CN113813228B - Injection with JAK kinase inhibitory activity and preparation method and application thereof - Google Patents

Injection with JAK kinase inhibitory activity and preparation method and application thereof Download PDF

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CN113813228B
CN113813228B CN202111180705.2A CN202111180705A CN113813228B CN 113813228 B CN113813228 B CN 113813228B CN 202111180705 A CN202111180705 A CN 202111180705A CN 113813228 B CN113813228 B CN 113813228B
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injection
inhibitory activity
solution
kinase inhibitory
jak kinase
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CN113813228A (en
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霍志强
吕永磊
戴信敏
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Beijing Xinkaiyuan Pharmaceuticals Co Ltd
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Beijing Xinkaiyuan 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
    • A61K9/08—Solutions
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention belongs to the field of medicines, and particularly relates to an injection with JAK kinase inhibitory activity, a preparation method and application thereof, wherein each 1000ml of the injection with JAK kinase inhibitory activity comprises the following components: 10-20 g of active ingredients; 5-10 g of osmotic pressure regulator; adding 1000mL of water for injection; adjusting the pH of the injection having JAK kinase inhibitory activity with a pH adjusting agent; the injection with JAK kinase inhibitory activity has a pH value of 6.2-6.7. The injection is colorless and clear, does not contain organic solvents, has higher safety, and has good stability by controlling the pH value of the injection to be 6.2-6.7.

Description

Injection with JAK kinase inhibitory activity and preparation method and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to an injection with JAK kinase inhibitory activity, and a preparation method and application thereof.
Background
Janus kinase (JAK) belongs to tyrosine kinase family, composed of JAK1, JAK2, JAK3 and TYK2, and plays an important role in cytokine signal transduction, and JAK/STAT signal pathway is a signal transduction pathway stimulated by various cytokine receptors, and the factors include interleukins (such as IL-2-7, IL-9, IL-10, IL-15, IL-21 and the like), interferons (IFN-alpha, IFN-beta), erythropoietin and the like, and play a key role in participating in biological processes such as immune regulation, immune cell proliferation and the like. Aberrant activation of the JAK/STAT transduction pathway is associated with a variety of diseases, such as common allergies (asthma), autoimmune diseases (transplant rejection, rheumatoid arthritis, multiple sclerosis), and solid and hematologic malignancies, such as leukemias and lymphomas.
A compound having the structure of formula (I) wherein R is a novel JAK kinase inhibitor 1 Represents hydrogen, carbonyl, substituted or unsubstituted C1-C5 alkyl, R 2 Represents a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkylcarbonyl group, wherein when R is as defined 1 Represents substitutedWhen said R is C1-C5 alkyl, the substituent is fluorine 1 When represents an unsubstituted C1-C5 alkyl group, said R1 is selected from one of the following structures:
Figure BDA0003297034170000011
when said R is 2 When representing substituted C1-C6 alkyl, the substituent is cyano or fluoro, when said R is 2 When representing a substituted C1-C6 alkylcarbonyl group, the substituent is fluorine, amino, phenyl or pyridyl. The compound with the structure shown in the formula I is used as a JAK kinase inhibitor and has important significance for developing tumor medicaments.
The injection is a sterile solution prepared from the medicines and used for being injected into a body, and has quick absorption and quick action. Especially, intravenous injection can make the liquid medicine directly enter blood circulation, and the injection does not pass through gastrointestinal tract, so it is not affected by digestive system and food, so the dosage is accurate and the action is reliable. In the prior art, only the compound with the structure of formula I is researched, and no related report about the injection of the compound is provided.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide an injection with JAK kinase inhibitory activity, a preparation method and application thereof, so as to solve the problem that the prior art has no related report about the injection of the compound with the structure shown in the formula I.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides an injection having JAK kinase inhibitory activity, comprising per 1000ml of the injection having JAK kinase inhibitory activity:
10-20 g of active ingredients;
5-10 g of osmotic pressure regulator;
adding 1000mL of water for injection;
adjusting the pH of the injection having JAK kinase inhibitory activity with a pH adjusting agent;
the pH value of the injection with JAK kinase inhibitory activity is 6.2-6.7;
the active ingredient is a compound with a structure shown in a formula I or a pharmaceutically acceptable salt thereof:
Figure BDA0003297034170000021
in the formula, R 1 Represents hydrogen, carbonyl, substituted or unsubstituted C1-C5 alkyl; r 2 Represents a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkylcarbonyl group; wherein when said R is 1 When represents a substituted C1-C5 alkyl group, the substituent is fluorine; when said R is 1 When represents an unsubstituted C1-C5 alkyl group, said R 1 Selected from one of the following structures:
Figure BDA0003297034170000031
when said R is 2 When represents a substituted C1-C6 alkyl group, the substituent is cyano or fluorine;
when said R is 2 When representing a substituted C1-C6 alkylcarbonyl group, the substituent is fluorine, amino, phenyl or pyridyl.
