CN117580571A

CN117580571A - Wo Luxi forest administration regimen and methods of treatment comprising said regimen

Info

Publication number: CN117580571A
Application number: CN202280041001.3A
Authority: CN
Inventors: D·戈尔德; A·F·帕尔
Original assignee: Mei Pharma Inc
Current assignee: Mei Pharma Inc
Priority date: 2021-04-10
Filing date: 2022-04-10
Publication date: 2024-02-20

Abstract

The present disclosure relates to a formulation comprising malonic acid Wo Luxi forest (voruciclib malonate). The present disclosure further provides a method of treating hematological cancer using the formulation and optionally a BCL-2 inhibitor, the formulation and the optional BCL-2 inhibitor being administered in various dosage regimens.

Description

Wo Luxi forest administration regimen and methods of treatment comprising said regimen

Cross reference to related applications

This application is an international application claiming priority from U.S. provisional application No. 63/173,398 filed on 10 month 2021 and U.S. provisional application No. 63/173,361 filed on 10 month 2021, each of which is incorporated herein by reference in its entirety.

Technical Field

The present disclosure provides novel methods of treatment using Wo Luxi forests (voruciclib) and salts thereof.

Background

At any particular time, many cancer-related therapeutic agents are in phase I or phase II clinical trials and evaluations; however, most of them will not be able to make progress. In fact, it is estimated that more than 90% of cancer-related therapeutics will fail phase I or phase II clinical trial evaluation. The failure rate of phase III trials is almost 50%, and the cost of new drug development from discovery to phase III trials is between $ 8 billion dollars to $ 17 billion dollars and may require eight to ten years. In addition, many patients do not respond even to standard drugs that have proven effective. Individual patients may not respond to standard drug therapies for reasons that are currently unknown or difficult to assess. In some cases, administration of a combination of drugs may be more effective in treating cancer than the drug administered alone. These combinations of drugs may act synergistically to enhance the anticancer activity of the drug. In some cases, a drug that is not particularly effective may find new and unexpected uses when combined with additional drug therapies.

Disclosure of Invention

The present disclosure provides a formulation comprising about 15% to about 35% w/w malonic acid Wo Luxi forest (voruciclib malonate) and one or more pharmaceutically acceptable excipients. In some embodiments, the formulation comprises about 18% to about 30% w/w malonic acid Wo Luxi forest. In some embodiments, the formulation comprises about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, or about 28% w/w malonic acid Wo Luxi forest. In some embodiments, the formulation comprises about 20% to about 23% w/w malonic acid Wo Luxi forest. In some embodiments, the one or more pharmaceutically acceptable excipients comprise about 5% to about 37% w/w microcrystalline cellulose. In some embodiments, the one or more pharmaceutically acceptable excipients comprise about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% w/w microcrystalline cellulose. In some embodiments, the one or more pharmaceutically acceptable excipients comprise about 1% to about 48% w/w lactose monohydrate. In some embodiments, the one or more pharmaceutically acceptable excipients comprise about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% w/w lactose monohydrate. In some embodiments, the one or more pharmaceutically acceptable excipients comprise about 20% to about 70% w/w dibasic calcium phosphate dihydrate. In some embodiments, the one or more pharmaceutically acceptable excipients comprise about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50% w/w dibasic calcium phosphate dihydrate. In some embodiments, the one or more pharmaceutically acceptable excipients comprise about 0.1% to about 15% w/w sodium bicarbonate. In some embodiments, the one or more pharmaceutically acceptable excipients include about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% w/w sodium bicarbonate. In some embodiments, the one or more pharmaceutically acceptable excipients comprise about 1% to about 20% w/w sodium starch glycolate. In some embodiments, the one or more pharmaceutically acceptable excipients comprise about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% w/w sodium starch glycolate. In some embodiments, the one or more pharmaceutically acceptable excipients comprise about 0.01% to about 10% w/w magnesium stearate. In some embodiments, the one or more pharmaceutically acceptable excipients include about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 3%, about 4%, or about 5% w/w magnesium stearate. In some embodiments, the one or more pharmaceutically acceptable excipients comprise about 0.01% to about 10% w/w colloidal silicon dioxide. In some embodiments, the one or more pharmaceutically acceptable excipients comprise about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 3%, about 4%, or about 5% w/w colloidal silica. In some embodiments, the formulation is included in a tablet. In some embodiments, the tablet is coated with a film coating. In some embodiments, malonic acid Wo Luxi forest comprises a crystalline form of malonic acid Wo Luxi forest characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from 7.30 ° ± 0.2 °, 13.58 ° ± 0.2 °, 14.06 ° ± 0.2 °, 15.18 ° ± 0.2 °, 15.66 ° ± 0.2 °, 17.50 ° ± 0.2 °, 18.94 ° ± 0.2 °, 19.54 ° ± 0.2 °, 22.22 ° ± 0.2 °, 23.38 ° ± 0.2 °, 24.10 ° ± 0.2 °, 24.98 ° ± 0.2 °, 25.94 ° ± 0.2 °, 27.26 ° ± 0.2 °, 28.50 ° ± 0.2 ° and 32.82 ° ± 0.2 ° 2Θ. In some embodiments, the malonic acid Wo Luxi forest comprises a crystalline form of malonic acid Wo Luxi forest, said crystalline form characterized by an X-ray powder diffraction pattern, the X-ray powder diffraction pattern includes a peak selected from the group consisting of 6.36 ° ± 0.2 ° 2θ, 13.88 ° ± 0.2 ° 2θ, 7.31 ° ± 0.2 ° 2θ, 9.34 ° ± 0.2 ° 2θ, 10.05 ° ± 0.2 ° 2θ, 13.59 ° ± 0.2 ° 2θ, 14.08 ° ± 0.2 ° 2θ, 15.21 ° ± 0.2 ° 2θ, 15.67 ° ± 0.2 ° 2θ, 17.53 ° ± 0.2 ° 2θ, 18.70 ° ± 0.2 ° 2θ, 18.98 ° ± 0.2 ° 2θ, 19.38 ° ± 0.2 ° 2θ, 19.67 ° ± 0.2 ° 2θ, 20.16 ° ± 0.2 ° 2θ, 20.39 ° ± 0.2 ° 2θ, 21.01 ° ± 0.2 ° 2θ, 22.27 ° ± 0.2 ° 2θ, 23.35 ° ± 0.24 ° ± 24.27 ° ± 0.25 ° ± 2 ° 2θ, and a peak. In some embodiments, the crystalline form is a crystalline anhydrate. In some embodiments, the crystalline form is a crystalline hydrate.

The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective formulation described herein. The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective formulation comprising about 15% to 35% w/w malonic acid Wo Luxi forest, about 5% to 37% w/w microcrystalline cellulose, about 1% to about 48% w/w lactose monohydrate, about 20% to about 70% w/w dibasic calcium phosphate dihydrate, about 0.1% to about 15% w/w sodium bicarbonate, about 1% to about 20% w/w sodium starch glycolate, and about 0.01% to about 10% w/w magnesium stearate. In some embodiments, the malonic acid Wo Luxi forest comprises a crystalline form of malonic acid Wo Luxi forest characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.30 ° ± 0.2 °, 13.58 ° ± 0.2 °, 14.06 ° ± 0.2 °, 15.18 ° ± 0.2 °, 15.66 ° ± 0.2 °, 17.50 ° ± 0.2 °, 18.94 ° ± 0.2 °, 19.54 ° ± 0.2 °, 22.22 ° ± 0.2 °, 23.38 ° ± 0.2 °, 24.10 ° ± 0.2 °, 24.98 ° ± 0.2 °, 25.94 ° ± 0.2 °, 27.26 ° ± 0.2 °, 28.50 ° ± 0.2 ° and 32.82 ° ± 0.2 ° 2Θ. In some embodiments, the malonic acid Wo Luxi forest comprises a crystalline form of malonic acid Wo Luxi forest, said crystalline form characterized by an X-ray powder diffraction pattern, the X-ray powder diffraction pattern includes a peak selected from the group consisting of 6.36 ° ± 0.2 ° 2θ, 13.88 ° ± 0.2 ° 2θ, 7.31 ° ± 0.2 ° 2θ, 9.34 ° ± 0.2 ° 2θ, 10.05 ° ± 0.2 ° 2θ, 13.59 ° ± 0.2 ° 2θ, 14.08 ° ± 0.2 ° 2θ, 15.21 ° ± 0.2 ° 2θ, 15.67 ° ± 0.2 ° 2θ, 17.53 ° ± 0.2 ° 2θ, 18.70 ° ± 0.2 ° 2θ, 18.98 ° ± 0.2 ° 2θ, 19.38 ° ± 0.2 ° 2θ, 19.67 ° ± 0.2 ° 2θ, 20.16 ° ± 0.2 ° 2θ, 20.39 ° ± 0.2 ° 2θ, 21.01 ° ± 0.2 ° 2θ, 22.27 ° ± 0.2 ° 2θ, 23.35 ° ± 0.24 ° ± 24.27 ° ± 0.25 ° ± 2 ° 2θ, and a peak. In some embodiments, the formulation includes about 0.01% to about 10% w/w colloidal silica. In some embodiments, the formulation is included into a tablet and the tablet is coated with a film coating. In some embodiments, the disease or disorder is leukemia. In some embodiments, the blood cancer is selected from Acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), acute Lymphocytic Lymphoma (ALL), and Chronic Lymphocytic Leukemia (CLL). In some embodiments, the formulation is administered to the subject such that the subject receives a daily Wo Luxi forest dose of between about 50mg and about 100mg, between about 100mg and about 150mg, between about 150mg and about 200mg, between about 200mg and about 250mg, between about 250mg and about 300mg, between about 300mg and about 350mg, between about 350mg and about 400mg, between about 400mg and about 450mg, between about 450mg and about 500mg, between about 500mg and about 550mg, between about 550mg and about 600mg, between about 600mg and about 650mg, between about 650mg and about 700mg, between about 700mg and about 750mg, between about 750mg and about 800mg, between about 800mg and about 850mg, between about 850mg and about 900mg, between about 900mg and about 950mg, or between about 950mg and about 1,000 mg. In some embodiments, the formulation is administered to the subject such that the subject receives a daily Wo Luxi forest dose of about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, about 700mg, about 750mg, about 800mg, about 850mg, about 900mg, about 950mg, or about 1,000 mg. In some embodiments, the formulation is administered to the subject such that the subject receives a daily Wo Luxi forest dose of about 200mg or about 250 mg. In some embodiments, the formulation is administered to the subject such that the subject receives a daily Wo Luxi forest dose of no more than 350 mg. In some embodiments, the Wo Luxi forest dose is a Wo Luxi forest free base dose. In some embodiments, the formulation is administered to the subject daily for about one day, about two days, about three days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days. In some embodiments, the formulation is administered to the subject daily for about one week, about two weeks, about three weeks, or about 4 weeks. In some embodiments, administration of the formulation is suspended for about one day, about two days, about three days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days. In some embodiments, administration of the formulation is suspended for about one week, about two weeks, about three weeks, or about 4 weeks. In some embodiments, the formulation is administered to the subject on a14 day/14 day off schedule. In some embodiments, the formulation is administered for about one month, about two months, about three months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months. In some embodiments, the formulation is administered in combination with a BCL-2 inhibitor. In some embodiments, the BCL-2 inhibitor is selected from the group consisting of Navitock (navitocrax), venetoclax, A-1155463, A-1331852, ABT-737, obacicla (obatocrax), S44563, TW-37, A-1210477, AT101, HA14-1, BAM7, sha Butuo grams (sabotoclax), UMI-77, gambogic acid, marigogram (mariroclax), MIM1, methylprednisolone (methylprednisolone), iMAC2, bax inhibitor peptide V5, bax inhibitor peptide P5, bax channel blocker, and ARRY 520 trifluoroacetate or a pharmaceutically acceptable salt of any of these. In some embodiments, the BCL-2 inhibitor is valnemulin or a pharmaceutically acceptable salt thereof. In some embodiments, the BCL-2 inhibitor is administered to the subject daily for about one day, about two days, about three days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days. In some embodiments, the BCL-2 inhibitor is administered to the subject daily for about one week, about two weeks, about three weeks, or about 4 weeks. In some embodiments, the administration of the BCL-2 inhibitor is suspended for about one day, about two days, about three days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days. In some embodiments, administration of the BCL-2 inhibitor is suspended for about one week, about two weeks, about three weeks, or about 4 weeks. In some embodiments, the BCL-2 inhibitor is administered to the subject on a14 day/14 day off schedule. In some embodiments, the BCL-2 inhibitor is administered to the subject for about one month, about two months, about three months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months.

Drawings

The foregoing summary, as well as the following detailed description of the present disclosure, will be better understood when read in conjunction with the appended drawings.

FIGS. 1A and 1B show reduced expression of c-MYC in solid tumors: 10 gene biomarkers were evaluated in a phase 1 daily dosing study; 17 out of 25 patients (68%) had reduced c-MYC expression.

FIGS. 2A-2C illustrate CR in a patient with lung metastasis; fig. 2A: baseline CT scan; fig. 2B: radiological CR based on official radiological reports 2 months after starting the trial; fig. 2C: the patient only lasted for 12 months after the start of the trial, and the CR lasted for 14 months.

Figures 3A-3D demonstrate that Wo Luxi forest shows preferential tumor accumulation in preclinical models.

Fig. 4A and 4B show the synergy with valnemorque in Wo Luxi Lin Zaiwei netoolk sensitive and resistant cell lines.

Fig. 5 is a flow chart of a process for producing malonic acid Wo Luxi Lin Pianji.

FIG. 6 is a chromatogram of a dissolution test of 50mg malonic acid Wo Luxi forest tablet.

Fig. 7 is a graph depicting the dissolution of Wo Luxi forest hydrochloride capsules and malonic acid Wo Luxi Lin Pianji.

Fig. 8A shows the molecular structure (stereochemistry) of malonic acid Wo Luxi forest. FIG. 8B is the X-ray crystal structure of malonic acid Wo Luxi forest drug substance (lot 20-07211).

FIG. 9 is a superposition of HR-XRPD patterns (monolithic and simulated single crystals) generated using the Mercury software of the Cambridge crystallographic data center based on atomic positions obtained from single crystal analysis.

Fig. 10 is an XRPD diffraction pattern of malonic acid Wo Luxi forest.

FIG. 11 shows a synthesis scheme for the synthesis of malonic acid Wo Luxi forest.

Fig. 12 is a flow chart of a process for producing malonic acid Wo Luxi forest. Abbreviations: RSM = starting material; ac (Ac) ₂ O=acetic anhydride; DCM = dichloromethane; DM = dimethylformamide; et (Et) ₃ N=triethylamine; naH = sodium hydride; 2-methyl-thf=2-methyltetrahydrofuran; BF (BF) ₃ Et ₂ O=boron trifluoride diethyl etherate; ipa=isopropanol

Fig. 13A-13F depict chemical transformations for the manufacture of malonic acid Wo Luxi forest. Fig. 13A depicts the synthesis of intermediate 1. Fig. 13B depicts the synthesis of intermediate 2. Fig. 13C depicts the synthesis of intermediate 3. Fig. 13D depicts the synthesis of intermediate 4. Fig. 13E depicts the synthesis of intermediate 5. Fig. 13F depicts the synthesis of malonic acid Wo Luxi forest from intermediate 5.

Detailed Description

While preferred embodiments of the present disclosure are illustrated and described herein, such embodiments are provided by way of example only and are not intended to limit the scope of the present disclosure in any way. Various alternatives to the described embodiments of the present disclosure may be used to practice the present disclosure.

Definition of the definition

Unless defined otherwise, 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 disclosure belongs. All patents and publications mentioned herein are incorporated by reference in their entirety.

The term "solid form" may refer to a crystalline solid form or phase comprising crystalline free base and crystalline salt.

As used herein, the terms "co-administration," "combined with … (administered in combination with)" and "combined with … (administering in combination with)" encompass administration of two or more agents to a subject such that both agents and/or metabolites thereof are present in the subject at the same time. Co-administration includes simultaneous administration as separate compositions, administration at different times as separate compositions, or administration as a composition in which two or more agents are present.

The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of compounds that is sufficient to achieve the intended use, including but not limited to, treatment of a disease, as described herein. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo) or the subject and the disease condition being treated (e.g., the weight, age, and sex of the subject), the severity of the disease condition, the manner of administration, and the like, as can be readily determined by one of ordinary skill in the art. The term also applies to doses that will induce a particular response (e.g., CDK inhibition) in a target cell. The specific dosage will vary depending upon the particular compound selected, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue in which the compound is administered, and the physical delivery system in which the compound is carried.

As used herein, the term "synergistic" generally refers to an effect in which the combined effect or effects of the composition is greater than the effect or effects of each component alone, or it may be greater than the sum of the effect or effects of each component alone. Synergy may be about 10%, 20%, 30%, 50%, 75%, 100%, 110%, 120%, 150%, 200%, 250%, 350% or 500% or more than the effect of one of the components used alone on the subject or the additive effect of one of the components when administered alone. The effect may be any measurable effect described herein. Advantageously, such synergy between agents when combined may allow for the use of smaller doses of one or both agents, may provide greater efficacy at the same dose, and may prevent or delay the establishment of multidrug resistance. The Combination Index (CI) method of Chou and Talay may be used to determine the synergy, additive or antagonistic effect of a combination of agents. When the CI value is less than 1, there is a synergistic effect between the compounds used in combination; when the CI value is equal to 1, there is a summation effect between the compounds used in combination and when the CI value is greater than 1, there is antagonism. Synergism may be achieved by co-formulating the agents of the pharmaceutical combination. Synergy may be achieved by simultaneous or sequential administration of two or more agents as separate formulations.

Cyclin Dependent Kinases (CDKs) are a family of enzymes that are activated at specific stages of the cell cycle. CDKs consist of a catalytic subunit (the actual cyclin dependent kinase or CDK) and a regulatory subunit (cyclin). There are at least nine CDKs (CDK 1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, etc.) and at least 15 different types of cyclin (cyclin A, B, B2, D1, D2, D3, E, H, etc.). Each step of the cell cycle is regulated by such CDK complexes: G1/S switching (CDK 2/cyclin A, CDK 4/cyclin D1-D3, CDK 6/cyclin D3), S phase (CDK 2/cyclin A), G2 phase 30 (CDK 1/cyclin A), G2/M switching phase (CDK 1/cyclin B).

As used herein, the term "CDK inhibitor" refers to an agent capable of inhibiting one or more Cyclin Dependent Kinases (CDKs). Aberrant expression and overexpression of these kinases has been demonstrated in many disease conditions such as cancer. In the context of the present invention, the CDK inhibitor of the pharmaceutical combination described herein may be a compound of formula I, ia or Ib or a pharmaceutically acceptable salt thereof. Compounds of the present disclosure may specifically inhibit one or more of CDK 1/cyclin B, CDK 2/cyclin E, CDK 4/cyclin D, CDK/cyclin D1 and CDK 9/cyclin T1. In certain embodiments, the compounds of the present disclosure specifically inhibit CDK 9/cyclin T1 or CDK9.

Disclosed herein are combination therapies for treating cancers, such as leukemia, lymphoma, and breast cancer. The methods and compositions described herein may comprise a Cyclin Dependent Kinase (CDK) inhibitor, e.g., a compound of formula I, ia or Ib, or a pharmaceutically acceptable salt thereof. In some cases, the combination therapy may comprise a combination of a CDK inhibitor and a proteasome inhibitor. In other cases, the combination therapy may comprise a combination of a CDK inhibitor and a BCL-2 inhibitor.

In certain embodiments, the CDK inhibitors of the present disclosure are described in U.S. patent No. 7,271,193; 7,915,301; 8,304,449; 7,884,127; the compounds disclosed in 8,563,596 are representative, and the entire contents of each of the U.S. patents are incorporated herein by reference.

The term "QD", "QD" or "q.d." means once daily (quaque die, once a day or once day). The term "BID", "BID" or "b.i.d." means twice daily (bis in die, twice a day or twice day). The term "TID", "TID" or "t.i.d." means three times per day (ter in die, three times a day or three times daily). The term "QID", "QID" or "q.i.d." means four times per day (quater in die, four times a day or four times day).

The term "therapeutic effect" as used herein encompasses therapeutic benefits and/or prophylactic benefits as described above. Preventive effects include delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

As used herein, the term "free base dose" refers to the amount of a drug in its free base form that can be replaced by the amount of the salt of the drug by using a salt conversion factor.

The term "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions, including fumarate, maleate, phosphate, L-tartrate, ethanesulfonate, benzenesulfonate, hydrobromide, hydrochloride, citrate, gentisate, oxalate, sulfate counterions, and the like. Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids.

"pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is intended to encompass any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. Except insofar as any conventional medium or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the present disclosure is contemplated. Supplementary active ingredients may also be incorporated into the described compositions.

The term "in vivo" refers to an event that occurs in a subject.

The term "in vitro" refers to an event that occurs in vitro in a subject. In vitro assays encompass cell-based assays in which viable or dead cells are employed; and cell-free assays may also be contemplated in which intact cells are not employed.

The term "extragranular" refers to a substance that is external to the granule, such as a substance that is added to the granule (multiparticulate compact formed by the granulation process) and physically mixed with the granule, but not contained within the granule.

The term "intragranular" refers to the material within the granule (multiparticulate compact formed by the granulation process). The granules may be formed by processes such as wet granulation (i.e., prepared using moisture or steam, heat, melting, freezing, foaming, and other processes) or dry granulation.

The term "acidulant" refers to a substance that increases acidity.

When used in conjunction with powder X-ray diffraction, the term "transmission" or "transmission mode" refers to a transmission (also known as debye-scherrer) sampling mode. When used in conjunction with powder X-ray diffraction, the term "reflection" or "reflection mode" refers to a reflection (also known as bragg-brentun) sampling mode.

Unless otherwise indicated, chemical structures described herein are also intended to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, in which one or more hydrogen atoms are replaced by deuterium or tritium, or in which one or more carbon atoms are replaced by ¹³ C enrichment or ¹⁴ C-enriched carbon-substituted compounds are within the scope of the present disclosure.

When ranges are used herein to describe physical or chemical characteristics such as molecular weight or chemical formula, for example, it is intended to encompass all combinations and subcombinations of ranges as well as specific embodiments thereof. When referring to a number or range of values, the use of the term "about" or "approximately" means that the number or range of values referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or range of values may vary, for example, between 1% and 15% of the number or range of values. The term "comprising" (and related terms such as "comprises" or "comprising") or "having" or "including") encompasses those embodiments, e.g., embodiments of any composition of matter, method or process that "consists of" or "consists essentially of" the feature.

As used herein, "enantiomeric purity" refers to the relative amount of one particular enantiomer to another, expressed as a percentage. For example, if a compound that may have the configuration of the (R) -or (S) -isomer is present as a racemic mixture, the enantiomeric purity is about 50% relative to the (R) -or (S) -isomer. If one isomeric form of the compound predominates over the other, for example 80% (S) -isomer and 20% (R) -isomer, the enantiomeric purity of the compound relative to the (S) -isomeric form is 80%. The enantiomeric purity of a compound can be determined in a variety of ways including, but not limited to, chromatography using chiral carriers, optical rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shifting reagents including, but not limited to, lanthanide-containing chiral complexes or Pirkle reagents, or using chiral compounds such as Mosher acid derivative compounds followed by chromatography or nuclear magnetic resonance spectroscopy.

