0058] The term "substantially as shown" when referring to, for example, an XRPD pattern includes a pattern that is not necessarily identical to the pattern shown herein, but falls within experimental error or deviation as considered by one of ordinary skill in the art. The relative intensity of XRPD peaks may vary depending on particle size, sample preparation technique, sample mounting procedure, and the particular instrument used. Additionally, instrument variations and other factors may affect the 2-theta (2θ) values. Thus, when a specified 2-theta angle is given, it should be understood that the specified 2-theta angle may vary by ±0.5° (e.g., ±0.4°, ±0.3°, ±0.2°, or ±0.1°) from the specified value. As used herein, a "major peak" refers to an XRPD peak with a relative intensity of more than 30% (e.g., more 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.

[0059] Polymorph Form I may be characterized by an X-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern of polymorph Form I may be further characterized by one or more peaks selected from 16.0±0.3°, 18.8±0.3°, and 26.5±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern of polymorph Form I may be further characterized by one or more peaks selected from 12.3±0.3°, 28.0±0.3°, and 29.0±0.3°2-theta. In some embodiments, the X-ray powder diffraction pattern of polymorph Form I may be further characterized by one or more peaks 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.

[0060] In some embodiments, the disclosure provides a composition comprising endoxifen polymorphic Form I. Greater than 90%, greater than 95%, or greater than 99% by weight of the endoxifen in the composition can be polymorphic Form I. In some embodiments, the composition comprises between 0.01 mg and 200 mg of polymorphic Form I. In some embodiments, at least about 5% by weight, at least about 10% by weight, at least about 20% by weight, at least about 25% by weight, at least about 30% by weight, at least about 40% by weight, at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 91% by weight, at least about 92% by weight, at least about 93% by weight, at least about 94% by weight, at least about 95% by weight, at least about 96% by weight, at least about 97% by weight, at least about 98% by weight, at least about 99% by weight, at least about 99.5% by weight, at least about 99.99% by weight, or about 100% by weight of the total endoxifen in the composition may be present as polymorphic Form I.

[0061] In some embodiments, polymorph Form II is characterized by the X-ray powder diffraction pattern shown in Figure 3. The crystalline form of Form II of the compound of Formula (III) may be characterized by an X-ray powder diffraction pattern including major peaks at 7.0±0.3°, 11.9±0.3°, 14.0±0.3°, and 18.4±0.3°2-theta. The crystalline form of Form II of the compound of Formula (III) may be characterized by an X-ray powder diffraction pattern including major peaks at 7.0±0.3°, 11.9±0.3°, and 14.0±0.3°2-theta. In some cases, the XRPD pattern further includes at least one peak, or at least two peaks, at least three peaks, or at least four peaks selected from 18.4±0.3°, 22.0±0.3°, 6.6±0.3°, and 13.3±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, or at least two peaks, at least three peaks, at least four peaks, or at least five peaks selected from 20.0±0.3°, 6.6±0.3°, 13.3±0.3°, 20.0±0.3°, and 22.0±0.3°2-theta.

[0062] In some embodiments, polymorph Form III is characterized by the X-ray powder diffraction pattern depicted in Figure 4. The crystalline form of Form III of the compound of Formula (III) may be characterized by an XRPD pattern comprising major peaks at 11.9±0.3°, 13.9±0.3°, and 17.1±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, or at least two peaks, at least three peaks, or at least four peaks selected from 17.7±0.3°, 25.3±0.3°, 18.2±0.3°, and 22.5±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, or at least two peaks, at least three peaks, at least four peaks, or at least five peaks selected from 26.8±0.3°, 18.2±0.3°, 22.5±0.3°, 25.3±0.3°, and 26.8±0.3°2-theta.

[0063] In some embodiments, polymorphic Form IV may be characterized by the X-ray powder diffraction pattern shown in Figure 5. The crystalline form of Form IV of the compound of formula (III) may be characterized by an XRPD pattern comprising major peaks at 4.7±0.3°2-theta, 23.3±0.3°, and 13.6±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 23.8±0.3°, 14.2±0.3°, 22.5±0.3°, or 15.7±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 7.1±0.3°, 20.2±0.3°, or 9.5±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 7.1±0.3°, 9.5±0.3°, 14.2±0.3°, 15.7±0.3°, 20.2±0.3°, 22.5±0.3°, and 23.8±0.3°2-theta.

[0064] In some embodiments, polymorphic Form V may be characterized by the X-ray powder diffraction pattern shown in Figure 6. The crystalline form of Form V of the compound of formula (III) may be characterized by an XRPD pattern comprising major peaks at 12.5±0.3°, 19.6±0.3°, and 8.9±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 21.7±0.3°, 20.8±0.3°, 19.8±0.3°, or 16.0±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 22.0±0.3°, 13.5±0.3°, or 14.4±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 21.7±0.3°, 20.8±0.3°, 19.8±0.3°, 16.0±0.3°, 22.0±0.3°, 13.5±0.3°, and 14.4±0.3°2-theta.

[0065] In some embodiments, polymorphic Form VI may be characterized by the X-ray powder diffraction pattern shown in Figure 7. The crystalline form of Form VI of the compound of formula (III) may be characterized by an XRPD pattern comprising major peaks at 9.9±0.3°, 13.4±0.3°, and 13.7±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 17.6±0.3°, 18.6±0.3°, 17.3±0.3°, or 21.8±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 10.2±0.3°, 19.5±0.3°, or 14.2±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 17.6±0.3°, 18.6±0.3°, 17.3±0.3°, 21.8±0.3°, 10.2±0.3°, 19.5±0.3°, or 14.2±0.3°2-theta.

[0066] In some embodiments, polymorphic Form VII may be characterized by the X-ray powder diffraction pattern shown in Figure 8. The crystalline form of Form VII of the compound of formula (III) may be characterized by an XRPD pattern comprising major peaks at 20.0±0.3°, 22.6±0.3°, and 10.6±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 11.4±0.3°, 16.4±0.3°, 9.6±0.3°, or 13.3±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 18.2±0.3°, 13.1±0.3°, or 27.0±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 11.4±0.3°, 16.4±0.3°, 9.6±0.3°, 13.3±0.3°, 18.2±0.3°, 13.1±0.3°, or 27.0±0.3°2-theta.

[0067] In some embodiments, polymorphic Form VIII may be characterized by the X-ray powder diffraction pattern shown in Figure 9. The crystalline form of Form VIII of the compound of formula (III) may be characterized by an XRPD pattern comprising major peaks at 4.8±0.3°, 18.9±0.3°, and 9.5±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 23.7±0.3°, 21.9±0.3°, 21.2±0.3°, or 12.9±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 25.0±0.3°, 21.5±0.3°, or 16.4±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 23.7±0.3°, 21.9±0.3°, 21.2±0.3°, 12.9±0.3°, 25.0±0.3°, 21.5±0.3°, or 16.4±0.3°2-theta.

[0068] In some embodiments, polymorphic Form IX may be characterized by the X-ray powder diffraction pattern shown in Figure 10. The crystalline form of Form IX of the compound of formula (III) may be characterized by an XRPD pattern comprising major peaks at 19.0±0.3°, 12.9±0.3°, and 15.9±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 21.7±0.3°, 20.8±0.3°, 21.1±0.3°, or 8.9±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 16.4±0.3°, 4.2±0.3°, or 12.7±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 21.7±0.3°, 20.8±0.3°, 21.1±0.3°, 8.9±0.3°, 16.4±0.3°, 4.2±0.3°, or 12.7±0.3°2-theta.

[0069] In some embodiments, polymorphic Form X may be characterized by the X-ray powder diffraction pattern shown in Figure 11. The crystalline form of Form X of the compound of formula (III) may be characterized by an XRPD pattern comprising major peaks at 7.2±0.3°, 14.3±0.3°, and 18.7±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 21.5±0.3°, 22.7±0.3°, and 17.1±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 21.8±0.3°, 27.3±0.3°, or 29.4±0.3°2-theta.

[0070] In some embodiments, polymorphic Form XI may be characterized by the X-ray powder diffraction pattern shown in Figure 12. The crystalline form of Form XI of the compound of formula (III) may be characterized by an XRPD pattern comprising major peaks at 14.0±0.3°, 17.7±0.3°, and 11.9±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 18.4±0.3°, 23.9±0.3°, or 17.3±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 21.8±0.3°, 20.8±0.3°, and 23.0±0.3°, or 22.2±0.3°2-theta.

[0071] In some embodiments, polymorphic Form XII may be characterized by the X-ray powder diffraction pattern shown in Figure 13. The crystalline form of Form XII of the compound of formula (III) may be characterized by an XRPD pattern comprising major peaks at 12.5±0.3°, 15.6±0.3°, and 19.0±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 21.9±0.3°, 20.2±0.3°, 16.0±0.3°, or 21.6±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 22.4±0.3°, 16.8±0.3°, or 12.8±0.3°2-theta.

[0072] In some embodiments, polymorphic Form XIII in a mixture with Form XII can be characterized by the X-ray powder diffraction pattern shown in FIG.

[0073] In some embodiments, polymorphic Form XIV may be characterized by the X-ray powder diffraction pattern shown in Figure 15. The crystalline form of Form XIV of the compound of formula (III) may be characterized by an XRPD pattern comprising major peaks at 11.6±0.3°, 21.3±0.3°, and 19.3±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 17.5±0.3°, 15.4±0.3°, 21.6±0.3°, or 5.8±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 16.3±0.3°, 21.9±0.3°, or 23.9±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 17.5±0.3°, 15.4±0.3°, 21.6±0.3°, 5.8±0.3°, 16.3±0.3°, 21.9±0.3°, or 23.9±0.3°2-theta.

[0074] In some embodiments, polymorphic form XV may be characterized by the X-ray powder diffraction pattern shown in Figure 16. The crystalline form of form XV of the compound of formula (III) may be characterized by an XRPD pattern comprising major peaks at 9.8±0.3°, 4.7±0.3°, and 14.0±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 20.2±0.3°, 7.1±0.3°, 23.4±0.3°, or 22.4±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 21.7±0.3°, 22.7±0.3°, or 18.8±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 20.2±0.3°, 7.1±0.3°, 23.4±0.3°, 22.4±0.3°, 21.7±0.3°, 22.7±0.3°, or 18.8±0.3°2-theta.

[0075] In some embodiments, polymorphic Form XVII can be characterized by the X-ray powder diffraction pattern shown in FIG.

[0076] In some embodiments, polymorphic Form XVIII can be characterized by the X-ray powder diffraction pattern shown in FIG.

[0077] In some embodiments, polymorphic Form XIX may be characterized by the X-ray powder diffraction pattern shown in Figure 19. The crystalline form of Form XIX of the compound of formula (III) may be characterized by an XRPD pattern comprising major peaks at 4.7±0.3°, 23.6±0.3°, and 18.9±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 9.4±0.3°, 23.3±0.3°, 22.3±0.3°, or 20.1±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 19.6±0.3°, 7.1±0.3°, or 15.7±0.3°2-theta. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 9.4±0.3°, 23.3±0.3°, 22.3±0.3°, 20.1±0.3°, 19.6±0.3°, 7.1±0.3°, or 15.7±0.3°2-theta.