The injection provided by the invention is colorless and clear, does not contain organic solvents, has higher safety, and has good stability by controlling the pH value of the injection to be 6.2-6.7.
Preferably, the active ingredient is at least one of the compounds represented by the formulae (1) to (28):
Figure BDA0003297034170000032
/>
Figure BDA0003297034170000041
in any of the above embodiments, preferably, the osmotic pressure regulator is at least one of sodium chloride, glucose, mannitol, sorbitol, and glycerol.
In any of the above schemes, preferably, the pH regulator is at least one of hydrochloric acid, acetic acid, and citric acid.
In a second aspect, the present invention provides a method for preparing an injection having JAK kinase inhibitory activity according to the first aspect, comprising the steps of:
s1, dissolving the osmotic pressure regulator with the prescription amount in 60-90% of the injection water with the prescription amount to obtain a solution A;
s2, adding the active ingredient with the prescription amount into the solution A, adjusting the pH value of the solution A by using the pH regulator, and controlling the pH value of the solution A to be 6.0-6.6 to obtain a solution B;
s3, adding the water for injection into the solution B to a prescribed amount to obtain a solution C;
and S4, sterilizing and filtering the solution C by using a 0.45-micrometer and 0.22-micrometer microporous filter element to obtain a filtrate, subpackaging the filtrate, filling nitrogen, plugging and capping to obtain a filling liquid, and then sterilizing to obtain the injection with JAK kinase inhibitory activity.
The preparation method provided by the invention has the beneficial effects that: (1) The preparation method has simple process and convenient operation, and is suitable for large-scale industrial production; (2) The invention can improve the solubility of the active ingredient by controlling the pH value of the solution A to be 6.0-6.6, thereby shortening the dissolution time of the active ingredient; (3) The pH value of the finally prepared injection is 6.2-6.7, and the stability of the injection can be improved.
Preferably, before said dissolving the prescribed amount of said tonicity modifier in 60% to 90% of the prescribed amount of said water for injection, further comprising: weighing 60-90% of the prescription amount of the injection water, filling nitrogen below the liquid surface, and controlling the dissolved oxygen amount in the injection water to be less than 2mg/L.
In any of the above embodiments, preferably, in step S1, the temperature of the water for injection is 20 to 40 ℃.
In any of the above schemes, preferably, in step S4, the microporous filter element is a polyethersulfone microporous filter element.
In any of the above schemes, preferably, in step S4, the sterilizing step is to place the filling liquid in a water bath sterilization cabinet, and sterilize for 15min at 121 ℃.
In a third aspect, the invention provides a use of the injection with JAK kinase inhibitory activity in the first aspect as a JAK inhibitor in preparation of a medicament for preventing and/or treating tumor diseases related to JAK abnormalities.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more apparent, the present invention is further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The experimental reagents used in the following examples, unless otherwise specified, were all conventional biochemical reagents; the raw materials, instruments, equipment and the like used in the following examples are either commercially available or available by existing methods; the dosage of the experimental reagent is the dosage of the reagent in the conventional experimental operation if no special description exists; the experimental methods are conventional methods unless otherwise specified.
