P2x3 antagonist formulation

Abstract

The present invention relates to a pharmaceutical composition comprising a P2X3 antagonist, for example camlipixant. The pharmaceutical composition according to the invention comprises a P2X3 antagonist, at least one filler and a disintegrant.

Description

[0001] P2X3 ANTAGONIST FORMULATION

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a pharmaceutical composition comprising a P2X3 antagonist, for example camlipixant. The pharmaceutical composition is useful in the treatment of diseases associated with P2X3, in particular refractory chronic cough.

[0004] BACKGROUND TO THE INVENTION

[0005] P2X purinoreceptors are a family of ion channels that are activated by extracellular adenosine triphosphate (ATP). Purinoreceptors have been implicated in a variety of biological functions, especially those related to pain sensitivity. The P2X3 receptor subunit is a member of this family.

[0006] P2X3 is selectively expressed on nociceptive, small diameter sensory neurons (i.e., neurons that are stimulated by pain or injury), which is consistent with a role in pain sensitivity. And blocking P2X3 receptors has been reported to be analgesic in animal models of chronic inflammatory and neuropathic pain. It is, therefore, believed that a method for reducing the P2X3 level or activity would be useful for modulating pain sensation in a subject suffering from pain. Various other disorders also have been discussed as being treatable using P2X3 antagonists such as camlipixant, including chronic cough.

[0007] Camlipixant and pharmaceutically acceptable salts thereof, are disclosed in WO 2014 / 117274. Methods of making camlipixant and pharmaceutically acceptable salts thereof are disclosed in WO 2014 / 117274, WO 2021 / 161109 and WO 2023 / 021328. Methods to treat refractory chronic cough with camlipixant and pharmaceutically acceptable salts thereof are disclosed in WO 2019 / 064079.

[0008] It has surprisingly been found that the pharmaceutical compositions comprising P2X3 antagonists according to the present invention have desirable properties, in particular excellent stability. Thus, such compositions can be beneficial for use in the treatment of subjects having disease such as refractory chronic cough.

[0009] BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG 1. is a schematic of an exemplary manufacturing process of a pharmaceutical composition in accordance with the present invention.

[0011] FIG 2. is a table of stability data for camlipixant Film Coated Tablets of formulation B at 25°C ± 2°C / 60%RH ±5%RH in a bottle. FIG 3. is a table of stability data for camlipixant Film Coated Tablets of formulation B at 30°C ± 2°C / 75%RH ±5%RH in a bottle.

[0012] FIG 4. is a table of stability data for camlipixant Film Coated Tablets of formulation B at 40°C ± 2°C / 75%RH ±5%RH in a bottle.

[0013] FIG 5. is a table of stability data for camlipixant Film Coated Tablets of formulation A at 25°C ± 2°C / 60%RH ±5%RH in a blister pack.

[0014] FIG 6. is a table of stability data for camlipixant Film Coated Tablets of formulation A at 30°C ± 2°C / 75%RH ±5%RH in a blister pack.

[0015] FIG 7. is a table of stability data for camlipixant Film Coated Tablets of formulation A at 40°C ± 2°C / 75%RH ±5%RH in a blister pack.

[0016] FIG 8. is a table of stability data for camlipixant Film Coated Tablets of formulation B at 25°C ± 2°C / 60%RH ±5%RH in a blister pack.

[0017] FIG 9. is a table of stability data for camlipixant Film Coated Tablets of formulation B at 30°C ± 2°C / 75%RH ±5%RH in a blister pack.

[0018] FIG 10. is a table of stability data for camlipixant Film Coated Tablets of formulation B at 40°C ± 2°C / 75%RH ±5%RH in a blister pack.

[0019] FIG 11. is a table of stability data for camlipixant Film Coated Tablets of formulation C at 25°C ± 2°C / 75%RH ±5%RH in a bottle.

[0020] FIG 12. is a table of stability data for camlipixant Film Coated Tablets of formulation C at 40°C ± 2°C / 75%RH ±5%RH in a bottle.

[0021] FIG 13. is a graph showing the dissolution of a Film Coated 50 mg Tablet in 0.1 N HCI.

[0022] SUMMARY OF THE INVENTION

[0023] In a first aspect there is provided a pharmaceutical composition comprising, a) a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof; b) at least one filler; and c) a disintegrant.

[0024] In a second aspect, there is provided a method for the treatment of cough in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to the first aspect.

[0025] In a third aspect, there is provided a pharmaceutical composition according to the first aspect for use in therapy, particularly for use in cough.

[0026] In a fourth aspect, there is provided the use of a pharmaceutical composition according to the first aspect in the manufacture of a medicament for use in the treatment of cough.

[0027] DETAILED DESCRIPTION OF THE INVENTION

[0028] Statement of Invention

[0029] Definitions

[0030] As used herein, the term “composition”, as in pharmaceutical composition, is intended to encompass a drug product comprising an active drug substance or its pharmaceutically acceptable salts, solvates, polymorphs, stereoisomers or mixtures thereof, and the other inert / inactive ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions may be, in certain embodiments, synonymous with “formulation” and “dosage form”.

[0031] The term “excipient” means a pharmacologically inactive component such as a disintegrant, lubricant, filler, or carrier. Excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. Coprocessed excipients are also covered under the scope of present the invention.

[0032] The term “disintegrant” refers to a compound that expands and dissolves when wet causing a solid dosage form or tablet to break apart, for example, in the digestive tract, releasing the active ingredients for absorption. Disintegrants help rupturing of the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Thus, disintegrants ensure that when a tablet is in contact with water, it rapidly breaks down into smaller fragments, facilitating dissolution. The term “filler” refers to a compound that increases the bulk of a composition to facilitate compression or create sufficient bulk for homogenous blend for tablet formulations. As used herein, fillers are synonymous with “diluents”.

[0033] The term “lubricant” refers to compounds that prevent, reduce or inhibit adhesion or friction of materials. Without being limited as to theory, lubricants prevent, reduce or inhibit adhesion of powders in a blend. For example, they may prevent, reduce or inhibit intraparticulate friction or may prevent, reduce or inhibit electrostatic charging of a powder. Lubricants may prevent, reduce or inhibit the adhesion of a powder to the surfaces into which it comes in contact.

[0034] The term “coating” or “coat” refers to an outer layer of material that is applied to the surface of a dosage form in order to confer specific benefits over an uncoated equivalent version.

[0035] The term “granulation” refers to the process of binding particles of a dry powder composition through agglomeration to provide larger particles, known as granules that allow for production of pharmaceutical dosage form, such as tablets. Granulation is most often divided into two types: wet granulation, which requires a liquid in the process, and dry granulation, which does not require any liquid. Wet granulation uses a granulation liquid (binder / solvent) to facilitate the agglomeration by formation of a wet mass by adhesion while dry granulation uses mechanical compression, such as slugging, or compaction, such as roller compaction, to facilitate agglomeration.

[0036] As used herein, “intragranular components” refers to the ingredients included in a granule.

[0037] As used herein, “extragranular components” refers to ingredients added to the as-formed granule.

[0038] The term “roller compaction” refers to a method of powder compaction of dry powders into a solid mass. In roller compaction, ribbons are produced by passing the blend between the roller compactor rolls. The ribbons are then typically milled into granules. The roll pressure and gap distance (set between the two rolls) are key parameters that influence the ribbon thickness. In some embodiments of roll or roller compaction, powder is fed by gravity or by means of a screw through two counter-rotating rollers, rearranging the particles by the compaction pressure applied by the rollers, thus inducing a densification of the resulting material.

[0039] The terms “ribbon” and “ribbon thickness” are referred to with respect to a type of dry granulation that utilizes roll or roller compaction. The resulting material of roll or roller compaction is known as a “ribbon”, wherein a uniform and continuous flow of material is provided by the feeding system to form a “ribbon” of desired “ribbon thickness”. Ribbon thickness may be measured by any of the typical methods utilized in the art. The ribbon thickness is important in tailoring the final particle size of the granulation, as it will affect the milling efficiency of the ribbons. Ribbon thickness may be measured with a caliper throughout the process. One method of measuring thickness is to obtain a rectangular sample of ribbon, at least 1 in (2.54 cm) from the compaction process. The dimensions (length, width, and thickness) are measured using a caliper or other device for measuring accurately to between one tenth or hundredth of an inch. Another parameter that may be measured is ribbon density, which is calculated by dividing the mass of the ribbon sample divided by the approximate volume (lengthxwidthxthickness).

[0040] The term “tablet” refers to a dosage form in which particles of a drug substance or pharmaceutical agent, such as camlipixant, and certain excipients, such as any one of the excipients described herein, are pressed, compacted, or extruded together. Tablets can be made in a variety of shapes, including round, or elongated, such as flattened ovoid or cylindrical shapes.

[0041] The term “treatment” refers to ameliorating or stabilising the specified condition, reducing or eliminating the symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying reoccurrence of the condition in a previously afflicted patient or subject.

[0042] The term “prevention” refers to avoidance of the stated disease in a subject who is not suffering from the stated disease.

[0043] The term “therapeutically effective amount” refers to the quantity of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, which will elicit the desired biological response in a human body. It may vary depending on the compound, the disease and its severity and the age and weight of the subject to be treated.

[0044] The term "subject" refers to a human body.

[0045] The term “refractory chronic cough” refers to a cough lasting >8 weeks despite adequate treatment and investigation for cough-related aetiologies.

[0046] For the avoidance of doubt, a reference to a compound of Formula (I) encompasses a reference to any one of Formulae (l-a) and (l-b). The embodiments are disclosed with reference to any one of Formulae (l-a) and (l-b).

[0047] Formulations

[0048] In one aspect, the present disclosure provides a pharmaceutical composition comprising, a) a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof; b) at least one filler; and c) a disintegrant.

[0049] In an embodiment, the pharmaceutical composition further comprises a lubricant.

[0050] The pharmaceutical composition of the present invention can include from about 1.5 wt% to 30 wt% of the compound of Formula (I) based on the total weight of the composition. Other suitable amounts include from about 5 wt% to about 25 wt%, about 10 wt% to about 20 wt%, and about 12.5 wt% to about 17.5 wt%. For example, the compositions can include the compound of Formula (I) in an amount of about 15 wt% based on the total weight of the composition. In accordance with embodiments of the disclosure, the unit doses can be provided with a dosage amount of the compound of Formula (I) in a range of from about 20 mg to about 100 mg. In alternative embodiments, the dosage amount can include about 25 mg and about 50 mg of the compound of Formula (I). In one embodiment, the dosage strength is about 25 mg, i.e., the pharmaceutical composition according to the invention comprises about 25 mg of a compound of Formula (I). In another embodiment, the dosage strength is about 50 mg, i.e., the pharmaceutical composition according to the invention comprises about 50 mg of a compound of Formula (I).

