Solid dispersions, their preparation and use

Abstract

The present invention provides a solid dispersion, its preparation method and use, which comprises an active ingredient, a compound of Formula A or a derivative thereof, in a crystalline form, an amorphous form, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a carrier. The solid dispersion can significantly improve the oral bioavailability of the active ingredient, has good solid-state stability, and allows the active ingredient to exhibit high plasma exposure in rats.

Description

[Technical Field]

[0001] The present invention relates to the field of medicine, and specifically to solid dispersions, their preparation methods and uses. [Background technology]

[0002] Casein kinase 1α (CK1α), encoded by the gene CSNK1A1, is a widely expressed serine / threonine kinase in the CK1 kinase family. CK1α is involved in the regulation of many physiological and pathological processes in cells and regulates the regular progression of life through various signaling pathways (Jiang et al., Cell Commun Signal (2018) 16: 23). For example, as a key regulator of the Wnt / β-catenin pathway, CK1α directly phosphorylates β-catenin at Ser45, targeting it for proteasomal degradation (Liu et al., Cell (2002) 108: 837-847). CK1α is also thought to regulate the protein stability of the tumor suppressor p53 by modulating the activity of the MDM2 / MDMX E3 ligase complex (Huart et al., J Biol Chem (2009) 284: 32384-94; Wu et al., Mol Cell Biol (2012) 32:4821-4832). CK1α has been reported to be overexpressed in many types of human cancer, but the precise role of CK1α in the progression of each type of tumor remains unclear (Richter et al., BMC Cancer (2018) 18: 140). The Cancer Dependency Map (DepMap) database showed that inactivation of CK1α by CRISPR / cas9-mediated gene knockout or shRNA-mediated gene knockdown significantly reduced the proliferation and / or survival of many cancer cell lines across multiple cancer types (Tsherniak et al., Cell (2017) 170:564-576; Behan et al., Nature (2019) 568: 511-516). Furthermore, suppression of CK1α activity with shRNA interference or D4476 (a CK1α inhibitor) effectively suppressed the progression of MLL-AF9 leukemia while minimizing the impact on normal hematopoietic stem and progenitor cells (HSPCs) (Jaras et al., J Exp Med (2014) 211(4): 605-612). These data suggest that CK1α is a potential therapeutic target for hematological malignancies and solid tumor indications.

[0003] The compound of formula A is currently in early clinical research as a new generation of CK1α selective molecular adhesive degrader. [ka] However, no research or report has been found regarding the polymorphism, amorphous form, formulation, etc. of the compound of formula A.

[0004] Therefore, in the process of drug discovery, it is necessary to comprehensively screen drug compounds and consider multiple factors.In particular, for the compound of formula A used to treat the above-mentioned proliferative diseases, the development of a dosage form that may have medicinal value of the compound or its derivative, crystalline form, amorphous form, or its pharmaceutically acceptable salt, hydrate or solvate, and the improvement of the properties of the compound such as stability, solubility, bioavailability, etc., has potential medicinal and clinical value. Summary of the Invention

[0005] The present invention provides a solid dispersion containing the compound of formula A or its derivatives, crystalline form, amorphous form, or pharmaceutically acceptable salts, hydrates, or solvates thereof as an active ingredient, which allows the active ingredient, the compound of formula A, to have good oral bioavailability, and is of great value in the development and production of new drugs.

[0006] In the following description, some specific details are set forth to provide a thorough understanding of each embodiment of the present invention, but it will be understood by those skilled in the art that the present invention can be practiced without these details. The following description of several embodiments is made with the understanding that the present invention is to be considered as an example of the subject matter for which protection is sought, and is not intended to limit the appended claims to the specific embodiments set forth. The headings used throughout the description are for convenience and should not be construed as any limitation on the claims. An embodiment set forth under any heading can be combined with an embodiment set forth under any other heading.

[0007] In a first aspect, the present invention provides a solid dispersion comprising an active ingredient and a carrier, wherein the active ingredient is one or more of a compound of Formula A or a derivative, crystalline, amorphous, or pharmaceutically acceptable salt, hydrate, or solvate thereof, and the carrier is selected from one or more of homopolymers and copolymers of N-vinyl lactams, cellulosic derivatives, graft copolymers, high molecular weight polyalkylene oxides, polyacrylates and polymethacrylates, polyacrylamides, vinyl acetate polymers, oligo- or polysaccharides or copolymers thereof, or acrylic acid copolymers. [ka]

[0008] In some preferred embodiments, the N-vinyl lactam homopolymers and copolymers are povidone or copolymers of PVP and polyvinyl acetate, preferably the povidone is PVP K30, and preferably the PVP and polyvinyl acetate copolymer is PVP VA64.

[0009] In some preferred embodiments, the cellulosic derivative is hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, preferably the hydroxypropyl methylcellulose acetate succinate is one or more of HPMCAS 716G, HPMCAS 912G, HPMCAS 126G, HPMCAS 716F, HPMCAS 912F, HPMCAS 126F, HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMCAS LF, HPMCAS MF and HPMCAS HF, preferably the hydroxypropyl methylcellulose is HPMC E3, preferably the hydroxypropyl cellulose is HPMC SSL.

[0010] In some preferred embodiments, the high molecular weight polyalkylene oxides are polyethylene oxide, polypropylene oxide, and copolymers of ethylene oxide and propylene oxide (poloxamers).

[0011] In some preferred embodiments, the polyacrylic and polymethacrylic esters are methacrylic acid / ethyl acrylate copolymers, methacrylic acid / methyl methacrylate copolymers, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymers, poly(hydroxyalkyl acrylates) and poly(hydroxyalkyl methacrylates).

[0012] In some preferred embodiments, the vinyl acetate polymers are copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, and polyvinyl alcohol. In some preferred embodiments, the oligosaccharides or polysaccharides are carrageenans, galactomannans and xanthan gums, and mixtures of two or more thereof.

[0013] In some preferred embodiments, the solid dispersion comprises one or more polymeric carriers selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, and mixtures thereof. One specific example of a useful povidone is one that is composed of about 60% N-vinylpyrrolidone and about 40% vinyl acetate monomers. One specific example of a useful povidone is one that has a K value (a measure of the viscosity of an aqueous povidone solution) of about 30.

[0014] In some preferred embodiments, the acrylic copolymer is a methyl acrylate and methyl methacrylate copolymer, preferably the methyl acrylate and methyl methacrylate copolymer is Eudragit, preferably the Eudragit is one or more of Eudragit L100, Eudragit E100, Eudragit S100, Eudragit L100-55, Eudragit EPO. In some preferred embodiments, the graft copolymer is Soluplus.

[0015] In some preferred embodiments, the pharmaceutically acceptable salt of the compound of Formula A is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogensulfate, 2-hydroxyethanesulfonate, phosphate, hydrogenphosphate, acetate, adipate, alginate, lysine, arginine, histidine, aspartate, benzoate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, hydroxyethanesulfonate, salicylate, methanesulfonate, mesitylenesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, and 2-naphthalenesulfonate. The salts include phosphate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, glutamate, bicarbonate, undecanoate, lactate, citrate, tartrate, gluconate, ethanedisulfonate, benzenesulfonate, L-tartrate, maleate, sodium salt, potassium salt, choline salt, tromethamine salt, calcium salt, and p-toluenesulfonate salts, and preferably phosphate, sulfate, L-tartrate, hydrochloride, maleate, hydrobromide, methanesulfonate, lysine salt, arginine salt, histidine salt, sodium salt, potassium salt, choline salt, tromethamine salt, and calcium salt.

[0016] In some preferred embodiments, the hydrate of the compound of formula A is a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, decahydrate, eleven-hydrate, or dodecahydrate.

[0017] In some preferred embodiments, the carrier is selected from one or more of povidone, copolymers of PVP and polyvinyl acetate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acrylic acid copolymers, and graft copolymers.

[0018] In some preferred embodiments, the carrier is selected from one or more of PVP K30, PVP VA64, Soluplus, HPMC E3, HPMCAS MG, HPMCAS HG, HPC SSL, Eudragit L100.

[0019] In some preferred embodiments, the carrier is selected from one or more of PVP VA64, Soluplus, and HPC SSL. In some preferred embodiments, the carrier is an HPC SSL.

[0020] The solid dispersion of the present invention is in amorphous form, and more importantly, the amorphous solid dispersion has good solid stability, can be stored for a long period of time, and has no potential impact on the performance of the drug product.

