CN116898852A - Pharmaceutical composition of oxopyridazine amide derivatives, and preparation method and medical application thereof - Google Patents

Pharmaceutical composition of oxopyridazine amide derivatives, and preparation method and medical application thereof Download PDF

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Publication number
CN116898852A
CN116898852A CN202310457404.2A CN202310457404A CN116898852A CN 116898852 A CN116898852 A CN 116898852A CN 202310457404 A CN202310457404 A CN 202310457404A CN 116898852 A CN116898852 A CN 116898852A
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pharmaceutical composition
weight
sodium
solid preparation
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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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

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  • Chemical & Material Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
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  • Inorganic Chemistry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition of an oxo-pyridazine amide derivative, a preparation method and medical application thereof. The pharmaceutical composition contains an active ingredient compound A or a pharmaceutically acceptable salt thereof and one or more excipients, and the D90 of the pharmaceutical composition is less than 100 μm, preferably less than 90 μm, 80 μm, 60 μm, 50 μm, 40 μm, 30 μm. The excipient is selected from acrylic resin, cellulose acetate, acetate fiber titanate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, povidone or copovidone.

Description

Pharmaceutical composition of oxopyridazine amide derivatives, and preparation method and medical application thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition of an oxo-pyridazine amide derivative, a preparation method and medical application thereof.
Background
Cardiovascular and cerebrovascular diseases such as global cerebral vessels, cerebral infarction, myocardial infarction, coronary heart disease, arteriosclerosis and the like take 1200 tens of thousands of lives, are close to 1/4 of the total number of deaths in the world, and become the first enemy of human health. 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. 62:41-57), 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 Haemost 2011; 105:269-273).
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 comprising an active ingredient compound A or a pharmaceutically acceptable salt thereof and one or more excipients,
d of the pharmaceutical composition 90 < 100 μm, preferably < 90 μm, 80 μm, 60 μm, 50 μm, 40 μm, 30 μm.
As a preferred embodiment of the present invention, the excipient is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, acrylic resin, cellulose acetate titanate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, povidone, and copovidone.
As a preferred technical scheme of the invention, the pharmaceutical composition is a co-powder of the compound A or pharmaceutically acceptable salt thereof and more than one excipient.
As a preferred embodiment of the present invention, the weight ratio of the excipient to the active ingredient is 3:1 to 3:1, such as 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, etc.
As a preferred technical scheme of the invention, the pH of the pharmaceutical composition is more than 5.5, preferably more than 6, such as pH not less than 6.1, pH not less than 6.2, pH not less than 6.3, pH not less than 6.4, pH not less than 6.5, pH not less than 6.6, pH not less than 6.7, pH not less than 6.8, pH not less than 6.9, pH not less than 7.0, pH not less than 7.1, pH not less than 7.2, pH not less than 7.3, pH not less than 7.4, pH not less than 7.5, pH not less than 7.6, pH not less than 7.7, pH not less than 7.8, pH not less than 7.9, pH not less than 8.0, pH not less than 8.1, pH not less than 8.2, pH not less than 8.3, pH not less than 8.4, pH not less than 8.5 and the like.
As a preferred embodiment of the present invention, the pharmaceutical composition contains more than one alkalizing agent.
As a preferred embodiment of the present invention, the alkalizing agent is selected from the group consisting of sodium bicarbonate, sodium carbonate, meglumine, magnesium oxide, dibasic calcium phosphate, tribasic calcium carbonate, tribasic magnesium carbonate, dibasic sodium phosphate buffer system and monobasic potassium phosphate buffer system, preferably sodium carbonate.
As a preferred embodiment of the present invention, the pharmaceutical composition is further dry granulated.
As a preferable technical scheme of the invention, the proportion of 80 mesh screen oversize material of the granules after dry granulation is more than 50%.
The invention provides a solid preparation which comprises the pharmaceutical composition, wherein the solid preparation is selected from tablets, pills, granules or capsules.
