CN116898808A - FXIa pharmaceutical composition, and preparation method and medical application thereof - Google Patents

FXIa pharmaceutical composition, and preparation method and medical application thereof Download PDF

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Publication number
CN116898808A
CN116898808A CN202310458361.XA CN202310458361A CN116898808A CN 116898808 A CN116898808 A CN 116898808A CN 202310458361 A CN202310458361 A CN 202310458361A CN 116898808 A CN116898808 A CN 116898808A
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weight
solid preparation
pharmaceutical composition
solid
cellulose
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李凤
叶冠豪
王贝
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Shenzhen Salubris Pharmaceuticals Co Ltd
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Shenzhen Salubris Pharmaceuticals Co Ltd
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    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition of FXIa, a preparation method and medical application thereof, and particularly relates to a pharmaceutical composition of an oxo-pyridazine amide derivative, a preparation method and medical application thereof.

Description

FXIa pharmaceutical composition, and preparation method and medical application thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and provides a pharmaceutical composition of FXIa, a preparation method and medical application thereof, in particular relates to a pharmaceutical composition of an oxo-pyridazine amide derivative, a preparation method and medical application thereof.
Background
The thrombus problem caused by cardiovascular and cerebrovascular diseases, diabetes and complications thereof becomes an unprecedented problem to be solved at present.
The human blood coagulation process consists of an endogenous pathway (intrinsic pathway), an exogenous pathway (extrinsic pathway) and a common pathway (annu. Rev. Med.2011. 62:4157), and is a chain reaction in which the process is continuously enhanced and amplified by sequential activation of various zymogens. The coagulation cascade is initiated by endogenous (also known as contact activation) and exogenous (also known as tissue factor) pathways to produce FXa, which in turn produces thrombin (FIIa) via a common pathway, ultimately forming fibrin.
The endogenous pathway is activated by factor XII to form XIa-VIIIa-Ca 2+ P L complex and activates factor X, the extrinsic coagulation pathway is released from Tissue Factor (TF) to TF-VIIa-Ca 2+ The process of complex formation and activation of factor X. The common pathway is the process of activating prothrombin and ultimately producing fibrin, which is the process by which factor Xa is formed, and in which FXI is essential for maintaining the endogenous pathway and plays a key role in the amplification of the coagulation cascade. In the coagulation cascade, thrombin can feedback activate FXI, which in turn causes large amounts of thrombin to be produced, thereby amplifying the coagulation cascade. Therefore, antagonists of FXI are widely developed for the treatment of various thrombosis.
Traditional anticoagulants, such as warfarin, heparin, low Molecular Weight Heparin (LMWH), and new drugs marketed in recent years, such as FXa inhibitors (rivaroxaban, apixaban, etc.) and thrombin inhibitors (dabigatran etexilate, hirudin, etc.), have good effects on reducing thrombosis, occupying the vast cardiovascular and cerebrovascular markets with their remarkable effectiveness, but their side effects are also more and more remarkable, wherein "bleeding risk" is one of the most serious problems that it is primarily in (N Engl J Med 1991;325:153-8, blood.2003; 101:4783-4788).
Inhibition of FXIa factor in a thrombotic model was found to be effective in inhibiting thrombosis, but in the case of more severe thrombosis, FXIa had very little effect (blood.2010; 116 (19): 3981-3989). Clinical statistics show that increasing the amount of FXIa increases the prevalence of VTE (Blood 2009; 114:2878-2883), whereas severely FXIa deficient individuals are at reduced risk of having DVT (Thromb Haemost2011; 105:269273).
As an emerging target for inhibiting thrombosis, patent applications for compounds having FXIa inhibitory activity are WO9630396, WO9941276, WO2013093484, WO2004002405, WO2013056060, WO2017005725, WO2017/023992, WO2018041122, etc.
PCT/CN2020/117257 discloses an oxo-pyridazine amide derivative which can be used as FXIa antagonist for treating diseases such as thromboembolism, and the general formula and specific compounds are shown as the following formula:
for use in patients for the treatment of related diseases, further investigation of suitable pharmaceutical compositions is required.
Disclosure of Invention
The invention provides a pharmaceutical composition of FXIa, a preparation method and medical application thereof, and in particular relates to a pharmaceutical composition of an oxo-pyridazine amide derivative, a preparation method and medical application thereof.
The invention provides a pharmaceutical composition which is a solid dispersion and contains an active ingredient compound A or pharmaceutically acceptable salt thereof and a carrier material. Wherein the active ingredient is dispersed in the drug-carrying material to form a co-dispersion of the drug and the carrier material.
In particular to a pharmaceutical composition which is a solid dispersion and contains an active ingredient compound A or pharmaceutically acceptable salt thereof,
and a carrier material, wherein the carrier material is hydroxypropyl methylcellulose acetate succinate, acrylic resin, cellulose acetate titanate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, povidone or copovidone, and the weight ratio of the carrier material to the active ingredient is not less than 0.2:1.In an alternative embodiment, when the weight ratio of the carrier material to the active ingredient used in the pharmaceutical composition is at least 0.2:1, a uniform dispersion system of the active ingredient and the carrier is obtained by a preparation method in an experiment, wherein the active ingredient is amorphous, so that the solubility of the drug and the absorption of the drug in a body are improved, the drug takes effect quickly after oral administration, the bioavailability is high, and the pharmaceutical composition is stable.
As a preferred technical solution of the present invention, the weight ratio of the carrier material to the active ingredient is 0.2:1-4:1, which may be 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3:1, 3.2:1, 3.4:1, 3.6:1, 3.8:1, 4:1, etc.
