Cedazuridine combination preparation

Abstract

The present disclosure relates generally to pharmaceutical dosage forms comprising azacitidine and cedazuridine.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 312,712, filed February 22, 2022, U.S. Provisional Application No. 63 / 312,714, filed February 22, 2022, and U.S. Provisional Application No. 63 / 377,312, filed September 27, 2022, each of which is incorporated by reference in its entirety.

[0002] The present disclosure relates to a combination formulation comprising azacitidine or a pharma- ceutically acceptable salt thereof and cedazuridine or a pharma- ceutically acceptable salt thereof. [Background technology]

[0003] Cancer is a global health problem, with the World Health Organization estimating that in 2020, nearly 10 million people died from cancer worldwide. Every cancer type requires a specific treatment regimen, and cancers may develop resistance to certain treatments. Combination therapies can reduce the development of resistance, improve overall survival (OS), and / or delay disease progression (progression-free survival (PFS)).

[0004] It has been shown that cancers that acquire resistance to cytidine analogue drugs often overexpress cytidine deaminase (CDA) (Leuk. Res. 1990, 14, 751-754). Leukemia cells expressing high levels of CDA can become resistant to cytosine metabolic antagonists, thereby limiting the antitumor activity of such therapeutic agents (Biochem. Pharmacol. 1993, 45, 1857-1861). Inhibitors of CDA are useful in combination chemotherapy regimens that include cytidine analogue drugs.

[0005] No increase in fetal hemoglobin (Hb F) levels was found when the cytidine analog drug azacitidine was orally administered (8 mg / kg) to repeatedly bled baboons (PCV <20%), indicating very low oral bioavailability (DeSimone et al (1985) Amer. J. of Hem. 18:283-288). The low bioavailability of cytidine analogs is likely due to degradation of cytidine analogs by cytidine deaminase as well as their inherent chemical instability in the acidic gastric environment. To date, only one orally administered azacitidine product has been approved, showing an average oral bioavailability of approximately 11% compared to subcutaneous administration. There is a need for formulations of cytidine analogs such as azacitidine that can increase the bioavailability of azacitidine.

[0006] Fixed-dose combination (FDC) formulations are also desirable because they can reduce the medication burden for patients undergoing combination chemotherapy and improve patient compliance with treatment regimens. There is a need for FDC formulations that include a combination of a cytidine analog and a CDA inhibitor. Summary of the Invention

[0007] It has been reported that some cytidine analogs (e.g., 5-azacitidine) are acid-unstable, and enteric coating of such drugs has been introduced. For example, see US2004 / 0162263. It has now been discovered that the intestinal release of azacitidine increases the bioavailability of azacitidine, and that coadministration with the CDA inhibitor cedazuridine further increases the bioavailability of azacitidine. The gastric release of cedazuridine further enhances the absorption-increasing effect of azacitidine, allowing the amount of oral azacitidine to be reduced. The present disclosure provides a fixed-dose combination (FDC) formulation that allows for the immediate release of cedazuridine and the delayed intestinal release of azacitidine, thereby achieving a desired level of azacitidine bioavailability with a reduced amount of azacitidine.

[0008] In one embodiment, the present disclosure provides a pharmaceutical dosage form comprising cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, wherein the cedazuridine is formulated for immediate release and at least a portion of the azacitidine is formulated for modified release and provided as an enteric coated minitablet or pellet. In some embodiments, the cedazuridine is formulated for immediate release. In some embodiments, substantially all of the azacitidine is configured to be released outside the stomach.

[0009] Provided herein is a pharmaceutical dosage form comprising cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, wherein the cedazuridine is formulated for immediate release and the azacitidine is formulated as a modified release minitablet having an enteric coating. In some embodiments, the cedazuridine is provided as an uncoated minitablet, pellet, or powder.

[0010] Provided herein is a capsule comprising one or more modified release formulated azacitidine minitablets and immediate release cedazuridine in the form of uncoated powder or minitablets.The azacitidine minitablets comprise azacitidine or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and an enteric coating.The immediate release cedazuridine comprises cedazuridine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] Provided herein is a method of treating cancer in a patient comprising administering a pharmaceutical dosage form. Also provided herein is a pharmaceutical dosage form for use in the treatment of cancer or for use in the manufacture of a medicament for the treatment of cancer. Also provided herein is the use of a pharmaceutical dosage form for the treatment of cancer or for the manufacture of a medicament for the treatment of cancer. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows the dissolution release profile of azacitidine from coated FDC tablets containing cedazuridine and azacitidine with 12% or 15% (coating) weight gain of one embodiment at pH 6.8.

[0013] [Diagram 2] FIG. 1 shows the dissolution release profile of azacitidine from capsules containing uncoated or coated azacitidine minitablets of one embodiment at pH 6.8.

[0014] [Diagram 3] 1 shows the dissolution profiles of azacitidine from capsules containing 50% azacitidine (10 mg) uncoated (immediate release) and 50% azacitidine (10 mg) coated (delayed release) azacitidine minitablets of one embodiment at pH 6.8.

[0015] [Figure 4] 1 shows the dissolution profile of azacitidine from a capsule containing one embodiment of uncoated azacitidine minitablets at a 1:1 or 1:2 ratio of coated azacitidine minitablets at pH 6.8.

[0016] [Diagram 5] 1 shows the dissolution profile of azacitidine from a capsule containing an embodiment of azacitidine minitablets having 15% or 20% (coating) weight gain at pH 6.8.

[0017] [Figure 6]1 shows the dissolution release profile of azacitidine from capsules containing one embodiment of uncoated cedazuridine minitablets and azacitidine minitablets coated with 75:25 and 80:20 ethylcellulose with intragranular and extragranular layers at pH 6.8 (wg refers to weight gain from coating).

[0018] [Figure 7] 1 shows dissolution data for coated azacitidine minitablets of one embodiment from pH 1 to pH 6.8.

[0019] [Figure 8] 1 shows dissolution data for coated azacitidine minitablets of one embodiment from pH 1 to pH 6.8.

[0020] [Figure 9] 1 shows the dissolution profile of an embodiment of immediate release cedazuridine minitablets from pH 1 to pH 6.8.

[0021] [Figure 10] 1 shows the dissolution profile of coated azacitidine minitablets of one embodiment from pH 1 to pH 6.8.

[0022] [Figure 11] 1 shows the dissolution profile of coated azacitidine minitablets of one embodiment at pH 2.3, 3.0, 4.5, 5.2, 5.5, and 6.0.

[0023] [Figure 12] 1 shows the time profiles of mean azacitidine concentrations for the three groups on days 1 and 2 in a monkey pharmacokinetic (PK) study.

[0024] [Figure 13]1 shows the time profiles of mean cedazuridine concentrations in the three groups on days 1 and 2 in a monkey pharmacokinetic (PK) study.

[0025] [Figure 14] 1 shows the time profiles of mean azacitidine concentrations for the three groups on days 1 and 2 in a monkey pharmacokinetic (PK) study.

[0026] [Figure 15] 1 shows the mean azacitidine concentration profile of minitablets coated with a 15% weight gain in an 80 / 20 ratio from the Part 1 PK study.

[0027] [Figure 16] 1 shows the mean azacitidine concentration profile of minitablets coated with a 20% weight gain in a 75 / 25 ratio from the Part 2 PK study.

[0028] [Figure 17] 1 shows the azacitidine mean concentration profile of 5.3% Eudragit® coated azacitidine minitablets from a monkey PK study.

[0029] [Figure 18A] 1 shows the dissolution profile of cedazuridine from a capsule of one embodiment.

[0030] [Figure 18B] 1 shows the dissolution profile of azacitidine from a capsule of one embodiment.

[0031] [Figure 19] 1 shows plasma exposure for cedazuridine from a pharmacokinetic (PK) study in monkeys.

[0032] [Figure 20] 1 shows plasma exposure for azacitidine from a PK study in monkeys.

[0033] It will be appreciated that some or all of the drawings are schematic representations for illustrative purposes. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] Attempts to increase the bioavailability of cytosine analogs are described, for example, in US Patent Publication No. 2004 / 0162263 (Sands, et al.). This publication discloses the delivery of decitabine in an enteric coated formulation such that the drug is preferably absorbed in the upper regions of the small intestine, such as the jejunum. US Patent Publication No. 2008 / 0057086 (Pharmion) describes the delivery of azacitidine to the upper regions of the large intestine. The bioavailability of an 80 mg oral dose in three patients was improved by 6.3%, 24%, and 22% compared to SC administration. The T of three subjects administered the 80 mg dose was 0.01 mg / kg / day. max occurred at 1.5, 2.0, and 1.0 hours post-dose.

[0035] The stomach is an area of ​​high acidity (about pH 1-3). The pH of material leaving the stomach is raised to about pH 6.0-6.5 by certain glands and organs that drain into the small intestine. The large intestine and colon generally have a pH of about 6.4-7.0. The transit time through the small intestine is about 3 hours. In contrast, the transit time through the large intestine is about 35 hours. It is believed that gastric acid degrades azacitidine. Furthermore, longer colonic transit times result in more enzymatic degradation of azacitidine, resulting in lower bioavailability. Thus, release and absorption of azacitidine outside the stomach is desirable to achieve higher bioavailability. In some embodiments, the enzymatic degradation of azacitidine can be reduced by coadministration of cedazuridine, a cytidine deaminase inhibitor. In some embodiments, the release of azacitidine at a pH of about 6.8 in the proximal region of the small intestine can increase absorption of azacitidine.

[0036] In some embodiments, the compositions described herein enhance the bioavailability of azacitidine regardless of the release location of azacitidine in the intestine. In some such embodiments, cedazuridine is co-administered and / or combined with azacitidine. Furthermore, the release location of cedazuridine affects the enhancement of the bioavailability of azacitidine. In some embodiments, when cedazuridine and azacitidine are administered in a fixed dose composition described herein, the immediate release of cedazuridine in the stomach enhances the bioavailability of azacitidine to a greater extent than the delayed release of cedazuridine.

[0037] The bioavailability of azacitidine is further enhanced by the modified release dosage form of azacitidine described herein. Furthermore, the variability of exposure to the drug is reduced. In some embodiments, azacitidine is released at pH>3. In some embodiments, azacitidine is released outside the stomach. In some embodiments, the absorption and / or bioavailability of azacitidine can be enhanced when cedazuridine is co-administered and released before the release of azacitidine. For example, cedazuridine can be released in the stomach and azacitidine can be released outside the stomach, thereby improving the absorption and / or bioavailability of azacitidine.

[0038] definition In the following description, exemplary embodiments of the present technology are described, however, it should be recognized that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

[0039] As used herein, the following words, phrases and symbols are generally intended to have the meanings indicated below, unless otherwise indicated by the context in which they are used.

[0040] Reference herein to a value or parameter "about" includes (and describes) embodiments directed to that value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In certain other embodiments, the term "about" includes the indicated amount ±1%. The term "about X" includes a description of "X".

[0041] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the dosage form" includes a plurality of such dosage forms.

[0042] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur.

[0043] The term "polymer" refers to a compound or mixture of compounds comprised of repeating structural units produced by a polymerization process. Suitable polymers useful in the present dosage forms are described throughout.

[0044] "Blend" refers to a solid form in which an active agent is mixed with additional additives, including but not limited to fillers, glidants, and / or lubricants. The ratio of active agent to additives may vary and depends on the properties of the active agent. Typically, the blend is in the form of a powder.

[0045] In some embodiments, a "granule" is a particle having an irregular shape. In some embodiments, a "granule" is a solid agglomerate of powder particles.

[0046] A "pellet" is a solid mass containing an active agent and / or additional filler. Pellets include, but are not limited to, disks, beads, prolate spheroids, oblate spheroids, ellipsoids, cylinders, and the like. A "minitablet" is a rounded compressed solid dosage form having a smaller diameter than a tablet (i.e., diameter 6 mm or less), the compressed solid mass containing the active agent and / or additional filler. In some embodiments, a "pellet" includes a "minitablet" and vice versa. In some embodiments, "pellets" and "minitablets" may be used interchangeably. A "pellet" and / or a "minitablet" may refer to a subunit of a unit pharmaceutical dosage form, such as a capsule or a tablet.

[0047] In some embodiments, a "tablet" is a cylinder of compressed solid mass, typically with a height equal to or less than its diameter. In some embodiments, a "tablet" may refer to a pharmaceutical dosage form, which may include one or more subunits, such as pellets, minitablets, granules, or powders.

[0048] "FDC" or "fixed dose combination" refers to a pharmaceutical dosage form that contains two or more drugs contained in a single dosage form, such as a capsule or tablet.

[0049] "Modified release" refers to release of drug that occurs substantially outside the stomach. In some embodiments, the modified release is not sensitive to pH fluctuations that occur outside the stomach. By way of example only, a hydroxypropyl methylcellulose coating is substantially insensitive to pH fluctuations outside the stomach, and modified release can occur at any pH higher than the pH in the stomach. In some embodiments, the modified release is pH sensitive, and release at a desired pH is achieved by use of an appropriate coating. By way of example only, coatings of polymethacrylate polymers such as Eudragit® are adjustable and can be tailored to cause release to occur at pH>5.5 (duodenum targeted), pH 6-7 (jejunum), or pH>7 (ileum and colon).

[0050] "Enteric release" refers to the release of a drug substantially in the intestine, thereby preventing degradation of the drug from acid-catalyzed hydrolysis in the stomach. "Enteric coat" or "enteric coating" refers to a coating that can release a drug substantially in the intestine. In some embodiments, the enteric release is "delayed release" or "sustained release", is pH sensitive, and occurs at pH > 5.5 (duodenum targeted), at pH 6-7 (jejunum), or at pH > 7 (ileum and colon). "Delayed release coating" or "delayed release coat" refers to a coating that is sensitive to pH fluctuations in the intestine, and release of the drug is delayed until the target pH environment is available. In some embodiments, the enteric coating is a delayed release coating.

[0051] "Seal coat" refers to a coating that is layered onto uncoated pellets prior to coating with an enteric coating. The seal coat forms an intermediate layer to prevent interaction between the core containing the active agent and the enteric coating. In some embodiments, the seal coat comprises a polymer that allows for intermediate release.

[0052] As used herein, the term "% w / w" of an ingredient refers to the weight of the ingredient based on the total weight of the dosage form containing the ingredient. For example, if ingredient A is present in an amount of 50% w / w in a 100 mg dosage form, then ingredient A is present in an amount of 50 mg.

[0053] The term "bulking agent" refers to a compound used to dilute the compound of interest. Bulking agents can also help stabilize the compound. Non-limiting examples of bulking agents include starch, sugars, disaccharides, sucrose, lactose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium carbonate or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, cellulose, compressed sugar, calcium hydrogen phosphate anhydrous, mannitol, microcrystalline cellulose, and tricalcium phosphate.

[0054] The term "glidant" refers to an additive used to promote powder flow by reducing interparticle friction and cohesion. Glidants can improve flow properties during tablet compression and provide anti-caking benefits. Non-limiting examples of glidants include colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, magnesium carbonate, and bentonite. Glidants are generally used in conjunction with lubricants.

[0055] The term "lubricant" refers to an additive added to a powder blend to prevent the compacted powder mass from sticking to equipment during processing. It can aid in the ejection of the compacted solid mass from the die and improve the flow of the powder. Non-limiting examples of lubricants include magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearyl fumarate, talc, and solubilizers such as lauric acid, oleic acid, and fatty acids, including C8 / C10 fatty acids.

[0056] "Substantially" all azacitidine means greater than 70%, or greater than 75%, or greater than 80%, or greater than 85%, or greater than 90%, or greater than 95%, or greater than 99% azacitidine. "Substantially" drug release outside the stomach means greater than 70%, or greater than 75%, or greater than 80%, or greater than 85%, or greater than 90%, or greater than 95%, or greater than 99% of the drug is released outside the stomach.

[0057] "pH fluctuations in the intestine" refers to the change in pH in the intestinal lumen as it progresses from the stomach to the rectum. For example, the pH in the duodenum is about 5.5 or higher, the pH in the jejunum is about 6-7, the pH in the ileum and colon is about 7 or higher, the pH in the cecum is about 5.7, and the pH in the rectum is about 6.7.

[0058] An enteric coating that is "not pH sensitive" refers to a coating that is capable of releasing a drug at any pH found outside the stomach. An enteric coating that is "pH sensitive" is capable of releasing a drug at a target pH in a target region, for example, within the intestinal lumen.

[0059] As used herein, "hydroxypropyl methylcellulose" is used interchangeably with "HPMC" and / or "hypromellose." "HPMC" includes hypromellose acetate succinate (HPMCAS) and / or commercially available grades of HPMCAS.

[0060] As used herein, Eudragit® refers to a class of polymethacrylate-based copolymers. It includes anionic, cationic, and / or neutral copolymers based on methacrylic acid and methacrylic / acrylic acid esters or their derivatives. Various grades of the polymers are commercially available, including but not limited to L 30 D-55, FS 30 D, and FL 30 D-55. Anionic Eudragit® L dissolves at pH>6 and is used for enteric coating, while Eudragit® S, soluble at pH>7, is used for colonic targeting. Eudragit® S and Eudragit® L can be combined to obtain drug release at pH<7. Eudragit® RL and RS, which have quaternary ammonium groups, are water insoluble but swellable / permeable polymers suitable for sustained release film coating applications.

[0061] "Cedazuridine" includes epimers of cedazuridine and is not limited to the isomers described herein.

[0062] "Amino acid salt" in the context of a buffer refers to a buffer salt that includes one or more amino acids, such as histidine, glycine, or any other amino acid known to those of skill in the art. Amino acids have a positively charged amino group and a negatively charged carboxyl group. The charged regions of these molecules can bind hydrogen and hydroxyl ions, and thus function as buffers.

[0063] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0064] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in the preparation of pharmaceutical compositions suitable for veterinary or human medical use.

[0065] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. In addition, when a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of NH3, or primary, secondary, and tertiary amines, such as salts derived from N-containing heterocycles, N-containing heteroaromatic rings, or salts of the formula N(R N )3 (e.g., HN + (R N )3 or (alkyl)N + (R N ) 3), wherein each R Nare independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted with one or more (e.g., 1-5 or 1-3) substituents (e.g., halo, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy), etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0066] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl), or 1 to 4 carbon atoms (i.e., C 1-4 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbons is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons can be encompassed, thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0067] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0068] "Alkynyl" refers to an alkynyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 The term "alkynyl" also includes groups having one triple bond and one double bond.

[0069] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0070] "Haloalkyl" refers to an alkyl group, as defined above, and "haloalkoxy" refers to an alkoxy group, as defined above, in which one or more of the hydrogen atoms of the alkyl or alkoxy group is replaced by a halogen.

[0071] As used herein, the term “amino” refers to a group of the formula —N(R N ) 2 amine, wherein each R Nis independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more (e.g., 1-5 or 1-3) substituents (e.g., halo, cyano, hydroxy, -NH, -NH(alkyl), -N(alkyl), alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy).

[0072] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to an aromatic carbocyclic group having 6 to 20 ring carbon atoms (i.e., C 6~20 aryl), 6 to 12 carbon ring atoms (i.e., C 6~12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6~10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl.

[0073] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to a cyclic group having 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0074] "Halogen" or "halo" includes fluoro, chloro, bromo and iodo.

[0075] "Heteroaryl" refers to an aromatic group having a monocyclic, polycyclic, or fused polycyclic rings that contains one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to an aromatic group having 1 to 20 ring carbon atoms (i.e., C 1-20 Heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 Heteroaryl) and contains 1-5 heteroatoms, 1-4 heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be attached via any ring of the fused system. Any aromatic ring having a single or multiple fused rings containing at least one heteroatom is considered heteroaryl regardless of the mode of attachment (i.e., via any one of the fused rings) to the remainder of the molecule. Heteroaryl does not encompass or overlap with aryl as defined above.