[0021] The amount of the carrier used in the present invention may be the amount commonly used in this field, and the weight ratio of the active ingredient to the carrier is 0.1:10 to 10:0.1. In some preferred embodiments, the weight ratio of the active ingredient to the carrier is 1:10 to 10:1, preferably 1:4 to 1:1.

[0022] In some preferred embodiments, the weight ratio of active ingredient to carrier is 1:4, 3:7, 4:6 or 1:1. In some preferred embodiments, the carrier is PVP VA64, preferably in a weight ratio of the active ingredient to PVP VA64 of 1:4.

[0023] In some preferred embodiments, the carrier is Soluplus, preferably in a weight ratio of the active ingredient to Soluplus of 1:4. In some preferred embodiments, the carrier is an HPC SSL, preferably in a weight ratio of the active ingredient to HPC SSL of 1:4, 3:7, 4:6 or 1:1. In some preferred embodiments, the active ingredient is an amorphous form of the compound of formula A, having an XRPD pattern essentially as shown in FIG.

[0024] In another preferred embodiment, the amorphous form of the compound of formula A further optionally has one or more of the following characteristics: 1) In TGA, there is a weight loss of 2.79 wt% before the temperature reaches 210±2.0°C; 2) In mDSC, there is one glass transition temperature at 129.30±2.0℃; 3) Essentially as per the TGA graph shown in Figure 3; 4) Basically, it is as per the mDSC chart shown in Figure 2.

[0025] In some preferred embodiments, the active ingredient is a compound of Formula A, and the solid dispersion of the compound of Formula A and Soluplus in a 1:4 weight ratio is amorphous as shown in PLM Figure 7, has an XRPD pattern essentially as shown in Figure 8, and optionally has one or more of the following characteristics: 1) In the TGA graph, there is a weight loss of 0.96 wt% before the temperature reaches 180.00±2.0℃; 2) In the mDSC chart, there is one glass transition temperature at the intermediate temperature of 99.79±2.0℃; 3) essentially according to the TGA graph shown in Figure 9; and / or 4) Basically, it is as per the mDSC chart shown in Figure 10.

[0026] In some preferred embodiments, the active ingredient is a compound of Formula A, and a solid dispersion of the compound of Formula A and PVP VA64 in a 1:4 weight ratio is amorphous as shown in PLM Figure 11, has an XRPD pattern essentially as shown in Figure 12, and optionally has one or more of the following characteristics: 1) In the TGA graph, there is a weight loss of 1.90 wt% before the temperature reaches 210±2.0°C; 2) In the mDSC chart, there is one glass transition temperature at the intermediate temperature of 118.74±2.0℃; 3) essentially according to the TGA graph shown in Figure 13; and / or 4) Basically, it is as per the mDSC chart shown in Figure 14.

[0027] In some preferred embodiments, the active ingredient is a compound of Formula A, and the solid dispersion of the compound of Formula A and HPC SSL in a 1:4 weight ratio is amorphous as shown in PLM Figure 15, has an XRPD pattern essentially as shown in Figure 16, and optionally has one or more of the following characteristics: 1) In the TGA graph, there is a weight loss of 1.00 wt % before the temperature reaches 180±2.0°C; 2) In the mDSC chart, there is one glass transition temperature at a temperature of 70.72±2.0℃; 3) essentially according to the TGA graph shown in Figure 17; and / or 4) Basically, it is as per the mDSC chart shown in Figure 18.

[0028] In some preferred embodiments, the active ingredient is a compound of Formula A, and the solid dispersion of the compound of Formula A and HPC SSL in a weight ratio of 3:7 is amorphous as shown in PLM Figure 24, has an XRPD pattern essentially as shown in Figure 25, and optionally has one or more of the following characteristics: 1) In the TGA graph, there is a weight loss of 0.75 wt% before the temperature reaches 180±2.0°C; 2) In the mDSC chart, there is one glass transition temperature at a temperature of 77.43±2.0℃; 3) essentially according to the TGA graph shown in Figure 26; and / or 4) Basically, it is as per the mDSC chart shown in Figure 27.

[0029] In some preferred embodiments, the active ingredient is a compound of Formula A, and the solid dispersion of compound of Formula A and HPC SSL in a weight ratio of 4:6 is amorphous as shown in PLM Figure 28, has an XRPD pattern essentially as shown in Figure 29, and optionally has one or more of the following characteristics: 1) In the TGA graph, there is a weight loss of 1.53 wt% before the temperature reaches 180±2.0℃; 2) In the mDSC chart, there is one glass transition temperature at a temperature of 84.97±2.0℃; 3) essentially according to the TGA graph shown in Figure 30; and / or 4) Basically, it is as per the mDSC chart shown in Figure 31.

[0030] In some preferred embodiments, the active ingredient is a compound of Formula A, and the solid dispersion of the compound of Formula A and HPC SSL in a 1:1 weight ratio is amorphous as shown in PLM Figure 32, has an XRPD pattern essentially as shown in Figure 33, and optionally has one or more of the following characteristics: 1) In the TGA graph, there is a weight loss of 1.35 wt% before the temperature reaches 180±2.0°C; 2) In the mDSC chart, there is one glass transition temperature at a temperature of 82.54±2.0℃; 3) essentially according to the TGA graph shown in Figure 34; and / or 4) Basically, it is as per the mDSC chart shown in Figure 35.

[0031] In one embodiment, the solid dispersion has the following characteristics: The area under the blood drug concentration-time curve of the active ingredient in the solid dispersion is 1.5 to 7 times, preferably 5 to 6 times, the area under the blood drug concentration-time curve when the active ingredient is administered alone.

[0032] In a second aspect, the present invention provides a method for producing a solid dispersion according to the first aspect, the method comprising the steps of: Method 1 mixing one or more of the compound of formula A or a derivative thereof, crystalline form, amorphous form, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and optionally other components, with a solvent to form a solution or suspension, and removing the solvent to obtain the solid dispersion; or Method 2 one or more of the compound of formula A or its derivatives, crystalline form, amorphous form, or pharmaceutically acceptable salts, hydrates or solvates thereof, and optionally other components are mixed together, heated, and then extruded to obtain the solid dispersion; or Method 3 One or more of the compound of formula A or its derivatives, crystalline form, amorphous form, or pharmaceutically acceptable salts, hydrates or solvates thereof, and optionally other components, are mixed with a solvent and spray-dried to obtain the solid dispersion.

[0033] In some preferred embodiments, in Method 1 or 3, the solvent is one or more of water, alcoholic solvents, ester solvents, ketone solvents, halogenated hydrocarbon solvents, nitrile solvents, and ether solvents, wherein the alcoholic solvent is preferably ethanol and / or methanol, the ester solvent is preferably ethyl acetate, the ketone solvent is preferably acetone, the halogenated hydrocarbon solvent is preferably dichloromethane, the nitrile solvent is preferably acetonitrile, and the ether solvent is preferably tetrahydrofuran, and preferably the solvent is dichloromethane and / or ethanol. Preferably, the solvent is acetone and / or water.

[0034] In some preferred embodiments, the mass / volume ratio of "one or more of the compound of formula A or its derivatives, crystalline form, amorphous form, or pharmaceutically acceptable salt, hydrate or solvate thereof" to the solvent is (0.1-30):1 mg / mL, preferably (1-10):1 mg / mL, more preferably 5:1.5 mg / mL.

[0035] In some preferred embodiments, the solvent is an alcohol-based solvent, in some preferred embodiments, a halogenated hydrocarbon solvent, wherein the alcohol-based solvent is preferably methanol, and the halogenated hydrocarbon solvent is preferably dichloromethane, preferably, the solvent is dichloromethane and methanol, wherein the volume ratio of dichloromethane to methanol is preferably 9:1 to 1:1.

[0036] In some preferred embodiments, the solvent is an alcoholic solvent, in some preferred embodiments, a halogenated hydrocarbon solvent, wherein the alcoholic solvent is preferably ethanol, and the halogenated hydrocarbon solvent is preferably dichloromethane, preferably, the solvent is dichloromethane and ethanol, wherein the volume ratio of dichloromethane to methanol is preferably 9:1 to 1:1.

[0037] In some preferred embodiments, the solvent is acetone and water, where the volume ratio of acetone to water is preferably 7:1 to 10:1. In some preferred embodiments, the inlet temperature of the spray dryer is set to 40°C to 200°C, preferably 80°C to 120°C.

