WO2016184367A1 - Somcl-9112固体分散体、其制备方法及包含其的somcl-9112固体制剂 - Google Patents

Somcl-9112固体分散体、其制备方法及包含其的somcl-9112固体制剂 Download PDF

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WO2016184367A1
WO2016184367A1 PCT/CN2016/082044 CN2016082044W WO2016184367A1 WO 2016184367 A1 WO2016184367 A1 WO 2016184367A1 CN 2016082044 W CN2016082044 W CN 2016082044W WO 2016184367 A1 WO2016184367 A1 WO 2016184367A1
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somcl
solid dispersion
preparation
solid
weight
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French (fr)
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郭仕艳
甘勇
张翱
缪泽鸿
高丽
丁健
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SHANGHAI ACEBRIGHT PHARMACEUTICALS CO Ltd
Shanghai Institute of Materia Medica of CAS
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SHANGHAI ACEBRIGHT PHARMACEUTICALS CO Ltd
Shanghai Institute of Materia Medica of CAS
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Priority to EP16795854.5A priority Critical patent/EP3299014B1/en
Priority to US15/574,557 priority patent/US11191761B2/en
Priority to JP2018512468A priority patent/JP6522853B2/ja
Priority to AU2016263338A priority patent/AU2016263338B2/en
Publication of WO2016184367A1 publication Critical patent/WO2016184367A1/zh
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and relates to a solid dispersion of SOMCL-9112, a preparation method thereof, a solid pharmaceutical preparation comprising the solid dispersion, and the use of the solid dispersion for preparing a medicament for treating cancer.
  • SOMCL-9112 chemical name 4-(4-fluoro-3-(5-methyl-3-(trifluoromethyl)-5,6,7,8-4H-[1,2,4]triazole And [4,3-a] piperazine-7-carbonyl)benzyl)pyridazine-1(2H)-one, molecular formula: C 23 H 18 F 4 N 6 O 2 , molecular weight: 486.4, having the following chemical structure :
  • SOMCL-9112 and its use are disclosed and enumerated in CN103833756A and PCT/CN2013/079998, and in the previous study, SOMCL-9112 was treated as a novel highly selective poly(ADP-ribose polymerase-1) (PARP1) inhibitor.
  • PARP-related diseases especially in the treatment of cancer, such as breast cancer, pancreatic cancer, ovarian cancer, and the like.
  • SOMCL-9112 is particularly effective in treating cancers whose cells are defective in homologous recombination (HR)-dependent DNA double-strand break (DSB) repair pathways.
  • the BRCA1 (NM_007295) and BRCA2 (NM_000059) genetic breast/ovarian cancer genes are only two of the many proteins in the HR-dependent DNA DSB repair pathway.
  • Treatment of brca1 -/- and/or brca2 -/- type breast or ovarian cancer with PARP inhibitors is more effective than cancer without defective homologous recombination (HR)-dependent DNA double-strand break (DSB) repair pathway; Achieve effective monotherapy and/or combination therapy.
  • SOMCL-9112 has a balanced solubility of less than 0.10 mg/ml in a pH 1.2-6.8 buffered saline solution and is a poorly water-soluble drug.
  • SOMCL-9112 When studied using the Caco-2 cell line, SOMCL-9112 had a permeability coefficient comparable to that of the low permeability positive control atenolol, and the Caco-2 Papp value was 0.72 x 10 -6 cm/s (see Experimental Example 1).
  • SOMCL-9112 is poorly absorbed in the body and has low bioavailability. The bioavailability of oral SOMCL-9112 in patients depends to some extent on the dissolution rate and solubility of the drug in the GI gut.
  • the bioavailability of SOMCL-9112 after administration of different formulations can be assessed by measuring the drug concentration in the plasma of SOMCL-9112 and calculating the area under the curve of the drug.
  • the in vivo exposure of SOMCL-9112 nanocrystal preparation was extremely low (see Experimental Example 2), and the area under the curve at 24 h after administration was only 126 h*ng/ml, which affected the normal efficacy of the drug. Therefore, research has been conducted to improve the bioavailability of SOMCL-9112.
  • poorly soluble drugs are modified by prodrugs to form salts which are widely used to improve their solubility and bioavailability.
  • the above methods have certain limitations, such as complicated operation, many intermediate products, high cost, etc., and it is difficult to achieve large-scale industrial production.
  • Sekiguchi et al. first applied solid dispersion technology to improve the solubility and bioavailability of poorly soluble drugs.
  • Many pharmaceutical researchers conducted extensive and in-depth research on solid dispersions, further demonstrating the formation of solid dispersions of poorly soluble drugs. It is one of the most promising methods for improving its solubility and bioavailability.
  • pharmaceutical preparations prepared by the solid dispersion technique have been commercialized, for example, Kaletra (lopinavir/ritonavir).
  • the invention develops a SOMCL-9112 pharmaceutical preparation with high bioavailability, which satisfies the requirements of clinical administration under the premise of achieving sufficient drug load and stability.
  • the solid dispersion of SOMCL-9112 can form a stable mixed micelle with an average particle diameter of ⁇ 100 nm in the simulated gastrointestinal fluid, and can increase the solubility of SOMCL-9112 from ⁇ 10 ⁇ g/ml to more than 300 ⁇ g/ml, through the glue.
  • the principle of sputum lysis improves the solubility of the drug and prevents the precipitation of the drug, thereby improving the bioavailability of the drug.
  • Increased bioavailability helps reduce the amount of SOMCL-9112 required to achieve comparable exposures observed with conventional formulations, reducing the effective therapeutic dose of the drug, increasing drug efficacy, saving drug costs, and reducing the toxic side effects of the drug.
  • a solid dispersion of SOMCL-9112 comprising the following starting materials, made by weight:
  • the proportion of SOMCL-9112 in the amorphous form in SOMCL-9112 ranges from 70% to 100%, preferably 80% or more, more preferably 90% or more. Preferably 95% or more, and most preferably SOMCL-9112 is present substantially entirely in amorphous form.
  • the SOMCL-9112 solid dispersion can stabilize SOMCL-9112 in an amorphous form and can reduce the possibility of SOMCL-9112 conversion or reversal into other forms.
  • the solid dispersion of SOMCL-9112 provided by the invention can overcome the disadvantages of poor physical stability and aging of conventional solid dispersions.
  • the solid dispersion prepared from SOMCL-9112 and the pharmaceutically acceptable matrix polymer remains in a stable amorphous form after standing for 6 months under accelerated conditions with good stability.
  • the pharmaceutically acceptable matrix polymer has a Tg of at least about 50 ° C and may be selected from the group consisting of copovidone, povidone, hydroxypropyl Methylcellulose phthalate (HPMPCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), 2-hydroxy- ⁇ -cyclodextrin (HPBCD), hydroxypropyl methylcellulose ( Hypromellose, HPMC), polymethacrylate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), hydroxypropyl cellulose (HPC) and acetic acid phthalic acid
  • cellulose CAP
  • CAP is preferably one or more selected from the group consisting of copolyvidone, Soluplus, and hydroxypropylmethylcellulose acetate succinate.
  • Copolyvidone is a water-soluble organic polymer compound and is a linear copolymer of N-vinylpyrrolidone (NVP) and vinyl acetate (VA).
  • NDP N-vinylpyrrolidone
  • VA vinyl acetate
  • Mw average molecular weight
  • the weight ratio of SOMCL-9112 to the pharmaceutically acceptable matrix polymer is from 1:0.25 to 1:10, preferably from 1:0.3 to 1:7, more preferably from 1:0.5 to 1:5, more preferably 1 : 2 to 1:4.
  • the surfactant further enhances the therapeutic potential of the solid dispersion of the present invention.
  • Suitable surfactants include: anionic surfactants such as sodium lauryl sulfate (sodium lauryl sulfate), sodium docusate; cationic surfactants such as bromotrimethylammonium, benzethonium chloride, ten Hexaalkylpyridinium chloride and lauric acid; nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters (specifically, Tween 80, 60, 40 and 20), Polyoxyethylene castor oil derivatives (particularly such as Cremophor RH40), polyoxyethylene stearate and poloxamer; preferably sodium lauryl sulfate.
  • anionic surfactants such as sodium lauryl sulfate (sodium lauryl sulfate), sodium docusate
  • cationic surfactants such as bromotrimethylammoni
  • the glidant is one or more selected from the group consisting of colloidal silica, animal or vegetable fat, wax, and the like.
  • plasticizer increases the processability of the solid dispersion.
  • Suitable plasticizers are selected from the group consisting of acetyl tributyl citrate, acetyl triethyl citrate, benzyl benzoate, chlorobutanol, dextrin, dibutyl phthalate, diethyl phthalate.
  • Ester dimethyl phthalate, glycerin, glyceryl monostearate, mannitol, mineral oil, lanolin alcohol, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, 2- One or more of pyrrolidone, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, and triethyl citrate.
