Pharmaceutical composition for oral administration of dnmt inhibitor

Abstract

The present disclosure provides a pharmaceutical composition for oral administration comprising core particles, a protective layer and an enteric layer, the pharmaceutical composition being characterized in that: (a) the core particles each comprise compound I and an additive; (b) the protective layer comprises an additive coated on the core particles; and (c) the enteric layer comprises an enteric polymer coated on the protective layer.

Description

Pharmaceutical compositions for oral administration of DNMT inhibitors

[0001] The present disclosure relates to an orally administered pharmaceutical composition containing an orally administrable DNMT inhibitor that has high stability against the hydrolytic metabolic enzyme cytidine deaminase and can replace 5-azacytidine or its 2'-deoxy form.

[0002] DNMTs is an abbreviation for DNA-methyltransferases, a group of enzymes that catalyze the methylation of the amino group at position 6 of the adenine ring in DNA (Adenine N6-specific DNA-methyltransferase: EC 2.1.1.72), the amino group at position 4 of the cytosine ring (Cytosine N4-specific DNA-methyltransferase: EC 2.1.1.113), or the methylation of position 5 of the cytosine ring (Cytosine C5-specific DNA-methyltransferase: EC 2.1.1.37). 5-Azacytidine and its 2'-deoxy derivative (decitabine) are known as selective enzyme inhibitors of DNA methyltransferase (DNMT) (DNA methylation inhibitors, DNA demethylating agents).

[0003] Vidaza (registered trademark), a subcutaneous or intravenous injection of 5-azacytidine indicated for the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), is usually administered to adults at a dose of 75 mg / m as azacitidine. ２ This is an administration therapy in which the drug is administered subcutaneously or intravenously over 10 minutes once a day for 7 days (body surface area), followed by a 3-week drug break, which constitutes one cycle, and this cycle is repeated.

[0004] Dacogen®, an intravenous formulation of decitabine indicated for the treatment of myelodysplastic syndromes, is administered once daily at 20 mg / m ２ This is an administration therapy in which decitabine is administered by continuous intravenous infusion over at least one hour for five consecutive days, followed by a 23-day rest period, making up one cycle.

[0005] The administration route of the drugs is parenteral, either subcutaneously or intravenously, and therefore patients who require treatment with drug administration are required to undergo multiple treatment cycles, which requires long-term outpatient visits.

[0006] Clinical studies have reported on administration methods that maximize the demethylation effect while reducing side effects by reducing the dose of decitabine administered per treatment cycle, shortening the intravenous administration time, and extending the administration interval (Non-Patent Documents 1 and 2). However, with the injectable formulations used in these administration methods, it is still difficult to control the rapid rise in decitabine blood concentrations or to maintain effective blood concentrations.

[0007] In recent years, pharmaceutical compositions for oral administration have been discovered, typified by oral combination preparations in which decitabine is combined with a prodrug that is metabolized to decitabine in the body after subcutaneous administration and exhibits its pharmacological effect, or a decitabine metabolic enzyme inhibitor that inhibits the degradation of decitabine when administered orally.

[0008] Guadecitabine (compound SGI-110) (Patent Documents 1 and 2), a prodrug of decitabine that is highly stable against cytidine deaminase, a hydrolytic metabolic enzyme of decitabine, is highly polar due to its dinucleotide structure and is therefore thought to be difficult to permeate through cell membranes (Non-Patent Documents 3 and 4). In addition, its route of administration is subcutaneous administration, so it is thought that there is still room for improvement as a pharmaceutical composition for oral administration.

[0009] INQOVI® (oral C-DEC, ASTX727) (decitabine 35 mg / cedazuridine 100 mg), an oral combination drug consisting of decitabine and the cytidine deaminase inhibitor cedazuridine, is indicated for the treatment of myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML). ２ It has been reported that this formulation exhibits pharmacokinetics, pharmacodynamics, safety, and tolerability comparable to those of intravenous administration (Non-Patent Document 5). However, the blood concentration profile of this formulation is similar to that of the intravenous formulation Dacogen (registered trademark), and therefore, it is believed that there is still a need for an oral pharmaceutical composition that can sustainably maintain blood concentrations.

[0010] US Publication No. 2007072796 (Japanese Patent No. 5030958) International Publication No. 2013033176 (Japanese Patent No. 6038921)

[0011] CANCER June 1, 2008 / Volume 112 / Number 11 Blood (2007) 109 (1): 52-57 Oncotarget, 2017, Vol. 8, No. 2, pp. 2949-2959 Epigenetics, 2016, Vol. 11, No. 10, pp. 709-720 Blood, 2021, Vol. 138, No. 6, pp. 3682-3685

[0012] The present disclosure aims to solve the problems involved in conventional tumor treatment methods using DNMT inhibitors, and to provide a pharmaceutical composition of a DNMT inhibitor that is orally absorbable and that suppresses decomposition of the compound under normal distribution and storage conditions for formulations, since compound I represented by formula (I) is chemically unstable.

[0013] In order to solve the above-mentioned problems, the present inventors prepared a composition (granules) comprising core particles containing compound I represented by formula (I) and an additive, the core particles coated with a protective layer containing an additive, and the protective layer coated with an enteric layer containing an enteric base. As a result, they discovered for the first time that an oral pharmaceutical composition containing the granules exhibits good stability under storage conditions for distribution and simultaneously achieves a favorable in vivo absorption rate and a reduced DNA methylation rate, and have completed the present invention.

[0014] Furthermore, the present inventors have surprisingly found that the stability against acid depends on the weight ratio of the additive to the active ingredient used in the core particles and the thickness of the protective layer and the enteric layer, and have thus completed the present invention.

