Pharmaceutical composition

Abstract

This specification relates to a pharmaceutical composition, for example, a tablet having immediate-release properties, comprising compound [I], ((S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)piperidine-4-carboxamide), microcrystalline cellulose (MCC), and anhydrous dicalcium phosphate (DCPA). [Formula 1] JPEG2026518000000019.jpg45128

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to European Patent Application No. 23175788.1, filed on 26 May 2023, the disclosure thereof being incorporated in its entirety by reference.

[0002] (Field of invention) This specification relates to a pharmaceutical composition comprising (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)piperidine-4-carboxamide (compound[I]), a selective AKT inhibitor, or a pharmaceutically acceptable salt thereof, and certain pharmaceutically acceptable excipients. Compound[I] is also known as capivacertib and AZD5363, and is disclosed as Example 9 in International Publication No. 2009 / 047563.

[0003] [ka]

[0004] This specification further relates to oral solid dosage forms, such as tablets, comprising compound [I] or a pharmaceutically acceptable salt thereof, and certain pharmaceutically acceptable excipients. The pharmaceutical compositions and oral solid dosage forms according to this specification have advantageous properties that facilitate large-scale manufacturing, as well as good storage stability and other useful features. This facilitates their use in therapeutic methods, such as methods for treating cancer. [Background technology]

[0005] AKT is part of the cAMP-dependent protein kinase A, cGMP-dependent protein kinase G, and phospholipid-dependent protein kinase C (AGC) families. Mammalian cells express three closely related AKT isoforms: AKT1 (protein kinase Bα [PKBα]), AKT2 (PKBβ), and AKT3 (PKBγ), all encoded by different genes. AKT is a node in multiple signaling pathways that promote tumorigenesis, inhibit apoptosis, influence the cell cycle, and promote invasion and migration. The phosphoinositide 3-kinase / protein kinase / phosphatase and tensin homolog (PI3K / AKT / PTEN) pathways regulate cell growth, proliferation, and survival (Brown JS, Banerji U. Pharmacol THER 2017;172:101-15) and are frequently deregulated in cancer.

[0006] Capivacertib (compound [I]) is a potent, selective inhibitor of the kinase activity of all three AKT isoforms. It is being developed as a potential treatment for solid and hematological malignancies (see clinical trials for capivacertib, AZD5363, and / or (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)piperidine-4-carboxamide on clinicaltrials.gov [e.g., clinical trials NCT03997123, NCT04305496, NCT04862663, NCT05348577, or NCT04493853], nih.gov, clinicaltrialsregister.eu, or similar public clinical trial repositories).

[0007] The high drug load required to achieve the necessary dose of capivacertib in tablets of globally acceptable size and shape necessitates careful formulation to counteract the exceptional aggregation and adhesive properties of the drug substance (see Example 4). The "stickiness" of the active pharmaceutical ingredient distinguishes it from other drug substances, meaning that known formulations may be difficult to apply to capivacertib, and that new formulations suitable for therapeutic and commercial manufacture are needed.

[0008] To address this need, this specification discloses pharmaceutical compositions of capivacertib comprising a combination of microcrystalline cellulose (MCC) and anhydrous dicalcium phosphate (DCPA, also known as anhydrous calcium hydrogen phosphate). These compositions have not only been found to be suitable for oral administration to patients (e.g., providing immediate drug release), but their physical properties (including tensile strength, strain rate sensitivity, and ability to assist deformation compression) also provide significant advantages in terms of improved tablet manufacturability, for example, with respect to powder flow into roller compactors after dry granulation, punch filming, and tablet appearance after coating (see Examples 1-6). [Overview of the Initiative]

[0009] In a first aspect, this specification provides a pharmaceutical composition comprising compound [I] or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, and anhydrous dicalcium phosphate. The pharmaceutical composition according to this specification may further comprise excipients, such as disintegrants and / or lubricants.

[0010] In a further embodiment, this specification provides an oral solid dosage form comprising compound [I] or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, and anhydrous dicalcium phosphate. The oral solid dosage form according to this embodiment may comprise further excipients, such as disintegrants or lubricants, and may be provided as capsules or tablets.

[0011] In a further embodiment, the Specified provides a method for producing tablets according to the Specified, comprising: i) blending a mixture comprising compound [I] or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, anhydrous dicalcium phosphate, and optionally a disintegrant and / or lubricant to form a blend; ii) dry granulating the blend; and iii) compressing the dry granulated blend into tablets.

[0012] In a further embodiment, this specification provides a pharmaceutical composition for use in the treatment of, for example, cancer, comprising compound [I] or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, and anhydrous dicalcium phosphate, or an oral solid dosage form comprising such a pharmaceutical composition.

[0013] In a further embodiment, this specification provides for the use of a pharmaceutical composition for the manufacture of a pharmacopoeia for use in the treatment of cancer, comprising compound [I] or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, and anhydrous dicalcium phosphate, or an oral solid dosage form comprising such a pharmaceutical composition.

[0014] In a further embodiment, the Specified provides a method for treating cancer in a patient requiring treatment for cancer, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising compound [I] or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, and anhydrous dicalcium phosphate, or an oral solid dosage form comprising such a pharmaceutical composition.

[0015] Further aspects of this disclosure will be apparent to those skilled in the art by reading this specification. [Brief explanation of the drawing]

[0016] Refer to the following diagram. [Figure 1] Disintegration times of the formulations in Examples 1e to 1h when compressed into tablets under various pressures. [Modes for carrying out the invention]

[0017] The invention described in detail herein should not be construed as being limited to any of the individually recited embodiments. Other embodiments will be readily apparent to those skilled in the art.

[0018] Throughout this specification, all weight % (w / w) are expressed relative to the total weight of the pharmaceutical composition, unless otherwise indicated.

[0019] Throughout this specification, the ratios described are weight ratios of the specific components, unless otherwise indicated.

[0020] Pharmaceutical composition As described above, this specification provides a pharmaceutical composition comprising compound [I], or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, and dicalcium phosphate anhydrous.

[0021] The compositions according to this specification have various advantageous properties that are useful in the field of medicine. For example, the good flow properties of the blend of compound [I] and specific excipients enable efficient processing for the manufacture of oral solid dosage forms, such as processing by dry granulation. Oral solid dosage forms, such as tablets formed from the compositions according to this specification, have good stability, immediate release properties, and exhibit excellent structural integrity. They also have favorable tensile strength, strain rate sensitivity, and deformation compression assist properties that provide significant advantages in terms of improved tablet manufacturability, for example, with respect to ease of roller compression, punch filming, and appearance after coating.

[0022] In one embodiment, a pharmaceutical composition is provided comprising compound [I], or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, and dicalcium phosphate anhydrous.

[0023] In an embodiment, a pharmaceutical composition is provided comprising compound [I], microcrystalline cellulose, and dicalcium phosphate anhydrous.

[0024] In embodiments, compound [I] exists as crystalline form B. Crystallized form B is disclosed in International Publication No. 2013 / 156772.

[0025] In one embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable salt of compound [I], microcrystalline cellulose, and anhydrous dicalcium phosphate.

[0026] In embodiments where the w / w% of the pharmaceutically acceptable salt of compound [I] is stated, the w / w% is calculated based on the equivalent weight of compound [I].

[0027] The term "pharmaceutically acceptable" is used to identify that a substance (e.g., a salt or excipient) is suitable for use in a patient. An exemplary list of pharmacopoeialy acceptable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use," PHStahl and CGWermuth, editors, Weinheim / Zurich: Wiley-VCH / VFiCA, 2002, or earlier / later editions.

[0028] Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Examples of inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids from which salts can be derived include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Examples of inorganic bases from which salts can be derived include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Examples of organic bases from which salts can be derived include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0029] In the embodiment, the pharmaceutical composition contains up to 65% w / w of compound [I] or a pharmaceutically acceptable salt thereof.

[0030] In the embodiment, the pharmaceutical composition contains up to 65% w / w of compound [I].

[0031] In the embodiment, the pharmaceutical composition contains 40% to 50% w / w of compound [I] or a pharmaceutically acceptable salt thereof.

[0032] In the embodiment, the pharmaceutical composition contains 40% to 50% w / w of compound [I].

[0033] In the embodiment, the pharmaceutical composition contains about 50% w / w of compound [I] or a pharmaceutically acceptable salt thereof.

[0034] In the embodiment, the pharmaceutical composition contains about 50% w / w of compound [I].