  • the solid dispersion of the present invention may further contain other additives such as a lubricant, a filler, a disintegrant, a stabilizer (for example, an antioxidant, a light stabilizer, a radical scavenger, a stabilizer against microbial attack, etc.) as needed. )Wait.
  • additives such as a lubricant, a filler, a disintegrant, a stabilizer (for example, an antioxidant, a light stabilizer, a radical scavenger, a stabilizer against microbial attack, etc.) as needed. )Wait.
  • a lubricant for example, a filler, a disintegrant, a stabilizer (for example, an antioxidant, a light stabilizer, a radical scavenger, a stabilizer against microbial attack, etc.)
  • a stabilizer for example, an antioxidant, a light stabilizer, a radical scavenger, a stabilizer against microbial attack, etc
  • the disintegrant promotes rapid disintegration of the solid preparation in the stomach and keeps the released particles separated from each other.
  • Suitable disintegrants include crosslinked polymers such as croscarmellose sodium, crosslinked polyvinylpyrrolidone (i.e., crospovidone PVPP).
  • Suitable fillers are one or more selected from the group consisting of lactose, sucrose, mannitol, calcium hydrogen phosphate, microcrystalline cellulose, starch, isomaltose and the like.
  • Suitable lubricants are one or more selected from the group consisting of polyethylene glycol (e.g., molecular weight 1000 to 6000), magnesium stearate, calcium stearate, sodium stearyl fumarate, and the like.
  • the solid dispersion of SOMCL-9112 provided by the invention can form a stable average particle size in the simulated gastrointestinal fluid ⁇ 100nm mixed micelles can increase the solubility of SOMCL-9112 from ⁇ 10 ⁇ g/ml to more than 300 ⁇ g/ml.
  • the formed mixed micelle can avoid the precipitation of the drug while increasing the solubility of the drug by the principle of micelle lysis, and overcomes the disadvantage that the ordinary solid dispersion drug is easy to precipitate.
  • the solid dispersion provided by the present invention can improve the bioavailability of the drug by increasing the solubility of the drug and preventing the precipitation of the drug.
  • Another aspect of the present invention provides a method of preparing the above SOMCL-9112 solid dispersion, comprising the steps of:
  • the above SOMCL-9112 solid dispersion can be prepared by a solvent evaporation method or a melt extrusion method, preferably a melt extrusion method.
  • the melt extrusion process produces a melt by applying heat and/or mechanical stress
  • the "melt” refers to a liquid state or a rubbery state in which one component may be uniformly embedded in other components.
  • one component melts and the other components dissolve in the melt to form a melt.
  • the formation of a melt typically involves the softening point of a pharmaceutically acceptable matrix polymer, and the preparation of the melt can occur by a variety of methods.
  • the mixing of the components can be carried out before, during or after the formation of the melt. For example, the mixing of the components is first carried out, followed by heating or simultaneous mixing and heating.
  • the active material in the melt should be uniformly dispersed and the melt be mushy or viscous.
  • the heating temperature is from 70 ° C to 250 ° C, preferably from 80 ° C to 200 ° C, most preferably from 100 ° C to 180 ° C.
  • melt extrusion the melt production and extrusion in steps (1), (2) can be carried out in a conventional apparatus for this purpose.
  • extruders and kneaders are extruders and kneaders.
  • Suitable extruders can be extruded in a rod, including single screw extruders, twin screw extruders or other multi-screw extruders, preferably twin screw extruders, which can be rotated or reversed and optionally mounted There is a kneading disk.
  • the operating temperature will also be determined by the type of extruder or the type of construction of the extruder used. Part of the energy required to melt, mix and dissolve the components in the extruder can be provided by the heating element.
  • Friction and shear of the material in the extruder can also provide a substantial amount of energy to the mixture, helping to form a uniform melt.
  • the extrudate can be realized using a molding module of the extruder, and the extrudate can be cut into pieces before or after curing.
  • the method for preparing the SOMCL-9112 solid dispersion comprises the following steps:
  • the heating temperature in the step (1a) is from 70 ° C to 250 ° C, preferably from 80 ° C to 200 ° C, most preferably from 100 ° C to 180 ° C.
  • the method for preparing the SOMCL-9112 solid dispersion comprises the following steps:
  • a suitable solvent may be selected according to a pharmaceutically acceptable matrix polymer selected from the group consisting of acetone and C. Ketone/dichloromethane, methanol/dichloromethane, acetone/water, acetone/methanol, acetone/ethanol, dichloromethane/ethanol or ethanol/water, etc., wherein "/" means a mixed solvent of the two.
  • the method of evaporating the solvent in the step (2b) includes rotary evaporation, spray drying, lyophilization, and thin film evaporation.
  • solvent removal can be achieved by cryogenic freezing followed by lyophilization.
  • Other techniques such as melt extrusion, solvent controlled precipitation, pH controlled precipitation, and low temperature co-milling can also be used.
  • a further aspect of the invention provides a solid formulation of SOMCL-9112 comprising the SOMCL-9112 solid dispersion and optional pharmaceutical additives.
  • the pharmaceutical additive may be one or more selected from the group consisting of a self-flowing agent, a disintegrating agent, a filler, a lubricant, and a coating agent.
  • the film coating improves the taste and provides a refined appearance.
  • the film coating can be an enteric coating if desired.
  • Film coatings typically comprise polymeric film forming materials such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and acrylate or methacrylate copolymers.
  • the film coating may further comprise a plasticizer such as polyethylene glycol, a surfactant such as Tween, and optionally a pigment such as titanium dioxide or iron oxide.
  • the film coating may also contain talc as an anti-adherent agent.
  • Such additives may comprise from about 0 to about 20% by weight of the total weight of the solid formulation.
  • the film coating of the tablets also contributes to the comfort of swallowing.
  • the present invention also provides a method of preparing the SOMCL-9112 solid preparation, comprising the steps of: treating the SOMCL-9112 solid dispersion with a pharmaceutically acceptable additive to prepare a preparation.
  • the treatment means that the solid dispersion of SOMCL-9112 is made into a powder or granule suitable for formulation, and the treatment includes, for example, pulverization, milling or grinding.
  • the SOMCL-9112 solid preparation may comprise from 2 to 1500 mg of SOMCL-9112.
  • the patient can be an adult or a child, but treatment with other mammals is also contemplated.
  • the pharmaceutically acceptable matrix polymer used is copovidone
  • the SOMCL-9112 solid formulation of the present invention has a higher bioavailability than the formulation obtained in other manners (in these respects)
  • the relative bioavailability of the SOMCL-9112 solid formulation is 724.6% of the nanocrystal suspension (Experimental Example 2)
  • the absolute bioavailability of the SOMCL-9112 solid formulation is 40.2% (Experimental Example 3)
  • Increased bioavailability helps reduce the amount of SOMCL-9112 required to achieve comparable exposures observed with conventional formulations such as SOMCL-9112IR tablets, reducing the effective therapeutic dose of the drug, increasing drug efficacy, and saving drug costs. Reduce the toxic side effects of the drug.
  • the solid preparation of SOMCL-9112 provided by the present invention is a preparation suitable for transmucosal administration to a patient, that is, it can be administered to the mucosa to be absorbed through the membrane.
  • suitable routes of administration include administration by inhalation, as well as oral, intranasal and rectal administration. Oral administration is particularly preferred.
  • the skilled artisan can select a tablet, capsule or other form of preparation depending on the route of administration. However, other routes of administration, such as parenteral, are not excluded.
  • the solid preparation of SOMCL-9112 according to the present invention may be a tablet, a capsule, a granule, a powder or the like.
  • the invention also provides the use of the solid dispersion of SOMCL-9112 in the manufacture of a medicament for the treatment of cancer.
  • SOMCL-9112 has a significant inhibitory effect on poly-ADP-ribose polymerase (PARP), which can be used to prepare drugs for the treatment of cancer, such as breast or ovarian cancer, especially with defective homologous recombination (HR).
  • PARP poly-ADP-ribose polymerase
  • HR homologous recombination
  • DSB DNA double-strand breaks
  • the present invention seeks to increase the bioavailability of SOMCL-9112 in a sufficiently high drug loading formulation.
  • the drug loading amount of the invention can reach 60%, but the larger the drug load, the greater the possibility of instability. Therefore, although a preparation having a drug loading of 60% can be produced, it is preferred to use a lower drug loading amount to maintain stability. .
  • polymer refers to a macromolecule composed of repeating structural units joined by covalent bonds.
  • the term includes both linear and branched polymers, cyclic polymers such as cyclooligosaccharides (including cyclodextrins), homopolymers and copolymers, whether of natural, synthetic or semi-synthetic origin.
  • matrix polymer refers to a material that exhibits low hygroscopicity and high softening temperature, including polymers or blends of two or more polymers.
  • high softening temperature means that the material has a glass transition temperature (Tg) or a melting point (Tm) of >100 ° C as measured by differential scanning calorimetry (DSC), wherein Tg is suitable for an amorphous state or form.