[0015] The present disclosure includes the following features: [1] An oral pharmaceutical composition having a core particle, a protective layer, and an enteric layer, wherein (a) the core particle contains compound I represented by the following formula (I) and an additive, (b) the protective layer contains an additive coated on the core particle, and (c) the enteric layer contains an enteric polymer coated on the protective layer. [2] The oral pharmaceutical composition according to [1], wherein the additive of the core particles is at least one selected from the group consisting of excipients and binders. [3] The oral pharmaceutical composition according to [2], wherein the excipient is at least one selected from the group consisting of lactose, D-mannitol, starch, partially pregelatinized starch, talc, low-substituted hydroxypropyl cellulose, crystalline cellulose, and sucrose. [4] The oral pharmaceutical composition according to [2], wherein the binder is at least one selected from the group consisting of polyethylene glycol, glyceryl monostearate, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, povidone, carmellose sodium, pregelatinized starch, polyvinyl alcohol, and polyvinyl alcohol-acrylic acid-methacrylic acid copolymer. [5] The oral pharmaceutical composition according to [1], wherein the additive of the protective layer is at least one selected from the group consisting of excipients and binders. [6] The oral pharmaceutical composition of [5], wherein the excipient is at least one selected from the group consisting of talc, titanium oxide, gelatin, light anhydrous silicic acid, hydrous silicon dioxide, and magnesium aluminometasilicate. [7] The oral pharmaceutical composition of [5], wherein the binder is at least one selected from the group consisting of methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, pregelatinized starch, povidone, carmellose sodium, polyvinyl alcohol, and polyvinyl alcohol-acrylic acid-methacrylic acid copolymer. [8] The oral pharmaceutical composition of [1], wherein the enteric layer further comprises an excipient and a plasticizer. [9] The oral pharmaceutical composition of [1], wherein the enteric polymer is at least one selected from the group consisting of methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, hypromellose acetate succinate, hypromellose phthalate, and carboxymethylethylcellulose.

[10] The oral pharmaceutical composition according to [8], wherein the excipient is selected from the group consisting of talc, titanium oxide, light anhydrous silicic acid, hydrous silicon dioxide, and magnesium aluminometasilicate.

[11] The oral pharmaceutical composition according to [8], wherein the plasticizer is at least one selected from the group consisting of triethyl citrate, glycerol monostearate, triacetin, and polyethylene glycol.

[12] The oral pharmaceutical composition according to any one of [1] to

[11] , wherein the amount of Compound I is 20 parts by mass or more per 100 parts by mass of core particles.

[13] The oral pharmaceutical composition according to any one of [1] to

[11] , wherein the amount of the protective layer is 15 parts by mass or more per 100 parts by mass of core particles.

[14] The oral pharmaceutical composition according to any one of [1] to

[11] , wherein the thickness of the protective layer is 15 μm or more.

[15] The oral pharmaceutical composition according to any one of [1] to

[11] , wherein the amount of the enteric layer is 14 parts by mass or more per 100 parts by mass of granules comprising core particles coated with a protective layer.

[16] The oral pharmaceutical composition according to any one of [1] to

[11] , wherein the thickness of the enteric layer is 20 μm or more.

[17] The oral pharmaceutical composition according to any one of [1] to

[11] , wherein the amount of compound I is 20 parts by mass or more, the amount of the protective layer is 15 parts by mass or more, and the amount of the enteric layer is 14 parts by mass or more, relative to 100 parts by mass of core particles.

[18] The oral pharmaceutical composition according to any one of [1] to

[11] , wherein the amount of compound I is 20 parts by mass or more, relative to 100 parts by mass of core particles, the thickness of the protective layer is 15 μm or more, and the thickness of the enteric layer is 20 μm or more, relative to 100 parts by mass of core particles.

[19] The oral pharmaceutical composition according to any one of [1] to

[18] , wherein the composition having core particles, a protective layer, and an enteric layer is in the form of granules.

[20] The oral pharmaceutical composition according to any one of [1] to

[19] , wherein the composition contains core particles, a protective layer, and an enteric layer.

[21] The oral pharmaceutical composition according to any one of [1] to

[20] , wherein the composition is in the form of granules.

[22] The oral pharmaceutical composition according to any one of [1] to

[21] , which is a capsule or stick formulation containing the granules or granules.

[23] The oral pharmaceutical composition according to any one of [1] to

[20] , which is a tablet containing the granules.

[24] The oral pharmaceutical composition according to any one of [1] to

[23] , which is an agent for preventing or treating tumors.

[25] The oral pharmaceutical composition according to any one of [1] to

[23] , which is an agent for preventing or treating myelodysplastic syndrome, chronic myelomonocytic leukemia, acute myeloid leukemia, or chronic myeloid leukemia.

[0016] According to the present disclosure, an oral pharmaceutical composition is provided that is expected to reduce DNA methylation rates while reducing the risk of side effects by being continuously absorbed into the body through oral administration in tumor treatment with a DNMT inhibitor. According to the present disclosure, an oral pharmaceutical composition is provided that is expected to provide significant convenience to patients who must repeatedly visit a hospital over a long period of time to receive treatment by intravenous administration in tumor treatment with a DNMT inhibitor. According to the present disclosure, an oral pharmaceutical composition is provided that is expected to significantly improve the quality of life (QOL) of patients who require multiple treatment cycles in tumor treatment with a DNMT inhibitor by reducing the number of visits to a hospital.

[0017] Figure 1 shows the results of measuring the mean plasma concentration of decitabine released from Compound I following oral administration of Granules I of the present disclosure and the mean plasma concentration on day 1 of intravenous administration of decitabine (DAC in the figure is shown as the abbreviation for generic name decitabine). Figure 2 shows the results of LINE-1 methylation transition on day 5 of oral administration of Granules I of the present disclosure and intravenous administration of decitabine (DAC in the figure is shown as the abbreviation for generic name decitabine).

[0018] The oral pharmaceutical composition and the like of the present disclosure will be described in detail below. However, the following description is merely an example for explaining the present disclosure, and is not intended to limit the present disclosure to the scope of the description.

[0019] The present disclosure provides an oral pharmaceutical composition having a core particle, a protective layer, and an enteric layer, characterized in that (a) the core particle contains compound I represented by formula (I) and an additive, (b) the protective layer contains an additive coated on the core particle, and (c) the enteric layer contains an enteric polymer coated on the protective layer.

[0020] Core Particles The core particles of the present disclosure contain Compound I represented by the following formula (I) and an additive.

