Omeka Mucib Mekarvir Preparation

Abstract

Provided herein is a tablet comprising a core comprising omecamtiv mecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of the pharmaceutically acceptable salt thereof, an excipient, a binder, a flow agent, and a lubricant, and a coating film on the core, the coating film comprising a release-modifying polymer and a pore-forming agent. Also provided are a process for producing the tablet and a method for treating a cardiovascular condition, such as heart failure, using the tablet.

Description

Background Art

[0001] Omecamtiv mecarbil (OM) is a myosin activator of the heart muscle that directly targets the contraction mechanism of cardiomyocytes, and is intended to enhance myocardial contractility in patients presenting with cardiovascular conditions such as heart failure. OM is currently in Phase 3 clinical trials. In order to reduce the maximum plasma concentration (C max ) and safely supply an effective amount of OM to patients, an orally administered modified release (MR) tablet with a size of 14.4 mm × 8.4 mm (see International Patent Application Publication No. WO2014 / 152236A1) has been developed for adult patients. However, in order to ensure patient compliance with medication, an OM formulation that is easy to swallow and administer and suitable for use in specific patient populations such as pediatric patients (e.g., 6 - 18 years old) and adult patients with difficulty swallowing is required.

Summary of the Invention

Means for Solving the Problems

[0002] The present specification provides a tablet comprising a core containing omecamtiv mecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt thereof; an excipient; a binder; a fluidizing agent; and a lubricant; and a coating film on the core, the coating film containing a release - controlling polymer and a pore - forming agent.

[0003] The present specification also provides a process for the manufacture of the disclosed tablet and the use of the disclosed tablet for treating patients presenting with cardiovascular conditions such as heart failure.

Brief Description of the Drawings

[0004]

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DETAILED DESCRIPTION OF THE INVENTION

[0005] Prior to the formulations disclosed herein, many conventional formulations have been investigated in attempts to obtain omecamtiv mecarbil formulations suitable for pediatric patients (e.g., 6 - 18 years old, or 6 - 12 years old) or adult patients with difficulty swallowing. For example, miniaturized tablets have been evaluated. However, as shown in Figure 1, simply reducing the physical size and dosage of the sustained-release (MR) tablets containing omecamtiv mecarbil hydrochloride dihydrate by half results in an undesirably significant increase in the dissolution rate of omecamtiv mecarbil, thereby increasing C max which can be undesirably high. When C max is higher, there is a possibility of an increase in adverse events.

[0006] Tablets for pediatric patients or adult patients with dysphagia will exhibit physical properties (e.g., shape and size) that will facilitate patient compliance (e.g., swallowability) and should exhibit appropriate pharmacokinetic performance (e.g., appropriate C max and reproducible release rate). Desirable qualities of the tablets include one or more of the following: a core having a circular and biconvex shape; a diameter and height of less than 3 mm; a weight of approximately 12.5 mg; a dosage strength of 1-3 mg of omeprazole tivabecarbil that is pH-independent and 100% of the omeprazole tivabecarbil is released within 60 minutes, but are not limited thereto. The MR coating provides a pH-independent and adjustable release rate depending on the nature of the coating.

[0007] Disclosed herein are tablets comprising a core having a coating film on the core, the coating film comprising a release-modulating polymer and a pore-forming agent. The core comprises omeprazole tivabecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt thereof, and in an uncoated core, the omeprazole tivabecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt thereof is released immediately. The core comprises intragranular components and extragranular components. The intragranular components comprise omeprazole tivabecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt thereof as an active ingredient, one or more excipients, and one or more binders. The extragranular components comprise one or more fluidizing agents and one or more lubricants. The intragranular components and the extragranular components can form a core using appropriate methods as described herein. The core can then be coated with a coating film using suitable methods to provide the disclosed tablets.

[0008] The core of the disclosed tablet comprises omecamtiv mecarbil, its pharmaceutically acceptable salts, or pharmaceutically acceptable hydrates of its pharmaceutically acceptable salts; excipients; binders; fluidizing agents; and lubricants. The coating film on the core of the disclosed tablet comprises a release control polymer (sometimes referred to as a release controlling agent) and a pore forming agent. In some embodiments, for any of the component amounts disclosed herein, the stated amount or weight percent of a component may vary by ±5%.

[0009] In some embodiments, the tablet has a form or size (s) suitable for the intended patient population (e.g., pediatric patients). Thus, the tablet may have a diameter of 5 mm or less, such as 4.5 mm or less, 4 mm or less, or 3.5 mm or less. Alternatively, or in addition, the tablet may have a diameter of 0.5 mm or more, such as 1 mm or more, 1.5 mm or more, 2 mm or more, 2.5 mm or more, or 3 mm or more. Thus, the tablet may have a diameter bounded by any of the above endpoints. For example, the tablet may have a diameter of 0.5 - 5 mm, 1 - 4.5 mm, 1.5 - 4 mm, 2 - 3.5 mm, or 2.5 - 3 mm.

[0010] In some embodiments, the tablet has a diameter of up to 3 mm (e.g., 0.5 mm, 1 mm, 1.5 mm, 2 mm, 2.5 mm, or 3 mm).

[0011] The formulations disclosed herein can provide the desirable release characteristics of omecamtiv mecarbil. The release, or dissolution characteristics of the formulations can be measured using any suitable method. Exemplary methods are the parameters: the apparatus is USP <711> Apparatus II (paddle); the vessel size / type is 1000 mL clear glass, round bottom; the rotation speed is 75 rpm; the media volume is 500 mL; the test temperature is 37.0 ± 0.5 °C; the dissolution media is phosphate buffer (pH 6.8); and the sampling times are 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours, which is the United States Pharmacopeia (USP) II method. The test solution is analyzed using high performance liquid chromatography (HPLC) under the following conditions: the pump is isocratic; a reverse phase column (e.g., X-Bridge, 150 × 3 mm (id), C18, particle size 3.5 μm, commercially available from Waters); UV detection (235 nm); injection volume 75 μL; flow rate 0.5 mL / min; the column temperature is 30 °C; the autosampler temperature is ambient temperature; and the runtime is 6 minutes.

[0012] In some embodiments, the tablets release up to 50%, such as up to 45%, up to 40%, up to 35%, up to 30%, up to 25%, up to 20%, up to 15% of omecamtiv mecarbil in 1 hour, or release up to 10% of omecamtiv mecarbil in 1 hour. In some embodiments, the tablets release 5 - 10% of omecamtiv mecarbil in 1 hour, such as 7% of omecamtiv mecarbil in 1 hour. In some embodiments, the tablets release 15 - 25% of omecamtiv mecarbil in 1 hour, such as 20% of omecamtiv mecarbil in 1 hour. In some embodiments, the tablets release 35 - 45% of omecamtiv mecarbil in 1 hour, such as 41% of omecamtiv mecarbil in 1 hour.

[0013] In some embodiments, the tablet releases up to 70%, for example, up to 65%, up to 60%, up to 55%, up to 50%, up to 45%, up to 40%, up to 35% of omecamtiv mecarbil in 2 hours, or releases up to 30% of omecamtiv mecarbil in 2 hours. In some embodiments, the tablet releases 25 - 35%, for example, 28% of omecamtiv mecarbil in 2 hours. In some embodiments, the tablet releases 35 - 45%, for example, 40% of omecamtiv mecarbil in 2 hours. In some embodiments, the tablet releases 60 - 70%, for example, 66% of omecamtiv mecarbil in 2 hours.

[0014] In some embodiments, the tablet releases up to 90%, for example, up to 85%, up to 80% of omecamtiv mecarbil in 8 hours, or releases up to 75% of omecamtiv mecarbil in 8 hours. In some embodiments, the tablet releases 70 - 75%, for example, 72% of omecamtiv mecarbil in 8 hours. In some embodiments, the tablet releases 75 - 80%, for example, 77% of omecamtiv mecarbil in 8 hours. In some embodiments, the tablet releases 85 - 90%, for example, 87% of omecamtiv mecarbil in 8 hours.

[0015] In some embodiments, the tablet releases up to 95%, for example up to 90%, up to 85% of omecamtiv mecarbil in 16 hours, or releases up to 80% of omecamtiv mecarbil in 16 hours. In some embodiments, the tablet releases 78 - 83% of omecamtiv mecarbil in 16 hours, for example 81% of omecamtiv mecarbil in 16 hours. In some embodiments, the tablet releases 85 - 90% of omecamtiv mecarbil in 16 hours, for example 86% of omecamtiv mecarbil in 16 hours. In some embodiments, the tablet releases 90 - 95% of omecamtiv mecarbil in 16 hours, for example 93% of omecamtiv mecarbil in 16 hours.

[0016] In some embodiments, the tablet provides the omecamtiv mecarbil release characteristics that up to 50% of omecamtiv mecarbil is released in 1 hour; 60 - 70% of omecamtiv mecarbil is released in 2 hours; 85 - 90% of omecamtiv mecarbil is released in 8 hours; and 90% or more of omecamtiv mecarbil is released in 16 hours.

[0017] In some embodiments, the tablet provides the omecamtiv mecarbil release characteristics that up to 25% of omecamtiv mecarbil is released in 1 hour; 35 - 45% of omecamtiv mecarbil is released in 2 hours; 75 - 80% of omecamtiv mecarbil is released in 8 hours; and 85% or more of omecamtiv mecarbil is released in 16 hours.

[0018] In some embodiments, the tablet provides the omecamtiv mecarbil release characteristics that up to 10% of omecamtiv mecarbil is released in 1 hour; 25 - 35% of omecamtiv mecarbil is released in 2 hours; 70 - 75% of omecamtiv mecarbil is released in 8 hours; and 78% or more of omecamtiv mecarbil is released in 16 hours.

[0019] When the tablet is administered to a patient, a suitable C of omecamtiv mecarbil maxTo provide. In some embodiments, when administered to a patient, the tablet provides a C of omecamtiv mecarbil of 100 ng / mL or more max , for example, when administered to a patient, a C of omecamtiv mecarbil of 125 ng / mL or more, 150 ng / mL or more, 175 ng / mL or more, 200 ng / mL or more, 225 ng / mL or more, 250 ng / mL or more, 275 ng / mL or more, 300 ng / mL or more, 325 ng / mL or more, 350 ng / mL or more, 375 ng / mL or more, 400 ng / mL or more, 425 ng / mL or more, 450 ng / mL or more, 475 ng / mL or more, or 500 ng / mL or more max Alternatively, or in addition, when administered to a patient, the tablet provides a C of omecamtiv mecarbil of 1000 ng / mL or less max , for example, when administered to a patient, a C of omecamtiv mecarbil of 975 ng / mL or less, 950 ng / mL or less, 925 ng / mL or less, 900 ng / mL or less, 875 ng / mL or less, 850 ng / mL or less, 825 ng / mL or less, 800 ng / mL or less, 775 ng / mL or less, 750 ng / mL or less, 725 ng / mL or less, 700 ng / mL or less, 675 ng / mL or less, 650 ng / mL or less, 625 ng / mL or less, 600 ng / mL or less, 575 ng / mL or less, 550 ng / mL or less, or 525 ng / mL or less max To provide.

[0020] Thus, the tablet can provide a C of omecamtiv mecarbil to the patient, with the endpoints of any two of the above as the limits max , for example, when administered to a patient, a C of omecamtiv mecarbil of 100 - 1000 ng / mL, 125 - 975 ng / mL, 150 - 950 ng / mL, 175 - 925 ng / mL, 200 - 900 ng / mL, 225 - 875 ng / mL, 250 - 850 ng / mL, 275 - 825 ng / mL, 300 - 800 ng / mL, 325 - 775 ng / mL, 350 - 750 ng / mL, 375 - 725 ng / mL, 400 - 700 ng / mL, 425 - 675 ng / mL, 450 - 650 ng / mL, 475 - 625 ng / mL, 500 - 600 ng / mL, or 525 - 575 ng / mLmax can be provided.

[0021] In some embodiments, when the tablet is administered to a patient, the C of omecamtiv mecarbil is 100-1000 ng / mL or 300-1000 ng / mL max is provided.

[0022] Omecamtiv mecarbil Omecamtiv mecarbil (AMG 423, CK-1827452) has the following structure:

Chemical formula

[0005] )

[0023] The omecamtiv mecarbil used in the disclosed formulation may exist as the omecamtiv mecarbil free base, or a pharmaceutically acceptable salt thereof or a hydrate of the pharmaceutically acceptable salt.

[0024] “Pharmaceutically acceptable salts” include (1) acid addition salts, (a) salts formed with inorganic acids such as hydrochloride (i.e., hydrochloride), phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, and salts of the same kind; or (b) malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate salts (e.g., acetate, HOOC--(CH2) where n is 0-4 nSalts formed with organic acids, such as --COOH and salts of the same kind, and (2) salts formed when the acidic proton of omecamtiv mecarbil is replaced by a pharmaceutically acceptable cation (including, but not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium). Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0025] In some cases, the tablets contain omecamtiv mecarbil. In one embodiment, the tablets contain omecamtiv mecarbil dihydrochloride. In a further embodiment, the tablets contain omecamtiv mecarbil dihydrochloride monohydrate. In yet another embodiment, the tablets contain omecamtiv mecarbil dihydrochloride monohydrate Form A as disclosed in International Patent Application Publication No. WO2014 / 152270A1.

[0026] Form A can be characterized by a powder X-ray diffraction (XRPD) pattern having peaks at 6.6, 14.9, 20.1, 21.4, and 26.8 ± 0.2° 2θ with Cu Kα irradiation, as obtained as described in WO2014 / 152270A1. Optionally, Form A can be further characterized by an XRPD pattern having additional peaks at 8.4, 24.2, 26.0, 33.3 ± 0.2° 2θ with Cu Kα irradiation. Optionally, Form A can be even further characterized by an XRPD pattern having additional peaks at 6.2, 9.7, 13.2, 14.3, 15.4, 16.3, 16.9, 18.9, 19.5, 20.7, 21.8, 22.8, 23.6, 25.1, 27.3, 27.7, 28.4, 29.4, 30.2, 31.2, 31.5, 31.9, 33.9, 34.5, 34.9, 36.1, 36.8, 37.7, 38.5, and 39.7 ± 0.2° 2θ with Cu Kα irradiation. In various cases, Form A can be characterized by an XRPD pattern having peaks at 6.2, 6.6, 8.4, 9.7, 13.2, 14.3, 14.9, 15.4, 16.3, 16.9, 18.9, 19.5, 20.1, 20.7, 21.4, 21.8, 22.8, 23.6, 24.3, 25.1, 26.0, 26.8, 27.3, 27.7, 28.4, 29.4, 30.2, 31.2, 31.5, 31.9, 33.3, 33.9, 34.5, 34.9, 36.1, 36.8, 37.7, 38.5, and 39.7 ± 0.2° 2θ with Cu Kα irradiation. In some embodiments, Form A can be characterized substantially by an X-ray powder diffraction pattern as shown in FIG. 13, where "substantially" means that the reported peaks can vary by ± 0.2°. In the field of XRPD, while the relative peak heights of the spectrum depend on many factors such as sample preparation and the shape of the apparatus, it is well known that the peak positions are relatively unaffected by experimental details.

[0027] In some embodiments, the tablets comprise omecamtiv mecarbil dihydrochloride Form B. In some embodiments, the tablets comprise omecamtiv mecarbil dihydrochloride Form C. The polymorphs of omecamtiv mecarbil Forms B and C are metastable anhydrous dihydrochloride forms and can be formed under various conditions and temperatures as described in WO2014 / 152270A1.

[0028] As described in WO2014 / 152270A1, Form B can be characterized by an XRPD pattern having peaks at 6.8, 8.8, 14.7, 17.7, and 22.3 ± 0.2° 2θ with Cu Kα irradiation. Optionally, Form B can be further characterized by an XRPD pattern having additional peaks at 9.6, 13.5, 19.2, 26.2 ± 0.2° 2θ with Cu Kα irradiation. Form B can be characterized by an XRPD pattern having peaks at 6.2, 6.8, 8.8, 9.6, 13.5, 14.4, 14.7, 15.4, 16.3, 17.0, 17.7, 18.3, 19.2, 19.9, 20.5, 20.8, 21.8, 22.3, 22.7, 23.0, 24.8, 25.1, 25.5, 26.2, 26.4, 26.8, 27.5, 28.5, 30.2, 30.6, 31.1, 31.5, 32.1, 32.7, 34.1, 34.4, 35.5, 35.9, 38.1, 38.9 ± 0.2° 2θ with Cu Kα irradiation. In some embodiments, Form B can be characterized substantially by an XRPD pattern as shown in WO2014 / 152270A1, where "substantially" means that the reported peaks can vary by ±0.2°.

