WO2023185852A1 - 一种环状内酰胺类化合物的注射用药物组合物及其制备方法 - Google Patents

一种环状内酰胺类化合物的注射用药物组合物及其制备方法 Download PDF

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WO2023185852A1
WO2023185852A1 PCT/CN2023/084402 CN2023084402W WO2023185852A1 WO 2023185852 A1 WO2023185852 A1 WO 2023185852A1 CN 2023084402 W CN2023084402 W CN 2023084402W WO 2023185852 A1 WO2023185852 A1 WO 2023185852A1
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injection
solution
compound
freeze
formula
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PCT/CN2023/084402
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English (en)
French (fr)
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王利
王建伟
蒋炜
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四川海思科制药有限公司
艾克赛特赫拉制药有限责任公司
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Publication of WO2023185852A1 publication Critical patent/WO2023185852A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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

Definitions

  • the present invention relates to the field of pharmaceutical preparations, and specifically relates to an injectable pharmaceutical composition of compound (I) used for systemic anticoagulation in hemodialysis and intraoperative patients and a preparation method thereof.
  • Compound (I) is a novel, potent, selective small molecule factor XIa inhibitor (FXIa) designed to prevent thrombosis and limit the risk of bleeding.
  • FXIa factor XIa inhibitor
  • the object of the present invention is to provide a new injection pharmaceutical composition of compound (I) and its preparation method, so as to obtain a finished preparation that is beneficial to industrial production, has qualified quality, good stability and good safety.
  • the object of the present invention is to provide an injectable pharmaceutical composition of compound (I), which is prepared by combining compound (I), a cosolvent and a pH regulator or other inactive ingredients.
  • the composition of the present invention is beneficial to industry. Production, good stability, qualified quality and good safety.
  • the invention provides an injectable pharmaceutical composition of compound (I) for systemic anticoagulation in hemodialysis and intraoperative patients, which contains the active ingredient compound (I), as well as pharmaceutically acceptable solvents, pH regulators, etc. It is prepared through reasonable compatibility of excipients.
  • the invention provides an injection pharmaceutical composition of compound (I), which adopts appropriate co-solvent and dosage, controls a reasonable pH value, has good stability and is of qualified quality.
  • the invention provides a freeze-dried preparation for injection, which adopts appropriate auxiliary materials and dosage and controls the solution before freeze-drying within a reasonable pH value range, which is beneficial to industrial production.
  • the prepared finished preparation has good stability and meets the quality requirements.
  • One object of the present invention is to provide an injectable pharmaceutical composition of compound (I):
  • Another object of the present invention is to provide a method for preparing the pharmaceutical composition for injection.
  • Another object of the present invention is to provide the use of the pharmaceutical composition for injection.
  • the present invention provides an injectable pharmaceutical composition, comprising the above-mentioned compound of general formula (I) or its stereoisomer or prodrug, water for injection, pH adjuster and co-solvent, wherein the pharmaceutical composition
  • the pH value is 4 to 9
  • the cosolvent is selected from weakly alkaline reagents, such as weakly base or weakly alkaline buffer system/buffer pair, preferably any one or any of arginine, sodium carbonate or sodium bicarbonate. Several mixtures in any proportion.
  • the pH value of the pharmaceutical composition is 7 to 9, preferably 7.3 to 8.5, and more preferably 7.61 to 8.3.
  • the mass ratio of the cosolvent to the compound of formula (I) is 0.2 to 2:1.
  • the mass ratio of arginine to the compound of formula (I) is 0.5-2:1, preferably 0.9-1.2:1, and more preferably 1.2:1, 1.1:1, 1:1, and more preferably 1.1:1.
  • the mass ratio of sodium carbonate to the compound of formula (I) is 0.3 to 1:1, preferably 0.5 to 1:1.
  • the mass ratio of sodium carbonate: sodium bicarbonate: compound of formula (I) is 0.3-1:0.1-0.5:1.
  • the pH adjuster is selected from any one or a mixture of any of several pharmaceutically acceptable inorganic acids or organic acids in any proportion.
  • the inorganic acid is selected from sulfuric acid, hydrochloric acid, and phosphoric acid;
  • the organic acid is selected from acetic acid, benzoic acid, tartaric acid, lactic acid, methanesulfonic acid, citric acid, and maleic acid.
  • the concentration of the compound of formula (I) is 10 mg/ml to 100 mg/ml (calculated as C 19 H 26 N 4 O 4 ) in free base form, preferably 15 mg/ml to 50 mg/ml. , more preferably 15mg/ml ⁇ 25mg/ml.
  • the concentration of the compound of formula (I) is 10 mg/ml to 200 mg/ml (calculated as C 19 H 26 N 4 O 4 ) in free base form, preferably 15 mg/ml to 150 mg/ml. , more preferably 25 mg/ml ⁇ 100 mg/ml.
  • the purity of the compound of formula (I) is greater than or equal to 90.0%, preferably greater than or equal to 95.0%, more preferably 98.0% or more.
  • the present invention also provides a freeze-dried preparation for injection.
  • the above pharmaceutical composition for injection is further freeze-dried to obtain a freeze-dried preparation for injection.
  • the present invention includes the compound of general formula (I) or its stereoisomer or prodrug, a pH adjuster and a co-solvent, wherein the co-solvent is selected from From weakly alkaline reagents, such as weakly alkaline or weakly alkaline buffer systems/buffer pairs, any one of arginine, sodium carbonate or sodium bicarbonate or a mixture of any of them in any proportion is preferred.
  • weakly alkaline reagents such as weakly alkaline or weakly alkaline buffer systems/buffer pairs, any one of arginine, sodium carbonate or sodium bicarbonate or a mixture of any of them in any proportion is preferred.
  • the present invention relates to when the co-solvent is selected from arginine, the mass ratio of arginine to the compound of formula (I) is 0.5-2:1, preferably 0.9-1.2 :1, more preferably 1.2:1, 1.1:1, 1:1, even more preferably 1.1:1.
  • the present invention relates to when the co-solvent is selected from sodium carbonate, the mass ratio of sodium carbonate to the compound of formula (I) is 0.3 to 1:1, preferably 0.5 to 1:1.
  • the present invention relates to the case where the co-solvent is selected from a mixture of sodium carbonate and sodium bicarbonate, and the mass ratio of sodium carbonate: sodium bicarbonate: compound of formula (I) is 0.3 to 1 :0.1 ⁇ 0.5:1.
  • the present invention has a pH value of an aqueous solution of the freeze-dried preparation of 7 to 9, preferably 7.3 to 8.5, and more preferably 7.61 to 8.3.
  • the present invention relates to the amount of active ingredient in each unit preparation of the freeze-dried preparation being selected from 1 mg to 1500 mg, preferably from 10 to 1000 mg, such as 10 mg, 20 mg, 30 mg, 40 mg , 50mg, 60mg, 80mg, 100mg, 120mg, 125mg, 150mg, 160mg, 200mg, 250mg, 400mg, 500mg, 600mg, 700mg, 800mg, 1000mg, the active ingredient is calculated as free base (calculated as C 19 H 26 N 4 O 4 ).
  • the present invention provides a preparation method of the above-mentioned freeze-dried preparation for injection, wherein the preparation method is selected from any one of the following:
  • Method 1) includes the following steps:
  • Method 2 includes the following steps:
  • the amount of water for injection added in step 1.1 and step 1.2 is 40-60% (w/v%) of the total solution volume.