[0021] Formula (I):

[0022] 5'-O-triethylsilyl-2'-deoxy-5-azacytidine (also referred to as Compound I of the present disclosure, Compound I, or OP-2100) represented by the formula (I) can be prepared, isolated, or obtained by any method known to those skilled in the art. For example, it can be prepared according to the method described in Japanese Patent No. 6,162,349, the disclosure of which is incorporated herein by reference in its entirety. Compound I of the present disclosure is a prodrug that has high stability against cytidine deaminase, the hydrolytic metabolic enzyme of decitabine, and can gradually release the corresponding decitabine under physiological conditions.

[0023] The compound I of the present disclosure may be crystalline, and may have a single crystalline form or a mixture of multiple crystalline forms. The crystals of compound I can be produced by crystallizing compound I using a known crystallization method, a crystallization method disclosed in the present application, or a method similar thereto.

[0024] Compound I of the present disclosure may be a solvate (e.g., a hydrate, etc.), and both solvate and non-solvate (e.g., anhydrous, etc.) forms are encompassed by Compound I. In some embodiments, Compound I of the present disclosure is a hemihydrate (also referred to as a hemihydrate).

[0025] In some embodiments, the core particle of the present disclosure is placed at the center of the oral pharmaceutical composition of the present disclosure, and its form includes, but is not particularly limited to, particles, etc. In some embodiments, the average particle size of the core particle is preferably within the range of 50.0 to 950.0 μm, more preferably 400.0 to 900.0 μm, and even more preferably 700.0 to 850.0 μm.

[0026] The additives contained in the core particles of the present disclosure are not particularly limited, as long as they contain components that are used as additives (inactive substances) in pharmaceuticals.

[0027] The additive contained in the core particle of the present disclosure may include at least one selected from the group consisting of an excipient and a binder.

[0028] In some embodiments, examples of excipients contained in the core particles of the present disclosure include, but are not limited to, lactose hydrate, anhydrous lactose, crystalline cellulose, D-mannitol, erythritol, xylitol, sorbitol, isomalt, maltitol, maltose, white sugar, sucrose, glucose, starch (corn starch, potato starch, rice starch, wheat starch, etc.), hydroxypropyl starch, pregelatinized starch, partially pregelatinized starch, talc, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, dextrin, powdered reduced maltose syrup, ammonioalkyl methacrylate copolymer, ethyl cellulose, calcium hydrogen phosphate, etc.

[0029] In some embodiments, examples of excipients contained in the core particles of the present disclosure include, but are not limited to, at least one or more selected from the group consisting of lactose, D-mannitol, starch, partially pregelatinized starch, talc, low-substituted hydroxypropyl cellulose, crystalline cellulose, and sucrose.

[0030] In some embodiments, examples of binders contained in the core particles of the present disclosure include, but are not limited to, alkyl celluloses (e.g., methyl cellulose), hydroxyalkyl celluloses (e.g., hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose), hydroxyalkyl alkyl celluloses (e.g., hydroxyethyl methyl cellulose, hypromellose), carboxyvinyl polymers, polyvinyl alcohol, polyvinyl alcohol-based copolymers (copolymers in which polyvinyl alcohol is one of the monomers, such as polyvinyl alcohol-acrylic acid-methyl methacrylate copolymers and polyvinyl alcohol-polyethylene glycol graft copolymers), polyvinylpyrrolidone, carmellose sodium, and pregelatinized starch.

[0031] In some embodiments, examples of binders contained in the core particles of the present disclosure include, but are not limited to, at least one selected from the group consisting of polyethylene glycol, glycerin monostearate, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, povidone, carmellose sodium, pregelatinized starch, polyvinyl alcohol, and polyvinyl alcohol-acrylic acid-methacrylic acid copolymer.

[0032] In some embodiments, in the core particle of the present disclosure, the amount of Compound I relative to 100 parts by mass of the core particle is, for example, 20 parts by mass or more, 30 parts by mass or more, or 40 parts by mass or more.

[0033] In some embodiments, the core particles of the present disclosure contain compound I in an amount of 20 parts by mass or more relative to 100 parts by mass of the core particles. The upper limit of the amount of compound I is preferably 60 parts by mass or less relative to 100 parts by mass of the core particles. In some embodiments, the core particles of the present disclosure contain compound I in an amount of preferably 20 to 60 parts by mass, more preferably 25 to 55 parts by mass, relative to 100 parts by mass of the core particles.

[0034] Protective Layer The protective layer of the present disclosure is a suitable polymer intermediate layer coated on the surface of the core particle of the present disclosure (between the core particle and the enteric substrate) in order to suppress or prevent chemical decomposition of Compound I due to contact with the enteric substrate. The protective layer of the present disclosure is not particularly limited as long as it has the function of suppressing chemical decomposition of Compound I contained in the core particle of the present disclosure due to contact with the enteric substrate.

[0035] In some embodiments, the amount of the protective layer of the present disclosure is, for example, 15 parts by weight or more, 20 parts by weight or more, or 25 parts by weight or more, per 100 parts by weight of the core particles.

[0036] In some embodiments, the amount of the protective layer in the protective layer of the present disclosure is 15 parts by mass or more per 100 parts by mass of the core particles. The upper limit of the amount of the protective layer is preferably 45 parts by mass or less per 100 parts by mass of the core particles. In some embodiments, the amount of the protective layer in the protective layer of the present disclosure is preferably 15 to 45 parts by mass, more preferably 15 to 40 parts by mass, per 100 parts by mass of the core particles.

[0037] In some embodiments, the protective layer of the present disclosure has a thickness of, for example, 15 μm or more, 20 μm or more, 25 μm or more, or 30 μm or more. The upper limit of the protective layer thickness is preferably 50 μm or less. In some embodiments, the protective layer of the present disclosure has a thickness of preferably 15 to 50 μm, more preferably 20 to 40 μm.

[0038] In some embodiments, the protective layer of the present disclosure has a thickness, including but not limited to, about 32 μm.

[0039] In some embodiments, the protective layer of the present disclosure comprises an additive coated on the core particle of the present disclosure.

[0040] In some embodiments, the protective layer of the present disclosure comprises an additive coated directly on the surface of the core particle of the present disclosure.

