CN110193012B - Pharmaceutical composition of oxopyridine amide derivatives and preparation method thereof - Google Patents
Pharmaceutical composition of oxopyridine amide derivatives and preparation method thereof Download PDFInfo
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- CN110193012B CN110193012B CN201910142401.3A CN201910142401A CN110193012B CN 110193012 B CN110193012 B CN 110193012B CN 201910142401 A CN201910142401 A CN 201910142401A CN 110193012 B CN110193012 B CN 110193012B
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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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
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The invention relates to a pharmaceutical composition of an oxopyridine amide derivative and a preparation method thereof. Specifically provided are solid dispersion formulations of (S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -3-phenylpropionylamino) benzoic acid or a pharmaceutically acceptable salt thereof and methods for preparing the same. The pharmaceutical composition prepared from the solid dispersion has high release rate and bioavailability.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a (S) -4- (2- (4- (2-acetyl-5-chlorphenyl) -5-methoxyl-2-oxopyridine-1 (2H) -yl) -3-phenylpropionylamino) benzoic acid or a pharmaceutical salt solid dispersion thereof and a preparation method thereof.
Background
The life of nearly 1200 million people is lost in global cardiovascular and cerebrovascular diseases such as cerebrovascular diseases, cerebral infarction, myocardial infarction, coronary heart disease, arteriosclerosis and the like every year, the number of people is close to 1/4 of the total death number in the world, and the disease becomes the first major enemy of human health. The number of people who die from cardiovascular diseases in China each year reaches more than 260 thousands, 75% of the surviving patients cause disability, and more than 40% of the patients have serious disability. The problem of thrombus caused by cardiovascular and cerebrovascular diseases, diabetes and complications thereof becomes an irreparable problem to be solved at present.
Traditional anticoagulant drugs such as warfarin, heparin, Low Molecular Weight Heparin (LMWH), and new drugs on the market in recent years such as FXa inhibitors (rivaroxaban, apixaban, etc.) and thrombin inhibitors (dabigatran etexilate, hirudin, etc.) have good effects on reducing thrombosis, and occupy the wide cardiovascular and cerebrovascular markets with remarkable effectiveness, but have more and more remarkable side effects, wherein the bleeding risk (bleedings) is one of the most serious problems (N Engl J Med 1991; 325:153-8, blood.2003; 101: 4783-.
Human FXI deficiency (FXI activity < 15U/dL), also known as hemophilia C, is mild in bleeding phenotype, slightly spontaneous bleeding occurs, the hemostatic function of the body is not affected even in injury or operation, and hemophilia C can be born normally (ArteriosclerThrombVasc biol. 2010; 30: 388-. Therefore, the FXIa safety is obviously better than that of FXa. Therefore, the target FXIa is the hot research of various large companies and research institutions. Studies have found that inhibition of FXIa factor is effective in inhibiting thrombus formation in thrombus models, but in more severe cases, FXIa has little effect (blood. 2010; 116(19): 3981-. Clinical statistics show that increasing amounts of FXIa increase the prevalence of VTE (Blood 2009; 114: 2878-.
As an emerging target FXIa, patent applications disclosing compounds with FXIa inhibitory activity are WO9630396, WO9941276, WO2013093484, WO2004002405, WO2013056060 and US 20050171148. Among them, only Bayer's antisense oligonucleotides (ASO) BAY-2306001 were introduced into clinical secondary studies and showed good results. In phase I clinical trials with this drug, subjects showed a sustained, dose-dependent decrease in FXI activity with prolonged aPTT, and no drug-related bleeding symptoms, even when FXI was reduced to undetectable levels in vivo, showing the potential for FXIa as an emerging target (arteriosclerthromb vasoc Biol,2013,33(7) 1670-. However, FXI ASO requires injection administration, has a slow onset of action, requires several weeks to develop an antithrombotic effect, and may be limited in its use as a prophylactic or therapeutic agent. In terms of small molecule inhibitors, only the FXIa inhibitor of BMS enters the first stage of the clinic in 2014, and no clinical results are reported so far, so that research on novel FXIa inhibitors is of great significance.
WO2018041122(PCT/CN2017/099579) discloses a novel small molecule FXIa antagonist (S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -3-phenylpropionylamino) benzoic acid. It has higher activity, shows excellent anticoagulation effect on human blood and has good pharmacokinetic activity. Can be used for effectively treating and/or preventing cardiovascular and cerebrovascular diseases and thrombosis symptoms, and is shown as the formula (I):
the compound belongs to BCS-II, has poor water solubility, and has low bioavailability in gastrointestinal tract. Therefore, researchers are required to intensively study how to solve the problem of drug formation of the active compound.