In a preferred embodiment, the enantiomerically enriched composition has a higher potency per unit mass of therapeutic effect than the racemic mixture of the composition. Enantiomers may be separated from the mixture by methods known to those skilled in the art, including chiral High Pressure Liquid Chromatography (HPLC) and formation and crystallization of chiral salts; or the preferred enantiomer may be prepared by asymmetric synthesis. See, e.g., jacques et al (Enantiomers, racemates and resolution (Enantomers, racemates and Resolutions)), willi International science publication of New York (Wiley Interscience, new York), 1981; eliel, stereochemistry of carbon compounds (Stereochemistry of Carbon Compounds), maxwell-Hill, N.Y., 1962, and Eliel and Wilen, stereochemistry of organic compounds (Stereochemistry of Organic Compounds), wiley International science publication of New York (Wiley-Interscience, new York), 1994.

As used herein, the terms "enantiomerically enriched" and "non-racemic" refer to compositions in which the weight percent of one enantiomer is greater than the amount of the one enantiomer in a control mixture of the racemic composition (e.g., greater than 1:1 weight). For example, an enantiomerically enriched preparation of an (S) -enantiomer means a preparation of a compound having more than 50% (such as at least 75% by weight or such as at least 80% by weight) of the (S) -enantiomer relative to the (R) -enantiomer. In some embodiments, the enrichment can be substantially greater than 80% by weight, providing a "substantially enantiomerically enriched" or "substantially non-racemic" formulation, meaning a formulation having at least 85% by weight, such as at least 90% by weight, or such as at least 95% by weight, of the composition relative to one enantiomer. The term "enantiomerically pure" or "substantially enantiomerically pure" refers to compositions comprising at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.

"moiety" refers to a particular segment or functional group of a molecule. Chemical moieties are generally recognized chemical entities that are either embedded in a molecule or attached to a molecule.

"tautomers" are structurally different isomers that are interconverted by tautomerization. "tautomerization" is a form of isomerization and includes proton-isomorphous or proton-displaced tautomerism, which is considered a subset of acid-base chemistry. "proton-hetero-tautomerization" or "proton-shift tautomerization" involves the migration of protons, accompanied by a change in bond order, typically the exchange of a single bond with an adjacent double bond. In the case where tautomerization may occur (e.g., in solution), chemical equilibrium of the tautomers may be reached. An example of tautomerism is keto-enol tautomerism. Specific examples of keto-enol tautomerism are the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-ketone tautomerization. The formation of solid forms under different tautomeric states is known as "stationarity", and such forms are known as "stationarity".

The compositions of the present disclosure also include crystalline forms of formula (1), including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including non-hydrates) and conformational polymorphs, as well as mixtures thereof. "crystalline forms", "forms" and "polymorphs" are intended to include all crystalline forms of a compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including non-hydrates) and conformational polymorphs, as well as mixtures thereof, unless a specific crystalline form is mentioned.

"solvate" refers to a crystalline phase of a compound that is physically associated with one or more molecules of a solvent. The crystalline phase of a compound that is physically associated with one or more molecules of water is referred to as a "hydrate".

By "amorphous form" is meant a form of a compound or salt or molecular complex of a compound that lacks long-range crystalline order.

Wo Luxi forest

Wo Luxi is a CDK inhibitor described, for example, in U.S. Pat. Nos. 7,271,193, 7,915,301, 8,304,449, 7,884,127, and 8,563,596, which are incorporated herein by reference in their entirety.

Wo Luxi forest

In some embodiments, wo Luxi forest refers to (+) -trans-2- (2-chloro-4-trifluoromethylphenyl) -5, 7-dihydroxy-8- (2-hydroxymethyl-1-methylpyrrolidin-3-yl) -chromen-4-one. In some embodiments, wo Luxi forest refers to 2- (2-chloro-4-trifluoromethylphenyl) -5, 7-dihydroxy-8- ((2 r,3 s) -2-hydroxymethyl-1-methylpyrrolidin-3-yl) -4H-chromen-4-one.

Wo Luxi forest salts and/or polymorphs thereof and methods of making and using the same are described, for example, in International patent application publication WO 2020/210760, which is incorporated herein in its entirety.

The present disclosure provides pharmaceutically acceptable salts of any of the compounds described herein, e.g., wo Luxi forest, BCL-2 inhibitors, proteasome inhibitors, and the like. Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts. The acid added to the compound to form the acid addition salt may be an organic acid or an inorganic acid. The base added to the compound to form the base addition salt may be an organic base or an inorganic base. In some cases, the pharmaceutically acceptable salt is a metal salt. In some cases, the pharmaceutically acceptable salt is an ammonium salt.

Acid addition salts may result from the addition of an acid to the compounds described herein. In some cases, the acid is organic. In some cases, the acid is inorganic. Non-limiting examples of suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, phosphoric acid, nicotinic acid, isonicotinic acid, lactic acid, salicylic acid, 4-aminosalicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, citric acid, oxalic acid, malonic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, glycolic acid, malic acid, cinnamic acid, mandelic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, enbergic acid, phenylacetic acid, N-cyclohexylsulfamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1, 2-disulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, 2-phosphoglyceric acid, 3-phosphoglyceric acid, glucose-6-phosphoric acid, and amino acids.

The metal salts may result from the addition of an inorganic base to the compounds of the present invention. The inorganic base consists of a metal cation, such as hydroxide, carbonate, bicarbonate or phosphate, paired with a basic counter ion. The metal may be an alkali metal, an alkaline earth metal, a transition metal or a main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

In some embodiments, the metal salt is a lithium salt, sodium salt, potassium salt, cesium salt, cerium salt, magnesium salt, manganese salt, iron salt, calcium salt, strontium salt, cobalt salt, titanium salt, aluminum salt, copper salt, cadmium salt, or zinc salt.

Ammonium salts can be produced by adding ammonia or an organic amine to the compounds described herein. Non-limiting examples of suitable organic amines include triethylamine, diisopropylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, methylphenazole, imidazole, pyrazine, methylphenazine, ethylenediamine, N' -dibenzylethylenediamine, procaine, chloroprocaine, choline, dicyclohexylamine and N-methylglucamine.

Non-limiting examples of suitable ammonium salts include triethylamine, diisopropylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, methylphenazole, imidazole, pyrazine, piperazine, ethylenediamine, N' -dibenzylethylenediamine, procaine, chloroprocaine, choline, dicyclohexylamine and N-methylglucamine salts.

Non-limiting examples of suitable acid addition salts include hydrochloride, hydrobromide, hydroiodide, nitrate, nitrite, sulfate, sulfite, phosphate, hydrogen phosphate, dihydrogen phosphate, carbonate, bicarbonate, nicotinate, isonicotinate, lactate, salicylate, 4-aminosalicylate, tartrate, ascorbate, gentisate, gluconate, glucuronate, sucrose, formate, benzoate, glutamate, pantothenate, acetate, propionate, butyrate, fumarate, succinate, citrate, oxalate, maleate, hydroxymaleate, maleate, methyl maleate, glycolate, malate, cinnamate, mandelate, 2-phenoxybenzoate, 2-acetoxybenzoate, benzoate, N-cyclohexylsulfamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, ethane-1, 2-disulfonate, 4-methylbenzenesulfonate, naphthalene-2-sulfonate, naphthalene-1, 5-disulfonate, 2-phosphoglycerate, 3-glycerophosphate, glucose-6-phosphate, and sulfamate.

In some aspects, a combination described herein, e.g., a CDK inhibitor in combination with a BCL-2 inhibitor or a proteasome inhibitor, may be used to treat cancer. The combination therapies described herein may reduce the likelihood of metastasis in a subject in need thereof. In some embodiments, the metastasis is a solid tumor. In some embodiments, the metastasis is a liquid tumor. Cancers that are liquid tumors may be those that occur in, for example, blood, bone marrow, and lymph nodes, and may include, for example, leukemia, myelogenous leukemia, lymphocytic leukemia, lymphoma, hodgkin's lymphoma, melanoma, and multiple myeloma. Leukemias include, for example, acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), and hairy cell leukemia. Cancers as solid tumors include, for example, prostate cancer, testicular cancer, breast cancer, brain cancer, pancreatic cancer, colon cancer, thyroid cancer, stomach cancer, lung cancer, ovarian cancer, kaposi's sarcoma, skin cancer, squamous cell skin cancer, renal cancer, head and neck cancer, laryngeal cancer, squamous cell cancer formed on moist mucosal lining of nose, mouth, throat, bladder cancer, osteosarcoma, cervical cancer, endometrial cancer, esophageal cancer, liver cancer, and renal cancer. In some embodiments, the condition treated by the methods described herein is metastasis of a melanoma cell, a prostate cancer cell, a testicular cancer cell, a breast cancer cell, a brain cancer cell, a pancreatic cancer cell, a colon cancer cell, a thyroid cancer cell, a gastric cancer cell, a lung cancer cell, an ovarian cancer cell, a kaposi's sarcoma cell, a skin cancer cell, a renal cancer cell, a head or neck cancer cell, a laryngeal cancer cell, a squamous cell carcinoma cell, a bladder cancer cell, a osteosarcoma cell, a cervical cancer cell, an endometrial cancer cell, an esophageal cancer cell, a liver cancer cell, or a renal cancer cell.

The methods described herein may also be used to inhibit metastatic cancer tumorsProgress. Non-limiting examples of cancers include adrenocortical cancer, childhood adrenocortical cancer, AIDS-related cancer, anal cancer, appendiceal cancer, basal cell carcinoma, childhood basal cell carcinoma, bladder cancer, childhood bladder cancer, bone cancer, brain tumor, childhood astrocytoma, childhood brain stem glioma, childhood central nervous system atypical teratoma/rhabdomyoma, childhood central nervous system embryo tumor, childhood central nervous system germ cell tumor, childhood craniopharyngeal tumor brain tumor, childhood ependymal tumor brain tumor, breast cancer, childhood bronchial tumor, carcinoid tumor, childhood carcinoid tumor, gastrointestinal carcinoid tumor, unknown primary cancer, childhood heart tumor, cervical cancer, childhood chordoma, chronic myeloproliferative disease, colon cancer, colorectal cancer childhood colorectal cancer, extrahepatic cholangiocarcinoma, ductal Carcinoma In Situ (DCIS), endometrial cancer, esophageal cancer, childhood olfactory neuroblastoma, ocular cancer, bone malignant fibrous histiocytoma, gall bladder cancer, gastric (gastric) cancer, childhood gastric cancer, gastrointestinal stromal tumor (GIST), childhood extracranial germ cell tumor, extragonadal germ cell tumor, gestational trophoblastoma, glioma, head and neck cancer, childhood head and neck cancer, hepatocellular carcinoma, hypopharyngeal cancer, renal cell renal cancer, wilms tumor (Wilms tumor), childhood renal tumor, langerhans' cell histiocytosis, laryngeal cancer, childhood laryngeal cancer, leukemia, acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), chronic Lymphoblastic Leukemia (CLL), glioblastoma, chronic myelogenous leukemia (cml), hairy cell leukemia, lip cancer, liver cancer (primary), pediatric liver cancer (primary), lobular Carcinoma In Situ (LCIS), lung cancer, non-small cell lung cancer, lymphoma, AIDS-related lymphoma, burkitt's lymphoma, cutaneous t-cell lymphoma, hodgkin's lymphoma, non-Hodgkin's lymphoma, primary central nervous system lymphoma (CNS), melanoma, childhood melanoma, intraocular melanoma, merck's cell carcinoma, malignant mesothelioma, childhood malignant mesothelioma, primary focal occult metastatic cervical squamous cell carcinoma, midline carcinoma involving the NUT gene, oral cancer, childhood multiple endocrine tumor syndrome, mycosis fungoides, bone Myelodysplastic syndrome, myelodysplastic tumor, myeloproliferative tumor, multiple myeloma, nasal cavity cancer, nasopharyngeal cancer, childhood nasopharyngeal cancer, neuroblastoma, oral cancer, childhood oral cancer, oropharyngeal cancer, ovarian cancer, childhood ovarian cancer, epithelial ovarian cancer, low malignant potential tumor ovarian cancer, pancreatic cancer, childhood pancreatic cancer, pancreatic neuroendocrine tumor (islet cell tumor), childhood papillomatosis, paraganglioma, paranasal sinus cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasmacytoma, childhood pleural pneumoblastoma, prostate cancer, rectal cancer renal pelvis transitional cell carcinoma, retinoblastoma, salivary gland carcinoma, childhood salivary gland carcinoma, ewing's sarcoma family, kaposi's sarcoma, osteosarcoma, rhabdomyosarcoma, childhood rhabdomyosarcoma, soft tissue sarcoma, uterine sarcoma, sezary's syndrome, childhood skin carcinoma, non-melanoma skin carcinoma, small intestine carcinoma, squamous cell carcinoma, childhood squamous cell carcinoma, testicular carcinoma, childhood testicular carcinoma, laryngeal carcinoma, thymoma and thymus carcinoma, childhood thymoma and thymus carcinoma, thyroid carcinoma, childhood thyroid carcinoma, ureteral transitional cell carcinoma, urethral carcinoma, endometrial carcinoma, vaginal carcinoma, vulvar carcinoma, and waldenstrom's macroglobulinemia macroglobulinemia)。

The combination therapies described herein may be used with other therapies such as radiation therapy. Chemotherapy and radiation therapy treatment regimens may include a limited number of cycles of medication and subsequent withdrawal of medication, or a limited time frame including administration of chemotherapy or radiation therapy. The regimen may be determined by clinical trials, drug labels and clinical staff in combination with the subject to be treated. The number of cycles of chemotherapy or radiation therapy or the total length of time of the chemotherapy or radiation therapy regimen may vary depending on the subject's response to the cancer therapy. The pharmaceutical agents described herein may be administered after the treatment regimen of chemotherapy or radiation therapy is completed.

In some aspects, the combinations described herein may be used to treat a subject in need thereof. In some cases, the subject treated by the methods and compositions disclosed herein can be a human subject. The subject treated by the methods and compositions disclosed herein can be a non-human animal. Non-limiting examples of non-human animals can include non-human primates, livestock animals, domestic pets, and laboratory animals.

Crystalline forms

In an embodiment, the present disclosure provides a crystalline solid form of Wo Luxi forest. In an embodiment, the present disclosure provides a crystalline solid form of Wo Luxi forest free base. In an embodiment, the present disclosure provides a crystalline solid form of Wo Luxi forest salt. The present disclosure provides polymorphs, e.g., crystalline forms, of Wo Luxi forest. In some embodiments, the polymorph comprises the free base Wo Luxi forest. In some embodiments, the polymorph comprises a salt of Wo Luxi, the salt of Wo Luxi comprising a counter ion corresponding to an acid selected from the group consisting of 1, 5-naphthalenedisulfonic acid, 1-hydroxy-2-naphthoic acid, benzenesulfonic acid, benzoic acid, dibenzoyl-L-tartaric acid, ethanesulfonic acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malonic acid, oxalic acid, orthophosphoric acid, sulfuric acid, and p-toluenesulfonic acid.

Any of the crystalline forms described herein may be characterized by X-ray diffraction. In some embodiments, X-ray diffraction refers to X-ray powder diffraction. In some embodiments, the X-ray diffraction may be measured using either a transmissive mode or a reflective mode. In an embodiment, the X-ray diffraction pattern of any of the embodiments herein is measured in a transmissive mode. In an embodiment, the X-ray diffraction pattern of any of the embodiments herein is measured in a reflective mode. It is known in the art that X-ray powder diffraction patterns can be obtained with one or more measurement errors depending on the measurement conditions, such as the equipment, sample preparation or the instrument used. In particular, it is generally known that the intensity in an X-ray powder diffraction pattern may vary depending on the measurement conditions and sample preparation. For example, those skilled in the art of X-ray powder diffraction will recognize that the relative intensities of the peaks may vary depending on the orientation of the test sample and on the type and setting of instrument used. The skilled person will also appreciate that the position of the reflection may be affected by the exact height of the sample in the diffractometer, the surface flatness of the sample and the zero calibration of the diffractometer. It will be understood by those skilled in the art that the diffraction pattern data presented herein should not be construed as absolute, and that any crystalline form that provides substantially the same power diffraction pattern as those disclosed herein falls within the scope of the present disclosure. For further information see, for example, jenkins and Snyder, introduction to X-ray powder diffraction (Introduction to X-Ray Powder Diffractometry), john Wiley parent-child publishing company (John Wiley & Sons), 1996.

The different crystalline forms may provide surprising advantages over the non-crystalline forms, including improved thermodynamic stability, faster dissolution rates, improved performance in the stomach and stomach environment (including avoiding or reducing precipitation of the solution at a higher pH), improved mammalian exposure, and superior processability of the drug formulation into a finished product suitable for the patient.

In one embodiment, the present disclosure provides a crystalline form of malonic acid Wo Luxi forest and/or a polymorph crystalline form of malonic acid Wo Luxi forest (Mao 1), characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of:

in some embodiments, each peak may independently comprise a variation of ±0.1°, ±0.2°, or ±0.3°.

In one embodiment, the present disclosure provides a crystalline form of oxalic acid Wo Luxi forest and/or a polymorph crystalline form of oxalic acid Wo Luxi forest (Oxa 1) characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of:

In one embodiment, the present disclosure provides a crystalline form of phosphoric acid Wo Luxi forest and/or a polymorph crystalline form of phosphoric acid Wo Luxi forest (Pho 1) characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of:

In one embodiment, the present disclosure provides a crystalline form of Wo Luxi forest characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from 7.30 ° ± 0.2 °, 13.58 ° ± 0.2 °, 14.06 ° ± 0.2 °, 15.18 ° ± 0.2 °, 15.66 ° ± 0.2 °, 17.50 ° ± 0.2 °, 18.94 ° ± 0.2 °, 19.54 ° ± 0.2 °, 22.22 ° ± 0.2 °, 23.38 ° ± 0.2 °, 24.10 ° ± 0.2 °, 24.98 ° ± 0.2 °, 25.94 ° ± 0.2 °, 27.26 ° ± 0.2 °, 28.50 ° ± 0.2 ° and 32.82 ° ± 0.2 ° 2Θ. In some embodiments, the X-ray diffraction pattern comprises at least one peak selected from the above-described peak groups, at least two peaks, at least three peaks, at least four peaks, at least five peaks, and the like. In some embodiments, the crystalline form comprises malonic acid Wo Luxi forest. In some embodiments, the crystalline form comprises malonic acid hydrate Wo Luxi forest. In some embodiments, the crystalline form comprises anhydrous malonic acid Wo Luxi forest.

In one embodiment, the present disclosure provides a crystalline form of Wo Luxi forest characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from 5.06 ° ± 0.2 °, 6.42 ° ± 0.2 °, 9.34 ° ± 0.2 °, 10.14 ° ± 0.2 °, 12.30 ° ± 0.2 °, 13.66 ° ± 0.2 °, 14.14 ° ± 0.2 °, 15.82 ° ± 0.2 °, 17.02 ° ± 0.2 °, 19.74 ° ± 0.2 °, 20.38 ° ± 0.2 °, 21.82 ° ± 0.2 °, 22.66 ° ± 0.2 °, 24.62 ° ± 0.2 °, 25.78 ° ± 0.2 °, 26.58 ° ± 0.2 °, 28.66 ° ± 0.2 ° and 29.98 ° ± 0.2 ° 2 θ. In some embodiments, the X-ray diffraction pattern comprises at least one peak selected from the above-described peak groups, at least two peaks, at least three peaks, at least four peaks, at least five peaks, and the like. In some embodiments, the crystalline form comprises dibenzoyltartaric acid Wo Luxi forest. In some embodiments, the crystalline form comprises dibenzoyltartaric acid Wo Luxi forest hydrate. In some embodiments, the crystalline form comprises anhydrous dibenzoyltartaric acid Wo Luxi forest.

In one embodiment, the present disclosure provides a crystalline form of Wo Luxi forest characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.94 ° ± 0.2 °, 6.78 ° ± 0.2 °, 9.34 ° ± 0.2 °, 10.94 ° ± 0.2 °, 12.70 ° ± 0.2 °, 13.38 ° ± 0.2 °, 14.90 ° ± 0.2 °, 15.66 ° ± 0.2 °, 17.54 ° ± 0.2 °, 18.82 ° ± 0.2 °, 22.02 ° ± 0.2 °, 23.98 ° ± 0.2 °, 24.78 ° ± 0.2 °, 25.30 ° ± 0.2 °, 26.66 ° ± 0.2 ° and 29.98 ° ± 0.2 ° 2Θ. In some embodiments, the X-ray diffraction pattern comprises at least one peak selected from the above-described peak groups, at least two peaks, at least three peaks, at least four peaks, at least five peaks, and the like. In some embodiments, the crystalline form comprises Wo Luxi forest of phosphoric acid. In some embodiments, the crystalline form comprises hydrated phosphoric acid Wo Luxi forest. In some embodiments, the crystalline form comprises anhydrous phosphoric acid Wo Luxi forest.

In one embodiment, the present disclosure provides a crystalline form of Wo Luxi forest characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from 6.86 ° ± 0.2 °, 12.66 ° ± 0.2 °, 13.58 ° ± 0.2 °, 14.74 ° ± 0.2 °, 15.98 ° ± 0.2 °, 19.38 ° ± 0.2 °, 23.94 ° ± 0.2 °, 24.78 ° ± 0.2 ° and 25.94 ° ± 0.2 ° 2Θ. In some embodiments, the X-ray diffraction pattern comprises at least one peak selected from the above-described peak groups, at least two peaks, at least three peaks, at least four peaks, at least five peaks, and the like. In some embodiments, the crystalline form comprises oxalic acid Wo Luxi forest. In some embodiments, the crystalline form comprises oxalic acid Wo Luxi forest hydrate. In some embodiments, the crystalline form comprises anhydrous oxalic acid Wo Luxi forest.

In one embodiment, the present disclosure provides a crystalline form of Wo Luxi forest characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from 9.02 ° ± 0.2 °, 10.50 ° ± 0.2 °, 11.06 ° ± 0.2 °, 12.30 ° ± 0.2 °, 12.82 ° ± 0.2 °, 13.90 ° ± 0.2 °, 14.82 ° ± 0.2 °, 15.30 ° ± 0.2 °, 15.94 ° ± 0.2 °, 17.26 ° ± 0.2 °, 19.34 ° ± 0.2 °, 20.62 ° ± 0.2 °, 22.18 ° ± 0.2 °, 22.86 ° ± 0.2 °, 24.58 ° ± 0.2 °, 25.42 ° ± 0.2 °, 25.86 ° ± 0.2 °, 27.38 ° ± 0.2 ° and 28.66 ° ± 0.2 °. In some embodiments, the X-ray diffraction pattern comprises at least one peak selected from the above-described peak groups, at least two peaks, at least three peaks, at least four peaks, at least five peaks, and the like. In some embodiments, the crystalline form comprises naphthalene disulfonic acid Wo Luxi forest. In some embodiments, the crystalline form comprises hydrated naphthalene disulfonic acid Wo Luxi forest. In some embodiments, the crystalline form comprises anhydrous naphthalene disulfonic acid Wo Luxi forest.

