Oral formulations of (z)-endoxifen and methods of use thereof

Abstract

The present disclosure provides oral formulations comprising (Z)-endoxifen particles and methods of use thereof. In various embodiments, the present oral formulations are administered to patients who are not suitable for administering traditional oral dosage forms or who have a preference for alternative dosage forms. Provided herein are enteric and delayed-release formulations comprising coated (Z)-endoxifen microparticles for oral delivery, which enhance patient compliance and treatment efficacy for overall improved treatment outcomes.

Description

ORAL FORMULATIONS OF (Z)-ENDOXIFEN AND METHODS OF USE THEREOF CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 611,659, filed December 18, 2023, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Many pharmaceutical compounds are administered orally as tablets or capsules. Despite the convenience and efficacy of these dosage forms, swallowing large pills can be challenging for some patients, including children, the elderly, and individuals with throat or esophageal conditions. Particularly for diseases like cancers which may require regular administration of pharmaceutical compositions and strict adherence to dosing schedules, there remains a need for dosage forms which can be easily and comfortably taken orally regardless of age or health status.

[0003] Childhood cancers represent a diverse group of malignancies that affect individuals under the age of 18. These cancers are relatively rare, accounting for approximately 1% of all new cancer diagnoses in the United States. However, they remain the leading cause of disease- related death among children and adolescents. The most common types of childhood cancers include leukemias, brain and central nervous system tumors, lymphomas, neuroblastomas, and sarcomas. Each of these cancer types presents unique challenges in terms of diagnosis, treatment, and long-term outcomes. There is a need for formulations that can be orally administered to children or other patients who may have difficulty taking traditional oral dosage forms.SUMMARY

[0004] In various aspects, the present disclosure provides an oral formulation comprising a microparticle, wherein the microparticle comprises an endoxifen composition and a coating, wherein the endoxifen composition comprises a compound of Formula (I):Formula (I) wherein at least 90% by weight of the compound of Formula (I) is (Z)-endoxifen.

[0005] In some aspects, the oral formulation includes a plurality of microparticles including between them a total of from 0.01 mg to 200 mg, 5 mg to 80 mg, 5 mg to 60 mg, 5 mg to 40 mg,10 mg to 80 mg, 40 mg to 80 mg, or 50 to 100 mg of (Z)-endoxifen. In some aspects, the oral formulation includes a plurality of microparticles including between them a total of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, or 40 mg of (Z)-endoxifen. In some aspects, the oral formulation is a capsule. In some aspects, oral formulation is an enteric capsule. In some aspects, the coating includes hydroxypropylmethyl cellulose.

[0006] In some aspects, the oral formulation is formulated for addition to a beverage, a solid food, a cream, a gel, a colloid, a syrup, or a combination thereof. In some aspects, the oral formulation is formulated for suspension in liquid. In some aspects, the liquid is an aqueous solution. In some aspects, a dose of the formulation is 0.01 mL to 10 mL of the aqueous solution per kg body weight. In some aspects, the dose of the formulation is 0.01 mL, 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, or 1 mL of the aqueous solution per kg body weight. In some aspects, the oral formulation includes a dose of (Z)- endoxifen of 0.01 to 3 mg / kg of body weight. In some aspects, the oral formulation, includes a dose of (Z)-endoxifen of 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / .kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, or 3 mg / kg of body weight.

[0007] In some aspects, the aqueous solution includes a sugar, a sugar alcohol, a sweetener, a flavoring, an alcohol, glycerol, propylene glycol, or combinations thereof. In some aspects, the liquid is viscous. In some aspects, the microparticle further includes a filler. In some aspects, the filler includes talc, calcium carbonate, a sugar, a salt, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, or combinations thereof. In some aspects, the microparticle further includes a disintegrant. In some aspects, the microparticle further includes a lubricant. In some aspects, the lubricant includes calcium stearate, magnesium stearate, zinc stearate, mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil, ethyl oleate, ethyl laureate, agar, or combinations thereof. In some aspects, the microparticle further includes croscarmellose sodium.

[0008] In some aspects, the microparticle is no more than 500 pm, no more than 300 pm, no more than 200 pm, no more than 150 pm, no more than 100 pm, no more than 75 pm, no more than 50 pm, or no more than 25 pm in diameter as measured by microscopy, scanning electron microscopy, transmission electron microscopy, dynamic light scattering, laser diffraction, Coulter counter, or sedimentation. In some aspects, the coating is from 1 nm to 100 nm thick. In some aspects, the coating is from 1 nm to 10 nm, from 20 nm to 30 nm, from 30 nm to 40 nm, from 40 nm to 50 nm, from 50 nm to 60 nm, from 60 nm to 70 nm, from 70 nm to 80 nm, from 80 nm to 90 nm, or from 90 nm to 100 nm thick.

[0009] In some aspects, the (Z)-endoxifen has a half-life of between 4 to 24 hours in pH 1.2 simulated gastric fluid at 37°C. In some aspects, the (Z)-endoxifen has a half-life of between 2 to 72 hours in pH 6.7 simulated intestinal fluid at 37°. In some aspects, the (Z)-endoxifen has a half-life of between 12 to 144 hours in pH 7.0 deionized water at 25°C.

[0010] In some aspects, the coating is an enteric coating. In some aspects, the coating includes a pH-dependent polymer. In some aspects, the coating includes an acid insoluble polymer. In some aspects, the acid insoluble polymer is cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, an alginic acid salt, shellac, pectin, an acrylic acid-methylacrylic acid copolymer, or a combination thereof. In some aspects, the microparticle further includes a plasticizer, a disintegrant, a control release agent, a sustained release agent, a lubricant, or a combination thereof.

[0011] In some aspects, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of the compound of Formula (I) is (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutically acceptable salt of (Z)-endoxifen is selected from the group consisting of: arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (Embonate), pantothenate, phosphate / diphosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, Teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc. In some aspects, the pharmaceutically acceptable salt of (Z)-endoxifen is (Z)-endoxifen gluconate. In some aspects, the (Z)-endoxifen is (Z)-endoxifen free base.

[0012] In some aspects, the (Z)-endoxifen includes less than 2%, less than 1.5%, less than 1%, or less than 0.5% impurities. In some aspects, the (Z)-endoxifen is stable for at least 9 months at 25 °C and 60% relative humidity. In some aspects, the (Z)-endoxifen is stable for at least 3 months at 40 °C and 75% relative humidity. In some aspects, the (Z)-endoxifen has an aerobic bacterial plate count of 0.05 g / mL to 20,000 g / mL.

[0013] In some aspects, the (Z)-endoxifen has a water content of not more than 1.0% as tested by Method Ic of USP 921. In some aspects, the (Z)-endoxifen has a water activity (Aw) of less than 0.9. In some aspects, the (Z)-endoxifen has a residue on ignition of not more than 0.1% as tested by a method of USP 281. In some aspects, the (Z)-endoxifen includes not more than 20 ppm of heavy metals as tested by Method II of USP 231. In some aspects, the (Z)-endoxifen includes not more than 3000 ppm methanol, not more than 720 ppm tetrahydro furan, not morethan 5000 ppm isopropanol, not more than 5000 ppm ethyl acetate; not more than 5000 ppm n- Heptane, not more than 5000 ppm ethanol, or any combination thereof, as tested by a validated HPLC method. In some aspects, the (Z)-endoxifen includes not more than 3000 ppm methanol, not more than 720 ppm tetrahydrofuran, not more than 5000 ppm isopropanol, not more than 5000 ppm ethyl acetate, not more than 5000 ppm heptane, and not more than 5000 ppm ethanol, as tested by a validated HPLC method.

[0014] In some aspects, the (Z)-endoxifen: includes less than 2%, less than 1.5%, less than 1%, or less than 0.5% impurities; is stable for at least 9 months at 25 °C and 60% relative humidity; is stable for at least 3 months at 40 °C and 75% relative humidity; has an aerobic bacterial plate count of 0.05 g / mL to 20,000 g / mL; has a water content of not more than 1.0% as tested by Method Ic of USP 921; has a water activity (Aw) of less than 0.9; has a residue on ignition of not more than 0.1% as tested by a method of USP 281; includes not more than 20 ppm of heavy metals as tested by Method II of USP 231; includes not more than 3000 ppm methanol, not more than 720 ppm tetrahydrofuran, not more than 5000 ppm isopropanol, not more than 5000 ppm ethyl acetate; not more than 5000 ppm n-Heptane, not more than 5000 ppm ethanol, or any combination thereof, as tested by a validated HPLC method; or any combination thereof. In some aspects, the oral formulation is formulated as an enteric tablet, an enteric caplet, or an enteric capsule.

[0015] In some aspects, the techniques described herein relate to a method of treating a disease in a subject in need thereof, including administering the oral formulation to the subject, thereby treating the disease. In some aspects, the oral formulation is added to a beverage, a solid food, a cream, a gel, a colloid, or a syrup prior to administration. In some aspects, the oral formulation is suspended in a liquid prior to administration. In some aspects, the liquid is an aqueous solution. In some aspects, the aqueous solution includes a sugar, a sugar alcohol, a sweetener, a flavoring, an alcohol, glycerol, propylene glycol, or combinations thereof. In some aspects, the liquid is viscous.

[0016] In some aspects, the administering includes oral ingestion of the oral formulation. In some aspects, the oral formulation includes a plurality of microparticles including between them a total of from 0.01 mg to 200 mg, 5 mg to 80 mg, 5 mg to 60 mg, 5 mg to 40 mg, 10 mg to 80 mg, 40 mg to 80 mg, or 50 to 100 mg of (Z)-endoxifen. In some aspects, a dose of the oral formulation is 0.01 mL to 10 mL of the aqueous solution per kg body weight. In some aspects, the dose of the oral formulation is 0.01 mL, 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, or 1 mL of the aqueous solution per kg body weight. In some aspects, a dose of (Z)-endoxifen is 0.01 to 3 mg / kg of body weight. In some aspects, the dose of (Z)-endoxifen is 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / .kg, 0.4 mg / kg, 0.5mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, or 3 mg / kg of body weight.

[0017] In some aspects, the subject is a child.INCORPORATION BY REFERENCE

[0018] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0020] FIG. 1 is an X-ray powder diffraction (XRPD) pattern obtained from a sample of Form I of the compound of Formula (I).

[0021] FIG. 2 is an XRPD pattern obtained from a sample of Form I of the compound of Formula (I).

[0022] FIG. 3 is an XRPD pattern obtained from a sample of Form I of the compound of Formula (I).

[0023] FIG. 4 is an XRPD pattern obtained from a sample of Form II of the compound of Formula (I).

[0024] FIG. 5 is an XRPD pattern obtained from a sample of Form III of the compound of Formula (I).

[0025] FIG. 6 provides an X-ray powder diffraction (XRPD) spectrum of a polymorph of Form IV, consistent with the present disclosure.

[0026] FIG. 7 provides an XRPD spectrum of a polymorph of Form V, consistent with the present disclosure.

[0027] FIG. 8 provides an XRPD spectrum of a polymorph of Form VI, consistent with the present disclosure.

[0028] FIG. 9 provides an XRPD spectrum of a polymorph of Form VII, consistent with the present disclosure.

[0029] FIG. 10 provides an XRPD spectrum of a polymorph of Form VIII, consistent with the present disclosure.

[0030] FIG. 11 provides an XRPD spectrum of a polymorph of Form IX, consistent with the present disclosure.

[0031] FIG. 12 provides an XRPD spectrum of a polymorph of Form X, consistent with the present disclosure.

[0032] FIG. 13 provides an XRPD spectrum of a polymorph of Form XI, consistent with the present disclosure.

[0033] FIG. 14 provides an XRPD spectrum of a polymorph of Form XII, consistent with the present disclosure.

[0034] FIG. 15 provides an XRPD spectrum of a polymorph of Form XIV, consistent with the present disclosure.

[0035] FIG. 16 provides an XRPD spectrum of a polymorph of Form XV, consistent with the present disclosure.

[0036] FIG. 17 provides an XRPD spectrum of a polymorph of Form XIX, consistent with the present disclosure.DETAILED DESCRIPTION

[0037] The present disclosure provides oral formulations of (Z)-endoxifen suitable for administering to individuals for whom administering traditional oral dosage forms (e.g., standard-size caplets or tablets) are not suitable, such as in the case of certain elderly and young patients. Some neurological disorders, anatomical abnormalities, and muscular disorders also can make swallowing traditional oral dosage forms problematic. The present oral formulations are easy to administer orally and advantageously increase patient compliance, dosage certainty, and treatment effectiveness for patients not able or willing to swallow traditional oral dosage forms. The present oral liquid formulations are developed to effectively deliver (Z)-endoxifen to individuals who may struggle taking traditional oral dosage forms and include enteric and delayed-release (Z)-endoxifen particles, including, for example, microparticles. The formulations presented herein provide effective and accessible dosing of (Z)-endoxifen for individuals who would be difficult to treat in the absence of these oral liquid formulations.

[0038] The present disclosure provides therapeutic particles useful for treating cancer and amenable to multiple forms of administration. The particles can contain (Z)-endoxifen within a degradable coating and may provide targeted or sustained (Z)-endoxifen release upon administration to a subject. In some embodiments, the particles contain an enteric coating which prevents (Z)-endoxifen release in the stomach, thereby avoiding acid-mediated degradation and isomerization of the (Z)-endoxifen, and promotes (Z)-endoxifen release in the small intestinewhere it can be readily absorbed into the bloodstream. The particles can have high aqueous stabilities, enabling formulation within foods, beverages, and syrups.

[0039] Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0040] As used herein, the terms “a,” “an,” and “the” include plural reference unless the context dictates otherwise.

[0041] As used herein, the terms “active pharmaceutical ingredient”, “active ingredient”, “API,” “drug,” “active,” “actives” or “therapeutic agent” may be used interchangeably to refer to the pharmaceutically active compound(s) in a pharmaceutical composition. This is in contrast to other ingredients in the compositions, such as excipients, which are substantially or completely pharmaceutically inert. A suitable active pharmaceutical ingredient (API) in accordance with the present disclosure is one where there is or likely may be patient compliance issues for treating a certain disease, condition, or disorder. The therapeutic agent as used herein includes the active compound and its salts, prodrugs, and metabolites. As used herein the term “drug” means a compound intended for use in diagnosis, cure, mitigation, treatment, and / or prevention of disease in man or other animals.

[0042] As used herein, “adjuvant therapy” refers to a therapy that follows a primary therapy and that is administered to subjects at risk of relapsing. Adjuvant systemic therapy in case of cancer, for example with tamoxifen, treatment usually begins soon after primary therapy to delay recurrence, prolong survival or cure a subject.

[0043] As used herein, the term “tamoxifen” refers to (Z)-2-[4-(l,2-diphenyl-l- butenyl)phenoxy]-N,N-dimethylethanamine. Tamoxifen can also refer to E-isomer or a combination of E-isomer and Z-isomer.

[0044] As used herein, the term “(Z)-endoxifen” refers to (Z)-4-hydroxy-N-desmethyl- tamoxifen. It is a secondary active metabolite of tamoxifen.

[0045] As used herein and in the claims, the terms “comprising,” “containing,” and “including” are inclusive, open-ended and do not exclude additional unrecited elements, compositional components or method steps. Accordingly, the terms “comprising” and “including” encompass the more restrictive terms “consisting of’ and “consisting essentially of.”

[0046] As used herein, the term “Combination Therapy” refers to the use of an inventive composition described herein in combination with one or more of treatments. Treatment in Combination Therapy can be any treatment such as any prophylactic agent, additional therapeutic agent (example as chemotherapy and immunotherapy), radiotherapy, surgery, and the like. The combination can refer to inclusion of a therapeutic or prophylactic agent in a samecomposition as an inventive composition disclosed herein (for example, in the same capsule, tablet, caplet, etc.) or in separate compositions (for example, in 2 separate tablets). The separate compositions may be in a different dosage form or administered via different routes of administration. The use of the terms “Combination Therapy” and “in combination with” does not restrict the order in which an inventive composition described herein and prophylactic and / or therapeutic agent and / or treatment are administered to a subject in need thereof. Compositions of the present disclosure can be administered prior to (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 1 year before), concomitant with, or subsequent to (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 1 year after) administration of one or more prophylactic and / or therapeutic agents or treatment to a subject in thereof. Combination therapy as used herein can also refer to treatment of a subject having a single disease or multiple diseases or conditions, for example, various types of cancers in adults or children.

[0047] As used herein, the terms “test sample” means sample of blood obtained from a subject. It is to be understood that when blood sample is obtained from a subject, subject's blood as whole blood, plasma, and / or serum is used for determining the subject's (Z)-endoxifen levels and / or other biomarkers that may be measured or tested. As used herein “plasma (Z)-endoxifen” is used to refer to (Z)-endoxifen levels in the subject's test sample whether the test is conducted on whole blood, plasma, and / or serum unless indicated expressly otherwise.