Disclosure of Invention
The invention provides a solid dispersion which contains an active ingredient (S) -4- (2- (4- (2-acetyl-5-chlorphenyl) -5-methoxyl-2-oxopyridine-1 (2H) -group) -3-phenylpropionylamino) benzoic acid or a medicinal salt thereof and a carrier material. Wherein the active ingredient is dispersed in the structure of the drug-loaded material to form a co-dispersed system of the drug and the carrier material.
In an alternative embodiment, when the weight ratio of the carrier material to the active ingredient in the solid dispersion of the present invention is at least 0.5:1, a uniform dispersion system of the active ingredient and the carrier is obtained by a preparation method in an experiment, wherein the crystalline state of the active ingredient is changed and is amorphous, thereby improving the solubility of the drug and the absorption of the drug in vivo, and the solid dispersion has the advantages of fast onset of drug effect after oral administration, high bioavailability and stability.
In an alternative embodiment, the higher the content of carrier material in the solid dispersion, the easier it is to change the active ingredient from crystalline to amorphous, and the higher the bioavailability of the corresponding solid dispersion. In view of the balance between drug loading and bioavailability, the weight ratio of carrier material to active ingredient in the present invention may be 0.5:1 to 4:1, may be 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, preferably 0.8:1 to 3:1, more preferably 3: 1.
Further, the carrier material according to the present invention may be selected from, but is not limited to, 3, 4-dimethyl-benzyl carbamate, hypromellose acetate succinate, hypromellose phthalate, poloxamer 188, poloxamer 407, poly (meth) acrylates, homopolymers of N-vinyl-2-pyrrolidone, povidone, copovidone, carboxymethylethylcellulose, cellulose acetate phthalate, methacrylic acid copolymers, aminoalkyl methacrylate copolymers E, poly (vinylacetal) diethylaminoacetate, polyvinylpyrrolidone, ethylcellulose, methacrylic acid copolymers RS, polyvinyl alcohol, vinylpyrrolidone and vinyl acetate copolymers, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethyl-cellulose acetate, and mixtures thereof, Sodium carboxymethylcellulose, dextrin, pullulan, acacia, sodium alginate, lecithin, block copolymers of ethylene oxide and propylene oxide, polyethylene glycol, cellulose trimellitate hypromellose acetate and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers, preferably selected from hypromellose acetate succinate, hydroxypropyl methylcellulose, povidone and vinylpyrrolidone and vinyl acetate copolymers.
In a preferred embodiment, the solid dispersion according to the invention consists of the active ingredient 4- (2- (4- (2-acetyl-5-chlorophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -3-phenylpropionylamino) benzoic acid or a pharmaceutically acceptable salt thereof, and a carrier material.
Methods for preparing solid dispersions are known to the person skilled in the art and are used for the preparation of different active solid dispersions, such as melt, solvent-melt processes. Other methods utilize the co-dissolution principle, form eutectic mixture by grinding, dissolve the drug in organic solvent, disperse and adsorb on inert material to form solid surface adsorbate.
The solvent method is a coprecipitation method, and is to dissolve the drug and the carrier in an organic solvent together or respectively and then mix the drug and the carrier uniformly, or suspend and disperse the carrier material in the organic solvent of the active ingredient, and remove the solvent to obtain the solid dispersion. The method for removing the solvent is known to or can be determined by a person skilled in the art, and can be a mode of dropwise adding a large-polarity organic solution to a low-polarity solvent to precipitate a solid; spray drying or reduced pressure drying may be used.
The melting method is that the medicine and the carrier are mixed evenly and heated to be molten, or the carrier is heated to be molten, then the medicine is added and stirred to be dissolved, and then the melt is rapidly cooled to be solid under violent stirring or is directly filled into a capsule and then cooled.
The solvent-melting method is to dissolve the medicine with a small amount of organic solvent and then mix the dissolved medicine with the melted carrier uniformly, evaporate the organic solvent, and cool and solidify the medicine.
In a preferred embodiment, the solid dispersion according to the invention is prepared by the solvent method (coprecipitation method), i.e. the carrier material is dissolved together with the active ingredient in an organic solvent, or the carrier material is suspended and dispersed in an organic solvent for the active ingredient, and the organic solvent is then removed to obtain the solid dispersion.
The method for removing the organic solvent is known to those skilled in the art or can be determined, and is selected from evaporation, spray drying, freeze drying or fluidized bed drying, or a method of precipitating a solid by dropping a highly polar organic solution into a low polar solvent or aqueous solvent, i.e., a method of elution or a method of elution, preferably a spray drying method or a fluidized bed drying method.