[0078] In some embodiments, the composition contains endoxifen 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 10 ... %, 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 endoxifen as a single polymorphic form (e.g., Form I, Form II, Form III, Form IV, Form V, Form VI, Form VI, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVII, Form XVIII, or Form XIX). In some embodiments, the compositions for treating various cancers contain 90% or more of a single polymorphic form of endoxifen (e.g., Form I, Form II, Form III, Form IV, Form V, Form VI, Form VI, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVII, Form XVIII, or Form XIX) wt / wt of total endoxifen in the composition. In another embodiment, the composition comprises 95% or more of a single polymorphic form of endoxifen (e.g., Form I, Form II, Form III, Form IV, Form V, Form VI, Form VI, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVII, Form XVIII, or Form XIX) wt / wt of total endoxifen in the composition.In some embodiments, the composition comprises 96% or more, 97% or more, 98% or more, 99% or more, or 99.5% or more of a single polymorphic form of endoxifen (e.g., Form I, Form II, Form III, Form IV, Form V, Form VI, Form VI, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVII, Form XVIII, or Form XIX) wt / wt of the total endoxifen in the composition. When a particular weight percentage of endoxifen is a single polymorphic form, the remainder of the composition may be some combination of amorphous endoxifen and / or one or more polymorphic forms of endoxifen other than the single polymorphic form. When polymorphic endoxifen is defined as one particular form of endoxifen, the remainder may be comprised of amorphous endoxifen and / or one or more polymorphic forms other than the specified particular form. Examples of single polymorphic forms include Form I, Form II, Form III, Form IV, Form V, Form VI, Form VI, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVII, Form XVIII, and Form XIX of endoxifen, as well as descriptions of single polymorphic forms characterized by one or more properties described herein.

[0079] In other embodiments, compositions comprising endoxifen comprise between 0.01% and 20%, between 0.05% and 15%, or between 0.1% and 10% of a single polymorphic form of endoxifen (e.g., Form I, Form II, Form III, Form IV, Form V, Form VI, Form VI, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVII, Form XVIII, or Form XIX) wt / wt or w / v of the composition. In at least one embodiment, compositions comprising endoxifen comprise between 0.01% and 20% of a single polymorphic form of endoxifen (e.g., Form I, Form II, Form III, Form IV, Form V, Form VI, Form VI, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVII, Form XVIII, or Form XIX) wt / wt or w / v of the composition. In various other embodiments, the compositions comprising endoxifen comprise 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 10%, or 20% of a single polymorphic form of endoxifen (e.g., Form I, Form II, Form III, Form IV, Form V, Form VI, Form VI, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVII, Form XVIII, or Form XIX) wt / wt of the composition. In one embodiment, a composition comprising a single polymorphic form of endoxifen (e.g., Form I, Form II, Form III, Form IV, Form V, Form VI, Form VI, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVII, Form XVIII, or Form XIX), further comprises a second polymorphic form of endoxifen.

[0080] In some embodiments, the endoxifen composition may comprise 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 10%, or 20% or less (wt / wt) of E-endoxifen relative to the total endoxifen. In some embodiments, the endoxifen composition may comprise 99.9%, 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, or 70% or more (wt / wt) of Z-endoxifen relative to the total endoxifen. In some embodiments, the endoxifen composition may contain less than 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 10%, or 20% (wt / wt) of Z-endoxifen. In some embodiments, the endoxifen composition may contain more than 99.9%, 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, or 70% (wt / wt) of Z-endoxifen by weight of the total composition.

[0081] High-dose formulation High-dose endoxifen formulations, such as enteric-resistant delayed-release high-dose endoxifen compositions, can pose challenges due to the relatively high percentage of active pharmaceutical ingredient (% API) present in the formulation. Endoxifen formulations with a high percentage of endoxifen relative to the total composition fill weight (e.g., at least about 4% endoxifen, at least about 10% endoxifen, at least about 15% endoxifen, or about 15% to about 20% endoxifen) can exhibit increased reactivity with the encapsulating layer (e.g., coating or capsule) compared to lower-dose formulations (e.g., less than about 4% endoxifen). For example, high-dose endoxifen compositions comprising at least about 4% endoxifen by weight relative to the total fill weight can exhibit significant cross-linking with the surrounding capsule. Such reactivity (e.g., cross-linking) can adversely affect the bioavailability of endoxifen upon administration of the composition. For example, cross-linking between endoxifen and an enteric-resistant delayed-release capsule encapsulating endoxifen can inhibit dissolution of the capsule when administered orally, preventing release of endoxifen. The reactivity of high dose endoxifen compositions may be mitigated by pharmaceutical excipients added to the endoxifen composition.

[0082] The high-dose endoxifen compositions (e.g., enteric-resistant delayed release high-dose endoxifen formulations) of the present disclosure may include an amount of (Z)-endoxifen formulated as a dosage form such as a tablet or capsule. In some embodiments, a single high-dose endoxifen dosage form (e.g., a single capsule or a single tablet) may include about 10 mg, about 12 mg, about 15 mg, about 16 mg, about 20 mg, about 22 mg, about 24 mg, about 25 mg, about 28 mg, about 30 mg, about 32 mg, about 35 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg of (Z)-endoxifen. In some embodiments, a single high dose endoxifen dosage form may contain about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 50 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, or about 10 mg to about 30 mg of (Z)-endoxifen.

[0083] In some embodiments, the high-dose endoxifen composition comprises about 4% to about 40% by weight, about 5% to about 40% by weight, about 8% to about 40% by weight, about 10% to about 40% by weight, about 12% to about 40% by weight, about 13% to about 40% by weight, about 14% to about 40% by weight, about 15% to about 40% by weight, about 16% to about 40% by weight, about 17% to about 40% by weight, about 18% to about 40% by weight, about 4% to about 30% by weight of the total fill weight of the composition. , about 5% to about 30% by weight, about 8% to about 30% by weight, about 10% to about 30% by weight, about 12% to about 30% by weight, about 13% to about 30% by weight, about 14% to about 30% by weight, about 15% to about 30% by weight, about 16% by weight Amount % to about 30% by weight, about 17% to about 30% by weight, about 18% to about 30% by weight, about 4% to about 25% by weight, about 5% to about 25% by weight, about 8% to about 25% by weight, about 10% to about 25% by weight, about 12% to about 25% by weight Amount %, about 13% to about 25% by weight, about 14% to about 25% by weight, about 15% to about 25% by weight, about 16% to about 25% by weight, about 17% to about 25% by weight, about 18% to about 25% by weight, about 4% to about 22% by weight, about 5% to about 22% by weight, about 8% to about 22% by weight, about 10% to about 22% by weight, about 12% to about 22% by weight, about 13% to about 22% by weight, about 14% to about 22% by weight, about 15% to about 22% by weight, about 16% by weight The composition may contain about 22% by weight, about 17% to about 22% by weight, about 18% to about 22% by weight, about 4% to about 20% by weight, about 5% to about 20% by weight, about 8% to about 20% by weight, about 10% to about 20% by weight, about 12% to about 20% by weight, about 13% to about 20% by weight, about 14% to about 20% by weight, about 15% to about 20% by weight, about 16% to about 20% by weight, about 17% to about 20% by weight, or about 18% to about 20% by weight of (Z)-endoxifen.

[0084] Disintegrants can be included in the high-dose endoxifen composition of the present disclosure to inhibit cross-linking between endoxifen and the encapsulation layer (e.g., capsule).In some embodiments, disintegrants can include croscarmellose sodium, agar, alginic acid, calcium carbonate, microcrystalline cellulose, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or combinations thereof.For example, croscarmellose sodium can be included in the high-dose endoxifen composition to inhibit cross-linking between endoxifen and the enteric-resistant delayed-release capsule that encapsulates the endoxifen composition.

[0085] Disintegrants (e.g., croscarmellose sodium) may be included in the high-dose endoxifen composition of the present disclosure in an amount of at least about 0.1% by weight, at least about 0.5% by weight, at least about 0.8% by weight, at least about 1.0% by weight, at least about 1.2% by weight, at least about 1.4% by weight, at least about 1.5% by weight, at least about 1.6% by weight, at least about 1.8% by weight, at least about 2.0% by weight, at least about 2.2% by weight, at least about 2.4% by weight, at least about 2.5% by weight, at least about 2.6% by weight, at least about 2.8% by weight, or at least about 2.9% by weight of the total fill weight of the composition.For example, the high-dose endoxifen composition may include at least about 2% by weight of croscarmellose sodium by weight of the total fill weight of the composition.

[0086] In some embodiments, the disintegrant (e.g., croscarmellose sodium) is present in the high dose endoxifen compositions of the present disclosure in an amount ranging from about 0.1% to about 10% by weight of the total fill weight of the composition, from about 1.0% to about 10% by weight, from about 1.5% to about 10% by weight, from about 2.0% to about 10% by weight, from about 2.5% to about 10% by weight, from about 2.6% to about 10% by weight, from about 2.8% to about 10% by weight, from about 2.9% to about 10% by weight, from about 3.0% to about 10% by weight, from about 3.5% to about 10% by weight, from about 3.6% to about 10% by weight, from about 3.8% to about 10% by weight, from about 3.9 ... 9% to about 10% by weight, about 0.1% to about 8.0% by weight, about 1.0% to about 8.0% by weight, about 1.5% to about 8.0% by weight, about 2.0% to about 8.0% by weight, about 2.5% to about 8.0% by weight Amount%, about 2.6% to about 8.0%, about 2.8% to about 8.0%, about 2.9% to about 8.0%, about 0.1% to about 5.0%, about 1.0% to about 5.0%, about 1.5% by weight %~about 5.0 weight%, about 2.0 weight%~about 5.0 weight%, about 2.5 weight%~about 5.0 weight%, about 2.6 weight%~about 5.0 weight%, about 2.8 weight%~about 5.0 weight%, about 2.9 weight%~about 5.0 weight% , about 0.1% to about 4.0% by weight, about 1.0% to about 4.0% by weight, about 1.5% to about 4.0% by weight, about 2.0% to about 4.0% by weight, about 2.5% to about 4.0% by weight, about 2.6% by weight It may be present in an amount of about 4.0% by weight, about 2.8% to about 4.0% by weight, about 2.9% to about 4.0% by weight, about 0.1% to about 3.0% by weight, about 1.0% to about 3.0% by weight, about 1.5% to about 3.0% by weight, about 2.0% to about 3.0% by weight, about 2.5% to about 3.0% by weight, about 2.6% to about 3.0% by weight, about 2.8% to about 3.0% by weight, or about 2.9% to about 3.0% by weight. For example, a high-dose endoxifen composition may contain about 1% to about 4% croscarmellose sodium by weight of the total fill weight of the composition.