[0029] As described in WO2014 / 152270A1, Form C can be characterized by an XRPD pattern having peaks at 6.7, 14.8, 17.4, 20.6, and 26.2 ± 0.2° 2θ with Cu Kα irradiation. Optionally, Form C can be further characterized by an XRPD pattern having additional peaks at 8.7, 22.0, 27.1, and 27.7 ± 0.2° 2θ with Cu Kα irradiation. Form C can be characterized by an XRPD pattern having peaks at 6.2, 6.7, 8.7, 9.6, 13.5, 14.5, 14.8, 15.4, 16.4, 17.1, 17.4, 18.4, 19.3, 19.5, 19.9, 20.6, 20.8, 21.8, 22.0, 22.5, 22.8, 24.3, 24.7, 25.1, 25.6, 26.2, 26.5, 27.1, 27.3, 27.7, 28.5, 30.0, 30.5, 31.0, 31.5, 32.2, 32.8, 34.1, 35.2, 36.0, 36.9, and 38.8 ± 0.2° 2θ with Cu Kα irradiation. In some embodiments, Form C can be characterized substantially by an XRPD pattern as shown in WO2014 / 152270A1, where "substantially" means that the reported peaks can vary by ±0.2°.

[0030] The tablets contain an optional suitable amount of omecamtiv mecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt thereof. If the amount of omecamtiv mecarbil contained in the tablets is too low, the pill burden on the patient is unduly increased. In contrast, if the amount of omecamtiv mecarbil contained in the tablets is too high, the tablets may exhibit undesirable properties (e.g., undesirable C in the patient max and / or infeasibility of manufacture on a commercial scale).

[0031] The description herein regarding the amount of omecamtiv mecarbil, its pharmaceutically acceptable salts, or pharmaceutically acceptable hydrates of its pharmaceutically acceptable salts will be understood to relate to the salt or hydrate form of the active ingredient. The amount of omecamtiv mecarbil described herein refers to the amount (or equivalent) of omecamtiv mecarbil free base. For example, if a tablet is indicated as having 1 mg of omecamtiv mecarbil, the tablet contains 1.22 mg of omecamtiv mecarbil dihydrochloride monohydrate (MW 492.37 g / mol) which supplies 1 mg of omecamtiv mecarbil (molecular weight (MW) 401.43 g / mol).

[0032] In some embodiments, the tablet comprises omecamtiv mecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt thereof, in an amount of 0.1 wt% or more, based on the total weight of the tablet. For example, omecamtiv mecarbil in any form (e.g., salt, salt hydrate, or free base) of omecamtiv mecarbil present in the tablet is included in an amount of 0.5 wt% or more, 1 wt% or more, 2 wt% or more, 3 wt% or more, 4 wt% or more, 5 wt% or more, 6 wt% or more, 7 wt% or more, 8 wt% or more, 9 wt% or more, 10 wt% or more, 11 wt% or more, 12 wt% or more, 13 wt% or more, 14 wt% or more, 15 wt% or more, 16 wt% or more, 17 wt% or more, 18 wt% or more, 19 wt% or more, 20 wt% or more, 21 wt% or more, 22 wt% or more, 23 wt% or more, 24 wt% or more, 25 wt% or more, 26 wt% or more, 27 wt% or more, 28 wt% or more, 29 wt% or more, 30 wt% or more, 31 wt% or more, 32 wt% or more, 33 wt% or more, 34 wt% or more, 35 wt% or more, 36 wt% or more, 37 wt% or more, 38 wt% or more, 39 wt% or more, or 40 wt% or more. Alternatively, or in addition, the tablet comprises omecamtiv mecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt thereof, in an amount of 80 wt% or less, based on the total weight of the tablet. For example, omecamtiv mecarbil in any form (e.g., salt, salt hydrate, or free base) of omecamtiv mecarbil present in the tablet is included in an amount of 79 wt% or less, 78 wt% or less, 77 wt% or less, 76 wt% or less, 75 wt% or less, 74 wt% or less, 73 wt% or less, 72 wt% or less, 71 wt% or less, 70 wt% or less, 69 wt% or less, 68 wt% or less, 67 wt% or less, 66 wt% or less, 65 wt% or less, 64 wt% or less, 63 wt% or less, 62 wt% or less, 61 wt% or less, 60 wt% or less, 59 wt% or less, 58 wt% or less, 57 wt% or less, 56 wt% or less, 55 wt% or less, 54 wt% or less, 53 wt% or less, 52 wt% or less, 51 wt% or less, 50 wt% or less, 49 wt% or less, 48 wt% or less, 47 wt% or less, 46 wt% or less, 45 wt% or less, 44 wt% or less, 43 wt% or less, 42 wt% or less, or 41 wt% or less.

[0033] Thus, the tablet contains omecamtiv mecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt thereof, in an amount limited by any two of the above-mentioned endpoints. For example, the tablet contains omecamtiv mecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt thereof, in an amount of 0.1 to 80 wt% based on the total weight of the tablet. For example, omecamtiv mecarbil in any form (e.g., salt, salt hydrate, or free base) of omecamtiv mecarbil present in the tablet is in an amount of 0.5 to 79 wt%, 1 to 78 wt%, 2 to 77 wt%, 3 to 76 wt%, 4 to 75 wt%, 5 to 74 wt%, 6 to 73 wt%, 7 to 72 wt%, 8 to 71 wt%, 9 to 70 wt%, 10 to 69 wt%, 11 to 68 wt%, 12 to 67 wt%, 13 to 66 wt%, 14 to 65 wt%, 15 to 64 wt%, 16 to 63 wt%, 17 to 62 wt%, 18 to 61 wt%, 19 to 60 wt%, 20 to 59 wt%, 21 to 58 wt%, 22 to 57 wt%, 23 to 56 wt%, 24 to 55 wt%, 25 to 54 wt%, 26 to 53 wt%, 27 to 52 wt%, 28 to 51 wt%, 29 to 50 wt%, 30 to 49 wt%, 31 to 48 wt%, 32 to 47 wt%, 33 to 46 wt%, 34 to 45 wt%, 35 to 44 wt%, 36 to 43 wt%, 37 to 42 wt%, 38 to 41 wt%, or 39 to 40 wt%.

[0034] In some embodiments, the tablet contains omecamtiv mecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt thereof, in an amount of 5 to 10 wt% based on the total weight of the tablet. For example, in an amount of 5.5 wt%, 6 wt%, 6.5 wt%, 7 wt%, 7.5 wt%, 8 wt%, 8.5 wt%, 9 wt%, or 9.5 wt%.

[0035] In some embodiments, the core of the tablet contains omecamtiv mecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt thereof, in an amount of 8 wt% (as omecamtiv mecarbil free base) based on the total weight of the core.

[0036] In some embodiments, the tablet may exist as omecamtiv mecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt thereof, and contains 1 to 3 mg of omecamtiv mecarbil (free base). In some embodiments, the tablet may exist as omecamtiv mecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt thereof, and contains 1 mg of omecamtiv mecarbil (free base).

[0037] Tablet core The tablets disclosed herein include a core coated with a coating film. The core includes omecamtiv mecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt thereof (as described above), an excipient, a binder, a fluidizing agent, and a lubricant.

[0038] As described herein, unless otherwise specified, the weight percentages of the specific components of the tablets disclosed herein are based on the total weight of the tablets (i.e., the entire tablet). In some cases, it may be more convenient to discuss the amount or concentration of a component based on the total weight of a part of the tablet (e.g., the core or the coating film).

[0039] The tablets include one or more excipients. In some cases, the tablets include one excipient. In some cases, the tablets include two or more excipients (e.g., two, three, or four excipients). The tablets include any suitable amount of excipient. If the tablets contain too little excipient, the tablets may exhibit undesirable properties (e.g., inability to be manufactured on a commercial scale). In contrast, if the tablets contain too much excipient, the tablets may exhibit undesirable properties (e.g., an increase in the pill burden on the patient).

[0040] As used herein, the term "excipient" refers to a substance that can be added to the components of a pharmaceutical formulation to increase the bulk weight of the raw materials to be formulated (e.g., tableted) in order to achieve the desired weight. Examples of excipients include, but are not limited to, starch, lactose, cellulose derivatives, sugar alcohols, etc. Examples of various grades of starch include, but are not limited to, corn starch, potato starch, rice starch, wheat starch, pregelatinized starch (commercially available as PCS PC10 from Signet Chemical Corporation), and Colorcon's Starch 1500, Starch 1500 LM grade (low moisture content grade), fully pregelatinized starch (commercially available as National 78-1551 from Essex Grain Products), etc. Examples of various grades of lactose include, but are not limited to, lactose monohydrate, lactose DT (direct compression), lactose anhydrous, Flowlac (trademark) (available from Meggle products), Pharmatose (trademark) (available from DMV), etc. Examples of various cellulose derivatives that can be used include crystalline cellulose such as microcrystalline cellulose, and powdered cellulose. Examples of various sugar alcohols that can be used include mannitol (such as Pearlitol (trademark) SD 200), sorbitol, and xylitol.

[0041] In some cases, the excipient includes microcrystalline cellulose having a particle size of 50 μm and a water content of 3 to 5% (for example, Avicel PH101), or microcrystalline cellulose having a particle size of 100 μm and a water content of 3 to 5% (for example, Avicel PH102), or microcrystalline cellulose having a particle size of 180 μm and a water content of 2 to 5% (for example, Avicel PH200), or lactose monohydrate, or crystalline 325-mesh fine powder lactose monohydrate (for example, Unisweet L-313 or Pharmatose 110M), or crystalline 200-mesh fine powder lactose monohydrate (for example, Unisweet L-312), or a spray-dried mixture of crystalline and amorphous lactose monohydrate having a particle size of 60 to 120 μm (for example, Fast Flo 316), or a combination thereof.

[0042] This tablet contains excipients of 20 wt% or more based on the total weight of the tablet, for example, 21 wt% or more, 22 wt% or more, 23 wt% or more, 24 wt% or more, 25 wt% or more, 26 wt% or more, 27 wt% or more, 28 wt% or more, 29 wt% or more, 30 wt% or more, 31 wt% or more, 32 wt% or more, 33 wt% or more, 34 wt% or more, 35 wt% or more, 36 wt% or more, 37 wt% or more, 38 wt% or more, 39 wt% or more, 40 wt% or more, 41 wt% or more, 42 wt% or more, 43 wt% or more, 44 wt% or more, 45 wt% or more, 46 wt% or more, 47 wt% or more, 48 wt% or more, 49 wt% or more, or 50 wt% or more of excipients based on the total weight of the tablet. Alternatively, or in addition, this tablet contains excipients of 90 wt% or less based on the total weight of the tablet, for example, 89 wt% or less, 88 wt% or less, 87 wt% or less, 86 wt% or less, 85 wt% or less, 84 wt% or less, 83 wt% or less, 82 wt% or less, 81 wt% or less, 80 wt% or less, 79 wt% or less, 78 wt% or less, 77 wt% or less, 76 wt% or less, 75 wt% or less, 74 wt% or less, 73 wt% or less, 72 wt% or less, 71 wt% or less, 70 wt% or less, 69 wt% or less, 68 wt% or less, 67 wt% or less, 66 wt% or less, 65 wt% or less, 64 wt% or less, 63 wt% or less, 62 wt% or less, 61 wt% or less, 60 wt% or less, 59 wt% or less, 58 wt% or less, 57 wt% or less, 56 wt% or less, 55 wt% or less, 54 wt% or less, 53 wt% or less, 52 wt% or less, or 51 wt% or less of excipients based on the total weight of the tablet.

[0043] Thus, the tablet contains an excipient in an amount limited by the endpoints of any two of the above. For example, the tablet contains 20 - 90 wt% of an excipient based on the total weight of the tablet, for example, 21 - 89 wt%, 22 - 88 wt%, 23 - 87 wt%, 24 - 86 wt%, 25 - 85 wt%, 26 - 84 wt%, 27 - 83 wt%, 28 - 82 wt%, 29 - 81 wt%, 30 - 80 wt%, 31 - 79 wt%, 32 - 78 wt%, 33 - 77 wt%, 34 - 76 wt%, 35 - 75 wt%, 36 - 74 wt%, 37 - 73 wt%, 38 - 72 wt%, 39 - 71 wt%, 40 - 70 wt%, 41 - 69 wt%, 42 - 68 wt%, 43 - 67 wt%, 44 - 66 wt%, 45 - 65 wt%, 46 - 64 wt%, 47 - 63 wt%, 48 - 62 wt%, 49 - 61 wt%, 50 - 60 wt%, 51 - 59 wt%, 52 - 58 wt%, 53 - 57 wt%, or 54 - 56 wt% of an excipient.

[0044] In some embodiments, the tablet contains 60 wt% - 90 wt%, 77.9 wt%, 74.5 wt%, or 65.9 wt% of an excipient based on the total weight of the tablet. In some embodiments, the core of the tablet contains 85.6 wt% of an excipient based on the total weight of the core of the tablet.

[0045] In some embodiments, the excipient includes microcrystalline cellulose, lactose monohydrate, or a combination thereof. Two or more excipients (e.g., two, three, four or more excipients) may be present in the tablets disclosed herein. For example, in some embodiments, the excipient includes microcrystalline cellulose and lactose monohydrate. In embodiments where the tablet contains two or more excipients, it is understood that the total amount of the excipients present falls within the amounts described herein.

[0046] In some embodiments, the tablets contain, based on the total weight of the tablets, 10 to 45 wt% microcrystalline cellulose and 10 to 45 wt% lactose monohydrate, for example, based on the total weight of the tablets, 10 to 40 wt% microcrystalline cellulose and 10 to 40 wt% lactose monohydrate, 30 to 40 wt% microcrystalline cellulose and 30 to 40 wt% lactose monohydrate, 39 wt% microcrystalline cellulose and 39 wt% lactose monohydrate, 38 wt% microcrystalline cellulose and 38 wt% lactose monohydrate, 37 wt% microcrystalline cellulose and 37 wt% lactose monohydrate, 36 wt% microcrystalline cellulose and 36 wt% lactose monohydrate, 35 wt% microcrystalline cellulose and 35 wt% lactose monohydrate, 34 wt% microcrystalline cellulose and 34 wt% lactose monohydrate, or 33 wt% microcrystalline cellulose and 33 wt% lactose monohydrate, 32 wt% microcrystalline cellulose and 32 wt% lactose monohydrate, or 31 wt% microcrystalline cellulose and 31 wt% lactose monohydrate as excipients. In some embodiments, the core of the tablets contains 42.8 wt% microcrystalline cellulose and 42.8 wt% lactose monohydrate based on the total weight of the core of the tablets.

[0047] In some embodiments, the tablets disclosed herein contain a binder. In some cases, the tablets contain one binder. In some cases, the tablets contain two or more binders (e.g., two, three, or four binders). The tablets contain any suitable amount of binder. If the amount of binder contained in the tablets is too small, the tablets may, for example, lack stability. In contrast, if the amount of binder contained in the tablets is too large, the tablets may exhibit unfavorable pharmacokinetic properties (e.g., slow release rate).

[0048] As used herein, the term "binder" refers to a substance used in the tablet to hold the pharmaceutically active ingredient and the inert ingredient together in the form of cohesive granules. Suitable binders include, for example, but are not limited to, sodium carboxymethylcellulose USP, hypromellose USP, hydroxyethylcellulose NF, and hydroxypropylcellulose NF. In addition, other binders include polyvidone, polyvinylpyrrolidone, gelatin NF, natural gums (such as acacia, tragacanth, guar, and pectin), starch paste, pregelatinized starch NF, sucrose NF, corn syrup, polyethylene glycol, and sodium alginate, ammonium alginate, calcium alginate, magnesium aluminum silicate, polyethylene glycol. In certain embodiments, the binder comprises hydroxypropylcellulose.

[0049] In some embodiments, the binder comprises hydroxypropylcellulose (HPC) having a Brookfield viscosity (10%) of 300 - 600 mPa-s (e.g., Klucel EXF).