  • the temperature of the solution 1 in step 1.1 and the Chinese medicinal solution 4 in step 2.1 is cooled to 0 to 25°C, preferably 0 to 15°C.
  • the present invention relates to some embodiments of the above-mentioned preparation method of freeze-dried injection preparations.
  • the appropriate amount of water for injection added in step 2.1 is 60-100% (w/v%) of the total liquid preparation amount; the step The co-solvent in 2.2 is added in solid form, or dissolved into a solution at 1 to 20% (w/v%) of the total liquid volume.
  • the present invention also provides a method for treating or preventing a disease or condition related to Factor XIa in a mammal, which method includes administering any of the above injectable pharmaceutical compositions to a subject.
  • the present invention also provides the use of the above-mentioned pharmaceutical composition for injection in the preparation of medicaments for treating or preventing diseases or conditions related to Factor XIa in mammals.
  • the present invention also provides the use of the above-mentioned pharmaceutical composition for injection in the preparation of drugs for systemic anticoagulation in hemodialysis and intraoperative patients.
  • the disease or condition associated with Factor XIa includes a thromboembolic disease.
  • the mass fraction may be a mass unit well known in the medical field such as ⁇ g, mg, g, kg, etc.;
  • mM mmol/L, millimole per liter.
  • Solution dripping Add the concentrated liquid of compound (I) dropwise to the blank alkali solution at an appropriate rate, adjust the pH with hydrochloric acid of an appropriate concentration, dilute to volume, and pre-filter to obtain the compound (I) intermediate solution;
  • Sterilization, filling, and freeze-drying Add water for injection to make the volume, pre-filter the compound (I) intermediate solution and then filter and sterilize it with a microporous filter membrane. After filling, freeze-dry to obtain the finished product.
  • the appropriate amount of water for injection added in step 1) is 40-60% of the total liquid volume
  • step 1) the blank alkali solution is cooled to 0-25°C;
  • the appropriate amount of water for injection added in step 2) is 40-60% of the total liquid volume
  • the pH adjustment range in step 3) is 4-9.
  • Sterilization, filling, and freeze-drying Add water for injection to make the volume, pre-filter the compound (I) intermediate solution and then filter and sterilize it with a microporous filter membrane. After filling, freeze-dry to obtain the finished product.
  • the appropriate amount of water for injection added in step 1) is 60-100% of the total liquid volume
  • the compound (I) liquid is cooled to 0-25°C;
  • the co-solvent is added in solid form, or dissolved into a solution in the amount of 1 to 20% of the total liquid volume;
  • the pH adjustment range in step 3) is 4-9.
  • Test solution Take 1 bottle of this product, add 5 ml of water to dissolve, dilute with solvent and transfer quantitatively to a 50 ml measuring flask, dilute with solvent to the mark, and shake well.
  • Control solution Precisely measure 1 ml of the test solution, place it in a 100 ml measuring bottle, dilute to the mark with solvent, and shake well.
  • System suitability solution Take appropriate amounts of compound (I) and reference substance respectively, dissolve and dilute with solvent to prepare a mixed solution containing approximately 2.7 mg of compound (I) reference substance and 0.015 mg of compound (II) reference substance per 1 ml.
  • Chromatographic conditions Use octadecylsilane bonded silica gel as filler (Agilent Zorbax Eclipse XDB-C18, 50 ⁇ 4.6mm, 5 ⁇ m or equivalent performance chromatographic column); use 0.1% trifluoroacetic acid aqueous solution as mobile phase A, 0.07 % trifluoroacetic acid acetonitrile solution is mobile phase B; perform gradient elution according to the table below; the flow rate is 1.5ml per minute; the detection wavelength is 210nm; the column temperature is 35°C; the injection volume is 5 ⁇ l, and the sample chamber temperature is 6°C, specifically See the table below for conditions:
  • Determination method Precisely measure the test solution and control solution, inject them into the liquid chromatograph, and record the chromatogram.
  • the impurities are compounds of the following formula (II), and their sources are produced by the degradation of compound (I):
  • Test solution Take 4 bottles of this product, add 5ml of water to dissolve each, dilute with solvent and quantitatively transfer to the same 100ml measuring bottle, dilute with solvent to the mark, shake well, accurately measure an appropriate amount, and quantitatively dilute with solvent to prepare A solution containing approximately 0.25 mg of compound (I) (calculated as C 19 H 26 N 4 O 4 ) per 1 ml.
  • Reference substance solution Take an appropriate amount of compound (I) reference substance, dissolve it with a solvent and quantitatively dilute it to prepare a solution containing approximately 0.25 mg of compound (I) (calculated as C 19 H 26 N 4 O 4 ) per 1 ml.
  • Chromatographic conditions See under related substances.
  • Determination method Precisely measure the test solution and reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculated by peak area according to external standard method.
  • the first part used dilute hydrochloric acid to adjust the pH value to 7.02, and a large amount of precipitation occurred; the second part used dilute hydrochloric acid to adjust the pH value to 7.61, and diluted the volume to 6 ml; the third part directly measured the pH value to 8.99, sampled 2 ml, and diluted the remaining volume to 6 ml.
  • Use compound (I) water for injection, sodium carbonate, and dilute hydrochloric acid to prepare solutions, and then adjust them to pH1.61, pH3.43, pH7.02, pH9.09, and pH10.15 for sampling, respectively, and adjust the volume to 25 mg/ml ( Under the conditions of pH 3.43 and pH 7.02, a solution that cannot meet 25 mg/ml) is precipitated and then filtered to examine the stability of the solution at 25°C.
  • the test results are shown in the table below:
  • the pH tolerance range of the normal human body is: 4 to 9. Within the pH tolerance range of the human body, the known impurity compound (II) and total impurities of the aqueous solution of compound (I) increased significantly, indicating that compound (I) is present in the aqueous solution. It is easily hydrolyzed and unstable in the state, and the stability of aqueous solution decreases with the increase of pH value.
  • Example 1 Prepare an aqueous solution of compound (I) of 7.3 mg/ml to 60.9 mg/ml. Use sodium carbonate and hydrochloric acid to adjust the pH to (pH1.46, pH2.09, pH3.43, pH7.02, pH7.61, pH8.99, pH9.91), examine its concentration under different pH conditions. The test results are shown in the table below:
  • Table 3 shows that compound (I) has great differences in solubility under different pH conditions, and has good solubility at pH 7 to 9. Taking into account the solubility and solution stability of the human body's pH tolerance range, the preparation of this application The pH value is preferably 7 to 9.
  • test data are as follows:
  • Prescription 4 Weigh 823.36 mg of arginine and add 10 ml of water to dissolve it completely to form an alkali solution. Weigh 823.19 mg of compound (I) and add 10 ml of water to dissolve it completely to form a medicinal solution. Add the medicinal solution dropwise to the alkali solution and dissolve it completely. Determine the pH value to be 7.59, then adjust the volume to 30ml.
  • Prescription 5 Weigh 905.73 mg of arginine and add 10 ml of water to dissolve it completely to prepare an alkaline solution. Weigh 823.13 mg of compound (I) and add 10 ml of water to dissolve it completely to prepare a medicinal solution. Add the medicinal solution dropwise to the alkaline solution and dissolve it completely. Determine the pH value to be 8.04, use dilute hydrochloric acid to adjust the pH value to 7.75, and then adjust the volume to 30 ml.
