Pharmaceutical composition and use thereof

Abstract

The present application relates to a pharmaceutical composition and the use thereof, in particular to a pharmaceutical composition containing (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine or a pharmaceutically acceptable salt thereof and the use thereof.

Description

A pharmaceutical composition and its application Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a pharmaceutical composition containing the compound (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine or a pharmaceutically acceptable salt thereof, and applications thereof. Background Art

[0002] Patent application WO2012167733A1 discloses a small molecule compound (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine, whose chemical structure is shown in Formula A. It has the effect of effectively inhibiting Syk kinase activity and is mainly used to treat diseases responsive to inhibition of Syk kinase activity, such as autoimmune diseases, inflammatory diseases and cancer (preferably hematological malignancies), in particular for the treatment of rheumatoid arthritis, autoimmune hemolytic anemia, immune thrombocytopenia, Hodgkin's lymphoma and non-Hodgkin's lymphoma and other diseases.

[0003] Patent application WO2019037737A1 discloses the acetate salt of the compound of formula A, as well as the AI-type crystal form of the monoacetate salt of the compound of formula A. This crystal form has good crystal stability and chemical stability, and has more advantages than the compound of formula A itself in terms of solubility, etc., and can be used to prepare drugs for treating diseases responsive to inhibition of Syk kinase activity.

[0004] When preparing a compound of Formula A or a pharmaceutically acceptable salt thereof into a solid pharmaceutical composition, we found that the active pharmaceutical ingredient has strong viscosity and very poor fluidity, which is not conducive to preparation into a pharmaceutical formulation, resulting in reduced drug solubility. It also causes stickiness and astringency during long-term production of formulations, such as tablets. Furthermore, the product yield is relatively low, which cannot meet the needs of large-scale formulation production. Therefore, there is an urgent need for a pharmaceutical composition comprising a compound of Formula A or a pharmaceutically acceptable salt thereof with excellent performance in various aspects. The present invention meets the above needs. Summary of the Invention

[0005] The main purpose of the present invention is to provide a pharmaceutical composition that dissolves rapidly, has good fluidity and stability, and has a simple preparation process, which can better meet the needs of industrial large-scale production.

[0006] In one aspect, the present invention provides a pharmaceutical composition, particularly an oral pharmaceutical composition, containing the active pharmaceutical ingredient compound (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (i.e., a compound of formula A) or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the pharmaceutical composition of the present invention comprises an active pharmaceutical ingredient and a filler; the active pharmaceutical ingredient is compound (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine or a pharmaceutically acceptable salt thereof, such as acetate, p-toluenesulfonate or malate, preferably acetate, more preferably monoacetate; the filler comprises microcrystalline cellulose and pregelatinized starch.

[0008] In some embodiments, in the pharmaceutical composition of the present invention, the weight percentage content of the active pharmaceutical ingredient is about 3-40%, for example, about 5-30%, about 7-20%, about 12-18%, for example, about 5%, about 7.8%, about 10%, about 12.8%, about 13.2%, about 15%, about 18%, about 20% or about 25%, etc., based on the total weight of the pharmaceutical composition.

[0009] In some embodiments, the weight percentage of the filler is about 10-85%; preferably about 30-80%; more preferably about 45-75%; for example, about 50%, about 55%, about 60%, about 65%, about 68%, about 70%, about 72%, about 75%, about 78%, about 80% or about 82%, based on the total weight of the pharmaceutical composition.

[0010] In some embodiments, the weight ratio of microcrystalline cellulose to pregelatinized starch is about 1:1 to 10:1; preferably about 3:1 to 8:1; more preferably about 4:1 to 7:1; for example, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1 or about 9:1.

[0011] In some embodiments, the microcrystalline cellulose is selected from the microcrystalline cellulose described in the detailed description, such as microcrystalline cellulose PH101, microcrystalline cellulose PH102, microcrystalline cellulose PH200, microcrystalline cellulose KG-802, and microcrystalline cellulose UF-702.

[0012] In some embodiments, the pharmaceutical composition of the present invention may further comprise other fillers.

[0013] In some embodiments, the other fillers are selected from one or more of mannitol, lactose monohydrate, and cyclodextrin; preferably, selected from one or two of mannitol and lactose monohydrate.

[0014] In some embodiments, the weight percentage of the other filler is about 10-80%; preferably about 30-70%; more preferably about 30-50%; for example, about 15%, about 20%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70% or about 75%, based on the total weight of the pharmaceutical composition.

[0015] In some embodiments, the filler in the pharmaceutical composition of the present invention consists of microcrystalline cellulose and pregelatinized starch.

[0016] In some embodiments, the pharmaceutical composition of the present invention may further comprise a disintegrant.

[0017] In some embodiments, the disintegrant is selected from one or more of crospovidone, sodium carboxymethyl starch, crospovidone sodium and low-substituted hydroxypropyl cellulose; preferably crospovidone.

[0018] In some embodiments, the weight percentage content of the disintegrant is about 1-20%; preferably about 1-10%; more preferably about 3-6%; for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% or about 15%, based on the total weight of the pharmaceutical composition.

[0019] In some embodiments, the pharmaceutical compositions of the present invention may further comprise a lubricant.