[0076] "Heterocyclyl" refers to a saturated or unsaturated cyclic alkyl group containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. Heterocyclyls may be monocyclic or polycyclic, and polycyclic rings may be fused, bridged, or spiro. All non-aromatic rings containing at least one heteroatom are considered heterocyclyls, regardless of the mode of attachment (i.e., they may be attached via a carbon atom or a heteroatom). Additionally, the term heterocyclyl is intended to encompass all non-aromatic rings containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the mode of attachment to the remainder of the molecule. As used herein, heterocyclyl refers to a heterocyclic ring having 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3-6Heterocyclyl) having 1-5 ring heteroatoms, 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term "bridged heterocyclyl" refers to a 4-10 membered ring moiety that is linked at two non-adjacent atoms of the heterocyclyl to one or more (e.g., 1 or 2) 4-10 membered ring moieties having at least one heteroatom, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. As used herein, bridged heterocyclyl includes bicyclic and tricyclic ring systems. Also, as used herein, the term "spiro-heterocyclyl" refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more additional rings, where one or more of the additional rings is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclyl, and where an atom of the one or more additional rings is also an atom of the 3- to 10-membered heterocyclyl. Examples of spiro-heterocyclyl rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be attached via either ring of the fused system.

[0077] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0078] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable additive" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0079] A "solvate" is formed by the interaction of a solvent with a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0080] The "medicaments" or "medicaments" referred to herein can be prepared by conventional processes involving combining one or more compounds of the present disclosure with a pharma- ceutical acceptable carrier. For example, in the context of the present disclosure, a medicament may include both azacitidine and cedazuridine.

[0081] Azacitidine and Cedazuridine Combination In one embodiment, provided herein is a pharmaceutical dosage form or composition comprising azacitidine or a pharma- ceutically acceptable salt thereof. The pharmaceutical dosage form or composition may further comprise a CDA inhibitor, such as cedazuridine or a pharma- ceutically acceptable salt thereof, thereby enhancing the bioavailability of azacitidine.

[0082] In one embodiment, provided herein is a fixed dose combination, pharmaceutical dosage form or composition comprising cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof. The chemical structures of both cedazuridine and azacitidine are shown below. [ka]

[0083] Azacitidine release profile It has now been discovered that the intestinal release of azacitidine in the intestine is more favorable to the bioavailability of azacitidine compared to the release in the stomach, and at least a portion of the azacitidine in the pharmaceutical dosage form or composition can be formulated to be released in the intestine rather than the stomach.In one embodiment, the fixed dose combination, pharmaceutical dosage form or composition comprises azacitidine or a pharma- ceutically acceptable salt thereof, and at least a portion of the azacitidine is formulated for modified release.For example, about 5%, 10%, 15%, 20%, 25%, 30%, 33.3%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% by weight of the azacitidine can be formulated for modified release. In some embodiments, about 1 / 3 or 2 / 3 of the azacitidine may be formulated for modified release, by weight based on the total weight of the azacitidine in the tablet or capsule. In some embodiments, not all of the azacitidine is formulated for immediate release (e.g., release in the stomach), and the azacitidine is formulated for modified release. In some such embodiments, the azacitidine formulated for modified release is coated. In some embodiments, the coated azacitidine is in the form of pellets. In some embodiments, the coated azacitidine is in the form of minitablets.

[0084] In some embodiments of the pharmaceutical dosage form, the portion of azacitidine formulated for modified release is formulated for enteric release. In some such embodiments, the portion of azacitidine formulated for modified release is formulated for enteric release, which is delayed release at a target pH (e.g., the pH of the duodenum, jejunum, ileum, or colon). In some embodiments of the pharmaceutical dosage form, the portion of azacitidine formulated for immediate release is provided as uncoated minitablets or pellets. Such uncoated minitablets or pellets form a core that is optionally coated with a modified release coating. In some embodiments of the pharmaceutical dosage form, the portion of azacitidine formulated for modified release is provided as enteric minitablets or pellets. In some embodiments, the enteric coating or modified release coating is pH sensitive.

[0085] In some embodiments, at least a portion of the azacitidine is formulated for immediate release (e.g., release in the stomach). For example, about 5%, 10%, 15%, 20%, 25%, 30%, 33.3%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% by weight of the azacitidine may be formulated for immediate release. In some embodiments, about 1 / 3 or 2 / 3 by weight of the azacitidine may be formulated for immediate release. In some such embodiments, the azacitidine formulated for immediate release is uncoated. In some embodiments, the uncoated azacitidine is a powder. In some embodiments, the uncoated azacitidine is a blend (e.g., a powder blend). In some embodiments, the uncoated azacitidine is in the form of granules. In some embodiments, the uncoated azacitidine is in the form of pellets. In some embodiments, the uncoated azacitidine is in the form of minitablets.

[0086] In some embodiments of the pharmaceutical dosage form, about 0% to about 60% of the azacitidine is provided as uncoated minitablets or pellets, and about 100% to about 50% of the azacitidine is provided as modified release coated minitablets or pellets. In some embodiments of the pharmaceutical dosage form, about 0% to about 70% of the azacitidine is provided as uncoated minitablets or pellets, and about 100% to about 30% of the azacitidine is provided as modified release coated minitablets or pellets. In some embodiments of the pharmaceutical dosage form, about 10% to about 65% of the azacitidine is provided as uncoated minitablets or pellets, and about 90% to about 35% of the azacitidine is provided as modified release coated minitablets or pellets. In some embodiments of the pharmaceutical dosage form, about 20% to about 60% of the azacitidine is provided as uncoated minitablets or pellets, and about 80% to about 40% of the azacitidine is provided as modified release coated minitablets or pellets. In some embodiments of the pharmaceutical dosage form, about 30% to about 65% of the azacitidine is provided as uncoated minitablets or pellets, and about 70% to about 35% of the azacitidine is provided as modified release coated minitablets or pellets. In some embodiments of the pharmaceutical dosage form, about 30% to about 60% of the azacitidine is provided as uncoated minitablets or pellets, and about 70% to about 40% of the azacitidine is provided as modified release coated minitablets or pellets. In some embodiments of the pharmaceutical dosage form, about 37% to about 60% of the azacitidine is provided as uncoated minitablets or pellets and about 40% to about 63% of the azacitidine is provided as modified release coated minitablets or pellets.

[0087] In some embodiments of the pharmaceutical dosage form, all of the azacitidine is formulated for modified release. In some embodiments of the pharmaceutical dosage form, all of the azacitidine is not formulated for immediate release. In some embodiments of the pharmaceutical dosage form, substantially all of the azacitidine is formulated for modified release. In some of such embodiments, substantially all of the azacitidine is released outside the stomach (e.g., in the intestine).

[0088] Cedazuridine release profile Cedazuridine enhances the bioavailability of azacitidine, and it has been discovered that the location of release of cedazuridine influences the enhancement of azacitidine bioavailability, with immediate release (gastric release) of cedazuridine further helping to enhance the bioavailability of azacitidine.

[0089] In one embodiment, the fixed dose combination, pharmaceutical dosage form or composition comprises cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, and at least a portion of the cedazuridine is formulated for immediate release. In some embodiments, a portion of the cedazuridine is formulated for immediate release, and the remainder of the cedazuridine is formulated for modified release. For example, about 5%, 10%, 15%, 20%, 25%, 30%, 33.3%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% by weight of the cedazuridine may be formulated for immediate release. In some embodiments, about 1 / 3 or 2 / 3 by weight of the cedazuridine may be formulated for immediate release. In some embodiments, the cedazuridine is formulated for immediate release and not all of the cedazuridine is formulated for modified release. In some embodiments, substantially all of the cedazuridine is formulated for immediate release. In some such embodiments, the cedazuridine formulated for immediate release is uncoated. In some embodiments, the uncoated cedazuridine is a powder. In some embodiments, the uncoated cedazuridine is a blend (e.g., a powder blend). In some embodiments, the uncoated cedazuridine is in the form of granules. In some embodiments, the uncoated cedazuridine is in the form of pellets. In some embodiments, the uncoated cedazuridine is in the form of minitablets. In some embodiments of the pharmaceutical dosage form, the portion of the cedazuridine formulated for modified release is formulated for enteric release. In some embodiments of the pharmaceutical dosage form, the portion of the cedazuridine formulated for immediate release is provided as uncoated minitablets or pellets. Such uncoated minitablets or pellets form a core that is optionally coated with a modified release coating.

[0090] Fixed-dose combination (immediate-release cedazuridine + modified-release azacitidine) In some embodiments, the fixed dose combination, pharmaceutical dosage form or composition comprises cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, where at least a portion of the azacitidine is formulated for modified release and at least a portion of the cedazuridine is formulated for immediate release. In some embodiments, the fixed dose combination, pharmaceutical dosage form or composition comprises cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, where at least a portion of the azacitidine is formulated for modified release and all or substantially all of the cedazuridine is formulated for immediate release. In some embodiments, the fixed dose combination, pharmaceutical dosage form or composition comprises cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, where all or substantially all of the azacitidine is formulated for modified release and at least a portion of the cedazuridine is formulated for immediate release.

[0091] In some embodiments, the fixed dose combination, pharmaceutical dosage form or composition comprises cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, where the azacitidine is formulated for modified release and the cedazuridine is formulated for immediate release. The azacitidine formulated for modified release may be coated. In some embodiments, the coated azacitidine is in the form of pellets or minitablets. In some such embodiments, the cedazuridine formulated for immediate release is uncoated. In some embodiments, the uncoated cedazuridine is a powder. In some embodiments, the uncoated cedazuridine is a blend (e.g., a powder blend). In some embodiments, the uncoated cedazuridine is in the form of granules. In some embodiments, the uncoated cedazuridine is in the form of pellets. In some embodiments, the uncoated cedazuridine is in the form of minitablets. Each of the cedazuridine and azacitidine can be formulated as described below. For example, a fixed dose combination, pharmaceutical dosage form or composition may comprise cedazuridine in the form of an uncoated minitablet or pellet as described herein and azacitidine in the form of a modified release coated minitablet or pellet as described herein. The fixed dose combination may be provided in the form of a capsule.

[0092] Cedazuridine preparations The cedazuridine in the fixed dose combination, pharmaceutical dosage form or composition can be formulated to achieve the effect of increasing the bioavailability of azacitidine. The cedazuridine in the fixed dose combination, pharmaceutical dosage form or composition can be in the form of minitablets, tablets, powders, blends, granules or pellets and can further include lactose monohydrate, fillers, binders, disintegrants, glidants and / or lubricants. In some embodiments, the pharmaceutical dosage form of cedazuridine (i.e., cedazuridine minitablets, tablets, powders, blends, granules, or pellets) is about 10%-90% w / w, about 10%-80% w / w, about 10%-60% w / w, or about 10%-40% w / w cedazuridine, about 50%-90% w / w cedazuridine, about 60%-90% w / w cedazuridine, about 50%-85% w / w cedazuridine, about 60%-85% w / w cedazuridine, about 70%-90% w / w cedazuridine, about 70%-85% w / w cedazuridine, about 75%-85% w / w cedazuridine, about 75%-80 ... about 80%-85% w / w cedazuridine, about 80%-90% w / w cedazuridine, or about 70%-80% w / w cedazuridine, about 15%-40% w / w cedazuridine, about 25%-40% w / w cedazuridine, about 20%-40% w / w cedazuridine, about 30%-40% w / w cedazuridine, about 15%-35% w / w cedazuridine, about 15%-30% w / w cedazuridine, or about 20%-30% w / w cedazuridine, the weight percentages being based on the total weight of the uncoated cedazuridine minitablets, tablets, powder, blend, granules, or pellets.

[0093] In some embodiments, the cedazuridine is in the form of one or more tablets, minitablets, or pellets. For example, the fixed dose combination, pharmaceutical dosage form, or composition may include azacitidine or a pharma- ceutically acceptable salt thereof and cedazuridine or a pharma- ceutically acceptable salt thereof, and the cedazuridine is in the form of one or more tablets, minitablets, or pellets, and the cedazuridine tablets, minitablets, or pellets can include about 10%-40% w / w cedazuridine, about 10%-30% w / w, about 15%-40% w / w, about 15%-30% w / w, or about 15%-25% w / w cedazuridine, the weight percentages being based on the total weight of the uncoated cedazuridine tablets, minitablets, or pellets. In some embodiments, the cedazuridine tablets, minitablets, or pellets further comprise about 40%-80% w / w lactose monohydrate, about 0.5-10% w / w hydroxypropyl methylcellulose (HPMC), about 1%-10% w / w croscarmellose sodium, about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated cedazuridine tablets, minitablets, or pellets. In some embodiments, the cedazuridine pellets or minitablets comprise about 10%-30% w / w cedazuridine, 40%-80% w / w lactose monohydrate, about 0.5-10% w / w hydroxypropyl methylcellulose (HPMC), about 1%-10% w / w croscarmellose sodium, about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated cedazuridine tablet, minitablet, or pellet.In some embodiments, the cedazuridine tablets, minitablets, or pellets comprise about 20% w / w cedazuridine, about 71.5% w / w lactose monohydrate, about 2% w / w hydroxypropylmethylcellulose (HPMC), about 5% w / w croscarmellose sodium, about 1.0% w / w silicon dioxide, and about 0.5% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated cedazuridine tablets, minitablets, or pellets.

[0094] In some embodiments, the cedazuridine is in the form of a powder, blend, or granules. For example, the fixed dose combination, pharmaceutical dosage form, or composition may include azacitidine or a pharma- ceutically acceptable salt thereof and cedazuridine or a pharma- ceutically acceptable salt thereof, and the cedazuridine is in the form of a powder or granules, and the cedazuridine powder or granules can include about 70%-90% w / w cedazuridine, about 70%-85% w / w cedazuridine, about 75%-90% w / w cedazuridine, or about 75%-85% w / w cedazuridine, the weight percentages being based on the total weight of the uncoated cedazuridine powder or granules. The cedazuridine powder or granules may further comprise about 10%-20% w / w lactose monohydrate, about 1%-10.5% w / w croscarmellose sodium, about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated cedazuridine powder or granules. In some embodiments, the cedazuridine powder or granules comprise about 80% w / w cedazuridine, 13.5% w / w lactose monohydrate, about 5% w / w croscarmellose sodium, about 1.0% w / w silicon dioxide, and about 0.5% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated cedazuridine powder or granules.

[0095] Azacitidine preparations The azacitidine in the fixed dose combination, pharmaceutical dosage form or composition can be formulated to enhance the bioavailability of azacitidine. In some embodiments of the fixed dose combination, pharmaceutical dosage form or pharmaceutical composition, azacitidine is provided as minitablets or pellets. Uncoated azacitidine minitablets or pellets form a core that is optionally coated with a modified release coating. In some embodiments of the pharmaceutical dosage form, the portion of azacitidine that is formulated for modified release is provided as enteric coated minitablets or pellets. In some embodiments, the enteric coating or modified release coating is pH sensitive.

[0096] Azacitidine minitablets or pellets contain azacitidine and one or more pharma- ceutically acceptable excipients, such as lactose monohydrate, a filler, a binder, a disintegrant, a glidant, and / or a lubricant. Azacitidine minitablets or pellets of azacitidine can contain about 10%-70% w / w, about 10%-60% w / w, about 10%-50% w / w, about 10%-40% w / w, about 15%-40% w / w, about 20%-40% w / w, about 25%-40% w / w, about 30%-40% w / w, about 20%-60% w / w, about 25%-50% w / w, about 25%-45% w / w, about 30%-45% w / w, about 20%-60% w / w, about 20%-50% w / w, about 30%-50% w / w, or about 35%-45% w / w of azacitidine, the weight percentages being based on the total weight of the uncoated minitablets or pellets. In some embodiments, the azacitidine minitablets or pellets contain about 40% w / w azacitidine, where the weight percentage is based on the total weight of the uncoated azacitidine minitablets or pellets.

[0097] In some embodiments, the pharmaceutical dosage form comprises about 10%-60% w / w lactose monohydrate, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the pharmaceutical dosage form comprises about 10%-50% w / w, about 10%-40% w / w, about 10%-30% w / w, or about 10%-20% w / w lactose monohydrate, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the pharmaceutical dosage form comprises about 10%-60% w / w microcrystalline cellulose, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the pharmaceutical dosage form comprises about 10%-50% w / w, about 20%-40% w / w, or about 20%-30% w / w microcrystalline cellulose, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the pharmaceutical dosage form comprises about 0.5-10% w / w hydroxypropyl methylcellulose (HPMC), the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the pharmaceutical dosage form comprises about 0.5-8% w / w, about 0.5-6% w / w, about 0.5-4% w / w, or about 1-4% w / w hydroxypropyl methylcellulose (HPMC), the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the pharmaceutical dosage form comprises about 1%-10% w / w croscarmellose sodium, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the pharmaceutical dosage form comprises about 1%-8% w / w, about 2%-8% w / w, or about 3%-6% w / w croscarmellose sodium, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets.In some embodiments, the pharmaceutical dosage form comprises about 0.1%-3% w / w silicon dioxide, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the pharmaceutical dosage form comprises about 0.1%-2% w / w, or about 0.5%-2% w / w silicon dioxide, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the pharmaceutical dosage form comprises about 0.1%-3% w / w magnesium stearate, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the pharmaceutical dosage form comprises about 0.1%-2% w / w, or about 0.1%-1% magnesium stearate, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets.

[0098] In some embodiments, the azacitidine minitablets or pellets comprise about 20%-50% w / w azacitidine, about 10%-60% w / w lactose monohydrate, about 2%-50% w / w microcrystalline cellulose, about 1%-10% w / w croscarmellose sodium, about 0.5%-10% w / w hydroxypropyl methylcellulose (HPMC), about 0.1%-4% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the azacitidine minitablets or pellets comprise about 40% w / w azacitidine, about 19.7% w / w lactose monohydrate, about 30% w / w microcrystalline cellulose, about 5% w / w croscarmellose sodium, about 2% w / w hydroxypropyl methylcellulose (HPMC), about 2.1% w / w silicon dioxide, and about 1.2% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated azacitidine minitablets or pellets.

[0099] In some embodiments of the fixed dose combination, pharmaceutical dosage form or composition, the azacitidine uncoated minitablets or pellets comprise one or more layers, for example, the azacitidine uncoated minitablets or pellets comprise one or more layers, which may include an intragranular layer and an extragranular layer.

[0100] In some embodiments, the intragranular layer comprises about 70%-92% w / w azacitidine minitablets or pellets, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the intragranular layer comprises about 70%-95% w / w, about 75%-95% w / w, about 80%-95% w / w, about 85%-95% w / w, or about 90%-92% azacitidine minitablets or pellets, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the intragranular layer comprises about 90.5% w / w azacitidine minitablets or pellets, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets.

[0101] In some embodiments, in each uncoated minitablet or pellet, the intragranular layer comprises about 20%-50% w / w azacitidine, the weight percentage being based on the total weight of the uncoated azacitidine minitablet or pellet. In some embodiments, the intragranular layer comprises about 20%-60% w / w, about 25%-50% w / w, about 25%-45% w / w, about 30%-45% w / w, or about 35%-45% w / w azacitidine, the weight percentage being based on the total weight of the uncoated azacitidine minitablet or pellet. In some embodiments, the intragranular layer comprises about 10%-60% w / w lactose monohydrate, the weight percentage being based on the total weight of the uncoated azacitidine minitablet or pellet. In some embodiments, the intragranular layer comprises about 10%-40% w / w, about 10%-30% w / w, or about 15%-25% w / w lactose monohydrate, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the intragranular layer comprises about 2%-50% w / w microcrystalline cellulose, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the intragranular layer comprises about 2%-40% w / w, about 5%-40% w / w, about 10%-40% w / w, about 15%-30% w / w, or about 20%-30% w / w microcrystalline cellulose, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the intragranular layer comprises about 1%-10% w / w croscarmellose sodium, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the intragranular layer comprises about 1%-10% w / w, about 1%-8% w / w, about 1%-6% w / w, or about 1%-4% w / w croscarmellose sodium, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets.In some embodiments, the intragranular layer comprises about 0.5%-10% w / w hydroxypropyl methylcellulose (HPMC), the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the intragranular layer comprises about 0.5%-8% w / w, about 0.5%-6% w / w, about 0.5%-4% w / w, or about 1%-4% w / w hydroxypropyl methylcellulose (HPMC), the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the intragranular layer comprises about 0.1%-3% w / w silicon dioxide, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the intragranular layer comprises about 0.1%-2% w / w, or about 0.1%-1% w / w silicon dioxide, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the intragranular layer comprises about 0.1%-3% w / w magnesium stearate, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets, hi some embodiments, the intragranular layer comprises about 0.1%-2% w / w, or about 0.1%-1% w / w magnesium stearate, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets.

