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 administration of traditional oral dosage forms or who prefer an alternative dosage form. Provided herein are enteric and delayed release formulations comprising coated (Z)-endoxifen microparticles for oral delivery that enhance patient compliance and therapeutic efficacy for overall improved therapeutic outcomes.

Description

Cross-referencing

[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 Technology

[0002] Many pharmaceutical compounds are administered orally as tablets or capsules. While these dosage forms are convenient and effective, swallowing large pills can be challenging for some patients, including children, the elderly, and individuals with throat or esophageal disorders. Especially for diseases that may require regular administration of pharmaceutical compositions and strict adherence to dosing schedules (such as cancer), there remains a need for dosage forms that are easy and comfortable to take orally regardless of age or health status.

[0003] Childhood cancers represent different groups of malignancies affecting 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 a leading cause of disease-related death in children and adolescents. The most common types of childhood cancers include leukemia, brain and central nervous system tumors, lymphoma, neuroblastoma, and sarcoma. Each of these types presents unique challenges in diagnosis, treatment, and long-term outcomes. There is a need for formulations that can be administered orally to children or other patients who may have difficulty taking traditional oral dosage forms. Summary of the Invention

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

[0005] In some aspects, the oral formulation comprises a plurality of microparticles, with a total of 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)-indoxifene between the microparticles. In some aspects, the oral formulation comprises a plurality of microparticles, with 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)-indoxifene between the microparticles. In some aspects, the oral formulation is a capsule. In some aspects, the oral formulation is an enteric-coated capsule. In some aspects, the coating comprises hydroxypropyl methylcellulose.

[0006] In some aspects, the oral formulation is formulated for addition to beverages, solid foods, creams, gels, colloids, syrups, or combinations thereof. In some aspects, the oral formulation is formulated for suspension in a liquid. In some aspects, the liquid is an aqueous solution. In some aspects, the dosage of the formulation is an aqueous solution of 0.01 mL to 10 mL per kg body weight. In some aspects, the dosage of the formulation is an aqueous solution of 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 per kg body weight. In some aspects, the oral formulation contains a dose of (Z)-indoxifene of 0.01 to 3 mg / kg body weight. In some respects, oral formulations contain (Z)-indoxifene in doses 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 body weight.

[0007] In some aspects, the aqueous solution includes sugars, sugar alcohols, sweeteners, flavoring agents, alcohols, glycerol, propylene glycol, or combinations thereof. In some aspects, the liquid is viscous. In some aspects, the microparticles also include fillers. In some aspects, fillers include talc, calcium carbonate, sugars, salts, microcrystalline cellulose, methylcellulose, carboxymethyl cellulose, kaolin, mannitol, silica, sorbitol, starch, pregelatinized starch, or combinations thereof. In some aspects, the microparticles also include disintegrants. In some aspects, the microparticles also include lubricants. In some aspects, lubricants include calcium stearate, magnesium stearate, zinc stearate, mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil, ethyl oleate, ethyl laurate, agar, or combinations thereof. In some aspects, the microparticles also include croscarmellose sodium.

[0008] In some aspects, as measured by microscopy, scanning electron microscopy, transmission electron microscopy, dynamic light scattering, laser diffraction, Coulter counter, or sedimentation, the diameter of the particles is not greater than 500 μm, not greater than 300 μm, not greater than 200 μm, not greater than 150 μm, not greater than 100 μm, not greater than 75 μm, not greater than 50 μm, or not greater than 25 μm. In some aspects, the coating is 1 nm to 100 nm thick. In some aspects, the coating is 1 nm to 10 nm, 20 nm to 30 nm, 30 nm to 40 nm, 40 nm to 50 nm, 50 nm to 60 nm, 60 nm to 70 nm, 70 nm to 80 nm, 80 nm to 90 nm, or 90 nm to 100 nm thick.

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

[0010] In some aspects, the coating is an enteric coating. In some aspects, the coating comprises a pH-dependent polymer. In some aspects, the coating comprises an acid-insoluble polymer. In some aspects, the acid-insoluble polymer is cellulose acetate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, alginate, shellac, pectin, acrylic acid-methacrylic acid copolymer, or combinations thereof. In some aspects, the microparticles also comprise plasticizers, disintegrants, controlled-release agents, sustained-release agents, lubricants, or combinations 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)-indoxifene or a pharmaceutically acceptable salt thereof. In some aspects, a pharmaceutically acceptable salt of (Z)-indoxifene is selected from the group consisting of: arecoline, benzenesulfonate, bicarbonate, tartrate, butyl bromide, citrate, camphorsulfonate, gluconate, glutamate, glycolyllarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, hydroxyethanesulfonate, malate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucilage, naphthalenesulfonate, nitrate, and pamaoate. (Z)-Indoxifene contains various salts including: (Z)-indoxifene salts, pantothenate salts, phosphates / bisphosphates, polygalacturonic acid salts, salicylates, stearates, sulfates, tannic acid salts, teaclate, triethyliodine, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth salts, lithium, magnesium, potassium, and zinc. In some aspects, the pharmaceutically acceptable salt of (Z)-indoxifene is (Z)-indoxifene gluconate. In some aspects, (Z)-indoxifene is (Z)-indoxifene free base.

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

[0013] In some aspects, as tested by method Ic of USP 921, (Z)-indoxifene has a water content of not more than 1.0%. In some aspects, (Z)-indoxifene has a water activity (Aw) of less than 0.9. In some aspects, as tested by method Ic of USP 281, (Z)-indoxifene has a residue on ignition of not more than 0.1%. In some aspects, as tested by method II of USP 231, (Z)-indoxifene contains not more than 20 ppm of heavy metals. In some aspects, as tested by a validated HPLC method, (Z)-indoxifene contains not more than 3000 ppm of methanol, not more than 720 ppm of tetrahydrofuran, not more than 5000 ppm of isopropanol, not more than 5000 ppm of ethyl acetate; not more than 5000 ppm of n-heptane, not more than 5000 ppm of ethanol, or any combination thereof. In some aspects, as tested by a validated HPLC method, (Z)-indoxifene comprises no more than 3000 ppm methanol, no more than 720 ppm tetrahydrofuran, no more than 5000 ppm isopropanol, no more than 5000 ppm ethyl acetate, no more than 5000 ppm heptane and no more than 5000 ppm ethanol.

[0014] In some respects, (Z)-Indoxifene contains 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 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 method 281 of USP 281; contains not more than 20 ppm of heavy metals as tested by method II of USP 231; contains not more than 3000 ppm of methanol, not more than 720 ppm of tetrahydrofuran, not more than 5000 ppm of isopropanol, not more than 5000 ppm of ethyl acetate as tested by a validated HPLC method; and not more than 5000 ppm of... ppm n-heptane, not more than 5000 ppm ethanol, or any combination thereof; or any combination thereof. In some aspects, the oral formulation is formulated as enteric-coated tablets, enteric-coated capsules, or enteric-coated capsules.

[0015] In some aspects, the techniques described herein relate to methods for treating a disease in a subject in need, the methods comprising administering an oral formulation to the subject, thereby treating the disease. In some aspects, the oral formulation is added to a beverage, solid food, cream, gel, colloid, or 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 contains sugars, sugar alcohols, sweeteners, flavoring agents, alcohols, glycerol, propylene glycol, or combinations thereof. In some aspects, the liquid is viscous.

[0016] In some aspects, administration includes oral ingestion of an oral formulation. In some aspects, the oral formulation comprises a plurality of microparticles, with a total concentration of (Z)-indoxifene between said microparticles of 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. In some aspects, the oral formulation is administered in a dose of 0.01 mL to 10 mL of aqueous solution per kg body weight. In some aspects, the oral formulation is administered in a dose of 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 aqueous solution per kg body weight. In some aspects, the dose of (Z)-indoxifene is 0.01 to 3 mg / kg body weight. In some cases, the dosage of (Z)-indoxifene 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 body weight.

[0017] In some cases, the subjects were children.

[0018] By incorporating references All publications, patents and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication, patent or patent application were specifically and individually indicated to the extent of their incorporation by reference. Attached Figure Description

[0019] The novel features of the invention are specifically set forth in the appended claims. A better understanding of the features and advantages of the invention will be obtained by referring to the following detailed description and accompanying drawings, in which illustrative embodiments utilizing the principles of the invention are set forth: Figure 1 X-ray powder diffraction (XRPD) pattern of a sample of form I derived from compound (I).

[0020] Figure 2 XRPD pattern of a sample of form I obtained from compound (I).

[0021] Figure 3 XRPD pattern of a sample of form I obtained from compound (I).

[0022] Figure 4 XRPD pattern of a sample obtained from form II of compound (I).

[0023] Figure 5 XRPD pattern of a sample obtained from form III of compound (I).

[0024] Figure 6 X-ray powder diffraction (XRPD) spectra of polymorphs of form IV consistent with this disclosure are provided.

[0025] Figure 7 XRPD spectra of polymorphs of form V consistent with this disclosure are provided.

[0026] Figure 8 XRPD spectra of polymorphs consistent with Form VI of this disclosure are provided.

[0027] Figure 9 XRPD spectra of polymorphs consistent with form VII of this disclosure are provided.

[0028] Figure 10 XRPD spectra of polymorphs consistent with Form VIII of this disclosure are provided.

[0029] Figure 11 XRPD spectra of polymorphs of form IX, consistent with this disclosure, are provided.

[0030] Figure 12 XRPD spectra of polymorphs of form X consistent with this disclosure are provided.

[0031] Figure 13 XRPD spectra of polymorphs in form XI consistent with this disclosure are provided.

[0032] Figure 14 XRPD spectra of polymorphs of form XII consistent with this disclosure are provided.

[0033] Figure 15 XRPD spectra of polymorphs of form XIV consistent with this disclosure are provided.

[0034] Figure 16 XRPD spectra of polymorphs of XV consistent with this disclosure are provided.

[0035] Figure 17 XRPD spectra of polymorphs of XIX in form consistent with this disclosure are provided. Detailed Implementation

[0036] This disclosure provides oral formulations of (Z)-indoxifene suitable for administration to individuals unsuitable for conventional oral dosage forms (e.g., standard-sized capsules or tablets), such as in certain elderly and younger patients. Some neurological disorders, anatomical abnormalities, and muscle disorders can also make swallowing conventional oral dosage forms problematic. The oral formulations of the present invention are easy to administer orally and advantageously increase patient compliance, dosage certainty, and treatment effectiveness for patients who cannot or do not wish to swallow conventional oral dosage forms. The oral liquid formulations of the present invention are developed to efficiently deliver (Z)-indoxifene to individuals who may have difficulty taking conventional oral dosage forms and include enteric-coated and delayed-release (Z)-indoxifene particles, including, for example, microparticles. The formulations presented herein provide effective and accessible (Z)-indoxifene administration to individuals who are difficult to treat in the absence of these oral liquid formulations.

[0037] This disclosure provides therapeutic particles suitable for treating cancer and applicable in various forms of administration. The particles may contain (Z)-indoxifene within a biodegradable coating and may provide targeted or sustained release of (Z)-indoxifene upon administration to a subject. In some embodiments, the particles contain an enteric coating that prevents release of (Z)-indoxifene in the stomach, thereby avoiding acid-mediated degradation and isomerization of (Z)-indoxifene, and promotes release of (Z)-indoxifene in the small intestine, where it is readily absorbed into the bloodstream. The particles may have high water stability, enabling formulation in foods, beverages, and syrups.

[0038] Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0039] Unless the context otherwise requires, the terms “a / an” and “the” as used herein include a number of indicators.

[0040] As used herein, the terms “active pharmaceutical ingredient,” “active component,” “API,” “drug,” “active,” “active agent,” or “therapeutic agent” are used interchangeably to refer to a pharmaceutically active compound in a pharmaceutical composition. This contrasts with other components in the composition, such as excipients, which are substantially or entirely pharmaceutically inert. A suitable active pharmaceutical ingredient (API) according to this disclosure is an API for which there are or may be patient compliance issues in treating a disease, ailment, or condition. As used herein, a therapeutic agent includes an active compound and its salts, prodrugs, and metabolites. As used herein, the term “drug” means a compound intended for the diagnosis, cure, relief, treatment, and / or prevention of diseases in humans or other animals.

[0041] As used in this article, "adjuvant therapy" refers to a therapy administered to subjects at risk of recurrence after primary therapy. In the case of cancer, adjuvant systemic therapy (such as the use of tamoxifen) is typically initiated shortly after primary therapy to delay recurrence, prolong survival, or cure the subject.

[0042] As used herein, the term "tamoxifen" refers to (Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine. Tamoxifen may also refer to the E-isomer or a combination of the E-isomer and the Z-isomer.

[0043] As used herein, the term "(Z)-indoxifene" refers to (Z)-4-hydroxy-N-demethyl-tamoxifen, which is a secondary active metabolite of tamoxifen.

[0044] As used herein and in the claims, the terms “comprising,” “containing,” and “including” are inclusive, open-ended, and do not exclude other unlisted elements, constituent components, or method steps. Therefore, the terms “comprising” and “including” encompass the more restrictive terms “consisting of” and “substantially consisting of”.

[0045] As used herein, the term "combination therapy" refers to the use of the composition of the invention described herein in combination with one or more treatments. The treatment in a combination therapy can be any treatment, such as any prophylactic agent, additional therapeutic agents (e.g., chemotherapy and immunotherapy), radiotherapy, surgery, etc. "Combination" can mean the inclusion of a therapeutic agent or prophylactic agent in the same composition as the composition of the invention disclosed herein (e.g., in the same capsules, tablets, pouches, etc.) or in a separate composition (e.g., in two separate tablets). The separate compositions can be in different dosage forms or administered via different routes of administration. The use of the terms "combination therapy" and "in combination with" does not limit the order in which the composition of the invention described herein and the prophylactic agent and / or therapeutic agent and / or treatment are administered to the subject of need. The compositions disclosed herein may be administered to subjects in need before, simultaneously with, or after (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, 6 months, 9 months, or 1 year prior to, during, or after (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, 6 months, 9 months, or 1 year after) administration of one or more prophylactic and / or therapeutic agents or treatments to subjects in need. Administered over a period of 6 months (m), 9 months, or 1 year. As used herein, combination therapy may also refer to treatment of subjects with a single disease or multiple diseases or conditions (e.g., various types of cancer in adults and children).

[0046] As used herein, the term “test sample” means a blood sample obtained from a subject. It should be understood that when a blood sample is obtained from a subject, the subject’s blood is used as whole blood, plasma, and / or serum to determine the subject’s (Z)-indoxifene levels and / or other measurable or testable biomarkers. Unless otherwise expressly indicated, as used herein, “plasma (Z)-indoxifene” refers to the (Z)-indoxifene level in a subject’s test sample, whether the test is performed on whole blood, plasma, and / or serum.

[0047] As used herein, the term “dosage form” means the form in which the compounds or compositions of this disclosure are delivered to a patient.

[0048] As used herein, the terms "pharmaceuticalally acceptable" or "pharmacologically acceptable" mean a material, composition, or vehicle that is compatible with other components of a formulation and will not materially produce adverse effects (such as toxicity, allergic reactions, or immune responses) when administered to a subject. It may be approved by, for example, a regulatory agency of the U.S. Federal or state governments or listed in the U.S. Pharmacopeia or other recognized pharmacopoeia for use in animals, and more specifically in humans.

[0049] As used herein, the term "pharmaceutically acceptable carrier" or "carrier" means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in carrying or transporting one or more compounds of this disclosure from a tissue, organ, or part of the body or through the skin.

[0050] As used herein, the term "pharmaceutical composition" means a combination of an active agent (e.g., an active pharmaceutical compound or ingredient, API) with an inert or active carrier (e.g., phospholipids) that makes the composition particularly suitable for in vitro, in vivo, or ex vivo diagnostic, preventive, or therapeutic use.

[0051] As used herein, "primary therapy" refers to the first-line treatment following an initial diagnosis of a subject's disease (such as cancer). Exemplary primary therapies may include surgery, a broad range of chemotherapy, and radiation therapy.