[0020] In some embodiments, the lubricant is selected from one or more of colloidal silicon dioxide, magnesium stearate, glyceryl behenate, sodium fumarate and talc; preferably selected from one or more of colloidal silicon dioxide, magnesium stearate and glyceryl behenate; more preferably selected from one or both of colloidal silicon dioxide and magnesium stearate.

[0021] In some embodiments, the weight percentage content of the lubricant is about 0.5-15%, preferably about 1-10%, more preferably about 1.5-6%, for example, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 7%, about 8%, about 9%, about 10% or about 12%, based on the total weight of the pharmaceutical composition.

[0022] In some embodiments, the lubricant is a combination of colloidal silicon dioxide and magnesium stearate.

[0023] In some embodiments, based on the total weight of the pharmaceutical composition, the weight percentage content of colloidal silicon dioxide is about 0.5-10%, preferably about 0.5-6%, more preferably about 3-5%, for example, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 7%, about 8% or about 9%; the weight percentage content of magnesium stearate is about 0.5-10%, preferably about 0.5-5%, more preferably about 1-3%, for example, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 7%, about 8% or about 9%.

[0024] In some embodiments, the present invention also provides a pharmaceutical composition comprising an active pharmaceutical ingredient, a filler, a disintegrant and a lubricant; the active pharmaceutical ingredient is compound (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine or a pharmaceutically acceptable salt thereof, preferably acetate, more preferably monoacetate; the filler comprises microcrystalline cellulose and pregelatinized starch, and optionally comprises other fillers.

[0025] In some embodiments, based on the total weight of the pharmaceutical composition, the active pharmaceutical ingredient is present in an amount of about 5-30% by weight; the filler is present in an amount of about 30-80% by weight; the disintegrant is present in an amount of about 1-10% by weight; and the lubricant is present in an amount of about 1-10% by weight.

[0026] In some embodiments, based on the total weight of the pharmaceutical composition, the weight percentage content of the active pharmaceutical ingredient is about 7-20%, preferably about 12-18%; the weight percentage content of the filler is about 45-75%; the weight percentage content of the disintegrant is about 3-6%; and the weight percentage content of the lubricant is about 1.5-6%.

[0027] In some embodiments, the other filler is selected from one or both of mannitol and lactose monohydrate, preferably mannitol; the disintegrant is cross-linked polyvinylpyrrolidone; and the lubricant is selected from one or both of colloidal silicon dioxide and magnesium stearate.

[0028] In some embodiments, based on the total weight of the pharmaceutical composition, the active pharmaceutical ingredient is present in an amount of about 7-20% by weight, preferably about 12-18% by weight; the weight ratio of microcrystalline cellulose to pregelatinized starch is about 3:1 to 8:1, preferably about 4:1 to 7:1; the other filler is mannitol, and its weight percentage content is about 0-50%, for example, about 10-50%, 30-50%, for example, about 15%, 20%, 25%, 30%, 35%, 40% or 45%; the disintegrant is cross-linked polyvinylpyrrolidone, and its weight percentage content is about 3-6%; and the lubricant is a combination of colloidal silicon dioxide and magnesium stearate, the weight percentage content of colloidal silicon dioxide is about 0.5-6%, preferably about 3-5%, and the weight percentage content of magnesium stearate is about 0.5-5%, preferably about 1-3%.

[0029] In some embodiments, the present invention also provides a pharmaceutical composition comprising an active pharmaceutical ingredient, a filler, a disintegrant, and a lubricant; the active pharmaceutical ingredient is compound (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine or its acetate, preferably monoacetate; based on the total weight of the pharmaceutical composition, the weight percentage content of the active pharmaceutical ingredient is about 5-30%, preferably about 7-20%, and more preferably about 12-18%; the filler is microcrystalline cellulose and The invention relates to a combination of pregelatinized starch, wherein the weight ratio of microcrystalline cellulose to pregelatinized starch is about 3:1 to 8:1, preferably about 4:1 to 7:1; the weight percentage content of the filler is about 30-80%, preferably about 45-75%; the disintegrant is cross-linked polyvinylpyrrolidone, and its weight percentage content is about 1-10%, preferably about 3-6%; and the lubricant is a combination of colloidal silicon dioxide and magnesium stearate, wherein the weight percentage content of the colloidal silicon dioxide is about 0.5-6%, preferably about 3-5%, and the weight percentage content of the magnesium stearate is about 0.5-5%, preferably about 1-3%.

[0030] In some embodiments, the microcrystalline cellulose is selected from the microcrystalline cellulose described in the detailed description, such as microcrystalline cellulose PH101, microcrystalline cellulose PH102, microcrystalline cellulose PH200, microcrystalline cellulose KG-802, and microcrystalline cellulose UF-702.

[0031] In some embodiments, to ensure that the dissolution of the prepared pharmaceutical composition meets the dissolution requirements of ordinary solid immediate-release preparations, the active pharmaceutical ingredient needs to be pulverized and its particle size D90 is controlled to be less than or equal to about 200 μm, for example, the particle size D90 is controlled to be within the range of about 5-160 μm.

[0032] In some embodiments, the active pharmaceutical ingredient has a particle size D90 of about 150 μm or less. In some embodiments, the active pharmaceutical ingredient has a particle size D90 of about 141 μm or less, such as in the range of about 49-141 μm. In some embodiments, the active pharmaceutical ingredient has a particle size D90 in the range of about 77-141 μm.

