WO2024120438A1 - 一种固体分散体、其制备方法和应用 - Google Patents

一种固体分散体、其制备方法和应用 Download PDF

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Publication number
WO2024120438A1
WO2024120438A1 PCT/CN2023/136781 CN2023136781W WO2024120438A1 WO 2024120438 A1 WO2024120438 A1 WO 2024120438A1 CN 2023136781 W CN2023136781 W CN 2023136781W WO 2024120438 A1 WO2024120438 A1 WO 2024120438A1
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Prior art keywords
solid dispersion
solvent
lymphoma
cell
compound
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PCT/CN2023/136781
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English (en)
French (fr)
Inventor
付利强
戚祖德
王峥
孔繁迪
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Hangzhou Glubio Pharmaceutical Co Ltd
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Hangzhou Glubio Pharmaceutical Co Ltd
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Priority to JP2025533474A priority Critical patent/JP2025541840A/ja
Priority to EP23900012.8A priority patent/EP4631496A1/en
Priority to CN202380084001.6A priority patent/CN120322222A/zh
Publication of WO2024120438A1 publication Critical patent/WO2024120438A1/zh
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers

Definitions

  • the present invention belongs to the field of medicine, and in particular, relates to a solid dispersion, a preparation method and application thereof.
  • Casein kinase 1 ⁇ (CK1 ⁇ ), encoded by the gene CSNK1A1, is a ubiquitously expressed serine/threonine protein kinase in the CK1 kinase family.
  • CK1 ⁇ is involved in regulating a variety of physiological and pathological processes in cells and coordinates the orderly progress of life through different signal transduction pathways (Jiang et al., Cell Commun Signal (2016) 16: 23).
  • CK1 ⁇ as a key regulator of the Wnt/ ⁇ -catenin pathway, directly phosphorylates ⁇ -catenin at Ser45, making it a target for proteomic degradation (Liu et al., Cell (2002) 108: 837-847).
  • CK1 ⁇ is also thought to regulate the protein stability of the tumor suppressor p53 by regulating 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).
  • CK1 ⁇ has been reported to be overexpressed in many types of human cancers, however, the exact role of CK1 ⁇ in the development of each tumor type has not been clearly elucidated (Richter et al., BMC Cancer (2016) 18: 140).
  • the Cancer Dependency Map (DepMap) database showed that inactivation of CK1 ⁇ by CRISPR/cas9-mediated gene knockout or shRNA-mediated gene inhibition significantly reduced the proliferation and/or survival of many cancer cell lines in multiple cancer types (Tsherniak et al., Cell (2017) 170: 564-576; Behan et al., Nature (2019) 568: 511-516).
  • CK1 ⁇ inhibition by using shRNA interference or D4476 was able to effectively inhibit the progression of MLL-AF9 leukemia and had little effect on normal hematopoietic stem and progenitor cells (HSPCs) (Jaras et al., J Exp Med (2014) 211 (4): 605-612).
  • HSPCs normal hematopoietic stem and progenitor cells
  • the compound of formula A is a new generation of CK1 ⁇ selective molecular glue degrader and is currently in the early clinical research stage.
  • the present invention provides a solid dispersion with a compound of formula A or its derivative, crystal form, amorphous form, or pharmaceutically acceptable salt, hydrate or solvate as an active ingredient.
  • the solid dispersion enables the active ingredient compound of formula A to have good oral bioavailability, which is of great value to the development and production of new drugs.
  • 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 its derivatives, crystalline forms, amorphous forms, or pharmaceutically acceptable salts, hydrates or solvates, and the carrier is selected from: homopolymers and copolymers of N-vinyl lactam, cellulose derivatives, graft copolymers, high molecular weight polyalkylene oxides, polyacrylates and polymethacrylates, polyacrylamides, vinyl acetate polymers, oligosaccharides or polysaccharides or their copolymers, or one or more of acrylic acid copolymers.
  • the homopolymer and copolymer of N-vinyl lactam is povidone, or a copolymer of PVP and polyvinyl acetate; preferably, the povidone is PVP K30; preferably, the copolymer of PVP and polyvinyl acetate is PVP VA64.
  • the cellulose derivative is hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl 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 HPC SSL.
  • the high molecular weight polyalkylene oxide is polyethylene oxide, polypropylene oxide, and copolymers of ethylene oxide and propylene oxide (poloxamers).
  • the polyacrylates and polymethacrylates are methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl methacrylate copolymers, butyl methacrylate/2-dimethylaminoethyl methacrylate copolymers, poly(hydroxyalkyl acrylates) and poly(hydroxyalkyl methacrylates).
  • the vinyl acetate polymer is a copolymer of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, and polyvinyl alcohol.
  • the oligosaccharide or polysaccharide is carrageenan, galactomannan and xanthan gum, and a mixture of two or more thereof.
  • the solid dispersion carrier includes one or more polymer carriers selected from the group consisting of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, and mixtures thereof.
  • a specific example of a useful copolyvidone is composed of about 60% N-vinyl pyrrolidone and about 40% vinyl acetate monomers.
  • a specific example of a useful povidone is a povidone having a K value (a measure of the viscosity of a povidone aqueous solution) of about 30.
  • the acrylic copolymer is a methacrylic acid copolymer and a methacrylate copolymer; preferably, the methacrylic acid copolymer and the methacrylate copolymer are Eudragit; preferably, the Eudragit is one or more of Eudragit L100, Eudragit E100, Eudragit S100, Eudragit L100-55, and Eudragit EPO.
  • the graft copolymer is Soluplus.
  • the pharmaceutically acceptable salt of the compound of formula A is hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, lysine, arginine, histidine, aspartate, benzoate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptane
  • the salts of the present invention are bis(iota)sulfate, bis(iota)sulfate, bis(iota)sulfate, bis(iota)sulfate, bis(iota)sulfate, bis(iota)sulfate, bis(iota)sulfate, bis(iota)sulfate, bis(iota)sulfate, bis
  • the hydrate of the compound of formula A is hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, decahydrate, undecahydrate, or dodecahydrate.
  • the carrier is selected from one or more of: povidone, copolymer of PVP and polyvinyl acetate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acrylic acid copolymer and graft copolymer.
  • the carrier is selected from one or more of: PVP K30, PVP VA64, Soluplus, HPMC E3, HPMCAS MG, HPMCAS HG, HPC SSL, and Eudragit L100.
  • the carrier is selected from one or more of: PVP VA64, Soluplus and HPC SSL.
  • the carrier is HPC SSL.
  • the solid dispersion of the present invention is in an amorphous form. More importantly, the amorphous solid dispersion has good solid stability, can be stored for a long time, and will not potentially affect the performance of the drug product.
  • the amount of the carrier used in the present invention can be conventional in the art, and the weight ratio of the active ingredient to the carrier is 0.1:10 to 10:0.1.
  • the weight ratio of the active ingredient to the carrier is 1:10 to 10:1, preferably 1:4 to 1:1.
  • the weight ratio of the active ingredient to the carrier is 1:4, 3:7, 4:6 or 1:1.
  • the carrier is PVP VA64, and preferably, the weight ratio of the active ingredient to PVP VA64 is 1:4.
  • the carrier is Soluplus, and preferably, the weight ratio of the active ingredient to Soluplus is 1:4.
  • the carrier is HPC SSL, preferably, the active ingredient and HPC SSL
  • the weight ratio is 1:4, 3:7, 4:6 or 1:1.
  • the active ingredient is an amorphous form of the compound of Formula A having an XRPD pattern substantially as shown in FIG. 4 .
  • the amorphous form of the compound of formula A optionally has one or more of the following characteristics:
  • the active ingredient is a compound of formula A
  • the solid dispersion having a weight ratio of the compound of formula A to Soluplus of 1:4 is an amorphous form as shown in PLM Figure 7, has an XRPD pattern substantially as shown in Figure 8, and optionally has one or more of the following characteristics:
  • the active ingredient is a compound of formula A
  • the solid dispersion having a weight ratio of 1:4 of the compound of formula A and PVP VA64 is an amorphous form as shown in PLM Figure 11, has an XRPD pattern substantially as shown in Figure 12, and optionally has one or more of the following characteristics:
  • the active ingredient is a compound of formula A
  • the solid dispersion having a weight ratio of the compound of formula A to HPC SSL of 1:4 is amorphous as shown in PLM Figure 15, has an XRPD pattern substantially as shown in Figure 16, and optionally has one or more of the following characteristics:
  • the active ingredient is a compound of formula A
  • the solid dispersion having a weight ratio of the compound of formula A to HPC SSL of 3:7 is amorphous as shown in PLM Figure 24, has an XRPD pattern substantially as shown in Figure 25, and optionally has one or more of the following characteristics:
  • the active ingredient is a compound of formula A
  • the solid dispersion having a weight ratio of the compound of formula A to HPC SSL of 4:6 is amorphous as shown in PLM Figure 28, has an XRPD pattern substantially as shown in Figure 29, and optionally has one or more of the following characteristics:
  • the active ingredient is a compound of formula A
  • the solid dispersion having a weight ratio of the compound of formula A to HPC SSL of 1:1 is amorphous as shown in PLM Figure 32, has an XRPD pattern substantially as shown in Figure 33, and optionally has one or more of the following characteristics:
  • the solid dispersion has the following characteristics:
  • the area under the drug-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 drug-time curve when the active ingredient is administered alone.
  • the present invention provides a method for preparing the solid dispersion according to the first aspect, comprising the steps of:
  • the compound of formula A or its derivatives, crystal forms, amorphous forms, or one or more of their pharmaceutically acceptable salts, hydrates or solvates, and optionally other components, are mixed with a solvent to form a solution or suspension, and the solvent is removed to obtain the solid dispersion; or
  • the compound of formula A or its derivative, crystalline form, amorphous form, or one or more of its pharmaceutically acceptable salts, hydrates or solvates, and optionally other components are mixed, heated and then extruded to obtain the solid dispersion; or
  • the compound of formula A or its derivatives, crystal forms, amorphous forms, or one or more of their pharmaceutically acceptable salts, hydrates or solvates, and optionally other components, are mixed with a solvent and spray-dried to obtain the solid dispersion.
  • 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; the ether solvent is preferably tetrahydrofuran; preferably, the solvent is dichloromethane and/or ethanol.
  • the solvent is acetone and/or water.
  • the mass volume ratio of "the compound of formula A or its derivative, crystalline form, amorphous form, or one or more of its pharmaceutically acceptable salts, hydrates or solvates" to the solvent is (0.1-30):1 mg/mL, preferably (1-10):1 mg/mL, and more preferably 5:1.5 mg/mL.
  • the solvent is an alcohol solvent and/or a halogenated hydrocarbon solvent, wherein the alcohol solvent is preferably methanol; 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.
  • the solvent is an alcohol solvent and/or a halogenated hydrocarbon solvent, wherein the alcohol solvent is preferably ethanol; 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.
  • the solvent is acetone and water, wherein the volume ratio of acetone to water is preferably 7:1 to 10:1.
  • the spray drying air inlet temperature is set to 40°C to 200°C, preferably 80°C to 120°C.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the solid dispersion, the solid dispersion comprising an active ingredient and a carrier, the active ingredient being one or more of a compound of formula A or its derivatives, crystalline forms, amorphous forms, or pharmaceutically acceptable salts, hydrates or solvates, the carrier being selected from one or more of homopolymers and copolymers of N-vinyl lactam, cellulose derivatives, and/or graft copolymers or acrylic acid copolymers.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition may include other excipients, such as excipients used as fillers, binders, disintegrants, glidants and lubricants. Therefore, the solid pharmaceutical composition comprising a compound of formula A or a pharmaceutically acceptable salt thereof may also optionally include one or more conventional pharmaceutically acceptable excipients.