[0050] In various embodiments, the tablet comprises at least 0.5 wt% binder, based on the total weight of the tablet, for example, at least 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, 5 wt%, 5.5 wt%, 6 wt%, 6.5 wt%, 7 wt%, or 7.5 wt% binder, based on the total weight of the tablet. Alternatively, or in addition, the tablet comprises at most 15 wt% binder, based on the total weight of the tablet, for example, 14.5 wt% or less, 14 wt% or less, 13.5 wt% or less, 13 wt% or less, 12.5 wt% or less, 12 wt% or less, 11.5 wt% or less, 11 wt% or less, 10.5 wt% or less, 10 wt% or less, 9.5 wt% or less, 9 wt% or less, 8.5 wt% or less, or 8 wt% or less binder, based on the total weight of the tablet.

[0051] Thus, the tablet contains a binder in an amount limited by any of the above endpoints. For example, the tablet contains 0.5 - 15 wt% binder, such as 1 - 14.5 wt%, 1.5 - 14 wt%, 2 - 13.5 wt%, 2.5 - 13 wt%, 3 - 12.5 wt%, 3.5 - 12 wt%, 4 - 11.5 wt%, 4.5 - 11 wt%, 5 - 10.5 wt%, 5.5 - 10 wt%, 6 - 9.5 wt%, 6.5 - 9 wt%, 7 - 8.5 wt%, or 7.5 - 8 wt% binder based on the total weight of the tablet. In some embodiments, the tablet contains 1 - 8 wt% binder, such as 2 - 5 wt%, or 2 - 4 wt% binder. In some embodiments, the core of the tablet contains 2 - 5 wt% binder based on the total weight of the tablet. In any of the above embodiments, the binder can be HPC.

[0052] In embodiments where the binder includes, for example, HPC, the tablet contains 1 - 8 wt% HPC, such as 1 - 5 wt% HPC based on the total weight of the tablet. In some embodiments, the core of the tablet contains 3 wt% HPC based on the total weight of the core of the tablet. In some embodiments, the tablet contains 2.7 wt% HPC based on the total weight of the tablet. In some embodiments, the tablet contains 2.6 wt% HPC based on the total weight of the tablet. In various embodiments, the tablet contains 2.3 wt% HPC based on the total weight of the tablet. In some embodiments, the core of the tablet contains 3 wt% HPC based on the total weight of the core of the tablet.

[0053] In some embodiments, the tablets disclosed herein include a glidant. Optionally, the tablets include one glidant. Optionally, the tablets include two or more glidants (e.g., two, three, or four glidants). A glidant is an extra-granular component added to improve the fluidity of the composition. The tablets include any suitable amount of glidant. If the composition contains too little glidant, the tablets may have insufficient fluidity, making processing during tablet manufacture difficult. In contrast, if the composition contains too much glidant, the handling characteristics of the tablets may be unfavorable and / or the cost efficiency of the tablets may be low.

[0054] As used herein, the term "glidant" refers to a substance added to a powder formulation blend to improve its fluidity. Suitable glidants include, for example, silica, colloidal silicon dioxide, colloidal anhydrous silica (e.g., Aerosil 200), magnesium trisilicate, powdered cellulose, starch, talc, and combinations thereof, but are not limited thereto.

[0055] The tablets disclosed herein include a glidant of 0.1 wt% or more, based on the total weight of the tablets, for example, 0.25 wt% or more, 0.5 wt% or more, 0.75 wt% or more, 1 wt% or more, 1.25 wt% or more, 1.5 wt% or more, 1.75 wt% or more, 2 wt% or more, 2.25 wt% or more, 2.5 wt% or more, 2.75 wt% or more, or 3 wt% or more of a glidant, based on the total weight of the tablets. Alternatively, or in addition, the tablets include a glidant of 5 wt% or less, based on the total weight of the tablets, for example, 4.75 wt% or less, 4.5 wt% or less, 4.25 wt% or less, 4 wt% or less, 3.75 wt% or less, 3.5 wt% or less, or 3.25 wt% or less of a glidant.

[0056] Thus, the tablet contains a fluidizing agent in an amount limited by any of the above endpoints. For example, the tablet contains 0.1 to 5 wt% of a fluidizing agent based on the total weight of the tablet, such as 0.25 to 4.75 wt%, 0.5 to 4.5 wt%, 0.75 to 4.25 wt%, 1 to 4 wt%, 1.25 to 3.75 wt%, 1.5 to 3.5 wt%, 1.75 to 3.25 wt%, 2 to 3 wt%, or 2.25 to 2.75 wt% of a fluidizing agent based on the total weight of the tablet. In some embodiments, the tablet contains 0.1 to 5 wt% of a fluidizing agent based on the total weight of the tablet, such as 0.1 to 2 wt% of a fluidizing agent or 0.2 to 1 wt% of a fluidizing agent. In some embodiments, the core of the tablet contains 0.2 to 0.8 wt% of a fluidizing agent based on the total weight of the tablet. In any of the above embodiments, the fluidizing agent can be colloidal silicon dioxide.

[0057] In embodiments where the fluidizing agent includes, for example, colloidal silicon dioxide, the tablet contains 0.5 wt% of colloidal silicon dioxide based on the total weight of the tablet. In some embodiments, the tablet contains 0.4 wt% of colloidal silicon dioxide based on the total weight of the tablet. In some embodiments, the core of the tablet contains 0.5 wt% of colloidal silicon dioxide based on the total weight of the core of the tablet.

[0058] In some embodiments, the tablets disclosed herein contain a lubricant. In some cases, the tablet contains one lubricant. In some cases, the tablet contains two or more lubricants (e.g., two, three, or four lubricants). The lubricant is an extra-granular component added to improve the handling of the composition. The tablet contains any suitable amount of lubricant. If the composition contains too little lubricant, the tablet may have insufficient handling characteristics and the processing during the manufacture of the tablet may be difficult. In contrast, if the composition contains too much lubricant, the tablet may exhibit undesirable characteristics and / or the cost efficiency of the tablet may be low.

[0059] As used herein, the term "lubricant" refers to a substance that can be added to the tablet components of the present invention to reduce sticking of the solid preparation to the apparatus used in the manufacture of the unit dosage form. Examples of lubricants include stearic acid, hydrogenated vegetable oil, hydrogenated soybean oil, and hydrogenated soybean oil & hydrogenated castor oil, stearyl alcohol, leucine, magnesium stearate, glycerin monostearate, stearic acid, glyceryl behenate, ethylene oxide polymer, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, and dl-leucine, and mixtures thereof. In some cases, the lubricant includes magnesium stearate.

[0060] The tablets disclosed herein contain a lubricant in an amount of 0.2 wt% or more, based on the total weight of the tablets, for example, 0.25 wt% or more, 0.3 wt% or more, 0.4 wt% or more, 0.5 wt% or more, 0.6 wt% or more, 0.7 wt% or more, 0.8 wt% or more, 0.9 wt% or more, or 1 wt% or more of the lubricant, based on the total weight of the tablets. Alternatively, or in addition, the tablets contain a lubricant in an amount of 2 wt% or less, based on the total weight of the tablets, for example, 1.9 wt% or less, 1.8 wt% or less, 1.7 wt% or less, 1.6 wt% or less, 1.5 wt% or less, 1.4 wt% or less, 1.3 wt% or less, 1.2 wt% or less, or 1.1 wt% or less of the lubricant, based on the total weight of the tablets.

[0061] Thus, the tablets disclosed herein contain a lubricant in an amount limited by any of the above endpoints. For example, the tablets contain 0.2 - 2 wt% of the lubricant, based on the total weight of the tablets, for example, 0.25 - 1.9 wt%, 0.3 - 1.8 wt%, 0.4 - 1.7 wt%, 0.5 - 1.6 wt%, 0.6 - 1.5 wt%, 0.7 - 1.4 wt%, 0.8 - 1.3 wt%, 0.9 - 1.2 wt%, or 1 - 1.1 wt% of the lubricant, based on the total weight of the tablets. In some embodiments, the core of the tablets contains 0.8 - 1.2 wt% of the lubricant (for example, 1 wt% of the lubricant), based on the total weight of the tablets. In any of the above embodiments, the lubricant can be magnesium stearate.

[0062] For example, in some embodiments where the lubricant includes magnesium stearate, the tablet contains 0.25 to 3 wt% magnesium stearate based on the total weight of the tablet. In various embodiments where the lubricant includes magnesium stearate, the tablet contains 0.5 to 3 wt% magnesium stearate based on the total weight of the tablet. In some embodiments, the tablet contains 1 wt% magnesium stearate based on the total weight of the tablet. In various embodiments, the tablet contains 0.9 wt% magnesium stearate based on the total weight of the tablet. In some embodiments, the tablet contains 0.8 wt% magnesium stearate based on the total weight of the tablet. In some embodiments, the core of the tablet contains 1.0 wt% magnesium stearate based on the total weight of the core of the tablet.

[0063] In various embodiments, the tablets disclosed herein do not contain a pH adjuster or are substantially pH adjuster-free. Examples of pH adjusters include maleic acid, citric acid, malic acid, fumaric acid, sulfuric acid, tartaric acid, lactic acid, salicylic acid, aspartic acid, aminosalicylic acid, malonic acid, glutamic acid, or combinations thereof. In some cases, the pH adjuster is fumaric acid.

[0064] The applicant has surprisingly discovered that in a core containing fumaric acid, the release of omecamtiv mecarbil is not promoted in a 6.8 buffer. Without wishing to be bound by any particular theory, fumaric acid is thought to act as a pH regulator by providing a micro low-pH environment inside the immediate-release small tablet core in a neutral pH 6.8 environment. The low pH inside the small tablet core solubilizes omecamtiv mecarbil, and as a result, the release of omecamtiv mecarbil at neutral pH 6.8 is promoted. However, as shown by the data in Figures 6-8 herein, fumaric acid did not promote the release of omecamtiv mecarbil in a 6.8 buffer. Without wishing to be bound by any particular theory, this effect may be due to fumaric acid being neutralized by buffer ions at the initial stage of elution, resulting in the loss of the function of lowering the pH inside the small tablet in a pH 6.8 buffer. The data in Figures 6-8 surprisingly show that fumaric acid did not promote the release of omecamtiv mecarbil at neutral pH, thus suggesting that fumaric acid is not a necessary component for immediate-release small tablets.

[0065] In some embodiments, the core of the tablet comprises 8-11 wt% of omecamtiv mecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt thereof; 83-86 wt% of an excipient; 2-5 wt% of a binder; 0.2-0.8 wt% of a glidant; and 0.8-1.2 wt% of a lubricant, based on the total weight of the core.

[0066] Coating film The tablets disclosed herein comprise a coating film on the core. The coating film comprises a release-modulating polymer (i.e., a release control agent) and a pore-forming agent. In some embodiments, the coating film further comprises a plasticizer. In some embodiments, the pore-forming agent also acts as a plasticizer.

[0067] As used herein, the term "release-modulating polymer" (which may alternatively be referred to herein as "release control agent") refers to a substance that controls and promotes the release of omecamtiv mecarbil, its pharmaceutically acceptable salts, or pharmaceutically acceptable hydrates of its pharmaceutically acceptable salts, from tablets. In some cases, the coating film contains one release-modulating polymer. In some cases, the coating film contains two or more release-modulating polymers (e.g., two, three, or four release-modulating polymers). The release-modulating polymer can form a semipermeable film upon hydration. Examples of release-modulating polymers include, but are not limited to, cellulose acetate (CA), copolymers of ethyl acrylate and methyl methacrylate (e.g., poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1 (Eudragit RS); and poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2 (Eudragit RL)), ethyl cellulose, or polyvinyl acetate, or combinations thereof.

[0068] In various embodiments, the release-modulating polymer of the coating film includes ethyl cellulose, poly(ethyl acrylate-co-methyl methacrylate), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride), cellulose acetate, polyvinyl acetate, or combinations thereof. In some embodiments, the release-modulating polymer includes cellulose acetate.

[0069] The tablet contains any suitable amount of the release-modulating polymer. If the amount of the release-modulating polymer contained in the tablet is too small, the release rate of omecamtiv mecarbil from the tablet may increase. In contrast, if the amount of the release control agent contained in the tablet is too large, the release rate of omecamtiv mecarbil from the tablet may be too slow.

[0070] In embodiments where the release-modulating polymer comprises, for example, cellulose acetate, the tablet comprises cellulose acetate in an amount of 3 wt% or more, for example, 4 wt% or more, 5 wt% or more, 6 wt% or more, 7 wt% or more, 8 wt% or more, 9 wt% or more, 10 wt% or more, 11 wt% or more, or 12 wt% or more, based on the total weight of the tablet. Alternatively, or in addition, the tablet comprises cellulose acetate in an amount of 20 wt% or less, for example, 19 wt% or less, 18 wt% or less, 17 wt% or less, 16 wt% or less, 15 wt% or less, 14 wt% or less, or 13 wt% or less, based on the total weight of the tablet.

[0071] Thus, the tablet comprises cellulose acetate in any amount bounded by the above endpoints. For example, the tablet comprises 3 to 20 wt% cellulose acetate, for example, 4 to 19 wt%, 5 to 18 wt%, 6 to 17 wt%, 7 to 16 wt%, 8 to 15 wt%, 9 to 14 wt%, 10 to 13 wt%, or 11 to 12 wt% cellulose acetate, based on the total weight of the tablet. In some embodiments, the tablet comprises 5.4 wt% cellulose acetate, based on the total weight of the tablet. In some embodiments, the tablet comprises 7.8 wt% cellulose acetate, based on the total weight of the tablet. In some embodiments, the tablet comprises 13.8 wt% cellulose acetate, based on the total weight of the tablet.

[0072] In some embodiments, the coating film comprises a release control polymer of 40 wt% or more, based on the total weight of the coating film, for example, 41 wt% or more, 42 wt% or more, 43 wt% or more, 44 wt% or more, 45 wt% or more, 46 wt% or more, 47 wt% or more, 48 wt% or more, 49 wt% or more, 50 wt% or more, 51 wt% or more, 52 wt% or more, 53 wt% or more, 54 wt% or more, 55 wt% or more, 56 wt% or more, 57 wt% or more, 58 wt% or more, 59 wt% or more, 60 wt% or more, 61 wt% or more, 62 wt% or more, 63 wt% or more, 64 wt% or more, or 65 wt% or more of the release control polymer, based on the total weight of the coating film. Alternatively, or in addition, the coating film comprises a release control polymer of 90 wt% or less, based on the total weight of the coating film, for example, 89 wt% or less, 88 wt% or less, 87 wt% or less, 86 wt% or less, 85 wt% or less, 84 wt% or less, 83 wt% or less, 82 wt% or less, 81 wt% or less, 80 wt% or less, 79 wt% or less, 78 wt% or less, 77 wt% or less, 76 wt% or less, 75 wt% or less, 74 wt% or less, 73 wt% or less, 72 wt% or less, 71 wt% or less, 70 wt% or less, 69 wt% or less, 68 wt% or less, 67 wt% or less, or 66 wt% or less of the release control polymer, based on the total weight of the coating film.

[0073] Thus, the coating film contains the release control polymer in an amount that is any amount bounded by the two endpoints described above. For example, the coating film comprises a release control polymer of 40 - 90 wt%, based on the total weight of the coating film, for example, 41 - 89 wt%, 42 - 88 wt%, 43 - 87 wt%, 44 - 86 wt%, 45 - 85 wt%, 46 - 84 wt%, 47 - 83 wt%, 48 - 82 wt%, 49 - 81 wt%, 50 - 80 wt%, 51 - 79 wt%, 52 - 78 wt%, 53 - 77 wt%, 54 - 76 wt%, 55 - 75 wt%, 56 - 74 wt%, 57 - 73 wt%, 58 - 72 wt%, 59 - 71 wt%, 60 - 70 wt%, 61 - 69 wt%, 62 - 68 wt%, 63 - 67 wt%, or 64 - 66 wt% of the release control polymer, based on the total weight of the coating film.

[0074] In some embodiments, the coating film comprises 40-90 wt%, 50-80 wt%, 60-70 wt%, or 55-65 wt% of a release-modulating polymer, based on the total weight of the coating film. In some embodiments, the coating film comprises 60 wt% of a release-modulating polymer, based on the total weight of the coating film.