[0033] In some embodiments, the particle size D90 of the active pharmaceutical ingredient is in the range of about 9-35 μm, such as in the range of about 9-17 μm, such as in the range of about 19-31 μm.

[0034] During in-depth research on the preparation of the compound of formula A or a pharmaceutically acceptable salt thereof, the inventors unexpectedly discovered that the pharmaceutical composition provided by the present invention, due to the addition of microcrystalline cellulose and pregelatinized starch, greatly improves the solubility of the active pharmaceutical ingredient, dissolving rapidly and completely, thereby facilitating the rapid onset of the drug's effect in the body and greatly improving the stability of the preparation.

[0035] In some embodiments, the pharmaceutical composition provided by the present invention is in various dosage forms suitable for oral administration, such as tablets or capsules, preferably tablets.

[0036] In some embodiments, the pharmaceutical composition provided herein is a tablet prepared using a direct compression process. The direct compression process employed in preparing the pharmaceutical composition of the present invention simplifies the process, improves drug dissolution and stability, and facilitates drug efficacy.

[0037] In some embodiments, the pharmaceutical compositions provided herein are prepared into granules using dry granulation, and ultimately into tablets. The dry granulation process employed in preparing the pharmaceutical compositions of the present invention improves the fluidity of the granular mixture, increases bulk density, facilitates tableting, and results in uniform and stable tablet weight. This significantly increases product yield, reaching over 85%, further meeting the needs of large-scale, process-based production. Furthermore, dry granulation ensures the stability of the active pharmaceutical ingredient, eliminates the generation of new degradation products, and allows for rapid drug dissolution, facilitating effective drug delivery.

[0038] The pharmaceutical composition provided by the present invention has rapid dissolution, good fluidity and stability, and can meet the needs of large-scale preparation production.

[0039] In some embodiments, the present invention provides the formulations disclosed in the examples of the present invention, especially Examples 1, 2, 3 and 4. In addition, based on the formulations disclosed in the examples, embodiments resulting from fluctuations of 50%, 40%, 30%, 20%, 10%, 5% or 2% in the content of each component in these formulations are also included in the present application.

[0040] In another aspect, the present invention also provides a method for preparing the above pharmaceutical composition, comprising mixing the active pharmaceutical ingredient with the filler, disintegrant and / or lubricant as described in the above pharmaceutical composition.

[0041] In some embodiments, the method for preparing the above pharmaceutical composition comprises mixing the active pharmaceutical ingredient with the microcrystalline cellulose and pregelatinized starch.

[0042] The present invention further provides a method for preparing the above pharmaceutical composition, comprising mixing the active pharmaceutical ingredient with the filler, disintegrant and lubricant.

[0043] In some embodiments, in the method for preparing the above-mentioned pharmaceutical composition, the active pharmaceutical ingredient is pre-pulverized, and its particle size D90 is controlled to be less than or equal to about 200 μm, for example, the particle size D90 is controlled to be in the range of about 5-160 μm.

[0044] In some embodiments, in the method for preparing the above pharmaceutical composition, the particle size D90 of the active pharmaceutical ingredient is less than or equal to about 150 μm. In some embodiments, in the method for preparing the above pharmaceutical composition, the particle size D90 of the active pharmaceutical ingredient is less than or equal to about 141 μm, for example, in the range of about 49-141 μm.

[0045] In some embodiments, the method comprises dry granulating the active pharmaceutical ingredient with a filler, disintegrant, and / or lubricant as described in the pharmaceutical composition above to form granules, which are then prepared into tablets. In some embodiments, the method comprises dry granulating the active pharmaceutical ingredient with a filler, disintegrant, and lubricant as described in the pharmaceutical composition above to form granules, which are then prepared into tablets. In some embodiments, the filler, disintegrant, and lubricant may be added during and / or after dry granulation. In some embodiments, the active pharmaceutical ingredient is mixed with about 30-90% by weight (e.g., about 40-80%, about 50-70%, about 60-80%, such as about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80% by weight) of the filler, about 0-60% by weight (e.g., about 10-50%, about 20-40%, such as about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40% by weight) of the filler. The disintegrant is preferably a pharmaceutical composition comprising a pharmaceutical composition comprising a disintegrant and a lubricant. The disintegrant is preferably ...

[0046] It should be understood that the present invention also includes pharmaceutical compositions, preferably tablets, prepared by the method described above.

[0047] The pharmaceutical composition provided by the present invention has rapid dissolution and significant onset of effect, and can be used to treat diseases that respond to inhibition of Syk kinase activity.

[0048] In another aspect, the present invention also provides a method for treating a disease responsive to inhibition of Syk kinase activity, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of the present invention containing a compound of formula A or a pharmaceutically acceptable salt thereof.

[0049] On the other hand, the present invention also provides a use of the above-mentioned pharmaceutical composition containing the compound of formula A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases responsive to inhibition of Syk kinase activity, such as autoimmune diseases, inflammatory diseases and cancers (preferably hematological malignancies).

[0050] In some embodiments, the autoimmune disease, inflammatory disease and cancer are selected from systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, IgA nephropathy, autoimmune hemolytic anemia, immune thrombocytopenia, multiple sclerosis, myasthenia gravis, allergic rhinitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, asthma, psoriasis, lymphoma (such as B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma), leukemia (such as chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia and chronic myeloid leukemia) and multiple myeloma.