  • Tg glass transition temperature
  • Tm melting point
  • a measure of the polymer, Tm is a measure of the polymer suitable for the crystalline state or form.
  • surfactant refers to a pharmaceutically acceptable surfactant.
  • the formulations of the present invention do not comprise or comprise more than one surfactant having an HLB value of greater than about 4.
  • the HLB system is a numerical property of the surfactant, the lipophilic substance obtains a low HLB value, and the hydrophilic substance obtains a high HLB value.
  • solid dispersion refers to a system in which SOMCL-9112 is dispersed in an excipient carrier.
  • the solid dispersion may include, in this sense, a composition in which the drug is dispersed in a discrete domain of crystalline or amorphous drug or as a separate molecule in an excipient carrier.
  • the solid dispersion may be a relatively large solid material such as pellets, tablets, films or strands; or they may be used as primary or microscale primary particles or A free flowing powder of aggregates is present.
  • the definition of solid dispersion does not include physical mixtures from dry or wet or dry blending operations and simple mixtures of SOMCL-9112 crystals with other excipients.
  • AUC refers to the area under the curve of the drug, using its conventional meaning, i.e., the area under the plasma concentration-time curve from 0 to 24 hours. AUC has a concentration multiplied by the unit of time. Once the test concentration-time point is determined, the AUC can be conveniently calculated, for example, by a computer program or by a trapezoidal method.
  • Figure 1 is an XRPD diffraction pattern of the solid dispersion of SOMCL-9112 prepared in Preparation Example 1 of the present invention for 0 month and accelerated conditions for 6 months.
  • Example 2 is a DSC chart of the SOMCL-9112 solid dispersion prepared in Example 1 of the present invention for 0 month and accelerated conditions for 6 months.
  • FIG. 3 is a particle size diagram of the solid dispersion of SOMCL-9112 prepared in Preparation Example 1 of the present invention after being diluted by simulated gastric juice and simulated intestinal juice, respectively: (A) simulated gastric juice; (B) simulated intestinal fluid.
  • the source and trade name of the reagents and equipment used are indicated on the first occurrence, and the same reagents used thereafter are the same as those indicated for the first time unless otherwise specified.
  • the conventional unlabeled reagents are purchased from Sinopharm Chemical Group Limited. the company. Among them, SOMCL-9112 bulk drug is synthesized by Shanghai Pharmaceutical Research Institute.
  • Experimental animals 6 healthy SD rats, male, weighing 200-220 g; 6 beagle dogs, male, weighing 10-12 kg.
  • the source is the Experimental Animal Center of Shanghai Institute of Materia Medica.
  • the test animals were adapted for feeding at the test site 3-7 days before the test day.
  • copolyvidone (73.5 parts by weight) (N-vinylpyrrolidone / vinyl acetate copolymer weight ratio 60:40, manufactured by BASF, Germany, model: VA64), sodium lauryl sulfate (0.5 parts by weight) (manufactured by Anhui Shanhe Pharmaceutical Excipient Co., Ltd.) and SOMCL-9112 (25.0 parts by weight) and colloidal dioxide Silicon (1.0 parts by weight) (manufactured by Evonik Industries, Germany, model: Aerosil) was mixed, and then the powder mixture was charged into a twin-screw extruder with a screw speed of 100 rpm and a temperature of 170 ° C (screw diameter 11 mm, Thermo Scientific) The mixture was extruded through a screw; the hot melt extruded strip was pulverized and passed through a 60 mesh sieve to obtain a solid dispersion of SOMCL-9112.
  • the XOM ray diffraction and differential scanning calorimetry (DSC) of the SOMCL-9112 solid dispersion powder prepared in this example showed that the drug was dispersed in the carrier material in an amorphous form (0 month), and the accelerated condition (40 ° C ⁇ 2 ° C) , 75% ⁇ 5% RH) X-ray diffraction and DSC results of the solid dispersion powder after standing for 6 months showed that the drug was still dispersed in the carrier material in an amorphous form (Fig. 1, Fig. 2).
  • the SOMCL-9112 solid dispersion powder prepared in this example was respectively added with pH 1.2 simulated gastric juice (containing 2 g of KCl and 7 ml of hydrochloric acid per liter) and pH 6.8 simulated intestinal fluid (containing 6.8 g of potassium dihydrogen phosphate and 0.944 g per liter).
  • pH 1.2 simulated gastric juice containing 2 g of KCl and 7 ml of hydrochloric acid per liter
  • pH 6.8 simulated intestinal fluid containing 6.8 g of potassium dihydrogen phosphate and 0.944 g per liter.
  • the particle size of the formed polymer micelles was determined (Zetasizer Nano ZS laser particle size analyzer, Malvern Instruments, UK), and the average particle size of the product was measured in simulated gastric juice to be 125.5 nm; The average particle size of the product was measured to be 116.9 nm (Fig. 3).
  • the solubility of SOMCL-9112 was determined by taking the SOMCL-9112 solid dispersion prepared in this example and the SOMCL-9112 bulk drug powder in water, pH 1.2 simulated gastric juice, pH 4.5 phosphate buffer solution and pH 6.8 simulated intestinal juice ( The mixture was shaken at 37 ° C and 100 rpm for 8 h), and the solid dispersion group was sampled at 4 h and 8 h.
  • the measurement results are shown in Table 1. This example shows that the solid dispersion of SOMCL-9112 prepared by the present invention can significantly improve the solubility of SOMCL-9112, and the drug can maintain good solubility at 8h, which can effectively prevent drug precipitation and ensure effective absorption of the drug in the body.
  • the solid dispersion powder prepared in this example was placed in an accelerated condition (40 ° C ⁇ 2 ° C, 75% ⁇ 5% RH) for 6 months, and the solubility was measured (37 ° C, shaking at 100 rpm for 8 h), and the solubility in water was 453.1 ⁇ g /
  • the solubility in the above-mentioned pH 1.2 simulated gastric juice was 430.4 ⁇ g/ml; the solubility in the above pH 4.5 phosphate buffer was 312.6 ⁇ g/ml; and the solubility in the above simulated pH 6.8 was 418.3 ⁇ g/ml. It is shown that the solid dispersion of the present invention still has a good mashing action on SOMCL-9112 after the accelerated condition is placed for 6 months.
  • the solid dispersion prepared in this example was excellent in stability according to the above powder X-ray diffraction, DSC results, and solubility measurement results.
  • Preparation method polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (70.0 parts by weight) (Soluplus, manufactured by BASF, Germany), Cremerphor RH40 (4.0 parts by weight) (manufactured by BASF, Germany) and SOMCL - 9112 (25.0 parts by weight) and colloidal silica (1.0 parts by weight) were mixed, and then the powdery mixture was charged into a twin-screw extruder (screw diameter: 11 mm) at an extrusion speed of 150 rpm and a temperature of 160 ° C, and the mixture was subjected to a mixture. The screw was extruded in strips; the hot melt extruded strip was pulverized and passed through a 60 mesh sieve to obtain a solid dispersion of SOMCL-9112.
  • the SOMCL-9112 solid dispersion prepared in this example was used to determine the solubility of SOMCL-9112 in water, pH 1.2 simulated gastric juice, pH 4.5 phosphate buffer and pH 6.8 simulated intestinal fluid (37 ° C, 100 rpm shaking for 8 h). ).
  • the solubility of SOMCL-9112 solid dispersion in water was determined to be 421.7 ⁇ g/ml, the solubility in simulated gastric juice at pH 1.2 was 411.4 ⁇ g/ml, and the solubility in pH 4.5 phosphate buffer was 308.5 ⁇ g/ml.
  • the solubility in the simulated intestinal juice at pH 6.8 was 403.1 ⁇ g/ml.
  • This example shows that the preparation of a solid dispersion of SOMCL-9112 can significantly increase the solubility of SOMCL-9112.
  • Preparation method Hydroxypropylmethylcellulose acetate succinate (64.0 parts by weight) (HPMCAS, manufactured by Shin-Etsu Chemical Co., Ltd.), sodium lauryl sulfate (2.0 parts by weight) (manufactured by BASF, Germany), lemon Triethyl ethoxide (3.0 parts by weight) (Anhui Fengyuan Pharmaceutical Co., Ltd.) was mixed with SOMCL-9112 (30.0 parts by weight) and colloidal silica (1.0 parts by weight), and then the powder mixture was squeezed A twin-screw extruder with a rotation speed of 100 rpm and a temperature of 140 ° C (screw diameter: 11 mm), and the mixture was extruded through a screw; the hot melt extruded strip was pulverized and passed through a 60 mesh sieve to obtain SOMCL-9112. Solid dispersion.
  • HPMCAS Hydroxypropylmethylcellulose acetate succinate
  • sodium lauryl sulfate 2.0 parts
  • the solid dispersion of SOMCL-9112 prepared in this example was used to determine the solubility of SOMCL-9112 in simulated intestinal juice at pH 6.8 (37 ° C, shaking at 100 rpm for 8 h), and the solid dispersion of SOMCL-9112 was determined to simulate intestinal fluid at pH 6.8.