[0052] As used herein, the terms “subject,” “patient,” “participant,” and “individual” are used interchangeably and refer to mammals, such as humans. Mammals also include pet animals, such as dogs and cats; laboratory animals, such as rats and mice; and farm animals, such as cows and horses. Unless otherwise stated, mammals may have any sex.

[0053] As used herein, the term "tamoxifen refractory" refers to a subject who has been given tamoxifen daily for at least 2 days and has a plasma (Z)-indoxifene level of less than 30 nM (e.g., less than 20 nM, less than 25 nM, or less than 30 nM). As used herein, the term "tamoxifen resistance" refers to two types of resistance: (a) neonatal resistance (…). de novo(a) Resistance, i.e., no response to tamoxifen therapy from the start of treatment, and (b) acquired resistance, i.e., no response to tamoxifen therapy after initial response or tamoxifen-dependent / stimulated growth, while continuing to express estrogen receptors (Minsun Chang. Biomol. Ther. 20(3), 256-267 (2012)). Acquired resistance to tamoxifen can develop as early as 3 months to 1 year and as late as 5 to 10 years. As used herein, the term “reference plasma (Z)-indoxifene level” refers to a value of 30 nM.

[0054] As used herein, the term “unit dosage form” refers to a physical discrete unit of a unit dose suitable for a subject, each unit containing a predetermined amount of active material and suitable pharmaceutical excipients calculated to produce the desired therapeutic effect.

[0055] Terms such as "include / including", "contain / containing", or "has / having" mean "to contain".

[0056] The pharmacokinetic (PK) parameters used in this article are defined and calculated as follows: C max : The maximum observed plasma / serum concentration obtained directly from the data.

[0057] T max : The time to reach the maximum observed concentration, taken directly from the data. If the maximum plasma / serum concentration occurs at more than one time point, the first time point is selected.

[0058] AUC 0-tlast or AUC last The area under the plasma / serum concentration curve relative to time is calculated using the linear trapezoidal rule from time 0 to time t, where t is the time of the last quantifiable concentration.

[0059] Λz: The terminal elimination rate constant of the slope of the curve obtained by fitting the endpoint of the logarithmic concentration-time curve via linear least squares regression.

[0060] AUC inf The area under the plasma / serum concentration versus time curve from zero to infinity is calculated as (AUC). 0-tlast + Ct last / λz), where Ct last This represents the final quantifiable concentration.

[0061] AUC tau The plasma / serum concentration relative to the area under the time curve during the dosing interval (tau) is calculated using the linear trapezoidal rule.

[0062] t ½ Apparent terminal half-life, calculated as (ln(2) / λz).

[0063] CL / F: Apparent total plasma / serum clearance of the drug after oral administration, where F is the fraction of drug absorbed, calculated as (dose / AUC). inf ).

[0064] CL / F ss The apparent total plasma / serum clearance of the drug after multiple oral administrations, where F is the fraction of drug absorbed, calculated as (dose / AUC). tau ).

[0065] V z / F: Apparent volume of distribution during the terminal period after oral administration, calculated as (CL / F / λz).

[0066] C min The minimum observed plasma / serum concentration within the dose interval directly obtained from the data.

[0067] C avg Or C 平均值 The mean plasma / serum concentration at steady state is calculated as (AUC). tau / tau).

[0068] AI: Cumulative Index, calculated as (AUC) tau Day 39 dose / AUC inf Day 1 dose).

[0069] AUC determined by extrapolation inf Partial, %AUC extrap Determined to be 100 x (AUC) inf - AUC 0-tlast ) / AUC inf .

[0070] The term "bioavailability," as defined in 21 CFR §320.1(a), refers to the rate and extent to which an active ingredient or active portion is absorbed from a pharmaceutical product and becomes available at its site of action. For pharmaceutical products not intended for absorption into the bloodstream, bioavailability can be assessed by measurements designed to reflect the rate and extent to which the active ingredient or active portion becomes available at its site of action. For example, bioavailability can be measured as the amount of active ingredient in the blood (serum or plasma) that changes over time. Measured values ​​such as AUC, C... max or T max The pharmacokinetic parameters can be used to measure and assess bioavailability.

[0071] It should be explicitly understood that any numerical value cited herein, including all values ​​from lower to higher (i.e., all possible combinations of values ​​between the listed lowest and highest values), should be considered as expressly stated in this application, and the endpoints of all ranges are included within said ranges and can be combined independently. For example, if a concentration range or beneficial range is stated as 1% to 50%, values ​​such as 2% to 40%, 10% to 30%, 1% to 3%, 1.5% to 2.5%, etc., are expected to be expressly listed in this specification. It should also be understood that if a concentration or dose is stated as a specific value such as 1 mg or 10 mg, or stated as “about 1 mg” or “about 10 mg,” the stated concentration or dose is intended to include a 10% variation. As another example, a stated concentration of 20% or “about 20%” is intended to include values ​​±10%. As another example, if a ratio of 1:10 to 10:1 or "about 1:10 to about 10:1" is stated, then ratios such as 1:9 to 9:1, 1:8 to 8:1, 1:7 to 7:1, 1:6 to 6:1, 1:5 to 5:1, 1:4 to 4:1, 1:3 to 3:1, 1:2 to 2:1, 1:1 to 2:1, 0.9:10.1 to 10.1 to 0.9, or 2:5 to 3:5 are explicitly expected. Only a few instances of explicit expectation exist. Unless otherwise stated, the values ​​of the components or parts of the composition are expressed as a weight percentage of each component or part in the core composition.

[0072] It should be understood that all compounds include all possible isotopes of the atoms present in the compound. Isotopes include those atoms that have the same atomic number but different mass numbers. By way of example, but not limited to, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include... 11 C 13 C and 14 C.

[0073] Unless otherwise indicated or otherwise obviously contradicted by the context, all methods described herein may be performed in a suitable order. Unless otherwise required, the use of any and all instances or exemplary language (e.g., “for example” and “such as”) is intended only to illustrate the invention and not to limit its scope. The language in this specification should not be construed as indicating that any unstated element is essential for practicing the invention as used herein.

[0074] (Z)-Indoxifene Granules This disclosure relates to nanoparticles and microparticles (Z)-indoxifene formulations. In one aspect, this disclosure provides a particle containing a (Z)-indoxifene composition (e.g., powdered or microcrystalline (Z)-indoxifene, optionally including a formulation set of excipients) and a pharmaceutically acceptable coating. The particle can be formulated as a powder that can be added to food, beverages, and other applicable compositions. The coating prevents the (Z)-indoxifene composition from degrading or isomerizing in the applicable composition or at physiological sites not intended for (Z)-indoxifene delivery. Specifically, the coating may be stable in the applicable composition (e.g., in a syrup suspension or in yogurt) and in the stomach, but may release (Z)-indoxifene in the small intestine.

[0075] Granules are suitable for oral administration. Granules may be provided in the form of powders (e.g., multiple instances of granules), which may be added to foods, beverages (e.g., juice, smoothies, or water), tablets, gels, creams, or syrups. For example, powders may be added to yogurt, nut butter, or salad dressing for easy ingestion. Powders are suitable for a wide range of media, allowing subjects to choose new beverages or foods to mix with the powder during each administration. Powders may be provided in dry form, such as as a single dose in a ruptured capsule or small capsule. Powders may also be pre-formulated in edible media, such as food or beverages. For example, a pharmacist may create a syrup suspension containing powder after prescribing it to a subject.

[0076] In some aspects, multiple microparticles contain a total of approximately 0.01 mg to approximately 200 mg of (Z)-indoxifene, such as approximately 0.01 mg, approximately 0.1 mg, approximately 0.2 mg, approximately 0.3 mg, approximately 0.4 mg, approximately 0.5 mg, approximately 0.6 mg, approximately 0.7 mg, approximately 0.8 mg, approximately 0.9 mg, approximately 1.0 mg, approximately 1.1 mg, approximately 1.2 mg, approximately 1.3 mg, approximately 1.4 mg, approximately 1.5 mg, approximately 1.6 mg, approximately 1.7 mg, approximately 1.8 mg, approximately 1.9 mg, approximately 2.0 mg, approximately 2.1 mg, approximately 2.2 mg, approximately 2.3 mg, approximately 2.4 mg, approximately 2.5 mg, approximately 2.6 mg, approximately 2.7 mg, approximately 2.8 mg, approximately 2.9 mg, approximately 3.0 mg, approximately 3.1 mg, approximately 3.2 mg, approximately 3.3 mg, and approximately 3.4 mg. 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, about 4.2 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 within the range formed by any two of the foregoing values.

[0077] In some aspects, the oral formulation is administered in the form of an aqueous solution of 0.01 mL to 10 mL per kg body weight. In some aspects, the formulation is administered in the form of an aqueous solution of 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 per kg body weight. In some aspects, the (Z)-indoxifene dosage is 0.01 to 3 mg / kg body weight. In some aspects, the technology described herein relates to an oral formulation comprising (Z)-indoxifene in doses 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 body weight.

[0078] In some aspects, the coating is a capsule. In some aspects, the capsule is an enteric-coated capsule. In some aspects, the enteric-coated capsule contains hydroxypropyl methylcellulose. In some aspects, the oral formulation is formulated for addition to beverages, solid foods, creams, gels, colloids, syrups, or combinations thereof. In some aspects, the oral formulation is formulated for suspension in a liquid. In some aspects, the liquid is an aqueous solution.

[0079] In some aspects, the dosage of the formulation is an aqueous solution of 0.01 mL to 10 mL per kg body weight. In some aspects, the dosage of the formulation is an aqueous solution of 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 per kg body weight. In some aspects, the dosage of (Z)-indoxifene is 0.01 to 3 mg / kg body weight. In some aspects, the technology described herein relates to an oral formulation comprising (Z)-indoxifene in doses 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 body weight. In some aspects, the aqueous solution comprises sugar, sugar alcohol, sweetener, flavoring agent, alcohol, glycerol, propylene glycol, or combinations thereof. In some aspects, the liquid is viscous.

[0080] The particles can be nanoparticles or microparticles. In many cases, the coating defines the outer surface of the particles and the cavity or space containing the (Z)-indoxifene composition. The coating can surround a single (Z)-indoxifene solid, (Z)-indoxifene powder, (Z)-indoxifene suspension, (Z)-indoxifene composition, (Z)-indoxifene solution, or a combination thereof. In some cases, the coating is a thin layer covering the (Z)-indoxifene composition. In some cases, the coating defines the surface of a sphere surrounding the (Z)-indoxifene composition. For example, the coating can be a capsule, a spin-on polymer coating, a spray hard candy coating, or a combination thereof. The (Z)-indoxifene composition can also be dispersed throughout the coating. In such cases, the coating can be formed as a continuous material having (Z)-indoxifene composition inclusions and can be formed from a suspension of the (Z)-indoxifene composition in a pre-cured coating material.

[0081] In some cases, such as those measured by microscopy, scanning electron microscopy, transmission electron microscopy, dynamic light scattering, laser diffraction, Coulter counter, or sedimentation, the diameter of the particles may be no greater than about 500 μm, no greater than about 300 μm, no greater than about 200 μm, no greater than about 150 μm, no greater than about 100 μm, no greater than about 75 μm, no greater than about 50 μm, or no greater than about 25 μm. In some aspects, the coating on the nanoparticles is 1 nm to 100 nm thick. In some aspects, the coating is about 1 nm to 10 nm, 20 nm to 30 nm, 30 nm to 40 nm, 40 nm to 50 nm, 50 nm to 60 nm, 60 nm to 70 nm, 70 nm to 80 nm, 80 nm to 90 nm, or 90 nm to 100 nm thick. In some aspects, the coating is 1 nm to 30 nm, 30 nm to 60 nm, 40 nm to 80 nm, or 70 nm to 100 nm thick. In some aspects, the coating on the nanoparticles is 1 μm to 100 μm thick. In some aspects, the coating is 1 μm to 10 μm, 20 μm to 30 μm, 30 μm to 40 μm, 40 μm to 50 μm, 50 μm to 60 μm, 60 μm to 70 μm, 70 μm to 80 μm, 80 μm to 90 μm, or 90 μm to 100 μm thick. In some aspects, the coating is 1 μm to 30 μm, 30 μm to 60 μm, 40 μm to 80 μm, or 70 μm to 100 μm thick.

[0082] In some cases, the size of the particle population can be uniform. The diameter variation of a uniform particle population may not exceed approximately 50%, approximately 40%, approximately 30%, approximately 20%, approximately 10%, approximately 5%, or approximately 2%. The volume variation of a uniform particle population may not exceed approximately 50%, approximately 40%, approximately 30%, approximately 20%, approximately 10%, approximately 5%, or approximately 2%.

[0083] In many cases, enteric coating is pharmaceutically acceptable. Enteric coating allows for delivery across the stomach without degradation or isomerization of indoxifene and release of indoxifene in the intestine, thereby increasing its efficacy and limiting side effects. Enteric coatings can be configured to remain 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 indoxifene in the small intestine 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 hours to 100 hours.

[0084] The coating may be any pharmaceutically acceptable coating disclosed herein. In some cases, the coating comprises glyceryl monostearate, glyceryl distearate, polymethacrylate, hydroxypropyl methylcellulose (HPMC), polyacrylate, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate (hydroxypropyl methylcellulose succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, shellac, cellulose trimellitate, sodium alginate, synthetic wax, microcrystalline wax, paraffin wax, palm wax, beeswax, polyethoxylated castor oil derivatives, hydrogenated oil, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl monostearate, glyceryl distearate (such as stearyl alcohol, cetyl alcohol, polyethylene glycol), copolymers thereof, and mixtures thereof.

[0085] The particles can be nanometer, micrometer, or millimeter in size. In some cases, the particles have a maximum size between about 10 nm and 2 mm (correspondingly, multiple instances of the particles may have an average or median maximum size between about 10 nm and 2 mm). In some cases, the particles have a maximum size between about 10 and 100 nm, about 25 and 250 nm, about 50 and 500 nm, about 100 and 500 nm, about 200 nm and 1 μm, about 1 and 25 μm, about 10 and 100 μm, about 25 and 250 μm, about 50 and 500 μm, about 100 and 500 μm, about 200 μm and 1 mm, or about 400 μm and 2 mm. In some cases, the particles are substantially spherical. In some cases, the particles have an elliptical or irregular structure. In some cases, the particles are nanoparticles. In some cases, the particles are microparticles.

[0086] In some aspects, (Z)-indoxifene has a half-life of 4 to 24 hours in simulated gastric fluid at pH 1.2 at 37°C. In some aspects, (Z)-indoxifene has a half-life of 2 to 72 hours in simulated intestinal fluid at pH 6.7 at 37°C. In some aspects, (Z)-indoxifene has a half-life of 12 to 144 hours in deionized water at pH 7.0 at 25°C.

[0087] Multiple instances of particles (e.g., powders containing particles) may be homogeneous or heterogeneous. For example, multiple instances of particles may 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, multiple instances of particles may 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.

[0088] In some cases, a pharmaceutically acceptable coating is about 5% to 95% of the particle weight.

[0089] In some cases, the granules include plasticizers. Plasticizers control the softness or flexibility of the granules and can improve their mechanical properties for application and enteric delivery. Suitable plasticizers include, but are not limited to, petroleum (e.g., paraffinic oils, naphthenic oils, and aromatic oils), squalene, squalane, vegetable oils (e.g., olive oil, camellia oil, castor oil, tall oil, and peanut oil), silicone oils, diesters (e.g., dibutyl phthalate and dioctyl phthalate), liquid rubbers (e.g., polybutene and liquid isoprene rubber), liquid fatty acid esters (e.g., isopropyl myristate ISM), hexyl laurate, diethyl sebacate and diisopropyl sebacate, triethyl citrate, triacetylglycerol, diethylene glycol, polyethylene glycol, polypropylene glycol, phthalates, sorbitol, ethylene glycol salicylate, crotaminton, and glycerin or mixtures thereof. The amount of plasticizer may vary depending on the chemical composition of the pharmaceutical formulation. In one embodiment, the coating contains sorbitol, isosorbide dimethyl ether, or glycerol. In another embodiment, the plasticizer is 1% to 10% of the coating, such as 3% to 5% (wt / wt). In yet another embodiment, the plasticizer is 1% to 10% of the particles, such as 3% to 5% (wt / wt).