[0087] In some embodiments, fillers can be included in the high-dose endoxifen composition of the present disclosure.Examples of fillers include, but are not limited to, microcrystalline cellulose, talc, calcium carbonate (e.g., granules or powder), sugar (e.g., dextrose, sucrose, lactose), salt (e.g., calcium carbonate, calcium phosphate, sodium carbonate, sodium phosphate), starch, powdered cellulose, cellulosic base (e.g., methylcellulose, carboxymethylcellulose dextrates), kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0088] The filler (e.g., microcrystalline cellulose) may be present in the high dose endoxifen compositions of the present disclosure in an amount of about 10% to about 99% by weight, about 20% to about 99% by weight, about 30% to about 99% by weight, about 40% to about 99% by weight, about 50% to about 99% by weight, about 60% to about 99% by weight, about 70% to about 99% by weight, about 75% by weight, or about 80% by weight of the total fill weight of the composition. ~99% by weight, approximately 10% by weight ~ approximately 97% by weight, approximately 20% by weight ~ approximately 97% by weight, approximately 30% by weight ~ approximately 97% by weight, approximately 40% by weight ~ approximately 97% by weight, approximately 50% by weight ~ approximately 97% by weight, Approximately 60% to approximately 97% by weight, approximately 70% to approximately 97% by weight, approximately 75% to approximately 97% by weight, approximately 10% to approximately 95% by weight, approximately 20% to approximately 95% by weight, approximately 30% to approximately 95% by weight, about 40% to about 95% by weight, about 50% to about 95% by weight, about 60% to about 95% by weight, about 70% to about 95% by weight, about 75% to about 95% by weight, about 10% to approximately 90% by weight, approximately 20% to approximately 90% by weight, approximately 30% to approximately 90% by weight, approximately 40% to approximately 90% by weight, approximately 50% to approximately 90% by weight, approximately 60% to approximately 9 0%, about 70% to about 90%, about 75% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, about 60% to about 80%, about 70% to about 80%, or about 75% to about 80% by weight. For example, a high-dose endoxifen composition may comprise about 50% to about 95% microcrystalline cellulose by weight of the total fill weight of the composition.

[0089] In some embodiments, lubricants can be included in the high-dose endoxifen composition of the present disclosure. Examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, magnesium stearate or potassium stearate, ethyl oleate, ethyl laurate, agar, and combinations thereof. Additional lubricants include, for example, syloid silica gels (e.g., AEROSIL® 200 manufactured by WRGRACE® Co., Baltimore, Md.), coagulated aerosols of synthetic silica (e.g., sold by DEGUSSA® Co., Plano, Tex.), fumed silica (e.g., the pyrogenic silicon dioxide product CAB-O-SIL® sold by CABOT® Co., Boston, Mass.), silicone fluids (e.g., Q7-9120 manufactured by DOW CORNING®), and combinations thereof.

[0090] Lubricants (e.g., magnesium stearate) can be included in the high-dose endoxifen composition of the present disclosure in an amount of at least about 0.1% by weight, at least about 0.2% by weight, at least about 0.3% by weight, at least about 0.4% by weight, at least about 0.5% by weight, at least about 0.5% by weight, at least about 0.6% by weight, at least about 0.8% by weight, at least about 0.8% by weight, or at least about 1.0% by weight of the total fill weight of the composition.For example, the high-dose endoxifen composition can include at least about 0.8% by weight of magnesium stearate of the total fill weight of the composition.

[0091] In some embodiments, the lubricant (e.g., magnesium stearate) is present in the high dose endoxifen compositions of the present disclosure at about 0.1% to about 5.0% by weight, about 0.2% to about 5.0% by weight, about 0.3% to about 5.0% by weight, about 0.4% to about 5.0% by weight, about 0.5% to about 5.0% by weight, about 0.6% to about 5.0% by weight, about 0.7% to about 5.0% by weight, about 0.8% to about 5.0% by weight, about 0.9% to about 5.0% by weight, about 1.0% to about 5.0% by weight, about 0.1% to about 4.0% by weight, about 0.2 ...4% to about 5.0% by weight, about 0.5% to about 5.0% by weight, about 0.6% to about 5.0% by weight, about 0.7% to about 5.0% by weight, about 0.8% to about 5.0% by weight, about 0.9% to about 5.0% by weight, about 1.0% to about 5.0% by weight, about 0.1% to about 4 Amount %~about 4.0 weight%, about 0.3 weight%~about 4.0 weight%, about 0.4 weight%~about 4.0 weight%, about 0.5 weight%~about 4.0 weight%, about 0.6 weight%~about 4.0 weight%, about 0.7 weight%~about 4.0 weight%, about 0.8 weight%~about 4.0 weight%, about 0.9 weight%~about 4.0 weight%, about 1 0.0% to 4.0% by weight, 0.1% to 3.0%, 0.2% to 3.0%, 0.3% to 3.0%, 0.4% to 3.0%, 0.5% to 3.0%, 0.6% to 3.0%, 0.7% to 3.0% by weight , about 0.8% to about 3.0% by weight, about 0.9% to about 3.0% by weight, about 1.0% to about 3.0% by weight, about 0.1% to about 2.0% by weight, about 0.2% to about 2.0% by weight, about 0.3% to about 2.0% by weight, about 0.4% to about 2.0% by weight, about 0.5% to about 2.0% by weight Weight %, about 0.6 weight % to about 2.0 weight %, about 0.7 weight % to about 2.0 weight %, about 0.8 weight % to about 2.0 weight %, about 0.9 weight % to about 2.0 weight %, about 1.0 weight % to about 2.0 weight %, about 0.1 weight % to about 1.5 weight %, about 0.2 weight % to about 1.5 weight %, about 0.3 weight % to about 1.5 weight%, about 0.4 weight% to about 1.5 weight%, about 0.5 weight% to about 1.5 weight%, about 0.6 weight% to about 1.5 weight%, about 0.7 weight% to about 1.5 weight%, about 0.8 weight% to about 1.5 weight%, about 0.9 weight% to about 1.5 weight%, about 1.0 weight% to about 1.5 weight%, about 0.1 weight% % to about 1.2% by weight, about 0.2% to about 1.2% by weight, about 0.3% to about 1.2% by weight, about 0.4% to about 1.2% by weight, about 0.5% to about 1.2% by weight, about 0.6% to about 1.2% by weight, about 0.7% to about 1.2% by weight, about 0.8% to about 1.2% by weight, about 0.It may be present in an amount of from about 9% to about 1.2% by weight, or from about 1.0% to about 1.2% by weight. For example, a high-dose endoxifen composition may contain from about 0.5% to about 2% magnesium stearate by weight of the total fill weight of the composition.

[0092] Additional agents that may be included in the high-dose endoxifen compositions of the present disclosure include binders, fillers, lubricants, and other pharma- ceutically acceptable excipients. Binders suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, sucrose, starches such as corn starch, potato starch, or starch paste, pregelatinized starch, starch such as Starch 1500, PEG 6000, methocel, WALOCEL® HM, LUVITEC®, caparolactam, AVICEL®, SMCC, UNI-PURE®, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose (e.g., 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL® PH 101, AVICEL® PH 103, AVICEL® RC 581, AVICEL® PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. In some embodiments, the binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose. Suitable anhydrous or low moisture excipients or additives include AVICEL® PH 103 and Starch 1500 LM.

[0093] An example of a high-dose endoxifen composition may comprise, based on the total fill weight of the composition, about 10% to about 30% (Z)-endoxifen, about 1% to about 5% croscarmellose sodium, about 60% to about 95% microcrystalline cellulose, and about 0.5% to about 3% magnesium stearate. The composition may be encapsulated in an enteric-resistant delayed-release capsule (e.g., a capsule comprising about 85% to about 97% hydroxypropylmethylcellulose and about 3% to about 10% gellan gum). In some embodiments, the high-dose endoxifen formulation may be formulated to contain about 10 mg, about 20 mg, about 40 mg, or about 80 mg (Z)-endoxifen per dosage unit (e.g., per capsule).

[0094] Further examples of high-dose endoxifen compositions may include, by weight, about 15% to about 20% (Z)-endoxifen, about 2% to about 4% croscarmellose sodium, about 70% to about 80% microcrystalline cellulose, and about 0.5% to about 2% magnesium stearate. The compositions may be encapsulated in an enteric-resistant delayed-release capsule (e.g., a capsule containing about 85% to about 97% hydroxypropylmethylcellulose and about 3% to about 7% gellan gum). In some embodiments, the high-dose endoxifen formulation may be formulated to include about 10 mg, about 20 mg, about 40 mg, or about 80 mg (Z)-endoxifen per dosage unit (e.g., per capsule). Enteric-coated, resistant, delayed-release endoxifen compositions

[0095] The endoxifen composition described herein can be formulated as an enteric-resistant delayed release formulation for oral delivery.The enteric-resistant delayed release endoxifen formulation can resist dissolution in the acidic environment of the stomach after oral administration, slowing or preventing the release of endoxifen in the stomach, and can dissolve easily in the less acidic environment of the intestine, releasing most of the endoxifen in the intestine.The enteric-resistant delayed release formulation of the present disclosure can facilitate the delivery of (Z)-endoxifen by protecting (Z)-endoxifen from the acidic environment of the stomach and preventing isomerization to (E)-endoxifen.

[0096] The enteric resistance and delayed release properties of the endoxifen composition can be evaluated using dissolution assays, which can be performed using a variety of techniques. In some embodiments, the dissolution properties of the endoxifen composition can be quantified using the dissolution assays described in Table 4 of Example 2. The endoxifen composition (e.g., an endoxifen formulation encapsulated in an enteric resistance delayed release capsule) can be placed in an acidic solution having a pH of less than about 2 for about 120 minutes with stirring at a temperature of about 37±0.5°C. The dissolution rate under acidic conditions that mimic the stomach environment can be evaluated by measuring the concentration of endoxifen in the solution at multiple time points (e.g., 30 minutes, 60 minutes, 90 minutes, 120 minutes, or combinations thereof). After about 120 minutes, the acidic solution is replaced with a buffer solution having a pH of about 6.8 and about 0.75% polysorbate 80 and stirred for about 90 minutes at a temperature of about 37±0.5°C. Dissolution rates under less acidic conditions that mimic the intestinal environment can be assessed by measuring the concentration of endoxifen in solution at multiple time points (e.g., 15, 30, 45, 60, 90 minutes, or combinations thereof). Alternatively, dissolution rates can be measured using the United States Pharmacopeia (USP) dissolution method or the Japanese Pharmacopeia (JP) dissolution method.

[0097] The enteric resistant delayed release formulation may release about 1% or less, about 2% or less, about 3% or less, about 4% or less, about 5% or less, about 6% or less, about 7% or less, about 8% or less, about 9% 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 about 40% of the (Z)-endoxifen in the composition within about 2 hours. In some embodiments, the enteric resistant delayed release formulation may release about 0% to about 1%, about 0% to about 2%, about 0% to about 3%, about 0% to about 4%, about 0% to about 5%, about 0% to about 10%, about 0% to about 15%, about 0% to about 20%, about 1% to about 2%, about 1% to about 3%, about 1% to about 4%, about 1% to about 5%, about 1% to about 10%, about 1% to about 15%, about 1% to about 20%, about 3% to about 3%, about 3% to about 4%, about 3% to about 5%, about 3% to about 10%, about 3% to about 15%, or about 3% to about 20% of the (Z)-endoxifen in the composition in an acidic solution having a pH of less than about 2 within about 2 hours.