[0051] In some embodiments, the medicament is used to treat autoimmune diseases, inflammatory diseases, and cancer.

[0052] In some embodiments, the autoimmune disease, inflammatory disease, and cancer is selected from rheumatoid arthritis, autoimmune hemolytic anemia, immune thrombocytopenia, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

[0053] On the other hand, the present invention also provides a method for treating diseases responsive to inhibition of Syk kinase activity, such as autoimmune diseases, inflammatory diseases and cancer, by combining a pharmaceutical composition containing a compound of formula A or a pharmaceutically acceptable salt thereof with one or more other therapeutic agents, wherein the pharmaceutical composition is administered simultaneously or sequentially with the other therapeutic agents, for example, before or after administration of the other therapeutic agents; the other therapeutic agents are selected from anti-immunotherapeutic agents, steroids, chemotherapeutic agents, and targeted therapeutic agents.

[0054] Non-limiting examples of anti-immunotherapeutic agents include adrenocortical hormones (e.g., fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide, or budesonide), disease-modifying agents (e.g., antimalarials, methotrexate, sulfasalazine salicylate, masalazone, azathioprine, 6-mercaptopurine, metronidazole, D-penicillamine), nonsteroidal anti-inflammatory drugs (e.g., acetaminophen, aspirin, sodium salicylate, sodium chlorambucil, magnesium salicylate, choline magnesium salicylate), Salsalate, ibuprofen, naproxen, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, piroxicam, indomethacin, ketoprofen, ketorolac tromethamine, meclofenamic acid base conjugate, meclofenamic acid sodium, mefenamic acid, naproxen, oxaprozin, butylphenyl nitrone, sulindac, or toluidine pyridine acetate), COX-2 inhibitors, cytokine synthesis / release inhibitors (such as anti-cytokine antibodies, anti-cytokine receptor antibodies, etc.

[0055] Non-limiting examples of chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and its analogs or metabolites, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, daunorubicin, and daunomycin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carbamazepine, lomustine, methyllomustine, streptozotocin, decarbazine, methotrexate, mitoflash, chlorambucil, chlorambucil, busulfan, thiotepa, ifosfamide, carbamazepine, lomustine, methyllomustine, streptozotocin, decameron, methotrexate, mitoflash, cytoxan ... and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); free radical generators such as bleomycin; nucleoside analogs (e.g., 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea); paclitaxel, docetaxel, and related analogs; vincristine, vinblastine, and related analogs; sedatives and related analogs (e.g., CC-5013 and CC-4047).

[0056] Targeted therapeutic agents include various small molecule or macromolecule targeted therapeutic agents, non-limiting examples of which include: protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); NF-κB inhibitors, including IκB kinase inhibitors; CDK inhibitors; PI3Kδ inhibitors; BTK inhibitors (e.g., ibrutinib); JAK inhibitors; Bcl-2 inhibitors (e.g., ABT-199); BRAF inhibitors (e.g., dabrafenib); MEK inhibitors (e.g., trametinib); mTOR inhibitors (e.g., rapamycin); anti-CD40 antibodies ( for example, APX005M, RO7009789); antibodies that bind to proteins overexpressed in cancer and thereby downregulate cell replication, such as anti-CD20 antibodies (such as rituximab, ibritumomab tiuxetan, tositumomab, ofatumumab, atezolizumab), anti-Her2 monoclonal antibodies (such as trastuzumab), anti-EGFR antibodies (such as cetuximab), and anti-VEGF antibodies (such as bevacizumab); anti-angiogenic drugs such as lenalidomide; and other protein or enzyme inhibitors, which are known to be upregulated, overexpressed, or activated in cancer, and whose inhibition can downregulate cell replication.

[0057] For the avoidance of doubt, those skilled in the art will understand that references herein to particular aspects of the invention (e.g. the first aspect of the invention) will include references to all embodiments and specific features thereof, which may be combined to form other embodiments and features of the invention.

[0058] It should be understood that ranges consisting of two specific values ​​listed herein as endpoints, or ranges consisting of a specific value and a range endpoint as a new endpoint, are contemplated by the present invention as if they were specifically disclosed herein.

[0059] definition

[0060] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. For interpreting this specification, the following definitions are preferably used.

[0061] The term "about" when used in conjunction with a numerical value is meant to encompass the numerical value within a range having a lower limit that is 20% less than the specified numerical value and an upper limit that is 20% greater than the specified numerical value.

[0062] As used herein, the term "and / or" means any one of the alternatives or two or more of the alternatives.

[0063] As used herein, the term "comprising" or "including" means including the elements, integers or steps described, but not excluding any other elements, integers or steps. In this article, when the term "comprising" or "including" is used, unless otherwise indicated, it also covers the situation consisting of the elements, integers or steps described, that is, it covers the scheme "consisting of..."

[0064] The term "effective amount" refers to that amount or dosage of the active pharmaceutical ingredient which, after administration to a patient in single or multiple doses, produces the desired effect in a patient in need of treatment or prevention.