  • the solubility in the solution was 379.4 ⁇ g/ml. This example shows that the preparation of a solid dispersion of SOMCL-9112 can significantly increase the solubility of SOMCL-9112.
  • Preparation method copolyvidone (N-vinylpyrrolidone / vinyl acetate copolymer weight ratio of 60:40) (70.0 parts by weight) and SOMCL-9112 (30.0 parts by weight) dissolved in acetone / ethanol (volume ratio of 4:1)
  • a mixed solvent the solvent is then evaporated on a rotary evaporator at 30 ° C, and the obtained material is dried in a vacuum oven at 40 ° C for more than 12 hours to remove residual organic solvent, and the obtained solid material is pulverized and passed through a 60 mesh sieve.
  • a solid dispersion of SOMCL-9112 was obtained.
  • the SOMCL-9112 solid dispersion prepared in this example was used to determine the solubility of SOMCL-9112 in water, pH 1.2 simulated gastric juice, pH 4.5 phosphate buffer and pH 6.8 simulated intestinal fluid (37 ° C, 100 rpm shaking for 8 h). ).
  • the solubility of SOMCL-9112 solid dispersion in water was determined to be 463.5 ⁇ g/ml, the solubility in simulated gastric juice at pH 1.2 was 425.7 ⁇ g/ml, and the solubility in pH 4.5 phosphate buffer was 321.6 ⁇ g/ml.
  • the solubility in the simulated intestinal juice at pH 6.8 was 422.6 ⁇ g/ml.
  • This example shows that the preparation of a solid dispersion of SOMCL-9112 can significantly increase the solubility of SOMCL-9112.
  • the solubility of SOMCL9112 in a range of solvents include water, pH 1.2 simulated gastric juice, pH 4.5 phosphate buffer, pH 6.8 simulated intestinal juice, and about 0.5 g of SOMCL-9112 API. 100 ml of each of the above solvents was added, and the mixture was shaken at 37 ° C for 100 hours at 100 rpm, and the supernatant was centrifuged at 8000 rpm for 15 minutes, and the concentration of SOMCL-9112 was determined by HPLC. The solubility of SOMCL-9112 in different media is shown in Table 2.
  • Permeability study The permeability of SOMCL-9112 was evaluated using a Caco-2 cell model.
  • the results are shown in Table 3.
  • SOMCL-9112 has a low permeability characteristic and has a significant efflux effect on Caco-2 cells in the range of 2.00-50.0 ⁇ M.
  • the extracted sample was diluted 4 times and then irradiated by ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IVA), the absorbance was measured at the wavelength of 240 nm, the dissolution amount of the corresponding preparation was calculated, and the dissolution curve was drawn (see Fig. 4). ).
  • the SOMCL-9112 solid preparation prepared in the preparation examples 5, 6, and 7 of the present invention can significantly improve the dissolution rate and solubility of SOMCL-9112 compared with the conventional IR preparation, and the dissolution behavior of the preparation of the present invention does not occur after the accelerated condition is placed. Significantly changed, the drug is well soluble and has good stability.
  • Preparation Example 1 The sample administration method was carried out by suspending purified water to a solution containing 2 mg/ml of SOMCL-9112 immediately before use, and each preparation was administered at a dose of 20 mg/kg. Fasting for 12 hours before the test, free to drink water. Uniformly eaten 2 hours after administration.
  • venous blood was taken from the posterior venous plexus of rats before administration (0 h) and 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 24 h after administration, placed in heparinized tubes, centrifuged at 11,000 rpm for 5 min. Plasma was separated and stored frozen in a refrigerator at –20 °C for testing.
  • the concentration of SOMCL-9112 in the sample was determined by LC-MS.
  • the pharmacokinetic parameters of SOMCL-9112 after administration of SD rats were calculated using the non-compartmental model of Phoenix 1.3 software (Pharsight, USA). The data is summarized in Table 4.
  • the preparation prepared by the present invention can significantly increase the exposure of SOMCL-9112 in SD rats compared with the nanocrystalline preparation of SOMCL-9112, and can significantly improve the relative bioavailability of SOMCL-9112.