[0098] In some embodiments, the enteric resistant delayed release formulation may release about 1% or less, about 2% or less, about 3% or less, about 4% or less, about 5% or less, about 6% or less, about 7% or less, about 8% or less, about 9% 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, or about 40% or less of the (Z)-endoxifen in the composition within about 2 hours under acidic conditions as measured in Table 4 of Example 2. In some embodiments, the enteric resistant delayed release formulation may release about 0% to about 1%, about 0% to about 2%, about 0% to about 3%, about 0% to about 4%, about 0% to about 5%, about 0% to about 10%, about 0% to about 15%, about 0% to about 20%, about 1% to about 2%, about 1% to about 3%, about 1% to about 4%, about 1% to about 5%, about 1% to about 10%, about 1% to about 15%, about 1% to about 20%, about 3% to about 3%, about 3% to about 4%, about 3% to about 5%, about 3% to about 10%, about 3% to about 15%, or about 3% to about 20% of the (Z)-endoxifen in the composition within about 2 hours under acidic conditions, as measured in Table 4 of Example 2.

[0099] The enteric resistant delayed release formulation may release 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 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of the (Z)-endoxifen in the composition within 1.5 hours in a solution containing about 0.75% polysorbate 80 and a pH of about 6.8.In some embodiments, the enteric resistant delayed release formulation achieves about 50% to about 95%, about 60% to about 95%, about 70% to about 95%, about 80% to about 95%, about 85% to about 95%, about 86% to about 95%, about 87% to about 95%, about 88% to about 95%, about 89% to about 95%, about 90% to about 95%, about 91% to about 95%, about 92% to about 95%, about 93% to about 95%, about 94% to about 95%, or about 96% to about 96% of the composition within about 1.5 hours. ~ about 95%, about 50% to about 97%, about 60% to about 97%, about 70% to about 97%, about 80% to about 97%, about 85% to about 97%, about 86% to about 97%, about 87% to about 97%, about 88% to about 97%, about 89% to about 97%, about 90% to about 97%, about 91% to about 97%, about 92% to about 97%, about 93% to about 97%, about 94% to about 97%, about 95% to about 97%, about 50% to about 99%, about 60% to about 99%, About 70% to about 99%, about 80% to about 99%, about 85% to about 99%, about 86% to about 99%, about 87% to about 99%, about 88% to about 99%, about 89% to about 99%, about 90% to about 99%, about 91% to about 99%, about 92% to about 99%, about 93% to about 99%, about 94% to about 99%, about 95% to about 99%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 8 From about 5% to about 100%, from about 86% to about 100%, from about 87% to about 100%, from about 88% to about 100%, from about 89% to about 100%, from about 90% to about 100%, from about 91% to about 100%, from about 92% to about 100%, from about 93% to about 100%, from about 94% to about 100%, or from about 95% to about 100% of the (Z)-endoxifen may be released in a solution containing about 0.75% polysorbate 80 and a pH of about 6.8.

[0100] In some embodiments, the enteric resistant delayed release formulation may release 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 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of the (Z)-endoxifen in the composition within about 1.5 hours in a solution containing about 0.75% polysorbate 80 and a pH of about 6.8, as measured in Table 4 of Example 2.In some embodiments, the enteric resistant delayed release formulation has about 50% to about 95%, about 60% to about 95%, about 70% to about 95%, about 80% to about 95%, about 85% to about 95%, about 86% to about 95%, about 87% to about 95%, about 88% to about 95%, about 89% to about 95%, about 90% to about 95%, about 91% to about 95%, about 92% to about 95%, about 93% to about 95%, about 94% to about 95%, about 95% to about 95%, about 96% to about 95%, about 97% to about 95%, about 98% to about 95%, about 99% to about 95%, about 100% to about 100%, about 101% to about 102%, about 103% to about 104%, about 105% to about 105%, about 106% to about 106%, about 107% to about 107%, about 108% to about 108%, about 109% to about 109%, about 110% to about 111%, about 112% to about 112%, about 113% to about 113%, about 114% to about 114%, about 115% to about 115%, about 116% to about 115%, about 117% to about 116%, about 118% to about 117%, about 119% to about 118%, about 120% to about 120%, about 121% to about 121%, about 122% to about 122%, about 123% to about 123%, about 124% to about 124%, about 1 % to about 95%, about 94% to about 95%, about 50% to about 97%, about 60% to about 97%, about 70% to about 97%, about 80% to about 97%, about 85% to about 97%, about 86% to about 97%, about 87% to about 97%, about 88% to about 97%, about 89% to about 97%, about 90% to about 97%, about 91% to about 97%, about 92% to about 97%, about 93% to about 97%, about 94% to about 97%, about 95% to about 97%, about 50% to about 99%, about 60 % to about 99%, about 70% to about 99%, about 80% to about 99%, about 85% to about 99%, about 86% to about 99%, about 87% to about 99%, about 88% to about 99%, about 89% to about 99%, about 90% to about 99%, about 91% to about 99%, about 92% to about 99%, about 93% to about 99%, about 94% to about 99%, about 95% to about 99%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100 %, about 85% to about 100%, about 86% to about 100%, about 87% to about 100%, about 88% to about 100%, about 89% to about 100%, about 90% to about 100%, about 91% to about 100%, about 92% to about 100%, about 93% to about 100%, about 94% to about 100%, or about 95% to about 100% of the (Z)-endoxifen may be released in a solution containing about 0.75% polysorbate 80 and a pH of about 6.8.

[0101] In some embodiments, the endoxifen formulation (e.g., high-dose oral endoxifen formulation) is in the form of a solid dosage form, such as a capsule, tablet, mini-tablet, bead, microbead, granule, spherical particle, multiparticulate, etc. The endoxifen composition of the present disclosure may be formulated to target release in the intestine and colon. Thus, in some embodiments, the endoxifen composition is in the form of an enteric-resistant delayed release capsule, an enteric-coated delayed release tablet, an enteric-coated delayed release tablet-in-tablet, an enteric-coated delayed release tablet-in-capsule, a bead-in-capsule, a sphere-in-capsule, etc. For example, the endoxifen formulation can be encapsulated in an enteric-resistant delayed release capsule (e.g., a hydroxypropyl methylcellulose (also known as HPMC or hypromellose) capsule) to form an enteric-resistant delayed release endoxifen composition. In some embodiments, the endoxifen (e.g., (Z)-endoxifen) can be homogenously dispersed in the endoxifen composition.

[0102] The enteric-resistant delayed release capsule, also referred to as the enteric-resistant delayed release capsule, can encapsulate the endoxifen formulation (e.g., high-dose endoxifen formulation) of the present disclosure. In some embodiments, the enteric-resistant delayed release capsule can include hydroxypropylmethylcellulose, gellan gum, gelatin, hydroxypropylmethylcellulose phthalate, coloring agent, opacifier, or any combination thereof. The enteric-resistant delayed release capsule can include at least about 50% by weight, at least about 55% by weight, at least about 60% by weight, at least about 65% by weight, at least about 70% by weight, at least about 75% by weight, at least about 80% by weight, at least about 85% by weight, at least about 90% by weight, or at least about 95% by weight of hydroxypropylmethylcellulose based on the total weight of the capsule (e.g., not including the endoxifen formulation fill). In some embodiments, the enteric resistant delayed release capsule comprises, based on the total weight of the capsule, about 50% to about 99% by weight, about 55% to about 99% by weight, about 60% to about 99% by weight, about 65% to about 99% by weight, about 70% to about 99% by weight, about 75% to about 99% by weight, about 80% to about 99% by weight, about 85% to about 99% by weight, about 50% to about 95% by weight, about 55% to about 95% by weight, about 60% to about 95 ... The composition may contain about 95% by weight, about 70% to about 95% by weight, about 75% to about 95% by weight, about 80% to about 95% by weight, about 85% to about 95% by weight, about 50% to about 90% by weight, about 55% to about 90% by weight, about 60% to about 90% by weight, about 65% to about 90% by weight, about 70% to about 90% by weight, about 75% to about 90% by weight, about 80% to about 90% by weight, or about 85% to about 90% by weight of hydroxypropyl methylcellulose.

[0103] The enteric resistant delayed release capsule can comprise at least about 1% by weight, at least about 2% by weight, at least about 3% by weight, at least about 4% by weight, at least about 5% by weight, at least about 6% by weight, at least about 7% by weight, at least about 8% by weight, at least about 9% by weight, or at least about 10% by weight of gellan gum, gelatin, or a combination thereof, based on the total weight of the capsule. In some embodiments, the enteric resistant delayed release capsule comprises about 1% to about 10% by weight, about 2% to about 10% by weight, about 3% to about 10% by weight, about 4% to about 10% by weight, about 5% to about 10% by weight, about 1% to about 9% by weight, about 2% to about 9% by weight, about 3% to about 9% by weight, about 4% to about 9% by weight, about 5% to about 9% by weight, about 1% to about 8% by weight, about 2% to about 8% by weight, about 3% to about 8% by weight, about 4% to about 8% by weight, The gellan gum, gelatin, or combinations thereof may comprise about 5% to about 8% by weight, about 1% to about 7% by weight, about 2% to about 7% by weight, about 3% to about 7% by weight, about 4% to about 7% by weight, about 5% to about 7% by weight, about 1% to about 6% by weight, about 2% to about 6% by weight, about 3% to about 6% by weight, about 4% to about 6% by weight, about 5% to about 6% by weight, about 1% to about 5% by weight, about 2% to about 5% by weight, about 3% to about 5% by weight, or about 4% to about 5% by weight.

[0104] Plasticizers can be added to control the softness or flexibility of oral dosage forms such as capsules, caplets, or tablet shells, and thus improve the mechanical properties of pH-sensitive materials of capsules or coatings of oral dosage forms.Suitable plasticizers include, but are not limited to, petroleum-based oils (e.g., paraffinic process oils, naphthenic process oils, and aromatic process oils), squalene, squalane, vegetable oils (e.g., olive oil, camellia oil, castor oil, tall oil, and peanut oil), silicone oils, dibasic acid esters (e.g., dibutyl phthalate and dioctyl phthalate), liquid rubbers (e.g., polybutene and liquid isoprene rubber), liquid fatty acid esters (e.g., isopropyl myristate ISM), hexyl laurate, diethyl sebacate, diisopropyl sebacate, triethyl citrate, triacetin, diethylene glycol, polyethylene glycol, polypropylene glycol, phthalates, sorbitol, glycol salicylate, crotamine, glycerin, or mixtures thereof. The amount of plasticizer may vary depending on the chemical composition of the pharmaceutical preparation. In one embodiment, at least one plasticizer is sorbitol, dimethyl isosorbide, or glycerol. In another embodiment, the plasticizer is 1%-10%, for example, 3%-5% (wt / wt) of the composition.