[0102] In some embodiments, the intragranular layer comprises about 20%-50% w / w azacitidine, about 10%-60% w / w lactose monohydrate, about 2%-50% w / w microcrystalline cellulose, about 1%-10% w / w croscarmellose sodium, about 0.5%-10% w / w hydroxypropyl methylcellulose (HPMC), about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated azacitidine minitablet or pellet. In some embodiments, the intragranular layer comprises about 40% w / w azacitidine, about 19.7% w / w lactose monohydrate, about 25% w / w microcrystalline cellulose, about 2.5% w / w croscarmellose sodium, about 2% w / w HPMC, about 0.5% w / w silicon dioxide, and about 0.8% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated azacitidine minitablet or pellet.

[0103] In some embodiments, the extragranular layer comprises about 1%-60% w / w microcrystalline cellulose, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the extragranular layer comprises about 1%-50% w / w, about 1%-40% w / w, about 1%-30%, about 1%-20% w / w, or about 1%-10% w / w microcrystalline cellulose, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the extragranular layer comprises about 1%-10% w / w croscarmellose sodium, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the extragranular layer comprises about 1%-8% w / w, about 1%-6% w / w, about 1%-4% w / w, or about 2%-4% w / w of croscarmellose sodium, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the extragranular layer comprises about 0.1%-3% w / w of silicon dioxide, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the extragranular layer comprises about 0.1%-2% w / w of silicon dioxide, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the extragranular layer comprises about 0.1%-3% w / w of magnesium stearate, the weight percentage being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the extragranular layer comprises about 0.1%-2% w / w or about 0.1%-1% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated azacitidine minitablets or pellets.

[0104] In some embodiments, the extragranular layer comprises about 1%-60% w / w microcrystalline cellulose, about 1%-10% w / w croscarmellose sodium, about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the extragranular layer comprises about 5% w / w microcrystalline cellulose, about 2.5% w / w croscarmellose sodium, about 1.6% w / w silicon dioxide, and about 0.4% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated azacitidine minitablets or pellets.

[0105] In some embodiments of the fixed dose combination, pharmaceutical dosage form or composition, the azacitidine uncoated minis or pellets comprise an extragranular layer and an intragranular layer, the intragranular layer being comprised of about 20%-50% w / w azacitidine, about 10%-60% w / w lactose monohydrate, about 2%-50% w / w microcrystalline cellulose, about 1%-10% w / w croscarmellose sodium, about 0.5%-10% w / w hydroxypropyl methylcellulose (HPMC), the extragranular layer comprises about 1%-60% w / w microcrystalline cellulose, about 1%-10% w / w croscarmellose sodium, about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated azacitidine minitablets or pellets. In some embodiments, the intragranular layer comprises about 40% w / w azacitidine, about 19.7% w / w lactose monohydrate, about 25% w / w microcrystalline cellulose, about 2.5% w / w croscarmellose sodium, about 2% w / w HPMC, about 0.5% w / w silicon dioxide, and about 0.8% w / w magnesium stearate, and the extragranular layer comprises about 5% w / w microcrystalline cellulose, about 2.5% w / w croscarmellose sodium, about 1.6% w / w silicon dioxide, and about 0.4% w / w magnesium stearate, wherein the weight percentages are based on the total weight of the uncoated azacitidine minitablets or pellets.

[0106] In some embodiments of the fixed dose combination, pharmaceutical dosage form or composition, the azacitidine uncoated minitablets or pellets comprise an extragranular layer and an intragranular layer, the intragranular layer being comprised of about 20%-50% w / w azacitidine, about 10%-30% w / w lactose monohydrate, about 2%-50% w / w microcrystalline cellulose, about 1%-10% w / w croscarmellose sodium, about 0.5%-10% w / w hydroxypropyl methylcellulose (HPMC), about 0.1%-3% w / w silicon dioxide, about 0.5%-5% w / w binder (e.g., Kollidon The extragranular layer comprises about 1%-60% w / w microcrystalline cellulose, about 1%-10% w / w croscarmellose sodium, about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate, weight percentages being based on the total weight of the uncoated azacitidine minitablets or pellets. The extragranular layer comprises about 2%-10% w / w microcrystalline cellulose, about 1%-5% w / w croscarmellose sodium, about 0.1%-1% w / w magnesium stearate, and about 1%-5% binder (e.g., Kollidon VA64).

[0107] In some embodiments, the azacitidine minitablets or pellets are not separated into two layers and contain about 2%-10% w / w azacitidine, about 50%-90% w / w lactose monohydrate, about 2%-10% w / w croscarmellose sodium, about 1-5% w / w HPMC, about 0.1%-3% colloidal silicon dioxide, and 0.1%-3% magnesium stearate.

[0108] coating In some embodiments of the fixed dose combination, pharmaceutical dosage form, or composition, the azacitidine formulated for modified release comprises the azacitidine minitablets or pellets described herein coated with one or more layers that allow for intestinal release. In some embodiments of the fixed dose combination, pharmaceutical dosage form, or composition, the azacitidine formulated for modified release comprises the uncoated azacitidine minitablets or pellets described herein coated with one or more layers of a seal coat. In some embodiments, the minitablets or pellets coated with a seal coat are further coated with a second seal coat, or an intermediate coat. In some embodiments, the minitablets or pellets coated with a seal coat and a second seal coat are further coated with an enteric coating, a modified release coating, or a delayed release coating to provide a three-layer coating. By way of example only, Examples 4 and 5 show such embodiments. In some embodiments of the fixed dose combination, the minitablets or pellets may be coated with a seal coat and an enteric coating or a modified release coating to provide a two-layer coating.

[0109] In some embodiments, the seal coat or second seal coat comprises a component to protect the core, such as hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), magnesium oxide, or other components suitable for seal coating a drug.

[0110] The enteric or modified release coating comprises ingredients that protect the core minitablets or pellets from the acidity of the stomach and allow for release in the small intestine. In some embodiments, the delayed release coating comprises ethylcellulose or an ethylcellulose-based polymer. For example, the delayed release coating comprises Suarease® E-7-19040. In some embodiments, the delayed release coating is insensitive to pH fluctuations in the intestine. In some such embodiments, the azacitidine is released outside the stomach.

[0111] In some embodiments of the fixed dose combination, pharmaceutical dosage form, or composition, the enteric or delayed release coating comprises a methacrylate-based polymer. In some embodiments, the enteric or delayed release coating can comprise Eudragit® L30D 55, FS 30 D, FL 30 D-55, or L100. In some embodiments, the enteric or delayed release coating can comprise methyl methacrylate-methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, cellulose acetate succinate, polyvinyl acetate phthalate, or copolymers thereof. The enteric or delayed release coating can further comprise triethyl citrate and / or talc. In some embodiments, the enteric delayed release coating is sensitive to pH variations in the intestine. In some such embodiments, depending on the polymers present in the coating, the enteric or delayed release coating is selected to provide release in the duodenum, jejunum, ileum, or colon. In some such embodiments, the azacitidine is released outside the stomach. By way of example only, Example 6 provides such an embodiment.

[0112] The coating of the azacitidine minitablets or pellets can be applied in a suitable amount to obtain the desired release profile. In some embodiments, the total coating of the azacitidine minitablets or pellets can have a weight gain of about 5-25%, about 10-25%, about 15-25%, about 20-25%, about 5-20%, about 10-20%, about 15-20%, about 5-15%, about 10-15%, or about 5-10% compared to the uncoated azacitidine minitablets or pellets. In some embodiments, the enteric or delayed release coating of the azacitidine minitablets or pellets can have a weight gain of about 3-15%, about 3-12%, about 3-10%, about 4-10%, or about 4-7% compared to the uncoated azacitidine minitablets or pellets.

[0113] Embodiment In some or any of the above embodiments, provided herein is a fixed dose combination, pharmaceutical dosage form, or pharmaceutical composition comprising cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, wherein the cedazuridine is formulated for immediate release and provided as a powder, granule, pellet, or minitablet, and all the azacitidine is formulated for modified release and provided as an enteric coated minitablet or pellet. The fixed dose combination may be provided as a capsule.

[0114] In some such embodiments, the azacitidine minitablets or pellets have an intragranular layer and an extragranular layer. The intragranular layer comprises about 20%-50% w / w azacitidine, about 10%-60% w / w lactose monohydrate, about 2%-50% w / w microcrystalline cellulose, about 1%-10% w / w croscarmellose sodium, about 0.5%-10% w / w hydroxypropyl methylcellulose (HPMC), about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate. The extragranular layer comprises about 1%-60% w / w microcrystalline cellulose, about 1%-10% w / w croscarmellose sodium, about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated azacitidine minitablets or pellets. In some of such embodiments, the intragranular layer comprises about 40% w / w azacitidine, about 19.7% w / w lactose monohydrate, about 25% w / w microcrystalline cellulose, about 2.5% w / w croscarmellose sodium, about 2% w / w HPMC, about 0.5% w / w silicon dioxide, and about 0.8% w / w magnesium stearate, and the extragranular layer comprises about 5% w / w microcrystalline cellulose, about 2.5% w / w croscarmellose sodium, about 1.6% w / w silicon dioxide, and about 0.4% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated azacitidine minitablets or pellets. In some of such embodiments, the azacitidine minitablets or pellets are coated with a seal coat and an enteric or modified release coating. The enteric or modified release coating comprises a polymethacrylate polymer and is sensitive to the pH of the intestine, such that the azacitidine is released substantially outside the stomach.

[0115] In some such embodiments, the cedazuridine is provided as pellets or minitablets, the cedazuridine pellets or minitablets comprising about 10%-30% w / w cedazuridine, 40%-80% w / w lactose monohydrate, about 0.5-10% w / w hydroxypropyl methylcellulose (HPMC), about 1%-10% w / w croscarmellose sodium, about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated cedazuridine tablet, minitablet, or pellet. In some of such embodiments, the cedazuridine tablets, minitablets, or pellets comprise about 20% w / w cedazuridine, about 71.5% w / w lactose monohydrate, about 2% w / w hydroxypropylmethylcellulose (HPMC), about 5% w / w croscarmellose sodium, about 1.0% w / w silicon dioxide, and about 0.5% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated cedazuridine tablets, minitablets, or pellets.

[0116] In other such embodiments, the cedazuridine is in the form of a powder, and the cedazuridine powder can comprise about 70%-90% w / w cedazuridine, about 10%-20% w / w lactose monohydrate, about 1%-10.5% w / w croscarmellose sodium, about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated cedazuridine powder or granules. In some embodiments, the cedazuridine powder or granules comprises about 80% w / w cedazuridine, 13.5% w / w lactose monohydrate, about 5% w / w croscarmellose sodium, about 1.0% w / w silicon dioxide, and about 0.5% w / w magnesium stearate, the weight percentages being based on the total weight of the uncoated cedazuridine powder or granules.

[0117] In some or any of the above-mentioned embodiments, the present invention provides a pharmaceutical dosage form comprising cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, wherein the cedazuridine is formulated for immediate release, at least a portion of the azacitidine is formulated for immediate release and provided as an uncoated minitablet or pellet, and the remainder of the azacitidine is formulated for modified release and provided as an enteric-coated minitablet or pellet.In some of such embodiments, the azacitidine minitablet or pellet is homogeneous (i.e., does not have an intragranular layer and an extragranular layer).In other of such embodiments, the azacitidine minitablet or pellet has an intragranular layer and an extragranular layer.

[0118] In some or any of the above embodiments, provided herein is a pharmaceutical dosage form comprising cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, wherein the cedazuridine is formulated for immediate release and all of the azacitidine is formulated for modified release and provided as delayed release minitablets or pellets. In some of such embodiments, the azacitidine pellets have an intragranular layer and an extragranular layer. In other of such embodiments, the azacitidine pellets are homogenous (i.e., do not have an intragranular layer and an extragranular layer).

[0119] Fixed-dose combination - tablets In some embodiments, provided herein is a fixed dose combination ("FDC") pharmaceutical dosage form comprising cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, wherein the cedazuridine and azacitidine are formulated for immediate release. In some such embodiments, the dosage form is a tablet. In some embodiments, the tablet is an uncoated tablet, such as the FDC tablet of Example 12.

[0120] In some embodiments, the FDC tablet has an intragranular layer and an extragranular layer. In some embodiments, the intragranular layer is about 50%-90% w / w of the FDC tablet, the weight percentages being based on the total weight of the FDC tablet. In some embodiments, the extragranular layer is about 10%-50% w / w of the FDC tablet, the weight percentages being based on the total weight of the FDC tablet. In some embodiments, the intragranular layer is about 80% w / w of the FDC tablet and the extragranular layer is about 20% w / w of the FDC tablet, the weight percentages being based on the total weight of the FDC tablet.

[0121] In some embodiments, the intragranular layer of the FDC tablet comprises about 1%-10% w / w cedazuridine, the weight percentage being based on the total weight of the FDC tablet. In some embodiments, the intragranular layer of the FDC tablet comprises about 1%-10% w / w azacitidine, the weight percentage being based on the total weight of the FDC tablet. In some embodiments, the intragranular layer of the FDC tablet comprises about 10%-60% w / w lactose monohydrate, the weight percentage being based on the total weight of the FDC tablet. In some embodiments, the intragranular layer of the FDC tablet comprises about 10%-50% w / w microcrystalline cellulose, the weight percentage being based on the total weight of the FDC tablet. In some embodiments, the intragranular layer of the FDC tablet comprises about 1%-10% w / w croscarmellose sodium, the weight percentage being based on the total weight of the FDC tablet. In some embodiments, the intragranular layer of the FDC tablet comprises about 1%-10% w / w HPMC, the weight percentage being based on the total weight of the FDC tablet. In some embodiments, the intragranular layer of the FDC tablet comprises about 0.1%-5% w / w silicon dioxide, the weight percentage being based on the total weight of the FDC tablet. In some embodiments, the intragranular layer of the FDC tablet comprises about 0.1%-5% w / w magnesium stearate, the weight percentage being based on the total weight of the FDC tablet.

[0122] In some embodiments, the extragranular layer of the FDC tablet comprises about 5%-30% w / w microcrystalline cellulose, the weight percentage being based on the total weight of the FDC tablet. In some embodiments, the extragranular layer of the FDC tablet comprises about 1%-10% w / w croscarmellose sodium, the weight percentage being based on the total weight of the FDC tablet. In some embodiments, the extragranular layer of the FDC tablet comprises about 1%-5% w / w silicon dioxide, the weight percentage being based on the total weight of the FDC tablet. In some embodiments, the intragranular layer of the FDC tablet comprises about 0.1%-5% w / w magnesium stearate, the weight percentage being based on the total weight of the FDC tablet.

[0123] In some embodiments, provided herein is a pharmaceutical dosage form of a fixed dose combination comprising cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, wherein the cedazuridine and azacitidine are formulated for immediate release, and the dosage form is further coated with an enteric coating. In some such embodiments, the dosage form is a tablet. In some embodiments, the tablet is a coated tablet, such as the coated FDC tablet of Example 1. In some embodiments, the tablet is coated with a seal coat and then coated with an enteric coating.

[0124] Fixed-dose combination - enteric-coated capsule In some embodiments, provided herein is a fixed dose combination dosage form comprising cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, wherein the cedazuridine and azacitidine are formulated for immediate release, and the dosage form is a capsule. In some embodiments, the capsule may be coated to provide an enteric capsule.

[0125] In one embodiment, provided herein is a capsule comprising azacitidine, the capsule having an enteric capsule shell. In some embodiments, the capsule further comprises cedazuridine. In some such embodiments, the azacitidine and / or cedazuridine may be filled into the capsule together with additional additives. In some embodiments, the azacitidine and / or cedazuridine filled into the capsule may be in the form of a powder, blend, granule, pellet, minitablet, or combination thereof.

[0126] In some embodiments, the capsule shell is an enteric capsule shell comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS) and / or hydroxypropyl methylcellulose (HPMC). In some embodiments, the capsule shell is a Capsugel® Vcaps® enteric capsule. The Vcaps® enteric capsule is manufactured using pharmaceutical grade cellulosic enteric derivatives (e.g., HPMCAS, HPMC). In some embodiments, the capsule further comprises a gelling agent and water. In some embodiments, the capsule further comprises at least one basic compound or composition capable of neutralizing the succinic acid groups on HPMCAS, including, but not limited to, a basic hydroxide compound such as potassium hydroxide (KOH), sodium hydroxide (NaOH), calcium hydroxide (Ca(OH)2), or other basic compounds or compositions, such as ammonium hydroxide, cationic polymers such as Eudragit® E PO, and mixtures thereof. In some embodiments, such enteric capsule shells allow release of azacitidine and / or cedazuridine substantially outside the stomach. In some embodiments, such enteric capsule shells allow release of azacitidine in the intestine. In some embodiments, the intestinal release is a delayed release that is sensitive to pH fluctuations in the intestine.

[0127] In some embodiments, the enteric capsule shell comprises a solid filled into the enteric capsule shell. In some embodiments, the solid filled into the enteric capsule shell comprises azacitidine and additional excipients. In some embodiments, the solid filled into the enteric capsule shell comprises azacitidine and additional excipients, and further comprises cedazuridine and additional excipients.

[0128] In some embodiments, the capsule comprises a buffer salt therein, which in some embodiments is selected from sodium phosphate (including sodium dihydrogen phosphate, disodium hydrogen phosphate), potassium phosphate, 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris), sodium hydroxide, sodium citrate, sodium acetate, potassium acetate, citric acid and sodium or potassium citrate, amino acid salts, malic acid and sodium or potassium malate, tartaric acid and potassium or sodium tartrate, glutamic acid and sodium or potassium glutamate, and sodium carbonate.

[0129] In some embodiments, the capsule further comprises about 10%-50% w / w, about 10%-40% w / w, about 10%-30% w / w, or about 10%-20% w / w lactose monohydrate, the weight percentage being based on the total weight of the solids filled in the capsule shell. In some embodiments, the capsule further comprises about 26.2% w / w lactose monohydrate, the weight percentage being based on the total weight of the solids filled in the capsule shell. In some embodiments, the capsule further comprises about 10%-50% w / w, about 10%-40% w / w, about 10%-30% w / w, or about 20%-30% w / w microcrystalline cellulose, the weight percentage being based on the total weight of the solids filled in the capsule shell. In some embodiments, the capsule further comprises about 25.7% w / w microcrystalline cellulose, the weight percentage being based on the total weight of the solids filled in the capsule shell. In some embodiments, the capsule further comprises about 1%-25% w / w, about 1%-20% w / w, about 5%-20% w / w, about 5%-15% w / w, or about 5%-10% w / w of croscarmellose sodium, the weight percentage being based on the total weight of the solids filled in the capsule shell. In some embodiments, the capsule further comprises about 8% w / w of croscarmellose sodium, the weight percentage being based on the total weight of the solids filled in the capsule shell. In some embodiments, the capsule further comprises about 1%-10% w / w, about 1%-8% w / w, about 1%-6% w / w, or about 1%-4% w / w of HPMC, the weight percentage being based on the total weight of the solids filled in the capsule shell. In some embodiments, the capsule further comprises about 2% w / w of HPMC, the weight percentage being based on the total weight of the solids filled in the capsule shell. In some embodiments, the capsule further comprises about 1%-10% w / w, about 1%-8% w / w, about 1%-6% w / w, or about 1%-4% w / w of silicon dioxide, the weight percentages being based on the total weight of solids filled into the capsule shell.In some embodiments, the capsule further comprises about 2.1% w / w silicon dioxide, the weight percentage being based on the total weight of the solids filled in the capsule shell. In some embodiments, the capsule further comprises about 0.1-10% w / w, about 0.1-8% w / w, about 0.1-5% w / w, about 0.1-2% w / w, or about 0.1-1% w / w magnesium stearate, the weight percentage being based on the total weight of the solids filled in the capsule shell. In some embodiments, the capsule further comprises about 1% w / w magnesium stearate, the weight percentage being based on the total weight of the solids filled in the capsule shell.