  • Prescription 6 Weigh 988.09 mg of arginine and add 10 ml of water to dissolve it completely to prepare an alkaline solution. Weigh 823.29 mg of compound (I) and add 10 ml of water to dissolve it completely to prepare a medicinal solution. Add the medicinal solution dropwise to the alkaline solution and dissolve it completely. Determine the pH value to be 8.35, use dilute hydrochloric acid to adjust the pH value to 7.78, and then adjust the volume to 30 ml.
  • the amount of co-solvent affects the pH value of the intermediate solution and thus the solubility of compound (I). If the amount of co-solvent is too low, the pH value will decrease, causing the raw material drug to be unable to be completely dissolved or the dissolution process is difficult. The amount of co-solvent is too much. The pH of the solution will increase, the stability will become worse and the osmotic pressure will be too high. The results show that when the dosage ratio of cosolvent arginine and compound (I) is 0.9:1 to 1.2:1, the stability of the solution obtained is better.
  • Recipe 7 Weigh 1000.43 mg of compound (I) (this batch of raw materials has low purity) and dissolve it in about 10 ml of water for injection to obtain solution 2. Weigh 450.68 mg of sodium carbonate and dissolve it in about 25 ml of water for injection to obtain solution 1. Slowly add solution 2 to the continuously stirring solution 1, add 502.97mg sodium carbonate, stir until completely dissolved, add a small amount of water for injection to adjust the volume to 40ml, stir evenly (pH 8.68), filter and fill 2ml into each vial freeze-drying.
  • Prescription 8 Weigh 1645.24 mg of compound (I) and dissolve it in about 25 ml of water for injection to obtain solution 2. Weigh 790.18 mg of sodium carbonate and 164.42 mg of sodium bicarbonate, and dissolve them in about 25 ml of water for injection to obtain solution 1. Slowly add solution 2 to the continuously stirring solution 1 and stir until it is completely dissolved (pH 8.31). After the dropwise addition, adjust the pH to 7.77 with dilute hydrochloric acid. Add a small amount of water for injection to adjust the volume to 60 ml. Stir evenly and then filter and fill 5 ml. into each vial for lyophilization.
  • Prescription 9 Weigh 1645.74 mg of compound (I) and dissolve it in about 25 ml of water for injection to obtain a solution. Weigh 740.16 mg of sodium carbonate and 164.42 mg of sodium bicarbonate, and dissolve them in about 25 ml of water for injection. Slowly add the API solution to the continuously stirring alkali solution and stir until it is completely dissolved (pH 8.24). After the dropwise addition, use dilute hydrochloric acid to adjust the pH to 7.81. Add a small amount of water for injection to adjust the volume to 60ml. Stir evenly before filtering and filling. 5ml into each vial for lyophilization.
  • Preparation of dilute hydrochloric acid measure 30ml of hydrochloric acid (36.0% ⁇ 38.0% (g/g)), and add water to 150ml.
  • Preparation of solution 2 Start the cooling cycle of the liquid preparation tank, add 2.25kg of water for injection to the liquid preparation tank, add 151.0g of arginine to the liquid preparation tank, stir until the arginine is completely dissolved, and continue to cool to 14°C. spare.
  • Dropwise addition Control the temperature of solution 1 to 14°C, slowly add solution 2 dropwise into solution 1, start stirring during the dropwise addition, and the main drug will be completely dissolved after 40 minutes of dropwise addition and stirring, and continue stirring for 10 minutes. After completion, take a sample and measure the initial pH value of the solution to be 8.74 (19.8°C).
  • Adjust pH Use 77ml of dilute hydrochloric acid to slowly adjust the pH of the solution to 7.85 (20°C). After complete dissolution, stir for 10 minutes. Stabilize the volume: Add 0.46kg room temperature water for injection to the constant mass (5.08kg), stir for about 3 minutes after constant volume, take a sample and measure the pH value to be 7.77 (20.2°C). After pre-filtration with 0.45 ⁇ m micropores, the medicinal solution is sterilized and filtered through a 0.22 ⁇ m filter element, and then 5 ml is filled into each vial for freeze-drying.
  • freeze-dried preparations prepared by prescriptions 8, 9, and 10 are of qualified quality and have good stability.
  • Sodium carbonate, sodium bicarbonate, and arginine can be used as suitable cosolvents.
  • Prescription 11 Weigh 1645.74 mg of compound (I) and dissolve it in about 25 ml of water for injection to obtain solution 2.
  • Recipe 12 Preparation of dilute hydrochloric acid: measure 30ml of hydrochloric acid (36.0% ⁇ 38.0% (g/g)), and add water to 150ml.
  • Solution 2 preparation weigh 2.25kg. Add 151.0g of arginine to water for injection at about 36°C, stir for 5 minutes and check that the solution in the tank has dissolved; cool down to 13°C and set aside.
  • Preparation of solution 1 Weigh 2kg and prepare water for injection at about 25°C. Add part of the weighed water for injection into the beaker of 137.2 g of compound (I). After the raw materials are moistened, pour it into the 5L beaker. Rinse the cup with the remaining water for injection and pour it into the 5L beaker.
  • Preparation by dropwise addition slowly add solution 2 dropwise into solution 1, start stirring during the dropwise addition, and stir for 46 minutes. After the solution is completely dissolved, continue stirring for 10 minutes. After completion, take a sample and measure the initial pH value of the solution to be 8.95 (14.7°C).
  • Adjust pH Use about 88ml of dilute hydrochloric acid to slowly adjust the pH of the solution to 7.78 (20.7°C). After complete dissolution, stir for 8 minutes. Stabilize the volume: Add 0.49kg of room temperature water for injection to the constant mass (5.08kg), stir for about 3 minutes after the volume is reached. After pre-filtration with 0.45 ⁇ m micropores, the medicinal solution is sterilized and filtered through a 0.22 ⁇ m filter element, and then 5 ml is filled into each vial for freeze-drying.
  • Solution preparation dilute hydrochloric acid preparation: measure 30ml hydrochloric acid (36.0% ⁇ 38.0% (g/g)) in a 50ml graduated cylinder, place it in a 250ml graduated cylinder and add water for injection to adjust the volume to 150ml.
  • Preparation of alkali solution The liquid preparation tank [magnetic stirring batching tank, 10L, Shanghai Dongfulong Technology Co., Ltd.] starts the cooling cycle, adds 2.25kg of water for injection to the liquid preparation tank, and adds the weighed water to the liquid preparation tank. Arginine, stir until arginine is completely dissolved, continue to cool to 13°C, and set aside.
  • Preparation of medicinal solution Add 2kg of water for injection into the bucket, cool to 25°C, and add the weighed amount into the bucket. Compound (I) was stirred ultrasonically until completely dissolved.
  • Preparation by dropwise addition Slowly add the medicinal solution into the alkali solution dropwise, start stirring during the dripping, and continue stirring for 10 minutes after the main ingredient is completely dissolved. After completion, take a sample and measure the pH value of the solution to be 8.95. Adjust pH: Use dilute hydrochloric acid to slowly adjust the pH of the solution to 7.78. After complete dissolution, stir for 10 minutes. Stabilize the volume: Add room temperature water for injection to 5.08kg. Stir for about 3 minutes after reaching a constant volume. Filtration: The medicinal solution is pre-filtered through a 0.45 ⁇ m polyethersulfone microporous filter, and then filtered through a 0.22 ⁇ m polyethersulfone filter element for sterilization.
  • Filling is carried out according to the filling volume range of 4.877g-5.283g [filling and stoppering machine, KGS18, Chutian Technology Co., Ltd.], and then freeze-dried. After the freeze-drying is completed, remove the plugged product.