[0051] In an embodiment, the pharmaceutical composition of the present invention can include the compound of Formula (I) in an amount of from about 1.5 wt% to about 35 wt% based on the total weight of the composition. In an embodiment, the pharmaceutical composition of the present invention can include the compound of Formula (I) in an amount of from about 20 wt% to about 35 wt% based on the total weight of the composition. In an embodiment, the pharmaceutical composition of the present invention can include the compound of Formula (I) in an amount of from about 25 wt% to about 35 wt% based on the total weight of the composition. In an embodiment, the pharmaceutical composition of the present invention can include the compound of Formula (I) in an amount of about 30 wt% based on the total weight of the composition. In an embodiment, the pharmaceutical composition of the present invention can include the compound of Formula (I) in an amount of about 25 wt% based on the total weight of the composition. In an embodiment, the pharmaceutical composition of the present invention can include the compound of Formula (I) in an amount of about 20 wt% based on the total weight of the composition. In accordance with embodiments of the disclosure, the unit doses can be provided with a dosage amount of the compound of Formula (I) in a range of from about 95 mg to about 105 mg. In one embodiment, the dosage strength is about 100 mg, i.e., the pharmaceutical composition according to the invention comprises about 100 mg of a compound of Formula (I).

[0052] In some embodiments, the compound of Formula (I) is a compound of Formula (l-a)

[0053] (l-a)

[0054] In some embodiments, the compound of Formula (I) is a compound of Formula (l-b)

[0055] (l-b)

[0056] In some embodiments, the compound of Formula (I) is camlipixant. Camlipixant has the chemical name methyl (2S)-2-({2-[2,6-difluoro-4-(methylcarbamoyl)phenyl]-7- methylimidazo[1 ,2-a]pyridine-3-yl}morpholine-4-carboxylate, as set out in the WHO Drug Information, Vol. 37, No.1 , 2023, Recommended INN List 89, and is also referred to in the literature as BLU-5937.

[0057] Suitable fillers for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), and cyclodextrins. Combinations of one or more fillers can also be used. In some embodiments provided herein, the fillers are selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, dibasic calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc.

[0058] In an embodiment, the pharmaceutical composition comprises at least one or more fillers. For example, the composition may comprise one, two or three fillers. In an embodiment, the composition of the invention comprises two fillers, i.e. a first and a second filler. The combined fillers can be included in an amount of from about 60 wt% to about 95 wt%, about 65 wt% to about 95 wt%, about 70 wt% to about 90 wt%, or about 75 wt% to about 85 wt%, based on the total weight of the composition. In some embodiments, the fillers are present in an amount of about 80 wt% based on the total weight of the composition. In some embodiments, the combined fillers are present in an amount of about 79.75 wt% based on the total weight of the composition.

[0059] In some embodiments, the fillers are present in an amount of 60 wt% to about 70 wt% based on the total weight of the composition. In some embodiments, the combined fillers are present in an amount of about 64.5 wt% based on the total weight of the composition.

[0060] In some embodiments, particularly where the pharmaceutical composition includes the compound of Formula (I) in an amount of about 20 to about 35 wt% based on the total weight of the composition or in an amount of about 25 to about 35 wt% (for example about 20 wt% or about 30 wt%), the fillers are present in an amount of 60 wt% to about 70 wt% based on the total weight of the composition. In some embodiments, the combined fillers are present in an amount of about 64.5 wt% based on the total weight of the composition.

[0061] In some embodiments, the pharmaceutical composition comprises a first filler and a second filler. In some embodiments, the first filler is used to adjust the brittleness of the composition and the second filler is used to adjust the plasticity of the composition.

[0062] In some embodiments, the first filler is present in an amount of from about 30 wt% to about 50 wt% based on the total weight of the composition. In some embodiments, the first filler is present in an amount of about 35 wt% to about 45 wt% based on the total weight of the composition. In some embodiments, the first filler is present in an amount of about 40 wt% to about 45 wt% based on the total weight of the composition. In some embodiments, the first filler is present in an amount of from about 40 wt%, about 41 wt%, or about 42 wt% to about 45 wt% based on the total weight of the composition. In some embodiments, the first filler is present in an amount of about 42.75 wt% based on the total weight of the composition. In some embodiments, the first filler is present in an amount of from about 30 wt% to about 40 wt% based on the total weight of the composition. In some embodiments, the first filler is present in an amount of about 34.5 wt% based on the total weight of the composition.

[0063] In some embodiments, particularly where the pharmaceutical composition includes the compound of Formula (I) in an amount of about 20 to about 35 wt% based on the total weight of the composition or in an amount of about 25 to about 35 wt% (for example about 20 wt% or about 30 wt%), the first filler is present in an amount of from about 30 wt% to about 40 wt% based on the total weight of the composition. In some embodiments, the first filler is present in an amount of about 34.5 wt% based on the total weight of the composition.

[0064] In an embodiment, the first filler is mannitol or dibasic calcium phosphate.

[0065] In an embodiment, the first filler is soluble.

[0066] In an embodiment, the first filler is water soluble.

[0067] In an embodiment, the first filler is mannitol.

[0068] In an embodiment, the first filler is mannitol 100 SD.

[0069] In an embodiment, the first filler is mannitol and is present in an amount of from about 30 wt% to about 50 wt% based on the total weight of the composition. In an embodiment, the first filler is mannitol and is present in an amount of from about 40 wt% to about 45 wt% based on the total weight of the composition. In an embodiment, the first filler is mannitol and is present in an amount of about 42.75 wt% based on the total weight of the composition.

[0070] In an embodiment, particularly where the pharmaceutical composition includes the compound of Formula (I) in an amount of about 20 to about 35 wt% based on the total weight of the composition or in an amount of about 25 to about 35 wt% (for example about 20 wt% or about 30 wt%), the first filler is mannitol and is present in an amount of from about 30 wt% to about 40 wt% based on the total weight of the composition.

[0071] In an embodiment, particularly where the pharmaceutical composition includes the compound of Formula (I) in an amount of about 20 to about 35 wt% based on the total weight of the composition or in an amount of about 25 to about 35 wt% (for example about 20 wt% or about 30 wt%), the first filler is mannitol and is present in an amount of about 35 wt% based on the total weight of the composition.

[0072] In an embodiment, particularly where the pharmaceutical composition includes the compound of Formula (I) in an amount of about 20 to about 35 wt% based on the total weight of the composition or in an amount of about 25 to about 35 wt% (for example about 20 wt% or about 30 wt%), the first filler is mannitol and is present in an amount of about 34.5 wt% based on the total weight of the composition.

[0073] In some embodiments, a second filler is present in an amount of from about 30 wt% to about 50 wt% based on the total weight of the composition. In some embodiments, the second filler is present in an amount of from about 35 wt% to about 45 wt% based on the total weight of the composition. In some embodiments, the second filler is present in an amount of from about 35 wt% to about 40 wt% based on the total weight of the composition. In some embodiments, the second filler is present in an amount of from about 35 wt%, about 36 wt% to about 39 wt%, based on the total weight of the composition. In some embodiments, the second filler is present in an amount of about 37 wt% based on the total weight of the composition.

[0074] In some embodiments, particularly where the pharmaceutical composition includes the compound of Formula (I) in an amount of about 20 to about 35 wt% based on the total weight of the composition or in an amount of about 25 to about 35 wt% (for example about 20 wt% or about 30 wt%), a second filler is present in an amount of from about 25 wt% to about 35 wt% based on the total weight of the composition. In some embodiments, particularly where the pharmaceutical composition includes the compound of Formula (I) in an amount of about 20 to about 35 wt% based on the total weight of the composition or in an amount of about 25 to about 35 wt% (for example about 20 wt% or about 30 wt%), the second filler is present in an amount of about 30 wt% based on the total weight of the composition.

[0075] In an embodiment, the second filler is microcrystalline cellulose.

[0076] In an embodiment, the second filler is microcrystalline cellulose 102.

[0077] In an embodiment, the second filler is microcrystalline cellulose and is present in an amount of from about 30 wt% to about 50 wt% based on the total weight of the composition. In an embodiment, the second filler is microcrystalline cellulose and is present in an amount of from about 35 wt% to about 40 wt% based on the total weight of the composition.

[0078] In an embodiment, the second filler is microcrystalline cellulose and is present in an amount of about 37 wt% based on the total weight of the composition.

[0079] In an embodiment, particularly where the pharmaceutical composition includes the compound of Formula (I) in an amount of about 20 to about 35 wt% based on the total weight of the composition or in an amount of about 25 to about 35 wt% (for example about 20 wt% or about 30 wt%), the second filler is microcrystalline cellulose and is present in an amount of from about 25 wt% to about 35 wt% based on the total weight of the composition. In an embodiment, particularly where the pharmaceutical composition includes the compound of Formula (I) in an amount of about 20 to about 35 wt% based on the total weight of the composition or in an amount of about 25 to about 35 wt% (for example about 20 wt% or about 30 wt%), the second filler is microcrystalline cellulose and is present in an amount of about 30 wt% based on the total weight of the composition.

[0080] In some embodiments, the first filler is mannitol, and the second filler is microcrystalline cellulose.

[0081] In some embodiments, the first filler is mannitol, and the second filler is microcrystalline cellulose 102. In some embodiments, the first filler is mannitol 100 SD, and the second filler is microcrystalline cellulose. In some embodiments, the first filler is mannitol 100 SD, and the second filler is microcrystalline cellulose 102.

[0082] In some embodiments, the first filler is mannitol and is present in an amount of about 30 wt% to about 50 wt% based on the total weight of the composition and the second filler is microcrystalline cellulose and is present in an amount of about 30 wt% to about 50 wt% based on the total weight of the composition.

[0083] In some embodiments, the first filler is mannitol and is present in an amount of about 40 wt% to about 45 wt% based on the total weight of the composition and the second filler is microcrystalline cellulose and is present in an amount of about 35 wt% to about 40 wt% based on the total weight of the composition.

[0084] In some embodiments, the pharmaceutical composition includes the compound of Formula (I) in an amount of about 10 wt% to about 20 wt% based on the total weight of the composition, the first filler is mannitol and is present in an amount of about 30 wt% to about 50 wt% based on the total weight of the composition and the second filler is microcrystalline cellulose and is present in an amount of about 30 wt% to about 50 wt% based on the total weight of the composition.