Further, the solvent used in the method for preparing the solid dispersion is selected from, but not limited to, alcohols such as methanol, ethanol, isopropanol, etc., ethers such as tetrahydrofuran, halogenated hydrocarbons such as dichloromethane, dichloroethane, trichloromethane, carbon tetrachloride, etc., ketones such as acetone, butanone, etc., the solvent is preferably selected from at least one of methanol, ethanol, isopropanol, acetone, butanone, tetrahydrofuran, dichloromethane, dichloroethane, trichloromethane, or carbon tetrachloride, and more preferably at least one of methanol, dichloromethane, or tetrahydrofuran.
In some embodiments, the solid dispersion is formed by co-dissolving the active ingredient and the carrier material in a solvent, followed by removal of the solvent using a spray drying process.
In some embodiments, the active ingredient is obtained by co-dissolving the active ingredient and the carrier material in a first solvent, followed by dropwise addition of the resulting solution to a second solvent.
The preparation method of the solid dispersion further comprises any one of filtering, washing or drying.
Further, the first solvent is a highly polar organic solvent, known or determinable by those skilled in the art, and selected from, but not limited to, sulfone solvents such as dimethyl sulfoxide, amide solvents such as N, N-dimethylformamide, N-dimethylacetamide, ketone solvents such as acetone, halogenated hydrocarbon solvents such as carbon tetrachloride, alcohol solvents such as ethanol and methanol, preferably at least one of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, ethanol or methanol.
The second solvent is a low-polarity solvent (or called a low-polarity solvent, i.e. the solvent is miscible with the first solvent, and the solubility of the system to the active ingredient becomes small after the solvent is miscible with the first solvent), and is selected from but not limited to alkane solvents such as n-hexane and petroleum ether, alcohol solvents such as ethanol and methanol, furan solvents such as tetrahydrofuran, ether solvents such as diethyl ether and propyl ether, and water or acidic aqueous solution, preferably at least one of methanol, ethanol or water.
In an alternative embodiment, the solid dispersion of the present invention can be further prepared into solid preparations, such as tablets, pills, granules, capsules, and the like.
The content of active ingredients in the solid preparation is 5-60%, and 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%, based on the weight of the solid preparation; in an embodiment, the amount (weight or mass) of the active ingredient of the present invention is 10 to 500mg, and may be 200mg, 190mg, 180mg, 170mg, 160mg, 150mg, 140mg, 130mg, 120mg, 110mg, 100mg, 95mg, 75mg, 50mg, 25mg, 15mg or 10mg, preferably 200mg, 100mg or 25 mg.
Further, the solid preparation of the present invention further comprises a pharmaceutically acceptable excipient, which is well known or can be determined by those skilled in the art, and is selected from at least one of a disintegrant, a filler, a binder, a glidant and a lubricant.
The disintegrant of the present invention is known or can be identified by those skilled in the art, and is selected from at least one of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, pregelatinized starch, or alginic acid; preferably, the disintegrant is 1 to 20% 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 or 20.0%, preferably 5 to 15% 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, but not limited to, at least one of dextrin, lactose, sucrose, dibasic calcium phosphate, starch, anhydrous dibasic calcium phosphate, microcrystalline cellulose, or mannitol; preferably, the amount of the filler is 30 to 90%, more preferably 35 to 60% by 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 of the solid preparation.
The binder of the present invention is known or can be identified by those skilled in the art, and is selected from but not limited to at least one of polyvinylpyrrolidone, starch, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, or alginate, preferably at least one of polyvinylpyrrolidone (trade name K30), hydroxypropylcellulose; 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.
Glidants of the present invention are known or can be identified by those skilled in the art and are selected from, but not limited to, at least one of fumed silica (e.g., Aerosil200), 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 formulation, 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, 8.0, 8.2, 8.4, 8.6, 8.8, 9.8, 9.0, 9.9.0, 9.9.9, 9.0, 9.6, 9.0% by weight of the solid formulation.
The lubricant of the present invention is known or can be identified by those skilled in the art, and is selected from but not limited to at least one of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax or sodium stearyl fumarate; preferably, the lubricant of the present invention is used in an amount of 0.1 to 5% by weight of the solid formulation, 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 0% by weight of the solid formulation, preferably 0 to 5% by weight of the solid formulation.
In some alternative embodiments, the solid formulation of the present invention comprises:
1)10mg to 500mg of active ingredient;
2) 5-15% by weight of a disintegrant.
In some alternative embodiments, the solid formulation of the present invention comprises:
1)10mg to 500mg of active ingredient;
2) 5-15% by weight of a disintegrant;
3)30 to 90% by weight of a filler.
In a preferred embodiment, the solid preparation of the present invention comprises:
1)10mg to 500mg of active ingredient;
2) 5-15% by weight of a disintegrant;
3)30 to 90% by weight of a filler;
4)0.5 to 10% by weight of a binder.