  • the present invention provides a pharmaceutical preparation comprising the above-mentioned pharmaceutical composition; wherein the pharmaceutical preparation may be a solid preparation, or may be a powder, granule, tablet, capsule, pill or film preparation.
  • the present invention provides a use of the above-mentioned solid dispersion, pharmaceutical composition or pharmaceutical preparation in the preparation of a drug for treating a proliferative disease
  • the proliferative disease includes breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic cancer, 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, lymphoid organ cancer and hematological malignancies including leukemia (acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (CLL), acute myeloid leukemia (CLL), acute
  • CLL chronic myeloid leukemia
  • AOL hairy cell leukemia
  • HCL hairy cell leukemia
  • T-PLL T-cell prolymphocytic leukemia
  • large granular lymphocytic leukemia adult T-cell leukemia
  • lymphoma small lymphocytic lymphoma (SLL)
  • Hodgkin lymphoma nodular sclerosis, mixed cellularity, lymphocyte-rich, lymphocyte-depleted or non-depleted, and nodular lymphocyte-predominant Hodgkin lymphoma), non-Hodgkin lymphoma (all subtypes), chronic lymphocytic leukemia/small lymphocytic lymphoma
  • B-cell prolymphocytic leukemia lymphoma (such as macroglobulinemia), splenic marginal zone lymphoma, plasma cell neoplasms (plasma cell myeloma, plasmacytoma
  • the present invention provides a method for treating a proliferative disease, comprising the step of administering a therapeutically effective amount of the solid dispersion of the first aspect of the present invention, the pharmaceutical composition of the third aspect of the present invention, or the pharmaceutical preparation of the fourth aspect of the present invention to a subject in need thereof.
  • the subject is a mammal, such as a human.
  • Figure 1 is a PLM diagram of API amorphous.
  • FIG2 is the mDSC graph of API amorphous form.
  • FIG3 is a TGA graph of amorphous API.
  • FIG4 is an XRPD pattern of the amorphous API.
  • FIG5 is an XRPD overlay of the rapid solvent evaporation product.
  • FIG. 6 is a solubility curve of the rapid evaporation product.
  • Figure 7 is a PLM diagram of the formulation API + Soluplus solid dispersion.
  • FIG8 is an XRPD diagram of the formulation API+Soluplus solid dispersion.
  • FIG. 9 is a TGA graph of the formulation API+Soluplus solid dispersion.
  • FIG. 10 is the mDSC graph of the formulation API+Soluplus solid dispersion.
  • Figure 11 is the PLM diagram of the prescription API+PVP VA64 solid dispersion.
  • Figure 12 is the XRPD pattern of the solid dispersion of API+PVP VA64.
  • Figure 13 is the TGA graph of the solid dispersion of API+PVP VA64.
  • Figure 14 is the mDSC graph of the solid dispersion of API+PVP VA64.
  • Figure 15 is the PLM diagram of the prescription API+HPC SSL solid dispersion.
  • Figure 16 is the XRPD pattern of the prescription API+HPC SSL solid dispersion.
  • Figure 17 is the TGA graph of the solid dispersion of formulation API+HPC SSL.
  • Figure 18 is the mDSC graph of the formulation API+HPC SSL solid dispersion.
  • FIG. 19 is a graph showing the redispersion solubility curves of solid dispersions with different formulations.
  • FIG. 20 is an XRPD pattern of solid dispersions of different formulations at 25° C./60% RH (open) for one week.
  • FIG. 21 is an XRPD pattern of solid dispersions of different formulations at 40° C./75% RH (open) for one week.
  • Figure 22 is the PK graph of three solid dispersions (prescription API+Soluplus, prescription API+PVP VA64 and prescription API+HPC SSL).
  • Figure 23 is the PK graph of different drug loading amounts of the prescription API+HPC SSL solid dispersion.
  • Figure 24 is the PLM diagram of the solid dispersion of prescription API+HPC SSL (3:7, w/w).
  • Figure 25 is the XRPD pattern of the solid dispersion of formulation API+HPC SSL (3:7, w/w).
  • Figure 26 is the TGA graph of the solid dispersion of formulation API+HPC SSL (3:7, w/w).
  • Figure 27 is the mDSC graph of the solid dispersion of formulation API+HPC SSL (3:7, w/w).
  • Figure 28 is the PLM diagram of the solid dispersion of prescription API+HPC SSL (4:6, w/w).
  • Figure 29 is the XRPD pattern of the solid dispersion of formulation API+HPC SSL (4:6, w/w).
  • Figure 30 is the TGA graph of the solid dispersion of formulation API+HPC SSL (4:6, w/w).
  • Figure 31 is the mDSC graph of the solid dispersion of formulation API+HPC SSL (4:6, w/w).
  • FIG. 32 is a PLM diagram of the solid dispersion of the formulation API+HPC SSL (1:1, w/w).
  • Figure 33 is the XRPD pattern of the solid dispersion of formulation API+HPC SSL (1:1, w/w).
  • Figure 34 is the TGA graph of the solid dispersion of formulation API+HPC SSL (1:1, w/w).
  • Figure 35 is the mDSC graph of the solid dispersion of formulation API+HPC SSL (1:1, w/w).
  • Figure 36 is the redispersion solubility curve of the formulation API+HPC SSL.
  • Figure 37 is the XRPD pattern of the formulation API+HPC SSL solid dispersion at 25°C/60% RH (open) for 4 weeks.
  • Figure 38 is the XRPD pattern of the formulation API+HPC SSL solid dispersion at 40°C/75% RH (open) for 4 weeks.
  • Figure 39 is the XRPD pattern of API Form G.
  • FIG40 is a DSC graph of API Form G.
  • Figure 41 is a TGA chart of API Form G.
  • Figure 42-1 and Figure 42-2 are XRPD images of the solid dispersion prepared using API Form G as raw material.
  • Figures 43-1 and 43-2 are DSC graphs of the solid dispersion prepared using API Form G as raw material.
  • Figures 44-1 and 44-2 are TGA graphs of the solid dispersion prepared using API Form G as raw material.
  • the inventors have developed a solid dispersion with excellent pharmacokinetic characteristics after extensive and in-depth research.
  • the solid dispersion of the present invention exhibits a higher plasma exposure in rats, i.e., a higher peak drug concentration and a larger area under the drug-time curve, and its area under the drug-time curve is 1.5 to 7 times (preferably 5 to 6 times) the area under the drug-time curve when its active ingredient is administered alone.
  • the present invention was completed.
  • active pharmaceutical ingredient refers to one or more of a compound of formula A as an active ingredient, or its derivatives, crystalline forms, amorphous forms, or pharmaceutically acceptable salts, hydrates or solvates thereof, wherein the chemical name of the compound of formula A is N-((S)-5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide.
  • Solid dispersion refers to a dispersed system in solid form formed by highly dispersing the active ingredients in a (solid) carrier.
  • solid dispersions include solid solutions, glass solutions, glass suspensions, amorphous precipitations in a crystalline carrier, eutectic mixtures or monotectics, mixed or composite formations, and combinations thereof.
  • the solid dispersion of the present invention can be prepared by the following method, however, the conditions of the method, such as carrier, solvent, amount of each component, preparation temperature, preparation time, etc. are not limited to the following explanation.
  • the solid dispersion of the present invention can also be conveniently prepared by optionally combining various synthesis methods described in this specification or known in the art, and such combination can be easily performed by a person skilled in the art to which the present invention belongs.
  • the preparation method of the present invention can adopt, for example, hot melt extrusion, hot melt coating, granulation, freezing and congealing, and solvent evaporation methods (such as layering, coating, and granulation).
  • the solid dispersion of the present invention is prepared by the following method:
  • the compound of formula A or one or more of its derivatives, crystalline forms, amorphous forms, or pharmaceutically acceptable salts, hydrates or solvates, and optionally other components such as the carrier of the present invention, the carrier is selected from: homopolymers and copolymers of N-vinyl lactam, cellulose derivatives, graft copolymers, high molecular weight polyalkylene oxides, polyacrylates and polymethacrylates, polyacrylamides, vinyl acetate polymers, oligosaccharides or polysaccharides or copolymers thereof, or acrylic acid copolymers) are mixed with a solvent (such as water, ethanol, methanol, ethyl acetate, acetone, dichloromethane, acetonitrile, tetrahydrofuran, or a combination thereof) to form a solution or suspension, and the solvent is removed to obtain the solid dispersion;
  • a solvent such as water, ethanol, methanol, ethyl
  • the compound of formula A or its derivatives, crystalline forms, amorphous forms, or one or more of their pharmaceutically acceptable salts, hydrates or solvates, optionally other components (such as the carrier described above), are mixed with a solvent (such as water, ethanol, methanol, ethyl acetate, acetone, dichloromethane, acetonitrile, tetrahydrofuran, or a combination thereof), and spray dried (the inlet air temperature is set at 40°C to 200°C, preferably 80°C to 120°C) to obtain the solid dispersion.
  • a solvent such as water, ethanol, methanol, ethyl acetate, acetone, dichloromethane, acetonitrile, tetrahydrofuran, or a combination thereof
  • the mass volume ratio of one or more of the compound of formula A or its derivative, 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, and more preferably 5:1.5 mg/mL;
  • the solvent is an alcohol solvent and/or a halogenated hydrocarbon solvent, wherein the alcohol solvent is preferably methanol or ethanol; 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;
  • the solvent is acetone and water, wherein the volume ratio of acetone to water is preferably 7:1 to 10:1.
  • the pharmaceutical composition of the present invention can be prepared by various methods well known in the art, which can be prepared by mixing a therapeutically effective amount of the solid dispersion with one or more pharmaceutically acceptable excipients into a dosage form suitable for human administration, such as the above-mentioned tablets, capsules, granules, etc.
  • “Therapeutically effective amount” refers to the amount of active ingredient according to the present invention, which, when administered to a patient in need thereof, is sufficient to achieve treatment of a disease state, condition or disorder for which the active ingredient has utility. Such an amount will be sufficient to elicit the biological or medical response of a tissue system or patient sought by a researcher or clinician.
  • the pharmaceutical composition of the present invention comprises a safe and effective amount of the solid dispersion of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient.
  • safe and effective amount means: the amount of the solid dispersion is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1 to 2000 mg of the solid dispersion of the present invention per dose, and more preferably, contains 10 to 200 mg of the solid dispersion of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • Excipients refer to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be of sufficient purity and sufficiently low toxicity.
  • “Compatibility” here means that the components in the composition can be mixed with the solid dispersion of the present invention and with each other without significantly reducing the solid The efficacy of the dispersion.
  • Some examples of pharmaceutically acceptable excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), starches, monosaccharides or polysaccharides, gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • starches such as sodium carboxymethyl cellulose
  • the administration method of the solid dispersion or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the solid dispersion is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, microcrystalline cellulose, mannitol and silicic acid; (b) binders, for example, hydroxypropyl methylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, cross-linked sodium carboxymethyl cellulose and sodium carbonate; (e) solubilizing agents, for example, paraffin; (f) absorption accelerators, for example
  • Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the solid dispersion in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the solid dispersion can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed
  • composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes.
  • suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these and the like.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these and the like.
  • compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage forms of the solid dispersion of the present invention for topical administration include ointments, powders, patches, 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 that may be required if necessary.