  • the preparation amount of the preparation example 5 was 100 mg/mouse. Fasting for 12 hours before the test, food supply after 4 weeks of administration, the whole test process can not be prohibited.
  • These preparations were administered with 30 ml of water. Blood samples were taken 0.8 ml before administration (0 h) and 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 h after administration; in heparin anticoagulation tubes, centrifuged at 3500 rpm for 10 min, plasma was separated, – Store in a 70 ° C freezer for testing.
  • 0.8 ml of blood samples were taken before administration (0h) and 5 minutes after administration, 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24h, placed in heparin anticoagulation tubes, centrifuged at 3500 rpm for 10 min, and plasma was separated. Store in a freezer at -70 °C for testing.
  • the concentration of SOMCL-9112 in the sample was determined by LC-MS.
  • the pharmacokinetic parameters of SOMCL-9112 after Beagle administration were calculated using the non-compartmental model of Phoenix 1.3 software (Pharsight, USA). The data is summarized in Table 5.

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Abstract

本发明公开了一种SOMCL-9112固体分散体，其特征在于，包括下述原料，按重量百分比制成：SOMCL-9112 5%～60%，可药用基质聚合物5%-90%，表明活性剂0%～20%，助流剂0%～20%，增塑剂0%～20%。本发明还公开了其制备方法、包含所述固体分散体的固体药物制剂以及所述固体分散体用于制备治疗癌症的药物的用途。

Description

SOMCL-9112固体分散体、其制备方法及包含其的SOMCL-9112固体制剂 技术领域
本发明属于药物制剂领域，涉及一种SOMCL-9112固体分散体、其制备方法、包含所述固体分散体的固体药物制剂以及所述固体分散体用于制备治疗癌症的药物的用途。
背景技术
SOMCL-9112，化学名称为4-(4-氟-3-(5-甲基-3-(三氟甲基)-5,6,7,8-4H-[1,2,4]三唑并[4,3-a]哌嗪-7-羰基)苄基)酞嗪-1(2H)-酮，分子式：C23H18F4N6O2，分子量：486.4，具有下述化学结构：
Figure PCTCN2016082044-appb-000001
在CN103833756A及PCT/CN2013/079998中公开和列举了SOMCL-9112和其用途，SOMCL-9112在前期研究中作为新型高选择性聚腺苷二磷酸核糖聚合酶-1(PARP1)抑制剂在治疗与PARP相关的疾病中的用途，尤其是治疗癌症，如乳腺癌、胰腺癌、卵巢癌等。
SOMCL-9112特别有效地治疗其细胞在同源重组(HR)依赖性DNA双链断裂(DSB)修复通路中有缺陷的癌症。BRCA1(NM_007295)和BRCA2(NM_000059)遗传乳腺癌/卵巢癌基因仅是HR依赖性DNA DSB修复通路众多蛋白质中的两种。用PARP抑制剂治疗brca1-/-和/或brca2-/-型乳腺癌或卵巢癌可比没有缺陷性同源重组(HR)依赖性DNA双链断裂(DSB)修复通路的癌症疗效更好；可能实现有效的单药治疗和/或联合治疗。
SOMCL-9112在pH1.2～6.8缓冲盐水溶液中平衡溶解度低于0.10mg/ml，为水难溶性药物。当使用Caco-2细胞系研究时，SOMCL-9112与低渗透性阳性对照阿替洛尔的渗透系数相当，Caco-2Papp值为0.72×10-6cm/s(参见实验实施例1)。根据药物的溶解度和渗透量测量结果预测，SOMCL-9112在体内吸收差，生物利用度低。患者口服SOMCL-9112的生物利用度在一定程度上取决于该药物在GI肠道中的溶出率和溶解度。通过测定SOMCL-9112血浆中药物浓度并计算药时曲线下面积可评估不同制剂给药后SOMCL-9112的生物利用度。在大鼠PK试验中，SOMCL-9112纳米晶制剂的体内暴露量极低(参见实验实施例2)，给药后24h药时曲线下面积仅为126h*ng/ml，影响药物正常疗效的发挥，因此对提高SOMCL-9112的生物利用度进行了研究。
目前，将难溶性药物进行前药修饰，制成盐以被广泛应用于提高其溶解度与生物利用度。但上述方法存在一定的局限性，如操作复杂，中间产物多，成本高等，难以实现大规模的工业化生产。1961年Sekiguchi等首次将固体分散体技术应用于提高难溶性药物的溶解度和生物利用度，诸多药剂研究者对固体分散体进行了广泛而深入的研究，进一步证明将难溶性药物制成固体分散体是提高其溶解度和生物利用度最具开发潜力的方法之一，目前采用固体分散体技术制备的药物制剂已有商业化先例如Kaletra(洛匹那韦/利托那韦)。
发明内容
本发明开发了一种具有高生物利用度的SOMCL-9112药物制剂，在实现充足药物载量和稳定性的前提下满足临床给药的需求。本发明中SOMCL-9112固体分散体在模拟胃肠液中可形成稳定的平均粒径～100nm的混合型胶束，可将SOMCL-9112溶解度由～10μg/ml提升至大于300μg/ml，通过胶束増溶原理提高药物溶解度和防止药物沉淀进而提高药物的生物利用度。提高的生物利用度有助于降低取得使用常规制剂观察到的相当暴露量的SOMCL-9112所需的剂量，可降低药物有效治疗剂量、提高药物疗效，节约药物成本、减少药物的毒副作用。
根据本发明的第一个方面，提供了一种SOMCL-9112固体分散体，其包括下述原料，按重量百分比制成：
Figure PCTCN2016082044-appb-000002
本发明提供的SOMCL-9112固体分散体中，以非晶形式存在的SOMCL-9112在SOMCL-9112中所占的比例范围为70％～100％，优选80％以上，更优选90％以上，再优选95％以上，最优选SOMCL-9112大体上全部以非晶形式存在。该SOMCL-9112固体分散体可以以非晶形式稳定其中的SOMCL-9112并可以降低SOMCL-9112转化或逆转成其它形式的可能。本发明提供的SOMCL-9112固体分散体可克服常规固体分散体物理稳定性差，易老化的缺点。在本发明的一个实施例中，SOMCL-9112和可药用基质聚合物制备的固体分散体在加速条件下放置6个月后药物仍为稳定的非晶形式，稳定性良好。
所述可药用基质聚合物具有至少约50℃的Tg，可为选自共聚维酮、聚维酮、羟丙基 甲基纤维素邻苯二甲酸酯(HPMPCP)、醋酸羟丙基甲基纤维素琥珀酸酯(HPMCAS)、2-羟基-β-环糊精(HPBCD)、羟丙基甲基纤维素(羟丙甲纤维素、HPMC)、聚甲基丙烯酸酯、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(Soluplus)、羟丙基纤维素(HPC)和醋酸邻苯二甲酸纤维素(CAP)中的一种或多种，优选为选自共聚维酮、Soluplus和醋酸羟丙基甲基纤维素琥珀酸酯中的一种或多种。共聚维酮为水溶性有机高分子化合物，是N-乙烯基吡咯烷酮(NVP)与醋酸乙烯酯(VA)的线型共聚物。其中，VA含量标称为约40％(但可能不同，例如35～41％)。其平均分子量(Mw)为24 000至30 000。
进一步优选的，SOMCL-9112与可药用基质聚合物重量比为1：0.25～1：10，优选为1：0.3～1：7，更优选为1：0.5～1：5，更优选为1：2～1：4。
本发明中，所述表面活性剂可进一步增强本发明固体分散体的治疗潜力的提高。合适的表面活性剂包括：阴离子型表面活性剂，如十二烷基硫酸钠(月桂基硫酸钠)、多库酯钠；阳离子型表面活性剂，如溴棕三甲铵、苄索氯铵、十六烷基氯化吡啶鎓和月桂酸；非离子型表面活性剂，如聚氧乙烯烷基醚、聚氧乙烯山梨糖醇酐脂肪酸酯(具体如吐温80、60、40和20)、聚氧乙烯蓖麻油衍生物(具体如Cremophor RH40)、聚氧乙烯硬脂酸酯和泊洛沙姆；优选为十二烷基硫酸钠。
所述助流剂为选自胶态二氧化硅、动物或植物脂肪、蜡等中的一种或多种。