[0105] Examples of lubricants include, but are not limited to, colloidal silicon dioxide, cellulose, calcium phosphate (di- or tribasic), and the like.

[0106] The compositions disclosed herein that are formulated for oral delivery, such as tablets, caplets, and capsules, can be coated with one or more enteric coating agents, controlled release agents, or film-forming agents to control or delay the disintegration or absorption of the compositions that contain endoxifen or its salt in the digestive tract, and provide a sustained effect over a longer period of time.Thus, in some embodiments, the tablet can be an enteric-coated tablet, the caplet can be an enteric-coated caplet, or the capsule can be an enteric-coated capsule.The enteric-coated tablet, enteric-coated caplet, or enteric-coated capsule of the present disclosure can be prepared by techniques known in the art.

[0107] The pharmaceutical preparations disclosed herein may include controlled release agents. Examples of controlled release agents suitable for use include, but are not limited to, pH-dependent polymers, acid-insoluble polymers, methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, sodium alginate, zein, waxes (including synthetic waxes, microcrystalline wax, paraffin wax, carnauba wax, and beeswax), polyethoxylated castor oil derivatives, hydrogenated oils, glyceryl mono-, di-tribenate, glyceryl monostearate, glyceryl distearate, long chain alcohols such as stearyl alcohol, cetyl alcohol, and polyethylene glycols, and mixtures thereof. In some embodiments, a time delay material (e.g., glyceryl monostearate or glyceryl distearate) can be employed. In other embodiments, the controlled release agent is a digestible waxy substance such as solid paraffin wax.

[0108] In some embodiments, a pharmaceutical composition comprising endoxifen (e.g., Z-endoxifen) may be formulated as a sustained release composition. In some embodiments, a pharmaceutical composition comprising a phosphoinositide 3-kinase inhibitor (e.g., alpelisib) may be formulated as a sustained release composition. The sustained release agent present in the sustained release composition of the present disclosure may be any sustained release agent known in the art for slowing the release of a hydrophobic drug, such as (Z)-endoxifen or a polymorph or salt thereof.

[0109] Examples of sustained release agents include cellulose-based ethers, gums, acrylic resins (e.g., polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, methyl methyl acrylate, and combinations thereof), polyvinylpyrrolidine, and protein-derived compounds. Examples of cellulose-based ethers include hydroxyalkylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC or hypromellose, e.g., 2208, 2906, 2910), hydroxypropylmethylcellulose phthalate (HPMCP or hypromellose phthalate), carboxyalkylcellulose, and carboxymethylcellulose. In some embodiments, at least one sustained release agent is a pH sustained release agent, such as an acid-insoluble polymer, which becomes 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, hydroxypropyl methylcellulose phthalate, alginates (e.g., sodium or potassium alginate), shellac, pectin, acrylic acid-methylacrylic acid copolymers (including those commercially available from EVONIK® or ROHM® (e.g., EUDRAGIT® sustained release polymers EUDRAGIT® RL (high permeability), EUDRAGIT® RS (low permeability), and EUDRAGIT® NM 30D (low permeability)); used alone or in any combination thereof to achieve the desired permeability for sustained release).

[0110] In some embodiments, the composition may include one or more pH-dependent polymers (e.g., acid-insoluble polymers). pH-dependent polymers are highly permeable above pH 5.0, but are impermeable below pH 5.0. Meanwhile, acid-insoluble polymers are soluble in neutral to slightly alkaline conditions. Such controlled release polymers target the upper small intestine and colon. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate, alginates (e.g., sodium alginate or potassium alginate), shellac, pectin, acrylic acid-methylacrylic acid copolymers (available as a powder or a 30% aqueous dispersion under the tradenames EUDRAGIT® L and EUDRAGIT® S from Rohm America Inc., Piscataway, NJ, or as a 30% dispersion under the tradename EASTACRYL® from Eastman Chemical Co., Kingsport, TN). Further examples include EUDRAGIT® L100-55, EUDRAGIT® L30D-55, EUDRAGIT® L100, EUDRAGIT® L100 12,5, EUDRAGIT® S100, EUDRAGIT® S12,5, EUDRAGIT® FS 30D, EUDRAGIT® E100, EUDRAGIT® E 12,5, and EUDRAGIT® PO. In at least one embodiment, the composition comprises EUDRAGIT® L100-55. EUDRAGIT® RS and RL, as well as EUDRAGIT® NE and NM, are also useful polymers for purposes of the present disclosure. In some embodiments, the composition comprises EUDRAGIT® L30D 55. In another embodiment, the preparation comprises EUDRAGIT® FS 30D. Those of ordinary skill in the art will recognize that at least some of the acid-insoluble polymers listed herein are also biodegradable.

[0111] Commercially available delayed release capsules (e.g., capsules available from Capsugel (e.g., VCAPS® Plus enteric capsules)) can be used to prepare enteric-resistant delayed release capsules and are encompassed by the present disclosure. In some embodiments, the enteric-resistant delayed release capsules can be non-animal-based capsules, such as hypromellose capsules (e.g., commercially available self-gelling VCAPS®, VCAPS® Plus, VCAPS® Enteric, XCELLODOSE®, DRCAPS®, Encap Colonic Delivery (ENCODE), and other enteric-coated capsules made using ENTRINSICT™ drug delivery technology from CAPSUGEL®). Other technologies known in the art and commercially available (e.g., QUALICAPS® (USA), NutraScience (USA), etc.) can also be utilized to formulate enteric forms of oral solid dosage forms. For example, the endoxifen formulations of the present disclosure can be encapsulated in DRCAPS® enteric-resistant delayed release capsules. In at least one embodiment, the capsule is an API in capsule, which means that (Z)-endoxifen free base or its salt is filled in the capsule in a pure state.In such an oral dosage form in which the API is in capsule, the active ingredient (Z)-endoxifen or its salt can be a flowable powder or fine powder.When the dosage form is a capsule, in at least one embodiment, the capsule can be a seamless capsule or a banded capsule.

[0112] The oral dosage form can be of any shape suitable for oral administration, such as spherical (0.05-5 mL), elliptical (0.05-7 mL), oval, pear-shaped (0.3-5 mL), cylindrical, cubic, regular and / or irregular shapes, etc. The oral dosage form can be of any size suitable for oral administration, e.g., size 0, size 2, etc.

[0113] An example of an enteric resistant delayed release endoxifen composition may include an enteric resistant delayed release capsule containing about 65% to about 95% hydroxypropyl methylcellulose and about 3% to about 10% gellan gum by weight, based on the total weight of the unfilled capsule, encapsulating an endoxifen composition containing about 10% to about 30% (Z)-endoxifen, about 1% to about 5% croscarmellose sodium, about 60% to about 95% microcrystalline cellulose, and about 0.5% to about 3% magnesium stearate by weight, based on the total fill weight of the composition. In some embodiments, the enteric resistant delayed release endoxifen composition may be formulated to contain about 10 mg, about 20 mg, about 40 mg, or about 80 mg (Z)-endoxifen per capsule.

[0114] Treatment method The endoxifen compositions (e.g., high dose enteric resistant delayed release endoxifen formulations) of the present disclosure can be used in methods of treating a disease or disorder in a subject (e.g., a human subject). In some embodiments, the subject can be a female subject. For example, the subject can be a premenopausal (e.g., less than about 55 years of age) female. In some embodiments, the disease can be cancer, a hormone-dependent breast disorder, or a hormone-dependent reproductive tract disorder. In some embodiments, the cancer is breast cancer, cervical cancer, ovarian cancer, endometrial cancer, uterine cancer, vaginal cancer, vulvar cancer, melanoma, colon cancer, gastric cancer, neuroblastoma, pancreatic cancer, esophageal cancer, rectal cancer, or bile duct cancer. For example, the cancer can be breast cancer (e.g., triple-negative breast cancer, ductal carcinoma in situ, lobular carcinoma in situ, invasive ductal carcinoma, or invasive lobular carcinoma). In some embodiments, the hormone-dependent breast disorder or hormone-dependent reproductive tract disorder is benign breast disorder, hyperplasia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, precocious puberty, or McCune-Albright syndrome. In some embodiments, the compositions described herein can be used to treat tamoxifen-resistant or tamoxifen-refractory disease (e.g., tamoxifen-resistant or tamoxifen-refractory cancer).

[0115] The enteric resistant delayed release endoxifen composition can be orally administered to a subject so that the (Z)-endoxifen in the composition is delivered to the intestine of the subject. In some embodiments, about 1% or less, about 2% or less, about 3% or less, about 4% or less, about 5% or less, about 6% or less, about 7% or less, about 8% or less, about 9% 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, or about 40% or less of the (Z)-endoxifen in the composition is released in the stomach of the subject. In some embodiments, 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 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of the (Z)-endoxifen in the composition is released into the intestine of the subject.

[0116] The enteric resistant delayed release formulation may release about 1% or less, about 2% or less, about 3% or less, about 4% or less, about 5% or less, about 6% or less, about 7% or less, about 8% or less, about 9% 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, or about 40% or less of the (Z)-endoxifen in the composition in the stomach of a subject after oral administration. In some embodiments, the enteric resistant delayed release formulation may release about 0% to about 1%, about 0% to about 2%, about 0% to about 3%, about 0% to about 4%, about 0% to about 5%, about 0% to about 10%, about 0% to about 15%, about 0% to about 20%, about 1% to about 2%, about 1% to about 3%, about 1% to about 4%, about 1% to about 5%, about 1% to about 10%, about 1% to about 15%, about 1% to about 20%, about 3% to about 3%, about 3% to about 4%, about 3% to about 5%, about 3% to about 10%, about 3% to about 15%, or about 3% to about 20% of the (Z)-endoxifen in the composition in the stomach of a subject after oral administration.

[0117] The enteric resistant delayed release formulation may release 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 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of the (Z)-endoxifen in the composition into the intestine of a subject following oral administration. In some embodiments, the enteric resistant delayed release formulation provides, following oral administration, about 50% to about 95%, about 60% to about 95%, about 70% to about 95%, about 80% to about 95%, about 85% to about 95%, about 86% to about 95%, about 87% to about 95%, about 88% to about 95%, about 89% to about 95%, about 90% to about 95%, about 91% to about 95%, about 92% to about 95%, about 93% to about 95%, about 94% to about 95%, about 95% to about 95%, about 96% to about 95%, about 97% to about 95%, about 98% to about 95%, about 99% to about 95%, about 100% to about 100%, about 101% to about 102%, about 103% to about 104%, about 105% to about 105%, about 106% to about 106%, about 107% to about 107%, about 108% to about 108%, about 109% to about 109%, about 200% to about 200%, about 201% to about 201%, about 202% to about 203%, about 203% to about 204%, about 205% to about 205%, about 206% to about 207%, about 207% to about 208%, about 208% to about 209%, about 210% to about 211%, about 212% to about 213%, about 213% to about 214%, about 214% to about 215%, about 215% to about 216%, about 217% to about 21 About 95%, about 93% to about 95%, about 94% to about 95%, about 50% to about 97%, about 60% to about 97%, about 70% to about 97%, about 80% to about 97%, about 85% to about 97%, about 86% to about 97%, about 87% to about 97%, about 88% to about 97%, about 89% to about 97%, about 90% to about 97%, about 91% to about 97%, about 92% to about 97%, about 93% to about 97%, about 94% to about 97%, about 95% ~ about 97%, about 50% to about 99%, about 60% to about 99%, about 70% to about 99%, about 80% to about 99%, about 85% to about 99%, about 86% to about 99%, about 87% to about 99%, about 88% to about 99%, about 89% to about 99%, about 90% to about 99%, about 91% to about 99%, about 92% to about 99%, about 93% to about 99%, about 94% to about 99%, about 95% to about 99%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 85% to about 100%, about 86% to about 100%, about 87% to about 100%, about 88% to about 100%, about 89% to about 100%, about 90% to about 100%, about 91% to about 100%, about 92% to about 100%, about 93% to about 100%, about 94% to about 100%, or about 95% to about 100% may be released into the intestine of the subject.