As a preferred embodiment of the present invention, the carrier material of the present invention may be selected from, but is not limited to, 3, 4-dimethyl-benzyl carbamate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, poloxamer 188, poloxamer 407, poly (meth) acrylate, homopolymers of N-vinyl-2-pyrrolidone, povidone, copolyvidone, carboxymethyl ethylcellulose, cellulose acetate phthalate, methacrylic acid copolymers, aminoalkyl methacrylate copolymers E, poly (vinyl acetal) diethylaminoacetate, polyvinylpyrrolidone, ethylcellulose, methacrylic acid copolymers RS, polyvinyl alcohol, vinyl pyrrolidone and vinyl acetate copolymers, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, dextrin, pullulan, acacia, sodium alginate, phospholipids, block copolymers of ethylene oxide and propylene oxide, polyethylene glycol, cellulose meta-phthalate, hydroxypropyl cellulose acetate and polyvinyl caprolactam-acetate copolymers, preferably from among the group consisting of polyvinyl acetate, polyvinyl caprolactam and polyvinyl acetate, and polyvinyl pyrrolidone copolymers.
Wherein the hydroxypropyl methylcellulose acetate succinate is HPMCAS. Further selected from HPMCAS-MG, HPMCAS-MF, HPMCAS-MP, preferably the povidone is K30, and the copovidone is PVP/VA; is superior to the technical proposal that the carrier material is selected as the ethyl cellulose.
As a preferred technical scheme capable of remarkably improving the in-vivo absorption of animals, the weight ratio of the carrier material to the active ingredient is preferably 0.3:1-3:1.
As a preferred embodiment of the present invention, the preparation method comprises dissolving the carrier material and the active ingredient in an organic solvent, or dispersing the carrier material in suspension in an organic solvent containing the active ingredient, and removing the organic solvent, or hot-melt extruding, or melting to prepare the pharmaceutical composition.
As a preferred embodiment of the present invention, the method for removing the organic solvent is selected from evaporation, spray drying, freeze drying or fluidized bed drying.
As a preferred embodiment of the present invention, the organic solvent is at least one selected from methanol, ethanol, isopropanol, acetone, butanone, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
The present invention further provides a solid formulation comprising the aforementioned pharmaceutical composition, said solid formulation being selected from the group consisting of tablets, pills, granules or capsules.
As a preferred embodiment of the present invention, the solid preparation further comprises a pharmaceutically acceptable excipient selected from at least one of a disintegrant, a filler, a binder, a glidant, a surfactant, or a lubricant.
As a preferable technical scheme of the invention, the disintegrating agent is at least one selected from low-substituted hydroxypropyl cellulose, crosslinked sodium carboxymethyl cellulose, crosslinked povidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, starch, pregelatinized starch, microcrystalline cellulose, silicon dioxide, effervescent ingredients or alginic acid, and the dosage of the disintegrating agent is 1-50% of the weight of the solid preparation.
Wherein, as a preferable technical scheme, the disintegrating agent is a combination containing two disintegrating agents, and comprises: the mass ratio of the low-substituted hydroxypropyl cellulose to the carboxymethyl cellulose is 1:2-2:1, preferably 1:1.
The filler is at least one selected from dextrin, lactose, sucrose, calcium hydrophosphate, starch, anhydrous calcium hydrophosphate, microcrystalline cellulose, silicified microcrystalline cellulose, microcrystalline cellulose lactose compound or mannitol, and the dosage of the filler accounts for 30-90% of the weight of the solid preparation;
the adhesive is at least one selected from polyvinylpyrrolidone, starch, methylcellulose, carboxyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose or alginate, and the dosage of the adhesive is 0.5-10% of the weight of the solid preparation.
The glidant is at least one selected from fumed silica, magnesium trisilicate, powdery cellulose, starch or talcum powder, and the dosage of the glidant is 0.1-10% of the weight of the solid preparation;
the surfactant is at least one of sodium dodecyl benzene sulfonate, sodium dodecyl sulfate, poloxamer and docusate sodium, and the dosage of the surfactant is 0.1-10% of the weight of the solid preparation;
the lubricant is at least one of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talcum powder, carnauba wax or sodium stearyl fumarate, and the dosage of the lubricant is 0.1-5% of the weight of the solid preparation.
In alternative embodiments, the pharmaceutical composition of the present invention may be further prepared into solid formulations, which are tablets, pills, granules, capsules, and the like.
The capsule comprises: gastric sol capsules, enteric sol capsules and microcapsules.
Among them, the gastric-soluble capsule is the most common capsule, and after oral administration, the capsule is dissolved in stomach and the drug is released to produce the drug effect.
The enteric capsule is one of hard capsule and soft capsule, and is prepared through adding special medicinal polymer material into the capsule shell or special treatment, so that it is insoluble in gastric juice, and can disintegrate and dissolve in intestinal juice to release active component, so as to obtain enteric effect.
The microcapsule is prepared by wrapping solid medicine particles or liquid medicine microdroplets into a microcapsule with the diameter of 1-500 microns by using natural or synthetic polymer materials.
The solid preparation contains 5-60% of active ingredients, which can be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55 or 60%, preferably 8-25% by weight of the solid preparation; in embodiments, the amount (weight or mass) of the active ingredient of the present invention is 10 to 500mg, and may be 400mg, 390mg, 380mg, 370mg, 360mg, 350mg, 340mg, 330mg, 320mg, 310mg, 300mg, 290mg, 280mg, 270mg, 260mg, 250mg, 240mg, 230mg, 220mg, 210mg, 200mg, 190mg, 180mg, 170mg, 160mg, 150mg, 140mg, 130mg, 120mg, 110mg, 100mg, 95mg, 90mg, 85mg, 80mg, 75mg, 70mg, 65mg, 60mg, 55mg, 50mg, 45mg, 40mg, 35mg, 30mg, 25mg, 20mg, 15mg or 10mg.