[0085] In some embodiments, the pharmaceutical composition includes the compound of Formula (I) in an amount of about 15 wt% based on the total weight of the composition, the first filler is mannitol and is present in an amount of about 40 wt% to about 45 wt% based on the total weight of the composition and the second filler is microcrystalline cellulose and is present in an amount of about 35 wt% to about 40 wt% based on the total weight of the composition.

[0086] In some embodiments, the first filler is mannitol and is present in an amount of about 42.75 wt% based on the total weight of the composition, and the second filler is microcrystalline cellulose and is present in an amount of about 37 wt% based on the total weight of the composition. In some embodiments, the pharmaceutical composition includes a compound of Formula (I) in an amount of about 15 wt% based on the total weight of the composition, the first filler is mannitol and is present in an amount of about 42.75 wt% based on the total weight of the composition, and the second filler is microcrystalline cellulose and is present in an amount of about 37 wt% based on the total weight of the composition.

[0087] In some embodiments, the first filler is mannitol and is present in an amount of about 34.5 wt% based on the total weight of the composition, and the second filler is microcrystalline cellulose and is present in an amount of about 30 wt% based on the total weight of the composition.

[0088] In some embodiments, particularly where the pharmaceutical composition includes the compound of Formula (I) in an amount of about 20 to about 35 wt% based on the total weight of the composition or in an amount of about 25 to about 35 wt% (for example about 20 wt% or about 30 wt%), the first filler is mannitol and is present in an amount of about 34.5 wt% based on the total weight of the composition, and the second filler is microcrystalline cellulose and is present in an amount of about 30 wt% based on the total weight of the composition.

[0089] In an embodiment, the pharmaceutical composition includes a compound of Formula (I) in an amount of about 25 to 35 wt% based on the total weight of the composition, the first filler is mannitol and is present in an amount of about 40 wt% to 50 wt% based on the total weight of the composition, and the second filler is microcrystalline cellulose and is present in an amount of about 30 wt% to about 40 wt% base don the total weight of the composition. Suitable lubricants for use in the pharmaceutical composition described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali-metal and alkaline earth metal salts, such as calcium, magnesium, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate. In some embodiments, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes. In some embodiments provided herein, the lubricant is magnesium stearate or sodium stearyl fumarate.

[0090] In some embodiments provided herein, the lubricant is magnesium stearate.

[0091] In some embodiments, the lubricant is present in an amount of from about 0.1 wt% to about 5 wt% based on the total weight of the composition. In some embodiments, the lubricant is present in an amount of from about 0.5 wt% to about 3 wt% based on the total weight of the composition. In some embodiments, the lubricant is present in an amount of from about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8% wt%, about 0.9 wt%, about 1 wt%, 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 2 wt%, or about 2.5 wt%, to about 3 wt% based on the total weight of the composition. In some embodiments, the lubricant is present in an amount of from about 1 to about 1.5 wt% based on the total weight of the composition. In some embodiments, the lubricant is present in an amount of from about 1.25 to about 1.5 wt% based on the total weight of the composition. In some embodiments, the lubricant is present in an amount of about 1 .25 wt% based on the total weight of the composition.

[0092] In some embodiments, the lubricant is present in an amount of about 1.5 wt% based on the total weight of the composition.

[0093] In some embodiments, the lubricant is present in an amount of about 2 wt% based on the total weight of the composition.

[0094] In some embodiments, the lubricant is magnesium stearate and is present in an amount of from about 1.25 to about 1.5 wt% based on the total weight of the composition. In some embodiments, the lubricant is magnesium stearate and is present in an amount of about 1 .25 wt% based on the total weight of the composition.

[0095] In some embodiments, the lubricant is magnesium stearate and is present in an amount of about 1 .5 wt% based on the total weight of the composition.

[0096] In some embodiments, the lubricant is magnesium stearate and is present in an amount of about 2 wt% based on the total weight of the composition.

[0097] In some embodiments provided herein, the disintegrant is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, or a gum.

[0098] In an embodiment, the disintegrant is croscarmellose sodium or sodium starch glycolate.

[0099] In an embodiment, the disintegrant is croscarmellose, particularly wherein the disintegrant is croscarmellose sodium.

[0100] In some embodiments, the disintegrant is present in an amount of from about 0.1 to about 10 wt% based on the total weight of the composition. In some embodiments, the disintegrant is present in an amount of from about 1 to about 5 wt% based on the total weight of the composition. In some embodiments, the disintegrant is present in an amount of from about 3 to about 5 wt% based on the total weight of the composition. In some embodiments, the disintegrant is present in an amount of from about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt% to about 4.5 wt%, based on the total weight of the composition. In some embodiments, the disintegrant is present in an amount of about 4 wt% based on the total weight of the composition.

[0101] In an embodiment, the disintegrant is croscarmellose sodium and is present in an amount of from about 1 to about 5 wt% based on the total weight of the composition.

[0102] In an embodiment, the disintegrant is croscarmellose sodium and is present in an amount of about 4 wt% based on the total weight of the composition.

[0103] In an embodiment, the disintegrant is croscarmellose sodium and is present in an amount of from about 5 to about 10 wt% based on the total weight of the composition.

[0104] In another embodiment disclosed herein is a pharmaceutical composition comprising the following components on a weight percentage basis, based on the total weight of the composition

[0105] (i) about 1 .5 to about 35% of a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0106] (ii) about 30 to about 50% of a first filler;

[0107] (iii) about 30 to about 50% of a second filler; and

[0108] (iv) about 0.1 to about 10% of a disintegrant.

[0109] In another embodiment disclosed herein is a pharmaceutical composition comprising the following components on a weight percentage basis, based on the total weight of the composition (i) about 1 .5 to about 35% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0110] (ii) about 30 to about 50% of a first filler;

[0111] (iii) about 30 to about 50% of a second filler; and

[0112] (iv) about 0.1 to about 10% of a disintegrant.

[0113] In another embodiment disclosed herein is a pharmaceutical composition comprising the following components on a weight percentage basis, based on the total weight of the composition

[0114] (i) about 1 .5 to about 30% of a pharmaceutically effective amount of a compound of Formula

[0115] (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0116] (ii) about 30 to about 50% of a first filler;

[0117] (iii) about 30 to about 50% of a second filler; and

[0118] (iv) about 0.1 to about 10% of a disintegrant.

[0119] In another embodiment disclosed herein is a pharmaceutical composition comprising the following components on a weight percentage basis, based on the total weight of the composition

[0120] (i) about 1 .5 to about 30% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0121] (ii) about 30 to about 50% of a first filler;

[0122] (iii) about 30 to about 50% of a second filler; and

[0123] (iv) about 0.1 to about 10% of a disintegrant.

[0124] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0125] (i) about 5 to about 25% of a pharmaceutically effective amount of a compound of Formula

[0126] (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0127] (ii) about 35 to about 45% of a first filler;

[0128] (iii) about 35 to about 45% of a second filler; and

[0129] (iv) about 1 to about 5% of a disintegrant.

[0130] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0131] (i) about 5 to about 25% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0132] (ii) about 35 to about 45% of a first filler;

[0133] (iii) about 35 to about 45% of a second filler; and

[0134] (iv) about 1 to about 5% of a disintegrant.

[0135] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0136] (i) about 25 to about 35% of a pharmaceutically effective amount of a compound of Formula

[0137] (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0138] (ii) about 30 to about 40% of a first filler;

[0139] (iii) about 25 to about 35% of a second filler; and

[0140] (iv) about 1 to about 5% of a disintegrant.

[0141] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0142] (i) about 20 to about 35% of a pharmaceutically effective amount of a compound of Formula (lb)

[0143] or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0144] (ii) about 30 to about 40% of a first filler;

[0145] (iii) about 25 to about 35% of a second filler; and

[0146] (iv) about 1 to about 5% of a disintegrant.

[0147] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0148] (i) about 25 to about 35% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0149] (ii) about 30 to about 40% of a first filler;

[0150] (iii) about 25 to about 35% of a second filler; and

[0151] (iv) about 1 to about 5% of a disintegrant.

[0152] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0153] (i) about 12.5% to about 17.5% of a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0154] (ii) about 40 to about 45% of a first filler;

[0155] (iii) about 35 to about 40% of a second filler; and

[0156] (iv) about 3 to about 5% of a disintegrant.

[0157] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0158] (i) about 12.5% to about 17.5% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0159] (ii) about 40 to about 45% of a first filler;

[0160] (iii) about 35 to about 40% of a second filler; and

[0161] (iv) about 3 to about 5% of a disintegrant. In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0162] (i) about 25 to about 35% of a pharmaceutically effective amount of a compound of Formula (I)

[0163] or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0164] (ii) about 30 to about 40% of a first filler;

[0165] (iii) about 25 to about 35% of a second filler; and

[0166] (iv) about 3 to about 5% of a disintegrant.

[0167] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0168] (i) about 25 to about 35 % of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0169] (ii) about 30 to about 40% of a first filler;

[0170] (iii) about 25 to about 35% of a second filler; and

[0171] (iv) about 3 to about 5% of a disintegrant.

[0172] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0173] (i) about 25 to about 35 % of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0174] (ii) about 30 to about 40% of a first filler;

[0175] (iii) about 25 to about 35% of a second filler; and

[0176] (iv) about 5 to about 10% of a disintegrant.

[0177] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0178] (i) about 15 wt% of a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0179] (ii) about 42.75% of a first filler;

[0180] (iii) about 37% of a second filler; and

[0181] (iv) about 4% of a disintegrant.

[0182] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0183] (i) about 15 wt% of a pharmaceutically effective amount of a compound of Formula (lb) (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0184] (ii) about 42.75% of a first filler;

[0185] (iii) about 37% of a second filler; and

[0186] (iv) about 4% of a disintegrant.

[0187] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0188] (i) about 30 wt% of a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0189] (ii) about 34.5% of a first filler;

[0190] (iii) about 30% of a second filler; and

[0191] (iv) about 4% of a disintegrant.

[0192] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0193] (i) about 30 wt% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0194] (ii) about 34.5% of a first filler;

[0195] (iii) about 30% of a second filler; and

[0196] (iv) about 4% of a disintegrant. In another embodiment disclosed herein is a pharmaceutical composition comprising the following components on a weight percentage basis, based on the total weight of the composition

[0197] (i) about 1 .5 to about 35% of a pharmaceutically effective amount of a compound of Formula

[0198] (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0199] (ii) mannitol in an amount of from about 30 to about 50%;

[0200] (iii) microcrystalline cellulose in an amount of from about 30 to about 50%; and

[0201] (iv) croscarmellose sodium in an amount of from about 0.1 to about 10%.