[0048] As used herein, the term “dosage form” means the form in which the compounds or compositions of the present disclosure are delivered to a patient.

[0049] As used herein, the term “pharmaceutically acceptable” or “pharmacologically acceptable” means materials, compositions, or vehicles that are compatible with other ingredients of the formulation and that they do not substantially produce adverse reactions, e.g., toxic, allergic, or immunological reactions, when administered to a subject. They may be approved by a regulatory agency, e.g., of the U.S. Federal or state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0050] As used herein, the term “pharmaceutically acceptable carrier” or “carrier” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting one or more of the compounds of the present disclosure from one tissue, organ, or portion of the body or across the skin.

[0051] As used herein, the term “pharmaceutical composition” means a combination of the active agent (e.g., an active pharmaceutical compound or ingredient, API) with a carrier, inert or active (e.g., a phospholipid), making the compositions especially suitable for diagnostic, prophylactic, or therapeutic uses in vitro, in vivo, or ex vivo.

[0052] As used herein “primary therapy” refers to a first line of treatment upon initial diagnosis of a disease, such as a cancer, in a subject. Exemplary primary therapies may involve surgery, a wide range of chemotherapies, and radiotherapy.

[0053] 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 pet animals such as dogs, cats, laboratory animals, such as rats, mice, and farm animals such as cows and horses. Unless otherwise specified, a mammal may be of any gender or sex.

[0054] As used herein, the term “tamoxifen refractory” refers to subjects that have been dosed daily with tamoxifen for at least 2 days and have a level of plasma (Z)-endoxifen of less than 30 nM (e.g., less than 20 nM, less than 25 nM, or less than 30 nM). As used herein, the term “tamoxifen resistance” refers to two classes of resistance: (a) de novo resistance, i.e., nonresponsiveness to tamoxifen therapy from the beginning of the treatment, and (b) acquired resistance, i.e., non-responsiveness to tamoxifen therapy after initial responsiveness or tamoxifen-dependent growth / stimulated growth while continuing to express estrogen receptors (Minsun Chang. Biomol. Ther. 20(3), 256-267 (2012)). The acquired resistance to tamoxifen may develop as early as 3 m to 1 year to as late as 5 to 10 years. As used herein the term “reference plasma (Z)-endoxifen level” refers to a value of 30 nM.

[0055] As used herein, the term “Unit Dosage Form” refers to physically discrete units suitable for unitary dosages for subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0056] Terms such as “include,” “including,” “contain,” “containing,” “has,” or “having,” and the like, mean “comprising.”

[0057] Pharmacokinetic (PK) parameters used herein are defined and calculated as follows:

[0058] Cmax: Maximum observed plasma / serum concentration obtained directly from the data.

[0059] Tmax: Time to maximum observed concentration, taken directly from the data. If the maximum plasma / serum concentration occurs at more than one time point, the first is chosen.

[0060] AUCo-tiast or AUCiast: Area under the plasma / serum concentration versus time curve, calculated using the linear trapezoidal rule from time 0 to time t, where t is the time of last quantifiable concentration.

[0061] Az: Terminal elimination rate constant obtained from the slope of the line, fitted by linear least squares regression through the terminal points of the logarithmic concentration-time profdes.

[0062] AUCinf: Area under the plasma / serum concentration versus time curve from zero to infinity, calculated as (AUCo-tiast + Ctiast / Xz), where Ctiast is the last quantifiable concentration.

[0063] AUCtau: Area under the plasma / serum concentration versus time curve over the interdosing interval (tau), calculated using the linear trapezoidal rule.

[0064] t> / 2: Apparent terminal half-life, calculated as (ln(2) / Xz).

[0065] CL / F: Apparent total plasma / serum clearance of drug after oral administration, where F is the fraction of drug absorbed, calculated as (Dose / AUCinf).

[0066] CL / FSS: Apparent total plasma / serum clearance of drug after multiple oral administration, where F is the fraction of drug absorbed, calculated as (Dose / AUCtau).

[0067] Vz / F: Apparent volume of distribution during terminal phase after oral administration, calculated as (CL / F / Xz).

[0068] Cmin: Minimum observed plasma / serum concentration over the inter-dose interval obtained directly from the data.

[0069] Cavg or Caverage: Average plasma / serum concentration at steady-state calculated as (AUC tau / tau).

[0070] Al Accumulation index calculated as (AUCtau Day 39 dose / AUCinf Day 1 dose).

[0071] The portion of AUCinf determined by extrapolation, %AUCextraP, determined as 100 x (AUCinf - AUCo-tlast) / AUCinf.

[0072] The term “bioavailability,” which has the meaning defined in 21 C.F.R. §320.1(a), refers to the rate and extent to which an active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action. For example, bioavailability can be measured as the amount of active ingredient in the blood (serum or plasma) as a function of time. Pharmacokinetic parameters such as AUC, Cmax or Tmax may be used to measure and assess bioavailability.

[0073] It is specifically understood that any numerical value cited herein includes all values from the lower value to the upper value, i.e., all possible combination of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application and the endpoint of all ranges are included within the range and independently combinable. For example, if a concentration range or beneficial range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, 1% to 3%, 1.5 to 2.5%,etc., are expressly enumerated in this specification. It is also to be understood that if a concentration or dose is stated as a specific value such as 1 mg or 10 mg or as “about 1 mg” or “about 10 mg”, it is intended that it is intended to include 10% variation. As another example, a stated concentration of 20% or “about 20% is intended to include values ±10%. Yet another example, if a ratio of 1:10 to 10:1 or “about 1:10 to about 10:1” is stated, then it is intended that ratios such as 1:9 to 9:1, from 1:8 to 8:1, from 1:7 to 7:1, from 1:6 to 6:1, from 1:5 to 5:1, from 1:4 to 4:1, from 1:3 to 3:1, from 1:2 to 2:1, from 1:1 to 2:1, 0.9: 10.1 to 10.1 to 0.9, or from 2:5 to 3:5 etc. are specifically intended. There are only some examples of what is specifically intended. Unless specified otherwise, the values of the constituents or components of the compositions are expressed in weight percent of each ingredient or component in the core composition.

[0074] All compounds are understood to include all possible isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon includenC,13C and14C.

[0075] All methods described herein can be performed in a suitable order unless otherwise indicated or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as” and “the like”) is intended merely to illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as any indicating any non-claimed element as essential to practice of the invention as used herein.(Z)-Endoxifen Particles

[0076] The present disclosure relates to nanoparticle and microparticle (Z)-endoxifen formulations. In aspects, the present disclosure provides a particle containing an (Z)-endoxifen composition (e.g., powdered or micro crystalline (Z)-endoxifen, optionally including a formulary on an excipient) and a pharmaceutically acceptable coating. The particle can be formulated as a powder which can be added to food, beverages, and other administrable compositions. The coating can prevent the (Z)-endoxifen composition from degrading or isomerizing while in an administrable composition or a physiological location not intended for (Z)-endoxifen delivery. In particular, the coating may be stable in the administrable composition (e.g., in a syrup suspension or in a yogurt) and in the stomach but may release (Z)-endoxifen in the small intestine.

[0077] The particle can be amenable to oral administration. The particle can be provided in the form of a powder (e.g., a plurality of instances of the particle) which can be added to food,drinks (e.g., juice, milkshakes, or water), lozenges, gels, creams, or syrups. For example, the powder can be added to a yogurt, nut butter, or salad dressing to ease ingestion. The powder may be amenable for use in a broad range of vehicles, such that a subject can choose a new beverage or food to mix with the powder during each incidence of administration. The powder can be provided in dry form, for example as a single dose in a breakable capsule or sachet. The powder can also be preformulated within an edible medium, such as a food or drink. For example, a pharmacist may generate a syrup suspension with the powder upon prescription to a subject.

[0078] In some aspects, the plurality of microparticles includes between them a total of from about 0.01 mg to about 200 mg of (Z)-endoxifen, such as about 0.01 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, or any value contained within a range formed by any two of the preceding values.

[0079] In some aspects, a dose of the oral formulation is 0.01 mL to 10 mL of the aqueous solution per kg body weight. In some aspects, the dose of the formulation is 0.01 mL, 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, or 1 mL of the aqueous solution per kg body weight. In some aspects, a dose of (Z)-endoxifen of 0.01 to 3 mg / kg of body weight. In some aspects, the techniques described herein relate to an oral formulation, including a dose of (Z)-endoxifen of 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / .kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, or 3 mg / kg of body weight.

[0080] In some aspects, the coating is a capsule. In some aspects, the capsule is an enteric capsule. In some aspects, the enteric capsule comprises hydroxypropylmethyl cellulose. In some aspects, the oral formulation is formulated for addition to a beverage, a solid food, a cream, a gel, a colloid, a syrup, or a combination thereof. In some aspects, the oral formulation is formulated for suspension in liquid. In some aspects, the liquid is an aqueous solution.

[0081] In some aspects, a dose of the formulation is 0.01 mL to 10 mL of the aqueous solution per kg body weight. In some aspects, the dose of the formulation is 0.01 mL, 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, or 1 mL of the aqueous solution per kg body weight. In some aspects, a dose of (Z)-endoxifen of 0.01 to 3 mg / kg of body weight. In some aspects, the techniques described herein relate to an oral formulation, including a dose of (Z)-endoxifen of 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / .kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, or 3 mg / kg of body weight. In some aspects, the aqueous solution comprises a sugar, a sugar alcohol, a sweetener, a flavoring, an alcohol, glycerol, propylene glycol, or combinations thereof. In some aspects, the liquid is viscous.

[0082] The particle can be a nanoparticle or a microparticle. In many cases, the coating defines an exterior surface of the particle and an inner cavity or space which contains the (Z)-endoxifen composition. The coating can surround a single (Z)-endoxifen solid, an (Z)-endoxifen powder, an (Z)-endoxifen suspension, an (Z)-endoxifen composition, an (Z)-endoxifen solution, or a combination thereof. In some cases, the coating is a thin layer encompassing the (Z)-endoxifen composition. In some cases, the coating defines a surface of a sphere surrounding the (Z)- endoxifen composition. For example, the coating may be a capsule, a spun-on polymeric coating, a sprayed-on hard sugar coating, or combinations thereof. The (Z)-endoxifen composition can also be interspersed throughout the coating. In such cases, the coating may be formed as a continuous material with the (Z)-endoxifen composition inclusions and may be formed from a suspension of the (Z)-endoxifen composition in pre-hardened coating material.

[0083] In some cases, a microparticle may be no more than about 500 pm, no more than about 300 pm, no more than about 200 pm, no more than about 150 pm, no more than about 100 pm, no more than about 75 pm, no more than about 50 pm, or no more than about 25 pm in diameter as measured by microscopy, scanning electron microscopy, transmission electron microscopy, dynamic light scattering, laser diffraction, Coulter counter, or sedimentation. In some aspects, a coating on the nanoparticle is from 1 nm to 100 nm thick. In some aspects, the coating is from about 1 nm to 10 nm, from 20 nm to 30 nm, from 30 nm to 40 nm, from 40 nm to 50 nm, from 50 nm to 60 nm, from 60 nm to 70 nm, from 70 nm to 80 nm, from 80 nm to 90 nm, or from 90 nm to 100 nm thick. In some aspects, the coating is from 1 nm to 30 nm, from 30 nm to 60 nm, from 40 nm to 80 nm, or from 70 nm to lOOnm thick. In some aspects, a coating on the nanoparticle is from 1 pm to 100 pm thick. In some aspects, the coating is from 1 pm to 10 pm, from 20 pm to 30 pm, from 30 pm to 40 pm, from 40 pm to 50 pm, from 50 pm to 60 pm, from 60 pm to 70 pm, from 70 pm to 80 pm, from 80 pm to 90 pm, or from 90 pm to 100 pm thick.In some aspects, the coating is from 1 pm to 30 pm, from 30 pm to 60 pm, from 40 pm to 80 pm, or from 70 pm to 100 pm thick.

[0084] In some cases, a population of microparticles may be uniform in size. A uniform population of microparticles may vary in diameter by no more than about 50%, no more than about 40%, no more than about 30%, no more than about 20%, no more than about 10%, no more than about 5%, or no more than about 2%. A uniform population of microparticles may vary in volume by no more than about 50%, no more than about 40%, no more than about 30%, no more than about 20%, no more than about 10%, no more than about 5%, or no more than about 2%.

[0085] In many cases, the pharmaceutically acceptable coating is an enteric coating. The enteric coating can enable transit through the stomach without endoxifen degradation or isomerization, and release the endoxifen in the intestines, thereby increasing its potency and limiting side effects. The enteric coating can be configured to last in the stomach for at least 30 minutes, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 3 hours, or at least 4 hours without dissolving or degrading. The enteric coating can then release the endoxifen in the small intestines with a half-life of about 3 hours to 100 hours, about 3 hours to 15 hours, about 5 hours to 20 hours, about 10 hours to 30 hours, or about 20 to 100 hours.

[0086] The coating can be any pharmaceutically acceptable coating disclosed herein. In some cases, the coating comprises glyceryl monostearate, glyceryl distearate, polymethacrylate, hypromellose (HPMC), polyacrylate, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate -methacrylic acid copolymers, shellac, cellulose acetate trimellitate, sodium alginate, synthetic waxes, microcrystalline waxes, paraffin wax, carnauba wax, beeswax, polyethoxylated castor oil derivatives, hydrogenated oils, glyceryl mono-, di-tribenates, glyceryl monostearate, glyceryl distearate, such as stearyl alcohol, cetyl alcohol, polyethylene glycol, copolymers thereof, and mixtures thereof.

[0087] The particle may be nanometer, micron, or millimeter dimensioned. In some cases, the particle has a largest dimension of between about 10 nm and 2 mm (correspondingly, a plurality of instances of the particle can have a mean or median largest dimension of between about 10 nm and 2 mm). In some cases, the particle has a largest dimension of between about 10 and 100 nm, between about 25 and 250 nm, between about 50 and 500 nm, between about 100 and 500 nm, between about 200 nm and 1 pm, between about 1 and 25 pm, between about 10 and 100 pm, between about 25 and 250 pm, between about 50 and 500 pm, between about 100 and 500 pm, between about 200 pm and 1 mm, or between about 400 pm and 2 mm. In some cases, theparticle is substantially spherical. In some cases, the particle has an oblong or irregular structure. In some cases, the particle is a nanoparticle. In some cases, the particle is a microparticle.

[0088] In some aspects, the (Z)-endoxifen has a half-life of between 4 to 24 hours in pH 1.2 simulated gastric fluid at 37°C. In some aspects, the (Z)-endoxifen has a half-life of between 2 to 72 hours in pH 6.7 simulated intestinal fluid at 37°. In some aspects, the (Z)-endoxifen has a half-life of between 12 to 144 hours in pH 7.0 deionized water at 25°C.

[0089] A plurality of instances of the particle (e.g., a powder comprising the particle) can be uniform or heterogeneous. For example, a plurality of instances of the particle can be characterized by a polydispersity index (PDI) of less than about 5, less than about 4.5, less than about 4, less than about 3.5, less than about 3, less than about 2.5, less than about 2, less than about 1.5, less than about 1, less than about 0.75, less than about 0.5, less than about 0.25, or less than about 0.1. In some cases, a plurality of instances of the particle can be characterized by a polydispersity index of at least about 0.1, at least about 0.25, at least about 0.5, at least about 0.75, at least about 1, at least about 1.5, at least about 2, at least about 2.5, at least about 3, at least about 3.5, at least about 4, at least about 4.5, or at least about 5.

[0090] In some cases, the pharmaceutically acceptable coating is about 5% to 95% of the weight of the particle. In some cases, the pharmaceutically acceptable coating is about 5% to 25%, about 10% to 30%, about 20% to 50%, about 30% to 60%, about 40% to 80%, about 50% to 90%, or about 60% to 95% of the weight of the particle.

[0091] In some cases, the particle includes a plasticizer. A plasticizer may control the softness or pliability of the particle and may improve its mechanical properties for administration and enteric delivery. Suitable plasticizers, include, without limitation, petroleum oils (for e.g., a paraffinic process oil, a naphthenic process oil, and an aromatic process oil), squalene, squalane, plant oils, (e.g., olive oil, camelia oil, castor oil, tall oil, and a peanut oil), silicon oils, dibasic acid esters, (e.g., dibutyl phthalate, and dioctyl phthalate), liquid rubbers (e.g., polybutene and a liquid isoprene rubber), liquid fatty acid esters (e.g., isopropyl mynstate ISM), hexyl laurate, diethyl sebacate, and diisopropyl sebacate, triethyl citrate, triacetin, diethylene glycol, polyethylene glycols, polypropylene glycol, phthalates, sorbitol, glycol salicylate, crotaminton, and glycerin or mixtures thereof. The amount of plasticizer may vary depending upon the chemical composition of the pharmaceutical preparation. In one embodiment, the coating contains sorbitol, dimethyl isosorbide, or a glycerol. In another embodiment, the plasticizer is 1% to 10%, such as 3% to 5% (wt / wt), of the coating. In another embodiment, the plasticizer is 1% to 10%, such as 3% to 5% (wt / wt), of the particle.