In a preferred embodiment, the solid preparation of the present invention comprises:
1)10mg to 500mg of active ingredient;
2) 5-15% by weight of a disintegrant;
3)30 to 90% by weight of a filler;
4)0.5 to 10% by weight of a binder;
5) 0.1-10% by weight of a glidant.
In a preferred embodiment, the solid preparation of the present invention comprises:
1)10mg to 500mg of active ingredient;
2) 5-15% by weight of a disintegrant;
3)30 to 90% by weight of a filler;
4)0.5 to 10% by weight of a binder;
5) 0.1-10% by weight of a glidant;
6)0.1 to 5% by weight of a lubricant.
The dissolution test is carried out under the condition of simulating a medium for converting fasting gastrointestinal fluid, namely, the dissolution test is carried out by a paddle method with the rotating speed of 50rpm, the pharmaceutical composition is dissolved for 15min in a solution with the pH value of 1.6 and 300 mLFaSGF (medium simulating fasting gastric juice), 600mL of a solution with the pH value of 6.5 is added, and the dissolution is continued.
The present invention also provides a solid preparation comprising an active ingredient (S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -3-phenylpropionylamino) benzoic acid or a pharmaceutically acceptable salt thereof, and a carrier material. The solid preparation has dissolution rate (%) of active ingredient in solid preparation of 85% or more, which can be greater than or equal to 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100%, preferably 90% or more 15min after FaSSIF is added under the medium condition simulating conversion of fasting gastrointestinal fluid; further, the dissolution rate (%) of the active ingredient in the solid preparation reaches 70% or more, which may be 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% 10min after the FASSIF is added.
The solid preparation provided by the invention can not be aged after being placed for 3 months under the conditions that the temperature is 40 +/-2 ℃ and the relative humidity is 75 +/-5%, and all assessment indexes (such as related substances, dissolution rate and the like) are not obviously changed.
The solid preparation provided by the invention can not be aged after being placed for 6 months under the conditions that the temperature is 40 +/-2 ℃ and the relative humidity is 75 +/-5%, and all assessment indexes (such as related substances, dissolution rate and the like) are not obviously changed.
The solid preparation provided by the invention can not be aged after being placed for 12 months under the conditions that the temperature is 40 +/-2 ℃ and the relative humidity is 75 +/-5%, and all assessment indexes (such as related substances, dissolution rate and the like) are not obviously changed.
The solid preparation is placed for 12 months under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 60 +/-10 percent, and all examination indexes (such as related substances, dissolution rate and the like) are not obviously changed.
The solid preparation is placed for 24 months under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 60 +/-10 percent, and all examination indexes (such as related substances, dissolution rate and the like) are not obviously changed.
The present invention also provides a method for producing the aforementioned solid preparation, which comprises: firstly, crushing the (S) -4- (2- (4- (2-acetyl-5-chlorphenyl) -5-methoxy-2-oxopyridine-1 (2H) -yl) -3-phenylpropionylamino) benzoic acid or the solid dispersion of the pharmaceutically acceptable salt thereof, then uniformly mixing the crushed solid dispersion with a filling agent and/or a disintegrating agent required by solid preparation forming, adding an adhesive for wet granulation or dry granulation, drying, sieving, finishing granules, uniformly mixing the granules with a lubricant, and preparing pills or granules or tabletting or capsules; the solid dispersion can also be directly packaged into capsules or tabletted into tablets by adding proper auxiliary materials. The granules, tablets or capsules may be further coated as required.
The pharmaceutically acceptable salt of (S) -4- (2- (4- (2-acetyl-5-chlorphenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -3-phenylpropionylamino) benzoic acid of the present invention is selected from the group consisting of, but not limited to, potassium, sodium and calcium salts.
The dosage numerical range of the active ingredients or other types of pharmaceutical excipients is calculated by the weight of the tablet core without the coating agent according to the weight of the solid preparation.
The spray drying apparatus used in the present invention may be a GB210 spray dryer manufactured by yamat, japan.
The pharmaceutical excipients or reagents of the invention can be commercially available, such as hypromellose acetate succinate; a compound A: (S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -3-phenylpropionylamino) benzoic acid.
Drawings
The above and other objects and features of the present invention will become apparent when taken in conjunction with the following drawings, each of which shows:
FIG. 1: compound a is compared to the solid dispersion XRPD in example 1.
FIG. 2: in vitro release profiles of example 6, example 7 and comparative example 1.
FIG. 3: the blood concentration profiles in vivo of the formulations of example 8, example 9 and example 10.
The specific implementation mode is as follows:
the invention is further illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.