Pharmaceutical composition

In an embodiment, the present disclosure provides a pharmaceutical composition comprising a crystalline form of wo Lu Xilin free base. In an embodiment, the present disclosure provides a pharmaceutical composition comprising a crystalline form of a salt of wo Lu Xilin. The pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of the solid form of Wo Luxi forest in the form of the active ingredient or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In the desired case, the pharmaceutical composition contains a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, permeation enhancers, solubilizers, or adjuvants. The pharmaceutical composition may also contain an acidulant, as described herein.

In some embodiments, the concentration of Wo Luxi forest (including any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein) provided in the pharmaceutical composition of the present disclosure in solid form is independently less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.002% or 0.001% w/v or v/v, relative to the total mass or total volume of the pharmaceutical composition. In embodiments, the solid form of Wo Luxi forest is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In some embodiments, the composition is administered, relative to the total mass or volume of the pharmaceutical composition, the concentration of Wo Luxi forest (including any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein) in solid form provided in the pharmaceutical compositions of the present disclosure is independently greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12.75%, 11.50%, 11.25% >. 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002% or 0.001% w/v, or w/v. In embodiments, the solid form of Wo Luxi forest is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In some embodiments, the concentration of Wo Luxi forest (including any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein) provided in the pharmaceutical composition of the present disclosure is independently within the range of about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 6% to about 9% w/about 10% to about 15%, or about 0.0.0% to about 15% in solid form relative to the total mass or total volume of the pharmaceutical composition. In embodiments, the solid form of Wo Luxi forest is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In some embodiments, the concentration of Wo Luxi forest (including any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein) provided in the pharmaceutical composition of the present disclosure in solid form is independently in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w/w, w/v, or v/v, relative to the total mass or total volume of the pharmaceutical composition. In embodiments, the solid form of Wo Luxi forest is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In some embodiments of the present invention, in some embodiments, the amount of Wo Luxi forest (including any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein) is independently equal to or less than 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g or 0.0001g. In embodiments, the solid form.

In some embodiments of the present invention, in some embodiments, the amount of Wo Luxi forest (including any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein) in solid form is independently greater than 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5 or 3g. In embodiments, the solid form of Wo Luxi forest is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

Each solid form of Wo Luxi forest comprising any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein is effective over a wide dosage range. For example, in treating an adult, dosages ranging independently from 0.01mg to 1000mg per day, from 0.5mg to 100mg per day, from 1mg to 50mg per day, from 2 to 40mg per day, and from 5mg to 25mg per day are examples of dosages that may be used. The exact dosage will depend on the route of administration, the form of administration of the compound, the sex and age of the individual to be treated, the weight of the individual to be treated, and the preferences and experience of the attending physician. In embodiments, the solid form of Wo Luxi forest is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In selected embodiments, the present disclosure provides a pharmaceutical composition for oral administration comprising warfarin, comprising any of the Wo Luxi forest free base polymorphs described herein or any of the Wo Luxi forest salt polymorphs described herein, and a pharmaceutical excipient suitable for oral administration. In embodiments, the solid form of Wo Luxi forest is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In selected embodiments, the present disclosure provides a solid pharmaceutical composition for oral administration comprising: (i) An effective amount of Wo Luxi forest comprising any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein, and (ii) a pharmaceutical excipient suitable for oral administration. In selected embodiments, the composition further comprises (iii) an effective amount of another active pharmaceutical ingredient. In embodiments, the solid form of Wo Luxi forest is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In selected embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the present disclosure suitable for oral administration may be presented in discrete dosage forms, such as capsules, sachets or tablets, or liquid or aerosol sprays, solutions, or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions or water-in-oil emulsions each containing a predetermined amount of the active ingredient in powder or granule form. The pharmaceutical compositions of the present disclosure also comprise powders for reconstitution, powders for oral administration, bottles (e.g., powders or liquids in bottles), mouth dissolving films, lozenges, pastes, tubes, gums, and packages. Such dosage forms may be prepared by any pharmaceutical method, but all methods comprise the step of associating the active ingredient with a carrier that constitutes one or more essential ingredients. Typically, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation form. For example, tablets may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form (such as a powder or granules) optionally mixed with excipients such as, but not limited to, binding agents, lubricants, inert diluents and/or surfactants or dispersants. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The present disclosure further encompasses anhydrous pharmaceutical compositions and dosage forms, as water may promote degradation of some compounds. For example, in the pharmaceutical arts, water (e.g., 5%) may be added as a means to simulate long-term storage to determine the characteristics of the formulation over time, such as shelf life or stability. Anhydrous pharmaceutical compositions and dosage forms of the present disclosure can be prepared using anhydrous or low moisture content ingredients and low moisture or low humidity conditions. The pharmaceutical compositions and dosage forms of the present disclosure containing lactose may be rendered free of water if substantial contact with moisture and/or humidity is expected during manufacture, packaging and/or storage. The anhydrous pharmaceutical composition may be prepared and stored in such a way that the anhydrous nature of the anhydrous pharmaceutical composition is maintained. Thus, anhydrous compositions may be packaged using materials known to prevent exposure to water, such that the compositions may be contained in a suitable prescribed kit. Examples of suitable packages include, but are not limited to, sealed foils, plastics, and the like, unit dose containers, blister packs, and strip packs.

Each solid form of Wo Luxi forest comprising any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein can be combined in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical mixing techniques. The carrier may take a variety of forms depending on the desired form of preparation for administration. In preparing compositions in oral dosage form, in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used; or in the case of oral solid formulations, any of the usual pharmaceutical media such as starch, sugar, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, diluents, granulating agents, lubricants, glidants, binders, and disintegrants may be used, in some embodiments lactose is not used. For example, in the case of solid oral formulations, suitable carriers include powders, capsules and tablets. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums (e.g., acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum), cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powders), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

Disintegrants may be used in the compositions of the present disclosure to provide tablets that disintegrate upon exposure to an aqueous environment. Too much disintegrant may result in tablets that disintegrate in the bottle. Too little disintegrant may be insufficient for disintegration to occur and thus alter the rate and extent of release of one or more active ingredients from the dosage form. Thus, a sufficient amount of disintegrant (without adversely altering the release of one or more active ingredients by too little or too much) can be used to form a dosage form of the compounds disclosed herein. The amount of disintegrant used can vary based on the type of formulation and mode of administration and can be readily discerned by one of ordinary skill in the art. About 0.5 to about 15 weight percent of the disintegrant or about 1 to about 5 weight percent of the disintegrant may be used in the pharmaceutical composition. Disintegrants that may be used to form the pharmaceutical compositions and dosage forms of the present disclosure include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium (polacrilin potassium), sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

Lubricants that may be used to form the pharmaceutical compositions and dosage forms of the present disclosure include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, synthetic silica gel, coagulated aerosols of synthetic silica, silicified microcrystalline cellulose, or mixtures thereof. Optionally, the lubricant may be added in an amount of less than about 1% by weight of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oral administration, the basic active ingredient therein may be admixed with various sweetening or flavouring agents, colouring matter or dyes and, if desired, emulsifying and/or suspending agents and such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, an isochronous material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants, a mixture of lipophilic surfactants, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

The empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of the nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Suitable hydrophilic surfactants may typically have an HLB value of at least 10, while suitable lipophilic surfactants may typically have an HLB value of about 10 or less. Surfactants with lower HLB values are more lipophilic or hydrophobic and have greater solubility in oil, while surfactants with higher HLB values are more hydrophilic and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, a lipophilic (i.e., hydrophobic) surfactant is a compound having an HLB value equal to or less than about 10. However, the HLB value of surfactants is only a rough guide that is commonly used to achieve formulation of industrial, pharmaceutical and cosmetic emulsions.

The hydrophilic surfactant may be an ionic or nonionic surfactant. Suitable ionic surfactants include, but are not limited to, alkyl ammonium salts; fusidate; fatty acid derivatives of amino acids, oligopeptides and polypeptides; glyceride derivatives of amino acids, oligopeptides and polypeptides; lecithin and hydrogenated lecithin; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; alkyl sulfate; a fatty acid salt; docusate sodium; acyl lactylates; monoacetylated and diacetylated tartaric acid esters of mono-and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of mono-and diglycerides; and mixtures thereof.

In the above group, the ionic surfactant includes, for example: lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; alkyl sulfate; a fatty acid salt; docusate sodium; acyl lactylates; monoacetylated and diacetylated tartaric acid esters of mono-and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of mono-and diglycerides; and mixtures thereof.

The ionic surfactant may be in the following ionized form: lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactate, stearoyl-2-lactate, stearoyl lactate, succinylated monoglyceride, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholesterol sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, tetradecyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauric acid polyethylene glycol glyceride; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ether; polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenol; polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid ester; polyglycerin fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; a hydrophobic transesterification product of a polyol having at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives and analogs thereof; polyoxyethylenated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of polyols having at least one member of the group consisting of triglycerides, vegetable oils and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or sugar.

Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 triolein, PEG-32 dioleate, PEG-20 glycerol laurate, PEG-30 glycerol laurate, PEG-20 glycerol stearate, PEG-20 glycerol oleate PEG-30 glycerol oleate, PEG-30 glycerol laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 corn oil, PEG-6 capric/caprylic glyceride, PEG-8 capric/caprylic glyceride, polyglycerol-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soybean sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 dodecyl ether, POE-23 dodecyl ether, POE-10 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglycerol-10 oleate, tween 40, tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, and poloxamer.

By way of example only, suitable lipophilic surfactants include: fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, lactic acid derivatives of mono-and diglycerides, and hydrophobic transesterification products of polyols having at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, and mixtures thereof. Within this group, preferred lipophilic surfactants comprise glycerol fatty acid esters, propylene glycol fatty acid esters and mixtures thereof, or hydrophobic transesterification products of polyols having at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils and triglycerides.

In an embodiment, the composition may include a solubilizing agent to ensure good solubilization and/or dissolution of the compounds of the present disclosure and to minimize precipitation of the compounds of the present disclosure. This is particularly important for compositions for non-oral use, such as injectable compositions. Solubilizing agents may also be added to increase the solubility of the hydrophilic drug and/or other components such as surfactants or to maintain the composition as a stable or homogeneous solution or dispersion.

Examples of suitable solubilizing agents include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, xylitol, still oxydiol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycogenol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, epsilon-caprolactam, N-alkylpyrrolidone, N-hydroxyalkyl pyrrolidone, N-alkylpiperidone, N-alkyl caprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyltriethyl citrate, acetyltributyl citrate, triethyl citrate, ethyl oleate, ethyl octanoate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, epsilon-caprolactone and isomers thereof, delta-valerolactone and isomers thereof, beta-butyrolactone and isomers thereof; and other solubilizing agents known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, caprylic acid monoglyceride, diethylene glycol monoethyl ether, and water.

Mixtures of solubilizing agents may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl octanoate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethyl pyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycogenol, antipruritic glycols (transcutol), propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizing agents include sorbitol, glycerol, triacetin, ethanol, PEG-400, glycogen and propylene glycol.

The amount of the solubilizing agent that can be contained is not particularly limited. The amount of a given solubilizing agent can be limited to a biologically acceptable amount that can be readily determined by one of skill in the art. In some cases, it may be advantageous to include a solubilizing agent in an amount well in excess of the biologically acceptable amount, e.g., to maximize the concentration of the drug, wherein the excess solubilizing agent is removed prior to providing the composition to the patient using conventional techniques such as distillation or evaporation. Thus, the weight ratio of the solubilizing agent (if present) may be 10 wt%, 25 wt%, 50 wt%, 100 wt%, or up to about 200 wt%, based on the combined weight of the drug and other excipients. Very small amounts of solubilizers, such as 5%, 2%, 1% or even less, may also be used if desired. Typically, the solubilizing agent may be present in an amount of from about 1% to about 100% by weight, more typically from about 5% to about 25% by weight.

The composition may further comprise one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, anti-blocking agents, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity modifiers (tonicity), fragrances, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants and mixtures thereof.

In addition, acids or bases may be incorporated into the pharmaceutical compositions to facilitate processing, enhance stability, or achieve other objectives. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic hydrocalcite (hydrocalcite), magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, TRIS (hydroxymethyl) aminomethane (TRIS), and the like. Also suitable are bases that are salts of pharmaceutically acceptable acids such as acetic acid, acrylic acid, adipic acid, alginic acid, methanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid (hydroquinosulfonic acid), isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like. Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate may also be used. When the base is a salt, the cation may be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, and alkaline earth metals. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, methanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid and uric acid.

Dosage and dosing regimen

The amount of Wo Luxi forest administered in solid form comprising any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein will depend on the severity of the mammal, disorder or condition to be treated, the rate of administration, the disposition of the compound, and the discretion of the prescribing physician. However, the effective dosage, whether in single or divided doses, is in the range of about 0.001mg to about 100mg per kg body weight per day, such as about 1 mg/kg/day to about 35 mg/kg/day. For a 70kg person this would correspond to about 0.05 g/day to 7 g/day, such as about 0.05 g/day to 2.5 g/day. In some cases, dosage levels below the lower limit of the above range may exceed sufficient amounts, while in other cases still larger doses may be employed without causing any adverse side effects, for example by dividing such larger doses into several small doses for administration throughout the day.

In selected embodiments, wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein is administered in a single dose. Typically, such administration will be by injection, for example by intravenous injection, to rapidly introduce the active pharmaceutical ingredient. However, other approaches may be used as appropriate. A single dose of Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein can also be used to treat an acute condition.

In selected embodiments, wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein is administered in multiple doses. The administration may be performed about once a day, twice a day, three times a day, four times a day, five times a day, six times a day, or more than six times a day. The administration may be about once monthly, biweekly, weekly, or every other day. In other embodiments, wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein is administered about once per day to about 6 times per day. In another embodiment, the administration of Wo Luxi forest comprising the solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein lasts less than about 7 days. In yet another embodiment, administration lasts more than about 6 days, 10 days, 14 days, 28 days, two months, six months, or one year. In some cases, continuous administration is achieved and continued administration is continued for a desired period of time. In embodiments, the solid form of Wo Luxi forest is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

Administration of the active pharmaceutical ingredient of the present disclosure may proceed as long as necessary. In selected embodiments, wo Luxi comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, wo Luxi comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In selected embodiments, wo Luxi which comprises a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein is administered on a continuous basis for a long period of time, e.g., for the treatment of chronic effects. In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In some embodiments, an effective dose of Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein is in the range of about 1mg to about 500mg, about 10mg to about 300mg, about 20mg to about 250mg, about 25mg to about 200mg, about 10mg to about 200mg, about 20mg to about 150mg, about 30mg to about 120mg, about 10mg to about 90mg, about 20mg to about 80mg, about 30mg to about 70mg, about 40mg to about 60mg, about 45mg to about 55mg, about 48mg to about 52mg, about 50mg to about 150mg, about 60mg to about 140mg, about 70mg to about 130mg, about 80mg to about 120mg, about 90mg to about 110mg, about 95mg to about 105mg, about 150mg to about 250mg, about 160mg to about 240mg, about 170mg to about 230mg, about 180mg to about 220mg, about 190mg to about 210mg, about 205mg to about 202mg, or about 198 mg. In some embodiments, an effective dose of Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein is about 25mg, about 50mg, about 75mg, about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225mg, about 250mg, about 275mg, about 300mg, about 325mg, about 350mg, about 375mg, about 400mg, about 425mg, about 450mg, about 475mg, or about 500mg. In some embodiments, the effective dose of Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein is 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, or 500mg. In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In some embodiments, an effective dose of Wo Luxi forest comprising a solid form of any of the Wo Luxi forest free base polymorphs described herein or any of the Wo Luxi forest salt polymorphs described herein is in the range of about 0.01mg/kg to about 4.3mg/kg, about 0.15mg/kg to about 3.6mg/kg, about 0.3mg/kg to about 3.2mg/kg, about 0.35mg/kg to about 2.85mg/kg, about 0.15mg/kg to about 2.85mg/kg, about 0.3mg to about 2.15mg/kg, about 0.45mg/kg to about 1.7mg/kg, about 0.15mg/kg to about 1.3mg/kg, about 0.3mg/kg to about 1.15mg/kg, about 0.45mg/kg to about 1mg/kg, about 0.55mg/kg to about 0.85mg/kg, about 0.65mg/kg to about 0.8mg/kg, about 0.7mg to about 2.15mg/kg, about 7.45 mg/kg to about 1.7mg/kg to about 1.15mg/kg, about 0.15mg/kg to about 1.5mg/kg, about 0.5 mg to about 3mg/kg to about 1.5mg/kg, about 3mg/kg to about 1.5 mg/kg. In some embodiments, an effective dose of Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein is about 0.35mg/kg, about 0.7mg/kg, about 1mg/kg, about 1.4mg/kg, about 1.8mg/kg, about 2.1mg/kg, about 2.5mg/kg, about 2.85mg/kg, about 3.2mg/kg, or about 3.6mg/kg. In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In some embodiments, wo Luxi forest, including any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein, in solid form is administered at a dose of 10 to 400mg once daily (QD), including a dose of 5mg, 10mg, 12.5mg, 25mg, 50mg, 75mg, 100mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, and 500mg once daily (QD). In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In some embodiments, wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein is administered at a dose of 10 to 400mg BID comprising doses of 5mg, 10mg, 12.5mg, 25mg, 50mg, 75mg, 100mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, and 500mg BID. In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In some embodiments, wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein is administered at a dose of 10 to 400mg TID comprising doses of 5mg, 10mg, 12.5mg, 25mg, 50mg, 75mg, 100mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, and 500mg TID. In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

An effective amount of Wo Luxi in solid form comprising any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein can be administered in single or multiple doses by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant by any recognized mode of administration of the active pharmaceutical ingredient having similar utility (including rectal, buccal, intranasal, and transdermal routes).

Pharmaceutical composition for overcoming the effect of acid reducing agents

The compositions and methods described herein may be used to overcome the effects of acid reducing agents. Acid reducing agents can greatly limit exposure of weakly acidic drugs to mammals. Smelick et al, mol. Pharmaceuticals, 2013,10,4055-4062. The acid reducing agent includes proton pump inhibitors such as omeprazole (omeprazole), esomeprazole (esomeprazole), lansoprazole (lansoprazole), dexlansoprazole, pantoprazole (pantoprazole), rabeprazole (rabeprazole), and ilaprazole; h ₂ Receptor antagonists such as cimetidine (cimetidine), ranitidine (ranitidine) and famotidine (famotidine); and antacids such as the bicarbonate, carbonate and hydroxide of aluminum, calcium, magnesium, potassium and sodium, as well as mixtures of antacids with agents targeting gastric secretion mechanisms. Overcoming the effects of acid reducing agents is an important issue in treating patients suffering from cancer, inflammatory diseases, immune diseases, and autoimmune diseases, as these patients often co-administer acid reducing agents to treat gastric irritation that is often accompanied by their pathology, as acid reducing agents are some of the most common prescribed medications in north america and western europe. Most oral cancer therapeutic agents recently approved have pH-dependent solubility and therefore have potential drug-drug interactions associated with acid reducing agents. Of cancer patients, it is estimated that 20-33% of patients are using some form of acid reducing agent. In specific cancers such as pancreatic cancer or gastrointestinal cancer, up to 60-80% of patients use acid reducing agents. Smelick et al, molecular pharmaceutical 2013,10,4055-4062.

In embodiments, the pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant. In an embodiment, the pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant selected from the group consisting of: fumaric acid, tartaric acid, ascorbic acid, alginic acid, sodium alginate, potassium alginate and Carbopol 971P (carboxypolyethylene). In an embodiment, the pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant selected from the group consisting of: fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, erythorbic acid (also known as erythronic acid and D-arabinoascorbic acid), alginic acid, propionic acid F120 NM, propionic acid AR 1112 (also known as alginic acid NF), carbomer 941 (polyacrylic acid), and Carbopol 971P (carboxypolyethylene). In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein. In an embodiment, the acidulant is extragranular. In an embodiment, the acidulant is intragranular.

Alginic acid is a polysaccharide copolymer, beta-D-mannuronic acid (M) and alpha-L-guluronic acid (G) linked by 1-4 glycosidic bonds. In an embodiment, a pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant that is alginic acid or a salt thereof, wherein the alginic acid or salt thereof exhibits an M/G ratio selected from the group consisting of: 0.1 to 0.5, 0.2 to 0.6, 0.3 to 0.7, 0.4 to 0.8, 0.5 to 0.9, 0.6 to 1.0, 0.7 to 1.1, 0.8 to 1.2, 0.9 to 1.3, 1.0 to 1.4, 1.1 to 1.5, 1.2 to 1.6, 1.3 to 1.7, 1.4 to 1.8, 1.5 to 1.9, 1.6 to 2.0, 1.7 to 2.1, 1.8 to 2.2, 1.9 to 2.3, 2.0 to 2.4, and 2.1 to 2.5. In an embodiment, a pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant that is alginic acid or a salt thereof, wherein the alginic acid or salt thereof exhibits an M/G ratio selected from the group consisting of: less than 0.5, less than 1.0, less than 1.5, less than 2.0, and less than 2.5. In an embodiment, a pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant that is alginic acid or a salt thereof, wherein the alginic acid or salt thereof exhibits an M/G ratio selected from the group consisting of: greater than 0.5, greater than 1.0, greater than 1.5, greater than 2.0, and greater than 2.5. In an embodiment, a pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant that is alginic acid or a salt thereof, wherein the alginic acid or salt thereof exhibits an M/G ratio selected from the group consisting of: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4 and 2.5. In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

The M/G ratio and the fraction of M and G groups, the fraction of MM and GG "diads", the fraction of "triplets" (e.g., MGG), and the fraction of larger sequences of M and G groups can be determined by methods known to those of ordinary skill in the art, including Nuclear Magnetic Resonance (NMR) spectroscopy (with or without digestion) and mass spectrometry. Larsen et al, carbohydrate research (carbohydrate. Res.), 2003,338,2325-2336.