[0092] The particle can include a disintegrant. Disintegrants can enhance particle disintegration upon exposure to an aqueous environment. Particles that contain too much disintegrant maydisintegrate in storage or upon formulation in an aqueous medium, such as a syrup, while those that contain too disintegrant little may not disintegrate at a desired rate or under the desired conditions (e.g., disintegrate enterically). Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used in a particle formulation. In some embodiments, the disintegrant is buried within a particle to delay disintegration. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art.

[0093] A particle can contain between 0.5% to 15% (wt / wt) of the disintegrant. In some cases, the particle contains between 1% and 5% (wt / wt) of the disintegrant. In another embodiment, the particle contains between 1% to 25%, 2% to 20%, 5% to 15%, 8% to 12%, or about 10% (wt / wt) of the disintegrant. Disintegrants that can be used in the particles provided herein include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0094] The particle can include a control release agent. Examples of control release agent suitable for use include, without limitation, pH-dependent polymers, acid-insoluble polymers, methyl aery late-methacry lie acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose 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 waxes, paraffin wax, carnauba wax, and beeswax; polyethoxylated castor oil derivatives, hydrogenated oils, glyceryl mono-, di- tribenates, glyceryl monostearate, glyceryl distearate, long chain alcohols, such as stearyl alcohol, cetyl alcohol, and polyethylene glycol; and mixtures thereof. In some embodiments, a time delay material such as glyceryl monostearate or glyceryl distearate may be used. In other embodiments, the controlled release reagent is a digestible waxy substance such as hard paraffin wax.

[0095] The particle can contain a pH-dependent polymer, such as an acid insoluble polymer. The pH-dependent polymer can become increasingly permeable above pH 5.0 and impermeable at pH below 5.0. Alternatively, the pH-dependent polymer can become increasingly permeable below pH 5.0 and increasingly permeable at pH above 5.0. pH-dependent polymers can configure the particle to release (Z)-endoxifen in the colon and upper small intestines. The pH- dependent polymer may prevent (Z)-endoxifen release in the high pH environment of the stomach and become permeable in the higher pH environment of the small intestines, therebyensuring (Z)-endoxifen release following transit through the stomach. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, alginic acid salts such as sodium or potassium alginate, shellac, pectin, acrylic acid- methylacrylic acid copolymers (commercially available under the tradename EUDRAGIT® L and EUDRAGIT® S from Rohm America Inc., Piscataway, NJ as a powder or a 30% aqueous dispersion; or under the tradename EASTACRYL®, from Eastman Chemical Co., Kingsport, TN, as a 30% dispersion). Additional examples include EUDRAGIT® LI 00-55, EUDRAGIT® L30D-55, EUDRAGIT® L100, EUDRAGIT® L100 12,5, EUDRAGIT® S 100, EUDRAGIT® S12, 5, EUDRAGIT® FS 30D, EUDRAGIT® El 00, EUDRAGIT® E 12,5, and EUDRAGIT® PO. In at least one embodiment, the composition comprises EUDRAGIT® LI 00-55.

[0096] EUDRAGIT® RS and RL and EUDRAGIT®NE and NM polymers may also be included in a particle of the present disclosure. In some embodiments, the particle comprises EUDRAGIT® L30D 55. In another embodiment, the particle comprises EUDRAGIT® FS 30D. One of skill in the art will recognize that at least some acid insoluble polymers listed herein will also be biodegradable.

[0097] In some cases, the particle contains at least one sustained release agent. Non-limiting examples of sustained release agents compatible with particles of the present disclosure include Hypromellose (HPMC), acrylic resins, methacrylic resins, polyvinyl pyrrolidine, hydroxyalkyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl celluloses, carboxyalkyl cellulose, and carboxymethyl cellulose. The sustained release agent may be present in from about 0.1% to about 99%, from about 0.1% to about 90%, from about 5% to about 90%, from about 5% to about 80%, from about 5% to about 70%, and from about 5% to about 60% w / w of the particle. In some embodiments, the sustained release agent is present in an amount of from about 10% to about 40%, from about 10% to about 50%, from about 10% to about 60%, from about 20% to about 40%, from about 20% to about 50%, from about 20% to about 60%. In some embodiments, the sustained release agent is present in an amount of at least about 10%, at least about 20%, at least about 30%, or at least about 40% (w / w).

[0098] In some cases, the particle contains a lubricant. Exemplary lubricants include, but are not limited to, stearic acid, calcium stearate, magnesium stearate, zinc stearate, potassium stearate, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycols, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, talc, ethyl oleate, ethyl laureate, agar, waxes, and combinations thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), Q7-9120 (Dow Corning), and combinations thereof. In some embodiments, the lubricant is magnesium stearate. The lubricant can reduce the friction between the (Z)-endoxifen, coating, and optionally other ingredients (e.g., filler in the (Z)-endoxifen composition) during particle formation. The particle can include at least one lubricant in an amount ranging from about 0.01% to about 5%, from about 0.2% to about 2%, or from about 0.5% to about 1.5% on a w / w basis relative to the weight of the sustained release composition. In certain embodiments, the particle includes magnesium stearate in an amount ranging from about 0.01% to about 5%, from about 0.2% to about 2%, or from about 0.5% to about 1.5% on a w / w basis.

[0099] The particle can exhibit a sustained release profile. In some cases, the particle releases (Z)-endoxifen or polymorphs or salts thereof in a sustained manner for at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 24 hours, at least 48 hours, and at least 72 hours. In some embodiments, the therapeutic agent in the sustained release composition is released over a period of from 6 hours to 48 hours. In some embodiments, the (Z)-endoxifen is released over a period of from 2 hours to 72 hours as tested by USP II method and using pH 1.2 at 37°C for 2 hours in simulated gastric fluid and pH 6.8 at 37°C for 24 hours in simulated intestinal fluid. In some embodiments, the particle has a half-life of between about 4 and 24 hours, between about 6 and 48 hours, between about 2 and 12 hours, between about 16 and 72 hours, or between about 48 and 280 hours in pH 1.2 simulated gastric fluid at 37°C. In some embodiments, the particle has a half-life of between about 2 and 72 hours, between about 6 and 48 hours, between about 2 and 12 hours, between about 16 and 72 hours, or between about 48 and 280 hours in pH 6.7 simulated intestinal fluid at 37°C.

[0100] In some cases, (Z)-endoxifen is about 5% to 95% of the weight of the particle. In some cases, the (Z)-endoxifen is about 5% to 25%, about 10% to 30%, about 20% to 50%, about 30% to 60%, about 40% to 80%, about 50% to 90%, or about 60% to 95% of the weight of the particle. In some cases, the (Z)-endoxifen is a powder. In some cases, the (Z)-endoxifen is microcrystalline. In some cases, the (Z)-endoxifen is nanocrystalline.

[0101] In some cases, the (Z)-endoxifen is isomerically pure. In some cases, the (Z)-endoxifen is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% (Z)- endoxifen.

[0102] The (Z)-endoxifen composition can include a filler. The filler may stabilize the (Z)- endoxifen, prevent cross-reaction of the (Z)-endoxifen with the coating or another constituent of the (Z)-endoxifen composition, act as a pharmaceutical excipient, or affect its release profile. Non-limiting examples of fillers include talc, calcium carbonate, a sugar, a salt, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and combinations thereof.

[0103] The pharmaceutically acceptable coating can have a high aqueous stability, enabling formulation of the particle within an aqueous medium. In some cases, the particle is dispersed within an aqueous medium, such as a beverage or a syrup, a gel such as gelatin, a colloid such as a fruit preserve or nut butter, or a cream such as cake icing. The particle can have an aqueous half-life of between about 5 and 25 hours, between about 10 and 50 hours, between about 20 and 100 hours, or between about 50 and 250 hours. The particle can have a substantially enhanced half-life in room-temperature water relative to human body temperature water. For example, the particle can have a half-life of between about 50 and 250 hours in 25°C simulated intestinal fluid, and a half-life of between about 10 and 50 hours in 37°C simulated intestinal fluid. In some cases, the particle is configured to release less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 12%, less than about 10%, less than about 8%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1% of the (Z)-endoxifen following 1 month of storage in pH 7 water at 25 °C. In some cases, the particle is configured to release at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 8%, at least about 10%, at least about 12%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, or at least about 50% of the (Z)-endoxifen following 1 day of storage in pH 7 water at 37°C.Sustained Release

[0104] The particle can be configured for controlled and sustained release. The particle can release (Z)-endoxifen over a span of hours, days, weeks, or months. The particle can be designed to release (Z)-endoxifen following administration. In many cases, the particle provides prolonged release in the intestines after the passage of the compositions from the stomach to allow for uptake of the therapeutic agent ((Z)-endoxifen or a polymorph or a salt thereof) from the intestines and / or colon into the blood stream of a subject. The rate of release of (Z)- endoxifen, or a polymorph or a salt thereof, from the particle can be slower than that observed for the reference product (the Capsule) which has been described in W02019051416A1. Theparticles can provide a controlled and prolonged exposure of the subject to the (Z)-endoxifen over a time period from at least about 2 hours to about 270 hours following administration. Sustained (Z)-endoxifen release can reduce the frequency of dosing and / or the rate of uptake of the (Z)-endoxifen agent into blood stream, which can improve tolerance to the (Z)-endoxifen by the patient. Intermittent dosing facilitated by the sustained release particles can also increase patient convenience and compliance by decreasing self-administration requirements. The slow and prolonged (or sustained) release can lower peak systemic levels of the (Z)-endoxifen, which may reduce local and / or systemic side effects, toxicity, and (Z)-endoxifen accumulation as compared with other dosage forms such as the reference product.

[0105] A sustained release agent present in a particle of the present disclosure may be any sustained release agent known in the art to slow the release of a hydrophobic drug such as (Z)- endoxifen or a polymorph or a salt thereof. In some cases, the sustained release agent constitutes at least about 25%, at least about 50%, at least about 75%, at least about 90%, or at least about 95% of the coating by weight. In some cases, the sustained release agent constitutes at least about 25%, at least about 50%, at least about 75%, at least about 90%, or at least about 95% of the particle by weight.

[0106] Examples of sustained release agents include cellulosic ethers, gums, acrylic resins such as polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, methyl methylacrylate, and combinations thereof, polyvinyl pyrrolidine, and protein-derived compounds. Examples of cellulosic ethers include hydroxyalkyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropylmethyl celluloses (HPMC or hypromellose, for example Nos. 2208, 2906, 2910), carboxyalkyl celluloses, and carboxymethyl celluloses. In some embodiments, the at least one sustained release agent is a pH sustained release agent such as acid insoluble polymers which become increasingly soluble and permeable above pH 5.0 but remaining impermeable below pH 5.0. Such controlled release polymers target upper small intestines and / or colon. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, alginic acid salts such as sodium or potassium alginate, shellac, pectin, acrylic acid-methylacrylic acid copolymers, including those available commercially from Evonik or Rohm ((EUDRAGIT® sustained release polymers EUDRAGIT® RL (high permeability), EUDRAGIT® RS (low permeability) and EUDRAGIT® NM 30D (low permeability)) - alone or in any combination thereof to achieve the desired permeability for sustained release. The viscosity of sustained release agents may be any viscosity suitable for sustained release of (Z)-endoxifen or a polymorph or a salt thereof. In certain embodiments, the viscosity of the at least sustained release agent ranges from about 1000 mPa.s to about 150,000 mPa.s. In some embodiments, thesustained release delivery system includes one or more SR / release rate controlling agents with viscosity ranging from about 1000 mPa.s to about 10,000 mPa.s, from about 10,000 mPa.s to about 70,000 mPa.s, from about 70,000 mPa.s to about 150,000 mPa.s. or a combination thereof. In some embodiments, the present disclosure provides that the sustained release delivery system includes two or more sustained release agents. Each sustained release agent may have the same viscosity or a differing viscosity, for example one sustained release agent may have a viscosity ranging from about 1000 mPa.s to about 10,000 mPa.s, while other sustained release agent may have a viscosity of about 10,000 mPa.s to about 70,000 mPa.s or about 70,000 mPa.s to about 150,000 mPa.s.

[0107] In some embodiments, the sustained release agent is HPMC / hypromellose (e.g., Nos. 2208, 2906, 2910). Hypromellose to be used in the present disclosure has a weight molecular average of about 20,000-500,000. In some embodiments, hypromellose has a molecular weight average of generally 20,000 - 250,000. Hypromellose is commercially available from Dow Chemicals under the trade name METHOCELL™, for example, METHOCELL™ KI 00 (average molecular weight 26,000, 2% viscosity; 75,000 - 140,000 mPa.s); METHOCELL™ K15M (average molecular weight 120,000, 2% viscosity; 15,000 cP, 13275 - 24,780 mPa.s); METHOCELL™ K4M (average molecular weight 86,000, 2% viscosity; 4,000 cP, 75,000 - 140,000 mPa.s). Hypromellose of one grade may be used alone or in combination with another grade.

[0108] A sustained release agent, such as Hypromellose, can have an average molecular weight generally ranging from 15,000 to 140,000 Daltons. In at least one embodiment, the average molecular weight of about 15,000 Daltons.

[0109] The amount of sustained release agent in the particle may be any amount effective to delay the release of the therapeutic agent (Z)-endoxifen, or a polymorph or a salt thereof, for about 2 hours post-dose to protect the therapeutic agent from the acidic environment of the stomach and allow passage of the therapeutic agent through the stomach into the intestines and prolong such release for a period of about 2 hours to about 72 hours. The amount of sustained release agent in the particle may be any amount effective to provide a slower rate of release of the therapeutic agent (Z)-endoxifen, or a polymorph or a salt thereof as compared with the reference product. In some embodiments, the amount of sustained release agent in the composition may be any amount effective to delay the release of the therapeutic agent (Z)- endoxifen, or a polymorph or a salt thereof, for at least about 1 hour, at least about 1.1 hours, at least about 1.2 hours, at least about 1.3 hours, at least about 1.4 hours, at least about 1.5 hours, at least about 1.6 hours, at least about 1.7 hours, at least about 1.8 hours, at least about 1.9 hours, at least about 2 hours, at least about 2.1 hours, at least about 2.2 hours, at least about 2.3 hours, atleast about 2.4 hours, or at least about 2.5 hours post-dose, as compared with the reference product.

[0110] A particle may exhibit a sustained release profile. For example, the particle can have a dissolution ranging from about 0% to 35% at 3 hours, from about 35% to about 55% at 12 hours, and from about 65% to 85% at 24 hours in a dissolution test according to the 75 RPM USP paddle method and using pH 1.2 at 37°C for 2 hours in simulated gastric fluid and pH 6.8 at 37°C for 24 hours in simulated intestinal fluid as a test medium.(Z)-Endoxifen

[0111] Unless specifically referred to by the prefix (Z), (E) or (E / Z), endoxifen used generally without a prefix is used herein to include to any or all endoxifen isoforms. A mixture of (E)- endoxifen and (Z)-endoxifen, can be represented by Formula (I):Formula (I).

[0112] In an aspect, the present disclosure provides that the sustained release compositions of the present disclosure specifically include, in some embodiments, polymorphic crystalline forms of endoxifen, such as Form I, Form II, or Form III, as described in Applicant’s patent publication W02019051416 (Al) (incorporated herein by reference).

[0113] In some cases, Formula (I) is primarily the (Z)-isomer. In some cases, Formula (I) is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% (Z)- endoxifen.

[0114] Examples of salts of (Z)-endoxifen suitable for the particles of the present disclosure include pharmacologically acceptable salts such as salts with inorganic acids, salts with organic acids, salts with amino acids and the like. Examples of (Z)-endoxifen salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. In some embodiments, the present disclosure provides (Z)-endoxifen salts with inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

[0115] Examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.

[0116] Examples of the salts with acidic amino acids include salts with aspartic acid, glutamic acid, citric acid, and the like. In some embodiments, the present disclosure provides (Z)- endoxifen salts with aspartic acid, citric acid, or glutamic acid.

[0117] Examples of anion salts of (Z)-endoxifen include arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (Embonate), pantothenate, phosphate / diphosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, Teoclate, and triethiodide.

[0118] Examples of cation salts of (Z)-endoxifen selected from the group consisting of benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc, and the like.

[0119] In some embodiments, the present disclosure provides that embodiments include salts made with acids that are not pharmaceutically acceptable.