[0118] The treatment method may include administering to the subject an endoxifen composition daily. In some embodiments, about 10 mg to about 100 mg, about 20 mg to about 100 mg, about 30 mg to about 100 mg, about 40 mg to about 100 mg, about 60 mg to about 100 mg, about 80 mg to about 100 mg, about 10 mg to about 90 mg, about 20 mg to about 90 mg, about 30 mg to about 90 mg, about 40 mg to about 90 mg, about 60 mg to about 90 mg, about 80 mg to about 90 mg, about 10 mg to about 80 mg, about 20 mg to about 80 mg, about 30 mg to about 80 mg, about 40 mg to about 80 mg, about 50 mg to about 80 mg, about 10 mg to about 60 mg, about 20 mg to about 60 mg, about 30 mg to about 60 mg, about 40 mg to about 60 mg, or about 50 mg to about 60 mg of (Z)-endoxifen is administered to the subject per day. In some embodiments, (Z)-endoxifen can be administered in the form of an enteric-coated, resistant, delayed-release capsule containing about 10 mg, about 20 mg, about 40 mg, or about 80 mg of (Z)-endoxifen per capsule.

[0119] The compositions of the present disclosure may be administered to a subject for a period of about 7 to about 1 year. In some embodiments, the compositions may be administered daily. In some embodiments, the endoxifen compositions of the present disclosure are administered until the disease or condition is treated. For example, the endoxifen compositions may be administered daily to a subject for up to about 6 months, or until the disease or condition is treated. In another example, the endoxifen compositions may be administered daily to a subject for about 28 days to about 6 months, or until the disease or condition is treated. Treating a disease or condition includes alleviating one or more symptoms of the disease, or reducing or eliminating the disease. For example, the endoxifen compositions may be administered daily to a subject with a tumor until the subject's tumor begins to shrink, reduces in size by a predetermined amount, or becomes undetectable.

[0120] After administration, the plasma concentration of endoxifen in the subject can be measured.In some embodiments, after oral administration of the endoxifen composition of the present disclosure, the plasma concentration of endoxifen can include at least about 50% by weight, at least about 55% by weight, at least about 60% by weight, at least about 65% by weight, at least about 70% by weight, at least about 75% by weight, at least about 80% by weight, at least about 85% by weight, at least about 86% by weight, at least about 87% by weight, at least about 88% by weight, at least about 89% by weight, at least about 90% by weight, at least about 91% by weight, at least about 92% by weight, at least about 93% by weight, at least about 94% by weight, at least about 95% by weight, at least about 96% by weight, at least about 97% by weight, at least about 98% by weight, at least about 99% by weight, or about 100% by weight of endoxifen in the (Z)-isoform based on the total endoxifen present in the plasma of the subject.

[0121] In some embodiments, the endoxifen composition may be administered to a subject in combination with an additional therapeutic agent. Examples of additional therapeutic agents that may be used in combination with the endoxifen formulations disclosed herein include, but are not limited to, bicalutamide, enzalutamide, or anticancer drugs, such as trastuzumab, antineoplastic agents, such as capecitabine (e.g., XELODA®), carboplatin (e.g., PARAPLATIN®), cisplatin (e.g., PLATINOL®), cyclophosphamide (e.g., NEOSAR®), docetaxel (e.g., DOCEFREZ®, TAXOTERE®), doxorubicin (e.g., ADRIAMYCIN®), PEGylated liposomal doxorubicin (e.g., PEG-100001), PEG-100001, PEG-100002, PEG-100003, PEG-100004, PEG-100005, PEG-100006, PEG-100007, PEG-100008, PEG-100009, PEG-100009, PEG-100008, PEG-100009, PEG-100009, PEG-100001, PEG-100002, PEG-100004, PEG-100005, PEG-100006, PEG-100007, PEG-100008, PEG-100009, PEG-100009, PEG-100009, PEG-100009, PEG-100001, PEG-100002, PEG-100003, PEG-100004, PEG-10 These include sorbic acid (e.g., DOXIL®), epirubicin (e.g., ELLENCE®), fluorouracil (5-FU, e.g., ADRUCIL®), gemcitabine (e.g., GEMZAR®), methotrexate (several trade names), paclitaxel (e.g., TAXOL®), protein-bound paclitaxel (e.g., ABRAXANE®), vinorelbine (e.g., NAVELBINE®), eribulin (e.g., HALAVEN®), ixabepilone (e.g., IXEMPRA®), and ATP cassette binding protein transport inhibitors.

[0122] As used herein, the terms "about" and "approximately" in reference to numerical values ​​are used herein to include numerical values ​​that fall within a range of 10%, 5%, or 1% in either direction (greater or less) of that numerical value, unless otherwise specified or otherwise clear from the context (unless such numerical value exceeds 100% of its possible values).

[0123] As used herein, the terms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise.

[0124] It is specifically understood that any numerical value cited herein includes all values ​​from the lower limit to the upper limit, i.e., all possible combinations of numerical values ​​between the lowest and highest values ​​recited are considered to be expressly set forth in this application, and all range endpoints are included within this range and are independently combinable. For example, if a concentration range or useful range is described as 1%-50%, it is intended that values ​​such as 2%-40%, 10%-30%, or 1%-3%, etc. are explicitly recited herein. Also, it is understood that when a concentration or dose is described as a specific value, such as 1 mg or 10 mg, it is intended to include a 10% variation. As another example, a description of a concentration of 20% is intended to include values ​​of ±10%. As another example, if a ratio of 1:10-10:1 is described, 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, or 2:5-3:5 are specifically contemplated. These are just some examples. Unless otherwise specified, values ​​for components or elements of a composition are expressed as the weight percent of each component in the component.

[0125] As used herein, the terms "active pharmaceutical ingredient", "active ingredient", "API", "drug", "active", "active substance", or "therapeutic agent" may be used interchangeably to refer to a pharma- ceutical active compound(s) in a pharmaceutical composition. This is in contrast to other ingredients (e.g., excipients) in the composition that are substantially or completely pharma- ceutical inactive. Suitable APIs according to the present disclosure have or may have patient compliance issues in the treatment of certain diseases, conditions, or disorders. As used herein, therapeutic agents include active compounds and their salts, prodrugs, and metabolites. As used herein, the term "drug" refers to a compound intended for use in the diagnosis, cure, mitigation, treatment, and / or prevention of disease in humans or other animals.

[0126] As used herein, "adjuvant therapy" refers to therapy administered following primary therapy to a subject at risk of recurrence. In the case of breast and reproductive tract cancers, systemic adjuvant therapy, for example with tamoxifen, is usually initiated soon after primary therapy to delay recurrence, prolong survival, or cure the subject.

[0127] Throughout this specification, embodiments that refer to "compounds" (e.g., compounds of Formula (I) or Formula (II)) include polymorphs, salts, free bases, co-crystals, and solvates of the formulas and / or compounds disclosed herein.

[0128] The terms "crystalline form", "polymorph", and "form" may be used interchangeably herein and are meant to include all crystalline and amorphous forms, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, nonsolvated polymorphs (including anhydrous), conformational polymorphs, and amorphous forms, and mixtures thereof, unless a specific crystalline or amorphous form is referred to. Compounds of the present disclosure include crystalline and amorphous forms of these compounds, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, nonsolvated polymorphs (including anhydrous), conformational polymorphs, and amorphous forms, and mixtures thereof, of the compounds.

[0129] As used in this specification and claims, "comprising," "containing," and "inclusive" are inclusive and 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."

[0130] As used herein, the term "combination therapy" refers to the use of the compositions described herein in combination with one or more additional treatments. The treatment in the combination therapy can be any treatment, such as any prophylactic agent, therapeutic agent (e.g., chemotherapy), radiation therapy, surgery, etc. Combination can refer to the inclusion of a therapeutic or prophylactic agent in the same composition (e.g., the same capsule, tablet, ointment, etc.) or in separate compositions (e.g., two separate capsules) as the compositions disclosed herein. Separate compositions may be in different dosage forms. The use of the terms "combination therapy" and "in combination with" does not limit the order in which the compositions described herein and prophylactic and / or therapeutic agents and / or treatments are administered to a subject in need thereof. Compositions of the disclosure may be administered within 1 minute (min), 5 min, 15 min, 30 min, 45 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 1 m (wk), 2 wk, 3 wk, 4 wk, 5 wk, 6 wk, 8 wk, 12 wk, 6 months (m), 9 m, or The subject therein may be administered a combination therapy, such as one year prior to administration, simultaneously with administration, or one year after administration (e.g., 1 minute (min), 5 min, 15 min, 30 min, 45 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 1 week (wk), 2 wk, 3 wk, 4 wk, 5 wk, 6 wk, 8 wk, 12 wk, 6 months (m), 9 m, or one year later). As used herein, combination therapy can also refer to the treatment of a subject with one disease or multiple diseases, such as prostate cancer and gynecomastia in men.

[0131] As used herein, the term "pharmaceutical acceptable carrier" or "carrier" means a pharma- ceutically 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 through a tissue, organ, or part of the body, or across the skin.

[0132] As used herein, the term "pharmaceutical acceptable salt" refers to any salt of a compound of the present disclosure (e.g., obtained by reaction with an acid or base) that is physiologically acceptable in a subject (e.g., a mammal, and / or in a cell, tissue, or organ in vivo, ex-vivo, or in vitro). The "salts" of the compounds of the present disclosure can be derived from inorganic or organic acids and bases. Examples of suitable anionic salts include arecoline, besylate, bicarbonate, bitartrate, butyl bromide, citrate, camsylate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methyl bromide, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacronate, salicylate, stearate, sulfate, tannate, teoclate, fatty acid anions, and triethiodide.

[0133] Suitable cations include benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc.

[0134] As used herein, the term "pharmaceutical composition" means a combination of an active agent (e.g., an active pharmaceutical compound or ingredient, API) with an inert or active carrier (e.g., a phospholipid), which makes the composition particularly suitable for diagnostic or therapeutic use in vitro, in vivo, or ex vivo.