In an embodiment, the pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant at a concentration (mass%) selected from the group consisting of: 1% to 5%, 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, and 30% to 35%. In an embodiment, the pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant at a concentration (mass%) selected from the group consisting of: 1% to 5%, 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, and 30% to 35%, wherein the acidulant is selected from the group consisting of: fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic acid, ascorbic acid, erythorbic acid (also known as erythronic acid and D-arabinoascorbic acid), alginic acid, sodium alginate, potassium alginate, propionic acid F120 NM, propionic acid AR 1112 (also known as alginic acid NF) and Carbopol 971P (carboxypolyethylene). In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In an embodiment, the pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant at a concentration (mass%) selected from the group consisting of: less than 1%, less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, and less than 35%. In an embodiment, the pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant at a concentration (mass%) selected from the group consisting of: less than 1%, less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, and less than 35%, wherein the acidulant is selected from the group consisting of: fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic acid, ascorbic acid, erythorbic acid (also known as erythronic acid and D-arabinoascorbic acid), alginic acid, sodium alginate, potassium alginate, propionic acid F120 NM, propionic acid AR 1112 (also known as alginic acid NF) and Carbopol 971P (carboxypolyethylene). In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In an embodiment, the pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant at a concentration (mass%) selected from the group consisting of: greater than 1%, greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, and greater than 35%. In an embodiment, the pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant at a concentration (mass%) selected from the group consisting of: more than 1%, more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, and more than 35%, wherein the acidulant is selected from the group consisting of: fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic acid, ascorbic acid, erythorbic acid (also known as erythronic acid and D-arabinoascorbic acid), alginic acid, sodium alginate, potassium alginate, propionic acid F120 NM, propionic acid AR 1112 (also known as alginic acid NF) and Carbopol 971P (carboxypolyethylene). In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In an embodiment, the pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant at a concentration (mass%) selected from the group consisting of: about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, and about 40%. In an embodiment, the pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant at a concentration (mass%) selected from the group consisting of: about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, and about 40%, wherein the acidulant is selected from the group consisting of: fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic acid, ascorbic acid, erythorbic acid (also known as erythronic acid and D-arabinoascorbic acid), alginic acid, sodium alginate, potassium alginate, propionic acid F120 NM, propionic acid AR 1112 (also known as alginic acid NF) and Carbopol 971P (carboxypolyethylene). In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In an embodiment, the pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an extragranular acidifying agent, wherein the extragranular acidifying agent is selected from the group consisting of: fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, erythorbic acid (also known as erythronic acid and D-arabinoascorbic acid), alginic acid, sodium alginate, potassium alginate, propionic acid F120 NM, propionic acid AR 1112 (also known as alginic acid NF), and Carbopol 971P (carboxypolyethylene), and combinations thereof. In embodiments, the pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an extra-granular acidulant, wherein the extra-granular acidulant is fumaric acid at a concentration of about 15 wt% to about 33 wt%. In embodiments, the pharmaceutical composition comprises Wo Luxi forest in solid form comprising any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an extragranular acidulant, wherein the extragranular acidulant is alginic acid or a salt thereof (such as sodium or potassium alginate) at a concentration of about 5% to about 33% by weight. In an embodiment, the pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an extragranular acidulant, wherein the extragranular acidulant is L-tartaric acid at a concentration of about 25 wt% to about 33 wt%. In an embodiment, the pharmaceutical composition comprises Wo Luxi forest in solid form comprising any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein, and an extragranular acidulant, wherein the extragranular acidulant is ascorbic acid at a concentration of about 20 wt% to about 50 wt% and Carbopol 971P (Carbopol) at a concentration of about 2.5 wt% to about 10 wt%. In embodiments, the pharmaceutical composition comprises Wo Luxi forest in solid form comprising any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an extragranular acidulant, wherein the extragranular acidulant is fumaric acid at a concentration of about 5% to about 15% by weight and alginic acid or a salt thereof at a concentration of about 15% to about 33% by weight. In an embodiment, the pharmaceutical composition comprises Wo Luxi forest in solid form comprising any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an extragranular acidulant, wherein the extragranular acidulant is L-tartaric acid at a concentration of about 5% to 15% by weight and alginic acid at a concentration of about 15% to about 33% by weight.

In an embodiment, the pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant, wherein the acidulant is selected from the group consisting of: fumaric acid, maleic acid, phosphoric acid, L-tartaric acid, citric acid, gentisic acid, oxalic acid and sulfuric acid. In an embodiment, the pharmaceutical composition comprises Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and an acidulant, wherein the acidulant is selected from the group consisting of: fumaric acid, maleic acid, phosphoric acid, L-tartaric acid, citric acid, gentisic acid, oxalic acid and sulfuric acid, and wherein the acidulant is a salt counter ion comprised in any of the crystalline forms described herein.

In embodiments, the pharmaceutical composition comprises, in addition to the acidulant, an excipient to prolong exposure of Wo Luxi forest comprising any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein in solid form to an acidic microenvironment. In embodiments, this excipient is a polymer of natural, synthetic or semi-synthetic origin. The polymer may contain acidic, anionic or nonionic monomers, oligomers or polymers, or mixtures of acidic, anionic and nonionic monomers or copolymers. In one version, the excipient is selected from the group consisting of: hydroxypropyl methylcellulose, low substituted hydroxypropyl cellulose, tocopheryl polyethylene glycol succinate (D-alpha-tocopheryl polyethylene glycol succinate, TPGS or vitamin E TPGS), methylcellulose, carboxymethylcellulose sodium, methacrylate, ethyl acrylate, copolymers of methyl and ethyl acrylate, hydroxypropyl methylcellulose acetate succinate, gelatin, corn starch, pea starch, modified corn starch, potato starch, modified potato starch, sodium starch glycolate, crosslinked carboxymethylcellulose, crosslinked povidone, copovidone, polyethylene glycol, polypropylene glycol, polyethylene glycol and polypropylene glycol copolymers, polyvinyl alcohol and polyethylene oxide copolymers. Copolymers of the foregoing polymers may also be used where applicable. The copolymer may be a block, branched or terminal copolymer. In embodiments, the polymer exhibits swelling, binding or gelling properties that inhibit disintegration, dissolution and erosion of the pharmaceutical composition to prolong dissolution or increase total dissolution. In an embodiment, the inclusion of the polymer increases the dissolution rate and degree of dissolution compared to the use of the acidulant alone. In one embodiment, the swelling, binding or gelling properties are pH dependent, wherein the polymer swells, binds or gels at one pH or pH range in a different manner than at another pH. In one embodiment, this may reduce dissolution at lower pH than at higher pH, and vice versa. In another embodiment, this results in similar dissolution of Wo Luxi forest in solid form comprising any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein at acidic, neutral, or basic pH. This results in similar plasma exposure independent of gastric pH.

The dissolution profile of a formulation containing one or more swelling, gelling or binding excipients may exhibit zero-order, first-order or second-order different rates at one or more pH values or a mixture of different rate levels at different pH values. In an embodiment, the pharmaceutical composition will provide a constant level of drug into the gastrointestinal tract of the mammal by dissolution. When Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein is absorbedThis results in sustained plasma levels of the drug over a period of time, delaying t _max And reduced equivalent dose of immediate release formulation comprising the solid form of Wo Luxi forest c of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein _max . In another embodiment, this results in similar exposure in mammals regardless of gastric pH.

Wo Luxi forest solid formulation

In one embodiment, the present disclosure provides a solid formulation comprising malonic acid Wo Luxi forest. In one embodiment, the solid formulation comprises about 10% to 35% w/w, about 12% to 32% w/w, about 14% to 30% w/w, about 16% to 28% w/w, about 18% to 26% w/w, or about 20% to 24% w/w of malonic acid Wo Luxi forest. In one embodiment, the formulation comprises about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35% w/w of malonic acid Wo Luxi forest. In one embodiment, the formulation comprises about 20mg to 100mg, about 25mg to 95mg, about 30mg to 90mg, about 35mg to 85mg, about 40mg to 80mg, about 45mg to 75mg, about 50mg to 70mg, or about 55mg to 65mg malonic acid Wo Luxi forest. In one embodiment, the formulation comprises about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 61mg, about 62mg, about 63mg, about 64mg, about 65mg, about 66mg, about 67mg, about 68mg, about 69mg, or about 70mg malonic acid Wo Luxi forest. In another embodiment, the formulation comprises from about 80mg to 160mg, from about 85mg to 155mg, from about 90mg to 150mg, from about 95mg to 145mg, from about 100mg to 140mg, from about 105mg to 135mg, from about 110mg to 130mg, from about 115mg to 125mg, or from about 120mg to 124mg malonic acid Wo Luxi forest. In one embodiment, the formulation comprises about 112mg, about 113mg, about 114mg, about 115mg, about 116mg, about 117mg, about 118mg, about 119mg, about 120mg, about 121mg, about 122mg, about 123mg, about 124mg, about 125mg, about 126mg, about 127mg, about 128mg, about 129mg, about 130mg, about 131mg, or about 132mg malonic acid Wo Luxi forest.

In one embodiment, the solid formulation further comprises microcrystalline cellulose. In one embodiment, the formulation comprises about 2% to 40% w/w, about 4% to 35% w/w, about 4% to 30% w/w, about 4% to 25% w/w, about 4% to 20% w/w, about 10% to 20% w/w, or about 12% to 16% w/w microcrystalline cellulose. In one embodiment, the formulation comprises about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, or about 24% w/w microcrystalline cellulose. In one embodiment, the formulation comprises about 1mg to 80mg, about 5mg to 75mg, about 10mg to 70mg, about 15mg to 65mg, about 20mg to 60mg, about 25mg to 55mg, about 30mg to 50mg, about 35mg to 45mg, or about 38mg to 42mg microcrystalline cellulose. In one embodiment, the formulation comprises about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, or about 50mg microcrystalline cellulose. In another embodiment, the formulation comprises about 20mg to 120mg, about 25mg to 115mg, about 30mg to 110mg, about 35mg to 105mg, about 40mg to 100mg, about 45mg to 95mg, about 50mg to 90mg, about 55mg to 85mg, about 60mg to 85mg, about 65mg to 85mg, about 70mg to 85mg, about 75mg to 85mg, or about 78mg to 82 microcrystalline cellulose. In one embodiment, the formulation comprises about 70mg, about 71mg, about 72mg, about 73mg, about 74mg, about 75mg, about 76mg, about 77mg, about 78mg, about 79mg, about 80mg, about 81mg, about 82mg, about 83mg, about 84mg, about 85mg, about 86mg, about 87mg, about 88mg, about 89mg, or about 90mg microcrystalline cellulose.

In one embodiment, the solid formulation further comprises lactose monohydrate. In one embodiment, the formulation comprises about 1% to 50% w/w, about 1% to 45% w/w, about 1% to 40% w/w, about 1% to 35% w/w, about 1% to 30% w/w, about 1% to 25% w/w, about 1% to 20% w/w, about 1% to 15% w/w, about 5% to 15% w/w, or about 8% to 12% w/w lactose monohydrate. In one embodiment, the formulation comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% w/w lactose monohydrate. In one embodiment, the formulation comprises about 1mg to 50mg, about 1mg to 45mg, about 1mg to 40mg, about 5mg to 40mg, about 10mg to 35mg, about 15mg to 35mg, about 20mg to 35mg, about 25mg to 35mg, or about 25mg to 30mg lactose monohydrate. In one embodiment, the formulation comprises about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 21mg, about 22mg, about 23mg, about 24mg, about 25mg, about 26mg, about 27mg, about 28mg, about 29mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, or about 40mg lactose monohydrate. In another embodiment, the solid formulation comprises about 5mg to 90mg, about 10mg to 85mg, about 15mg to 80mg, about 20mg to 75mg, about 25mg to 70mg, about 30mg to 65mg, about 35mg to 60mg, about 40mg to 55mg, or about 45mg to 50mg lactose monohydrate. In one embodiment, the formulation comprises about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, or about 55mg lactose monohydrate.

In one embodiment, the solid formulation further comprises dibasic calcium phosphate dihydrate. In one embodiment, the formulation comprises about 5% to 80% w/w, about 10% to 75% w/w, about 15% to 70% w/w, about 20% to 65% w/w, about 25% to 60% w/w, about 30% to 55% w/w, about 35% to 50% w/w, or about 40% to 45% w/w dibasic calcium phosphate dihydrate. In one embodiment, the formulation comprises about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, or about 52% w/w of dibasic calcium phosphate dihydrate. In one embodiment, the formulation comprises about 80mg to 160mg, about 85mg to 155mg, about 90mg to 150mg, about 95mg to 145mg, about 100mg to 140mg, about 105mg to 135mg, about 110mg to 130mg, about 115mg to 125mg, or about 120mg to 124mg dibasic calcium phosphate dihydrate. In one embodiment, the formulation comprises about 112mg, about 113mg, about 114mg, about 115mg, about 116mg, about 117mg, about 118mg, about 119mg, about 120mg, about 121mg, about 122mg, about 123mg, about 124mg, about 125mg, about 126mg, about 127mg, about 128mg, about 129mg, about 130mg, about 131mg, or about 132mg dibasic calcium phosphate dihydrate. In another embodiment, the solid formulation comprises about 200mg to 300mg, about 205mg to 295mg, about 210mg to 290mg, about 215mg to 285mg, about 220mg to 280mg, about 225mg to 275mg, about 230mg to 270mg, about 235mg to 265mg, about 235mg to 260mg, about 235mg to 255mg, about 235mg to 250mg, or about 240mg to 245mg dibasic calcium phosphate dihydrate. In one embodiment, the formulation comprises about 230mg, about 231mg, about 232mg, about 233mg, about 234mg, about 235mg, about 236mg, about 237mg, about 238mg, about 239mg, about 240mg, about 241mg, about 242mg, about 243mg, about 244mg, about 245mg, about 246mg, about 247mg, about 248mg, about 249mg, or about 250mg dibasic calcium phosphate dihydrate.

In one embodiment, the solid formulation further comprises sodium bicarbonate. In one embodiment, the formulation comprises about 0.01% to 20% w/w, about 0.01% to 18% w/w, about 0.01% to 16% w/w, about 0.01% to 14% w/w, about 0.01% to 12% w/w, about 0.01% to 10% w/w, about 1% to 8% w/w, about 1% to 6% w/w, or about 2% to 6% w/w of sodium bicarbonate. In one embodiment, the formulation comprises about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 13%, about 14%, or about 15% w/w sodium bicarbonate. In one embodiment, the formulation comprises about 1mg to 40mg, about 1mg to 35mg, about 1mg to 30mg, about 1mg to 25mg, about 1mg to 20mg, about 5mg to 15mg, or about 8mg to 14mg sodium bicarbonate. In one embodiment, the formulation comprises about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 21mg, about 22mg, about 23mg, about 24mg, about 25mg, about 26mg, about 27mg, about 28mg, about 29mg, or about 30mg sodium bicarbonate. In another embodiment, the solid formulation comprises about 5mg to 80mg, about 10mg to 75mg, about 10mg to 70mg, about 10mg to 65mg, about 10mg to 60mg, about 10mg to 55mg, about 10mg to 50mg, about 10mg to 45mg, about 10mg to 40mg, about 10mg to 35mg, about 10mg to 30mg, about 15mg to 25mg, or about 18mg to 24mg sodium bicarbonate. In one embodiment, the formulation comprises about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 21mg, about 22mg, about 23mg, about 24mg, about 25mg, about 26mg, about 27mg, about 28mg, about 29mg, about 30mg, about 31mg, or about 32mg sodium bicarbonate.

In one embodiment, the solid formulation comprises about 0.01% to 40% w/w, about 0.01% to 35% w/w, about 0.01% to 30% w/w, about 0.01% to 25%, about 0.01% to 20%, about 0.01% to 15% w/w, about 0.01% to 10% w/w, about 4% to about 8% w/w sodium starch glycolate. In one embodiment, the formulation comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% w/w sodium starch glycolate. In one embodiment, the formulation comprises about 1mg to 40mg, about 1mg to 35mg, about 1mg to 30mg, about 1mg to 25mg, about 5mg to 25mg, about 10mg to 20mg, or about 15mg to 20mg of sodium starch glycolate. In one embodiment, the formulation comprises about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 21mg, about 22mg, about 23mg, about 24mg, about 25mg, or about 26mg of sodium starch glycolate. In another embodiment, the formulation comprises about 5mg to 70mg, about 10mg to 65mg, about 15mg to 60mg, about 20mg to 55mg, about 25mg to 50mg, about 25mg to 45mg, about 25mg to 40mg, or about 30mg to 35mg of sodium starch glycolate. In one embodiment, the formulation comprises about 23mg, about 24mg, about 25mg, about 26mg, about 27mg, about 28mg, about 29mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, or about 43mg of sodium starch glycolate.

In one embodiment, the solid formulation further comprises magnesium stearate. In one embodiment, the formulation comprises about 0.001% to 20% w/w, about 0.001% to 18% w/w, about 0.001% to 16% w/w, about 0.001% to 14% w/w, about 0.001% to 12% w/w, about 0.001% to 10% w/w, about 0.01% to 8% w/w, about 0.01% to 6%, about 0.01% to 4% or about 1% to 4% w/w magnesium stearate. In one embodiment, the formulation comprises about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% w/w magnesium stearate. In one embodiment, the formulation comprises about 0.001mg to 15mg, about 0.001mg to 12mg, about 0.001mg to 10mg, about 0.001mg to 8mg, about 0.001mg to 6mg, about 0.01mg to 6mg, about 0.1mg to 6mg, or about 2.5mg to about 4.5mg magnesium stearate. In one embodiment, the formulation comprises about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, or about 14mg magnesium stearate. In another embodiment, the formulation comprises about 0.1mg to 25mg, about 0.1mg to 22mg, about 0.1mg to 20mg, about 0.1mg to 18mg, about 0.1mg to 16mg, about 0.1mg to 14mg, about 0.1mg to 12mg, about 0.1mg to 10mg, about 2mg to 8mg, or about 3mg to 7mg magnesium stearate. In one embodiment, the formulation comprises about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, or about 15mg magnesium stearate.

In one embodiment, the solid formulation further comprises colloidal silica. In one embodiment, the solid formulation comprises about 0.001% to 20% w/w, about 0.001% to 18% w/w, about 0.001% to 16% w/w, about 0.001% to 14% w/w, about 0.001% to 12% w/w, about 0.001% to 10% w/w, about 0.01% to 8% w/w, about 0.01% to 6%, about 0.01% to 4% or about 1% to 4% w/w colloidal silica. In one embodiment, the formulation comprises about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% w/w colloidal silica. In one embodiment, the formulation comprises about 0.001mg to 15mg, about 0.001mg to 12mg, about 0.001mg to 10mg, about 0.001mg to 8mg, about 0.001mg to 6mg, about 0.01mg to 6mg, about 0.1mg to 6mg, or about 2.5mg to about 4.5mg colloidal silica. In one embodiment, the formulation comprises about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, or about 14mg colloidal silica. In another embodiment, the formulation comprises about 0.1mg to 30mg, about 0.1mg to 25mg, about 0.1mg to 20mg, about 0.1mg to 18mg, about 0.1mg to 15mg, about 1mg to 14mg, about 1mg to 12mg, about 1mg to 10mg, about 1mg to 8mg, or about 3mg to 8mg colloidal silica. In one embodiment, the formulation comprises about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, or about 15mg colloidal silica.

In one embodiment, the solid formulation is a tablet. In one embodiment, the tablet is coated with a film coating. In one embodiment, the film coating is Opadry II 85F18422 white.

In one embodiment, the solid formulation is a tablet comprising about 61mg of malonic acid Wo Luxi forest, which is about 50mg of free base Wo Luxi forest (i.e., a 50mg tablet). In one embodiment, the 50mg tablet further comprises about 40mg microcrystalline cellulose, about 24mg lactose monohydrate, about 121mg dibasic calcium phosphate dihydrate, about 11mg sodium bicarbonate, about 17mg sodium starch glycolate, about 3mg colloidal silicon dioxide, and about 3mg magnesium stearate.

In another embodiment, the solid formulation is a tablet comprising about 122mg of malonic acid Wo Luxi forest, which is about 100mg of free base Wo Luxi forest (i.e., a 100mg tablet). In one embodiment, the 100mg tablet further comprises about 80mg microcrystalline cellulose, about 48mg lactose monohydrate, about 243mg dibasic calcium phosphate dihydrate, about 22mg sodium bicarbonate, about 34mg sodium starch glycolate, about 6mg colloidal silicon dioxide, and about 6mg magnesium stearate.

Treating solid tumor cancer, hematological malignancy, inflammatory disease, autoimmune disease, immune disease and other diseases Is a method of (2)

The pharmaceutical compositions described herein may be used in methods of treating diseases. In a preferred embodiment, the pharmaceutical composition is for use in the treatment of hyperproliferative disorders. The pharmaceutical compositions may also be used to treat other conditions as described herein and in the following paragraphs.

In some embodiments, the present disclosure provides a method of treating a hyperproliferative disorder in a mammal, the method comprising administering to the mammal a therapeutically effective amount of Wo Luxi in a crystalline solid form comprising any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein or a pharmaceutical composition comprising Wo Luxi in a crystalline solid form comprising any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein, as described herein. In a preferred embodiment, the mammal is a human. In some embodiments, the hyperproliferative disorder is cancer. In a preferred embodiment, the cancer is selected from the group consisting of: chronic lymphocytic leukemia, non-hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and waldenstrom's macroglobulinemia. In a preferred embodiment, the cancer is selected from the group consisting of: non-hodgkin's lymphoma (e.g., diffuse large B-cell lymphoma), acute myelogenous leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral and oropharyngeal bladder, stomach (gastro-gastric), pancreas, bladder, breast, cervical, head, neck, kidney (renal/kudney), liver, ovary, prostate, colorectal, bone (e.g., metastatic bone), esophagus, testis, gynaecology, thyroid, CNS, PNS, AIDS-associated (e.g., lymphoma and kaposi's sarcoma), virus-induced cancers such as cervical cancer (human papilloma virus), B-cell lymphoproliferative diseases and nasopharyngeal carcinoma (epstein-barr virus), kaposi's sarcoma and primary exudative lymphomas (kaposi's herpes virus), hepatocellular carcinoma (hepatitis B and hepatitis c virus) and T-cell leukemia (human T-cell leukemia virus-1), B-cell acute lymphoblastic leukemia, burkitt leukemia, myelomonocytic leukemia, hairy cell leukemia, capillary lymphoblastic leukemia, capillary leukemia, multiple sclerosis, and multiple hypertrophy. In selected embodiments, the methods involve treating a non-cancerous hyperproliferative disorder, such as benign skin hyperplasia (e.g., psoriasis), restenosis, or a prostate condition (e.g., benign Prostatic Hypertrophy (BPH)). In some embodiments, the hyperproliferative disorder is an inflammatory, immune, or autoimmune disorder. In some embodiments, the hyperproliferative disorder is selected from the group consisting of: tumor angiogenesis, chronic inflammatory diseases, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangiomas, glioma and melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondyloarthritis, uveitis, behcet's disease, polymyalgia rheumatica, giant cell arteritis, sarcoidosis, kawasaki's disease, juvenile idiopathic arthritis, suppurative sweat gland inflammation, sjogren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, crohn's disease, lupus and lupus nephritis. In an embodiment, the solid form of Wo Luxi in any of the preceding embodiments comprising any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein is selected from malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In an embodiment, the method of any of the preceding embodiments further comprises the step of administering an acid reducing agent to the mammal. In an embodiment, the acid reducing agent is selected from the group consisting of: proton pump inhibitors such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole and ilaprazole; h ₂ Receptor antagonists such as cimetidine, ranitidine and famotidine; and antacids such as the bicarbonate, carbonate and hydroxide of aluminum, calcium, magnesium, potassium and sodium, as well as mixtures of antacids with agents targeting gastric secretion mechanisms.

