Solid dosage form containing an inhibitor of the K-RAS protein having a G12C mutation, and method for preparing it.

Abstract

This disclosure generally relates to rapid-release drug dosage unit tablets containing small molecule API pharmaceuticals. In some examples, the API is an inhibitor of the Ras protein, such as K-Ras, H-Ras, and N-Ras, which have the G12C mutation. Such tablets also contain disintegrants and excipients. More specifically, this disclosure relates to drug dosage unit tablets containing divalasib or a pharmaceutically acceptable salt thereof, an extragranular disintegrant, and an extragranular excipient, and to a method for preparing tablets from granules formed by dry granulation.

Description

[Background technology]

[0001] This disclosure generally relates to a pharmaceutical dosage unit tablet containing a drug, a disintegrant, and an excipient, as well as a method for forming a tablet.

[0002] In some aspects of this disclosure, the drugs are inhibitors of the Ras protein. Ras is a small GTP-binding protein that functions as a nucleotide-dependent switch in the central proliferation signaling pathway. In response to extracellular signals, Ras is converted from a GDP-bound (RasGDP) state to a GTP-bound (RasGTP) state by catalysis by guanine nucleotide exchange factors (GEFs), particularly the SOS1 protein. Active RasGTP mediates its diverse proliferation-stimulating functions through direct interactions with effectors, including Raf, PI3K, and the Ral guanine nucleotide dissociation stimulator. Subsequently, the intrinsic GTPase activity of Ras hydrolyzes GTP to GDP, terminating Ras signaling. Ras GTPase activity can be further accelerated by interaction with GTPase-activating proteins (GAPs), including the neurofibromin-1 tumor suppressor.

[0003] Mutant Ras has reduced GTPase activity, which sustains the activated structure of Ras, thereby promoting Ras-dependent signaling and cancer cell survival or proliferation. Mutations in Ras that affect the ability to interact with GAP or convert GTP back to GDP result in sustained activation of the protein, consequently sustained signals that tell cells to continue proliferating and dividing. Since these signals lead to cell proliferation and division, excessively active RAS signaling can ultimately lead to cancer. Mutations in any one of the three main isoforms of the RAS gene (H-Ras, N-Ras, or K-Ras) are common events in human tumorigenesis. Of the three Ras isoforms (K, N, and H), K-Ras is the most frequently mutated.

[0004] The most common K-Ras mutations are found at residues G12 and G13 of the P-loop, as well as residue Q61. G12C is a frequently occurring mutation in the K-Ras gene (glycine-12 is replaced with cysteine). G12D and G13D are other frequently occurring mutations. Mutations in Ras are associated with poor prognosis in cancer. Inactivation of oncogenic Ras in mice results in tumor reduction. Therefore, Ras is widely considered a very important oncological target.

[0005] Immediate-release compressed tablets (e.g., caplets) are an effective form for delivering pharmaceutically active drugs. A problem is that some combinations of drugs, excipients, and disintegrants (to confer rapid-release properties) can delay the disintegration time of the tablet. Initial formulations containing divalasib exhibited slow disintegration, resulting in incomplete disintegration even after prolonged retention in the stomach. Rapid delivery of the divalasib API is necessary, for example, to avoid alterations in pharmacokinetic properties. Therefore, there is a need for improved tablet compositions containing the drug (e.g., divalasib), excipients, and disintegrants, as well as related preparation methods that enable tablets with the sufficient dissolution and disintegration properties required for immediate-release tablets. [Overview of the project]

[0006] In some aspects of this disclosure, a method for preparing a drug dosage unit tablet core is provided. This method is (a) Mix divalasib, an internal excipient, and an internal disintegrant to form a premixture, (b) Compressing the premixture by applying a compressive force, (c) Crushing and sieving the compressed premixture to form granules, (d) Mixing granules with an external excipient and an external disintegrant to form a granule mixture, (e) Compressing the granular mixture into tablets by applying a compressive force to form a drug administration unit tablet core, Includes.

[0007] In one embodiment, the method further comprises mixing a premixture with an internal lubricant before compression. In another embodiment, the method further comprises mixing granules, an external excipient and an external disintegrant with an external lubricant before tableting to form a granular mixture.

[0008] In other aspects of this disclosure, a drug dosage unit tablet core is provided. The tablet core is (a) Divalasib and, (b) A disintegrant in an amount of approximately 2% to 13% by weight based on the weight of the drug administration unit tablet core, (c) Excipients in an amount of approximately 15% to 50% by weight based on the weight of the tablet core of the pharmaceutical administration unit, Includes. [Brief explanation of the drawing]

[0009] [Figure 1] This figure shows the tableting process of the present disclosure.

[0010] [Figure 2] As described in Example 2, the effects of various excipients on disintegration time are shown. MCC = microcrystalline cellulose, DCP = dicalcium phosphate.

[0011] [Figure 3] As explained in Example 3, the effect of extragranular microcrystalline cellulose content on the average disintegration time is shown. MCC = microcrystalline cellulose, ExG = extragranular, InG = intragranular, TS = tensile strength, NaCMC = croscarmellose sodium.

[0012] [Figure 4] As described in Example 4, the effects of intragranular and extragranular croscarmellose sodium on the mean disintegration time are shown. ExG = extragranular, InG = intragranular, TS = tensile strength, NaCMC = croscarmellose sodium.

[0013] [Figure 5]As described in Example 5, the effect of the extragranular microcrystalline cellulose grade on the average disintegration time is shown. MCC = microcrystalline cellulose, ExG = extragranular, InG = intragranular, TS = tensile strength, NaCMC = croscarmellose sodium.

[0014] [Figure 6] As described in Example 6, the disintegration behavior of tablets formulated by dry granulation is shown compared to tablets formulated by high-shear wet granulation. MCC = microcrystalline cellulose, ExG = extragranular, InG = intragranular, TS = tensile strength, NaCMC = croscarmellose sodium, DG = dry granulation, HSWG = high-shear wet granulation, SF = solids fraction.

[0015] [Figure 7] As described in Example 7, it is a flowchart illustrating the manufacturing process of divalproex tablets and the in-process property evaluation. API = active pharmaceutical ingredient (i.e., divalproex).

[0016] [Figure 8] As described in Example 7, the tableting profile of divalproex tablets is shown.

[0017] [Figure 9] As described in Example 7, the disintegration times of tablets having target hardnesses of 20 kp and 30 kp are shown. DL = drug content, CCS = croscarmellose sodium, Ave = average.

Mode for Carrying Out the Invention

[0018] According to some aspects of the present disclosure, as described herein, there is provided a pharmaceutical dosage form tablet comprising an active drug having a free base (FB) content of up to about 44 weight percent (wt%), a disintegrant, and an excipient, the tablet exhibiting a rapid dissolution rate. According to some other aspects of the present disclosure, as described herein, there is provided a method for preparing a pharmaceutical dosage form tablet containing an active drug from granules.

[0019] In some aspects of this disclosure, the active drug is 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-yl)propa-2-en-1-one free base or a pharmaceutically acceptable salt thereof (hereinafter referred to as "divalasib"). Divalasib has the following structure: [ka]

[0020] As used herein, the term “divalasib free base” refers to divalasib (1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3-methylpiperazine-1-yl)propa-2-en-1-one) as a free base (i.e., not as a salt).

[0021] Divalasib, its preparation method and therapeutic use are disclosed in International Publication No. 2020 / 097537, which is incorporated herein by reference. In one embodiment, divalasib is prepared according to the procedure described in Example 17a of International Publication No. 2020 / 097537, which is incorporated herein by reference.

[0022] As used herein, the term “divalasib adipate” refers to the adipate form of divalasib (1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3-methylpiperazine-1-yl)propa-2-en-1-one).

[0023] In some embodiments, divalasib adipinate is prepared by dissolving divalasib free base in a solvent (e.g., methyl ethyl ketone, "MEK"), dissolving adipic acid in a solvent (e.g., MEK), and combining the divalasib free base solution with the adipic acid solution to form divalasib adipinate. In certain embodiments, gentle heating (40-80°C) may be required to ensure complete dissolution. In some embodiments, the method further includes adding a seed crystal of divalasib adipinate to the mixture. In one embodiment, divalasib adipinate is synthesized as described, for example, in International Publication No. 2022035790. In another embodiment, divalasib adipinate is synthesized as described, for example, in International Publication No. 2023 / 150653.

[0024] Although this specification makes specific references to the active drug divalasib, the compositions, formulations, and methods disclosed herein are applicable to and encompass other active drugs besides divalasib.

[0025] It has been found that water penetration into divalasib tablets affects the disintegration time of the tablets. As demonstrated in the examples herein, it has been further found that including a certain amount of extragranular (ExG) water-absorbing excipient in addition to the extragranular disintegrant improves water penetration into the tablets, resulting in substantially faster disintegration times. In certain embodiments, the tablets of the present disclosure have disintegration times of about 15 minutes or less, about 10 minutes or less, or about 5 minutes or less, for example, about 10 minutes, about 9 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, about 1.5 minutes, about 1.3 minutes, or about 1 minute, and disintegration times in the range of about 1 minute to about 10 minutes, about 1 minute to about 8 minutes, about 1 minute to about 6 minutes, about 1 minute to about 5 minutes, about 1 minute to about 4 minutes, about 1 minute to about 3 minutes, or about 1 minute to about 2 minutes. The disintegration time can be measured using the method described in the examples.

[0026] As used herein, "intragranule" refers to an ingredient added before granulation so that it is incorporated into the granule. Furthermore, as used herein, "extragranule" refers to an ingredient combined with the granule before compression, such as in a tablet press.

[0027] Tablet ingredients Active drug. The tablet compositions of this disclosure contain up to about 44% by weight or up to about 40% by weight of an active drug (free base content), and may contain about 5% by weight or more of an active drug, for example, about 1% by weight, about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or about 44% by weight of an active drug (free base content), and ranges thereof, for example, about 1% by weight to about 44% by weight, about 1% by weight to about 40% by weight, about 5% by weight to about 44% by weight, about 10% by weight to about 44% by weight, about 15% by weight to about 44% by weight, about 20% by weight to about 44% by weight, about 25% by weight to about 44% by weight, about 30% by weight to about 40% by weight, or about 35% by weight to about 40% by weight of an active drug (free base content). Where used herein, weight percent is given based on the weight of the tablet core of the pharmacopoeia dose unit unless otherwise indicated.