Further, the solid preparation of the present invention further comprises pharmaceutically acceptable excipients, which are well known or determinable by those skilled in the art, and are selected from at least one of, but not limited to, disintegrants, fillers, binders, glidants, lubricants.
The disintegrating agent is known or identifiable by the person skilled in the art and is selected from at least one of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, starch, pregelatinized starch, microcrystalline cellulose, silicon dioxide, effervescent ingredients or alginic acid; preferably, the disintegrant is used in an amount of 1 to 50% by weight of the solid preparation, and may be 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0%,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48 or 50% by weight, preferably, 50% by weight of the solid preparation.
The filler of the present invention is known or determinable by those skilled in the art and is selected from at least one of dextrin, lactose, sucrose, dibasic calcium phosphate, starch, dibasic anhydrous dibasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, microcrystalline cellulose lactose complex, or mannitol; preferably, the filler is used in an amount of 30 to 90% by weight, more preferably 35 to 60% by weight, based on the weight of the solid preparation, and may be 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60% by weight, based on the weight of the solid preparation.
The binder of the present invention is known or identifiable by those skilled in the art and is selected from, but not limited to, at least one of polyvinylpyrrolidone, starch, methylcellulose, carboxycellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, or alginate, preferably at least one of polyvinylpyrrolidone (preferably povidone with trade name K30), hydroxypropyl cellulose; preferably, the binder is used in an amount of 0.5 to 10% by weight of the solid formulation, and may be 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, 8.2, 8.4, 8.6, 8.8, 9.0, 9.2, 9.4, 9.6, 9.8 or 10.0% by weight of the solid formulation.
The glidant is known or identifiable by those skilled in the art and is selected from at least one of fumed silica (e.g. Aerosil 200), magnesium trisilicate, powdered cellulose, starch, talc, preferably fumed silica; the glidant is used in an amount of 0.5-10% by weight of the solid preparation, and may be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.2, 8.4, 8.6, 8.8, 9.0, 9.2, 9.4, 9.6, 9.9.0 or 10.0% by weight of the solid preparation.
The surfactant is known or identifiable by the person skilled in the art and is selected from at least one of sodium dodecyl benzene sulfonate, sodium dodecyl sulfate, poloxamer and docusate sodium; preferably, the surfactant according to the present invention is used in an amount of 0.1 to 10% by weight of the solid preparation, and may be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5.0% by weight, preferably 0.1 to 2% by weight of the solid preparation.
The lubricant of the present invention is known or identifiable by those skilled in the art and is selected from at least one of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax or sodium stearyl fumarate; preferably, the lubricant according to the present invention is used in an amount of 0.1 to 5% by weight of the solid preparation, and may be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5.0% by weight, preferably 0.1 to 2% by weight of the solid preparation.
The invention also provides a method for preparing the solid preparation, which comprises the following steps: crushing the compound A or the pharmaceutical composition of the pharmaceutically acceptable salt thereof, then uniformly mixing the crushed compound A or the pharmaceutical composition of the pharmaceutically acceptable salt thereof with filling agents, disintegrating agents and the like required by the molding of solid preparations, adding an adhesive for wet granulation or dry granulation, drying and sieving the prepared granules, uniformly mixing the prepared granules with a lubricant, and preparing pills, granules, tablets or capsules; or directly making capsule or tablet by adding proper adjuvant into the medicinal composition. The granules, tablets or capsules may be further coated, etc., as needed.
As a preferable embodiment of the present invention, the solid preparation contains 1) the aforementioned solid dispersion containing 10mg to 600mg by weight of the active ingredient;
further optionally one or more excipients of the following composition:
2) 5-15% by weight of a disintegrant;
3) 30-90% by weight of a filler;
4) 0.5 to 10% by weight of a binder;
5) 0.1 to 10% by weight of a glidant;
6) 0.1 to 10% by weight of a surfactant;
7) 0.1 to 5% by weight of a lubricant;
the sum of the components of the solid preparation is 100 percent.
As a preferred embodiment of the present invention, the composition further optionally comprises a combination of the following excipients:
combination 1
Povidone K30
Crosslinked povidone XL
Microcrystalline cellulose
Lactose monohydrate
Croscarmellose sodium
Silica dioxide
Magnesium stearate
The preparation method comprises the following steps: dissolving an API in a solvent system, and dissolving PVP in an API solution to obtain an adhesive solution; premixing crospovidone XL, microcrystalline cellulose and lactose in a fluidized bed, spraying a binder solution for granulating, adding croscarmellose sodium, silicon dioxide and magnesium stearate for total mixing, and filling into capsules to obtain capsules.
As a preferable embodiment of the present invention, the solid preparation contains 1) the aforementioned solid dispersion containing 10mg to 600mg by weight of the active ingredient;
further optionally one or more excipients of the following composition:
2) 5-50% by weight of a disintegrant;
3) 0.1 to 5% by weight of a lubricant;
the sum of the components of the solid preparation is 100 percent.
As a preferred embodiment of the present invention, the composition further optionally comprises a combination of the following excipients:
combination 2
HPMCAS-MG
Carboxymethylcellulose calcium
Low substituted hydroxypropyl cellulose
Magnesium stearate
The preparation method comprises the following steps: and (3) dissolving the API and the HPMCAS-MG in an organic solvent together, performing rotary evaporation or spray drying to obtain a solid dispersion, adding a disintegrating agent into the solid dispersion for dry granulation, and finally adding magnesium stearate to fill the capsule to obtain the capsule.