In some embodiments, the present disclosure provides pharmaceutical compositions comprising Wo Luxi forest in solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein for use in treating cancers such as thymus cancer, brain cancer (e.g., glioma), lung cancer, squamous cell carcinoma, skin cancer (e.g., melanoma), eye cancer, retinoblastoma cancer, intraocular melanoma cancer, oral cancer, oropharyngeal cancer, bladder cancer, gastric cancer (cancer/cancer), pancreatic cancer, bladder cancer, breast cancer, cervical cancer, head and neck cancer, kidney cancer (renal cancer/kidney cancer), liver cancer, ovarian cancer, prostate cancer, colorectal cancer, colon cancer, esophageal cancer, testicular cancer, gynaecological cancer, ovarian cancer, thyroid cancer, CNS cancer, PNS cancer, AIDS-related cancers (e.g., lymphoma and kaposi's sarcoma), virus-induced cancers, and epidermoid cancer. In some embodiments, the present disclosure provides pharmaceutical compositions comprising Wo Luxi forest in solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein for use in treating a non-cancerous hyperproliferative disorder, such as benign skin hyperplasia (e.g., psoriasis), restenosis, or prostate (e.g., benign Prostatic Hypertrophy (BPH)). In some embodiments, the present disclosure provides pharmaceutical compositions comprising Wo Luxi forest in solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein for use in treating a disorder such as myeloproliferative disorder (MPD), myeloproliferative neoplasm, polycythemia Vera (PV), essential Thrombocythemia (ET), primary Myelofibrosis (PMF), myelodysplastic syndrome, chronic myeloid leukemia (BCR-ABL 1-positive), chronic neutrophilic leukemia, chronic eosinophilic leukemia, or mastocytosis. The present disclosure also provides compositions for treating angiogenesis or angiogenesis-related diseases in a mammal that may be manifested as tumor angiogenesis, chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and hemangiomas. In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In some embodiments, the present disclosure provides methods of treating solid tumor cancer with a composition comprising Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein. In some embodiments, the present disclosure provides methods of treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, squamous cell carcinoma including head and neck cancer, or blood cancer. In embodiments, the present disclosure provides methods for treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, colorectal cancer, or blood cancer using a combination of Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein and a second agent selected from the group consisting of: bendamustine (bendamustine), valnemulin (vemurafenib), albumin-bound paclitaxel (abaxane), encilnidine (enastibinib), hypomethylating agent, gemcitabine (gemcitabine), albumin-bound paclitaxel (matrimin-bound paclitaxel), rituximab (rituximab), oxybutyramizumab (obinutuzumab), ofatumumab (ofatumumab), pembrolizumab (pembrolizumab), nivolumab (nivolumab), devaluzumab (durvaluzumab), aviuzumab (avelumab), alemtuzumab (azazolizumab), bortezomib (bortezomib), maruzumab (marizomib), sha Zuo m (izumab), disulfiram (disuzumab), 3-methylglucamine (face-3-g), and (oxygambir-3-g, and (ces) of the other than drugs, or the other than the toxin (18-toxin, 35 MG, 35-35 f or the other than the toxin salts. In embodiments, the present disclosure provides methods for treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, colorectal cancer, or blood cancer using a combination of a CDK inhibitor and bendamustine, vinatorac, vitamin Mo Feini, albumin-bound paclitaxel, exendin, hypomethylating agent, gemcitabine, albumin-bound paclitaxel, rituximab, obitumumab, ofatuzumab, pembrolizumab, nal Wu Shankang, dewaruzumab, avistuzumab, avitiuzumab, and atrazuzumab. For certain methods described herein, the proteasome inhibitor is selected from bortezomib, ma Lizuo meters, il Sha Zuomi, disulfiram, epicatechin-3-gallate, salidroamide a, carfilzomib, ONX 0912, CEP-18770, MLN9708, epothilone, or MG13, wherein the CDK inhibitor is Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein. In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In some embodiments, the present disclosure provides methods of treating solid tumor cancer with a composition comprising Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein. In some embodiments, the present disclosure provides methods of treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, squamous cell carcinoma including head and neck cancer. In embodiments, the present disclosure provides methods for treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, and colorectal cancer using Wo Luxi forest comprising any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein in solid form. In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In some embodiments, the disclosure relates to methods of treating an inflammatory, immune, or autoimmune disorder in a mammal with a composition comprising Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein. In selected embodiments, the present disclosure also relates to a method of treating a disease with a composition comprising Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein, wherein the disease is selected from the group consisting of: tumor angiogenesis, chronic inflammatory diseases, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangiomas, glioma and melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondyloarthritis, uveitis, behcet's disease, polymyalgia rheumatica, giant cell arteritis, sarcoidosis, kawasaki's disease, juvenile idiopathic arthritis, suppurative sweat gland inflammation, sjogren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, crohn's disease, lupus and lupus nephritis. In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In some embodiments, the disclosure relates to a method of treating a hyperproliferative disorder in a mammal with a composition comprising Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein, wherein the hyperproliferative disorder is a B cell hematological malignancy selected from the group consisting of: chronic Lymphocytic Leukemia (CLL), small Lymphocytic Leukemia (SLL), non-hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular Lymphoma (FL), mantle Cell Lymphoma (MCL), hodgkin's lymphoma, B-cell acute lymphoblastic leukemia (B-ALL), burkitt's lymphoma, waldenstrom's Macroglobulinemia (WM), burkitt's lymphoma, multiple myeloma, myelodysplastic syndrome, or myelofibrosis. In some embodiments, the disclosure relates to a method of treating a hyperproliferative disorder in a mammal with a composition comprising Wo Luxi forest comprising a solid form of any Wo Luxi forest free base polymorph described herein or any Wo Luxi forest salt polymorph described herein, wherein the hyperproliferative disorder is selected from the group consisting of: chronic myelogenous leukemia, acute myelogenous leukemia, DLBCL (comprising Activated B Cell (ABC) and germinal center B cell (GCB) subtypes), follicular center lymphoma, hodgkin's disease, multiple myeloma, indolent non-hodgkin's lymphoma, and mature B cell ALL. In an embodiment, the solid form of Wo Luxi forest in any of the preceding embodiments is selected from the group consisting of malonic acid Wo Luxi forest, dibenzoyltartaric acid Wo Luxi forest, phosphoric acid Wo Luxi forest, oxalic acid Wo Luxi forest, and naphthalene disulfonic acid Wo Luxi forest, each as described herein.

In some embodiments, the hyperproliferative disease is a subtype of CLL. Many subtypes of CLL have been characterized. CLL is often classified as an immunoglobulin heavy chain variable region (IgV) in leukemia cells _H ) Mutation status. N. damle et al, blood 1999,94,1840-47; T.J.Hamblin et al, blood 1999,94,1848-54. With IgV _H Patients with mutations are generally compared to patients without IgV _H The patient with mutation survived longer. ZAP70 expression (positive or negative) was also used to characterize CLL. L.z. rasseti et al, 2004,351,893-901, new england journal of medicine (n.engl.j.med.). Methylation of ZAP-70 at CpG3 is also used to characterize CLL, for example by pyrosequencing. Claus et al, J.Clin.Oncol.) (2012,30,2483-91; J.A. Woyach et al, blood 2014,123,1810-17. CLL is also classified by disease stage according to Binet or Rai criteria. J.L.Binet et al, cancer 1977,40,855-64; K.R.Rai, T.Han, 1990,4,447-56, hematol.Oncol.Clin.North Am., north America. Other common mutations such as 11q deletions, 13q deletions, and 17p deletions can be assessed using well known techniques such as Fluorescence In Situ Hybridization (FISH). In an embodiment, the disclosure relates to a method of treating CLL in a human, wherein the CLL is selected from the group consisting of: igV (Igv) _H Mutation negative CLL, ZAP-70 positive CLL, ZAP-70 methylated at CpG3 CLL, CD38 positive CLL, chronic lymphocytic leukemia characterized by a 17p13.1 (17 p) deletion and CLL characterized by a 11q22.3 (11 q) deletion.

In some embodiments, the hyperproliferative disorder is CLL, wherein the CLL has undergone rickett conversion (Richter's transformation). Methods for assessing the conversion of Ricket, also known as Richter 'ssyndrome, are described in Jain and O' Brien, oncology (Oncology), 2012,26,1146-52. The rickett transformation is a subtype of CLL observed in 5-10% of patients. It involves the development of invasive lymphomas from CLL and often has a poor prognosis.

In some embodiments, the hyperproliferative disorder is CLL or SLL in a patient, wherein the patient is susceptible to lymphocytosis. In embodiments, the disclosure relates to methods of treating CLL or SLL in a patient, wherein the patient exhibits lymphocytosis caused by a disorder selected from the group consisting of: viral infection, bacterial infection, protozoal infection or post-splenectomy status. In an embodiment, the viral infection in any of the preceding embodiments is selected from the group consisting of: infectious mononucleosis, hepatitis and cytomegalovirus. In an embodiment, the bacterial infection in any of the preceding embodiments is selected from the group consisting of: pertussis, tuberculosis and brucellosis.

In some embodiments, the hyperproliferative disorder is a blood cancer. In certain embodiments, the leukemia is a leukemia, such as Acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), acute Lymphocytic Lymphoma (ALL), and Chronic Lymphocytic Leukemia (CLL). In certain embodiments, the blood cancer is a non-hodgkin's lymphoma, such as a B-cell or T-cell lymphoma. B-cell lymphomas include diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small Lymphocytic Lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, burkitt's lymphoma, lymphoplasmacytic lymphoma, and primary central nervous system lymphoma. T cell lymphomas include precursor T lymphoblastic lymphomas, peripheral T cell lymphomas, cutaneous T cell lymphomas, adult T cell lymphomas with subtypes: smoldering chronic, acute and lymphomas, angioimmunoblastic T cell lymphomas, extranodal natural killer/T cell lymphomas, nasal forms, enteropathy-associated intestinal T cell lymphomas (EATL) with subtypes I and II, and Anaplastic Large Cell Lymphomas (ALCL). Methods of treating blood cancers using Wo Luxi forest are described in WO 2017/172826, which is incorporated herein by reference in its entirety.

The following clauses describe certain embodiments.

Clause 1. A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of Wo Luxi forest, wherein the disease or disorder is selected from the group consisting of chronic lymphocytic leukemia, non-hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, B-cell lymphoproliferative disease, B-cell acute lymphoblastic leukemia, waldenstrom's macroglobulinemia, burkitt's leukemia, hodgkin's disease, multiple myeloma, acute myelogenous leukemia, juvenile myelomonocytic leukemia, hairy cell leukemia, mast cell leukemia, mastocytosis, myeloproliferative disorder (MPD), myeloproliferative neoplasm, polycythemia Vera (PV), primary thrombocythemia (ET), primary Myelofibrosis (PMF), myelodysplastic syndrome, chronic myelogenous leukemia (BCR-ABL 1-positive), chronic neutrophilic leukemia, chronic eosinophilic leukemia, primary Central Nervous System (CNS), primary nervous system(s), multiple tumors(s), squamous cell carcinoma, lymphoma, squamous cell carcinoma, lymphomas (e.g., melanoma), eye cancer, retinoblastoma, intraocular melanoma, oral and oropharyngeal cancer, bladder cancer, gastric cancer, pancreatic cancer, breast cancer, cervical cancer, head and neck cancer, renal cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, bone cancer (e.g., metastatic bone cancer), esophageal cancer, testicular cancer, renal cancer, ovarian cancer, colorectal cancer, renal cancer, ovarian cancer, prostate cancer, colorectal cancer, and renal cancer, gynaecological cancer, thyroid cancer, epidermoid cancer, AIDS-related cancers (e.g., lymphomas), virus-induced cervical cancer (human papilloma virus), nasopharyngeal cancer (epstein-barr virus), kaposi's sarcoma, primary exudative lymphomas (kaposi's herpes virus), hepatocellular carcinoma (hepatitis b and hepatitis c virus), T-cell leukemia (human T-cell leukemia virus-1), benign skin hyperplasia, restenosis, benign prostatic hypertrophy, tumor angiogenesis, chronic inflammatory diseases, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, ulcerative colitis, atopic dermatitis, colon pouchitis, spondylitis, uveitis, behcet's disease, polymyalgia rheumatica, giant cell arteritis, sarcoidosis, kawasaki, juvenile idiopathic arthritis, suppurative dermatitis, sjogren's, sarcoidosis, psoriasis, rheumatoid arthritis, lupus erythematosus, systemic lupus, and nephritis.

Clause 2. A method of treating a hyperproliferative disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of Wo Luxi forest, wherein the hyperproliferative disease or disorder is selected from acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphoblastic leukemia, non-hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, B-cell lymphoproliferative disease, B-cell acute lymphoblastic leukemia, and waldenstrom's macroglobulinemia.

Clause 3. A method of treating leukemia in a subject, the method comprising administering to the subject a therapeutically effective amount of Wo Luxi forest.

Clause 4. The method of clause 3, wherein the blood cancer is selected from Acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), acute Lymphocytic Lymphoma (ALL), and Chronic Lymphocytic Leukemia (CLL).

Clause 5. A method of treating a hyperproliferative disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of Wo Luxi forest, wherein the hyperproliferative disease or disorder is a KRAS mutant cancer.

Clause 6 the method of clause 5, wherein the KRAS mutant cancer is characterized by a mutation selected from G12A, G C, G12D, G12S, G12V, G13C, G D and Q61H.

Clause 7 the method of clause 5 or 6, wherein the cancer is selected from Acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), acute Lymphocytic Lymphoma (ALL) and Chronic Lymphocytic Leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small Lymphocytic Lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, spleen marginal zone B-cell lymphoma, burkitt lymphoma, lymphoplasmacytic lymphoma, and primary central nervous system lymphoma.

The method of any one of clauses 5 to 7, wherein the cancer is selected from pancreatic cancer, lung cancer, colorectal cancer, esophageal cancer, and ovarian cancer.

The method of any one of clauses 5 to 7, wherein the cancer is selected from NSCLC, SCLC, CRC, pancreas, TNBC, melanoma, breast cancer, and liver cancer.

Clause 10 the method of any of clauses 1 to 9, wherein the disease or disorder is a recurrent/refractory (R/R) disease or disorder.

Clause 11 the method of any of clauses 1 to 10, wherein the waruzole comprises a Wo Luxi salt, the Wo Luxi salt comprising a counterion corresponding to an acid selected from the group consisting of 1, 5-naphthalenedisulfonic acid, 1-hydroxy-2-naphthoic acid, benzenesulfonic acid, benzoic acid, dibenzoyl-L-tartaric acid, ethanesulfonic acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malonic acid, oxalic acid, orthophosphoric acid, sulfuric acid, and p-toluenesulfonic acid.

The method of any one of clauses 1-10, wherein the waruzole comprises a crystalline form of Wo Luxi, which comprises Wo Luxi a free base of the forest or a salt of the forest Lu Xilin, the salt of Wo Luxi comprising a counterion corresponding to an acid selected from the group consisting of 1, 5-naphthalenedisulfonic acid, 1-hydroxy-2-naphthoic acid, benzenesulfonic acid, benzoic acid, dibenzoyl-L-tartaric acid, ethanesulfonic acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malonic acid, oxalic acid, orthophosphoric acid, sulfuric acid, and p-toluenesulfonic acid.

The method of any one of clauses 1-10, wherein the valacyline comprises a crystalline form of Wo Luxi, the crystalline form characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from 7.30 ° ± 0.2 °, 13.58 ° ± 0.2 °, 14.06 ° ± 0.2 °, 15.18 ° ± 0.2 °, 15.66 ° ± 0.2 °, 17.50 ° ± 0.2 °, 18.94 ° ± 0.2 °, 19.54 ° ± 0.2 °, 22.22 ° ± 0.2 °, 23.38 ° ± 0.2 °, 24.10 ° ± 0.2 °, 24.98 ° ± 0.2 °, 25.94 ° ± 0.2 °, 27.26 ° ± 0.2 °, 28.50 ° ± 0.2 ° and 32.82 ° ± 0.2°2Θ.

Clause 14 the method of clause 13, wherein the crystalline form comprises malonic acid Wo Luxi forest.

The method of any one of clauses 1-10, wherein the valacyline comprises a crystalline form of Wo Luxi, the crystalline form characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from 5.06 ° ± 0.2 °, 6.42 ° ± 0.2 °, 9.34 ° ± 0.2 °, 10.14 ° ± 0.2 °, 12.30 ° ± 0.2 °, 13.66 ° ± 0.2 °, 14.14 ° ± 0.2 °, 15.82 ° ± 0.2 °, 17.02 ° ± 0.2 °, 19.74 ° ± 0.2 °, 20.38 ° ± 0.2 °, 21.82 ° ± 0.2 °, 22.66 ° ± 0.2 °, 24.62 ° ± 0.2 °, 25.78 ° ± 0.2 °, 26.58 ° ± 0.2 °, 28.66 ° ± 0.2 ° and 29.98 ° ± 0.2°2Θ.

Clause 16 the method of clause 15, wherein the crystalline form comprises dibenzoyltartaric acid Wo Luxi forest.

The method of any one of clauses 1-10, wherein the waluzole comprises a crystalline form of Wo Luxi, the crystalline form characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.94 ° ± 0.2 °, 6.78 ° ± 0.2 °, 9.34 ° ± 0.2 °, 10.94 ° ± 0.2 °, 12.70 ° ± 0.2 °, 13.38 ° ± 0.2 °, 14.90 ° ± 0.2 °, 15.66 ° ± 0.2 °, 17.54 ° ± 0.2 °, 18.82 ° ± 0.2 °, 22.02 ° ± 0.2 °, 23.98 ° ± 0.2 °, 24.78 ° ± 0.2 °, 25.30 ° ± 0.2 °, 26.66 ° ± 0.2 ° and 29.98 ° ± 0.2 ° 2 Θ.

Clause 18 the method of clause 17, wherein the crystalline form comprises a phosphate Wo Luxi forest.

The method of any one of clauses 1-10, wherein the waluicillin comprises a crystalline form of Wo Luxi, said crystalline form characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.86 ° ± 0.2 °, 12.66 ° ± 0.2 °, 13.58 ° ± 0.2 °, 14.74 ° ± 0.2 °, 15.98 ° ± 0.2 °, 19.38 ° ± 0.2 °, 23.94 ° ± 0.2 °, 24.78 ° ± 0.2 ° and 25.94 ° ± 0.2 ° 2Θ.

Clause 20 the method of clause 19, wherein the crystalline form comprises oxalic acid Wo Luxi forest.

The method of any one of clauses 1-10, wherein the valacyline comprises a crystalline form of Wo Luxi, the crystalline form characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from 9.02 ° ± 0.2 °, 10.50 ° ± 0.2 °, 11.06 ° ± 0.2 °, 12.30 ° ± 0.2 °, 12.82 ° ± 0.2 °, 13.90 ° ± 0.2 °, 14.82 ° ± 0.2 °, 15.30 ° ± 0.2 °, 15.94 ° ± 0.2 °, 17.26 ° ± 0.2 °, 19.34 ° ± 0.2 °, 20.62 ° ± 0.2 °, 22.18 ° ± 0.2 °, 24.58 ° ± 0.2 °, 25.42 ° ± 0.2 °, 25.86 ° ± 0.2 °, 27.38 ° ± 0.2 ° and 28.66 ° ± 0.2°2Θ.

Clause 22 the method of clause 21, wherein the crystalline form comprises naphthalene disulfonic acid Wo Luxi forest.

The method of any one of clauses 12 to 22, wherein the crystalline form is a crystalline anhydrate.

The method of any one of clauses 12 to 22, wherein the crystalline form is a crystalline hydrate.

Clause 25 the method of any of clauses 1 to 10, wherein Wo Luxi forest comprises a crystalline form of malonic acid Wo Luxi forest, the crystalline form characterized by an X-ray powder diffraction pattern, the X-ray powder diffraction pattern includes a peak selected from the group consisting of 6.36 ° ± 0.2 ° 2θ, 13.88 ° ± 0.2 ° 2θ, 7.31 ° ± 0.2 ° 2θ, 9.34 ° ± 0.2 ° 2θ, 10.05 ° ± 0.2 ° 2θ, 13.59 ° ± 0.2 ° 2θ, 14.08 ° ± 0.2 ° 2θ, 15.21 ° ± 0.2 ° 2θ, 15.67 ° ± 0.2 ° 2θ, 17.53 ° ± 0.2 ° 2θ, 18.70 ° ± 0.2 ° 2θ, 18.98 ° ± 0.2 ° 2θ, 19.38 ° ± 0.2 ° 2θ, 19.67 ° ± 0.2 ° 2θ, 20.16 ° ± 0.2 ° 2θ, 20.39 ° ± 0.2 ° 2θ, 21.01 ° ± 0.2 ° 2θ, 22.27 ° ± 0.2 ° 2θ, 23.35 ° ± 0.24 ° ± 24.27 ° ± 0.25 ° ± 2 ° 2θ, and a peak.

Clause 26 the method of any of clauses 1 to 10, wherein Wo Luxi forest comprises a crystalline form of oxalic acid Wo Luxi forest, the crystalline form characterized by an X-ray powder diffraction pattern, the X-ray powder diffraction pattern includes a diffraction pattern selected from the group consisting of 6.86 ° ± 0.2 ° 2θ, 9.70 ° ± 0.2 ° 2θ, 10.84 ° ± 0.2 ° 2θ, 12.50 ° ± 0.2 ° 2θ, 12.66 ° ± 0.2 ° 2θ, 12.81 ° ± 0.2 ° 2θ, 13.41 ° ± 0.2 ° 2θ, 13.71 ° ± 0.2 ° 2θ, 14.54 ° ± 0.2 ° 2θ, 15.35 ° ± 0.2 ° 2θ, 15.83 ° ± 0.2 ° 2θ, 18.70 ° ± 0.2 ° 2θ, 19.00 ° ± 0.2 ° 2θ, 19.43 ° ± 0.2 ° 2θ one or more peaks of 19.62 ° ± 0.2 ° 2θ, 21.75 ° ± 0.2 ° 2θ, 22.75 ° ± 0.2 ° 2θ, 23.35 ° ± 0.2 ° 2θ, 23.47 ° ± 0.2 ° 2θ, 23.81 ° ± 0.2 ° 2θ, 23.98 ° ± 0.2 ° 2θ, 24.36 ° ± 0.2 ° 2θ, 24.60 ° ± 0.2 ° 2θ, 24.86 ° ± 0.2 ° 2θ, 25.11 ° ± 0.2 ° 2θ, 25.60 ° ± 0.2 ° 2θ, 25.75 ° ± 0.2 ° 2θ and 26.25 ° ± 0.2 ° 2θ.