[0202] In another embodiment disclosed herein is a pharmaceutical composition comprising the following components on a weight percentage basis, based on the total weight of the composition

[0203] (i) about 1 .5 to about 35% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0204] (ii) mannitol in an amount of from about 30 to about 50%;

[0205] (iii) microcrystalline cellulose in an amount of from about 30 to about 50%; and

[0206] (iv) croscarmellose sodium in an amount of from about 0.1 to about 10%. In another embodiment disclosed herein is a pharmaceutical composition comprising the following components on a weight percentage basis, based on the total weight of the composition

[0207] (i) about 1 .5 to about 30 % of a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0208] (ii) mannitol in an amount of from about 30 to about 50%;

[0209] (iii) microcrystalline cellulose in an amount of from about 30 to about 50%; and

[0210] (iv) croscarmellose sodium in an amount of from about 0.1 to about 10%.

[0211] In another embodiment disclosed herein is a pharmaceutical composition comprising the following components on a weight percentage basis, based on the total weight of the composition

[0212] (i) about 1 .5 to about 30% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0213] (ii) mannitol in an amount of from about 30 to about 50%;

[0214] (iii) microcrystalline cellulose in an amount of from about 30 to about 50%; and

[0215] (iv) croscarmellose sodium in an amount of from about 0.1 to about 10%.

[0216] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition (i) about 5 to about 25% of a pharmaceutically effective amount of a compound of Formula

[0217] (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0218] (ii) mannitol in an amount of from about 35 to about 45%;

[0219] (iii) microcrystalline cellulose in an amount of from about 35 to about 45%; and

[0220] (iv) croscarmellose sodium in an amount of from about 1 to about 5%.

[0221] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0222] (i) about 5 to about 25% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0223] (ii) mannitol in an amount of from about 35 to about 45%;

[0224] (iii) microcrystalline cellulose in an amount of from about 35 to about 45%; and

[0225] (iv) croscarmellose sodium in an amount of from about 1 to about 5%.

[0226] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0227] (i) about 25 to about 35% of a pharmaceutically effective amount of a compound of Formula

[0228] (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0229] (ii) mannitol in an amount of from about 30 to about 40%;

[0230] (iii) microcrystalline cellulose in an amount of from about 25 to about 35%; and

[0231] (iv) croscarmellose sodium in an amount of from about 1 to about 5%.

[0232] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0233] (i) about 25 to about 35% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0234] (ii) mannitol in an amount of from about 30 to about 40%;

[0235] (iii) microcrystalline cellulose in an amount of from about 25 to about 35%; and

[0236] (iv) croscarmellose sodium in an amount of from about 1 to about 5%.

[0237] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0238] (i) about 20 to about 35% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0239] (ii) mannitol in an amount of from about 30 to about 40%;

[0240] (iii) microcrystalline cellulose in an amount of from about 25 to about 35%; and

[0241] (iv) croscarmellose sodium in an amount of from about 5 to about 10%.

[0242] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0243] (i) about 12.5% to about 17.5% of a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0244] (ii) mannitol in an amount of from about 40 to about 45%;

[0245] (iii) microcrystalline cellulose in an amount of from about 35 to about 40%; and

[0246] (iv) croscarmellose sodium in an amount of from about 3 to about 5%.

[0247] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0248] (i) about 12.5% to about 17.5% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0249] (ii) mannitol in an amount of from about 40 to about 45%;

[0250] (iii) microcrystalline cellulose in an amount of from about 35 to about 40%; and

[0251] (iv) croscarmellose sodium in an amount of from about 3 to about 5%.

[0252] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0253] (i) about 25% to about 35% of a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0254] (ii) mannitol in an amount of from about 30 to about 40%;

[0255] (iii) microcrystalline cellulose in an amount of from about 25 to about 35%; and

[0256] (iv) croscarmellose sodium in an amount of from about 3 to about 5%.

[0257] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0258] (i) about 25% to about 35% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0259] (ii) mannitol in an amount of from about 30 to about 40%;

[0260] (iii) microcrystalline cellulose in an amount of from about 25 to about 35%; and

[0261] (iv) croscarmellose sodium in an amount of from about 3 to about 5%.

[0262] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0263] (i) about 15 wt% of a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0264] (ii) about 40 to about 45% of a first filler;

[0265] (iii) about 35 to about 40% of a second filler; and

[0266] (iv) about 3 to about 5% of a disintegrant.

[0267] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0268] (i) about 15 wt% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0269] (ii) about 40 to about 45% of a first filler;

[0270] (iii) about 35 to about 40% of a second filler; and

[0271] (iv) about 3 to about 5% of a disintegrant.

[0272] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0273] (i) about 30 wt% of a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0274] (ii) about 30 to about 40% of a first filler;

[0275] (iii) about 25 to about 35% of a second filler; and

[0276] (iv) about 3 to about 5% of a disintegrant.

[0277] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0278] (i) about 30 wt% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0279] (ii) about 30 to about 40% of a first filler;

[0280] (iii) about 25 to about 35% of a second filler; and

[0281] (iv) about 3 to about 5% of a disintegrant.

[0282] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0283] (i) about 15 wt% of a pharmaceutically effective amount of a compound of Formula (I)

[0284] or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0285] (ii) mannitol in an amount of from about 42.75%;

[0286] (iii) microcrystalline cellulose in an amount of from about 37%;

[0287] (iv) croscarmellose sodium in an amount of from about 4%.

[0288] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0289] (i) about 15 wt% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0290] (ii) mannitol in an amount of from about 42.75%;

[0291] (iii) microcrystalline cellulose in an amount of from about 37%; and

[0292] (iv) croscarmellose sodium in an amount of from about 4%.

[0293] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0294] (i) about 30 wt% of a pharmaceutically effective amount of a compound of Formula (I) (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0295] (ii) mannitol in an amount of about 34.5%;

[0296] (iii) microcrystalline cellulose in an amount of about 30%;

[0297] (iv) croscarmellose sodium in an amount of about 4%.

[0298] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0299] (i) about 30 wt% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0300] (ii) mannitol in an amount of about 34.5%;

[0301] (iii) microcrystalline cellulose in an amount of about 30%; and

[0302] (iv) croscarmellose sodium in an amount of about 4%.

[0303] In another embodiment disclosed herein is a pharmaceutical composition comprising the following components on a weight percentage basis, based on the total weight of the composition

[0304] (i) about 1 .5 to about 35% of a pharmaceutically effective amount of a compound of Formula

[0305] (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0306] (ii) about 30 to about 50% of a first filler;

[0307] (iii) about 30 to about 50% of a second filler; (iv) about 0.1 to about 10% of a disintegrant; and

[0308] (v) about 0.1 to about 5% of a lubricant.

[0309] In another embodiment disclosed herein is a pharmaceutical composition comprising the following components on a weight percentage basis, based on the total weight of the composition

[0310] (i) about 1 .5 to about 35% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0311] (ii) about 30 to about 50% of a first filler;

[0312] (iii) about 30 to about 50% of a second filler;

[0313] (iv) about 0.1 to about 10% of a disintegrant; and

[0314] (v) about 0.1 to about 5% of a lubricant.

[0315] In another embodiment disclosed herein is a pharmaceutical composition comprising the following components on a weight percentage basis, based on the total weight of the composition

[0316] (i) about 1 .5 to about 30% of a pharmaceutically effective amount of a compound of Formula

[0317] (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0318] (ii) about 30 to about 50% of a first filler;

[0319] (iii) about 30 to about 50% of a second filler; (iv) about 0.1 to about 10% of a disintegrant; and

[0320] (v) about 0.1 to about 5% of a lubricant.

[0321] In another embodiment disclosed herein is a pharmaceutical composition comprising the following components on a weight percentage basis, based on the total weight of the composition

[0322] (i) about 1 .5 to about 30% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0323] (ii) about 30 to about 50% of a first filler;

[0324] (iii) about 30 to about 50% of a second filler;

[0325] (iv) about 0.1 to about 10% of a disintegrant; and

[0326] (v) about 0.1 to about 5% of a lubricant.

[0327] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0328] (i) about 5 to about 25 % of a pharmaceutically effective amount of a compound of Formula

[0329] (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0330] (ii) about 35 to about 45% of a first filler;

[0331] (iii) about 35 to about 45% of a second filler;

[0332] (iv) about 1 to about 5% of a disintegrant; and (v) about 0.5 to about 3% of a lubricant.

[0333] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0334] (i) about 5 to about 25 % of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0335] (ii) about 35 to about 45% of a first filler;

[0336] (iii) about 35 to about 45% of a second filler;

[0337] (iv) about 1 to about 5% of a disintegrant; and

[0338] (v) about 0.5 to about 3% of a lubricant.

[0339] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0340] (i) about 25 to about 35% of a pharmaceutically effective amount of a compound of Formula

[0341] (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0342] (ii) about 30 to about 40% of a first filler;

[0343] (iii) about 25 to about 35% of a second filler;

[0344] (iv) about 1 to about 5% of a disintegrant; and

[0345] (v) about 0.5 to about 3% of a lubricant. In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0346] (i) about 25 to about 35 % of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0347] (ii) about 30 to about 40% of a first filler;

[0348] (iii) about 25 to about 35% of a second filler;

[0349] (iv) about 1 to about 5% of a disintegrant; and

[0350] (v) about 0.5 to about 3% of a lubricant.

[0351] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0352] (i) about 20 to about 35 % of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0353] (ii) about 30 to about 40% of a first filler;

[0354] (iii) about 25 to about 35% of a second filler;

[0355] (iv) about 1 to about 10% of a disintegrant; and

[0356] (v) about 0.5 to about 3% of a lubricant. In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0357] (i) about 12.5% to about 17.5% of a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0358] (ii) about 40 to about 45% of a first filler;

[0359] (iii) about 35 to about 40% of a second filler;

[0360] (iv) about 3 to about 5% of a disintegrant; and

[0361] (v) about 1 to about 1.5% of a lubricant.

[0362] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0363] (i) about 12.5% to about 17.5% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0364] (ii) about 40 to about 45% of a first filler;

[0365] (iii) about 35 to about 40% of a second filler;

[0366] (iv) about 3 to about 5% of a disintegrant; and

[0367] (v) about 1 to about 1.5% of a lubricant.