[0075] As used herein, the term "pore-forming agent" refers to a substance that increases the porosity of a water-insoluble film and promotes the diffusion of a drug. When exposed to water or body fluid, the pore-forming agent dissolves and drug release channels are formed in the water-insoluble film wall. In some cases, the coating film comprises one pore-forming agent. In some cases, the coating film comprises two or more pore-forming agents (e.g., two, three, or four pore-forming agents). Suitable pore-forming agents for the coating film include, but are not limited to, hydroxypropylmethylcellulose, polyvinylpyrrolidone, sorbitol, triethyl citrate, polyethylene glycol, or combinations thereof. Suitable pore-forming agents include, for example, polyethylene glycol (e.g., PEG3350), sorbitol, hypromellose having a methoxy content of 28-30% and a hydroxypropyl content of 7-12% and a viscosity of 4-6 cP in 2% in water at 20 °C (e.g., Methocel E5), hypromellose having a methoxy content of 28-30% and a hydroxypropyl content of 7-12% and a viscosity of 5-7 cP in 2% in water at 20 °C (e.g., Methocel E6), or a polyvinyl alcohol-polyethylene glycol graft copolymer having a molecular weight of 45 kDa, a melting point of 209 °C, and a viscosity of 115 mPa-s as a 20% solution (e.g., Kollicoat IR), or combinations thereof, but are not limited thereto.

[0076] In some embodiments, the pore former comprises polyethylene glycol (PEG). An exemplary polyethylene glycol is PEG 3350 (CAS number 25322-68-3) having a molecular weight (MW) of 3350 g / mol and a melting point of 56 °C.

[0077] As used herein, the term "plasticizer" refers to a substance that reduces plasticity or reduces the attractive forces between polymer chains to make the polymer chains more flexible, thereby preventing the formation of cracks or peeling in the polymer film. In some cases, the coating film contains one plasticizer. In some cases, the coating film contains two or more plasticizers (e.g., two, three, or four plasticizers). Suitable plasticizers include, for example, polyethylene glycol (e.g., PEG 3350), diethyl phthalate, triethyl citrate, dibutyl sebacate, or triacetin, or combinations thereof, but are not limited thereto. In some cases, the pore former may exhibit plasticizer properties, and a component may be both a pore former and a plasticizer. Suitable plasticizers include, for example, PEG, diethyl phthalate, triethyl citrate, dibutyl sebacate, triacetin, or combinations thereof, but are not limited thereto. In some cases, the plasticizer contains PEG.

[0078] In some embodiments, the pore former is also a plasticizer. In some cases, the pore former that is also a plasticizer contains PEG, for example, PEG 3350.

[0079] The tablet contains any suitable amount of pore former. If the amount of pore former contained in the tablet is too small, the release rate of ome-camtiv mecarbil from the tablet may become too slow. In contrast, if the amount of pore former contained in the tablet is too large, the release rate of ome-camtiv mecarbil from the tablet may become too fast.

[0080] The tablet contains a pore-forming agent of 2 wt% or more, based on the total weight of the tablet. For example, it contains a pore-forming agent of 3 wt% or more, 4 wt% or more, 5 wt% or more, 6 wt% or more, 7 wt% or more, 8 wt% or more, 9 wt% or more, 10 wt% or more, 11 wt% or more, 12 wt% or more, 13 wt% or more, 14 wt% or more, 15 wt% or more, 16 wt% or more, 17 wt% or more, 18 wt% or more, 19 wt% or more, 20 wt% or more, 21 wt% or more, 22 wt% or more, 23 wt% or more, 24 wt% or more, 25 wt% or more, 26 wt% or more, 27 wt% or more, or 28 wt% or more, based on the total weight of the tablet. Alternatively, or in addition, the tablet contains a pore-forming agent of 50 wt% or less, based on the total weight of the tablet. For example, it contains a pore-forming agent of 49 wt% or less, 48 wt% or less, 47 wt% or less, 46 wt% or less, 45 wt% or less, 44 wt% or less, 43 wt% or less, 42 wt% or less, 41 wt% or less, 40 wt% or less, 39 wt% or less, 38 wt% or less, 37 wt% or less, 36 wt% or less, 35 wt% or less, 34 wt% or less, 33 wt% or less, 32 wt% or less, 31 wt% or less, 30 wt% or less, or 29 wt% or less, based on the total weight of the tablet.

[0081] Thus, the tablet contains a pore-forming agent in an amount limited by the endpoints of any two of the above. For example, the coating film contains a pore-forming agent of 2 - 50 wt%, based on the total weight of the tablet. For example, it contains a pore-forming agent of 3 - 49 wt%, 4 - 48 wt%, 5 - 47 wt%, 6 - 46 wt%, 7 - 45 wt%, 8 - 44 wt%, 9 - 43 wt%, 10 - 42 wt%, 11 - 41 wt%, 12 - 40 wt%, 13 - 39 wt%, 14 - 38 wt%, 15 - 37 wt%, 16 - 36 wt%, 17 - 35 wt%, 18 - 34 wt%, 19 - 33 wt%, 20 - 32 wt%, 21 - 31 wt%, 22 - 30 wt%, 23 - 29 wt%, 24 - 28 wt%, or 25 - 27 wt%, based on the total weight of the tablet. In some embodiments, the coating film contains a pore-forming agent of 2 - 50 wt%, or 20 - 40 wt%, based on the total weight of the tablet.

[0082] In embodiments where the pore-forming agent includes, for example, PEG, the tablet contains 2 to 15 wt% PEG, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 wt% PEG based on the total weight of the tablet. In some embodiments, the tablet contains 3.6 wt% PEG based on the total weight of the tablet. In various embodiments, the tablet contains 5.2 wt% PEG based on the total weight of the tablet. In further various embodiments, the tablet contains 9.2 wt% PEG based on the total weight of the tablet.

[0083] The tablet contains any suitable amount of plasticizer. If the amount of plasticizer contained in the tablet is too small, the coating film may become brittle and prone to cracking. In contrast, if the amount of plasticizer contained in the tablet is too large, the adhesiveness of the coating film may show a high level, and the coating process may be insufficient.

[0084] The tablet contains 0.25 wt% or more of plasticizer based on the total weight of the tablet, for example, 0.3 wt% or more, 0.4 wt% or more, 0.5 wt% or more, 0.6 wt% or more, 0.7 wt% or more, 0.8 wt% or more, 0.9 wt% or more, 1 wt% or more, 1.1 wt% or more, 1.2 wt% or more, 1.3 wt% or more, 1.4 wt% or more, 1.5 wt% or more, 1.6 wt% or more, 1.7 wt% or more, 1.8 wt% or more, 1.9 wt% or more, 2 wt% or more, 2.1 wt% or more, 2.2 wt% or more, 2.3 wt% or more, 2.4 wt% or more, or 2.5 wt% or more of plasticizer based on the total weight of the tablet. Alternatively, or in addition, the tablet contains 5 wt% or less of plasticizer, for example, 4.9 wt% or less, 4.8 wt% or less, 4.7 wt% or less, 4.6 wt% or less, 4.5 wt% or less, 4.4 wt% or less, 4.3 wt% or less, 4.2 wt% or less, 4.1 wt% or less, 4.0 wt% or less, 3.9 wt% or less, 3.8 wt% or less, 3.7 wt% or less, 3.6 wt% or less, 3.5 wt% or less, 3.4 wt% or less, 3.3 wt% or less, 3.2 wt% or less, 3.1 wt% or less, 3 wt% or less, 2.9 wt% or less, 2.8 wt% or less, 2.7 wt% or less, or 2.6 wt% or less of plasticizer based on the total weight of the tablet.

[0085] Thus, the tablet contains a plasticizer in an amount limited by any two of the above-mentioned endpoints. For example, the tablet contains 0.25 to 5.0 wt% of a plasticizer based on the total weight of the tablet, for example, 0.3 to 4.9 wt%, 0.4 to 4.8 wt%, 0.5 to 4.7 wt%, 0.6 to 4.6 wt%, 0.7 to 4.5 wt%, 0.8 to 4.4 wt%, 0.9 to 4.3 wt%, 1.0 to 4.2 wt%, 1.1 to 4.1 wt%, 1.2 to 4.0 wt%, 1.3 to 3.9 wt%, 1.4 to 3.8 wt%, 1.5 to 3.7 wt%, 1.6 to 3.6 wt%, 1.7 to 3.5 wt%, 1.8 to 3.4 wt%, 1.9 to 3.2 wt%, 2.0 to 3.1 wt%, 2.1 to 3.0 wt%, 2.2 to 2.9 wt%, 2.3 to 2.8 wt%, 2.4 to 2.7 wt%, or 2.5 to 2.6 wt% of a plasticizer based on the total weight of the tablet.

[0086] In some embodiments, the tablet contains 0.25 to 5.0 wt% of a plasticizer based on the total weight of the tablet.

[0087] The coating film, as well as each component of the coating film, is present in an amount that provides the desired omecamtiv mecarbil release characteristics. Thus, the amount of the coating film, as well as the coating film components, can be adjusted to regulate the release of omecamtiv mecarbil.

[0088] In some embodiments, the coating film of the tablet comprises, based on the total weight of the coating film, 50 to 90 wt% of a release control polymer and 10 to 50 wt% of a pore former and a plasticizer (if present), for example, based on the total weight of the coating film, 60 wt% of a release control polymer and 40 wt% of a pore former and a plasticizer (if present). In some embodiments, the coating film comprises, based on the total weight of the coating film, 60 wt% of a release control polymer and 40 wt% of a pore former and a plasticizer (if present). In some embodiments, the coating film is composed of 9 wt% of the total weight of the tablet. In some embodiments, the coating film is composed of 13 wt% of the total weight of the tablet. In some embodiments, the coating film is composed of 23 wt% of the total weight of the tablet. The coating can be applied to the core using any suitable coating method. Non-limiting coating methods include, for example, the pan coating method and the fluidized bed coating method.

[0089] In some cases, the coating is applied using a coating composition. The coating composition comprises a coating solvent, a release control polymer, a pore former, and a plasticizer (if present). Any suitable coating solvent(s) can be used to prepare the coating composition. Suitable coating solvents include, but are not limited to, water, acetone, and any combination thereof. The coating composition can have 5 to 10 wt% solids and 90 to 95 wt% solvent.

[0090] In some embodiments, the coating solvent is composed of acetone and water (e.g., weight ratio 9:1).

[0091] Tablet In some embodiments, the tablets contain, based on the total weight of the tablets, 5 to 40 wt% of omecamtiv mecarbil hydrochloride dihydrate monohydrate; 10 to 45 wt% of microcrystalline cellulose; 10 to 45 wt% of lactose monohydrate; 1 to 8 wt% of hydroxypropyl cellulose; 0.1 to 2 wt% of colloidal silicon dioxide; 0.25 to 3 wt% of magnesium stearate; 3 to 20 wt% of cellulose acetate; and 2 to 15 wt% of polyethylene glycol.

[0092] In some embodiments, the tablets contain, based on the total weight of the tablets, 5 to 10 wt% of omecamtiv mecarbil hydrochloride dihydrate monohydrate; 30 to 45 wt% of microcrystalline cellulose; 30 to 45 wt% of lactose monohydrate; 1 to 5 wt% of hydroxypropyl cellulose; 0.1 to 2 wt% of colloidal silicon dioxide; 0.5 to 3 wt% of magnesium stearate; 3 to 20 wt% of cellulose acetate; and 2 to 15 wt% of polyethylene glycol.

[0093] In some embodiments, the tablets contain, based on the total weight of the tablets, 9 wt% of omecamtiv mecarbil hydrochloride dihydrate monohydrate; 38.9 wt% of microcrystalline cellulose; 38.9 wt% of lactose monohydrate; 2.7 wt% of hydroxypropyl cellulose; 0.5 wt% of colloidal silicon dioxide; 1 wt% of magnesium stearate; 5.4 wt% of cellulose acetate; and 3.6 wt% of polyethylene glycol.

[0094] In some embodiments, the tablets contain, based on the total weight of the tablets, 8.5 wt% of omecamtiv mecarbil hydrochloride dihydrate monohydrate; 37.3 wt% of microcrystalline cellulose; 37.3 wt% of lactose monohydrate; 2.6 wt% of hydroxypropyl cellulose; 0.4 wt% of colloidal silicon dioxide; 0.9 wt% of magnesium stearate; 7.8 wt% of cellulose acetate; and 5.2 wt% of polyethylene glycol.

[0095] In some embodiments, the tablet contains 7.5 wt% of omecamtiv mecarbil hydrochloride dihydrate; 33 wt% of microcrystalline cellulose; 33 wt% of lactose monohydrate; 2.3 wt% of hydroxypropyl cellulose; 0.4 wt% of colloidal silicon dioxide; 0.8 wt% of magnesium stearate; 13.8 wt% of cellulose acetate; and 9.2 wt% of polyethylene glycol, based on the total weight of the tablet.

[0096] In some embodiments, the core of the tablet contains 9.8 wt% of omecamtiv mecarbil hydrochloride dihydrate; 42.8 wt% of microcrystalline cellulose; 42.8 wt% of lactose monohydrate; 3 wt% of hydroxypropyl cellulose; 0.5 wt% of colloidal silicon dioxide; and 1 wt% of magnesium stearate, based on the total weight of the core. The coating of the coating film increases the weight of the tablet by 10% based on the total weight of the core. Here, the coating film contains 60 wt% of cellulose acetate and 40 wt% of polyethylene glycol, based on the total weight of the coating film.

[0097] In some embodiments, the core of the tablet contains 9.8 wt% of omecamtiv mecarbil hydrochloride dihydrate; 42.8 wt% of microcrystalline cellulose; 42.8 wt% of lactose monohydrate; 3 wt% of hydroxypropyl cellulose; 0.5 wt% of colloidal silicon dioxide; and 1 wt% of magnesium stearate, based on the total weight of the core. The coating of the coating film increases the weight of the tablet by 15% based on the total weight of the core. Here, the coating film contains 60 wt% of cellulose acetate and 40 wt% of polyethylene glycol, based on the total weight of the coating film.

[0098] In some embodiments, the core of the tablet comprises, based on the total weight of the core, 9.8 wt% of omecamtiv mecarbil hydrochloride monohydrate; 42.8 wt% of microcrystalline cellulose; 42.8 wt% of lactose monohydrate; 3 wt% of hydroxypropyl cellulose; 0.5 wt% of colloidal silicon dioxide; and 1 wt% of magnesium stearate, and the weight of the tablet is increased by 30% based on the total weight of the core by coating with a coating film, wherein the coating film comprises 60 wt% of cellulose acetate and 40 wt% of polyethylene glycol based on the total weight of the coating film.

[0099] In various embodiments, the omecamtiv mecarbil release characteristics of the tablets are pH independent.

[0100] Tablet manufacturing method Also provided herein is a process for manufacturing the disclosed tablets. As described herein, the process for manufacturing a tablet core comprises preparing granules comprising one or more components and then forming a tablet core from the granules. Any suitable granulation method may be used. The method includes dry granulation, wet granulation, or a combination thereof.

[0101] In some embodiments, the process for manufacturing a tablet comprises direct compression of the core components.

[0102] In some embodiments, the tablet manufacturing process comprises mixing omecamtiv mecarbil, its pharmaceutically acceptable salts, or pharmaceutically acceptable hydrates of its pharmaceutically acceptable salts, excipients, and binders, and granulating to form a granule mixture; mixing the granule mixture and a granulating solvent, and granulating to form wet granules; drying the wet granules to form dry granules; pulverizing the dry granules to form pulverized granules; mixing the pulverized granules, a fluidizing agent, and a lubricant, and tableting the mixture to form a core; mixing the core with a precoating film mixture comprising a release control polymer, a plasticizer, and a film coating solvent to coat the core with a coating film; and drying the coated core to form a tablet.

[0103] In some embodiments, the mixing of omecamtiv mecarbil, excipients, and binders is performed in a high-shear granulator.

[0104] In the tablet preparation process, any suitable granulating solvent(s) may be used. In various cases, the granulating solvent is inert and has the ability to form a proper granule mixture of the components. In certain embodiments, the granulating solvent contains water.

[0105] In embodiments of the process including pulverizing the dry granules, the pulverizing of the dry granules can be performed using an impact mill.

[0106] In some embodiments of the process, the step of mixing the pulverized granules, a fluidizing agent, and a lubricant is performed stepwise by mixing the pulverized granules and the fluidizing agent, and then mixing the resulting mixture with the lubricant.

[0107] In some embodiments, the process includes mixing the core and the precoating film mixture in a fluidized bed coater.

[0108] In some embodiments, the tablet manufacturing process comprises mixing omecamtiv mecarbil, its pharmaceutically acceptable salts, or pharmaceutically acceptable hydrates of its pharmaceutically acceptable salts, excipients, and binders, and granulating to form a granule mixture; grinding the granule mixture to form ground granules; mixing the ground granules, a fluidizing agent, and a lubricant, and tableting the mixture to form a core; mixing the core with a precoating film mixture comprising a release-modulating polymer, a pore-forming agent, and a film-coating solvent to coat the core with a coating film; and drying the coated core to form a tablet.