Clause 27 the method of any of clauses 1 to 10, wherein Wo Luxi forest comprises a crystalline form of phosphoric acid Wo Luxi forest, the crystalline form characterized by an X-ray powder diffraction pattern, the X-ray powder diffraction pattern includes a diffraction pattern selected from the group consisting of 4.93 ° ± 0.2 ° 2θ, 6.79 ° ± 0.2 ° 2θ, 9.35 ° ± 0.2 ° 2θ, 10.58 ° ± 0.2 ° 2θ, 10.91 ° ± 0.2 ° 2θ, 12.64 ° ± 0.2 ° 2θ, 13.35 ° ± 0.2 ° 2θ, 13.58 ° ± 0.2 ° 2θ, 14.81 ° ± 0.2 ° 2θ, 15.60 ° ± 0.2 ° 2θ, 17.18 ° ± 0.2 ° 2θ, 17.52 ° ± 0.2 ° 2θ, 18.32 ° ± 0.2 ° 2θ, 18.78 ° ± 0.2 ° 2θ one or more peaks of 19.34 ° ± 0.2 ° 2θ, 19.64 ° ± 0.2 ° 2θ, 19.78 ° ± 0.2 ° 2θ, 22.02 ° ± 0.2 ° 2θ, 23.20 ° ± 0.2 ° 2θ, 23.67 ° ± 0.2 ° 2θ, 24.00 ° ± 0.2 ° 2θ, 24.71 ° ± 0.2 ° 2θ, 25.21 ° ± 0.2 ° 2θ, 25.39 ° ± 0.2 ° 2θ, 26.55 ° ± 0.2 ° 2θ, 27.22 ° ± 0.2 ° 2θ, 28.07 ° ± 0.2 ° 2θ and 29.90 ° ± 0.2 ° 2θ.

The method of any one of clauses 1-27, wherein Wo Luxi forest is administered in a daily dose of about 50mg to about 100mg, about 100mg to about 150mg, about 150mg to about 200mg, about 200mg to about 250mg, about 250mg to about 300mg, about 300mg to about 350mg, about 350mg to about 400mg, about 400mg to about 450mg, about 450mg to about 500mg, about 500mg to about 550mg, about 550mg to about 600mg, about 600mg to about 650mg, about 650mg to about 700mg, about 700mg to about 750mg, about 750mg to about 800mg, about 800mg to about 850mg, about 850mg to about 900mg, about 900mg to about 950mg, or about 950mg to about 1,000 mg.

The method of any one of clauses 1-27, wherein Wo Luxi forest is administered in a daily dose of about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, about 700mg, about 750mg, about 800mg, about 850mg, about 900mg, about 950mg, or about 1,000.

The method of any one of clauses 1-29, wherein Wo Luxi forest is administered daily for about one day, about two days, about three days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

Clause 31 the method of any of clauses 1 to 29, wherein the Wo Luxi forest is administered daily for about one week, about two weeks, about three weeks, or about 4 weeks.

The method of any one of clauses 1-31, wherein Wo Luxi forest administration is suspended for about one day, about two days, about three days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

Clause 33 the method of any of clauses 1 to 31, wherein the Wo Luxi forest administration is suspended for about one week, about two weeks, about three weeks, or about 4 weeks.

Clause 34 the method of any of clauses 1 to 29, wherein the Wo Luxi forest is administered on a 14 day/14 day off schedule.

The method of any one of clauses 1-34, wherein Wo Luxi forest is administered for about one month, about two months, about three months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months.

The method of any one of clauses 1-35, wherein Wo Luxi forest is administered in combination with an additional therapeutic agent.

The method of clause 37, wherein the therapeutic agent is an anticancer agent.

The method of clause 38, wherein the anti-cancer agent is selected from AMG510, MRTX849, an Fansai, volasertib, and ME-344.

Clause 39 the method of clause 38, wherein the anti-cancer agent is selected from the group consisting of KRAS inhibitors, tki+raf inhibitors, RAF inhibitors, raf+mek inhibitors, MEK inhibitors, and ERK inhibitors.

Clause 40 the method of clause 38, wherein the anti-cancer agent is a BCL-2 inhibitor selected from the group consisting of nanotoloch (navitocrax), valnemotox, a-1155463, a-1331852, ABT-737, obackra (obatocrax), TW-37, a-1210477, AT101, HA14-1, BAM7, S44563, sha Butuo grams (sabotoclax), UMI-77, gambogic acid, maritox (maritocrax), MIM1, methylprednisolone, iMAC2, bax inhibitor peptide V5, bax inhibitor peptide P5, bax channel blocker, and ARRY 520 trifluoroacetate.

Clause 41. The method of clause 38, wherein the anticancer agent is a proteasome inhibitor selected from bortezomib, ma Lizuo meters, i Sha Zuomi, disulfiram, epicatechin-3-gallate, salinomycin a, carfilzomib, ONX 0912, CEP-18770, MLN9708, epothilone, MG132, and any pharmaceutically acceptable salts thereof.

The method of any one of clauses 36 to 41, wherein the additional therapeutic agent is administered daily for about one day, about two days, about three days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

The method of any one of clauses 36 to 41, wherein the additional therapeutic agent is administered daily for about one week, about two weeks, about three weeks, or about 4 weeks.

The method of any one of clauses 36 to 43, wherein the suspension of administration of the additional therapeutic agent occurs for about one day, about two days, about three days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

Clause 45 the method of any of clauses 36 to 43, wherein the administration of the additional therapeutic agent is suspended for about one week, about two weeks, about three weeks, or about 4 weeks.

Clause 46 the method of any of clauses 36 to 41, wherein the additional therapeutic agent is administered on a 14 day/14 day off schedule.

The method of any one of clauses 36 to 46, wherein the additional therapeutic agent administration is for about one month, about two months, about three months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months.

Clause 48 a malonic acid Wo Luxi forest formulation as described herein.

Clause 101 is a formulation comprising about 15% to about 35% w/w malonic acid Wo Luxi forest (voruciclib malonate) and one or more pharmaceutically acceptable excipients.

Clause 102 the formulation of clause 101, comprising about 18 to about 30 percent w/w malonic acid Wo Luxi forest.

Clause 103 the formulation of clause 101, comprising about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, or about 28% w/w malonic acid Wo Luxi forest.

Clause 104 the formulation of clause 101, comprising about 20 to about 23 percent w/w malonic acid Wo Luxi forest.

The formulation of any one of clauses 101 to 104, wherein the one or more pharmaceutically acceptable excipients comprise about 5% to about 37% w/w microcrystalline cellulose.

The formulation of any one of clauses 101 to 104, wherein the one or more pharmaceutically acceptable excipients comprise about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19% or about 20% w/w microcrystalline cellulose.

Clause 107 the formulation of any of clauses 101 to 106, wherein the one or more pharmaceutically acceptable excipients comprise about 1 to about 48% w/w lactose monohydrate.

The formulation of any one of clauses 101 to 106, wherein the one or more pharmaceutically acceptable excipients comprise about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% w/w lactose monohydrate.

The formulation of any one of clauses 101 to 108, wherein the one or more pharmaceutically acceptable excipients comprise about 20% to about 70% w/w dibasic calcium phosphate dihydrate.

The formulation of any one of clauses 101 to 108, wherein the one or more pharmaceutically acceptable excipients comprise about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50% w/w of dibasic calcium phosphate dihydrate.

Clause 111 the formulation of any of clauses 101 to 110, wherein the one or more pharmaceutically acceptable excipients comprise about 0.1 to about 15% w/w sodium bicarbonate.

The formulation of any one of clauses 101 to 110, wherein the one or more pharmaceutically acceptable excipients comprise about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% w/w sodium bicarbonate.

The formulation of any one of claims 1-12, wherein the one or more pharmaceutically acceptable excipients comprises about 1% to about 20% w/w sodium starch glycolate.

The formulation of any one of clauses 101-112, wherein the one or more pharmaceutically acceptable excipients comprise about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% w/w sodium starch glycolate.

The formulation of any one of clauses 101 to 114, wherein the one or more pharmaceutically acceptable excipients comprise about 0.01% to about 10% w/w magnesium stearate.

Clause 116 the formulation of any of clauses 101 to 114, wherein the one or more pharmaceutically acceptable excipients comprise about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 3%, about 4% or about 5% w/w magnesium stearate.

The formulation of any one of clauses 101 to 116, wherein the one or more pharmaceutically acceptable excipients comprise about 0.01% to about 10% w/w colloidal silicon dioxide.

The formulation of any one of clauses 101 to 116, wherein the one or more pharmaceutically acceptable excipients comprise about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 3%, about 4% or about 5% w/w colloidal silicon dioxide.

Clause 119 the formulation of any of clauses 101 to 118, wherein the formulation is included into a tablet.

Clause 120 the formulation of clause 119, wherein the tablet is coated with a film coating.

The formulation of any one of clauses 101 to 120, wherein malonic acid Wo Luxi forest comprises a crystalline form of malonic acid Wo Luxi forest characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from 7.30 ° ± 0.2 °, 13.58 ° ± 0.2 °, 14.06 ° ± 0.2 °, 15.18 ° ± 0.2 °, 15.66 ° ± 0.2 °, 17.50 ° ± 0.2 °, 18.94 ° ± 0.2 °, 19.54 ° ± 0.2 °, 22.22 ° ± 0.2 °, 23.38 ° ± 0.2 °, 24.10 ° ± 0.2 °, 24.98 ° ± 0.2 °, 25.94 ° ± 0.2 °, 27.26 ° ± 0.2 °, 28.50 ° ± 0.2 ° and 32.82 ° ± 0.2°2 θ.

Clause 122 the formulation of any of clauses 101 to 120, wherein the malonic acid Wo Luxi forest comprises a crystalline form of malonic acid Wo Luxi forest, the crystalline form characterized by an X-ray powder diffraction pattern, the X-ray powder diffraction pattern includes a peak selected from the group consisting of 6.36 ° ± 0.2 ° 2θ, 13.88 ° ± 0.2 ° 2θ, 7.31 ° ± 0.2 ° 2θ, 9.34 ° ± 0.2 ° 2θ, 10.05 ° ± 0.2 ° 2θ, 13.59 ° ± 0.2 ° 2θ, 14.08 ° ± 0.2 ° 2θ, 15.21 ° ± 0.2 ° 2θ, 15.67 ° ± 0.2 ° 2θ, 17.53 ° ± 0.2 ° 2θ, 18.70 ° ± 0.2 ° 2θ, 18.98 ° ± 0.2 ° 2θ, 19.38 ° ± 0.2 ° 2θ, 19.67 ° ± 0.2 ° 2θ, 20.16 ° ± 0.2 ° 2θ, 20.39 ° ± 0.2 ° 2θ, 21.01 ° ± 0.2 ° 2θ, 22.27 ° ± 0.2 ° 2θ, 23.35 ° ± 0.24 ° ± 24.27 ° ± 0.25 ° ± 2 ° 2θ, and a peak.

Clause 123 the formulation of clause 121 or 122, wherein the crystalline form is a crystalline anhydrate.

Clause 124 the formulation of clause 121 or 122, wherein the crystalline form is a crystalline hydrate.

Clause 125. A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective formulation according to any of clauses 101-124.

Clause 126. A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective formulation comprising about 15% to 35% w/w malonic acid Wo Luxi forest, about 5% to 37% w/w microcrystalline cellulose, about 1% to about 48% w/w lactose monohydrate, about 20% to about 70% w/w dibasic calcium phosphate dihydrate, about 0.1% to about 15% w/w sodium bicarbonate, about 1% to about 20% w/w sodium starch glycolate, and about 0.01% to about 10% w/w magnesium stearate.

The method of clause 127, wherein the malonic acid Wo Luxi forest comprises a crystalline form of malonic acid Wo Luxi forest characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.30 ° ± 0.2 °, 13.58 ° ± 0.2 °, 14.06 ° ± 0.2 °, 15.18 ° ± 0.2 °, 15.66 ° ± 0.2 °, 17.50 ° ± 0.2 °, 18.94 ° ± 0.2 °, 19.54 ° ± 0.2 °, 22.22 ° ± 0.2 °, 23.38 ° ± 0.2 °, 24.10 ° ± 0.2 °, 24.98 ° ± 0.2 °, 25.94 ° ± 0.2 °, 27.26 ° ± 0.2 °, 28.50 ° ± 0.2 ° and 32.82 ° ± 0.2 ° 2Θ.

Clause 128 the method of clause 126, wherein the malonic acid Wo Luxi forest comprises a crystalline form of malonic acid Wo Luxi forest, the crystalline form characterized by an X-ray powder diffraction pattern, the X-ray powder diffraction pattern includes a peak selected from the group consisting of 6.36 ° ± 0.2 ° 2θ, 13.88 ° ± 0.2 ° 2θ, 7.31 ° ± 0.2 ° 2θ, 9.34 ° ± 0.2 ° 2θ, 10.05 ° ± 0.2 ° 2θ, 13.59 ° ± 0.2 ° 2θ, 14.08 ° ± 0.2 ° 2θ, 15.21 ° ± 0.2 ° 2θ, 15.67 ° ± 0.2 ° 2θ, 17.53 ° ± 0.2 ° 2θ, 18.70 ° ± 0.2 ° 2θ, 18.98 ° ± 0.2 ° 2θ, 19.38 ° ± 0.2 ° 2θ, 19.67 ° ± 0.2 ° 2θ, 20.16 ° ± 0.2 ° 2θ, 20.39 ° ± 0.2 ° 2θ, 21.01 ° ± 0.2 ° 2θ, 22.27 ° ± 0.2 ° 2θ, 23.35 ° ± 0.24 ° ± 24.27 ° ± 0.25 ° ± 2 ° 2θ, and a peak.

Clause 129 the method of any of clauses 126 to 128, wherein the formulation comprises about 0.01 to about 10 percent w/w colloidal silica.

The method of any one of clauses 126 to 129, wherein the formulation is included into a tablet and the tablet is coated with a film coating.

Clause 131 the method of any of clauses 125 to 130, wherein the disease or condition is a leukemia.

Clause 132a the method of clause 131, wherein the blood cancer is selected from Acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), acute Lymphocytic Lymphoma (ALL), and Chronic Lymphocytic Leukemia (CLL).

The method of clause 132b, wherein the blood cancer is selected from the group consisting of leukemia: acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), acute Lymphocytic Lymphoma (ALL), and Chronic Lymphocytic Leukemia (CLL).

Clause 132c the method of clause 131, wherein the blood cancer is a non-hodgkin's lymphoma, such as a B-cell or T-cell lymphoma, wherein the B-cell lymphoma is selected from diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small Lymphocytic Lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, burkitt's lymphoma, lymphoplasmacytomer lymphoma, and primary central nervous system lymphoma.

The method of clause 132d, wherein the blood cancer is a T cell lymphoma selected from the group consisting of: precursor T lymphoblastic lymphoma, peripheral T cell lymphoma, cutaneous T cell lymphoma, adult T cell lymphoma of subtype: smoldering chronic, acute and lymphomas, angioimmunoblastic T cell lymphomas, extranodal natural killer/T cell lymphomas, nasal forms, enteropathy-associated intestinal T cell lymphomas (EATL) with subtypes I and II, and Anaplastic Large Cell Lymphomas (ALCL).

The method of any one of clauses 125 to 132, wherein the formulation is administered to the subject such that the subject receives a daily dose of between about 50mg and about 100mg, between about 100mg and about 150mg, between about 150mg and about 200mg, between about 200mg and about 250mg, between about 250mg and about 300mg, between about 300mg and about 350mg, between about 350mg and about 400mg, between about 400mg and about 450mg, between about 450mg and about 500mg, between about 500mg and about 550mg, between about 550mg and about 600mg, between about 600mg and about 650mg, between about 650mg and about 700mg, between about 700mg and about 750mg, between about 750mg and about 800mg, between about 800mg and about 850mg, between about 850mg and about 900mg, between about 900mg and about 950mg, or between about 950mg and about Wo Luxi mg.

The method of any one of clauses 125 to 132, wherein the formulation is administered to the subject such that the subject receives a daily Wo Luxi forest dose of about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, about 700mg, about 750mg, about 800mg, about 850mg, about 900mg, about 950mg, or about 1,000 mg.

The method of any one of clauses 125 to 132, wherein the formulation is administered to the subject such that the subject receives a daily Wo Luxi forest dose of about 200mg or about 250 mg.

The method of any one of clauses 125 to 132, wherein the formulation is administered to the subject such that the subject receives a daily Wo Luxi forest dose of no more than 350 mg.

The method of any one of clauses 133 to 136, wherein the Wo Luxi forest dose is a Wo Luxi forest free base dose.

The method of any one of clauses 125 to 137, wherein said formulation is administered to said subject daily for about one day, about two days, about three days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

The method of any one of clauses 125 to 137, wherein the formulation is administered to the subject daily for about one week, about two weeks, about three weeks, or about 4 weeks.

The method of any one of clauses 125 to 139, wherein the administration of the formulation is suspended for about one day, about two days, about three days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

The method of any one of clauses 125 to 139, wherein the administration of the formulation is suspended for about one week, about two weeks, about three weeks, or about 4 weeks.

The method of any one of clauses 125 to 141, wherein said formulation is administered to said subject on a 14 day/14 day off schedule.

Clause 143 the method of any of clauses 125 to 142, wherein the administration of the formulation is for about one month, about two months, about three months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months.

The method of any one of clauses 125 to 143, wherein the formulation is administered in combination with a BCL-2 inhibitor.

The method of clause 144, wherein the BCL-2 inhibitor is selected from the group consisting of nano-vickers, vitamin e-troke, a-1155463, a-1331852, ABT-737, obbar-clar, S44563, TW-37, a-1210477, AT101, HA14-1, BAM7, sha Butuo g, UMI-77, gambogic acid, martolochic, MIM1, methylprednisolone, iMAC2, bax inhibitor peptide V5, bax inhibitor peptide P5, bax channel blocker, and ARRY 520 trifluoroacetate or a pharmaceutically acceptable salt of any of these.

The method of clause 146, wherein the BCL-2 inhibitor is valnemulin or a pharmaceutically acceptable salt thereof.

The method of any one of clauses 144 to 146, wherein the BCL-2 inhibitor is administered to the subject daily for about one day, about two days, about three days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

The method of any one of clauses 144 to 146, wherein the BCL-2 inhibitor is administered to the subject daily for about one week, about two weeks, about three weeks, or about 4 weeks.

The method of any one of clauses 144 to 148, wherein the suspension of administration of the BCL-2 inhibitor lasts for about one day, about two days, about three days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

The method of any one of clauses 144 to 148, wherein the suspension of administration of the BCL-2 inhibitor lasts for about one week, about two weeks, about three weeks, or about 4 weeks.

The method of any one of clauses 144 to 150, wherein the BCL-2 inhibitor is administered to the subject on a 14 day/14 day off schedule.

The method of any one of clauses 144 to 151, wherein the BCL-2 inhibitor is administered to the subject for about one month, about two months, about three months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months.

Examples

Example 1: monotherapy phase 1 study of solid tumors

Dosing for 2 weeks/1 week off schedule: 75 to 850mg; dose escalation/expansion occurred in 29 patients at the 600mg cohort; 41% disease control rate; 1 PR and 8 SD lasting 2 to 6 months.

Daily continuous schedule: 75 to 500mg; dose escalation/expansion occurred in 39 patients at the 350mg cohort; 31% disease control rate; median 12 SDs for 15 weeks.

Safety characteristics: the most common AE involves the GI tract; there was no evidence of hemolysis.

Reduction of c-MYC expression in solid tumors: 10 gene biomarkers were evaluated in a phase 1 daily dosing study; 17 out of 25 patients tested (68%) had reduced c-MYC expression (fig. 1A and 1B).

Example 2: research of Wo Luxi Lin+Vimod in BRAF mutant advanced/inoperable malignant melanoma Study of

Wo Luxi forest 150mg daily plus either 22 mg of vemurafenib or 960mg BID over a 28 day period; 9 patients treated prior to study termination; 8 patients for whom efficacy assessment was possible; 5 patients were BRAFi refractory, response = PD;3 patients were BRAF/MEK naive, 1 CR and 2 PR for 3 to 14 months; the most common AEs are fatigue, constipation, diarrhea, joint pain and headache; 1 DLT = grade 3 fatigue.

Example 3: CR of patients suffering from lung metastases

Example 4: CDK9 modulation using MCL 1: phase 1 study of R/R B cell malignancy and AML

Study population: recurrent/refractory B-cell malignancy; recurrent/refractory AML; dose escalation using standard 3+3 designs.

Endpoint: safety and tolerability, pharmacokinetics, biological related studies (BH 3 profiling, MCL-1 expression, molecular mutation analysis), response rate.

Wo Luxi single agent dose escalation: 50mg >100mg >150mg >200mg.

Phase 1 study in hematological malignancies: 24 patients treated at 3 dose levels, 10 AML and 14B-cell malignancies, no GI toxicity or neutropenia at the dose studied, PK profile favorable in all voruscarin studies (half-life 24-28 hours supporting once daily dosing, cmax and AUC of dose ratio; high distribution volume indicates broad tissue entry); a dosage of 150-200mg may achieve a plasma concentration sufficient to inhibit the molecular target.

Example 5: wo Luxi forest shows preferential tumor accumulation in preclinical models

Wo Luxi forest showed preferential tumor accumulation in preclinical models (FIGS. 3A-3D). Xenograft of HCT-116CRC cells in SCID mice. 8 mice per time point (2 controls, 6 orally administered Wo Luxi forest at 100 mpk). Animals were randomly divided into 2 groups when tumor diameters reached 100 mm. Group a was dispensed as a single dose. Group B was dosed for 5 days. 8 mice per time point (2 controls, 6 orally administered Wo Luxi forest at 100 mpk). Drug concentrations in tumor and plasma were measured after the last dose at the following time points: 0. 4, 8, 24, 48, 72 hours. 5 days after repeated dosing, the cumulative index of Wo Luxi in tumors was 1.45. Wo Luxi Lin Nongdu in plasma is in μg/ml and tumor is in μg/g. Indicating a Wo Luxi woodfold increase in tumor relative to plasma.

Higher levels (> 5-fold) of Wo Luxi were found in tumors at 8 hours compared to 24 hours after dosing. At 24 hours, negligible Wo Luxi forest levels were observed in plasma. Furthermore, the tumor to plasma ratio was found to be > 5-fold at both time points.

Example 6: evidence of biological activity in AML

Differentiation syndrome (WBC increase without increase in blast cells, bone pain, lung symptoms; response to corticosteroids) was observed in 5 patients (50%).

Differentiation syndromes using ATRA, idi and other AML targeted therapies.

Example 7: synergistic effects with valnemulin in Wo Luxi Lin Zaiwei Netropism and resistant cell lines

Fig. 4A and 4B show the synergy with valnemorque in Wo Luxi Lin Zaiwei netoolk sensitive and resistant cell lines. Fig. 4A: vitamin naitock sensitivity; fig. 4B: resistance to valnemulin.

Phase 1 study of Wo Luxi forest+valnemtock in AML; study population: recurrent/refractory B-cell malignancy; recurrent/refractory AML; dose escalation using standard 3+3 designs.

Endpoint: safety and tolerability; pharmacokinetics; biological related studies (BH 3 profiling, MCL-1 expression, molecular mutation analysis); response rate.

Wo Luxi single agent dose escalation: 50mg >100mg >150mg >200mg

Wo Luxi forest+valnemulin dose escalation: 100mg >150mg >200mg.

Example 8: wo Luxi forest dosage regimen

PK data for 2 weeks of daily dosing followed by 1 week of no dosing in a 21 day cycle are presented in table 1 and PK data for continuous daily dosing are presented in table 2.

Table 1: descriptive statistics (mean ± standard deviation) of PK parameters for Wo Luxi forest on day 1 and day 13

* The median value (range) of Tmax is reported.