[0028] The tablet compositions of this disclosure may contain up to about 60% by weight or up to about 54% by weight of divalasib adipine, and may contain about 5% by weight or more of divalasib adipine, for example, about 1% by weight, about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 54% by weight, about 55% by weight, and The product comprises approximately 60% by weight of divalacib adipate, and the range thereof, for example, approximately 1% to approximately 60% by weight, approximately 1% to approximately 54% by weight, approximately 5% to approximately 60% by weight, approximately 10% to approximately 60% by weight, approximately 15% to approximately 60% by weight, approximately 20% to approximately 60% by weight, approximately 25% to approximately 55% by weight, approximately 30% to approximately 50% by weight, or approximately 35% to approximately 45% by weight of divalacib adipate.

[0029] Excipients. The tablets of this disclosure comprise one or more excipients. Excipients or fillers have conventionally been included in tablets, for example, to assist in the direct compression (tableting) of granules prepared by dry granulation. However, divalasib (e.g., divalasib adipate) tablets prepared using conventional formulation approaches have been found to have slow tablet disintegration times (e.g., more than 20 minutes). While not intended to be bound by any particular theory, water penetration into the tablet is considered a limiting factor in the disintegration time of divalasib (e.g., divalasib adipate) tablets.

[0030] Based on previous experimental results, it has been found that including a water-absorbing excipient in divalasib (e.g., divalasib adipate) tablets can improve the disintegration time of the tablets. In particular, it has been found that including a certain amount of extragranular (ExG) water-absorbing excipient substantially shortens the disintegration time of divalasib (e.g., divalasib adipate) tablets.

[0031] Excipients may be appropriately added to the premixture before granulation to form intragranular (InG) excipients. Furthermore, excipients may be combined with the granulation premixture before tableting to form extragranular (ExG) excipients.

[0032] Accordingly, in one embodiment, the tablets of the present disclosure include an excipient selected from the group consisting of microcrystalline cellulose (MCC), silicated MCC, pre-gelatinized starch, starch, and combinations thereof. In one embodiment, the excipient is selected from the group consisting of MCC and starch. In a particular embodiment, the excipient is MCC.

[0033] In certain embodiments, the MCC may have an average particle size of about 20um to about 180um, or about 20um to about 100um, or about 35um to about 95um, or about 40um to about 75um, or about 45um to about 55um, for example, about 20um, about 25um, about 30um, about 35um, about 40um, about 45um, about 50um, about 55um, about 50um, about 65um, about 70um, about 75um, about 80um, about 85um, about 90um, about 95um, or about 100um. In a particular embodiment, the MCC has an average particle size of about 50um. Suitable MCCs include, but are not limited to, Avicel® PH 101, Avicel® PH 102, and Avicel® PH 105. In a particular embodiment, the MCC is Avicel® PH 101.

[0034] The total excipient content based on tablet core weight is approximately 15% by weight, 16% by weight, 17% by weight, 18% by weight, 19% by weight, 20% by weight, 21% by weight, 22% by weight, 23% by weight, 24% by weight, 25% by weight, approximately 26% by weight, approximately 27% by weight, approximately 28% by weight, approximately 29% by weight, approximately 30% by weight, approximately 31% by weight, approximately 32% by weight, approximately 33% by weight, approximately 34% by weight, approximately 35% by weight, approximately 36% by weight, approximately 37% by weight, approximately 38% by weight, or approximately 39% by weight. This includes weight%, approximately 40% by weight, approximately 41% by weight, approximately 42% by weight, approximately 43% by weight, approximately 44% by weight, approximately 45% by weight, approximately 46% by weight, approximately 47% by weight, approximately 48% by weight, approximately 49% by weight, or approximately 50% by weight, and the ranges therefrom, for example, approximately 15% to approximately 50% by weight, approximately 20% to approximately 45% by weight, approximately 30% to approximately 40% by weight, approximately 32% to approximately 38% by weight, approximately 33% to approximately 37% by weight, or approximately 34% to approximately 36% by weight.

[0035] The total content of the in-granule (InG) excipients based on the tablet core weight is approximately 10% by weight, approximately 11% by weight, approximately 12% by weight, approximately 13% by weight, approximately 14% by weight, approximately 15% by weight, approximately 16% by weight, approximately 17% by weight, approximately 18% by weight, approximately 19% by weight, approximately 20% by weight, approximately 21% by weight, approximately 22% by weight, approximately 23% by weight, approximately 24% by weight, approximately 25% by weight, approximately 26% by weight, approximately 27% by weight, approximately 28% by weight, approximately 29% by weight, or approximately 30% by weight, and the range thereof, for example, approximately 10% by weight to approximately 30% by weight, approximately 15% by weight to approximately 25% by weight, approximately 16% by weight to approximately 24% by weight, approximately 17% by weight to approximately 23% by weight, approximately 18% by weight to approximately 22% by weight, approximately 19% by weight to approximately 21% by weight, or approximately 20% by weight to approximately 21% by weight.

[0036] As will be shown in the examples herein, the amount of extragranular (ExG) excipients can affect the disintegration time of divalasib (e.g., divalasib adipate) tablets. Specifically, the use of certain water-absorbing excipients, such as MCC, surprisingly improves water penetration into the tablets and, consequently, the tablet disintegration time. Therefore, in one embodiment, the total content of extragranular (ExG) excipients based on the tablet core weight is approximately 5% by weight, approximately 6% by weight, approximately 7% by weight, approximately 8% by weight, approximately 9% by weight, approximately 10% by weight, approximately 11% by weight, approximately 12% by weight, approximately 13% by weight, approximately 14% by weight, approximately 15% by weight, approximately 16% by weight, approximately 17% by weight, approximately 18% by weight, approximately 19% by weight, or approximately 20% by weight, and in the range thereof, for example, approximately 5% to approximately 20% by weight, approximately 8% to approximately 18% by weight, approximately 10% to approximately 20% by weight, approximately 10% to approximately 15% by weight, approximately 11% to approximately 19% by weight, approximately 12% to approximately 18% by weight, or approximately 14% to approximately 16% by weight.

[0037] Disintegrants. Disintegrants are used to ensure that tablets disintegrate rapidly. This is achieved, for example, by rapid swelling upon contact with an aqueous medium. Disintegrants may be appropriately added to a premixture before granulation to form an intragranular (InG) disintegrant. Furthermore, disintegrants may be combined with a granular premixture before tableting to form an extragranular (ExG) disintegrant. Disintegrants are known in the art. Non-limiting examples include modified starches such as sodium carboxymethyl starch (sodium starch glycolate, "SSG"), cross-linked polyvinylpyrrolidones such as crospovidone ("crossPVP"), modified celluloses such as croscarmellose sodium ("NaCMC" or "CCS"), gums such as cross-linked alginic acid, gellan gum and xanthan gum, and calcium silicate. In some aspects of this disclosure, the disintegrant is croscarmellose sodium, crospovidone, sodium starch glycolate, or a combination thereof. In some aspects of this disclosure, the disintegrant is croscarmellose sodium.

[0038] The total amount of tablet disintegrant added, based on the tablet core weight, may be approximately 2% by weight, approximately 3% by weight, approximately 4% by weight, approximately 5% by weight, approximately 6% by weight, approximately 7% by weight, approximately 8% by weight, approximately 9% by weight, approximately 10% by weight, approximately 11% by weight, approximately 12% by weight, or approximately 13% by weight and its range, for example, approximately 2% to approximately 13% by weight, approximately 3% to approximately 12% by weight, approximately 4% to approximately 11% by weight, approximately 5% to approximately 10% by weight, approximately 6% to approximately 9% by weight, or approximately 7% to approximately 8% by weight.

[0039] The total amount of tablet granule disintegrant added, based on the tablet core weight, may be approximately 1% by weight, approximately 1.5% by weight, approximately 2% by weight, approximately 2.5% by weight, approximately 3% by weight, approximately 3.5% by weight, approximately 4% by weight, approximately 4.5% by weight, or approximately 5% by weight and its range, for example, approximately 1% to approximately 5% by weight, approximately 1.5% to approximately 4.5% by weight, approximately 2% to approximately 4% by weight, approximately 2.5% to approximately 3.5% by weight, or approximately 2.75% to approximately 3.25% by weight.

[0040] The total amount of extragranular disintegrant added to the tablet, based on the tablet core weight, may be approximately 1% by weight, approximately 1.5% by weight, approximately 2% by weight, approximately 2.5% by weight, approximately 3% by weight, approximately 3.5% by weight, approximately 4% by weight, approximately 4.5% by weight, approximately 5% by weight, approximately 5.5% by weight, approximately 6% by weight, approximately 6.5% by weight, approximately 7% by weight, approximately 7.5% by weight, or approximately 8% by weight and its range, for example, approximately 1% to approximately 8% by weight, approximately 1.5% to approximately 7.5% by weight, approximately 2% to approximately 7% by weight, approximately 2.5% to approximately 6.5% by weight, approximately 3% to approximately 6% by weight, approximately 3.5% to approximately 5.5% by weight, or approximately 4% to approximately 5% by weight.

[0041] Based on previous experimental results, it has been found that, surprisingly, the total amount of extragranular excipients and extragranular disintegrants can affect the penetration of water into the tablet, and therefore result in tablets with shorter disintegration times. Thus, in one embodiment, the total amount of extragranular excipients and extragranular disintegrants based on the tablet core weight may be about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, or about 25% by weight, and in the range thereof, for example, about 15% to about 25% by weight, about 16% to about 24% by weight, about 17% to about 23% by weight, about 18% to about 22% by weight, or about 19% to about 20% by weight.