[0090] The granules may contain a disintegrant. The disintegrant enhances the disintegration of the granules upon exposure to an aqueous environment. Granules containing too much disintegrant may disintegrate during storage or after formulation in an aqueous medium (such as syrup), while those containing too little disintegrant may not disintegrate at the desired rate or under the desired conditions (e.g., enteric disintegration). Therefore, an adequate amount of disintegrant should be used in granule formulation, neither too much nor too little, as both can detrimentally alter the release of the active ingredient. In some embodiments, the disintegrant is embedded within the granules to delay disintegration. The amount of disintegrant used varies depending on the type of formulation and is readily discernible to those skilled in the art.

[0091] The granules may contain between 0.5% and 15% (wt / wt) of disintegrant. In some cases, the granules contain between 1% and 5% (wt / wt) of disintegrant. In another embodiment, the granules contain 1% to 25%, 2% to 20%, 5% to 15%, 8% to 12%, or about 10% (wt / wt) of disintegrant. Disintegrants that may be used in the granules provided herein include, but are not limited to, agar, alginate, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium hydroxyacetic acid starch, potato or cassava starch, pregelatinized starch, other starches, clay, other alginates, other celluloses, gums, and mixtures thereof.

[0092] The particles may contain a controlled-release agent. Examples of suitable controlled-release agents include, but are not limited to, pH-dependent polymers, acid-insoluble polymers, methyl acrylate-methacrylic acid copolymers, cellulose acetate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate (hydroxypropyl methyl cellulose succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose trimellitate, sodium alginate, corn gluten, waxes (including synthetic waxes, microcrystalline waxes, paraffin wax, palm wax, and beeswax); polyethoxylated castor oil derivatives, hydrogenated oils, glyceryl monobenzyl, glyceryl dibenzyl, glyceryl tribenzyl, glyceryl monostearate, glyceryl distearate, long-chain alcohols (such as octadecyl alcohol, hexadecyl alcohol, and polyethylene glycol); and mixtures thereof. In some embodiments, delay-release materials, such as glyceryl monostearate or glyceryl distearate, may be used. In other embodiments, the controlled release agent is a digestible waxy substance, such as anhydrite.

[0093] The granules may contain pH-dependent polymers, such as acid-insoluble polymers. pH-dependent polymers become increasingly permeable above pH 5.0 and impermeable below pH 5.0. Alternatively, pH-dependent polymers become increasingly permeable below pH 5.0 and increasingly permeable above pH 5.0. The pH-dependent polymers may be configured to release (Z)-indoxifene in the colon and upper small intestine. The pH-dependent polymers prevent the release of (Z)-indoxifene in the high pH environment of the stomach and become permeable in the higher pH environment of the small intestine, thereby ensuring the release of (Z)-indoxifene after it has been delivered across the stomach. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, alginates (such as sodium or potassium alginate), shellac, pectin, and acrylic-methacrylic acid copolymers (which may be traded under the name EUDRAGIT). ® L and EUDRAGIT® S are available from Rohm America Inc., Piscataway, NJ as powder or 30% aqueous dispersion; or can be obtained under the brand name EASTACRYL. ® Purchased from Eastman Chemical Co., Kingsport, TN as a 30% dispersion. Other 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. ® L100-55.

[0094] EUDRAGIT ® RS and RL and EUDRAGIT ® NE and NM polymers may also be included in the particles disclosed herein. In some embodiments, the particles contain EUDRAGIT. ® L30D 55. In another embodiment, the particles contain EUDRAGIT. ® FS30D. Those skilled in the art will recognize that at least some of the acid-insoluble polymers listed herein will also be biodegradable.

[0095] In some cases, the particles contain at least one sustained-release agent. Non-limiting examples of sustained-release agents compatible with the particles of this disclosure include hydroxypropyl methylcellulose (HPMC), acrylic resins, methacrylic resins, polyvinylpyrrolidone, hydroxyalkyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxyl cellulose, and carboxymethyl cellulose. The sustained-release agent may be present in particles at amounts of about 0.1% to about 99%, about 0.1% to about 90%, about 5% to about 90%, about 5% to about 80%, about 5% to about 70%, and about 5% to about 60% w / w. In some embodiments, the sustained-release agent is present in amounts of about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 20% to about 40%, about 20% to about 50%, and about 20% to about 60%. In some embodiments, the sustained-release agent is present in amounts of at least about 10%, at least about 20%, at least about 30%, or at least about 40% (w / w).

[0096] In some cases, the particles contain lubricants. Exemplary lubricants include, but are not limited to, stearic acid, calcium stearate, magnesium stearate, zinc stearate, potassium stearate, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), mineral oil, light mineral oil, glycerin, sorbitol, mannitol, ethylene glycol, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, talc, ethyl oleate, ethyl laurate, agar, waxes, and combinations thereof. Other lubricants include, for example, syloid silica gel (AEROSIL 200, manufactured by WR Grace Co. of Baltimore, Md.), condensed aerosols of synthetic silica (sold by Degussa Co. of Plano, Tex.), CAB O SIL (a pyrolytic silica 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 reduces friction between (Z)-indoxifene, the coating, and optional other components (e.g., fillers in the (Z)-indoxifene composition) during particle formation. The particles may contain at least one lubricant in an amount ranging from about 0.01% to about 5%, about 0.2% to about 2%, or about 0.5% to about 1.5% by weight relative to the continuously releasing composition. In some embodiments, the particles contain magnesium stearate in an amount ranging from about 0.01% to about 5%, about 0.2% to about 2%, or about 0.5% to about 1.5% by weight.

[0097] The particles can exhibit a sustained release profile. In some cases, the particles release (Z)-indoxifene or its polymorphs or salts 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 6 hours to 48 hours. In some embodiments, as tested by the USP II method and at 37°C in simulated gastric fluid at pH 1.2 for 2 hours and at 37°C in simulated intestinal fluid at pH 6.8 for 24 hours, (Z)-indoxifene is released over a period of 2 hours to 72 hours. In some embodiments, the particles have a half-life of approximately 4 to 24 hours, approximately 6 to 48 hours, approximately 2 to 12 hours, approximately 16 to 72 hours, or approximately 48 to 280 hours in simulated gastric fluid at pH 1.2 at 37°C. In some embodiments, the particles have a half-life of approximately 2 to 72 hours, approximately 6 to 48 hours, approximately 2 to 12 hours, approximately 16 to 72 hours, or approximately 48 to 280 hours in simulated intestinal fluid at pH 6.7 at 37°C.

[0098] In some cases, (Z)-indoxifene is approximately 5% to 95% of the particle weight. In some cases, (Z)-indoxifene is approximately 5% to 25%, approximately 10% to 30%, approximately 20% to 50%, approximately 30% to 60%, approximately 40% to 80%, approximately 50% to 90%, or approximately 60% to 95% of the particle weight. In some cases, (Z)-indoxifene is a powder. In some cases, (Z)-indoxifene is microcrystals. In some cases, (Z)-indoxifene is nanocrystals.

[0099] In some cases, (Z)-indoxifene is isomerically pure. In some cases, (Z)-indoxifene 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)-indoxifene.

[0100] (Z)-Indoxifene compositions may include fillers. The fillers may stabilize (Z)-Indoxifene, prevent cross-reactions between (Z)-Indoxifene and the coating or another component of the (Z)-Indoxifene composition, act as pharmaceutical excipients, or affect its release profile. Non-limiting examples of fillers include talc, calcium carbonate, sugars, salts, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, kaolin, mannitol, silica, sorbitol, starch, pregelatinized starch, and combinations thereof.

[0101] Pharmaceutically acceptable coatings can exhibit high water stability, enabling the formulation of particles in aqueous media. In some cases, particles are dispersed in aqueous media (such as beverages or syrups), gels (such as gelatin), colloids (such as fruit preserves or nut butters), or creams (such as cake icings). Particles can have an aqueous half-life of approximately 5 to 25 hours, approximately 10 to 50 hours, approximately 20 to 100 hours, or approximately 50 to 250 hours. Particles can exhibit a substantially enhanced half-life in water at room temperature relative to human body temperature. For example, particles can have a half-life of approximately 50 to 250 hours in simulated intestinal fluid at 25°C and a half-life of approximately 10 to 50 hours in simulated intestinal fluid at 37°C. In some cases, the granules are 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 (Z)-indoxifene after storage for 1 month at 25°C in water at pH 7. In some cases, the granules are 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 (Z)-indoxifene after storage.

[0102] Continue to release The granules can be configured for controlled and sustained release. The granules can release (Z)-indoxifene over a span of hours, days, weeks, or months. The granules can be programmed to release (Z)-indoxifene upon administration. In many cases, the granules provide a prolonged release in the intestine after the composition has passed through the stomach to allow uptake of the therapeutic agent ((Z)-indoxifene or its polymorphs or salts) from the intestine and / or colon into the bloodstream of the subject. The rate of release of (Z)-indoxifene or its polymorphs or salts from the granules may be slower than the rate of release observed in a reference product (capsule), described in WO2019051416A1. The granules can provide a subject with controlled and prolonged exposure to (Z)-indoxifene for a period of at least about 2 hours to about 270 hours after administration. Sustained (Z)-indoxifene release reduces dosing frequency and / or the rate at which (Z)-indoxifene is absorbed into the bloodstream, which improves patient tolerability to (Z)-indoxifene. Intermittent dosing facilitated by sustained-release particles also increases patient convenience and compliance by reducing self-administration requirements. Slow and prolonged (or sustained) release reduces peak systemic levels of (Z)-indoxifene, which, compared to other dosage forms (such as the reference product), reduces local and / or systemic side effects, toxicity, and (Z)-indoxifene accumulation.

[0103] The sustained-release agent present in the particles of this disclosure may be any sustained-release agent known in the art for slowing the release of hydrophobic drugs, such as (Z)-indoxifene or its polymorphs or salts. 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 particles by weight.

[0104] Examples of sustained-release agents include cellulose ethers, gums, acrylic resins (such as polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, methyl methacrylate, and combinations thereof), polyvinylpyrrolidone, and protein-derived compounds. Examples of cellulose ethers include hydroxyalkyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC or hydroxypropyl methylcellulose, e.g., numbers 2208, 2906, 2910), carboxyl cellulose, and carboxymethyl cellulose. In some embodiments, at least one sustained-release agent is a pH-sustaining sustained-release agent, such as an acid-insoluble polymer that becomes increasingly soluble and permeable above pH 5.0 but remains impermeable below pH 5.0. Such controlled-release polymers target the upper small intestine and / or colon. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, alginates (such as sodium alginate or potassium alginate), shellac, pectin, and acrylic-methacrylic acid copolymers, including those copolymers available from Evonik or Rohm (EUDRAGIT). ® Continuous release of polymer 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 the sustained-release agent can be any viscosity suitable for the sustained release of (Z)-indoxifene or its polymorphs or salts. In some embodiments, the viscosity of at least one sustained-release agent is in the range of about 1000 mPa·s to about 150,000 mPa·s. In some embodiments, the sustained-release delivery system comprises one or more SR / release rate control agents with viscosities in the range of about 1000 mPa·s to about 10,000 mPa·s, about 10,000 mPa·s to about 70,000 mPa·s, about 70,000 mPa·s to about 150,000 mPa·s, or combinations thereof. In some embodiments, the sustained-release delivery system provided herein comprises two or more sustained-release agents. Each sustained-release agent may have the same viscosity or different viscosities. For example, one sustained-release agent may have a viscosity in the range of about 1,000 mPa·s to about 10,000 mPa·s, while another 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.

[0105] In some embodiments, the sustained-release agent is HPMC / hydroxypropyl methylcellulose (e.g., numbers 2208, 2906, 2910). The hydroxypropyl methylcellulose intended for use in this disclosure has an average molecular weight of about 20,000-500,000. In some embodiments, the hydroxypropyl methylcellulose has an average molecular weight typically of 20,000-250,000. Hydroxypropyl methylcellulose is available from Dow Chemicals under the brand name METHOCELL™, such as METHOCELL™ K100 (average molecular weight 26,000, 2% viscosity; 75,000-140,000 mPa·s); METHOCELL™ K15M (average molecular weight 120,000, 2% viscosity; 15,000 cP, 13275-24,780 mPa·s); and METHOCELL™ K4M (average molecular weight 86,000, 2% viscosity; 4,000 cP, 75,000-140,000 mPa·s). One grade of hydroxypropyl methylcellulose can be used alone or in combination with another grade.

[0106] Sustained-release agents (such as hydroxypropyl methylcellulose) may have an average molecular weight typically in the range of 15,000 to 140,000 Daltons. In at least one embodiment, the average molecular weight is about 15,000 Daltons.

[0107] The amount of sustained-release agent in the granules may be any amount that effectively delays the release of the therapeutic agent (Z)-indoxifene or its polymorphs or salts for approximately 2 hours after administration to protect the therapeutic agent from the acidic environment of the stomach and allow the therapeutic agent to pass through the stomach into the intestines, thereby extending such release for a period of approximately 2 hours to approximately 72 hours. Compared to the reference product, the amount of sustained-release agent in the granules may be any amount that effectively provides a slower release rate of the therapeutic agent (Z)-indoxifene or its polymorphs or salts. In some embodiments, the amount of the sustained-release agent in the composition, compared to the reference product, may be any amount that effectively delays the release of the therapeutic agent (Z) - indoxifene or its polymorph or salt 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, at least about 2.4 hours, or at least about 2.5 hours after administration.

[0108] The particles can exhibit a sustained release profile. For example, in a dissolution test using the 75 RPM USP paddle method and with the test medium at 37°C in simulated gastric fluid at pH 1.2 for 2 hours and at 37°C in simulated intestinal fluid at pH 6.8 for 24 hours, the particles can have a dissolution range of approximately 0% to 35% at 3 hours, approximately 35% to approximately 55% at 12 hours, and approximately 65% ​​to 85% at 24 hours.

[0109] (Z)-Indoxifene Unless explicitly mentioned by the prefixes (Z), (E), or (E / Z), the unprefixed form of indoxifene is used herein to refer to any or all indoxifene isoforms. A mixture of (E)-indoxifene and (Z)-indoxifene can be represented by formula (I): Formula (I).

[0110] In one aspect, this disclosure provides that the sustained-release compositions of this disclosure specifically comprise, in some embodiments, polycrystalline forms of indoxifene, such as form I, form II, or form III, as described in the applicant’s patent publication WO2019051416 (A1) (incorporated herein by reference).

[0111] In some cases, formula (I) is primarily (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)-indoxifene.

[0112] Examples of (Z)-indoxifene salts suitable for use with the particles of this disclosure include pharmacologically acceptable salts, such as salts with inorganic acids, salts with organic acids, salts with amino acids, etc. Examples of (Z)-indoxifene salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. In some embodiments, this disclosure provides (Z)-indoxifene salts with inorganic acids selected from the group consisting of: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.

[0113] Examples of salts with organic acids include salts with the following organic acids: formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

[0114] Examples of salts with acidic amino acids include salts with the following acidic amino acids: aspartic acid, glutamic acid, citric acid, etc. In some embodiments, this disclosure provides (Z)-indoxifene salts with aspartic acid, citric acid, or glutamic acid.

[0115] Examples of (Z)-indoxifene anionic salts include arecoline, benzenesulfonate, bicarbonate, tartrate, butyl bromide, citrate, camphorsulfonate, gluconate, glutamate, p-hydroxyacetaminophenarsine, hexylresorcinol, halamine, hydrobromide, hydrochloride, hydroxynaphthylcarboxylate, hydroxyethanesulfonate, malate, mandelate, methanesulfonate, methyl bromide, methyl bromide, methyl nitrate, methyl sulfate, mucilage, naphthalenesulfonate, nitrate, bis(hydroxynaphthyl)naphthyl (embosate), pantothenate, phosphate / bisphosphate, polygalacturonate, salicylate, stearate, sulfate, tannate, theochloroate, and triethyliodide.