N=1, #n=2, +=11 and ≡n=15

Because there are not enough time points to characterize the elimination period AUC0- ≡, there is no way to characterize the elimination period for patients 106 (day 1), 202 (day 1), 204 (day 1), 216 (day 13), 302 (day 1), 306 (day 1), 409 (day 13), 410 (day 1), 418 (day 1), and,

419 T [ g2]1/2[/g2] and Vz/F were calculated (day 1), 501 (day 1) and 501 (day 13).

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Wo Luxi forest half-life is designated in the table as t1/2 (in hours). The steady state (i.e., day 13-15) half-life ranges from 16 hours to 358 hours, on average 24 to 48 hours. There is inter-patient variability, accounting for outliers. When the drug stops, about 5 half-lives, or 5-10 days, are required to eliminate the drug from the plasma.

The distribution volume of Wo Luxi forest is designated as Vz/F (in liters). The steady state (i.e., days 13-15) distribution volume ranged from 185L to 982L, with an average of about 300L (and outliers). The blood volume is about 5L and thus, in some embodiments, the Wo Luxi forest distribution volume is about 60 times the blood volume, indicating widespread distribution into the tissue. When the drug stopped, it took 3 days to clear from the tissue after plasma removal.

Without wishing to be bound by any particular theory, it is believed that by using a 14 day regimen followed by a 14 day regimen of drug withdrawal, there is sufficient time for the drug to be eliminated from the plasma (day 19 to day 24) and for the other 3 days (day 22 to day 27) for the tissue, thereby preventing accumulation into the tissue by continuous daily dosing, as well as potential toxicity. Without wishing to be bound by any particular theory, it is believed that administration of Wo Luxi forest on a 14 day/14 day off schedule prevents tissue toxicity. In some embodiments, such dosing regimens may match the dosing schedule of the combination drug.

Example 9: summary of formulation development of malonic acid Wo Luxi forest

Depending on the other chemicals present, wo Luxi can form gels when dissolved in various media. In contrast to Wo Luxi forest hydrochloride, wo Luxi forest malonate does not form a gel in water or aqueous buffer over the entire pH range. However, during development of immediate release tablet formulations of malonate, the tablet was observed to gel at an acidic pH (medium for testing dissolution) depending on the excipients present in the formulation.

Efforts to find tablet formulations that do not form gels during dissolution are summarized below:

1. attempts were made to formulate drugs with poorly water-soluble excipients and at various concentrations-but without positive effects.

2. Attempts have been made to formulate drugs with a variety of poorly water-soluble excipients and at various concentrations-but without positive effects.

3. Attempts have been made to formulate drugs with combinations of water-soluble and poorly water-soluble excipients at various concentrations-but without positive effects.

4. Attempts were made to formulate with high levels of disintegrant-but without positive effects.

5. Attempts to add different concentrations of sodium bicarbonate to the formulation-the idea is that adding sodium bicarbonate will interact with the acid to produce CO2 that helps to break down the tablet. At higher concentrations of sodium bicarbonate, gelation is reduced or eliminated. Unfortunately, increasing sodium bicarbonate causes tablet manufacturing problems (poor flowability, high tablet weight) and causes the tablet to float in the dissolution test, resulting in poor dissolution profiles.

6. It was found that flowability can be improved by lowering the sodium bicarbonate level and increasing dibasic calcium phosphate eliminates tablet floating, which results in improved dissolution profile while eliminating gelation problems.

7. It was also found that for certain formulations, flotation can be eliminated by varying the size, shape and weight of the tablets.

Table 3: formulations of the present disclosure

Composition of the components	％w/w	mg/tablet
			Malonic acid Wo Luxi forest	23.49	61.07
Avicel pH 102	19.23	50.00
			Lactose monohydrate 316Fast Flo	15.55	40.43
Dibasic calcium phosphate	32.69	85.00
			Sodium bicarbonate, NF	4.00	10.40
Sodium starch glycolate	4.04	10.50
			Magnesium stearate	1.00	2.60

Excipient compatibility studies were performed by preparing binary mixtures of malonic acid Wo Luxi forest with the excipients listed in table 4. These binary (drug: excipient, 1:1) mixtures were stored at 40 ℃/75% Relative Humidity (RH) and assayed for content and related substances at weeks 0, 2 and 4.

Table 4: evaluation of compatibility of excipients with malonic acid Wo Luxi forest

Excipient	Function of
		Lactose monohydrate	Diluent agent
Microcrystalline cellulose	Diluent agent
		Silicified microcrystalline cellulose	Diluent agent
Mannitol (mannitol)	Diluent agent
		Dicalcium phosphate	Diluent agent
Croscarmellose sodium	Disintegrating agent
		Sodium starch glycolate	Disintegrating agent
Magnesium stearate	Lubricant
		Stearic acid	Lubricant
Colloidal silica	Leveling agent
		Crosslinked povidone	Adhesive agent
Povidone	Adhesive agent
		Hydroxypropyl methylcellulose (HPMC)	Adhesive agent
Sodium dodecyl sulfate	Surface active agent
		Poloxamer (poloxamer)	Surface active agent
Polyethylene glycol (PEG)	Solubilizer
		Propylene glycol	Solubilizer

Based on the results of the excipient compatibility study, the excipients listed in table 4 were selected for the initial formulation screening study. It has been previously observed that Wo Luxi and its salts gel upon hydration of the drug and that such gelling affects the disintegration and dissolution of Wo Luxi from the drug formulation. Excipients of the tablet formulation were selected based on their compatibility with malonic acid Wo Luxi forest and their ability to facilitate the manufacture of malonic acid Wo Luxi Lin Pianji and reduce gelation of malonic acid Wo Luxi Lin Pianji.

An initial prototype formulation without sodium bicarbonate was developed and it was found that disintegration and dissolution (in 0.1N HCl medium) were unacceptable due to gelation of this initial formulation. Attempts to change the formulation evaluate the effect of changing the microcrystalline cellulose, lactose, dibasic calcium phosphate and sodium starch glycolate levels to overcome the observed gelation problem. These changes only lead to a minor improvement of the gelation problem. Sodium bicarbonate was then added to the formulation to aid in the disintegration of malonic acid Wo Luxi Lin Pianji, thereby reducing the impact of gelation on the dissolution test.

The development method was to use a common granulation method and to manufacture different tablet strengths by adjusting the total weight of the tablet (table 5).

Table 5: excipients and ranges used in the development of malonic acid Wo Luxi forest tablet formulations

Excipient	Function of	Test Range (% w/w)
			Malonic acid Wo Luxi forest ^a	API	20.36–30.54
Microcrystalline cellulose (PH-102)	Diluent agent	14.32–37.00
			Lactose monohydrate	Diluent agent	8.55–46.46
Dibasic calcium phosphate dihydrate	Diluent agent	0–43.32
			Sodium bicarbonate	Help disintegrate	0–6.92
Sodium starch glycolate	Disintegrating agent	3.5–8.00
			Magnesium stearate	Lubricant	0.87–1.00

^a Correction for accurate amounts of drug substance determination (based on anhydrous, solvent-free base)

Based on the results of the formulation development study, the formulations listed in table 6 were selected and scaled up to a batch size of about 0.3 kg.

Table 6: malonic acid Wo Luxi forest development tablet composition (batch size 0.3 kg)

^a The exact amount of drug substance measured was corrected (based on anhydrous, solvent-free base). The salt conversion factor was 0.8187, so 61.07 mg malonic acid Wo Luxi forest was equal to 50 mg Wo Luxi forest free base.

The formulations listed in table 6 perform as expected in terms of disintegration and dissolution (e.g., gelation is no longer a problem and rapid dissolution is observed), but there is a need to improve the flowability of the blend to ensure manufacturability of the formulation. To improve flowability, colloidal silica (1.0%) was added to the formulation and the final formulation intended for clinical trials was obtained and is listed in table 7.

The final core tablets were coated with 3% w/w Opadry II nonfunctional coating as depicted in table 7.

Table 7: formulations of the present disclosure

^a The exact amount of drug substance measured was corrected (based on anhydrous, solvent-free base). The salt conversion factor was 0.8187, so that 61.07 mg of malonic acid Wo Luxi forest was equal to 50 mg of Wo Luxi forest free base and 122.14 mg of malonic acid Wo Luxi forest was equal to 100 mg of Wo Luxi forest free base.

The manufacturing process was developed as a simple direct compression tablet blend of malonic acid Wo Luxi forest with dibasic calcium phosphate dihydrate, microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, and sodium bicarbonate. Colloidal silica is added to improve the flowability of the blend. The blend was lubricated with magnesium stearate. As the molecules move through the development process, additional process development will take place.

In some embodiments, the use of sodium bicarbonate reduces or eliminates gelation. In some embodiments, the use of dicalcium phosphate with sodium bicarbonate reduces or eliminates gelation. In some embodiments, the use of dicalcium phosphate prevents the tablet from floating. In some embodiments, the ratio of sodium bicarbonate to dicalcium phosphate adjusts the formulation of Wo Luxi forest so that it does not gel, does not float, and has a reproducible dissolution profile. In some embodiments, the combination of tablet size, shape, and formulation prevents the tablet from floating.

Conventional HDPE bottles, induction seal liners, polypropylene child-resistant caps and desiccant cans were selected as container closure systems for malonic acid Wo Luxi forest tablets. As the formulation progresses through the development process, the need for a desiccant will be assessed. Table 8 provides the specifications for 50mg and 100mg malonic acid Wo Luxi forest tablets.

Table 8:50mg and 100mg malonic acid Wo Luxi forest tablet specification

Abbreviations: CFU = colony forming unit; NMT = no more than; USP = united states pharmacopeia; HPLC = high performance liquid chromatography; ^a testing only on release

^b Maximum unspecified degradation products>0.05% area. Peaks designated as synthetic impurities at the time of analysis were excluded.

^c The sum of degradation products is more than or equal to 0.05 percent

Table 9 provides batch analysis data for 50mg malonic acid Wo Luxi Lin Pianji for a development batch produced on a laboratory scale. The formulation differs from the intended clinical formulation in that it does not contain colloidal silica. The manufacturing process for this batch was similar to that described in example 10, except that no colloidal silica was added during processing.

Table 9: batch release data for 50mg and 100mg engineered batches of malonic acid Wo Luxi Lin Pianji

Abbreviations: HPLC = high performance liquid chromatography; RRT = relative retention time; KF = karl fischer; NMT = no more than; USP = united states pharmacopeia

^b Acceptance criteria for applications during development

^c Testing only on release

^d The maximum unspecified degradation product is not less than 0.05% by area. Peaks designated as synthetic impurities at the time of analysis were excluded.

^e The sum of degradation products is more than or equal to 0.05 percent

Table 10 provides batch analysis data for 50mg malonic acid Wo Luxi Lin Pianji for a development batch produced on a laboratory scale. The formulation is a contemplated clinical formulation containing colloidal silica. Example 10 describes the manufacturing process for this batch.

Table 10: batch analysis of malonic acid Wo Luxi forest drug substance, batch 02MEI06-01-107

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Abbreviations: nlt=no less than; NMT = no more than; NMR = nuclear magnetic resonance; HPLC = high performance liquid chromatography; RRT = relative retention time; GC = gas chromatography; ppm = parts per million; ICP-MS = inductively coupled plasma-mass spectrometry; XRPD = X-ray powder diffraction; x = particle size distribution; TBD = unmeasured

Example 10: manufacture of malonic acid Wo Luxi Lin Pianji

Table 11 provides batch formulations for the manufacture of 50mg and 100mg malonic acid Wo Luxi Lin Pianji. Engineered batch sizes range from 1.2 to 1.3kg, but clinical batch sizes will vary based on need.

Table 11: batch formulation g of 50mg and 100mg malonic acid Wo Luxi Lin Pianji

Abbreviations: n/a = inapplicable.

^a The exact amount of drug substance measured was corrected (based on anhydrous, solvent-free base). The salt conversion factor was 0.8187, so 261.72g of malonic acid Wo Luxi forest was equal to 214.3g of Wo Luxi forest free base and 283.53g of malonic acid Wo Luxi forest was equal to 232.1g of Wo Luxi forest free base. Any adjustments to malonic acid Wo Luxi forest were accompanied by adjustments to lactose monohydrate to maintain the target core tablet weight.

^b The amount of 3% target weight gain based on a 1,100 gram tablet lot size included about 2 times the tooling allowance.

^c The target weight of the film coating was increased by 3% and water was removed during processing.

^d The film coating applied to the tablets was a non-pharmacopoeial, proprietary excipient supplied by the carrekang company (Colorcon), and all components were of pharmacopoeial grade.

Malonic acid Wo Luxi forest and all excipients (microcrystalline cellulose, lactose monohydrate, dibasic calcium phosphate dihydrate, sodium bicarbonate, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate) were screened before use (fig. 5).

A blend of microcrystalline cellulose and malonic acid Wo Luxi Lin Zhibei was used. The screened dibasic calcium phosphate dihydrate, sodium bicarbonate and sodium starch glycolate were added to the initial blend and blended. The screened lactose monohydrate and colloidal silica are screened, added to the blend, and blended. Magnesium stearate was screened, added to the blend, and blended. The final blend is tableted using a suitable tablet press. The core tablets were dust removed and passed through a metal detector before being coated with Opadry II 85F18422 white in a suitable pan coater. The coated tablets were inspected before being batched into LDPE (Low Density polyethylene) plastic bags and sealed. This plastic bag was placed in a second plastic bag along with two 100 gram desiccant bags and sealed. The double plastic bag tablets were then placed in a hard sided shipping container. Bulk tablets are transported to a packaging site where they are packaged in desiccant-bearing high density polyethylene bottles and polypropylene seals.

Table 12 presents process control and observations of malonic acid Wo Luxi forest tablet manufacturing.

Table 12: process control of 50mg and 100mg malonic acid Wo Luxi forest tablets

Procedure	Test parameters	Acceptance criterion
			Sheeting	Individual tablet weight	Within + -5% of the target weight
Sheeting	Average tablet weight (based on 10 tablets)	Within + -3.0% of the target weight
			Sheeting	Average hardness (10 pieces)	Reporting results
Sheeting	Average thickness (10 pieces)	Reporting results
			Sheeting	Disintegration (6 tablets)	NMT 3 min
Sheeting	Friability degree of friability	NMT compared to 1.0% loss
			Coating layer	Weight of tablet increases (10 tablets)	Average tablet weight +2-4% (target 3%)

Nmt=no more than

Example 11: dissolution of malonic acid Wo Luxi Lin Pianji

Dissolution testing was performed according to USP <711> using apparatus 2 (paddles with sinkers) at 50 rpm. Because of the sodium bicarbonate contained in the formulation, a sinker was used, which may cause the tablet to float. The dissolution medium was 900ml of 0.1n HCl, which was detected by the isocratic HPLC method described in table 13. The sample time point was 30 minutes. An example chromatogram is shown in fig. 6.

The elution profile of malonic acid Wo Luxi Lin Pianji (50 mg, batch 000011382) was also compared to the elution profile of hydrochloric acid Wo Luxi forest capsule (50 mg, batch XZGC) (table 14 and fig. 7).

Table 13: reversed phase HPLC method for dissolution testing of 50 and 100mg malonic acid Wo Luxi forest tablets

Abbreviations: TFA = trifluoroacetic acid; UV = ultraviolet spectroscopy

Table 14: dissolution time of malonic acid Wo Luxi Lin Pianji and Wo Luxi forest hydrochloride capsules

Example 12: stability of malonic acid Wo Luxi forest tablet

Stability data for development lot 108700C1 was generated (tables 15-17). The formulation differs from the intended clinical formulation in that it does not contain colloidal silica. The manufacturing process for this batch was similar to that described in example 10, except that no colloidal silica was added during the process. Stability study samples were packaged in containers as described in example 9.

Table 15: stability data for 50mg development lot 108700C1 malonic acid Wo Luxi forest tablets stored in HDPE bottles at 25 ℃/60% RH

Abbreviations: NMT = no more than; HPLC = high performance liquid chromatography; RH = relative humidity

^a Maximum unspecified degradation products>0.05% area. Peaks designated as synthetic impurities at the time of analysis were excluded.

^b The sum of degradation products is more than or equal to 0.05 percent

Table 16: stability data for 50mg development lot 108700C1 malonic acid Wo Luxi forest tablets stored in HDPE bottles at 40 ℃/75% RH

^b The sum of degradation products is more than or equal to 0.05 percent

Table 17: stability data for 50mg development lot 108700C1 malonic acid Wo Luxi forest tablets stored in HDPE bottles at 50 ℃/ambient RH

^b The sum of degradation products is more than or equal to 0.05 percent

Stability data for 50mg of development lot 108700C1 for malonic acid Wo Luxi forest tablets showed no significant change in any of the properties tested, stored for three months at 25 ℃/60% Relative Humidity (RH) or 40 ℃/75% RH storage conditions, and for two months at 50 ℃/ambient RH.

Stability data for development lot 02MEI06-01-107 was generated (tables 18 and 19). The formulation contains colloidal silica. The manufacturing process for this batch was similar to that described in example 10. Stability study samples were packaged in containers as described in example 9.

Table 18: stability data for malonic acid Wo Luxi Lin Pici 02MEI06-01-107 at 25℃and 60% RH

Abbreviations: HPLC = high performance liquid chromatography; KF = karl fischer; nlt=no less than; XRPD = X-ray powder diffraction; RRT = relative retention time; RH = relative humidity

^a The acceptance criteria listed are criteria for testing the batch at release.

Table 19: stability data for malonic acid Wo Luxi Lin Pici 02MEI06-01-107 at 40 ℃/75% RH

Abbreviations: HPLC = high performance liquid chromatography; KF = karl fischer; nlt=no less than; XRPD = X-ray powder diffraction; RRT = relative retention time; RH = relative humidity; "-" =below the reporting threshold.

Tables 18 and 19 present stability data obtained from malonic acid Wo Luxi forest of lot 02MEI 06-01-107. No significant change was observed after 6 months of storage under long term conditions (25 ℃/60% Relative Humidity (RH)) or after 6 months of storage under accelerated conditions (40 ℃/75% RH).

Table 20 shows the stability profile of 50 mg development lot 108700C1 malonic acid Wo Luxi forest tablets. This batch was manufactured in the laboratory and was different from the intended clinical formulation because it did not contain colloidal silica. The manufacturing process for this batch was similar to that described in example 10, except that no colloidal silica was added during the process. The batches were tested by the analytical procedure described herein. Stability study samples were packaged in the containers described in example 9, except 7 tablets per bottle instead of 14.

Table 20:50 Experimental parameters for stability study of mg development batch 108700C1 malonic acid Wo Luxi forest tablets

() Time point of choice =

X = appearance, measurement and organic impurities, moisture content and dissolution

RH = relative humidity

Table 21 shows stability profiles for laboratory scale manufactured 50 mg and 100mg malonic acid Wo Luxi Lin Pianji (engineered batches 0000113822 and 0000113823). These batches were made according to the process described in example 10. The batches were tested by the analytical procedure described herein. Stability study samples were packaged in the containers described in example 9, except 7 tablets per bottle instead of 14.

Table 21:50 Determination parameters for stability studies of mg and 100mg malonic acid Wo Luxi Lin Pianji (engineered batches 0000113822 and 0000113823)

R = release test;

x = appearance, assay and organic impurities, moisture content and dissolution;

c=occasional. Store the sample but only test if the accelerated test fails

- =unplanned;

RH = relative humidity

A first batch of 50 mg and 100mg malonic acid Wo Luxi forest tablets for clinical trials were manufactured according to the process described in example 10 and stability tests were performed according to the protocol shown in table 22. Stability study samples were packaged in containers (14) as described in example 9.

Table 22:50 Determination parameters for stability studies of mg and 100 mg clinical batches of malonic acid Wo Luxi forest tablets

R = release test;

m = microbial limit and specified microbes;

x = appearance, assay and organic impurities, moisture content and dissolution;

c=occasional. Store the sample but only test if the accelerated test fails

- =unplanned;

RH = relative humidity

Stability data for the 50mg development lot 108700C1 malonic acid Wo Luxi forest tablets presented in tables 15-17 showed no significant change in any of the properties tested, stored for three months at 25 ℃/60% Relative Humidity (RH) or 40 ℃/75% RH storage conditions, and for two months at 50 ℃/ambient RH.

Example 13: properties of malonic acid Wo Luxi forest

The chemical name (IUPAC) of malonic acid Wo Luxi forest is (2 r,3 s) -3- (2- (2-chloro-4- (trifluoromethyl) phenyl) -5, 7-dihydroxy-4-oxo-4H-chromen-8-yl) -2- (hydroxymethyl) -1-methylpyrrolidin-1-ium-2-carboxyacetate. Common synonyms for malonic acid Wo Luxi are (2R, 3S) -3- (2- (2-chloro-4- (trifluoromethyl) phenyl) -5, 7-dihydroxy-4-oxo-4H-chromen-8-yl) -2- (hydroxymethyl) -1-methylpyrrolidin-1-ium malonate and 2- (2-chloro-4- (trifluoromethyl) phenyl) -5, 7-dihydroxy-8- ((2R, 3S) -2- (hydroxymethyl) -1-methylpyrrolidin-3-yl) -4H-chromen-4-one malonate. Table 23 provides some general properties of malonic acid Wo Luxi forest.

Table 23: general Properties of malonic acid Wo Luxi forest

Abbreviations: DMSO = dimethyl sulfoxide; meoh=methanol; DSC = differential scanning calorimetry.

Table 24: solubility of malonic acid Wo Luxi forest in a biologically relevant medium in pH range

Abbreviations: faSSGF = fasted state simulated gastric fluid; FEDGAS = feeding status simulated gastric fluid; feSSIF = fed state simulated intestinal fluid; faSSIF = fasted state simulated intestinal fluid.

^a Duplicate tests were performed on the samples and two values were recorded.

The solubility and gelation exhibited by Wo Luxi forest depends on a number of factors, including concentration (of the suspension used for solubility measurement), pH, and buffer system. Generally, wo Luxi forest forms gelling more easily when the suspension concentration is >5mg/mL and the solubility is >0.5 mg/mL. Gelation was observed at pH 1.6 (FaSSGF) and pH 6.5 (FaSSIF) (Table 24).

X-ray crystallography

Single crystal measurements were performed on a Nonius Kappa-CCD instrument. Data was collected at 296K. Global volume data was collected when θ=27.5° was reached, yielding 20755 reflections (5650 independent). Data reduction was performed using HKL Scalepak and cell parameters were obtained from 26946 reflections in the θ range 1 to 27.5 ° using Denzo and Scalepak. The structure is solved by SHEXT-2014/7 using a direct method. The structure was refined by least squares full matrix refinement using SHELXL-2014/7. During refinement, it is evident that the trifluoromethyl and alcohol groups of the malonic acid Wo Luxi Lin Yang ion are disordered into two positions. The application model of disorder is refined anisotropically, with the same thermal parameters for all atoms in the disordered group. All H atoms are implemented from molecular geometry (C and N linked) or hydrogen bond based geometry. During refinement, all H atoms retain 150% or 120% of the adjacent non-H atom thermal parameters. The absolute configuration was established using the fly parameter, which had a value of x=0.06±0.05, and was determined using 1377 quotients [ (i+) - (I-) ]/[ (i+) + (I-) ]. The X-ray crystal structure confirmed the chemical structure of malonic acid Wo Luxi forest (fig. 8B).