[0135] As used herein, the terms "subject," "patient," "participant," and "individual" may be used interchangeably herein and refer to a mammal, such as a human. Mammals also include companion animals, such as dogs and cats, laboratory animals, such as rats and mice, and farm animals, such as cows and horses. Unless otherwise specified, mammals may be of any gender or sex.

[0136] All methods described herein may be performed in any suitable order unless otherwise indicated or clearly contradicted by context. Any examples or use of exemplary language provided herein (e.g., "such as" and "like") are intended to merely illustrate the specification and do not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention used herein. EXAMPLES

[0137] The present invention is further illustrated by the following non-limiting examples.

[0138] Example 1 pH-Dependent Solubility of (Z)-Endoxifen This example describes the pH-dependent solubility of (Z)-endoxifen. (Z)-endoxifen was dissolved in solution under different pH conditions and the solubility was measured. Because (Z)-endoxifen converts to the E-form under acidic conditions, the solubility of (Z)-endoxifen and (E)-endoxifen was measured separately and the ratio of Z-form:E-form was determined. [Table 1]

[0139] As shown in Table 1, the ratio of Z-form:E-form increased with increasing pH, indicating that (Z)-endoxifen converts to (E)-endoxifen more readily under acidic conditions than at more neutral pHs (e.g., pH 6.8). At pH 6.8, any Z-form → E-form equilibrium was below the detection limit. Because the active form of endoxifen is (Z)-endoxifen, this data suggested that a delivery mechanism that bypasses the acidic conditions of the stomach may allow endoxifen to be delivered in its active Z-form. A decrease in the total solubility of endoxifen (Z and E forms) was also observed with increasing pH.

[0140] Example 2 Lytic assay development This example describes the development of a dissolution assay to measure the solubility of endoxifen formulations. Because the solubility of endoxifen decreases with decreasing pH acidity, as shown in Example 1, additional experiments were performed to improve the solubility of endoxifen in a buffer at pH 6.8. To improve solubility and mimic the intestinal environment, the non-ionic surfactant polysorbate 80 (PS80) was added at various concentrations. Surfactants such as polysorbate 80 create micelles in the medium that mimic bile acid aggregates in the small intestine. These micelles facilitate the diffusion and transport of the product in the medium. [Table 2]

[0141] As shown in Table 2, the addition of polysorbate 80 improved the solubility of endoxifen at pH 6.8.

[0142] Based on this solubility data, dissolution methods were developed to test the solubility of encapsulated endoxifen formulations. Improved dissolution assays were developed based on a combination of the United States Pharmacopeia (USP) and Japanese Pharmacopeia (JP) dissolution methods. The media used in each of these methods are summarized in Table 3. [Table 3]

[0143] In the modified dissolution method, 0.5% or 0.75% polysorbate 80 was added to the buffer medium to mimic intestinal conditions and enhance the solubility of endoxifen. The modified dissolution method is summarized in Table 4. [Table 4]

[0144] Briefly, the encapsulated endoxifen formulation was pushed down into a container by a sinker and incubated in 1000 mL of acidic medium at approximately 37° C. for 2 hours with mixing using a paddle. Samples were taken at 30, 60, 90, and 120 minutes to measure the amount of capsule and endoxifen formulation dissolved in the medium. After 2 hours, the acid medium was replaced with 1000 mL of buffer medium and incubated for an additional 1.5 hours. Samples were taken 15, 30, 45, 60, and 90 minutes after the buffer replacement.

[0145] Samples taken at each pull time were assayed using HPLC-UV to quantify the percent release of endoxifen over time. Chromatography was performed using a Waters Xselect CSH Phenyl-Hexyl 3.5 μm, 4.6 mm×150 mm column or equivalent at a flow rate of 0.8 mL / min, a runtime of 18 min, and an injection volume of 80 μL. The column was held at approximately 50° C. and the UV of the eluent was measured at 243 nm. The autosampler was held at 5° C. to ensure sample stability. A gradient between mobile phase A (10 mM ammonium formate in water) and mobile phase B (ammonium formate in methanol) was run as shown in Table 5. [Table 5]

[0146] This modified dissolution assay was used to measure the solubility of high dose (Z)-endoxifen formulations.

[0147] Example 3 In vitro solubility of high-dose (Z)-endoxifen formulations This example describes the in vitro dissolution of high dose (Z)-endoxifen formulations. (Z)-endoxifen formulations containing 40 mg (Z)-endoxifen (active pharmaceutical ingredient (API)), magnesium stearate, and microcrystalline cellulose were encapsulated in enteric resistant delayed release capsules (DRCAPS®, CAPSUGEL® (USA)) containing hypromellose and gellan gum. The 40 mg (Z)-endoxifen formulation contained approximately 18% API (by total fill weight). Initial dissolution assays showed failure of the capsules to disintegrate, preventing the release of (Z)-endoxifen. The failure of the capsules to disintegrate was speculated to be due to cross-linking between the (Z)-endoxifen API and the capsule shell. This cross-linking effect was not observed in the lower dose formulations (including 1 mg, 2 mg, and 4 mg formulations) or in the lower % API formulations (including formulations containing up to 4% (Z)-endoxifen (by total fill weight)).

[0148] Croscarmellose sodium was added as a disintegrant to 40 mg (Z)-endoxifen formulations to reduce cross-linking. To test the effect of croscarmellose sodium on cross-linking between (Z)-endoxifen API and capsules, dissolution assays were performed as described in Tables 4 and 5 of Example 2. Test formulations (V1-V6) contained 40 mg (Z)-endoxifen, 173.78 mg microcrystalline cellulose, 6.5 mg croscarmellose sodium, and 2.23 mg magnesium stearate per capsule for a total fill weight of 222.5 mg and 18% API. The formulations were encapsulated in enteric-coated resistant delayed release capsules containing hypromellose and gellan gum (DRCAPS®, CAPSUGEL® (USA)), and the same capsules were used for dissolution assays with formulations lacking croscarmellose sodium.

[0149] Dissolution assays performed in the presence of 0.5% polysorbate 80 showed complete disintegration of the capsules, suggesting reduced or absent cross-linking, but incomplete dissolution of (Z)-endoxifen. The results of this assay are shown in Table 6. [Table 6]

[0150] Dissolution tests performed in the presence of 0.75% polysorbate 80 similarly demonstrated complete disintegration of the capsules as well as complete dissolution of (Z)-endoxifen. The results of this assay are shown in Table 7. [Table 7]

[0151] In contrast to the high-dose endoxifen formulation lacking croscarmellose sodium, which did not dissolve in the dissolution assay, the high-dose endoxifen formulation containing croscarmellose sodium showed complete capsule disintegration and complete (Z)-endoxifen dissolution. These results indicate that the addition of croscarmellose sodium reduced cross-linking between the API and the capsule, allowing the capsule to disintegrate completely.

[0152] Example 4 Manufacturing of high dose (Z)-endoxifen formulation This example describes the preparation of a high dose (Z)-endoxifen formulation. A 40 mg (Z)-endoxifen (18% API) formulation was prepared and validated that included croscarmellose sodium to prevent cross-linking between the endoxifen API and the capsule, as assayed in Example 4. The formulation and weight percent of drug formulation (excluding capsule) per capsule are shown in Table 8. [Table 8]

[0153] (Z)-endoxifen, microcrystalline cellulose, and croscarmellose sodium were transferred simultaneously and blended. Magnesium stearate was transferred separately and mixed with the endoxifen blend for 2 minutes. The final blend was filled into size 0 hypromellose enteric-coated resistant delayed release capsules (DRCAPS®, CAPSUGEL®, USA) to a fill weight of 222.5 mg±1 mg.

[0154] The (Z)-endoxifen formulations were assayed by HPLC to verify composition. The contents of five (Z)-endoxifen capsules were transferred to 180 mL of diluent that was sonicated for 5 minutes to empty the capsules. The dissolved samples were equilibrated to room temperature and diluted to 0.05 mg / mL (Z)-endoxifen in diluent. The HPLC chromatogram of the 0.5 mg / mL (Z)-endoxifen sample (Figure 1A) was compared to the chromatogram of the 0.05 mg / mL (Z)-endoxifen reference sample (Figure 1B) and diluent alone (Figure 1C). The manufactured (Z)-endoxifen sample closely matched the (Z)-endoxifen reference sample.

[0155] Example 5 Oral administration of high-dose (Z)-endoxifen formulations This example describes the oral administration of high-dose (Z)-endoxifen formulations. Human subjects are orally administered 80 mg (Z)-endoxifen in the form of two 40 mg enteric-resistant delayed-release capsules or one 80 mg enteric-resistant delayed-release capsule. Each 40 mg capsule contains 40 mg (Z)-endoxifen, 173.78 mg microcrystalline cellulose, 6.50 mg croscarmellose sodium, and 2.23 mg magnesium stearate, enclosed in a hypromellose capsule (delayed-release capsule). When administered orally, the capsule remains largely intact in the acidic environment of the stomach. The capsule begins to dissolve once it leaves the stomach and enters the intestine. It releases less than about 10% of the (Z)-endoxifen in the stomach. Once in the intestine, the capsule dissolves completely, releasing the remaining (Z)-endoxifen into the intestine. Plasma and serum levels of endoxifen in subjects indicate that at least 90% of the endoxifen is the active Z form and less than 10% of the endoxifen is the E form.

[0156] Example 6 Treatment of breast cancer with a high-dose (Z)-endoxifen formulation This example describes the treatment of breast cancer with a high-dose (Z)-endoxifen formulation. A patient with breast cancer is orally administered 80 mg (Z)-endoxifen per day for up to six months or until the breast cancer is treated. 80 mg (Z)-endoxifen is formulated as two 40 mg enteric-resistant delayed-release capsules or one 80 mg enteric-resistant delayed-release capsule. The capsule is resistant to dissolution in the acidic environment of the stomach, such that the capsule dissolves primarily in the less acidic environment of the intestine after administration of the capsule to a subject. As a result, at least about 85% of the (Z)-endoxifen is released in the intestine of the subject, and about 10% or less of the (Z)-endoxifen is released in the stomach of the subject. After oral administration of the (Z)-endoxifen enteric-resistant delayed-release formulation, at least about 85% of the endoxifen present in the plasma and serum of the subject is the Z-isoform.

[0157] High doses of (Z)-endoxifen administered orally can cause breast cancer to disappear, slow its spread, shrink, or reduce the symptoms, thereby treating the cancer.

[0158] Example 7 Treatment of ovarian cancer with a high-dose (Z)-endoxifen formulation This example describes the treatment of ovarian cancer with a high-dose (Z)-endoxifen formulation. A patient with ovarian cancer is orally administered 80 mg (Z)-endoxifen per day for up to six months or until the ovarian cancer is treated. 80 mg (Z)-endoxifen is formulated as two 40 mg enteric-resistant delayed-release capsules or one 80 mg enteric-resistant delayed-release capsule. The capsule is resistant to dissolution in the acidic environment of the stomach, so that the capsule dissolves primarily in the less acidic environment of the intestine after administration of the capsule to a subject. As a result, at least about 85% of the (Z)-endoxifen is released in the intestine of the subject, and about 10% or less of the (Z)-endoxifen is released in the stomach of the subject. After oral administration of the (Z)-endoxifen enteric-resistant delayed-release formulation, at least about 85% of the endoxifen present in the plasma and serum of the subject is the Z-isoform.