[0038] In a third aspect, the present invention provides a pharmaceutical composition comprising the solid dispersion, wherein the solid dispersion comprises an active ingredient and a carrier, wherein the active ingredient is one or more of a compound of Formula A or its derivatives, crystalline form, amorphous form, or pharmaceutically acceptable salts, hydrates, or solvates thereof, and the carrier is selected from one or more of N-vinyl lactam homopolymers and copolymers, cellulose-based derivatives, and / or graft copolymers or acrylic acid copolymers. The pharmaceutical composition comprises: (1) a solid dispersion as described above; and (2) a pharmaceutically acceptable excipient.

[0039] In some preferred embodiments, the drug composition may contain other excipients, such as excipients used as fillers, binders, disintegrants, glidants, and lubricants. Thus, a solid drug composition comprising a compound of formula A or a pharmaceutically acceptable salt thereof may further optionally contain one or more conventional pharmaceutically acceptable excipients.

[0040] In a fourth aspect, the present invention provides a pharmaceutical formulation comprising the above-described pharmaceutical composition, which may be a solid formulation, or may be a powder, granules, tablet, capsule, drop pill or film.

[0041] In a fifth aspect, the present invention provides a use of the solid dispersion, drug composition or drug formulation as described above in the manufacture of a medicament for treating a proliferative disease, preferably wherein the proliferative disease is selected from the group consisting of breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic adenocarcinoma, ovarian cancer, head and neck cancer, melanoma, colorectal cancer, gastric cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neuroblastoma, leukemia (acute lymphocytic leukemia (ALL), acute bone marrow cancer, leukemia (acute myeloid leukemia (ALL), acute myeloid leukemia (ACLL ... Myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMOL), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia), lymphoma (small lymphocytic lymphoma (SLL), Hodgkin's lymphoma (nodular sclerosing, mixed cell, lymphocyte-rich, lymphopenic or non-reduced and nodular lymphocyte) Hodgkin's lymphoma (primary), non-Hodgkin's lymphoma (all subtypes), chronic lymphocytic leukemia / small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, lymphoma (e.g., Waldenstrom's macroglobulinemia), splenic marginal zone lymphoma, plasma cell neoplasms (plasma cell myeloma, plasmacytoma, monoclonal gammopathy, heavy chain disease), extranodal marginal zone B-cell lymphoma (MALT lymphoma), lymphoma (NMZL) ), follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma (nasal type), enteropathy-type T-cell lymphoma, hepatosplenic Uses include cancers of the lymphoid organs and hematological malignancies, including T-cell lymphoma, blastic NK-cell lymphoma, mycosis fungoides / Sezary syndrome, primary cutaneous CD30-positive T-cell lymphoma disease, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (non-specific), anaplastic large cell lymphoma), multiple myeloma (plasma cell myeloma or Kahler's disease).

[0042] In a sixth aspect, the present invention provides a method of treating a proliferative disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the solid dispersion of the first aspect of the invention or the pharmaceutical composition of the third aspect of the invention or the pharmaceutical formulation of the fourth aspect of the invention. In some preferred embodiments, the subject is a mammal, for example, a human. [Brief explanation of the drawings]

[0043] [Figure 1] Figure 1 is a PLM diagram of API amorphous. [Figure 2] Figure 2 is an mDSC chart of the amorphous API. [Figure 3] FIG. 3 is a TGA graph of the API amorphous form. [Figure 4] Figure 4 is the XRPD pattern of the amorphous API. [Figure 5] FIG. 5 is an XRPD overlay pattern of the fast solvent evaporation product.

[0044] [Figure 6] FIG. 6 is a solubility curve diagram of the fast evaporation product. [Figure 7] FIG. 7 is a PLM diagram of the formulated API+Soluplus solid dispersion. [Figure 8] FIG. 8 is the XRPD pattern of the formulated API+Soluplus solid dispersion. [Figure 9] FIG. 9 is a TGA graph of the formulated API+Soluplus solid dispersion. [Figure 10] FIG. 10 is an mDSC chart of the formulated API+Soluplus solid dispersion.

[0045] [Figure 11] FIG. 11 is a PLM diagram of the formulated API+PVP VA64 solid dispersion. [Figure 12] FIG. 12 is the XRPD pattern of the formulated API+PVP VA64 solid dispersion. [Figure 13]FIG. 13 is a TGA graph of the formulated API+PVP VA64 solid dispersion. [Figure 14] FIG. 14 is an mDSC chart of the formulated API+PVP VA64 solid dispersion. [Figure 15] FIG. 15 is a PLM diagram of the formulated API+HPC SSL solid dispersion.

[0046] [Figure 16] FIG. 16 is the XRPD pattern of the formulated API+HPC SSL solid dispersion. [Figure 17] FIG. 17 is a TGA graph of the formulated API+HPC SSL solid dispersion. [Figure 18] FIG. 18 is an mDSC chart of the formulated API+HPC SSL solid dispersion. [Figure 19] FIG. 19 shows the redispersion solubility curves of solid dispersions with different formulations. [Figure 20] FIG. 20 shows the XRPD patterns of solid dispersions with different formulations at 25° C. / 60% RH (open) after 1 week.

[0047] [Figure 21] FIG. 21 shows the XRPD patterns of solid dispersions with different formulations at 40° C. / 75% RH (open) after 1 week. [Figure 22] FIG. 22 shows PK diagrams for three solid dispersions (formulated API+Soluplus, formulated API+PVP VA64, and formulated API+HPC SSL). [Figure 23] FIG. 23 is a PK diagram of formulated API+HPC SSL solid dispersions with different drug loadings. [Figure 24] FIG. 24 is a PLM diagram of the formulated API+HPC SSL (3:7, w / w) solid dispersion. [Figure 25] FIG. 25 is the XRPD pattern of the formulated API+HPC SSL (3:7, w / w) solid dispersion.

[0048] [Figure 26]FIG. 26 is a TGA graph of the formulated API+HPC SSL (3:7, w / w) solid dispersion. [Figure 27] FIG. 27 is an mDSC chart of the formulated API+HPC SSL (3:7, w / w) solid dispersion. [Figure 28] FIG. 28 is a PLM diagram of the formulated API+HPC SSL (4:6, w / w) solid dispersion. [Figure 29] FIG. 29 is the XRPD pattern of the formulated API+HPC SSL (4:6, w / w) solid dispersion. [Figure 30] Figure 30 is a TGA graph of the formulated API+HPC SSL (4:6, w / w) solid dispersion.

[0049] [Figure 31] FIG. 31 is an mDSC chart of the formulated API+HPC SSL (4:6, w / w) solid dispersion. [Figure 32] FIG. 32 is a PLM diagram of formulated API+HPC SSL (1:1, w / w) solid dispersion. [Figure 33] Figure 33 is the XRPD pattern of the formulated API+HPC SSL (1:1, w / w) solid dispersion. [Figure 34] Figure 34 is a TGA graph of formulated API+HPC SSL (1:1, w / w) solid dispersion. [Figure 35] FIG. 35 is an mDSC chart of the formulated API+HPC SSL (1:1, w / w) solid dispersion.

[0050] [Figure 36] FIG. 36 is a redispersion solubility curve of formulated API+HPC SSL. [Figure 37] Figure 37 is the XRPD pattern of formulated API+HPC SSL solid dispersion at 25°C / 60% RH (open) at 4 weeks. [Figure 38] Figure 38 is the XRPD pattern of formulated API+HPC SSL solid dispersion at 40°C / 75% RH (open) at 4 weeks. [Figure 39]FIG. 39 is an XRPD pattern of API crystalline form G. [Figure 40] FIG. 40 is a DSC chart of API crystalline form G.

[0051] [Figure 41] FIG. 41 is a TGA graph of API crystalline form G. [Figure 42-1] Figures 42-1 and 42-2 are XRPD patterns of solid dispersions prepared using API crystalline form G as a starting material. [Figure 42-2] Figures 42-1 and 42-2 are XRPD patterns of solid dispersions prepared using API crystalline form G as a starting material. [Figure 43-1] Figures 43-1 and 43-2 are DSC charts of a solid dispersion produced using API crystalline form G as a raw material. [Figure 43-2] Figures 43-1 and 43-2 are DSC charts of a solid dispersion produced using API crystalline form G as a raw material. [Figure 44-1] Figures 44-1 and 44-2 are TGA graphs of solid dispersions prepared using API crystalline form G as a starting material. [Figure 44-2] Figures 44-1 and 44-2 are TGA graphs of solid dispersions prepared using API crystalline form G as a starting material. DETAILED DESCRIPTION OF THE INVENTION

[0052] The present inventors have conducted extensive and in-depth research and have developed a solid dispersion with excellent pharmacokinetic characteristics. The solid dispersion of the present invention exhibits high plasma exposure in rats, i.e., high peak drug concentration and a large area under the blood drug concentration-time curve, and the area under the blood drug concentration-time curve is 1.5 to 7 times (preferably 5 to 6 times) the area under the blood drug concentration-time curve when the active ingredient is administered alone. Based on this, the present invention has been completed.