[0368] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition (i) about 25 to about 35% of a pharmaceutically effective amount of a compound of Formula

[0369] (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0370] (ii) about 30 to about 40% of a first filler;

[0371] (iii) about 25 to about 35% of a second filler; and

[0372] (iv) about 3 to about 5% of a disintegrant; and

[0373] (v) about 1 to about 2% of a lubricant.

[0374] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0375] (i) about 25 to about 35 % of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0376] (ii) about 30 to about 40% of a first filler;

[0377] (iii) about 25 to about 35% of a second filler; and

[0378] (iv) about 3 to about 5% of a disintegrant; and

[0379] (v) about 1 to about 2% of a lubricant.

[0380] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0381] (i) about 25 to about 35 % of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0382] (ii) about 30 to about 40% of a first filler;

[0383] (iii) about 25 to about 35% of a second filler; and

[0384] (iv) about 1 to about 10% of a disintegrant; and

[0385] (v) about 1 to about 2% of a lubricant.

[0386] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0387] (i) about 15 wt% of a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0388] (ii) about 42.75% of a first filler;

[0389] (iii) about 37% of a second filler;

[0390] (iv) about 4% of a disintegrant; and

[0391] (v) about 1 .25% of a lubricant.

[0392] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0393] (i) about 15 wt% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0394] (ii) about 42.75% of a first filler;

[0395] (iii) about 37% of a second filler;

[0396] (iv) about 4% of a disintegrant; and

[0397] (v) about 1 .25% of a lubricant.

[0398] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0399] (i) about 30 wt% of a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0400] (ii) about 34.5% of a first filler;

[0401] (iii) about 30% of a second filler;

[0402] (iv) about 4% of a disintegrant; and

[0403] (v) about 1 .5% of a lubricant.

[0404] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0405] (i) about 30 wt% of a pharmaceutically effective amount of a compound of Formula (lb)

[0406] or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0407] (ii) about 34.5% of a first filler;

[0408] (iii) about 30% of a second filler;

[0409] (iv) about 4% of a disintegrant; and

[0410] (v) about 1 .5% of a lubricant.

[0411] In another embodiment disclosed herein is a pharmaceutical composition comprising the following components on a weight percentage basis, based on the total weight of the composition

[0412] (i) about 1 .5 to about 35% of a pharmaceutically effective amount of a compound of Formula

[0413] (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0414] (ii) mannitol in an amount of from about 30 to about 50%;

[0415] (iii) microcrystalline cellulose in an amount of from about 30 to about 50%;

[0416] (iv) croscarmellose sodium in an amount of from about 0.1 to about 10%; and

[0417] (v) magnesium stearate in an amount of from about 0.1 to about 5%.

[0418] In another embodiment disclosed herein is a pharmaceutical composition comprising the following components on a weight percentage basis, based on the total weight of the composition

[0419] (i) about 1 .5 to about 35% of a pharmaceutically effective amount of a compound of Formula (lb)

[0420] or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0421] (ii) mannitol in an amount of from about 30 to about 50%;

[0422] (iii) microcrystalline cellulose in an amount of from about 30 to about 50%;

[0423] (iv) croscarmellose sodium in an amount of from about 0.1 to about 10%; and

[0424] (v) magnesium stearate in an amount of from about 0.1 to about 5%.

[0425] In another embodiment disclosed herein is a pharmaceutical composition comprising the following components on a weight percentage basis, based on the total weight of the composition

[0426] (i) about 1 .5 to about 30% of a pharmaceutically effective amount of a compound of Formula

[0427] (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0428] (ii) mannitol in an amount of from about 30 to about 50%;

[0429] (iii) microcrystalline cellulose in an amount of from about 30 to about 50%;

[0430] (iv) croscarmellose sodium in an amount of from about 0.1 to about 10%; and

[0431] (v) magnesium stearate in an amount of from about 0.1 to about 5%.

[0432] In another embodiment disclosed herein is a pharmaceutical composition comprising the following components on a weight percentage basis, based on the total weight of the composition

[0433] (i) about 1 .5 to about 30 % of a pharmaceutically effective amount of a compound of Formula (lb)

[0434] or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0435] (ii) mannitol in an amount of from about 30 to about 50%;

[0436] (iii) microcrystalline cellulose in an amount of from about 30 to about 50%;

[0437] (iv) croscarmellose sodium in an amount of from about 0.1 to about 10%; and

[0438] (v) magnesium stearate in an amount of from about 0.1 to about 5%.

[0439] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0440] (i) about 25 to about 35% of a pharmaceutically effective amount of a compound of Formula

[0441] (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0442] (ii) mannitol in an amount of from about 30 to about 40%;

[0443] (iii) microcrystalline cellulose in an amount of from about 25 to about 35%;

[0444] (iv) croscarmellose sodium in an amount of from about 1 to about 5%; and

[0445] (v) magnesium stearate in an amount of from about 0.1 to about 5%.

[0446] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0447] (i) about 25 to about 35% of a pharmaceutically effective amount of a compound of Formula (lb)

[0448] or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0449] (ii) mannitol in an amount of from about 30 to about 40%;

[0450] (iii) microcrystalline cellulose in an amount of from about 25 to about 35%;

[0451] (iv) croscarmellose sodium in an amount of from about 1 to about 5%; and

[0452] (v) magnesium stearate in an amount of from about 0.1 to about 5%.

[0453] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0454] (i) about 5 to about 25% of a pharmaceutically effective amount of a compound of Formula

[0455] (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0456] (ii) mannitol in an amount of from about 35 to about 45%;

[0457] (iii) microcrystalline cellulose in an amount of from about 35 to about 45%;

[0458] (iv) croscarmellose sodium in an amount of from about 1 to about 5%; and

[0459] (v) magnesium stearate in an amount of from about 0.5 to about 3%.

[0460] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0461] (i) about 5 to about 25% of a pharmaceutically effective amount of a compound of Formula (lb)

[0462] or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0463] (ii) mannitol in an amount of from about 35 to about 45%;

[0464] (iii) microcrystalline cellulose in an amount of from about 35 to about 45%;

[0465] (iv) croscarmellose sodium in an amount of from about 1 to about 5%; and

[0466] (v) magnesium stearate in an amount of from about 0.5 to about 3%.

[0467] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0468] (i) about 25 to about 35% of a pharmaceutically effective amount of a compound of Formula

[0469] (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0470] (ii) mannitol in an amount of from about 30 to about 40%;

[0471] (iii) microcrystalline cellulose in an amount of from about 25 to about 35%;

[0472] (iv) croscarmellose sodium in an amount of from about 1 to about 5%; and

[0473] (v) magnesium stearate in an amount of from about 0.5 to about 3%.

[0474] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0475] (i) about 25 to about 35% of a pharmaceutically effective amount of a compound of Formula (lb)

[0476] or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0477] (ii) mannitol in an amount of from about 30 to about 40%;

[0478] (iii) microcrystalline cellulose in an amount of from about 25 to about 35%;

[0479] (iv) croscarmellose sodium in an amount of from about 1 to about 5%; and

[0480] (v) magnesium stearate in an amount of from about 0.5 to about 3%.

[0481] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0482] (i) about 20 to about 35% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0483] (ii) mannitol in an amount of from about 30 to about 40%;

[0484] (iii) microcrystalline cellulose in an amount of from about 25 to about 35%;

[0485] (iv) croscarmellose sodium in an amount of from about 1 to about 10%; and

[0486] (v) magnesium stearate in an amount of from about 0.5 to about 3%.

[0487] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0488] (i) about 12.5% to about 17.5% of a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0489] (ii) mannitol in an amount of from about 40 to about 45%;

[0490] (iii) microcrystalline cellulose in an amount of from about 35 to about 40%;

[0491] (iv) croscarmellose sodium in an amount of from about 3 to about 5%; and

[0492] (v) magnesium stearate in an amount of from about 1 to about 1.5%.

[0493] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0494] (i) about 12.5% to about 17.5% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0495] (ii) mannitol in an amount of from about 40 to about 45%;

[0496] (iii) microcrystalline cellulose in an amount of from about 35 to about 40%;

[0497] (iv) croscarmellose sodium in an amount of from about 3 to about 5%; and

[0498] (v) magnesium stearate in an amount of from about 1 to about 1.5%.

[0499] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0500] (i) about 25% to about 35% of a pharmaceutically effective amount of a compound of Formula (I)

[0501] or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0502] (ii) mannitol in an amount of from about 25 to about 35%;

[0503] (iii) microcrystalline cellulose in an amount of from about 30 to about 40%;

[0504] (iv) croscarmellose sodium in an amount of from about 3 to about 5%; and

[0505] (v) magnesium stearate in an amount of from about 1 to about 1.5%.

[0506] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0507] (i) about 25% to about 35% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0508] (ii) mannitol in an amount of from about 30 to about 40%;

[0509] (iii) microcrystalline cellulose in an amount of from about 25 to about 35%;

[0510] (iv) croscarmellose sodium in an amount of from about 3 to about 5%; and

[0511] (v) magnesium stearate in an amount of from about 1 to about 2%.

[0512] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0513] (i) about 15 wt% of a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0514] (ii) about 40 to about 45% of a first filler;

[0515] (iii) about 35 to about 40% of a second filler;

[0516] (iv) about 3 to about 5% of a disintegrant; and

[0517] (v) about 1 to about 1.5% of a lubricant.

[0518] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0519] (i) about 15 wt% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0520] (ii) about 40 to about 45% of a first filler;

[0521] (iii) about 35 to about 40% of a second filler;

[0522] (iv) about 3 to about 5% of a disintegrant; and

[0523] (v) about 1 to about 1.5% of a lubricant.

[0524] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0525] (i) about 30 wt% of a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0526] (ii) about 30 to about 40% of a first filler;

[0527] (iii) about 25 to about 35% of a second filler;

[0528] (iv) about 3 to about 5% of a disintegrant; and

[0529] (v) about 1 to about 2% of a lubricant.

[0530] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0531] (i) about 30 wt% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0532] (ii) about 30 to about 40% of a first filler;

[0533] (iii) about 25 to about 35% of a second filler;

[0534] (iv) about 1 to about 10% of a disintegrant; and

[0535] (v) about 1 to about 2% of a lubricant.

[0536] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0537] (i) about 25 wt% or about 20 wt% of a pharmaceutically effective amount of a compound of Formula (lb) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0538] (ii) about 30 to about 40% of a first filler;

[0539] (iii) about 25 to about 35% of a second filler;

[0540] (iv) about 3 to about 5% of a disintegrant; and

[0541] (v) about 1 to about 2% of a lubricant.