[0130] In some embodiments, the capsule further comprises about 10%-50% w / w lactose monohydrate, about 10%-50% w / w microcrystalline cellulose, about 1%-20% w / w croscarmellose sodium, about 1%-10% w / w HPMC, about 1%-10% w / w silicon dioxide, and about 0.1%-5% w / w magnesium stearate, the weight percentages being based on the total weight of the solids filled into the capsule shell. In some embodiments, the capsule further comprises about 26.2% w / w lactose monohydrate, about 25.7% w / w microcrystalline cellulose, about 8% w / w croscarmellose sodium, about 2% w / w HPMC, about 2.1% w / w silicon dioxide, and about 1% w / w magnesium stearate, the weight percentages being based on the total weight of the solids filled into the capsule shell.

[0131] In some embodiments, the capsule comprises about 5%-40% w / w azacitidine, the weight percentage being based on the total weight of solids loaded into the capsule shell. In some embodiments, the capsule comprises about 5%-30% w / w, about 5%-25% w / w, about 5%-20% w / w, or about 5%-15% w / w azacitidine, the weight percentage being based on the total weight of solids loaded into the capsule shell. In some embodiments, the capsule comprises about 10% w / w azacitidine, the weight percentage being based on the total weight of solids loaded into the capsule shell.

[0132] In some embodiments, the capsule comprises about 5%-40% w / w cedazuridine, the weight percentage being based on the total weight of the solids loaded into the capsule shell. In some embodiments, the capsule comprises about 5%-30% w / w, about 5%-25% w / w, about 5%-20% w / w, or about 5%-15% w / w cedazuridine, the weight percentage being based on the total weight of the solids loaded into the capsule shell. In some embodiments, the capsule comprises about 10% w / w cedazuridine, the weight percentage being based on the total weight of the solids loaded into the capsule shell.

[0133] In some embodiments, the capsule further comprises about 5%-25% w / w sodium phosphate, the weight percentage being based on the total weight of the solids filled in the capsule shell. In some embodiments, the capsule further comprises about 1%-30% w / w, about 1%-25% w / w, about 1%-20% w / w, about 1%-10% w / w, about 5%-20% w / w, or about 5%-10% w / w sodium phosphate, the weight percentage being based on the total weight of the solids filled in the capsule shell. In some embodiments, the capsule further comprises about 15% w / w sodium phosphate, the weight percentage being based on the total weight of the solids filled in the capsule shell. In any of these embodiments, the sodium phosphate is anhydrous disodium hydrogen phosphate.

[0134] In some embodiments, the capsule comprises about 2%-20% w / w cedazuridine, the weight percentage being based on the total weight of the solids loaded into the capsule shell. In some embodiments, the capsule comprises about 2%-20% azacytidine, the weight percentage being based on the total weight of the solids loaded into the capsule shell. In some embodiments, the capsule comprises about 1%-40% w / w lactose monohydrate, the weight percentage being based on the total weight of the solids loaded into the capsule shell. In some embodiments, the capsule comprises about 1%-40% w / w microcrystalline cellulose (e.g., Avicel PH 102, Avicel PH 200), the weight percentage being based on the total weight of the solids loaded into the capsule shell. In some embodiments, the capsule comprises about 5%-25% w / w sodium phosphate, the weight percentage being based on the total weight of the solids loaded into the capsule shell. In some such embodiments, the sodium phosphate is disodium hydrogen phosphate. In some such embodiments, the sodium phosphate is anhydrous. In some other embodiments, the capsule does not comprise sodium phosphate. In some embodiments, the capsule comprises about 1%-10% w / w croscarmellose sodium, the weight percentage being based on the total weight of the solids loaded into the capsule shell. In some embodiments, the capsule comprises about 0%-15% HPMC (also referred to herein as hypromellose). In some embodiments, the capsule does not comprise HPMC. In some embodiments, the capsule comprises about 1%-4% colloidal silicon dioxide, the weight percentage being based on the total weight of the solids loaded into the capsule shell. In some embodiments, the capsule comprises about 0.25%-4% magnesium stearate, the weight percentage being based on the total weight of the solids loaded into the capsule shell.

[0135] In some embodiments, the capsule comprises about 8-10% w / w cedazuridine, the weight percentage being based on the total weight of the solids loaded into the capsule shell. In some embodiments, the capsule comprises about 8%-10% azacytidine, the weight percentage being based on the total weight of the solids loaded into the capsule shell. In some embodiments, the capsule comprises about 25%-35% w / w lactose monohydrate, the weight percentage being based on the total weight of the solids loaded into the capsule shell. In some embodiments, the capsule comprises about 22%-26% w / w microcrystalline cellulose (e.g., Avicel PH 102, Avicel PH 200), the weight percentage being based on the total weight of the solids loaded into the capsule shell. In some embodiments, the capsule comprises about 15% w / w sodium phosphate, the weight percentage being based on the total weight of the solids loaded into the capsule shell. In some such embodiments, the sodium phosphate is disodium hydrogen phosphate, the weight percentage being based on the total weight of the solids loaded into the capsule shell. In some such embodiments, the sodium phosphate is anhydrous. In some other embodiments, the capsule does not contain sodium phosphate. In some embodiments, the capsule contains about 8% w / w croscarmellose sodium, the weight percentage being based on the total weight of the solids filled in the capsule shell. In some embodiments, the capsule contains about 2% HPMC (also referred to herein as hypromellose), the weight percentage being based on the total weight of the solids filled in the capsule shell. In some embodiments, the capsule does not contain any HPMC, the weight percentage being based on the total weight of the solids filled in the capsule shell. In some embodiments, the capsule contains about 2% to 2.5% colloidal silicon dioxide, the weight percentage being based on the total weight of the solids filled in the capsule shell. In some embodiments, the capsule contains about 1% to 1.5% magnesium stearate, the weight percentage being based on the total weight of the solids filled in the capsule shell.

[0136] dose In some embodiments, the pharmaceutical dosage form comprises about 5 to about 200 mg, about 10 to about 300 mg, about 20 to about 300 mg, about 20 to about 200 mg, about 20 to about 100 mg, about 5 to about 100 mg, about 5 to about 80 mg, about 20 to about 80 mg, about 5 to about 60 mg, about 20 to about 60 mg, about 5 to about 50 mg, about 30 to about 50 mg, about 10 to 30 mg, about 30 to 300 mg, The pharmaceutical dosage form contains about 40 to about 300 mg, about 50 to about 300 mg, about 50 to about 250 mg, about 50 to about 200 mg, about 60 to about 150 mg, about 70 to about 150 mg, about 70 to about 140 mg, about 80 to about 130 mg, about 90 to about 120 mg, about 90 to about 110 mg, about 10 to about 100 mg, about 10 to about 70 mg, or about 20 to about 50 mg of cedazuridine as an active pharmaceutical ingredient. In some embodiments, the pharmaceutical dosage form contains about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg of cedazuridine as an active pharmaceutical ingredient.

[0137] In some embodiments, the pharmaceutical dosage form contains about 5 to about 100 mg, about 20 to about 120 mg, about 40 to about 120 mg, about 60 to about 120 mg, about 80 to about 120 mg, about 100 to about 120 mg, about 5 to about 80 mg, about 10 to about 80 mg, about 10 to about 70 mg, about 20 to about 70 mg, about 20 to about 65 mg, about 25 to about 65 mg, about 25 to about 60 mg, about 30 to about 55 mg, about 30 to about 50 mg, about 35 to about 50 mg, or about 35 to about 45 mg of azacitidine as an active pharmaceutical ingredient. In some embodiments, the pharmaceutical dosage form comprises about 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, or 120 mg of azacitidine as the active pharmaceutical ingredient.

[0138] Any suitable combination of the contents of azacitidine and cedazuridine described herein can be included in the fixed dose combination formulation. For example, the fixed dose combination may contain about 5 to about 200 mg of cedazuridine and about 20 to about 160 mg of azacitidine. In some of such embodiments, the fixed dose combination may contain about 5 to about 100 mg of cedazuridine and about 20 to about 140 mg of azacitidine. In some of such embodiments, the fixed dose combination may contain about 5 to about 80 mg of cedazuridine and about 40 to about 140 mg of azacitidine. In some such embodiments, the fixed dose combination may include about 5 to about 60 mg cedazuridine and about 60 to about 140 mg azacitidine, about 5 to about 40 mg cedazuridine and about 60 to about 120 mg azacitidine, or about 10 to about 40 mg cedazuridine and about 80 to about 120 mg azacitidine. In some embodiments, the fixed dose combination may include about 20 mg cedazuridine and about 80 mg azacitidine. In some embodiments, the fixed dose combination may include about 20 mg cedazuridine and about 84 mg azacitidine. In some embodiments, the fixed dose combination may include about 20 mg cedazuridine and about 88 mg azacitidine. In some embodiments, the fixed dose combination may include about 20 mg cedazuridine and about 92 mg azacitidine. In some embodiments, the fixed dose combination may include about 20 mg of cedazuridine and about 96 mg of azacitidine. In some embodiments, the fixed dose combination may include about 20 mg of cedazuridine and about 100 mg of azacitidine. In some embodiments, the fixed dose combination may include about 20 mg of cedazuridine and about 104 mg of azacitidine. In some embodiments, the fixed dose combination may include about 20 mg of cedazuridine and about 108 mg of azacitidine. In some embodiments, the fixed dose combination may include about 20 mg of cedazuridine and about 112 mg of azacitidine. In some embodiments, the fixed dose combination may include about 20 mg of cedazuridine and about 120 mg of azacitidine. In some embodiments, the fixed dose combination may include about 100 mg of cedazuridine and about 40 mg of azacitidine.In some embodiments, the fixed dose combination may include about 20 mg cedazuridine and about 40 mg azacitidine. In some embodiments, the fixed dose combination may include about 40 mg cedazuridine and about 100 mg azacitidine. In some embodiments, the fixed dose combination may include about 40 mg cedazuridine and about 80 mg azacitidine, about 40 mg cedazuridine and about 84 mg azacitidine, about 40 mg cedazuridine and about 88 mg azacitidine, about 40 mg cedazuridine and about 92 mg azacitidine, or about 40 mg cedazuridine and about 96 mg azacitidine.

[0139] In some embodiments, the pharmaceutical dosage form or fixed dose combination contains cedazuridine and azacitidine in a weight ratio of cedazuridine to azacitidine of about 1:20 to about 10:1, about 1:10 to about 10:1, about 1:8 to about 1:1, about 1:8 to about 1:2, about 1:8 to about 1:4, about 1:6 to about 1:1, about 1:6 to about 1:2, about 1:6 to about 1:3, about 1:6 to about 1:4, about 1:6 to about 1:5, about 1:5 to about 5:1, about 1:5 to about 1:1, about 1:5 to about 1:2, about 1:5 to about 1:3, about 1:5 to about 1:4, about 1:4 to about 4:1, about 1:4 to about 1:1, about 1:3 to about 1:3, or about 1:2 to about 1:2, about 1:1 to about 1:5, about 1:1 to about 1:4, about 1:1 to about 1:3, or about 1:1 to about 1:2. In some embodiments, the fixed dose combination can include cedazuridine and azacitidine in a weight ratio of cedazuridine to azacitidine of about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 3:4, about 3:5, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1.5:1, about 2:1, about 2.5:1, about 4:3, about 4:1, or about 5:3.

[0140] The specific dosage level of the compositions of the present application for any particular subject will depend on a variety of factors, including the activity of the specific compound used, the age, weight, general health, sex, diet, time of administration, route of administration, and excretion rate in the subject being treated, drug combinations, and the severity of the particular disease. For example, dosages can be expressed as milligrams of the compounds described herein per kilogram of subject body weight (mg / kg). Doses of about 0.1-150 mg / kg of cedazuridine and / or azacytidine may be appropriate. In some embodiments, between about 0.1 and 100 mg / kg may be appropriate. In other embodiments, doses of 0.5-60 mg / kg may be appropriate. Normalizing according to subject body weight is particularly useful when using drugs in both children and adults, or when adjusting dosages between subjects of widely differing sizes, such as occurs when translating effective doses in non-human subjects, such as dogs, to doses appropriate for human subjects.

[0141] The daily dose can also be described as the total amount of cedazuridine and / or azacitidine administered per administration or per day. The daily dose of cedazuridine and / or azacitidine can be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

[0142] When administered orally, the total daily dose for a human subject can be between 1 mg and 1,000 mg, about 1,000 to 2,000 mg / day, about 10 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 100 to 150 mg / day.

[0143] The compositions of the present application may be administered once, twice, three times, or four times a day using any suitable mode described above. Administration or treatment with the compound may also continue for several days, for example, treatment generally continues for at least 7 days, 14 days, or 28 days during one cycle of treatment. Treatment cycles are known in cancer chemotherapy and are frequently alternated with rest periods of about 1 to 28 days, generally about 7 days or about 14 days, between cycles. In other embodiments, treatment cycles may also be continuous.

[0144] Treatment Methods and Uses "Treatment" or "treating" is an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition and / or reducing the severity of the disease or condition), b) slowing or halting the progression of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition), and / or c) relieving the disease, i.e., causing a reduction in clinical symptoms (e.g., improving the disease state, causing partial or complete remission of the disease or condition, enhancing the effect of another drug, slowing the progression of the disease, improving quality of life, and / or prolonging survival).

[0145] "Prevention" or "preventing" refers to any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. In some embodiments, the compounds can be administered to subjects (including humans) at risk for or who have a family history of a disease or condition.

[0146] "Subject" refers to an animal, such as a mammal (including a human), that has been or is the object of treatment, observation or experiment. The methods described herein may be useful in human treatment and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0147] The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, means an amount sufficient to effect a treatment when administered to a subject, such as to obtain a therapeutic benefit, such as amelioration of symptoms or delay of disease progression. For example, a therapeutically effective amount may be an amount sufficient to reduce symptoms of cancer. The therapeutically effective amount may vary depending on the subject and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, the method of administration, and can be readily determined by one of ordinary skill in the art.

[0148] Provided herein is a method of treating cancer in a patient, comprising administering any of the dosage forms described herein to a patient in need thereof. In some embodiments, the cancer is selected from hematological cancer and solid cancer. In further embodiments, the hematological cancer is selected from myelodysplastic syndrome (MDS) and leukemia. In further embodiments, the solid cancer is selected from pancreatic cancer, ovarian cancer, prostate cancer, peritoneal cancer, non-small cell lung cancer, and breast cancer. In still further embodiments, the leukemia is acute myeloid leukemia (AML) or chronic myeloid leukemia (CML). In some embodiments, the AML can be relapsed or refractory AML. In some embodiments, the AML can be pre- or post-hematopoietic cell transplantation. In some embodiments, the cancer is mucosal melanoma. In some embodiments, the leukemia is relapsed or refractory biphenotypic acute leukemia. In some embodiments, the AML patient may have achieved initial complete remission (CR) or complete remission with incomplete blood count recovery (CRi) after intensive induction chemotherapy and is unable to complete intensive curative therapy.

[0149] In some embodiments, the cancer is selected from previously treated or untreated de novo or secondary myelodysplastic syndrome (MDS), previously treated or untreated de novo or secondary chronic myelomonocytic leukemia (CMML or CMMol), previously treated or untreated de novo or secondary chronic myelogenous leukemia (CML), and previously treated or untreated de novo or secondary juvenile myelomonocytic leukemia (JMML). In some embodiments, the MDS may be in the intermediate-1, intermediate-2, and high-risk groups according to the International Prognostic Scoring System.

[0150] In some embodiments, the cancer is associated with refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), or refractory anemia with excess blasts in transition (RAEB-T).

[0151] In some embodiments, the cancer is selected from malignant peripheral nerve sheath tumors (MPNST), brain and spinal cord tumors, breast cancer, hormone receptor positive tumors, head and neck cancer, primary enchondroma, myeloproliferative neoplasms (MPN), recurrent B-cell non-Hodgkin's lymphoma, recurrent diffuse large B-cell lymphoma, recurrent Hodgkin's lymphoma, relapsed / refractory multiple myeloma (RRMM), metastatic colorectal cancer (mCRC), metastatic castration-resistant prostate cancer (mCRPC), and lung cancer.

[0152] In some embodiments, the patient has moderate or severe liver dysfunction, hi some embodiments, the patient has normal liver function.

[0153] In some embodiments, the patient has moderate or severe renal impairment, hi some embodiments, the patient has normal renal function.

[0154] In some embodiments, the pharmaceutical dosage forms described herein may be administered orally. In some embodiments, the pharmaceutical dosage forms described herein may be administered once, twice, or three times a day. In some embodiments, the pharmaceutical dosage forms described herein may be administered once a day, or once every 2, 3, 4, 5, 6, or 7 days. In some embodiments, the pharmaceutical dosage forms described herein may be administered in cycles. For example, the pharmaceutical dosage forms described herein may be administered for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 days in each cycle.

[0155] Also provided is a pharmaceutical dosage form described herein for use in the treatment of cancer.

[0156] Combination therapy In one embodiment, the compounds, pharmaceutical compositions, and / or dosage forms disclosed herein can be used in combination with one or more additional therapeutic agents being used and / or developed to treat cancer, T-cell lymphoma, such as bone marrow / stem cell transplantation and / or CAR T cell therapy. In some embodiments, the pharmaceutical compositions or dosage forms described herein may include one or more anti-cancer agents in addition to azacitidine and cedazuridine.

[0157] The various agents can be administered sequentially or simultaneously (in separate compositions or the same composition). Classes of agents useful for combination therapy include, but are not limited to, kinase inhibitors, CDA inhibitors, and anti-PD-1 monoclonal antibodies.

[0158] In some embodiments, the one or more additional therapeutic agents can be trinapant or venetoclax. In some embodiments, the dosage form can include trinapant and / or venetoclax in addition to azacitidine and cedazuridine.

[0159] In some embodiments, the pharmaceutical composition comprising azacitidine and cedazuridine can be administered in combination with other therapeutic agents. In some embodiments, the other therapeutic agents can be ADI-PEG 20, AMG-176, APG-115, APR-246, avelumab, bendamustine, bisantrene, brentuximab vedotin, capecitabine, CB-839, cisplatin, CS-01, cusatuzumab, cyclophosphamide, cytarabine, dasatinib, daunorubicin, DCLL9718S, decitabine, deferasirox, dexamethasone, durvalumab, eltrombopag, enadidenib, entinostat, entrezolamide, cefotaxime ... Cuctinib, enzalutamide, epacadostat, erythropoietin, etoposide, evoluptacept, filgrastim, fludarabine phosphate, flumatinib, gemcitabine, gemtuzumab ozogamicin, gilteritinib, GM-CSF, GSK2879552, HMPL-523, homoharringtonine, IBI188, ibrutinib, idarubicin, itacitinib, ivosidenib, jactinib, KPT-8602, LDE 255, lenalidomide, lirilumab, LP-108, magrolimab, MAX-40279, mitoxantrone, mitoxantrone liposome, mocetinostat, moxifloxacin, nivolumab, ortasidenib, omacetaxine, oxaliplatin, paclitaxel, pembrolizumab, pevonedistat, pinometostat, prasinostat, quizartinib, revlimid, rigosertib, rituximab, romidepsin, RP721 4, S64315, S65487, sabatolimab, seclidemstat, selumetinib, siremadrine, sirolimus, SL-401, SNDX-5613, sorafenib, talazoparib, tamibarotene, trinapant, trastuzumab, tucidinostat, tyrosine kinase inhibitors, uprolaseran, velcade, venetoclax, vincristine, visilizumab, vorinostat, and vosaroxin. In treating any of the conditions described herein, the pharmaceutical compositions or dosage forms described herein can be administered in combination with non-chemotherapeutic treatments, such as iron, all-trans retinoic acid, allogeneic stem cell transplantation, and / or platelet transfusions.