[0053] active ingredient As used herein, the term "active pharmaceutical ingredient (API)" (also referred to herein as "active ingredient") refers to one or more of the active ingredients, the compound of Formula A, or its derivatives, crystalline forms, amorphous forms, or pharmaceutically acceptable salts, hydrates, or solvates, the chemical name of which is N-((S)-(5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide. [ka]

[0054] solid dispersion A solid dispersion is a dispersion system in which the active ingredient is present in a solid form by being highly dispersed in a (solid) carrier. In the present invention, solid dispersions include solid solutions, glassy solutions, glassy suspensions, amorphous precipitates in crystalline carriers, eutectics or monotectics, mixed or composite formations and combinations thereof.

[0055] Method for producing solid dispersion The solid dispersion described in the present invention can be produced by the following method, but the conditions of the method, such as the amount of carrier, solvent, and each component, the production temperature, and the time required for production, are not limited to the following interpretation. Furthermore, the solid dispersion described in the present invention can be conveniently produced by any combination of various synthesis methods described herein or known in the art, and such combinations can be easily performed by a person skilled in the art.

[0056] The manufacturing method of the present invention can use, for example, hot melt extrusion, hot melt coating, granulation, freezing, and solvent evaporation methods (eg, layering, coating, and granulation).

[0057] Preferably, the solid dispersion of the present invention is prepared by the following method: Method 1 mixing the compound of formula A or one or more of its derivatives, crystalline form, amorphous form, or pharmaceutically acceptable salts, hydrates, or solvates, and optionally other components (e.g., a carrier according to the present invention, wherein the carrier is selected from one or more of N-vinyl lactam homopolymers and copolymers, cellulosic derivatives, graft copolymers, high molecular weight polyalkylene oxides, polyacrylic and polymethacrylic acid esters, polyacrylamides, vinyl acetate polymers, oligosaccharides or polysaccharides or copolymers thereof, or acrylic acid copolymers) with a solvent (e.g., water, ethanol, methanol, ethyl acetate, acetone, dichloromethane, acetonitrile, tetrahydrofuran, or a combination thereof) to form a solution or suspension, and removing the solvent to obtain the solid dispersion; Method 2 one or more of the compound of formula A or its derivatives, crystalline form, amorphous form, or pharmaceutically acceptable salts, hydrates, or solvates thereof, and optionally other components (including, for example, the carriers described above) are mixed, heated, and then extruded to obtain the solid dispersion; Method 3 One or more of the compound of formula A or its derivatives, crystalline form, amorphous form, or pharmaceutically acceptable salts, hydrates, or solvates thereof, and optionally other components (including, for example, a carrier as described above) are mixed with a solvent (for example, water, ethanol, methanol, ethyl acetate, acetone, dichloromethane, acetonitrile, tetrahydrofuran, or a combination thereof), and spray-dried (the inlet temperature is set at 40°C to 200°C, preferably 80°C to 120°C) to obtain the solid dispersion.

[0058] Preferably, the mass / volume ratio of the compound of formula A or one or more of its derivatives, crystalline forms, amorphous forms, or pharmaceutically acceptable salts, hydrates or solvates to the solvent is (0.1-30):1 mg / mL, preferably (1-10):1 mg / mL, more preferably 5:1.5 mg / mL; and / or the solvent is an alcoholic solvent and / or a halogenated hydrocarbon solvent, wherein the alcoholic solvent is preferably methanol or ethanol, and the halogenated hydrocarbon solvent is preferably dichloromethane, preferably the solvent is dichloromethane and methanol or dichloromethane and ethanol, wherein the volume ratio of dichloromethane to methanol or dichloromethane to ethanol is preferably 9:1 to 1:1; and / or the solvent is acetone and water, where the volume ratio of acetone to water is preferably 7:1 to 10:1.

[0059] Drug Composition The pharmaceutical composition according to the present invention can be prepared by various methods well known in the art, and can be prepared into dosage forms suitable for administration to the human body, such as the above-mentioned tablets, capsules, granules, etc., by mixing a therapeutically effective amount of the solid dispersion with one or more pharmaceutically acceptable adjuvants.

[0060] A "therapeutically effective amount" is an amount of an active ingredient according to the present invention that, when administered to a patient in need thereof, is sufficient to effect treatment of a disease state, condition, or disorder for which the active ingredient acts. Such amount is sufficient to produce the biological or medical response in a tissue or system or patient that is desired by a researcher or clinician.

[0061] The pharmaceutical composition of the present invention contains the solid dispersion or a pharmaceutically acceptable salt of the present invention and a pharmacologically acceptable excipient in a safe and effective amount. Here, the term "safe and effective amount" refers to an amount of the solid dispersion sufficient to significantly improve the condition without causing severe side effects. Typically, the pharmaceutical composition contains the solid dispersion of the present invention in an amount of 1 to 2000 mg / preparation, preferably 10 to 200 mg / preparation. Preferably, the "preparation" is a capsule or tablet.

[0062] An excipient refers to one or more compatible solid or liquid fillers or gel substances that are applicable to humans and must have sufficient purity and sufficiently low toxicity. "Compatible" means that each component in the composition can be blended with the solid dispersion of the present invention and with each other without significantly reducing the effectiveness of the solid dispersion. Some examples of pharmaceutically acceptable excipients include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), starches, monosaccharides or polysaccharides, gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tallow, sorbitol, etc.), and the like. R ), humectants (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free distilled water, etc.

[0063] The mode of administration of the solid dispersion or drug composition of the present invention is not particularly limited, but representative modes of administration include, but are not limited to, oral administration, intratumoral administration, rectal administration, parenteral gastrointestinal administration (intravenous, intramuscular, or subcutaneous), and topical administration.

[0064] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the solid dispersion is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or the following ingredients: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, microcrystalline cellulose, mannitol, and silicic acid; (b) binders, such as hydromethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; and (d) disintegrants, such as agar, calcium carbonate, and maltodextrin. Potato starch or tapioca starch, alginic acid, some complex silicates, croscarmellose sodium and sodium carbonate, (e) solution retarders such as paraffin, (f) absorption accelerators such as ammonium compounds, (g) wetting agents such as cetanol, sodium dodecyl sulfate, glycerin monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0065] Solid dosage forms, such as tablets, pills, capsules, pills, and granules, can be prepared with coatings and shells, such as enteric coatings and other materials known in the art. Opacifying agents may be included, and in such compositions, the release of the solid dispersion may be delayed in a certain part of the digestive tract. Examples of encapsulating materials that can be used include polymeric and wax-based materials. If necessary, the solid dispersion can be formed into a microcapsule with one or more of the above-mentioned excipients.

[0066] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, compatibilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0067] Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In addition to the solid dispersion, the suspension may contain suspending agents such as ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, methoxyaluminium and agar or mixtures of these substances.

[0068] Compositions for parenteral injection include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions and emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0069] Dosage forms of the solid dispersion of the present invention for topical administration include ointments, powders, poultices, sprays, and inhalants. The solid dispersion of the present invention is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants, as needed.

[0070] The solid dispersion of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When used as a pharmaceutical composition, a safe and effective amount of the solid dispersion of the present invention is administered to a mammal (e.g., a human) in need of treatment, and the dosage is a pharmaceutically effective dosage. For a human weighing 60 kg, the daily dosage is usually 0.2 to 2000 mg, preferably 1 to 500 mg, and more preferably 1 to 200 mg. Of course, the specific dosage should be determined taking into account factors such as the mode of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0071] Specific carriers according to the present invention, such as PVP K30, PVP VA64, HPMCAS 716G, HPMCAS 912G, HPMCAS 126G, HPMCAS 716F, HPMCAS 912F, HPMCAS 126F, HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMCAS LF, HPMCAS MF, HPMCAS HF, HPC SSL, Eudragit L100, Eudragit E100, Eudragit S100, Eudragit L100-55, Eudragit EPO, and Soluplus, are all commercially available products with disclosed structures, compositions, and / or properties. For detailed information on specific structures and properties, please refer to the instructions for use of the relevant products.