[0041] In some embodiments, the additive contained in the protective layer of the present disclosure is at least one selected from the group consisting of an excipient and a binder.

[0042] In some embodiments, examples of excipients contained in the protective layer of the present disclosure include, but are not limited to, at least one selected from the group consisting of talc, titanium oxide, gelatin, light anhydrous silicic acid, hydrous silicon dioxide, and magnesium aluminometasilicate.

[0043] In some embodiments, examples of binders contained in the protective layer of the present disclosure include, but are not limited to, at least one water-soluble polymer selected from the group consisting of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pregelatinized starch, povidone, carmellose sodium, polyvinyl alcohol, and polyvinyl alcohol-acrylic acid-methacrylic acid copolymer.

[0044] In some embodiments, the content of the excipient contained in the protective layer of the present disclosure is 60 parts by weight to 80 parts by weight per 100 parts by weight of the protective layer of the present disclosure.

[0045] The enteric layer of the present disclosure is a suitable polymer layer coated on the surface of the protective layer of the present disclosure in order to suppress or prevent chemical decomposition of Compound I of the present disclosure from gastric acid. The enteric layer of the present disclosure is not particularly limited as long as it has the function of suppressing or preventing chemical decomposition of Compound I contained in the core particles of the present disclosure from gastric acid.

[0046] In some embodiments, the amount of the enteric layer of the present disclosure is, for example, 14 parts by weight or more or 28 parts by weight or more per 100 parts by weight of granules in which core particles are coated with a protective layer.

[0047] In some embodiments, the amount of the enteric layer of the present disclosure is 14 parts by mass or more relative to 100 parts by mass of granules in which core particles are coated with a protective layer. The upper limit of the amount of the enteric layer is preferably 45 parts by mass or less relative to 100 parts by mass of granules in which core particles are coated with a protective layer. In some embodiments, the amount of the enteric layer of the present disclosure is preferably 14 to 45 parts by mass, more preferably 14 to 40 parts by mass, relative to 100 parts by mass of granules in which core particles are coated with a protective layer.

[0048] In some embodiments, the enteric layer of the present disclosure has a thickness of, for example, 20 μm or more, 30 μm or more, or 40 μm or more. The upper limit of the enteric layer thickness is preferably 50 μm or less. In some embodiments, the enteric layer of the present disclosure has a thickness of preferably 20 to 50 μm, more preferably 20 to 40 μm.

[0049] In some embodiments, the enteric layer of the present disclosure has a thickness, including but not limited to, about 38 μm.

[0050] The enteric layer of the present disclosure is a polymer layer comprising an enteric polymer coated on the protective layer of the present disclosure.

[0051] In some embodiments, examples of the enteric polymer contained in the enteric layer of the present disclosure include, but are not limited to, at least one selected from the group consisting of methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, hypromellose acetate succinate, hypromellose phthalate, and carboxymethylethylcellulose.

[0052] In some embodiments, the enteric layer of the present disclosure may further comprise excipients and plasticizers.

[0053] In some embodiments, the excipient contained in the enteric layer of the present disclosure includes, but is not limited to, at least one selected from the group consisting of talc, titanium oxide, light anhydrous silicic acid, hydrous silicon dioxide, and magnesium aluminometasilicate.

[0054] In some embodiments, the plasticizer included in the enteric layer of the present disclosure may include, but is not limited to, at least one selected from the group consisting of triethyl citrate, glyceryl monostearate, triacetin, and polyethylene glycol.

[0055] In the present disclosure, the amount of the additive of the present disclosure to be added is not particularly limited as long as it does not impair the effect of the oral pharmaceutical composition of the present disclosure.

[0056] The present disclosure provides a tumor prophylactic / therapeutic agent comprising the oral pharmaceutical composition of the present disclosure.

[0057] In some embodiments, the present disclosure provides an agent for the prophylaxis or treatment of myelodysplastic syndrome, chronic myelomonocytic leukemia, acute myeloid leukemia, or chronic myeloid leukemia, comprising the oral pharmaceutical composition of the present disclosure.

[0058] The composition comprising the core particles, protective layer, and enteric layer of the present disclosure forms granules. The pharmaceutical composition of the present disclosure is an oral pharmaceutical composition containing the granules. The dosage form of the oral pharmaceutical composition of the present disclosure is not particularly limited as long as it contains the granules, and examples include, but are not limited to, granules containing the granules, capsules encapsulating the granules, tablets containing the granules, and sticks encapsulating the granules.

[0059] In some embodiments, the present disclosure provides granules or capsules encapsulating the granules.

[0060] In some embodiments, the present disclosure provides a tablet containing granules and excipients.

[0061] In some embodiments, additives contained in the tablets of the present disclosure may include commonly used stabilizers, lubricants, binders, excipients, disintegrants, etc., and other additives such as flavoring agents and coloring agents may also be used as needed.

[0062] In some embodiments, stabilizers included in the tablets of the present disclosure may include, but are not limited to, hydrous silicon dioxide, citric acid hydrate, light anhydrous silicic acid, macrogol 4000, and the like.

[0063] In some embodiments, lubricants included in the tablets of the present disclosure can include, but are not limited to, hydrogenated oils, calcium stearate, magnesium stearate, talc, sodium stearyl fumarate, and the like.

[0064] In some embodiments, binders included in tablets of the present disclosure can include, but are not limited to, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, povidone, and the like.

[0065] In some embodiments, excipients contained in tablets of the present disclosure may include, but are not limited to, crystalline cellulose, lactose, crystalline cellulose, corn starch, potato starch, D-mannitol, sucrose, sucrose, glucose, etc.

[0066] In some embodiments, examples of disintegrants included in the tablets of the present disclosure include, but are not limited to, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, and partially pregelatinized starch.

[0067] In some embodiments, flavoring agents included in the tablets of the present disclosure can include, but are not limited to, sucralose, aspartame, and the like.

[0068] In some embodiments, coloring agents included in the tablets of the present disclosure can include, but are not limited to, ferric oxide, yellow ferric oxide, and the like.

[0069] The oral pharmaceutical composition of the present disclosure can be prepared by a general manufacturing method in the art depending on the dosage form.