[0042] Lubricants. Lubricants are added to tableting compositions to reduce friction between the surface of the manufacturing equipment and the surface of the organic solid in the tablet composition, to facilitate ejection from the tablet press, to affect the dynamics of the dry granulation and tableting process, and to affect the mechanical properties of the tablets. Lubricants may be appropriately added to the premixture before granulation to form an intragranular lubricant. Furthermore, lubricants may be combined with the granulation premixture before tableting to form an extragranular lubricant. Lubricants are known in the art. Non-limiting examples include magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, polyethylene glycol (4000-6000), and sodium lauryl sulfate. In some aspects of this disclosure, the lubricant is magnesium stearate, sodium stearyl fumarate, stearic acid, and combinations thereof. In one aspect, the lubricant is magnesium stearate.

[0043] The total amount of tablet lubricant added to the tablet core base may be approximately 1% by weight, approximately 1.25% by weight, approximately 1.5% by weight, approximately 1.75% by weight, approximately 2% by weight, approximately 2.25% by weight, approximately 2.5% by weight, approximately 2.75% by weight, or approximately 3% by weight and its range, for example, approximately 1% to approximately 3% by weight, approximately 1.5% to approximately 2.5% by weight, approximately 1.75% to approximately 2.5% by weight, or approximately 2% to approximately 2.5% by weight.

[0044] The total amount of lubricant added to the tablet granules in the tablet core base may be approximately 0.1% by weight, approximately 0.15% by weight, approximately 0.2% by weight, approximately 0.25% by weight, approximately 0.3% by weight, approximately 0.4% by weight, approximately 0.5% by weight, approximately 0.75% by weight, approximately 1% by weight, approximately 1.25% by weight, approximately 1.5% by weight, approximately 2.0% by weight, approximately 2.5% by weight, or approximately 3.0% by weight, and in their ranges, for example, approximately 0.1% to approximately 1.5% by weight, approximately 0.2% to approximately 1.25% by weight, approximately 0.5% to approximately 1.25% by weight, or approximately 1% to approximately 3% by weight.

[0045] The total amount of extragranular lubricant added to the tablet core may be approximately 0.5% by weight, approximately 0.75% by weight, approximately 1% by weight, approximately 1.25% by weight, approximately 1.5% by weight, approximately 1.75% by weight, approximately 2% by weight, approximately 2.25% by weight, approximately 2.5% by weight, or approximately 3% by weight, and their ranges, for example, approximately 0.5% to approximately 3% by weight, approximately 0.5% to approximately 2.5% by weight, approximately 0.75% to approximately 2.25% by weight, approximately 0.75% to approximately 2% by weight, approximately 1% to approximately 3% by weight, approximately 1% to approximately 2% by weight, approximately 1% to approximately 1.75% by weight, or approximately 1.25% to approximately 1.5% by weight. In some specific embodiments, the lubricant is present in the granules at a level ranging from 0.75% to 1.25% and outside the granules at a level ranging from 1% to 1.50%, with a total additive amount of 1.75% to 2.75%.

[0046] Tablet coating. The tablets (tablet cores) of this disclosure are preferably coated with a film coating to provide tablets that are primarily tasteless and odorless and easy to swallow. Furthermore, the film coating prevents dust formation during packaging and ensures robustness during transport. Commercially available coating compositions are suitable for the purposes of this disclosure and include, but are not limited to, Opadry® YS grades such as Opadry® YS-1-7003 and Opadry® YS-1-18202, and Opadry® II grades such as Opadry® II White 85F18422 and Opadry® II Brown 85F26792. In any of the various coating embodiments, the surface of the tablet core is coated with a film coating in an amount of about 2% to about 6% by weight, or about 2% to about 4% by weight, based on the weight of the tablet core. In some aspects of this disclosure, the film coating comprises about 30% to about 50% by weight, about 35% to about 45% by weight, or 38% to 42% by weight of a coating agent (e.g., polyvinyl alcohol), about 20% to about 30% by weight, or 23.8% to 26.3% by weight of a pigment (e.g., titanium dioxide), about 15% to about 25% by weight, or 19.2% to 21.2% by weight of a plasticizer (e.g., macrogol / PEG3350), and about 10% to about 20% by weight, or 14.1% to 15.5% by weight of an anti-caking agent (e.g., talc).

[0047] Any ingredient. Other optional tablet core ingredients include talc (anti-adhesive / lubricant), fumed silicon dioxide (i.e., colloidal silicon dioxide) (anti-adhesive / lubricant), citric acid (pH adjuster), and tartaric acid (pH adjuster).

[0048] Tablet manufacturing method The tablet manufacturing method of this disclosure utilizes standard and conventional pharmaceutical operations such as sieving, mixing, dry granulation, compression, and film coating.

[0049] In one embodiment, the method of the present disclosure includes: mixing an active drug (e.g., divalasib adipate) with an internal excipient (e.g., MCC) and an internal disintegrant (e.g., NaCMC) to form a premixture; compressing the premixture by applying a compressive force; crushing and sieving the compressed premixture to form granules; mixing the granules with an external excipient (e.g., MCC) and an external disintegrant (e.g., NaCMC) to form a granular mixture; and tableting the granular mixture by applying a tablet compressive force to form a tablet core. In certain embodiments, the method may further include mixing the premixture with an internal lubricant (e.g., magnesium stearate "MgSt") before compression. In certain embodiments, the method may further include mixing the granules, external excipient and external disintegrant with an external lubricant to form a granular mixture before tableting.

[0050] More specifically, in one process of the present disclosure shown in Figure 1, excipients and disintegrants are combined with an active drug (e.g., divalacib adipinate) to form a premixture, and the premixture is sieved. A lubricant is further combined with the premixture in a bottle or blender. In some arbitrary embodiments, the excipients and disintegrants are sieved, combined with an active drug (e.g., divalacib adipinate), mixed for a first mixing period, followed by the addition of the sieved lubricant, mixed for a second mixing period to form a premixture. As described herein, the excipients, disintegrants, and lubricants in the premixture are referred to as granules. In any arbitrary embodiment, the powder flowability, density, and / or true density of the premixture can be determined using conventional means.

[0051] Next, the premixture is processed by roller compression granulation, followed by grinding and sieving to form granules. In any one embodiment, the particle size, granular flowability, and density of the granules can be determined using conventional means. The granules are combined with additional sieved lubricant, sieved disintegrant, and sieved excipient and mixed to form a granular mixture. In some arbitrary embodiments, the granules are combined with the sieved disintegrant and sieved excipient, mixed for a first period, followed by the addition of the sieved lubricant and mixed for a second mixing period to form a granular mixture. The disintegrant, excipient, and lubricant combined with the granules are called extragranular. In any one embodiment, the powder flowability, true density, and adhesion to the punch of the granular mixture can be determined using conventional means. The granular mixture is compressed using any suitable tableting apparatus known in the art to form a tablet core. The tablet core is coated with a film coating to form the finished tablet.

[0052] In one particular method of this disclosure, an internal excipient (e.g., MCC) and a disintegrant (e.g., croscarmellose sodium) are sieved and combined with an active drug (e.g., divalasib adipate) in a first premixing step and mixed. The first mixture material is combined with a sieved lubricant (e.g., magnesium stearate) and mixed in a second premixing step to form a premixture. The premixture is granulated by roller compression granulation, crushed, and sieved to form granules. The granules are combined with a sieved external excipient and a sieved external disintegrant and mixed in a first final mixing step. The first mixture material is combined with a sieved external lubricant and mixed in a second final mixing step to form a granular mixture. A granular mixture is compressed using any suitable tableting apparatus known in the art to form a tablet core. A solid film coating material is suspended together with an aqueous carrier. The tablet core is coated with the film coating suspension to form a finished tablet.

[0053] Premixing. Premixing is designed to bring substantial homogeneity of the components within the granules before roller compression granulation. Premixing equipment and associated process parameters used to obtain an essentially homogeneous mixture are known to those skilled in the art and are not considered strictly limited. Suitable blenders are known in the art, and any equipment commonly used in the pharmaceutical industry to homogeneously mix two or more components is known, such as V-blenders, double-cone blenders, bin (container) blenders, and rotary drum blenders. The volume of the mixing blender, the fill of the blender, the rotation speed, and the rotation time can be appropriately determined by those skilled in the art based on usual experiments to achieve an essentially homogeneous mixture of components. Blender volumes are appropriately 5L, 10L, 25L, 50L, 100L, 200L, 250L or more. The blender filling selection allows for convection and three-dimensional material movement and is appropriately around 25%, 30%, 35%, 40%, 50%, 60%, or 70%, and its range, for example, 30% to 60%, 45% to 65%, 32% to 53%, or 40% to 50%. The mixing time is appropriately 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, or 60 minutes or more. The rotation speed is appropriately 2 rpm, 3 rpm, 4 rpm, 5 rpm, 6 rpm, 7 rpm, 8 rpm, 9 rpm, or 10 rpm.

[0054] Excipients, lubricants, and disintegrants are typically crushed by sieving before mixing. Sieving methods are known to those skilled in the art.

[0055] In one particular embodiment of the premixing method of this disclosure, an excipient (e.g., MCC) and a disintegrant (e.g., croscarmellose sodium) are sieved to break up agglomerates and combined with an active drug (e.g., divalacib adipate) in a blender, and the contents of the blender are mixed at a constant rotation speed (e.g., 6 rpm) for a mixing time (e.g., 30 minutes). A lubricant (e.g., magnesium stearate) is sieved to break up and added to the blender containing the combined excipient, disintegrant, and active drug (e.g., divalacib adipate). The contents of the blender are mixed at a constant rotation speed (e.g., 6 rpm) for a mixing time (e.g., 8 minutes) to form a premixture.

[0056] In another example of one premixture embodiment of the present disclosure, an active drug (e.g., divalasib adipate) is mixed with a crushed disintegrant (e.g., croscarmellose sodium) for a mixing time (e.g., 5 minutes at 6 rpm). A crushed excipient (e.g., MCC) is added to the blender and the contents are mixed for a mixing time (e.g., several minutes at 6 rpm). A crushed lubricant (e.g., magnesium stearate) is added to the blender and the contents are mixed for a mixing time (e.g., 2 minutes).