  • Capping Carry out capping and check during the process.
  • Solution preparation dilute hydrochloric acid preparation: measure 30ml hydrochloric acid (36.0% ⁇ 38.0% (g/g)), add water to 150ml.
  • Preparation of alkali solution The liquid preparation tank [magnetic stirring batching tank, 10L, Shanghai Dongfulong Technology Co., Ltd.] starts the cooling cycle, adds 2.25kg of water for injection to the liquid preparation tank, and adds the weighed water to the liquid preparation tank. Arginine, stir until arginine is completely dissolved, continue to cool to 14°C, and set aside.
  • Preparation of medicinal solution Add 2 kg of water for injection into the barrel, cool to 17°C, add weighed compound (I) into the barrel, and stir ultrasonically until completely dissolved.
  • Preparation by dripping Control the temperature of the alkali solution to 14°C, add the drug dropwise to the alkali solution, start stirring during the dripping, and continue stirring for 10 minutes after the main drug is completely dissolved. After completion, take a sample and measure the pH value of the solution to be 8.74. Adjust pH: Use dilute hydrochloric acid to slowly adjust the pH of the solution to 7.85. After complete dissolution, stir for 10 minutes. Stabilize the volume: Add room temperature water for injection to 5.08kg. Stir for about 3 minutes after reaching a constant volume. Filtration: The medicinal solution is pre-filtered through a 0.45 ⁇ m polyethersulfone microporous filter, and then filtered through a 0.22 ⁇ m polyethersulfone filter element for sterilization.
  • Filling is carried out according to the filling volume range of 4.877g-5.283g [filling and stoppering machine, KGS18, Chutian Technology Co., Ltd.], and then freeze-dried. After the freeze-drying is completed, remove the plugged product.
  • Capping Carry out capping and check during the process.
  • Solution preparation Preparation of dilute hydrochloric acid: Measure 150ml hydrochloric acid (36.0% ⁇ 38.0% (g/g)), add room temperature water for injection and dilute to 750ml.
  • Preparation of alkali solution The liquid preparation tank [magnetic stirring batching tank, 50L, Shanghai Ritai Pharmaceutical Equipment Engineering Co., Ltd.] starts the cooling cycle, adds 11.25kg of water for injection to the liquid preparation tank, and adds the weighed water to the liquid preparation tank. Arginine, stir until arginine is completely dissolved, continue to cool to 13°C, and set aside.
  • Preparation of medicinal solution Add 10kg of water for injection into the barrel, cool to 22°C, add weighed compound (I) into the barrel, and stir ultrasonically until completely dissolved.
  • Preparation by dripping Control the temperature of the alkali solution to 14°C, add the drug dropwise to the alkali solution, start stirring during the dripping, and continue stirring for 10 minutes after the main drug is completely dissolved. After completion, take a sample and measure the pH value of the solution to be 8.70. Adjust pH: Use dilute hydrochloric acid to slowly adjust the pH of the solution to 7.81. After complete dissolution, stir for 10 minutes. Stabilize the volume: Add room temperature water for injection to 25.40kg. Stir for about 3 minutes after reaching a constant volume. Filtration: The medicinal solution is pre-filtered through a 0.45 ⁇ m polyethersulfone microporous filter, and then filtered through a 0.22 ⁇ m polyethersulfone filter element for sterilization.
  • Filling is carried out according to the filling volume range of 4.877g-5.283g [filling and stoppering machine, KGS18, Chutian Technology Co., Ltd.], and then freeze-dried. After the freeze-drying is completed, remove the plugged product.
  • Capping Carry out capping and check during the process.
  • Lyophilized preparation C is basically stable within 6 hours at room temperature after being combined with 5 ml of 0.9% sodium chloride injection, which meets the needs of clinical lyophilized preparations.
  • Lyophilized preparation A prepared in recipe 17 was tested under high humidity (RH 92.5%), high temperature (40°C) and light (5000lx, 90 ⁇ w/cm2) conditions for 5, 10 and 30 days. The results are shown in the table below:
  • Lyophilized preparations B and C prepared in prescriptions 18 and 19 were placed for 6 months respectively in 1) at a temperature of 25°C ⁇ 2°C and RH 60% ⁇ 5%, and on days 0, 1, 2, 3, 6, and 9 , take samples once in December to test various indicators; or 2) take samples once in 0, 1, 3, 6, 9, 12, 18, 24, 36, 48, and 60 months under the temperature of 5°C ⁇ 3°C , testing various indicators; the results are as follows:
  • Solution preparation Preparation of dilute hydrochloric acid: Measure 90 ml of hydrochloric acid (36.0% ⁇ 38.0% (g/g)), add 360 ml of water to prepare dilute hydrochloric acid. Preparation of alkaline solution: add 1.8kg of water to arginine and heat to 30°C to dissolve. Preparation of medicinal solution: Compound (I) is dissolved in 1.6kg of water. Preparation by dropwise addition: Slowly add the compound (I) solution to the arginine solution. Adjust pH: Use dilute hydrochloric acid to adjust pH to 7.76 (20°C). Subsequent steps include setting the volume, filtering, filling 5ml, freeze-drying, and capping. Lyophilized formulation D of prescription 20 was obtained.
  • Recipe 21 Weigh compound (I) and dissolve it in 16.8 ml of water for injection. Weigh the arginine, add 12.8 ml of water for injection and stir at a constant temperature of 13°C. Slowly add the compound (I) solution to the continuously stirring arginine solution and stir until it is completely dissolved. After the dropwise addition, use dilute hydrochloric acid to adjust the pH value, and add a small amount of water for injection to adjust the volume to 40 ml.
  • Solution preparation dilute hydrochloric acid preparation: measure 120ml hydrochloric acid (36.0% ⁇ 38.0% (g/g)), add 400ml of water to prepare dilute hydrochloric acid.
  • Preparation of alkaline solution Add 1.59kg of water to arginine, stir to form a suspension, and cool to 12°C for later use.
  • Preparation of medicinal solution Add compound (I) to 2.1kg of water to dissolve, and cool to 17°C.
  • Preparation by dropwise addition Slowly add the compound (I) solution to the arginine solution. During the process, the solution temperature is 9°C. After the addition is completed, the solution becomes clear.
  • Adjust pH Use dilute hydrochloric acid to adjust pH to 7.75 (20.3°C). Subsequent steps include setting the volume, filtering, filling 5ml, freeze-drying, and capping. A 500 mg lyophilized preparation E of prescription 22 was obtained.
  • Solution preparation Preparation of dilute hydrochloric acid: Measure 30 ml of hydrochloric acid (36.0% ⁇ 38.0% (g/g)), add 150 ml of water to prepare dilute hydrochloric acid.
  • Preparation of alkali solution add 1.10kg of water to anhydrous sodium carbonate to dissolve, cool to 15°C and set aside.
  • Preparation of medicinal solution Add compound (I) to 1.11kg of water to dissolve, and cool to 16°C.
  • Preparation by dropwise addition Slowly add the compound (I) solution to the anhydrous sodium carbonate solution. During the process, the solution temperature is 15°C. After the addition is completed, the solution becomes clear.
  • Adjust pH Use dilute hydrochloric acid to adjust pH to 7.78 (19.9°C). Subsequent steps include setting the volume, filtering, filling 5ml, freeze-drying, and capping. The 125 mg lyophilized preparation F of prescription 23 was obtained.
  • the freeze-dried preparation D prepared by prescription 20 has been subjected to high humidity (RH 92.5%) and light (5000lx, 90 ⁇ w/cm2).
  • the freeze-dried preparations E and F prepared from prescriptions 22 and 23 have been subjected to high temperature (40°C) and light (5000lx, 90 ⁇ w/cm2). 90 ⁇ w/cm2) conditions were investigated for 5, 10, and 30 days. The results are shown in the table below:

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Abstract

一种环状内酰胺类化合物(I)的注射用药物组合物，以及该注射用药物组合物的制备方法，和该药物组合物在制备治疗与XIa因子相关的疾病或病况的药物中的用途。

Description

一种环状内酰胺类化合物的注射用药物组合物及其制备方法 技术领域
本发明涉及药物制剂领域，具体涉及一种用于血液透析及术中患者的全身抗凝的化合物(I)的注射用药物组合物及其制备方法。
背景技术
化合物(I)是一种新型、有效、选择性小分子XIa因子抑制剂(FXIa)，旨在预防血栓形成且限制出血风险。
本发明目的在于提供一种新的化合物(I)的注射用药物组合物及其制备方法，未即获得有利于工业生产、质量合格、稳定性好、安全性好的成品制剂。
发明内容
本发明的目的在于提供一种化合物(I)的注射用药物组合物，该组合物通过将化合物(I)、助溶剂和pH调节剂或其它非活性成分共同制备，本发明组合物有利于工业生产、稳定性好、质量合格、安全性好。
本发明提供一种用于血液透析及术中患者的全身抗凝的化合物(I)的注射用药物组合物，包含活性成分化合物(I)，以及助溶剂、pH调节剂等药学上可接受的赋形剂经合理配伍制得。
本发明提供一种化合物(I)的注射用用药物组合物，该组合物采用适宜的助溶剂与用量、控制合理的pH值，稳定性好、质量合格。
本发明提供一种注射用冻干制剂，采用适宜的辅料与用量、控制冻干前溶液于合理的pH值范围内，有利于工业生产。制备得到的成品制剂拥有良好的稳定性且质量合格符合规定。
本发明的一个目的是提供化合物(I)的注射用药物组合物：
本发明的另一个目的是提供制备所述注射用药物组合物的方法。
本发明的另一个目的是提供制备所述注射用药物组合物的用途。
在一个方面，本发明提供一种注射用药物组合物，包含上述通式(I)化合物或者其立体异构体或前药、注射用水、pH调节剂以及助溶剂，其中，所述药物组合物的pH值为4～9，所述助溶剂选自弱碱性试剂，如弱碱或弱碱性缓冲体系/缓冲对，优选精氨酸、碳酸钠或碳酸氢钠中的任一种或任几种任意比例的混合物。
本发明的一些实施方案中，所述药物组合物的pH值为7～9，优选为7.3～8.5，更优选为7.61～8.3。
本发明的一些实施方案中，所述助溶剂与式(I)化合物的质量比为0.2～2:1。
本发明的一些实施方案中，所述助溶剂选自精氨酸时，精氨酸与式(I)化合物的质量比为为0.5～2：1，优选为0.9～1.2:1，更优选为1.2:1，1.1:1，1:1，进一步优选为1.1:1。
本发明的一些实施方案中，所述助溶剂选自碳酸钠时，碳酸钠与式(I)化合物的质量比为0.3～1：1，优选0.5～1：1。
本发明的一些实施方案中，所述助溶剂选自碳酸钠和碳酸氢钠的混合物时，碳酸钠：碳酸氢钠：式(I)化合物的质量比为0.3～1：0.1～0.5：1。
本发明的一些实施方案中，所述pH调节剂选自药学上可接受的无机酸或有机酸中的任一种或任几种任意比例的混合物。
本发明的一些实施方案中，所述无机酸选自硫酸、盐酸、磷酸；所述有机酸选自醋酸、苯甲酸、酒石酸、乳酸、甲磺酸、枸橼酸、马来酸。
本发明的一些实施方案中，式(I)化合物的浓度以游离碱形式计算为10mg/ml～100mg/ml(按C19H26N4O4计)，优选为15mg/ml～50mg/ml，更优选15mg/ml～25mg/ml。
本发明的一些实施方案中，式(I)化合物的浓度以游离碱形式计算为10mg/ml～200mg/ml(按C19H26N4O4计)，优选为15mg/ml～150mg/ml，更优选25mg/ml～100mg/ml。
本发明的一些实施方案中，式(I)化合物的纯度大于等于90.0％，优选大于等于 95.0％，更优选大于等于98.0％。
本发明还提供一种注射用冻干制剂，将上述注射用药物组合物进一步冻干，得到注射用冻干制剂。
本发明涉及上述注射用冻干制剂的一些实施方案中，所述制剂包含上述通式(I)化合物或者其立体异构体或前药、pH调节剂以及助溶剂，其中，所述助溶剂选自弱碱性试剂，如弱碱或弱碱性缓冲体系/缓冲对，优选精氨酸、碳酸钠或碳酸氢钠中的任一种或任几种任意比例的混合物。
本发明涉及上述注射用冻干制剂的一些实施方案中，所述助溶剂选自精氨酸时，精氨酸与式(I)化合物的质量比为0.5～2：1，优选为0.9～1.2:1，更优选为1.2:1，1.1:1，1:1，进一步优选为1.1:1。
本发明涉及上述注射用冻干制剂的一些实施方案中，所述助溶剂选自碳酸钠时，碳酸钠与式(I)化合物的质量比为0.3～1：1，优选0.5～1：1。
本发明涉及上述注射用冻干制剂的一些实施方案中，所述助溶剂选自碳酸钠和碳酸氢钠的混合物时，碳酸钠：碳酸氢钠：式(I)化合物的质量比为0.3～1：0.1～0.5：1。
本发明涉及上述注射用冻干制剂的一些实施方案中，所述冻干制剂的水溶液pH值为7～9，优选为7.3～8.5，更优选为7.61～8.3。
本发明涉及上述注射用冻干制剂的一些实施方案中，所述冻干制剂的每个单位制剂中活性成分的量选自1mg～1500mg，优先自10～1000mg，例如10mg、20mg、30mg、40mg、50mg、60mg、80mg、100mg、120mg、125mg、150mg、160mg、200mg、250mg、400mg、500mg、600mg、700mg、800mg、1000mg，活性成分以游离碱计(按C19H26N4O4计)。
在另一方面，本发明提供上述注射用冻干制剂的制备方法，其中，所述的制备方法选自以下任意一种：
方法1)包含如下步骤：
1.1称取处方量的助溶剂加入适量的注射用水溶解降温，制备成均匀的空白溶液①；
1.2称取式(I)化合物溶于适量注射用水中，制备成式(I)化合物药液②；
1.3将药液②以适当速率滴加到溶液①中，并用适当浓度的盐酸调节pH，即得式(I)化合物中间体溶液③；
1.4溶液③加注射用水定容，预过滤后用微孔滤膜过滤除菌，灌装后冷冻干燥得成品。
方法2)包含如下步骤：
2.1称取式(I)化合物溶于适量注射用水中，降温，制备成式(I)化合物药液④；
2.2称量处方量的助溶剂加入到药液④中；
2.3将pH调节剂加入药液④中，即得式(I)化合物中间体溶液⑤；
2.4溶液⑤加注射用水定容，预过滤后用微孔滤膜过滤除菌，灌装后冷冻干燥得成品。
本发明涉及上述注射用冻干制剂制备方法的一些实施方案中，所述步骤1.1和步骤1.2中加入的适量注射用水，加入量为总配液量的40～60％(w/v％)。
本发明涉及上述注射用冻干制剂制备方法的一些实施方案中，所述步骤1.1中溶液①和步骤2.1中药液④降温至0～25℃，优选为0～15℃。
本发明涉及上述注射用冻干制剂制备方法的一些实施方案中，所述步骤2.1中加入的适量注射用水，加入量为总配液量的60～100％(w/v％)；所述步骤2.2中助溶剂以固体形式加入，或以总配液量的1～20％(w/v％)溶解成溶液加入。
本发明还提供一种治疗或预防哺乳动物与XIa因子相关的疾病或病况的方法，所述方法包括给予受试者施用上述任一项的注射用药物组合物。
本发明还提供上述注射用药物组合物在制备治疗或预防哺乳动物与XIa因子相关的疾病或病况的药物中的用途。
本发明还提供上述注射用药物组合物在制备用于血液透析及术中患者的全身抗凝的药物中的用途。
本发明的一些实施方案中，所述与XIa因子相关的疾病或病况包括血栓栓塞疾病。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
所述质量份数可以是μg、mg、g、kg等医学领域公知的质量单位；
本发明所述“符合规定”，是指符合《中国药典2020》标准。
具体实施方式
以下结合实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限 于此。
本发明实施例中所使用的材料，如无特殊说明，均为可从商业途径得到的材料。
本发明中mM＝mmol/L，毫摩尔每升。
本发明的注射用冻干制剂制备工艺：
工艺一：
1)空白碱溶液的制备：称取处方量的助溶剂加入适量的注射用水溶解降温，制备成均匀的空白碱溶液；
2)化合物(I)药液的制备：将称取的化合物(I)原料药溶于适量注射用水中；
3)溶液滴加：将化合物(I)浓药液以适当速率滴加到空白碱溶液中，并用适当浓度的盐酸调节pH，定容、预过滤后即得化合物(I)中间体溶液；
4)除菌、灌装、冻干：加注射用水定容，将化合物(I)中间体溶液预过滤后用微孔滤膜过滤除菌，灌装后冷冻干燥得成品。
为了进一步理解本发明，下面对本发明的部分内容进行解释说明，但不应该构成对本发明的限制，在上述所述的制备方法中：
所述步骤1)中加入的适量注射用水，加入量为总配液量的40～60％；
所述步骤1)中空白碱溶液降温至0～25℃；
所述步骤2)中加入的适量注射用水，加入量为总配液量的40～60％；
所述步骤3)中pH调节范围为4～9。
工艺二：
1)化合物(I)药液的制备：将称取的化合物(I)原料药溶于适量注射用水中；
2)助溶剂的加入：称量处方量的助溶剂加入到化合物(I)药液中；
3)调节pH：将pH调节剂加入药液中，定容、预过滤后即得化合物(I)中间体溶液；
4)除菌、灌装、冻干：加注射用水定容，将化合物(I)中间体溶液预过滤后用微孔滤膜过滤除菌，灌装后冷冻干燥得成品。
为了进一步理解本发明，下面对本发明的部分内容进行解释说明，但不应该构成对本发明的限制，在上述所述的制备方法中：
所述步骤1)中加入的适量注射用水，加入量为总配液量的60～100％；
所述步骤1)中化合物(I)药液降温至0～25℃；
所述步骤2)中助溶剂以固体形式加入，或以总配液量的1～20％溶解成溶液加入；
所述步骤3)中pH调节范围为4～9。
测试方法：
有关物质 照高效液相色谱法(中国药典2020年版四部通则0512)测定。
溶剂：70％乙腈
供试品溶液：取本品1瓶，加水5ml溶解后，用溶剂稀释并定量转移至50ml量瓶中，用溶剂稀释至刻度，摇匀。
对照溶液：精密量取供试品溶液1ml，置100ml量瓶中，用溶剂稀释至刻度，摇匀。
系统适用性溶液：分别取适量化合物(I)和对照品，用溶剂溶解并稀释制成每1ml中约含化合物(I)对照品2.7mg和化合物(II)对照品0.015mg的混合溶液。
色谱条件：用十八烷基硅烷键合硅胶为填充剂(Agilent Zorbax Eclipse XDB-C18，50×4.6mm，5μm或效能相当的色谱柱)；以0.1％三氟乙酸水溶液为流动相A，0.07％三氟乙酸乙腈溶液为流动相B；按照下表进行梯度洗脱；流速为每分钟1.5ml；检测波长为210nm；柱温为35℃；进样体积为5μl，样品室温度6℃，具体条件见下表：
表1
备注：第6分钟到6.1分钟回到初始梯度比例(A:B＝95:5)平衡基线，维持该比例平衡时间，建议7分钟，可根据实际情况调整。
系统适用性要求：系统适用性溶液色谱图中，化合物(II)和主峰的分离度应符合要求。
测定法：精密量取供试品溶液与对照溶液，注入液相色谱仪，记录色谱图。
其中杂质为如下式(II)化合物，来源为化合物(I)降解产生：