[0120] The present disclosure provides that in some embodiments the sustained release compositions comprises salts of (Z)-endoxifen selected from the group consisting of acetate, arecoline, benzathine, benzoic, besylate, benzosulfonate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, formate, fumarate, glucolate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, maleate, mandelate, meglumine, mesylate, methylbromide, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate, napsylate, nitric, nitrate, oxalate, pamaoate (Embonate), pantothenate, perchloric, phosphate, diphosphate, piperazine, procaine, polygalacuronate, p-toluenesulfonate, salicylate, stearate, succinate, sulfate, sulfonate, sulfuric, tannate, tartarate, teoclate, triethiodide, trifluoroacetate, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc, or any combination thereof.

[0121] In some aspects, the pharmaceutically acceptable salt of (Z)-endoxifen is selected from the group consisting of: arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (Embonate), pantothenate, phosphate / diphosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, Teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine,diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc. In some aspects, the pharmaceutically acceptable salt of (Z)-endoxifen is (Z)-endoxifen gluconate.In some aspects, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of the compound of Formula (I) is (Z)-endoxifen or a pharmaceutically acceptable salt thereof.

[0122] In some aspects, the (Z)-endoxifen is (Z)-endoxifen free base. In some aspects, the (Z)- endoxifen includes less than 2%, less than 1.5%, less than 1%, or less than 0.5% impurities. In some aspects, the (Z)-endoxifen is stable for at least 9 months at 25 °C and 60% relative humidity. In some aspects, the (Z)-endoxifen is stable for at least 3 months at 40 °C and 75% relative humidity. In some aspects, the (Z)-endoxifen has an aerobic bacterial plate count of 0.05 g / mL to 20,000 g / mL. In some aspects, the (Z)-endoxifen has a water content of not more than 1.0% as tested by Method Ic of USP 921. In some aspects, the (Z)-endoxifen has a water activity (Aw) of less than 0.9. In some aspects, the (Z)-endoxifen has a residue on ignition of not more than 0.1% as tested by a method of USP 281.

[0123] In some aspects, the (Z)-endoxifen includes not more than 20 ppm of heavy metals as tested by Method II of USP 231. In some aspects, the (Z)-endoxifen includes not more than 3000 ppm methanol, not more than 720 ppm tetrahydrofuran, not more than 5000 ppm isopropanol, not more than 5000 ppm ethyl acetate; not more than 5000 ppm n-Heptane, not more than 5000 ppm ethanol, or any combination thereof, as tested by a validated HPLC method. In some aspects, the (Z)-endoxifen includes not more than 3000 ppm methanol, not more than 720 ppm tetrahydrofuran, not more than 5000 ppm isopropanol, not more than 5000 ppm ethyl acetate, not more than 5000 ppm heptane, and not more than 5000 ppm ethanol, as tested by a validated HPLC method.

[0124] In some aspects, the (Z)-endoxifen: includes less than 2%, less than 1.5%, less than 1%, or less than 0.5% impurities; is stable for at least 9 months at 25 °C and 60% relative humidity; is stable for at least 3 months at 40 °C and 75% relative humidity; has an aerobic bacterial plate count of 0.05 g / mL to 20,000 g / mL; has a water content of not more than 1.0% as tested by Method Ic of USP 921; has a water activity (Aw) of less than 0.9; has a residue on ignition of not more than 0.1% as tested by a method of USP 281; includes not more than 20 ppm of heavy metals as tested by Method II of USP 231; includes not more than 3000 ppm methanol, not more than 720 ppm tetrahydrofuran, not more than 5000 ppm isopropanol, not more than 5000 ppm ethyl acetate; not more than 5000 ppm n-Heptane, not more than 5000 ppm ethanol, or any combination thereof, as tested by a validated HPLC method; or any combination thereof.

[0125] In some aspects, the oral formulation is formulated as an enteric tablet, an enteric caplet, or an enteric capsule.

[0126] In certain embodiments, the (Z)-endoxifen is at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1%, at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.99%, and 100% in free base form (e.g., w / w of total (Z)-endoxifen in the particle).

[0127] In some embodiments, the particle further comprises (E)-endoxifen. In some embodiments, the particle has a ratio of (E)-endoxifen to (Z)-endoxifen (E / Z-ratio) of about 1:999, about 5:995, about 1:99; about 5:95; about 10:90, about 15:85; about 20:80, about 25:75; about 30:70; about 40:70, about 45:55; about 50:50; about 55:45; about 60:40; about 65:45; or about 70:30. In other embodiments, sustained release compositions comprise (Z)-endoxifen having E / Z-ratio ranging from about 10:90 to about 70:30. In further embodiments, sustained release compositions comprise (Z)-endoxifen having E / Z-ratio ranging from about 0.1:99.9 to 10:90, about 0.5:99.5 to 5:95, or about 1:99 to 10:90. In still other embodiments, sustained release compositions comprise (Z)-endoxifen having E / Z-ratio ranging from about 45:55 to about 55:45.Polymorphs

[0128] In certain aspects, the present disclosure provides crystalline forms of (Z)-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 (Z)-endoxifen comprising the crystalline forms described herein. A crystalline form of (Z)-endoxifen may provide the advantage of bioavailability and stability, suitable for use as an active ingredient in a pharmaceutical composition. 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 a pharmaceutical drug product 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 such as noncrystalline or amorphous forms, crystalline forms may provide desired or suitable hygroscopicity, particle size controls, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control. Thus, crystalline forms of (Z)- endoxifen may provide advantages such as: improving the manufacturing process of an activeagent or the stability or storability of a drug product form of the compound or an active ingredient, and / or having suitable bioavailability and / or stability as an active agent.

[0129] The terms “crystalline form”, “polymorph” and “Form” may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. Compound of the present disclosure include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0130] The use of certain solvents and fractional crystallization methods has been found to produce different polymorphic forms of (Z)-endoxifen, including any one or more of polymorphic Forms I-XII, XIV, XV, and XIX, which may exhibit one or more favorable characteristics described above. In some embodiments, a polymorphic form may affect one or more properties of a composition comprising (Z)-endoxifen. For example, a polymorphic form of a therapeutic agent (e.g., (Z)-endoxifen) may affect one or more of the dissolution rate, the solubility, the absorption rate, the Cmax, the AUC, the Tmax, or the ti / 2, of the therapeutic agent in a composition of the present disclosure. In some embodiments, the polymorphic form of (Z)- endoxifen may confer one or more properties that favorably contribute to manufacturability of a composition of the present disclosure (e.g., a particle comprising (Z)-endoxifen). In some embodiments, the polymorphic form of (Z)-endoxifen may confer improved stability to a composition of the present disclosure.

[0131] The (Z)-endoxifen can be amorphous, polycrystalline, or monocrystalline. In some cases, the (Z)-endoxifen is of a single crystalline form. In some cases, the (Z)-endoxifen is Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XIX, or a combination thereof. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XIX, or the combination thereof. In some cases, the (Z)-endoxifen is Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, or Form XIX. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%,at least about 98%, or at least about 99% of the (Z)-endoxifen is Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, or Form XIX. In some cases, the (Z)-endoxifen is Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XIX, or a combination thereof. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XIX, or a combination thereof. In some cases, the (Z)-endoxifen is Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XIX. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, or Form XIX. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form I. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form II. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form III. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form IV. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)- endoxifen is Form V. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form VI. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form VII. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form VIII. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at leastabout 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form IX. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form X. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form XI. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)- endoxifen is Form XII. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form XIII. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form XIV. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form XV. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form XIX. The processes for the preparation of the polymorphs described herein, and characterization of these polymorphs are described in greater detail below.Formula (I), Form I

[0132] In certain aspects, the present disclosure provides polymorphic Form I of a compound of Formula (I), wherein at least 90% by weight of the compound of Formula (I) in the composition is the (Z)-isomer (i.e., (Z)-endoxifen). In some embodiments, polymorphic Form I exhibits an x- ray powder diffraction (XRPD) pattern substantially as shown in FIG. 1, FIG. 2, or FIG. 3. In some embodiments, polymorphic Form I has an XRPD pattern comprising at least two, at least three, at least four, at least five, or at least six of the major peaks as the XRPD pattern substantially as shown in FIG. 1, FIG. 2, or FIG. 3.

[0133] The term “substantially as shown in” when referring, for example, to an XRPD pattern, includes a pattern that is not necessarily identical to those depicted herein, but that falls within the limits of experimental error or deviations when considered by one of ordinary skill in the art. The relative intensities of XRPD peaks can vary, depending upon the particle size, the sample preparation technique, the sample mounting procedure and the particular instrument employed. Moreover, instrument variation and other factors can affect the two theta (20) values.Accordingly, when a specified two theta angle is provided, it is to be understood that the specified two theta angle can vary by the specified value ± 0.5°, such as ± 0.4°, ± 0.3°, ± 0.2°, or ± 0.1°. As used herein, “major peak” refers to an XRPD peak with a relative intensity greater than 30%, such as greater than 35%. Relative intensity is calculated as a ratio of the peak intensity of the peak of interest versus the peak intensity of the largest peak in the XRPD pattern.

[0134] In certain embodiments, polymorphic Form I is characterized by an x-ray powder diffraction pattern comprising major peaks at 16.8 ± 0.3°, 17.1 ± 0.3° and 21.8 ± 0.3° two theta. In some embodiments, polymorphic Form I is characterized by an x-ray powder diffraction pattern comprising peaks at 16.0 ± 0.3°, 18.8 ± 0.3° and 26.5 ± 0.3° two theta. In some embodiments, polymorphic Form I is characterized by an x-ray powder diffraction pattern comprising major peaks at 16.8 ± 0.3°, 17.1 ± 0.3° and 21.8 ± 0.3° two theta, and at least one peak selected from 16.0 ± 0.3°, 18.8 ± 0.3° and 26.5 ± 0.3° two theta. In some embodiments, polymorphic Form I is characterized by an x-ray powder diffraction pattern comprising peaks at 12.3 ± 0.3°, 28.0 ± 0.3° and 29.0 ± 0.3° two theta. In some embodiments, polymorphic Form I is characterized by an x-ray powder diffraction pattern comprising major peaks at 16.8 ± 0.3°, 17.1 ± 0.3° and 21.8 ± 0.3° two theta, and at least one peak selected from 12.3 ± 0.3°, 28.0 ± 0.3° and 29.0 ± 0.3° two theta. In some embodiments, polymorphic Form I is characterized by an x-ray powder diffraction pattern comprising major peaks at 16.8 ± 0.3°, 17.1 ± 0.3° and 21.8 ± 0.3° two theta, and at least one peak selected from 12.3 ± 0.3°, 16.0 ± 0.3°, 18.8 ± 0.3°, 26.5 ± 0.3°, 28.0 ± 0.3° and 29.0 ± 0.3° two theta. In some embodiments, polymorphic Form I is characterized by an x-ray powder diffraction pattern comprising major peaks at 16.8 ± 0.3°, 17.1 ± 0.3° and 21.8 ± 0.3° two theta, and peaks at 12.3 ± 0.3°, 16.0 ± 0.3°, 18.8 ± 0.3°, 26.5 ± 0.3°, 28.0 ± 0.3° and 29.0 ± 0.3° two theta.

[0135] In certain embodiments, the present disclosure provides a composition comprising polymorphic Form I. Greater than 90%, 95% or 99% by weight of the compound of Formula (I) in the composition may be polymorphic Form I. In some embodiments, the composition comprises 0.01 mg to 200 mg of polymorphic Form I. In some embodiments, the composition comprises about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg or 20 mg of polymorphic Form I.Formula (I), Form II

[0136] In certain aspects, the present disclosure provides polymorphic Form II of a compound of Formula (I), wherein the composition comprises the (E)-isomer and the (Z)-isomer of the compound of Formula (I) (i.e., (E)-endoxifen and (Z)-endoxifen) in an E / Z ratio between 0.9 and 1.3, such as about 1.1. In some embodiments, polymorphic Form II exhibits an x-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 4. In some embodiments, polymorphic Form II has an XRPD pattern comprising at least two, at least three, at least four, at least five, or at least six of the major peaks as the XRPD pattern substantially as shown in FIG. 4.

[0137] In certain embodiments, polymorphic Form II is characterized by an x-ray powder diffraction pattern comprising major peaks at 7.0 ± 0.3°, 11.9 ± 0.3°, 14.0 ± 0.3° and 18.4 ± 0.3° two theta. In some embodiments, polymorphic Form II is characterized by an x-ray powder diffraction pattern comprising a peak at 22.0 ± 0.3° two theta. In some embodiments, polymorphic Form II is characterized by an x-ray powder diffraction pattern comprising major peaks at 7.0 ± 0.3°, 11.9 ± 0.3°, 14.0 ± 0.3° and 18.4 ± 0.3° two theta and a peak at 22.0 ± 0.3° two theta. In some embodiments, polymorphic Form II is characterized by an x-ray powder diffraction pattern comprising at least one peak selected from 6.6 ± 0.3°, 13.3 ± 0.3° and 20.0 ± 0.3° two theta. In some embodiments, polymorphic Form II is characterized by an x-ray powder diffraction pattern comprising major peaks at 7.0 ± 0.3°, 11.9 ± 0.3°, 14.0 ± 0.3° and 18.4 ± 0.3° two theta, and at least one peak selected from 6.6 ± 0.3°, 13.3 ± 0.3° and 20.0 ± 0.3° two theta. In some embodiments, polymorphic Form II is characterized by an x-ray powder diffraction pattern comprising major peaks at 7.0 ± 0.3°, 11.9 ± 0.3°, 14.0 ± 0.3° and 18.4 ± 0.3° two theta, and at least one peak selected from 6.6 ± 0.3°, 13.3 ± 0.3°, 20.0 ± 0.3° and 22.0 ± 0.3° two theta. In some embodiments, polymorphic Form II is characterized by an x-ray powder diffraction pattern comprising major peaks at 7.0 ± 0.3°, 11.9 ± 0.3°, 14.0 ± 0.3° and 18.4 ± 0.3° two theta, and peaks at 6.6 ± 0.3°, 13.3 ± 0.3°, 20.0 ± 0.3° and 22.0 ± 0.3° two theta.

[0138] In certain embodiments, the present disclosure provides a composition comprising polymorphic Form II. Greater than 90%, 95% or 99% by weight of the compound of Formula (I) in the composition may be polymorphic Form II. In some embodiments, the composition comprises 0.01 mg to 200 mg of polymorphic Form II. In some embodiments, the composition comprises about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg or 20 mg of polymorphic Form II.Formula (I), Form HI

[0139] In certain aspects, the present disclosure provides polymorphic Form III of a compound of Formula (I), wherein the composition comprises the (E)-isomer and the (Z)-isomer of the compound of Formula (I) (i.e., (E)-endoxifen and (Z)-endoxifen) in an E / Z ratio between 0.9 and 1.3, such as about 1.1. In some embodiments, polymorphic Form III exhibits an x-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 5. In some embodiments, polymorphic Form III has an XRPD pattern comprising at least two, at least three, at least four, at least five, or at least six of the major peaks as the XRPD pattern substantially as shown in FIG. 5.

[0140] In certain embodiments, polymorphic Form III is characterized by an x-ray powder diffraction pattern comprising major peaks at 11.9 ± 0.3°, 13.9 ± 0.3°, 17.1 ± 0.3° and 17.7 ± 0.3° two theta. In some embodiments, polymorphic Form III is characterized by an x-ray powder diffraction pattern comprising a peak at 25.3 ± 0.3° two theta. In some embodiments, polymorphic Form III is characterized by an x-ray powder diffraction pattern comprising major peaks at 11.9 ± 0.3°, 13.9 ± 0.3°, 17.1 ± 0.3° and 17.7 ± 0.3° two theta and a peak at 25.3 ± 0.3° two theta. In some embodiments, polymorphic Form III is characterized by an x-ray powder diffraction pattern comprising at least one peak selected from 18.2 ± 0.3°, 22.5 ± 0.3° and 26.8 ± 0.3° two theta. In some embodiments, polymorphic Form III is characterized by an x-ray powder diffraction pattern comprising major peaks at 11.9 ± 0.3°, 13.9 ± 0.3°, 17.1 ± 0.3° and 17.7 ± 0.3° two theta, and at least one peak selected from 18.2 ± 0.3°, 22.5 ± 0.3° and 26.8 ± 0.3° two theta. In some embodiments, polymorphic Form III is characterized by an x-ray powder diffraction pattern comprising major peaks at 11.9 ± 0.3°, 13.9 ± 0.3°, 17.1 ± 0.3° and 17.7 ± 0.3° two theta, and at least one peak selected from 18.2 ± 0.3°, 22.5 ± 0.3°, 25.3 ± 0.3° and 26.8 ± 0.3° two theta. In some embodiments, polymorphic Form III is characterized by an x-ray powder diffraction pattern comprising major peaks at 11.9 ± 0.3°, 13.9 ± 0.3°, 17.1 ± 0.3° and 17.7 ± 0.3° two theta, and peaks at 18.2 ± 0.3°, 22.5 ± 0.3°, 25.3 ± 0.3° and 26.8 ± 0.3° two theta.