[0057] Granulation and sizing. Granulation and sizing can be achieved using any suitable means known to those skilled in the art. In some specific aspects of this disclosure, granulation and sizing include dry granulation, grinding and sieving. In some other aspects of this disclosure, dry granulation is roller compression granulation.

[0058] Granulation and sizing improve the flow and compressibility of mixtures of active drugs and excipients. Roller compression granulation is a process that causes premixture powder particles to adhere to each other, resulting in larger granular multi-particle entities. Roller compression granulation generally involves three basic operations: a feed system, a compression unit, and a grinding / sieving unit. In the compression unit, the premixture is compressed by applying a roller compression force (expressed as kN / cm) between rolls rotating in opposite directions to form a compressed material-forming mass such as a ribbon or sheet. The distance between the rolls is the gap width. The formed compressed material ribbon is processed in a size reduction unit by grinding to form granules, which are then sieved to produce multiple granules with the desired particle size distribution.

[0059] Roller compression granulation and grinding equipment is commercially available from several manufacturers, including Gerteis, Fitzpatrick®, and Freund-Vector. Such equipment generally allows control of the roller compression force, gap width, roller speed, and feed rate. The roller surfaces may be smooth, knurled, or one roller surface may be smooth and the other knurled. In any of the various embodiments, a premixture is fed into a roller compactor feed hopper. Roller compression granulation is performed with a specified force and gap size, and the process is preferably carried out under gap control. The formed ribbons are ground through a sieve to produce granules. In some embodiments of this disclosure, the sieve is integrated with the mill.

[0060] While not bound by any particular theory, the properties of ribbons and the granules formed therefrom are thought to be influenced by various variables in roller compression granulation and grinding, such as roller compression force, gap width, mass of raw material passing through, sieve size, and the uniformity and composition of the premixture. Furthermore, the properties of the formed ribbons (influenced by gap size, roller compression force, etc.) are thought to affect the appearance of the tablets, among other effects, due to film formation / adhesion to the punch. In addition, the variables of roller compression granulation are thought to affect the granule size distribution, granule density (and therefore compressibility), and granule flowability. The gap size in roller compression granulation is thought to affect the cohesiveness of the final mixture particles, with smaller gap sizes resulting in granules that tend to adhere more. Furthermore, with small gap sizes, film formation on the punch during tablet compression and the production of tablets with poor appearance are thought to occur. The roller compression force is thought to affect the densification of the premixture during granulation, affecting granule properties and the in vitro dissolution of the resulting tablets. Increasing the roller compression force can produce a final mixture with better fluidity, reducing variations in main compression force and tablet weight, and improving control over the uniformity of the dosage unit. The sieve size for grinding can affect the particle size distribution of the granules. The particle size distribution affects fluidity, which in turn can affect the uniformity of the dosage unit. For example, poor fluidity can affect die filling with tablet weight variations. In tablet embodiments where the disintegrant is present both inside and outside the granules, tablet disintegration is generally considered to be unaffected by granule size.

[0061] The combination of roller compression force and gap size is thought to affect ribbon / granule density, particularly as the gap decreases, and thus influence the in vitro dissolution of the resulting tablets. Gap size, along with roller compression force, has also been observed to affect the tendency of the final mixture to adhere during tablet compression and the production of tablets with poor appearance.

[0062] In any of the various aspects of this disclosure, the gap size (gap width) is about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, or about 6 mm, and a range thereof, for example, about 1 mm to about 6 mm, about 2 mm to about 5 mm, about 2 mm to about 4 mm, about 3 mm to about 5 mm, or about 4 mm to about 5 mm. Based on previous experimental evidence, such gap sizes are generally sufficient to reduce adhesion. The roller compressive force is about 1 kN / cm, about 2 kN / cm, about 3 kN / cm, about 4 kN / cm, about 5 kN / cm, about 6 kN / cm, about 7 kN / cm, or about 8 kN / cm, and a range thereof, for example, about 1 kN / cm to about 8 kN / cm, about 2 kN / cm to about 5 kN / cm, or about 2 kN / cm to about 4 kN / cm.

[0063] In any of the various aspects of this disclosure, the grinding sieve sizes are 0.5 mm, 0.75 mm, 0.8 mm, 1.0 mm, 1.25 mm, 1.5 mm, 1.75 mm, 2.0 mm, 2.25 mm, or 2.5 mm, and their ranges, for example, about 0.5 mm to about 2.5 mm, about 0.5 mm to about 2.0 mm, about 0.5 mm to about 1.5 mm, about 0.5 mm to about 1.25 mm, about 0.75 mm to about 2.5 mm, about 0.75 mm to about 2.0 mm, about 0.75 mm to about 1.5 mm, and about 0.75 mm to about 1.25 mm. In some specific aspects of this disclosure, a 1.0 mm grinding sieve is used.

[0064] The gap ribbon density (defined as the ribbon throughput per unit of operation time divided by the calculated volume per unit of time) is a result of the combination of roller compression granulation parameters and is considered to correlate with granule properties and processability during tablet compression. The gap ribbon density is appropriately approximately 0.85 g / mL, 0.9 g / mL, 0.95 g / mL, 1.0 g / mL, 1.05 g / mL, 1.1 g / mL, 1.15 g / mL, 1.2 g / mL, 1.25 g / mL, or 1.3 g / mL and its range, for example, approximately 0.85 g / mL to 1.3 g / mL, approximately 0.9 g / mL to 1.25 g / mL, or approximately 0.95 g / mL to 1.2 g / mL. In some aspects of this disclosure, a low gap ribbon density of approximately 0.85 g / mL to approximately 95 g / mL or approximately 0.9 g / mL to approximately 0.95 g / mL is selected and controlled. In some other aspects of this disclosure, a center point gap ribbon density of approximately 0.95 g / mL to approximately 1.1 g / mL, approximately 0.95 g / mL to approximately 105 g / mL, approximately 1 g / mL to approximately 1.10 g / mL or approximately 1 g / mL to approximately 1.05 g / mL is selected and controlled. In yet another aspect of this disclosure, high gap ribbon densities of approximately 1.1 g / mL to approximately 1.3 g / mL, approximately 1.1 g / mL to approximately 1.25 g / mL, approximately 1.1 g / mL to approximately 1.2 g / mL, approximately 1.1 g / mL to approximately 1.15 g / mL, approximately 1.15 g / mL to approximately 1.3 g / mL, approximately 1.15 g / mL to approximately 1.25 g / mL, or approximately 1.15 g / mL to approximately 1.2 g / mL are selected and controlled.

[0065] Final mixing. In the final mixing step, the granules formed by roller compression granulation and grinding are introduced into a blender, and any external components of the disintegrant (e.g., croscarmellose sodium), excipient (e.g., MCC), and lubricant (e.g., magnesium stearate) are added to the blender to form a mixture. The final mixing step results in an essentially uniform distribution of any external disintegrant, excipient, and lubricant, providing acceptable processability during tablet compression. Suitable blenders and associated process variables are described above.

[0066] In some embodiments, the disintegrant and / or excipient is crushed before being added to the blender, and the disintegrant and / or excipient is mixed with the granules under a first set of mixing conditions (e.g., 29 rpm for 2 minutes). In a second final mixing step, the lubricant is crushed, added to the blender, and mixed under a second set of mixing conditions (e.g., 29 rpm for about 6 minutes).

[0067] In any of the various embodiments of this disclosure, the bulk density of the granular mixture is about 0.4 g / mL, about 0.45 g / mL, about 0.5 g / mL, about 0.55 g / mL, about 0.6 g / mL, about 0.65 g / mL, about 0.7 g / mL, or about 0.75 g / mL and its range, for example, about 0.4 g / mL to about 0.75 g / mL, about 0.45 g / mL to about 0.7 g / mL, or 0.51 g / mL to 0.63 g / mL. The final mixture is preferably easily flowable or free-flowing and has at least 4 flow function coefficients.

[0068] Tableting. In the tableting process, the final mixture material is filled into a tableting die, the mixture is compressed to form a tablet core, and then ejected. Suitable tablet presses are known in the art and are commercially available, for example, from Korsch AG, Riva-Piccola, Fette, Bosch Packaging Technology, GEA, and Natoli Engineering Company. Generally, each tablet is made by pressing granules inside a die made of hardened steel. The die is disc-shaped with a hole running through its center. The powder is compressed in the center of the die by two hardened steel punches that fit into the top and bottom of the die, thereby forming the tablet. Tablet compression may be carried out in two stages: in the first pre-compression stage, the powder is tamped to slightly compress the mixture, and then the main compressive force for tablet formation is applied. The tablet is ejected from the die after compression.

[0069] The primary compressive force affects tablet properties such as hardness and appearance. The primary compressive force also influences the adhesion of the final mixture to the tablet tool during compression; increased force reduces adhesion, resulting in fewer tablets with appearance defects. Furthermore, the compressibility of the final mixture can affect the quality of the resulting tablet core (presence or absence of defects). Compression processing parameters such as compressive force and execution time can also have an effect. The attributes of the final mixture material and compression processing parameters can also affect the variability and content of the tablet weight. Additionally, variations in the attributes of the final mixture material and compression processing parameters can affect the variability of the tablet weight, which directly relates to the uniformity of the dosage unit. Furthermore, tablet core quality attributes such as tablet disintegration, hardness, abrasion, and porosity are related to dissolution and are affected by the compression processing parameters.

[0070] In some aspects of this disclosure, the compressive force (tablet compressive force) is about 4kN, about 5kN, about 6kN, about 7kN, about 8kN, about 9kN, about 10kN, about 11kN, about 12kN, about 13kN, about 14kN, about 15kN, about 16kN, about 17kN, about 18kN, about 19kN, or about 20kN, and their ranges, for example, about 4kN to about 20kN, about 14kN to about 19kN, about 14kN to about 18kN, or about 8kN to about 13kN. In some aspects of this disclosure, a tablet containing about 100mg of active drug may be formed with a compressive force of about 6kN to about 9kN. In other aspects of this disclosure, a tablet containing about 400mg of active drug may be formed with a compressive force of about 9kN to about 12kN.