[0160] kit Provided herein is a kit comprising a dosage form of the present disclosure in suitable packaging. In one embodiment, the kit further comprises a label and / or instructions for use of the dosage form in treating an indication, including a disease or condition described herein.

[0161] Dosage forms and excipients The oral dosage forms described herein are prepared in a manner known in the pharmaceutical arts, see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0162] Some embodiments described herein can be modified to include any additional suitable additive.Some examples of suitable additives include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose.The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate, sweeteners, and flavoring agents.

[0163] To prepare solid compositions such as tablets or capsules, the principal active ingredient may be mixed with pharmaceutical excipients to form solid preformulation compositions containing a homogenous mixture of the compounds described herein or their pharma- ceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs. When these preformulation compositions are referred to as homogenous, the active ingredient is dispersed evenly throughout the composition, such that the compositions may be readily subdivided into equally effective unit dosage forms, such as, for example, tablets, pills, and capsules.

[0164] The tablets or pills of the compounds described herein can be formulated to provide a dosage form that provides the advantage of sustained action or to protect against the acidic conditions of the stomach.For example, the tablets or pills can comprise an inner dosage component and an outer dosage component, the latter being in the form of an outer membrane that covers or coats the former.The two components can be separated by a seal coat that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be delayed in release.Various materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0165] In some embodiments, the pellets and / or tablets described herein further comprise a film coating, for example to limit photodegradation. A suitable film coating is selected by routine screening of commercially available preparations. In one embodiment, the film coating may be a polyvinyl alcohol-based coating. In some embodiments, the pharmaceutical composition described herein is formulated into a unit dosage form or pharmaceutical dosage form. The term "unit dosage form" or "pharmaceutical dosage form" refers to a physically separate unit suitable as a unitary dose for human patients and other mammals, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients, and is provided as, for example, a capsule. The dosage form is generally administered in a pharmacologic effective amount. In some embodiments, the dosage form is stored in aluminum strip packaging, moisture-proof blister foil, or bottle pack.

[0166] Embodiment Embodiment 1. A pharmaceutical dosage form comprising cedazuridine, or a pharma- ceutically acceptable salt thereof, and azacitidine, or a pharma- ceutically acceptable salt thereof, wherein at least a portion of the azacitidine is formulated for modified release.

[0167] Embodiment 2. The dosage form of embodiment 1, wherein at least a portion of the azacitidine is formulated for immediate release.

[0168] Embodiment 3. The dosage form of embodiment 1 or embodiment 2, wherein the cedazuridine is formulated for immediate release.

[0169] Embodiment 4. The dosage form of embodiment 3, wherein the cedazuridine is uncoated and in the form of minitablets, powder, blend, granules, or pellets.

[0170] Embodiment 5. A dosage form according to any of the preceding embodiments, comprising about 10%-40% w / w cedazuridine, based on the total weight of the uncoated cedazuridine minitablets, powder, blend, granules, or pellets.

[0171] Embodiment 6. The dosage form of embodiment 5, comprising about 20% w / w cedazuridine, based on the total weight of the uncoated cedazuridine minitablets, powder, blend, granules, or pellets.

[0172] Embodiment 7. The dosage form of any of the previous embodiments, further comprising, in weight percentages based on the total weight of the uncoated cedazuridine minitablets, powder, blend, granules, or pellets, about 40%-80% w / w lactose monohydrate, about 0.5-10% w / w hydroxypropyl methylcellulose (HPMC), about 1%-10% w / w croscarmellose sodium, about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate.

[0173] Embodiment 8. The dosage form of embodiment 7, further comprising, by weight percentage based on the total weight of the uncoated cedazuridine minitablets, powder, blend, granules, or pellets, about 71.5% w / w lactose monohydrate, about 2% w / w hydroxypropyl methylcellulose (HPMC), about 5% w / w croscarmellose sodium, about 1% w / w silicon dioxide, and about 0.5% w / w magnesium stearate.

[0174] Embodiment 9. The dosage form of any one of the previous embodiments, wherein the cedazuridine is in the form of minitablets or pellets.

[0175] Embodiment 10. The dosage form of any one of the preceding embodiments, wherein the portion of the azacitidine that is formulated for modified release is formulated for enteric release.

[0176] Embodiment 11. The dosage form of any one of the previous embodiments, wherein the portion of the azacitidine formulated for immediate release is provided as uncoated minitablets.

[0177] Embodiment 12. The dosage form of embodiment 1, wherein the portion of azacitidine formulated for modified release is provided as enteric coated minitablets.

[0178] Embodiment 13. A dosage form according to any one of the preceding embodiments, comprising about 20%-60% w / w azacitidine, based on the total weight of the uncoated azacitidine minitablets.

[0179] Embodiment 14. A dosage form according to any one of the preceding embodiments, comprising about 40% w / w azacitidine, based on the total weight of the uncoated azacitidine minitablets.

[0180] Embodiment 15. The dosage form of any one of the previous embodiments, further comprising lactose monohydrate, a filler, a binder, a disintegrant, a glidant, and a lubricant.

[0181] Embodiment 16. The dosage form of any one of the preceding embodiments, further comprising, in weight percentages based on the total weight of the uncoated azacitidine minitablets, about 10%-60% w / w lactose monohydrate, about 10%-60% w / w microcrystalline cellulose, about 0.5-10% w / w hydroxypropyl methylcellulose (HPMC), about 1%-10% w / w croscarmellose sodium, about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate.

[0182] Embodiment 17. The dosage form of any one of the preceding embodiments, further comprising, in weight percentages based on the total weight of the uncoated azacitidine minitablets, about 48.5% w / w lactose monohydrate, about 25% w / w microcrystalline cellulose, about 2% w / w hydroxypropyl methylcellulose (HPMC), about 5% w / w croscarmellose sodium, about 1% w / w silicon dioxide, and about 0.5% w / w magnesium stearate.

[0183] Embodiment 18. The dosage form of embodiment 11, wherein the uncoated azacitidine minitablets have an intragranular layer and an extragranular layer.

[0184] Embodiment 19. The dosage form of embodiment 18, wherein the intragranular layer comprises, in weight percentages based on the total weight of the uncoated azacitidine minitablets, about 20%-50% w / w azacitidine, about 10%-60% w / w lactose monohydrate, about 2%-60% w / w microcrystalline cellulose, about 1%-10% w / w croscarmellose sodium, about 0.5%-10% w / w hydroxypropyl methylcellulose (HPMC), about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate.

[0185] Embodiment 20. The dosage form of embodiment 18 or 19, wherein the extragranular layer comprises, in weight percentages based on the total weight of the uncoated azacitidine minitablets, about 1%-60% w / w microcrystalline cellulose, about 1%-10% w / w croscarmellose sodium, about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate.

[0186] Embodiment 21. The dosage form of any one of the preceding embodiments, wherein the portion of azacitidine formulated for enteric release comprises uncoated minitablets of azacitidine coated with a seal coat.

[0187] Embodiment 22. The dosage form of embodiment 21, wherein the seal coat comprises hydroxypropyl methylcellulose (HPMC).

[0188] Embodiment 23. A dosage form according to embodiment 21 or 22, wherein the minitablets coated with a seal coat are further coated with an enteric coating.

[0189] Embodiment 24. The dosage form of embodiment 23, wherein the enteric coating comprises ethylcellulose.

[0190] Embodiment 25. A dosage form according to embodiment 23 or 24, wherein the enteric coating is insensitive to pH fluctuations in the intestine.

[0191] Embodiment 26. A dosage form according to embodiment 23, wherein the enteric coating comprises polymethacrylate or a copolymer thereof.

[0192] Embodiment 27. A dosage form according to embodiment 23 or 26, wherein the enteric coating is sensitive to pH fluctuations in the intestine.

[0193] Embodiment 28. The dosage form of any one of the preceding embodiments, wherein about 0% to about 60% of the azacitidine is provided as uncoated minitablets and about 100% to about 50% of the azacitidine is provided as modified release coated minitablets.

[0194] Embodiment 29. The dosage form of any one of embodiments 1 to 27, wherein about 37% to about 60% of the azacitidine is provided as uncoated minitablets and about 40% to about 63% of the azacitidine is provided as modified release coated minitablets.

[0195] Embodiment 30. The dosage form of any one of embodiments 1, 3-28, wherein all of the azacitidine is formulated for modified release.

[0196] Embodiment 31. The dosage form of any one of embodiments 1, 3-28, wherein substantially all of the azacitidine is released outside the stomach.

[0197] Embodiment 32. A pharmaceutical dosage form comprising cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, wherein the cedazuridine is formulated for immediate release, at least a portion of the azacitidine is formulated for immediate release and provided as uncoated minitablets, and the remainder of the azacitidine is formulated for modified release and provided as enteric coated minitablets.

[0198] Embodiment 33. A pharmaceutical dosage form comprising cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, wherein the cedazuridine is formulated for immediate release and the azacitidine is formulated for modified release and provided as enteric coated minitablets.

[0199] Embodiment 34. A dosage form according to embodiment 32 or embodiment 33, wherein the azacitidine minitablets have an intragranular layer and an extragranular layer.

[0200] Embodiment 35. A pharmaceutical dosage form comprising cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, wherein the cedazuridine is formulated for immediate release and the azacitidine is formulated for modified release and provided as delayed release minitablets.

[0201] Embodiment 36. The dosage form of embodiment 35, wherein the azacitidine minitablets have an intragranular layer and an extragranular layer.

[0202] Embodiment 37. A dosage form according to any one of embodiments 32 to 36, wherein the cedazuridine is uncoated and in the form of minitablets, powder, blend, granules, or pellets.

[0203] Embodiment 38. The dosage form of embodiment 37, comprising about 20% w / w cedazuridine, based on the weight percentage of the total weight of the uncoated cedazuridine minitablets, powder, blend, granules, or pellets.

[0204] Embodiment 39. A dosage form according to any one of embodiments 32 to 38, comprising about 40% w / w azacitidine, based on the total weight of the uncoated azacitidine minitablets.

[0205] Embodiment 40. The dosage form of any one of the preceding embodiments, wherein the dosage form is a capsule comprising one or more cedazuridine minitablets and one or more azacitidine minitablets.

[0206] Embodiment 41. A pharmaceutical dosage form of a fixed dose combination comprising cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, wherein the cedazuridine and azacitidine are formulated for immediate release.

[0207] Embodiment 42. The dosage form of embodiment 41, wherein the dosage form is a tablet.

[0208] Embodiment 43. A pharmaceutical dosage form of a fixed dose combination comprising cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, wherein the cedazuridine and azacitidine are formulated for immediate release, and the dosage form is further coated with an enteric coating.

[0209] Embodiment 44. The dosage form of embodiment 43, wherein the dosage form is a tablet.

[0210] Embodiment 45. A pharmaceutical dosage form comprising cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof in the form of one or more azacitidine minitablets.

[0211] Embodiment 46. A pharmaceutical dosage form according to embodiment 45, wherein each azacitidine minitablet is coated with an enteric coating.

[0212] Embodiment 47. A pharmaceutical dosage form according to embodiment 46, wherein the enteric coating comprises polymethacrylate or a copolymer thereof.

[0213] Embodiment 48. A pharmaceutical dosage form according to embodiment 46 or 47, wherein the enteric coating is sensitive to pH fluctuations in the intestine.

[0214] Embodiment 49. A pharmaceutical dosage form according to any one of embodiments 46 to 48, wherein each azacitidine minitablet further comprises a seal coat.

[0215] Embodiment 50. The pharmaceutical dosage form of embodiment 49, wherein the seal coat comprises hydroxypropyl methylcellulose (HPMC).

[0216] Embodiment 51. A pharmaceutical dosage form according to any one of embodiments 45 to 50, wherein each azacitidine minitablet contains about 20% to 50% w / w azacitidine, as a weight percentage relative to the total weight of the uncoated azacitidine minitablets.

[0217] Embodiment 52. A pharmaceutical dosage form according to any one of embodiments 45 to 51, wherein each of the azacitidine minitablets has an intragranular layer and an extragranular layer.

[0218] Embodiment 53. A pharmaceutical dosage form according to embodiment 52, wherein the intragranular layer comprises, in weight percentages based on the total weight of the uncoated azacitidine minitablets, about 20%-50% w / w azacitidine, about 10%-60% w / w lactose monohydrate, about 2%-60% w / w microcrystalline cellulose, about 1%-10% w / w croscarmellose sodium, about 0.5%-10% w / w hydroxypropyl methylcellulose (HPMC), about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate.

[0219] Embodiment 54. A pharmaceutical dosage form according to embodiment 52 or 53, wherein the extragranular layer comprises, in weight percentages based on the total weight of the uncoated azacitidine minitablets, about 1%-60% w / w microcrystalline cellulose, about 1%-10% w / w croscarmellose sodium, about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate.

[0220] Embodiment 55. A pharmaceutical dosage form according to any one of embodiments 45 to 54, wherein each azacitidine minitablet contains about 4 mg of azacitidine.

[0221] Embodiment 56. A pharmaceutical dosage form according to any one of embodiments 45 to 65, comprising 8, 9 or 10 azacitidine minitablets.

[0222] Embodiment 57. A pharmaceutical dosage form according to any one of embodiments 45 to 56, comprising about 32 mg, 36 mg, or 40 mg of azacitidine.

[0223] Embodiment 58. A pharmaceutical dosage form according to any one of embodiments 45 to 57, wherein the cedazuridine is formulated for immediate release.

[0224] Embodiment 59. A pharmaceutical dosage form according to any one of embodiments 45 to 58, wherein the cedazuridine is in the form of uncoated minitablets, pellets or powder.

[0225] Embodiment 60. A pharmaceutical dosage form according to any one of embodiments 45 to 59, wherein the cedazuridine minitablets contain about 10% to 40% w / w cedazuridine, as a percentage by weight based on the total weight of the uncoated cedazuridine minitablets.

[0226] Embodiment 61. The dosage form of embodiment 60, comprising about 20% w / w cedazuridine, based on the total weight of the uncoated cedazuridine minitablets.

[0227] Embodiment 62. The dosage form of embodiment 60 or 61, further comprising, in weight percentages based on the total weight of the uncoated cedazuridine minitablets, powder, blend, granules, or pellets, about 40%-80% w / w lactose monohydrate, about 0.5-10% w / w hydroxypropyl methylcellulose (HPMC), about 1%-10% w / w croscarmellose sodium, about 0.1%-3% w / w silicon dioxide, and about 0.1%-3% w / w magnesium stearate.

[0228] Embodiment 63. A pharmaceutical dosage form according to any one of embodiments 45 to 62, comprising about 100 mg of cedazuridine.

[0229] Embodiment 64. A pharmaceutical dosage form according to any one of embodiments 51 to 63, further comprising venetoclax.

[0230] Embodiment 65. A capsule comprising a pharmaceutical dosage form according to embodiments 32 to 40.

[0231] Embodiment 66. A capsule comprising azacitidine and cedazuridine, the capsule having an enteric capsule shell.

[0232] Embodiment 67. A capsule according to embodiment 65 or 66, wherein the enteric capsule shell comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS) and / or hydroxypropyl methylcellulose (HPMC).

[0233] Embodiment 68. A capsule according to any one of embodiments 65 to 67, wherein the enteric capsule shell comprises a solid filled into the enteric capsule shell.

[0234] Embodiment 69. A capsule according to any one of embodiments 65 to 68, further comprising a buffer salt.

[0235] Embodiment 70. The capsule of embodiment 69, wherein the buffer salts are selected from sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris), sodium hydroxide, sodium citrate, sodium acetate, potassium acetate, citric acid and sodium or potassium citrate, amino acid salts, malic acid and sodium or potassium malate, tartaric acid and potassium or sodium tartrate, glutamic acid and sodium or potassium glutamate, and sodium carbonate.

[0236] Embodiment 71. A capsule according to any one of embodiments 65 to 70, further comprising about 10% to 50% w / w lactose monohydrate, about 10% to 50% w / w microcrystalline cellulose, about 1% to 20% w / w croscarmellose sodium, about 1% to 10% w / w HPMC, about 1% to 10% w / w silicon dioxide, and about 0.1% to 5% w / w magnesium stearate.

[0237] Embodiment 72. A capsule according to any one of embodiments 65 to 71, further comprising about 26.2% w / w lactose monohydrate, about 25.7% w / w microcrystalline cellulose, about 8% w / w croscarmellose sodium, about 2% w / w HPMC, about 2.1% w / w silicon dioxide, and about 1% w / w magnesium stearate.

[0238] Embodiment 73. A capsule according to any one of embodiments 65 to 72, comprising about 5% to 40% w / w azacitidine.

[0239] Embodiment 74. A capsule according to any one of embodiments 65 to 73, comprising about 10% w / w azacitidine.

[0240] Embodiment 75. A capsule according to any one of embodiments 66 to 74, comprising about 5% to 40% w / w cedazuridine.

[0241] Embodiment 76. A capsule according to any one of embodiments 66 to 75, comprising about 10% w / w cedazuridine.

[0242] Embodiment 77. A capsule according to any one of embodiments 65 to 76, further comprising about 5% to 25% w / w sodium phosphate.

[0243] Embodiment 78. A capsule according to any one of embodiments 65 to 77, further comprising about 15% w / w sodium phosphate.

[0244] Embodiment 79. A method for treating cancer in a patient, comprising administering to a patient in need thereof a dosage form described in any one of embodiments 1 to 64 or a capsule described in any one of embodiments 65 to 78.

[0245] Embodiment 80. The method of embodiment 79, wherein the cancer is leukemia.

[0246] Embodiment 81. The method of embodiment 79, wherein the cancer is selected from previously treated or untreated de novo or secondary myelodysplastic syndromes (MDS), previously treated or untreated de novo or secondary chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML), malignant peripheral nerve sheath tumors (MPNST), brain and spinal cord tumors, breast cancer, hormone receptor positive tumors, head and neck cancer, primary enchondroma, myeloproliferative neoplasms (MPN), recurrent B-cell non-Hodgkin's lymphoma, recurrent diffuse large B-cell lymphoma, recurrent Hodgkin's lymphoma, relapsed / refractory multiple myeloma (RRMM), metastatic colorectal cancer (mCRC), metastatic castration-resistant prostate cancer (mCRPC), and lung cancer.

[0247] Embodiment 82. The method of any one of embodiments 79 to 81, wherein the cancer is selected from previously treated or untreated de novo or secondary myelodysplastic syndrome (MDS), previously treated or untreated de novo or secondary chronic myelomonocytic leukemia (CMML), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML).

[0248] Embodiment 83. The method of any one of embodiments 79-82, wherein the cancer is associated with refractory anemia, refractory anemia with ringed sideroblasts, or refractory anemia with excess blasts.

[0249] Embodiment 84. The method of any one of claims 79 to 83, further comprising another therapeutic agent.