[0116] Examples of (Z)-indoxifene cationic salts are selected from the group consisting of: benzathine penicillin, cririmazole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc, etc.

[0117] In some embodiments, the present disclosure provides for embodiments including salts prepared with pharmaceutically unacceptable acids.

[0118] This disclosure provides, in some embodiments, a composition comprising a salt of (Z)-indoxifene selected from the group consisting of: acetate, arecoline, benzathine penicillin, benzoic acid, besylate, benzosulfonate, bicarbonate, tartrate, butyl bromide, citrate, camphor sulfonate, crimetazole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, formate, fumarate, glucolate, gluconate, glutamate, p-hydroxyacetaminophenarsine, hexylresorcinol, halamine, hydrobromide, hydrochloride, hydroxyl... Naphthyl carbamate, hydroxyethanesulfonate, malate, maleate, mandelate, meglumine, mesylate, methyl bromide, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, mucilage, naphthalenesulfonate, nitric acid, nitrate, oxalate, bis(hydroxynaphthalene) salt (embosate), pantothenate, perchlorate, phosphate, diphosphate, piperazine, procaine, polygalacturonate, p-toluenesulfonate, salicylate, stearate, succinate, sulfate, sulfonate, sulfuric acid, tannic acid, tartrate, theochlorate, triethyliodine, trifluoroacetate, aluminum, barium, bismuth, lithium, magnesium, potassium and zinc, aluminum, barium, bismuth, lithium, magnesium, potassium and zinc or any combination thereof.

[0119] In some respects, pharmaceutically acceptable salts of (Z)-indoxifene are selected from the group consisting of: arecoline, benzenesulfonate, bicarbonate, tartrate, butyl bromide, citrate, camphorsulfonate, gluconate, glutamate, p-hydroxyacetaminophenarsine, hexylresorcinol, halamine, hydrobromide, hydrochloride, hydroxynaphthylcarboxylate, hydroxyethanesulfonate, malate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucilage, naphthalenesulfonate, nitrate, bis(hydroxynaphthyl)naphthyl (embosate), pantothenate, phosphate / bisphosphonate, polygalacturonate, salicylate, stearate, sulfate, tannate, theochlorate, triethyliodine, benzathine penicillin, crimetazole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc. In some aspects, a pharmaceutically acceptable salt of (Z)-indoxifene is (Z)-indoxifene gluconate. In some aspects, a compound of formula (I) comprising at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight is (Z)-indoxifene or a pharmaceutically acceptable salt thereof.

[0120] In some aspects, (Z)-indoxifene is the free base of (Z)-indoxifene. In some aspects, (Z)-indoxifene contains less than 2%, less than 1.5%, less than 1%, or less than 0.5% impurities. In some aspects, (Z)-indoxifene is stable for at least 9 months at 25°C and 60% relative humidity. In some aspects, (Z)-indoxifene is stable for at least 3 months at 40°C and 75% relative humidity. In some aspects, (Z)-indoxifene has an aerobic bacterial plate count of 0.05 g / mL to 20,000 g / mL. In some aspects, (Z)-indoxifene has a water content of not more than 1.0%, as tested by method Ic of USP 921. In some aspects, (Z)-indoxifene has a water activity (Aw) of less than 0.9. In some respects, as tested by the method of USP281, (Z)-indoxifene has a residue on ignition of no more than 0.1%.

[0121] In some aspects, as tested by method II of USP 231, (Z)-Indoxifene contains no more than 20 ppm of heavy metals. In some aspects, as tested by a validated HPLC method, (Z)-Indoxifene contains no more than 3000 ppm methanol, no more than 720 ppm tetrahydrofuran, no more than 5000 ppm isopropanol, no more than 5000 ppm ethyl acetate, no more than 5000 ppm n-heptane, no more than 5000 ppm ethanol, or any combination thereof. In some aspects, as tested by a validated HPLC method, (Z)-Indoxifene contains no more than 3000 ppm methanol, no more than 720 ppm tetrahydrofuran, no more than 5000 ppm isopropanol, no more than 5000 ppm ethyl acetate, no more than 5000 ppm heptane, and no more than 5000 ppm ethanol.

[0122] In some respects, (Z)-Indoxifene contains 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 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 method 281 of USP 281; contains not more than 20 ppm of heavy metals as tested by method II of USP 231; contains not more than 3000 ppm of methanol, not more than 720 ppm of tetrahydrofuran, not more than 5000 ppm of isopropanol, not more than 5000 ppm of ethyl acetate as tested by a validated HPLC method; and not more than 5000 ppm of... ppm of n-heptane, not more than 5000 ppm of ethanol or any combination thereof; or any combination thereof.

[0123] In some cases, oral formulations are prepared as enteric-coated tablets, enteric-coated capsules, or enteric-coated capsules.

[0124] In some embodiments, (Z)-indoxifene is present in free base form 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% (e.g., w / w of total (Z)-indoxifene in the granules).

[0125] In some embodiments, the particles further comprise (E)-indoxifene. In some embodiments, the particles have a (E)-indoxifene to (Z)-indoxifene ratio (E / Z ratio) of about 1:999, about 5:995, about 1:99; about 5:95; about 10:90, about 15:85; about 20:80, about 25:75; about 30:70; about 40:70, about 45:55; about 50:50; about 55:45; about 60:40; about 65:45; or about 70:30. In other embodiments, the sustained-release composition comprises (Z)-indoxifene having an E / Z ratio in the range of about 10:90 to about 70:30. In other embodiments, the sustained-release composition comprises (Z)-indoxifene having an E / Z ratio in the range of about 0.1:99.9 to 10:90, about 0.5:99.5 to 5:95, or about 1:99 to 10:90. In other embodiments, the sustained-release composition comprises (Z)-indoxifene having an E / Z ratio in the range of about 45:55 to about 55:45.

[0126] Polymorphs In some aspects, this disclosure provides crystalline forms of (Z)-indoxifene, including crystalline forms of the free base of (Z)-indoxifene and crystalline forms of mixtures of (E)-indoxifene and (Z)-indoxifene. This disclosure further provides pharmaceutical compositions of (Z)-indoxifene comprising the crystalline forms described herein. The crystalline forms of (Z)-indoxifene offer advantages in bioavailability and stability, making them suitable for use as an active ingredient in pharmaceutical compositions. Variations in the crystal structure of a pharmaceutical raw material or active ingredient can affect the dissolution rate of the pharmaceutical product or active ingredient (which can affect bioavailability, etc.), manufacturability (e.g., ease of handling, the ability to consistently prepare doses of known strength), and stability (e.g., thermal stability, shelf life, etc.). Such variations can affect the preparation or formulation of pharmaceutical compositions in different dosage forms or delivery formats (such as solid oral dosage forms including tablets and capsules). Compared to other forms (such as amorphous or noncrystalline forms), crystalline forms offer the desired or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control. Therefore, the crystalline form of (Z)-indoxifene offers advantages such as improved methods of manufacturing the active agent or the stability or storability of the pharmaceutical product form of the compound or active ingredient, and / or suitable bioavailability and / or stability as an active agent.

[0127] The terms “crystalline form,” “polymorph,” and “form” are used interchangeably herein and are intended to include all crystalline and amorphous forms of compounds, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrous forms), conformational polymorphs, amorphous forms, and mixtures thereof, unless a specific crystalline or amorphous form is mentioned. The compounds disclosed herein include those compounds in their crystalline and amorphous forms, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrous forms), conformational polymorphs, amorphous forms, and mixtures thereof.

[0128] It has been found that different polymorphic forms of (Z)-indoxifene can be produced using certain solvents and fractional crystallization methods, including any or more of polymorphic forms I-XII, XIV, XV, and XIX, which may exhibit one or more of the aforementioned advantageous features. In some embodiments, the polymorphic form can affect one or more properties of the composition comprising (Z)-indoxifene. For example, the polymorphic form of a therapeutic agent (e.g., (Z)-indoxifene) can affect one or more of the following: the dissolution rate, solubility, absorption rate, and C0 of the therapeutic agent in the compositions disclosed herein. max AUC, T max or t 1 / 2In some embodiments, the polymorphic form of (Z)-indoxifene may impart one or more properties that advantageously contribute to the manufacturability of the compositions of this disclosure (e.g., particles containing (Z)-indoxifene). In some embodiments, the polymorphic form of (Z)-indoxifene may impart improved stability to the compositions of this disclosure.

[0129] (Z)-Indoxofen can be amorphous, polycrystalline, or monocrystalline. In some cases, (Z)-Indoxofen has a single crystalline form. In some cases, (Z)-Indoxofen is in 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 combinations 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 (Z)-Indoxofen is in 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 combinations thereof. In some cases, (Z)-indoxifene is in 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 (Z)-indoxifene is in 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, (Z)-indoxifene is in 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, (Z)-indoxifene is in the form of 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% in the form of 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, (Z)-indoxifene is in the form of 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 (Z)-indoxifene is in form IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, or 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 (Z)-indoxifene is in 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 (Z)-indoxifene is in form II. In some cases, (Z)-indoxifene is present in form III 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%. In some cases, (Z)-indoxifene is present in form IV 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%. In some cases, (Z)-indoxifene is present in form V 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%. In some cases, (Z)-indoxifene is present in form VI 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%. In some cases, (Z)-indoxifene is present in form VII 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%. In some cases, (Z)-indoxifene is present in form VIII 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%. In some cases, (Z)-indoxifene is in form IX, 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%. In some cases, (Z)-indoxifene is in form X, 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%.In some cases, (Z)-indoxifene is present in form XI 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%. In some cases, (Z)-indoxifene is present in form XII 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%. In some cases, (Z)-indoxifene is present in form XIII 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%. 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 (Z)-indoxifene is in 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 (Z)-indoxifene is in 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 (Z)-indoxifene is in form XIX. The methods for preparing the polymorphs described herein and the characterization of these polymorphs are described in more detail below.

[0130] Formula (I), Form I In some aspects, this disclosure provides a 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)-indoxifene). In some embodiments, polymorphic form I exhibits substantially as Figure 1 , Figure 2 or Figure 3 The X-ray powder diffraction (XRPD) pattern shown is illustrated. 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 main peaks, as substantially as... Figure 1 , Figure 2 or Figure 3 The XRPD pattern shown.

[0131] The term "substantially as shown" when referring to, for example, XRPD patterns includes patterns that are not necessarily identical to those depicted herein, but which, in the opinion of someone skilled in the art, fall within the limits of experimental error or deviation. The relative intensity of XRPD peaks can vary depending on particle size, sample preparation technique, sample installation procedure, and the specific instrument used. Furthermore, instrument variations and other factors can affect both θ (2θ) values. Therefore, when a specified 2θ angle is provided, it should be understood that the specified 2θ angle can vary by a specified value ± 0.5°, such as ± 0.4°, ± 0.3°, ± 0.2°, or ± 0.1°. As used herein, "dominant peak" refers to an XRPD peak with a relative intensity greater than 30%, such as greater than 35%. Relative intensity is calculated as the ratio of the peak intensity of the peak of interest in the XRPD pattern to the peak intensity of the largest peak.

[0132] In some embodiments, polymorphic form I is characterized by an X-ray powder diffraction pattern comprising a main peak at 16.8 ± 0.3°, 17.1 ± 0.3°, and 21.8 ± 0.3° 2θ. In some embodiments, polymorphic form I is characterized by an X-ray powder diffraction pattern comprising a main peak at 16.0 ± 0.3°, 18.8 ± 0.3°, and 26.5 ± 0.3° 2θ, and at least one peak selected from 16.0 ± 0.3°, 18.8 ± 0.3°, and 26.5 ± 0.3° 2θ. 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° 2θ. In some embodiments, polymorphic form I is characterized by an X-ray powder diffraction pattern comprising a main peak at 16.8 ± 0.3°, 17.1 ± 0.3°, and 21.8 ± 0.3° 2θ and at least one peak selected from 12.3 ± 0.3°, 28.0 ± 0.3°, and 29.0 ± 0.3° 2θ. In some embodiments, polymorphic form I is characterized by an X-ray powder diffraction pattern comprising a main peak at 16.8 ± 0.3°, 17.1 ± 0.3°, and 21.8 ± 0.3° 2θ, 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° 2θ. In some embodiments, polymorphic form I is characterized by an X-ray powder diffraction pattern comprising a main peak at 16.8 ± 0.3°, 17.1 ± 0.3°, and 21.8 ± 0.3° 2θ, 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° 2θ.

[0133] In some embodiments, this disclosure provides a composition comprising polymorphic form I. More 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.

[0134] Form (I), Form II In some aspects, this disclosure provides a polymorphic form II of a compound of formula (I), wherein the composition comprises the (E)-isomer and (Z)-isomer of the compound of formula (I) (i.e., (E)-indoxifene and (Z)-indoxifene) having an E / Z ratio between 0.9 and 1.3, such as about 1.1. In some embodiments, the polymorphic form II exhibits substantially the following properties: Figure 4 The X-ray powder diffraction (XRPD) pattern shown is illustrated. 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 main peaks, as substantially as... Figure 4 The XRPD pattern shown.

[0135] In some embodiments, polymorphic form II is characterized by an X-ray powder diffraction pattern comprising a main peak at 7.0 ± 0.3°, 11.9 ± 0.3°, 14.0 ± 0.3°, and 18.4 ± 0.3° 2θ. In some embodiments, polymorphic form II is characterized by an X-ray powder diffraction pattern comprising a peak at 22.0 ± 0.3° 2θ. In some embodiments, polymorphic form II is characterized by an X-ray powder diffraction pattern comprising a main peak at 7.0 ± 0.3°, 11.9 ± 0.3°, 14.0 ± 0.3°, and 18.4 ± 0.3° 2θ and a peak at 22.0 ± 0.3° 2θ. 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° 2θ. In some embodiments, polymorph form II is characterized by an X-ray powder diffraction pattern comprising a main peak at 7.0 ± 0.3°, 11.9 ± 0.3°, 14.0 ± 0.3°, and 18.4 ± 0.3° 2θ, and at least one peak selected from 6.6 ± 0.3°, 13.3 ± 0.3°, and 20.0 ± 0.3° 2θ. In some embodiments, polymorph form II is characterized by an X-ray powder diffraction pattern comprising a main peak at 7.0 ± 0.3°, 11.9 ± 0.3°, 14.0 ± 0.3°, and 18.4 ± 0.3° 2θ, and at least one peak selected from 6.6 ± 0.3°, 13.3 ± 0.3°, 20.0 ± 0.3°, and 22.0 ± 0.3° 2θ. In some embodiments, polymorphic form II is characterized by an X-ray powder diffraction pattern comprising a main peak at 7.0 ± 0.3°, 11.9 ± 0.3°, 14.0 ± 0.3°, and 18.4 ± 0.3° 2θ, and peaks at 6.6 ± 0.3°, 13.3 ± 0.3°, 20.0 ± 0.3°, and 22.0 ± 0.3° 2θ.

[0136] In some embodiments, this disclosure provides a composition comprising polymorphic form II. More 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.

[0137] Form (I), Form III In some aspects, this disclosure provides a polymorphic form III of a compound of formula (I), wherein the composition comprises the (E)-isomer and (Z)-isomer of the compound of formula (I) (i.e., (E)-indoxifene and (Z)-indoxifene) having an E / Z ratio between 0.9 and 1.3, such as about 1.1. In some embodiments, polymorphic form III exhibits substantially the following properties: Figure 5 The X-ray powder diffraction (XRPD) pattern shown is illustrated. 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 main peaks, as substantially as... Figure 5 The XRPD pattern shown.