[0071] Film coating. The tablet core is film-coated to ensure that the tablet is essentially tasteless and odorless and easy to swallow. Film coating also prevents dust formation during packaging and ensures robustness during transport. Film coating can be adequately carried out by methods known in the art, such as pan coating. Suitable coating apparatuses include, but are not limited to, the O'Hara Labcoat® system.

[0072] In some aspects of the present disclosure, the tablet core is filled into a coating pan and heated to a target temperature. The coating suspension is prepared to a target solids content. When the tablets are within the target temperature range, drum rotation and spraying are carried out at a target speed designed to achieve a predetermined weight gain of about 3 wt%, about 4 wt% or about 5 wt%. The outlet air temperature is maintained within a range that ensures that the target product temperature is obtained throughout the coating. Once spraying is complete, the coated tablets are dried, cooled, and then the film-coated tablets are discharged. The solids content of the coating suspension is suitably about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, or about 20 wt%, and ranges thereof, such as about 12 wt% to about 20 wt%, or about 14 wt% to about 20 wt%. The coating spray rate per 1 kg of tablet core is suitably about 0.8, about 1, about 1.5, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4 or about 2.5, and ranges thereof, such as about 0.8 to about 2.5, or about 1 to about 2.1. The coating temperature is suitably about 35°C, about 39°C, about 40°C, about 45°C, about 47°C, about 48°C, about 49°C, about 50°C or about 55°C, and ranges thereof, such as about 35°C to about 50°C, or about 39°C to about 47°C. The pan rotation speed is suitably about 2 rpm, about 4 rpm, about 5 rpm, about 8 rpm, about 10 rpm, about 12 rpm, about 15 rpm or about 20 rpm, and ranges thereof, such as about 2 to about 20 rpm, about 4 to about 15 rpm, or about 8 to about 12 rpm. The amount of inlet air varies depending on the batch size and is suitably about 100 m 3 / h, about 300 m 3 / h, about 450 m 3 / h, about 600 m 3 / h, about 750 m 3 / h, about 1000 m 3 / h, about 1250 m 3 / h, or about 1500 m 3 / h, and ranges thereof, such as about 100 m 3 / h to about 1500 m 3 / h, about 300 to about 1500 m 3 / h, about 450 to about 1200 m 3 / h, or approximately 1000-1250m 3 It is / h.

[0073] Tablet cores and coated tablets. In some aspects of this disclosure, the tablet core contains each component in its concentration range in weight percent based on the weight of the core, as shown in Table 1.

[0074] [Table 1]

[0075] In some aspects of this disclosure, the tablet core contains each component in its concentration range in weight percent based on the core weight, as shown in Table 2.

[0076] [Table 2]

[0077] In some aspects of this disclosure, the tablet core contains each component in its concentration range in weight percent based on the core weight, as shown in Table 3.

[0078] [Table 3]

[0079] In some aspects of this disclosure, the tablet core contains each component in its concentration range in weight percent based on the core weight, as shown in Table 4.

[0080] [Table 4]

[0081] In some aspects of this disclosure, the tablet core contains each component in its concentration range in weight percent based on the core weight, as shown in Table 5.

[0082] [Table 5]

[0083] In some aspects of this disclosure, the tablet core is coated and contains each component in its concentration range in weight percent based on the core weight, as shown in Table 6. Table 7 shows the components and concentrations in weight percent of exemplary film coating compositions. Other standard film coatings, including but not limited to Opadry® products, may also be used.

[0084] [Table 6]

[0085] [Table 7]

[0086] The tablets and tablet cores of this disclosure may have a tensile strength (TS) of about 2.0 MPa to about 3.0 MPa, for example, about 2.0 MPa, about 2.5 MPa, and about 3.0 MPa. The tablets and tablet cores of this disclosure may have a solids content (SF) of about 0.80 to about 0.90.

[0087] In one embodiment, the tablet and tablet core are as shown in one of the formulations provided in Tables 8, 9, 10, 12, 13, 14, 15, or 16. In such one embodiment, the tablet and / or tablet core are as shown in Table 8 of this specification. In another such embodiment, the tablet and / or tablet core are as shown in Table 9 of this specification. In another such embodiment, the tablet and / or tablet core are as shown in Table 10 of this specification. In another such embodiment, the tablet and / or tablet core are as shown in Table 12 of this specification. In another such embodiment, the tablet and / or tablet core are as shown in Table 13 of this specification. In another such embodiment, the tablet and / or tablet core are as shown in Table 14 of this specification. In another such embodiment, the tablet and / or tablet core are as shown in Table 15 of this specification. In another such embodiment, the tablet and / or tablet core are as shown in Table 16 of this specification.

[0088] Embodiments: Several exemplary embodiments of the present invention are provided below.

[0089] Embodiment 1. A tablet core for a drug administration unit, wherein the tablet core is (a) Divalasib and, (b) A disintegrant in an amount of approximately 2% to 13% by weight based on the weight of the drug administration unit tablet core, (c) Excipients in an amount of approximately 15% to 50% by weight based on the weight of the tablet core of the pharmaceutical administration unit, A tablet core containing the drug dosage unit.

[0090] Embodiment 2. The drug dose unit tablet core according to Embodiment 1, wherein the free base content of divalasib is up to approximately 44% by weight, based on the weight of the drug dose unit tablet core.

[0091] Embodiment 3. The drug administration unit tablet core according to Embodiment 1, wherein divalasib is divalasib adipine salt.

[0092] Embodiment 4. The drug dose unit tablet core according to Embodiment 3, wherein the divalasib adipate content is up to approximately 60% by weight, based on the weight of the drug dose unit tablet core.

[0093] Embodiment 5. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 4, wherein the disintegrant is selected from the group consisting of croscarmellose sodium (CCS), sodium starch glycolate (SSG), crospovidone (crosPVP), and combinations thereof.

[0094] Embodiment 6. The pharmaceutical administration unit tablet core according to Embodiment 5, wherein the disintegrant is CCS.

[0095] Embodiment 7. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 6, wherein the excipient is selected from the group consisting of starch, microcrystalline cellulose (MCC), and combinations thereof.

[0096] Embodiment 8. The pharmaceutical administration unit tablet core according to Embodiment 7, wherein the excipient is MCC.

[0097] Embodiment 9. A pharmaceutical administration unit tablet core according to Embodiment 8, wherein the average particle size of the MCC is approximately 20 μm to approximately 180 μm.

[0098] Embodiment 10. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 9, further comprising a lubricant in an amount of about 1% to about 3% by weight based on the weight of the pharmaceutical dosage unit tablet core.

[0099] Embodiment 11. The pharmaceutical dosage unit tablet core according to Embodiment 10, wherein the lubricant is magnesium stearate.

[0100] Embodiment 12. A drug administration unit tablet core according to any one of Embodiments 1 to 11, wherein the drug administration unit tablet core has a tensile strength of approximately 2.0 MPa to approximately 3.0 MPa.

[0101] Embodiment 13. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 12, wherein the pharmaceutical dosage unit tablet core has a solid content ratio of approximately 0.80 to approximately 0.90.

[0102] Embodiment 14. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 13, further comprising a film coating on the surface of the tablet core.

[0103] Embodiment 15. A drug administration unit tablet core according to any one of Embodiments 1 to 14, wherein the disintegration time of the drug administration unit tablet core is approximately 15 minutes or less.

[0104] Embodiment 16. A drug administration unit tablet core according to any one of Embodiments 1 to 15, wherein the disintegration time of the drug administration unit tablet core is approximately 10 minutes or less.

[0105] Embodiment 17. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 16, wherein the disintegration time of the pharmaceutical dosage unit tablet core is approximately 5 minutes or less.

[0106] Embodiment 18. A method for preparing a drug dosage unit tablet core, (a) Mix divalasib, an internal excipient, and an internal disintegrant to form a premixture, (b) Compressing the premixture by applying a compressive force, (c) Crushing and sieving the compressed premixture to form granules, (d) Mixing granules with an external excipient and an external disintegrant to form a granule mixture, (e) Compressing the granular mixture into tablets by applying a compressive force to form a drug administration unit tablet core, Methods that include...

[0107] Embodiment 19. The method according to Embodiment 18, wherein the excipient in the granules is selected from the group consisting of starch, microcrystalline cellulose (MCC), and combinations thereof.

[0108] Embodiment 20. The method according to Embodiment 19, wherein the excipient in the granules is MCC.

[0109] Embodiment 21. The method according to any one of Embodiments 18 to 20, wherein the content of the granular excipient is about 10% by weight to about 30% by weight, based on the weight of the drug administration unit tablet core.

[0110] Embodiment 22. The method according to Embodiment 21, wherein the content of the excipient in the granules is about 15% to about 25% by weight, based on the weight of the drug administration unit tablet core.

[0111] Embodiment 23. The method according to Embodiment 22, wherein the content of the excipient in the granules is about 20% by weight to about 21% by weight, based on the weight of the drug administration unit tablet core.

[0112] Embodiment 24. The method according to any one of Embodiments 18 to 23, wherein the granular disintegrant is selected from the group consisting of croscarmellose sodium (CCS), sodium starch glycolate (SSG), crospovidone (crosPVP), and combinations thereof.

[0113] Embodiment 25. The method according to Embodiment 24, wherein the granular disintegrant is CCS.

[0114] Embodiment 26. The method according to any one of Embodiments 18 to 25, wherein the content of the granule disintegrant is about 1% by weight to about 5% by weight, based on the weight of the drug administration unit tablet core.

[0115] Embodiment 27. The method according to Embodiment 26, wherein the content of the granule disintegrant is about 2% to about 4% by weight, based on the weight of the drug administration unit tablet core.

[0116] Embodiment 28. The method according to Embodiment 27, wherein the content of the granule disintegrant is about 3% by weight, based on the weight of the drug dose unit tablet core.

[0117] Embodiment 29. The method according to any one of Embodiments 18 to 28, wherein the granular excipient is selected from the group consisting of starch, microcrystalline cellulose (MCC), and combinations thereof.

[0118] Embodiment 30. The method according to Embodiment 29, wherein the granular excipient is MCC.