The organic solvent may be selected from acetone, ethanol, dichloromethane, methanol, etc., or a mixed solvent of two or more of the above solvents, or a mixed solvent of the above solvents and water, for example, a mixed solvent of dichloromethane and methanol, the weight ratio of the two solvents is: 1:1-32:1; hydrous ethanol, hydrous acetone and the like.
The dissolution test of the solid preparation of the present invention is carried out by "medium simulating conversion of fasting gastrointestinal fluid" conditions for 15min to 50% or more, such as 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95%.
The solid preparation provided by the invention can not age after being placed for more than 3 months (such as 3 months, 6 months, 12 months, 18 months, 24 months and the like) at the temperature of 40+/-2 ℃ and relative humidity of 75+/-5%, and various assessment indexes (related substances, dissolution rate and the like) are not obviously changed.
The pharmaceutically acceptable salts of the compound A are selected from, but not limited to, sodium salt, potassium salt, meglumine salt, calcium salt, choline salt and the like, preferably sodium salt and meglumine salt.
The "weight of the solid preparation" is the numerical range of the usage amount of active ingredients or other kinds of pharmaceutical excipients calculated by the weight of tablet cores without coating agents.
The formulation apparatus and pharmaceutical excipients or agents of the present invention are commercially available.
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the invention are not limited thereto.
The structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR shift (. Delta.) is given in units of 10-6 (ppm). NMR was performed using Bruker AVANCE-III nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform(CDCl 3 ) The internal standard is Tetramethylsilane (TMS).
The MS was determined by ISQ EC mass spectrometry (manufacturer: thermo, model: ISQ EC).
High Performance Liquid Chromatography (HPLC) analysis used a Thermo U3000 HPLC DAD high performance liquid chromatograph.
The CombiFlash rapid preparation instrument uses CombiFlash rf+ LUMEN (TELEDYNE ISCO).
The thin layer chromatography silica gel plate uses the tabacco silver dragon HSGF254 or GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.17 mm-0.23 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Silica gel column chromatography generally uses 100-200 mesh silica gel of Shangbang silica gel as a carrier.
Example 1
Synthesis of (S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid
The specific synthetic route is as follows:
step A: synthesis of 5-bromo-6-hydroxy-2- (4-methoxybenzyl) pyridazin-3 (2H) -one
Bromomaleic anhydride (2.00 g, 11.3 mmol) and 4-methoxybenzyl hydrazine hydrochloride (2..13 g, 11.3 mmol) were added to glacial acetic acid (50.0 ml) at room temperature and reacted at 100 ℃ for 3 hours.
After the reaction is finished, cooling to room temperature, pouring the reaction solution into water, precipitating a large amount of solids, stirring for a period of time, carrying out suction filtration, washing a filter cake with water, and drying the filter cake to obtain 1.50 g of light yellow solid 5-bromo-6-hydroxy-2- (4-methoxybenzyl) pyridazin-3 (2H) -ketone which is directly used for the next reaction without purification. LCMS: rt=3.44 min, [ m+h] + ＝311.03。
And (B) step (B): synthesis of 5-bromo-6-methoxy-2- (4-methoxybenzyl) pyridazin-3 (2H) -one
5-bromo-6-hydroxy-2- (4-methoxybenzyl) pyridazin-3 (2H) -one (1.50 g, 4.82 mmol) and potassium carbonate (2.66 g, 19.29 mmol) were added to N, N-dimethylformamide (15.0 ml) at room temperature, stirred at 80℃for 15min, at which temperature methyl iodide (1.2 ml) was added and the reaction continued for 30 min.
At the end of the reaction, quench with water, extract the mixture with ethyl acetate (50 ml. Times.3), combine the organic phases, first with saturated brine (50 ml. Times.2), then dry over anhydrous sodium sulfate, and finally concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/3). 1.10 g of 5-bromo-6-methoxy-2- (4-methoxybenzyl) pyridazin-3 (2H) -one were obtained as a white solid (yield: 70.3%). LCMS: rt=3.87 min, [ m+h] + ＝325.01。
Step C: synthesis of 6-acetyl-3-chlorobenzoic acid pinacol ester
2-bromo-4-chloroacetophenone (5.00 g, 21.41 mmol), pinacol biborate (8.16 g, 32.12 mmol) and potassium acetate (4.20 g, 42.82 mmol) were added to a three-necked flask at room temperature, nitrogen was replaced, 1, 4-dioxane (60.0 ml) was added, nitrogen was replaced, 1' -bis-diphenylphosphino ferrocene palladium dichloride (1.75 g, 2.14 mmol) was added, nitrogen was replaced, and the temperature was raised to 80℃for reaction for 3 hours.
At the end of the reaction, quench with water, filter with celite, wash the filter cake with ethyl acetate, extract the filtrate with ethyl acetate (80 ml x 3 times), combine the organic phases, first with saturated brine (50 ml x 2 times), then dry over anhydrous sodium sulfate, and finally concentrate under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/50). 2.1 g is obtainedYellow solid 6-acetyl-3-chlorobenzoic acid pinacol ester (yield: 35.0%). LCMS: rt=4.26 min, [ M-H] - ＝279.08。
Step D: synthesis of 5- (2-acetyl-5-chlorophenyl) -6-methoxy-2- (4-methoxybenzyl) pyridazin-3 (2H) -one
5-bromo-6-methoxy-2- (4-methoxybenzyl) pyridazin-3 (2H) -one (1.10 g, 3.39 mmol), 6-acetyl-3-chlorophenylboronic acid pinacol ester (949 mg, 3.39 mmol) and sodium carbonate (718 mg, 6.78 mmol) were added to a three-necked flask at room temperature, nitrogen was replaced, a mixed solvent (10 ml, 1, 2-dimethoxyethane: ethanol: water=8:1:1) was added, nitrogen was replaced, 1' -bisdiphenylphosphino ferrocene palladium dichloride (249 mg, 0.34 mmol) was added, nitrogen was replaced, and the temperature was raised to 90℃for reaction for 1 hour.