[0250] Embodiment 85. The additional therapeutic agent is ADI-PEG20, AMG-176, APG-115, APR-246, avelumab, bendamustine, bisantrene, brentuximab vedotin, capecitabine, CB-839, cisplatin, CS-01, cusatuzumab, cyclophosphamide, cytarabine, dasatinib, daunorubicin, DCLL9718S, decitabine, deferasirox, dexamethasone, durvalumab, eltrombopag, enadidenib, enezimidazole ... entinostat, entrectinib, enzalutamide, epacadostat, erythropoietin, etoposide, evoluptacept, filgrastim, fludarabine phosphate, flumatinib, gemcitabine, gemtuzumab ozogamicin, gilteritinib, GM-CSF, GSK2879552, HMPL-523, homoharringtonine, IBI188, ibrutinib, idarubicin, itacitinib, ivosidenib, jactinib, KPT-8602, L DE255, lenalidomide, lirilumab, LP-108, magrolimab, MAX-40279, mitoxantrone, mitoxantrone liposome, mocetinostat, moxifloxacin, nivolumab, ortasidenib, omacetaxine, oxaliplatin, paclitaxel, pembrolizumab, pevonedistat, pinometostat, prasinostat, quizartinib, revlimid, rigosertib, rituximab, romidepsin, RP7214, S6431 5, S65487, sabatolimab, seclidemstat, selumetinib, siremadrine, sirolimus, SL-401, SNDX-5613, sorafenib, talazoparib, tamibarotene, trinapanto, trastuzumab, tucidinostat, tyrosine kinase inhibitors, uprolaseran, velcade, venetoclax, vincristine, visilizumab, vorinostat, and vosaroxine.

[0251] Embodiment 86. A dosage form according to any one of embodiments 1 to 64 or a capsule according to any one of embodiments 65 to 78 for use in the treatment of cancer.

[0252] Embodiment 87. A dosage form according to any one of embodiments 1 to 64 or a capsule according to any one of embodiments 65 to 78 for use in the manufacture of a medicament for the treatment of cancer.

[0253] Embodiment 88. The dosage form of embodiment 87, wherein the cancer is leukemia.

[0254] Embodiment 89. The dosage form of embodiment 87, wherein the cancer is selected from previously treated or untreated de novo or secondary myelodysplastic syndromes (MDS), previously treated or untreated de novo or secondary chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML), malignant peripheral nerve sheath tumors (MPNST), neurocarcinoma, breast cancer, hormone receptor positive tumors, head and neck cancer, primary central chondrosarcoma, myeloproliferative neoplasms (MPN), recurrent B-cell non-Hodgkin's lymphoma, recurrent diffuse large B-cell lymphoma, recurrent Hodgkin's lymphoma, relapsed / refractory multiple myeloma (RRMM), metastatic colorectal cancer (mCRC), metastatic castration-resistant prostate cancer (mCRPC), and lung cancer.

[0255] Embodiment 90. The dosage form of any one of embodiments 86 to 89, wherein the cancer is selected from previously treated or untreated de novo or secondary myelodysplastic syndrome (MDS), previously treated or untreated de novo or secondary chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML).

[0256] Embodiment 91. The dosage form of any one of embodiments 86 to 90, wherein the cancer is associated with refractory anemia, refractory anemia with ringed sideroblasts, or refractory anemia with excess blasts.

[0257] Embodiment 92. Use of a dosage form according to any one of embodiments 1 to 64 or a capsule according to any one of embodiments 65 to 78 for the treatment of cancer.

[0258] Embodiment 93. Use of a dosage form according to any one of embodiments 1 to 64 or a capsule according to any one of embodiments 65 to 78 for the manufacture of a medicament for the treatment of cancer.

[0259] Embodiment 94. The use according to embodiment 92 or 93, wherein the cancer is leukemia.

[0260] Embodiment 95. The use according to embodiment 92 or 93, wherein the cancer is selected from previously treated or untreated de novo or secondary myelodysplastic syndromes (MDS), previously treated or untreated de novo or secondary chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML), malignant peripheral nerve sheath tumors (MPNST), brain and spinal cord tumors, breast cancer, hormone receptor positive tumors, head and neck cancer, primary enchondroma, myeloproliferative neoplasms (MPN), recurrent B-cell non-Hodgkin's lymphoma, recurrent diffuse large B-cell lymphoma, recurrent Hodgkin's lymphoma, relapsed / refractory multiple myeloma (RRMM), metastatic colorectal cancer (mCRC), metastatic castration-resistant prostate cancer (mCRPC), and lung cancer.

[0261] Embodiment 96. The use according to any one of embodiments 92 to 95, wherein the cancer is selected from previously treated or untreated de novo or secondary myelodysplastic syndrome (MDS), and previously treated or untreated de novo or secondary chronic myelomonocytic leukemia (CMML).

[0262] Embodiment 97. The use according to any one of embodiments 92 to 96, wherein the cancer is associated with refractory anemia, refractory anemia with ringed sideroblasts, or refractory anemia with excess blasts.

[0263] Embodiment 98. A combination for treating cancer, comprising cedazuridine or a pharma- ceutically acceptable salt thereof and azacitidine or a pharma- ceutically acceptable salt thereof, wherein the cedazuridine is formulated for immediate release and the azacitidine is formulated for modified release and provided as delayed release minitablets.

[0264] Embodiment 99. A capsule comprising azacitidine, the capsule having an enteric capsule shell.

[0265] Embodiment 100. A capsule as described in embodiment 99, further comprising cedazuridine.

[0266] Embodiment 101. A capsule according to embodiment 99 or 100, wherein the enteric capsule shell comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS) and / or hydroxypropyl methylcellulose (HPMC).

[0267] Embodiment 102. A capsule according to any one of embodiments 99 to 101, wherein the enteric capsule shell comprises a solid filled into the enteric capsule shell.

[0268] Embodiment 103. A capsule according to any one of embodiments 99 to 102, further comprising a buffer salt.

[0269] Embodiment 104. A capsule according to embodiment 103, wherein the buffer salts are selected from sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris), sodium hydroxide, sodium citrate, sodium acetate, potassium acetate, citric acid and sodium or potassium citrate, amino acid salts, malic acid and sodium or potassium malate, tartaric acid and potassium or sodium tartrate, glutamic acid and sodium or potassium glutamate, and sodium carbonate.

[0270] Embodiment 105. A capsule according to any one of embodiments 99 to 104, further comprising about 10%-50% w / w lactose monohydrate, about 10%-50% w / w microcrystalline cellulose, about 1%-20% w / w croscarmellose sodium, about 1%-10% w / w HPMC, about 1%-10% w / w silicon dioxide, and about 0.1%-5% w / w magnesium stearate.

[0271] Embodiment 106. The capsule of embodiments 99-105, further comprising about 26.2% w / w lactose monohydrate, about 25.7% w / w microcrystalline cellulose, about 8% w / w croscarmellose sodium, about 2% w / w HPMC, about 2.1% w / w silicon dioxide, and about 1% w / w magnesium stearate.

[0272] Embodiment 107. A capsule according to any one of embodiments 99 to 106, comprising about 5% to 40% w / w azacitidine.

[0273] Embodiment 108. A capsule according to any one of embodiments 99 to 107, comprising about 10% w / w azacitidine.

[0274] Embodiment 109. A capsule according to any one of embodiments 100 to 108, comprising about 5% to 40% w / w cedazuridine.

[0275] Embodiment 110. A capsule according to any one of embodiments 100 to 109, comprising about 10% w / w cedazuridine.

[0276] Embodiment 111. A capsule as described in embodiments 99 to 110, further comprising about 5% to 25% w / w sodium phosphate.

[0277] Embodiment 112. The capsule of any one of embodiments 99 to 111, further comprising about 15% w / w sodium phosphate.

[0278] Embodiment 113. A method for treating cancer in a patient, comprising administering to a patient in need thereof a capsule described in any one of embodiments 99 to 113.

[0279] Embodiment 114. The method of embodiment 113, wherein the cancer is selected from previously treated or untreated de novo or secondary myelodysplastic syndrome (MDS), and previously treated or untreated de novo or secondary chronic myelomonocytic leukemia (CMML).

[0280] Embodiment 115. The method of embodiment 113 or 114, wherein the cancer is associated with refractory anemia, refractory anemia with ringed sideroblasts, or refractory anemia with excess blasts.

[0281] Embodiment 116. A capsule of embodiments 99 to 113 for use in treating cancer. EXAMPLES

[0282] The following examples are included to demonstrate specific embodiments of the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in these examples represent techniques that work well in the implementation of the present disclosure and therefore can be considered to constitute specific modes for its implementation. However, those skilled in the art should understand in light of the present disclosure that many changes can be made to the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the present disclosure.

[0283] Example 1: Coated FDC Cedazuridine and Azacitidine Tablets Both azacitidine and cedazuridine were formulated for modified release. Fixed dose combination (FDC) 20 mg azacitidine and cedazuridine oval tablets (Table 1) with a core tablet weight of 500 mg were first seal coated and then coated with a 70 / 30 ratio of Surelease®:HPMC pore former as a functional coating at 12% and 15% coating weight gain. The compositions of the seal and Surelease® coats are shown in Tables 1-2 and 1-3, respectively. PK studies were performed on both the 12% and 15% weight gain modified release tablets. [Table 1] [Table 2] [Table 3] *Suarease dispersion with 25% solids

[0284] Manufacturing Process Azacitidine, cedazuridine, and all the intragranular layer excipients were dispensed into separate containers and sieved manually through 30 mesh. The sieved azacitidine, cedazuridine, and the intragranular layer excipients, except for magnesium stearate, were added to a Turbula T2 blender with appropriate capacity and mixed at 25 rpm for 15 minutes. The intragranular layer magnesium stearate was then sieved and added to the blend and lubrication blended in the Turbula T2 mixer blender at 25 rpm for 3 minutes.

[0285] The inner granular layer blend was then roller compacted into ribbons and the ribbons were crushed into granules. The crushed granules were blended with the sieved outer granular layer additives to make the final blend. The final blend was compressed into tablets using oval tooling on a Ronchi single punch eccentric tablet press. The target tablet weight was 500 mg ± 10%.

[0286] Uncoated tablets were seal coated at 1% weight gain followed by a functional coating of Suarease to adjust the dissolution profile. Coloron's HPMC (Opadry® Complete Coating System YS-1-19025-A-Clear) was used for both the seal coat and the pore former in an ethylcellulose dispersion (Suarease®) for the functional coating. Seal coated tablets were coated with Suarease®: pore former at 12% and 15% weight gain. Coating was done in a pan coater.

[0287] Dissolution Profile The coated FDC tablets (12% and 15% weight gain) were tested for dissolution in a basket in 500 mL of pH 6.8, 50 mM sodium phosphate buffer at a bath temperature of 37° C. and an agitation speed of 75 rpm. Drug release data was collected at 30, 60, 90, 120, 180, 300 minutes, and at 315 minutes at a speed of 250 rpm as infinity. The drug release profile of azacitidine is shown in Figure 1.

[0288] Example 2: Uncoated Cedazuridine 20 mg Tablets and Coated / Uncoated Azacitidine 5 mg Minitablets Manufacturing Process Azacitidine and cedazuridine were sieved through a 30 mesh and premixed with all excipients listed in Tables 2-1 and 2-2, except for magnesium stearate. Magnesium stearate was then sieved and added to the blend and blended. The final blend was compressed into 0.25 inch round minitablets by direct compression. The target weight of the minitablets was 100 mg ± 7.5 mg. [Table 4] [Table 5]

[0289] A portion of the azacitidine minitablets were first seal coated at 2% weight gain, followed by a functional coating of Sulease® with pore formers at a ratio of 70:30. Colorcon's Opadry complete coating system YS-1-19025-A-Clear was used as the pore former in the ethylcellulose dispersion (Sulease) for both the seal coat and the functional coating. The seal coated azacitidine minitablets were further coated with an enteric coating at 12% weight gain using Sulease / HPMC pore formers. Coating was performed in a pan coater. The compositions of the seal coat and enteric coating are listed in Tables 2-3 and 2-4. [Table 6] [Table 7]

[0290] Dissolution profile of azacitidine Both coated and uncoated azacitidine minitablets were tested in a dissolution study. Dissolution data was collected by placing four coated or uncoated azacitidine minitablets (5 mg) in a size 0 HPMC capsule (Vcap plus). Dissolution testing was performed in a basket in 500 mL of pH 6.8, 50 mM sodium phosphate buffer at a bath temperature of 37° C. and an agitation speed of 75 rpm. Drug release data was collected at 120 minutes (considered to be infinity) at speeds of 15, 30, 45, 60, 90, 105, and 250 rpm. The release data for azacitidine is shown in FIG. 2.

[0291] As shown in FIG. 2, four uncoated azacitidine minitablets (total 20 mg) showed immediate release with over 85% released in 30 minutes, while the coated azacitidine minitablets had a lag time of 30 minutes followed by complete release in 90 minutes.

[0292] For the combination of coated and uncoated azacitidine tablets in capsules, the dissolution profile was tested under the same conditions for two uncoated azacitidine minitablets and the remaining two coated azacitidine minitablets. Drug release data was collected at 15, 30, 45, 60, 90, and 105 minutes. The azacitidine release data is shown in Figure 3.

[0293] The dissolution release profiles of azacitidine from dosage forms containing coated and uncoated azacitidine minitablets in ratios of 1:1 and 1:2 (uncoated:coated) at pH 6.8 are shown in Figure 4. As shown in Figure 4, dosage forms with more coated azacitidine minitablets showed a more delayed release of azacitidine.

[0294] Example 3: Uncoated cedazuridine 20 mg tablets and 4 mg azacitidine (intragranular and extragranular layers) minitablets Manufacturing Process 20 mg cedazuridine round tablets were prepared by direct compression. The composition of the cedazuridine core is shown in Table 3-1. Each excipient and cedazuridine, except magnesium stearate, were sieved through 30 mesh and blended in a 1.5 L V-blender at 25 rpm for 15 minutes. The blended cedazuridine and excipients were then mixed with hand sieved magnesium stearate and blended again at 25 rpm for 3 minutes. The final blend was compressed into round (0.25 inch) tablets by direct compression in a Korsch XL-100 press. The cedazuridine tablets were not coated and were used as immediate release minitablets. [Table 8]

[0295] Azacitidine minitablets with intragranular and extragranular layers were prepared with two different compositions ("Core 1" and "Core 2") in Table 3-2. Azacitidine and all intragranular layer excipients were dispensed into separate containers and sieved through 30 mesh. The sieved azacitidine and intragranular layer excipients, except magnesium stearate, were added to a blender with appropriate capacity and mixed at 25 rpm for a predetermined time. Magnesium stearate for the intragranular layer was then sieved and added to the blend for lubrication blending. The intragranular layer blend was then roller compacted into ribbons and the ribbons were milled into granules. The milled granules were blended with the extra sieved extragranular layer excipients to make the final blend. The final blend was compressed into minitablet tablets using 2.5 mm circular plain face tooling. The target weight of the tablets was 10 mg ± 10% and the target hardness range was between 1-3 kp. [Table 9]

[0296] Uncoated tablets were seal coated at 5% weight gain followed by a functional coating of Suarease to adjust the dissolution profile. Coloron's HPMC (Opadry® Complete Coating System YS-1-19025-A-Clear) was used for both the seal coat and the pore former in the ethylcellulose dispersion (Suarease) for the functional coat. "Core 1" minitablets were coated with 75:25 (Suarease®:pore former) at 20% weight gain and "Core 2" minitablets were coated with 80:20 Suarease:pore former at 15% weight gain. The coating compositions are listed in Tables 3-3 and 3-4. Both the seal coat and functional coating of the minitablets were done in a Wuster coater. [Table 10] [Table 11] * Suarease dispersion with 25% solids

[0297] Dissolution Profile In the dissolution study, five coated or uncoated azacitidine minitablets at each weight gain (15% and 20%) were tested for dissolution in a size 0 VCAPS Plus capsule for a total dose of 20 mg. The dissolution study was carried out in a basket in 500 mL of pH 6.8, 50 mM sodium phosphate buffer at a bath temperature of 37° C. and an agitation speed of 75 rpm. Drug release data was collected at 0, 30, 45, 60, 90, 120, 180 minutes and at 195 minutes (considered to be infinity) at a speed of 250 rpm. The release profiles of all three groups are shown in FIG. 6.

[0298] Dissolution results showed that uncoated azacitidine minitablets released azacitidine within 30 minutes, followed by 15% coated azacitidine minitablets with an 80 / 20 Surelease:pore former ratio, and then 20% coated azacitidine minitablets with a 75 / 25 Surelease:pore former ratio, as shown in Figure 6. Drug release was extended to 90 and 120 minutes for the 15% and 20% coated minitablets, respectively.

[0299] Example 4: Uncoated cedazuridine 20 mg tablets and triple-coated 4 mg azacitidine (intragranular and extragranular layers) minitablets Manufacturing method Uncoated cedazuridine 20 mg minitablets and uncoated azacitidine 4 mg minitablets were prepared using the method described in Example 3. The compositions of the cedazuridine and azacitidine minitablets are shown in Tables 4-1 and 4-2. [Table 12] [Table 13]

[0300] Uncoated azacitidine minitablets were seal coated at a 2% weight gain, followed by an intermediate coating at a 20% weight gain, and a final coating with Eudragit® polymer at a 5.3% weight gain with the two polymers, corresponding to a total weight gain of 8.5%.

[0301] Both the seal coat and functional coat of the minitablets were done on a Wuster coater. The compositions of the seal, intermediate and functional coats are shown in Tables 4-3, 4-4 and 4-5, respectively. [Table 14] [Table 15] [Table 16]

[0302] Dissolution Test In the dissolution study, five coated azacitidine minitablets with a polymer weight gain of 5.3% were placed in a size 1 VCAPS plus capsule for a total dose of 20 mg and tested for dissolution.

[0303] Dissolution tests were performed in 500 mL of dissolution medium in a basket at a bath temperature of 37° C. and an agitation speed of 75 rpm in two stages, namely an acid stage of 0.1 N HCl, pH 1.2, and a buffer stage of 50 mM phosphate buffer, pH 6.8. Minitablets coated with Eudragit® polymer prevented the release of azacitidine in the acid stage, followed by a rapid release in the buffer stage at pH 6.8 after switching the medium at 120 min (FIG. 7). As shown in FIG. 7, azacitidine was not released during the first 2 h under acidic conditions, but azacitidine was mostly released after transfer to pH 6.8, confirming the pH sensitivity of the Eudragit® L30D coating. Furthermore, Eudragit® coated minitablets with a 5.3% weight gain showed sufficient protection in the acid stage, followed by a rapid release in the buffer stage at pH 6.8 after switching the medium at 120 min.

[0304] Example 5-1: Uncoated cedazuridine 20 mg tablets and bilayer coated 4 mg azacitidine (intragranular and extragranular layers) minitablets Uncoated cedazuridine 20 mg tablets of Example 4 were provided. Azacitidine and all intragranular layer additives except magnesium stearate listed in Table 5-1 were dispensed into an 8 quart V Shell attached to a PK blender and mixed for 10 minutes at 25 rpm. The preblend was sieved through a Quadro Comil Model U3 equipped with a 032R screen and a circular impeller at a speed of 4500 + / - 100 rpm. The sieved material was returned to the blender and mixed again for 10 minutes at 25 rpm. Magnesium stearate was hand sieved through 30 mesh and added to the blender and mixed for 10 minutes at 25 rpm. The intragranular layer blend was roller compacted in an Alexander Burke roller compactor at a roller speed of 4.0 rpm, a compaction force of 4.0 KN / cm, and a feed screw speed of 20 rpm. The ribbons were milled on a granulator equipped with a 0.80 mm screen at a speed of 100 rpm. The amount of extragranular layer additives was adjusted based on the yield of the milled granules of the inner granule layer. The extragranular layer additives were hand sieved through 30 mesh. Both the milled granules of the inner granule layer and the extragranular layer additives except for magnesium stearate were transferred to a blender and mixed for 10 minutes at 25 rpm. The sieved magnesium stearate was added to the blended material and mixed for 3 minutes at 25 rpm. The final blend was compressed into mini-tablets using 2.5 mm diameter circular tooling on a Natoli RD30 press. The target weight of the mini-tablets was 10 mg ± 1.0 mg and the hardness measured by Scotax hardness tester was 1-3 KP. [Table 17]

[0305] Uncoated azacitidine 4 mg minitablets were coated with the ingredients listed in Tables 5-2 and 5-3 using the method described in Example 2. A weight gain of 15% or 20% was used. [Table 18] [Table 19]

[0306] The dissolution profiles of coated azacitidine minitablets (15% and 20% weight gain) were measured using the method described in Example 2. Drug release data were collected at 0, 30, 45, 60, 90, 120, 180 and 195 minutes (considered to be infinity). Figure 5 shows the dissolution release profile of azacitidine at pH 6.8.