[0119] Embodiment 31. The method according to any one of Embodiments 18 to 30, wherein the content of the granular excipient is about 5% to about 20% by weight, based on the weight of the drug administration unit tablet core.

[0120] Embodiment 32. The method according to Embodiment 31, wherein the content of the granular excipient is about 10% to about 20% by weight, based on the weight of the drug administration unit tablet core.

[0121] Embodiment 33. The method according to Embodiment 32, wherein the content of the granular excipient is about 15% to about 20% by weight, based on the weight of the drug administration unit tablet core.

[0122] Embodiment 34. The method according to Embodiment 33, wherein the content of the granular excipient is about 15% by weight, based on the weight of the drug administration unit tablet core.

[0123] Embodiment 35. The method according to any one of Embodiments 18 to 34, wherein the extragranular disintegrant is selected from the group consisting of croscarmellose sodium (CCS), sodium starch glycolate (SSG), crospovidone (crosPVP), and combinations thereof.

[0124] Embodiment 36. The method according to Embodiment 35, wherein the extragranular disintegrant is CCS.

[0125] Embodiment 37. The method according to any one of Embodiments 18 to 36, wherein the content of the extragranular disintegrant is about 1% by weight to about 8% by weight, based on the weight of the drug administration unit tablet core.

[0126] Embodiment 38. The method according to Embodiment 37, wherein the content of the extragranular disintegrant is about 4% to about 5% by weight, based on the weight of the drug administration unit tablet core.

[0127] Embodiment 39. The method according to Embodiment 38, wherein the content of the extragranular disintegrant is about 5% by weight, based on the weight of the drug dose unit tablet core.

[0128] Embodiment 40. The method according to any one of Embodiments 18 to 39, further comprising mixing the premixture with the granular lubricant before compression.

[0129] Embodiment 41. The method according to Embodiment 40, wherein the granular lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, and combinations thereof.

[0130] Embodiment 42. The method according to Embodiment 41, wherein the lubricant within the granules is magnesium stearate.

[0131] Embodiment 43. The method according to any one of Embodiments 42 to 43, wherein the content of the granular lubricant is about 1% by weight to about 3% by weight, based on the weight of the drug dose unit tablet core.

[0132] Embodiment 44. The method according to Embodiment 43, wherein the content of the lubricant within the granules is about 1% by weight, based on the weight of the drug dose unit tablet core.

[0133] Embodiment 45. The method according to any one of Embodiments 18 to 44, further comprising mixing granules, an external excipient and an external disintegrant with an external lubricant to form a granular mixture before tableting.

[0134] Embodiment 46. The method according to Embodiment 45, wherein the granular external lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, and combinations thereof.

[0135] Embodiment 47. The method according to Embodiment 46, wherein the granular external lubricant is magnesium stearate.

[0136] Embodiment 48. The method according to any one of Embodiments 45 to 47, wherein the content of the extragranular lubricant is about 1% by weight to about 3% by weight, based on the weight of the pharmaceutical dosage unit tablet core.

[0137] Embodiment 49. The method according to Embodiment 48, wherein the content of the extragranular lubricant is about 1% by weight to about 2% by weight, based on the weight of the drug administration unit tablet core.

[0138] Embodiment 50. The method according to Embodiment 49, wherein the content of the extragranular lubricant is about 1.25% by weight, based on the weight of the pharmaceutical dosage unit tablet core.

[0139] Embodiment 51. The method according to any one of Embodiments 18 to 50, wherein the free base content of divalasib is up to about 44% by weight, based on the weight of the drug dose unit tablet core.

[0140] Embodiment 52. The method according to Embodiment 51, wherein the free base content of divalasib is up to about 40% by weight, based on the weight of the drug dose unit tablet core.

[0141] Embodiment 53. The method according to Embodiment 52, wherein the free base content of divalasib is about 1% to about 44% by weight, based on the weight of the drug dose unit tablet core.

[0142] Embodiment 54. The method according to Embodiment 53, wherein the free base content of divalasib is about 1% to about 40% by weight, based on the weight of the drug dose unit tablet core.

[0143] Embodiment 55. The method according to Embodiment 54, wherein the free base content of divalasib is about 40% by weight, based on the weight of the drug dose unit tablet core.

[0144] Embodiment 56. The method according to any one of Embodiments 18 to 55, wherein divalasib is divalasib adipate.

[0145] Embodiment 57. The method according to Embodiment 56, wherein the content of divalasib adipate is up to about 60% by weight, based on the weight of the drug dose unit tablet core.

[0146] Embodiment 58. The method according to Embodiment 56, wherein the content of divalasib adipate is up to about 54% by weight, based on the weight of the drug dose unit tablet core.

[0147] Embodiment 59. The method according to Embodiment 56, wherein the content of divalasib adipate is about 1% to about 60% by weight, based on the weight of the drug dose unit tablet core.

[0148] Embodiment 60. The method according to Embodiment 59, wherein the content of divalasib adipate is about 1% to about 54% by weight, based on the weight of the pharmaceutical dosage unit tablet core.

[0149] Embodiment 61. The method according to Embodiment 59, wherein the content of divalasib adipate is about 54% by weight, based on the weight of the drug dose unit tablet core.

[0150] Embodiment 62. The method according to any one of Embodiments 18 to 61, wherein the compressive force is approximately 1 kN / cm to approximately 8 kN / cm.

[0151] Embodiment 63. The method according to any one of Embodiments 18 to 62, wherein the tablet compression force is approximately 4 kN to approximately 20 kN.

[0152] Embodiment 64. The method according to any one of Embodiments 18 to 63, wherein a premixture is compressed between at least two rotating rolls having a gap width of about 1 mm to about 6 mm to form a ribbon, the ribbon is crushed and sieved to form granules.

[0153] Embodiment 65. The method according to any one of Embodiments 18 to 64, wherein the sieve size is approximately 0.5 mm to approximately 2.5 mm.

[0154] Embodiment 66. The method according to any one of Embodiments 18 to 65, further comprising applying a film coating to the surface of the drug dosage unit tablet core.

[0155] Embodiment 67. The method according to any one of Embodiments 18 to 66, wherein the bulk density of the granular mixture is approximately 0.4 g / mL to approximately 0.75 g / mL.

[0156] Embodiment 68. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 17 or the method according to any one of Embodiments 18 to 67, wherein the pharmaceutical dosage unit tablet core comprises the formulation shown in Table 8.

[0157] Embodiment 69. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 17 or the method according to any one of Embodiments 18 to 67, wherein the pharmaceutical dosage unit tablet core comprises the formulation shown in Table 9.

[0158] Embodiment 70. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 17 or the method according to any one of Embodiments 18 to 67, wherein the pharmaceutical dosage unit tablet core comprises the formulation shown in Table 10.

[0159] Embodiment 71. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 17 or the method according to any one of Embodiments 18 to 67, wherein the pharmaceutical dosage unit tablet core comprises the formulation shown in Table 12.

[0160] Embodiment 72. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 17 or the method according to any one of Embodiments 18 to 67, wherein the pharmaceutical dosage unit tablet core comprises the formulation shown in Table 13.

[0161] Embodiment 73. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 17 or the method according to any one of Embodiments 18 to 67, wherein the pharmaceutical dosage unit tablet core comprises the formulation shown in Table 14.

[0162] Embodiment 74. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 17 or the method according to any one of Embodiments 18 to 67, wherein the pharmaceutical dosage unit tablet core comprises the formulation shown in Table 15.

[0163] Embodiment 75. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 17 or the method according to any one of Embodiments 18 to 67, wherein the pharmaceutical dosage unit tablet core comprises the formulation shown in Table 16.

[0164] Embodiment 76. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 17 or the method according to any one of Embodiments 18 to 67, wherein the pharmaceutical dosage unit tablet core comprises the formulation shown in Table 1.

[0165] Embodiment 77. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 17 or the method according to any one of Embodiments 18 to 67, wherein the pharmaceutical dosage unit tablet core comprises the formulation shown in Table 2.

[0166] Embodiment 78. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 17 or the method according to any one of Embodiments 18 to 67, wherein the pharmaceutical dosage unit tablet core comprises the formulation shown in Table 3.

[0167] Embodiment 79. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 17 or the method according to any one of Embodiments 18 to 67, wherein the pharmaceutical dosage unit tablet core comprises the formulation shown in Table 4.

[0168] Embodiment 80. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 17 or the method according to any one of Embodiments 18 to 67, wherein the pharmaceutical dosage unit tablet core comprises the formulation shown in Table 5.

[0169] Embodiment 81. A pharmaceutical dosage unit tablet core according to any one of Embodiments 1 to 17 or the method according to any one of Embodiments 18 to 67, wherein the pharmaceutical dosage unit tablet core comprises the formulation shown in Table 6.

[0170] The following examples are presented as illustrations, not as limitations. [Examples]

[0171] Various testing and analytical methods are described herein.

[0172] High shear wet granulation (HSWG) The tablets were prepared using high-shear wet granulation according to the following procedure.

[0173] All granular components were placed in a granulation bowl equipped with an impeller and chopper. After dry mixing of the powder mixture, water was added at a controlled rate using a peristaltic pump and spray nozzle. The resulting wet mass was passed through a #10 mesh sieve (1.70 mm) and subjected to fluidized bed drying. The dried material was passed through a #18 mesh sieve (1.00 mm) or a #35 mesh sieve (0.50 mm) to form "coarse" or "fine" granules, respectively.

[0174] Dry granulation (DG) The tablets were prepared using dry granulation according to the following procedure. A flowchart illustrating the manufacturing process is shown in Figure 7.

[0175] Sieving and weighing of APIs and excipients: The active pharmaceutical ingredient (API) (i.e., divalasib adipate) and all excipients except magnesium stearate were sieved through a #18 mesh (sieve size: 1 mm) sieve. Magnesium stearate was sieved through a #30 mesh (sieve size: 0.60 mm) sieve before use.

[0176] Powder mixing (including pre-mixing and final mixing): All powder mixing processes were carried out by mixing the powders at 34 rpm in appropriately sized bottles using a Turbula® mixer.