[0542] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0543] (i) about 15 wt% of a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0544] (ii) mannitol in an amount of from about 42.75%;

[0545] (iii) microcrystalline cellulose in an amount of from about 37%;

[0546] (iv) croscarmellose sodium in an amount of from about 4%; and

[0547] (v) magnesium stearate in an amount of from about 1.25%.

[0548] In an embodiment, the pharmaceutical composition comprises the following components on a weight percentage basis, based on the total weight of the composition

[0549] (i) about 15 wt% of a pharmaceutically effective amount of a compound of Formula (lb)

[0550] or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0551] (ii) mannitol in an amount of from about 42.75%;

[0552] (iii) microcrystalline cellulose in an amount of from about 37%;

[0553] (iv) croscarmellose sodium in an amount of from about 4%; and

[0554] (v) magnesium stearate in an amount of from about 1.25%.

[0555] Exemplary pharmaceutical compositions include those described herein.

[0556] In one embodiment, an exemplary pharmaceutical composition comprises about 15 wt% of the compound of Formula (I), about 42.75 wt% of mannitol, about 37 wt% of microcrystalline cellulose, and about 4 wt% of croscarmellose sodium based on the total weight of the composition.

[0557] In one embodiment, an exemplary pharmaceutical composition comprises about 30 wt% of the compound of Formula (I), about 34.5 wt% of mannitol, about 30 wt% of microcrystalline cellulose, and about 4 wt% of croscarmellose sodium based on the total weight of the composition.

[0558] In one embodiment, an exemplary pharmaceutical composition comprises about 15 wt% of the compound of Formula (I), about 42.75 wt% of mannitol, about 37 wt% of microcrystalline cellulose, about 4 wt% of croscarmellose sodium, and about 1.25 wt% of magnesium stearate based on the total weight of the composition.

[0559] In one embodiment, an exemplary pharmaceutical composition comprises about 30 wt% of the compound of Formula (I), about 34.5 wt% of mannitol, about 30 wt% of microcrystalline cellulose, about 4 wt% of croscarmellose sodium, and about 1.5 wt% of magnesium stearate based on the total weight of the composition.

[0560] In one embodiment, an exemplary pharmaceutical composition comprises camlipixant in an amount of from about 1.5 wt% to about 30 wt%, the first filler in an amount of from about 30 wt% to about 50 wt%, the second filler in an amount of about 30 wt% to about 50 wt%; and the disintegrant in an amount of about 0.1 wt% to about 10 wt% based on the total weight of the composition. In one embodiment, an exemplary pharmaceutical composition comprises camlipixant in an amount of from about 1.5 wt% to about 30 wt%, the first filler in an amount of from about 30 wt% to about 50 wt%, the second filler in an amount of about 30 wt% to about 50 wt%, the disintegrant in an amount of about 0.1 wt% to about 10 wt% and the lubricant in an amount of about 0.1 wt% to about 5 wt% based on the total weight of the composition.

[0561] In one embodiment, an exemplary pharmaceutical composition comprises camlipixant in an amount of from about 12.5 wt% to about 17.5 wt%, mannitol in an amount of from about 40 wt% to about 45 wt%, microcrystalline cellulose in an amount of from about 35 wt% to about 40 wt% and croscarmellose sodium in an amount of from about 3 wt% to about 5 wt% based on the total weight of the composition.

[0562] In one embodiment, an exemplary pharmaceutical composition comprises camlipixant in an amount of from about 20 wt% to about 35 wt%, mannitol in an amount of from about 30 wt% to about 40 wt%, microcrystalline cellulose in an amount of from about 25 wt% to about 35 wt% and croscarmellose sodium in an amount of from about 1 wt% to about 10 wt% based on the total weight of the composition.

[0563] In one embodiment, an exemplary pharmaceutical composition comprises camlipixant in an amount of from about 25 wt% to about 35 wt%, mannitol in an amount of from about 30 wt% to about 40 wt%, microcrystalline cellulose in an amount of from about 25 wt% to about 35 wt% and croscarmellose sodium in an amount of from about 3 wt% to about 5 wt% based on the total weight of the composition.

[0564] In one embodiment, an exemplary pharmaceutical composition comprises camlipixant in an amount of from about 12.5 wt% to about 17.5 wt%, mannitol in an amount of from about 40 wt% to about 45 wt%, microcrystalline cellulose in an amount of from about 35 wt% to about 40 wt%, croscarmellose sodium in an amount of from about 3 wt% to about 5 wt%, and magnesium stearate in an amount of from about 1 wt% to about 1 .5 wt% based on the total weight of the composition.

[0565] In one embodiment, an exemplary pharmaceutical composition comprises about 15 wt% of camlipixant, about 42.75 wt% of mannitol, about 37 wt% of microcrystalline cellulose, and about 4 wt% of croscarmellose sodium based on the total weight of the composition based on the total weight of the composition.

[0566] In one embodiment, an exemplary pharmaceutical composition comprises about 30 wt% of camlipixant, about 34.5 wt% of mannitol, about 30 wt% of microcrystalline cellulose, and about 4 wt% of croscarmellose sodium based on the total weight of the composition based on the total weight of the composition. In one embodiment, an exemplary pharmaceutical composition comprises about 15 wt% of camlipixant, about 42.75 wt% of mannitol, about 37 wt% of microcrystalline cellulose, about 4 wt% of croscarmellose sodium, and about 1.25 wt% of magnesium stearate based on the total weight of the composition based on the total weight of the composition.

[0567] In one embodiment, an exemplary pharmaceutical composition comprises about 30 wt% of camlipixant, about 34.5 wt% of mannitol, about 30 wt% of microcrystalline cellulose, about 4 wt% of croscarmellose sodium, and about 1 .5 wt% of magnesium stearate based on the total weight of the composition.

[0568] In one embodiment, an exemplary pharmaceutical composition comprises camlipixant, mannitol in an amount of from about 30 wt% to about 40 wt%, microcrystalline cellulose in an amount of from about 25 wt% to about 35 wt% and croscarmellose sodium in an amount of from about 1 wt% to about 10 wt% based on the total weight of the composition.

[0569] In one embodiment, an exemplary pharmaceutical composition comprises camlipixant, mannitol in an amount of from about 30 wt% to about 40 wt%, microcrystalline cellulose in an amount of from about 25 wt% to about 35 wt%, croscarmellose sodium in an amount of from about 1 wt% to about 10 wt%, and magnesium stearate in an amount of about 1 wt% to about 5 wt% based on the total weight of the composition.

[0570] In one embodiment, an exemplary pharmaceutical composition comprises camlipixant, a first filler in an amount of from about 30 wt% to about 40 wt%, a second filler in an amount of from about 25 wt% to about 35 wt% and a disintegrant in an amount of from about 1 wt% to about 10 wt% based on the total weight of the composition.

[0571] In one embodiment, an exemplary pharmaceutical composition comprises camlipixant, a first filler in an amount of from about 30 wt% to about 40 wt%, a second filler in an amount of from about 25 wt% to about 35 wt%, a disintegrant in an amount of from about 1 wt% to about 10 wt%, and a lubricant in an amount of about 1 wt% to about 5 wt% based on the total weight of the composition.

[0572] In a particular embodiment, the pharmaceutical composition comprises about 25 mg of camlipixant. In another particular embodiment, the pharmaceutical composition comprises about 50 mg of camlipixant.

[0573] In a particular embodiment, the pharmaceutical composition comprises about 100 mg of camlipixant. In a particular embodiment, the pharmaceutical composition comprises 25 mg of camlipixant. In another particular embodiment, the pharmaceutical composition comprises 50 mg of camlipixant.

[0574] In one embodiment, an exemplary pharmaceutical composition comprises about 25 mg of camlipixant, about 71.15 mg of mannitol, about 61.61 mg of microcrystalline cellulose, about 6.66 mg of croscarmellose sodium, and about 2.08 mg of magnesium stearate.

[0575] In one embodiment, an exemplary pharmaceutical composition comprises about 50 mg of camlipixant, about 142.31 mg of mannitol, about 123.21 mg of microcrystalline cellulose, about 13.32 mg of croscarmellose sodium, and about 4.16 mg of magnesium stearate.

[0576] In one embodiment, an exemplary pharmaceutical composition comprises about 100 mg of camlipixant, about 114.8 mg of mannitol, about 99.9 mg of microcrystalline cellulose, about 13.32 mg of croscarmellose sodium, and about 4.99 mg of magnesium stearate.

[0577] In one embodiment, the pharmaceutical composition according to the invention is stable for 18 months at 25°C ± 2°C 160%RH ±5%RH or at 30°C ± 2°C / 75%RH ±5%RH.

[0578] In one embodiment, the pharmaceutical composition according to the invention is stable for 6 months at 40°C ± 2°C 175%RH ±5%RH.

[0579] Dosage Forms

[0580] In an embodiment, the pharmaceutical composition is suitable for administration to a subject by oral administration

[0581] Moreover, the pharmaceutical compositions described herein, which include the compound of Formula (I) can be formulated into any suitable dosage form, including but not limited to, solid oral dosage forms, fast melt formulations, effervescent formulations, tablets, powders, pills, capsules, multiparticulate formulations, and mixed immediate release. In an embodiment, the pharmaceutical composition as described herein is in a solid dosage form.

[0582] In some embodiments, the solid dosage forms disclosed herein may be in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapiddisintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol. In other embodiments, the pharmaceutical composition is in the form of a powder. In an embodiment, the pharmaceutical composition is in the form of a tablet.

[0583] In an embodiment, the pharmaceutical composition is in the form of an immediate release tablet.

[0584] As used herein, the term “immediate release” is a term well understood by those of skill in the art and is generally intended to refer to a dosage form (for example, a tablet), which releases active agent substantially immediately upon contact with gastric juices and will result in substantially complete dissolution within about one hour.

[0585] In an embodiment, the pharmaceutical composition is an immediate release composition and releases the compound of Formula (I) substantially in the stomach following oral administration.

[0586] In some embodiments, the tablet is prepared from direct compression using suitable punches or dies. In some embodiments, the tablet is prepared from injection or compression molding using suitable molds fitted to a compression unit. In some embodiments, the tablet is prepared from granulation, such as but not limited to fluid bed or high shear granulation or roller compaction, followed by compression. In some embodiments, the tablet is prepared from extrusion of a paste into a mold or to an extrudate to be cut into lengths.