含量测定 照高效液相色谱法(中国药典2020年四部通则0512)测定。
溶剂：70％乙腈
供试品溶液：取本品4瓶，分别加水5ml溶解后，用溶剂稀释并定量转移至同一100ml量瓶中，用溶剂稀释至刻度，摇匀，精密量取适量，用溶剂定量稀释制成每1ml中约含化合物(I)(按C19H26N4O4计)0.25mg的溶液。
对照品溶液：取化合物(I)对照品适量，用溶剂溶解并定量稀释制成每1ml中约含化合物(I)(按C19H26N4O4计)0.25mg的溶液。
色谱条件：见有关物质项下。
系统适用性要求：理论板数按化合物(I)峰计算不低于5000。
测定法：精密量取供试品溶液与对照品溶液，分别注入液相色谱仪，记录色谱图。按外标法以峰面积计算。
实施例1
化合物(I)水溶液在不同pH条件下的稳定性考察
取化合物(I)907.98mg溶解于12ml注射用水，均分为3份。第1份定容至5.5ml后测定pH值1.46，取样1.5ml，剩余定容至8ml后测定pH值1.61；第2份逐渐加入碳酸钠，产生大量析出，超声15min后测定pH值2.09；第3份逐渐加入碳酸钠，产生大量析出，超声15min后测定pH值3.43。
取1362.56mg化合物(I)溶解于10ml注射用水配成药液，取1053.80mg碳酸钠溶解于10ml注射用水配成碱溶液，将药液逐渐加入碱溶液，溶解完全后均分为4份。第1份使用稀盐酸调节pH值至7.02，有大量析出；第2份使用稀盐酸调节pH值至7.61，定容至6ml；第3份直接测定pH值为8.99，取样2ml，剩余定容至8ml后测定pH值9.09；第4份逐渐加入碳酸钠调节pH值至9.91，取样2ml，剩余定容至8ml后测定pH值10.15。
使用化合物(I)、注射用水、碳酸钠、稀盐酸制备溶液，然后分别调节至pH1.61、pH3.43、pH7.02、pH9.09、pH10.15取样，分别定容成25mg/ml(pH3.43、pH7.02条件下有析出无法满足25mg/ml)的溶液后过滤，考察溶液在25℃的稳定性。试验结果见下表：
表2
结论：正常人体的pH耐受范围为：4～9，在人体pH耐受范围内化合物(I)水溶液的已知杂质化合物(II)和总杂质均有明显增加，提示化合物(I)在水溶液状态下易水解不稳定，且水溶液稳定性随pH值的升高而降低。
实施例2：筛选pH对处方影响
2.1不同pH对化合物(I)溶解度的影响
样品制备过程见实施例1，配制7.3mg/ml～60.9mg/ml的化合物(I)水溶液分别用碳酸钠与盐酸调节pH为(pH1.46、pH2.09、pH3.43、pH7.02、pH7.61、pH8.99、pH9.91)，考察其在不同pH条件下的浓度。试验结果见下表：
表3
结论：表3表明，化合物(I)处于不同pH条件下溶解度有较大差异，pH值7～9具有较好的溶解度，综合考虑溶解性和人体pH耐受范围的溶液稳定性，本申请制剂pH值优选7～9。
2.2不同pH对溶液的稳定性影响
表4-1
处方13～15制备方法：
称取处方量的精氨酸加入10ml水溶解后放置于15℃水浴配制成溶液1，称取处方量的化合物(I)溶解于10ml 15℃水中配制成溶液2，约40min将溶液2加入溶液1中，检测pH值，若pH值未达到处方要求，加入稀盐酸调节pH值处方要求。
将处方13～15放置于25℃环境下检测0h、4h的有关物质，试验数据如下表：
表4-2
结论：上述数据表明，溶液pH值范围在7-9时，溶液均较为稳定。
实施例3：不同种类助溶剂筛选
3.1助溶剂种类筛选
称取处方量的助溶剂，加入10ml水溶解完全配成溶液1；称取6877.9mg化合物(I)(纯度96.0％)加150ml水溶解完全配成溶液2(游离碱浓度40mg/ml)。在搅拌状态下将溶液2缓慢定量加入各溶液1中，当溶解困难时(出现少量浑浊)记录加入的溶液2的体积。试验结果如下表：
表5

注：137.19mg为拟定规格，制备过程中中间体溶液浓度为25mg/ml(按C19H26N4O4计)。
结论：化合物(I)溶解度受pH值影响较大，需要助溶剂控制pH值以提供良好的溶解度，不同的助溶剂对化合物(I)溶解度有较大影响。
3.2不同助溶剂处方溶液稳定性研究
通过研究溶液稳定性来对比筛选出对化合物(I)较为适宜的助溶剂，检测处方1、2、3制备的中间体溶液的有关物质等，结果如下表：
表6
结论：弱碱性试剂如碳酸钠和精氨酸可作为适宜的助溶剂。
3.3助溶剂比例的处方筛选：
表7

处方4～6制备方法：
处方4：称取823.36mg精氨酸加入10ml水溶解完全后配成碱溶液，称取823.19mg化合物(I)加入10ml水溶解完全配成药液，将药液滴加入碱溶液中溶解完全后测定pH值为7.59，之后定容至30ml。
处方5：称取905.73mg精氨酸加入10ml水溶解完全后配成碱溶液，称取823.13mg化合物(I)加入10ml水溶解完全配成药液，将药液滴加入碱溶液中溶解完全后测定pH值为8.04，使用稀盐酸调节pH值至7.75，之后定容至30ml。
处方6：称取988.09mg精氨酸加入10ml水溶解完全后配成碱溶液，称取823.29mg化合物(I)加入10ml水溶解完全配成药液，将药液滴加入碱溶液中溶解完全后测定pH值为8.35，使用稀盐酸调节pH值至7.78，之后定容至30ml。
检测处方4、5、6制备的溶液的渗透压、有关物质等结果如下表：
表8
结论：助溶剂的用量影响中间体溶液pH值从而影响化合物(I)的溶解度，助溶剂的用量过低会使pH值降低从而造成原料药无法完全溶解或溶解过程困难，助溶剂的用量过多会使溶液pH变大，稳定性变差同时渗透压过高。结果显示，助溶剂精氨酸与化合物(I)的用量比例为0.9:1～1.2:1时，得到的溶液稳定性较好。
实施例4化合物(I)的冻干制剂
4.1不同比例助溶剂的冻干制剂
表9