[0141] In certain embodiments, the present disclosure provides a composition comprising polymorphic Form III. Greater than 90%, 95% or 99% by weight of the compound of Formula (I) in the composition may be polymorphic Form III. In some embodiments, the composition comprises 0.01 mg to 200 mg of polymorphic Form III. In some embodiments, the composition comprises about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg or 20 mg of polymorphic Form III.Formula (I), Form IV

[0142] A composition can comprise Form IV of the compound of Formula (I). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (I) is Form IV.

[0143] The crystalline form of Form IV of the compound of Formula (I) can be characterized by an XRPD pattern comprising major peaks at 4.7± 0.3°20, 23.3± O.3°20, and 13.6± O.3°20. 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± O.3°20, 14.2± O.3°20, 22.5± O.3°20, or 15.7± O.3°20. 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± O.3°20, 20.2± O.3°20, or 9.5± O.3°20. In some cases, the XRPD pattern further comprises at least one peak, comprises 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± O.3°20, 9.5± O.3°20, 14.2± O.3°20, 15.7± O.3°20, 20.2± O.3°20, 22.5± O.3°20, and 23.8± O.3°20. In some cases, the crystalline form of the compound of Formula (I) is characterized by an x-ray diffraction pattern substantially as set forth in FIG. 6.

[0144] In some cases, the crystalline form of the compound of Formula (I) comprises between about 1% and about 30% solvent by weight as determined by TGA analysis. In some cases, the crystalline form loses solvent upon heating to a temperature between 70°C and 130°C as determined by TGA analysis. In some cases, the solvent comprises 2-propanol, heptane, or a combination thereof.Formula (I), Form V

[0145] A composition can comprise Form V of the compound of Formula (I). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (I) is Form V.

[0146] The crystalline form of Form V of the compound of Formula (I) can be characterized by an XRPD pattern comprising major peaks at 12.5± O.3°20, 19.6± O.3°20, and 8.9± O.3°20. 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± O.3°20, 20.8± O.3°20, 19.8± O.3°20, or 16.0± O.3°20. 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± O.3°20, 13.5± O.3°20, or 14.4± O.3°20. In some cases, the XRPD pattern further comprises at least one peak, comprises 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±O.3°20, 20.8± O.3°20, 19.8± 0.3°20, 16.0± 0.3°20, 22.0± 0.3°20, 13.5± 0.3°20, and 14.4± 0.3°20. In some cases, the crystalline form of the compound of Formula (I) is characterized by an x-ray diffraction pattern substantially as set forth in FIG. 7.Formula (I), Form VI

[0147] A composition can comprise Form VI of the compound of Formula (I). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (I) is Form VI.

[0148] The crystalline form of Form VI of the compound of Formula (I) can be characterized by an XRPD pattern comprising major peaks at 9.9± 0.3°20, 13.4± O.3°20, and 13.7± O.3°20. 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± O.3°20, 18.6± O.3°20, 17.3± O.3°20, or 21.8± O.3°20. 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± O.3°20, 19.5± O.3°20, or 14.2± O.3°20. In some cases, the XRPD pattern further comprises at least one peak, comprises 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± O.3°20, 18.6± O.3°20, 17.3± O.3°20, 21.8± O.3°20, 10.2± O.3°20, 19.5± O.3°20, or 14.2± O.3°20.

[0149] In some cases, the crystalline form of the compound of Formula (I) is characterized by an x-ray diffraction pattern substantially as set forth in FIG. 8.Formula (I), Form VII

[0150] A composition can comprise Form VII of the compound of Formula (I). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (I) is Form VII.

[0151] The crystalline form of Form VII of the compound of Formula (I) can be characterized by an XRPD pattern comprising major peaks at 20.0± O.3°20, 22.6± O.3°20, and 10.6± O.3°20. 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± O.3°20, 16.4± O.3°20, 9.6± O.3°20, or 13.3± O.3°20. 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± O.3°20, 13.1± O.3°20, or 27.0± O.3°20. In some cases, the XRPD pattern further comprises at least one peak, comprises 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± O.3°20, 16.4± O.3°20, 9.6± O.3°20, 13.3± O.3°20, 18.2± O.3°20, 13.1± O.3°20, or 27.0± O.3°20. Insome cases, the crystalline form of the compound of Formula (I) is characterized by an x-ray diffraction pattern substantially as set forth in FIG. 9.Formula (I), Form VIII

[0152] A composition can comprise Form VIII of the compound of Formula (I). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (I) is Form VIII.

[0153] The crystalline form of Form VIII of the compound of Formula (I) can be characterized by an XRPD pattern comprising major peaks at 4.8± 0.3°20, 18.9± O.3°20, and 9.5± O.3°20. 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± O.3°20, 21.9± O.3°20, 21.2± O.3°20, or 12.9± O.3°20. 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± O.3°20, 21.5± O.3°20, or 16.4± O.3°20. In some cases, the XRPD pattern further comprises at least one peak, comprises 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± O.3°20, 21.9± O.3°20, 21.2± O.3°20, 12.9± O.3°20, 25.0± O.3°20, 21.5± O.3°20, or 16.4± O.3°20. In some cases, the crystalline form of the compound of Formula (I) is characterized by an x-ray diffraction pattern substantially as set forth in FIG. 10.Formula (I), Form IX

[0154] A composition can comprise Form IX of the compound of Formula (I). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (I) is Form IX.

[0155] The crystalline form of Form IX of the compound of Formula (I) can be characterized by an XRPD pattern comprising major peaks at 19.0± O.3°20, 12.9± O.3°20, and 15.9± O.3°20. 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± O.3°20, 20.8± O.3°20, 21.1± O.3°20, or 8.9± O.3°20. 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± O.3°20, 4.2± O.3°20, or 12.7± O.3°20. In some cases, the XRPD pattern further comprises at least one peak, comprises 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± O.3°20, 20.8± O.3°20, 21.1± O.3°20, 8.9± O.3°20, 16.4± O.3°20, 4.2± O.3°20, or 12.7± O.3°20. In some cases, the crystalline form of the compound of Formula (I) is characterized by an x-ray diffraction pattern substantially as set forth in FIG. 11.Formula (I), Form X

[0156] A composition can comprise Form X of the compound of Formula (I). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (I) is Form X.

[0157] The crystalline form of Form X of the compound of Formula (I) can be characterized by an XRPD pattern comprising major peaks at 7.2± 0.3°20, 14.3± O.3°20, 18.7± O.3°20, 21.5± O.3°20, and 22.7± O.3°20. In some cases, the XRPD pattern further comprises a peak at 17.1± O.3°20. 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± O.3°20, 27.3± O.3°20, or 29.4± O.3°20. In some cases, the crystalline form of the compound of Formula (I) is characterized by an x-ray diffraction pattern substantially as set forth in FIG. 12.Formula (I), Form XI

[0158] A composition can comprise Form XI of the compound of Formula (I). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (I) is Form XI.

[0159] The crystalline form of Form XI of the compound of Formula (I) can be characterized by an XRPD pattern comprising major peaks at 14.0± O.3°20, 17.7± O.3°20, 11.9± O.3°20, 18.4± O.3°20, 23.9± O.3°20, 17.3± O.3°20, 21.8± O.3°20, 20.8± O.3°20, and 23.0± O.3°20. In some cases, the XRPD pattern further comprises at least one peak or at least two peaks selected from 22.2± O.3°20 or 16.6 ± O.3°20. In some cases, the crystalline form of the compound of Formula (I) is characterized by an x-ray diffraction pattern substantially as set forth in FIG. 13.Formula (I), Form XII

[0160] A composition can comprise Form XII of the compound of Formula (I). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (I) is Form XII.

[0161] The crystalline form of Form XII of the compound of Formula (I) can be characterized by an XRPD pattern comprising major peaks at 12.5± O.3°20, 15.6± O.3°20, and 19.0± O.3°20. 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± O.3°20, 20.2± O.3°20, 16.0± O.3°20, or 21.6± O.3°20. 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± O.3°20, 16.8± O.3°20, or 12.8± O.3°20. In somecases, the XRPD pattern further comprises at least one peak, comprises at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 21.9± 0.3°20, 20.2± 0.3°20, 16.0± 0.3°20, 21.6± 0.3°20, 22.4± 0.3°20, 16.8± 0.3°20, or 12.8± 0.3°20. In some cases, the crystalline form of the compound of Formula (I) is characterized by an x-ray diffraction pattern substantially as set forth in FIG. 14.Formula (I), Form XIV

[0162] A composition can comprise Form XIV of the compound of Formula (I). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (I) is Form XIV.

[0163] The crystalline form of Form XIV of the compound of Formula (I)can be characterized by an XRPD pattern comprising major peaks at 11.6± 0.3°20, 21.3± O.3°20, and 19.3± O.3°20. 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± O.3°20, 15.4± O.3°20, 21.6± O.3°20, or 5.8± O.3°20. 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± O.3°20, 21.9± O.3°20, or 23.9± O.3°20. In some cases, the XRPD pattern further comprises at least one peak, comprises 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± O.3°20, 15.4± O.3°20, 21.6± O.3°20, 5.8± O.3°20, 16.3± O.3°20, 21.9± O.3°20, or 23.9± O.3°20. In some cases, the crystalline form of the compound of Formula (I) is characterized by an x-ray diffraction pattern substantially as set forth in FIG. 15.Formula (I), Form XV

[0164] A composition can comprise Form XV of the compound of Formula (I). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (I) is Form XV.

[0165] The crystalline form of Form XV of the compound of Formula (I) can be characterized by an XRPD pattern comprising major peaks at 9.8± O.3°20, 4.7± O.3°20, and 14.0± O.3°20. 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± O.3°20, 7.1± O.3°20, 23.4± O.3°20, or 22.4± O.3°20. 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± O.3°20, 22.7± O.3°20, or 18.8± O.3°20. In some cases, the XRPD pattern further comprises at least one peak, comprises 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±O.3°20, 7.1± O.3°20, 23.4± 0.3°20, 22.4± 0.3°20, 21.7± 0.3°20, 22.7± 0.3°20, or 18.8± 0.3°20. In some cases, the crystalline form of the compound of Formula (I) is characterized by an x-ray diffraction pattern substantially as set forth in FIG. 16.Formula (I), Form XIX

[0166] A composition can comprise Form XIX of the compound of Formula (I). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (I) is Form XIX.

[0167] The crystalline form of Form XIX of the compound of Formula (I) can be characterized by an XRPD pattern comprising major peaks at 4.7± 0.3°20, 23.6± O.3°20, and 18.9± O.3°20. 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± O.3°20, 23.3± O.3°20, 22.3± O.3°20, or 20.1± O.3°20. 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± O.3°20, 7.1± O.3°20, or 15.7± O.3°20. In some cases, the XRPD pattern further comprises at least one peak, comprises 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± O.3°20, 23.3± O.3°20, 22.3± O.3°20, 20.1± O.3°20, 19.6± O.3°20, 7.1± O.3°20, or 15.7± O.3°20. In some cases, the crystalline form of the compound of Formula (I) is characterized by an x-ray diffraction pattern substantially as set forth in FIG. 17.Dosing and Formulation

[0168] In an aspect, a composition comprising a (Z)-endoxifen particle contains between about 0.1 mg to about 200 mg (Z)-endoxifen in a unit dose. In various embodiments, the composition comprises 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg and 40 mg of a polymorphic Form of (Z)-endoxifen. While the content of (Z)-endoxifen or a polymorph or a salt thereof in the particles of the present disclosure varies depending on the dosage form of the sustained-release composition, target disease, severity of disease, and the like, it is an amount generally corresponding or equivalent to from about 0.01 mg to about 200 mg of (Z)-endoxifen. One of skill in the art will recognize that when particles include salts of (Z)-endoxifen, the endoxifen salt will be in an equivalent amount on the basis of (Z)-endoxifen to be released.

[0169] (Z)-endoxifen and polymorphs and salts thereof may be diluted with a diluent generally used in the medical field, food field, and the like.

[0170] One of skill will recognize that the amounts of (Z)-endoxifen polymorphs and salts will be present in the particles in amount equivalent, on a molar basis, to the pharmacologically active (Z)-endoxifen free form.

[0171] In an aspect, the present disclosure provides particles configured for sustained release of (Z)-endoxifen, or a polymorph or a salt thereof, over a period of about 2 hours to about 72 hours. In some embodiments, the particles show a sustained release of the drug (Z)-endoxifen, or a polymorph or a salt thereof, over a period of about 4 hours to about 24 hours or more. In some embodiments, the particles release (Z)-endoxifen, or a polymorph or a salt thereof, in a sustained manner over a period of at least 2 hours, at least 3 hours at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 24 hours, at least 48 hours, and at least 72 hours. In some embodiments, the particles release (Z)-endoxifen or a polymorph or a salt thereof over a period of from 6 hours to 48 hours. In some embodiments, the (Z)-endoxifen or a polymorph or a salt thereof is released from the particles after about 2 hours pose dose for a period ranging from about 2 hours to about 72 hours. In some embodiments, after about 2 hours post dose the (Z)-endoxifen or a polymorph or a salt thereof is released from the particles for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours and about 24 hours. In some embodiments, the rate of release of the (Z)-endoxifen or a polymorph or a salt thereof is slower and more sustained or prolonged than that of a reference product, the enteric resistant delayed release (Z)-endoxifen capsule (“Capsule” or “Control” as used interchangeably herein) as shown herein this disclosure.

[0172] In dissolution tests of certain sustained release compositions of the present disclosure conducted according to USP I Method, the sustained release compositions show percentage dissolution ranging from about 0% to 35% at 3 hours, from about 35% to about 55% at 12 hours, and from about 65% to 85% at 24 hours in a dissolution test according to the 75 RPM USP I method and using pH 1.2 at 37°C for 2 hours in simulated gastric fluid and pH 6.8 at 37°C for 24 hours in simulated intestinal fluid as a test medium.

[0173] A method for measuring a dissolution of a composition (e.g., a particle) may comprise measuring the dissolution in an acid phase (e.g., simulated gastric fluid) followed by a buffer phase (e.g., simulated intestinal fluid). The acid phase may comprise placing 750 mL of 0.1 N hydrochloric acid in the vessel, and assembling the apparatus (e.g., the paddle apparatus or the basket apparatus). The medium may be allowed to equilibrate to a temperature of 37 ± 0.5°. Onedosage unit may be placed in the apparatus, the vessel covered, and the apparatus operated at the specified rate. After 2 hours of operation in 0.1 N hydrochloric acid, an aliquot of the fluid may be withdrawn. Then the method may proceed immediately as directed under the buffer stage. An analysis of the aliquot may be performed using a suitable assay method. While operating the apparatus at a specified rate, 250 mL of 0.20 M tribasic sodium phosphate that has been equilibrated to 37 ± 0.5° may be added to the fluid in the vessel. The fluid may be adjusted, if necessary, with 2N hydrochloric acid or 2 N sodium hydroxide to a pH of 6.8 ± 0.05. The apparatus may continue to be operated for 45 minutes, or for the specified time. At the end of the time period, an aliquot of fluid may be withdrawn, and an analysis of the aliquot may be performed using a suitable assay method.

[0174] In some embodiments, the percentage dissolution is measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and at 37°C from hours 0-2, and in simulated intestinal fluid at pH 6.8 and at 37°C after hour 2. The percentage dissolution refers to the percentage of the composition that has dissolved, by weight percent. The percentage dissolution refers to the weight percent dissolution of (Z)-endoxifen, or the polymorph or salt thereof, during the dissolution study. As a non-limiting example, if a tablet comprises 4 mg of (Z)- endoxifen, and during the dissolution study at a time point of 3 hours, 1 mg of the (Z)-endoxifen is dissolved into the solution, then the percentage dissolution at 3 hours is 25%. The percentage dissolution can be determined by, for example, high pressure liquid chromatography.

[0175] In some embodiments, the particle has a percentage dissolution ranging from about 5% to about 35%, from about 10% to about 15%, from about 20% to about 25%, from about 30% to about 35%, from about 5% to about 30%, from about 5% to about 25%, from about 5% to about 20%, from about 5% to about 15%, from about 5% to about 10%, from about 10% to about 15%, from about 15% to about 20%, from about 20% to about 25%, from about 25% to about 30%, or from about 30% to about 35% at 3 hours, measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and at 37°C from hours 0-2, and in simulated intestinal fluid at pH 6.8 and at 37°C after hour 2.

[0176] In some embodiments, the particle has a percentage dissolution at 2 hours of no more than about 5%, no more than about 10%, no more than about 15%, no more than about 20%, no more than about 25%, no more than about 30%, no more than about 35%, no more than about 40%, no more than about 45%, or no more than about 50%, measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and at 37°C from hours 0-2, and in simulated intestinal fluid at pH 6.8 and at 37°C after hour 2. In some embodiments, the particle has a percentage dissolution of not more than (NMT) about 30%, NMT about 25%, NMT about 20%, NMT about 15%, NMT about 10%, or NMT about 5% at 3 hours.