  • the solid dispersion of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the solid dispersion of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage.
  • the daily dosage is usually 0.2 to 2000 mg, preferably 1 to 500 mg, and more preferably 1 to 200 mg.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health status, which are all within the skill range of skilled physicians.
  • the specific carriers involved in 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, Soluplus, etc. are all commercially available products with disclosed structural compositions and/or properties. For detailed information such as specific structures and properties, please refer to the relevant product instructions.
  • the solid dispersion, pharmaceutical composition or pharmaceutical preparation provided by the present invention has acceptable bioabsorption performance. Such bioabsorption can be demonstrated by pharmacokinetic (PK) properties, more particularly by Cmax or AUC under a specific dose or within a dosage range. And, bioavailability can be measured by PK studies in humans or in any suitable model species. Solid dispersion of the present invention can significantly improve the oral bioavailability of compound A and has good solid stability.
  • PK pharmacokinetic
  • PLM Polarized light microscopy
  • XRPD X-ray powder diffractometer
  • TGA Thermogravimetric analysis
  • the compound of formula A was prepared according to the method of Example 15 of PCT/CN2022/097236, and its chemical name is N-((S)-5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindole-5- Formamide
  • Benzenesulfonic acid (1.1 g, 7.21 mmol) was added to a solution of compound 3 in CH 3 CN (13 mL). The mixture was stirred at 70° C. for 14 hours under N 2 environment, diluted with DCM (60 mL), washed with saturated NaHCO 3 aqueous solution (30 mL x 2) and then washed with H 2 O (30 mL x 2), the organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a crude product, which was slurried and filtered with EA (5 mL) and MTBE (5 mL) to obtain a filter cake of the compound of formula A, which was defined as API control after drying.
  • API control filter cake was added to 30 mL of acetonitrile, ultrasonically treated for 5 minutes to uniformly disperse it into a slurry solution, and then 70 mL of water was added to make the entire solution clear and transparent. After freeze-drying, an amorphous off-white solid of the compound of formula A was obtained, which was defined as API amorphous, with a yield of 87% and a purity of 99%.
  • PLM, XRPD, mDSC and TGA were used for characterization.
  • PLM and XRPD show that it is amorphous, and the diffraction peaks (characteristic peaks) of the compound of formula A all disappear, and it exists in an amorphous or molecular form.
  • diffraction peaks characteristic peaks
  • FIG 3 there is a weight loss of 2.79% by weight before the temperature is 210 ⁇ 2.0°C.
  • mDSC shows a glass transition temperature of 129.30 ⁇ 2.0°C.
  • the resulting clear solution was rapidly evaporated at 80°C until there was no liquid to prepare a solid dispersion.
  • the API reference substance of the compound of formula A was also treated separately in the same manner. As shown in FIG5 , two products (API+HPMC E3 and API+HMCAS MG) had crystalline diffraction peaks, and among the remaining samples, except for the API reference substance of Formula A compound, all other rapid solvent evaporation products were amorphous.
  • Spray drying parameter setting Set the spray drying parameters according to Table 3.
  • Table 4 shows the results of characterization of solid dispersions of different formulations by PLM, XRPD, mDSC, TGA and HPLC.
  • the solid dispersion of prescription 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 show that it is amorphous, and the XRPD diffraction peaks (characteristic peaks) of the API in the solid dispersion all disappear, existing in an amorphous form. As shown in Figure 9, the weight loss was 0.96% at 180 ⁇ 2.0°C. As shown in Figure 10, mDSC showed a glass transition temperature of 99.79 ⁇ 2.0°C. The HPLC detection result was 103.15%, and the purity did not change significantly, about 99.32%.
  • 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 showed that it was amorphous. The XRPD diffraction peaks (characteristic peaks) of the API in the body all disappeared and existed in an amorphous form. As shown in Figure 13, the weight loss was 1.90% at 210 ⁇ 2.0°C. As shown in Figure 14, mDSC showed a glass transition temperature of 118.74 ⁇ 2.0°C. The HPLC detection result was 102.95%, and the purity did not change significantly, which was about 99.35%.
  • 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 show that it is amorphous, and the XRPD diffraction peaks (characteristic peaks) of the API in the solid dispersion all disappear, existing in an amorphous form. As shown in Figure 17, the weight loss was 1.00% at 180 ⁇ 2.0°C. As shown in Figure 18, mDSC showed a glass transition temperature of 70.72 ⁇ 2.0°C. The HPLC detection result was 103.30%, and the purity did not change significantly, about 99.29%.
  • Example 7 Drug loading optimization using the API + HPC SSL solid dispersion as an example
  • the drug loading optimization study was conducted using the solid dispersion of API+HPC SSL as an example.
  • Table 8 an appropriate amount of the API reference substance of Formula A compound and HPC SSL were weighed into a DCM:EtOH (9:1, v/v) solvent, and then all samples were stirred at 700 rpm until completely dissolved, and the sample solution was spray dried according to the equipment parameters shown in Table 8, and the obtained solid powder was further dried under vacuum conditions at 40°C for about 20 hours to obtain a solid dispersion sample.
  • API+HPC SSL solid dispersion with the formulation shown in Table 9 was characterized by PLM, XRPD, mDSC, TGA and HPLC.
  • the solid dispersion of API+HPC SSL (3:7, w/w) was characterized by PLM, XRPD, mDSC and TGA.
  • PLM and XRPD show that the sample is amorphous.
  • PLM has no birefringence, only XRPD halos, and the diffraction peaks (characteristic peaks) of API all disappear, existing in an amorphous form.
  • mDSC shows The glass transition temperature was 77.43 ⁇ 2.0°C.
  • the HPLC test results showed that the purity had no significant change.
  • the solid dispersion of API+HPC SSL (4:6, w/w) was characterized by PLM, XRPD, mDSC and TGA.
  • PLM and XRPD show that the sample is amorphous, PLM has no birefringence, only the halo of XRPD, and the API diffraction peaks (characteristic peaks) all disappear, existing in an amorphous form.
  • mDSC shows a glass transition temperature of 84.97 ⁇ 2.0°C.
  • the HPLC test results show that there is no significant change in purity.
  • the solid dispersion of API+HPC SSL (1:1, w/w) was characterized by PLM, XRPD, mDSC and TGA.
  • PLM and XRPD show that the sample is amorphous, PLM has no birefringence, only the halo of XRPD, and the diffraction peaks (characteristic peaks) of API all disappear, existing in an amorphous form.
  • mDSC shows a glass transition temperature of 82.54 ⁇ 2.0°C.
  • the HPLC test results show that there is no significant change in purity.
  • Formulated API+HPC SSL solid dispersions with different drug loadings were weighed into 3 mL SGF with a target API concentration of 2 mg/mL. After stirring at 500 rpm for 0.25 h and 0.5 h at 37 °C, approximately 200 ⁇ L of the suspension was centrifuged at 14,000 rpm for 5 min and the supernatant was diluted for HPLC analysis. Immediately after sampling at 0.5 h, 2 times the volume of SGF was added to the suspension and stirred for another 0.25 h, 0.5 h and 1.5 h before sampling for HPLC analysis and pH testing. As shown in Table 10 and Figure 36, three solid dispersions with different drug loadings, 30%, 40% and 50% (API:HPC SSL), showed no significant difference in solubility.
  • API+HPC SSL solid dispersions were stored at 25°C/60%RH (open) and 40°C/75%RH (closed). After one week and four weeks (1w and 4w), the sample appearance was visually observed, the crystal form change was tested by XRPD, and the sample purity was analyzed by HPLC. The results are shown in Tables 11 to 12 and Figures 37 to 38. The analysis results show that all three solid dispersions showed good solid stability.
  • the solid dispersion of the present invention can also be prepared using amorphous or other crystalline forms as raw materials, for example, using crystalline form G of the compound of formula A as a raw material.
  • the compound of formula A was prepared by referring to the method of Example 15 of PCT/CN2022/097236, and then the ring was closed under acidic conditions and crystallized in acetonitrile-water to obtain the crystalline form G of the compound of formula A.
  • the compound of formula A was identified as Form G by XRPD ( FIG. 39 ).
  • thermogravimetric analysis (TGA) Figure 41 there is a weight loss of 0.52 wt% before 150.00 ⁇ 2.0°C.
  • the solid powder in Table 14 was further dried at 60° C. under vacuum conditions for 24 hours to obtain a solid dispersion sample, which was then characterized and tested by XRPD, TGA, mDSC, PSD, GC, chiral purity and HPLC.
  • Plasma samples were stored at -75 ⁇ 15 ° C until the blood concentration of the compound of formula A was determined by LC-MS/MS.
  • the relevant pharmacokinetic parameters were calculated using the non-compartmental model and Linear/log trapezoidal method of Phoenix WinNonlin 6.1.
  • API + HPC SSL ie, API + HPC SSL (1:4, w/w)
  • Cmax 101,467 ng/mL
  • Tmax 1.67 hours
  • AUClast 647,047 h*ng/mL, which was significantly higher than other solid dispersion samples.
  • API+HPC SSL solid dispersion was used as an example to conduct PK experiments on API+HPC SSL solid dispersions with different drug loadings.
  • the results are shown in Table 17 and Figure 23.
  • 50% ASD-HPC SSL ie, API+HPC SSL (1:1, w/w)
  • had the highest plasma concentration (C max 115,000 ng/mL) at 1.00 hour (T max )
  • AUC last was 508,555 h*ng/mL, which was significantly higher than those of solid dispersion samples with other drug loading amounts.
  • the solid dispersion comprising an active ingredient and a carrier prepared by the present invention has good solid stability.
  • the solid dispersion containing active ingredients prepared by the present invention can significantly improve the oral bioavailability of the active ingredients.
  • the area under the drug-time curve of the active ingredient in plasma is 1.5 to 7 times, preferably 5 to 6 times, the area under the drug-time curve when the active ingredient is administered alone.