[0035] In the embodiment, the pharmaceutical composition contains 50% w / w of compound [I] or a pharmaceutically acceptable salt thereof.

[0036] In this embodiment, the pharmaceutical composition contains 50% w / w of compound [I].

[0037] In the embodiment, the pharmaceutical composition contains about 40% w / w of compound [I] or a pharmaceutically acceptable salt thereof.

[0038] In the embodiment, the pharmaceutical composition contains about 40% w / w of compound [I].

[0039] In the embodiment, the pharmaceutical composition contains 40% w / w of compound [I] or a pharmaceutically acceptable salt thereof.

[0040] In this embodiment, the pharmaceutical composition contains 40% w / w of compound [I].

[0041] In this embodiment, the pharmaceutical composition contains approximately 160 mg of compound [I].

[0042] In this embodiment, the pharmaceutical composition contains 160 mg of compound [I].

[0043] In this embodiment, the pharmaceutical composition contains approximately 200 mg of compound [I].

[0044] In this embodiment, the pharmaceutical composition contains 200 mg of compound [I].

[0045] In this embodiment, the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 45:55 to 70:30.

[0046] In this embodiment, the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 55:45 to 68:32.

[0047] In this embodiment, the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is approximately 6:4.

[0048] In this embodiment, the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 6:4.

[0049] As the examples show, these ratios of microcrystalline cellulose to anhydrous dicalcium phosphate are such that the pharmaceutical composition exhibits a) a strain rate sensitivity of less than about 20%, enabling high-speed processing, e.g., by dry granulation, and b) can be processed to deliver tablets with consistently high tensile strength (>2 MPa), among other advantages.

[0050] In the embodiment, the pharmaceutical composition contains 40% to 50% w / w of compound [I] or a pharmaceutically acceptable salt thereof, and the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 45:55 to 70:30.

[0051] In the embodiment, the pharmaceutical composition contains 40% to 50% w / w of compound [I], and the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 45:55 to 70:30.

[0052] In the embodiment, the pharmaceutical composition contains 40% to 50% w / w of compound [I] or a pharmaceutically acceptable salt thereof, and the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 55:45 to 68:32.

[0053] In the embodiment, the pharmaceutical composition contains 40% to 50% w / w of compound [I], and the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 55:45 to 68:32.

[0054] In the embodiment, the pharmaceutical composition contains about 50% w / w of compound [I] or a pharmaceutically acceptable salt thereof, and the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 55:45 to 68:32.

[0055] In the embodiment, the pharmaceutical composition contains approximately 50% w / w of compound [I], and the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 55:45 to 68:32.

[0056] In the embodiment, the pharmaceutical composition contains about 50% w / w of compound [I], and the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is about 6:4.

[0057] In the embodiment, the pharmaceutical composition contains about 40% w / w of compound [I] or a pharmaceutically acceptable salt thereof, and the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 45:55 to 70:30.

[0058] In the embodiment, the pharmaceutical composition contains about 40% w / w of compound [I], and the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 45:55 to 70:30.

[0059] In the embodiment, the pharmaceutical composition contains about 40% w / w of compound [I], and the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is about 6:4.

[0060] In this embodiment, the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate in the pharmaceutical composition is 15% w / w to 65% w / w.

[0061] In this embodiment, the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate in the pharmaceutical composition is 30% w / w to 65% w / w.

[0062] In this embodiment, the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate in the pharmaceutical composition is 40% w / w to 60% w / w.

[0063] In this embodiment, the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate in the pharmaceutical composition is 50% w / w to 60% w / w.

[0064] In this embodiment, the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate in the pharmaceutical composition is 50% w / w to 55% w / w.

[0065] In this embodiment, the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate in the pharmaceutical composition is 53-54% w / w.

[0066] In this embodiment, the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate in the pharmaceutical composition is approximately 53.5% w / w.

[0067] In the embodiment, the pharmaceutical composition further comprises at least one disintegrant in an amount of up to 10% w / w.

[0068] In the pharmaceutical compositions described herein, the use of disintegrants helps to accelerate the disintegration of the composition when it comes into contact with a fluid such as water.

[0069] In the embodiment, the pharmaceutical composition further comprises at least one disintegrant in an amount of up to 5% w / w.

[0070] In the embodiment, the pharmaceutical composition further comprises at least one disintegrant in an amount of about 5% w / w.

[0071] In the embodiment, at least one disintegrant is croscarmellose sodium.

[0072] In the embodiment, the pharmaceutical composition further comprises at least one lubricant in an amount of up to 4% w / w.

[0073] The use of lubricants in the pharmaceutical compositions according to this specification helps ensure that the manufacturing of tablets is efficient, associated with favorably low ejection force from the tableting press, and minimization of defects in the product tablets.

[0074] In the embodiment, the pharmaceutical composition further comprises at least one lubricant in an amount of up to 1.5% w / w.

[0075] In one embodiment, the pharmaceutical composition further comprises at least one lubricant in an amount of about 1.5% w / w.

[0076] In one embodiment, at least one lubricant is magnesium stearate.

[0077] In one embodiment, the pharmaceutical composition is - Compound [I] and, - Microcrystalline cellulose and anhydrous dicalcium phosphate, wherein the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is approximately 6:4. - Disintegrant, A pharmaceutical composition is provided that includes a lubricant.

[0078] In one embodiment, the pharmaceutical composition is -40%~50% w / w compound [I], and A pharmaceutical composition is provided comprising microcrystalline cellulose and anhydrous dicalcium phosphate, wherein the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is approximately 6:4, and the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate is 40% to 60% w / w.

[0079] In one embodiment, the pharmaceutical composition is - Approximately 40% w / w of compound [I], - Microcrystalline cellulose and anhydrous dicalcium phosphate, wherein the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is approximately 6:4, and the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate is 50%~55% w / w. - Croscarmellose sodium and, A pharmaceutical composition is provided that contains magnesium stearate.

[0080] In one embodiment, the pharmaceutical composition is - Approximately 40% w / w of compound [I], - Microcrystalline cellulose and anhydrous dicalcium phosphate, wherein the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is approximately 6:4, and the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate is 50%~55% w / w. -Approximately 5% w / w of croscarmellose sodium, A pharmaceutical composition is provided, comprising approximately 1.5% w / w of magnesium stearate.

[0081] In one embodiment, the pharmaceutical composition is -40% w / w compound [I], - Microcrystalline cellulose and anhydrous dicalcium phosphate, wherein the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 6:4, and the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate is 53.5% w / w. -5% w / w amount of croscarmellose sodium, A pharmaceutical composition is provided, comprising -1.5% w / w of magnesium stearate.

[0082] In one embodiment, a pharmaceutical composition selected from Examples 1a, 1b, 2, 3a-3f, 5a, and 5b is provided.

[0083] In one embodiment, any pharmaceutical composition disclosed in the Examples section is provided.

[0084] Oral solid dosage form In one embodiment, an oral solid dosage form is provided that comprises any of the pharmaceutical compositions disclosed herein.

[0085] In some embodiments, the oral solid dosage form is an immediate-release oral solid dosage form.

[0086] "Immediate release" is used in its conventional sense to refer to a dosage form that provides the release of compound [I] immediately after administration. For example, an immediate-release pharmaceutical composition means a composition in which, in a dissolution test (paddle method) as described in the United States Pharmacopeia, using 900 mL of an appropriate test solution (e.g., USP buffer, pH 6.8, or pH 7.4) and under conditions of a paddle rotation speed of 50, 75, or 100 rpm, the dissolution rate of the drug from the composition 30 minutes from the start of the dissolution test is 80% or higher.

[0087] In some embodiments, the oral solid dosage form is a capsule or a tablet.

[0088] In some embodiments, the oral solid dosage form is a capsule.

[0089] In some embodiments, the oral solid dosage form is a capsule containing the pharmaceutical composition disclosed herein.

[0090] In some embodiments, the oral solid dosage form is a tablet.

[0091] In some embodiments, the tablet includes a core and a coating that covers the core.

[0092] In some embodiments, the core comprises a pharmaceutical composition as disclosed herein.

[0093] In some embodiments, the core consists of a pharmaceutical composition as disclosed herein.

[0094] Since coatings can protect tablets from light, moisture, and oxidation, they can advantageously and further increase the shelf life of tablets. Coatings can also be used to improve the mechanical strength of tablets and to mask odors or tastes, as well as to improve the aesthetic appearance of tablets.