[0177] In some embodiments, the particle has a percentage dissolution of (Z)-endoxifen or a polymorph or a salt thereof at 2 hours of less than about 5% and at 3 hours ranging from about 5% to about 80%, from about 10% to about 75%, from about 20% to about 70%, from about 30% to about 65%, from about 5% to about 75%, from about 5% to about 70%, from about 5% to about 60%, from about 5% to about 65%, from about 5% to about 60%, from about 10% to about 55%, from about 5% to about 50%, from about 30% to about 80%, from about 25% to about 75%, from about 35% to about 80%, or not less than about 70%, as measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and at 37°C from hours 0-2, and in simulated intestinal fluid at pH 6.8 and at 37°C after hour 2.

[0178] In some embodiments, the particle has a percentage dissolution of (Z)-endoxifen or a polymorph or a salt thereof at 7 hours of less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 31%, less than about 32%, less than about 33%, less than about 34%, less than about 35%, less than about 36%, less than about 37%, less than about 38%, less than about 39%, less than about 40%, as measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and at 37°C from hours 0-2, and in simulated intestinal fluid at pH 6.8 and at 37°C after hour 2.

[0179] In some embodiments, the particle has a percentage dissolution of (Z)-endoxifen or a polymorph or a salt thereof at 2 hours of less than about 5% and at 6 hours ranging from about 70% to about 99%, from about 75% to about 95%, from about 85% to about 95%, from about90% to about 95%, from about 75% to about 90%, from about 85% to about 90%, from about75% to about 85%, from about 80% to about 99%, from about 85% to about 99%, from about90% to about 99%, from about 95% to about 99% or not less than about 95%, as measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and at 37°C from hours 0-2, and in simulated intestinal fluid at pH 6.8 and at 37°C after hour 2.

[0180] In some embodiments, the particle has a percentage dissolution of (Z)-endoxifen or a polymorph or a salt thereof at 2 hours of less than about 5% and at 6 hours of not less (NLT) than about 20%, about 25%, about 30%, about 35%, or about 40%.

[0181] In some embodiments, the particle has a percentage dissolution of (Z)-endoxifen or a polymorph or a salt thereof at 2 hours of less than about 5% and at 9 hours of NLT about 40%, about 45%, about 50%, about 55%, or about 60%.

[0182] In some embodiments, the particle has a percentage dissolution ranging from about 35% to about 55%, from about 40% to about 55%, from about 45% to about 55%, from about 50% to about 55%, from about 35% to about 50%, from about 35% to about 45%, from about 35% to about 40%, from about 35% to about 40%, from about 40% to about 45%, from about 45% to about 50%, or from about 50% to about 55% at 12 hours, measured by the 75 rpm USP paddlemethod in simulated gastric fluid at pH 1.2 and at 37°C from hours 0-2, and in simulated intestinal fluid at pH 6.8 and at 37°C after hour 2.

[0183] In some embodiments, the particle has a percentage dissolution of (Z)-endoxifen or a polymorph or a salt thereof of less than 20% at 2 hours, and a percentage dissolution of at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% at 12 hours, measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and at 37°C from hours 0-2, and in simulated intestinal fluid at pH 6.8 and at 37°C after hour 2.

[0184] In some embodiments, the particle has a percentage dissolution of (Z)-endoxifen or a polymorph or a salt thereof of less than 20% at 2 hours, and a percentage dissolution of at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% at 24 hours, measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and at 37°C from hours 0-2, and in simulated intestinal fluid at pH 6.8 and at 37°C after hour 2.

[0185] In some embodiments, the particle has a percentage dissolution of (Z)-endoxifen or a polymorph or a salt thereof at 2 hours of less than about 5% and at 12 hours ranging from about 70% to about 99%, from about 75% to about 95%, from about 85% to about 95%, from about90% to about 95%, from about 75% to about 90%, from about 85% to about 90%, from about75% to about 85%, from about 80% to about 99%, from about 85% to about 99%, from about90% to about 99%, from about 95% to about 99% or about 100%, measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and at 37°C from hours 0-2, and in simulated intestinal fluid at pH 6.8 and at 37°C after hour 2.

[0186] In some embodiments, the particle has a percentage dissolution of (Z)-endoxifen or a polymorph or a salt thereof at 2 hours of less than about 5% and at 14 hours ranging from about 55% to about 90%, from about 60% to about 85%, from about 70% to about 80%, measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and at 37°C from hours 0-2, and in simulated intestinal fluid at pH 6.8 and at 37°C after hour 2. In some embodiments, the particle has a percentage dissolution of (Z)-endoxifen or a polymorph or a salt thereof at 2 hours of less than about 5% and at 14 hours of NLT about 70%, about 75%, about 80%, about 85%, or about 90%.

[0187] In some embodiments, the particle has a percentage dissolution ranging from about 65% to about 85%, from about 70% to about 85%, from about 75% to about 85%, from about 80% to about 85%, from about 65% to about 80%, from about 65% to about 75%, from about 65% toabout 70%, from about 65% to about 70%, from about 70% to about 75%, from about 75% to about 80%, or from about 80% to about 85%, at 24 hours, measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and at 37°C from hours 0-2, and in simulated intestinal fluid at pH 6.8 and at 37°C after hour 2.

[0188] In some embodiments, the particle has a percentage dissolution of (Z)-endoxifen or a polymorph or a salt thereof at 2 hours of less than about 5% and at 72 hours ranging from about 55% to about 100%, from about 60% to about 99%, from about 75% to about 90%, from about 80% to about 85%, from about 55% to about 99%, from about 65% to about 99%, from about 70% to about 99%, from about 75% to about 99%, from about 80% to about 99%, from about 90% to about 99%, from about 80% to about 95%, or from about 75% to about 95%, as measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and at 37°C from hours 0-2, and in simulated intestinal fluid at pH 6.8 and at 37°C after hour 2.

[0189] In dissolution tests of certain particles of the present disclosure conducted according to USP II Paddle Method, the particles show percentage dissolution ranging from about 0% to 35% at 3 hours, from about 35% to about 55% at 12 hours, and from about 65% to 85% at 24 hours in a dissolution test according to the 75 RPM USP paddle method and using pH1.2 at 37°C for 2 hours in simulated gastric fluid and pH 6.8 at 37°C for 24 hours in simulated intestinal fluid as a test medium.

[0190] In some embodiments, particles of the present disclosure show a percentage dissolution of (Z)-endoxifen, or a polymorph or a salt thereof about 0% to 30% at 3 hours, about 40% to about 50% at 12 hours and about 70% to 80% at 24 hours in a dissolution test according to the 75 rpm USP paddle method and using pH 1.2 at 37°C for 2 hours in simulated gastric fluid and pH 6.8 at 37°C for 24 hours in simulated intestinal fluid.

[0191] In some embodiments, particles of the present disclosure show a percentage dissolution of (Z)-endoxifen, or a polymorph or a salt thereof NMT 30% at 3 hours, NMT 50% at 12 hours and NLT 80% at 24 hours in a dissolution test according to the 75 rpm USP paddle method and using pH 1.2 at 37°C for 2 hours in simulated gastric fluid and pH 6.8 at 37°C for 24 hours in simulated intestinal fluid.

[0192] In some embodiments, the particles show percentage dissolution of (Z)-endoxifen, or a polymorph or a salt thereof of not more than (NMT) about 5% at 2 hours, not less than (NLT) 70% at 3 hours, NLT 90% at 6 hours, and about 100% at 12 hours in a dissolution test according to the 75 RPM USP II method and using pH 1.2 at 37°C for 2 hours in simulated gastric fluid and pH 6.8 at 37°C for 24 hours in simulated intestinal fluid

[0193] In some embodiments, the particles show percentage dissolution of (Z)-endoxifen, or a polymorph or a salt thereof of NMT about 5% at 2 hours, NLT about 10% at 3 hours, NLT about30% at 6 hours, NLT about 50% at 9 hours, and about 80% at 14 hours in a dissolution test according to the 75 RPM USP II method and using pH1.2 at 37°C for 2 hours in simulated gastric fluid and pH 6.8 at 37°C for 24 hours in simulated intestinal fluid.

[0194] In some embodiments, particles of the present disclosure show a percentage dissolution of (Z)-endoxifen, or a polymorph or a salt thereof at least 10%, at least 20%, at least 30%, or at least 40% after 24 hours in a dissolution test according to the 75 rpm USP paddle method and using pH 1.2 at 37°C for 2 hours in simulated gastric fluid and pH 6.8 at 37°C for 24 hours in simulated intestinal fluid. One of skill in the art will further recognize that compositions disclosed herein may comprise one or more of the excipients known in the art and disclosed herein in any combination appropriate for a desired formulation or preparation. Additional excipients may generally be found in Remington’s The Science and Practice of Pharmacy, Meade Publishing Co., United States Pharmacopeia / National Formulary. One of skill in the art will be able to select suitable excipients necessary for the preparation of the formulations and appropriate dosage forms compatible with the route of administration based on his or her skill and knowledge in the art and the disclosures made herein. In all cases, the ultimate dosage form should be sterile and stable under the conditions of manufacture and storage.Liquid Endoxifen Formulations

[0195] Aspects of the present disclosure provide a liquid formulation of (Z)-endoxifen comprising a solvent and the (Z)-endoxifen or a salt thereof. The (Z)-endoxifen or the salt thereof can be completely dissolved in the solvent, partially dissolved in the solvent, or substantially undissolved (e.g., at least about 99% in solid form) in the solvent. Liquid formulation of (Z)-endoxifen can be formulated for oral administration. In some embodiments, the liquid formulation can enhance (Z)-endoxifen free base or (Z)-endoxifen salt uptake following oral administration relative to an equivalent dosage of (Z)-endoxifen in solid, dry form.

[0196] While some solvents (e.g., gastric juices) can promote (Z)- and (E)-endoxifen isomerization, the liquid formulations disclosed herein can stabilize (Z)-endoxifen for long-term storage. For many of the liquid formulations disclosed herein, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 12%, less than about 10%, less than about 8%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1% of the (Z)-endoxifen in the liquid formulation converts to (E)-endoxifen following 1 month of storage at 25°C. To promote this stability, the liquid formulation can include a solvent which does not promote interconversion between (Z)- and (E)-endoxifen. Forexample, the solvent may be aprotic, thereby limiting acid and base-catalyzed isomerization. (Z)-endoxifen stability may be enhanced by storage in a stable solid form within the liquid formulation, for example as a slurry in which a limited amount of the (Z)-endoxifen is solubilized.

[0197] The solvent may be a pharmaceutically acceptable liquid carrier. The solvent can be biocompatible, such that it does not elicit adverse effects at the doses provided to a subject. The solvent may also be readily absorbed following administration to promote (Z)-endoxifen uptake. In some cases, the liquid formulation is aqueous (i.e., comprises water). In such cases, the solvent can be at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% water by weight. The aqueous liquid formulation can be isotonic, for example containing glucose or saline.

[0198] The liquid formulation can also be non-aqueous or substantially non-aqueous, for example comprising less than about 10%, less than about 8%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1% water by weight. To achieve low water content, the solvent, the (Z)-endoxifen or the salt thereof, or the combination thereof can be dried, for example by lyophilization or passage over a water adsorbent material such as calcium sulfate. In some cases, the liquid formulation includes a non-aqueous solvent selected from ethanol, glycerol, plant oil (e.g., olive, rapeseed, coconut, or peanut oil), polyethylene glycol, propylene glycol, methoxypropylene glycol, dimethyl acetamide (DMA), dimethylsulfoxide (DMSO), polyvinylpyrrolidone (PVP), methoxypropylene glycol (MPEG), glycerol, glycofurol, dimethylformamide (DMF), ethyl acetate, n-methyl pyrrolidone (NMP), propylene carbonate, methyl benzoate, ethyl benzoate, propyl benzoate, Capmul PG-8, Caprol MPGO, Capryol 90, Plurol Oleique CC 497, Capmul MCM, Labrafac PG, N-Decyl Alcohol, Caprol 10G10O, Lauryl Alcohol, Captex 355EP, Captex 500, Caplic Triglyceride, Peceol, Caprol ET, Labrafil M2125 CS, Labrafac CC, Labrafil M 1944 CS, Captex 8277, Nyristate, Caprol PGE 860, and a combination thereof. In some cases, the solvent is lipophilic, for example plant oil, polyethylene glycol, polypropylene glycol, Capmul PG-8, Caprol MPGO, Capryol 90, Plurol Oleique CC 497, Capmul MCM, Labrafac PG, N-Decyl Alcohol, Caprol 10G10O, Lauryl Alcohol, Captex 355EP, Captex 500, Caplic Triglyceride, Peceol, Caprol ET, Labrafil M2125 CS, Labrafac CC, Labrafil M 1944 CS, Captex 8277, Nyristate, Caprol PGE 860, or a combination thereof.

[0199] The liquid formulation can include a buffer. As (Z)-endoxifen isomerization can be acid and base mediated, in many cases, the formulation has a neutral, mildly acidic, or mildly basic pH. In some cases, the liquid formulation has a pH of between about 4.5 and 9.5, between about 5 and 9, between about 4.5 and 7, between about 6 and 8, between about 7 and 9.5, or between about 6.5 and 7.5. In some cases, the liquid formulation includes a buffer selected from histidine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophane, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, cysteine, methionine, proline, 4-hydroxyproline, N,N,N -trimethyllysine, 3 -methylhistidine, 5- hydroxylysine, O-phosphoserine, y-carboxyglutamate, c-N-acctyllysinc, co-N-methylarginine, glycine, glycyl-glycine, tricine, malate, formate, citrate, succinate, acetate, propionate, pyridine, succinate, ethanolamine, imidazole, TRIS, BES, TES, DIPSO, MOBS, TAPSO, HEPPSO, PIPES. POPSO, MOPS, HEPES, bicarbonate, phosphate, or a combination thereof. In some cases, the liquid formulation includes about 0.5 mM to about 200 mM of the buffer, between about 0.5 and 20 mM of the buffer, between about 5 and 50 mM of the buffer, between about 10 and 100 mM of the buffer, or between about 50 and 200 mM of the buffer.

[0200] The liquid formulation can include a stabilizer. The stabilizer may inhibit (Z)-endoxifen isomerization or degradation during packing, storage, and administration. In some cases, the stabilizer includes albumin, an immunoglobulin, a monosaccharide or oligosaccharide (e.g., trehalose, glucose, sucrose, sorbitol, dextran, maltose, mannose, raffinose, stachyose), a hydrogel, a polysaccharide, or a combination thereof. The stabilizer can include a material to which the (Z)-endoxifen or salt thereof adsorbs or intercalates, such as chitosan, and which can limit degradation and isomerization.

[0201] In some cases, the (Z)-endoxifen or the salt thereof is fully dissolved in the solvent. For example, the (Z)-endoxifen or the salt thereof can be at least about 99%, at least about 99.2%, at least about 99.4%, at least about 99.6%, or at least about 99.8% dissolved in the solvent when the liquid formulation is at 25°C. In such liquid formulations, the solvent can be supersaturated with the (Z)-endoxifen or the salt thereof, saturated with the (Z)-endoxifen or the salt thereof, or subsaturated (i.e., contains less (Z)-endoxifen than is soluble in the solvent) with the (Z)- endoxifen or the salt thereof.

[0202] In some cases, the liquid formulation is a slurry, also referred to as a suspension. The slurry can contain a solvent with solid (Z)-endoxifen or a salt thereof dispersed, suspended, or partially solubilized therein. The solid (Z)-endoxifen or salt thereof can be homogeneously or heterogeneously dispersed throughout the slurry. For example, the solid (Z)-endoxifen can be stochastically dispersed throughout the solvent, settled against a surface containing the solvent (e.g., an enteric capsule), or in an intermediary distribution thereof. The solid (Z)-endoxifen orsalt thereof can be a powder. The solid (Z)-endoxifen or salt thereof can be microcrystalline. The solid (Z)-endoxifen or salt thereof can be a millimeter-or-greater dimensioned continuous solid, such as a millimeter diameter crystal.

[0203] For slurry formulations, (Z)-endoxifen or salt thereof can be undissolved or partially dissolved in the solvent. In some cases, between about 5% and 95% of (Z)-endoxifen in a slurry is dissolved, and the remaining portion is solid. For example, between about 5% and 25%, between about 5% and 50%, between about 10% and 40%, between about 10% and 60%, between about 20% and 50%, between about 25% and 50%, between about 25% and 60%, between about 30% and 70%, between about 40% and 80%, between about 50% and 90%, between about 60% and 95%, or between about 75% and 95% of (Z)-endoxifen in a slurry is dissolved. The partially dissolved (Z)-endoxifen can be amorphous, monocrystalline, polycrystalline, or a combination thereof.