[0138] In some embodiments, polymorphic form III is characterized by an X-ray powder diffraction pattern comprising a main peak at 11.9 ± 0.3°, 13.9 ± 0.3°, 17.1 ± 0.3°, and 17.7 ± 0.3° 2θ. In some embodiments, polymorphic form III is characterized by an X-ray powder diffraction pattern comprising a peak at 25.3 ± 0.3° 2θ. In some embodiments, polymorphic form III is characterized by an X-ray powder diffraction pattern comprising a main peak at 11.9 ± 0.3°, 13.9 ± 0.3°, 17.1 ± 0.3°, and 17.7 ± 0.3° 2θ, and a peak at 25.3 ± 0.3° 2θ. 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° 2θ. In some embodiments, polymorphic form III is characterized by an X-ray powder diffraction pattern comprising a main peak at 11.9 ± 0.3°, 13.9 ± 0.3°, 17.1 ± 0.3°, and 17.7 ± 0.3° 2θ, and at least one peak selected from 18.2 ± 0.3°, 22.5 ± 0.3°, and 26.8 ± 0.3° 2θ. In some embodiments, polymorphic form III is characterized by an X-ray powder diffraction pattern comprising a main peak at 11.9 ± 0.3°, 13.9 ± 0.3°, 17.1 ± 0.3°, and 17.7 ± 0.3° 2θ, and at least one peak selected from 18.2 ± 0.3°, 22.5 ± 0.3°, 25.3 ± 0.3°, and 26.8 ± 0.3° 2θ. In some embodiments, polymorphic form III is characterized by an X-ray powder diffraction pattern comprising a main peak at 11.9 ± 0.3°, 13.9 ± 0.3°, 17.1 ± 0.3°, and 17.7 ± 0.3° 2θ, and peaks at 18.2 ± 0.3°, 22.5 ± 0.3°, 25.3 ± 0.3°, and 26.8 ± 0.3° 2θ.

[0139] In some embodiments, this disclosure provides a composition comprising polymorphic form III. More 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.

[0140] Form (I), Form IV The composition may 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 in form IV.

[0141] The crystalline form of compound (I) in form IV is characterized by an XRPD pattern comprising a main peak at 4.7 ± 0.3°2θ, 23.3 ± 0.3°2θ, and 13.6 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, or at least four peaks selected from 23.8 ± 0.3°2θ, 14.2 ± 0.3°2θ, 22.5 ± 0.3°2θ, or 15.7 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, or at least three peaks selected from 7.1 ± 0.3°2θ, 20.2 ± 0.3°2θ, or 9.5 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, at least four, at least five, or at least six peaks selected from 7.1 ± 0.3°2θ, 9.5 ± 0.3°2θ, 14.2 ± 0.3°2θ, 15.7 ± 0.3°2θ, 20.2 ± 0.3°2θ, 22.5 ± 0.3°2θ, and 23.8 ± 0.3°2θ. In some cases, the crystalline form of the compound of formula (I) is characterized by being substantially as Figure 6 The X-ray diffraction pattern shown.

[0142] In some cases, as determined by TGA analysis, the crystalline form of the compound (I) contains between about 1% and about 30% by weight of solvent. In some cases, as determined by TGA analysis, the crystalline form loses the solvent upon heating to a temperature between 70°C and 130°C. In some cases, the solvent contains 2-propanol, heptane, or a combination thereof.

[0143] Equation (I), Form V The composition may 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 in form V.

[0144] The crystalline form of compound V of formula (I) is characterized by an XRPD pattern comprising a main peak at 12.5 ± 0.3°2θ, 19.6 ± 0.3°2θ, and 8.9 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, or at least four peaks selected from 21.7 ± 0.3°2θ, 20.8 ± 0.3°2θ, 19.8 ± 0.3°2θ, or 16.0 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, or at least three peaks selected from 22.0 ± 0.3°2θ, 13.5 ± 0.3°2θ, or 14.4 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, at least four, at least five, or at least six peaks selected from 21.7 ± 0.3°2θ, 20.8 ± 0.3°2θ, 19.8 ± 0.3°2θ, 16.0 ± 0.3°2θ, 22.0 ± 0.3°2θ, 13.5 ± 0.3°2θ, and 14.4 ± 0.3°2θ. In some cases, the crystalline form of the compound of formula (I) is characterized by being substantially as Figure 7 The X-ray diffraction pattern shown.

[0145] Formula (I), Form VI The composition may 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.

[0146] The crystalline form of compound VI of formula (I) is characterized by an XRPD pattern comprising a main peak at 9.9 ± 0.3°2θ, 13.4 ± 0.3°2θ, and 13.7 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, or at least four peaks selected from 17.6 ± 0.3°2θ, 18.6 ± 0.3°2θ, 17.3 ± 0.3°2θ, or 21.8 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, or at least three peaks selected from 10.2 ± 0.3°2θ, 19.5 ± 0.3°2θ, or 14.2 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 17.6 ± 0.3°2θ, 18.6 ± 0.3°2θ, 17.3 ± 0.3°2θ, 21.8 ± 0.3°2θ, 10.2 ± 0.3°2θ, 19.5 ± 0.3°2θ, or 14.2 ± 0.3°2θ.

[0147] In some cases, the crystalline form of the compound of formula (I) is characterized by being substantially as Figure 8 The X-ray diffraction pattern shown.

[0148] Equation (I), Form VII The composition may 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.

[0149] The crystalline form of compound VII of formula (I) is characterized by an XRPD pattern comprising a main peak at 20.0 ± 0.3°2θ, 22.6 ± 0.3°2θ, and 10.6 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, or at least four peaks selected from 11.4 ± 0.3°2θ, 16.4 ± 0.3°2θ, 9.6 ± 0.3°2θ, or 13.3 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, or at least three peaks selected from 18.2 ± 0.3°2θ, 13.1 ± 0.3°2θ, or 27.0 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, at least four, at least five, or at least six peaks selected from 11.4 ± 0.3°2θ, 16.4 ± 0.3°2θ, 9.6 ± 0.3°2θ, 13.3 ± 0.3°2θ, 18.2 ± 0.3°2θ, 13.1 ± 0.3°2θ, or 27.0 ± 0.3°2θ. In some cases, the crystalline form of the compound of formula (I) is characterized by being substantially as Figure 9 The X-ray diffraction pattern shown.

[0150] Formula (I), Form VIII The composition may 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 in form VIII.

[0151] The crystalline form of compound (I) in form VIII is characterized by an XRPD pattern comprising a main peak at 4.8 ± 0.3°2θ, 18.9 ± 0.3°2θ, and 9.5 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, or at least four peaks selected from 23.7 ± 0.3°2θ, 21.9 ± 0.3°2θ, 21.2 ± 0.3°2θ, or 12.9 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, or at least three peaks selected from 25.0 ± 0.3°2θ, 21.5 ± 0.3°2θ, or 16.4 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, at least four, at least five, or at least six peaks selected from 23.7 ± 0.3°2θ, 21.9 ± 0.3°2θ, 21.2 ± 0.3°2θ, 12.9 ± 0.3°2θ, 25.0 ± 0.3°2θ, 21.5 ± 0.3°2θ, or 16.4 ± 0.3°2θ. In some cases, the crystalline form of the compound of formula (I) is characterized by being substantially as Figure 10 The X-ray diffraction pattern shown.

[0152] Equation (I), Form IX The composition may 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 in form IX.

[0153] The crystalline form of compound (I) IX is characterized by an XRPD pattern comprising a main peak at 19.0 ± 0.3°2θ, 12.9 ± 0.3°2θ, and 15.9 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, or at least four peaks selected from 21.7 ± 0.3°2θ, 20.8 ± 0.3°2θ, 21.1 ± 0.3°2θ, or 8.9 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, or at least three peaks selected from 16.4 ± 0.3°2θ, 4.2 ± 0.3°2θ, or 12.7 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, at least four, at least five, or at least six peaks selected from 21.7 ± 0.3°2θ, 20.8 ± 0.3°2θ, 21.1 ± 0.3°2θ, 8.9 ± 0.3°2θ, 16.4 ± 0.3°2θ, 4.2 ± 0.3°2θ, or 12.7 ± 0.3°2θ. In some cases, the crystalline form of the compound of formula (I) is characterized by being substantially as Figure 11 The X-ray diffraction pattern shown.

[0154] Equation (I), Form X The composition may comprise form X of a 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 in form X.

[0155] The crystalline form of compound X of formula (I) is characterized by an XRPD pattern including a main peak at 7.2 ± 0.3°2θ, 14.3 ± 0.3°2θ, 18.7 ± 0.3°2θ, 21.5 ± 0.3°2θ, and 22.7 ± 0.3°2θ. In some cases, the XRPD pattern also includes a peak at 17.1 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, or at least three peaks selected from 21.8 ± 0.3°2θ, 27.3 ± 0.3°2θ, or 29.4 ± 0.3°2θ. In some cases, the crystalline form of compound (I) is characterized by substantially as... Figure 12 The X-ray diffraction pattern shown.

[0156] Equation (I), Form XI The composition may 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 in form XI.

[0157] The crystalline form of compound XI of formula (I) is characterized by an XRPD pattern including a main peak at 14.0 ± 0.3°2θ, 17.7 ± 0.3°2θ, 11.9 ± 0.3°2θ, 18.4 ± 0.3°2θ, 23.9 ± 0.3°2θ, 17.3 ± 0.3°2θ, 21.8 ± 0.3°2θ, 20.8 ± 0.3°2θ, and 23.0 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one or at least two peaks selected from 22.2 ± 0.3°2θ or 16.6 ± 0.3°2θ. In some cases, the crystalline form of compound (I) is characterized by substantially as... Figure 13 The X-ray diffraction pattern shown.

[0158] Formula (I), Form XII The composition may 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 in form XII.

[0159] The crystalline form of compound XII of formula (I) is characterized by an XRPD pattern comprising a main peak at 12.5 ± 0.3°2θ, 15.6 ± 0.3°2θ, and 19.0 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, or at least four peaks selected from 21.9 ± 0.3°2θ, 20.2 ± 0.3°2θ, 16.0 ± 0.3°2θ, or 21.6 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, or at least three peaks selected from 22.4 ± 0.3°2θ, 16.8 ± 0.3°2θ, or 12.8 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, at least four, at least five, or at least six peaks selected from 21.9 ± 0.3°2θ, 20.2 ± 0.3°2θ, 16.0 ± 0.3°2θ, 21.6 ± 0.3°2θ, 22.4 ± 0.3°2θ, 16.8 ± 0.3°2θ, or 12.8 ± 0.3°2θ. In some cases, the crystalline form of the compound of formula (I) is characterized by being substantially as Figure 14 The X-ray diffraction pattern shown.

[0160] Formula (I), Form XIV The composition may 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 in form XIV.

[0161] The crystalline form of compound (I) XIV is characterized by an XRPD pattern comprising a main peak at 11.6 ± 0.3°2θ, 21.3 ± 0.3°2θ, and 19.3 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, or at least four peaks selected from 17.5 ± 0.3°2θ, 15.4 ± 0.3°2θ, 21.6 ± 0.3°2θ, or 5.8 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, or at least three peaks selected from 16.3 ± 0.3°2θ, 21.9 ± 0.3°2θ, or 23.9 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, at least four, at least five, or at least six peaks selected from 17.5 ± 0.3°2θ, 15.4 ± 0.3°2θ, 21.6 ± 0.3°2θ, 5.8 ± 0.3°2θ, 16.3 ± 0.3°2θ, 21.9 ± 0.3°2θ, or 23.9 ± 0.3°2θ. In some cases, the crystalline form of the compound of formula (I) is characterized by being substantially as Figure 15 The X-ray diffraction pattern shown.

[0162] Equation (I), Form XV The composition may comprise a compound of formula (I) in form XV. 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 in form XV.

[0163] The crystalline form of compound (I) XV is characterized by an XRPD pattern comprising a main peak at 9.8 ± 0.3°2θ, 4.7 ± 0.3°2θ, and 14.0 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, or at least four peaks selected from 20.2 ± 0.3°2θ, 7.1 ± 0.3°2θ, 23.4 ± 0.3°2θ, or 22.4 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, or at least three peaks selected from 21.7 ± 0.3°2θ, 22.7 ± 0.3°2θ, or 18.8 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, at least four, at least five, or at least six peaks selected from 20.2 ± 0.3°2θ, 7.1 ± 0.3°2θ, 23.4 ± 0.3°2θ, 22.4 ± 0.3°2θ, 21.7 ± 0.3°2θ, 22.7 ± 0.3°2θ, or 18.8 ± 0.3°2θ. In some cases, the crystalline form of the compound of formula (I) is characterized by being substantially as Figure 16 The X-ray diffraction pattern shown.

[0164] Equation (I), form XIX The composition may comprise a compound of formula (I) in form XIX. 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 in form XIX.

[0165] The crystalline form of compound (I) XIX is characterized by an XRPD pattern comprising a main peak at 4.7 ± 0.3°2θ, 23.6 ± 0.3°2θ, and 18.9 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, or at least four peaks selected from 9.4 ± 0.3°2θ, 23.3 ± 0.3°2θ, 22.3 ± 0.3°2θ, or 20.1 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, or at least three peaks selected from 19.6 ± 0.3°2θ, 7.1 ± 0.3°2θ, or 15.7 ± 0.3°2θ. In some cases, the XRPD pattern also includes at least one, at least two, at least three, at least four, at least five, or at least six peaks selected from 9.4 ± 0.3°2θ, 23.3 ± 0.3°2θ, 22.3 ± 0.3°2θ, 20.1 ± 0.3°2θ, 19.6 ± 0.3°2θ, 7.1 ± 0.3°2θ, or 15.7 ± 0.3°2θ. In some cases, the crystalline form of the compound of formula (I) is characterized by being substantially as Figure 17 The X-ray diffraction pattern shown.

[0166] Dosage and preparation In one aspect, the composition comprising (Z)-indoxifene granules contains between about 0.1 mg and 200 mg of (Z)-indoxifene per 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 polymorph of (Z)-indoxifene. While the content of (Z)-indoxifene or its polymorphs or salts in the granules of this disclosure varies depending on the dosage form of the sustained-release composition, the target disease, disease severity, etc., it generally corresponds to or is equivalent to an amount of about 0.01 mg to about 200 mg of (Z)-indoxifene. Those skilled in the art will recognize that when the granules contain a salt of (Z)-indoxifene, the indoxifene salt will be in an equivalent amount based on the (Z)-indoxifene to be released.

[0167] (Z)-Indoxifene and its polymorphs and salts can be diluted with diluents commonly used in the medical, food, and other fields.

[0168] Those skilled in the art will recognize that the amount of (Z)-indoxifene polymorphs and salts will be molar equivalent to the amount of pharmacologically active (Z)-indoxifene in the free form present in the particles.

[0169] In one aspect, this disclosure provides particles configured for the sustained release of (Z)-indoxifene or its polymorphs or salts over a period of about 2 hours to about 72 hours. In some embodiments, the particles exhibit sustained release of the drug (Z)-indoxifene or its polymorphs or salts over a period of about 4 hours to about 24 hours or longer. In some embodiments, the particles release (Z)-indoxifene or its polymorphs or salts in a sustained manner over periods 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)-indoxifene or its polymorphs or salts over a period of 6 hours to 48 hours. In some embodiments, (Z)-indoxifene or its polymorphs or salts are released from the granules for a period ranging from about 2 hours to about 72 hours after administration. In some embodiments, (Z)-indoxifene or its polymorphs or salts are released from the granules 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 after administration. In some embodiments, as shown herein, (Z)-indoxifene or its polymorphs or salts are released at a slower and more sustained or longer rate than the reference product, enteric-coated resistant delayed-release (Z)-indoxifene capsules (“capsules” or “control” are used interchangeably herein).

[0170] In dissolution tests of certain sustained-release compositions of this disclosure according to the USP I method, the sustained-release compositions showed a dissolution percentage in the range of about 0% to 35% at 3 hours, about 35% to about 55% at 12 hours, and about 65% to 85% at 24 hours, in simulated gastric fluid at 37°C using the 75 RPM USP I method and using pH 1.2 for 2 hours at 37°C and in simulated intestinal fluid at 37°C using pH 6.8 for 24 hours, according to the 75 RPM USP I method and using pH 1.2 for 2 hours at 37°C and in simulated intestinal fluid at 37°C as the test medium.