[0072] The above-provided solid dispersion, drug composition or drug formulation of the present invention has acceptable bioabsorption performance. Such bioabsorption is characterized by pharmacokinetic (PK) properties, particularly the C at a specific dose or dose range. max The bioavailability can be demonstrated by the AUC or AUC. The bioavailability can then be measured by PK studies in humans or any suitable model type. The solid dispersion of the present invention can significantly improve the oral bioavailability of the compound of Formula A and has good solid-state stability.

[0073] The present invention will be further described in the form of examples below, but the present invention is not limited to the scope of the described examples. In the following examples, experimental methods for which specific conditions are not described were selected according to conventional methods and conditions or product instructions.

[0074] The reagents and raw materials used in the following examples are commercially available or can be purchased from the following vendors. [Table A]

[0075] Abbreviation [Table B]

[0076] Polarized Light Microscopy (PLM) Measurement Method: Nikon LV100POL with 5MP CCD -Physical lens: 10x to 50x X-ray powder diffractometer (XRPD) measurement method: Samples are run in XRPD by the following method: -Tube: Cu:K-α (λ=1.54179Å) -Generator: Voltage: 40 kV; Current: 40 mA -Scanning range: 3~40 degrees -Sample rotation speed: 15 rpm -Scanning speed: 10 degrees / min Thermogravimetric analysis (TGA) measurements: - Place the sample (2-5 mg) in an aluminum dish and perform the following procedure: -The test is terminated when the sample loses more than 20% weight by heating from room temperature to 300°C at a rate of 10°C / min under atmospheric conditions. Differential scanning calorimetry (DSC) measurements: -Test sample (~1 mg) in a sealed aluminum pan with fine holes Heat from 30°C to 220°C at a rate of -10°C / min.

[0077] Preparation of Compounds of Formula A The compound of formula A, whose chemical name is N-((S)-(5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide, was prepared by the method of Example 15 of PCT / CN2022 / 097236. [ka]

[0078] A round-bottom flask containing DMAc (50 mL) was charged with compound 1 (3.25 g, 12.3 mmol, hydrochloride salt), compound 2 (4.67 g, 12.9 mmol), NMM (6.2 g, 61.3 mmol), and T3P (5.6 g, 17.6 mmol). The mixture was degassed and flushed with N2 three times. The mixture was stirred under N2 at 25 °C for 12 h. The mixture was poured into saturated aqueous sodium chloride (100 mL), filtered, and washed with water (100 mL). The cake was then dissolved in DCM (200 mL), washed with saturated aqueous NaHCO3 (100 mL), and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound 3 (6.5 g, 99.7% calculated yield based on compound 1) as a white solid.

[0079] A solution of compound 3 in CH3CN (13 mL) was charged with benzenesulfonic acid (1.1 g, 7.21 mmol). The mixture was stirred at 70 °C for 14 h under N2 atmosphere. The mixture was diluted with DCM (60 mL) and washed with saturated aqueous NaHCO3 (30 mL x 2), followed by HO (30 mL x 2). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was reslurried with EA (5 mL) and MTBE (5 mL) and filtered to give a cake of compound A, which was dried and designated as the API control. The cake of the API control was placed in 30 mL of acetonitrile and sonicated for 5 minutes to homogenize it into a slurry-like solution. 70 mL of water was added until the entire solution was clear and transparent, and the mixture was lyophilized to give an amorphous off-white solid of compound A, designated as the API amorphous, in 87% yield and 99% purity.

[0080] 1 H NMR (400 MHz, DMSO-d6) δ11.01 (s, 1H), 8.91 (d, J = 8.0 Hz, 1H), 8.57 - 8.52 (m, 1H),8.06 (s, 1H), 8.02 - 7.95 (m, 1H), 7.91 - 7.87 (m, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 5.19 - 5.05 (m, 2H), 4.57 - 4.34 (m, 2H), 2.97 - 2.81 (m, 2H), 2.65 - 2.56 (m, 1H), 2.45 - 2.35 (m, 1H), 2.12 - 1.97 (m, 2H), 1.91 - 1.71 (m, 5H); LCMS (ESI+): m / z 467.2 [M+H]+.

[0081] Example 1 Amorphous Characterization of Compound of Formula A (Active Pharmaceutical Ingredient, API) Characterization was carried out by PLM, XRPD, mDSC and TGA. As shown in Figures 1 and 4, PLM and XRPD revealed that the compound of Formula A was present in either an amorphous or molecular form, with all of the diffraction peaks (characteristic peaks) disappearing. As shown in Figure 3, there was a weight loss of 2.79 wt% before reaching a temperature of 210 ± 2.0 °C. As shown in Figure 4, mDSC indicated a glass transition temperature of 129.30 ± 2.0 °C.

[0082] Example 2 Approximate Solubility Test Approximately 5 mg of API reference compound of formula A was weighed into a 1.5 mL glass vial, and then predetermined amounts of different solvents (as shown in Table 1) were added in small increments until the solid dissolved or the total volume reached 1 mL. Compound of formula A has a high approximate solubility in a mixed solvent of DCM and MeOH. However, in another study, it was found that compound of formula A quickly racemized in MeOH, whereas compound of formula A maintained good chirality stability in acetone and ethanol. The approximate solubility results are shown in Table 1. Different solvents have different degrees of solubility for the compound of formula A. Considering the stability factor at the same time, both DCM:EtOH (9:1, v / v) and acetone:water (9:1, v / v) can be used as solvent systems to prepare the solid dispersion of the compound of formula A.

[0083] [Table 1]

[0084] Example 3 Rapid Solvent Evaporation Test Approximately 10 mg of the API reference compound of Formula A and 40 mg of the polymer carrier were transferred to 1 mL of DCM:EtOH = 9:1 (v / v) to prepare a solution with a drug loading of 20%. The resulting clear solution was rapidly evaporated at 80 °C until no liquid remained, producing a solid dispersion. The API reference compound of Formula A was also treated separately in the same manner. The results are shown in Figure 5. Two products (API + HPMC E3 and API + HMCAS MG) exhibited crystalline diffraction peaks, while in the remaining samples, all other rapid solvent evaporation products except for the API reference compound of Formula A were amorphous.

[0085] The effect of different polymers on the solubility of the compound of Formula A was evaluated by measuring the solubility of the evaporation products at different time points in simulated fasting intestinal fluid (FaSSIF), as shown in Table 2 and Figure 6. Comparing the API amorphous and the API control, the products using PVP K30, PVP VA64, and Soluplus as carriers showed relatively good improvement in the solubility of the compound of Formula A.

[0086] Considering the results of the inhibitory effect of polymer carriers on API crystalline form (crystalline form diffraction peak) and their solubility enhancement performance comprehensively, three polymers, namely PVP VA64, Soluplus and HPC SSL, were selected for further study. [Table 2]

[0087] Example 4 Preparation of solid dispersion by spray drying Setting of spray drying parameters: The spray drying parameters were set as shown in Table 3. [Table 3]

[0088] Based on the results of the fast solvent evaporation test, three kinds of polymer carriers including PVP VA64, Soluplus and HPC SSL were selected to prepare solid dispersions of the compound of formula A by the method of spray drying.

[0089] As shown in Table 3, the appropriate amounts of API reference compound of Formula A and the corresponding polymer carrier were weighed according to the formulation ratio, and then DCM:EtOH (9:1, v / v) solvent was added (DCM was added first to wet the API, and then EtOH was added).The mixture was then stirred at 700 rpm until all the samples were completely dissolved, and the sample solution was spray-dried according to the equipment parameters in Table 3. The resulting solid powder was further dried overnight (about 22 hours) under vacuum at 40°C to obtain a solid dispersion sample.

[0090] Table 4 shows the results of characterization of solid dispersions with different formulations by PLM, XRPD, mDSC, TGA and HPLC. [Table 4]

[0091] The solid dispersion of API + Soluplus (1:4, w / w) was characterized by PLM, XRPD, mDSC, and TGA. As shown in Table 4 and Figures 7 to 10, PLM and XRPD revealed that the solid dispersion was amorphous, and all of the XRPD diffraction peaks (characteristic peaks) of the API disappeared, indicating that the solid dispersion was in amorphous form. As shown in Figure 9, the weight loss was 0.96% at 180 ± 2.0 °C. As shown in Figure 10, mDSC indicated that the glass transition temperature was 99.79 ± 2.0 °C. The content was detected by HPLC to be 103.15%, with no obvious change in purity, approximately 99.32%.