[0095] The polymers used in the coating may be selected from cellulosic polymers such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and ethylcellulose (EC), as seen in, for example, Opadry® I (www.colorcon.com) and Aquarius coating systems (www.ashland.com), or vinyls such as polyvinyl alcohol. Plasticizers are used to improve the elasticity of the coating film and lower the film formation temperature of the polymer, thus enabling processing at lower temperatures. Suitable plasticizers include propylene glycol or polyethylene glycol, or glycerol, triacetin (glycerol triacetate), or glycerides such as triethyl citrate (TEC), acetylated monoglycerides, as well as mineral oils and vegetable oils. Colorants and pigments are used to increase the opacity and / or light protection of the film and to provide color. Suitable colorants include indigo carmine, tartrazine, allura red, and quinoline yellow; inorganic pigments such as titanium dioxide, iron oxide, and pearlescent pigments; and natural pigments such as vegetable juice, carotenoids, and turmeric.

[0096] The coating may also incorporate further functional components, such as flow enhancers, flavoring agents, and viscosity modifiers, all of which are well known in the art. For general details regarding pharmaceutical coatings, see Aulton's Pharmaceutics, 5 th This can be found in Edition, 2018, Elsevier, at egpages 580-596.

[0097] In this embodiment, the coating is a film coating.

[0098] In this embodiment, the coating is an immediate-release film coating.

[0099] In embodiments, the coating comprises hypromellose 2910, copovidone prasdone S630, polyethylene glycol 3350, polydextrose, at least one caprylic / capric triglyceride, and optionally at least one opacifying agent (e.g., titanium dioxide), and / or at least one coloring agent (e.g., iron oxide coloring agents, e.g., red iron oxide, yellow iron oxide, or black iron oxide).

[0100] In the embodiment, the coating comprises hypromellose 2910, copovidone prasdone S630, polyethylene glycol 3350, polydextrose, at least one caprylic / capric triglyceride, titanium dioxide, yellow iron oxide, red iron oxide, and black iron oxide.

[0101] In the embodiment, the coating contains hypromellose 2910, copovidone prasdone S630, polyethylene glycol 3350, polydextrose, at least one caprylic / capric triglyceride, titanium dioxide, yellow iron oxide, red iron oxide, and black iron oxide in w / w amounts as shown in Table 14 or Table 16.

[0102] In this embodiment, the coating is Aquarius® preferred beige (BPP315509).

[0103] In one embodiment, an oral solid dosage form is a tablet comprising a core and optionally a coating on the core, wherein the core is - Compound [I] and, - Microcrystalline cellulose and anhydrous dicalcium phosphate, wherein the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is approximately 6:4. - Disintegrant, - An oral solid dosage form is provided, containing a lubricant.

[0104] In one embodiment, an oral solid dosage form is provided, which is a tablet comprising a core and optionally a coating on the core, where the core is - Compound [I] and, - Microcrystalline cellulose and anhydrous dicalcium phosphate, wherein the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is approximately 6:4. - Croscarmellose sodium and, -Contains magnesium stearate,

[0105] In one embodiment, an oral solid dosage form is a tablet comprising a core and optionally a coating on the core, wherein the core is -40%~50% w / w compound [I], and - An oral solid dosage form is provided, comprising microcrystalline cellulose and anhydrous dicalcium phosphate, wherein the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is approximately 6:4, and the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate is 40% to 60% w / w.

[0106] In one embodiment, an oral solid dosage form is provided, which is a tablet comprising a core and optionally a coating on the core, where the core is -40%~50% w / w compound [I] and - Microcrystalline cellulose and anhydrous dicalcium phosphate, wherein the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is approximately 6:4, and the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate is 40% to 60% w / w. -Approximately 5% w / w of croscarmellose sodium, -Contains approximately 1.5% w / w of magnesium stearate.

[0107] In one embodiment, an oral solid dosage form is a tablet comprising a core and optionally a coating on the core, wherein the core is - Approximately 40% w / w of compound [I], - Microcrystalline cellulose and anhydrous dicalcium phosphate, wherein the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is approximately 6:4, and the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate is 50%~55% w / w. -Approximately 5% w / w of croscarmellose sodium, An oral solid dosage form is provided, comprising approximately 1.5% w / w of magnesium stearate.

[0108] In one embodiment, an oral solid preparation is a tablet comprising a core and optionally a coating on the core, wherein the core is - Approximately 40% w / w of compound [I], - Microcrystalline cellulose and anhydrous dicalcium phosphate, wherein the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is approximately 6:4, and the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate is approximately 53.5% w / w. -Approximately 5% w / w of croscarmellose sodium, An oral solid dosage form is provided, comprising approximately 1.5% w / w of magnesium stearate.

[0109] In embodiments where the w / w% of the core components (e.g., compound [I], microcrystalline cellulose, anhydrous dicalcium phosphate, croscarmellose sodium, and / or magnesium stearate) is mentioned, the w / w% is calculated based on the total weight of the core.

[0110] The oral solid dosage forms described herein contain compound [I] as a single dosage form or as multiple dosage forms in an amount suitable for administration to a patient in need. The dose of compound [I] required for the therapeutic or prophylactic treatment of a particular disease or medical condition will inevitably vary, for example, depending on the host being treated and the severity of the disease being treated. The amount of active compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the properties of the compound, and the discretion of the prescribing physician.

[0111] In the embodiments, the oral solid dosage form contains 80 mg, 160 mg, or 200 mg of compound [I] or a pharmaceutically acceptable salt thereof.

[0112] In the embodiments, the oral solid dosage form contains 80 mg, 160 mg, or 200 mg of compound [I].

[0113] In the embodiment, the oral solid dosage form contains 160 mg of compound [I].

[0114] In the embodiment, the oral solid dosage form contains 200 mg of compound [I].

[0115] In one embodiment, the oral solid dosage form is: -200 mg of compound [I] and -160.5 mg of microcrystalline cellulose, -107 mg of anhydrous dicalcium phosphate, -25mg of croscarmellose sodium, An oral solid dosage form is provided, comprising -7.5 mg of magnesium stearate.

[0116] In one embodiment, an oral solid dosage form is a tablet comprising a core and a coating on the core, wherein the core is -200 mg of compound [I] and -160.5 mg of microcrystalline cellulose, -107 mg of anhydrous dicalcium phosphate, -25mg of croscarmellose sodium, An oral solid dosage form is provided, comprising -7.5 mg of magnesium stearate.

[0117] In one embodiment, an oral solid dosage form is a tablet comprising a core and a coating on the core, wherein the core is -200 mg of compound [I] and -160.5 mg of microcrystalline cellulose, -107 mg of anhydrous dicalcium phosphate, -25mg of croscarmellose sodium, - Contains 7.5 mg of magnesium stearate, The coating provides an oral solid dosage form comprising hypromellose 2910, copovidone prasdone S630, polyethylene glycol 3350, polydextrose, at least one caprylic / capric triglyceride, and optionally at least one opacifying agent (e.g., titanium dioxide), and / or at least one coloring agent (e.g., an iron oxide coloring agent such as red iron oxide, yellow iron oxide, or black iron oxide).

[0118] In one embodiment, the oral solid dosage form is: -160 mg of compound [I] and -128.4 mg of microcrystalline cellulose, -85.6 mg of anhydrous dicalcium phosphate, -20mg of croscarmellose sodium, An oral solid dosage form is provided, containing -6 mg of magnesium stearate.

[0119] In one embodiment, an oral solid dosage form is a tablet comprising a core and a coating on the core, wherein the core is -160 mg of compound [I] and -128.4 mg of microcrystalline cellulose, -85.6 mg of anhydrous dicalcium phosphate, -20mg of croscarmellose sodium, An oral solid dosage form is provided, containing -6 mg of magnesium stearate.

[0120] In one embodiment, an oral solid dosage form is a tablet comprising a core and a coating on the core, wherein the core is -160 mg of compound [I] and -128.4 mg of microcrystalline cellulose, -85.6 mg of anhydrous dicalcium phosphate, -20mg of croscarmellose sodium, - Contains 6 mg of magnesium stearate, The coating provides an oral solid dosage form comprising hypromellose 2910, copovidone prasdone S630, polyethylene glycol 3350, polydextrose, at least one caprylic / capric triglyceride, and optionally at least one opacifying agent (e.g., titanium dioxide), and / or at least one coloring agent (e.g., an iron oxide coloring agent such as red iron oxide, yellow iron oxide, or black iron oxide).