[0177] Dry Granulation (Slugging): Dry granulation of the granular mixture was performed using a compression simulator. Specifically, a 24 mm flat circular punch die set was used for dry granulation. The powder was compacted according to a specially designed punch operating profile that simulated the densification of powder within the nip area in a full-scale roller compactor. The target solid content of the resulting molded body was achieved by adjusting the powder filling weight.

[0178] Grinding: The compressed material obtained by dry granulation was ground using a manual vibratory mill.

[0179] Tablet Compression: Tablet compression was performed using a compression simulator. For the test, a punch-die set for flat, concave tablets with a capsule shape of 19.0 × 9.50 mm was selected. The target tablet weight for the test in Example 7 was 1000 mg. Tablet compression followed the punch motion profile of a rotary press operated at a turret speed of 30 rpm.

[0180] Film coating Unless otherwise specified, film-coated tablets were prepared using a pan coater equipped with an 8.5-inch perforating pan. A coating suspension with a solids content of 0.15 was sprayed onto the tablets at a rate of 3 g / min. Airflow and exhaust temperature were maintained at 100 cfm and 42°C, respectively. Further drying was performed after spraying was complete. The target coating weight increase was 3%.

[0181] Collapse Time (DT) Tablet disintegration time is according to the United States Pharmacopeia (USP). <701> The determination was made using the procedure described in the general chapter "Collapse" of [the document]. Specifically, unless otherwise indicated, the following method was used in the examples described herein:

[0182] The tablet disintegration experiment was conducted using a tablet disintegration tester consisting of a basket-rack assembly with six transparent tubes and a 1000 mL beaker. The bottom plates of the tubes were woven stainless steel wire cloth with 2 mm openings. Tablets were placed in the tubes and moved up and down in a 37°C immersion solution (water). A tablet was considered completely disintegrated if no residual powder remained on the bottom plate.

[0183] Dissolution Unless otherwise specified, dissolution tests were performed in a USP II instrument containing 900 mL of 50 mM citrate buffer (pH 3.0) at a paddle speed of 75 rpm and 37°C.

[0184] hardness Tablet hardness testing is well known in the art and is a measure of the break point and structural integrity of tablets. In one compression test method, a gradually increasing force is continuously applied to aligned tablets using a testing apparatus until the tablets break, and the force at which they break indicates their hardness.

[0185] Example 1 In Example 1, the effect of various disintegrants on tablet disintegration time was evaluated. Tablets were prepared using HSWG according to the methods described herein and the formulations shown in Table 8 below.

[0186] [Table 8]

[0187] The disintegrants tested were croscarmellose sodium ("NaCMC", disintegrant 1), crospovidone ("crosPVP", disintegrant 2), and sodium starch glycolate ("SSG", disintegrant 3).

[0188] The tablets were compressed with a compressive force of 5.9 kN using an 8 mm flat, standard concave tool, resulting in a target weight of 200 mg. The disintegration time of the tablets was tested using the method described herein. The tablet properties and results are shown in Table 9.

[0189] [Table 9]

[0190] All tablets were eroded from the surface, and no significant swelling of the tablets was observed. The results demonstrate that NaCMC was superior to SSG and the neutral disintegrant (crosPVP) in improving disintegration time. Water penetration into the tablets was determined to be the rate-limiting factor in tablet disintegration.

[0191] Example 2 In Example 2, the effects of various extragranular (ExG) excipients on tablet disintegration time were evaluated. Tablets were prepared using HSWG according to the methods described herein and the formulations shown in Table 10 below. The control tablet formulations are shown in Table 11.

[0192] [Table 10]

[0193] [Table 11]

[0194] The tablets were compressed to a tensile strength of 2.5 MPa. External excipients were selected to evaluate the ability of water-soluble, low-compressibility, and highly hydrophilic excipients to increase the rate of water penetration into the tablets. The external excipients tested were as follows:

[0195] (1) MCC (Avicel PH 101) - a permeable matrix of hydrophilic polymer to enhance water wicking, (2) spray-dried lactose - a highly water-soluble excipient, (3) mannitol - a highly water-soluble excipient, and (4) dicalcium phosphate - an incompressible excipient.

[0196] The results are shown in Figure 2. As can be seen from these results, the disintegration time was shortened compared to other extragranular excipients by including highly hydrophilic excipients such as MCC.

[0197] Example 3 In Example 3, the effect of extragranular microcrystalline cellulose (MCC) content on tablet disintegration time was evaluated. Tablets were prepared using HSWG according to the methods described herein and the formulations shown in Table 12 below.

[0198] [Table 12]

[0199] The tablets were compressed to tensile strengths of 2.0 MPa, 2.5 MPa, or 3.0 MPa. The average disintegration time (for 3 samples) was measured. The results are shown in Figure 3.

[0200] Tablets containing 15% extragranular MCC disintegrated substantially faster than tablets containing only 10% extragranular MCC. A slight improvement in disintegration time was observed when the extragranular MCC content was increased to 20%. These results suggest that including a sufficient amount of extragranular MCC is important for improving disintegration time.

[0201] Example 4 In Example 4, the effect of intragranular and extragranular croscarmellose sodium (NaCMC) content on tablet disintegration time was evaluated. Tablets were prepared using HSWG according to the methods described herein and the formulations shown in Table 13 below.

[0202] [Table 13]

[0203] The tablets were compressed to tensile strengths of 2.0 MPa, 2.5 MPa, or 3.0 MPa. The mean disintegration time was measured. The results are shown in Figure 4.

[0204] As these results show, tablets containing 4% extragranular NaCMC had a shorter average disintegration time (3 samples) than tablets containing only 2% extragranular MCC.

[0205] Example 5 In Example 5, the effect of various grades of extracellular MCCs on tablet disintegration time was evaluated. Tablets were prepared using HSWG according to the methods described herein and the formulations shown in Table 14 below.

[0206] [Table 14]

[0207] The tablets were compressed to tensile strengths of 2.0 MPa, 2.5 MPa, or 3.0 MPa. The average disintegration time (for 3 samples) was measured. The results are shown in Figure 5.

[0208] Tablets formulated with MCC Avicel PH 101 as an external excipient had a faster mean disintegration time than tablets prepared with MCC Avicel PH 200 or MCC Avicel PH 105.

[0209] Example 6 In Example 6, the disintegration time of tablets formulated by dry granulation (DG) was compared with the disintegration time of tablets formulated by HSWG. The tablets were prepared using HSWG or DG according to the methods described herein and the formulations shown in Table 15 below.

[0210] [Table 15]

[0211] Tablet 2 was prepared using HSWG, and tablets 10 and 11 were prepared using DG. The tablets had tensile strengths of 2.0 MPa, 2.5 MPa, or 3.0 MPa. The mean disintegration time (3 samples) was measured. The results are shown in Figure 6.

[0212] As these results show, the tablets prepared using DG and the tablets prepared using HSWG exhibited similar disintegration behavior.

[0213] Example 7 In Example 7, the mechanical properties, disintegration time, and dissolution of various tablets formulated by dry granulation (DG) were evaluated. All formulations contained 15% MCC (Avicel PH 101) to aid in tablet disintegration. The tablets were prepared using DG according to the methods described herein and the formulations shown in Table 16 below.

[0214] [Table 16]

[0215] All batches contained 15% extragranular (ExG) MCC (Avicel PH 101), 0.75% intragranular (InG) magnesium stearate, and 3.0% intragranular croscarmellose sodium (NaCMC). Intragranular MCC (Avicel PH 102) was also incorporated to compensate for variations in other formulation components. All batches used API batch K2, and their characteristics are shown in Table 17 below.

[0216] [Table 17]

[0217] The manufacturing of the formulation batches was carried out in a material-saving manner by using small-scale simulating equipment. The batch size was 80-120 g. The manufacturing process for all tablet batches is shown in Figure 7.

[0218] Results and Discussion Tablet Characterization: Tablet compression was performed using a compression simulator with a target tablet weight of 1000 mg as described herein. For each batch, compression profiling was performed to identify the compressive forces that produced tablets with hardnesses of 20 kp and 30 kp. Following compression profiling, additional tablets with target hardnesses of 20 kp and 30 kp were manufactured for further analysis.

[0219] The tableting profiles for all batches are shown in Figure 8. The profiles indicate that the divalasib formulation exhibits generally superior tableting properties. A tablet tensile strength of 2.0 MPa can be achieved for all batches at a compression pressure of less than 100 MPa.

[0220] As shown in Figure 8, formulations with lower drug content exhibited slightly improved tableting properties. No effect of extragranular magnesium stearate and NaCMC content on tableting properties was observed. Table 18 shows additional tablet characterization data for the batch, including compression pressures resulting in tablet hardness of 20 kp and 30 kp, as well as tablet disintegration and dissolution data.

[0221] [Table 18]

[0222] The effects of drug, magnesium stearate, and NaCMC content on tablet disintegration time are clearly demonstrated in Figure 9. The most significant adverse effects result from high drug content, followed by low NaCMC content, and then high Mg stearate content. The data indicate that the incorporation of large amounts of extragranular NaCMC (up to 5% in the tests) can accelerate tablet disintegration, particularly for tablets with high drug content and manufactured under high compression pressure. Overall, acceptable tablet disintegration behavior can be achieved with 15% extragranular MCC and high levels of extragranular NaCMC.

[0223] Tablet dissolution data is shown in Table 18. All tablets were dissolved in 900 mL of 50 mM citrate buffer (pH 3.0) at a paddle speed of 75 rpm using USP apparatus 2. Some influence of tablet hardness and drug content can be observed at the 15-minute data point. Higher tablet hardness and higher drug content resulted in slower dissolution, but the content of extragranular magnesium stearate and NaCMC did not show any effect. However, at the 30-minute data point, all batches showed >95% dissolution (Table 18). This data suggests that while variations in formulation during the test may affect dissolution at the initial stage, the overall risk of delayed dissolution of the divalasib formulation is low, and an immediate-release profile can be achieved.

[0224] This specification uses examples to disclose the present invention in the best form and to enable the implementation of the invention, including the fabrication and use of any device or system by any person skilled in the art, and the execution of any incorporated process or method. The scope of the patentable invention is defined by the claims and may include other examples that are conceivable to a person skilled in the art. Such other examples are intended to be within the claims if they have structural elements that are not different from the language of the claims, or if they include equivalent structural elements that do not substantially differ from the language of the claims.