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Abstract

一种固体分散体、其制备方法和应用，所述固体分散体包括活性成分式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物，和载体。固体分散体能够显著提高活性成分的口服生物利用度，并且具有良好的固体稳定性，使活性成分在大鼠体内表现出较高血浆暴露量。

Description

一种固体分散体、其制备方法和应用 技术领域
本发明属于医药领域，具体地，涉及一种固体分散体、其制备方法和应用。
背景技术
酪蛋白激酶1α(CK1α),由基因CSNK1A1编码，是CK1激酶家族中一个普遍表达的丝氨酸/苏氨酸蛋白激酶。CK1α参与调节细胞的多种生理和病理过程，并通过不同的信号转导途径协调生命的有序进行(Jiang et al.,Cell Commun Signal(2018)16:23)。例如，CK1α作为Wnt/β-catenin途径的关键调控器，直接将β-catenin的Ser45处磷酸化，从而使其成为蛋白体降解的靶标(Liu et al.,Cell(2002)108:837-847)。CK1α也被认为通过调节MDM2/MDMX E3连接酶的活性复合物来调节肿瘤抑制因子p53的蛋白质稳定性(Huart et al.,J Biol Chem(2009)284:32384-94；Wu et al.,Mol Cell Biol(2012)32:4821-4832)。据报道，CK1α在许多类型的人类癌症中过度表达，然而，CK1α在每种肿瘤类型的发展中的确切作用还没有得到明确的阐明(Richter et al.,BMC Cancer(2018)18:140)。癌症依赖性图谱(DepMap)数据库显示，通过CRISPR/cas9介导的基因敲除或shRNA介导的基因抑制使CK1α的失活，显著降低了多种癌症类型的许多癌细胞系的增殖和/或存活(Tsherniak et al.,Cell(2017)170:564-576；Behan et al.,Nature(2019)568:511-516)。此外，通过使用shRNA干扰或D4476(一种CK1α抑制剂)抑制CK1α活性，该方法能够有效抑制MLL-AF9白血病的进展，而且对正常造血干细胞和祖细胞(HSPCs)影响小(Jaras et al,J Exp Med(2014)211(4):605-612)。总之，这些数据表明CK1α是潜在治疗血液系统恶性癌症和实体瘤适应症的潜在靶点。
式A化合物作为新一代CK1α选择性分子胶降解剂，现已处于早期临床研究阶段。

然而，未见关于式A化合物的多晶型、无定形、制剂等的任何研究与报道。
因此，在新药研发过程中需要对药物化合物进行全面筛选，从多重因素进行考虑。特别地，对于上述用于治疗增值性病症的式A化合物而言，开发该化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的可能具有药用价值的剂型，对提高化合物的稳定性、溶解度、生物利用度等特性具有潜在的药用和临床价值。
发明内容
本发明提供一种式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物为活性成分的固体分散体。该固体分散体使活性成分式A化合物具有良好的口服生物利用度，对新药的开发和生产具有十分重要的价值。
在以下描述中，阐述了某些具体细节以便提供对本发明各种实施方式的透彻理解。然而，本领域技术人员将理解，可以在没有这些细节的情况下实践本发明。以下对若干实施方式的描述是在理解本发明被视为所要求保护的主题的示例的情况下进行的，并且无意于将所附权利要求限制于所示的特定实施方式。贯穿本发明使用的标题仅是为了方便而提供的，不应被解释为以任何方式限制权利要求。在任何标题下示出的实施方式可以与在任何其他标题下示出的实施方式组合。
在第一方面中，本发明提供了一种固体分散体，包括活性成分和载体，其中，所述活性成分为式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的一种或多种，所述载体选自：N-乙烯基内酰胺的均聚物和共聚物、纤维素类衍生物、接枝共聚物、高分子量聚烯化氧、聚丙烯酸酯和聚甲基丙烯酸酯、聚丙烯酰胺、醋酸乙烯酯聚合物、寡糖或多糖或其共聚物、或丙烯酸共聚物的一种或多种。
在一些优选实施方式中，所述N-乙烯基内酰胺的均聚物和共聚物为聚维酮，或者是PVP与聚乙酸乙烯酯的共聚物；较佳地，所述聚维酮为PVP K30；较佳地，所述PVP与聚乙酸乙烯酯的共聚物为PVP VA64。
在一些优选实施方式中，所述纤维素类衍生物为醋酸羟丙甲纤维素琥珀酸酯、羟丙基甲基纤维素、羟丙纤维素、甲基纤维素、乙基纤维素；较佳地，所述醋酸羟丙甲纤维素琥珀酸酯为HPMCAS 716G、HPMCAS 912G、HPMCAS 126G、HPMCAS 716F、HPMCAS 912F、HPMCAS 126F、HPMCAS LG、HPMCAS MG、HPMCAS HG、HPMCAS LF、HPMCAS MF和HPMCAS HF中的一种或多种；较佳地，所述羟丙基甲基纤维素为HPMC E3；较佳地，所述羟丙纤维素为HPC SSL。
在一些优选实施方式中，高分子量聚烯化氧为聚氧化乙烯、聚氧化丙烯和氧化乙烯和氧化丙烯的共聚物(泊洛沙姆)。
在一些优选实施方式中，聚丙烯酸酯和聚甲基丙烯酸酯为甲基丙烯酸/丙烯酸乙酯共聚物、甲基丙烯酸/甲基丙烯酸甲酯共聚物、甲基丙烯酸丁酯/2-甲基丙烯酸二甲氨基乙酯共聚物、聚(羟烷基丙烯酸酯)和聚(羟烷基甲基丙烯酸酯)。
在一些优选实施方式中，醋酸乙烯酯聚合物为醋酸乙烯酯和巴豆酸的共聚物、部分水解的聚醋酸乙烯酯和聚乙烯醇。
在一些优选实施方式中，寡糖或多糖为卡拉胶、半乳甘露聚糖和黄原胶，和其两种或多种的混合物。
在一些优选实施方式中，固体分散体载体包括一或多种选自下列的聚合物载体：聚乙烯吡咯烷酮、羟丙基甲基纤维素和其混合物。有用的共聚维酮的一个具体例子是由大约60％N-乙烯基吡咯烷酮和大约40％醋酸乙烯酯单体组成的。有用的聚维酮的一个具体例子是具有大约30的K值(聚维酮水溶液的粘度量度标准)的聚维酮。
在一些优选实施方式中，丙烯酸共聚物为甲基丙烯酸共聚物和甲基丙烯酸酯共聚物；较佳地，所述甲基丙烯酸共聚物和甲基丙烯酸酯共聚物为Eudragit；较佳地，所述Eudragit为Eudragit L100、Eudragit E100、Eudragit S100、Eudragit L100-55、Eudragit EPO中的一种或多种。
在一些优选实施方式中，所述接枝共聚物为Soluplus。
在一些优选实施方式中，所述的式A化合物的药学上可接受的盐为盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、2-羟基乙磺酸盐、磷酸盐、磷酸氢盐、乙酸盐、己二酸盐、藻酸盐、赖氨酸盐、精氨酸盐、组氨酸盐、天冬氨酸盐、苯甲酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、甘油磷酸盐、半硫酸盐、庚 酸盐、己酸盐、甲酸盐、丁二酸盐、反丁烯二酸盐、顺丁烯二酸盐、抗坏血酸盐、羟乙基磺酸盐、水杨酸盐、甲磺酸盐、均三甲苯磺酸盐、萘磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、三氯乙酸盐、三氟乙酸盐、谷氨酸盐、碳酸氢盐、十一烷酸盐、乳酸盐、柠檬酸盐、酒石酸盐、葡萄糖酸盐、乙二磺酸盐、苯磺酸盐、L-酒石酸盐、马来酸盐、钠盐、钾盐、胆碱盐、氨丁三醇盐、钙盐或对甲苯磺酸盐，优选地为磷酸盐、硫酸盐、L-酒石酸盐、盐酸盐、马来酸盐、氢溴酸盐、甲磺酸盐、赖氨酸盐、精氨酸盐、组氨酸盐、钠盐、钾盐、胆碱盐、氨丁三醇盐、钙盐。
在一些优选实施方式中，所述的式A化合物的水合物为半水合物、一水合物、二水合物、三水合物、四水合物、五水合物、六水合物、七水合物、八水合物、九水合物、十水合物、十一水合物、十二水合物。
在一些优选实施方式中，所述载体选自：聚维酮、PVP与聚乙酸乙烯酯的共聚物、醋酸羟丙甲纤维素琥珀酸酯、羟丙基甲基纤维素、羟丙纤维素、丙烯酸共聚物和接枝共聚物中的一种或多种。
在一些优选实施方式中，所述载体选自：PVP K30、PVP VA64、Soluplus、HPMC E3、HPMCAS MG、HPMCAS HG、HPC SSL、Eudragit L100中的一种或多种。
在一些优选实施方式中，所述载体选自：PVP VA64、Soluplus和HPC SSL中的一种或多种。
在一些优选实施方式中，所述载体为HPC SSL。
本发明的固体分散体为无定形形式。更为重要的是，该无定形固体分散体具有良好的固体稳定性，可以长期储存，并且不会潜在地影响药物产品的性能。
本发明所述载体的用量可为本领域常规，所述活性成分和载体的重量比为0.1:10～10:0.1。
在一些优选实施方式中，所述活性成分和载体的重量比为1:10～10:1，优选地为1:4～1:1。
在一些优选实施方式中，所述活性成分和载体的重量比为1:4、3:7、4:6或1:1。
在一些优选实施方式中，载体为PVP VA64，优选地，所述活性成分和PVP VA64的重量比为1:4。
在一些优选实施方式中，载体为Soluplus，优选地，所述活性成分和Soluplus的重量比为1:4。
在一些优选实施方式中，载体为HPC SSL，优选地，所述活性成分和HPC SSL 的重量比为1:4、3:7、4:6或1:1。
在一些优选实施方式中，所述活性成分为式A化合物的无定形，具有基本上如图4所示的XRPD图。
在另一优选例中，式A化合物的无定形还任选地具有以下一个或多个特征：
1)在TGA中，在温度210±2.0℃之前有2.79重量％的失重；
2)在mDSC中，在温度129.30±2.0℃处有1个玻璃化转变温度；
3)基本上如图3所示的TGA图；
4)基本上如图2所示的mDSC图。
在一些优选实施方式中，所述活性成分为式A化合物，式A化合物和Soluplus的重量比为1:4的固体分散体为PLM图7所示的无定形，具有基本上如图8所示的XRPD图，并任选地具有以下一个或多个特征：
1)在TGA图中，在温度180.00±2.0℃之前有0.96重量％的失重；
2)在mDSC图中，在中间温度99.79±2.0℃处有1个玻璃化转变温度；
3)基本上如图9所示的TGA图；和/或
4)基本上如图10所示的mDSC图。
在一些优选实施方式中，所述活性成分为式A化合物，式A化合物和PVP VA64的重量比为1:4的固体分散体为PLM图11所示的无定形，具有基本上如图12所示的XRPD图，并任选地具有以下一个或多个特征：
1)在TGA图中，在温度210±2.0℃之前有1.90重量％的失重；
2)在mDSC图中，在中间温度118.74±2.0℃处有1个玻璃化转变温度；
3)基本上如图13所示的TGA图；和/或
4)基本上如图14所示的mDSC图。
在一些优选实施方式中，所述活性成分为式A化合物，式A化合物和HPC SSL的重量比为1:4的固体分散体为PLM图15所示的无定形，具有基本上如图16所示的XRPD图，并任选地具有以下一个或多个特征：
1)在TGA图中，在温度180±2.0℃之前有1.00重量％的失重；
2)在mDSC图中，在温度70.72±2.0℃处有1个玻璃化转变温度；
3)基本上如图17所示的TGA图；和/或
4)基本上如图18所示的mDSC图。
在一些优选实施方式中，所述活性成分为式A化合物，式A化合物和HPC SSL的重量比为3:7的固体分散体为PLM图24所示的无定形，具有基本上如图25所示的XRPD图，并任选地具有以下一个或多个特征：
1)在TGA图中，在温度180±2.0℃之前有0.75重量％的失重；
2)在mDSC图中，在温度77.43±2.0℃处有1个玻璃化转变温度；
3)基本上如图26所示的TGA图；和/或
4)基本上如图27所示的mDSC图。