[0121] In one embodiment, an oral solid dosage form is provided, which is a tablet comprising a core consisting of the core components listed in Table 16 (i.e., Example 6a or Example 6b, optionally including relative amounts).

[0122] In one embodiment, an oral solid dosage form is provided, which is a tablet comprising a core consisting of core components listed in Table 16 (i.e., Example 6a or Example 6b, optionally including relative amounts) and a coating on the core consisting of coating components listed in Table 16 (i.e., Example 6a or Example 6b, optionally including relative amounts).

[0123] Manufacturing of pharmaceutical compositions In one embodiment, the pharmaceutical composition described herein is a dry-granulated pharmaceutical composition.

[0124] In one embodiment, a dry-granulated formulation is obtained by a method comprising the following steps: (a) blending compound [I] or a pharmaceutically acceptable salt thereof with microcrystalline cellulose and anhydrous dicalcium phosphate, and optionally a disintegrant and / or lubricant to form a blend; and (b) dry-granulating the blend and optionally blending it with a lubricant.

[0125] In one embodiment, a dry-granulated compound is obtained by a method comprising the following steps: (a) blending compound [I] or a pharmaceutically acceptable salt thereof with microcrystalline cellulose, anhydrous dicalcium phosphate, a disintegrant, and a lubricant to form a blend; and (b) dry-granulating the blend and optionally blending it with a further lubricant.

[0126] In one embodiment, the dry granulation process in step (b) is carried out by roller compression of the blend, followed by grinding.

[0127] Tablet manufacturing method A typical tableting method begins by introducing a bulk powder mixture or granules into a feeder frame, either in batches or continuously, which fills a tableting die with a predetermined weight of material in a consistent manner. The contents of the filled tableting die are then typically compressed by the action of upper and lower punches to form a compressed formulation, which is then ejected to form an intact tablet.

[0128] Tablets prepared from the pharmaceutical compositions according to this specification have advantageously high tensile strength and, consequently, good mechanical stability. The compositions according to this specification comprise a blend of an active pharmaceutical ingredient (API), compound [I], and MCC and DCPA exhibiting a good strain rate sensitivity (SRS) of about 20% or less. This low strain rate sensitivity allows for rapid blending of the API and excipients in the production of tablets containing high w / w amounts of compound [I]. The compositions according to this specification can be reproducibly manufactured without overcompression and deliver tablets with porosity values ​​corresponding to a reproducible dissolution profile.

[0129] Tablets according to this specification are prepared from the compositions according to this specification by standard techniques, including roller compression or direct compression.

[0130] In one embodiment, a method for producing an oral solid dosage form, which is a tablet, comprising the following steps: i) A step of blending a mixture comprising compound [I] or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, anhydrous dicalcium phosphate, and optionally a disintegrant and / or lubricant to form a blend, ii) The step of dry granulating the blend, iii) A method is provided which includes the step of compressing a dry granulation blend into tablets.

[0131] In some embodiments, the dry granulation process in step ii) is carried out by roller compression of the blend, followed by grinding.

[0132] In one embodiment, a method for producing an oral solid dosage form, which is a tablet, comprising the following steps: i) A step of mixing a blend comprising compound [I] or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, anhydrous dicalcium phosphate, a disintegrant, and a lubricant to form a mixture, ii) The step of dry granulating the blend, iii) A step of blending additional lubricants into the dry granulation blend, A method is provided which includes the step of compressing the blend from step iv) and iii) into a tablet.

[0133] In some embodiments, the dry granulation process in step ii) is carried out by roller compression of the blend, followed by grinding.

[0134] In one embodiment, a method for producing an oral solid dosage form, which is a tablet comprising a core and a coating on the core, comprising the following steps: i) A step of blending a mixture comprising compound [I] or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, anhydrous dicalcium phosphate, and optionally a disintegrant and / or lubricant to form a blend, ii) The step of dry granulating the blend, iii) The step of compressing the dry granulated blend into a core, iii) A method is provided which includes the step of applying a coating to a core.

[0135] In some embodiments, the dry granulation process in step ii) is carried out by roller compression of the blend, followed by grinding.

[0136] In one embodiment, a method for producing an oral solid dosage form, which is a tablet comprising a core and a coating on the core, comprising the following steps: i) A step of mixing a blend comprising compound [I] or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, anhydrous dicalcium phosphate, a disintegrant, and a lubricant to form a mixture, ii) The step of dry granulating the blend, iii) A step of blending additional lubricants into the dry granulation blend, iv) The step of compressing the blend from step iii) into the core, A method is provided which includes the step of applying a coating to a core.

[0137] In some embodiments, the dry granulation process in step ii) is carried out by roller compression of the blend, followed by grinding.

[0138] In some embodiments, the method for producing an oral solid dosage form is for producing an oral solid dosage form described herein.

[0139] In some embodiments, the oral solid dosage forms described herein can be obtained by processes for manufacturing the oral solid dosage forms described herein.

[0140] In the embodiment, the method for producing the oral solid dosage form may be a continuous direct compression method.

[0141] medical use Due to their ability to inhibit AKT, the pharmaceutical compositions and oral solid dosage forms described herein have applications in the treatment of AKT-mediated diseases, such as cancer.

[0142] In one embodiment, any pharmaceutical composition or oral solid dosage form described herein is provided for use in treatment.

[0143] In one embodiment, any pharmaceutical composition or oral solid dosage form described herein is provided for use in the treatment of cancer.

[0144] The terms “treat,” “treating,” and “treatment” refer to at least partially alleviating, inhibiting, preventing, and / or improving a condition, disorder, or disease, such as cancer. The term “treatment of cancer” includes both in vitro and in vivo treatments, including treatment in warm-blooded animals such as humans. The effectiveness of cancer treatment can be evaluated in a variety of ways, including but not limited to: inhibiting cancer cell proliferation (including reversing cancer growth), promoting cancer cell death (e.g., by promoting apoptosis or another cell death mechanism), symptom improvement, duration of response to treatment, delay of disease progression, and extension of survival. Treatment can also be evaluated in terms of the nature and extent of side effects associated with the treatment. Furthermore, effectiveness can be evaluated in terms of biomarkers, such as levels of protein expression or phosphorylation known to be associated with certain biological phenomena. Other evaluations of effectiveness are known to those skilled in the art.

[0145] In one embodiment, the use of any pharmaceutical composition or oral solid dosage form described herein for the preparation of a pharmaceutical for use in the treatment of cancer is provided.

[0146] In one embodiment, a method is provided for treating cancer in a patient (e.g., a human patient) who requires cancer treatment, the method comprising administering to the patient an effective therapeutic amount of any pharmaceutical composition or oral solid dosage form described herein.

[0147] The term "therapeutic effective amount" refers to the amount of a compound or combination of compounds described herein that is sufficient to produce the intended application, including but not limited to the treatment of a disease. The therapeutic effective amount may vary depending on the intended application (in vitro or in vivo), the control being treated, the disease state (e.g., the control's weight, age, and sex), the severity of the disease state, the mode of administration, etc., which can be readily determined by those skilled in the art. The term also applies to the dose that induces a specific response in target cells (e.g., the amount of apoptosis). The specific dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system through which the compound is carried.

[0148] In addition to their usefulness in treating human patients, the compositions herein may also be useful in the veterinary treatment of companion animals, exotic animals, and livestock, including mammals, rodents, etc. Such animals include horses, dogs, and cats.

[0149] In some embodiments, the cancer is selected from breast cancer and prostate cancer.

[0150] In some embodiments, the cancer is breast cancer.

[0151] In some embodiments, the cancer is hormone receptor-positive (HR+), HER2-negative breast cancer.

[0152] In one embodiment, the cancer is histologically confirmed HR+ / HER2- breast cancer, determined from the most recent tumor sample (primary or metastatic) as described in the American Society of Clinical Oncology and College of American Pathologists guidelines (Hammond MEH et al., J Clin Oncol 2010, 28(16), 2784-95; Erratum in: J Clin Oncol. 2010, 28(21), 3543; Wolff AC et al., Arch Pathol Lab Med 2018, 142(11), 1364-82). To meet the requirements for an HR+ disease, the breast cancer must express the estrogen receptor (ER), with or without co-expression of the progesterone receptor. Therefore, the tumor must be: (a) Estrogen receptor positivity (ER+) is defined as an Allred IHC score of ≥3 / 8, where ≥1% of tumor cells are positive for ER by immunohistochemistry (IHC), or ≥3 / 8 if the percentage is not available. (b) Progesterone receptor positivity is defined in IHC as an Allred IHC score of ≥3 / 8 or higher, where ≥1% of tumor cell staining is positive for the progesterone receptor, or if the percentage is not available, - or progesterone receptor negative is defined in IHC as an Allred IHC score of ≤2 / 8 or lower, where <1% of tumor cell staining is positive for the progesterone receptor, or if the percentage is not available, or the progesterone receptor is unknown. (c) HER2- is defined as having an intensity of 0 or 1+ on IHC, or an intensity of 2+ on IHC and no evidence of amplification on hybridization (ISH).