增塑剂的存在可提高该固体分散体的可加工性。合适的增塑剂为选自柠檬酸乙酰三丁酯、柠檬酸乙酰三乙酯、苯甲酸苄酯、三氯叔丁醇、糊精、邻苯二甲酸二丁酯、邻苯二甲酸二乙酯、邻苯二甲酸二甲酯、甘油、单硬脂酸甘油酯、甘露醇、矿物油、羊毛脂醇、棕榈酸、聚乙二醇、聚乙酸邻苯二甲酸乙烯酯、丙二醇、2-吡咯烷酮、山梨糖醇、硬脂酸、三醋精、柠檬酸三丁酯、三乙醇胺和柠檬酸三乙酯中的一种或多种。
本发明的固体分散体中根据需要还可以包含其他添加剂，例如润滑剂、填充剂、崩解剂、稳定剂(例如抗氧剂、光稳定剂、自由基清除剂、对抗微生物攻击的稳定剂等)等。所述其他添加剂的具体选择范围和用量是本领域技术人员的常规选择。
崩解剂促进固体制剂在胃中快速崩解，并保持释放出的颗粒彼此分隔。适宜的崩解剂包括交联聚合物，例如交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮(即交联聚维酮PVPP)。
适宜的填充剂为选自乳糖、蔗糖、甘露醇、磷酸氢钙、微晶纤维素、淀粉、异麦芽糖等中的一种或多种。
适宜的润滑剂为选自聚乙二醇(例如分子量为1000至6000)、硬脂酸镁、硬脂酸钙、硬脂酰富马酸钠等中的一种或多种。
本发明提供的SOMCL-9112固体分散体在模拟胃肠液中可形成稳定的平均粒径～ 100nm的混合型胶束，可将SOMCL-9112溶解度由～10μg/ml提升至大于300μg/ml。较普通固体分散体而言，形成的混合型胶束可通过胶束増溶原理在增加药物溶解度的同时避免药物沉淀，克服了普通固体分散体药物容易沉淀的缺点。本发明所提供的固体分散体可通过提高药物溶解度和防止药物沉淀，提高药物的生物利用度。
本发明的另一方面提供了上述SOMCL-9112固体分散体的制备方法，包括如下步骤：
(1)通过熔解或溶解将原料均匀混合，得到均匀分散体；
(2)使均匀分散体固化以得到SOMCL-9112以非晶形式存在的SOMCL-9112固体分散体。
上述SOMCL-9112固体分散体的制备方法可以采用溶剂蒸发法或熔体挤出法，优选熔体挤出法。
所述熔体挤出法是通过施加热和/或机械应力来制造熔体，“熔体”指液体状态或似橡胶状态，其中可能一组分均匀包埋于其它组分中。一般，一种组分熔化，其它组分溶于熔化物中，形成熔体。形成熔体通常涉及药用基质聚合物的软化点，熔体的制备可通过多种方法来发生。在熔体形成之前、形成期间或形成之后可进行组分的混合。例如，首先进行组分的混合，然后加热或同时混合和加热。通常，熔体中活性物质应均匀分散，熔体呈糊状或粘稠状。通常，加热温度为70℃-250℃，优选80℃-200℃，最优选为100℃-180℃。
使用熔体挤出法，步骤(1)、(2)中该熔体产生、挤出可在用于该目的的常规装置中进行。特别适合的是挤压机和捏合机。适宜的挤压机可以以杆式挤出，包括单螺杆挤压机、双螺杆挤压机或其它多螺杆挤压机，优选双螺杆挤压机，其可以顺转或逆转，并任意地装有捏合盘。应该理解，工作温度也将由挤压机类型或所使用的挤压机的构造类型来决定。在挤压机中组分的熔化、混合和溶解所需要的部分能量可通过加热元件来提供。挤压机中材料的摩擦和剪切也可给混合物提供大量的能量，帮助组分均匀熔体的形成。挤出物可利用挤压机的成型模块实现，在固化前或固化后挤出物可切成块。
在一个实施方式中，所述SOMCL-9112固体分散体的制备方法，包括如下步骤：
(1a)将原料混合，加热以产生熔体；
(2a)挤出该熔体以固化产生SOMCL-9112固体分散体。
步骤(1a)所述加热温度为70℃-250℃，优选80℃-200℃，最优选为100℃-180℃。
在另一实施方式中，所述SOMCL-9112固体分散体的制备方法，包括如下步骤：
(1b)将原料溶解于溶剂中；
(2b)蒸发溶剂以产生SOMCL-9112以非晶形式存在的SOMCL-9112固体分散体。
步骤(1b)中可以根据可药用基质聚合物来选择适合的溶剂，所述溶剂选自丙酮、丙 酮/二氯甲烷、甲醇/二氯甲烷、丙酮/水、丙酮/甲醇、丙酮/乙醇、二氯甲烷/乙醇或乙醇/水等，其中，“/”表示二者的混合溶剂。
步骤(2b)中蒸发溶剂的方法包括旋转蒸发、喷雾干燥、冻干和薄膜蒸发。或者，可以通过低温冰冻接着冻干来实现除去溶剂。也可以使用其它技术，如熔体挤出、溶剂控制的沉淀、pH控制的沉淀和低温共研磨等。
本发明的再一方面提供了一种SOMCL-9112固体制剂，其包括所述SOMCL-9112固体分散体和非必需的药用添加剂。
所述药用添加剂可以为选自助流剂、崩解剂、填充剂、润滑剂和包衣剂等中的一种或多种。
所述助流剂、崩解剂、填充剂和润滑剂的描述与前述相同。
膜包衣可改善味道和提供精致的外观。如果需要，膜包衣可以是肠溶包衣。膜包衣通常包含聚合成膜材料，例如羟丙甲基纤维素、羟丙基纤维素和丙烯酸酯或甲基丙烯酸酯共聚物。除成膜聚合物外，膜包衣还可包含增塑剂如聚乙二醇，表面活性剂例如吐温类，以及任选的颜料例如二氧化钛或铁氧化物。膜包衣也可包含作为抗粘剂的滑石粉。此类添加剂可占固体制剂总重量大约0到大约20％。片剂的膜包衣还可助于可吞咽的舒适性。
本发明还提供了制备所述SOMCL-9112固体制剂的方法，包括如下步骤：将该SOMCL-9112固体分散体处理后与药用添加剂混合，制成制剂。
所述处理是指，将SOMCL-9112固体分散体制成适合制成制剂的粉末或颗粒，处理的方法包括例如粉碎、碾磨或研磨。
所述SOMCL-9112固体制剂可包含2至1500mg SOMCL-9112。患者可以是成年人或儿童，但也预期其它哺乳动物的治疗。在这些方面的一个实施例中，所用可药用基质聚合物是共聚维酮，本发明的SOMCL-9112固体分制剂与其它方式获得的制剂相比具有更高的生物利用度(在这些方面的一个实施例中，SOMCL-9112固体制剂的相对生物利用度是纳米晶混悬液的724.6％(实验实施例2)，SOMCL-9112固体制剂的绝对生物利用度是40.2％(实验实施例3)。提高的生物利用度有助于降低取得使用常规制剂如SOMCL-9112IR片剂观察到的相当暴露量的SOMCL-9112所需的剂量，可降低药物有效治疗剂量、提高药物疗效，节约药物成本、减少药物的毒副作用。
本发明提供的SOMCL-9112固体制剂是适合经粘膜给药于患者的制剂，即可给药于粘膜以透膜吸收。为此，合适的给药途径包括通过吸入给药，以及口服、鼻内和直肠给药。特别优选口服给药。技术人员可根据给药途径选择片剂、胶囊剂或其它制剂形式。但是，不排除其它给药途径，例如肠道外。
例如，根据本发明的SOMCL-9112固体制剂可以为片剂、胶囊剂、颗粒剂、散剂等。
本发明还提供了所述SOMCL-9112的固体分散体在制备治疗癌症的药物中的用途。
SOMCL-9112对聚-ADP-核糖聚合酶(PARP)具有显著抑制作用，这种作用可用于制备治疗癌症的药物，例如乳腺癌或卵巢癌，特别是具有缺陷性同源重组(HR)依赖性DNA双链断裂(DSB)修复通路的癌症，如brca1-/-和/或brca2-/-癌症。
考虑到提高SOMCL-9112治疗潜力的目的，本发明试图实现在足够高载药量制剂中提高SOMCL-9112的生物利用度。本发明载药量可达60％，但药物载量越大，不稳定的可能性越大，因此，尽管可以产生具有60％药物载量的制剂，优选采用较低载药量以保持稳定性。
本文所用术语“聚合物”是指由通过共价键连接的重复结构单元构成的大分子。该术语包括线型和支化聚合物、环状聚合物，如环寡糖(包括环糊精)、均聚物和共聚物，无论是天然、合成还是半合成来源的。
本文所用术语“基质聚合物”是指表现出低吸湿性和高软化温度的材料，包括聚合物或两种或更多聚合物的共混物。
本文所用术语“高软化温度”是指材料通过差式扫描量热法(DSC)测得玻璃态转化温度(Tg)或熔点(Tm)＞100℃，其中，Tg是适合非晶状态或形式的聚合物的量度，Tm是适合结晶状态或形式的聚合物的量度。
本文所用术语“表面活性剂”是指可药用的表面活性剂。本发明的制剂不包含或包含一种以上HLB值约大于4的表面活性剂。HLB系统是表面活性剂的数值属性，亲脂性物质获得低HLB值，亲水性物质获得高HLB值。
本文所用术语“固体分散体”是指将SOMCL-9112分散在赋形剂载体中的体系。就该体系中的药物状态而言，固体分散体在这种意义上可包括其中药物以结晶或非结晶药物的离散域或以独立分子分散在赋形剂载体内的组合物。就整个药物-赋形剂复合物而言，固体分散体可以是相对较大的固体物质，如丸粒、片剂、薄膜或条束；或它们可作为由微米级或纳米级初级粒子或其聚集体构成的自由流动粉末存在。本发明中，固体分散体的定义不包括来自干混或湿混或干掺合操作的物理混合物以及SOMCL-9112晶体与其它辅料的简单混合物。
本文所用术语“AUC”是指药时曲线下面积，使用其常规含义，即，如从0至24小时的血浆浓度-时间曲线下的面积。AUC具有浓度乘以时间的单位。一旦确定了试验浓度-时间点，即可方便的计算AUC，例如通过计算机程序或通过梯形法计算。
附图说明
图1是本发明制备实施例1制备的SOMCL-9112固体分散体0月及加速条件6月的XRPD衍射图。
图2是本发明制备实施例1制备的SOMCL-9112固体分散体0月及加速条件6月的DSC图。
图3是本发明制备实施例1制备的SOMCL-9112固体分散体分别经模拟胃液和模拟肠液稀释后的粒径图：(A)模拟胃液；(B)模拟肠液。
图4是本发明制备实施例5、6、7和对比实施例1制备的各种SOMCL-9112制剂的体外溶出(n＝6)。
图5是本发明制备实施例5、6、7制备的各种SOMCL-9112制剂加速条件放置6月后的体外溶出与0月体外溶出对比图(n＝6)。
具体实施方式
下面结合具体的实施例，并参照数据进一步详述本发明。应理解，这些实施例只是为了举例说明本发明，旨在说明本发明的具体配方组成、制备方法及其功能和效果，而非以任何方式限制本发明的范围。在以下实施例中，未详细描述的各种过程和方法是本领域中公知的常规方法。