[0587] In some embodiments, the tablet is a solid tablet. In some embodiments, the tablet has a core and a coating.

[0588] In some embodiments, the pharmaceutical composition according to the invention is in the form of a tablet. In some embodiments, the pharmaceutical composition comprises a tablet core. In some embodiments, the pharmaceutical composition according to the invention is a tablet core, which may be coated with a coating.

[0589] In some embodiments, the tablet is formed using preservatives, colouring and opacifying agents, flavourings and sweeteners, sugars, gastroresistant substances, or combinations thereof.

[0590] In some embodiments, the tablet is coated with a coating.

[0591] In some embodiments, the coating covering the tablet includes, but is not limited to, immediate release coatings, protective coatings, barrier coatings, seal coatings, or combinations thereof.

[0592] Some advantages of tablet coatings are taste masking, odour masking, physical and chemical protection. For dosage forms that include coatings, such as film coated tablets, weight by weight percentages (wt%) of the compound of Formula (I) or excipients in the composition as used herein refer to the weight based on the total weight of the core (e.g., tablet core) and exclude any weight of the exterior coatings.

[0593] The wt% amount of coating is calculated based on the total weight of the tablet core. As an example, if the total weight of the tablet core is 166.5 mg, and a 3 wt% amount of coating is required, this means that the coating will amount to 5 mg. As a further example, if the total weight of the tablet core is 333 mg, and a 3 wt% amount of coating is required, this means the coating will amount to 10 mg.

[0594] In some embodiments, the coating is present in an amount of from about 0.1 wt% to about 10 wt%. In some embodiments, the coating is present in an amount of from about 0.1 wt% to about 5 wt%. In some embodiments, the coating is present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.5 wt%, about 2 wt%, about

[0595] 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about

[0596] 3.5 wt%, about 4 wt%, about 4.5 wt%, or about 5 wt%. In some embodiments, the coating is present in an amount of from about 2.5 wt% to about 3.5 wt%. In some embodiments, the coating is present in an amount of about 3 wt%.

[0597] In some embodiments, the tablet is coated with a film coating.

[0598] In some embodiments, the film coating comprises a polymer, pigment, plasticizer, flavour, surfactant, adhesion enhancer, vehicle(s) and any combination thereof. In some embodiments, the film coating comprises a polymer, pigment, and a plasticizer.

[0599] In some embodiments, the film coating comprises a dispersion prepared using different solvents such as water, alcohols, ketones, esters, chlorinated hydrocarbons and any combination thereof. In some embodiments, the dispersion comprises water and alcohols. In some embodiments, the dispersion comprises water.

[0600] In some embodiments, the film coating comprises, OPADRY, OPADRY II, OPADRY QX, OPADRY SGR, OPADRY AMB, OPADRY fx, OPADRY ns-g, OPADRY NS, OPADRY tm, OPALLIX, OPADRY EZ and any combination thereof.

[0601] In some embodiments, the film coating comprises OPADRY II.

[0602] In some embodiments, the film coating is present in an amount of from about 0.1 wt% to about 10 wt%. In some embodiments, the film coating is present in an amount of from about 0.1 wt% to about 5 wt%. In some embodiments, the film coating is present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt%, or about 5 wt%. In some embodiments, the film coating is present in an amount of from about 2.5 wt% to about 3.5 wt%. In some embodiments, the film coating is present in an amount of about 3 wt%.

[0603] In some embodiments, the coating is OPADRY II and is present in an amount of from about 0.1 wt% to about 10 wt%. In some embodiments, the OPADRY II is present in an amount of from about 0.1 wt% to about 5 wt%. In some embodiments, the OPADRY II is present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1 .5 wt%, about 2 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt%, or about 5 wt%. In some embodiments, the OPADRY II is present in an amount of from about 2.5 wt% to about 3.5 wt%. In some embodiments, the OPADRY II is present in an amount of about 3 wt%. In some embodiments, the OPADRY II is present in an amount of about 3 wt%.

[0604] In an embodiment, in an exemplary coated tablet, the tablet core comprises about 15 wt% of a compound of Formula (I), about 42.75 wt% of mannitol, about 37 wt% of microcrystalline cellulose, about 4 wt% of croscarmellose sodium, about 1.25 wt% of magnesium stearate based on the total weight of the composition (e.g., the tablet core), and about 3 wt% of OPADRY II calculated based on the total weight of the tablet core.

[0605] In an embodiment, in an exemplary coated tablet, the tablet core comprises about 15 wt% of camlipixant, about 42.75 wt% of mannitol, about 37 wt% of microcrystalline cellulose, about 4 wt% of croscarmellose sodium, about 1.25 wt% of magnesium stearate based on the total weight of the composition (e.g., the tablet core), and about 3 wt% of OPADRY II calculated based on the total weight of the tablet core.

[0606] In an embodiment, in an exemplary coated tablet, the tablet core comprises about 30 wt% of a compound of Formula (I), about 34.5 wt% of mannitol, about 30 wt% of microcrystalline cellulose, about 4 wt% of croscarmellose sodium, about 1.5 wt% of magnesium stearate based on the total weight of the composition (e.g., the tablet core), and about 3 wt% of OPADRY II calculated based on the total weight of the tablet core.

[0607] In an embodiment, in an exemplary coated tablet, the tablet core comprises about 30 wt% of camlipixant, about 34.5 wt% of mannitol, about 30 wt% of microcrystalline cellulose, about 4 wt% of croscarmellose sodium, about 1.5 wt% of magnesium stearate based on the total weight of the composition (e.g., the tablet core), and about 3 wt% of OPADRY II calculated based on the total weight of the tablet core.

[0608] Advantageously, film coated tablets showed good weight and colour uniformity, physico- mechanical properties and rapid disintegration.

[0609] It has also advantageously been found that the oral dosage forms disclosed herein improve the manufacturability of the form by reducing the stickiness / adherence of the active pharmaceutical ingredient during the tablet manufacturing process.

[0610] In accordance with an embodiment of the disclosure, a tablet can comprise the composition of any of the foregoing embodiments or embodiments disclosed herein. In accordance with other embodiments of the disclosure, the tablet can consist of the composition of any of the foregoing embodiments or embodiments disclosed herein.

[0611] Manufacture

[0612] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with a compound according to Formula (I), in particular camlipixant, optionally compressing and milling the resulting mixture into granules, and processing the mixture of granules to obtain tablets.

[0613] In another aspect, the present invention provides a process for the preparation of a pharmaceutical composition (e.g., pharmaceutical compositions formulated as a tablet). In embodiments, a process described herein can be used to prepare a composition described herein (e.g., any of the tablet compositions described herein).

[0614] In some embodiments, dry granulation is used to prepare the formulations disclosed herein.

[0615] In an embodiment, dry granulation is carried out using roller compaction.

[0616] It has been found that the use of dry granulation, in particular roller compaction, results in blends having higher bulk densities and satisfactory flow properties necessary for tablet compression. Blends prepared by roller compaction produced tablets having good physical and mechanical properties. Wet granulation processes may be problematic and lead to changes in the drug substance crystal structure as a result of solubilisation and subsequent recrystallisation in the water added as granulation fluid. Dry granulation, in particular roller compaction, was shown to avoid these potential concerns.

[0617] Provided herein in one aspect is a process for the preparation of a pharmaceutical composition according to the invention (e.g., a pharmaceutical composition in the form of a tablet) comprising a compound of Formula (I) comprising: i) combining a compound of Formula (I), at least one filler, a lubricant, and a disintegrant to form a composition; ii) dry granulation of the composition comprising a compound of Formula (I), at least one filler, a lubricant, and a disintegrant to form granules; iii) combining the granules with further lubricant; and

[0618] (iv) forming a tablet by compression of the mixture obtained from step iii); and optionally

[0619] (v) coating the tablet formed in step (iv) with a coating.

[0620] In an embodiment, is a process for the preparation of a pharmaceutical composition (e.g., a pharmaceutical composition in the form of a tablet) comprising a compound of Formula (I), the process comprising: i) combining a compound of Formula (I), mannitol, magnesium stearate, croscarmellose sodium, and microcrystalline cellulose to form a composition; and ii) dry granulation of the composition comprising a compound of Formula (I), mannitol, magnesium stearate, croscarmellose sodium, and microcrystalline cellulose to form granules; iii) combining the granules with further magnesium stearate; and

[0621] (iv) forming a tablet by compression of the mixture obtained from step iii); and optionally

[0622] (v) coating the tablet formed in step (iv) with a coating.

[0623] In an embodiment, step (ii) optionally comprises a milling step following the dry granulation before addition of further lubricant in step (iv).

[0624] It was found that powder blends obtained by dry granulation using roller compaction produced higher bulk densities, when compared to direct compression, with satisfactory flow properties required for tablet compression.

[0625] In an embodiment, dry granulation comprises roller compaction.

[0626] In an embodiment, dry granulation comprises milling.

[0627] In an embodiment, dry granulation comprises roller compaction and milling.

[0628] It was further found that premixing excipients at certain stages can aid in ensuring good distribution of the components. Therefore, in an embodiment, in step (i) the composition comprising a compound of Formula (I), at least one filler, and disintegrant is blended prior to addition of lubricant. In an embodiment, in step (i) the composition comprising camlipixant, mannitol, croscarmellose sodium, and microcrystalline cellulose is blended prior to addition of magnesium stearate.

[0629] Figure 1 illustrates an exemplary manufacturing process. Intragranular ingredients (the compound of Formula (I), disintegrant, and filler(s)) are first pre-blended and passed through a screen for the purposes of sizing / de-agglomeration, followed by further mixing in a blender. The blend is then lubricated, and roller compacted. The resulting ribbons are milled into granules. An additional amount of extra-granular lubricant is added, and the final lubricated blend compacted on a tablet press. Finally, the compressed tablets are film coated to achieve the desired weight.

[0630] Purity

[0631] In another aspect, the present invention provides a pharmaceutical composition comprising,

[0632] (a) a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0633] (b) at least one filler; and

[0634] (c) a disintegrant, wherein the composition comprises less than about 0.2 wt% of any single degradation product.

[0635] In an embodiment, the present invention provides a pharmaceutical composition comprising,

[0636] (a) a pharmaceutically effective amount of a compound of Formula (l-b)

[0637] (l-b) or a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0638] (b) at least one filler; and

[0639] (c) a disintegrant, wherein the composition comprises less than about 0.2 wt% of any single degradation product.