[0204] The solid form or forms of (Z)-endoxifen can be stable in the slurry. For many of the slurries disclosed herein, the form or forms of (Z)-endoxifen used to generate the slurry remain following storage. While the (Z)-endoxifen may be in a dynamic equilibrium between solid and dissolved states, residual solid (Z)-endoxifen may seed reformation into a particular crystal form during crystallization or precipitation. Alternatively, or in addition thereto, the form or forms of solid (Z)-endoxifen may be enthalpically and / or entropically favored solid forms in the slurry, such that (Z)-endoxifen the form or forms of solid (Z)-endoxifen are maintained throughout liquid-solid equilibration by the (Z)-endoxifen. The form or forms of (Z)-endoxifen formulated in the slurry can be stable for at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 10 days, at least about 14 days, at least about 20 days, at least about 30 days, at least about 40 days, at least about 50 days, at least about 75 days, at least about 100 days, at least about 150 days, at least about 200 days, at least about 250 days, at least about 300 days, at least about 400 days, or at least about 500 days at 25°C. For some slurries disclosed herein, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of solid (Z)-endoxifen is in the forms used to generate the slurry following 1 day, following 2 days, following 3 days, following 4 days, following 5 days, following 6 days, following 7 days, following 10 days, following 14 days, following 20 days, following 30 days, following 40 days, following 50 days, following 75 days, following 100 days, following 150 days, following 200 days, following 250 days, following 300 days, following 400 days, or following 500 days of storage at 25°C. For example, a slurry generated with (Z)-endoxifen Forms IV and VI and water may contain greater than 95% Forms IV and VI following 300 days of storage at 25 °C. Alternatively, a solid form of(Z)-endoxifen may convert during storage of the slurry, such as at a rate of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 8%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% per month under 25°C storage.

[0205] In some cases, the slurry contains mono- or polycrystalline (Z)-endoxifen (i.e., the (Z)- endoxifen is poly crystalline or of a single crystalline form). In some cases, the (Z)-endoxifen is of a single crystalline form. In some cases, the (Z)-endoxifen is Form I, Form IV, Form V, FormVI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XIX, or a combination thereof. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form I, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XIX, or the combination thereof. In some cases, the (Z)-endoxifen is Form I, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, or Form XIX. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form I, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, or Form XIX. In some cases, the (Z)-endoxifen is Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XIX, or a combination thereof. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XIX, or the combination thereof. In some cases, the (Z)-endoxifen is Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XIX. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the (Z)-endoxifen is Form IV, Form V, Form VI, FormVII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, or Form XIX.

[0206] In some cases, the liquid formulation comprises an emulsion. As used herein, the term “emulsion” can denote a dispersion of two or more liquids with low miscibility, such as oil inwater. In many cases, the emulsion includes an organic solvent in which the (Z)-endoxifen or the salt thereof has high or moderate solubility and water. In such formulations, the (Z)-endoxifen or the salt thereof can primarily partition into the organic solvent.

[0207] The liquid formulation can be suited for oral delivery. In order to prevent isomerization in the stomach (e.g., upon contact with stomach acids), the liquid formulation can be contained within an enteric coating which prevents release until the liquid formulation passes through the stomach. For example, the liquid formulation can be contained within a gel capsule which, upon administration, passes through the stomach and degrades in the small intestine, thereby releasing the (Z)-endoxifen in an uptake-compatible manner. The enteric coating may be inert to the liquid formulation, thereby stably containing the liquid formulation until contacting a solution or condition which promotes its degradation. The enteric coating can encapsulate between about 50 pL and 1.5 mL of the liquid formulation, between about 100 and 500 pL of the liquid formulation, or between about 250 pL and 1.5 mL of the liquid formulation. The liquid formulation may contain solid (Z)-endoxifen (e.g., be in the form of a slurry), dissolved (Z)- endoxifen, or a combination thereof. The liquid formulation can be formulated for oral delivery without an enteric coating. For example, the liquid formulation can be in the form of a beverage, a gel, a cream, or a colloidal food (e.g., a nut butter) configured for ingestion. In such cases, the (Z)-endoxifen or salt thereof may be co-administered with a stabilizer, such as chitosan.

[0208] The liquid formulation can be configured for transdermal delivery. In such cases, the liquid formulation can include a skin-permeating solvent, such as DMSO or gammabutyrolactone. In many cases, transdermal liquid formulations include dissolved (Z)-endoxifen to facilitate transport with the skin permeable solvent. However, the (Z)-endoxifen can also be crystalline (e.g., microcrystalline), and may be formulated to dissolve in sweat, oil, or other liquids present on the skin. In some cases, the liquid formulation is provided within a skin patch.Methods of Treatment

[0209] In one aspect, there is provided a method of treating a disease in a subject in need thereof, including administering to the subject an oral formulation including a microparticle, wherein the microparticle includes a (Z)-endoxifen composition and a coating, wherein the (Z)- endoxifen composition includes a compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt thereof, wherein at least 90% by weight of the compound of Formula (I) is (Z)-endoxifen or a pharmaceutically acceptable salt thereof.

[0210] The oral formulation may be an oral formulation according to any of the aspects, or combinations of aspects, described herein.

[0211] A particle, a plurality of instances of the particle, or a composition containing the particle or the plurality of instances thereof may be used for the treatment of disorders such as cancers, including but not limited to childhood and adult cancers.

[0212] In one aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a particle prepared according to any one of the processes disclosed herein.

[0213] In another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation prepared according to any one of the processes disclosed herein.

[0214] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein.

[0215] In some aspects, the method includes administering to the subject an oral formulation which includes from 0.01 mg to 200 mg, 5 mg to 80 mg, 5 mg to 60 mg, 5 mg to 40 mg, 10 mg to 80 mg, 40 mg to 80 mg, or 50 to 100 mg of (Z)-endoxifen. In some aspects, the method includes administering to the subject an oral formulation which includes 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, or 40 mg of (Z)-endoxifen.

[0216] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle prepared according to any one of the processes disclosed herein, wherein the subject has or is at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both.

[0217] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle prepared according to any one of the processes disclosed herein, wherein the subject has or is at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both, wherein the hormone-dependent breast disorder or the hormone-dependent reproductive tract disorder is a benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer,precocious puberty, McCune-Albright Syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer.

[0218] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the subject has breast cancer.

[0219] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the subject has breast cancer, and wherein the breast cancer is a precancer, an early stage cancer, a non-metastatic cancer, a pre-metastatic cancer, a locally advanced cancer, or a metastatic cancer.

[0220] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the subject has prostate cancer and wherein the subject further has or is at risk of having gynecomastia.

[0221] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the subject has tamoxifen-refractory or tamoxifen resistant hormonedependent breast disorder or hormone-dependent reproductive tract disorder.

[0222] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the liquid formulation or the particle is administered to the subject at a unit dose of 1.0 mg, 1.5 mg, 2.0 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 20 mg, 25 mg, 40 mg, 50 mg, 80 mg, 100 mg, 120 mg, 160 mg, or 200 mg.

[0223] In some aspects, a dose of the formulation is 0.01 mL to 10 mL of the aqueous solution per kg body weight. In some aspects, the dose of the formulation is 0.01 mL, 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, or 1 mL of the aqueous solution per kg body weight. In some aspects, a dose of (Z)-endoxifen is 0.01 to 3 mg / kg of body weight. In some aspects, the dose of (Z)-endoxifen is 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / .kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, or 3 mg / kg of body weight.

[0224] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the liquid formulation or the particle is administered once a day, twice, a day, thrice a day, four times a day, every other day, twice a week, weekly, fortnightly, twice a month, monthly, quarterly, once every six months, or annually.

[0225] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein administration of the liquid formulation or particle orally maintains the subject's plasma (Z)-endoxifen at a steady state level greater than 30 nM.

[0226] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein administration of the liquid formulation or particle orally achieves the subject's plasma (Z)-endoxifen at a steady state level greater than 30 nM by day 14 after the administration of the first dose (on day 1).

[0227] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof, wherein administration of the liquid formulation or particle orally achieves the subject's plasma (Z)-endoxifen at a steady state level greater than 30 nM by day 14 after the administration of the first dose (on day 1).

[0228] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein administration of the liquid formulation or particle orally achieves a time to maximal plasma levels of (Z)-endoxifen in the subject from 2 to 10 hours after administration (post-dose).

[0229] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof, wherein administration of the liquid formulation or particle orally achieves a time to maximal plasma levels of (Z)-endoxifen in the subject from 2 to 10 hours after administration (post-dose).

[0230] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)-endoxifen or a salt or polymorph thereof, wherein the mean terminal elimination half-life of (Z)- endoxifen in the subject ranges from 30 to 60 hours post dose.

[0231] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof, wherein the mean terminal elimination half-life of (Z)- endoxifen in the subject ranges from 40 to 55 hours post dose.

[0232] In another aspect, the present disclosure relates to a method of treating a subject having or at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both, the method comprising administering an oral liquid formulation or particle comprising (Z)-endoxifen or a salt or polymorph thereof, wherein administration of the liquid formulation or particle achieves: a mean half-life of (Z)-endoxifen in the subject ranging from 30 hours to 60 hours after administration; a time to maximum plasma levels of (Z)- endoxifen ranging from 2 hours to 10 hours after administration; and a steady state plasma level of (Z)-endoxifen greater than 30 nM.

[0233] In another aspect, the present disclosure relates to a method of treating a subject having or at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder selected from the group consisting of benign breast disorders, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright Syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering an oral liquid formulation or particle comprising (Z)- endoxifen or a salt or polymorph thereof, wherein administration of the liquid formulation or particle achieves: a mean half-life of (Z)-endoxifen in the subject ranging from 30 hours to 60 hours after administration; a time to maximum plasma levels of (Z)-endoxifen ranging from 2 hours to 10 hours after administration; and a steady state plasma level of (Z)-endoxifen greater than 30 nM.

[0234] In another aspect, the present disclosure relates to a method of treating a subject having or at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder selected from the group consisting of benign breast disorders, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright Syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer and vulvar cancer, the method comprising administering an oral liquid formulation or particle comprising (Z)- endoxifen or a salt or polymorph thereof formulated as an enteric tablet, an enteric caplet, an enteric capsule, a delayed-release tablet, a delayed-release caplet, or a delayed-release capsule,wherein administration of the liquid formulation or particle achieves: a mean half-life of (Z)- endoxifen in the subject ranging from 30 hours to 60 hours after administration; a time to maximum plasma levels of (Z)-endoxifen ranging from 2 hours to 10 hours after administration; and a steady state plasma level of (Z)-endoxifen greater than 30 nM.

[0235] In another aspect, the present disclosure relates to a method of treating a subject having or at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder selected from the group consisting of benign breast disorders, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright Syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering an oral liquid formulation or particle comprising (Z)- endoxifen or a salt or polymorph thereof formulated as an enteric tablet, an enteric caplet, an enteric capsule, a delayed-release tablet, a delayed-release caplet, or a delayed-release capsule, wherein administration of the liquid formulation or particle achieves: a mean half-life of (Z)- endoxifen in the subject ranging from 30 hours to 60 hours after administration; a time to maximum plasma levels of (Z)-endoxifen ranging from 2 hours to 10 hours after administration; and a steady state plasma level of (Z)-endoxifen greater than 30 nM; and wherein at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of the (Z)-endoxifen is released in the intestines.

[0236] In another aspect, the present disclosure relates to a method of treating a subject having or at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder selected from the group consisting of benign breast disorders, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright Syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering an oral liquid formulation or particle comprising 0.01 mg to 200 mg of (Z)-endoxifen or a salt or polymorph thereof formulated as an enteric tablet, an enteric caplet, an enteric capsule, a delayed-release tablet, a delayed-release caplet, or a delayed- release capsule, wherein administration of the liquid formulation or particle achieves: a mean half-life of (Z)-endoxifen in the subject ranging from 30 hours to 60 hours after administration; a time to maximum plasma levels of (Z)-endoxifen ranging from 2 hours to 10 hours after administration; and a steady state plasma level of (Z)-endoxifen greater than 30 nM; and wherein at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of the (Z)- endoxifen is released in the intestines.

[0237] In another aspect, the present disclosure relates to a method of treating a subject having or at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder selected from the group consisting of benign breast disorders, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright Syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering daily an oral liquid formulation or particle comprising 0.01 mg to 200 mg of (Z)-endoxifen or a salt or polymorph thereof formulated as an enteric tablet, an enteric caplet, an enteric capsule, a delayed-release tablet, a delayed-release caplet, or a delayed- release capsule, wherein administration of the liquid formulation or particle achieves: a mean half-life of (Z)-endoxifen in the subject ranging from 30 hours to 60 hours after administration; a time to maximum plasma levels of (Z)-endoxifen ranging from 2 hours to 10 hours after administration; and a steady state plasma level of (Z)-endoxifen greater than 30 nM.

[0238] In another aspect, the present disclosure relates to a method of treating a subject having or at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder selected from the group consisting of benign breast disorders, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright Syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering daily an oral liquid formulation or particle comprising 0.01 mg to 200 mg of (Z)-endoxifen or a salt or polymorph thereof formulated as an enteric tablet, an enteric caplet, an enteric capsule, a delayed-release tablet, a delayed-release caplet, or a delayed- release capsule, wherein administration of the liquid formulation or particle achieves: a mean half-life of (Z)-endoxifen in the subject ranging from 30 hours to 60 hours after administration; a time to maximum plasma levels of (Z)-endoxifen ranging from 2 hours to 10 hours after administration; and a steady state plasma level of (Z)-endoxifen greater than 30 nM; and wherein at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of the (Z)- endoxifen is released in the intestines.

[0239] In another aspect, the present disclosure relates to a method of treating a subject having or at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder selected from the group consisting of benign breast disorders, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright Syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering daily an oral liquid formulation or particle comprising 0.01mg to 200 mg of (Z)-endoxifen or a salt or polymorph thereof formulated as an enteric tablet, an enteric caplet, an enteric capsule, a delayed-release tablet, a delayed-release caplet, or a delayed- release capsule, wherein administration of the liquid formulation or particle achieves: a mean half-life of (Z)-endoxifen in the subject ranging from 30 hours to 60 hours after administration; a time to maximum plasma levels of (Z)-endoxifen ranging from 2 hours to 10 hours after administration; and a steady state plasma level of (Z)-endoxifen greater than 30 nM; wherein the mean area under the curve extrapolated to time infinity (AUCO-inf) is 200 hr*ng / mL to 10000 hr*ng / mL, 300 hr*ng / mL to 8000 hr*ng / mL, 400 hr*ng / mL to 6000 hr*ng / mL or 700 hr*ng / mL to 6000 hr*ng / mL; and wherein at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of the (Z)-endoxifen is released in the intestines.

[0240] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the method is a primary therapy, a neo-adjuvant therapy, or an adjuvant therapy.

[0241] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein a liquid formulation or a particle is administered to a subject as combination therapy.

[0242] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein a liquid formulation or a particle is administered to a subject either alone in combination with a second therapeutic agent.

[0243] In still another aspect, the present disclosure relates to a method of treating a subject in need thereof comprising administering a liquid formulation or a particle comprising (Z)- endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the liquid formulation or the particle is administered to a subject with a second therapeutic agent selected from the group consisting of bicalutamide, enzalutamide, or an anticancer drug such as trastuzumab, antineoplastics such as capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinol), cyclophosphamide (Neosar), docetaxel (Docefrez, Taxotere), doxorubicin (Adriamycin), PEGylated liposomal doxorubicin (Doxil), epirubicin (Ellence), fluorouracil (5-FU, Adrucil), gemcitabine (Gemzar), methotrexate (multiple brand names), paclitaxel (Taxol), protein-bound paclitaxel (Abraxane), vinorelbine (Navelbine),eribulin (Halaven), ixabepilone (Ixempra), and ATP-cassette binding protein transport inhibitors.

[0244] In still another aspect, the present disclosure relates to a use for the treatment and prevention of a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both, in a subject, the use comprising: dosing the subject with a first liquid formulation or particle comprising tamoxifen; determining the subject's tamoxifen-metabolites profile in a test sample obtained from the subject; determining a reduced level of subject's plasma (Z)-endoxifen based on subject's tamoxifen-metabolites profile as to compared to a level of plasma (Z)-endoxifen in a reference tamoxifen-metabolites profile; and administering to the subject a liquid formulation or a particle of the present disclosure.