As a preferred embodiment of the present invention, the solid preparation further comprises other pharmaceutically acceptable excipients selected from at least one of a disintegrant, a filler, a binder, a glidant, a surfactant, or a lubricant.
As a preferred technical scheme of the invention, the content of the active ingredient in the solid preparation is 5-60%, 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.
As a preferable technical scheme of the invention, the disintegrating agent is at least one selected from low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, starch, pregelatinized starch, microcrystalline cellulose, silicon dioxide, effervescent ingredient or alginic acid, and the dosage of the disintegrating agent is 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.
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: firstly, co-pulverizing the compound A or the pharmaceutical composition of the pharmaceutically acceptable salt thereof and an excipient, preferably further performing dry granulation (crushing after large tablet compression), drying, sieving and granulating the prepared granules, uniformly mixing with other excipients, and preparing pills or granules or tabletting or encapsulating; 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 technical scheme of the invention, the solid preparation contains 1) the medicine composition, and comprises 10 mg-600 mg of active ingredient by weight;
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.
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.
Drawings
FIG. 1 shows dissolution profiles of Compound A and Compound A sodium salt, compound A meglumine salt in solutions of different pH.
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 ) Internal standardIs 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.
The method for measuring the pH value comprises the following steps: the compound or preparation sample is added to 10ml of water, dissolved, dispersed or sonicated for 5min, then left to stand at room temperature and the pH is measured with a pH meter.
Particle size measurement method: according to the third method light scattering method (dry method) operation of the four-part rule 0982 particle size and particle size distribution measurement method of the Chinese pharmacopoeia 2020 edition, the measurement is carried out by adopting a laser particle sizer.
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.
Reaction junctionAnd (3) bundling, 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, wherein the light yellow solid 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 of 6-acetyl-3-chlorobenzoic acid pinacol ester was obtained as a yellow solid (yield: 35.0%). LCMS, [ M-H ] - = 279.08, rt=4.26 min.
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, synthesizing 5- (2-ethyltyryl-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.
At the end of the reaction, quench with water, extract the mixture with ethyl acetate (30 ml. Times.3), combine the organic phases, first with saturated brine (30 ml. Times.2), 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=1/1). 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
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)，7.38-7.24(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)，3.56-3.41(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.
The dissolution graphs of the compound A, the sodium salt of the compound A and the meglumine salt of the compound A in solutions with different pH values are shown in figure 1.
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)，7.36-7.22(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-18UPLC column, 100 x 2.1mm,1.7 μm.
Mobile phase: gradient elution with water (0.1% formic acid) -acetonitrile was performed as follows
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.
Pharmaceutical compositions of the compounds of the invention
Example 9
Material name Dosage of
API (Compound A meglumine salt) 50mg (calculated as free acid)
Povidone K30 22.6mg
After premixing API, povidone K30 was co-pulverized in a jet mill (particle size D 90 About 18 μm) to obtain co-powder, and encapsulating to obtain capsule.
Example 10
Material name Dosage of
API (Compound A sodium salt) 400mg (calculated as free acid)
Povidone K30 181.0mg
Magnesium stearate 5mg
Premixing API and povidone K30, and co-pulverizing in jet mill to obtain co-powder (particle diameter D of co-powder 90 About 18 μm), pressing into large pieces with a dry granulator, crushing with a 1.0mm screen of a granulator to obtain particles and powder, taking a part of 80-mesh screen with the oversize product ratio of more than 75%, adding magnesium stearate, mixing, and encapsulating to obtain capsules.
Example 11
Material name Dosage of
API (Compound A sodium salt) 200mg (calculated as free acid)
Povidone K30 90.5mg
Magnesium stearate 2.5mg
Premixing API and povidone K30, and co-pulverizing in jet mill to obtain co-powder (particle diameter D of co-powder 90 About 10 μm), pressing into large pieces with a dry granulator, crushing with a 1.0mm screen of a granulator to obtain particles and powder, taking a part of 80-mesh screen with the oversize product ratio of more than 75%, adding magnesium stearate, mixing, and encapsulating to obtain capsules.