Example 1: preparation of solid dispersions
Respectively taking 5g of the compound A and 15g of hydroxypropyl methylcellulose acetate succinate (HPMC-AS MG), adding 480g of a mixed solvent of dichloromethane and methanol with equal mass ratio, stirring and dispersing uniformly, and preparing into dry compound A solid dispersion powder by adopting a spray drying method under the conditions that the air inlet temperature is 70 ℃ and the liquid spraying speed is 3 ml/min.
Example 2: preparation of solid dispersions
Respectively taking 5g of the compound A and 5g of HPMC-AS MG, adding 490g of a mixed solvent of dichloromethane and methanol with equal mass ratio, stirring and dispersing uniformly, and preparing into dry compound A solid dispersion powder by adopting a spray drying method under the conditions that the air inlet temperature is 70 ℃ and the liquid spraying speed is 3 ml/min.
Example 3: preparation of solid dispersions
Respectively taking 5g of the compound A and 10g of HPMC-AS MG, adding 485g of a mixed solvent of dichloromethane and methanol with equal mass ratio, stirring to uniformly disperse, and preparing dry compound A solid dispersion powder by adopting a spray drying method under the conditions that the air inlet temperature is 70 ℃ and the liquid spraying speed is 3 ml/min.
Example 4: preparation of solid dispersions
Respectively taking 2g of the compound A and 6g of HPMC-AS MG, adding 59g of mixed solvent of tetrahydrofuran and methanol with the same volume ratio, stirring to uniformly disperse, and preparing dry compound A solid dispersion powder by adopting a spray drying method under the conditions that the air inlet temperature is 65 ℃ and the liquid spraying speed is 1.5 ml/min.
Example 5: preparation of solid dispersions
Respectively taking 5g of the compound A and 15g of copovidone (PVP/VA), adding 480g of mixed solvent of dichloromethane and methanol with equal mass ratio, stirring to uniformly disperse, and preparing the dry compound A solid dispersion powder by adopting a spray drying method under the conditions that the air inlet temperature is 70 ℃ and the liquid spraying speed is 3 ml/min.
Example 6: preparation of solid Dispersion tablets
The preparation method comprises the following steps:
10.7g of the solid dispersion powder prepared in example 1, 6.0g of microcrystalline cellulose PH101, 0.40g of croscarmellose sodium and 0.4g of fumed silica were mixed, and the mixture was subjected to dry tableting and granulation, and then pulverized by a granulator. And (3) adding 11.38g of the prepared product into 0.26g of magnesium stearate and 0.26g of croscarmellose sodium, uniformly mixing, tabletting and directly tabletting.
Example 7: preparation of solid Dispersion tablets
The preparation method comprises the following steps:
11.8g of the solid dispersion powder prepared in example 5, 6.0g of microcrystalline cellulose pH101, 0.40g of croscarmellose sodium and 0.4g of fumed silica were mixed uniformly, and then the mixture was subjected to dry tableting and granulation, and then pulverized by a granulator. 14.0g of the prepared product is taken, added with 0.30g of magnesium stearate and 0.30g of croscarmellose sodium, evenly mixed and tabletted, and directly tabletted.
Example 8: preparation of solid Dispersion tablets
The preparation method comprises the following steps:
and (3) uniformly mixing the solid dispersion powder prepared in the example 2, the cellulose lactose, the croscarmellose sodium, the fumed silica and the magnesium stearate, and directly tabletting the powder to obtain the tablet.
Example 9: preparation of solid Dispersion tablets
The preparation method comprises the following steps:
and (3) uniformly mixing the solid dispersion powder prepared in the embodiment 3, the cellulose lactose, the croscarmellose sodium, the fumed silica and the magnesium stearate, and directly tabletting the powder to obtain the tablet.
Example 10: preparation of solid Dispersion tablets
The preparation method comprises the following steps:
the solid dispersion powder was prepared according to the method in example 1, and mixed with the cellulose lactose, croscarmellose sodium, fumed silica and magnesium stearate, and the powder was directly tableted to obtain.
Comparative example 1: preparation of plain capsules
The preparation method comprises the following steps:
the particle size of compound a in the formulation was measured using a Mastersizer laser particle sizer as follows: d90 was about 7.7 μm, D50 was about 2.5 μm, and D10 was about 0.69 μm.
Weighing the compound A, the hydroxypropyl methylcellulose E5 and the sodium docusate according to the formula, sieving with a 80-mesh sieve for three times, uniformly mixing to obtain mixed powder, and filling into a No. 0 capsule.
Example 11: in vitro Release Studies
The tablets or capsules of example 6, example 7 and comparative example 1 were added to a dissolution apparatus using the paddle method, rotation speed: at the temperature of 37 ℃ and at the speed of 50 r/min, 300 mLFaSGF (medium simulating fasting gastric juice) solution with the pH value of 1.6 is firstly used for dissolution for 15 minutes, then 900ml of simulated fasting intestinal juice (FaSSIF, pH6.5) is used as a solvent for dissolution test, and samples are taken at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours and 3 hours, and the accumulated dissolution is calculated by liquid phase method measurement. The dissolution data are shown in Table 1 and the dissolution profile is shown in FIG. 2.