In a first aspect, embodiments of the present invention provide an injection having JAK kinase inhibitory activity, including per 1000ml of the injection having JAK kinase inhibitory activity:
10-20 g of active ingredients;
5-10 g of osmotic pressure regulator;
adding 1000mL of water for injection;
adjusting the pH of the injection having JAK kinase inhibitory activity with a pH adjuster;
the pH value of the injection with JAK kinase inhibitory activity is 6.2-6.7;
the active ingredient is a compound with a structure shown in a formula I or a pharmaceutically acceptable salt thereof:
Figure BDA0003297034170000061
in the formula, R 1 Represents hydrogen, carbonyl, substituted or unsubstituted C1-C5 alkyl; r 2 Represents a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkylcarbonyl group; wherein when said R is 1 When represents a substituted C1-C5 alkyl group, the substituent is fluorine; when said R is 1 When represents an unsubstituted C1-C5 alkyl group, said R 1 Selected from one of the following structures:
Figure BDA0003297034170000071
when said R is 2 When represents a substituted C1-C6 alkyl group, the substituent is cyano or fluorine;
when said R is 2 When representing a substituted C1-C6 alkylcarbonyl group, the substituent is fluoro, amino, phenyl or pyridyl.
The injection provided by the embodiment of the invention is colorless and clear, does not contain organic solvent, has higher safety, and has good stability by controlling the pH value of the injection to be 6.2-6.7.
Further, the active ingredient is at least one of the compounds represented by the formulae (1) to (28):
Figure BDA0003297034170000072
/>
Figure BDA0003297034170000081
further, the osmotic pressure regulator is at least one of sodium chloride, glucose, mannitol, sorbitol and glycerol, and preferably, the osmotic pressure regulator is sodium chloride.
Further, the pH regulator is at least one of hydrochloric acid, acetic acid and citric acid.
In a second aspect, the embodiment of the present invention provides a method for preparing an injection with JAK kinase inhibitory activity according to the first aspect, comprising the following steps:
s1, dissolving a prescribed amount of the osmotic pressure regulator in 60% -90% of prescribed amount of the water for injection (such as 60% of prescribed amount, 70% of prescribed amount, 80% of prescribed amount or 90% of prescribed amount) to obtain a solution A;
s2, adding the active ingredient with the prescription amount into the solution A, adjusting the pH value of the solution A by using the pH regulator, and controlling the pH value of the solution A to be 6.0-6.6 to obtain a solution B;
s3, adding the water for injection into the solution B to a prescribed amount to obtain a solution C;
and S4, sterilizing and filtering the solution C by using a 0.45-micrometer and 0.22-micrometer microporous filter element to obtain a filtrate, subpackaging the filtrate, filling nitrogen, plugging and capping to obtain a filling liquid, and then sterilizing to obtain the injection with JAK kinase inhibitory activity.
If 1000mL of an injection having JAK kinase inhibitory activity is to be prepared, 60% -90% of the prescribed amount of the water for injection means 600 mL-900 mL of the water for injection, and the addition of the water for injection to the prescribed amount in step S3 means addition of the water for injection to 1000mL.
The preparation method provided by the invention has the beneficial effects that: (1) The preparation method has simple process and convenient operation, and is suitable for large-scale industrial production; (2) The pH value of the solution A is controlled to be 6.0-6.6, so that the over-high acidity of the solution A can be avoided, the solution A reacts with active ingredients, the impurity content of the injection is increased, the solubility of the active ingredients can be improved, and the dissolving time of the active ingredients is shortened; (3) The pH value of the finally prepared injection is 6.2-6.7, so that the active ingredients can be prevented from reacting in a low-pH-value solution for a long time to generate impurities, the stability of the injection is improved, and the stimulation and pain of the injection part of a human body can be reduced.
Further, before said dissolving the prescribed amount of said osmolality adjusting agent in 60% to 90% of the prescribed amount of said water for injection, further comprising: weighing 60-90% of the injection water according to the prescription amount, filling nitrogen below the liquid level, and controlling the dissolved oxygen amount in the injection water to be less than 2mg/L. The nitrogen is filled during liquid preparation and filling, so that the stability of the injection in the liquid preparation process and the long-term storage process is ensured, activated carbon adsorption is not adopted, the risk of introducing new impurities and activated carbon residues is avoided, and the medication safety is improved.
Further, in step S1, the temperature of the water for injection is 20 to 40 ℃, and for example, the temperature of the water for injection may be 20 ℃, 25 ℃, 30 ℃, 35 ℃ or 40 ℃. By controlling the temperature of the water for injection to be 20-40 ℃, a low-temperature environment is created, the decomposition and oxidation of active ingredients under the high-temperature condition can be effectively avoided, the generation of impurities is reduced, and the safety of medication and the stability of injection are improved.