[0307] Example 5-2: Uncoated cedazuridine 20 mg tablets and triple-coated 4 mg azacitidine (intragranular and extragranular layers) minitablets Instead of the coating described in Example 5-1, uncoated azacitidine 4 mg minitablets having an intragranular layer and an extragranular layer were seal coated with two layers using the ingredients listed in Table 5-4 (first layer) and Table 5-5 (second layer). The seal coated azacitidine pellets were further coated with a delayed release coating using the ingredients listed in Table 5-6. [Table 20] [Table 21] [Table 22]

[0308] Example 6: Uncoated cedazuridine 20 mg tablets and bilayer coated 4 mg azacitidine (intragranular and extragranular layers) minitablets Manufacturing Process 20 mg cedazuridine round tablets were prepared by direct compression. The composition of the cedazuridine core tablet is listed in Table 6-1. The individual excipients and cedazuridine, except for magnesium stearate, were sieved through 30 mesh and blended in a 1.5 L V-blender for 15-20 minutes. The blended cedazuridine and excipients were then mixed with the sieved magnesium stearate and blended again in the V-blender for 5 minutes. The cedazuridine tablets were compressed into round (0.25 inch) tablets by direct compression in a Korsch XL-100 press. [Table 23]

[0309] Azacitidine and all the intragranular layer excipients were dispensed into separate containers and sieved through 30 mesh. The composition of the azacitidine core tablets is listed in Table 6-2. The sieved azacitidine and the intragranular layer excipients, except for magnesium stearate, were added to a 5L Bohle blender and mixed at 25 rpm for 10 minutes. Magnesium stearate was then sieved and added to the blend and lubrication blended in a 5L Bohle blender at 25 rpm for 3 minutes. The intragranular layer blend was roller compacted into ribbons in a Gereteis FMX1064 and the ribbons were milled into granules. The milled granules were blended with the sieved extragranular layer excipients, except for magnesium stearate, in the same 5L Bohle blender at 25 rpm for 10 minutes. The sieved magnesium stearate was added to the remainder of the blend and mixed again at 25 rpm for 3 minutes. The final blend was compressed into minitablets using 2.5 mm circular plain face tooling. The target tablet weight was 10 mg ± 10% and the target hardness range was 1-3 kp. [Table 24]

[0310] The uncoated tablets were seal coated at a weight gain of 2% and then functionally coated with Eudragit® polymer (L30D-55) at a weight gain of 4.0% polymer. Both the seal and functional coating of the minitablets were done in a Wurster coater, GPCG2, 3L. The compositions of the seal coat and enteric coat are shown in Tables 38 and 40, and the process parameters are shown in Tables 6-3 and 6-4. [Table 25] [Table 26]

[0311] Dissolution Test In the dissolution study, five coated azacitidine minitablets with 4.0% weight gain with polymer were tested for dissolution in a size 1 VCAP plus capsule for a total dose of 20 mg. The dissolution study was performed in two stages, an acid stage of 0.1 N HCl, pH 1.2, and a buffer stage of 50 mM phosphate buffer, pH 6.8, in a basket with 500 mL of dissolution medium at a bath temperature of 37° C. and an agitation speed of 75 rpm. As shown in FIG. 8, the minitablets coated with Eudragit® polymer prevented the release of azacitidine in the acid stage, followed by rapid release in the buffer stage at pH 6.8 after switching media at 120 min.

[0312] Example 7: Uncoated Cedazuridine 100 mg Tablets and Coated Azacitidine 4 mg Minitablets Uncoated cedazuridine 100 mg tablets were prepared using the ingredients listed in Table 7-1 and the method described in Example 6. Eudragit® coated azacitidine 4 mg minitablets were prepared using the ingredients listed in Table 7-2. [Table 27] [Table 28]

[0313] In the dissolution test, 100 mg of uncoated cedazuridine tablets were placed in size 0 Vcaps®Plus capsules and tested for dissolution. The dissolution test was carried out in 900 mL of dissolution medium in a basket at a bath temperature of 37° C. and an agitation speed of 75 rpm in two stages, namely an acid stage of 0.1 N HCl, pH 1.2 and a buffer stage of 50 mM phosphate buffer, pH 6.8, with a switchover at 120 minutes. Drug release data was collected at 0, 15, 30, 60, 90, 120, and 135 minutes (considered to be infinity). The release profile is shown in FIG. 9. As shown in FIG. 9, the uncoated cedazuridine tablets are completely dissolved in about 30 minutes of the acid stage before the medium changeover.

[0314] In the dissolution test, five enteric coated azacitidine minitablets were placed in size 0 Vcaps®Plus capsules and tested for dissolution. The dissolution test was performed in 500 mL of dissolution medium in a basket at a bath temperature of 37° C. and an agitation speed of 75 rpm in two stages: an acid stage of 0.1 N HCl, pH 1.2, and a buffer stage of 50 mM phosphate buffer, pH 6.8. The minitablets coated with Eudragit® polymer prevented the release of azacitidine in the acid stage, followed by rapid release in the buffer stage at pH 6.8 after switching media at 120 minutes. Drug release data was collected at 0, 60, 120, 135, 150, 165, 180, and 195 minutes (considered to be infinity). The release profile is shown in FIG. 10. As shown in FIG. 10, minitablets coated with Eudragit® polymer prevented the release of azacitidine in the acid stage, followed by rapid release in the buffer stage at pH 6.8 after medium switching at 120 min.

[0315] To test the dissolution of enteric coated azacitidine minitablets at various pH, five enteric coated azacitidine minitablets were placed in size 0 Vcaps®Plus capsules and tested for dissolution. Dissolution tests were performed in six groups each of pH 2.3, 3.0, 4.5, 5.2, 5.5, and 6.0 buffers at a bath temperature of 37° C. in a basket at an agitation speed of 75 rpm. Drug release data was collected at 120 minutes (considered to be infinity) at speeds of 0, 15, 30, 45, 60, 90, and 250 rpm. The release profiles of all six groups are shown in FIG. 11. As shown in FIG. 11.

[0316] Example 8: Preparation of Cedazuridine Blend Powder Cedazuridine blend powders having the composition in Table 8-1 are prepared and can be used in capsules, optionally in place of uncoated tablets of cedazuridine. Cedazuridine and all other excipients except magnesium stearate are hand sieved through 30 mesh and transferred to a 5L Bohle blender and mixed for 10 minutes at 25 rpm. Magnesium stearate is hand sieved through 30 mesh and transferred to a blender and mixed with the drug and other excipients for 3 minutes at 25 rpm. The cedazuridine powder blend formulation can be filled into capsules. [Table 29]

[0317] Example 9: Preparation of capsules containing the combination of Example 7 An uncoated 100 mg cedazuridine tablet (from Example 7) and ten coated 4 mg azacitidine minitablets (from Example 7) were placed into a Vcaps® Plus capsule. The composition of the resulting capsule is listed in Table 9. [Table 30]

[0318] Example 10: Preparation of capsules containing cedazuridine powder and coated azacitidine minitablets 100 mg of cedazuridine powder from Example 8 and 10 coated 4 mg azacitidine minitablets from Example 7 are placed in a Vcaps®Plus capsule. In the dissolution test, 100 mg of cedazuridine powder is placed in a size 0 Vcaps®Plus capsule and tested for dissolution. The dissolution test is performed in 900 mL of dissolution medium in a basket at a bath temperature of 37° C. and an agitation speed of 75 rpm in two stages, namely an acid stage of 0.1 N HCl, pH 1.2 and a buffer stage of 50 mM phosphate buffer, pH 6.8, with a switching time of 120 minutes. Drug release data is collected at 0 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes and 195 minutes (considered to be infinity).

[0319] In the dissolution test, the enteric coated azacitidine minitablets are placed in size 0 Vcaps®Plus capsules and tested for dissolution. The dissolution test is carried out in 500 mL of dissolution medium in a basket at a bath temperature of 37° C., stirring speed of 75 rpm in two stages: an acid stage of 0.1 N HCl, pH 1.2 and a buffer stage of 50 mM phosphate buffer, pH 6.8. Drug release data is collected at 0, 30, 45, 60, 90, 120, 180 and 195 minutes (considered to be infinity).

[0320] Example 11: Enteric-coated capsules filled with azacitidine and cedazuridine Approximately 8-10 gram batches of a powder mix of cedazuridine and azacitidine were prepared and filled into capsule shells. The powder composition is shown in the table below.

[0321] The cedazuridine and azacitidine in powder form, half of the lactose monohydrate, half of the Avicel® PH-102, and the remaining excipients except for magnesium stearate were individually sieved through a 0.6 mm sieve and transferred to an 8 oz. container.

[0322] The remaining lactose monohydrate and Avicel® PH-102 were used to dry wash the cedazuridine and decitabine containers, respectively. Half of the total amount of Avicel® PH-102 and lactose monohydrate listed in the table below were used for the dry wash. After the dry wash, both additives were sieved through a 0.6 mm sieve and added to the blending vessel. The mixture was premixed in a Turbula shaker at 25 rpm for 15 minutes, followed by sieving through a 0.6 mm sieve and blending for another 15 minutes at 25 rpm. The weight of the resulting blend was weighed and used to adjust the amount of magnesium stearate, which was hand sieved through a 0.6 mm sieve. The sieved magnesium stearate was then added to the blend and blended for 3 minutes at 25 rpm.

[0323] The final blend was hand filled into Vcaps® enteric capsule shells (purchased from Capsugel) at a predetermined fill weight of 200 mg±3 mg per capsule.

[0324] The capsules were packaged in eight 30cc white HDPE bottles with 2 x 1g desiccant canisters per bottle. The bottles were capped with 28mm child resistant closures and induction sealed.

[0325] The ingredients and weight ratios for a capsule containing 20 mg azacitidine and 20 mg cedazuridine are shown in Table 11 below. [Table 31]

[0326] Example 12: Cedazuridine and Azacitidine FDC Tablets Both azacitidine and cedazuridine were formulated for immediate release. Fixed dose combination (FDC) oval tablets of 20 mg azacitidine and cedazuridine were prepared using the method described in Example 1 with a core tablet weight of 500 mg (Table 12). [Table 32]

[0327] Example 13: Pharmacokinetic (PK) study in monkeys using the dosage form of Example 1 Twelve monkeys were divided into three groups of four monkeys each, and group 1 received uncoated 20 mg cedazuridine / 20 mg azacitidine tablets as a control, group 2 received coated tablets with a 12% weight gain, and group 3 received coated tablets with a 15% weight gain orally into the stomach via a gastric tube once daily. Blood samples (approximately 0.8 mL) were collected pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours post-dose on days 1 and 2. PK data were evaluated from the collected blood samples. The PK data for azacitidine are shown in Tables 13-1 and 13-2 and in FIG. [Table 33] [Table 34]

[0328] The data show that the release profile of azacitidine can be modified using Sulease® (ethylcellulose) coating with a pore former. As shown in Figure 12, tablets coated with 12% and 15% weight gains gave lag times of 30 minutes to 1.5 hours, respectively. Drug release was extended to 4-5 hours for 12-15% coated tablets versus 30 minutes for uncoated tablets. The 12% and 15% coated tablets performed poorly in PK studies compared to uncoated tablets. As shown in Tables 13-1 and 13-2, the 15% weight gain tablets performed worse than the 12%. AUC and C max The decrease in may be a result of the longer lag time and sustained release of 4-5 hours for the 12% and 15% coated tablets.

[0329] Example 14: Pharmacokinetic (PK) study in monkeys with the combination of Example 2 Two different doses of azacitidine, 20 mg and 30 mg, are studied in monkeys to evaluate the pharmacokinetics (PK), with 10 mg delivered as immediate release and the remainder of the azacitidine dose delivered as delayed release.

[0330] PK data in monkeys was collected for coated minitablets at 12% weight gain at two different dose levels of azacitidine, 20 mg and 30 mg, in combination with uncoated cedazuridine minitablets. Either 50% or 33% of the total azacitidine dose was administered as immediate release, and the remaining dose was administered as delayed release. Control group 1 contained both uncoated azacitidine and cedazuridine at a dose of 20 mg. The dose groups for the PK study were as follows:

[0331] Group 1 (control): 20 mg cedazuridine immediate release + 20 mg azacitidine immediate release.Group 2: 20 mg cedazuridine immediate release + 10 mg azacitidine immediate release + 10 mg azacitidine controlled release.Group 3: 20 mg cedazuridine immediate release + 10 mg azacitidine immediate release + 20 mg azacitidine controlled release.The dosing protocol is shown in Table 14-1. [Table 35]

[0332] Tables 14-2 and 14-3 show data from days 1 and 2 of the study. [Table 36] * Include outliers [Table 37] * Includes one outlier

[0333] Figure 13 shows the time profile of the mean cedazuridine concentration for the three groups on days 1 and 2. Figure 14 shows the time profile of the mean azacitidine concentration for the three groups on days 1 and 2. Azacitidine round minitablets containing 5 mg azacitidine coated with 12% weight gain of Suarease®:pore former (70:30) extended the release of drug to 90 minutes. Bioavailability and exposure were improved by delivering cedazuridine as immediate release and azacitidine as a combination of immediate release and modified release. On day 2, the plasma concentration of group 2, in which a 20 mg azacitidine dose was delivered as 50% immediate release and 50% modified release, was slightly lower compared to the azacitidine plasma concentration in the control group. However, Group 3, with a 30 mg azacitidine dose in which 33% of the azacitidine dose was delivered as immediate release and 67% of the azacitidine dose was delivered as modified release, had higher plasma concentrations compared to the control group.

[0334] Example 15: Pharmacokinetic (PK) study in monkeys using the combination of Example 3 In this study, azacitidine was delivered only as delayed release at three different dose levels: 20mg, 32mg and 40mg, and two different coating weight gains (15%, 20%). The dose of cedazuridine remained constant at 20mg in all groups and was delivered as immediate release as described in Example 3. Azacitidine was delivered in the form of minitablets in HPMC capsules in this round of PK study. Each minitablet contained 4mg of azacitidine as described in Example 3. The PK study was divided into two parts, corresponding to the three different azacitidine doses and the two different coating weight gains.

[0335] Dose arm of PK study The composition of the different dose groups for the PK study is summarized below and in Table 15-1. The PK study was divided into two parts based on the drug release data for the two different coating weight gains. The dose of azacitidine was incrementally increased between groups from 20 mg to 40 mg. Cedazuridine was delivered at a dose of 20 mg as an immediate release.

[0336] Part 1 of the PK study, total of 4 arms (faster release) Group 1 (control): 20 mg immediate release cedazuridine + 20 mg immediate release azacitidine. Group 2: 20 mg immediate release cedazuridine + 20 mg 80 / 20 coated azacitidine at 15% weight gain. Group 3: 20 mg immediate release cedazuridine + 32 mg 80 / 20 coated azacitidine at 15% weight gain. Group 4: 20 mg immediate release cedazuridine + 40 mg 80 / 20 coated azacitidine at 15% weight gain.

[0337] Part 2 of the PK study, total of 4 arms (slower release) Group 1 (control): 20 mg immediate release cedazuridine + 20 mg immediate release azacitidine. Group 5: 20 mg immediate release cedazuridine + 20 mg 75 / 25 coated azacitidine at 20% weight gain. Group 6: 20 mg immediate release cedazuridine + 32 mg 75 / 25 coated azacitidine at 20% weight gain. Group 7: 20 mg immediate release cedazuridine + 40 mg 75 / 25 coated azacitidine at 20% weight gain. [Table 38]

[0338] Part 1 PK study PK data in monkeys was collected for 15% and 20% coated minitablets at three different dose levels of azacitidine, 20 mg, 32 mg, and 40 mg, in combination with uncoated cedazuridine tablets. Control group 1 contained both uncoated azacitidine and cedazuridine at a dose of 20 mg. Part 1 of the PK study was conducted with the coated minitablets at a 15% weight gain. PK data for Part 1 of the study are shown in Tables 15-2 and 15-3 and Figure 15. Based on the PK data collected in Part 1 of the study, the mean exposure in Group 2 was comparable to control Group 1 with the same dose of azacitidine, although two of the three animals showed much lower exposure. The higher doses of 30 mg and 40 mg offset the loss of absorption with the coated minitablets. [Table 39] [Table 40]

[0339] Part 2 PK study Minitablets coated with 20% weight gain were used in Part 2 of the PK study. PK data for Part 2 of the study are in Tables 15-4 and 15-5. Figure 16 shows the mean azacitidine concentration profile for minitablets coated with 20% weight gain in a 75 / 25 ratio. In Group 5, which received the same dose of azacitidine 20 mg in a delayed release format, the AUC 0-inf is 265ng * hr / mL to 229ng * However, groups 6 and 7 outperformed control group 1, with exposure levels equal to or higher than the control group on day 2. [Table 41] [Table 42]

[0340] As shown in Figures 15 and 16, 20 mg azacitidine minitablets coated with Surelease:pore former (80:20) at a 15% weight gain extended the release of azacitidine to 90 minutes, and minitablets coated with Surelease:pore former (75:25) at a 20% weight gain extended the release of azacitidine to 120 minutes.

[0341] As shown in Tables 15-2 and 15-4, based on the azacitidine data on Day 2, the AUC 0-last In the 20 mg azacitidine dose delivered as modified release, the azacitidine AUC was slightly lower compared to the control group in which azacitidine was delivered as immediate release. However, in all other groups, Groups 3 and 6 (32 mg dose) and Groups 4 and 7 (40 mg dose), azacitidine exposure was higher compared to the AUC of the control group.

[0342] Example 16: Pharmacokinetic (PK) study in monkeys using the combination of Example 4 In this study, azacitidine was delivered as delayed release at two different dose levels, 20 mg and 40 mg, with a weight gain of 5.3% enteric coating. The dose of cedazuridine remained constant at 20 mg in all groups and was delivered as immediate release. In the PK study, azacitidine was delivered in the form of minitablets in HPMC capsules. Each minitablet contained 4 mg of azacitidine. The azacitidine minitablets were coated with Eudragit® enteric coating, a three-layer enteric coating that prevents the release of the drug in the acidic phase (pH 1.2) followed by rapid release in the subsequent buffer phase at pH 6.8. The innermost layer is a seal coat, followed by an intermediate coat containing an alkaline agent and a final outer enteric coating with Eudragit® polymer. Eudragit® L30-D55 polymer was used to obtain the enteric coating on the azacitidine minitablets.

[0343] PK research The PK dose groups used in this study were: Group 1 (control): 20 mg immediate release cedazuridine + 20 mg immediate release azacitidine; Group 2: 20 mg immediate release cedazuridine + 20 mg 5.3% Eudragit® coated azacitidine; Group 3: 20 mg immediate release cedazuridine + 40 mg 5.3% Eudragit® coated azacitidine.

[0344] PK data in monkeys was collected for 5.3% coated minitablets at two different dose levels of azacitidine, 20 mg and 40 mg, in combination with uncoated cedazuridine tablets. Control group 1 contained both uncoated azacitidine and cedazuridine at a dose of 20 mg. The dose groups are listed in Table 16-1. [Table 43]

[0345] The PK data for minitablets coated with Eudragit® at 5.3% polymer weight gain is shown in Figure 17 and tabulated in Tables 16-2 and 16-3. In the PK study, 5 minitablets or 10 minitablets were placed into size 1 HPMC-based capsules (Vcaps Plus). The exposure levels of azacitidine in Group 2 on Day 2 were slightly lower compared to the control group. However, the exposure levels of the higher dose (40 mg dose) were higher compared to the control group. The higher azacitidine dose offset the loss of exposure caused by the delayed release. [Table 44] [Table 45]

[0346] Delivery of cedazuridine as an immediate release component in a fixed dose combination improved azacitidine bioavailability and exposure. Based on the azacitidine data on day 2, the exposure in Group 2, with a 20 mg azacitidine dose delivered as delayed release, was slightly lower compared to the azacitidine exposure in the control group, where azacitidine was delivered as immediate release. However, in Group 3 (40 mg dose), azacitidine exposure was higher compared to the control group. pH-sensitive coated azacitidine in combination with uncoated cedazuridine in an immediate release capsule provided similar exposure to uncoated azacitidine, but may require a higher dose.