[0153] In some embodiments, the cancer is locally advanced or metastatic HR+, HER2-negative breast cancer.

[0154] In some embodiments, the cancer is endocrine-resistant HR+, HER2-negative breast cancer. Endocrine-resistant HR+, HER2-negative breast cancer occurs when the cancer in question becomes unresponsive to endocrine therapy (e.g., selective estrogen receptor modulators such as tamoxifen, and / or aromatase inhibitors such as anastrozole or letrozole).

[0155] In some embodiments, the cancer is metastatic hormone-sensitive prostate cancer.

[0156] In some embodiments, the cancer is metastatic castration-resistant prostate cancer.

[0157] The granular characterization of the cancers shown is detailed in the trials for capivacertib, AZD5363, and / or (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolyl[2,3-d]pyrimidine-4-yl)piperidine-4-carboxamide on clinicaltrials.gov [e.g., trials NCT03997123, NCT04305496, NCT04862663, NCT05348577, or NCT04493853], nih.gov, clinicaltrialsregister.eu, or similar public clinical trial repositories.

[0158] In one embodiment, any pharmaceutical composition or oral solid dosage form described herein is provided for use in the treatment of cancer, the pharmaceutical composition or oral solid dosage form being administered in combination with an additional anticancer agent.

[0159] In one embodiment, a method is provided for treating cancer in an animal patient requiring treatment, comprising administering to the animal patient a first amount of any pharmaceutical composition or oral solid dosage form described herein, and a second amount of an additional anticancer agent, wherein the first and second amounts together constitute a therapeutically effective amount.

[0160] The phrase "in combination with" and similar terms encompass the administration of two or more active pharmaceutical ingredients to a subject (e.g., a patient), including simultaneous administration in separate compositions, administration in separate compositions at different times, or administration in compositions containing two or more active pharmaceutical ingredients.

[0161] In the embodiments, the administration of the pharmaceutical composition, or oral solid dosage form, and additional anticancer agents may be separate, sequential, or simultaneous.

[0162] In this embodiment, the administration of the pharmaceutical composition or oral solid dosage form and additional anticancer agents are separate.

[0163] In the embodiment, the administration of the pharmaceutical composition, or oral solid dosage form, and additional anticancer agents is sequential.

[0164] In this embodiment, the administration of the pharmaceutical composition, or oral solid dosage form, and the additional anticancer agent are simultaneous.

[0165] In one embodiment, any pharmaceutical composition or oral solid dosage form described herein is provided for use in the treatment of cancer, wherein the cancer is metastatic triple-negative breast cancer, and the pharmaceutical composition or oral solid dosage form is administered in combination with chemotherapy (e.g., paclitaxel [e.g., Taxol®] or docetaxel [e.g., Taxotere®]).

[0166] In one embodiment, any pharmaceutical composition or oral solid dosage form described herein is provided for use in the treatment of cancer, wherein the cancer is metastatic triple-negative breast cancer, and the pharmaceutical composition or oral solid dosage form is administered in combination with paclitaxel.

[0167] In one embodiment, any pharmaceutical composition or oral solid dosage form described herein is provided for use in the treatment of cancer, wherein the cancer is endocrine-resistant HR+, HER2-negative breast cancer, and the pharmaceutical composition or oral solid dosage form is administered in combination with a selective estrogen receptor degrader ("SERD", e.g., fulvestrant [e.g., Faslodex®] or a pharmaceutically acceptable salt thereof, giledestrant or a pharmaceutically acceptable salt thereof, elastestrant or a pharmaceutically acceptable salt thereof, imurunestrant or a pharmaceutically acceptable salt thereof, or camizestrant or a pharmaceutically acceptable salt thereof).

[0168] In one embodiment, any pharmaceutical composition or oral solid dosage form described herein is provided for use in the treatment of cancer, wherein the cancer is endocrine-resistant HR+, HER2-negative breast cancer, and the pharmaceutical composition or oral solid dosage form is administered in combination with fulvestrant or a pharmaceutically acceptable salt thereof.

[0169] In one embodiment, any pharmaceutical composition or oral solid dosage form described herein is provided for use in the treatment of cancer, which is endocrine-resistant HR+, HER2-negative breast cancer, the pharmaceutical composition or oral solid dosage form being administered in combination with SERDs (e.g., fulvestrant or a pharmaceutically acceptable salt thereof, giledestrant or a pharmaceutically acceptable salt thereof, elastrant or a pharmaceutically acceptable salt thereof, imurunestrant or a pharmaceutically acceptable salt thereof, or camizestrant or a pharmaceutically acceptable salt thereof) and CDK4 / 6 inhibitors (e.g., palbociclib [e.g., Ibrance®] or a pharmaceutically acceptable salt thereof, ribociclib [e.g., Kisqali®] or a pharmaceutically acceptable salt thereof, and / or abemaciclib [e.g., Verzenois®] or a pharmaceutically acceptable salt thereof).

[0170] In one embodiment, any pharmaceutical composition or oral solid dosage form described herein is provided for use in the treatment of cancer, wherein the cancer is endocrine-resistant HR+, HER2-negative breast cancer, and the pharmaceutical composition or oral solid dosage form is administered in combination with fulvestrant or a pharmaceutically acceptable salt thereof, and palbociclib or a pharmaceutically acceptable salt thereof.

[0171] In one embodiment, any pharmaceutical composition or oral solid dosage form described herein is provided for use in the treatment of cancer, wherein the cancer is endocrine-resistant HR+, HER2-negative breast cancer, and the pharmaceutical composition or oral solid dosage form is administered in combination with fulvestrant or a pharmaceutically acceptable salt thereof, and ribociclib or a pharmaceutically acceptable salt thereof.

[0172] In one embodiment, any pharmaceutical composition or oral solid dosage form described herein is provided for use in the treatment of cancer, wherein the cancer is metastatic hormone-sensitive prostate cancer, and the pharmaceutical composition or oral solid dosage form is administered in combination with abiraterone or a pharmaceutically acceptable salt thereof [e.g., Zytiga®].

[0173] In one embodiment, any pharmaceutical composition or oral solid dosage form described herein is provided for use in the treatment of cancer, wherein the cancer is metastatic castration-resistant prostate cancer, and the pharmaceutical composition or oral solid dosage form is administered in combination with docetaxel.

[0174] In embodiments, any pharmaceutical composition or oral solid dosage form described herein may be administered in accordance with any published capivacertib clinical trial protocol (e.g., with respect to patient characteristics, dosage, and / or frequency of administration), e.g., clinicaltrials.gov, nih.gov, clinicaltrialsregister.eu, or similar public clinical trial repositories, e.g., clinicaltrials.gov, nih.gov, clinicaltrialsregister.eu, referring to capivacertib, AZD5363, and / or (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolyl[2,3-d]pyrimidine-4-yl)piperidine-4-carboxamide, published in clinical trials NCT03997123, NCT04305496, NCT04862663, NCT05348577, and / or NCT04493853.

[0175] The pharmaceutical compositions and oral solid dosage forms described herein may be used for diagnostic purposes and as research tools. For example, a pharmaceutical composition containing compound [I] alone or in combination with other compounds may be used as a tool in differential and / or combinatorial analysis to elucidate the expression patterns of genes expressed in cells and tissues.

[0176] kit In one embodiment, a kit is provided comprising any pharmaceutical composition or oral solid dosage form described herein, and optionally, instructions for the use of the pharmaceutical composition or oral solid dosage form in accordance with the various medical indications described herein.

[0177] In embodiments, the kit may also include other supplementary information, such as references to scientific literature, package insert materials, clinical trial results, and / or summaries thereof, that demonstrate or establish the activity and / or benefits of the composition, and / or describe dosing, administration, side effects, drug interactions, or other information useful to healthcare providers. Such information may be based on the results of various studies, e.g., studies using experimental animals, including in vivo models, and studies based on human clinical trials. The kits described herein may be provided, sold, and / or promoted to healthcare providers, including physicians, nurses, pharmacists, and prescription staff.