Claims

1. A drug administration unit tablet core, wherein the tablet core is (a) Divalasib and, (b) A disintegrant in an amount of about 2% to about 13% by weight based on the weight of the drug administration unit tablet core, (c) an excipient in an amount of about 15% to about 50% by weight based on the weight of the drug administration unit tablet core, A tablet core containing the drug dosage unit.

2. The drug administration unit tablet core according to claim 1, wherein the content of the free base of divalasib is at most about 44% by weight, based on the weight of the drug administration unit tablet core.

3. The pharmaceutical administration unit tablet core according to claim 1, wherein divalasib is divalasib adipine salt.

4. The drug administration unit tablet core according to claim 3, wherein the content of divalasib adipate is at most about 60% by weight, based on the weight of the drug administration unit tablet core.

5. The pharmaceutical administration unit tablet core according to any one of claims 1 to 4, wherein the disintegrant is selected from the group consisting of croscarmellose sodium (CCS), sodium starch glycolate (SSG), crospovidone (crosPVP), and combinations thereof.

6. The pharmaceutical administration unit tablet core according to claim 5, wherein the disintegrant is CCS.

7. The pharmaceutical administration unit tablet core according to any one of claims 1 to 6, wherein the excipient is selected from the group consisting of starch, microcrystalline cellulose (MCC), and combinations thereof.

8. The pharmaceutical administration unit tablet core according to claim 7, wherein the excipient is MCC.

9. The pharmaceutical administration unit tablet core according to claim 8, wherein the average particle size of the MCC is about 20 μM to about 180 μM.

10. A pharmaceutical administration unit tablet core according to any one of claims 1 to 9, further comprising a lubricant in an amount of about 1% to about 3% by weight based on the weight of the pharmaceutical administration unit tablet core.

11. The pharmaceutical administration unit tablet core according to claim 10, wherein the lubricant is magnesium stearate.

12. The drug administration unit tablet core according to any one of claims 1 to 11, wherein the drug administration unit tablet core has a tensile strength of about 2.0 MPa to about 3.0 MPa.

13. The pharmaceutical administration unit tablet core according to any one of claims 1 to 12, wherein the pharmaceutical administration unit tablet core has a solid content ratio of about 0.80 to about 0.

90.

14. A pharmaceutical administration unit tablet core according to any one of claims 1 to 13, further comprising a film coating on the surface of the tablet core.

15. The drug administration unit tablet core according to any one of claims 1 to 14, wherein the disintegration time of the drug administration unit tablet core is approximately 15 minutes or less.

16. The drug administration unit tablet core according to any one of claims 1 to 15, wherein the disintegration time of the drug administration unit tablet core is approximately 10 minutes or less.

17. The drug administration unit tablet core according to any one of claims 1 to 16, wherein the disintegration time of the drug administration unit tablet core is approximately 5 minutes or less.

18. A method for preparing a drug dosage unit tablet core, (a) Mix divalasib, an internal excipient, and an internal disintegrant to form a premixture, (b) Compressing the premixture by applying a compressive force, (c) Crushing and sieving the compressed pre-mixture to form granules, (d) Mixing the granules with an external excipient and an external disintegrant to form a granular mixture, (e) Compressing the granular mixture into tablets by applying a tablet compression force to form the drug administration unit tablet core, Methods that include...

19. The method according to claim 18, wherein the excipient within the granules is selected from the group consisting of starch, microcrystalline cellulose (MCC), and combinations thereof.

20. The method according to claim 19, wherein the excipient in the granules is MCC.

21. The method according to any one of claims 18 to 20, wherein the content of the granular excipient is about 10% by weight to about 30% by weight, based on the weight of the drug administration unit tablet core.

22. The method according to claim 21, wherein the content of the granular excipient is about 15% by weight to about 25% by weight, based on the weight of the drug administration unit tablet core.

23. The method according to claim 22, wherein the content of the granular excipient is about 20% by weight to about 21% by weight, based on the weight of the drug administration unit tablet core.

24. The method according to any one of claims 18 to 23, wherein the granular disintegrant is selected from the group consisting of croscarmellose sodium (CCS), sodium starch glycolate (SSG), crospovidone (crosPVP), and combinations thereof.

25. The method according to claim 24, wherein the granular disintegrant is CCS.

26. The method according to any one of claims 18 to 25, wherein the content of the granule-disintegrating agent is about 1% by weight to about 5% by weight, based on the weight of the drug administration unit tablet core.

27. The method according to claim 26, wherein the content of the granular disintegrant is about 2% by weight to about 4% by weight, based on the weight of the drug administration unit tablet core.

28. The method according to claim 27, wherein the content of the granule-disintegrating agent is about 3% by weight, based on the weight of the drug administration unit tablet core.

29. The method according to any one of claims 18 to 28, wherein the granular excipient is selected from the group consisting of starch, microcrystalline cellulose (MCC), and combinations thereof.

30. The method according to claim 29, wherein the granular excipient is MCC.

31. The method according to any one of claims 18 to 30, wherein the content of the granular excipient is about 5% by weight to about 20% by weight, based on the weight of the drug administration unit tablet core.

32. The method according to claim 31, wherein the content of the granular excipient is about 10% by weight to about 20% by weight, based on the weight of the drug administration unit tablet core.

33. The method according to claim 32, wherein the content of the granular excipient is about 15% by weight to about 20% by weight, based on the weight of the drug administration unit tablet core.

34. The method according to claim 33, wherein the content of the granular excipient is about 15% by weight, based on the weight of the tablet core of the drug administration unit.

35. The method according to any one of claims 18 to 34, wherein the extragranular disintegrant is selected from the group consisting of croscarmellose sodium (CCS), sodium starch glycolate (SSG), crospovidone (crosPVP), and combinations thereof.

36. The method according to claim 35, wherein the granular extra-disintegrant is CCS.

37. The method according to any one of claims 18 to 36, wherein the content of the extragranular disintegrant is about 1% by weight to about 8% by weight, based on the weight of the drug administration unit tablet core.

38. The method according to claim 37, wherein the content of the extragranular disintegrant is about 4% by weight to about 5% by weight, based on the weight of the drug administration unit tablet core.

39. The method according to claim 38, wherein the content of the extragranular disintegrant is about 5% by weight, based on the weight of the drug administration unit tablet core.

40. The method according to any one of claims 18 to 39, further comprising mixing the pre-mixture with an intragranular lubricant before compression.

41. The method according to claim 40, wherein the granular lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, and combinations thereof.

42. The method according to claim 41, wherein the granular lubricant is magnesium stearate.

43. The method according to any one of claims 40 to 42, wherein the content of the granular lubricant is about 1% by weight to about 3% by weight, based on the weight of the drug administration unit tablet core.

44. The method according to claim 43, wherein the content of the granular lubricant is about 1% by weight, based on the weight of the drug administration unit tablet core.

45. The method according to any one of claims 18 to 44, further comprising mixing the granules, the external excipient and the external disintegrant with an external lubricant to form the granule mixture before tableting.

46. The method according to claim 45, wherein the granular lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, and combinations thereof.

47. The method according to claim 46, wherein the granular external lubricant is magnesium stearate.

48. The method according to any one of claims 45 to 47, wherein the content of the granular extra-lubricant is about 1% by weight to about 3% by weight, based on the weight of the drug administration unit tablet core.

49. The method according to claim 48, wherein the content of the granular extra-lubricant is about 1% by weight to about 2% by weight, based on the weight of the drug administration unit tablet core.

50. The method according to claim 49, wherein the content of the granular external lubricant is about 1.25% by weight, based on the weight of the drug administration unit tablet core.

51. The method according to any one of claims 18 to 50, wherein the free base content of divalasib is at most about 44% by weight, based on the weight of the drug administration unit tablet core.

52. The method according to claim 51, wherein the free base content of divalasib is at most about 40% by weight, based on the weight of the drug administration unit tablet core.

53. The method according to claim 52, wherein the content of the free base of divalasib is about 1% by weight to about 44% by weight, based on the weight of the drug administration unit tablet core.

54. The method according to claim 53, wherein the free base content of divalasib is about 1% by weight to about 40% by weight, based on the weight of the drug administration unit tablet core.

55. The method according to claim 54, wherein the free base content of divalasib is about 40% by weight, based on the weight of the drug administration unit tablet core.

56. The method according to any one of claims 18 to 55, wherein the pharmaceutically acceptable salt is an adipine salt.

57. The method according to claim 56, wherein the content of divalasib adipate is at most about 60% by weight, based on the weight of the drug administration unit tablet core.

58. The method according to claim 56, wherein the content of divalasib adipate is at most about 54% by weight, based on the weight of the drug administration unit tablet core.

59. The method according to claim 56, wherein the content of divalasib adipate is about 1% by weight to about 60% by weight, based on the weight of the drug administration unit tablet core.

60. The method according to claim 59, wherein the content of divalasib adipate is about 1% by weight to about 54% by weight, based on the weight of the drug administration unit tablet core.

61. The method according to claim 59, wherein the content of divalasib adipate is about 54% by weight, based on the weight of the drug administration unit tablet core.

62. The method according to any one of claims 18 to 61, wherein the compressive force is approximately 1 kN / cm to approximately 8 kN / cm.

63. The method according to any one of claims 18 to 62, wherein the tableting compression force is approximately 4 kN to approximately 20 kN.

64. The method according to any one of claims 18 to 63, wherein the premixture is compressed between at least two rotating rolls having a gap width of about 1 mm to about 6 mm to form a ribbon, and the ribbon is crushed and sieved to form granules.

65. The method according to any one of claims 18 to 64, wherein the sieve size is approximately 0.5 mm to approximately 2.5 mm.

66. The method according to any one of claims 18 to 65, further comprising applying a film coating to the surface of the drug administration unit tablet core.

67. The method according to any one of claims 18 to 66, wherein the bulk density of the granular mixture is about 0.4 g / mL to about 0.75 g / mL.

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