[0347] Example 17: Pharmacokinetic (PK) study in monkeys using the combination of Example 6 In this study, 20 mg of azacitidine was delivered as delayed release with an enteric coating of 4.0% weight gain as described in Example 6. The dose of cedazuridine remained constant at 20 mg in all groups and was delivered as immediate release. In the PK study, azacitidine was delivered in the form of minitablets in HPMC capsules. Each minitablet contained 4 mg of azacitidine as described in Example 6. The innermost layer was a seal coat, followed by a final outer enteric coating containing Eudragit® polymer. In this round of PK study, no intermediate coating was applied on the azacitidine minitablets. Eudragit® L30-D55 polymer was used to obtain the enteric coating on the azacitidine minitablets.

[0348] PK research The PK dose groups used in this study were: Group 1 (control): 20 mg immediate release cedazuridine + 20 mg immediate release azacitidine; Group 2: 20 mg immediate release cedazuridine + 20 mg 4.0% Eudragit® coated azacitidine.

[0349] A total of four monkeys were administered the Group 2 composition (20 mg immediate release cedazuridine + 20 mg 4.0% Eudragit® coated azacitidine) on days 1 and 2, and the Group 1 composition (control, 20 mg immediate release cedazuridine + 20 mg immediate release azacitidine) on days 8 and 9 orally into the stomach via a gastric tube once daily. Blood samples (approximately 0.8 mL) were collected pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post-dose on days 1 and 8 (first dosing day), and pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours post-dose on days 2 and 9 (second dosing day). PK data was evaluated from the collected blood samples. [Table 46]

[0350] The PK data for azacitidine minitablets coated with Eudragit® at 4.0% polymer weight gain is shown in Table 17-2. As shown in Table 17-2, the coated azacitidine minitablets had higher AUC and C at the same dose due to delayed absorption of azacitidine. max but the absorption of cedazuridine is not delayed. [Table 47]

[0351] Example 18: Dissolution studies of FDC capsules The United States Pharmacopoeia for Delayed Release Dosage Forms of six capsule samples of Capsule 1 and six samples of Capsule 2 (listed below) <711> A dissolution test was carried out according to Method A. [Table 48]

[0352] Since the dissolution of enteric coated capsules is pH dependent, dissolution was performed in two stages: an acid stage followed by a buffer stage. The dissolution method used a USP type 1 basket apparatus operated at 75 rpm. The dissolution medium was 500 mL of 0.1 N HCl maintained at 37°C. The capsule samples were sealed with a spiral sinker CAPWHT-XS and dropped into the dissolution vessel. The duration of the acid stage was 2 hours, with dissolution samples taken and analyzed at 30, 60, 90 and 120 minutes. At the end of the acid stage, the dissolution medium was switched to 50 mM phosphate buffer, pH 6.8, preheated to 37°C. Dissolution in the buffer stage was continued for an additional 90 minutes, with dissolution samples taken and analyzed at 135, 150, 165, 180 and 210 minutes. An infinity time rotation was also performed at 250 rpm for an additional 15 minutes. All dissolution tests were performed in the USP apparatus 1. At the final time point, called infinity, the rotation of the basket was increased from 75 to 250 rpm in the dissolution medium. The amount of cedazuridine and azacytidine released was determined by reverse phase HPLC method by comparing the response of the dissolution samples with that of reference standards (purchased from Shilpa Chemicals).

[0353] HPLC conditions are as follows: Mobile phase A (MPA): 10 mM sodium phosphate aqueous buffer, pH 6.8. Mobile phase B (MPB): 50 / 50 (v / v) 10 mM sodium phosphate aqueous buffer, pH 6.8 / ACN. Column: X select CSH phenyl-hexyl, 2.5 um, 4.6 x 75 mm, P / N 186006134. HPLC system: Waters Alliance system. Diluent: 0.1 N HCl and 50 mM 10 mM sodium phosphate aqueous buffer, pH 6.8. HPLC conditions: Column temperature: 23°C, injection volume: 10 μL. Gradient from 98:2 MPA:MPB to 80:20 MPA:MPB to 98:2 MPA:MPB in 12 minutes, flow rate 0.7 ml / min.

[0354] Due to the instability of azacitidine in dissolution media over the physiological pH range, the major degradation products were also included in the quantification of total dissolved azacitidine. Cedazuridine decomposed in the acid stage. Therefore, the major degradation products of cedazuridine and its epimers were also included in the quantification of total dissolved cedazuridine in the acid stage. In the buffer stage, the degradation of cedazuridine was minimal, and only the cedazuridine peak was included in the quantification of cedazuridine. The total dissolved amount shown includes the sum of the % dissolved in the acid stage and the buffer stage.

[0355] Figures 18A and 18B show the dissolution profiles of cedazuridine and azacitidine, respectively. As shown in Figures 18A and 18B, both azacitidine and cedazuridine were released slowly in the acid stage but rapidly in the buffer stage.

[0356] Example 19: Bioequivalence of Capsule Formulations in Cynomolgus Monkeys Male cynomolgus monkeys weighing 3-6 kg were used. A total of 12 animals were assigned to the study. Animals were administered tablets / capsules on both days 1 and 2 as shown in the table below. Dose levels were 20 mg azacitidine and 20 mg cedazuridine per animal. Test tablets (Example 12) / capsules (Example 11) were administered orally. [Table 49]

[0357] Blood samples for plasma were collected pre-dose (0), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours post-dose on day 1, and pre-dose (24 hours post-dose on day 1), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours post-dose on day 2. Blood samples were collected from the cephalic vein or an appropriate vein at the scheduled time points. 0.8 ml of blood was collected into tubes containing K2EDTA pre-spiked with 20 μL of 0.4 mg / mL (tetrahydrouridine) THU.

[0358] Hematological evaluations of each animal were performed once during the acclimation period (approximately 4 days prior to dosing day) and on day 9.

[0359] Tables 19-2 and 19-3 show the data from the above experiments. Figure 19 shows the plasma exposure of cedazuridine in monkeys using capsules of Example 17. Figure 20 shows the plasma exposure of azacitidine in monkeys using capsules of Example 17. [Table 50] [Table 51]

[0360] Example 20: Clinical data using the combination of Example 6 In this study, 20 mg of azacitidine was delivered as delayed release with an enteric coating of 4.0% weight gain as described in Example 6. The dose of cedazuridine remained constant at 20 mg in all groups and was delivered as immediate release. In the PK study, azacitidine was delivered in the form of minitablets in HPMC capsules. Each minitablet contained 4 mg of azacitidine as described in Example 6. The innermost layer was a seal coat, followed by a final outer enteric coating containing Eudragit® polymer. In this round of PK study, no intermediate coating was applied on the azacitidine minitablets. Eudragit® L30-D55 polymer was used to obtain the enteric coating on the azacitidine minitablets.

[0361] Human subjects (n=6) were administered azacitidine. The PK dose groups used in this study were: Group 1: 75 mg / m 2 injection of azacitidine 60 mg subcutaneously once daily, group 2: oral azacitidine 60 mg (4.0% Eudragit® coated) only, group 3: oral uncoated cedazuridine 60 mg once daily + oral azacitidine 60 mg (4.0% Eudragit® coated).

[0362] Human subjects (n=6) were administered the Group 2 composition (oral azacytidine only) on day -3 (before day 1) ("C1D-3"), the Group 1 composition (subcutaneous) on day 1 ("C1D1"), and the Group 3 composition once daily on days 2 through 7 ("C1D2" through "C1D7"). Blood samples were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 7, 9, and 24 hours post-dose. PK data was evaluated on the collected blood samples.

[0363] The PK data for azacitidine are shown in Table 20-1. As shown in Table 20-1, coadministration of cedazuridine significantly increased the T max , C max and AUC, indicating that immediate-release cedazuridine increases the bioavailability of delayed-release azacitidine. Furthermore, oral administration of azacitidine and cedazuridine demonstrated a more stable sustained release of azacitidine compared to subcutaneous administration of azacitidine. [Table 52] * * *

[0364] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0365] The present invention illustratively described herein can be suitably implemented in the absence of any element or limitation not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," etc., are to be read expansively and without limitation. In addition, the terms and expressions used herein are used as terms of description and not of limitation, and in the use of such terms and expressions, there is no intention to exclude any equivalents of the illustrated and described features or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as claimed.

[0366] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each was individually incorporated by reference. In the case of conflict, the present specification, including definitions, will control.

[0367] While the present disclosure has been described in conjunction with the above embodiments, it should be understood that the foregoing description and examples are intended to illustrate, but not to limit, the scope of the present disclosure. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which this disclosure pertains.

Claims

1. 1. A pharmaceutical dosage form comprising cedazuridine or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof, wherein at least a portion of the azacitidine is formulated for modified release.

2. 10. The pharmaceutical dosage form of claim 1, wherein the cedazuridine is formulated for immediate release.

3. 10. The pharmaceutical dosage form of claim 1, wherein the portion of the azacitidine formulated for modified release is formulated for enteric release.

4. 10. The pharmaceutical dosage form of claim 1, wherein the portion of azacitidine formulated for modified release is provided as minitablets comprising an enteric coating.

5. Each azacitidine minitablet contains, as a weight percentage of the total weight of the uncoated azacitidine minitablets: about 20% to 60% w / w azacitidine; and one or more pharmaceutically acceptable excipients.

6. 6. The pharmaceutical dosage form of claim 5, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of lactose monohydrate, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), croscarmellose sodium, silicon dioxide, and magnesium stearate.

7. 5. The pharmaceutical dosage form of claim 4, wherein the enteric coating comprises polymethacrylate or a copolymer thereof.

8. 5. The pharmaceutical dosage form of claim 4, wherein the enteric coating is sensitive to pH fluctuations in the intestine.

9. 5. The pharmaceutical dosage form of claim 4, wherein each azacitidine minitablet further comprises a seal coat beneath the enteric coating.

10. 10. The pharmaceutical dosage form of claim 9, wherein the seal coat comprises hydroxypropyl methylcellulose (HPMC).

11. 10. The pharmaceutical dosage form of claim 1, wherein the azacitidine is formulated for modified release and provided as minitablets comprising an enteric coating.

12. 10. The pharmaceutical dosage form of claim 1, wherein substantially all of the azacitidine is configured to be released outside the stomach.

13. 10. The pharmaceutical dosage form of claim 1, wherein the cedazuridine is uncoated and in the form of minitablets, tablets, powders, blends, granules, or pellets.

14. 14. The pharmaceutical dosage form of claim 13, wherein the uncoated minitablets, tablets, powder, blend, granules, or pellets contain about 10% to 40% w / w cedazuridine.

15. A pharmaceutical dosage form comprising cedazuridine or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof, the cedazuridine is formulated for immediate release; A pharmaceutical dosage form, wherein the azacitidine is formulated as modified-release minitablets comprising an enteric coating.

16. 16. The pharmaceutical dosage form of claim 15, wherein each azacitidine minitablet contains about 20% to 50% w / w azacitidine, expressed as a weight percentage based on the weight of the uncoated azacitidine minitablet.

17. 16. The pharmaceutical dosage form of claim 15, wherein each of the azacitidine minitablets has an intragranular layer and an extragranular layer.

18. 18. The pharmaceutical dosage form of claim 17, wherein the intragranular layer comprises, in weight percentages based on the total weight of the uncoated azacitidine minitablets, about 20% to 50% w / w azacitidine, about 10% to 60% w / w lactose monohydrate, about 2% to 60% w / w microcrystalline cellulose, about 1% to 10% w / w croscarmellose sodium, about 0.5% to 10% w / w hydroxypropylmethylcellulose (HPMC), about 0.1% to 3% w / w silicon dioxide, and about 0.1% to 3% w / w magnesium stearate.

19. 18. The pharmaceutical dosage form of claim 17, wherein the extragranular layer comprises, in weight percentages based on the total weight of the uncoated azacitidine minitablets, about 1% to 60% w / w microcrystalline cellulose, about 1% to 10% w / w croscarmellose sodium, about 0.1% to 3% w / w silicon dioxide, and about 0.1% to 3% w / w magnesium stearate.

20. 16. The pharmaceutical dosage form of claim 15, wherein the enteric coating comprises polymethacrylate or a copolymer thereof.

21. 16. The pharmaceutical dosage form of claim 15, wherein the enteric coating is sensitive to pH fluctuations in the intestine.

22. 16. The pharmaceutical dosage form of claim 15, wherein each azacitidine minitablet further comprises a seal coat.

23. 23. The pharmaceutical dosage form of claim 22, wherein the seal coat comprises hydroxypropyl methylcellulose (HPMC).

24. 16. The pharmaceutical dosage form of claim 15, comprising azacitidine and cedazuridine in a weight ratio of about 1:1 to about 1:

3.

25. 16. The pharmaceutical dosage form of claim 15, comprising about 60 mg to 100 mg of azacitidine.

26. 16. The pharmaceutical dosage form of claim 15, wherein the cedazuridine is in the form of uncoated minitablets, tablets, powders, blends, granules, or pellets.

27. 27. The pharmaceutical dosage form of claim 26, wherein the cedazuridine minitablets, tablets, powder, blend, granules, or pellets contain about 10% to 90% w / w cedazuridine, expressed as a weight percentage based on the total weight of the uncoated cedazuridine minitablets, tablets, powder, blend, granules, or pellets.

28. 27. The pharmaceutical dosage form of claim 26, wherein the cedazuridine minitablets, tablets, powder, blend, granules, or pellets further comprise about one or more selected from the group consisting of lactose monohydrate, hydroxypropyl methylcellulose (HPMC), croscarmellose sodium, silicon dioxide, and magnesium stearate.

29. 16. The pharmaceutical dosage form of claim 15, comprising about 5 mg to 60 mg of cedazuridine.

30. A capsule comprising a pharmaceutical dosage form according to any one of claims 1 to 29.

31. A capsule, one or more azacitidine minitablets formulated for modified release comprising azacitidine or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and an enteric coating; and immediate-release cedazuridine in the form of an uncoated powder or blend comprising cedazuridine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

32. A pharmaceutical dosage form according to any one of claims 1 to 29 for treating cancer in a patient.

33. 33. The pharmaceutical dosage form of claim 32, wherein the cancer is leukemia.

34. 33. The pharmaceutical dosage form of claim 32, wherein the cancer is selected from the group consisting of previously treated or untreated de novo or secondary myelodysplastic syndromes (MDS), previously treated or untreated de novo or secondary chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML), malignant peripheral nerve sheath tumors (MPNST), brain and spinal cord tumors, breast cancer, hormone receptor positive tumors, head and neck cancer, primary enchondroma, myeloproliferative neoplasms (MPN), relapsed B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma, relapsed Hodgkin's lymphoma, relapsed / refractory multiple myeloma (RRMM), metastatic colorectal cancer (mCRC), metastatic castration-resistant prostate cancer (mCRPC), and lung cancer.

35. 33. The pharmaceutical dosage form of claim 32, wherein the cancer is selected from the group consisting of previously treated or untreated de novo or secondary myelodysplastic syndrome (MDS), previously treated or untreated de novo or secondary chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), and chronic myelogenous leukemia (CML).

36. 33. The pharmaceutical dosage form of claim 32, wherein the cancer is associated with refractory anemia, refractory anemia with ringed sideroblasts, or refractory anemia with excess blasts.

37. 33. The pharmaceutical dosage form of claim 32, wherein another therapeutic agent is administered separately from the pharmaceutical dosage form.

38. The additional therapeutic agent is selected from the group consisting of ADI-PEG20, AMG-176, APG-115, APR-246, avelumab, bendamustine, bisantrene, brentuximab vedotin, capecitabine, CB-839, cisplatin, CS-01, cusatuzumab, cyclophosphamide, cytarabine, dasatinib, daunorubicin, DCLL9718S, decitabine, deferasirox, dexamethasone, durvalumab, eltrombopag, enadidenib, and entinostat. rituximab, entrectinib, enzalutamide, epacadostat, erythropoietin, etoposide, evoluptence, filgrastim, fludarabine phosphate, flumatinib, gemcitabine, gemtuzumab ozogamicin, gilteritinib, GM-CSF, GSK2879552, HMPL-523, homoharringtonine, IBI188, ibrutinib, idarubicin, itacitinib, ivosidenib, jactinib, KPT-8602, LDE25 5, lenalidomide, lirilumab, LP-108, magrolimab, MAX-40279, mitoxantrone, mitoxantrone liposome, mocetinostat, moxifloxacin, nivolumab, ortasidenib, omacetaxine, oxaliplatin, paclitaxel, pembrolizumab, pevonedistat, pinometostat, prasinostat, quizartinib, revlimid, rigosertib, rituximab, romidepsin, RP7214, S64315, S6 5487, sabatolimab, seclidemstat, selumetinib, siremadrine, sirolimus, SL-401, SNDX-5613, sorafenib, talazoparib, tamibarotene, trinapant, trastuzumab, tucidinostat, tyrosine kinase inhibitors, uproleseran, velcade, venetoclax, vincristine, visilizumab, vorinostat, and vosaroxine.

39. 31. The capsule of claim 30 for use in the treatment of cancer.

40. 31. The capsule of claim 30 for use in the manufacture of a medicament for the treatment of cancer.

41. 40. The capsule of claim 39, wherein the cancer is leukemia.

42. 40. The capsule of claim 39, wherein the cancer is selected from previously treated or untreated de novo or secondary myelodysplastic syndrome (MDS), previously treated or untreated de novo or secondary chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML), malignant peripheral nerve sheath tumors (MPNST), brain and spinal cord tumors, breast cancer, hormone receptor positive tumors, head and neck cancer, primary enchondroma, myeloproliferative neoplasms (MPN), relapsed B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma, relapsed Hodgkin's lymphoma, relapsed / refractory multiple myeloma (RRMM), metastatic colorectal cancer (mCRC), metastatic castration-resistant prostate cancer (mCRPC), and lung cancer.

43. 40. The capsule of claim 39, wherein the cancer is selected from previously treated or untreated de novo or secondary myelodysplastic syndrome (MDS), previously treated or untreated de novo or secondary chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML).

44. 40. The capsule of claim 39, wherein the cancer is associated with refractory anemia, refractory anemia with ringed sideroblasts, or refractory anemia with excess blasts.

45. Use of a pharmaceutical dosage form according to any one of claims 1 to 29 for the treatment of cancer.

46. Use of a pharmaceutical dosage form according to any one of claims 1 to 29 for the manufacture of a medicament for the treatment of cancer.

47. 46. ​​The use of claim 45, wherein the cancer is leukemia.

48. 46. ​​The use of claim 45, wherein the cancer is selected from previously treated or untreated de novo or secondary myelodysplastic syndromes (MDS), previously treated or untreated de novo or secondary chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML), malignant peripheral nerve sheath tumors (MPNST), brain and spinal cord tumors, breast cancer, hormone receptor positive tumors, head and neck cancer, primary enchondroma, myeloproliferative neoplasms (MPN), relapsed B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma, relapsed Hodgkin's lymphoma, relapsed / refractory multiple myeloma (RRMM), metastatic colorectal cancer (mCRC), metastatic castration-resistant prostate cancer (mCRPC), and lung cancer.

49. 46. ​​The use of claim 45, wherein the cancer is selected from previously treated or untreated de novo or secondary myelodysplastic syndrome (MDS), and previously treated or untreated de novo or secondary chronic myelomonocytic leukemia (CMML).

50. 46. ​​The use of claim 45, wherein the cancer is associated with refractory anemia, refractory anemia with ringed sideroblasts, or refractory anemia with excess blasts.

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