[0109] In some embodiments, the process for manufacturing a tablet comprises mixing omecamtiv mecarbil, its salts, or hydrates of its salts, excipients, binders, a fluidizing agent, and a lubricant, and tableting the mixture to form a core; mixing the core with a precoating film mixture comprising a release-modulating polymer, a pore-forming agent, and a film-coating solvent to coat the core with a coating film; and drying the coated core to form a tablet.

[0110] The tablet cores disclosed herein can be prepared by a method comprising converting a granule formulation into a core by rotary tableting using a multi-tip punch and die, following direct tableting of a core powder formulation, wet granulation of a core powder formulation, or dry granulation.

[0111] Method of Use Also provided herein is a method of using the disclosed tablets for the treatment of cardiovascular conditions such as, but not limited to, acute (or decompensated) congestive heart failure, chronic congestive heart failure, and heart failure with reduced ejection fraction; or cardiovascular conditions associated with cardiac systolic dysfunction. In certain embodiments, the disclosed tablets can be used for the treatment of heart failure with reduced ejection fraction (HFrEF). In certain embodiments, the disclosed tablets can be used to improve cardiac contractility in patients presenting with a cardiovascular condition, or to increase the ejection fraction in patients presenting with a cardiovascular condition such as HFrEF.

[0112] In a further embodiment, the disclosed tablets can be used for (1) improving exercise capacity measured by cardiopulmonary exercise testing (CPET), (2) improving ventilation efficiency measured by changes in the ventilation volume (VE) / carbon dioxide output (VCO2) slope during cardiopulmonary exercise testing (CPET), or (3) improving the average daily activity unit in patients presenting with cardiovascular conditions such as chronic heart failure and heart failure with reduced ejection fraction.

[0113] The disclosed method includes administering a therapeutically effective amount of the tablets to a patient in need thereof. In some embodiments, the patient is a pediatric patient. In some embodiments, the patient is an adult patient with dysphagia.

[0114] In some embodiments, the tablets are administered to the patient in an amount that provides 3 to 50 mg of omecamtiv mecarbil twice a day, based on the weight of the omecamtiv mecarbil free base. In some embodiments, the tablets are administered to the patient in an amount that provides 3 to 25 mg of omecamtiv mecarbil twice a day, based on the weight of the omecamtiv mecarbil free base.

[0115] The patient can be a pediatric patient, such as a child between 6 and 12 years old. In some cases, the patient is an adult with dysphagia.

[0116] Embodiment 1. Omecamtiv mecarbil, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt thereof; Excipients; Binders; Fluidizing agents; and Lubricants; A core comprising, and A coating film on the core, the coating film comprising a release control polymer and a pore former, Tablets comprising.

[0117] 2. The tablet according to Embodiment 1, wherein the omedetomidine is present as omedetomidine dihydrochloride monohydrate.

[0118] 3. The tablet according to Embodiment 1 or 2, wherein the excipient contains microcrystalline cellulose, lactose monohydrate, or a combination thereof.

[0119] 4. The tablet according to Embodiment 3, wherein the excipient contains microcrystalline cellulose and lactose monohydrate.

[0120] 5. The tablet according to any one of Embodiments 1 to 4, wherein the binder contains hydroxypropyl cellulose.

[0121] 6. The tablet according to any one of Embodiments 1 to 5, wherein the glidant contains silicon dioxide.

[0122] 7. The tablet according to any one of Embodiments 1 to 6, wherein the lubricant contains magnesium stearate.

[0123] 8. The core is 8 to 11 wt% of omedetomidine, its pharmaceutically acceptable salt, or a pharmaceutically acceptable hydrate of its pharmaceutically acceptable salt; 83 to 86 wt% of an excipient; 2 to 5 wt% of a binder; 0.2 to 0.8 wt% of a glidant; and 0.8 to 1.2 wt% of a lubricant The tablet according to any one of Embodiments 1 to 7, containing.

[0124] 9. The tablet according to any one of Embodiments 1 to 8, wherein the coating film further contains a plasticizer.

[0125] 10. The tablet according to any one of Embodiments 1 to 9, wherein the pore former is also a plasticizer.

[0126] 11. The release control polymer of the coating film is ethyl cellulose, poly(ethyl acrylate-co-methyl methacrylate), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride), cellulose acetate, polyvinyl acetate, or a combination thereof, and the tablet according to any one of Embodiments 1 to 10.

[0127] 12. The release control polymer contains cellulose acetate, and the tablet according to Embodiment 11.

[0128] 13. The pore former of the coating film is hypromellose, polyvinylpyrrolidone, sorbitol, triethyl citrate, polyethylene glycol, or a combination thereof, and the tablet according to any one of Embodiments 1 to 12.

[0129] 14. The pore former contains polyethylene glycol, and the tablet according to Embodiment 13.

[0130] 15. The polyethylene glycol is polyethylene glycol 3350, and the tablet according to Embodiment 14.

[0131] 16. The plasticizer is polyethylene glycol, diethyl phthalate, triethyl citrate, dibutyl sebacate, triacetin, or a combination thereof, and the tablet according to any one of Embodiments 9 to 15.

[0132] 17. The coating film is 50 to 90 wt% of the release control polymer; and 10 to 50 wt% of the pore former and plasticizer (if present) and the tablet according to any one of Embodiments 11 to 16.

[0133] 18. The coating film contains 60 wt% of the release control polymer and 40 wt% of the pore former and plasticizer (if present), and the tablet according to Embodiment 17.

[0134] 19. The coating film is the tablet according to any one of Embodiments 1 to 18, which is composed of 9 wt% of the total weight of the tablet.

[0135] 20. The coating film is the tablet according to any one of Embodiments 1 to 18, which is composed of 13 wt% of the total weight of the tablet.

[0136] 21. The coating film is the tablet according to any one of Embodiments 1 to 18, which is composed of 23 wt% of the total weight of the tablet.

[0137] 22. 5 to 40 wt% of omecamtiv mecarbil dihydrochloride monohydrate; 10 to 45 wt% of microcrystalline cellulose; 10 to 45 wt% of lactose monohydrate; 1 to 8 wt% of hydroxypropyl cellulose; 0.1 to 2 wt% of colloidal silicon dioxide; 0.25 to 3 wt% of magnesium stearate; 3 to 20 wt% of cellulose acetate; and 2 to 15 wt% of polyethylene glycol The tablet according to Embodiment 1, comprising.

[0138] 23. 5 to 10 wt% of omecamtiv mecarbil dihydrochloride monohydrate; 30 to 45 wt% of microcrystalline cellulose; 30 to 45 wt% of lactose monohydrate; 1 to 5 wt% of hydroxypropyl cellulose; 0.1 to 2 wt% of colloidal silicon dioxide; 0.5 to 3 wt% of magnesium stearate; 3 to 20 wt% of cellulose acetate; and 2 to 15 wt% of polyethylene glycol The tablet according to Embodiment 22, comprising.

[0139] 24. 9 wt% of omecamtiv mecarbil dihydrochloride monohydrate; 38.9 wt% microcrystalline cellulose; 38.9 wt% lactose monohydrate; 2.7 wt% hydroxypropyl cellulose; 0.5 wt% colloidal silicon dioxide; 1 wt% magnesium stearate; 5.4 wt% cellulose acetate; and 3.6 wt% polyethylene glycol The tablet according to embodiment 23, comprising the above.

[0140] 25.8.5 wt% omecamtiv mecarbil hydrochloride monohydrate; 37.3 wt% microcrystalline cellulose; 37.3 wt% lactose monohydrate; 2.6 wt% hydroxypropyl cellulose; 0.4 wt% colloidal silicon dioxide; 0.9 wt% magnesium stearate; 7.8 wt% cellulose acetate; and 5.2 wt% polyethylene glycol The tablet according to embodiment 23, comprising the above.

[0141] 26.7.5 wt% omecamtiv mecarbil hydrochloride monohydrate; 33 wt% microcrystalline cellulose; 33 wt% lactose monohydrate; 2.3 wt% hydroxypropyl cellulose; 0.4 wt% colloidal silicon dioxide; 0.8 wt% magnesium stearate; 13.8 wt% cellulose acetate; and 9.2 wt% polyethylene glycol The tablet according to embodiment 23, comprising the above.

[0142] 27. The core is 9.8 wt% omecamtiv mecarbil hydrochloride monohydrate; 42.8 wt% microcrystalline cellulose; 42.8 wt% lactose monohydrate; 3 wt% hydroxypropyl cellulose; 0.5 wt% colloidal silicon dioxide; and 1 wt% magnesium stearate comprising, the coating of the coating film increases the weight of the tablet by 10% based on the total weight of the core, wherein the coating film is composed of 60 wt% cellulose acetate and 40 wt% polyethylene glycol based on the total weight of the coating film, the tablet according to Embodiment 1.

[0143] 28. The core is 9.8 wt% omecamtiv mecarbil hydrochloride monohydrate; 42.8 wt% microcrystalline cellulose; 42.8 wt% lactose monohydrate; 3 wt% hydroxypropyl cellulose; 0.5 wt% colloidal silicon dioxide; and 1 wt% magnesium stearate comprising, the coating of the coating film increases the weight of the tablet by 15% based on the total weight of the core, wherein the coating film is composed of 60 wt% cellulose acetate and 40 wt% polyethylene glycol based on the total weight of the coating film, the tablet according to Embodiment 1.

[0144] 29. The core is 9.8 wt% omecamtiv mecarbil hydrochloride monohydrate; 42.8 wt% microcrystalline cellulose; 42.8 wt% lactose monohydrate; 3 wt% hydroxypropyl cellulose; 0.5 wt% colloidal silicon dioxide; and 1 wt% magnesium stearate comprising, By coating the coating film, the weight of the tablet is increased by 30% based on the total weight of the core. Here, the coating film is composed of 60 wt% cellulose acetate and 40 wt% polyethylene glycol based on the total weight of the coating film. The tablet according to Embodiment 1.

[0145] The tablet according to any one of Embodiments 1 to 29, containing 30.1 to 3 mg of omecamtiv mecarbil.

[0146] The tablet according to Embodiment 30, containing 31.1 mg of omecamtiv mecarbil.

[0147] 50% or less of omecamtiv mecarbil is released in 32.1 hours; 60 to 70% of omecamtiv mecarbil is released in 2 hours; 85 to 90% of omecamtiv mecarbil is released in 8 hours; and 90% or more of omecamtiv mecarbil is released in 16 hours. The tablet according to any one of Embodiments 1 to 24, 27, 30, and 31, having the omecamtiv mecarbil release characteristics as described above.

[0148] 25% or less of omecamtiv mecarbil is released in 33.1 hours; 35 to 45% of omecamtiv mecarbil is released in 2 hours; 75 to 80% of omecamtiv mecarbil is released in 8 hours; and 85% or more of omecamtiv mecarbil is released in 16 hours. The tablet according to any one of Embodiments 1 to 23, 25, 28, 30, and 31, having the omecamtiv mecarbil release characteristics as described above.

[0149] 10% or less of omecamtiv mecarbil is released in 34.1 hours; 25 to 35% of omecamtiv mecarbil is released in 2 hours; 70 to 75% of omecamtiv mecarbil is released in 8 hours; and 78% or more of omecamtiv mecarbil is released in 16 hours, The tablet according to any one of Embodiments 1 to 23, 26, and 29 to 31, having the omecamtiv mecarbil release characteristics as described above.

[0150] 35. When administered to a patient, the tablet provides a maximum plasma concentration (C max ) of 100 to 1000 ng / mL of omecamtiv mecarbil in the patient. The tablet according to any one of Embodiments 1 to 34.

[0151] 36. The tablet according to any one of Embodiments 1 to 35, which does not contain (is free of) a pH adjuster.

[0152] 37. The tablet according to any one of Embodiments 1 to 36, having a maximum diameter of 3 mm.

[0153] 38. A method for treating heart failure in a patient suffering from heart failure, the method comprising administering to the patient the tablet according to any one of Embodiments 1 to 37.

[0154] 39. The method according to Embodiment 38, wherein the heart failure is acute or chronic.

[0155] 40. The method according to Embodiment 38, wherein the heart failure is heart failure with reduced ejection fraction (HFrEF).

[0156] 41. The method according to any one of Embodiments 38 to 40, wherein the patient is a pediatric patient.

[0157] 42. The method according to Embodiment 41, wherein the tablet is administered to the pediatric patient in an amount that provides 3 to 25 mg of omecamtiv mecarbil twice a day.

[0158] 43. The method according to any one of Embodiments 38 to 40, wherein the patient is an adult patient with dysphagia.

[0159] 44. The method according to embodiment 43, wherein the adult patient is administered the tablets in an amount that provides 25 mg or 50 mg of omecamtiv mecarbil twice a day.

[0160] 45. A tablet according to any one of embodiments 1 to 37 for use in the treatment of heart failure.

[0161] 46. The tablet according to embodiment 45, wherein the heart failure is acute or chronic.

[0162] 47. The tablet according to embodiment 45, wherein the heart failure is heart failure with reduced ejection fraction (HFrEF).

[0163] 48. The tablet according to any one of embodiments 45 to 47, which is suitable for administration to pediatric patients.

[0164] 49. The tablet according to embodiment 48, wherein the pediatric patient is administered the tablets in an amount that provides 3 to 25 mg of omecamtiv mecarbil twice a day.

[0165] 50. The tablet according to any one of embodiments 45 to 47, which is suitable for administration to adult patients with dysphagia.

[0166] 51. The tablet according to embodiment 50, wherein the adult patient is administered the tablets in an amount that provides 25 mg or 50 mg of omecamtiv mecarbil twice a day.

[0167] 52. Use of a tablet according to any one of embodiments 1 to 37 in the preparation of a medicament for the treatment of heart failure.

[0168] 53. The use according to embodiment 52, wherein the heart failure is acute or chronic.

[0169] 54. The use according to embodiment 52, wherein the heart failure is heart failure with reduced ejection fraction (HFrEF).

[0170] 55. Use according to any one of embodiments 52 to 54, wherein the tablet is suitable for administration to pediatric patients.

[0171] 56. Use according to embodiment 55, wherein the pediatric patient is administered the tablet in an amount that provides 3 to 25 mg of omecamtiv mecarbil twice a day.

[0172] 57. Use according to any one of embodiments 52 to 54, wherein the tablet is suitable for administration to adult patients with dysphagia.

[0173] 58. Use according to embodiment 57, wherein the adult patient is administered the tablet in an amount that provides 25 mg or 50 mg of omecamtiv mecarbil twice a day.

[0174] 59. Mixing the omecamtiv mecarbil, its pharmaceutically acceptable salt, or its pharmaceutically acceptable hydrate of its pharmaceutically acceptable salt, the excipient, and the binder, and granulating to form a granule mixture; Mixing the granule mixture and a granulation solvent, and granulating to form wet granules; Drying the wet granules to form dry granules; Crushing the dry granules to form crushed granules; Mixing the crushed granules, the fluidizing agent, and the lubricant, and tableting the mixture to form the core; Mixing the core with a precoating film mixture containing the release control polymer, the plasticizer, and a film coating solvent to coat the core with the coating film; Drying the coated core to form the tablet; A process for manufacturing a tablet according to any one of embodiments 1 to 37, comprising:

[0175] 60. The mixing of the omecamtiv mecarbil, its pharmaceutically acceptable salt, or its pharmaceutically acceptable hydrate of its pharmaceutically acceptable salt, the excipient, and the binder is carried out in a high-shear granulator, the process according to embodiment 59.

[0176] 61. The granulation solvent contains water, the process according to embodiment 59 or 60.

[0177] 62. The pulverization of the dry granules is carried out using an impact mill, the process according to any one of embodiments 59 to 61.

[0178] 63. The mixing of the pulverized granules, the fluidizing agent, and the lubricant is carried out stepwise by mixing the pulverized granules and the fluidizing agent, and then mixing the resulting mixture with the lubricant, the process according to any one of embodiments 59 to 62.

[0179] 64. The film coating solvent contains acetone, water, or a mixture thereof, the process according to any one of embodiments 59 to 63.

[0180] 65. The film coating solvent contains acetone and water, the process according to embodiment 64.

[0181] 66. The film coating solvent is composed of acetone: water (9:1), the process according to embodiment 65.