[0171] A method for measuring the solubility of a composition (e.g., particles) may involve measuring solubility in an acidic phase (e.g., simulated gastric fluid) followed by a buffer phase (e.g., simulated intestinal fluid). The acidic phase may include placing 750 mL of 0.1 N hydrochloric acid in a container and assembling the apparatus (e.g., a paddle or basket apparatus). The culture medium may be allowed to equilibrate to a temperature of 37 ± 0.5°C. A dose unit may be placed in the apparatus, the container closed, and the apparatus operated at a specified rate. After 2 hours of operation in 0.1 N hydrochloric acid, an aliquot of the fluid may be removed. The method may then proceed immediately as indicated under the buffer phase. The aliquot may be analyzed using a suitable assay method. While operating the apparatus at the specified rate, 250 mL of 0.20 M trisodium phosphate, equilibrated to 37 ± 0.5°C, may be added to the fluid in the container. If necessary, the fluid may be adjusted to pH 6.8 ± 0.05 using 2 N hydrochloric acid or 2 N sodium hydroxide. The apparatus may continue to operate for 45 minutes or for the specified duration. At the end of the time period, equal portions of the fluid can be removed and analyzed using suitable analytical methods.

[0172] In some embodiments, the percentage of dissolution is measured by a 75 rpm USP paddle method from 0 to 2 hours in simulated gastric fluid at pH 1.2 and 37°C, and after 2 hours in simulated intestinal fluid at pH 6.8 and 37°C. The percentage of dissolution refers to the percentage of the composition dissolved by weight. The percentage of dissolution refers to the weight percentage of (Z)-indoxifene or its polymorphs or salts dissolved during the dissolution study. As a non-limiting example, if a tablet contains 4 mg of (Z)-indoxifene, and 1 mg of (Z)-indoxifene is dissolved in solution at time point 3 hours during the dissolution study, the percentage of dissolution at 3 hours is 25%. The percentage of dissolution can be determined by, for example, high-performance liquid chromatography.

[0173] In some embodiments, the particles, measured by the USP paddle method at 75 rpm from the 0-2 hour in simulated gastric fluid at pH 1.2 and 37°C and after the 2nd hour in simulated intestinal fluid at pH 6.8 and 37°C, have a solubility percentage at 3 hours in the range of about 5% to about 35%, about 10% to about 15%, about 20% to about 25%, about 30% to about 35%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, or about 30% to about 35%.

[0174] In some embodiments, the particles, measured by the USP paddle method at 75 rpm in simulated gastric fluid at pH 1.2 and 37°C from hour 0 to 2, and in simulated intestinal fluid at pH 6.8 and 37°C after hour 2, have a solubility percentage 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% at 2 hours. In some embodiments, the particles have a solubility percentage of no more than about 30%, about 25%, about 20%, about 15%, about 10%, or about 5% (NMT) at 3 hours.

[0175] In some embodiments, as measured by the USP paddle method at 75 rpm in simulated gastric fluid at pH 1.2 and 37°C from 0 to 2 hours and in simulated intestinal fluid at pH 6.8 and 37°C after 2 hours, the particles have a solubility percentage of (Z)-indoxifene or its polymorph or salt in the range of less than about 5% at 2 hours and in the range of about 5% to about 80%, about 10% to about 75%, about 20% to about 70%, about 30% to about 65%, about 5% to about 75%, about 5% to about 70%, about 5% to about 60%, about 5% to about 65%, about 5% to about 60%, about 10% to about 55%, about 5% to about 50%, about 30% to about 80%, about 25% to about 75%, about 35% to about 80%, or not less than about 70% at 3 hours.

[0176] In some embodiments, such as those measured by the USP paddle method at 75 rpm from 0-2 hours in simulated gastric fluid at pH 1.2 and 37°C and after 2 hours in simulated intestinal fluid at pH 6.8 and 37°C, the particles had a solubility percentage of (Z)-indoxifene or its polymorphs or salts of less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 31%, less than about 32%, less than about 33%, less than about 34%, less than about 35%, less than about 36%, less than about 37%, less than about 38%, less than about 39%, or less than about 40% at 7 hours.

[0177] In some embodiments, as measured by the USP paddle method at 75 rpm from 0 to 2 hours in simulated gastric fluid at pH 1.2 and 37°C and after 2 hours in simulated intestinal fluid at pH 6.8 and 37°C, the particles have a solubility percentage of (Z)-indoxifene or its polymorph or salt in the range of less than about 5% at 2 hours and in the range of about 70% to about 99%, about 75% to about 95%, about 85% to about 95%, about 90% to about 95%, about 75% to about 90%, about 85% to about 90%, about 75% to about 85%, about 80% to about 99%, about 85% to about 99%, about 90% to about 99%, about 95% to about 99%, or not less than about 95% at 6 hours.

[0178] In some embodiments, the particles have a solubility percentage of (Z)-indoxifen or its polymorphs or salts of less than about 5% at 2 hours and not less than about 20%, about 25%, about 30%, about 35% or about 40% (NLT) at 6 hours.

[0179] In some embodiments, the particles have a solubility percentage of (Z)-indoxifene or its polymorphs or salts of less than about 5% at 2 hours and about 40%, about 45%, about 50%, about 55% or about 60% of NLT at 9 hours.

[0180] In some embodiments, the particles, measured by the USP paddle method at 75 rpm from the 0-2 hour in simulated gastric fluid at pH 1.2 and 37°C and after the 2nd hour in simulated intestinal fluid at pH 6.8 and 37°C, have a solubility percentage at 12 hours in the range of about 35% to about 55%, about 40% to about 55%, about 45% to about 55%, about 50% to about 55%, about 35% to about 50%, about 35% to about 45%, about 35% to about 40%, about 35% to about 40%, about 40% to about 45%, about 45% to about 50%, or about 50% to about 55%.

[0181] In some embodiments, the particles, measured by the 75 rpm USP paddle method from 0-2 hours in simulated gastric fluid at pH 1.2 and 37°C and after 2 hours in simulated intestinal fluid at pH 6.8 and 37°C, have a solubility percentage of less than 20% (Z)-indoxifene or its polymorphs or salts at 2 hours, and 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.

[0182] In some embodiments, the particles, measured by the 75 rpm USP paddle method from 0-2 hours in simulated gastric fluid at pH 1.2 and 37°C and after 2 hours in simulated intestinal fluid at pH 6.8 and 37°C, have a solubility percentage of less than 20% (Z)-indoxifene or its polymorphs or salts at 2 hours, and 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.

[0183] In some embodiments, the particles, measured by the 75 rpm USP paddle method from 0-2 hours in simulated gastric fluid at pH 1.2 and 37°C and after 2 hours in simulated intestinal fluid at pH 6.8 and 37°C, have a solubility percentage of (Z)-indoxifene or its polymorph or salt in the range of less than about 5% at 2 hours and in the range of about 70% to about 99%, about 75% to about 95%, about 85% to about 95%, about 90% to about 95%, about 75% to about 90%, about 85% to about 90%, about 75% to about 85%, about 80% to about 99%, about 85% to about 99%, about 90% to about 99%, about 95% to about 99%, or about 100% at 12 hours.

[0184] In some embodiments, the particles, measured by the 75 rpm USP paddle method in simulated gastric fluid at pH 1.2 and 37°C from hour 0 to 2, and in simulated intestinal fluid at pH 6.8 and 37°C after hour 2, have a solubility percentage of (Z)-indoxifene or its polymorphs or salts of less than about 5% at 2 hours and in the range of about 55% to about 90%, about 60% to about 85%, and about 70% to about 80% at 14 hours. In some embodiments, the particles have a solubility percentage of (Z)-indoxifene or its polymorphs or salts of less than about 5% at 2 hours and in the range of about 70%, about 75%, about 80%, about 85%, or about 90% NLT at 14 hours.

[0185] In some embodiments, the particles, measured by the USP paddle method at 75 rpm from the 0-2 hour in simulated gastric fluid at pH 1.2 and 37°C and after the 2nd hour in simulated intestinal fluid at pH 6.8 and 37°C, have a solubility percentage at 24 hours in the range of about 65% to about 85%, about 70% to about 85%, about 75% to about 85%, about 80% to about 85%, about 65% to about 80%, about 65% to about 75%, about 65% to about 70%, about 65% to about 70%, about 70% to about 75%, about 75% to about 80%, or about 80% to about 85%.

[0186] In some embodiments, as measured by the USP paddle method at 75 rpm from 0 to 2 hours in simulated gastric fluid at pH 1.2 and 37°C and after 2 hours in simulated intestinal fluid at pH 6.8 and 37°C, the particles have a solubility percentage of (Z)-indoxifene or its polymorph or salt in the range of less than about 5% at 2 hours and in the range of about 55% to about 100%, about 60% to about 99%, about 75% to about 90%, about 80% to about 85%, about 55% to about 99%, about 65% to about 99%, about 70% to about 99%, about 75% to about 99%, about 80% to about 99%, about 90% to about 99%, about 80% to about 95%, or about 75% to about 95% at 72 hours.

[0187] In certain particle dissolution tests of this disclosure according to the USP II paddle method, the particles showed a dissolution percentage in the range of about 0% to 35% at 3 hours, about 35% to about 55% at 12 hours, and about 65% to 85% at 24 hours, using the 75 RPM USP paddle method and the test medium at 37°C in simulated gastric fluid with pH 1.2 for 2 hours and at 37°C in simulated intestinal fluid with pH 6.8 for 24 hours.

[0188] In some embodiments, in dissolution tests conducted according to the USP paddle method at 75 rpm and at 37°C in simulated gastric fluid at pH 1.2 for 2 hours and at 37°C in simulated intestinal fluid at pH 6.8 for 24 hours, the particles of this disclosure showed a solubility percentage of about 0% to 30% at 3 hours, about 40% to about 50% at 12 hours, and about 70% to 80% at 24 hours.

[0189] In some embodiments, in dissolution tests according to the USP paddle method at 75 rpm and at 37°C in simulated gastric fluid at pH 1.2 for 2 hours and at 37°C in simulated intestinal fluid at pH 6.8 for 24 hours, the particles of this disclosure showed a solubility percentage of (Z)-indoxifene or its polymorphs or salts at 3 hours, NMT 30% at 3 hours, NMT 50% at 12 hours, and NLT 80% at 24 hours.

[0190] In some embodiments, in dissolution tests according to the 75 RPM USP II method and at 37°C in simulated gastric fluid at pH 1.2 for 2 hours and at 37°C in simulated intestinal fluid at pH 6.8 for 24 hours, the particles showed a solubility percentage of (Z)-indoxifene or its polymorphs or salts of about 5% at 2 hours, about 70% at 3 hours, about 90% at 6 hours, and about 100% at 12 hours.

[0191] In some embodiments, in dissolution tests according to the 75 RPM USP II method and at 37°C in simulated gastric fluid at pH 1.2 for 2 hours and at 37°C in simulated intestinal fluid at pH 6.8 for 24 hours, the particles showed a dissolution percentage of (Z)-indoxifene or its polymorphs or salts of approximately 5% at 2 hours, approximately 10% at 3 hours, approximately 30% at 6 hours, approximately 50% at 9 hours, and approximately 80% at 14 hours.

[0192] In some embodiments, in dissolution tests according to the USP paddle method at 75 rpm and in simulated gastric fluid at pH 1.2 for 2 hours at 37°C and in simulated intestinal fluid at pH 6.8 for 24 hours at 37°C, the particles of this disclosure show a dissolution percentage of at least 10%, at least 20%, at least 30%, or at least 40% of (Z)-indoxifene or its polymorphs or salts after 24 hours. Those skilled in the art will further recognize that the compositions disclosed herein may comprise one or more excipients known in the art and disclosed herein, in any combination suitable for the desired formulation or preparation. Other excipients are generally found in Remington's *The Science and Practice of Pharmacy*, Meade Publishing Co., and the United States Pharmacopeia / International Formulary. Those skilled in the art will be able to select suitable excipients and appropriate dosage forms compatible with the route of administration based on their skill and knowledge in the art and the disclosure herein. In all cases, the final dosage form should be sterile and stable under the conditions of manufacture and storage.

[0193] Liquid Indoxifene Formulation This disclosure provides a liquid formulation of (Z)-indoxifene comprising a solvent and (Z)-indoxifene or a salt thereof. (Z)-indoxifene or a salt thereof may be completely soluble in the solvent, partially soluble in the solvent, or substantially insoluble in the solvent (e.g., at least about 99% in solid form). The liquid formulation of (Z)-indoxifene may be formulated for oral administration. In some embodiments, the liquid formulation may enhance the uptake of (Z)-indoxifene free base or (Z)-indoxifene salt after oral administration, relative to an equivalent dose of (Z)-indoxifene in solid, dry form.

[0194] While some solvents (e.g., gastric juice) can promote the isomerization of (Z)-indoxifene and (E)-indoxifene, the liquid formulations disclosed herein stabilize (Z)-indoxifene 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 (Z)-indoxifene in the liquid formulation is converted to (E)-indoxifene after storage at 25°C for one month. To promote this stability, the liquid formulation may contain a solvent that does not promote the interconversion between (Z)-indoxifene and (E)-indoxifene. For example, the solvent may be aprotic, thereby limiting acid- and base-catalyzed isomerization. The stability of (Z)-indoxifene can be enhanced by storing it in a stable solid form within a liquid formulation, such as a slurry in which a limited amount of (Z)-indoxifene is dissolved.

[0195] The solvent may be a pharmaceutically acceptable liquid carrier. The solvent may be biocompatible, ensuring that it does not cause adverse reactions at the dose delivered to the subject. The solvent may also be readily absorbed after administration to promote (Z)-indoxifene uptake. In some cases, the liquid formulation is aqueous (i.e., contains water). In such cases, the solvent may be water at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 99%, or about 99.5% by weight. Aqueous liquid formulations may be isotonic, for example, containing glucose or saline.

[0196] Liquid formulations may also be non-aqueous or substantially non-aqueous, for example, containing 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, (Z)-indoxifene or its salts or combinations thereof may be dried, for example, by lyophilization or by using a water-absorbing material (such as calcium sulfate). In some cases, liquid formulations include non-aqueous solvents selected from the following: ethanol, glycerin, vegetable oils (e.g., olive oil, rapeseed oil, coconut oil, or peanut oil), polyethylene glycol, propylene glycol, methoxypropylene glycol, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), polyvinylpyrrolidone (PVP), methoxypropylene glycol (MPEG), glycerin, tetrahydrofuran polyethylene glycol ether (glycofurol), dimethylformamide (DMF), ethyl acetate, n-methylpyrrolidone (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 triglycerides, Peceol, Caprol ET, Labrafil M2125 CS, Labrafac CC, Labrafil M 1944 CS, Captex 8277, Nyristate, Caprol PGE 860, and combinations thereof. In some cases, the solvent is lipophilic, such as vegetable 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 combinations thereof.

[0197] Liquid formulations may contain buffers. Because (Z)-indoxifene isomerization can be acid- and base-mediated, in many cases, the formulation has a neutral, weakly acidic, or weakly basic pH. In some cases, the liquid formulation has a pH between about 4.5 and 9.5, about 5 and 9, about 4.5 and 7, about 6 and 8, about 7 and 9.5, or about 6.5 and 7.5. In some cases, liquid formulations include buffers selected from the following: histidine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine, aspartic acid, glutamic acid, asparagine, glutamine, cysteine, methionine, proline, 4-hydroxyproline, N,N,N-trimethyllysine, 3-methylhistidine, 5-hydroxylysine, O-phosphoserine, γ-carboxyglutamic acid, ε-N-acetyllysine, ω-N-methylarginine, glycine, glycyl-glycine, tris(hydroxymethyl)methylglycine (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 combinations thereof. In some cases, the liquid formulation contains a buffer of about 0.5 mM to about 200 mM, a buffer of about 0.5 to 20 mM, a buffer of about 5 to 50 mM, a buffer of about 10 to 100 mM, or a buffer of about 50 to 200 mM.

[0198] Liquid formulations may contain stabilizers. Stabilizers can inhibit (Z)-indoxifene isomerization or degradation during packaging, storage, and administration. In some cases, stabilizers include albumins, immunoglobulins, monosaccharides or oligosaccharides (e.g., trehalose, glucose, sucrose, sorbitol, dextran, maltose, mannose, raffinose, stachyose), hydrogels, polysaccharides, or combinations thereof. Stabilizers may include materials that adsorb or intercalate (Z)-indoxifene or its salts, such as chitosan, and said materials may limit degradation and isomerization.