At the end of the reaction, quench with water, extract the mixture with ethyl acetate (50 ml. Times.3), combine the organic phases, first with saturated brine (50 ml. Times.2), then dry over anhydrous sodium sulfate, and finally concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/2). 676 mg of 5- (2-acetyl-5-chlorophenyl) -6-methoxy-2- (4-methoxybenzyl) pyridazin-3 (2H) -one were obtained as a yellow solid (yield: 50.2%). LCMS: rt=3.99 min, [ m+h] + ＝399.07。
Step E: synthesis of 5- (2-acetyl-5-chlorophenyl) -6-methoxypyridazin-3 (2H) -one
5- (2-acetyl-5-chlorophenyl) -6-methoxy-2- (4-methoxybenzyl) pyridazin-3 (2H) -one (676 mg, 1.70 mmol) was added to the mixed solvent (4 ml, acetonitrile: water=3:1) at 0℃and ceric ammonium nitrate (7.46 g, 13.60 mmol) was slowly added thereto, and the reaction was completed at room temperature for 30 minutes.
Reaction completionThe mixture was extracted with ethyl acetate (30 ml. Times.3 times), and the organic phases were combined, and the organic phases were first washed with saturated brine (30 ml. Times.2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/1). 238 mg of 5- (2-acetyl-5-chlorophenyl) -6-methoxypyridazin-3 (2H) -one were obtained as a yellow solid (yield: 50.0%). LCMS: rt=3.23 min, [ m+h] + ＝279.08。
Step F: synthesis of(s) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid tert-butyl ester
Tert-butyl 5- (2-acetyl-5-chlorophenyl) -6-methoxypyridazin-3 (2H) -one (50 mg, 0.18 mmol), (R) -4- (2- (((4-nitrophenyl) sulfonyl) oxy) -3-phenylpropionamido) benzoate (113 mg, 0.22 mmol) and potassium carbonate (50 mg, 0.36 mmol) were added to N, N-dimethylformamide (2.0 ml) at room temperature and reacted overnight at room temperature.
At the end of the reaction, quench with water, extract the mixture with ethyl acetate (10 ml. Times.3), combine the organic phases, first with saturated brine (10 ml. Times.2), then dry over anhydrous sodium sulfate, and finally concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/2). 75mg of (S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid tert-butyl ester was obtained as a pale yellow solid (yield: 66.7%). LCMS: rt=4.53 min, [ m+h] + ＝602.13。
Step G: synthesis of(s) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid
Tert-butyl (S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoate (75 mg, 0.12 mmol) was added to dichloromethane (2.0 ml), trifluoroacetic acid (0.25 ml) was added dropwise thereto at room temperature, and the reaction was carried out at room temperature for 3 hours.
At the end of the reaction, the dichloromethane was evaporated and trifluoroacetic acid was pumped down with an oil pump, the residue obtained was dissolved in dichloromethane (1.0 ml), it was added dropwise to n-hexane (10.0 ml), a white solid was precipitated, the filter cake was suction-filtered, washed with n-hexane, and dried to give 50mg of (S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid as a white solid (yield: 76.5%). LCMS: rt=3.98 min, [ M-H] - ＝544.10。 1 H NMR(500MHz，DMSO)δ12.79(s，1H)，10.52(s，1H)，7.99(d，J＝8.4Hz，1H)，7.91(d，J＝8.7Hz，2H)，7.72(d，J＝8.7Hz，2H)，7.69(dd，J＝8.3，2.1Hz，1H)，7.50(d，J＝2.1Hz，1H)，7.37-7.23(m，4H)，7.19(t，J＝7.1Hz，1H)，6.91(s，1H)，5.74(dd，J＝10.2，4.9Hz，1H)，3.67(s，3H)，3.52(dd，J＝14.1，10.3Hz，1H)，3.41(dd，J＝14.1，4.7Hz，1H)，2.53(s，3H)。
Example 2
(S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) sodium salt
Compound a, (S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid (7.5 g, 13.7 mmol) was added to purified water (75.0 ml) and stirring was turned on. At zero degrees celsius, a pre-formulated 5% sodium hydroxide solution (sodium hydroxide, 0.55 g, 13.7 mmol; purified water, 10.0 ml) was slowly added dropwise over about 30 minutes.
After the dripping is finished, 5% sodium hydroxide solution is continuously added to adjust the pH value of the water solution to 8-9. Heating to room temperature, stirring for 30-60 min to ensure complete dissolution of (S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid. The aqueous solution was filtered and lyophilized to give 7.5 g of sodium (S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoate.
Example 3
(S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid potassium salt
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To methanol (10.0 ml) containing (S) -4- (2- (4- (2- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid (100.0 mg, 0.18 mmol) was added dropwise an aqueous potassium hydroxide solution (potassium hydroxide; 10.3 mg, 0.18 mmol; water: 2.0 ml) at zero degrees celsius, and the reaction was continued for 5 hours.