[0178] In this embodiment, the kit may be sold directly to consumers. [Examples]

[0179] Compound [I] can be prepared according to the method disclosed in International Publication No. 2009 / 047563. Compound [I] was used in crystalline form B, which is disclosed in International Publication No. 2013 / 156772.

[0180] DCPA, also known as anhydrous dicalcium phosphate, anhydrous dibasic calcium phosphate, and anhydrous calcium hydrogen phosphate, is commercially available from various suppliers. Suitable free-flow grade DCPA for use in the pharmaceutical compositions herein include EMCOMPRESS® from JRS Pharma (www.jrspharma.com) and A-TAB from Innophos (www.innophos.com).

[0181] Microcrystalline cellulose (MCC) is commercially available from various suppliers. Suitable free-flowing, high-density grade MCCs for use in the pharmaceutical compositions herein include Avicel® pH102, Avicel® pH101, Avicel® pH200 (all from Dupont Pharma, www.dupont.co.uk), VIVAPUR® 102, and VIVAPUR® 200 (from JRS PHARMA GmbH&Co.KG, Rosenberg, Germany).

[0182] A suitable commercial-grade magnesium stearate for use in the pharmaceutical compositions described herein is LIGAMED® MF from Peter Greven (Peter Greven GmbH & Co. KG, www.peter-greven.de).

[0183] The fluidity coefficient [FFC] of different pharmaceutical composition blends was determined using a Schultz RST-XS ring shear tester (http: / / www.dietmar-schulze.com / rstxse.html) under normal stress, as well as under preliminary shear stresses of 1000, 2000, and 4000 Pa.

[0184] Particle size was measured for the dry powder by laser diffraction.

[0185] For tensile strength analysis, the weight, hardness, thickness, and diameter of 10 tablets manufactured by roller compression were determined using a Sotax HT100 (www.sotax.com). Tensile strength was calculated using Pitt's formula from the hardness data, as well as the tablet dimensions obtained from the Sotax HT100 and the compression tool dimensions (see KGPitt & M.G. Heasley, "Powder Technology", 2013

[0238] pp. 169-175).

[0186] Disintegration was measured using the pharmacopoeia disintegration test.

[0187] The dissolution experiment was performed at a temperature of 37°C using Apparatus II (paddle) dissolution. The test was conducted using 900 mL of pH 1.2 solution at a paddle speed of 50 rpm, and with pH 6.8 containing 0.4% tween at a paddle speed of 75 rpm.

[0188] The crushing test was conducted using the official crushing test machine.

[0189] Following the formulation development work, several prototype formulations containing compound [I] with various diluents, disintegrants, and lubricants were prepared by dry granulation for evaluation.

[0190] Initial development work produced suitable clinical formulations, such as those listed in Table 1 (Reference Example 1). However, the resulting tablets, while suitable for clinical use, were found to lack the ideal properties for tablet manufacturing. Therefore, further research was conducted to improve the formulations.

[0191] [Table 1] a- The w / w percentage of the amount of tablet core components is expressed relative to the weight of the core tablet. The weight of the b-core tablet is rounded to the nearest integer.

[0192] Example 1: Diluent Early studies focused on the amount and properties of diluents used in the formulations. A range of prototype compositions were investigated using 40% or 50% capivacertib drug loads (levels selected to ensure therapeutic effect in appropriate tablet sizes) along with diluent mixtures containing MCC and mannitol, or MCC and DCPA, in various ratios (Table 2).

[0193] [Table 2]

[0194] Formulations that fall within these parameters were determined by a set of preliminary manufacturability criteria, including: 1. To ensure a robust tablet core for further processing, packaging, transportation, and patient handling, a tensile strength exceeding 2 MPa is required. 2. Less than 15% strain rate sensitivity (i.e., sensitivity to tablet press rate) for high commercial rate processing, and 3. The total amount of microcrystalline cellulose (MCC) in the composition is 20% or more to ensure that there is a sufficient amount to act as a plastic deformation compression aid during the roller compression and tableting processes.

[0195] Analysis of the representative compositions in Table 2 revealed that a higher proportion of MCC increased tensile strength (point 1 above), but simultaneously increased strain rate sensitivity (point 2). This is thought to be due to the plastic deformation properties of MCC. However, DCPA was found to have the opposite effect, with higher levels decreasing both tensile strength and strain rate sensitivity. Based on predetermined criteria, at a 40% drug load, the filler ratio window that satisfies both criteria 1 and 2 above was determined to be 45:55 to 70:30 for MCC:DCPA. At a 50% drug load, a smaller operating window was determined for MCC:DCPA, ranging from 55:45 to 68:32.

[0196] For compositions based on mannitol / MCC diluent mixtures, it was determined that both 40% and 50% drug loads, even at the lowest acceptable level of MCC, left no filler ratio window for operation due to high strain rate sensitivity (i.e., at 50% load and MCC above 20% w / w, it was impossible to find an MCC:mannitol ratio that satisfied both conditions 1 and 2 above). Based on this, the MCC:mannitol combination was considered unsuitable for further development.

[0197] After selecting DCPA as the secondary diluent, further experiments were conducted to determine the appropriate drug load (Table 3).

[0198] [Table 3] a- The ratio of MCC to DCPA in all formulations is fixed at 6:4.

[0199] All formulation variations 1a-1c were prepared using the same manufacturing process parameters. The dry powder components (excluding the lubricant [magnesium stearate]) were placed in a blender and mixed. The powder was blended with the granular lubricant, granulated using a roller compressor, and then ribbon-ground. The granular lubricant was added to the granules and mixed, and then compressed into tablet cores to obtain a strength of 200 mg at various compression pressures and speeds. The compositions were characterized for powder fluidity (determined using a Schultz RST-XS ring shear tester [www.dietmar-schulze.com / rstxse.htmL] at normal stress and with preliminary shear stresses of 1000, 2000 and 4000 Pa), collapse time at different compressive forces, tensile strength at different compression speeds, and shatterability (see Table 4).

[0200] [Table 4] Compression at 200 MPa with a press speed of 50 rpm. Compression at 300 MPa with a press speed of b-50 rpm.

[0201] These results (and the results of the standard dissolution test) demonstrate the following: The 1.60% drug loading formulation (Example 1c) exhibits relatively low powder flow characteristics compared to alternatives for lighter drug loading. 2. The 40% drug loading formulation (Example 1a) exhibits improved powder flow characteristics compared to the 50% drug loading formulation. Variations of the 3.40% and 50% formulation achieved the target tensile strength at press speeds of 50 rpm and 90 rpm, respectively, suggesting that the composition is robust enough for large-scale / commercial production. The variants with 4.40% and 50% formulation showed rapid disintegration in 17 seconds or less, without significant influence of the applied compression pressure, and exhibited an effective disintegration mechanism. The variants with 5.40% and 50% formulation showed equivalent immediate release dissolution profiles in low and high pH media.

[0202] Based on the differences in the flow properties between the variants of the drug-loaded formulations, the 40% w / w composition (Example 1a) is more excellent in ensuring the robust flow of the powder to the roller compactor, and thus gives manufacturing advantages.

[0203] Using further experiments, the influence of MCC was determined. The DCPA ratio (3:2 vs 3:1) on the strain rate sensitivity (SRS). Two formulations were compared for the test (Table 5).

[0204]

Table 5

[0205] Using Sotax HT100 (www.sotax.com), the weight, hardness, thickness, and diameter of 10 tablets produced by roller compression from the formulation were determined. The envelope density E D Also, using the information from the tabletting tool and the Sotax HT100 tablet test system for 10 tablets, the tablet weight and tablet dimensions were determined. The true density T D was the weighted true density of the formulation components. Then, the porosity of the tablets was calculated according to the formula T p = 100 1 - E D / T D ). In the formula, T p = the porosity of the tablets, E D = the envelope density, and T D = the true density.

[0206] The results of the characterization are shown in Figure 1, which demonstrates the following. 1. The compression speed has little influence on the tensile strength in the case of the 3:2 (MCC:DCPA) formulation. 2. Increasing the proportion of DCPA reduces SRS. 3. Tablets with a higher DCPA content exhibited higher porosity at a given tensile strength.

[0207] Therefore, a 3:2 MCC:DCPA ratio is more advantageous than a 3:1 MCC:DCPA ratio in terms of reproducibility, reduced SRS, and higher porosity.