[0092] The solid dispersion of API + PVP VA64 (1:4, w / w) was characterized by PLM, XRPD, mDSC, and TGA. As shown in Table 4 and Figures 11 to 14, PLM and XRPD revealed that the solid dispersion was amorphous, and all of the XRPD diffraction peaks (characteristic peaks) of the API disappeared, indicating that the solid dispersion was in amorphous form. As shown in Figure 13, the weight loss was 1.90% at 210 ± 2.0 °C. As shown in Figure 14, mDSC indicated that the glass transition temperature was 118.74 ± 2.0 °C. The content was detected by HPLC to be 102.95%, with no obvious change in purity, approximately 99.35%.

[0093] The solid dispersion of API + HPC SSL (1:4, w / w) was characterized by PLM, XRPD, mDSC, and TGA. As shown in Table 4 and Figures 15 to 18, PLM and XRPD revealed that the solid dispersion was amorphous, and all of the XRPD diffraction peaks (characteristic peaks) of the API disappeared, indicating that the solid dispersion was in amorphous form. As shown in Figure 17, the weight loss was 1.00% at 180 ± 2.0 °C. As shown in Figure 18, mDSC indicated that the glass transition temperature was 70.72 ± 2.0 °C. The content was detected by HPLC to be 103.30%, with no obvious change in purity, approximately 99.29%.

[0094] Example 5 Redispersion solubility test of solid dispersion Method: Sample powders of the formulations shown in Table 5 were weighed into 3 mL of simulated gastric fluid (SGF) to achieve target API concentrations of 8 mg / mL or 2 mg / mL. After stirring at 500 rpm at 37°C for 0.25 and 0.5 hours, approximately 200 μL of the suspension was centrifuged at 14,000 rpm for 5 minutes. The supernatant was diluted 6-fold with diluent and subjected to HPLC analysis. After sampling at 0.5 hours, FaSSIF (2 times the volume of SGF) was immediately added to the suspension and stirred for an additional 0.25, 0.5, and 1.5 hours. The suspension was then sampled for HPLC analysis and pH testing. As shown in Table 5 and Figure 19, the formulations API + PVP VA64 and API + HPC SSL demonstrated good solubility.

[0095] [Table 5]

[0096] Example 6 One-week solid state stability study of solid dispersions According to Table 6, three solid dispersions, i.e., formulation API+Soluplus, formulation API+PVP VA64, and formulation API+HPC SSL, were stored at 25°C / 60%RH (open) and 40°C / 75%RH (open) for one week, after which the appearance of the samples was observed with the naked eye and the purity of the samples was analyzed by HPLC. The appearance results showed slight aggregation and a transparent gel at 40°C / 75%RH (open), as shown in Table 7. XRPD characterization is shown in Figures 20 and 21.

[0097] The results shown in Figure 22 indicate that the three solid dispersions, i.e., API + Soluplus, formulation API + PVP VA64, and formulation API + HPC SSL, had relatively poor chemical stability at 40°C / 75% SSL (open). The HPLC analysis results are shown in Table 6. However, all three solid dispersions exhibited good physical stability under similar conditions. Therefore, to prevent chemical degradation, storage of the solid dispersions should be avoided under high temperature and humidity conditions. [Table 6]

[0098] [Table 7]

[0099] Example 7: Optimization of drug loading using solid dispersion of formulated API + HPC SSL as an example Based on the results of Examples 1-6, the drug loading was optimized using the solid dispersion of the API+HPC SSL formulation as an example. As shown in Table 8, appropriate amounts of the API reference compound of Formula A and the HPC SSL were weighed into a DCM:EtOH (9:1, v / v) solvent, and then stirred at 700 rpm until all samples were completely dissolved. The sample solution was spray-dried using the equipment parameters shown in Table 8. The resulting solid powder was further dried under vacuum at 40°C for about 20 hours to obtain a solid dispersion sample.

[0100] Example 7-1 Preparation of API+HPC SSL solid dispersion with drug loading of 30-50% [Table 8]

[0101] Example 7 Characterization of the Formulated API+HPC SSL Solid Dispersion The solid dispersions of the formulated API+HPC SSL shown in Table 9 were characterized by PLM, XRPD, mDSC, TGA and HPLC. [Table 9]

[0102] The solid dispersion of API + HPC SSL (3:7, w / w) was characterized by PLM, XRPD, mDSC, and TGA. As shown in Table 9 and Figures 24-27, PLM and XRPD indicated that the sample was amorphous. PLM showed no birefringence, and XRPD showed only a halo. The API diffraction peaks (characteristic peaks) disappeared, indicating the sample was in amorphous form. As shown in Figure 26, there was a 0.75% weight loss before 180 ± 2.0 °C. As shown in Figure 27, mDSC indicated a glass transition temperature of 77.43 ± 2.0 °C. HPLC analysis indicated no significant change in purity.

[0103] The solid dispersion of API+HPC SSL (4:6, w / w) was characterized by PLM, XRPD, mDSC, and TGA. As shown in Table 9 and Figures 28-31, PLM and XRPD indicated that the sample was amorphous. PLM showed no birefringence, and XRPD showed only a halo. The API diffraction peaks (characteristic peaks) disappeared, indicating the sample was in amorphous form. As shown in Figure 30, there was a 1.53% weight loss before 180 ± 2.0 °C. As shown in Figure 31, mDSC indicated a glass transition temperature of 84.97 ± 2.0 °C. HPLC analysis indicated no significant change in purity.

[0104] The solid dispersion of API+HPC SSL (1:1, w / w) was characterized by PLM, XRPD, mDSC, and TGA. As shown in Table 9 and Figures 32-35, PLM and XRPD indicated that the sample was amorphous. PLM showed no birefringence, and XRPD showed only a halo. The API diffraction peaks (characteristic peaks) disappeared, indicating the sample was in amorphous form. As shown in Figure 32, there was a 1.35% weight loss before 180 ± 2.0 °C. As shown in Figure 35, mDSC indicated a glass transition temperature of 82.54 ± 2.0 °C. HPLC analysis indicated no significant change in purity.

[0105] Example 7-3 Redispersion Solubility of Formulated API+HPC SSL Solid Dispersions in Biologically Relevant Solvents Solid dispersions containing API and HPC SSL with different drug loadings were weighed into 3 mL of SGF, with a target API concentration of 2 mg / mL. After stirring at 500 rpm at 37°C for 0.25 and 0.5 hours, approximately 200 μL of the suspension was centrifuged at 14,000 rpm for 5 minutes, and the supernatant was diluted and subjected to HPLC analysis. After sampling at 0.5 hours, FaSSIF (2 times the volume of SGF) was immediately added to the suspension and stirred for an additional 0.25, 0.5, and 1.5 hours. The supernatant was then sampled for HPLC analysis and pH testing. As shown in Table 10 and Figure 36, the solid dispersions with three different drug loadings (30%, 40%, and 50% API:HPC SSL), respectively, showed no significant differences in solubility.

[0106] [Table 10]

[0107] Example 7-4 4-Week Solid State Stability Study of Formulated API+HPC SSL Solid Dispersion All solid dispersions of API+HPC SSL formulations were stored at 25°C / 60%RH (open) and 40°C / 75%RH (closed). After 1 week and 4 weeks (1w and 4w), the samples were visually observed for appearance, tested for changes in crystal form by XRPD, and analyzed for purity by HPLC. The results are shown in Tables 11-12 and Figures 37-38. The analytical results indicated that all three solid dispersions exhibited good solid-state stability.

[0108] [Table 11]

[0109] [Table 12]

[0110] Example 8 Preparation of a solid dispersion starting from crystalline form G of the compound of formula A Example 8-1 Characteristics of Crystal Form G of Compound of Formula A In addition to being prepared using the above API reference product as a starting material, the solid dispersion of the present invention can also be prepared using amorphous or other crystalline forms, such as crystalline form G of the compound of formula A as a starting material.