Further, in step S4, the microporous filter element is a polyethersulfone microporous filter element. By using the polyether sulfone microporous filter element, the adsorption of the microporous filter element on active ingredients is reduced, and the content of the active ingredients in the injection is greatly ensured.
Further, in step S4, the sterilization step is to place the filling liquid in a water bath sterilization cabinet, and sterilize for 15min at 121 ℃.
In a third aspect, the embodiment of the present invention provides a use of the injection with JAK kinase inhibitory activity according to the first aspect as a JAK inhibitor in preparation of a medicament for preventing and/or treating an oncological disease associated with JAK abnormalities.
The invention is described in further detail with reference to a part of the test results, which are described in detail below with reference to specific examples.
The active ingredients in the following examples and comparative examples were prepared according to the preparation method disclosed in patent No. 202010405089.5.
The contents of the components of the injection solutions having JAK kinase inhibitory activity provided in examples 1 to 4, in terms of 1000mL of the injection solution having JAK kinase inhibitory activity, are shown in table 1.
TABLE 1
Figure BDA0003297034170000101
The contents of the components of the injection having JAK kinase inhibitory activity provided in comparative examples 1 to 2, in terms of 1000mL of the injection having JAK kinase inhibitory activity, are shown in table 2.
TABLE 2
Figure BDA0003297034170000111
Example 1
The content of the components of the injection having JAK kinase inhibitory activity provided in this example is shown in table 1, and the active component of the injection is 4-methyl-3- (((2-oxo-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 2-dihydroquinolin-6-yl) methyl) amino) valeronitrile, and the chemical structure is shown in formula 2:
Figure BDA0003297034170000112
the preparation method comprises the following steps:
s1, taking 800mL of injection water, keeping the temperature at 30 ℃, filling nitrogen for 15 minutes below the liquid surface, controlling the dissolved oxygen amount in the injection water to be 2mg/L, weighing sodium chloride with the amount of a prescription, adding the weighed sodium chloride into the injection water, and stirring at the rotating speed of 600rpm until the sodium chloride is completely dissolved to obtain a solution A;
s2, slowly adding a proper amount of active ingredients and 1mol/L hydrochloric acid into the solution A, dissolving the active ingredients, keeping the pH value of the solution A at 6.0 until the active ingredients are added in the prescribed amount, and stirring for dissolving to obtain a solution B;
s3, adding water for injection into the solution B until the volume is 1000mL to obtain a solution C;
and S4, sterilizing and filtering the solution C by using a PES (polyether sulfone) microporous filter element with the particle size of 0.45 mu m and the particle size of 0.22 mu m to obtain filtrate, filling the filtrate into ampoules, subpackaging the ampoules into 100 mL/bottle, filling nitrogen (the headspace residual oxygen content is less than 5%) above the liquid level before sealing, plugging, capping, detecting leakage to obtain filling liquid, placing the filling liquid in a water bath sterilization cabinet, and sterilizing for 15min at the temperature of 121 ℃ to obtain the injection with JAK kinase inhibitory activity.
The injection having JAK kinase inhibitory activity prepared in this example was measured to have a pH of 6.2.
Example 2
The content of the components of the injection having JAK kinase inhibitory activity provided in this example is shown in table 1, and the active component of the injection is 3-cyclopentyl-3- (((2-oxo-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 2-dihydroquinolin-6-yl) methyl) amino) propionitrile, the chemical structure of which is shown in formula 5:
Figure BDA0003297034170000121
the preparation method comprises the following steps:
s1 is completely the same as S1 in the embodiment 1;
s2, which is substantially the same as S2 in example 1, except that the pH of the solution A is maintained at 6.2;
s3 is completely the same as S3 in the embodiment 1;
s4 is exactly the same as S4 in example 1.
The injection having JAK kinase inhibitory activity prepared in this example was measured to have a pH of 6.5.