[0640] In some embodiments, the pharmaceutical composition comprises less than about 0.2 wt%, 0.1 wt%, 0.09 wt%, 0.08 wt%, 0.07 wt%, or 0.06 wt% of any single degradation product. In some embodiments, the tablet comprises less than about 0.06 wt% of any single degradation product.

[0641] In embodiments, the pharmaceutical composition comprises less than about 0.2 wt% of any single degradation product. In embodiments, the pharmaceutical composition comprises less than about 0.2 wt% of any single degradation product after storage for about 1 month at about 25° C and about 60% relative humidity (RH). In embodiments, the pharmaceutical composition comprises less than about 0.2 wt% of any single degradation product after storage for about 2 months at about 25° C and about 60% relative humidity (RH).

[0642] In embodiments, the pharmaceutical composition comprises less than about 0.2 wt% of any single degradation product. In embodiments, the tablet comprises less than about 0.2 wt% of any single degradation product after storage for about 1 month at about 30 °C and about 75% relative humidity (RH). In embodiments, the pharmaceutical composition comprises less than about 0.2 wt% of any single degradation product after storage for about 2 months at about 30° C and about 75% relative humidity (RH).

[0643] In embodiments, the pharmaceutical composition comprises less than about 0.2 wt% of any single degradation product. In embodiments, the pharmaceutical composition comprises less than about 0.2 wt% of any single degradation product after storage for about 1 month at about 40° C and about 75% relative humidity (RH). In embodiments, the pharmaceutical composition comprises less than about 0.2 wt% of any single degradation product after storage for about 2 months at about 40° C and about 75% relative humidity (RH). Impurities or degradation products resulting from a chemical change in the drug substance brought about during manufacture and / or storage of the drug product by the effect of light, temperature, moisture or by reaction with an excipient are specifically quantitatively determined using techniques and equipment available and known to those having ordinary skill in the art. Exemplary methods include chromatographic methods such as high performance liquid chromatography (HPLC) (e.g., chiral chromatography, ion- exchange chromatography, ion-pair / affinity chromatography, reversed phase chromatography, and size-exclusion chromatography); gas chromatography (GC); and thin-layer chromatography (TLC). For example, a suitable method can be a validated, stability indicating gradient reverse-phased HPLC method with UV detection and using an external standard method. Mass spectrometry (MS) can be used alone or in tandem with chromatographic methods (e.g., HPLC-MS or GC-MS). Spectrophotometry (e.g., UV-Vis 10 spectrophotometry) can also be used. The impurity levels in the drug product are reported and controlled per the requirements of International Conference on Harmonization (ICH) Q3B guidelines.

[0644] Methods

[0645] In some embodiments, described herein is a method for treating a disorder associated with P2X3 activity in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition described herein.

[0646] In some embodiments, described herein is a method for treating cough in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments is a method for treating cough in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition described herein, wherein the cough is chronic cough. In some embodiments is a method for treating cough in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition described herein, wherein the cough is refractory chronic cough. In some embodiments is a method for treating cough in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition described herein, wherein the cough is an acute cough.

[0647] In another aspect the present invention provides the use of a pharmaceutical composition as described herein in the manufacture of a medicament for use in the treatment of cough. In some embodiments, described herein is the use of the pharmaceutical composition as defined herein in the manufacture of a medicament for use in the treatment of chronic cough. In some embodiments, described herein is the use of the pharmaceutical composition as defined herein in the manufacture of a medicament for use in the treatment of acute cough. In some embodiments, described herein is the use of the pharmaceutical composition as defined herein in the manufacture of a medicament for use in the treatment of refractory chronic cough.

[0648] In an embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof; at least one filler; and a disintegrant, for use in the treatment of refractory chronic cough, wherein the pharmaceutical composition is administered orally to a patient in need thereof and wherein the composition is immediate release and releases the compound according to Formula (I) substantially in the stomach following oral administration.

[0649] EXAMPLES

[0650] Tablets having the following compositions were tested for stability.

[0651] Table 1

[0652] A study was performed to evaluate the stability of camlipixant film coated tablets having 50 mg drug product, over a period when stored in a bottle at 25 °C / 60% relative humidity (RH), 30 °C / 75% RH and 40 °C / 75% RH. An overview of the stability results is outlined in Figures 2, 3, and 4.

[0653] A study was also performed to evaluate the stability of camlipixant film coated tablets having 25 mg drug product, over a period when stored in a blister pack at 25 °C / 60% relative humidity (RH), 30 °C / 75% RH and 40 °C / 75% RH. An overview of the stability results is outlined in Figure 5, 6, and 7.

[0654] A study was also performed to evaluate the stability of camlipixant film coated tablets having 50 mg drug product, over a period when stored in a blister pack at 25 °C / 60% relative humidity (RH), 30 °C / 75% RH and 40 °C / 75% RH. An overview of the stability results is outlined in Figure 8, 9, and 10.

[0655] Camlipixant film-coated tablets having the following composition comprising a 30% drug loading were also tested for stability.

[0656] Table 2

[0657] A study was performed to evaluate the stability of camlipixant film coated tablets having 100 mg drug product according to Formulation C, over a period when stored in a bottle at 25 °C / 60% relative humidity (RH) and 40 °C / 75% RH. An overview of the stability results is outlined in Figure 11 and 12. On the basis of the above examples, it has been shown that a pharmaceutical composition according to the present invention is stable under both ambient storage conditions for at least 18 months and elevated conditions for at least six months.

[0658] It was found that the level of lubricant in each of the exemplified compositions was sufficient to avoid sticking and picking during tablet manufacture. For each of Formulations A, B and C described herein, complete release of camlipixant is achieved (> 85% release after 30 minutes) from tablets using USP dissolution apparatus in the physiologically relevant media 0.1 N HCI (pH 1.2). The results are illustrated in Figure 13.

Claims

1. CLAIMS1. A pharmaceutical composition comprising, a) a pharmaceutically effective amount of a compound of Formula (I)or a tautomer thereof, or a pharmaceutically acceptable salt thereof; b) at least one filler; and c) a disintegrant.

2. The pharmaceutical composition of claim 1 , further comprising a lubricant.

3. The pharmaceutical composition of claim 2, wherein the lubricant is present in an amount of from about 0.1 to about 5 wt% based on the total weight of the composition.

4. The pharmaceutical composition of claim 2 or claim 3, wherein the lubricant is present in an amount of from about 1 to about 1.5 wt% based on the total weight of the composition.

5. The pharmaceutical composition of any one of claims 2 to 4, wherein the lubricant is present in an amount of from about 1.25 wt% based on the total weight of the composition.

6. The pharmaceutical composition of any one of claims 2 to 5, wherein the lubricant is magnesium stearate.

7. The pharmaceutical composition of any one of the preceding claims, wherein the disintegrant is croscarmellose.

8. The pharmaceutical composition of any one of the preceding claims, wherein the disintegrant is croscarmellose sodium.

9. The pharmaceutical composition of any one of the preceding claims, wherein the disintegrant is present in an amount of from about 0.1 wt% to about 10 wt% based on the total weight of the composition.

10. The pharmaceutical composition of any one of the preceding claims, wherein disintegrant is present in an amount of about 4 wt% based on the total weight of the composition.

11. The pharmaceutical composition of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (l-b)(l-b)12. The pharmaceutical composition of any one of the preceding claims, wherein the compound of Formula (I) or Formula (lb) is present in an amount of from about 10 wt% to about 20 wt% based on the total weight of the composition, or about 15 wt% based on the total weight of the composition.

13. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition comprises a first filler and a second filler.

14. The pharmaceutical composition of claim 13, wherein the first filler is mannitol.

15. The pharmaceutical composition of claim 13 or claim 14, wherein the first filler is present in an amount of from about 30 to about 50 wt% based on the total weight of the composition.

16. The pharmaceutical composition of any one of claims 13 to 15, wherein the first filler is present in an amount of about 42.75 wt% based on the total weight of the composition.

17. The pharmaceutical composition of any one of claims 13 to 16, wherein the second filler is microcrystalline cellulose.

18. The pharmaceutical composition of any one of claims 13 to 17, wherein the second filler is present in an amount of from about 30 to about 50 wt% based on the total weight of the composition.

19. The pharmaceutical composition of any one of claims 13 to 18, wherein the second filler is present in an amount of about 37 wt% based on the total weight of the composition.

20. The pharmaceutical composition of any one of claims 1 to 11 , claims 13 to 15 and claims 17 to 18, wherein the compound of Formula (I) or Formula (lb) is present in an amount of from about 20 wt% to about 35 wt% based on the total weight of the composition, or from about 25 wt% to about 35 wt% based on the total weight of the composition.

21. The pharmaceutical composition of claim 20, wherein the first filler is present in an amount of from about 30 wt% to about 40 wt% based on the total weight of the composition.

22. The pharmaceutical composition of claim 20 or 21 , wherein the second filler is present in an amount of from about 25 wt% to about 35 wt% based on the total weight of the composition.

23. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is suitable for administration to a subject by oral administration.

24. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is in the form of a tablet.

25. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is a tablet core.

26. The pharmaceutical composition of claim 25, wherein the tablet core is coated with a coating.

27. The pharmaceutical composition of claim 26, wherein the coating is a film coating comprising OPADRY II, optionally wherein the OPADRY II is present in an amount of about 3 wt% calculated based on the total weight of the tablet core.

28. The pharmaceutical composition of any one of claims 1 to 27, wherein the composition is stable for 18 months at 25°C ± 2°C I 60%RH ±5%RH or at 30°C ± 2°C / 75%RH ±5%RH.

29. The pharmaceutical composition of any one of claims 1 to 27, wherein the composition is stable for 6 months at 40°C ± 2°C / 75%RH ±5%RH.

30. The pharmaceutical composition of any one of claims 1 to 29, wherein the composition is an immediate release composition.

31. A method for the treatment of cough in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of any one of claims 1 to 30.

32. The method of claim 31 , wherein the cough is an acute cough or a chronic cough.

33. The method of claim 31 or claim 33, wherein the cough is refractory chronic cough.

34. The method of any one of claims 31 to 33, wherein the subject is a human.

35. The pharmaceutical composition according to any one of claims 1 to 30, for use in therapy.

36. Use of a pharmaceutical composition as defined in any one of claims 1 to 30, in the manufacture of a medicament for use in the treatment of cough.

37. The use of a pharmaceutical composition according to claim 36, wherein the cough is an acute cough or a chronic cough.

38. The use of a pharmaceutical composition according to claim 37, wherein the cough is refractory chronic cough.

Images