TABLE 1
Thus, the formulations of examples 6 and 7 were dissolved rapidly in FassIF at 15min, which was 85% or more, while the dissolution of comparative example 1 was significantly worse.
Example 12: pharmacokinetic study in monkeys
Cynomolgus monkeys, divided into 2 groups. After fasting overnight, 2 formulations (example 6 and comparative example 1) prepared in the examples according to the invention were administered, 1 dose (specification 90 mg/dose). Venous blood was collected at 14 time points, 10 minutes before dosing and 0.25, 0.5, 1, 2,4,6, 8, 12, 24 hours after dosing. Plasma drug concentrations of compound a in monkeys were determined by HPLC/MS-MS for 24 hours and pharmacokinetic parameters were calculated using DAS software. The specific data are shown in Table 2.
TABLE 2
And (4) conclusion:
as can be seen, Cmax and AUC of example 60-tThe solid dispersion preparation is obviously superior to the comparative example 1, and shows that the solid dispersion preparation not only can provide better in-vitro dissolution, but also shows superiority in absorption in an animal body, and can better solve the problems of dissolution, absorption and the like when insoluble medicines are prepared.
Example 13: in vivo Pharmacokinetics (PK)
The scheme is as follows: a, B, C three groups of the preparations of examples 8, 9 and 10 were administered separately (each specification was 50 mg/tablet).
PK: venous blood (12 samples in total) was collected on the day of administration (0h) and at 0.5, 1,3, 4,5, 6, 7, 9, 12, 24, 36 hours post-administration, and plasma drug concentrations of compound a were determined by HPLC/MS-MS method at 36 hours in vivo and their pharmacokinetic parameters were calculated using DAS software. See table 3. The blood concentration profile in vivo is shown in FIG. 3.
TABLE 3
And (4) conclusion:
as can be seen from AUC 0-t or AUC 0- ∞ of each group, the exposure of the active ingredient is better for each group.
Example 14: stability test
The samples of example 1, example 2 and example 3 were tested for stability at 25 deg.C, 60% RH and 40 deg.C, 75% RH.
Table 4 long term accelerated stability test results:
the stability test results in table 4 show that: example 1, example 2, example 3 exhibited excellent chemical stability upon standing at 25 ℃, 60% RH and 40 ℃, 75% RH for 6 months.
Example 15: preparation of Compound A
First step of
1- (4-chloro-2- (2, 5-dimethoxypyridin-4-yl) phenyl) ethanone 1e
2-bromo-4-chloroacetophenone 1c (1.27g, 5.46mmol), (2, 5-dimethoxypyridin-4-yl) boronic acid 1g (1.0g, 5.46mmol, prepared by the method disclosed in patent application "WO 063093"), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (230mg, 0.32mmol) and potassium carbonate (2.2g, 16.38mmol) were added to 25mL of 1, 4-dioxane, and the reaction was heated to 110 ℃ and stirred for 8 hours after the addition was completed. The reaction solution was naturally cooled to room temperature, 50mL of water was added to the reaction solution, extraction was performed with ethyl acetate (50 mL. times.3), the organic phases were combined, the organic phases were washed with water (50mL), a saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with an eluent of n-hexane/ethyl acetate system to obtain the title product 1e (1.0g, yield: 63.3%).
MS m/z(ESI):292.3[M+1]
Second step of
4- (2-acetyl-5-chlorophenyl) -5-methoxypyridin-2 (1H) -one 1f
1e (1.0g, 3.43mmol) was added to 10mL of N, N-dimethylformamide, pyridine hydrobromide (3.30g, 20.6mmol) was added, and after the addition, the mixture was heated to 105 ℃ and stirred for reaction for 3 hours. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50 mL. times.3), the organic phases were combined, and the organic phases were washed with water (50mL), a saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 1f (550mg, yield: 57.8%).
MS m/z(ESI):276.3[M-1]
The third step
Magnesium tert-butoxide (701.62mg, 7.2mmol) was dissolved in 250mL of tetrahydrofuran, and then (R) -2-bromo-3-phenylpropionic acid (4a1649.77mg, 7.2mmol) prepared by a known method "Chemical Communications (Cambridge, United Kingdom),2014,50(88), 13489-13491"), potassium tert-butoxide (404.07mg, 3.6mmol) and crude compound 1f (1000mg, 3.6mmol) were added and reacted at 60 ℃ for 16 hours. The reaction solution was cooled to room temperature, 1M hydrochloric acid was added dropwise to a reaction solution pH of 2 to 3, extraction was performed with ethyl acetate (50mL × 3), organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (Gilson-281, elution system: acetonitrile, water) to obtain the title compound 4b (350mg, yield: 20.5%).