[0070] The oral pharmaceutical composition of the present disclosure can be prepared, for example, by the following steps.

[0071] (Process for Producing Core Particles) In some embodiments, the core particles of the present disclosure can be produced by putting additives (e.g., excipients, etc.) into a fluidized bed granulator, and coating the mixture with a suspension of Compound I of the present disclosure and additives (e.g., binders, etc.) while spraying and drying.

[0072] (Step of coating the core particles with a protective layer) In some embodiments, the protective layer of the present disclosure can be produced by coating the granules obtained above (core particles of the present disclosure) with a suspension of additives (e.g., excipients, binders, etc.) while spraying and drying.

[0073] (Step of Coating the Protective Layer with an Enteric Layer) In some embodiments, the enteric layer of the present disclosure can be produced by coating the granules obtained above (the protective layer of the present disclosure) with a suspension of additives (e.g., enteric polymers, excipients, plasticizers, etc.) while spraying and drying.

[0074] (Granules of the present disclosure) The granules of the present disclosure are produced through the steps of producing the above-mentioned core particles, coating the core particles with a protective layer, and coating the protective layer with an enteric layer. The granules of the present disclosure can be used as an oral pharmaceutical composition by themselves. Furthermore, oral pharmaceutical compositions having dosage forms such as granules, tablets, capsules, and sticks can be produced using the granules of the present disclosure using methods commonly used in the technical field of pharmaceutical formulations.

[0075] The tablets of the present disclosure can be produced using the granules of the present disclosure by a common tablet production method in the art.

[0076] In some embodiments, the granules of the present disclosure can be mixed with additives (e.g., stabilizers, lubricants, binders, excipients, disintegrants, flavoring agents, coloring agents, etc.) and then compressed using a tablet press. The compression pressure when compressing using a tablet press is preferably 1 kN to 10 kN, and more preferably 1 kN to 5 kN.

[0077] The capsules of the present disclosure can be prepared by filling the granules of the present disclosure into capsules by a general filling method in the art.

[0078] In some embodiments, capsules of the present disclosure can be prepared by filling granules of the present disclosure into capsules by common filling methods in the art.

[0079] The capsules of the present disclosure may be conventional capsules used in the art, including, but not limited to, gelatin capsules, hydroxypropyl methylcellulose (HPMC) capsules, pullulan capsules (e.g., hydroxypropyl methylcellulose (HPMC) capsules), Licaps™ capsules, Vcaps™ capsules, Coni-Snap™ capsules, Press-fit™ capsules, and Xpress-fit™ capsules.

[0080] The capsules of the present disclosure may be sized, for example, but not limited to, capsules No. 1, No. 2, No. 3, No. 4, and No. 5. In some embodiments, capsules No. 4 or No. 5 are selected from the viewpoint of ease of administration.

[0081] The stick formulation of the present disclosure can be produced using the granules of the present disclosure by a method commonly used in the art for filling a stick package.

[0082] Hereinafter, the present disclosure will be described with reference to examples, but the present disclosure is not limited to the following examples.

[0083] 199.2 g of microcrystalline cellulose granules were placed in a fluidized bed granulator, and a solution of 40.0 g of methylcellulose dissolved in 1,240 g of purified water, in which 182.4 g of compound I (as hemihydrate) was dispersed and suspended, was sprayed and dried to obtain granules A. Subsequently, a solution of 22.0 g of hydroxypropylmethylcellulose dissolved in 550 g of purified water, in which 88.2 g of talc was dispersed and suspended, was sprayed and dried to obtain granules B. Finally, a solution of 12.88 g of glycerol monostearate, 6.48 g of triethyl citrate, and 1.3 g of polysorbate 80 dissolved in 300 g of purified water, in which 430.7 g of methacrylic acid copolymer LD (solid content: 129.2 g) was added, was gently mixed and stirred, and was sprayed and dried to obtain granules I.

[0084] 220.5 g of microcrystalline cellulose granules were placed in a fluidized bed granulator, and a solution of 25.0 g of methylcellulose dissolved in 775 g of purified water and 114.0 g of Compound I (as hemihydrate) dispersed and suspended therein was sprayed and dried to obtain granules A. Subsequently, a solution of 19.9 g of hydroxypropylmethylcellulose dissolved in 497 g of purified water and 79.7 g of talc dispersed and suspended therein was sprayed and dried to obtain granules B. Finally, a solution of 11.85 g of glycerol monostearate, 5.9 g of triethyl citrate, and 1.2 g of polysorbate 80 dissolved in 273 g of purified water was added with 394.3 g of methacrylic acid copolymer LD (solid content: 118.3 g), and the mixture was gently mixed and stirred. The mixture was sprayed and dried to obtain granules II.

[0085] 240.0 g of microcrystalline cellulose granules were placed in a fluidized bed granulator, and a solution of 20.0 g of methylcellulose dissolved in 620 g of purified water and 91.2 g of Compound I (as hemihydrate) dispersed and suspended therein was sprayed and dried to obtain granules A. Subsequently, a solution of 20.32 g of hydroxypropylmethylcellulose dissolved in 507 g of purified water and 81.24 g of talc dispersed and suspended therein was sprayed and dried to obtain granules B. Finally, a solution of 12.12 g of glycerol monostearate, 6.04 g of triethyl citrate, and 1.2 g of polysorbate 80 dissolved in 279 g of purified water was added with 403.3 g of methacrylic acid copolymer LD (solid content: 121.0 g), and the mixture was gently mixed and stirred. The mixture was sprayed and dried to obtain granules III.

[0086] 204.0 g of microcrystalline cellulose granules were placed in a fluidized bed granulator, and a solution of 17.0 g of methylcellulose dissolved in 527 g of purified water and 77.52 g of Compound I (as hemihydrate) dispersed and suspended therein was sprayed and dried to obtain granules A. Subsequently, a solution of 10.54 g of hydroxypropylmethylcellulose dissolved in 263.5 g of purified water and 42.16 g of talc dispersed and suspended therein was sprayed and dried to obtain granules B. Finally, a solution of 9.79 g of glycerol monostearate, 4.87 g of triethyl citrate, and 0.98 g of polysorbate 80 dissolved in 225.8 g of purified water was added with 326.4 g of methacrylic acid copolymer LD (solid content: 97.92 g), and the mixture was gently mixed and stirred. The mixture was sprayed and dried to obtain granules IV.