[0159] High doses of (Z)-endoxifen administered orally can eliminate, slow the spread, shrink, or reduce symptoms of ovarian cancer, thereby treating the cancer.

[0160] Example 8 Treatment of cervical cancer with a high-dose (Z)-endoxifen formulation This example describes the treatment of cervical cancer with a high-dose (Z)-endoxifen formulation. A patient with cervical cancer is orally administered 80 mg (Z)-endoxifen per day for up to six months or until the cervical cancer is treated. 80 mg (Z)-endoxifen is formulated as two 40 mg enteric-resistant delayed-release capsules or one 80 mg enteric-resistant delayed-release capsule. The capsule is resistant to dissolution in the acidic environment of the stomach, such that the capsule dissolves primarily in the less acidic environment of the intestine after administration of the capsule to a subject. As a result, at least about 85% of the (Z)-endoxifen is released in the intestine of the subject, and about 10% or less of the (Z)-endoxifen is released in the stomach of the subject. After oral administration of the (Z)-endoxifen enteric-resistant delayed-release formulation, at least about 85% of the endoxifen present in the plasma and serum of the subject is the Z-isoform.

[0161] High doses of (Z)-endoxifen administered orally can eliminate, slow the spread, shrink, or reduce the symptoms of cervical cancer, thereby treating it.

[0162] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Those skilled in the art will envision numerous variations, changes, and substitutions without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be used in the practice of the invention. The following claims define the scope of the invention, and it is intended that methods and structures encompassed within the scope of the claims, and their equivalents, be covered thereby.

Claims

1. A composition, (Z)-endoxiphene in an amount of 5% to 40% by weight, A drug formulation comprising a disintegrant in an amount of about 1.0% to about 10% by weight of the total filling weight of the composition, and Enteric-coated delayed-release capsule containing the aforementioned drug formulation The composition comprising the above.

2. The composition according to claim 1, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, agar, alginic acid, calcium carbonate, microcrystalline cellulose, crospovidone, polaritrin potassium, sodium starch glycolate, potato or tapioca starch, pregelatinized starch, clay, gum, and combinations thereof.

3. The composition according to claim 1, wherein the disintegrant is crospovidone.

4. The composition according to claim 1, wherein the disintegrant is sodium starch glycolate.

5. The composition according to claim 1, wherein the disintegrant is croscarmellose sodium.

6. The drug formulation is A disintegrant in an amount of 1% to 5% by weight of the total filling weight of the composition, or Disintegrant in an amount of 2% to 4% by weight of the total filling weight of the composition The composition according to claim 1, comprising:

7. The drug formulation is (Z)-endoxiphene in an amount of 10% to 25% by weight, 15% to 20% by weight of (Z)-endoxiphene, or (Z)-endoxiphen in an amount of 17% to 19% by weight The composition according to claim 1, comprising:

8. The composition according to claim 1, wherein the drug formulation comprises about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 50 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, or about 10 mg to about 30 mg of (Z)-endoxifen per enteric-coated delayed-release capsule.

9. The composition according to claim 1, wherein the drug formulation comprises about 10 mg, about 20 mg, about 40 mg, or about 80 mg of (Z)-endoxifene per enteric-coated delayed-release capsule.

10. The composition according to claim 1, wherein the drug formulation further comprises microcrystalline cellulose.

11. The drug formulation is Microcrystalline cellulose in an amount of approximately 50% to approximately 95% by weight of the total filling weight of the composition. Microcrystalline cellulose in an amount of 60% to 95% by weight of the total filling weight of the composition, Microcrystalline cellulose in an amount of 70% to 90% by weight of the total filling weight of the composition, or Microcrystalline cellulose in an amount of 75% to 80% by weight of the total filling weight of the composition. The composition according to claim 10, comprising:

12. The composition according to claim 1, wherein the drug formulation further comprises magnesium stearate.

13. The drug formulation is Magnesium stearate in an amount of 0.5% to 3% by weight of the total filling weight of the composition. Magnesium stearate in an amount of 0.5% to 2% by weight of the total filling weight of the composition, or Magnesium stearate in an amount of 0.5% to 1.5% by weight of the total filling weight of the composition. The composition according to claim 12, comprising:

14. The composition according to claim 1, wherein the enteric-coated delayed-release capsule comprises hydroxypropyl methylcellulose, gellan gum, gelatin, hydroxypropyl methylcellulose phthalate, a coloring agent, an opaler, or any combination thereof.

15. The composition according to claim 1 or claim 14, wherein the enteric-coated delayed-release capsule comprises hydroxypropyl methylcellulose.

16. The composition according to claim 15, wherein the enteric-coated delayed-release capsule contains 85% by weight or more and 97% by weight or less of hydroxypropyl methylcellulose based on the total weight of the capsule.

17. The composition according to claim 1 or claim 14, wherein the enteric-coated delayed-release capsule comprises gellan gum, gelatin, or a combination thereof.

18. The composition according to claim 17, wherein the enteric-coated resistant delayed-release capsule contains 3% by weight or more and 10% by weight or less of gelan gum, gelatin, or a combination thereof, based on the total weight of the capsule.

19. The composition according to claim 1, wherein the enteric-coated delayed-release capsule comprises about 65% to about 95% by weight of hydroxypropyl methylcellulose and about 3% to about 10% by weight of gellan gum based on the total weight of the capsule.

20. The (Z)-endoxiphene comprises polymorphic forms of endoxiphene, Morphology I is characterized by an X-ray powder diffraction pattern containing major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3°2 theta. Morphology II is characterized by an X-ray powder diffraction pattern containing major peaks at 7.0±0.3°, 11.9±0.3°, and 14.0±0.3° in theta 2. Morphology III is characterized by an X-ray powder diffraction pattern containing major peaks at 11.9±0.3°, 13.9±0.3°, and 17.1±0.3°2-theta. Morphology IV is characterized by an X-ray powder diffraction pattern containing major peaks at 4.7±0.3° 2-theta, 23.3±0.3°, and 13.6±0.3° 2-theta. Morphology V is characterized by an X-ray powder diffraction pattern containing major peaks at 12.5±0.3°, 19.6±0.3°, and 8.9±0.3° in theta 2. Morphology VI is characterized by an X-ray powder diffraction pattern containing major peaks at 9.9±0.3°, 13.4±0.3°, and 13.7±0.3° in theta 2. Morphology VII is characterized by an X-ray powder diffraction pattern containing major peaks at 20.0±0.3°, 22.6±0.3°, and 10.6±0.3°2 theta. Morphology VIII is characterized by an X-ray powder diffraction pattern containing major peaks at 4.8±0.3°, 18.9±0.3°, and 9.5±0.3° in theta 2. Morphology IX is characterized by an X-ray powder diffraction pattern containing major peaks at 19.0±0.3°, 12.9±0.3°, and 15.9±0.3° in theta 2. Morphology X is characterized by an X-ray powder diffraction pattern containing major peaks at 7.2±0.3°, 14.3±0.3°, and 18.7±0.3° in theta 2. Morphology XI is characterized by an X-ray powder diffraction pattern containing major peaks at 14.0±0.3°, 17.7±0.3°, and 11.9±0.3° in theta 2. Morphology XII is characterized by an X-ray powder diffraction pattern containing major peaks at 12.5±0.3°, 15.6±0.3°, and 19.0±0.3° in theta 2. Morphology XIV is characterized by an X-ray powder diffraction pattern containing major peaks at 11.6±0.3°, 21.3±0.3°, and 19.3±0.3° in theta 2. Morphology XV is characterized by an X-ray powder diffraction pattern containing major peaks at 9.8±0.3°, 4.7±0.3°, and 14.0±0.3° in theta 2. Morphology XIX, characterized by an X-ray powder diffraction pattern with major peaks at 4.7±0.3°, 23.6±0.3°, and 18.9±0.3°2 theta, or These combinations The composition according to claim 1, comprising:

21. The composition according to claim 20, wherein at least 90% by weight of the (Z)-endoxiphene is a polymorph of the endoxiphene.

22. a) Within two hours after the composition is introduced into the acidic step of an in vitro dissolution assay, 20% or less of the (Z)-endoxiphene is released. b) Within 1.5 hours after the composition is introduced into the buffering step of the in vitro lysis assay, 70% or more of the (Z)-endoxiphene is released, or c) These combinations, The composition according to claim 1, comprising an in vitro dissolution profile.

23. a) Within two hours after the composition is introduced into the acidic step of an in vitro dissolution assay, 20% or less of the (Z)-endoxiphene is released. b) Within 1.5 hours after the composition is introduced into the buffering step of the in vitro lysis assay, 70% or more of the (Z)-endoxiphene is released, or c) These are combinations, The composition according to claim 1, wherein the acidic step includes a pH of less than 2, and the buffering step includes a pH of about 6.

8.

24. 15% by weight or more and 20% by weight or less of (Z)-endoxiphene, Croscarmellose sodium in an amount of 2% to 4% by weight, 0.5% to 2% by weight of magnesium stearate, A drug formulation containing 70% to 80% by weight of microcrystalline cellulose, and Enteric-coated delayed-release capsule for enclosing the aforementioned drug formulation, 85% to 97% by weight of hydroxypropyl methylcellulose, The enteric-coated, delayed-release capsule contains 3% to 7% by weight of gellan gum. The composition according to claim 1, comprising:

25. The composition according to claim 1 for use in a method for treating a disorder in a subject, wherein the method comprises orally administering the composition to the subject to treat the disorder, the disorder being cancer, hormone-dependent breast disorder, or hormone-dependent reproductive tract disorder.

26. The composition for use according to claim 25, wherein the cancer is breast cancer, cervical cancer, ovarian cancer, endometrial cancer, uterine cancer, vaginal cancer, vulvar cancer, melanoma, colorectal cancer, gastric cancer, neuroblastoma, pancreatic cancer, esophageal cancer, rectal cancer, or bile duct cancer.

27. ​​The composition for use according to claim 26, wherein the breast cancer is triple-negative breast cancer, in situ ductal carcinoma, in situ lobular carcinoma, invasive ductal carcinoma, or invasive lobular carcinoma.

28. The composition for use according to claim 25, wherein the hormone-dependent breast disorder or hormone-dependent reproductive tract disorder is benign breast disorder, hyperplasia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, precocious puberty, or McCune-Albright syndrome.

29. The composition for use according to claim 25, wherein the disorder is tamoxifen resistance disorder or tamoxifen refractory disorder.

30. The composition for use according to claim 29, wherein the tamoxifen resistance disorder or the tamoxifen refractory disorder is a tamoxifen-resistant or tamoxifen-refractory cancer.

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