At the end of the reaction, methanol was distilled off, and the resulting aqueous solution was lyophilized to give 98.0 mg of (S) -4- (2- (4- (2- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid potassium salt (yield: 93.4%) as a white solid ([ m+h) for 2.00min at RT =lcms] + ＝546.22。 1 H NMR(400MHz，DMSO)δ10.23(s，1H)，7.98(d，J＝8.4Hz，1H)，7.77(d，J＝8.6Hz，2H)，7.68(dd，J＝8.3，2.2Hz，1H)，7.50(d，J＝2.1Hz，1H)，7.46(d，J＝8.5Hz，2H)，7.387.24(m，4H)，7.18(t，J＝7.1Hz，1H)，6.89(s，1H)，5.75(dd，J＝10.3，4.7Hz，1H)，3.68(s，3H)，3.563.41(m，2H)，2.52(s，3H)。
Example 4
Meglumine(s) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoate
(S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid (60 g,109.89 mmol) and meglumine (21.5 g,109.89 mmol) were added to a mixed solution of acetone and purified water (acetone, 1000 ml; purified water, 100.0 ml) at room temperature, and the solution was stirred. Stirring at room temperature for more than 24 hours.
After the reaction was completed, acetone was concentrated under reduced pressure, and the resulting aqueous solution was lyophilized to obtain 80.0 g of (S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid meglumine salt.
Example 5
Magnesium(s) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoate
To methanol (10.0 ml) containing sodium (S) -4- (2- (4- (2- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoate (100.0 mg, 0.18 mmol) was added dropwise an aqueous magnesium chloride solution (magnesium chloride; 16.8 mg, 0.18 mmol; water: 2.0 ml) at zero degrees celsius, and the reaction was maintained at that temperature for 5 hours.
At the end of the reaction, methanol was distilled off to precipitate a white solid, which was filtered off with suction and dried to give 62.0 mg of (S) -magnesium 4- (2- (4- (2- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoate as a white solid (yield: 30.9%). LCMS: rt=2.00 min, [ m+h] + ＝546.20。 1 H NMR(500MHz，DMSO)δ10.33(s，1H)，7.98(d，J＝8.4Hz，1H)，7.93(s，2H)，7.67(dd，J＝8.3，2.1Hz，1H)，7.59(d，J＝8.2Hz，2H)，7.49(d，J＝1.9Hz，1H)，7.367.22(m，4H)，7.17(t，J＝7.2Hz，1H)，6.88(s，1H)，5.73(dd，J＝10.2，4.8Hz，1H)，3.66(s，3H)，3.41(dd，J＝14.3，4.7Hz，2H)，2.51(s，3H)。
Example 6
(s) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid calcium salt
To methanol (10.0 ml) containing sodium (S) -4- (2- (4- (2- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoate (100.0 mg, 0.18 mmol) was added dropwise an aqueous solution of calcium chloride (calcium chloride; 20.0 mg, 0.18 mmol; water: 2.0 ml) at zero degrees celsius, and the reaction was maintained at that temperature for 5 hours.
At the end of the reaction, methanol was distilled off to precipitate a white solid, which was filtered off with suction, washed with water and dried to give 58.0 mg of (S) -4- (2- (4- (2- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid calcium salt (yield: 28.5%) as a white solid LCMS =2.00 min, [ m+h] + ＝546.17。
Example 7
(S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid choline salt
(S) -4- (2- (4- (2- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid and choline were added to acetone in a 1:1 equivalent ratio, and stirred at a temperature cycle (50 ℃ C. To 5 ℃ C., 0.1 ℃ C./min, 2 cycles) for 3 days to obtain a colloidal sample, and the colloidal sample was dried in vacuo at room temperature for 8 hours to obtain a solid powder of (S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-phenylpropionamido) benzoic acid choline salt.
Example 8: rat pharmacokinetic study of the Compounds of the invention
1. Experimental materials
SD rats: male, 180-250g, purchased from Beijing Vietnam laboratory animal technologies Co.
Reagent: physiological saline, heparin, acetonitrile, formic acid, propranolol (internal standard) are all commercially available.
Instrument: siemens flight LC-MS (U300 UPLC, TSQ QUANTAUMN ULTRA triple quadrupole mass spectrometry).
2. Experimental method
Weighing solid powder (calculated as free acid weight about 3.5 mg) of each compound, filling into No. 9 ToRPAC capsule, orally administering, collecting 200 μL venous blood in heparinized EP tube at 15min, 30min, 1h, 2h, 5h, 7h, 24h, centrifuging at 12000rpm for 2min, and collecting blood plasma at-80deg.C for freezing storage. A certain amount of test sample was precisely weighed and dissolved to 2mg/mL with DMSO to be used as a stock solution. Accurately absorbing a proper amount of compound stock solution, and adding acetonitrile to dilute the stock solution to prepare a standard series of solution. Accurately sucking 20 mu L of each standard series solution, adding 180 mu L of blank plasma, mixing uniformly by vortex, preparing into plasma samples with the plasma concentrations of 0.3, 1, 3, 10, 30, 100, 300, 1000 and 3000ng/mL, carrying out double-sample analysis on each concentration, and establishing a standard curve. 30. Mu.L of plasma was taken, 200. Mu.L of acetonitrile solution of internal standard propranolol (50 ng/mL) was added, after vortexing and mixing, 100. Mu.L of purified water was added, vortexing and mixing again, centrifugation at 4000rpm for 5min, and the supernatant was taken for LC-MS/MS analysis. LC-MS/MS detection conditions were as follows:
chromatographic column: the Siemens flight HyperSIL GOLD C-18 UPLC column, 100 x 2.1mm,1.7 μm.
Mobile phase: gradient elution with water (0.1% formic acid) -acetonitrile was performed as follows
Time (min) Water (0.1% formic acid) Acetonitrile
0 90％ 10％
0.6 90％ 10％
1 10％ 90％
2.6 10％ 90％
2.61 90％ 10％
4 90％ 10％
3. Data processing
After LC-MS/MS detects the blood concentration, the pharmacokinetic parameters are calculated by adopting WinNonlin 6.1 software and a non-atrioventricular model method, and the results are shown in the following table ten.