[0087] 199.2 g of microcrystalline cellulose granules were placed in a fluidized bed granulator, and a solution of 40.0 g of methylcellulose dissolved in 1,240 g of purified water, in which 182.4 g of Compound I (as hemihydrate) was dispersed and suspended, was sprayed and dried to obtain granules A. Subsequently, a solution of 22.0 g of hydroxypropylmethylcellulose dissolved in 550 g of purified water, in which 88.2 g of talc was dispersed and suspended, was sprayed and dried to obtain granules B. Finally, a solution of 6.4 g of glycerol monostearate, 3.2 g of triethyl citrate, and 0.64 g of polysorbate 80 dissolved in 148.1 g of purified water, in which 212.27 g of methacrylic acid copolymer LD (solid content: 63.68 g) was added, was gently mixed and stirred, and the mixture was sprayed and dried to obtain granules V.

[0088] 200.8 g of microcrystalline cellulose granules were placed in a fluidized bed granulator, and a solution of 60.0 g of methylcellulose dissolved in 1,860 g of purified water and 205.3 g of Compound I (as hemihydrate) dispersed and suspended therein was sprayed and dried to obtain granules A. Subsequently, a solution of 42.0 g of hydroxypropylmethylcellulose dissolved in 630 g of purified water and 78.0 g of talc dispersed and suspended therein was sprayed and dried to obtain granules B. Finally, a solution of 14.0 g of glycerol monostearate, 8.0 g of triethyl citrate, and 1.0 g of polysorbate 80 dissolved in 440 g of purified water was added with 470.0 g of methacrylic acid copolymer LD (solid content: 141.0 g), and the mixture was gently mixed and stirred. The mixture was sprayed and dried to obtain granules VI.

[0089] Granules VI (Example 6) 41.7 g, lactose hydrate 181.8 g, microcrystalline cellulose 75.0 g, and magnesium stearate 1.5 g were mixed in a polyethylene bag and then compressed in a tablet press at a compression pressure of 3 kN to obtain tablets (circular tablets, diameter 12.0 mm, thickness 5.0 mm) each weighing 600 mg.

[0090] Compound I (as a hemihydrate) can be prepared, for example, by the following method. Compound (I) was obtained as a white solid according to the method described in Japanese Patent No. 6,162,349. 1.71 g (5 mmol) of the white solid compound (I) was dissolved in 15 mL of acetone under heating. Then, while heating, 180 μL (10 mmol) of purified water and 75 mL of MTBE (methyl tert-butyl ether) were added and stirred overnight at room temperature. The resulting white solid was collected by filtration to obtain 1.07 g (63% recovery) of a crystalline powder of compound I (hemihydrate) (fine columnar crystals). The HPLC purity of the resulting crystalline powder was >99%. This crystalline powder exhibited a powder X-ray diffraction pattern with characteristic diffraction peaks at angles of 2θ=5.6°±0.2°, 12.5°±0.2°, 12.9°±0.2°, 13.2°±0.2°, 15.0°±0.2°, 15.4°±0.2°, 15.8°±0.2°, 16.1°±0.2°, 17.1°±0.2°, 19.1°±0.2°, 20.4°±0.2°, 22.4°±0.2°, 23.4°±0.2°, 25.1°±0.2°, 25.9°±0.2°, and 28.1°±0.2° with CuKα radiation of 1.5419 Å wavelength. Comparative Example 1

[0091] 438.5 g of microcrystalline cellulose granules were placed in a fluidized bed granulator, and a solution of 5.0 g of methylcellulose dissolved in 155 g of purified water and 22.8 g of Compound I (as hemihydrate) dispersed and suspended therein was sprayed and dried to obtain granules A. Subsequently, a solution of 30.0 g of hydroxypropylmethylcellulose dissolved in 750 g of purified water and 120.0 g of talc dispersed and suspended therein was sprayed and dried to obtain granules B. Finally, a solution of 19.2 g of glycerol monostearate, 9.6 g of triethyl citrate, and 1.92 g of polysorbate 80 dissolved in 450 g of purified water was added with 640.0 g of methacrylic acid copolymer LD (solid content: 192.0 g), and the mixture was gently mixed and stirred. The mixture was sprayed and dried to obtain granules VII. Comparative Example 2

[0092] 204.0 g of microcrystalline cellulose granules were placed in a fluidized bed granulator, and a solution of 17.0 g of methylcellulose dissolved in 527 g of purified water and 77.52 g of Compound I (as hemihydrate) dispersed and suspended therein was sprayed and dried to obtain granules A. Subsequently, a solution of 4.08 g of hydroxypropylmethylcellulose dissolved in 102 g of purified water and 16.32 g of talc dispersed and suspended therein was sprayed and dried to obtain granules B. Finally, a solution of 9.18 g of glycerol monostearate, 4.59 g of triethyl citrate, and 0.92 g of polysorbate 80 dissolved in 211.5 g of purified water was added with 306.0 g of methacrylic acid copolymer LD (solid content: 91.80 g), and the mixture was gently mixed and stirred. The mixture was sprayed and dried to obtain granules VIII. Comparative Example 3

[0093] 438.5 g of microcrystalline cellulose granules were placed in a fluidized bed granulator, and a solution of 5.0 g of methylcellulose dissolved in 155 g of purified water and 22.8 g of Compound I (as hemihydrate) dispersed and suspended therein was sprayed and dried to obtain granules A. Subsequently, a solution of 7.5 g of hydroxypropylmethylcellulose dissolved in 187.5 g of purified water and 30.0 g of talc dispersed and suspended therein was sprayed and dried to obtain granules B. Finally, a solution of 16.8 g of glycerol monostearate, 8.4 g of triethyl citrate, and 1.68 g of polysorbate 80 dissolved in 390 g of purified water was added with 560.0 g of methacrylic acid copolymer LD (solid content: 168.0 g), and the mixture was gently mixed and stirred. The mixture was sprayed and dried to obtain granules IX.