在一些优选实施方式中，所述活性成分为式A化合物，式A化合物和HPC SSL的重量比为4:6的固体分散体为PLM图28所示的无定形，具有基本上如图29所示的XRPD图，并任选地具有以下一个或多个特征：
1)在TGA图中，在温度180±2.0℃之前有1.53重量％的失重；
2)在mDSC图中，在温度84.97±2.0℃处有1个玻璃化转变温度；
3)基本上如图30所示的TGA图；和/或
4)基本上如图31所示的mDSC图。
在一些优选实施方式中，所述活性成分为式A化合物，式A化合物和HPC SSL的重量比为1:1的固体分散体为PLM图32所示的无定形，具有基本上如图33所示的XRPD图，并任选地具有以下一个或多个特征：
1)在TGA图中，在温度180±2.0℃之前有1.35重量％的失重；
2)在mDSC图中，在温度82.54±2.0℃处有1个玻璃化转变温度；
3)基本上如图34所示的TGA图；和/或
4)基本上如图35所示的mDSC图。
在一个实施方式中，所述的固体分散体，具有以下特征：
所述固体分散体中的活性成分的药时曲线下面积是所述活性成分单独给药时的药时曲线下面积的1.5～7倍，较佳地5～6倍。
在第二方面中，本发明提供了一种第一方面所述固体分散体的制备方法，包括步骤：
方法一
将所述式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的一种或多种、任选地其他组分，与溶剂混合，形成溶液或悬浮液，除去所述溶剂，得所述固体分散体；或
方法二
将所述式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的一种或多种、任选地其他组分混合，加热后挤出，得所述固体分散体；或
方法三
将所述式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的一种或多种、任选地其他组分，与溶剂混合，进行喷雾干燥，得所述固体分散体。
在一些优选实施方式中，方法一或三中，所述溶剂为水、醇类溶剂、酯类溶剂、酮类溶剂、卤代烃溶剂、腈类溶剂和醚类溶剂中的一种或多种，其中，所述醇类溶剂优选为乙醇和/或甲醇；所述酯类溶剂优选为乙酸乙酯；所述酮类溶剂优选为丙酮；所述卤代烃溶剂优选为二氯甲烷；所述腈类溶剂优选为乙腈；所述醚类溶剂优选为四氢呋喃；较佳地，所述溶剂为二氯甲烷和/或乙醇。较佳地，所述溶剂为丙酮和或水。
在一些优选实施方式中，“式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的一种或多种”与所述溶剂的质量体积比为(0.1～30):1mg/mL，优选为(1～10):1mg/mL，更优选为5:1.5mg/mL。
在一些优选实施方式中，所述溶剂为醇类溶剂和/或卤代烃溶剂，其中，所述醇类溶剂优选为甲醇；所述卤代烃溶剂优选为二氯甲烷；较佳地，所述溶剂为二氯甲烷和甲醇，其中，二氯甲烷和甲醇的体积比优选为9:1～1:1。
在一些优选实施方式中，所述溶剂为醇类溶剂和/或卤代烃溶剂，其中，所述醇类溶剂优选为乙醇；所述卤代烃溶剂优选为二氯甲烷；较佳地，所述溶剂为二氯甲烷和乙醇，其中，二氯甲烷和甲醇的体积比优选为9:1～1:1。
在一些优选实施方式中，所述溶剂为丙酮和水，其中，丙酮和水的体积比优选为7:1～10:1。
在一些优选实施方式中，所述喷雾干燥进风温度设定为40℃～200℃，优选为80℃～120℃。
在第三方面中，本发明提供了一种包含所述固体分散体的药物组合物，该固体分散体包括活性成分和载体，所述活性成分为式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的一种或多种，所述载体选自N-乙烯基内酰胺的均聚物和共聚物、纤维素类衍生物、和/或接枝共聚物或丙烯酸共聚物的一种或多种。该药物组合物包括：
(1)如上所述的固体分散体；和(2)药学上可接受的赋形剂。
在一些优选实施方式中，所述药物组合物可包括其它赋形剂，如用作填充剂、粘合剂、崩解剂、助流剂和润滑剂的赋形剂。因此，包括式A化合物或其药学上可接受的盐的固体药物组合物还任选地包括一种或多种常规药学上可接受的赋形剂。
在第四方面中，本发明提供了一种药物制剂，其包含上述的药物组合物；其中，所述的药物制剂可为固体制剂，也可为散剂、颗粒剂、片剂、胶囊剂、滴丸剂或膜剂。
在第五方面中，本发明提供一种上述固体分散体、药物组合物或药物制剂在制备治疗增殖性疾病的药物中的应用，优选地，所述增殖性疾病包括乳腺癌、结肠癌症、脑癌、前列腺癌、肾癌、胰腺癌、卵巢癌、头部以及颈部癌、黑色素瘤、结直肠癌、胃癌、鳞状细胞癌、小细胞癌肺癌、非小细胞肺癌、睾丸癌、Merkel细胞癌、胶质母细胞瘤、神经母细胞瘤，淋巴器官癌和血液恶性肿瘤包括白血病(急性淋巴细胞白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞白血病(CLL)、慢性粒细胞白血病(CML)、急性单核细胞白血病(AMOL)、毛细胞白血病(HCL)、T细胞前淋巴细胞白血病(T-PLL)、大颗粒淋巴细胞白血病、成人T细胞白血病)、淋巴瘤(小淋巴细胞淋巴瘤(SLL)、霍奇金淋巴瘤(结节性硬化，混合细胞、富含淋巴细胞、淋巴细胞耗竭或未耗竭以及结节淋巴细胞为主的霍奇金淋巴瘤)、非霍奇金淋巴瘤(所有亚型)，慢性淋巴细胞白血病/小淋巴细胞淋巴瘤，B细胞前淋巴细胞白血病、淋巴瘤(如巨球蛋白血症)、脾边缘区淋巴瘤、浆细胞肿瘤(浆细胞骨髓瘤、浆细胞瘤、单克隆免疫球蛋白沉积疾病、重链疾病)、淋巴结外边缘区B细胞淋巴瘤(MALT淋巴瘤)、淋巴瘤(NMZL)、滤泡性淋巴瘤、套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性积液淋巴瘤、伯基特淋巴瘤/白血病、T细胞前淋巴细胞白血病、T细胞大颗粒淋巴细胞白血病、侵袭性NK细胞白血病、成人T细胞白血病/淋巴瘤、结外NK/T细胞淋巴瘤(鼻型)、肠病T型细胞淋巴瘤、肝脾T细胞淋巴瘤、母细胞NK细胞淋巴瘤、真菌病蕈样肉芽肿/塞扎里综合征、原发性皮肤CD30阳性T细胞淋巴瘤疾病、原发性皮肤间变性大细胞淋巴瘤、淋巴瘤样丘疹病、血管免疫母细胞T细胞淋巴瘤、外周T细胞淋巴瘤(非特定的)、间变性大细胞淋巴瘤、多发性骨髓瘤(浆细胞骨髓瘤或Kahler病)。
在第六方面中，本发明提供一种治疗增殖性疾病的方法，包括步骤：给有需要的对象施用治疗有效量的本发明第一方面的固体分散体或本发明第三方面的药物组合物或本发明第四方面的药物制剂。
在一些优选实施方式中，所述的对象为哺乳动物，如人。
附图说明
图1为API无定形的PLM图。
图2为API无定形的mDSC图。
图3为API无定形的TGA图。
图4为API无定形的XRPD图。
图5为快速溶剂蒸发产物的XRPD叠加图。
图6为快速蒸发产物的溶解度曲线图。
图7为处方API+Soluplus固体分散体的PLM图。
图8为处方API+Soluplus固体分散体的XRPD图。
图9为处方API+Soluplus固体分散体的TGA图。
图10为处方API+Soluplus固体分散体的mDSC图。
图11为处方API+PVP VA64固体分散体的PLM图。
图12为处方API+PVP VA64固体分散体的XRPD图。
图13为处方API+PVP VA64固体分散体的TGA图。
图14为处方API+PVP VA64固体分散体的mDSC图。
图15为处方API+HPC SSL固体分散体的PLM图。
图16为处方API+HPC SSL固体分散体的XRPD图。
图17为处方API+HPC SSL固体分散体的TGA图。
图18为处方API+HPC SSL固体分散体的mDSC图。
图19为不同处方的固体分散体的重分散溶解度曲线图。
图20为不同处方的固体分散体在25℃/60％RH(敞口)下1周的XRPD图。
图21为不同处方的固体分散体在40℃/75％RH(敞口)下1周的XRPD图。
图22为三种固体分散体(处方API+Soluplus、处方API+PVP VA64和处方API+HPC SSL)的PK图。
图23为处方API+HPC SSL固体分散体不同载药量的PK图。
图24为处方API+HPC SSL(3:7,w/w)固体分散体的PLM图。
图25为处方API+HPC SSL(3:7,w/w)固体分散体的XRPD图。
图26为处方API+HPC SSL(3:7,w/w)固体分散体的TGA图。
图27为处方API+HPC SSL(3:7,w/w)固体分散体的mDSC图。
图28为处方API+HPC SSL(4:6,w/w)固体分散体的PLM图。
图29为处方API+HPC SSL(4:6,w/w)固体分散体的XRPD图。
图30为处方API+HPC SSL(4:6,w/w)固体分散体的TGA图。
图31为处方API+HPC SSL(4:6,w/w)固体分散体的mDSC图。
图32为处方API+HPC SSL(1:1,w/w)固体分散体的PLM图。
图33为处方API+HPC SSL(1:1,w/w)固体分散体的XRPD图。
图34为处方API+HPC SSL(1:1,w/w)固体分散体的TGA图。
图35为处方API+HPC SSL(1:1,w/w)固体分散体的mDSC图。
图36为处方API+HPC SSL的重分散溶解度曲线图。
图37为处方API+HPC SSL固体分散体在25℃/60％RH(敞口)下4周的XRPD图。
图38为处方API+HPC SSL固体分散体在40℃/75％RH(敞口)下4周的XRPD图。
图39为API晶型G的XRPD图。
图40为API晶型G的DSC图。
图41为API晶型G的TGA图。
图42-1和图42-2为以API晶型G为原料制备的固体分散体的XRPD图。
图43-1和图43-2为以API晶型G为原料制备的固体分散体的DSC图。
图44-1和图44-2为以API晶型G为原料制备的固体分散体的TGA图。
具体实施方式
本发明人经过广泛而深入地研究，开发了一种具有优异药代动力学特征的固体分散体。本发明的固体分散体在大鼠体内表现了较高血浆暴露量，即较高的药峰浓度和较大的药时曲线下面积，其药时曲线下面积是其活性成分单独给药时的药时曲线下面积的1.5～7倍(优选5～6倍)。在此基础上，完成了本发明。
活性成分
如本文所用，术语“活性药物成分(Active pharmaceutical ingredient，API，在本文中也称为“活性成分”)”指作为活性成分的式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的一种或多种，所述式A化合物的化学名为N-((S)-5-氯吡啶-2-基)(环丁基)甲基)-2-((S)-2,6-二氧哌啶-3-基)-1-氧异吲哚-5-甲酰胺(N-((S)-(5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide)。
固体分散体
固体分散体(solid dispersion)是指将活性成分高度分散于(固体)载体中形成的一种以固体形式存在的分散系统。
本发明中，固体分散体包括固体溶液、玻璃溶液、玻璃悬浮液、结晶载体中的无定形沉淀、低共熔混合物或偏晶(monotecics)、混合或复合形成物及其组合。
固体分散体的制备方法
本发明所述固体分散体可通过如下的方法制得，然而该方法的条件，例如载体、溶剂、各成分的量、制备温度、制备所需时间等不限于下面的解释。本发明所述固体分散体还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。
本发明制备方法可以采用例如热熔挤出、热熔融涂装、造粒、冻凝、溶剂蒸发法(例如分层、涂装、制粒)。
优选地，本发明的固体分散体采用以下方法制备：
方法一
将所述式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的一种或多种、任选地其他组分(如包括本发明所述载体，所述载体选自：N-乙烯基内酰胺的均聚物和共聚物、纤维素类衍生物、接枝共聚物、高分子量聚烯化氧、聚丙烯酸酯和聚甲基丙烯酸酯、聚丙烯酰胺、醋酸乙烯酯聚合物、寡糖或多糖或其共聚物、或丙烯酸共聚物的一种或多种)，与溶剂(如水、乙醇、甲醇、乙酸乙酯、丙酮、二氯甲烷、乙腈、四氢呋喃，或其组合)混合，形成溶液或悬浮液，除去所述溶剂，得所述固体分散体；