[0199] In some cases, (Z)-indoxifene or its salts are completely soluble in the solvent. For example, when the liquid formulation is at 25°C, (Z)-indoxifene or its salts may 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% soluble in the solvent. In such liquid formulations, the solvent may be supersaturated with (Z)-indoxifene or its salts, saturated with (Z)-indoxifene or its salts, or unsaturated with (Z)-indoxifene or its salts (i.e., containing less (Z)-indoxifene than is soluble in the solvent).

[0200] In some cases, the liquid formulation is a slurry, also known as a suspension. The slurry may contain a solvent in which solid (Z)-indoxifene or its salts are dispersed, suspended, or partially dissolved. The solid (Z)-indoxifene or its salts may be uniformly or non-uniformly dispersed throughout the slurry. For example, solid (Z)-indoxifene may be randomly dispersed throughout the solvent, settled on the surface containing the solvent (e.g., enteric-coated capsules), or distributed in the middle of it. Solid (Z)-indoxifene or its salts may be a powder. Solid (Z)-indoxifene or its salts may be microcrystalline. Solid (Z)-indoxifene or its salts may be a continuous solid with a size of millimeters or larger, such as millimeter-diameter crystals.

[0201] For slurry formulations, (Z)-indoxifene or its salts may be insoluble or partially soluble in the solvent. In some cases, approximately 5% to 95% of the (Z)-indoxifene in the slurry is dissolved, with the remainder being a solid. For example, approximately 5% to 25%, approximately 5% to 50%, approximately 10% to 40%, approximately 10% to 60%, approximately 20% to 50%, approximately 25% to 50%, approximately 25% to 60%, approximately 30% to 70%, approximately 40% to 80%, approximately 50% to 90%, approximately 60% to 95%, or approximately 75% to 95% of the (Z)-indoxifene is dissolved. The partially dissolved (Z)-indoxifene may be amorphous, monocrystalline, polycrystalline, or a combination thereof.

[0202] One or more solid forms of (Z)-indoxifene can be stable in slurries. For many of the slurries disclosed herein, one or more forms of (Z)-indoxifene used to produce the slurry are retained after storage. Although (Z)-indoxifene may be in a dynamic equilibrium between a solid and dissolved state, residual solid (Z)-indoxifene can be inoculated during crystallization or precipitation to recrystallize into a specific crystal form. Alternatively or otherwise, one or more solid forms of (Z)-indoxifene may be solid forms with favorable enthalpy and / or entropy in the slurry, such that one or more solid forms of (Z)-indoxifene are maintained by (Z)-indoxifene throughout the liquid-solid equilibrium. One or more forms of (Z)-indoxifene prepared in slurry are stable at 25°C 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. For some of the slurries disclosed herein, after storage at 25°C for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days, 20 days, 30 days, 40 days, 50 days, 75 days, 100 days, 150 days, 200 days, 250 days, 300 days, 400 days, or 500 days, 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 solids (Z)-indoxifene are in the form used to produce the slurry. For example, after storage at 25°C for 300 days, the slurry produced using (Z)-indoxifene forms IV and VI and water may contain greater than 95% of forms IV and VI. Alternatively, the solid form of (Z)-indoxifene may be converted during slurry storage, 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 when stored at 25°C.

[0203] In some cases, the slurry contains monocrystalline or polycrystalline (Z)-indoxifene (i.e., (Z)-indoxifene is polycrystalline or has a single crystalline form). In some cases, (Z)-indoxifene has a single crystalline form. In some cases, (Z)-indoxifene is in 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 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 (Z)-indoxifene is in 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 a combination thereof. In some cases, (Z)-indoxifene is in 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 (Z)-indoxifene is in 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, (Z)-indoxifene is in 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, (Z)-indoxifene is in the form of 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% in the form of 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, (Z)-indoxifene is in the form of 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 (Z)-indoxifen is in 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.

[0204] In some cases, liquid formulations contain emulsions. As used herein, the term "emulsion" can refer to a dispersion of two or more liquids with low miscibility (such as oil in water). In many cases, emulsions contain an organic solvent and water in which (Z)-indoxifene or a salt thereof has high or moderate solubility. In such formulations, (Z)-indoxifene or a salt thereof may partition primarily into the organic solvent.

[0205] Liquid formulations are suitable for oral delivery. To prevent isomerization in the stomach (e.g., upon contact with gastric acid), the liquid formulation may be contained in an enteric coating that prevents release until the liquid formulation passes through the stomach. For example, the liquid formulation may be contained in a gel capsule that, after administration, passes through the stomach and degrades in the small intestine, thereby releasing (Z)-indoxifene in an uptake-compatible manner. The enteric coating may be inert for the liquid formulation, thereby stably containing the liquid formulation until contact with a solution or conditions that promote its degradation. The enteric coating may encapsulate liquid formulations of about 50 μL to 1.5 mL, about 100 to 500 μL, or about 250 μL to 1.5 mL. The liquid formulation may contain solid (Z)-indoxifene (e.g., in slurry form), dissolved (Z)-indoxifene, or a combination thereof. The liquid formulation may be formulated for oral delivery without an enteric coating. For example, liquid formulations may be in the form of beverages, gels, creams, or colloidal foods (e.g., nut butter) prepared for ingestion. In such cases, (Z)-indoxifene or its salts may be co-administered with stabilizers (such as chitosan).

[0206] Liquid formulations can be formulated for transdermal delivery. In such cases, the liquid formulation may contain a skin-permeable solvent, such as DMSO or γ-butyrolactone. In many cases, transdermal liquid formulations include dissolved (Z)-indoxifene to facilitate transport with the skin-permeable solvent. However, (Z)-indoxifene may 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.

[0207] Treatment In one aspect, a method of treating a disease in a subject in need is provided, the method comprising administering to the subject an oral formulation comprising microparticles, wherein the microparticles comprise a (Z)-indoxifene composition and a coating, wherein the (Z)-indoxifene composition comprises a compound of formula (I): Formula (I) Or its pharmaceutically acceptable salt. At least 90% by weight of the compound of formula (I) is (Z)-indoxifene or a pharmaceutically acceptable salt thereof.

[0208] The oral formulation may be an oral formulation based on any one or a combination of the aspects described herein.

[0209] Particles, multiple instances of particles, or compositions containing particles or multiple instances of particles may be used to treat conditions such as cancer, including but not limited to childhood and adult cancers.

[0210] In one aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering granules prepared according to any of the methods disclosed herein.

[0211] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation prepared according to any of the methods disclosed herein.

[0212] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules containing (Z)-indoxifene or its salts or polymorphs prepared according to any of the methods disclosed herein.

[0213] In some aspects, the method includes administering to a subject an oral formulation comprising 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)-indoxifene. In some aspects, the method includes administering to a subject an oral formulation comprising 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)-indoxifene.

[0214] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules prepared according to any of the methods disclosed herein, wherein the subject suffers from hormone-dependent breast disease, hormone-dependent genital tract disease, or both, or is at risk of suffering from said disease.

[0215] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules prepared according to any of the methods disclosed herein, wherein the subject has hormone-dependent breast disease, hormone-dependent genital tract disease, or both, or is at risk of having said disease, wherein the hormone-dependent breast disease or hormone-dependent genital tract disease is benign breast disease, hyperplasia, dysplasia, 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.

[0216] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules containing (Z)-indoxifene or its salts or polymorphs prepared according to any of the methods disclosed herein, wherein the subject has breast cancer.

[0217] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules containing (Z)-indoxifene or its salts or polymorphs prepared according to any of the methods disclosed herein, wherein the subject has breast cancer, and wherein the breast cancer is precancerous, early-stage, non-metastatic, pre-metastatic, locally advanced, or metastatic.

[0218] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules containing (Z)-indoxifene or its salts or polymorphs prepared according to any of the methods disclosed herein, wherein the subject has prostate cancer and wherein the subject further has or is at risk of having gynecomastia.

[0219] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules containing (Z)-indoxifene or its salts or polymorphs prepared according to any of the methods disclosed herein, wherein the subject suffers from tamoxifen-refractory or tamoxifen-resistant hormone-dependent breast disease or hormone-dependent reproductive tract disease.

[0220] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules comprising (Z)-indoxifene or its salts or polymorphs prepared according to any of the methods disclosed herein, wherein the liquid formulation or granules are administered to the subject in unit doses 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.

[0221] In some aspects, the dosage of the formulation is an aqueous solution of 0.01 mL to 10 mL per kg body weight. In some aspects, the dosage of the formulation is an aqueous solution of 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 per kg body weight. In some aspects, the dosage of (Z)-indoxifene is 0.01 to 3 mg / kg body weight. In some cases, the dosage of (Z)-indoxifene 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 body weight.

[0222] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules containing (Z)-indoxifene or its salts or polymorphs prepared according to any of the methods disclosed herein, wherein the liquid formulation or granules are administered once a day, twice a day, three times a day, four times a day, every other day, twice a week, once a week, once every two weeks, twice a month, once a month, once a quarter, once every six months, or once a year.

[0223] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules prepared according to any of the methods disclosed herein, comprising (Z)-indoxifene or its salts or polymorphs, wherein oral administration of the liquid formulation or granules maintains the subject's plasma (Z)-indoxifene at a steady-state level greater than 30 nM.

[0224] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules prepared according to any of the methods disclosed herein, comprising (Z)-indoxifene or its salts or polymorphs, wherein oral administration of the liquid formulation or granules on day 14 following administration of the first dose (day 1) achieves the maintenance of the subject's plasma (Z)-indoxifene at a steady-state level greater than 30 nM.

[0225] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules comprising (Z)-indoxifene or its salts or polymorphs, wherein oral administration of the liquid formulation or granules on day 14 following administration of the first dose (day 1) achieves the maintenance of the subject's plasma (Z)-indoxifene at a steady-state level greater than 30 nM.

[0226] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules prepared according to any of the methods disclosed herein, comprising (Z)-indoxifene or its salts or polymorphs, wherein oral administration of the liquid formulation or granules achieves the time to reach the maximum plasma level of (Z)-indoxifene in the subject 2 to 10 hours after administration (post-dose).

[0227] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules comprising (Z)-indoxifene or its salts or polymorphs, wherein oral administration of the liquid formulation or granules achieves the time to reach the maximum plasma level of (Z)-indoxifene in the subject 2 to 10 hours after administration (post-dose).

[0228] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules comprising (Z)-indoxifene or its salts or polymorphs, wherein the mean terminal elimination half-life of (Z)-indoxifene in the subject is in the range of 30 to 60 hours after administration.

[0229] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules comprising (Z)-indoxifene or its salts or polymorphs thereof, wherein the mean terminal elimination half-life of (Z)-indoxifene in the subject is in the range of 40 to 55 hours after administration.

[0230] In another aspect, this disclosure relates to a method for treating a subject suffering from hormone-dependent breast disease, hormone-dependent reproductive tract disease, or both, or at risk of suffering from said diseases, the method comprising administering an oral liquid formulation or granules comprising (Z)-indoxifene or its salts or polymorphs, wherein the administration of the liquid formulation or granules achieves the following: the mean half-life of (Z)-indoxifene in the subject is in the range of 30 to 60 hours after administration; the time to reach maximum plasma levels of (Z)-indoxifene is in the range of 2 to 10 hours after administration; and the steady-state plasma level of (Z)-indoxifene is greater than 30 nM.

[0231] In another aspect, this disclosure relates to a method for treating a subject suffering from hormone-dependent breast disease or hormone-dependent genital tract disease, or at risk of suffering from said disease, the disease being selected from the group consisting of: benign breast disease, hyperplasia, dysplasia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McKenna-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering an oral liquid formulation or granules comprising (Z)-indoxifene or its salts or polymorphs, wherein the administration of the liquid formulation or granules achieves the following: the mean half-life of (Z)-indoxifene in the subject is in the range of 30 to 60 hours after administration; the time to reach maximum plasma levels of (Z)-indoxifene is in the range of 2 to 10 hours after administration; and the steady-state plasma level of (Z)-indoxifene is greater than 30 nM.

[0232] In another aspect, this disclosure relates to a method of treating a subject suffering from hormone-dependent breast disease or hormone-dependent genital tract disease, or at risk of suffering from said disease, said disease being selected from the group consisting of: benign breast disease, hyperplasia, dysplasia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McKenna-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, said method comprising administering (… (Z)-Indoxifene or its salts or polymorphs are oral liquid formulations or granules, said oral liquid formulations or granules being formulated as enteric-coated tablets, enteric-coated capsules, enteric-coated capsules, delayed-release tablets, delayed-release capsules or delayed-release capsules, wherein administration of the liquid formulations or granules achieves the following: the mean half-life of (Z)-Indoxifene in the subject is in the range of 30 to 60 hours after administration; the time to reach maximum plasma levels of (Z)-Indoxifene is in the range of 2 to 10 hours after administration; and the steady-state plasma level of (Z)-Indoxifene is greater than 30 nM.

[0233] In another aspect, this disclosure relates to a method of treating a subject suffering from hormone-dependent breast disease or hormone-dependent genital tract disease, or at risk of suffering from said disease, said disease being selected from the group consisting of: benign breast disease, hyperplasia, dysplasia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McKenna-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, said method comprising administering (… (Z)-Indoxifene or its salts or polymorphs are oral liquid formulations or granules, said oral liquid formulations or granules being formulated as enteric-coated tablets, enteric-coated capsules, enteric-coated capsules, delayed-release tablets, delayed-release capsules or delayed-release capsules, wherein administration of the liquid formulation or granules achieves the following: the mean half-life of (Z)-Indoxifene in the subject is in the range of 30 to 60 hours after administration; the time to reach maximum plasma levels of (Z)-Indoxifene is in the range of 2 to 10 hours after administration; and the steady-state plasma level of (Z)-Indoxifene is greater than 30 nM; and wherein at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of (Z)-Indoxifene is released in the intestine.

[0234] In another aspect, this disclosure relates to a method of treating a subject suffering from hormone-dependent breast disease or hormone-dependent genital tract disease, or at risk of suffering from said disease, the disease being selected from the group consisting of: benign breast disease, hyperplasia, dysplasia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McKenna-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering a solution containing 0.01 mg to 200 mg of... mg of (Z)-indoxifene or its salts or polymorphs in oral liquid formulations or granules, said oral liquid formulations or granules being formulated as enteric-coated tablets, enteric-coated capsules, enteric-coated capsules, delayed-release tablets, delayed-release capsules or delayed-release capsules, wherein administration of the liquid formulations or granules achieves the following: the mean half-life of (Z)-indoxifene in the subject is in the range of 30 to 60 hours after administration; the time to reach maximum plasma levels of (Z)-indoxifene is in the range of 2 to 10 hours after administration; and the steady-state plasma level of (Z)-indoxifene is greater than 30 nM; and wherein at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of (Z)-indoxifene is released in the intestine.

[0235] In another aspect, this disclosure relates to a method of treating a subject suffering from hormone-dependent breast disease or hormone-dependent genital tract disease, or at risk of suffering from said disease, the disease being selected from the group consisting of: benign breast disease, hyperplasia, dysplasia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McKenna-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising daily administration of a solution containing 0.01 mg to 200 mg. mg of (Z)-indoxifene or its salts or polymorphs in oral liquid formulations or granules, said oral liquid formulations or granules being formulated as enteric-coated tablets, enteric-coated capsules, enteric-coated capsules, delayed-release tablets, delayed-release capsules or delayed-release capsules, wherein administration of the liquid formulations or granules achieves the following: the mean half-life of (Z)-indoxifene in the subject is in the range of 30 to 60 hours after administration; the time to reach maximum plasma levels of (Z)-indoxifene is in the range of 2 to 10 hours after administration; and the steady-state plasma level of (Z)-indoxifene is greater than 30 nM.