[0094] The formulations of Examples 1 to 6 and Comparative Examples 1 to 3 are shown in Table 1. Table 1 Test Example 1

[0095] Granules I (Example 1) were orally administered to male cynomolgus monkeys at four different doses (2.9 mg / kg, 5.8 mg / kg, 11.6 mg / kg, and 23.2 mg / kg) once daily for five days. On the first day of administration, 1 mL of blood was collected at 30, 60, 90, 120, 150, 180, 240, 300, 360, and 420 minutes, and the mean plasma concentrations of Compound I and released decitabine were measured.

[0096] For comparison, decitabine was administered intravenously (infusion) to male cynomolgus monkeys at two doses (0.84 mg / kg and 1.67 mg / kg) once daily for 1 hour for 5 consecutive days. On Day 1, 1 mL of blood was collected at 30, 60, 90, 120, 150, 180, 240, 300, 360, and 420 minutes, and the mean plasma concentration of decitabine was measured. The 0.84 mg / kg dose of decitabine was prepared by diluting a 16.7 mg / mL decitabine solution 100-fold with a 1% cyclodextrin solution and administering the solution to the cynomolgus monkeys at a dose appropriate for their body weight. A dose of 1.67 mg / kg of decitabine was prepared by diluting a 33.4 mg / mL DMSO solution of decitabine 100 times with a 1% cyclodextrin solution, and the solution was administered according to the body weight of the cynomolgus monkey.

[0097] The results of measuring the mean plasma concentration of decitabine released from Compound I on Day 1 of oral administration of Granules I and the mean plasma concentration of decitabine on Day 1 of 1-hour intravenous administration are shown in Figure 1. The mean plasma concentration of decitabine released from Compound I following oral administration of Granules I exhibited a sustained behavior compared to intravenous administration of decitabine, and the AUC and Cmax increased dose-dependently. Test Example 2

[0098] In all administration groups in Test Example 1, 2 mL of blood was collected before administration and on days 1, 5, 8, 10, 12, 15, 19, 22, 26, and 29 of administration. DNA was extracted from 200 μL of collected whole blood using a QIAamp DNA mini Kit (QIAGEN). The extracted DNA was treated according to the protocol of the EZ DNA Methylation Kit (ZYMO RESEARCH). PCR was performed on this sample according to the protocol of the Monkey Line-1 Methylation Assay Kit (EPIGEN Dx), and the CpG island cytosine methylation rate of LINE-1 (Long interspersed nucleotide factor-1) was measured by pyrosequencing. The methylation rates of four CpG sites were measured, and the average value was calculated as the methylation rate. The difference between the values ​​before administration and those before administration in each treatment group was defined as LINE-1 CpG demethylation.

[0099] The results of the transition of LINE-1 methylation on day 5 after oral administration of Granule I and intravenous administration of decitabine are shown in Figure 2. The LINE-1 methylation level was observed over time after both oral administration of Granule I and intravenous administration of decitabine. The LINE-1 methylation level reached its maximum around 10 days after administration. Thereafter, the LINE-1 methylation level recovered to the same level as before administration. Furthermore, with oral administration of Granule I, the degree of methylation increased with increasing dose. Test Example 3

[0100] Granule I (Example 1), Granule II (Example 2), Granule III (Example 3), Granule IV (Example 4), Granule V (Example 5), Granule VI (Example 6), Granule VII (Comparative Example 1), Granule VIII (Comparative Example 2), and Granule IX (Comparative Example 3) were filled into transparent glass bottles, placed in aluminum bags, heat-sealed, and stored at 50°C for 14 days, after which a purity test was conducted. The total amount (total amount) of related substances (decomposition products of Compound I) and the amount of decitabine produced in each granule were measured at the start of the test and 3, 7, and 14 days after the start of the test. The results are shown in Table 2.

[0101] The sample solution for measuring related substances was prepared by taking an amount corresponding to approximately 22.8 mg of Compound I of the present disclosure, adding 20 mL of N,N-dimethylformamide, and subjecting the mixture to ultrasonic treatment for 10 minutes. This solution was then filtered through a membrane filter with a pore size of 0.45 μm or less, and the first 5 mL of filtrate was removed to obtain the next filtrate. 10 μL of this solution was tested by liquid chromatography under the following conditions. The peak areas of each of the sample solutions were measured by automatic integration, and the total amount (total related amount) and the amount of decitabine were calculated by the area percentage method. Test conditions: HPLC method (detector: ultraviolet absorption spectrophotometer (measurement wavelength: 254 nm)) Table 2

[0102] Granules I, II, III, IV, V, and VI had significantly lower increases in related substances (decomposition products of compound I) than granule VII, which had a lower amount of compound I relative to the amount of core particles, granule VIII, which had a thinner protective layer, and granule IX, which had a lower amount of compound I relative to the amount of core particles and a thinner protective layer, and the increase in related substances (decomposition products of compound I) was suppressed. Test Example 4

[0103] An amount corresponding to approximately 22.8 mg of Compound I of the present disclosure was taken, 20 mL of N,N-dimethylformamide was added, and the mixture was sonicated for 10 minutes. This solution was then filtered through a membrane filter with a pore size of 0.45 μm or less. The first 5 mL of the filtrate was removed, and the next filtrate was used as a sample solution. 10 μL of this solution was tested by liquid chromatography under the following conditions. Each peak area of ​​the sample solution was measured by automatic integration, and the total amount (total related amount) and the amount of decitabine were determined by the area percentage method. Test conditions: HPLC method (detector: ultraviolet absorption spectrophotometer (measurement wavelength: 254 nm))

[0104] Granules VI (Example 6) in an amount corresponding to approximately 41.05 mg of Compound I were filled into No. 4 hypromellose capsules, placed in polyethylene containers, and sealed with polypropylene caps equipped with desiccant. The capsules were then stored at 40°C and 75% RH for 6 months and at 25°C and 60% RH for 12 months, after which purity tests were carried out. The results of the purity tests, in which the total amount (total related amount) of related substances (decomposition products of Compound I) and the amount of decitabine produced in the granules at each time point were measured, are shown in Table 3.