方法二
将所述式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的一种或多种、任选地其他组分混合(如包括如上所述载体)，加热 后挤出，得所述固体分散体；
方法三
将所述式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的一种或多种、任选地其他组分(如包括如上所述载体)，与溶剂(如水、乙醇、甲醇、乙酸乙酯、丙酮、二氯甲烷、乙腈、四氢呋喃，或其组合)混合，进行喷雾干燥(进风温度设定为40℃～200℃，优选为80℃～120℃)，得所述固体分散体。
优选地，式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的一种或多种与所述溶剂的质量体积比为(0.1～30):1mg/mL，优选为(1～10):1mg/mL，更优选为5:1.5mg/mL；
和/或，所述溶剂为醇类溶剂和/或卤代烃溶剂，其中，所述醇类溶剂优选为甲醇或乙醇；所述卤代烃溶剂优选为二氯甲烷；较佳地，所述溶剂为二氯甲烷和甲醇或二氯甲烷和乙醇，其中，二氯甲烷和甲醇或二氯甲烷和乙醇的体积比优选为9:1～1:1；
和/或，所述溶剂为丙酮和水，其中，丙酮和水的体积比优选为7:1～10:1。
药物组合物
本发明所述药物组合物可以采用本领域所熟知的各种方法制备，其可将治疗有效量的所述固体分散体与一种或多种药学上可接受的辅料混合制备成适合人体服用的剂型，如上述片剂、胶囊剂、颗粒剂等。
“治疗有效量”是指根据本发明的活性成分的量，其当施用至有此需要的患者时，足以实现对于活性成分具有效用的疾病状态、病症或障碍的治疗。这样的量将足以引起研究人员或临床医生所寻求的组织系统或患者的生物或医学反应。
本发明的药物组合物包含安全有效量范围内的本发明固体分散体或其药理上可接受的盐及药理上可以接受的赋形剂。其中“安全有效量”指的是：固体分散体的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1～2000mg本发明固体分散体/剂，更佳地，含有10～200mg本发明固体分散体/剂。较佳地，所述的“一剂”为一个胶囊或药片。
赋形剂是指一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的固体分散体以及它们之间相互掺和，而不明显降低固体 分散体的药效。药学上可以接受的赋形剂部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、淀粉类、单元糖或多元糖、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明固体分散体或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，固体分散体与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、微晶纤维素、甘露醇和硅酸；(b)粘合剂，例如，羟丙甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、交联羧甲基纤维素钠和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇、十二烷基硫酸钠、单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中固体分散体的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，固体分散体也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖桨或酊剂。除了固体分散体外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、娇味剂和香料。
除了固体分散体外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明固体分散体的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。本发明固体分散体在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明固体分散体可以单独给药，或者与其他药学上可接受的化合物联合给药。使用药物组合物时，是将安全有效量的本发明固体分散体适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60 kg体重的人而言，日给药剂量通常为0.2～2000mg，优选1～500mg，更优选地为1～200mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明中涉及的具体载体，例如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、Soluplus等均为市售可得的商品，且具有公开的结构组成和/或性质，具体的结构和性质等详细信息可参考相关的产品使用说明。
本发明上述提供的固体分散体、药物组合物或药物制剂具有可接受的生物吸收性能。如这种生物吸收可以通过药代动力学(PK)特性来证明，更尤其通过具体剂量下或在剂量范围内的Cmax或AUC来证明。并且，可以在人中，或在任何合适的模型种类中通过PK研究来测定生物利用度。本发明固体分散体，能显著提高式A化合物口服生物利用度，并且具有良好的固体稳定性。
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
以下实施例中，所用试剂和原料均市售可得，也可从下述来源公司购得。
缩写

偏振光显微镜(PLM)测定方法：
-尼康LV100POL配备500万像素CCD
-物理镜头：10倍～50倍
X射线粉末衍射仪(XRPD)测定方法：
使用以下方法在XRPD上运行样品：
-管：Cu:K-α
-发电机：电压：40千伏；电流：40毫安
-扫描范围：3至40度
-样品转速：15转/分钟
-扫描速度：10度/分钟
热重分析(TGA)测定：
-将样品(2～5mg)放在铝盘上，按以下方法运行：
-在大气条件下以10℃/min的速率从室温加热至300℃，如果样品的失重超过20％，则测试完成。
差示扫描量热法(DSC)测定：
-使用具有针孔的密封铝盘测试样品(～1mg)
-以10℃/min的速率从30℃加热至220℃。
式A化合物的制备
按照PCT/CN2022/097236实施例15的方法制备得到式A化合物，其化学名为N-((S)-5-氯吡啶-2-基)(环丁基)甲基)-2-((S)-2,6-二氧哌啶-3-基)-1-氧异吲哚-5- 甲酰胺
(N-((S)-(5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide)。
在含有DMAc(50mL)的圆底烧中，加入化合物1(3.25g，12.3mmol，盐酸盐)，化合物2(4.67g，12.9mmol)，NMM(6.2g，61.3mmol)和T3P(5.6g，17.6mmol)。将混合物脱气并用N2吹扫3次。混合物在N2环境下25℃搅拌12小时。将混合物倒入饱和氯化钠水溶液(100mL)，然后过滤并用水(100mL)洗涤。之后滤饼溶于DCM(200mL)中，用饱和NaHCO3水溶液(100mL)洗涤，无水Na2SO4干燥有机相,减压过滤浓缩，得到化合物3(6.5g，以化合物1计收率99.7％)白色固体。
向化合物3的CH3CN(13mL)的溶液中加入苯磺酸(1.1g，7.21mmol)。在N2环境下，将混合物在70℃下搅拌14小时，混合物用DCM(60mL)稀释，用饱和NaHCO3水溶液(30mLⅹ2)洗涤然后用H2O(30mLⅹ2)洗涤，用无水Na2SO4干燥有机相，过滤并减压浓缩，得到粗产物用EA(5mL)和MTBE(5mL)打浆过滤得到式A化合物的滤饼，干燥后定义为API对照品(API control)。将API对照品滤饼加入到30mL乙腈中，超声波处理5分钟，使其均匀分散成浆状溶液，再加入70mL水，使得整个溶液澄清透明，冻干后得到式A化合物无定形的类白色固体，定义为API无定形，收率87％，纯度99％。
1H 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＝8.0Hz,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]+。
实施例1式A化合物(活性药物成分,Active Pharmaceutical Ingredient，API)无定形特征
采用PLM、XRPD、mDSC和TGA进行表征。
如图1和图4所示，PLM和XRPD显示它是无定形的，式A化合物的衍射峰(特征峰)全部消失，以无定形或分子形态存在。如图3所示，在温度210±2.0℃之前有2.79重量％的失重。如图4所示，mDSC显示玻璃化转变温度129.30±2.0℃。
实施例2近似溶解度测试
将约5mg的式A化合物API对照品称入1.5mL玻璃小瓶中，然后逐步加入一定量的不同溶剂(如表1所示)直至固体溶解或达到1mL的总体积。式A化合物在DCM和MeOH混合溶剂中具有较高近似溶解度。但是在另外的研究中发现式A化合物在MeOH中快速手性外消旋化；在丙酮和乙醇当中，式A化合物手性稳定较好。
近似溶解度结果如表1所示，不同溶剂对式A化合物有不同程度的溶解性，兼顾稳定性因素，DCM:EtOH(9:1，v/v)与Acetone:Water(9:1，v/v)均可作为溶剂系统用于式A化合物固体分散体的制备。
表1式A化合物的近似溶解度
实施例3快速溶剂蒸发试验
约10mg式A化合物API对照品和40mg聚合物载体转移到1mL DCM:EtOH＝9:1(v/v)中以制备20％载药量的溶液。得到的清液在80℃下快速蒸发，直至无液，制备固体分散体。式A化合物API对照品也以同样的方式单独处理。结 果如图5所示，两种产物(API+HPMC E3和API+HMCAS MG)发生晶体衍射峰，剩余样品中，除式A化合物API对照品外，所有其他快速溶剂蒸发产物均为无定形。
并且，如表2和图6所示，在模拟空腹肠液(FaSSIF)中测定蒸发产物在不同时间点的溶解度，以评价不同种类聚合物对于式A化合物溶解性的影响。与API无定形和API对照品相比较，采用PVP K30、PVP VA64和Soluplus作为载体的产物显示出相对较好的提高式A化合物溶解性。
综合聚合物载体对API晶型抑制作用的结果(晶型衍射峰)和溶解度提高性能，选择了PVP VA64、Soluplus和HPC SSL三种聚合物开展进一步的研究。
表2快速蒸发产物在FaSSIF中的溶解度结果
实施例4喷雾干燥制备固体分散体
喷雾干燥参数设置：按照表3设置喷雾干燥参数。
表3固体分散体的喷雾干燥参数

基于快速溶剂蒸发试验结果，遴选3种聚合物载体，包括PVP VA64、Soluplus和HPC SSL，通过喷雾干燥方法制备式A化合物的固体分散体。
如表3所示，根据该处方比例称量适量式A化合物API对照品和相应的聚合物载体，之后加入DCM:EtOH(9:1，v/v)溶剂(首先加入DCM以润湿API，然后加入EtOH)。之后将所有样品以700rpm搅拌直至完全溶解，依据表3中设备参数进行样品溶液的喷雾干燥，将获得的固体粉末进一步在40℃真空条件下干燥过夜(约22小时)，获得固体分散体样品。
表4显示不同处方的固体分散体通过PLM、XRPD、mDSC、TGA和HPLC进行表征的结果。
表4不同载体的固体分散体性质总结