[0111] Preparation method: The compound of formula A was prepared according to the method of Example 15 of PCT / CN2022 / 097236, and then the compound was ring-closed under acidic conditions and crystallized from acetonitrile-water to obtain crystalline form G of the compound of formula A. [ka]

[0112] Compound 1 (32.5 g, 121 mmol) and compound 2 (56 g, 155 mmol) were placed in N,N-dimethylacetamide (DMAc) (500 mL) and propylphosphonic anhydride (T3P) (46.7 g, 147 mmol) and N-methylmorpholine (NMM) (62 g, 613 mmol). The mixture was degassed and flushed with N2 three times. The mixture was stirred under N2 at 25 °C for 12 h. The mixture was poured into saturated aqueous sodium chloride (1000 mL), filtered, and washed with water (1000 mL). The cake was dissolved in DCM (2000 mL), washed with saturated aqueous NaHCO3 (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound 3 (66 g) as a white solid (HPLC purity >98%, chiral purity >98%).

[0113] Compound 3 (66 g) was dissolved in CHCN (660 mL) and benzenesulfonic acid (57.4 g, 363 mmol) was added. The mixture was stirred at 50 °C for 16 hours under N gas atmosphere, cooled to 0 °C, and the pH was adjusted to 7-8 with 7% NaHCO. The solution was slowly added dropwise to water (3300 mL), stirred for 3 hours, suction filtered, and the cake was washed with water (300 mL). The cake was dried under vacuum to obtain compound A (50 g) as a white solid. The yield for the two steps was 89%. The compound of formula A above was identified as crystalline form G by XRPD (Figure 39).

[0114] The compound has characteristic XRPD peaks at positions essentially shown in Table 13 below and / or an X-ray powder diffraction (XRPD) pattern essentially as shown in Figure 39. The X-ray powder diffraction (XRPD) pattern, expressed in 2θ angles, has at least three, at least four, at least five, or at least six characteristic peaks at 18.837±0.2°, 13.886±0.2°, 21.455±0.2°, 26.755±0.2°, 15.927±0.2°, and 15.953±0.2°. The parameters of each peak are as shown in Table 13.

[0115] [Table 13]

[0116] As shown in FIG. 40, the DSC chart shows one endothermic peak at 236.59°C ± 2°C. In the thermogravimetric analysis (TGA) Figure 41, there is a weight loss of 0.52 wt% before 150.00±2.0°C.

[0117] Example 8-2 Preparation of a solid dispersion of crystalline form G of compound of formula A The spray drying parameters were set according to Table 14. Appropriate amounts of two lots of crystalline form G of the compound of formula A and polymer carrier (HPC SSL, w / w) were weighed and added to a solvent of acetone:water=9:1 (v / v). Then, the mixture was stirred at 700 rpm until all the samples were completely dissolved, and then spray dried using a Buchi B-290 to obtain solid powders.

[0118] [Table 14]

[0119] The solid powders in Table 14 were further dried under vacuum at 60°C for 24 hours to obtain solid dispersion samples, which were then characterized and tested by XRPD, TGA, mDSC, PSD, GC, chiral purity and HPLC.

[0120] The results are shown in Table 15 and Figures 42-1 and 42-2. XRPD of the two lots showed that all solid dispersions were amorphous. mDSC showed that the Tg (glass transition temperature) was 82-85°C, as shown in Figures 43-1 and 43-2. ​​As shown in Figures 44-1 and 44-2, the solid dispersions lost 4.21-4.30 wt% at 148-155°C. The content of the solid dispersions was measured to be 99.34-99.77%, with no significant change in purity. The HPLC purity was approximately 99.35-99.37%, with no significant increase in isomers. The particle size D of the solid dispersions was 1.06-1.03%. 90 was 18.00 to 20.00 μm.

[0121] [Table 15]

[0122] Example 9 In vivo pharmacokinetic study of solid dispersion According to Table 16, three solid dispersions, namely, formulation API+Soluplus, formulation API+PVP VA64, and formulation API+HPC SSL, were selected to conduct in vivo pharmacokinetic tests with the corresponding amorphous API to study the pharmacokinetic characteristics of the solid dispersions with different formulations in animals.

[0123] Methods: Different formulations of solid dispersions were evaluated by their pharmacokinetic characteristics after intragastric administration in male Sprague Dawley (SD) rats. Materials: SD rats (male, 200-250 g, 6-8 weeks old, Zhejiang Vital River).

[0124] Procedure: SD rats were orally administered 300 mg / kg (dosage calculated based on the compound of Formula A) of the solid dispersion in the formulation shown in Table 16 to be tested. The vehicle was 25 mM citrate buffer containing 5% Tween 80, pH 3. All animals were allowed to eat and drink freely. Blood was collected from the jugular vein at 15 min (0.25 h), 30 min (0.5 h), 60 min (1 h), 2 h, 4 h, 6 h, 8 h, and 24 h after administration. Whole blood was collected into an anticoagulant tube containing EDTA-K2, mixed thoroughly, and centrifuged at 4000 g for 5 min at 4°C to separate plasma. Plasma samples were stored at -75 ± 15°C until plasma concentrations of the compound of Formula A were measured by LC-MS / MS. Relevant pharmacokinetic parameters were calculated using a non-compartmental linear / log trapezoidal method in Phoenix WinNonlin 6.1.

[0125] The results are shown in Table 16 and Figure 22. 20% API+HPC SSL (i.e., API+HPC SSL (1:4, w / w)) was 1.67 hours (T max ) at the highest plasma concentration (C max =101,467 ng / mL) and AUC last was 647,047 h·ng / mL, significantly higher than that of the other solid dispersion samples.

[0126] [Table 16]

[0127] To further demonstrate the PK effect of optimizing the drug loading, PK experiments were carried out on API+HPC SSL solid dispersions with different drug loadings. The results are shown in Table 17 and Figure 23. 50% ASD-HPC SSL (i.e., API+HPC SSL (1:1, w / w)) showed a PK improvement of 1.00 hours (T max ) at the highest plasma concentration (C max = 115,000 ng / mL) and AUC last The mean drug loading was 508,555 h·ng / mL, significantly higher than that of other solid dispersion samples with different drug loadings. [Table 17]

[0128] Conclusion: 1. The solid dispersion containing the active ingredient and carrier prepared by the present invention has good solid stability. 2. The solid dispersion containing an active ingredient produced by the present invention can significantly improve the oral bioavailability of the active ingredient, and in particular, when administered in the form of the solid dispersion of the present invention, the area under the blood concentration-time curve of the active ingredient in plasma is 1.5 to 7 times, preferably 5 to 6 times, the area under the blood concentration-time curve when the active ingredient is administered alone.

[0129] All documents related to the present invention are incorporated herein by reference as if each document were individually incorporated by reference. After reading the above content of the present invention, it should be understood that those skilled in the art can make various changes and modifications to the present invention, and that equivalents thereof are within the scope of the claims of the present invention.

Claims

1. A solid dispersion comprising: comprising an active ingredient and a carrier, The active ingredient is one or more of a compound of formula A or a derivative, crystalline form, amorphous form, or a pharmaceutically acceptable salt, hydrate, or solvate thereof: 【Chemistry 1】 The solid dispersion, wherein the carrier is selected from one or more of homopolymers and copolymers of N-vinyl lactams, cellulose derivatives, graft copolymers, high molecular weight polyalkylene oxides, polyacrylic acid esters and polymethacrylic acid esters, polyacrylamides, vinyl acetate polymers, oligosaccharides or polysaccharides or copolymers thereof, and acrylic acid copolymers.

2. The N-vinyl lactam homopolymers and copolymers are povidone (PVP) or copolymers of PVP and polyvinyl acetate, preferably the povidone is PVP K30, and preferably the copolymer of PVP and polyvinyl acetate is PVP VA64; and / or the cellulosic derivative is hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, preferably the hydroxypropyl methylcellulose acetate succinate is one or more of HPMCAS 716G, HPMCAS 912G, HPMCAS 126G, HPMCAS 716F, HPMCAS 912F, HPMCAS 126F, HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMCAS LF, HPMCAS MF and HPMCAS HF, preferably the hydroxypropyl methylcellulose is HPMC E3, preferably the hydroxypropyl cellulose is HPMC SSL; and / or wherein said acrylic copolymer is a methyl acrylate and methyl methacrylate copolymer, preferably said methyl acrylate and methyl methacrylate copolymer is Eudragit, preferably said Eudragit is one or more of Eudragit L100, Eudragit E100, Eudragit S100, Eudragit L100-55, Eudragit EPO; and / or the graft copolymer is Soluplus; and / or the pharmaceutically acceptable salt of the compound of Formula A is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogensulfate, 2-hydroxyethanesulfonate, phosphate, hydrogenphosphate, acetate, adipate, alginate, lysine, arginine, histidine, aspartate, benzoate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, hydroxyethanesulfonate, salicylate, methanesulfonate, mesitylenesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, salts, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, glutamate, bicarbonate, undecanoate, lactate, citrate, tartrate, gluconate, ethanedisulfonate, benzenesulfonate, L-tartrate, maleate, sodium salt, potassium salt, choline salt, tromethamine salt, calcium or p-toluenesulfonate, preferably phosphate, sulfate, L-tartrate, hydrochloride, maleate, hydrobromide, methanesulfonate, lysine salt, arginine salt, histidine salt, sodium salt, potassium salt, choline salt, tromethamine salt, calcium salt, 2. The solid dispersion of claim 1, wherein the hydrate of the compound of formula A is a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, decahydrate, eleven-hydrate, or dodecahydrate.