[0065] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effects and properties of the compound of formula A and is not biologically or otherwise undesirable. The compound of formula A of the present invention may exist as a pharmaceutically acceptable salt, such as an acid addition salt. In this context, the pharmaceutically acceptable salt is preferably acetate, p-toluenesulfonate, or malate, more preferably acetate.

[0066] As used herein, "subject" includes mammals. Mammals include, but are not limited to, domestic animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the subject is a human.

[0067] As used herein, the term "treat," ...

[0068] The term "pharmaceutical composition" refers to a composition that is in a form permitting the biological activity of the active pharmaceutical ingredient contained therein to be effective, and that contains no additional ingredients that are unacceptably toxic to a subject to which the composition would be administered.

[0069] The term "filler" refers to a pharmaceutical excipient used to increase the weight or volume of a pharmaceutical formulation, such as a tablet. Preferably, the filler is selected from one or more of microcrystalline cellulose, pregelatinized starch, mannitol, lactose monohydrate, and cyclodextrin; more preferably, the filler is a combination of microcrystalline cellulose and pregelatinized starch.

[0070] The term "disintegrant" refers to a pharmaceutical excipient that causes a formulation, such as a tablet or granule, to disintegrate and dissolve immediately in the stomach after swallowing, thereby rapidly exerting its therapeutic effect. Preferably, the disintegrant is selected from one or more of crospovidone, sodium starch glycolate, croscarmellose sodium, and low-substituted hydroxypropyl cellulose; more preferably, crospovidone.

[0071] The term "lubricant" refers to a pharmaceutical excipient that increases granule flowability, reduces friction between particles or between particles and the die, and exhibits a lubricating effect. Preferably, the lubricant is selected from one or more of colloidal silicon dioxide, magnesium stearate, glyceryl behenate, sodium fumarate, and talc; more preferably, it is selected from one or more of colloidal silicon dioxide, magnesium stearate, and glyceryl behenate; and even more preferably, it is selected from one or both of colloidal silicon dioxide and magnesium stearate.

[0072] In this document, unless otherwise specified and not contradictory to the context, percentages refer to percentages by weight. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] FIG1 shows the dissolution profile of the tablet of Example 1 in pH 4.5 acetate buffer.

[0074] FIG2 shows the dissolution profile of the tablet of Example 2 in pH 4.5 acetate buffer.

[0075] FIG3 shows the dissolution profile of the tablet of Example 4 in pH 4.5 acetate buffer.

[0076] FIG4 shows the dissolution profile of the tablet of Example 5 in pH 4.5 acetate buffer.

[0077] FIG5 shows the dissolution curve of the capsule of Example 6 in pH 4.5 acetate buffer. DETAILED DESCRIPTION

[0078] The technical solution of the present invention will be clearly and completely described below in conjunction with specific embodiments of the present invention. However, it should be understood that the scope of protection of the present invention is not limited to these embodiments, and any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the scope of protection of the present invention.

[0079] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial sources or prepared according to existing methods.

[0080] In the following examples, unless otherwise specified, microcrystalline cellulose can be selected from PH types widely used in the art, such as microcrystalline cellulose PH101, microcrystalline cellulose PH102, and microcrystalline cellulose PH200; for example, in the direct compression process, microcrystalline cellulose PH102 can be selected; and KG types with high moldability, such as microcrystalline cellulose KG-802, can also be added as needed; for example, in dry granulation, a combination of microcrystalline cellulose PH102 and microcrystalline cellulose KG-802 can be selected, and a combination of microcrystalline cellulose PH102 and microcrystalline cellulose KG-802 can be selected. The weight ratio of cellulose KG-802 can be, for example, about 5:1 to 1:10, such as about 4:1, about 3:1, about 2:1, about 1.5:1, about 1.3:1, about 1.2:1, about 1:1, about 1:1.2, about 1:1.3, about 1:1.5, about 1:2, about 1:3 or about 1:4; or a UF type combining high formability and high fluidity, such as microcrystalline cellulose UF-702, can be selected; those skilled in the art can select the corresponding type of microcrystalline cellulose as needed, for example, refer to: Paul JSheskey, Walter G Cook and Colin G Cable, Handbook of Pharmaceutical Excipients (8th Edition).

[0081] Example 1

[0082] Table 1.1 Prescription composition of the tablets of Example 1

[0083] The acetate salt of the compound of formula A (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (i.e., the acetate salt of the compound of formula A), microcrystalline cellulose and / or pregelatinized starch, cross-linked polyvinylpyrrolidone, colloidal silicon dioxide, and magnesium stearate are mixed according to the prescription ratio in Table 1.1, and then dry granulated, followed by tableting and coating to prepare tablets.

[0084] The tablets of Example 1 were subjected to dissolution testing according to the second method (paddle method) of the appendix to Part IV of the 2015 edition of the Chinese Pharmacopoeia. 900 ml of pH 4.5 acetate buffer was used as the dissolution medium, and the dissolution test was conducted at 37 ± 0.5°C with a paddle method at 75 rpm. The results are shown in Table 1.2 and Figure 1.

[0085] The results showed that in the tablets of Example 1-1, in which the formulation contained both microcrystalline cellulose and pregelatinized starch, the acetate of the compound of Formula A dissolved rapidly and completely; in the tablets of Example 1-2, in which the formulation contained only microcrystalline cellulose, the dissolution of the acetate of the compound of Formula A was significantly slowed; and in the tablets of Example 1-3, in which the formulation contained only pregelatinized starch, the acetate of the compound of Formula A dissolved slowly and incompletely.