处方API+Soluplus(1:4,w/w)固体分散体，采用PLM、XRPD、mDSC和TGA进行表征。如表4、图7至图10所示，PLM和XRPD显示它是无定形的，固体分散体中API的XRPD衍射峰(特征峰)全部消失，以无定形形态存在。如图9所示，180±2.0℃时重量减轻0.96％。如图10所示，mDSC显示玻璃化转变温度99.79±2.0℃。HPLC检测含量结果为103.15％，纯度无明显变化，约为99.32％。
处方API+PVP VA64(1:4,w/w)固体分散体，采用PLM、XRPD、mDSC和TGA进行表征。如表4、图11至图14所示，PLM和XRPD显示它是无定形的，固体分散 体中API的XRPD衍射峰(特征峰)全部消失，以无定形形态存在。如图13所示，210±2.0℃时重量减轻1.90％。如图14所示，mDSC显示玻璃化转变温度118.74±2.0℃。HPLC检测含量结果为102.95％，纯度无明显变化，约为99.35％。
处方API+HPC SSL(1:4,w/w)固体分散体，采用PLM、XRPD、mDSC和TGA进行表征。如表4、图15至图18所示，PLM和XRPD显示它是无定形的，固体分散体中API的XRPD衍射峰(特征峰)全部消失，以无定形形态存在。如图17所示，180±2.0℃时重量减轻1.00％。如图18所示，mDSC显示玻璃化转变温度70.72±2.0℃。HPLC检测含量结果为103.30％，纯度无明显变化，约为99.29％。
实施例5固体分散体重分散溶解度测试
方法：将表5所示的处方样品粉末称量在3mL的模拟胃液(SGF)中，目标API浓度为8mg/mL或2mg/mL。在37℃下以500rpm搅拌0.25小时和0.5小时后，将约200μL悬浮液以14000rpm离心5分钟，用稀释剂将上清液稀释6倍用于HPLC分析。在0.5小时取样后，立即向悬浮液中加入2倍SGF体积量的FaSSIF并再搅拌0.25小时，0.5小时和1.5小时，然后取样用于HPLC分析和pH测试。结果如表5和图19所示，处方API+PVP VA64和处方API+HPC SSL显示出较好的溶解性。
表5式A化合物固体分散体重分散溶解度测试结果
实施例6固体分散体一周固体稳定性研究
根据表6，将三种固体分散体，即处方API+Soluplus、处方API+PVP VA64和处方API+HPC SSL存放在25℃/60％RH(敞口)和40℃/75％RH(敞口)条件下一周后，目测观察样品外观，并通过HPLC分析样品纯度。外观结果如表7，40℃/75％RH(敞口)条件下呈现轻微团聚和透明凝胶。XRPD表征如图20和图21。
结果表明，三种固体分散体，即处方API+Soluplus、处方API+PVP VA64和处方API+HPC SSL在40℃/75％RH(敞口)条件下的化学稳定性相对较差，如表6所示HPLC分析结果。但三种固体分散体在相同的条件下均表现出较好的物理 稳定性。因此，固体分散体的储存应避免暴露在高温高湿条件，以防化学降解。
表6固体分散体一周固体稳定性的HPLC结果
表7固体分散体一周固体稳定性的外观表征
实施例7以处方API+HPC SSL固体分散体为例进行载药量优化
根据实施例1-6研究的结果，以API+HPC SSL的固体分散体为例进行载药量优化研究。如表8所示，将适量式A化合物API对照品和HPC SSL称量入DCM:EtOH(9:1,v/v)溶剂中，然后将所有样品以700rpm搅拌直至完全溶解，根据表8所示设备参数进行样品溶液的喷雾干燥，将获得的固体粉末进一步在40℃的真空条件下干燥约20小时，获得固体分散体样品。
实施例7-1以30～50％载药量制备API+HPC SSL固体分散体
表8 API+HPC SSL的喷雾干燥参数
实施例7-2处方API+HPC SSL固体分散体表征
通过PLM、XRPD、mDSC、TGA和HPLC表征表9所示处方API+HPC SSL固体分散体。
表9 API+HPC SSL的ASD特征
处方API+HPC SSL(3:7,w/w)固体分散体，采用PLM、XRPD、mDSC和TGA进行表征。如表9、图24至27所示，PLM和XRPD显示该样品为无定形的，PLM没有双折射，只有XRPD的光晕，API的衍射峰(特征峰)全部消失，以无定形形态存在。如图26所示，在180±2.0℃之前有0.75％的失重。如图27所示，mDSC显示 玻璃化转变温度77.43±2.0℃。HPLC检测结果显示纯度无明显变化。
处方API+HPC SSL(4:6,w/w)固体分散体，采用PLM、XRPD、mDSC和TGA进行表征。如表9、图28至图31所示，PLM和XRPD显示该样品为无定形的，PLM没有双折射，只有XRPD的光晕，API衍射峰(特征峰)全部消失，以无定形形态存在。如图30所示，180±2.0℃之前有1.53％的失重。如图31所示，mDSC显示玻璃化转变温度84.97±2.0℃。HPLC检测结果显示纯度无明显变化。
处方API+HPC SSL(1:1,w/w)固体分散体，采用PLM、XRPD、mDSC和TGA进行表征。如表9、图32至图35所示，PLM和XRPD显示该样品为无定形的，PLM没有双折射，只有XRPD的光晕，API的衍射峰(特征峰)全部消失，以无定形形态存在。如图32所示，180±2.0℃之前有1.35％的失重。如图35所示，mDSC显示玻璃化转变温度82.54±2.0℃。HPLC检测结果显示纯度无明显变化。
实施例7-3处方API+HPC SSL固体分散体的生物相关溶媒中的重分散溶解度
将不同载药量的处方API+HPC SSL固体分散体称重到3mL SGF中，目标API浓度为2mg/mL。在37℃下以500rpm搅拌0.25小时和0.5小时后，将约200μL悬浮液以14000rpm离心5分钟，稀释上清液用于HPLC分析。在0.5小时取样后，立即向悬浮液中加入2倍SGF体积量的FaSSIF并再搅拌0.25小时，0.5小时和1.5小时，然后取样用于HPLC分析和pH测试。如表10和图36结果显示，三种不同载药量的固体分散体，分别为30％，40％和50％(API:HPC SSL)，显示溶解度之间没有显著差异。
表10不同载药量的API+HPC SSL固体分散体的生物相关溶媒中的重分散溶解度
实施例7-4处方API+HPC SSL固体分散体的四周固体稳定性研究
所有处方API+HPC SSL固体分散体均存放在25℃/60％RH(敞口)和40℃/75％RH(密闭)条件下。一周和四周(1w和4w)后，目测观察样品外观，XRPD测试晶型变化，并通过HPLC分析样品纯度。结果如表11至12和图37至38所示。分析结果表明所有三种固体分散体均显示良好的固体稳定性。
表11不同载药量的API+HPC SSL固体分散体固体稳定性四周的HPLC结果
表12不同载药量的固体分散体在两种稳定性考察条件下一周和四周的外观特征
实施例8式A化合物晶型G为原料制备固体分散体
实施例8-1式A化合物晶型G的特征
本发明固体分散体除了以上述API对照品为原料制备，也可以使用无定形或其他晶型为原料制备，例如采用式A化合物晶型G为原料。
制备方法。参照PCT/CN2022/097236实施例15的方法制备式A化合物，然后在酸性条件下关环并在乙腈-水中结晶，得到式A化合物的晶型G。
化合物1(32.5g，121mmol)和化合物2(56g，155mmol)加入N,N-二甲基乙酰胺(DMAc)(500mL)中，加入丙基磷酸酐(T3P)(46.7g，147mmol)和N-甲基吗啉(NMM)(62g，613mmol)。将混合物脱气并用N2吹扫3次。混合物在N2环境下25℃搅拌12小时。将混合物倒入饱和氯化钠水溶液(1000mL)，然后过滤并用水(1000mL)洗涤。滤饼溶于DCM(2000mL)中，用饱和NaHCO3水溶液(1000mL)洗涤，无水Na2SO4干燥有机相，减压过滤浓缩，得到化合物3(66g)，白色固体(HPLC纯度大于98％，手性纯度大于98％)。
将化合物3(66g)溶于CH3CN(660mL)，加入苯磺酸(57.4克，363mmol)。在N2环境下，将混合物在50℃下搅拌16小时，降温至0℃，用7％NaHCO3调pH至7-8，将上述溶液缓慢滴加入水(3300mL)中，搅拌3h，抽滤，用水(300mL)洗滤饼，滤饼真空干燥得到式A化合物(50g)，白色固体。
两步的产率为89％。
上述式A化合物经XRPD(图39)鉴定，为晶型G。
具有基本上如以下表13中所示位置处的XRPD特征峰和/或基本上如图39所示的X射线粉末衍射(XRPD)图。其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个或至少六个特征峰：18.837±0.2°，13.886±0.2°，21.455±0.2°，26.755±0.2°，15.927±0.2°和15.953±0.2°。各个峰的参数如表13所示。
表13式A化合物晶型G的XRPD特征峰
如图40所示，在DSC图中，在236.59±2.0℃处有1个吸热峰。
在热重分析(TGA)图41中，在150.00±2.0℃之前有0.52重量％的失重。
实施例8-2式A化合物晶型G的固体分散体的制备
按照表14设置喷雾干燥参数并称量2个批次适量式A化合物晶型G和聚合物 载体(HPC SSL，w/w)，并加入丙酮:水＝9:1(v/v)溶剂。然后以700rpm搅拌所有样品直至完全溶解，然后通过Buchi B-290喷雾干燥获得固体粉末。
表14固体分散体的喷雾干燥参数
表14中固体粉末进一步在60℃真空条件下干燥24小时，获固体分散体样品，然后通过XRPD、TGA、mDSC、PSD、GC、手性纯度和HPLC进行表征和测试。
结果如表15、图42-1和42-2所示，两个批次XRPD显示所有固体分散体都是无定形的，如图43-1和图43-2所示，mDSC显示Tg(玻璃化转变温度)为82～85℃。如图44-1和图44-2所示在148～155℃时，固体分散体有4.21～4.30重量％的失重。固体分散体的含量测定结果为99.34％～99.77％；纯度无显著变化，HPLC纯度约为99.35％～99.37％；异构体无明显增加。固体分散体粒径D90为18.00～20.00μm。
表15喷雾干燥法制备固体分散体的表征结果

实施例9固体分散体的体内药代动力学试验
根据表16，选取三种固体分散体，即处方API+Soluplus、处方API+PVP VA64和处方API+HPC SSL与对应的API无定形进行体内药代动力学试验，研究不同处方固体分散体在动物体内的药代动力学特征。
方法：通过在雄性Sprague Dawley(SD)大鼠体内灌胃给药后的药代动力学特征评价不同处方固体分散体。
材料：SD大鼠(雄性，200～250g，6-8周龄，浙江维通利华)。
步骤：SD大鼠经口灌胃给予300mg/kg(剂量按式A化合物计算)测试表16处方中的固体分散体，溶媒为含5％Tween 80的25mM柠檬酸盐缓冲液pH3。动物均为自由饮食饮水。给药后15min(0.25h)、30min(0.5h)、60min(1h)、2h、4h、6h、8h和24h从颈静脉采血。全血收集在含EDTA-K2的抗凝管中，充分混合后在4℃、4000g离心5分钟，分离血浆。血浆样品保存在-75±15℃直至采用LC-MS/MS法测定式A化合物的血药浓度。使用Phoenix WinNonlin 6.1的非房室模型、Linear/log trapezoidal方法计算相关药代动力学参数。
结果如表16和图22所示，20％API+HPC SSL(即API+HPC SSL(1:4,w/w))在1.67小时(Tmax)具有最高血浆浓度(Cmax＝101,467ng/mL)，AUClast为647,047h*ng/mL，显著高于其他固体分散体样品。
表16 20％载药量的不同处方的固体分散体的PK结果
为了进一步证实载药量优化的PK效应，以API+HPC SSL固体分散体为例，对不同载药量的API+HPC SSL固体分散体进行PK实验。结果如表17和图23所示， 50％ASD-HPC SSL(即API+HPC SSL(1:1,w/w))在1.00小时(Tmax)具有最高血浆浓度(Cmax＝115,000ng/mL)，AUClast为508,555h*ng/mL，其显著高于其他载药量的固体分散体样品。