[0182] 67. The mixing of the core and the precoating film mixture is carried out in a fluidized bed coater, the process according to any one of embodiments 59 to 66.

[0183] 68. Mixing the omecamtiv mecarbil, its pharmaceutically acceptable salt, or its pharmaceutically acceptable hydrate of its pharmaceutically acceptable salt, the excipient, and the binder, and granulating to form a granule mixture; Pulverizing the granule mixture to form pulverized granules; Mixing the crushed granules, the fluidizing agent, and the lubricant, and tableting the mixture to form the core; Mixing the core with a precoating film mixture containing the release control polymer, the plasticizer (if present), and the film coating solvent to cover the core with the coating film, Drying the coated core to form the tablet, A process for manufacturing a tablet according to any one of Embodiments 1 to 37, comprising:

[0184] 69. Mixing the omecamtiv mecarbil, its pharmaceutically acceptable salt, or a pharmaceutically acceptable hydrate of its pharmaceutically acceptable salt, the excipient, the binder, the fluidizing agent, and the lubricant, and tableting the mixture to form the core; Mixing the core with a precoating film mixture containing the release control polymer, the plasticizer (if present), and the film coating solvent to cover the core with the coating film, Drying the coated core to form the tablet, A process for manufacturing a tablet according to any one of Embodiments 1 to 37, comprising:

Examples

[0185] The following examples further illustrate the disclosed tablets and processes, but should not be construed as limiting the scope in any way.

[0186] In the examples, the following abbreviations are used: IR refers to immediate release; OM refers to omecamtiv mecarbil; MCC refers to microcrystalline cellulose; HPC refers to hydroxypropyl cellulose; CA refers to cellulose acetate; PEG refers to polyethylene glycol; SSNMR refers to solid state nuclear magnetic resonance; AV refers to acceptance value; PK refers to pharmacokinetics; GLSM refers to geometric least squares mean; CI refers to confidence interval; and CV refers to coefficient of variation.

[0187] An exemplary process for manufacturing an immediate-release small tablet core is shown in Figure 2. The exemplary process includes the following steps: 1) mixing of screened intragranular components in a high-shear wet granulator; 2) granulation of the intragranular components while adding purified water; 3) drying of the wet mass to a pre-specified loss on drying (LOD) value; 4) pulverization of the dried granules using an impact mill; 5) blending of the pulverized granules with pre-screened colloidal silicon dioxide in a tumbler mixer; 6) blending of the product of step 5) with pre-screened magnesium stearate in a tumbler mixer; and 7) tableting of the final formulation using a rotary tableting machine (wherein the appearance, weight, thickness, and hardness of the tablets are monitored during the tableting process).

[0188] An exemplary process for coating an immediate-release small tablet core is shown in Figures 5 and 10. The exemplary process includes the following steps: 1) film coating of the small tablet core by MR coating in a fluidized bed coater; 2) drying of the coated small tablets in a fluidized bed dryer; and 3) screening of the dried small tablets through a sieve. The exemplary coating process was carried out on either a 0.15 kg scale (Figure 5) or a 4 kg scale (Figure 10).

[0189] Example 1 Small tablet core. This example describes omeprazole sodium bicarbonate dihydrochloride monohydrate contained in the core according to one aspect of the disclosed tablets. In particular, this example describes a small tablet core free of a pH adjuster and a small tablet core containing a pH adjuster.

[0190] Using the procedures described in the paragraphs of the general examples above, three types of tablet cores (cores 1A to 1C) were prepared to contain the components listed in Table 1. The components inside the granules were composed of omecamtiv mecarbil dihydrochloride monohydrate, microcrystalline cellulose (MCC, Avicel PH 101), lactose monohydrate (micronized 313), hydroxypropyl cellulose (HPC, Klucel EXF), and, optionally, fumaric acid (cores 1B and 1C). The components outside the granules were composed of colloidal silicon dioxide and magnesium stearate.

[0191] The small tablet cores were prepared using different amounts of fumaric acid as a pH adjuster. Core 1A contains substantially no fumaric acid, while in Core 1B, the weight ratio of fumaric acid to omecamtiv mecarbil is 1:1, and in Core 1C, the weight ratio of fumaric acid to omecamtiv mecarbil is 2:1.

Table 1

[0192] Analytical property evaluations were performed on cores 1A to 1C and the corresponding granules. The results are shown in Figures 3 and 4.

[0193] Figures 3 and 4 show the 19 F solid-state NMR (SSNMR) spectra of the immediate-release granules and immediate-release small tablet cores. The results demonstrate that omecamtiv mecarbil dihydrochloride monohydrate is stable during production and its physical form does not change during the manufacturing process.

[0194] Example 2 Release control coating. This example describes a release control coating in accordance with one aspect of the disclosed tablets.

[0195] The tablet cores of Example 1 (Cores 1A to 1C) were coated with a release control (MR) coating agent composed of CA:PEG (70:30) up to various weight gain target values by coating (i.e., 10%, 15%, or 20% weight gain). The MR coating agent containing cellulose acetate and polyethylene glycol was prepared as a 5 wt% solution in acetone:water (9:1). The cores were coated using a fluidized bed coater.

[0196] The dissolution characteristics of the MR-coated small tablets were measured by the United States Pharmacopeia (USP) II method using the following parameters: apparatus was USP <711> Apparatus II (paddle); vessel size / type was 1000 mL clear glass, round bottom; rotation speed was 75 rpm; medium volume was 500 mL; test temperature was 37.0 ± 0.5 °C; dissolution medium was phosphate buffer (pH 6.8); and sampling times were 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours. The test solution was analyzed by high performance liquid chromatography (HPLC) under the following conditions: pump was isocratic; reverse phase column (e.g., X-Bridge, 150 × 3 mm (id), C18, particle size 3.5 μm, commercially available from Waters); UV detection (235 nm); injection volume 75 μL; flow rate 0.5 mL / min; column temperature was 30 °C; autosampler temperature was ambient temperature; and runtime 6 minutes.

[0197] The results are shown in Figures 6 to 8.

[0198] Figure 6 shows the dissolution characteristics in pH 6.8 buffer of each immediate-release small tablet core containing 1 mg of omecamtiv mecarbil hydrochloride dihydrate, coated with CA:PEG (70:30) at a coating amount with a 10% increase rate. The dissolution characteristics indicate that fumaric acid in the immediate-release small tablet core did not promote the release of omecamtiv mecarbil in the pH 6.8 buffer.

[0199] Figure 7 shows the dissolution profiles in pH 6.8 buffer of immediate-release small tablet cores each containing 1 mg of omecamtiv mecarbil hydrochloride monohydrate, coated with CA:PEG (70:30) at a coating weight increase of 15%. The dissolution profiles indicate that fumaric acid in the small tablet cores did not promote the release of omecamtiv mecarbil in the pH 6.8 buffer.

[0200] Figure 8 shows the dissolution profiles in pH 6.8 buffer of immediate-release small tablet cores each containing 1 mg of omecamtiv mecarbil hydrochloride monohydrate, coated with CA:PEG (70:30) at a coating weight increase of 20%. The dissolution profiles indicate that fumaric acid did not promote the release of omecamtiv mecarbil in the pH 6.8 buffer.

[0201] The results of the dissolution tests suggest that fumaric acid is not necessary for the immediate-release small tablet cores.

[0202] Example 3 Release control coating. This example describes a release control coating in accordance with one aspect of the disclosed tablets.

[0203] The tablet core 1B of Example 1 was coated with two different MR coating agents containing cellulose acetate and PEG to a 10% weight gain. The coating compositions had either a CA:PEG ratio of 70:30 or 50:50. The dissolution profiles of the MR-coated small tablets were measured using the method described in Example 2. The results of the dissolution tests are shown in Figure 9.

[0204] As shown in Fig. 9, the dissolution characteristics indicate that for the coating agent composed of CA:PEG (50:50), which results in a 10% weight increase compared to the coating agent composed of CA:PEG (70:30), the release amount of omecamtiv mecarbil did not increase significantly. Without wishing to be bound by any particular theory, this result is considered to suggest that it should not be observed when the weight increase due to coating is larger. When the weight increase due to coating is equal to or greater, omecamtiv mecarbil will be released faster with the CA:PEG (50:50) coating agent than with the CA:PEG (70:30) coating agent. Therefore, it is expected that the release rate of omecamtiv mecarbil will be less affected by the weight increase due to coating with the coating agent composed of CA:PEG (50:50). For the coating agent composed of CA:PEG (50:50), the release rate is certain because it is less affected by the weight increase due to coating. However, to slow down the release rate using the CA:PEG (50:50) coating agent, it is necessary to increase the weight increase due to coating. Increasing the weight increase due to coating requires more coating time, thus reducing the manufacturing efficiency.

[0205] To balance the efficiency of the coating process and the certainty of the release rate, and with reference to the dissolution characteristics shown in Figs. 6 - 9, in order to achieve the target release characteristics of omecamtiv mecarbil, a coating agent composed of CA:PEG (60:40) was selected and used to coat the immediate-release small tablets of omecamtiv mecarbil at various weight increase rates due to coating.

[0206] Example 4 Tablets. This example describes one embodiment of the disclosed tablets.

[0207] Tables 2 and 3 show tablets containing immediate-release small tablet cores and MR coating agents. The tablet cores were prepared according to the process shown in Fig. 2, and the cores were coated using the process shown in Fig. 10.

Table 2

Table 3

[0208] Example 5 In vitro release rate. Tablets with three different in vitro release rates were developed by coating immediate-release small tablet cores with an MR coating agent at three different weight gain rates. Using the process shown in Figure 2, immediate-release small tablet cores were prepared in two batches (10 kg and 20 kg). As shown in Tables 4A and 4B, the immediate-release small tablet cores of Example 4 were coated with the MR coating agent up to a target weight gain rate of 10%, 15%, or 30% using the process shown in Figure 10 to achieve immediate release, medium release, and sustained release of omecamtiv mecarbil, respectively. Table 4A lists the weight percentages relative to the core weight. Table 4B lists the weight percentages relative to the total tablet weight.

Table 4

Table 5

[0209] Tables 5 and 6 show the characteristic evaluation data of the immediate-release small tablet cores and MR-coated small tablets of both batches. The data indicate that both the immediate-release small tablet cores and the MR-coated small tablets meet the target tablet weight, tablet hardness, content, and uniformity values. Figure 11 shows a comparison of the three release rates (immediate release, medium, and sustained release) for the two batches. These results demonstrate that the release rates are consistent for both batches.

Table 6

Table 7

[0210] Example 6 Stability test. The MR mini tablets prepared in Example 5 were placed in 45 cc HDPE bottles (total 150), and packaged with heat induction seal and polypropylene CRC. The stability of the formulation was monitored for 24 months under long-term (5°C) and accelerated (25°C / 60% RH) conditions. The stability results up to 1 month are summarized in Table 7 and Figure 12.

[0211] The assay of impurities was performed using HPLC under the following conditions: reverse phase column (e.g., X-Bridge, 150×3 mm (id), C18, particle size 3.5 μm, commercially available from Waters); UV detection (235 nm); injection volume 20 μL; flow rate 0.45 mL / min; column temperature 30°C; autosampler temperature ambient temperature; and runtime 26 minutes, using the following gradient conditions: [Table 8] (Here, mobile phase A is 0.2% ammonium hydroxide in water (e.g., 2 mL of ammonium hydroxide diluted with 1000 mL of purified filtered water Milli-Q), and mobile phase B is 0.2% ammonium hydroxide in acetonitrile (e.g., 2 mL of ammonium hydroxide diluted with 1000 mL of acetonitrile).)

[0212] The results indicate that there were no significant changes in appearance, content, water content, and dissolution after 1 month under the storage conditions. [Table 9-1] [Table 9-2]

[0213] Example 7 In vivo test. The main objective of this test was to evaluate the pharmacokinetics (PK) of OM in healthy adult subjects after single administration of the following: controlled-release (MR) tablets of 25 mg (1×25 mg), sustained-release small tablets of 25 mg (25×1 mg), immediate-release small tablets of 25 mg (25×1 mg), sustained-release small tablets of 6 mg (6×1 mg), and immediate-release small tablets of 6 mg (6×1 mg).

[0214] The secondary objective of this test was to evaluate the safety and tolerability of OM when administered as a single dose at a dose of 6 mg (administered as small tablets) or 25 mg (administered as MR tablets or small tablets) in healthy adult subjects.

[0215] This test was a Phase 1, single-site, non-blind, randomized, 5-period, 4-treatment sequence crossover test to investigate the pharmacokinetics, safety, and tolerability of the disclosed tablets and the conventional MR tablets of OM in healthy adult male and female subjects. Subjects were screened within 21 days prior to the first dose to evaluate eligibility for study participation. Subjects were admitted to the clinical laboratory on Day 1, confined to the clinical laboratory during Periods 1 to 5, and discharged at the end of the study. After randomization to one of the 4 treatment sequences, on Day 1 of each treatment period, subjects were administered one of the 5 treatments, and all 5 treatments were administered to all subjects. Blood was collected at predetermined time points to characterize the plasma concentration of OM. Safety and tolerability were monitored throughout the study.

[0216] Study Design A maximum of 20 subjects (5 per treatment sequence) were enrolled in the study. All data from the 20 subjects enrolled in the study were included in the PK and safety analyses. Healthy male or female subjects were selected according to the inclusion criteria and exclusion criteria. Subjects were divided into the following 5 treatment groups (A - E): Treatment Group A: 25 mg (1×25 mg) OM MR tablets; Treatment Group B: 25 mg (25×1 mg) OM sustained-release small tablets; Treatment Group C: 25 mg (25×1 mg) OM immediate-release small tablets; Dosing group D: 6 mg (6 × 1 mg) OM sustained-release small tablets; and Dosing group E: 6 mg (6 × 1 mg) OM immediate-release small tablets was assigned to one of these groups.

[0217] For dosing, after fasting for at least 10 hours overnight, it was orally administered with approximately 8 ounces (240 mL) of water. The subjects were instructed not to crush or chew the tablets and to complete the administration of all small tablets in less than 5 minutes. It was administered as a single oral dose on Day 1 of each dosing period, and a washout period of at least 7 days was provided between each dosing. All subjects received each of the five doses as a single dose.

[0218] Pharmacokinetics Blood samples were collected to analyze the plasma concentration of OM. The PK parameters determined from the plasma concentration of OM were as follows: maximum plasma concentration (C max ), area under the plasma concentration-time curve from time zero to the time point when the final concentration could be quantified (AUC)(AUC last ), AUC from time zero to infinite time (AUC inf ), time to reach the maximum plasma concentration (t max ), and apparent terminal phase elimination half-life (t 1 / 2 ), the proportion of the extrapolation from the time point when the final concentration could be measured to infinite time in AUC inf (%AUC extrap ), elimination rate constant (λ z ), correlation coefficient of the terminal elimination phase (R 2 ), the number of data points included in the determination of λ z (number of points), the difference between the start and end points of the exponential fit divided by t 1 / 2 (λ z interval ratio), lower limit of the terminal phase (start point of the exponential fit), upper limit of the terminal phase (end point of the exponential fit).

[0219] Safety Safety analysis included monitoring of adverse events during the study, clinical laboratory evaluations, 12-lead electrocardiograms (ECGs), and vital signs.

[0220] When administered to healthy subjects in this study, single-dose administration of OM MR tablets 25 mg (1 × 25 mg), sustained-release small tablets 25 mg (25 × 1 mg), immediate-release small tablets 25 mg (25 × 1 mg), sustained-release small tablets 6 mg (6 × 1 mg), and immediate-release small tablets 6 mg (6 × 1 mg) was safe and well-tolerated in healthy adult subjects. All adverse events were mild in severity and resolved by the end of the study. There were no serious adverse events, and no subjects had their trials interrupted due to adverse events that occurred during administration. Eight adverse events (including myalgia, dizziness, costochondritis, muscle contraction, and non-cardiac chest pain) that occurred during administration and were considered to be related to OM by the investigators were reported by 7 subjects. No clinically significant findings were observed in clinical laboratory evaluations, vital signs, or 12-lead ECGs during the study.

[0221] Statistical Analysis To examine the bioavailability based on the PK of various OM formulations, statistical analysis was performed by comparing the test administration group and the comparison group for AUC last , AUC inf , and C max . The comparisons of administrations were as follows, respectively, and in both cases, the administration group A was used as the reference. 1. OM, 25 × 1 mg oral sustained-release small tablets (administration group B) vs. OM, 1 × 25 mg oral MR tablets (administration group A) 2. OM, 25 × 1 mg oral immediate-release small tablets (administration group C) vs. OM, 1 × 25 mg oral MR tablets (administration group A)

[0222] The PK parameters transformed by the natural logarithm (ln) were analyzed using a mixed model. The model included the administration and administration order as fixed effects and the subjects nested within the administration order as random effects.