[0086] Table 1.2 Dissolution data of Example 1 tablets

[0087] Example 2

[0088] Table 2.1 Prescription composition of Example 2 tablets

[0089] The acetate of the compound of formula A, colloidal silicon dioxide, microcrystalline cellulose, pregelatinized starch, cross-linked polyvinylpyrrolidone, and magnesium stearate are mixed according to the prescription ratio in Table 2.1, then dry granulated, and finally compressed and coated to prepare tablets.

[0090] The tablets of Example 2 were subjected to dissolution testing according to the first method (basket method) of the appendix to Part IV of the 2015 edition of the Chinese Pharmacopoeia. 900 ml of pH 4.5 acetate buffer was used as the dissolution medium, and the dissolution test was conducted at 37 ± 0.5°C using the basket method at 100 rpm. The results are shown in Table 2.2 and Figure 2.

[0091] Table 2.2 Dissolution data of Example 2 tablets

[0092] Example 3

[0093] Table 3.1 Prescription composition of Example 3 tablets

[0094] The acetate of the compound of formula A, colloidal silicon dioxide, microcrystalline cellulose, pregelatinized starch, cross-linked polyvinylpyrrolidone, and magnesium stearate were mixed according to the prescription ratio in Table 3.1, and then dry granulated. Finally, tablets were compressed and coated to prepare tablets with a yield of 87.2%.

[0095] The results show that the tablets prepared using the prescription process of Example 3 have a high product yield of more than 85%.

[0096] Example 4

[0097] Table 4.1 Prescription composition of Example 4 tablets

[0098] The acetate of the compound of formula A, mannitol or lactose monohydrate, microcrystalline cellulose, pregelatinized starch, cross-linked polyvinylpyrrolidone, colloidal silicon dioxide, and magnesium stearate are mixed according to the prescription ratio in Table 4.1 and directly compressed to prepare tablets.

[0099] The tablets of Example 4 were subjected to dissolution testing according to the first method (basket method) of the appendix to Part IV of the 2015 edition of the Chinese Pharmacopoeia. 900 ml of pH 4.5 acetate buffer was used as the dissolution medium, and the dissolution test was performed at 37 ± 0.5°C using the basket method at 100 rpm. The results are shown in Table 4.2 and Figure 3.

[0100] Table 4.2 Dissolution data of Example 4 tablets

[0101] Example 5

[0102] Table 5.1 Prescription composition of Example 5 tablets

[0103] The acetate of the compound of formula A, mannitol, microcrystalline cellulose, pregelatinized starch, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone, colloidal silicon dioxide, and glyceryl behenate are mixed according to the prescription ratio in Table 5.1, and the mixture is wet granulated and compressed to prepare tablets.

[0104] The tablets of Example 5 were subjected to dissolution testing according to the first method (basket method) of the appendix to Part IV of the 2015 edition of the Chinese Pharmacopoeia. 900 ml of pH 4.5 acetate buffer was used as the dissolution medium, and the dissolution test was conducted at 37 ± 0.5°C using the basket method at 100 rpm. The results are shown in Table 5.2 and Figure 4.

[0105] Table 5.2 Dissolution data of Example 5 tablets

[0106] Example 6

[0107] Table 6.1 Prescription composition of Example 6 capsule

[0108] The acetate salt of the compound of formula A, mannitol, microcrystalline cellulose, pregelatinized starch, and glyceryl behenate are mixed according to the prescription ratio in Table 6.1 and filled into capsules.

[0109] The dissolution test of the capsules of Example 6 was conducted according to the first method (basket method) of the dissolution test in Appendix IV of the 2015 edition of the Chinese Pharmacopoeia. 900 ml of pH 4.5 acetate buffer was used as the dissolution medium, and the dissolution test was conducted at 37 ± 0.5°C using the basket method at 100 rpm. The results are shown in Table 6.2 and Figure 5.

[0110] Table 6.2 Dissolution data of capsules of Example 6

[0111] Example 7 Stability Study: Influencing Factors Test

[0112] The tablets prepared according to the prescription ratios and production processes in Examples 3 and 4-3, as well as the tablets of Example 5-2, were exposed and stored under high temperature conditions (60°C), high humidity conditions (92.5% ± 5% RH), and light conditions (LX 4500 ± 500) for 10 days to investigate the changes in total impurities and tablet dissolution. The total impurities were determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512). The dissolution method was the same as before. The results are shown in Tables 7.1, 7.2, and 7.3.

[0113] The results showed that, for the tablets prepared according to Example 3, under conditions of high temperature, high humidity and light, the total impurities and tablet dissolution did not change significantly, both meeting the requirements, and the tablets had good stability; for the tablets prepared according to Example 4-3, under conditions of high temperature, the impurities slightly increased, and the tablet dissolution did not change significantly, indicating that the tablets had good stability; while for the tablets prepared according to Example 5-2, the impurities increased significantly after being placed under high temperature conditions for 5 days and 10 days, and the tablet dissolution decreased significantly, indicating that the tablets were unstable under high temperature conditions.