[0245] In still another aspect, the present disclosure relates to a use for the treatment and prevention of a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both, in a subject, the use comprising: dosing the subject with a first composition comprising tamoxifen; determining the subject's tamoxifen-metabolites profile in a test sample obtained from the subject; determining a reduced level of subject's plasma (Z)-endoxifen based on subject's tamoxifen-metabolites profile as to compared to a level of plasma (Z)-endoxifen in a reference tamoxifen-metabolites profile; and administering to the subject a liquid formulation or a particle of the present disclosure; wherein the composition is administered orally in a dose sufficient to maintain the subject's plasma (Z)-endoxifen at a steady state level greater than 30 nM; wherein the tamoxifen-metabolites profile comprises a panel of at least tamoxifen, 4- hydroxytamoxifen, n-desmethyltamoxifen, or (Z)-endoxifen; wherein the hormone-dependent breast disorder or the hormone-dependent reproductive tract disorder is a benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright Syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer; wherein the hormone-dependent breast disorder is a pre-cancer, an early stage cancer, a non-metastatic cancer, a pre-metastatic cancer, a locally advanced cancer, or metastatic cancer; wherein the hormone-dependent breast disorder is a non-metastatic cancer; wherein the subject has prostate cancer, and wherein the subject further has or is at risk of having gynecomastia; or wherein the hormone-dependent breast disorder or hormone-dependent reproductive tract disorder is tamoxifen-refractory or tamoxifen resistant.

[0246] In still another aspect, the present disclosure relates to a kit for treating a subject having or at risk of having a hormone-dependent breast disorder or hormone dependent reproductive tract disorder, in a subject in need thereof comprising: (a) a liquid formulation or particle of thepresent disclosure; and (b) a sealed container for housing the liquid formulation or particle; and c) instructions for use of the orally administered liquid formulation or particle.

[0247] In still another aspect, the present disclosure relates to a kit for treating a subject having or at risk of having a hormone-dependent breast disorder or hormone dependent reproductive tract disorder, in a subject in need thereof comprising: (a) a liquid formulation or particle of the present disclosure; and (b) a sealed container for housing the liquid formulation or particle; and c) instructions for use of the orally administered liquid formulation or particle, wherein the kit comprises a second therapeutic agent selected from the group consisting of bicalutamide, enzalutamide and anticancer drugs such as trastuzumab, antineoplastics such as capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinol), cyclophosphamide (Neosar), docetaxel (Docefrez, Taxotere), doxorubicin (Adriamycin), PEGylated liposomal doxorubicin (Doxil), epirubicin (Ellence), fluorouracil (5-FU, Adrucil), gemcitabine (Gemzar), methotrexate (multiple brand names), paclitaxel (Taxol), protein-bound paclitaxel (Abraxane), vinorelbine (Navelbine), eribulin (Halaven), ixabepilone (Ixempra), and ATP-cassette binding protein transport inhibitors.

[0248] In still another aspect, the present disclosure relates to a method of administering a liquid formulation or particle prepared in accordance with any of the processes described herein to a subject in need thereof in accordance with instructions for use comprised in a kit comprising the liquid formulation or particle.

[0249] In one embodiment, the present disclosure provides methods of treating a subject having or at risk of having a hormone-dependent disorder, a mood disorder or any disorder susceptible to (Z)-endoxifen or a polymorph or a salt thereof, the method comprising administering a particle comprising (Z)-endoxifen and a coating.EXAMPLES

[0250] The invention is further illustrated by the following non-limiting examples.EXAMPLE 1Oral Administration of a (Z)-Endoxifen Particles

[0251] This example describes cancer treatment with (Z)-endoxifen particles. A subject is identified as positive for a form of cancer which is treatable by (Z)-endoxifen. The subject is provided dry (Z)-endoxifen particles and is instructed to orally self-administer the particles once weekly. The client self-administers the particles by adding them to food prior to consumption. The particles contain microcrystalline (Z)-endoxifen interspersed within a gastrically stable enteric coating material. The enteric coating material prevents (Z)-endoxifen release within the stomach but degrades intestinally to release the (Z)-endoxifen. The (Z)-endoxifen has greaterthan 95% isomeric purity, which increases treatment potency and decreases side effects relative to a 50:50 (E):(Z) endoxifen mixture. The (E):(Z) endoxifen ratio does not detectably change during storage or upon administration. The (Z)-endoxifen treatment is continued until the cancer diminishes in the subject, as determined by total detectable tumor volume by PET scan. The subject is provided the option to continue the (Z)-endoxifen treatment until the cancer becomes undetectable.EXAMPLE 2Cancer Treatment with Slurry of (Z)-Endoxifen Particles

[0252] This example covers cancer treatment with a suspension containing (Z)-endoxifen particles. A subject is identified as having a cancer which is treatable by (Z)-endoxifen. The subject is prescribed (Z)-endoxifen particles, which they are instructed to self-administer 3-times per week by syringing directly into their mouth. Upon receipt, the (Z)-endoxifen particles are suspended in a sweet syrup. The (Z)-endoxifen particles contain an enteric coating which surrounds a powder (Z)-endoxifen core, and which is stable in the syrup. After one month of storage at 25°C, the particle-containing syrup has a concentration of free endoxifen of less than 100 nM. The enteric coating material prevents (Z)-endoxifen release within the stomach but degrades intestinally to release the (Z)-endoxifen. The (E):(Z) endoxifen ratio does not detectably change during storage at 25 °C or upon administration. The (Z)-endoxifen treatment is continued until the cancer becomes undetectable in the subject through circulating tumor DNA (ctDNA) and circulating tumor cell analysis.EXAMPLE 3Cancer Treatment with a (Z)-Endoxifen Solution

[0253] This example covers cancer treatment with a (Z)-endoxifen solution. A subject is identified as having a cancer which is treatable by (Z)-endoxifen. The subject is provided a water-based solution containing dissolved (Z)-endoxifen, flavoring, and thickening agents, such that the solution has a flavor and texture akin to those of syrup. The (Z)-endoxifen has greater than 95% isomeric purity, which does not detectably decrease over one month of storage at 25 °C. The subject consumes 5 mL of the solution twice daily until the cancer is no longer detectable.EXAMPLE 4Hypromellose-Encapsulated (Z)-Endoxifen

[0254] This example covers cancer treatment with a (Z)-endoxifen microparticle formulation. The microparticles have a mean diameter of 400 pm and contain a powder dispersion of (Z)-endoxifen, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The powder dispersion is covered with a Hypromellose enteric resistant, delayed release coating. The croscarmellose sodium prevents crosslinking between the endoxifen and the Hypromellose coating.

[0255] 400 mg of the microparticles containing 20 mg (Z)-endoxifen are added to a fruit smoothie, and the fruit smoothie is consumed by a human child with cancer. The microparticles are stable in the smoothie and stomach of the child, releasing less than 10% of their (Z)- endoxifen prior to transit through the ileum. Greater than 60% of the (Z)-endoxifen is released in the small intestine of the human child. The child repeats this treatment twice daily until their cancer is remediated.

[0256] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. An oral formulation comprising a microparticle, wherein the microparticle comprises a(Z)-endoxifen composition and a coating, wherein the (Z)-endoxifen composition comprises a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein at least 90% by weight of the compound of Formula (I) is (Z)-endoxifen or a pharmaceutically acceptable salt thereof.

2. The oral formulation of claim 1, wherein the oral formulation comprises a plurality of microparticles comprising between them a total of from 0.01 mg to 200 mg, 5 mg to 80 mg, 5 mg to 60 mg, 5 mg to 40 mg, 10 mg to 80 mg, 40 mg to 80 mg, or 50 to 100 mg of (Z)- endoxifen.

3. The oral formulation of claim 1 or 2, wherein the oral formulation comprises a plurality of microparticles comprising between them a total of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, or 40 mg of (Z)-endoxifen.

4. The oral formulation of any one of claims 1-3, wherein the oral formulation is a capsule.

5. The oral formulation of any one of claims 1-3, wherein the oral formulation is an enteric capsule.

6. The oral formulation of any one of claims 1-3, wherein the coating comprises hydroxypropylmethyl cellulose.

7. The oral formulation of any one of claims 1-6, wherein the oral formulation is formulated for addition to a beverage, a solid food, a cream, a gel, a colloid, a syrup, or a combination thereof.

8. The oral formulation of any one of claims 1-7, wherein the oral formulation is formulated for suspension in liquid.

9. The oral formulation of claim 8, wherein the liquid is an aqueous solution.

10. The oral formulation of claim 9, wherein a dose of the oral formulation is 0.01 mL to 10 mL of the aqueous solution per kg body weight.

11. The oral formulation of claim 10, wherein the dose of the oral formulation is 0.01 mL, 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, or 1 mL of the aqueous solution per kg body weight.

12. The oral formulation of any one of claims 1-11, comprising a dose of (Z)-endoxifen of 0.01 to 3 mg / kg of body weight.

13. The oral formulation of claim 12, comprising a dose of (Z)-endoxifen of 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / .kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, or 3 mg / kg of body weight.

14. The oral formulation of claim 9, wherein the aqueous solution comprises a sugar, a sugar alcohol, a sweetener, a flavoring, an alcohol, glycerol, propylene glycol, or combinations thereof.

15. The oral formulation of any one of claims 8-14, wherein the liquid is viscous.

16. The oral formulation of any one of claims 1-15, wherein the microparticle further comprises a filler.

17. The oral formulation of claim 16, wherein the filler comprises talc, calcium carbonate, a sugar, a salt, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, or combinations thereof.

18. The oral formulation of any one of claims 1-17, wherein the microparticle further comprises a disintegrant.

19. The oral formulation of any one of claims 1-18, wherein the microparticle further comprises a lubricant.

20. The oral formulation of claim 19, wherein the lubricant comprises calcium stearate, magnesium stearate, zinc stearate, mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil, ethyl oleate, ethyl laureate, agar, or combinations thereof.

21. The oral formulation of any one of claims 1-20, wherein the microparticle further comprises croscarmellose sodium.

22. The oral formulation of any one of claims 1-21, wherein the microparticle is no more than 500 pm, no more than 300 pm, no more than 200 pm, no more than 150 pm, no more than 100 pm, no more than 75 pm, no more than 50 pm, or no more than 25 pm in diameter as measured by microscopy, scanning electron microscopy, transmission electron microscopy, dynamic light scattering, laser diffraction, Coulter counter, or sedimentation.

23. The oral formulation of any one of claims 1-22, wherein the coating is from 1 nm to 100 nm thick.

24. The oral formulation of claim 23, wherein the coating is from 1 nm to 10 nm, from 20 nm to 30 nm, from 30 nm to 40 nm, from 40 nm to 50 nm, from 50 nm to 60 nm, from 60 nm to 70 nm, from 70 nm to 80 nm, from 80 nm to 90 nm, or from 90 nm to 100 nm thick.

25. The oral formulation of any one of claims 1-24, wherein the (Z)-endoxifen has a half-life of between 4 to 24 hours in pH 1.2 simulated gastric fluid at 37°C.

26. The oral formulation of any one of claims 1-25, wherein the (Z)-endoxifen has a half-life of between 2 to 72 hours in pH 6.7 simulated intestinal fluid at 37°C.

27. The oral formulation of any one of claims 1-26, wherein the (Z)-endoxifen has a half-life of between 12 to 144 hours in pH 7.0 deionized water at 25°C.

28. The oral formulation of any one of claims 1-27, wherein the coating is an enteric coating.

29. The oral formulation of any one of claims 1-28, wherein the coating comprises a pH- dependent polymer.

30. The oral formulation of any one of claims 1-29, wherein the coating comprises an acid insoluble polymer.

31. The oral formulation of claim 30, wherein the acid insoluble polymer is cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, an alginic acid salt, shellac, pectin, an acrylic acid-methylacrylic acid copolymer, or a combination thereof.

32. The oral formulation of any one of claims 1-31, wherein the microparticle further comprises a plasticizer, a disintegrant, a control release agent, a sustained release agent, a lubricant, or a combination thereof.

33. The oral formulation of any one of claims 1-32, wherein at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of the compound of Formula (I) is (Z)-endoxifen or a pharmaceutically acceptable salt thereof.

34. The oral formulation of any one of claims 1-33, wherein the pharmaceutically acceptable salt of (Z)-endoxifen is selected from the group consisting of: arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (Embonate), pantothenate, phosphate / diphosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, Teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc.

35. The oral formulation of any one of claims 1-34, wherein the pharmaceutically acceptable salt of (Z)-endoxifen is (Z)-endoxifen gluconate.

36. The oral formulation of any one of claims 1-35, wherein the (Z)-endoxifen is (Z)- endoxifen free base.

37. The oral formulation of any one of claims 1-36, wherein the (Z)-endoxifen comprises less than 2%, less than 1.5%, less than 1%, or less than 0.5% impurities.

38. The oral formulation of any one of claims 1-37, wherein the (Z)-endoxifen is stable for at least 9 months at 25 °C and 60% relative humidity.

39. The oral formulation of any one of claims 1-38, wherein the (Z)-endoxifen is stable for at least 3 months at 40 °C and 75% relative humidity.

40. The oral formulation of any one of claims 1-39, wherein the (Z)-endoxifen has an aerobic bacterial plate count of 0.05 g / mL to 20,000 g / mL.

41. The oral formulation of any one of claims 1-40, wherein the (Z)-endoxifen has a water content of not more than 1.0% as tested by Method Ic of USP 921.

42. The oral formulation of any one of claims 1-41, wherein the (Z)-endoxifen has a water activity (Aw) of less than 0.9.

43. The oral formulation of any one of claims 1-42, wherein the (Z)-endoxifen has a residue on ignition of not more than 0.1% as tested by a method of USP 281.

44. The oral formulation of any one of claims 1-43, wherein the (Z)-endoxifen comprises not more than 20 ppm of heavy metals as tested by Method II of USP 231.

45. The oral formulation of any one of claims 1-44, wherein the (Z)-endoxifen comprises not more than 3000 ppm methanol, not more than 720 ppm tetrahydrofuran, not more than 5000 ppm isopropanol, not more than 5000 ppm ethyl acetate; not more than 5000 ppm n-Heptane, not more than 5000 ppm ethanol, or any combination thereof, as tested by a validated HPLC method.

46. The oral formulation of any one of claims 1-45, wherein the (Z)-endoxifen comprises not more than 3000 ppm methanol, not more than 720 ppm tetrahydrofuran, not more than 5000 ppm isopropanol, not more than 5000 ppm ethyl acetate, not more than 5000 ppm heptane, and not more than 5000 ppm ethanol, as tested by a validated HPLC method.

47. The oral formulation of any one of claims 1-46, wherein the (Z)-endoxifen: comprises less than 2%, less than 1.5%, less than 1%, or less than 0.5% impurities; is stable for at least 9 months at 25 °C and 60% relative humidity; is stable for at least 3 months at 40 °C and 75% relative humidity; has an aerobic bacterial plate count of 0.05 g / mL to 20,000 g / mL; has a water content of not more than 1.0% as tested by Method Ic of USP 921; has a water activity (Aw) of less than 0.9; has a residue on ignition of not more than 0.1% as tested by a method of USP 281; comprises not more than 20 ppm of heavy metals as tested by Method II of USP 231; comprises not more than 3000 ppm methanol, not more than 720 ppm tetrahydrofuran, not more than 5000 ppm isopropanol, not more than 5000 ppm ethyl acetate; not more than 5000 ppm n-Heptane, not more than 5000 ppm ethanol, or any combination thereof, as tested by a validated HPLC method; or any combination thereof.

48. The oral formulation of any one of claims 1-47, wherein the oral formulation is formulated as an enteric tablet, an enteric caplet, or an enteric capsule.

49. A method of treating a disease in a subject in need thereof, comprising administering the oral formulation of any one of claims 1-48 to the subject, thereby treating the disease.

50. The method of claim 49, wherein the oral formulation is added to a beverage, a solid food, a cream, a gel, a colloid, or a syrup prior to administration.

51. The method of claim 49 or 50, wherein the oral formulation is suspended in a liquid prior to administration.

52. The method of claim 51 , wherein the liquid is an aqueous solution.

53. The method of claim 52, wherein the aqueous solution comprises a sugar, a sugar alcohol, a sweetener, a flavoring, an alcohol, glycerol, propylene glycol, or combinations thereof.

54. The method of any one of claims 51-53, wherein the liquid is viscous.

55. The method of any one of claims 49-54, wherein the administering comprises oral ingestion of the oral formulation.

56. The method of any one of claims 49-55, wherein the oral formulation comprises a plurality of microparticles comprising between them a total of from 0.01 mg to 200 mg, 5 mg to 80 mg, 5 mg to 60 mg, 5 mg to 40 mg, 10 mg to 80 mg, 40 mg to 80 mg, or 50 to 100 mg of (Z)- endoxifen.

57. The method of any one of claims 52-56, wherein a dose of the oral formulation is 0.01 mL to 10 mL of the aqueous solution per kg body weight.

58. The method of claim 57, wherein the dose of the oral formulation is 0.01 mL, 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, or 1 mL of the aqueous solution per kg body weight.

59. The method of any one of claims 49-58, wherein a dose of (Z)-endoxifen is 0.01 to 3 mg / kg of body weight.

60. The method of claim 59, wherein the dose of (Z)-endoxifen is 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / .kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, or 3 mg / kg of body weight.

61. The method of any one of claims 49-60, wherein the subject is a child.

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