本发明中，所用试剂、设备的来源和商品名，均在首次出现时标明，其后所用相同试剂如无特殊说明，均与首次标明的内容相同，常规未标注试剂购自国药集团化学试剂有限公司。其中，SOMCL-9112原料药由上海药物研究所自行合成。
实验动物：健康SD大鼠6只，雄性，体重200-220g；比格犬6只，雄性，体重10～12kg。来源均为上海药物研究所实验动物中心。受试动物在试验日前3-7天均在试验场所进行适应性饲养。
制备实施例
制备实施例1
处方1：
Figure PCTCN2016082044-appb-000003
制备方法：将共聚维酮(73.5份重量)(N-乙烯基吡咯烷酮/醋酸乙烯酯共聚物重量比 60：40，德国巴斯夫公司制造，型号：VA64)、十二烷基硫酸钠(0.5份重量)(安徽山河药用辅料股份有限公司制造)与SOMCL-9112(25.0重量份)和胶态二氧化硅(1.0重量份)(德国赢创工业集团制造，型号：Aerosil)混合，然后将该粉末状混合物装入挤出转速100rpm和温度170℃的双螺杆挤出机(螺杆直径11mm，Thermo Scientific公司)，混合物经螺杆呈条状挤出；将热熔挤出的条状物经粉碎处理后过60目筛，得到SOMCL-9112固体分散体。
本实施例制备得到的SOMCL-9112固体分散体粉末X射线衍射和差式扫描量热分析(DSC)显示药物以非晶形式分散在载体材料中(0月)，加速条件(40℃±2℃、75％±5％RH)6月放置后固体分散体粉末X射线衍射和DSC结果显示药物仍以非晶形式分散在载体材料中(图1、图2)。
取本实施例制得的SOMCL-9112固体分散体粉末分别加pH1.2模拟胃液(每升含2g KCl和7ml盐酸)和pH6.8模拟肠液(每升含6.8g磷酸二氢钾和0.944g氢氧化钠)溶解后测定所形成聚合物胶束的粒径(Zetasizer Nano ZS激光粒度仪，英国马尔文仪器有限公司)，在模拟胃液中测得本品平均粒径为125.5nm；在模拟肠液中测得本品平均粒径为116.9nm(图3)。
取本实施例制得的SOMCL-9112固体分散体和SOMCL-9112原料药粉末于水、pH1.2模拟胃液、pH4.5磷酸盐缓冲液和pH6.8模拟肠液中测定SOMCL-9112的溶解度(37℃、100rpm振摇8h)，其中，固体分散体组于4h、8h取样，测定结果见表1。该实施例显示本发明制备的SOMCL-9112固体分散体可显著提高SOMCL-9112的溶解度，并且药物在8h时仍可保持良好的溶解度，可有效防止药物沉淀，确保药物在体内有效吸收。
表1 SOMCL-9112原料药及固体分散体溶解度测定
Figure PCTCN2016082044-appb-000004
1每升含2g氯化钾和7ml盐酸
2每升含12.9g柠檬酸和0.63g磷酸氢二钠
3每升含6.8g磷酸二氢钾和0.944g氢氧化钠
将本实施例制备的固体分散体粉末于加速条件(40℃±2℃、75％±5％RH)6月放置后测定溶解度(37℃、100rpm振摇8h)，在水中溶解度为453.1μg/ml；在上述pH1.2模拟胃液中溶解度为430.4μg/ml；在上述pH4.5磷酸盐缓冲液中溶解度为312.6μg/ml；在上述pH6.8模拟肠液中溶解度为418.3μg/ml。表明加速条件放置6月后，本发明的固体分散体对SOMCL-9112仍有良好的増溶作用。
根据上述粉末X射线衍射、DSC结果和溶解度测定结果，本实施例制备的固体分散体稳定性良好。
制备实施例2
处方2：
Figure PCTCN2016082044-appb-000005
制备方法：将聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(70.0份重量)(Soluplus，德国巴斯夫公司制造)、Cremerphor RH40(4.0份重量)(德国巴斯夫公司制造)与SOMCL-9112(25.0重量份)和胶态二氧化硅(1.0重量份)混合，然后将该粉末状混合物装入挤出转速150rpm和温度160℃的双螺杆挤出机(螺杆直径11mm)，混合物经螺杆呈条状挤出；将热熔挤出的条状物经粉碎处理后过60目筛，得到SOMCL-9112固体分散体。
取本实施例制得的SOMCL-9112固体分散体于水、pH1.2模拟胃液、pH4.5磷酸盐缓冲液和pH6.8模拟肠液中测定SOMCL-9112的溶解度(37℃、100rpm振摇8h)。经测定SOMCL-9112固体分散体在水中的溶解度为421.7μg/ml，在pH1.2模拟胃液中的溶解度为411.4μg/ml，在pH4.5磷酸盐缓冲液中的溶解度为308.5μg/ml，在pH6.8模拟肠液中的溶解度为403.1μg/ml。该实施例显示制备SOMCL-9112固体分散体可显著提高SOMCL-9112的溶解度。
制备实施例3
处方3：
Figure PCTCN2016082044-appb-000006
Figure PCTCN2016082044-appb-000007
制备方法：将醋酸羟丙基甲基纤维素琥珀酸酯(64.0份重量)(HPMCAS，日本信越化学株式会社制造)、十二烷基硫酸钠(2.0份重量)(德国巴斯夫公司制造)、柠檬酸三乙酯(3.0份重量)(安徽丰原药业股份有限公司)与SOMCL-9112(30.0重量份)和胶态二氧化硅(1.0重量份)混合，然后将该粉末状混合物装入挤出转速100rpm和温度140℃的双螺杆挤出机(螺杆直径11mm)，混合物经螺杆呈条状挤出；将热熔挤出的条状物经粉碎处理后过60目筛，得到SOMCL-9112固体分散体。
取本实施例制得的SOMCL-9112固体分散体于pH6.8模拟肠液中测定SOMCL-9112的溶解度(37℃、100rpm振摇8h)，经测定SOMCL-9112固体分散体在pH6.8模拟肠液中的溶解度为379.4μg/ml。该实施例显示制备SOMCL-9112固体分散体可显著提高SOMCL-9112的溶解度。
制备实施例4
处方4：
Figure PCTCN2016082044-appb-000008
制备方法：将共聚维酮(N-乙烯基吡咯烷酮/醋酸乙烯酯共聚物重量比60：40)(70.0份重量)与SOMCL-9112(30.0重量份)溶解于丙酮/乙醇(体积比4：1)混合溶剂中，然后将该溶剂用旋转蒸发仪于30℃挥干，将所得物质于40℃真空干燥箱干燥12h以上挥去残留有机溶剂，将所得固体物质经粉碎处理后过60目筛，得到SOMCL-9112固体分散体。
取本实施例制得的SOMCL-9112固体分散体于水、pH1.2模拟胃液、pH4.5磷酸盐缓冲液和pH6.8模拟肠液中测定SOMCL-9112的溶解度(37℃、100rpm振摇8h)。经测定SOMCL-9112固体分散体在水中的溶解度为463.5μg/ml，在pH1.2模拟胃液中的溶解度为425.7μg/ml，在pH4.5磷酸盐缓冲液中的溶解度为321.6μg/ml，在pH6.8模拟肠液中的溶解度为422.6μg/ml。该实施例显示制备SOMCL-9112固体分散体可显著提高SOMCL-9112的溶解度。
制备实施例5
取制备实施例1所得的SOMCL-9112固体分散体(80.0份重量)，与甘露醇(14.2份重量)(法国罗盖特公司制造)、交联聚维酮(4.8份重量)(PVPP，美国国际特品公司制造)和硬脂富马酸钠(1.0份重量)(德国JRS集团药用辅料公司制造)混合均匀，采用单冲压片机压制成500.0mg的片剂。然后将药片置于包衣锅中，于60℃温度下用薄膜包衣用水性分散液(Opadry，上海卡乐康包衣技术有限公司制造)对药片进行薄膜包衣。
制备实施例6
取制备实施例2所得的SOMCL-9112固体分散体(80.0份重量)，与微晶纤维素(13.8份重量)(台湾名台化工股份有限公司制造)、十二烷基硫酸钠(1.2份重量)、交联羧甲基纤维素钠(4.0份重量)(德国JRS集团药用辅料公司制造)和硬脂酸镁(1.0份重量)(安徽山河药用股份有限公司制造)混合均匀，采用单冲压片机压制成250.0mg的片剂。然后将药片置于包衣锅中，于60℃温度下用薄膜包衣用水性分散液(Opadry，上海卡乐康包衣技术有限公司制造)对药片进行薄膜包衣。
制备实施例7
取制备实施例3所得的SOMCL-9112固体分散体(66.7份重量)，与乳糖(26.3份重量)(荷兰DFE Pharma公司制造)、交联聚维酮(6.0份重量)和硬脂酸镁(1.0份重量)混合均匀，采用填充式胶囊灌装机以1#胶囊按250mg/粒灌装胶囊。
对比实施例
对比实施例1
取SOMCL-9112原料药(20.0份重量)，与聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(Soluplus，56.0份重量)、微晶纤维素(13.8份重量)、十二烷基硫酸钠(2.4份重量)、胶态二氧化硅(0.8份重量)、交联聚维酮(6.0份重量)和硬脂酸镁(1.0份重量)混合均匀，采用单冲压片机压制成250.0mg的常规IR片剂。然后将药片置于包衣锅中，于60℃温度下用薄膜包衣用水性分散液(Opadry，上海卡乐康包衣技术有限公司制造)对药片进行薄膜包衣。
对比实施例2
取SOMCL-9112原料药(0.5份重量)分散在0.2％泊洛沙姆407(99.5份重量)(德国巴斯夫公司制造)溶液中，高剪切3min，再采用微射流均质机Nano DB在20000PSI压力下均质10min(gap D8)，即制得平均粒径为359nm的纳米晶体混悬液
对比实施例3
取SOMCL-9112原料药(1.0份重量)，与丙二醇(25.0份重量)(美国陶氏化学公司 制造)、MCT(15.0份重量)(铁岭北亚药用油有限公司制造)和Solutol HS15(59.0份重量)(德国巴斯夫公司制造)置适宜容器中，在50～70℃下以300rpm速度搅拌至SOMCL-9112完全溶解，即得含SOMCL-9112浓度为10mg/ml(1％重量百分比)的SOMCL-9112液体制剂。