[0114] Table 7.1 Test results of factors affecting tablets prepared according to Example 3

[0115] Table 7.2 Test results of factors affecting tablets prepared according to Example 4-3

[0116] Table 7.3 Test results of factors affecting tablets of Example 5-2

[0117] Example 8 Stability Study: Accelerated Test and Long-term Test

[0118] The tablets prepared according to the prescription ratio and production process in Example 3 and Example 4-3, and the capsule of Example 6-1 were stored for a certain period of time under accelerated conditions (40°C, 75% RH) and room temperature conditions (25°C, 60% RH), respectively, to investigate the changes in total impurities and dissolution of the preparation. The total impurities were determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512). The dissolution method was the same as before. The results are shown in Tables 8.1, 8.2, 8.3, 8.4, 8.5 and 8.6.

[0119] The results showed that the tablets prepared according to Examples 3 and 4-3 did not show significant changes in total impurities and dissolution of the tablets under accelerated and room temperature conditions, both meeting the requirements and indicating good stability. However, the dissolution of the capsules prepared according to Example 6-1 decreased significantly over time after being placed under accelerated and room temperature conditions for 7 months, indicating that the capsules were unstable under accelerated and room temperature conditions.

[0120] Table 8.1 Stability data of tablets prepared according to Example 3 under accelerated conditions

[0121] Table 8.2 Stability data of tablets prepared according to Example 3 at room temperature

[0122] Table 8.3 Stability data of tablets prepared according to Example 4-3 under accelerated conditions

[0123] Table 8.4 Stability data of tablets prepared according to Example 4-3 at room temperature

[0124] Table 8.5 Stability data of capsules under accelerated conditions of Example 6-1

[0125] Table 8.6 Stability data of capsules of Example 6-1 under room temperature conditions

[0126] Those skilled in the art will appreciate that the foregoing description is exemplary and illustrative in nature and is intended to illustrate the present invention and its preferred embodiments. Through routine experimentation, the skilled artisan will appreciate that obvious modifications and variations can be made without departing from the spirit of the present invention. All such modifications within the scope of the appended claims are intended to be included therein. It is therefore intended that the present invention be defined not by the foregoing description but by the scope of the following claims and their equivalents. All publications cited in this specification are incorporated herein by reference.

Claims

1. A pharmaceutical composition comprising an active pharmaceutical ingredient and a filler, wherein, The active pharmaceutical ingredient is the compound (S)-7-(4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine or a pharmaceutically acceptable salt thereof, and the filler comprises microcrystalline cellulose and pregelatinized starch.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt is acetate, preferably monoacetate.

3. The pharmaceutical composition according to any one of claims 1-2, wherein, Based on the total weight of the pharmaceutical composition, the weight percentage content of the active pharmaceutical ingredient is about 3-40%, such as about 5-30%, about 7-20%, about 12-18%.

4. The pharmaceutical composition according to any one of claims 1-3, wherein, Based on the total weight of the pharmaceutical composition, the weight percentage content of the filler is about 10-85%; preferably about 30-80%; more preferably about 45-75%.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the weight ratio of microcrystalline cellulose to pregelatinized starch is about 1:1 to 10:1; preferably about 3:1 to 8:1; more preferably about 4:1 to 7:

1.

6. The pharmaceutical composition according to any one of claims 1-5, which further comprises other fillers.

7. The pharmaceutical composition according to claim 6, wherein the other filler is selected from one or more of mannitol, lactose monohydrate and cyclodextrin; preferably selected from one or two of mannitol and lactose monohydrate.

8. The pharmaceutical composition according to any one of claims 6-7, wherein, Based on the total weight of the pharmaceutical composition, the weight percentage content of the other filler is about 10-80%; preferably about 30-70%; more preferably about 30-50%.

9. The pharmaceutical composition according to any one of claims 1-8, which further comprises a disintegrant.

10. The pharmaceutical composition according to claim 9, wherein the disintegrant is selected from one or more of crospovidone, sodium carboxymethyl starch, croscarmellose sodium and low-substituted hydroxypropyl cellulose; preferably crospovidone.

11. The pharmaceutical composition according to any one of claims 9-10, wherein, Based on the total weight of the pharmaceutical composition, the weight percentage content of the disintegrant is about 1-20%; preferably about 1-10%; more preferably about 3-6%.

12. The pharmaceutical composition according to any one of claims 1-11, which further comprises a lubricant.

13. The pharmaceutical composition according to claim 12, wherein the lubricant is selected from one or more of colloidal silicon dioxide, magnesium stearate, glyceryl behenate, sodium stearyl fumarate and talc; preferably selected from one or more of colloidal silicon dioxide, magnesium stearate and glyceryl behenate; more preferably selected from one or two of colloidal silicon dioxide and magnesium stearate.

14. The pharmaceutical composition according to any one of claims 12-13, wherein, Based on the total weight of the pharmaceutical composition, the weight percentage content of the lubricant is about 0.5-15%, preferably about 1-10%, more preferably about 1.5-6%.

15. The pharmaceutical composition according to any one of claims 12-14, wherein the lubricant is a combination of colloidal silicon dioxide and magnesium stearate.