[0223] For each PK parameter individually, the least-squares mean value (LSM) of each administration group, the difference in LSM between the test administration group and the comparison administration group, and the corresponding 90% confidence interval (CI) were calculated, and then these values were back-transformed to obtain the geometric LSM (GLSM), GLSM ratio, and the corresponding 90% CI.

[0224] In addition, the integrated estimated value of the within-subject coefficient of variation (CV) (across all dosing groups) was calculated, and residual plots were created to evaluate the validity of the fitting model(s).

[0225] All safety data were listed. The adverse events that occurred during dosing were summarized by dosing, severity, and relationship to the test drug. The frequency of adverse events that occurred during dosing was summarized by dosing, major organ classification, and MedDRA preferred terms. Inferential statistical analysis was not planned.

[0226] The test results are summarized in Tables 8 and 9.

Table 10

Table 11

[0227] As shown in Tables 8 and 9, the OM t max median was earlier compared to the administration of a single 25 mg OM MR tablet, but the t max value range was comparable. The geometric mean AUC last and AUC inf values were comparable between the two dosing groups, but the C max value was higher after administration of the 25 × 1 mg OM sustained-release mini-tablets compared to the administration of a single 25 mg OM MR tablet. The arithmetic mean t 1 / 2 value of OM was comparable between the two dosing groups (Tables 8 and Figures 15A - 16B). The GLSM ratio (test group / comparator group) between the 25 × 1 mg OM sustained-release mini-tablets and the single 25 mg OM MR tablet was 0.9980, 0.9998, and 1.2858 for AUC last , AUC inf , and C max respectively (Table 9).

[0228] OM t after administration of 25 × 1 mg immediate-release small tablets of OM max The median was earlier compared with the administration of a single 25 mg OM MR tablet. The geometric mean AUC and C max -based exposure was higher after administration of 25 mg immediate-release small tablets of OM compared with the administration of a single 25 mg OM MR tablet. The arithmetic mean t 1 / 2 -value of OM was comparable between the two dosing groups (Table 8 and Figures 15A - 16B). The GLSM ratio (test / comparison) of 25 × 1 mg immediate-release small tablets of OM to 25 mg single OM MR tablet was 1.2560, 1.2503, and 2.2136 for AUC last AUC inf and C max respectively (Table 9).

[0229] As shown in Table 8, the median OM t max after administration of 6 × 1 mg sustained-release small tablets of OM was 2 hours later compared with the administration of 6 × 1 mg immediate-release small tablets of OM. The geometric mean AUC and C max -based exposure was higher after administration of 6 mg immediate-release small tablets of OM compared with the administration of 6 mg sustained-release small tablets of OM. The arithmetic mean t 1 / 2 -value of OM was comparable between the two dosing groups.

[0230] As demonstrated by the data shown in Tables 8 and 9, when OM was administered as 25 × 1 mg sustained-release small tablets of OM, AUC last AUC inf and C max were 0.9980-, 0.9998-, and 1.2858-fold those of a single 25 mg OM MR tablet, respectively. Also, when OM was administered as 25 × 1 mg immediate-release small tablets of OM, AUC last AUC inf and C max were 1.2560-, 1.2503-, and 2.2136-fold those of a single 25 mg OM MR tablet, respectively.

[0231] When administered as MR tablets 25 mg (1 × 25 mg), sustained-release small tablets 25 mg (25 × 1 mg), immediate-release small tablets 25 mg (25 × 1 mg), sustained-release small tablets 6 mg (6 × 1 mg), and immediate-release small tablets 6 mg (6 × 1 mg), single oral administration of OM was safe and well-tolerated in healthy adult subjects.

[0232] All adverse events that occurred during administration were mild in severity and resolved by the end of the study. There were no serious adverse events, that is, the study was not interrupted due to adverse events that occurred during administration.

[0233] All references, including publications, patent applications, and patents cited in this specification, are hereby incorporated by reference in their entirety, as if each reference were specifically and individually indicated as being incorporated by reference to the same extent as if set forth in full herein.

[0234] For the description of the present invention (especially with respect to the claims), in the use of the terms "a", "an", "the", "at least one", and similar indicators, unless otherwise indicated herein or clearly contradicted by the context, it should be construed to cover both the singular and plural forms. The use of the term "at least one" prior to the listing of one or more items (e.g., "at least one of A and B") should be construed to mean one item (A or B) selected from the listed items, or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by the context. The terms "comprising", "having", "including", and "containing" should be construed as open-ended terms (i.e., meaning "including but not limited to") unless specifically noted. The description of a range of values herein is intended only to serve as a shorthand way of referring individually to each separate value that falls within that range, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples, or exemplary terms (e.g., "such as") presented herein is merely intended to facilitate the understanding of the invention and does not limit the scope of the invention unless otherwise claimed. No term in this specification should be construed as indicating an essential element for the practice of the invention that is not claimed. In certain embodiments, for example, the following items are provided. (Item 1) Omecamtiv mecarbil, its pharmaceutically acceptable salts, or pharmaceutically acceptable hydrates of its pharmaceutically acceptable salts; Excipients; Binders; Glidants; and Lubricants; A core containing the same, and A coating film on the core, the coating film containing a release control polymer and a pore former, Tablets containing the same. (Item 2) The omecamtiv mecarbil exists as omecamtiv mecarbil dihydrochloride monohydrate, the tablet according to Item 1. (Item 3) The excipient contains microcrystalline cellulose, lactose monohydrate, or a combination thereof, the tablet according to Item 1 or 2. (Item 4) The excipient contains microcrystalline cellulose and lactose monohydrate, the tablet according to Item 3. (Item 5) The binder contains hydroxypropyl cellulose, the tablet according to any one of Items 1 to 4. (Item 6) The glidant contains silicon dioxide, the tablet according to any one of Items 1 to 5. (Item 7) The lubricant contains magnesium stearate, the tablet according to any one of Items 1 to 6. (Item 8) The core contains 8 - 11 wt% of omecamtiv mecarbil, its pharmaceutically acceptable salts, or pharmaceutically acceptable hydrates of its pharmaceutically acceptable salts; 83 - 86 wt% of excipients; 2 - 5 wt% of binders; 0.2 - 0.8 wt% of glidants; and 0.8 - 1.2 wt% of lubricants The tablet according to any one of Items 1 to 7 containing the same. (Item 9) The coating film further contains a plasticizer, the tablet according to any one of Items 1 to 8. (Item 10) The pore former is also a plasticizer, the tablet according to any one of Items 1 to 9. (Item 11) The release control polymer of the coating film contains ethyl cellulose, poly(ethyl acrylate - co - methyl methacrylate), poly(ethyl acrylate - co - methyl methacrylate - co - trimethylammonioethyl methacrylate chloride), cellulose acetate, polyvinyl acetate, or a combination thereof, the tablet according to any one of Items 1 to 10. (Item 12) The tablet according to item 11, wherein the release control polymer contains cellulose acetate. (Item 13) The tablet according to any one of items 1 to 12, wherein the pore former of the coating film contains hypromellose, polyvinylpyrrolidone, sorbitol, triethyl citrate, polyethylene glycol, or a combination thereof. (Item 14) The tablet according to item 13, wherein the pore former contains polyethylene glycol. (Item 15) The tablet according to item 14, wherein the polyethylene glycol is polyethylene glycol 3350. (Item 16) The tablet according to any one of items 9 to 15, wherein the plasticizer contains polyethylene glycol, diethyl phthalate, triethyl citrate, dibutyl sebacate, triacetin, or a combination thereof. (Item 17) The coating film contains 50 to 90 wt% of a release control polymer; and 10 to 50 wt% of a pore former and a plasticizer (if present) The tablet according to any one of items 11 to 16. (Item 18) The tablet according to item 17, wherein the coating film contains 60 wt% of a release control polymer and 40 wt% of a pore former and a plasticizer (if present). (Item 19) The tablet according to any one of items 1 to 18, wherein the coating film is composed of 9 wt% of the total weight of the tablet. (Item 20) The tablet according to any one of items 1 to 18, wherein the coating film is composed of 13 wt% of the total weight of the tablet. (Item 21) The tablet according to any one of items 1 to 18, wherein the coating film is composed of 23 wt% of the total weight of the tablet. (Item 22) 5 to 40 wt% of omecamtiv mecarbil dihydrochloride monohydrate; 10 to 45 wt% of microcrystalline cellulose; 10 to 45 wt% of lactose monohydrate; 1 to 8 wt% of hydroxypropylcellulose; 0.1 to 2 wt% of colloidal silicon dioxide; 0.25 to 3 wt% of magnesium stearate; 3 to 20 wt% of cellulose acetate; and 2 to 15 wt% of polyethylene glycol The tablet according to item 1. (Item 23) 5 to 10 wt% of omecamtiv mecarbil dihydrochloride monohydrate; 30 to 45 wt% of microcrystalline cellulose; 30 to 45 wt% of lactose monohydrate; 1 to 5 wt% of hydroxypropylcellulose; 0.1 to 2 wt% of colloidal silicon dioxide; 0.5 to 3 wt% of magnesium stearate; 3 to 20 wt% of cellulose acetate; and 2 to 15 wt% of polyethylene glycol The tablet according to item 22, comprising the same. (Item 24) 9 wt% of omecamtiv mecarbil dihydrochloride monohydrate; 38.9 wt% of microcrystalline cellulose; 38.9 wt% of lactose monohydrate; 2.7 wt% of hydroxypropyl cellulose; 0.5 wt% of colloidal silicon dioxide; 1 wt% of magnesium stearate; 5.4 wt% of cellulose acetate; and 3.6 wt% of polyethylene glycol The tablet according to item 23, comprising the same. (Item 25) 8.5 wt% of omecamtiv mecarbil dihydrochloride monohydrate; 37.3 wt% of microcrystalline cellulose; 37.3 wt% of lactose monohydrate; 2.6 wt% of hydroxypropyl cellulose; 0.4 wt% of colloidal silicon dioxide; 0.9 wt% of magnesium stearate; 7.8 wt% of cellulose acetate; and 5.2 wt% of polyethylene glycol The tablet according to item 23, comprising the same. (Item 26) 7.5 wt% of omecamtiv mecarbil dihydrochloride monohydrate; 33 wt% of microcrystalline cellulose; 33 wt% of lactose monohydrate; 2.3 wt% of hydroxypropyl cellulose; 0.4 wt% of colloidal silicon dioxide; 0.8 wt% of magnesium stearate; 13.8 wt% of cellulose acetate; and 9.2 wt% of polyethylene glycol The tablet according to item 23, comprising the same. (Item 27) The core comprises 9.8 wt% of omecamtiv mecarbil dihydrochloride monohydrate; 42.8 wt% of microcrystalline cellulose; 42.8 wt% of lactose monohydrate; 3 wt% of hydroxypropyl cellulose; 0.5 wt% of colloidal silicon dioxide; and 1 wt% of magnesium stearate and by coating with the coating film, the weight of the tablet is increased by 10% based on the total weight of the core, wherein the coating film is composed of 60 wt% of cellulose acetate and 40 wt% of polyethylene glycol based on the total weight of the coating film, the tablet according to item 1. (Item 28) The core comprises 9.8 wt% of omecamtiv mecarbil dihydrochloride monohydrate; 42.8 wt% of microcrystalline cellulose; 42.8 wt% of lactose monohydrate; 3 wt% of hydroxypropyl cellulose; 0.5 wt% of colloidal silicon dioxide; and 1 wt% magnesium stearate comprising wherein coating with the coating film increases the weight of the tablet by 15% based on the total weight of the core, and wherein the coating film is composed of 60 wt% cellulose acetate and 40 wt% polyethylene glycol based on the total weight of the coating film, the tablet according to item 1 (Item 29) The core comprises 9.8 wt% omecamtiv mecarbil dihydrochloride monohydrate; 42.8 wt% microcrystalline cellulose; 42.8 wt% lactose monohydrate; 3 wt% hydroxypropyl cellulose; 0.5 wt% colloidal silicon dioxide; and 1 wt% magnesium stearate comprising wherein coating with the coating film increases the weight of the tablet by 30% based on the total weight of the core, and wherein the coating film is composed of 60 wt% cellulose acetate and 40 wt% polyethylene glycol based on the total weight of the coating film, the tablet according to item 1 (Item 30) The tablet according to any one of items 1 to 29, comprising 1 to 3 mg of omecamtiv mecarbil (Item 31) The tablet according to item 30, comprising 1 mg of omecamtiv mecarbil (Item 32) releasing 50% or less of omecamtiv mecarbil in 1 hour; releasing 60 - 70% of omecamtiv mecarbil in 2 hours; releasing 85 - 90% of omecamtiv mecarbil in 8 hours; and releasing 90% or more of omecamtiv mecarbil in 16 hours, the tablet according to any one of items 1 to 24, 27, 30, and 31, having the omecamtiv mecarbil release characteristics as described above (Item 33) releasing 25% or less of omecamtiv mecarbil in 1 hour; releasing 35 - 45% of omecamtiv mecarbil in 2 hours; releasing 75 - 80% of omecamtiv mecarbil in 8 hours; and releasing 85% or more of omecamtiv mecarbil in 16 hours, the tablet according to any one of items 1 to 23, 25, 28, 30, and 31, having the omecamtiv mecarbil release characteristics as described above (Item 34) releasing 10% or less of omecamtiv mecarbil in 1 hour; releasing 25 - 35% of omecamtiv mecarbil in 2 hours; releasing 70 - 75% of omecamtiv mecarbil in 8 hours; and releasing 78% or more of omecamtiv mecarbil in 16 hours The tablet according to any one of items 1 to 23, 26, and 29 to 31, having the omecamtiv mecarbil release characteristics as described above. (Item 35) The tablet according to any one of items 1 to 34, which provides a maximum plasma concentration (C max) of omecamtiv mecarbil of 100 to 1000 ng / mL in the patient when administered to the patient. (Item 36) The tablet according to any one of items 1 to 35, which does not contain (is free of) a pH adjuster. (Item 37) The tablet according to any one of items 1 to 36, having a maximum diameter of 3 mm. (Item 38) A method for treating the heart failure in a patient suffering from heart failure, the method comprising administering to the patient the tablet according to any one of items 1 to 37. (Item 39) The method according to item 38, wherein the heart failure is acute or chronic. (Item 40) The method according to item 38, wherein the heart failure is heart failure with reduced ejection fraction (HFrEF). (Item 41) The method according to any one of items 38 to 40, wherein the patient is a pediatric patient. (Item 42) The method according to item 41, wherein the tablet is administered to the pediatric patient in an amount that provides 3 to 25 mg of omecamtiv mecarbil twice a day. (Item 43) The method according to any one of items 38 to 40, wherein the patient is an adult patient with dysphagia. (Item 44) The method according to item 43, wherein the tablet is administered to the adult patient in an amount that provides 25 mg or 50 mg of omecamtiv mecarbil twice a day. (Item 45) The tablet according to any one of items 1 to 37, for use in the treatment of heart failure. (Item 46) The tablet according to item 45, wherein the heart failure is acute or chronic. (Item 47) The tablet according to item 45, wherein the heart failure is heart failure with reduced ejection fraction (HFrEF). (Item 48) The tablet according to any one of items 45 to 47, which is suitable for administration to pediatric patients. (Item 49) The tablet according to item 48, wherein the tablet is administered to the pediatric patient in an amount that provides 3 to 25 mg of omecamtiv mecarbil twice a day. (Item 50) The tablet according to any one of items 45 to 47, which is suitable for administration to adult patients with dysphagia. (Item 51) The tablet according to item 50, wherein the tablet is administered to the adult patient in an amount that provides 25 mg or 50 mg of omecamtiv mecarbil twice a day. (Item 52) Use of the tablet according to any one of Items 1 to 37 in the preparation of a medicament for treating heart failure. (Item 53) Use according to Item 52, wherein the heart failure is acute or chronic. (Item 54) Use according to Item 52, wherein the heart failure is heart failure with reduced ejection fraction (HFrEF). (Item 55) Use according to any one of Items 52 to 54, wherein the tablet is suitable for administration to pediatric patients. (Item 56) Use according to Item 55, wherein the tablet is administered to the pediatric patient in an amount that provides 3 to 25 mg of omecamtiv mecarbil twice a day. (Item 57) Use according to any one of Items 52 to 54, wherein the tablet is suitable for administration to adult patients with dysphagia. (Item 58) Use according to Item 57, wherein the tablet is administered to the adult patient in an amount that provides 25 mg or 50 mg of omecamtiv mecarbil twice a day. (Item 59) Mixing the omecamtiv mecarbil, its pharmaceutically acceptable salt, or its pharmaceutically acceptable hydrate of its pharmaceutically acceptable salt, the excipient, and the binder, and granulating to form a granule mixture; Mixing the granule mixture and a granulating solvent, and granulating to form wet granules; Drying the wet granules to form dry granules; Crushing the dry granules to form crushed granules; Mixing the crushed granules, the fluidizing agent, and the lubricant, and tableting the mixture to form the core; Mixing the core with a precoating film mixture containing the release control polymer, the plasticizer, and a film coating solvent to coat the core with the coating film; Drying the coated core to form the tablet; A process for manufacturing a tablet according to any one of Items 1 to 37, including the above steps. (Item 60) The mixing of the omecamtiv mecarbil, its pharmaceutically acceptable salt, or its pharmaceutically acceptable hydrate of its pharmaceutically acceptable salt, the excipient, and the binder according to Item 59 is performed using a high-shear granulator. (Item 61) The granulating solvent according to Item 59 or 60 contains water. (Item 62) The crushing of the dry granules according to any one of Items 59 to 61 is performed using an impact crusher. (Item 63) The mixing of the crushed granules, the fluidizing agent, and the lubricant is carried out stepwise by mixing the crushed granules and the fluidizing agent and then mixing the resulting mixture with the lubricant, the process according to any one of items 59 to 62. (Item 64) The film coating solvent includes acetone, water, or a mixture thereof, the process according to any one of items 59 to 63. (Item 65) The film coating solvent includes acetone and water, the process according to item 64. (Item 66) The film coating solvent is composed of acetone: water (9:1), the process according to item 65. (Item 67) The mixing of the core and the precoating film mixture is carried out in a fluidized bed coater, the process according to any one of items 59 to 66. (Item 68) Mixing the omecamtiv mecarbil, its pharmaceutically acceptable salt, or a pharmaceutically acceptable hydrate of its pharmaceutically acceptable salt, the excipient, and the binder, and granulating to form a granule mixture; Crushing the granule mixture to form crushed granules; Mixing the crushed granules, the fluidizing agent, and the lubricant, and tableting the mixture to form the core; Mixing the core with a precoating film mixture containing the release control polymer, the plasticizer (if present), and the film coating solvent to cover the core with the coating film; Drying the coated core to form the tablet; A process for manufacturing a tablet according to any one of items 1 to 37, including. (Item 69) Mixing the omecamtiv mecarbil, its pharmaceutically acceptable salt, or a pharmaceutically acceptable hydrate of its pharmaceutically acceptable salt, the excipient, the binder, the fluidizing agent, and the lubricant, and tableting the mixture to form the core; Mixing the core with a precoating film mixture containing the release control polymer, the plasticizer (if present), and the film coating solvent to cover the core with the coating film; Drying the coated core to form the tablet; A process for manufacturing a tablet according to any one of items 1 to 37, including.