实验实施例
实验实施例1
平衡溶解度及渗透率考察
平衡溶解度考察：考察SOMCL9112原料在一系列溶剂中的溶解度，主要溶剂包括水、pH1.2模拟胃液、pH4.5磷酸盐缓冲液、pH6.8模拟肠液，取SOMCL-9112原料药约0.5g，加入上述溶剂各100ml，于37℃摇床100rpm振摇24h，取上清液以8000rpm离心15min后以HPLC测定SOMCL-9112的浓度。SOMCL-9112在不同介质中的溶解度见表2。
表2 SOMCL-9112在不同溶剂中的溶解度
溶剂 平衡溶解度(μg/ml)，24h
水 14.8
pH1.2模拟胃液 10.3
pH4.5磷酸盐缓冲液 18.6
pH6.8模拟肠液 16.2
渗透率考察：采用Caco-2细胞模型评价SOMCL-9112的渗透性。采用LC/MS/MS法测定SOMCL-9112、阳性对照药阿替洛尔、普萘洛尔和地高辛的浓度，计算表观渗透系数(Papp)和表观渗透系数的比率(Papp ratio＝Papp(B→A)/Papp(A→B)，并据此来评判该化合物的渗透性及其是否为P-gp的底物。结果见表3。
表3 SOMCL-9112在Caco-2细胞模型中渗透率考察结果(n＝3，±SD)
Figure PCTCN2016082044-appb-000009
注释：A＝顶端，B＝基底外侧
上述结果表明SOMCL-9112具有低渗透性的特征，且在2.00-50.0μM范围内在Caco-2细胞上有显著的外排作用。
实验实施例2
体外溶出试验考察
取上述制备实施例5、制备实施例6和制备实施例7、对比实施例1制得的制剂，根据中国药典2010年版二部附录X C)第二法装置(桨法)进行溶出度试验。将单个剂量单位的制剂在37℃和75rpm搅拌速度下置于900ml pH6.8的模拟肠液中，在15、30、60、90和120min后，取出8ml样品并给予同体积的补液。将取出的样品稀释4倍后照紫外-可见分光光度法(中国药典2010年版二部附录ⅣA)，在240nm的波长处分别测定吸光度，计算相应制剂的溶出量，并绘制溶出曲线(见图4)。
将本发明制备实施例5、6、7制备的SOMCL-9112固体制剂于40±2℃，75％±5％RH加速条件下放置6月后采用上述相同条件测定药物的溶出行为，并绘制溶出曲线(见图5)。
由结果可见，本发明制备实施例5、6、7制备的SOMCL-9112固体制剂较IR常规制剂可显著提高SOMCL-9112的溶出速度和溶解度，且加速条件放置后本发明的制剂溶出行为未发生显著改变，对药物増溶效果良好，稳定性良好。
实验实施例3
相对生物利用度研究
取上述制备实施例1、对比实施例2制得的制剂灌胃给予空腹SD大鼠(上海药物研究所实验动物中心)(n＝3)。制备实施例1样品给药方法为临用前以纯化水混悬成含SOMCL-9112 2mg/ml的溶液，各制剂给药剂量为20mg/kg。试验前禁食12h，自由饮水。给药后2h统一进食。在给药前(0h)及给药后0.25，0.5，1.0，2.0，3.0，4.0，6.0，8.0和24h经大鼠眼球后静脉丛取静脉血0.3ml，置肝素化试管中，11000rpm离心5min，分离血浆，于–20℃冰箱中冷冻保存待测。
取上述对比实施例2制剂(含SOMCL-9112 2mg/ml)，静脉注射给予空腹SD大鼠(上海药物研究所实验动物中心)(n＝3)，给药剂量为10mg/kg。在给药前(0h)及给药后5min，0.25，0.5，1.0，2.0，4.0，6.0，8.0和24h经大鼠眼球后静脉丛取静脉血0.3ml，置肝素化试管中，11000rpm离心5min，分离血浆，于–20℃冰箱中冷冻保存待测。
以LC-MS测定样品中SOMCL-9112的浓度。采用Phoenix 1.3软件(美国Pharsight公司)的非房室模型计算SD大鼠给药后SOMCL-9112的药代动力学参数，数据概要见表4。
表4 SOMCL-9112 SD大鼠体内药物动力学数据概要(n＝3)
Figure PCTCN2016082044-appb-000010
由结果可见，本发明制备的制剂可较SOMCL-9112的纳米晶制剂显著提高SOMCL-9112在SD大鼠体内的暴露量，可显著提高SOMCL-9112的相对生物利用度。
实验实施例4
绝对生物利用度研究
取上述制备实施例5制得的制剂口服给予空腹比格犬(上海药物研究所实验动物中心)(n＝3)。制备实施例5制剂给药量为100mg/只。试验前禁食12h，给药后4后提供食物，整个试验过程不禁水。用30ml水送服这些制剂。在给药前(0h)及给药后0.25、0.5、1.0、2.0、3.0、4.0、6.0、8.0、12和24h取血样0.8ml；置肝素抗凝试管中，3500rpm离心10min，分离血浆，–70℃冰箱中冷冻保存待测。
取上述对比实施例3制剂，以生理盐水稀释8倍后以SOMCL-9112 5mg/kg的剂量(2ml/kg)静脉注射给予空腹比格犬(n＝3)。给药前(0h)及给药后5min、0.25、0.5、1.0、2.0、3.0、4.0、6.0、8.0、12和24h取血样0.8ml，置肝素抗凝试管中，3500rpm离心10min，分离血浆，–70℃冰箱中冷冻保存待测。
以LC-MS测定样品中SOMCL-9112的浓度。采用Phoenix 1.3软件(美国Pharsight公司)的非房室模型计算比格犬给药后SOMCL-9112的药代动力学参数，数据概要见表5。
表5 SOMCL-9112的药物动力学数据概要(n＝3)
Figure PCTCN2016082044-appb-000011
由结果可见，本发明的SOMCL-9112固体制剂可显著提高SOMCL-9112的生物利用度，体内吸收良好。

Claims (10)

  1. 一种SOMCL-9112固体分散体，其特征在于，包括下述原料，按重量百分比制成：
    Figure PCTCN2016082044-appb-100001
  2. 如权利要求1所述的SOMCL-9112固体分散体，其特征在于：SOMCL-9112中，以非晶形式存在的SOMCL-9112占70％～100％。
  3. 如权利要求1所述的SOMCL-9112固体分散体，其特征在于：所述可药用基质聚合物为选自共聚维酮、聚维酮、羟丙基甲基纤维素邻苯二甲酸酯、醋酸羟丙基甲基纤维素琥珀酸酯、2-羟基-β-环糊精、羟丙基甲基纤维素、聚甲基丙烯酸酯、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、羟丙基纤维素和醋酸邻苯二甲酸纤维素中的一种或多种，优选为选自共聚维酮、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物和醋酸羟丙基甲基纤维素琥珀酸酯中的一种或多种；和/或
    所述表面活性剂为选自阴离子型表面活性剂、阳离子型表面活性剂、非离子型表面活性剂中的一种或多种；优选为选自十二烷基硫酸钠、多库酯钠、溴棕三甲铵、苄索氯铵、十六烷基氯化吡啶鎓、月桂酸、聚氧乙烯烷基醚、聚氧乙烯山梨糖醇酐脂肪酸酯、聚氧乙烯蓖麻油衍生物、聚氧乙烯硬脂酸酯和泊洛沙姆中的一种或多种；更优选为十二烷基硫酸钠；和/或
    所述助流剂为选自胶态二氧化硅、动物或植物脂肪、蜡中的一种或多种；和/或
    所述增塑剂为选自柠檬酸乙酰三丁酯、柠檬酸乙酰三乙酯、苯甲酸苄酯、三氯叔丁醇、糊精、邻苯二甲酸二丁酯、邻苯二甲酸二乙酯、邻苯二甲酸二甲酯、甘油、单硬脂酸甘油酯、甘露醇、矿物油、羊毛脂醇、棕榈酸、聚乙二醇、聚乙酸邻苯二甲酸乙烯酯、丙二醇、2-吡咯烷酮、山梨糖醇、硬脂酸、三醋精、柠檬酸三丁酯、三乙醇胺和柠檬酸三乙酯中的一种或多种。
  4. 如权利要求1所述的SOMCL-9112固体分散体，其特征在于：所述SOMCL-9112与所述可药用基质聚合物重量比为1：0.25～1：10，优选为1：0.3～1：7，更优选为1：0.5～1：5，更优选为1：2～1：4。
  5. 权利要求1-4中任一项所述SOMCL-9112固体分散体的制备方法，其特征在于，包括如下步骤：
    (1)通过熔解或溶解将原料均匀混合，得到均匀分散体；
    (2)使均匀分散体固化以得到SOMCL-9112以非晶形式存在的SOMCL-9112固体分散体。
  6. 如权利要求5所述的制备方法，其特征在于，包括如下步骤：
    (1a)将原料混合，加热以产生熔体；
    (2a)挤出该熔体固化以产生SOMCL-9112固体分散体优选地，步骤(1a)所述加热温度为70℃-250℃，优选80℃-200℃，最优选为100℃-180℃。
  7. 如权利要求5所述的制备方法，其特征在于，包括如下步骤：
    (1b)将原料溶解于溶剂中；
    (2b)蒸发溶剂以产生SOMCL-9112以非晶形式存在的SOMCL-9112固体分散体
    优选地，步骤(1b)中所述溶剂为丙酮、丙酮/二氯甲烷、甲醇/二氯甲烷、丙酮/水、丙酮/甲醇、丙酮/乙醇、二氯甲烷/乙醇或乙醇/水。
  8. 一种SOMCL-9112固体制剂，其包括权利要求1-4中任一项所述的SOMCL-9112固体分散体和非必需的药用添加剂。
  9. 根据权利要求8所述的SOMCL-9112固体制剂，其中，所述SOMCL-9112固体制剂是片剂、胶囊剂、颗粒剂或散剂。
  10. 权利要求1-4中任一项所述的SOMCL-9112固体分散体在制备治疗癌症的药物中的用途。
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