Example 12
Material name Dosage of
API (Compound A meglumine salt) 50mg (calculated as free acid)
Povidone K30 22.6mg
Sodium bicarbonate 300mg
Premixing API and povidone K30, and co-pulverizing in jet mill to obtain co-powder (particle diameter D of co-powder 90 About 43 μm), then adding sodium bicarbonate, mixing, and encapsulating,the capsule is obtained.
Example 13
Material name Dosage of
API (Compound A meglumine salt) 50mg (calculated as free acid)
Povidone K30 22.6mg
Sodium carbonate 80mg
Sodium dodecyl sulfate 8mg
Silica dioxide 2.5mg
Magnesium stearate 1.7mg
After premixing API, povidone K30 was co-pulverized in a jet mill (co-powder particle size D 90 About 43 μm) to obtain co-powder, adding sodium carbonate, sodium dodecyl sulfate, silicon dioxide and magnesium stearate, mixing, and encapsulating to obtain capsule.
Example 14
Material name Dosage of
API (Compound A sodium salt) 50mg (calculated as free acid)
Povidone K30 22.6mg
Sodium carbonate 80mg
Sodium dodecyl sulfate 8mg
Silica dioxide 2.5mg
Magnesium stearate 1.7mg
Premixing API and povidone K30, and co-pulverizing in hammer mill to obtain co-powder (particle diameter D of co-powder) 90 About 17 μm), pressing into large pieces by a dry granulator, crushing by a 1.0mm screen of a granulator to obtain particles and powder, taking a part of 80-mesh screen with the oversize product ratio of more than 85%, adding sodium carbonate, sodium dodecyl sulfate, silicon dioxide and magnesium stearate, mixing, and filling into capsules to obtain capsules.
Example 15
Material name Dosage of
API (Compound A sodium salt) 300mg (calculated as free acid)
Povidone K30 135.78mg
Sodium carbonate 150mg
After premixing API, povidone K30 was co-pulverized in a jet mill (co-powder particle size D 90 About 55 μm) to obtain co-powder, adding sodium carbonate, mixing, and making into enteric capsule.
Comparative example 1
Dissolving API in 80% acetone aqueous solution, and dissolving PVP in the API solution to obtain adhesive solution; the crosslinked povidone XL, microcrystalline cellulose and lactose are placed in a fluidized bed for premixing, then the adhesive solution is sprayed for granulating, and then the crosslinked sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are added for total mixing.
Comparative example 2
Material name Dosage of
API (Compound A meglumine salt) 50mg (calculated as free acid)
Povidone K30 22.6mg
Particle diameter D of the above sample after direct mixing 90 About 263 μm.
Research on the efficacy of pharmaceutical compositions of the compounds of the present invention
1. 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 120EC-C184 μm (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 16
The cynomolgus monkey cross test was performed with example 9 and comparative example 1, and 50mg was administered. The test results show that the Cmax and AUClast of example 9 are significantly better than those of the comparative example (wherein AUClast is increased by a factor of approximately 2), indicating that the co-powders of the compound and carrier, D, are prepared by the co-pulverizing process 90 About 18 mu m, can obviously improve the internal absorption of animals and can better solve the absorption problem of insoluble medicines.
Example 17
The cynomolgus monkey cross test was performed on example 10 and comparative example 1, and 400mg was administered. The test results show that the Cmax and AUClast of example 10 are significantly better than those of the comparative example (wherein AUClast is increased by a factor of approximately 2.6), indicating that the co-powders of the compound and carrier, D, were prepared by the co-pulverizing process 90 After dry granulation, the absorption in animals can be obviously improved by about 18 mu m, and the problem of absorption of insoluble medicines can be well solved.
Example 18
The cynomolgus monkey cross test was performed on example 11 and comparative example 1, and the dose of administration was 200mg. The test results showed that the Cmax and AUClast of example 11 were significantly better than those of comparative example (wherein AUClast was increased by approximately 2.5 times, and when 200mg was administered: AUClast of comparative example 1 was 11119.5h ng/ml), indicating that the co-powders of the compound and carrier prepared by co-pulverizing process, D 90 After dry granulation, the absorption in animals can be obviously improved by about 10 mu m, and the absorption problem of insoluble medicines can be better solved.
As can be seen from examples 15-17, the API and carrier are controlled to a suitable particle size, such as D 90 <30 mu m, can effectively improve the in vivo absorption effect of the medicine.
Example 19