3. the carrier is selected from one or more of povidone, copolymers of PVP and polyvinyl acetate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acrylic acid copolymers and graft copolymers; Preferably, the carrier is selected from one or more of PVP K30, PVP VA64, Soluplus, HPMC E3, HPMCAS MG, HPMCAS HG, HPC SSL, Eudragit L100; Preferably, the carrier is selected from one or more of PVP VA64, Soluplus and HPC SSL; The solid dispersion according to any one of claims 1 to 2, wherein the carrier is preferably HPC SSL.

4. The solid dispersion according to any one of claims 1 to 3, wherein the weight ratio of the active ingredient to the carrier is 0.1:10 to 10:0.

1.

5. The solid dispersion according to any one of claims 1 to 4, wherein the weight ratio of the active ingredient to the carrier is 1:4, 3:7, 4:6 or 1:

1.

6. The solid dispersion according to any one of claims 1 to 5, wherein the carrier is HPC SSL and the weight ratio of the active ingredient to HPC SSL is 1:4, 3:7, 4:6 or 1:

1.

7. the solid dispersion is Solid Dispersion 1, comprising the compound of Formula A and Soluplus in a weight ratio of 1:4, and the Solid Dispersion 1 is amorphous and has an XRPD pattern essentially as shown in FIG. 8; or or the solid dispersion is solid dispersion 2, comprising the compound of formula A and PVP VA64 in a weight ratio of 1:4, wherein the solid dispersion 2 is amorphous and has an XRPD pattern essentially as shown in FIG. 12; Alternatively, the solid dispersion is Solid Dispersion 3, comprising the compound of formula A and HPC SSL, in a weight ratio of 1:4, wherein the Solid Dispersion 3 is amorphous and has an XRPD pattern essentially as shown in FIG. 16 ; Preferably, said solid dispersion 1 further optionally has one or more of the following characteristics: 1) In the TGA graph, there is a weight loss of 0.95 wt % before the temperature reaches 180.00±2.0°C; 2) In the mDSC chart, there is one glass transition temperature at a temperature of 99.79±2.0°C; 3) essentially according to the TGA graph shown in Figure 9; and / or 4) Basically as shown in the mDSC chart in Figure 10; Preferably, said solid dispersion 2 further optionally has one or more of the following characteristics: 1) In the TGA graph, there is a weight loss of 1.89 wt % before the temperature reaches 210±2.0°C; 1) In the mDSC chart, there is one glass transition temperature at 118.74±2.0°C; 3) essentially according to the TGA graph shown in Figure 13; and / or 4) Basically as shown in the mDSC chart in Figure 14; Preferably, said solid dispersion 3 further optionally has one or more of the following characteristics: 1) In the TGA graph, there is a weight loss of 0.99 wt % before the temperature reaches 180±2.0°C; 1) In the mDSC chart, there is one glass transition temperature at 70.72±2.0°C; 3) essentially according to the TGA graph shown in Figure 17; and / or 4) Basically as shown in the mDSC chart in Figure 18; The solid dispersion according to any one of claims 1 to 4,

8. The solid dispersion according to any one of claims 1 to 7, wherein the area under the blood drug concentration-time curve (AUC) of the active ingredient in the solid dispersion is 1.5 to 7 times, preferably 5 to 6 times, the AUC when the active ingredient is administered alone.

9. A method for producing the solid dispersion according to any one of claims 1 to 8, comprising the steps of: Method 1 mixing one or more of said compound of formula A or its derivatives, crystalline forms, amorphous forms, or pharmaceutically acceptable salts, hydrates or solvates thereof, and optionally other components, with a solvent to form a solution or suspension, and removing said solvent to obtain said solid dispersion; or Method 2 mixing one or more of said compound of formula A or its derivatives, crystalline form, amorphous form, or pharmaceutically acceptable salts, hydrates or solvates thereof, and optionally other components, and heating and then extruding to obtain said solid dispersion; or Method 3 One or more of the compound of formula A or its derivatives, crystalline form, amorphous form, or pharmaceutically acceptable salts, hydrates or solvates thereof, and optionally other components are mixed with a solvent and spray-dried to obtain the solid dispersion. The method, characterized in that it comprises:

10. In the method 1 or the method 3, The solvent is one or more of water, alcohol solvents, ester solvents, ketone solvents, halogenated hydrocarbon solvents, nitrile solvents and ether solvents, wherein the alcohol solvent is preferably ethanol and / or methanol, the ester solvent is preferably ethyl acetate, the ketone solvent is preferably acetone, the halogenated hydrocarbon solvent is preferably dichloromethane, the nitrile solvent is preferably acetonitrile, and the ether solvent is preferably tetrahydrofuran, preferably the solvent is dichloromethane and / or ethanol, preferably the solvent is acetone and / or water; and / or the weight-to-volume ratio of the compound of formula A or one or more of its derivatives, crystalline forms, amorphous forms, or pharmaceutically acceptable salts, hydrates or solvates to the solvent is (0.1-30):1 mg / mL, preferably (1-10):1 mg / mL, more preferably 5:1.5 mg / mL; and / or the solvent is an alcoholic solvent and / or a halogenated hydrocarbon solvent, wherein the alcoholic solvent is preferably methanol or ethanol, and the halogenated hydrocarbon solvent is preferably dichloromethane, preferably the solvent is dichloromethane and methanol or dichloromethane and ethanol, wherein the volume ratio of dichloromethane to methanol or dichloromethane to ethanol is preferably 9:1 to 1:1; and / or the solvent is acetone and water, wherein the volume ratio of acetone to water is preferably between 7:1 and 10:1; and / or the spray-drying inlet temperature is set between 40°C and 200°C, preferably between 80°C and 120°C.

11. 1. A pharmaceutical composition comprising: (1) The solid dispersion according to any one of claims 1 to 8; and (2) Pharmaceutically acceptable excipients The pharmaceutical composition comprising:

12. A pharmaceutical formulation comprising the pharmaceutical composition of claim 11, which may be a solid formulation, wherein the dosage form of the solid formulation is selected from the group consisting of powder, granules, tablets, capsules, drop pills, and films.

13. 9. Use of the solid dispersion of any one of claims 1 to 8 in the manufacture of a medicament for treating a proliferative disease.

14. 10. A method for treating a proliferative disease, comprising administering to a subject in need thereof a therapeutically effective amount of the solid dispersion of any one of claims 1 to 8.

15. The proliferative diseases include breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic adenocarcinoma, ovarian cancer, head and neck cancer, melanoma, colorectal cancer, gastric cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neuroblastoma, leukemia (acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute monocytic leukemia, (AMOL), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia), lymphomas (small lymphocytic lymphoma (SLL), Hodgkin lymphoma (nodular sclerosing, mixed cell, lymphocyte-rich, lymphopenic or non-reduced, and nodular lymphocyte-dominated Hodgkin lymphoma), non-Hodgkin lymphoma (all subtypes) lymphomas (e.g., Waldenstrom's macroglobulinemia), splenic marginal zone lymphoma, plasma cell neoplasms (plasma cell myeloma, plasmacytoma, monoclonal gammopathy, heavy chain disease), extranodal marginal zone B-cell lymphoma (MALT lymphoma), lymphoma (NMZL), follicular lymphoma, mantle cell Lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma (nasal type), enteropathy-type T-cell lymphoma, hepatosplenic 15. The use according to claim 13 or the method according to claim 14, characterized in that the cancer is selected from cancers of the lymphoid organs and hematological malignancies, including T-cell lymphoma, blastic NK-cell lymphoma, mycosis fungoides / Sézary syndrome, primary cutaneous CD30-positive T-cell lymphoma disease, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (non-specific), anaplastic large cell lymphoma), multiple myeloma (plasma cell myeloma or Kahler's disease).

Images