MS m/z(ESI):426.4[M+1]
The fourth step
4- (2- (4- (2-acetyl-5-chlorophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -3-phenylpropionylamino) benzoic acid methyl ester 4d
Compound 4b (350mg, 0.82mmol), methyl p-aminobenzoate 4c (39.23mg, 0.26mmol, prepared by the well-known method "Chemical Communications (Cambridge, United Kingdom),2015,51(58), 11705-11708"), and N, N-diisopropylethylamine (0.57mL, 3.29mmol) were dissolved in 30mL of ethyl acetate, and a solution of 2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphoric acid-2, 4, 6-trioxyhydroxide in ethyl acetate (50%, 1569mg, 2.47mmol) was added dropwise, the reaction was warmed to 60 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with dichloromethane/methanol as an eluent to give the title compound 4d (140mg, yield: 28.9%).
MS m/z(ESI):559.5[M+1]
The fifth step
Compound 4d (120mg, 0.21mmol) was dissolved in 4mL of a mixed solvent of tetrahydrofuran and methanol (V/V ═ 3:1), and 1.28mL of a 1M lithium hydroxide solution was added, and after completion of addition, the reaction was carried out for 16 hours. 10% hydrochloric acid was added dropwise until the pH of the reaction solution became 3 to 4, extraction was performed with ethyl acetate (50 mL. times.2), the organic phases were combined, concentrated under reduced pressure, and the resulting residue was purified with high performance liquid chromatography (Gilson-281, eluent: acetonitrile, water) to give 4- (2- (4- (2-acetyl-5-chlorophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -3-phenylpropionylamino) benzoic acid (50mg, yield: 42.7%).
MS m/z(ESI):545.4[M+1]
1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.92(s,1H),7.90(s,1H),7.83-7.81(d,1H),7.74(s,1H),7.72(s,1H),7.62-7.59(dd,1H),7.43(s,1H)7.38(s,1H),7.30-7.25(m,4H),7.21-7.17(m,1H),6.31(s,1H),6.05-6.01(m,1H),3.54(s,3H),3.49-3.44(m,2H),2.37(s,3H).
4- (2- (4- (2-acetyl-5-chlorophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -3-phenylpropionylamino) benzoic acid (900mg, 1.65mmol) was subjected to chiral preparation (separation conditions: chiral preparation column Superchiral S-AD (Chiralway),2cm I.D. 25cm Length,5 um; mobile phase: carbon dioxide: ethanol: diethylamine ═ 60: 40: 0.05, flow rate: 50g/min), the corresponding fractions were collected and concentrated under reduced pressure to give Compound I.
MS m/z(ESI):545.4[M+1]；
Chiral HPLC analysis retention time 4.138 minutes, chiral purity: 98% (chromatographic column: Superchiral S-AD (Chiralway),2cm I.D. 25cm Length,5 um; mobile phase: ethanol/n-hexane/trifluoroacetic acid 50/50/0.05 (v/v/v)).
1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.92(s,1H),7.90(s,1H),7.83-7.81(d,1H),7.74(s,1H),7.72(s,1H),7.62-7.59(dd,1H),7.43(s,1H)7.38(s,1H),7.30-7.25(m,4H),7.21-7.17(m,1H),8.31(s,1H),6.05-6.01(m,1H),3.54(s,3H),3.49-3.44(m,2H),2.37(s,3H)
Test example 1 light absorption assay for detecting biological Activity of the Compound of the present invention against factor XIa inhibition
1. Experimental Material
Enzyme: factor XIa protease (Abcam, cat # ab62411)
Substrate: coagulation factor XIa specific substrate (HYPHEN1310med, Cat. Biophen cs-21(66))
Buffer solution: 100mM tris-HCl, 200mM NaCl, 0.02% Tween 20, pH7.4
2. Experimental procedure
20mM test compound dissolved in 100% DMSO was diluted to 200, 20, 2, 0.2, 0.02, 0.002. mu.M with 100% DMSO; mu.l of compound was added per well in 384-well plates, blank and control wells replaced with DMSO, centrifuged, and compound was removed to the bottom. Mu.l (2.5. mu.g/ml) of FXIa enzyme solution was added to each well, 10. mu.l of buffer was added to the blank well instead, and the enzyme solution was centrifuged to the bottom.
Finally, 10. mu.l of 2mM substrate was added to each well, centrifuged, and the substrate solution was centrifuged to the bottom.