The cynomolgus monkey cross-test was performed on example 12 and example 9, and 50mg was administered. Test results show that the Cmax and AUClast of the example 12 are obviously better than those of the example 9 (wherein AUClast is improved by nearly 1.8 times), and the addition of the alkalizing agent in the prescription can obviously improve the in-vivo absorption of animals and can better solve the absorption problem of insoluble drugs.
Example 20
The cynomolgus monkey cross-test was performed with example 13 and comparative example 1, and 50mg was administered. Test results show that the Cmax and AUClast of the example 13 are obviously better than those of the comparative example 1 (wherein AUClast is improved by nearly 2.5 times), and the addition of the alkalizing agent and the surfactant in the prescription can obviously improve the in-vivo absorption of animals and can better solve the absorption problem of insoluble drugs.
Example 21
The cynomolgus monkey cross-test was performed on example 14 and comparative example 1, and 200mg was administered. Test results show that the Cmax and AUClast of the example 14 are obviously better than those of the comparative example 1 (wherein AUClast is improved by nearly 6 times), and the addition of the alkalizing agent and the surfactant in the prescription and the combination of the co-crushing and dry granulation processes can obviously improve the absorption of animals and better solve the absorption problem of insoluble drugs.
It can be seen from a review of examples 15-21 that the API and carrier are controlled to a suitable particle size, such as D 90 <60 mu m, can effectively improve the in vivo absorption effect of the medicine.
Example 22
According to the above-mentioned pH value measuring method, the pH value of each pharmaceutical composition is measured as follows:
sequence number pH
Example 12 8.14
Example 13 11.19
Example 14 11.24
Example 15 11.30
Example 23
The pharmaceutical composition of the present invention has stable mass, taking example 14 as an example, and is placed at 40 ℃/75% RH to determine the change of impurities, and the increase of the total amount of impurities is superior to that of comparative example 1, and the result is as follows:
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 comprising an active ingredient compound A or a pharmaceutically acceptable salt thereof and one or more excipients,
the D90 of the pharmaceutical composition is < 100. Mu.m, preferably < 90. Mu.m, 80. Mu.m, 60. Mu.m, 50. Mu.m, 40. Mu.m, 30. Mu.m.
2. A pharmaceutical composition according to claim 1, wherein the excipient is an acrylic resin, cellulose acetate titanate, hypromellose phthalate, hypromellose, polyethylene glycol, povidone, or copovidone.
3. A pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is a co-powder of compound a or a pharmaceutically acceptable salt thereof and one or more excipients.
4. A pharmaceutical composition according to any of claims 1-3, wherein the weight ratio of excipient to active ingredient is 3:1 to 1:3.
5. The pharmaceutical composition according to any one of claims 1-4, wherein the pH of the pharmaceutical composition is >5.5, preferably pH >6.
6. The pharmaceutical composition according to any one of claims 1-5, wherein the pharmaceutical composition contains more than one alkalizing agent.
7. A pharmaceutical composition according to claim 6, wherein the alkalizing agent is selected from sodium bicarbonate, sodium carbonate, meglumine, magnesium oxide, dibasic calcium phosphate, tribasic calcium carbonate, magnesium carbonate, dibasic sodium phosphate and monobasic potassium phosphate buffer systems.
8. The pharmaceutical composition according to any one of claims 1-4, wherein the pharmaceutical composition is further dry granulated.
9. The pharmaceutical composition according to claim 8, wherein the proportion of particles after dry granulation is above 50% as 80 mesh screen oversize.
10. A solid formulation comprising the pharmaceutical composition of any one of claims 1-9, said solid formulation being selected from the group consisting of a tablet, a pill, a granule, or a capsule.
11. The solid formulation according to claim 10, characterized in that the solid formulation further comprises other pharmaceutically acceptable excipients selected from at least one of disintegrants, fillers, binders, glidants, surfactants or lubricants.
12. The solid preparation according to claim 11, 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.
13. The solid preparation according to any one of claims 10 to 12, characterized in that the solid preparation comprises:
1) A pharmaceutical composition according to any one of claims 1 to 9 comprising from 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.
CN202310457404.2A 2022-04-19 2023-04-18 Pharmaceutical composition of oxopyridazine amide derivatives, and preparation method and medical application thereof Pending CN116898852A (en)

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CN2022104137760 2022-04-19

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