Malonic acid Wo Luxi forest (form 1) crystallized in the monoclinic central symmetry space group P21 with one Active Pharmaceutical Ingredient (API) molecule and one malonic acid molecule in the asymmetric unit (table 22). The stereocenters of C3 and C8 are R and R, respectively _S Configuration. The data confirm the expected chemical structure shown in fig. 8A-8B. Table 25 reports the crystallization data showing the final refinement parameters.

Table 25: crystallization data for malonic acid Wo Luxi forest (ME-522) (form 1)

To confirm that the determined single crystal structure represents bulk material, a simulated powder plot of single crystal data was compared to a high resolution X-ray powder diffraction (HR-XRPD) plot obtained from bulk material (fig. 9). The matching XRPD patterns confirm that the single crystal obtained and the Wo Luxi forest of the received batch (batch 20-07211) are of the same form (form 1).

Amorphous malonic acid Wo Luxi forest was prepared by freeze drying a free base solution containing an equimolar amount of malonic acid. The polymorph screening experiments were started with amorphous malonic acid Wo Luxi forest to favor unbiased crystallization. Form 1 is the most commonly observed form. Form 1 is anhydrous and non-hygroscopic. Three other forms were observed, but only under specific recrystallization conditions, and all three new crystalline forms appeared to be hydrates. All three forms are physically unstable and convert to form 1 when dried under vacuum or exposed to stress conditions (40 ℃/75% relative humidity).

The single crystal structure of malonic acid Wo Luxi forest (form 1) is a monoclinic central symmetry space group P21 (fig. 8B), in which there is one API molecule and one malonic acid molecule in the asymmetric unit. The XRPD diffractogram of form 1 is presented in figure 10 and the characteristic peaks are listed in table 26.

Table 26: XRPD peak data

Example 14: synthesis of malonic acid Wo Luxi forest

Fig. 11 provides a scheme depicting the synthesis of malonic acid Wo Luxi forest, while fig. 12 provides a flow chart of the manufacturing process of malonic acid Wo Luxi forest.

Synthesis of intermediate 1

Acetic acid was charged to the reactor, followed by the addition of acetic anhydride (fig. 13A). RSM-1 was charged to the reactor and once the addition was complete, stirring was continued until the reaction was deemed complete by consumption of RSM-1. The reaction solution was treated with boron trifluoride diethyl etherate. Once the addition is complete, the reactor contents are heated with agitation until intermediate 1a is consumed.

The reaction mixture was cooled, and methylene chloride was added to the reaction mixture, followed by addition of an aqueous sodium carbonate solution. Once the addition is complete, the reaction mixture is stirred at a rate that ensures adequate mixing of the two-phase mixture. Agitation was stopped to separate the phases. The organic phase (bottom layer) was separated and filled into separate containers. The remaining aqueous phase was treated with methylene chloride and stirred at a rate that ensured proper mixing of the two phase mixture. Agitation was stopped to separate the phases. The organic phase (bottom layer) was separated and combined with the first organic phase. The aqueous phase was removed and the combined organic phases were charged back to the reactor and washed twice with aqueous sodium chloride. The reaction solution was concentrated by vacuum distillation. Methylene chloride was added to the reaction mixture and used in the next step.

Synthesis of intermediate 2

Methylene chloride, RSM-2 and diatomaceous earth were charged to the reactor and treated with dimethylformamide (fig. 13B). Oxalyl chloride was added to the reaction mixture and stirred. The reaction mixture was filtered, and the filtrate was concentrated by vacuum distillation. Methylene chloride was charged to the reactor containing intermediate 2 and stirred until a homogeneous solution was obtained. Intermediate 2 dissolved in dichloromethane was used for the next step.

Synthesis of intermediate 3

Methylene chloride and intermediate 1 were charged to the reactor and stirred while the internal temperature was adjusted to 0 ℃ (fig. 13C). Triethylamine was charged to the reactor followed by the addition of intermediate 2. Once the addition was complete, the reaction was stirred until intermediate 1 was consumed. Water was added to the reaction solution with stirring to quench the residual acid chloride. Agitation was stopped to separate the phases. The organic phase (bottom layer) was separated and filled into separate containers.

The remaining aqueous phase was treated with methylene chloride and stirred at a rate that ensured proper mixing of the two phase mixture. Agitation was stopped to separate the phases. The organic phase (bottom layer) was separated and combined with the first organic phase. The aqueous phase was removed and the combined organic phases were charged back to the reactor and washed with aqueous sodium bicarbonate solution and then with sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. 2-methyltetrahydrofuran was added to intermediate 3 and used in the next step.

Synthesis of intermediate 4

Sodium hydride and 2-methyltetrahydrofuran were charged to the reactor, and the reaction mixture was cooled to 0 ℃ (fig. 13D). Intermediate 3 was added to the reaction mixture while maintaining a constant internal temperature of 0 ℃. Once the addition is complete, the reactor contents are heated with agitation until intermediate 3 is consumed.

The reaction mixture was then cooled and treated with a solution in HCl 2-propanol (IPA). The reaction mixture was concentrated by vacuum distillation and treated with hydrochloric acid. The mixture was stirred until the reaction was deemed complete and then treated with 2-methyltetrahydrofuran. The reaction mixture was treated with an aqueous solution of sodium carbonate and methylene chloride and stirred at a rate that ensured adequate mixing of the two phase mixture.

Agitation was stopped to separate the phases. The organic phase (bottom layer) was separated and filled into separate containers. The remaining aqueous phase was treated with dichloromethane and stirred to ensure proper mixing of the two phase mixture. The aqueous phase was removed and the combined organic phases were charged back to the reactor and washed twice with aqueous sodium chloride. The organic phase was separated, dried over sodium sulfate and filtered.

The filtrate is usedTreated, filtered and concentrated by vacuum distillation. The concentrated reaction mixture was treated with isopropyl acetate to promote solid precipitation, which was then collected by vacuum filtration. The wet cake was washed with isopropyl acetate/heptane solution and dried to give intermediate 4.

Synthesis of intermediate 5

Intermediate 4, pyridine hydrochloride and pyridine were charged to the reactor and heated to reflux until the reaction mixture became homogeneous (fig. 13E). The mixture was stirred until intermediate 4, intermediate 4a and intermediate 4b were consumed. The reaction mixture was concentrated by atmospheric distillation and treated with methanol. The crude reaction mixture was then treated with aqueous sodium bicarbonate, at which time solids precipitated from the reaction mixture. The solid was collected by vacuum filtration, washed with water and heptane, and dried to give intermediate 5.

Synthesis of malonic acid Wo Luxi forest

Intermediate 5 and acetone were charged to the reactor and heated with stirring to reflux until the reaction mixture became homogeneous (fig. 13F). The reaction solution was treated with malonic acid and stirred at reflux temperature. The reaction mixture was cooled to 20 ℃ and held at this temperature until the solids began to precipitate. After additional stirring, the solid was collected by vacuum filtration and washed with acetone. The wet cake was dried under vacuum to give malonic acid Wo Luxi forest.

In some embodiments, any term herein may depend on any independent term or any dependent term. In one aspect, any clause (e.g., dependent or independent clause) may be combined with any other one or more clauses (e.g., dependent or independent clause). In one aspect, a claim may contain some or all of the words (e.g., steps, operations, means or components) recited in a clause, sentence, phrase or paragraph. In one aspect, a claim may contain some or all of the words recited in one or more clauses, sentences, phrases or paragraphs. In one aspect, some words in each clause, sentence, phrase, or paragraph may be deleted. In one aspect, additional words or elements may be added to a clause, sentence, phrase, or paragraph. In one aspect, the subject technology may be implemented without utilizing some of the components, elements, functions or operations described herein. In one aspect, the subject technology may be implemented with additional components, elements, functions, or operations.

The previous description is provided to enable any person skilled in the art to practice the various configurations described herein. While the subject technology has been described in detail with reference to various figures and configurations, it should be understood that these are for illustrative purposes only and should not be taken as limiting the scope of the subject technology.

There are many other ways in which the subject technology may be implemented. The various functions and elements described herein may be partitioned differently from those shown without departing from the scope of the subject technology. Various modifications to these configurations will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other configurations. Accordingly, many changes and modifications may be made to the subject technology by one of ordinary skill in the art without departing from the scope of the subject technology.

It should be understood that the specific order or hierarchy of steps in the processes disclosed is an illustration of exemplary approaches. Based on design preferences, it is understood that the specific order or hierarchy of steps in the processes may be rearranged. Some steps may be performed simultaneously. The accompanying method claims present elements of the various steps in a sample order, and are not meant to be limited to the specific order or hierarchy presented.

As used herein, the term "about" preceding an amount indicates a difference in the amount. The differences may be due to manufacturing tolerances or may be based on differences in measurement techniques. In some cases, the difference from the listed values may be as high as 10%. Those of ordinary skill in the art will appreciate that the particular amount of difference may be contextually relevant and, thus, for example, the micrometer or nanometer scale dimensional difference may be different than the meter scale difference.

As used herein, the phrase "…, at least one of which precedes a series of items, separates any item by the term" and "or" and modifies the list as a whole, rather than each member of the list (i.e., each item). The phrase "at least one of …" does not require selection of at least one of each item listed; rather, the meaning allowed by the phrase includes at least one of any one, and/or at least one of any combination of items, and/or at least one of each. For example, the phrase "at least one of A, B and C" or "at least one of A, B or C" each refer to a alone, B alone, or C alone; A. any combination of B and C; and/or at least one of A, B and C.

Terms such as "top," "bottom," "front," "rear," and the like as used in this disclosure should be understood to refer to any frame of reference, not the ordinary gravitational frame of reference. Thus, the top, bottom, front and rear surfaces may extend upwardly, downwardly, diagonally or horizontally in the gravitational frame of reference.

Furthermore, to the extent that the terms "includes," "including," "has," and the like are used in either the description or the claims, such terms are intended to be inclusive in a manner similar to the term "comprising" as "comprising" is interpreted when employed as a transitional word in a claim.

The word "exemplary" means "serving as an example, instance, or illustration" in this document. Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments.

Unless specifically stated otherwise, reference to a singular element does not mean "one and only one" but "one or more". Male pronouns (e.g., his) include female and neutral sexes (e.g., her and its (it)), and vice versa. The term "some" means one or more. The underlined and/or italicized headings and subheadings are for convenience only, do not limit the subject technology, and are not associated with the interpretation of the subject technology description. All structural and functional equivalents to the elements of the various configurations described throughout this disclosure that are known or later come to be known to those of ordinary skill in the art are expressly incorporated herein by reference and are intended to be encompassed by the subject technology.

Claims

1. A formulation comprising about 15% to about 35% w/w malonic acid Wo Luxi forest (voruciclib malonate) and one or more pharmaceutically acceptable excipients.

2. The formulation of claim 1, comprising about 18% to about 30% w/w malonic acid Wo Luxi forest.

3. The formulation of claim 1, comprising about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, or about 28% w/w malonic acid Wo Luxi forest.

4. The formulation of claim 1, comprising about 20% to about 23% w/w malonic acid Wo Luxi forest.

5. The formulation of any one of claims 1 to 4, wherein the one or more pharmaceutically acceptable excipients comprises about 5% to about 37% w/w microcrystalline cellulose.

6. The formulation of any one of claims 1 to 4, wherein the one or more pharmaceutically acceptable excipients comprises about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% w/w microcrystalline cellulose.

7. The formulation of any one of claims 1 to 6, wherein the one or more pharmaceutically acceptable excipients comprises about 1% to about 48% w/w lactose monohydrate.

8. The formulation of any one of claims 1 to 6, wherein the one or more pharmaceutically acceptable excipients comprises about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% w/w lactose monohydrate.

9. The formulation of any one of claims 1 to 8, wherein the one or more pharmaceutically acceptable excipients comprises about 20% to about 70% w/w dibasic calcium phosphate dihydrate.

10. The formulation of any one of claims 1 to 8, wherein the one or more pharmaceutically acceptable excipients comprises about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50% w/w dibasic calcium phosphate dihydrate.

11. The formulation of any one of claims 1 to 10, wherein the one or more pharmaceutically acceptable excipients comprises about 0.1% to about 15% w/w sodium bicarbonate.

12. The formulation of any one of claims 1 to 10, wherein the one or more pharmaceutically acceptable excipients comprises about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% w/w sodium bicarbonate.

13. The formulation of any one of claims 1 to 12, wherein the one or more pharmaceutically acceptable excipients comprises about 1% to about 20% w/w sodium starch glycolate.

14. The formulation of any one of claims 1 to 12, wherein the one or more pharmaceutically acceptable excipients comprises about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% w/w sodium starch glycolate.

15. The formulation of any one of claims 1 to 14, wherein the one or more pharmaceutically acceptable excipients comprises about 0.01% to about 10% w/w magnesium stearate.

16. The formulation of any one of claims 1 to 14, wherein the one or more pharmaceutically acceptable excipients comprises about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 3%, about 4%, or about 5% w/w magnesium stearate.

17. The formulation of any one of claims 1 to 16, wherein the one or more pharmaceutically acceptable excipients comprises about 0.01% to about 10% w/w colloidal silica.

18. The formulation of any one of claims 1 to 16, wherein the one or more pharmaceutically acceptable excipients comprises about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 3%, about 4%, or about 5% w/w colloidal silica.

19. The formulation of any one of claims 1 to 18, wherein the formulation is included into a tablet.

20. The formulation of claim 19, wherein the tablet is coated with a film coating.

21. The formulation of any one of claims 1 to 20, wherein malonic acid Wo Luxi forest comprises a crystalline form of malonic acid Wo Luxi forest characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from 7.30 ° ± 0.2 °, 13.58 ° ± 0.2 °, 14.06 ° ± 0.2 °, 15.18 ° ± 0.2 °, 15.66 ° ± 0.2 °, 17.50 ° ± 0.2 °, 18.94 ° ± 0.2 °, 19.54 ° ± 0.2 °, 22.22 ° ± 0.2 °, 23.38 ° ± 0.2 °, 24.10 ° ± 0.2 °, 24.98 ° ± 0.2 °, 25.94 ° ± 0.2 °, 27.26 ° ± 0.2 ° and 32.82 ° ± 0.2 ° 2Θ.

22. The formulation of any one of claims 1 to 20, wherein malonic acid Wo Luxi forest comprises a crystalline form of malonic acid Wo Luxi forest, said crystalline form characterized by an X-ray powder diffraction pattern, the X-ray powder diffraction pattern includes a peak selected from the group consisting of 6.36 ° ± 0.2 ° 2θ, 13.88 ° ± 0.2 ° 2θ, 7.31 ° ± 0.2 ° 2θ, 9.34 ° ± 0.2 ° 2θ, 10.05 ° ± 0.2 ° 2θ, 13.59 ° ± 0.2 ° 2θ, 14.08 ° ± 0.2 ° 2θ, 15.21 ° ± 0.2 ° 2θ, 15.67 ° ± 0.2 ° 2θ, 17.53 ° ± 0.2 ° 2θ, 18.70 ° ± 0.2 ° 2θ, 18.98 ° ± 0.2 ° 2θ, 19.38 ° ± 0.2 ° 2θ, 19.67 ° ± 0.2 ° 2θ, 20.16 ° ± 0.2 ° 2θ, 20.39 ° ± 0.2 ° 2θ, 21.01 ° ± 0.2 ° 2θ, 22.27 ° ± 0.2 ° 2θ, 23.35 ° ± 0.24 ° ± 24.27 ° ± 0.25 ° ± 2 ° 2θ, and a peak.

23. The formulation of claim 21 or 22, wherein the crystalline form is a crystalline anhydrate.

24. The formulation of claim 21 or 22, wherein the crystalline form is a crystalline hydrate.

25. A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective formulation according to any one of claims 1 to 24.

26. A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective formulation comprising about 15% to 35% w/w malonic acid Wo Luxi forest, about 5% to 37% w/w microcrystalline cellulose, about 1% to about 48% w/w lactose monohydrate, about 20% to about 70% w/w dibasic calcium phosphate dihydrate, about 0.1% to about 15% w/w sodium bicarbonate, about 1% to about 20% w/w sodium starch glycolate, and about 0.01% to about 10% w/w magnesium stearate.

27. The method of claim 26, wherein the malonic acid Wo Luxi forest comprises a crystalline form of malonic acid Wo Luxi forest characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.30 ° ± 0.2 °, 13.58 ° ± 0.2 °, 14.06 ° ± 0.2 °, 15.18 ° ± 0.2 °, 15.66 ° ± 0.2 °, 17.50 ° ± 0.2 °, 18.94 ° ± 0.2 °, 19.54 ° ± 0.2 °, 22.22 ° ± 0.2 °, 23.38 ° ± 0.2 °, 24.10 ° ± 0.2 °, 24.98 ° ± 0.2 °, 25.94 ° ± 0.2 °, 27.26 ° ± 0.2 °, 28.50 ° ± 0.2 ° and 32.82 ° ± 0.2 ° 2Θ.

28. The method of claim 26 or 27, wherein the malonic acid Wo Luxi forest comprises a crystalline form of malonic acid Wo Luxi forest, said crystalline form characterized by an X-ray powder diffraction pattern, the X-ray powder diffraction pattern includes a peak selected from the group consisting of 6.36 ° ± 0.2 ° 2θ, 13.88 ° ± 0.2 ° 2θ, 7.31 ° ± 0.2 ° 2θ, 9.34 ° ± 0.2 ° 2θ, 10.05 ° ± 0.2 ° 2θ, 13.59 ° ± 0.2 ° 2θ, 14.08 ° ± 0.2 ° 2θ, 15.21 ° ± 0.2 ° 2θ, 15.67 ° ± 0.2 ° 2θ, 17.53 ° ± 0.2 ° 2θ, 18.70 ° ± 0.2 ° 2θ, 18.98 ° ± 0.2 ° 2θ, 19.38 ° ± 0.2 ° 2θ, 19.67 ° ± 0.2 ° 2θ, 20.16 ° ± 0.2 ° 2θ, 20.39 ° ± 0.2 ° 2θ, 21.01 ° ± 0.2 ° 2θ, 22.27 ° ± 0.2 ° 2θ, 23.35 ° ± 0.24 ° ± 24.27 ° ± 0.25 ° ± 2 ° 2θ, and a peak.

29. The method of any one of claims 26 to 28, wherein the formulation comprises about 0.01% to about 10% w/w colloidal silica.

30. The method of any one of claims 26 to 29, wherein the formulation is included into a tablet and the tablet is coated with a film coating.

31. The method of any one of claims 25 to 30, wherein the disease or disorder is a hematological cancer.

32. The method of claim 31, wherein the blood cancer is selected from Acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), acute Lymphocytic Lymphoma (ALL), chronic Lymphocytic Leukemia (CLL), non-Hodgkin's lymphoma (non-Hodgkin's lymphoma), B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small Lymphocytic Lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, burkitt's lymphoma (Burkitt's lymphoma), lymphoplasmacytoid lymphoma, primary central nervous system lymphoma, T-cell lymphoma, precursor T-lymphoblastic lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, adult chronic T-cell lymphoma, adult T-cell lymphoma, tl-cell lymphoma, anaplastic T-cell lymphoma, and anaplastic lymphoma (anaplastic lymphoma, acute T-cell lymphoma, anaplastic tumor, and il-associated lymphomas).

33. The method of any one of claims 25-32, wherein the formulation is administered to the subject such that the subject receives a daily dose of Wo Luxi between about 50mg and about 100mg, between about 100mg and about 150mg, between about 150mg and about 200mg, between about 200mg and about 250mg, between about 250mg and about 300mg, between about 300mg and about 350mg, between about 350mg and about 400mg, between about 400mg and about 450mg, between about 450mg and about 500mg, between about 500mg and about 550mg, between about 550mg and about 600mg, between about 600mg and about 650mg, between about 650mg and about 700mg, between about 700mg and about 750mg, between about 750mg and about 800mg, between about 800mg and about 850mg, between about 850mg and about 900mg, between about 900mg and about 950mg, or between about 950mg and about 1,000 mg.

34. The method of any one of claims 25-32, wherein the formulation is administered to the subject such that the subject receives a daily Wo Luxi forest dose of about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, about 700mg, about 750mg, about 800mg, about 850mg, about 900mg, about 950mg, or about 1,000 mg.

35. The method of any one of claims 25-32, wherein the formulation is administered to the subject such that the subject receives a daily Wo Luxi forest dose of about 200mg or about 250 mg.

36. The method of any one of claims 25-32, wherein the formulation is administered to the subject such that the subject receives a daily Wo Luxi forest dose of no more than 350 mg.

37. The method of any one of claims 33 to 36, wherein the Wo Luxi forest dose is a Wo Luxi forest free base dose.

38. The method of any one of claims 25-37, wherein the formulation is administered to the subject daily for about one day, about two days, about three days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

39. The method of any one of claims 25-37, wherein the formulation is administered to the subject daily for about one week, about two weeks, about three weeks, or about 4 weeks.

40. The method of any one of claims 25 to 39, wherein administration of the formulation is suspended for about one day, about two days, about three days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

41. The method of any one of claims 25-39, wherein administration of the formulation is suspended for about one week, about two weeks, about three weeks, or about 4 weeks.

42. The method of any one of claims 25 to 41, wherein the formulation is administered to the subject on a14 day/14 day off schedule.

43. The method of any one of claims 25 to 42, wherein the formulation is administered for about one month, about two months, about three months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months.

44. The method of any one of claims 25-43, wherein the formulation is administered in combination with a BCL-2 inhibitor.

45. The method of claim 44, wherein the BCL-2 inhibitor is selected from the group consisting of Navinatoclax, venetoclax, A-1155463, A-1331852, ABT-737, obaketamax, S44563, TW-37, A-1210477, AT101, HA14-1, BAM7, sha Butuo g (sabutoclax), UMI-77, gambogic acid, maritoclax, MIM1, methylprednisolone, iMAC2, bax inhibitor peptide V5, bax inhibitor peptide P5, bax channel blocker and ARRY 520 trifluoroacetate or a pharmaceutically acceptable salt of any of these.

46. The method of claim 44, wherein the BCL-2 inhibitor is valnemulin or a pharmaceutically acceptable salt thereof.

47. The method of any one of claims 44-46, wherein the BCL-2 inhibitor is administered to the subject daily for about one day, about two days, about three days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

48. The method of any one of claims 44-46, wherein the BCL-2 inhibitor is administered to the subject daily for about one week, about two weeks, about three weeks, or about 4 weeks.

49. The method of any one of claims 44 to 48, wherein administration of the BCL-2 inhibitor is suspended for about one day, about two days, about three days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

50. The method of any one of claims 44-48, wherein administration of the BCL-2 inhibitor is suspended for about one week, about two weeks, about three weeks, or about 4 weeks.

51. The method of any one of claims 44 to 50, wherein the BCL-2 inhibitor is administered to the subject on a 14 day/14 day off schedule.

52. The method of any one of claims 44 to 51, wherein the BCL-2 inhibitor is administered to the subject for about one month, about two months, about three months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months.