[0105] Even in the commercially available formulation of Granules VI, the increase in the amount of related substances (decomposition products of Compound I) was significantly small, demonstrating that the compound is stable even under market distribution. Test Example 5

[0106] For Granules VI (Example 6) and Tablets (Example 7) in an amount corresponding to about 22.8 mg of Compound I, the dissolution rates of Compound I 120 minutes after the start of the test were determined by the dissolution test method (paddle method) in the General Testing Methods of the Japanese Pharmacopoeia, 18th Edition, and the results (n=3) are shown in Table 4.

[0107] Test conditions: GC method (detector: FID) Test solution: Japanese Pharmacopoeia Fluid 1 (dissolution test fluid 1, pH 1.2) Test solution volume: 900 mL Paddle rotation speed: 50 rpm Fluid temperature: 37°C Table 4

[0108] The dissolution rate of Compound I in the tablet in an acidic environment was kept as low as that of Granules VI, demonstrating that the formulation containing the granules of the present disclosure has the function of suppressing or preventing chemical decomposition of Compound I in gastric acid even in tablet form.

Claims

1. An oral pharmaceutical composition having a core particle, a protective layer, and an enteric layer, wherein: (a) the core particle contains a compound I represented by formula (I) and an additive; (b) the protective layer is coated on the core particle and contains an additive; and (c) the enteric layer is coated on the protective layer and contains an enteric polymer.

2. The oral pharmaceutical composition according to claim 1, wherein the additive of the nuclear particles is at least one selected from the group consisting of excipients and binders.

3. The oral pharmaceutical composition according to claim 2, wherein the excipient is at least one selected from the group consisting of lactose, D-mannitol, starch, partially pregelatinized starch, talc, low-substituted hydroxypropyl cellulose, crystalline cellulose, and sucrose.

4. The oral pharmaceutical composition according to claim 2, wherein the binder is at least one selected from the group consisting of polyethylene glycol, glycerin monostearate, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, sodium carboxymethylcellulose, pregelatinized starch, polyvinyl alcohol, and polyvinyl alcohol / acrylic acid / methacrylic acid copolymer.

5. The oral pharmaceutical composition according to claim 1, wherein the additive of the protective layer is at least one selected from the group consisting of excipients and binders.

6. The oral pharmaceutical composition according to claim 5, wherein the excipient is at least one selected from the group consisting of talc, titanium oxide, gelatin, light anhydrous silicic acid, hydrous silicon dioxide, and magnesium aluminometasilicate.

7. The oral pharmaceutical composition according to claim 5, wherein the binder is at least one selected from the group consisting of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pregelatinized starch, povidone, sodium carboxymethylcellulose, polyvinyl alcohol, and polyvinyl alcohol / acrylic acid / methacrylic acid copolymer.

8. The oral pharmaceutical composition according to claim 1, wherein the enteric layer further contains an excipient and a plasticizer.

9. The oral pharmaceutical composition according to claim 1, wherein the enteric polymer is at least one selected from the group consisting of methacrylic acid copolymer LD, dried methacrylic acid copolymer LD, hypromellose acetate succinate, hypromellose phthalate, and carboxymethyl ethyl cellulose.

10. The oral pharmaceutical composition according to claim 8, wherein the excipient is at least one selected from the group consisting of talc, titanium oxide, light anhydrous silicic acid, hydrous silicon dioxide, and magnesium aluminometasilicate.

11. The oral pharmaceutical composition according to claim 8, wherein the plasticizer is at least one selected from the group consisting of triethyl citrate, glycerin monostearate, triacetin, and polyethylene glycol.

12. The oral pharmaceutical composition according to any one of claims 1 to 11, wherein the amount of Compound I is 20 parts by mass or more with respect to 100 parts by mass of the nuclear particles.

13. The oral pharmaceutical composition according to any one of claims 1 to 11, wherein the amount of the protective layer is 15 parts by mass or more with respect to 100 parts by mass of the nuclear particles.

14. The oral pharmaceutical composition according to any one of claims 1 to 11, wherein the film thickness of the protective layer is 15 μm or more.

15. The oral pharmaceutical composition according to any one of claims 1 to 11, wherein the amount of the enteric layer is 14 parts by mass or more with respect to 100 parts by mass of the granules obtained by coating the nuclear particles with the protective layer.

16. The oral pharmaceutical composition according to any one of claims 1 to 11, wherein the film thickness of the enteric layer is 20 μm or more.

17. The oral pharmaceutical composition according to any one of claims 1 to 11, wherein the amount of Compound I is 20 parts by mass or more with respect to 100 parts by mass of the nuclear particles, the amount of the protective layer is 15 parts by mass or more, and the amount of the enteric layer is 14 parts by mass or more with respect to 100 parts by mass of the granules obtained by coating the nuclear particles with the protective layer.

18. The oral pharmaceutical composition according to any one of claims 1 to 11, wherein the amount of Compound I is 20 parts by mass or more with respect to 100 parts by mass of the nuclear particles, the film thickness of the protective layer is 15 μm or more, and the film thickness of the enteric layer is 20 μm or more.

19. The oral pharmaceutical composition according to any one of claims 1 to 18, wherein the composition having the nuclear particles, the protective layer, and the enteric layer is in the form of granules.

20. The oral pharmaceutical composition according to any one of claims 1 to 19, containing the said granules.

21. The oral pharmaceutical composition according to any one of claims 1 to 20, which is a granule agent.

22. The oral pharmaceutical composition according to any one of claims 1 to 21, which is a capsule agent or a stick agent encapsulating the said granules or granule agent.

23. The oral pharmaceutical composition according to any one of claims 1 to 20, which is a tablet containing the said granules.

24. The oral pharmaceutical composition according to any one of claims 1 to 23, which is a prophylactic and therapeutic agent for tumors.

25. The oral pharmaceutical composition according to any one of claims 1 to 23, which is a prophylactic and therapeutic agent for myelodysplastic syndrome, chronic myelomonocytic leukemia, acute myeloid leukemia or chronic myeloid leukemia.

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