Incubation at 37 ℃ for 10 min; the absorbance was then measured at 405 nm. Absorbance values were curve fitted with graphpad and IC was obtained50＝16。
Test example 2 determination of the in vitro anticoagulant Effect of the Compounds of the invention on human blood
1. Experimental Material
Plasma: collecting human blood in a blood collecting tube without anticoagulant, adding 3.8% sodium citrate (volume ratio 1: 9), centrifuging at room temperature 2500rpm for 10min, collecting blood plasma, packaging, and storing at-80 deg.C;
reagent: APTT reagent (activated partial thromboplastin time determination kit, SIEMENS, cat # B4218-1) and calcium chloride solution;
the instrument comprises the following steps: coagulometer (SYSMEX, CA-500).
2. Experimental detection
Melting the subpackaged blood plasma at room temperature, and mixing uniformly. 10000 μ M test compound dissolved in 100% DMSO was diluted to 3000, 300, 200, 150, 75, 30, 10, 3, 0.3 μ M in 100% DMSO and blank was 100% DMSO. And placing the reagent, the plasma and the compound into corresponding positions in a coagulometer, and carrying out APTT detection on the compound.
3. Data processing
CT was calculated by curve fitting through Prism2I.e. the concentration of compound corresponding to APTT of 2-fold blank, CT2＝2.0。
Claims (21)
1. A solid dispersion comprising an active ingredient (A)S) -4- (2- (4- (2-acetyl-5-chlorophenyl) -5-methoxy-2-oxopyridine-1 (2)H) -yl) -3-phenylpropionylamino) benzoic acid or a pharmaceutically acceptable salt thereof, and a carrier material, wherein the carrier material is hypromellose acetate succinate or copovidone, the weight ratio of the carrier material to the active ingredient is not less than 0.5:1, and the hypromellose acetate succinate is HPMC-AS MG.
2. The solid dispersion according to claim 1, characterized in that the weight ratio of the carrier material and the active ingredient is 0.5:1 to 4: 1.
3. The solid dispersion according to claim 1, characterized in that the weight ratio of the carrier material and the active ingredient is 0.8:1 to 3: 1.
4. A process for preparing a solid dispersion according to any one of claims 1 to 3, which comprises dissolving the carrier material with 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 to obtain a solid dispersion.
5. The method according to claim 4, wherein the organic solvent is removed by a method selected from the group consisting of evaporation, spray drying, freeze drying and fluidized bed drying.
6. The method according to claim 5, wherein the method for removing the organic solvent is a spray drying method or a fluidized bed drying method.
7. The method according to any one of claims 4 to 6, characterized in that the organic solvent is selected from at least one of methanol, ethanol, isopropanol, acetone, butanone, tetrahydrofuran, dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
8. The process according to claim 7, characterized in that the organic solvent is selected from at least one of methanol, dichloromethane or tetrahydrofuran.
9. A solid formulation comprising the solid dispersion of any one of claims 1-3, said solid formulation selected from a tablet, a pill, a granule, or a capsule.
10. The solid formulation according to claim 9, 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 or a lubricant.
11. Solid formulation according to claim 10, characterized in that the disintegrant is selected from at least one of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, pregelatinized starch or alginic acid.
12. The solid preparation according to claim 11, wherein the disintegrant is used in an amount of 1 to 20% by weight of the solid preparation.
13. Solid formulation according to claim 10, characterized in that the filler is selected from at least one of dextrin, lactose, sucrose, dibasic calcium phosphate, starch, anhydrous dibasic calcium phosphate, microcrystalline cellulose or mannitol.
14. The solid preparation according to claim 13, wherein the filler is used in an amount of 30 to 90% by weight based on the solid preparation.
15. The solid preparation according to claim 10, wherein the binder is at least one selected from the group consisting of polyvinylpyrrolidone, starch, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and alginate.
16. The solid preparation according to claim 15, wherein the binder is used in an amount of 0.5 to 10% by weight of the solid preparation.
17. Solid formulation according to claim 10, characterized in that the glidant is selected from at least one of fumed silica, magnesium trisilicate, powdered cellulose, starch or talc.
18. The solid preparation according to claim 17, wherein the glidant is used in an amount of 0.1-10% by weight of the solid preparation.
19. The solid formulation according to claim 10, characterized in that the lubricant is selected from at least one of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax or sodium stearyl fumarate.
20. The solid preparation according to claim 19, wherein the lubricant is used in an amount of 0.1 to 5% by weight of the solid preparation.
21. A solid formulation according to any one of claims 9 to 20, characterized in that it comprises:
a) 10mg to 500mg of active ingredient;
b) 5-15% by weight of a disintegrant;
c) 30 to 90% by weight of a filler;
d) 0.5 to 10% by weight of a binder;
e) 0.1-10% by weight of a glidant;
f) 0.1 to 5% by weight of a lubricant.
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