备注：处方7原料药纯度低，起始总杂2.9％。
处方7：称取化合物(I)(此批原料纯度低)1000.43mg，取约10ml注射用水溶解得到溶液2。称取碳酸钠450.68mg，取约25ml注射用水溶解得到溶液1。将溶液2缓慢加入持续搅拌的溶液1中，补加502.97mg碳酸钠，搅拌至完全溶解后，加入少量注射用水定容至40ml，搅拌均匀后(pH 8.68)过滤灌装2ml至每个西林瓶中进行冻干。
处方8：称取化合物(I)1645.24mg，取约25ml注射用水溶解得到溶液2。称取碳酸钠790.18mg、碳酸氢钠164.42mg，取约25ml注射用水溶解得到溶液1。将溶液2缓慢加入持续搅拌的溶液1中，搅拌至完全溶解(pH8.31)，滴加完毕后用稀盐酸调节pH至7.77，加入少量注射用水定容至60ml，搅拌均匀后过滤灌装5ml至每个西林瓶中进行冻干。
处方9：称取化合物(I)1645.74mg，取约25ml注射用水溶解得到溶液。称取碳酸钠740.16mg、碳酸氢钠164.42mg，取约25ml注射用水溶解。将API药液缓慢加入持续搅拌的碱溶液中，搅拌至完全溶解(pH8.24)，滴加完毕后使用稀盐酸调节pH至7.81，加入少量注射用水定容至60ml，搅拌均匀后过滤灌装5ml至每个西林瓶中进行冻干。
处方10：
稀盐酸配制：量取30ml盐酸(36.0％～38.0％(g/g))，加水至150ml。
溶液2配制：配液罐开启冷却循环，向配液罐中加入2.25kg的注射用水，向配液罐中加入151.0g的精氨酸，搅拌至精氨酸完全溶解，继续降温至14℃，备用。
溶液1配制：向桶中加入2.00kg的注射用水，冷却至17℃，向桶中加入137.2g化合物(I)，超声搅拌至完全溶解。
滴加：控制溶液1温度14℃，将溶液2缓慢滴加入溶液1中，滴加时开启搅拌，滴加搅拌40min后主药完全溶解，继续搅拌10分钟。完成后取样测量溶液初始pH值为8.74(19.8℃)。
调节pH：使用77ml稀盐酸缓慢调节药液pH值至7.85(20℃)，溶解完全后，搅拌10分钟。定容：补加0.46kg室温注射用水至定容质量(5.08kg)，定容后搅拌约3分钟，取样测量pH值为7.77(20.2℃)。药液经0.45μm微孔预过滤后，经0.22μm滤芯除菌过滤，之后灌装5ml至每个西林瓶中进行冻干。
结论：处方8、9、10制得的冻干制剂均质量合格且具有良好的稳定性，碳酸钠、碳酸氢钠、精氨酸均可以作为适宜的助溶剂。
实施例5
表10
处方11：称取化合物(I)1645.74mg，取约25ml注射用水溶解得到溶液2。称取碳酸钠740.16mg、碳酸氢钠164.42mg，取约25ml注射用水溶解得到溶液1。将溶液2缓慢加入持续搅拌的溶液1中，搅拌至完全溶解(pH8.24)，滴加完毕后使用稀盐酸调节pH至7.81，加入少量注射用水定容至60ml，搅拌均匀后过滤灌装5ml至每个西林瓶中进行冻干。
处方12：稀盐酸配制：量取30ml盐酸(36.0％～38.0％(g/g))，加水至150ml。
溶液2配制：称取2.25kg。约36℃注射用水加入151.0g的精氨酸，搅拌5min后查看罐内溶液已溶清；降温至13℃备用。
溶液1配制：称取2kg，约25℃注射用水备用。向137.2g化合物(I)的烧杯中加入已称取的部分注射用水，原料润湿后倒入5L烧杯，剩余注射用水涮杯后全部倒入5L烧杯。
滴加配制：将溶液2缓慢滴加入溶液1中，滴加时开启搅拌，滴加搅拌46min 后溶液完全溶解，继续搅拌10分钟。完成后取样测量溶液初始pH值为8.95(14.7℃)。
调节pH：使用约88ml稀盐酸缓慢调节药液pH值至7.78(20.7℃)，溶解完全后，搅拌8min。定容：补加0.49kg室温注射用水至定容质量(5.08kg)，定容后搅拌约3分钟。药液经0.45μm微孔预过滤后，经0.22μm滤芯除菌过滤，之后灌装5ml至每个西林瓶中进行冻干。
取处方7、11、12制备的冻干制剂，放置于25℃条件下进行稳定性研究，分别于0天、5天、10天、30天时取样，复溶后(保持和冻干前相同浓度)检测有关物质及含量，结果如下：
表11
结论：处方11、12制得的冻干制剂均质量合格且具有较好的稳定性。
实施例9
处方17：
注：工艺中使用到并最终去除的溶剂：注射用水
称量：称量化合物(I)、精氨酸。
配液：稀盐酸配制：50ml量筒量取30ml盐酸(36.0％～38.0％(g/g))，置于250ml量筒中加注射用水定容至150ml。碱溶液配制：配液罐[磁力搅拌配料罐，10L，上海东富龙科技股份有限公司]开启冷却循环，向配液罐中加入2.25kg的注射用水，向配液罐中加入称量好的精氨酸，搅拌至精氨酸完全溶解后，继续降温至13℃，备用。药液配制：向桶中加入配液量2kg的注射用水，冷却至25℃，向桶中加入称量好的 化合物(I)，超声搅拌至完全溶解。滴加配制：将药液缓慢滴加入碱溶液中，滴加时开启搅拌，待主药完全溶解后，继续搅拌10分钟。完成后取样测量溶液pH值为8.95。调节pH：使用稀盐酸缓慢调节药液pH值至7.78，溶解完全后，搅拌10分钟。定容：补加室温注射用水至5.08kg。定容后搅拌约3分钟。过滤：药液预过滤经0.45μm聚醚砜微孔过滤器过滤后，经0.22μm聚醚砜滤芯除菌过滤。
按照装量范围4.877g-5.283g进行灌装[灌装加塞机，KGS18，楚天科技股份有限公司]，然后冻干。冻干结束后将压完塞的制品取出。
轧盖：进行轧盖，过程中进行检查。
实施例10
处方18：
注：工艺中使用到并最终去除的溶剂：注射用水
称量：称量化合物(I)、精氨酸。
配液：稀盐酸配制：量取30ml盐酸(36.0％～38.0％(g/g))，加水至150ml。碱溶液配制：配液罐[磁力搅拌配料罐，10L，上海东富龙科技股份有限公司]开启冷却循环，向配液罐中加入2.25kg的注射用水，向配液罐中加入称量好的精氨酸，搅拌至精氨酸完全溶解后，继续降温至14℃，备用。药液配制：向桶中加入配液量2kg的注射用水，冷却至17℃，向桶中加入称量好的化合物(I)，超声搅拌至完全溶解。滴加配制：控制碱液温度14℃，将药液滴加入碱溶液中，滴加时开启搅拌，待主药完全溶解后，继续搅拌10分钟。完成后取样测量溶液pH值为8.74。调节pH：使用稀盐酸缓慢调节药液pH值至7.85，溶解完全后，搅拌10分钟。定容：补加室温注射用水至5.08kg。定容后搅拌约3分钟。过滤：药液预过滤经0.45μm聚醚砜微孔过滤器过滤后，经0.22μm聚醚砜滤芯除菌过滤。
按照装量范围4.877g-5.283g进行灌装[灌装加塞机，KGS18，楚天科技股份有限公司]，然后冻干。冻干结束后将压完塞的制品取出。
轧盖：进行轧盖，过程中进行检查。
实施例11
处方19：
注：工艺中使用到并最终去除的溶剂：注射用水
称量：称量化合物(I)、精氨酸。
配液：稀盐酸配制：量取150ml盐酸(36.0％～38.0％(g/g))，加室温注射用水稀释至750ml。碱溶液配制：配液罐[磁力搅拌配料罐，50L，上海日泰医药设备工程有限公司]开启冷却循环，向配液罐中加入11.25kg的注射用水，向配液罐中加入称量好的精氨酸，搅拌至精氨酸完全溶解后，继续降温至13℃，备用。药液配制：向桶中加入配液量10kg的注射用水，冷却至22℃，向桶中加入称量好的化合物(I)，超声搅拌至完全溶解。滴加配制：控制碱液温度14℃，将药液滴加入碱溶液中，滴加时开启搅拌，待主药完全溶解后，继续搅拌10分钟。完成后取样测量溶液pH值为8.70。调节pH：使用稀盐酸缓慢调节药液pH值至7.81，溶解完全后，搅拌10分钟。定容：补加室温注射用水至25.40kg。定容后搅拌约3分钟。过滤：药液预过滤经0.45μm聚醚砜微孔过滤器过滤后，经0.22μm聚醚砜滤芯除菌过滤。
按照装量范围4.877g-5.283g进行灌装[灌装加塞机，KGS18，楚天科技股份有限公司]，然后冻干。冻干结束后将压完塞的制品取出。
轧盖：进行轧盖，过程中进行检查。
实施例12
对处方17、18、19制备的冻干前溶液进行检测，结果如下表：
表12
对处方17、18、19制备的冻干制剂进行检测，结果如下表：
表13
注：将冻干制剂复溶后(保持和冻干前溶液相同浓度)进行检测有关物质和含量。
结论：处方17、18、19制备的冻干制剂均质量合格，符合《中国药典2020》标准。
实施例13：冻干制剂配伍稳定性研究
将处方19制备的冻干制剂C与配伍溶剂的相容性进行了研究，所用注射用化合物(I)及溶剂信息见下表：
表14
取冻干制剂C，每瓶加入5ml 0.9％氯化钠注射液，溶解，摇匀，室温放置，分别于0、2、4、6、7小时取样，检测各项指标，结果见下表：
表15

结论：冻干制剂C与5ml 0.9％氯化钠注射液配伍后，室温6小时内基本稳定，满足临床冻干制剂用药需求。
实施例14冻干制剂高温、高湿、光照考察
处方17制备的冻干制剂A经高湿(RH 92.5％)、高温(40℃)和光照(5000lx，90μw/cm2)条件考察5、10、30天，结果见下表：
表16
表17

结论：与0天结果比较，有关物质略有增加，其余各项指标均无明显变化，且均符合规定。
实施例15
加速试验、长期试验考察：
中硼硅玻璃管制注射剂瓶和注射用冷冻干燥用氯化丁基橡胶塞作为内包材，抗生素瓶用铝塑组合盖为配件。
处方18、19制备的冻干制剂B和C分别在1)温度为25℃±2℃，RH 60％±5％条件下放置6个月，于第0、1、2、3、6、9、12月分别取样一次，检测各项指标；或2)温度5℃±3℃条件下于第0、1、3、6、9、12、18、24、36、48、60月分别取样一次，检测各项指标；结果如下表：
表18