TABLE ten Compound salts of the invention and free acid to rat pharmacokinetic results
From the above results, it can be seen that the exposure of meglumine salt and sodium salt of compound a in vivo is significantly better than that of compound a free acid under the same orally disintegrating conditions, indicating better absorption relative to compound a free acid, using a capsule formulation.
EXAMPLE 9 pharmaceutical compositions of the Compounds of the invention
Material name Dosage of
API (Compound A meglumine salt) 50mg (calculated as free acid)
Povidone K30 22.6mg
Dissolving the API in an ethanol water system with the volume ratio of 90%, dissolving PVP in the API solution, setting the temperature to be 30-60 ℃, carrying out rotary evaporation and drying to obtain a solid dispersion, and filling capsules to obtain capsules.
Example 10
Dissolving the API in a dichloromethane and ethanol system with the weight ratio of 1:1, dissolving PVP in the API solution, performing rotary evaporation drying at the set temperature of 30-60 ℃ to obtain a solid dispersion, and filling capsules to obtain capsules.
Example 11
Material name Dosage of
API (Compound A meglumine salt) 50mg (calculated as free acid)
Povidone K30 33.9mg
Crosslinked povidone XL 20mg
Microcrystalline cellulose 30mg
Lactose monohydrate 30mg
Croscarmellose sodium 27.3mg
Silica dioxide 5.5mg
Magnesium stearate 1.8mg
Dissolving API in an aqueous solution of acetone with the volume ratio of 80%, and dissolving PVP in the API solution to obtain an adhesive solution; premixing crospovidone XL, microcrystalline cellulose and lactose in a fluidized bed, spraying a binder solution for granulating, adding croscarmellose sodium, silicon dioxide and magnesium stearate for total mixing, and filling into capsules to obtain capsules.
Example 12
Material name Dosage of
API (Compound A meglumine salt) 50mg (calculated as free acid)
Povidone K30 22.6mg
Dissolving API in an ethanol water system with the volume ratio of 90%, dissolving PVP in the API solution, and performing spray drying by a spray dryer to obtain solid dispersion, and filling capsules to obtain capsules.
Example 13
Names of raw and auxiliary materials Unit dose mg
API (Compound A sodium salt) 200mg (calculated as free acid)
HPMCAS-MG 416.11
Carboxymethylcellulose calcium 35.06
Low substituted hydroxypropyl cellulose 35.06
Magnesium stearate 7.01
The preparation process comprises the following steps:
the API and HPMCAS-MG are dissolved in an organic solvent (specifically, a mixed solvent of dichloromethane and methanol in a weight ratio of 16:1), spray drying is carried out to obtain a solid dispersion, the solid dispersion is added with a disintegrating agent for dry granulation, and finally, magnesium stearate is added for filling the gastric-soluble capsule.
Among them, the disintegrating effect of example 13 was significantly better than that of example 10. Under the same usage amount, the combination of the calcium carboxymethyl cellulose and the low-substituted hydroxypropyl cellulose (total 70.12mg according to the mass ratio of 1:1) is superior to the disintegration effect of using one of the calcium carboxymethyl cellulose (70.12 mg) and the low-substituted hydroxypropyl cellulose (70.12 mg) alone.
Comparative example 1
Material name Dosage of
API (Compound A meglumine salt) 50mg (calculated as free acid)
Silicified microcrystalline cellulose 89mg
Crosslinked povidone XL 8.4mg
Magnesium stearate 1.7mg
Mixing the above materials, tabletting, and controlling disintegration time to be not higher than 5min.
Research on the efficacy of pharmaceutical compositions of the compounds of the present invention
l, experimental materials
Cynomolgus monkey: male, 2.5-5kg, from Kang Long Chemicals New technology Co., ltd.
Medicament: API different formulations.
Instrument: waters APITQ-XS LC/MS/MS、AB SCIEX API 5500LC/MS/MS。
2. Experimental method
The absorption condition of each preparation is inspected by adopting a mode of 6 cynomolgus monkeys cross gastric lavage administration each time, animals are fasted overnight before the test, and each preparation is collected by vein blood centrifugation for preparing plasma after oral administration for 0.5h, 1h, 2h, 4h, 6h, 8h and 24h and is frozen at-80 ℃ for testing. Plasma samples were processed by protein precipitation and plasma samples at concentrations of 0.5, 1,2, 5, 10, 50, 100, 500, 1000 and 2000ng/mL were prepared from blank plasma, each concentration was subjected to double sample analysis, and a standard curve was established to detect drug concentrations in the plasma samples. The liquid phase conditions were as follows:
chromatographic column: agilent Poroshell 120 EC-C18.mu.m (50X 2.1 mm).
Mobile phase: gradient elution was performed as follows
3. Data processing
After LC/MS/MS detects the blood concentration, the non-atrioventricular model method is adopted to calculate the pharmacokinetic parameters.
Example 14
The cynomolgus monkey triple-crossing test was performed on example 9, example 11 and comparative example 1, and 50mg was administered.
Test results show that the Cmax and AUClast of the embodiment 9 and the embodiment 11 are obviously better than those of the comparative example 1 (wherein AUClast is respectively improved by more than 1 time and about 60 percent, and when the administration dosage is 50mg, AUClast of the comparative example 1 is 1860h ng/mL), the solid dispersion prepared by the carrier material can obviously improve the absorption of animals, and can better solve the absorption problem of insoluble drugs.
Example 15
The cynomolgus monkey cross test was performed on example 10 and example 11, and the dose of administration was 200mg.