表17不同载药量的API+HPC SSL固体分散体的PK结果
结论：
1.本发明制备的包含活性成分和载体的固体分散体具有良好的固体稳定性。
2.本发明制备的含有活性成分的固体分散体能够显著提高活性成分的口服生物利用度，尤其是，使用本发明的固体分散体给药时，其活性成分在血浆中的药时曲线下面积是其活性成分单独给药时的药时曲线下面积的1.5～7倍，较佳地5～6倍。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 一种固体分散体，其特征在于，包括活性成分和载体，其中，
    所述活性成分为式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的一种或多种，
    所述载体选自：N-乙烯基内酰胺的均聚物和共聚物、纤维素类衍生物、接枝共聚物、高分子量聚烯化氧、聚丙烯酸酯和聚甲基丙烯酸酯、聚丙烯酰胺、醋酸乙烯酯聚合物、寡糖或多糖或其共聚物、或丙烯酸共聚物的一种或多种。
  2. 如权利要求1所述的固体分散体，其特征在于，所述N-乙烯基内酰胺的均聚物和共聚物为聚维酮(PVP)，或者是PVP与聚乙酸乙烯酯的共聚物；较佳地，所述聚维酮为PVP K30；较佳地，所述PVP与聚乙酸乙烯酯的共聚物为PVP VA64；
    和/或，所述纤维素类衍生物为醋酸羟丙甲纤维素琥珀酸酯、羟丙基甲基纤维素、羟丙纤维素，较佳地，所述醋酸羟丙甲纤维素琥珀酸酯为HPMCAS 716G、HPMCAS 912G、HPMCAS 126G、HPMCAS 716F、HPMCAS 912F、HPMCAS 126F、HPMCAS LG、HPMCAS MG、HPMCAS HG、HPMCAS LF、HPMCAS MF和HPMCAS HF中的一种或多种；较佳地，所述羟丙基甲基纤维素为HPMC E3；较佳地，所述羟丙纤维素为HPC SSL；
    和/或，所述丙烯酸共聚物为甲基丙烯酸共聚物和甲基丙烯酸酯共聚物；较佳地，所述甲基丙烯酸共聚物和甲基丙烯酸酯共聚物为Eudragit；较佳地，所述Eudragit为Eudragit L100、Eudragit E100、Eudragit S100、Eudragit L100-55、Eudragit EPO中的一种或多种；
    和/或，所述接枝共聚物为Soluplus；
    和/或，所述式A化合物的药学上可接受的盐为盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、2-羟基乙磺酸盐、磷酸盐、磷酸氢盐、乙酸盐、己二酸盐、藻酸盐、赖氨酸盐、精氨酸盐、组氨酸盐、天冬氨酸盐、苯甲酸盐、丁酸盐、樟脑酸 盐、樟脑磺酸盐、二葡糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、甲酸盐、丁二酸盐、反丁烯二酸盐、顺丁烯二酸盐、抗坏血酸盐、羟乙基磺酸盐、水杨酸盐、甲磺酸盐、均三甲苯磺酸盐、萘磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、三氯乙酸盐、三氟乙酸盐、谷氨酸盐、碳酸氢盐、十一烷酸盐、乳酸盐、柠檬酸盐、酒石酸盐、葡萄糖酸盐、乙二磺酸盐、苯磺酸盐、L-酒石酸盐、马来酸盐、钠盐、钾盐、胆碱盐、氨丁三醇盐、钙盐或对甲苯磺酸盐，优选地为磷酸盐、硫酸盐、L-酒石酸盐、盐酸盐、马来酸盐、氢溴酸盐、甲磺酸盐、赖氨酸盐、精氨酸盐、组氨酸盐、钠盐、钾盐、胆碱盐、氨丁三醇盐、钙盐；
    和/或，所述的式A化合物的水合物为半水合物、一水合物、二水合物、三水合物、四水合物、五水合物、六水合物、七水合物、八水合物、九水合物、十水合物、十一水合物、十二水合物。
  3. 如权利要求1-2中任一项所述的固体分散体，其特征在于，所述载体选自：聚维酮、PVP与聚乙酸乙烯酯的共聚物、醋酸羟丙甲纤维素琥珀酸酯、羟丙基甲基纤维素、羟丙纤维素、丙烯酸共聚物和接枝共聚物中的一种或多种；
    优选地，所述载体选自：PVP K30、PVP VA64、Soluplus、HPMC E3、HPMCAS MG、HPMCAS HG、HPC SSL、Eudragit L100中的一种或多种；
    优选地，所述载体选自：PVP VA64、Soluplus和HPC SSL中的一种或多种；
    优选地，所述载体为HPC SSL。
  4. 如权利要求1-3中任一项所述的固体分散体，其特征在于，所述活性成分和所述载体的重量比为0.1:10～10:0.1。
  5. 如权利要求1-4中任一项所述的固体分散体，其特征在于，所述活性成分和所述载体的重量比为1:4、3:7、4:6或1:1。
  6. 如权利要求1-5中任一项所述的固体分散体，其特征在于，所述载体为HPC SSL，所述活性成分和HPC SSL的重量比为1:4、3:7、4:6或1:1。
  7. 如权利要求1-4中任一项所述的固体分散体，其特征在于，所述固体分散体为固体分散体1，其包括式A化合物和Soluplus，其重量比为1:4，所述固体分散体1为无定形，其具有基本上如图8所示的XRPD图；
    或所述固体分散体为固体分散体2，其包括式A化合物和PVP VA64，其重量比为1:4，所述固体分散体2为无定形，其具有基本上如图12所示的XRPD图；
    或所述固体分散体为固体分散体3，其包括式A化合物和HPC SSL，其重量比为1:4，所述固体分散体3为无定形，其具有基本上如图16所示的XRPD图；
    优选地，所述固体分散体1还任选地具有以下一个或多个特征：
    1)在TGA图中，在温度180.00±2.0℃之前有0.95重量％的失重；
    2)在mDSC图中，在温度99.79±2.0℃处有1个玻璃化转变温度；
    3)基本上如图9所示的TGA图；和/或
    4)基本上如图10所示的mDSC图；
    优选地，所述固体分散体2还任选地具有以下一个或多个特征：
    1)在TGA图中，在温度210±2.0℃之前有1.89重量％的失重；
    2)在mDSC图中，在温度118.74±2.0℃处有1个玻璃化转变温度；
    3)基本上如图13所示的TGA图；和/或
    4)基本上如图14所示的mDSC图；
    优选地，所述固体分散体3还任选地具有以下一个或多个特征：
    1)在TGA图中，在温度180±2.0℃之前有0.99重量％的失重；
    2)在mDSC图中，在温度70.72±2.0℃处有1个玻璃化转变温度；
    3)基本上如图17所示的TGA图；和/或
    4)基本上如图18所示的mDSC图。
  8. 如权利要求1-7中任一项所述的固体分散体，其特征在于，所述固体分散体中的活性成分的药时曲线下面积(AUC)是所述活性成分单独给药时的AUC的1.5～7倍，较佳地5～6倍。
  9. 一种制备权利要求1-8中任一项所述固体分散体的方法，其特征在于，包括如下步骤：
    方法一
    将所述式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的一种或多种、任选地其他组分，与溶剂混合，形成溶液或悬浮液，除去所述溶剂，得所述固体分散体；或
    方法二
    将所述式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的一种或多种、任选地其他组分混合，加热后挤出，得所述固体分散体；或
    方法三
    将所述式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的一种或多种、任选地其他组分，与溶剂混合，进行喷雾干燥，得所述固体分散体。
  10. 如权利要求9所述的方法，其特征在于，在所述方法一或所述方法三中，
    所述溶剂为水、醇类溶剂、酯类溶剂、酮类溶剂、卤代烃溶剂、腈类溶剂和醚类溶剂中的一种或多种，其中，所述醇类溶剂优选为乙醇和/或甲醇；所述酯类溶剂优选为乙酸乙酯；所述酮类溶剂优选为丙酮；所述卤代烃溶剂优选为二氯甲烷；所述腈类溶剂优选为乙腈；所述醚类溶剂优选为四氢呋喃；较佳地，所述溶剂为二氯甲烷和/或乙醇；较佳地，所述溶剂为丙酮和/或水；
    和/或，式A化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的一种或多种与所述溶剂的质量体积比为(0.1～30):1mg/mL，优选为(1～10):1mg/mL，更优选为5:1.5mg/mL；
    和/或，所述溶剂为醇类溶剂和/或卤代烃溶剂，其中，所述醇类溶剂优选为甲醇或乙醇；所述卤代烃溶剂优选为二氯甲烷；较佳地，所述溶剂为二氯甲烷和甲醇或二氯甲烷和乙醇，其中，二氯甲烷和甲醇或二氯甲烷和乙醇的体积比优选为9:1～1:1；
    和/或，所述溶剂为丙酮和水，其中，丙酮和水的体积比优选为7:1～10:1；
    和/或，所述喷雾干燥进风温度设定为40℃～200℃，优选为80℃～120℃。
  11. 一种药物组合物，其特征在于，所述药物组合物包括：
    (1)权利要求1-8任一项所述的固体分散体；和
    (2)药学上可接受的赋形剂。
  12. 一种药物制剂，其包含如权利要求11所述的药物组合物；其中，所述的药物制剂可为固体制剂，所述固体制剂的剂型选自下组：散剂、颗粒剂、片剂、胶囊剂、滴丸剂或膜剂。
  13. 一种如权利要求1-8任一项所述的固体分散体在制备治疗增殖性疾病的药物中的用途。
  14. 一种治疗增殖性疾病的方法，其特征在于，给有需要的对象施用治疗有效量的如权利要求1-8任一项所述的固体分散体。
  15. 如权利要求13所述的用途或如权利要求14所述的方法，其特征在于，所述增殖性疾病选自：乳腺癌、结肠癌症、脑癌、前列腺癌、肾癌、胰腺癌、卵巢癌、头部以及颈部癌、黑色素瘤、结直肠癌、胃癌、鳞状细胞癌、小细胞癌肺癌、非小细胞肺癌、睾丸癌、Merkel细胞癌、胶质母细胞瘤、神经母细胞瘤，淋巴器官癌和血液恶性肿瘤包括白血病(急性淋巴细胞白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞白血病(CLL)、慢性粒细胞白血病(CML)、急性单核细胞白血病(AMOL)、毛细胞白血病(HCL)、T细胞前淋巴细胞白血病 (T-PLL)、大颗粒淋巴细胞白血病、成人T细胞白血病)、淋巴瘤(小淋巴细胞淋巴瘤(SLL)、霍奇金淋巴瘤(结节性硬化，混合细胞、富含淋巴细胞、淋巴细胞耗竭或未耗竭以及结节淋巴细胞为主的霍奇金淋巴瘤)、非霍奇金淋巴瘤(所有亚型)，慢性淋巴细胞白血病/小淋巴细胞淋巴瘤，B细胞前淋巴细胞白血病、淋巴瘤(如巨球蛋白血症)、脾边缘区淋巴瘤、浆细胞肿瘤(浆细胞骨髓瘤、浆细胞瘤、单克隆免疫球蛋白沉积疾病、重链疾病)、淋巴结外边缘区B细胞淋巴瘤(MALT淋巴瘤)、淋巴瘤(NMZL)、滤泡性淋巴瘤、套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性积液淋巴瘤、伯基特淋巴瘤/白血病、T细胞前淋巴细胞白血病、T细胞大颗粒淋巴细胞白血病、侵袭性NK细胞白血病、成人T细胞白血病/淋巴瘤、结外NK/T细胞淋巴瘤(鼻型)、肠病T型细胞淋巴瘤、肝脾T细胞淋巴瘤、母细胞NK细胞淋巴瘤、真菌病蕈样肉芽肿/塞扎里综合征、原发性皮肤CD30阳性T细胞淋巴瘤疾病、原发性皮肤间变性大细胞淋巴瘤、淋巴瘤样丘疹病、血管免疫母细胞T细胞淋巴瘤、外周T细胞淋巴瘤(非特定的)、间变性大细胞淋巴瘤、多发性骨髓瘤(浆细胞骨髓瘤或Kahler病)。
PCT/CN2023/136781 2022-12-07 2023-12-06 一种固体分散体、其制备方法和应用 Ceased WO2024120438A1 (zh)

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