16. The pharmaceutical composition according to claim 15, wherein, Based on the total weight of the pharmaceutical composition, the weight percentage content of colloidal silica is about 0.5 - 10%, preferably about 0.5 - 6%, more preferably about 3 - 5%; the weight percentage content of magnesium stearate is about 0.5 - 10%, preferably about 0.5 - 5%, more preferably about 1 - 3%.

17. The pharmaceutical composition according to claim 1, which further comprises a disintegrant and a lubricant, wherein, Based on the total weight of the pharmaceutical composition, the weight percentage content of the active pharmaceutical ingredient is about 5 - 30%; the weight percentage content of the filler is about 30 - 80%; the weight percentage content of the disintegrant is about 1 - 10%; and the weight percentage content of the lubricant is about 1 - 10%, and it optionally contains other fillers.

18. The pharmaceutical composition according to claim 17, wherein, The pharmaceutically acceptable salt is acetate, preferably monoacetate.

19. The pharmaceutical composition according to any one of claims 17-18, wherein, Based on the total weight of the pharmaceutical composition, the weight percentage content of the active pharmaceutical ingredient is about 7 - 20%, preferably about 12 - 18%; the weight percentage content of the filler is about 45 - 75%; the weight percentage content of the disintegrant is about 3 - 6%; and the weight percentage content of the lubricant is about 1.5 - 6%.

20. The pharmaceutical composition according to any one of claims 17-19, wherein, The other filler is selected from one or both of mannitol and lactose monohydrate, preferably mannitol; the disintegrant is crospovidone; and the lubricant is selected from one or both of colloidal silica and magnesium stearate.

21. The pharmaceutical composition according to any one of claims 17-20, wherein, Based on the total weight of the pharmaceutical composition, the weight percentage content of the active pharmaceutical ingredient is about 7 - 20%, preferably about 12 - 18%; the weight ratio of microcrystalline cellulose to pregelatinized starch is about 3:1 to 8:1, preferably about 4:1 to 7:1; the other filler is mannitol, and its weight percentage content is about 0 - 50%; the disintegrant is crospovidone, and its weight percentage content is about 3 - 6%; and the lubricant is a combination of colloidal silica and magnesium stearate, the weight percentage content of colloidal silica is about 0.5 - 6%, preferably about 3 - 5%, and the weight percentage content of magnesium stearate is about 0.5 - 5%, preferably about 1 - 3%.

22. The pharmaceutical composition according to claim 1, further comprising a disintegrant and a lubricant, wherein, The active pharmaceutical ingredient is compound (S)-7-(4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine or its acetate; based on the total weight of the pharmaceutical composition, the weight percentage content of the active pharmaceutical ingredient is about 5 - 30%, preferably about 7 - 20%, more preferably about 12 - 18%; the filler is a combination of microcrystalline cellulose and pregelatinized starch, and the weight ratio of microcrystalline cellulose to pregelatinized starch is about 3:1 to 8:1, preferably about 4:1 to 7:1; the weight percentage content of the filler is about 30 - 80%, preferably about 45 - 75%; the disintegrant is crospovidone, and its weight percentage content is about 1 - 10%, preferably about 3 - 6%; and the lubricant is a combination of colloidal silica and magnesium stearate, the weight percentage content of colloidal silica is about 0.5 - 6%, preferably about 3 - 5%, and the weight percentage content of magnesium stearate is about 0.5 - 5%, preferably about 1 - 3%.

23. The pharmaceutical composition according to any one of claims 1-22, wherein, The particle size D90 of the active pharmaceutical ingredient is less than or equal to about 200 μm, for example, in the range of about 5 - 160 μm.

24. The pharmaceutical composition according to any one of claims 1 - 23, which is in the form of a tablet or a capsule; preferably in the form of a tablet.

25. The pharmaceutical composition according to claim 24, wherein, The tablet is prepared by a direct compression process during the preparation of the pharmaceutical composition.

26. The pharmaceutical composition according to claim 24, wherein, During the preparation of the pharmaceutical composition, dry granulation is used to prepare granules, and finally tablets are prepared.

27. The method for preparing the pharmaceutical composition according to any one of claims 1 - 26, comprising mixing the compound (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine or a pharmaceutically acceptable salt thereof with the filler, disintegrant, and / or lubricant according to one of claims 1 - 26.

28. The use of the pharmaceutical composition according to any one of claims 1 - 26 in the preparation of a medicament for treating a disease responsive to the inhibition of Syk kinase activity, such as autoimmune diseases, inflammatory diseases, and cancers (preferably hematological malignancies), wherein the autoimmune diseases, inflammatory diseases, and cancers are selected from systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, IgA nephropathy, autoimmune hemolytic anemia, immune thrombocytopenia, multiple sclerosis, myasthenia gravis, allergic rhinitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, asthma, psoriasis, lymphoma (such as B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma), leukemia (such as chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, and chronic myeloid leukemia), and multiple myeloma; Preferably, the medicament is used for treating autoimmune diseases, inflammatory diseases, and cancers, which are selected from rheumatoid arthritis, autoimmune hemolytic anemia, immune thrombocytopenia, Hodgkin lymphoma, and non-Hodgkin lymphoma; More preferably, the pharmaceutical composition is administered simultaneously or sequentially with other therapeutic agents; the other therapeutic agents include anti-immune therapeutic agents, steroids, chemotherapeutic agents, and targeted therapeutic agents.

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