[0208] Finally, specific experiments were conducted to compare the disintegration of MCC / mannitol and MCC / DCPA-based formulations. Four formulations (Examples 1d, 1e, 1f, and 1g; components are summarized in Table 6) were prepared by the following method: a wet granulation method was used for 100g batches. The API and excipients were dried and mixed together, and water (2 mL / min) was added during high-shear mixing using a MiPro granulator (0.5 L). The impeller speed was set to 400 rpm and the chopper to 1500 rpm. The resulting granules were dried to <2% w / w moisture content at 80°C using a Vector Fluid bed dryer and manually ground using a 1 mm sieve.

[0209] Next, the tablets were compressed according to the following process: The granules were lubricated for 4 minutes at 30 rpm using a Turbula T2C, and then compressed into 250 mg tablets using an F-press equipped with the instrument and a standard 8 mm concave punch. Batch of tablets was prepared by compressing to approximately 10 kN (187 MPa), 15 kN (281 MPa), and 20 kN (375 MPa).

[0210] [Table 6]

[0211] Tablets of each formulation were prepared under various compression conditions and then tested for disintegration using standard pharmacopoeia tests. The results are shown in Figure 1, which shows the disintegration times of Examples 1e, 1f, 1g, and 1h, prepared under various compression forces. It can be seen that the MCC / DCPA formulations 1e and 1f showed faster disintegration times compared to the MCC / mannitol formulations 1g and 1h.

[0212] Example 2: Disintegrant Croscarmellose sodium was selected for the study because preliminary experiments showed it could impart good stability and disintegration properties. The examples shown in Table 3 contained croscarmellose sodium (5% w / w) and exhibited a rapid and robust disintegration profile (17 seconds and 16 seconds for Examples 1a and 1b, respectively, when analyzed at pH 1.2 (50 rpm) and pH 6.8 [75 rpm] containing 0.4% tween). Confirmation tests were performed to investigate the sensitivity of the formulations to disintegrant levels. The level of croscarmellose sodium, the disintegrant, in the formulation was adjusted from 5% to 0% w / w, and the effect on disintegration and dissolution properties was evaluated. The level of fillers (but not their ratio) was adjusted to maintain the tablet compression weight (Table 7).

[0213] [Table 7] a- The ratio of MCC to DCPA in both formulations is fixed at 6:4.

[0214] Both variations were manufactured using the same manufacturing process parameters. The dry powder components (excluding the lubricant) were placed in a blender and mixed. The powder was blended with the lubricant inside the granules, granulated in a roller compressor, and then ribbon-ground. The lubricant outside the granules was added to the granules, mixed, and then compressed into tablet cores with a compressed weight of 500 mg.

[0215] As shown in Table 8, in both Example 1a and Example 2, disintegration and dissolution were rapid and complete, demonstrating that the formulation is a fast-release formulation robust to changes in disintegrant levels.

[0216] [Table 8] a-The results are the mean (± standard deviation, N=3). b- The results are the mean (± standard deviation, N=6).

[0217] Example 3: Lubricant Following initial screening, magnesium stearate was selected for further development due to its good stability in the prototype film-coated tablets. Further investigation of lubricant levels was conducted to evaluate the impact of higher levels of this hydrophobic and anti-adhesion material on the tablet's tensile strength and disintegration / dissolution profile.

[0218] Three variations were prepared from the same common granule batch using a consistent level of intragranular lubricant (0.5% w / w). By incorporating extragranular lubricant, variations with 0.75%, 1.0%, 1.25%, and 1.5% w / w were produced, equalizing the total levels of 1.25%, 1.5%, 1.75%, and 2.0% w / w, respectively (Table 9, Examples 3a-3d, respectively).

[0219] [Table 9]

[0220] To prepare Examples 3a-3d, the dry powder components (excluding the lubricant) were placed in a blender and mixed. The powder was blended with the granular lubricant, granulated using a roller compressor, and then ribbon-ground. The granules common to all three variations were roller-compressed with a relatively high roll force of 12 kN / cm as a "worst-case" for the compression and dissolution of commercially available tablets. The granular lubricant was then added to the granules, mixed together, and compressed into a tablet core with a compressed weight of 500 mg.

[0221] Next, the manufacturability of different variations was investigated, and the results shown in Table 10 were obtained.

[0222] [Table 10] Granules compressed with a roller at 12kN / cm and then compressed again at 35kN. b- The results are mean ± standard deviation, N=3. c-Results are mean ± standard deviation, N=6.

[0223] The following conclusions can be drawn: 1. A slight gradual decrease in the ejection force on the tablet press was observed at extragranular lubricant levels of 1.25% (w / w) or higher. However, no problems related to tablet ejection were observed, and therefore, these small differences in ejection force are practically negligible. At extragranular lubricant levels of 2.1.0% or higher, a gradual decrease in tensile strength was observed compared to the lowest level investigated (0.75%). However, all lubricant levels investigated achieved a tensile strength of over 1.5 MPa, which, while not as strong as 2 MPa, is still suitable for commercialization. 3. The disintegration and lysis of all variants were rapid and complete (>85% in 30 minutes), demonstrating that increased levels of magnesium stearate did not affect the in vitro performance of the tablets.

[0224] The level of lubricant within the granules was also investigated. Two variations (Examples 3e and 3f) were produced with 0.5% and 1.0% lubricant within the granules, respectively, at a consistent level of lubricant outside the granules (1.0%). Variations with 0.5% and 1.0% w / w lubricant were produced by incorporating the lubricant within the granules, resulting in total levels of 1.5% and 2.0% w / w, respectively (Table 11).

[0225] [Table 11]

[0226] To prepare Examples 3e and 3f, the dry powder components (excluding the lubricant) were placed in a blender and mixed. The powder was blended with the granular lubricant, granulated using a roller compressor, and then ribbon-ground. The granular lubricant was added to the granules and mixed together, and then compressed into tablet cores to a compressed weight of 500 mg.

[0227] Next, the manufacturability of Examples 3e and 3f was investigated, and the results shown in Table 12 were obtained.

[0228] [Table 12] Granules compressed with a roller at 12kN / cm and then compressed again at 35kN. b- The results are mean ± standard deviation, N=3.

[0229] The following conclusions can be drawn. 1. Tensile strengths exceeding 1.5 MPa were achieved for both granule lubricant levels investigated. The data demonstrated that varying the lubricant level within these ranges had only a negligible effect on the resulting tablet tensile strength. The disintegration of the 2.0.5% and 1.0% w / w magnesium stearate variants was rapid (<1 minute), indicating that increasing the level of intragranular lubricant did not affect the tablet disintegration performance.

[0230] Example 4: Particle size The range of the particle size of the drug substance was investigated to evaluate the impact on the quality attributes and manufacturability of the drug product. Three particle size variants were generated by grinding the drug substance to three different target D(v,0.9) particle sizes of approximately 70 μm, 100 μm, and 170 μm. All particle size variants were manufactured using the same formulation and manufacturing process parameters. The dry powder components (excluding the lubricant) were placed in a blender and mixed. Subsequently, the powder was blended with the intragranular lubricant, granulated using a roller compactor, and ribbon milled. The extragranular lubricant was added to the granules, mixed, and then compressed into tablet cores with a compression weight of 500 mg. The roll force and compression force were varied to evaluate the potential interaction effects with the particle size of the drug substance.

[0231]

Table 13

[0232] The following conclusions can be drawn. 1. For all particle size variants, the flow properties of the neat drug substance are poor (FFC85% in 30 minutes). 2. The poor and variable flow properties of the neat drug substance for all particle size variants are classified as improved from poor flow to easy flow for the dry blend. 3. The roller compaction process further improves the flow properties for the free flow of the granules and reduces the variation between the particle size variants of the drug substance. 4. For all particle size variants, a tensile strength of over 2 MPa was achieved. 5. The data demonstrated that changing the particle size of the drug substance does not affect the tensile strength of the resulting tablets (and that using the formulation blend can achieve good flow properties regardless of the particle size). And 6. The disintegration and dissolution of all modified forms were rapid and complete (>85% in 30 minutes), demonstrating that the particle size of the drug substance had only a negligible effect on the in vitro performance of the tablets within the range investigated.

[0233] Example 5: Coating Two studies were conducted to select a suitable coating system. The first study investigated the Opadry® I (HPMC-based) and Opadry® II (PVA-based) systems, evaluating the appearance, dissolution, and physical properties of debossed capivacertib tablets after coating with the different systems. Opadry® II was selected because it provided superior appearance quality for the debossed tablets. The second study investigated the abrasion problem observed with Opadry® II in large-scale manufacturing where the coating system and process parameters were not extensively evaluated. Aquarius Preferred was selected because it demonstrated a lower risk of abrasion while maintaining the appearance quality of the Opadry® II system. The compositions of the selected coating systems are shown in Table 14.