The test results show that the Cmax and AUClast of the example 10 are obviously better than those of the example 11 (wherein AUClast is improved by nearly 2 times), and the absorption of the insoluble medicine in animals can be better solved by adopting the carrier hydroxypropyl methylcellulose acetate succinate and the medicine to prepare a solid dispersion preparation.
Example 16
The cynomolgus monkey cross test was performed on example 12 and example 11, and 100mg was administered.
The test results show that the Cmax and AUClast of the example 12 are obviously better than those of the example 11 (wherein AUClast is improved by more than 1 time), the absorption in animals can be obviously improved, and the problem of absorption of insoluble drugs can be better solved.
In summary, by the embodiment, the solid preparation containing the carrier material of the invention can obviously improve the absorption of animals and better solve the absorption problem of insoluble drugs no matter the solid preparation is prepared into a solid dispersion by adopting an evaporation process, a spray drying process or a fluidized bed spray granulation process.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (13)

1. A pharmaceutical composition, characterized in that the pharmaceutical composition is a solid dispersion containing an active ingredient compound A or a pharmaceutically acceptable salt thereof,
and a carrier material, wherein the carrier material is hydroxypropyl methylcellulose acetate succinate, acrylic resin, cellulose acetate titanate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, povidone or copovidone, and the weight ratio of the carrier material to the active ingredient is not less than 0.2:1.
2. Pharmaceutical composition according to claim 1, characterized in that the weight ratio of carrier material to active ingredient is 0.2:1 to 4:1, preferably 0.3:1 to 3:1.
3. The pharmaceutical composition of claim 1, wherein the hypromellose acetate succinate is HPMCAS.
4. The pharmaceutical composition according to claim 1, wherein the hypromellose acetate succinate is HPMCAS selected from HPMCAS-MG, HPMCAS-MF, HPMCAS-MP, povidone is K30, and copovidone is PVP/VA.
5. The pharmaceutical composition according to claim 1, wherein the preparation method comprises dissolving the carrier material and the active ingredient in an organic solvent, or dispersing the carrier material in suspension in an organic solvent containing the active ingredient, and removing the organic solvent, or hot-melt extrusion, or melt preparation of the pharmaceutical composition.
6. The pharmaceutical composition according to claim 5, wherein the method for removing the organic solvent is selected from the group consisting of evaporation, spray drying, freeze drying and fluid bed drying.
7. The pharmaceutical composition according to claim 5, wherein the organic solvent is selected from at least one of methanol, ethanol, isopropanol, acetone, butanone, tetrahydrofuran, dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
8. A solid formulation comprising the pharmaceutical composition of any one of claims 1-7, said solid formulation being selected from the group consisting of a tablet, a pill, a granule, or a capsule.
9. The solid formulation according to claim 8, characterized in that the solid formulation further comprises a pharmaceutically acceptable excipient selected from at least one of a disintegrant, a filler, a binder, a glidant, a surfactant or a lubricant.
10. The solid preparation according to claim 9, wherein,
the disintegrating agent is at least one selected from low-substituted hydroxypropyl cellulose, crosslinked sodium carboxymethyl cellulose, crosslinked povidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, starch, pregelatinized starch, microcrystalline cellulose, silicon dioxide, effervescent components or alginic acid, and the dosage of the disintegrating agent accounts for 1-50% of the weight of the solid preparation;
the filler is at least one selected from dextrin, lactose, sucrose, calcium hydrophosphate, starch, anhydrous calcium hydrophosphate, microcrystalline cellulose, silicified microcrystalline cellulose, microcrystalline cellulose lactose compound or mannitol, and the dosage of the filler accounts for 30-90% of the weight of the solid preparation;
the adhesive is at least one selected from polyvinylpyrrolidone, starch, methylcellulose, carboxyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose or alginate, and the dosage of the adhesive is 0.5-10% of the weight of the solid preparation.
The glidant is at least one selected from fumed silica, magnesium trisilicate, powdery cellulose, starch or talcum powder, and the dosage of the glidant is 0.1-10% of the weight of the solid preparation;
the surfactant is at least one of sodium dodecyl benzene sulfonate, sodium dodecyl sulfate, poloxamer and docusate sodium, and the dosage of the surfactant is 0.1-10% of the weight of the solid preparation;
the lubricant is at least one of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talcum powder, carnauba wax or sodium stearyl fumarate, and the dosage of the lubricant is 0.1-5% of the weight of the solid preparation.
11. The solid preparation according to any one of claims 8 to 10, characterized in that the solid preparation comprises:
1) The solid dispersion of any one of claims 1-6, comprising 10mg to 600mg by weight of active ingredient;
further optionally one or more excipients of the following composition:
2) 5-50% by weight of a disintegrant;
3) 30-90% by weight of a filler;
4) 0.5 to 10% by weight of a binder;
5) 0.1 to 10% by weight of a glidant;
6) 0.1 to 10% by weight of a surfactant;
7) 0.1 to 5% by weight of a lubricant;
the sum of the components of the solid preparation is 100 percent.
12. The solid preparation according to any one of claims 8 to 10, characterized in that the solid preparation comprises:
1) The solid dispersion of any one of claims 1-6, comprising 10mg to 600mg by weight of active ingredient;
further optionally one or more excipients of the following composition:
2) 5-50% by weight of a disintegrant;
3) 0.1 to 5% by weight of a lubricant;
the sum of the components of the solid preparation is 100 percent.
13. The solid preparation according to claim 12, characterized in that the solid preparation comprises: the disintegrant comprises low substituted hydroxypropyl cellulose and calcium carboxymethyl cellulose.
CN202310458361.XA 2022-04-19 2023-04-18 FXIa pharmaceutical composition, and preparation method and medical application thereof Pending CN116898808A (en)

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