[0236] In another aspect, this disclosure relates to a method of treating a subject suffering from hormone-dependent breast disease or hormone-dependent genital tract disease, or at risk of suffering from said disease, the disease being selected from the group consisting of: benign breast disease, hyperplasia, dysplasia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McKenna-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising daily administration of a solution containing 0.01 mg to 200 mg. mg of (Z)-indoxifene or its salts or polymorphs in oral liquid formulations or granules, said oral liquid formulations or granules being formulated as enteric-coated tablets, enteric-coated capsules, enteric-coated capsules, delayed-release tablets, delayed-release capsules or delayed-release capsules, wherein administration of the liquid formulations or granules achieves the following: the mean half-life of (Z)-indoxifene in the subject is in the range of 30 to 60 hours after administration; the time to reach maximum plasma levels of (Z)-indoxifene is in the range of 2 to 10 hours after administration; and the steady-state plasma level of (Z)-indoxifene is greater than 30 nM; and wherein at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of (Z)-indoxifene is released in the intestine.

[0237] In another aspect, this disclosure relates to a method of treating a subject suffering from hormone-dependent breast disease or hormone-dependent genital tract disease, or at risk of suffering from said disease, the disease being selected from the group consisting of: benign breast disease, hyperplasia, dysplasia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McKenna-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising daily administration of a solution containing 0.01 mg to 200 mg. (Z)-indoxifene or its salts or polymorphs, in oral liquid formulations or granules, wherein the oral liquid formulation or granules are formulated as enteric-coated tablets, enteric-coated capsules, enteric-coated capsules, delayed-release tablets, delayed-release capsules, or delayed-release capsules, wherein administration of the liquid formulation or granules achieves the following: the mean half-life of (Z)-indoxifene in the subject is in the range of 30 to 60 hours after administration; the time to reach maximum plasma levels of (Z)-indoxifene is in the range of 2 to 10 hours after administration; and the steady-state plasma level of (Z)-indoxifene is greater than 30 nM; wherein the area under the curve extrapolated to infinity (AUC0-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. hr*ng / mL; and at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of (Z)-indoxifene is released in the intestine.

[0238] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules containing (Z)-indoxifene or its salts or polymorphs prepared according to any of the methods disclosed herein, wherein the method is a primary therapy, a neoadjuvant therapy, or an adjuvant therapy.

[0239] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules comprising (Z)-indoxifene or its salts or polymorphs prepared according to any of the methods disclosed herein, wherein the liquid formulation or granules are administered to the subject as a combination therapy.

[0240] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules comprising (Z)-indoxifene or its salts or polymorphs prepared according to any of the methods disclosed herein, wherein the liquid formulation or granules are administered to the subject alone or in combination with a second therapeutic agent.

[0241] In another aspect, this disclosure relates to a method of treating a subject in need, the method comprising administering a liquid formulation or granules prepared according to any of the methods disclosed herein, comprising (Z)-indoxifene or its salts or polymorphs, wherein the liquid formulation or granules are administered to the subject together with a second therapeutic agent selected from the group consisting of: bicalutamide, enzalutamide, or anticancer drugs (such as trastuzumab), antitumor drugs (such as capecitabine, paraplatin, cisplatin). Atinol, cyclophosphamide (Neosar), docetaxel (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), ixaprilone (Ixempra), and ATP box-binding protein transport inhibitors.

[0242] In another aspect, this disclosure relates to an use for treating and preventing hormone-dependent breast disease, hormone-dependent genital tract disease, or both in a subject, said use comprising: administering to the subject a first liquid formulation or granules containing tamoxifen; determining the tamoxifen-metabolite profile of the subject in a test sample obtained from the subject; determining a reduction in the subject's plasma (Z)-indoxifene level based on the subject's tamoxifen-metabolite profile compared to a reference tamoxifen-metabolite profile; and administering to the subject the liquid formulation or granules of this disclosure.

[0243] In another aspect, this disclosure relates to an use for treating and preventing hormone-dependent breast disease, hormone-dependent genital tract disease, or both in a subject, said use comprising: administering to the subject a first composition comprising tamoxifen; determining the subject's tamoxifen-metabolite profile in a test sample obtained from the subject; determining a reduction in the subject's plasma (Z)-indoxifene level based on the subject's tamoxifen-metabolite profile compared to a reference tamoxifen-metabolite profile; and administering to the subject a liquid formulation or granules of the present disclosure; wherein the composition is sufficient to maintain the subject's plasma (Z)-indoxifene level at a level greater than 30. The steady-state dose of nM is administered orally; wherein the tamoxifen metabolite profile includes at least one group of tamoxifen, 4-hydroxytamoxifen, n-demethyltamoxifen, or (Z)-indoxifene; wherein the hormone-dependent breast disease or hormone-dependent genital tract disease is benign breast disease, hyperplasia, dysplasia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McKean-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer; wherein the hormone-dependent breast disease is precancerous, early-stage cancer, non-metastatic cancer, pre-metastatic cancer, locally advanced cancer, or metastatic cancer; wherein the hormone-dependent breast disease is non-metastatic cancer; wherein the subject has prostate cancer, and wherein the subject further develops gynecomastia or is at risk of developing gynecomastia; or wherein the hormone-dependent breast disease or hormone-dependent genital tract disease is tamoxifen refractory or tamoxifen resistant.

[0244] In another aspect, this disclosure relates to a kit for treating subjects in need who have hormone-dependent breast disease or hormone-dependent genital tract disease or who are at risk of having said disease, the kit comprising: (a) a liquid formulation or granules of this disclosure; and (b) a sealed container for containing the liquid formulation or granules; and (c) instructions for oral administration of the liquid formulation or granules.

[0245] In another aspect, this disclosure relates to a kit for treating subjects in need who have hormone-dependent breast disease or hormone-dependent genital tract disease, or who are at risk of having said disease, the kit comprising: (a) a liquid formulation or granules of this disclosure; and (b) a sealed container for containing the liquid formulation or granules; and (c) instructions for oral administration of the liquid formulation or granules, wherein the test kit includes a second therapeutic agent selected from the group consisting of: bicalutamide, enzalutamide, and anticancer drugs (such as trastuzumab), antitumor drugs (such as capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinum)). Nol, 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), ixaprilone (Ixempra), and ATP box-binding protein transport inhibitors.

[0246] In another aspect, this disclosure relates to a method of administering to a subject in need a liquid formulation or granules prepared according to any of the processes described herein, according to an instruction for use contained in a pillbox, the pillbox comprising the liquid formulation or granules.

[0247] In one embodiment, this disclosure provides a method for treating a subject suffering from a hormone-dependent condition, a mood disorder, or any condition sensitive to (Z)-indoxifene or its polymorphs or salts, or at risk of suffering from said condition, the method comprising administering granules comprising (Z)-indoxifene and a coating.

[0248] Example The invention is further illustrated by the following non-limiting embodiments.

[0249] Example 1 (Z)-Oral administration of doxycycline granules This embodiment describes cancer treatment using (Z)-indoxifene granules. Subjects were identified as positive for a form of cancer treatable with (Z)-indoxifene. Dry (Z)-indoxifene granules were provided to the subjects, who were instructed to self-administer the granules orally once weekly. The subjects self-administered the granules by adding them to their food before consumption. The granules contained microcrystalline (Z)-indoxifene dispersed within a stomach-stable enteric coating material. The enteric coating material prevents the release of (Z)-indoxifene in the stomach but degrades in the intestine to release it. The (Z)-indoxifene had an isomer purity greater than 95% relative to a 50:50 (E):(Z)-indoxifene mixture, which increased therapeutic efficacy and reduced side effects. The (E):(Z)-indoxifene ratio did not undergo detectable changes during storage or after administration. Treatment with (Z)-indoxifene continued until the cancer in the subject decreased, as determined by the total detectable tumor volume via PET scan. Subjects were offered the option to continue (Z)-indoxifen treatment until the cancer became undetectable.

[0250] Example 2 Cancer treatment using (Z)-indoxifene granules in plasma This embodiment covers cancer treatment using a suspension containing (Z)-indoxifene particles. Subjects were identified as having cancer treatable with (Z)-indoxifene. (Z)-indoxifene particles were prescribed to subjects, instructing them to self-administer by direct injection into their mouths three times a week. Upon receipt, the (Z)-indoxifene particles were suspended in a sweet syrup. The (Z)-indoxifene particles contained an enteric coating that surrounded a powdered (Z)-indoxifene core and was stable in the syrup. After storage at 25°C for one month, the syrup containing the particles had a free indoxifene concentration of less than 100 nM. The enteric coating material prevented the release of (Z)-indoxifene in the stomach but degraded in the intestine to release (Z)-indoxifene. The (E):(Z)-indoxifene ratio did not change detectably during storage at 25°C or after administration. Continue (Z)-indoxifene treatment until the cancer becomes undetectable in the subject via circulating tumor DNA (ctDNA) and circulating tumor cell analysis.

[0251] Example 3 Cancer treatment using (Z)-indoxifene solution This embodiment covers cancer treatment using (Z)-indoxifene solution. Subjects were identified as having cancer treatable with (Z)-indoxifene. Subjects were provided with an aqueous solution containing dissolved (Z)-indoxifene, a flavoring agent, and a thickener, giving the solution a syrup-like flavor and texture. The (Z)-indoxifene had an isomer purity greater than 95%, and this isomer purity did not decrease detectably after storage at 25°C for more than one month. Subjects consumed 5 mL of the solution twice daily until the cancer was no longer detectable.

[0252] Example 4 (Z)-Indoxifene encapsulated in hydroxypropyl methylcellulose This embodiment covers cancer treatment using (Z)-indoxifene microparticle formulations. The microparticles have an average diameter of 400 μm and are a powder dispersion containing (Z)-indoxifene, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The powder dispersion is coated with an enteric-coated, resistant, delayed-release hydroxypropyl methylcellulose coating. Croscarmellose sodium prevents cross-linking between indoxifene and the hydroxypropyl methylcellulose coating.

[0253] 400 mg microparticles containing 20 mg (Z)-indoxifene were added to a fruit smoothie, which was consumed by a child with cancer. The microparticles were stable in the smoothie and the child's stomach, thus releasing less than 10% of its (Z)-indoxifene before it was passed through the ileum. More than 60% of the (Z)-indoxifene was released in the child's small intestine. This treatment was repeated twice daily for the child until their cancer was salvaged.

[0254] While preferred embodiments of the invention have been shown and described herein, such embodiments are provided by way of example only and will be apparent to those skilled in the art. Many variations, modifications, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that the invention can be practiced using various alternatives to the embodiments described herein. The following claims are intended to define the scope of the invention and thereby cover the methods and structures within the scope of these claims and their equivalents.

Claims

1. An oral formulation comprising microparticles, wherein the microparticles comprise a (Z)-indoxifene composition and a coating, wherein the (Z)-indoxifene composition comprises a compound of formula (I): Formula (I) Or its pharmaceutically acceptable salt. Wherein at least 90% by weight of the compound of formula (I) is (Z)-indoxifene or a pharmaceutically acceptable salt thereof.

2. The oral formulation of claim 1, wherein the oral formulation comprises a plurality of microparticles, and between the plurality of microparticles comprises a total of 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)-indoxifene.

3. The oral formulation of claim 1 or 2, wherein the oral formulation comprises a plurality of microparticles, and between the plurality of microparticles comprises 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)-indoxifene.

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

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

6. The oral formulation according to any one of claims 1-3, wherein the coating comprises hydroxypropyl methylcellulose.

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

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

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

10. The oral formulation of claim 9, wherein the dosage 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 dosage 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 according to any one of claims 1-11, comprising a dose of (Z)-indoxifene at a concentration of 0.01 to 3 mg / kg body weight.

13. The oral formulation of claim 12, comprising (Z)-indoxifene at doses 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 body weight.

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

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

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

17. The oral formulation of claim 16, wherein the filler comprises talc, calcium carbonate, sugar, salt, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, kaolin, mannitol, silica, sorbitol, starch, pregelatinized starch, or a combination thereof.

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

19. The oral formulation according to any one of claims 1-18, wherein the microparticles further comprise 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 laurate, agar, or a combination thereof.

21. The oral formulation according to any one of claims 1-20, wherein the microparticles further comprise sodium croscarmellose.

22. The oral formulation according to any one of claims 1-21, wherein the diameter of the particles is not greater than 500 μm, not greater than 300 μm, not greater than 200 μm, not greater than 150 μm, not greater than 100 μm, not greater than 75 μm, not greater than 50 μm, or not greater than 25 μm, as measured by microscopy, scanning electron microscopy, transmission electron microscopy, dynamic light scattering, laser diffraction, Coulter counter, or sedimentation.

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

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

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

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

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

28. The oral formulation according to 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, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, alginate, shellac, pectin, acrylic acid-methacrylic acid copolymer, or a combination thereof.

32. The oral formulation according to any one of claims 1-31, wherein the microparticles further comprise a plasticizer, a disintegrant, a controlled-release agent, a sustained-release agent, a lubricant, or a combination thereof.

33. The oral formulation according to 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)-indoxifene or a pharmaceutically acceptable salt thereof.

34. The oral formulation according to any one of claims 1-33, wherein the pharmaceutically acceptable salt of (Z)-indoxifene is selected from the group consisting of: arecoline, benzenesulfonate, bicarbonate, tartrate, butyl bromide, citrate, camphorsulfonate, gluconate, glutamate, p-hydroxyacetaminophenarsine, hexylresorcinol, halamine, hydrobromide, hydrochloride, hydroxynaphthylcarbamate, hydroxyethanesulfonate, malate, mandelate, Methanesulfonates, methyl bromide, methyl nitrate, methyl sulfate, mucilage, naphthalene sulfonate, nitrate, bis(hydroxynaphthalene) salt (embosate), pantothenate, phosphate / bisphosphate, polygalacturonate, salicylates, stearates, sulfates, tannins, theochlorate, triethyl iodine, benzathine penicillin, cririmazole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc.

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

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

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

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

39. The oral formulation according to any one of claims 1-38, wherein the (Z)-indoxifene 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)-indoxifene 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)-indoxifene has a water content of not more than 1.0%, as tested by method Ic of USP 921.

42. The oral formulation according to any one of claims 1-41, wherein the (Z)-indoxifene has a water activity (Aw) of less than 0.

9.

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

44. The oral formulation of any one of claims 1-43, wherein, as tested by method II of USP 231, the (Z)-indoxifene contains no more than 20 ppm of heavy metals.

45. The oral formulation of any one of claims 1-44, wherein, as tested by a validated HPLC method, the (Z)-indoxifene 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.

46. ​​The oral formulation of any one of claims 1-45, wherein, as tested by a validated HPLC method, the (Z)-indoxifene 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.

47. The oral formulation according to any one of claims 1-46, wherein the (Z)-indoxifene: It contains impurities of less than 2%, less than 1.5%, less than 1%, or less than 0.5%. Stable for at least 9 months at 25°C and 60% relative humidity; Stable for at least 3 months at 40°C and 75% relative humidity; Aerobic bacterial plate counting ranged from 0.05 g / mL to 20,000 g / mL; As tested by method Ic of USP 921, it has a water content of no more than 1.0%; It has a water activity (Aw) of less than 0.9; As tested by the method of USP 281, it has no more than 0.1% residue on ignition; As tested by Method II of USP 231, it contains no more than 20 ppm of heavy metals; As tested by a validated HPLC method, it contains no more than 3000 ppm methanol, no more than 720 ppm tetrahydrofuran, no more than 5000 ppm isopropanol, no more than 5000 ppm ethyl acetate; no more than 5000 ppm n-heptane, no more than 5000 ppm ethanol or any combination thereof. Or any combination thereof.

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

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

50. The method of claim 49, wherein the oral formulation is added to a beverage, solid food, cream, gel, colloid, or 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 sugar, sugar alcohol, sweetener, flavoring agent, alcohol, glycerol, propylene glycol, or a combination 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 administration 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, and between the plurality of microparticles comprises a total of 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)-indoxifene.

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

58. The method of claim 57, wherein the dosage 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 according to any one of claims 49-58, wherein the dose of (Z)-indoxifene is 0.01 to 3 mg / kg body weight.

60. The method of claim 59, wherein the dose of (Z)-indoxifene 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 body weight.

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

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