[0234] [Table 14]

[0235] 0.067 mg / mm³ 2 Typical levels of coating for immediate-release tablets were selected in the final formulation, corresponding to weight increases of 4.0% and 3.8% for 160 mg and 200 mg tablet strengths, respectively. Confirmation studies were conducted to ensure that the level of tablet coating did not significantly affect product quality attributes such as appearance and dissolution. Tablets were coated using a perforated drum coater, and samples were taken at 8 intervals throughout the coating process to achieve a range of tablet weight increases (1.1–7.2% w / w). All 8 samples taken within this range passed the criteria for coating uniformity and integrity without any minor or major physical defects.

[0236] Targets from the samples, as well as extreme weight-increasing variations (3.8% and up to 7.2%), were also evaluated for dissolution (Table 15). As expected from non-functional film coatings, the level of tablet co-coating did not have a significant effect on release.

[0237] [Table 15] a- The results are mean ± standard deviation, N=6.

[0238] Example 6: Final Capivacertib Tablets Following the above research, tablets having the components listed in Table 16 were selected as appropriate commercially available formulations.

[0239] [Table 16] The percentage of aw / w tablet core components is expressed relative to the core tablet weight, while the w / w percentage of coating components is expressed relative to the nominal coating weight. The weight of the b-core tablet is rounded to the nearest integer. The target amount of c corresponds to 4% of the core tablet weight for the 160 mg tablet and 3.8% of the core tablet weight for the 200 mg tablet. d-Purified water is used as a solvent / support during the film coating process and is ultimately removed during the process.

[0240] The stability of the tablets shown in Table 16 was confirmed through standard long-term stability tests throughout their typical shelf life. Tablets stored in HDPE bottles under different ambient conditions (humidity, temperature, etc.) were monitored for changes in tablet quality attributes (e.g., description, assay, organic impurities, chiral purity, solubility, water content, microbial content) for up to 5 years. The available data for capivacertib 160 mg and 200 mg tablets (i.e., Examples 6a and 6b, respectively) demonstrate that there are no significant changes in the tablets under long-term or accelerated storage conditions. The dissolution rate of the tablets slows with elapsed time regardless of the storage environment, but this is not significant as all batches met specifications after 5 years of storage under long-term conditions (25°C / 60%RH and 30°C / 75%RH). The data support a 5-year shelf life for capivacertib 160 mg and 200 mg tablets when stored in HDPE bottles at below 30°C.

[0241] As data elsewhere in this specification demonstrates, the tablets described in Table 16 have a good dissolution profile, enabling their use as immediate-release therapy. They also possess desirable physical properties (e.g., tensile strength, strain rate sensitivity, and compressive ability). This improves the manufacturability of the tablets, for example, with respect to the flow of powder into the roller compressor after dry granulation and punch-filming. Finally, the appearance of the tablets after coating is improved compared to previous formulations.

Claims

1. A pharmaceutical composition comprising compound [I] or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, and anhydrous dicalcium phosphate.

2. The pharmaceutical composition according to claim 1, comprising compound [I], microcrystalline cellulose, and anhydrous dicalcium phosphate.

3. The pharmaceutical composition according to claim 1 or 2, which is an immediate-release pharmaceutical composition.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition comprises up to 65% w / w of compound [I] or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition comprises 40% to 50% w / w of compound [I] or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition comprises about 50% w / w of compound [I] or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition comprises about 40% w / w of compound [I] or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the ratio of the microcrystalline cellulose to anhydrous dicalcium phosphate is 45:55 to 70:

30.

9. The pharmaceutical composition according to claim 8, wherein the ratio of the microcrystalline cellulose to anhydrous dicalcium phosphate is 55:45 to 68:

32.

10. The pharmaceutical composition according to claim 8 or 9, wherein the ratio of the microcrystalline cellulose to anhydrous dicalcium phosphate is about 6:

4.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the total amount of the microcrystalline cellulose and anhydrous dicalcium phosphate is 15% w / w to 65% w / w.

12. The pharmaceutical composition according to claim 11, wherein the total amount of the microcrystalline cellulose and anhydrous dicalcium phosphate is 30% w / w to 65% w / w.

13. The pharmaceutical composition according to claim 12, wherein the total amount of the microcrystalline cellulose and anhydrous dicalcium phosphate is 50% w / w to 55% w / w.

14. The pharmaceutical composition according to any one of claims 1 to 13, further comprising at least one disintegrant in an amount up to 10% w / w.

15. The pharmaceutical composition according to claim 14, wherein the at least one disintegrant is present in an amount of up to approximately 5%.

16. The pharmaceutical composition according to claim 14 or 15, wherein the at least one disintegrant is croscarmellose sodium.

17. The pharmaceutical composition according to any one of claims 1 to 16, further comprising at least one lubricant in an amount up to 4% w / w.

18. The pharmaceutical composition according to claim 17, wherein the at least one lubricant is present in an amount of up to approximately 1.5%.

19. The pharmaceutical composition according to claim 17 or 18, wherein the at least one lubricant is magnesium stearate.

20. A pharmaceutical composition according to claim 1, - Compound [I] at approximately 40% w / w, - Microcrystalline cellulose and anhydrous dicalcium phosphate, wherein the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is approximately 6:4, and the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate is 50% to 55% w / w, - Approximately 5% w / w of croscarmellose sodium, A pharmaceutical composition comprising approximately 1.5% w / w of magnesium stearate.

21. An oral solid dosage form comprising the pharmaceutical composition according to any one of claims 1 to 20, wherein the oral solid dosage form is a capsule.

22. An oral solid dosage form comprising the pharmaceutical composition according to any one of claims 1 to 20, wherein the oral solid dosage form is a tablet.

23. The oral solid dosage form according to claim 22, wherein the oral solid dosage form is a tablet comprising a core containing the pharmaceutical composition according to any one of claims 1 to 20 and a coating on the core.

24. An oral solid dosage form according to claim 23, wherein the core is - Compound [I] at approximately 40% w / w, - Microcrystalline cellulose and anhydrous dicalcium phosphate, wherein the ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is approximately 6:4, and the total amount of microcrystalline cellulose and anhydrous dicalcium phosphate is 50% to 55% w / w, - Approximately 5% w / w of croscarmellose sodium, - An oral solid dosage form containing approximately 1.5% w / w of magnesium stearate.

25. The oral solid dosage form according to claim 23 or claim 24, wherein the coating comprises hypromellose 2910, copovidone prasdone S630, polyethylene glycol 3350, polydextrose, at least one caprylic / capric triglyceride, titanium dioxide, yellow iron oxide, red iron oxide, and black iron oxide.

26. An oral solid dosage form according to any one of claims 21 to 25, containing 80 mg, 160 mg, or 200 mg of compound [I].

27. An oral solid dosage form according to any one of claims 21 to 26, -200 mg of compound [I] and - 160.5 mg of microcrystalline cellulose, - 107.0 mg of anhydrous dicalcium phosphate and - 25.0 mg of croscarmellose sodium, An oral solid dosage form containing -7.5 mg of magnesium stearate.

28. A method for producing an oral solid dosage form according to any one of claims 22 to 25, comprising the following steps: i) A step of blending a mixture comprising compound [I] or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, anhydrous dicalcium phosphate, and optionally a disintegrant and / or a lubricant to form a blend; ii) A step of dry granulating the blend, iii) A method comprising the step of compressing the dry granulated blend into tablets.

29. The method according to claim 28, wherein the dry granulation process in step ii) is carried out by roller compression of the blend, followed by grinding.

30. A pharmaceutical composition according to any one of claims 1 to 20, or an oral solid dosage form according to any one of claims 21 to 27, for use in therapeutic purposes.

31. A pharmaceutical composition according to any one of claims 1 to 20, or an oral solid dosage form according to any one of claims 21 to 27, for use in the treatment of cancer.

32. Use of a pharmaceutical composition according to any one of claims 1 to 20, or an oral solid dosage form according to any one of claims 21 to 27, for the preparation of a pharmaceutical for use in the treatment of cancer.

33. A method for treating cancer in a patient requiring cancer treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 20, or an oral solid dosage form according to any one of claims 21 to 27.

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