Claims

**Claim 1**: A core comprising 1 to 3 mg of omecamtiv mecarbil, its pharmaceutically acceptable salt, or a pharmaceutically acceptable hydrate of its pharmaceutically acceptable salt; an excipient; a binder; a fluidizing agent; and a lubricant; and a coating film on the core, the coating film comprising a release - controlling polymer and a pore - forming agent, wherein the weight ratio of the release - controlling polymer to the pore - forming agent is 60:40, a tablet comprising the above, the tablet having a diameter of 5 mm or less. **Claim 2** The tablet according to claim 1, wherein the omecamtiv mecarbil is present as omecamtiv mecarbil dihydrochloride monohydrate. **Claim 3** The tablet according to claim 1 or 2, wherein the excipient comprises microcrystalline cellulose, lactose monohydrate, or a combination thereof. **Claim 4** The tablet according to claim 3, wherein the excipient comprises microcrystalline cellulose and lactose monohydrate. **Claim 5** The tablet according to any one of claims 1 to 4, wherein the binder comprises hydroxypropyl cellulose. **Claim 6** The tablet according to any one of claims 1 to 5, wherein the fluidizing agent comprises silicon dioxide. **Claim 7** The tablet according to any one of claims 1 to 6, wherein the lubricant comprises magnesium stearate. **Claim 8** The core comprises 8 to 11 wt% of omecamtiv mecarbil, its pharmaceutically acceptable salt, or a pharmaceutically acceptable hydrate of its pharmaceutically acceptable salt; 83 to 86 wt% of an excipient; 2 to 5 wt% of a binder; 0.2 to 0.8 wt% of a fluidizing agent; and Tablets according to any one of claims 1 to 7, containing 0.8 to 1.2 wt% of a lubricant.

9. Tablets according to any one of claims 1 to 8, wherein the coating film further contains a plasticizer.

10. Tablets according to any one of claims 1 to 9, wherein the pore former is also a plasticizer.

11. Tablets according to any one of claims 1 to 10, wherein the release control polymer of the coating film contains ethyl cellulose, poly(ethyl acrylate-co-methyl methacrylate), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride), cellulose acetate, polyvinyl acetate, or a combination thereof.

12. Tablets according to claim 11, wherein the release control polymer contains cellulose acetate.

13. Tablets according to any one of claims 1 to 12, wherein the pore former of the coating film contains hypromellose, polyvinylpyrrolidone, sorbitol, triethyl citrate, polyethylene glycol, or a combination thereof.

14. Tablets according to claim 13, wherein the pore former contains polyethylene glycol.

15. Tablets according to claim 14, wherein the polyethylene glycol is polyethylene glycol 3350.

16. Tablets according to any one of claims 9 to 15, wherein the plasticizer contains polyethylene glycol, diethyl phthalate, triethyl citrate, dibutyl sebacate, triacetin, or a combination thereof.

17. Tablets according to claim 1, wherein the coating film contains 60 wt% of a release control polymer and 40 wt% of a pore former and a plasticizer (if present).

18. The coating film is composed of 9 wt% of the total weight of the tablet, and the tablet according to any one of claims 1 to 17.

19. The coating film is composed of 13 wt% of the total weight of the tablet, and the tablet according to any one of claims 1 to 17.

20. The coating film is composed of 23 wt% of the total weight of the tablet, and the tablet according to any one of claims 1 to 17.

21. 5 to 40 wt% of omecamtiv mecarbil dihydrochloride monohydrate; 10 to 45 wt% of microcrystalline cellulose; 10 to 45 wt% of lactose monohydrate; 1 to 8 wt% of hydroxypropyl cellulose; 0.1 to 2 wt% of colloidal silicon dioxide; 0.25 to 3 wt% of magnesium stearate; 3 to 20 wt% of cellulose acetate; and 2 to 15 wt% of polyethylene glycol The tablet according to claim 1, comprising.

22. 5 to 10 wt% of omecamtiv mecarbil dihydrochloride monohydrate; 30 to 45 wt% of microcrystalline cellulose; 30 to 45 wt% of lactose monohydrate; 1 to 5 wt% of hydroxypropyl cellulose; 0.1 to 2 wt% of colloidal silicon dioxide; 0.5 to 3 wt% of magnesium stearate; 3 to 20 wt% of cellulose acetate; and 2 to 15 wt% of polyethylene glycol The tablet according to claim 21, comprising.

23. 9 wt% of omecamtiv mecarbil dihydrochloride monohydrate; 38.9 wt% microcrystalline cellulose; 38.9 wt% lactose monohydrate; 2.7 wt% hydroxypropyl cellulose; 0.5 wt% colloidal silicon dioxide; 1 wt% magnesium stearate; 5.4 wt% cellulose acetate; and 3.6 wt% polyethylene glycol The tablet according to claim 22, comprising:

24. 8.5 wt% omecamtiv mecarbil dihydrochloride monohydrate; 37.3 wt% microcrystalline cellulose; 37.3 wt% lactose monohydrate; 2.6 wt% hydroxypropyl cellulose; 0.4 wt% colloidal silicon dioxide; 0.9 wt% magnesium stearate; 7.8 wt% cellulose acetate; and 5.2 wt% polyethylene glycol The tablet according to claim 22, comprising:

25. 7.5 wt% omecamtiv mecarbil dihydrochloride monohydrate; 33 wt% microcrystalline cellulose; 33 wt% lactose monohydrate; 2.3 wt% hydroxypropyl cellulose; 0.4 wt% colloidal silicon dioxide; 0.8 wt% magnesium stearate; 13.8 wt% cellulose acetate; and 9.2 wt% polyethylene glycol The tablet according to claim 22, comprising:

26. The core is 9.8 wt% omecamtiv mecarbil dihydrochloride monohydrate; 42.8 wt% microcrystalline cellulose; 42.8 wt% lactose monohydrate; 3 wt% hydroxypropyl cellulose; 0.5 wt% colloidal silicon dioxide; and 1 wt% magnesium stearate comprising By coating the coating film, the weight of the tablet increases by 10% based on the total weight of the core, where the coating film is composed of 60 wt% cellulose acetate and 40 wt% polyethylene glycol based on the total weight of the coating film. The tablet according to claim 1.

27. The core is 9.8 wt% omecamtiv mecarbil hydrochloride monohydrate; 42.8 wt% microcrystalline cellulose; 42.8 wt% lactose monohydrate; 3 wt% hydroxypropyl cellulose; 0.5 wt% colloidal silicon dioxide; and 1 wt% magnesium stearate comprising By coating the coating film, the weight of the tablet increases by 15% based on the total weight of the core, where the coating film is composed of 60 wt% cellulose acetate and 40 wt% polyethylene glycol based on the total weight of the coating film. The tablet according to claim 1.

28. The core is 9.8 wt% omecamtiv mecarbil hydrochloride monohydrate; 42.8 wt% microcrystalline cellulose; 42.8 wt% lactose monohydrate; 3 wt% hydroxypropyl cellulose; 0.5 wt% colloidal silicon dioxide; and 1 wt% magnesium stearate comprising By coating the coating film, the weight of the tablet increases by 30% based on the total weight of the core. Here, the coating film is composed of 60 wt% cellulose acetate and 40 wt% polyethylene glycol based on the total weight of the coating film. The tablet according to claim 1.

29. The tablet according to claim 1, comprising 1 mg of omecamtiv mecarbil.

30. 50% or less of omecamtiv mecarbil is released in 1 hour; 60 - 70% of omecamtiv mecarbil is released in 2 hours; 85 - 90% of omecamtiv mecarbil is released in 8 hours; and 90% or more of omecamtiv mecarbil is released in 16 hours. The tablet according to any one of claims 1 to 23, 26, and 29, having the omecamtiv mecarbil release characteristics as described above.

31. 25% or less of omecamtiv mecarbil is released in 1 hour; 35 - 45% of omecamtiv mecarbil is released in 2 hours; 75 - 80% of omecamtiv mecarbil is released in 8 hours; and 85% or more of omecamtiv mecarbil is released in 16 hours. The tablet according to any one of claims 1 to 22, 24, 27, and 29, having the omecamtiv mecarbil release characteristics as described above.

32. 10% or less of omecamtiv mecarbil is released in 1 hour; 25 - 35% of omecamtiv mecarbil is released in 2 hours; 70 - 75% of omecamtiv mecarbil is released in 8 hours; and 78% or more of omecamtiv mecarbil is released in 16 hours. The tablet according to any one of claims 1 to 22, 25, 28, and 29, having the omecamtiv mecarbil release characteristics as described above.

33. When the tablet is administered to a patient, it provides a maximum plasma concentration (C ｍａｘ ) of omecamtiv mecarbil of 100 to 1000 ng / mL in the patient. The tablet according to any one of claims 1 to 32.

34. The tablet according to any one of claims 1 to 33, which does not contain (is free of) a pH adjuster.

35. The tablet according to any one of claims 1 to 34, having a maximum diameter of 3 mm.

36. The tablet according to any one of claims 1 to 35, for use in the treatment of heart failure.

37. The tablet according to claim 36, wherein the heart failure is acute or chronic.

38. The tablet according to claim 36, wherein the heart failure is heart failure with reduced ejection fraction (HFrEF).

39. The tablet according to any one of claims 36 to 38, wherein the tablet is administered to pediatric patients.

40. The tablet according to claim 39, wherein the pediatric patients are administered the tablet in an amount that provides 3 to 25 mg of omecamtiv mecarbil twice a day.

41. The tablet according to any one of claims 36 to 38, wherein the tablet is administered to adult patients with dysphagia.

42. The tablet according to claim 41, wherein the adult patients are administered the tablet in an amount that provides 25 mg or 50 mg of omecamtiv mecarbil twice a day.

43. Use of the tablet according to any one of claims 1 to 35 in the preparation of a medicament for the treatment of heart failure.

44. The use according to claim 43, wherein the heart failure is acute or chronic.

45. The use according to claim 43, wherein the heart failure is heart failure with reduced ejection fraction (HFrEF).

46. The use according to any one of claims 43 to 45, wherein the tablet is administered to pediatric patients.

47. The use according to claim 46, wherein the tablet is administered to the pediatric patient in an amount supplying 3 to 25 mg of omecamtiv mecarbil twice a day.

48. The use according to any one of claims 43 to 45, wherein the tablet is administered to adult patients with dysphagia.

49. The use according to claim 48, wherein the tablet is administered to the adult patient in an amount supplying 25 mg or 50 mg of omecamtiv mecarbil twice a day.

50. Mixing the omecamtiv mecarbil, its pharmaceutically acceptable salt, or its pharmaceutically acceptable hydrate of its pharmaceutically acceptable salt, the excipient, and the binder, and granulating to form a granule mixture; Mixing the granule mixture and a granulating solvent, and granulating to form wet granules; Drying the wet granules to form dry granules; Crushing the dry granules to form crushed granules; Mixing the crushed granules, the fluidizing agent, and the lubricant, and tableting the mixture to form the core; Mixing the core with a precoating film mixture containing the release control polymer, the pore former, and a film coating solvent, and covering the core with the coating film; Drying the coated core to form the tablet; A process for manufacturing a tablet according to any one of claims 1 to 35, comprising:

51. The mixing of the omedetomidine, its pharmaceutically acceptable salt, or its pharmaceutically acceptable hydrate of its pharmaceutically acceptable salt, the excipient, and the binder is carried out in a high-shear granulator, the process according to claim 50.

52. The granulation solvent contains water, the process according to claim 50 or 51.

53. The pulverization of the dry granules is carried out using an impact mill, the process according to any one of claims 50 to 52.

54. The mixing of the pulverized granules, the fluidizing agent, and the lubricant is carried out stepwise by mixing the pulverized granules and the fluidizing agent and then mixing the resulting mixture with the lubricant, the process according to any one of claims 50 to 53.

55. The film coating solvent contains acetone, water, or a mixture thereof, the process according to any one of claims 50 to 54.

56. The film coating solvent contains acetone and water, the process according to claim 55.

57. The film coating solvent is composed of acetone: water (9:1), the process according to claim 56.

58. The mixing of the core and the precoating film mixture is carried out in a fluidized bed coater, the process according to any one of claims 50 to 57.

59. Mixing the omedetomidine, its pharmaceutically acceptable salt, or its pharmaceutically acceptable hydrate of its pharmaceutically acceptable salt, the excipient, and the binder, and granulating to form a granule mixture; Pulverizing the granule mixture to form pulverized granules; Mixing the pulverized granules, the fluidizing agent, and the lubricant, and tableting the mixture to form the core; Mixing the core with a precoating film mixture comprising the release control polymer, the pore former, the plasticizer (if present), and a film coating solvent to coat the core with the coating film; Drying the coated core to form the tablet; A process for manufacturing a tablet according to any one of claims 1 to 35, comprising.

60. Mixing the omecamtiv mecarbil, its pharmaceutically acceptable salt, or a pharmaceutically acceptable hydrate of its pharmaceutically acceptable salt, the excipient, the binder, the fluidizing agent, and the lubricant, and tableting the mixture to form the core; Mixing the core with a precoating film mixture comprising the release control polymer, the pore former, the plasticizer (if present), and a film coating solvent to coat the core with the coating film; Drying the coated core to form the tablet; A process for manufacturing a tablet according to any one of claims 1 to 35, comprising.

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