结论：数据表明，该冻干制剂对高温(25℃±2℃，RH 60％±5％)比较敏感，低温较为稳定。
同时，表明本品与包材(中硼硅玻璃管制注射剂瓶、注射用冷冻干燥用氯化丁基橡胶塞、抗生素瓶用铝塑组合盖)不发生相互作用，相容性良好。
实施例16
处方20：
注：工艺中使用到并最终去除的溶剂：注射用水
称量：称量化合物(I)、精氨酸。
配液：稀盐酸配制：量取90ml盐酸(36.0％～38.0％(g/g))，加水360ml配置成稀盐酸。碱溶液配制：精氨酸中加水1.8kg，加热30℃溶解。药液配制：化合物(I)加水1.6kg溶解。滴加配制：将化合物(I)溶液缓慢加入至精氨酸溶液中。调节pH：使用稀盐酸调节pH值至7.76(20℃)。后续进行定容、过滤、灌装5ml、冻干、轧盖。获得处方20的冻干制剂D。
实施例17
表19
处方21：称取化合物(I)，取16.8ml注射用水溶解。称取精氨酸，加入12.8ml注射用水13℃恒温搅拌。将化合物(I)溶液缓慢加入持续搅拌的精氨酸溶液中，搅拌至完全溶解，滴加完毕后使用稀盐酸调节pH值，加入少量注射用水定容至40ml。
将上述处方21制备的冻干前溶液进行检测，结果如下表：
表20
实施例18
处方22：
注：工艺中使用到并最终去除的溶剂：注射用水
称量：称量化合物(I)、精氨酸。
配液：稀盐酸配制：量取120ml盐酸(36.0％～38.0％(g/g))，加水400ml配置成稀盐酸。碱溶液配制：精氨酸中加水1.59kg，搅拌呈混悬状，降温至12℃备用。药液配制：化合物(I)加入2.1kg的水中溶解，冷却至17℃。滴加配制：将化合物(I)溶液缓慢加入至精氨酸溶液中，过程中溶液温度9℃，加入完成后溶液澄清。调节pH：使用稀盐酸调节pH值至7.75(20.3℃)。后续进行定容、过滤、灌装5ml、冻干、轧盖。获得处方22的500mg规格的冻干制剂E。
实施例19
处方23：
注：工艺中使用到并最终去除的溶剂：注射用水
称量：称量化合物(I)、无水碳酸钠。
配液：稀盐酸配制：量取30ml盐酸(36.0％～38.0％(g/g))，加水150ml配置成稀盐酸。碱溶液配制：无水碳酸钠中加水1.10kg溶解，降温至15℃备用。药液配制：化合物(I)加入1.11kg的水中溶解，冷却至16℃。滴加配制：将化合物(I)溶液缓慢加入至无水碳酸钠溶液中，过程中溶液温度15℃，加入完成后溶液澄清。调节pH：使用稀盐酸调节pH值至7.78(19.9℃)。后续进行定容、过滤、灌装5ml、冻干、轧盖。获得处方23的125mg规格的冻干制剂F。
实施例21冻干制剂配伍稳定性研究
处方20、23制备的冻干制剂D、F与配伍溶剂的相容性进行了研究，每瓶加入5ml注射用水，溶解，摇匀，在不同温度下放置，分别于各时间点取样，检测各项指标，结果见下表：
表21
实施例22冻干制剂高温、高湿、光照考察
处方20制备的冻干制剂D经高湿(RH 92.5％)和光照(5000lx，90μw/cm2)，处方22、23制备的冻干制剂E、F经经高温(40℃)和光照(5000lx，90μw/cm2)条件考察5、10、30天，结果见下表：
表22
表23

Claims (20)

  1. 一种注射用药物组合物，包含如下式(I)化合物或者其立体异构体或前药、注射用水、pH调节剂以及助溶剂，其中，
    所述药物组合物的pH值为4～9，所述助溶剂选自弱碱性试剂，如弱碱或弱碱性缓冲体系/缓冲对，优选精氨酸、碳酸钠或碳酸氢钠中的任一种或任几种任意比例的混合物。
  2. 根据权利要求1所述的注射用药物组合物，其中，所述药物组合物的pH值为7～9，优选为7.3～8.5，更优选为7.61～8.3。
  3. 根据权利要求1或2所述的注射用药物组合物，其中，所述助溶剂与式(I)化合物的质量比为0.2～2:1。
  4. 根据权利要求1-3中任一项所述的注射用药物组合物，其中，
    助溶剂为精氨酸时，精氨酸与式(I)化合物质量比为0.5～2：1，优选0.9～1.2:1，更优选1.1:1；
    助溶剂为碳酸钠时，碳酸钠与式(I)化合物质量比为0.3～1：1，优选0.5～1：1；
    助溶剂为碳酸钠和碳酸氢钠时，碳酸钠：碳酸氢钠与式(I)化合物质量比为0.3～1：0.1～0.5：1。
  5. 根据权利要求1-4中任一项所述的注射用药物组合物，所述pH调节剂选自药学上可接受的无机酸或有机酸中的任一种或任几种任意比例的混合物。
  6. 根据权利要求5所述的注射用药物组合物，所述无机酸选自硫酸、盐酸、磷酸；所述有机酸选自醋酸、苯甲酸、酒石酸、乳酸、甲磺酸、枸橼酸、马来酸。
  7. 根据权利要求1-6中任一项所述的注射用药物组合物，其中，式(I)化合物的浓度以游离碱形式计算为10mg/ml～200mg/ml(按C19H26N4O4计)，优选为15mg/ml～150mg/ml，更优选25mg/ml～100mg/ml。
  8. 根据权利要求7中所述的注射用药物组合物，其中，式(I)化合物的纯度大于等于90.0％，优选大于等于95.0％，更优选大于等于98.0％。
  9. 一种注射用冻干制剂，其中，将权利要求1-8中任一项所述的注射用药物组合物进一步冻干，得到注射用冻干制剂。
  10. 一种注射用冻干制剂，包含式(I)化合物或者其立体异构体或前药、pH调节剂和助溶剂，所述的助溶剂选自弱碱性试剂，如弱碱或弱碱性缓冲体系/缓冲对，优选精氨酸、碳酸钠或碳酸氢钠中的任一种或任几种任意比例的混合物。
  11. 根据权利要求10所述的注射用冻干制剂，
    助溶剂为精氨酸时，精氨酸与式(I)化合物质量比为0.5～2：1，优选0.9～1.2:1，更优选1.1:1；
    助溶剂为碳酸钠时，碳酸钠与式(I)化合物质量比为0.3～1：1，优选0.5～1：1；
    助溶剂为碳酸钠和碳酸氢钠时，碳酸钠：碳酸氢钠与式(I)化合物质量比为0.3～1：0.1～0.5：1。
  12. 根据权利要求10至11任一项所述的注射用冻干制剂，所述冻干制剂的水溶液pH值为7～9，优选为7.3～8.5，更优选为7.61～8.3。
  13. 根据权利要求10-12任意一项所述的注射用冻干制剂，所述冻干制剂的每个单位制剂中活性成分的量选自1mg～1500mg，优先自10～1000mg，活性成分以游离碱计(按C19H26N4O4计)。
  14. 一种制备权利要求10至13任一项所述注射用冻干制剂的方法，其中，所述的方法选自：
    方法1)包含如下步骤：
    1.1称取处方量的助溶剂加入适量的注射用水溶解降温，制备成均匀的空白溶液①；
    1.2称取式(I)化合物溶于适量注射用水中，制备成式(I)化合物药液②；
    1.3将药液②以适当速率滴加到溶液①中，并用适当浓度的盐酸调节pH，即得式(I)化合物中间体溶液③；
    1.4溶液③加注射用水定容，预过滤后用微孔滤膜过滤除菌，灌装后冷冻干燥得 成品。
    方法2)包含如下步骤：
    2.1称取式(I)化合物溶于适量注射用水中，降温，制备成式(I)化合物药液④；
    2.2称量处方量的助溶剂加入到药液④中；
    2.3将pH调节剂加入药液④中，即得式(I)化合物中间体溶液⑤；
    2.4溶液⑤加注射用水定容，预过滤后用微孔滤膜过滤除菌，灌装后冷冻干燥得成品。
  15. 根据权利要求14中所述注射用冻干制剂的制备方法，其中所述步骤1.1和步骤1.2中加入的适量注射用水，加入量为总配液量的40～60％(w/v％)。
  16. 根据权利要求14中所述注射用冻干制剂的制备方法，其中所述步骤1.1中溶液①和步骤2.1中药液④降温至0～25℃，优选为0～15℃。
  17. 根据权利要求14中所述注射用冻干制剂的制备方法，其中所述步骤2.1中加入的适量注射用水，加入量为总配液量的60～100％(w/v％)；所述步骤2.2中助溶剂以固体形式加入，或以总配液量的1～20％(w/v％)溶解成溶液加入。
  18. 一种治疗或预防哺乳动物与XIa因子相关的疾病或病况的方法，所述方法包括给予受试者权利要求1～8中任一项所述的注射用药物组合物或者权利要求9～13中任一项所述的注射用冻干制剂。
  19. 根据权利要求18所述的方法,其中，用于血液透析及术中患者的全身抗凝。
  20. 权利要求1～8中任一项所述的注射用药物组合物或者权利要求9～13中任一项所述的注射用冻干制剂在制备治疗或预防哺乳动物与XIa因子相关的疾病或病况的药物中的用途，优选用于血液透析及术中患者的全身抗凝。
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