Example 3
The content of the components of the injection having JAK kinase inhibitory activity provided in this example is shown in table 1, the active ingredient of the injection is 3, 3-trifluoro-2- ((((2-oxo-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 2-dihydroquinolin-6-yl) methyl) amino) methyl) propionitrile, and the chemical structure is shown in formula 6:
Figure BDA0003297034170000122
the preparation method comprises the following steps:
s1 is completely the same as S1 in the embodiment 1;
s2, substantially the same as S2 in example 1, except that the pH of the solution A was maintained at 6.3;
s3 is completely the same as S3 in the embodiment 1;
s4 is exactly the same as S4 in example 1.
The injection having JAK kinase inhibitory activity prepared in this example was measured to have a pH of 6.4.
Example 4
The content of the components of the injection having JAK kinase inhibitory activity provided in this example is shown in table 1, and the active component of the injection is 2-cyclobutyl-3- (((2-oxo-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 2-dihydroquinolin-6-yl) methyl) amino) propionitrile, the chemical structure of which is shown in formula 9:
Figure BDA0003297034170000131
the preparation method comprises the following steps:
s1 is completely the same as S1 in the embodiment 1;
s2, which is substantially the same as S2 in example 1, except that the pH of the solution A is maintained at 6.5;
s3 is completely the same as S3 in the embodiment 1;
s4 is exactly the same as S4 in example 1.
The injection having JAK kinase inhibitory activity prepared in this example was measured to have a pH of 6.7.
Comparative example 1
The content of the components of the injection having JAK kinase inhibitory activity provided in this comparative example is shown in table 2, the active ingredient of the injection is 4-methyl-3- (((2-oxo-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 2-dihydroquinolin-6-yl) methyl) amino) valeronitrile, the chemical structure of which is shown in formula 2, as is the active ingredient in example 1.
The preparation method comprises the following steps:
s1 is completely the same as S1 in the embodiment 1;
s2, slowly adding the active ingredients in the prescription amount into the solution A, and stirring to dissolve to obtain a solution B;
s3 is completely the same as S3 in the embodiment 1;
s4 is exactly the same as S4 in example 1.
The injection having JAK kinase inhibitory activity prepared in this example was found to have a pH of 7.4.
Comparative example 2
The content of the components of the injection having JAK kinase inhibitory activity provided in this comparative example is shown in table 2, the active ingredient of the injection is 4-methyl-3- (((2-oxo-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 2-dihydroquinolin-6-yl) methyl) amino) valeronitrile, the chemical structure of which is shown in formula 2, as is the active ingredient in example 1.
The preparation method comprises the following steps:
s1 is completely the same as S1 in the embodiment 1;
s2, basically the same as S2 in example 1, except that an appropriate amount of active ingredient and 1mol/L hydrochloric acid were slowly added to the solution A to dissolve the active ingredient and maintain the pH of the solution A at 4.5;
s3 is completely the same as S3 in the embodiment 1;
s4 is exactly the same as S4 in example 1.
The injection having JAK kinase inhibitory activity prepared in this example was measured to have a pH of 4.6.
Comparative example 3
The content of the components of the injection having JAK kinase inhibitory activity provided in this comparative example was the same as in example 1, and the active ingredient of the injection was 4-methyl-3- (((2-oxo-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 2-dihydroquinolin-6-yl) methyl) amino) valeronitrile, the chemical structure of which was shown in formula 2, which was the same as the active ingredient in example 1.
The preparation method comprises the following steps:
s1 to S3: is completely the same as S1 to S3 in the embodiment 1;
s4, substantially the same as S4 in example 1, except that solution C was sterile filtered through a 0.45 μm and a 0.22 μm PVDF (polyvinylidene fluoride) microporous filter to obtain a filtrate.
Comparative example 4
The comparative example provides an injection having JAK kinase inhibitory activity, which contains the same components as in example 1, and the active ingredient of the injection is 4-methyl-3- (((2-oxo-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 2-dihydroquinolin-6-yl) methyl) amino) valeronitrile, the chemical structure of which is shown in formula 2, as well as the active ingredient of example 1.
The preparation method comprises the following steps:
s1 to S3: is completely the same as S1 to S3 in the embodiment 1;
s4, substantially the same as S4 in example 1, except that solution C was sterile-filtered through a 0.45 μm and a 0.22 μm PTFE (Polytetrafluoroethylene) microporous filter to obtain a filtrate.
Experimental example 1 dissolution time of active ingredient and analysis of Properties of solution B
The dissolution time of the active ingredient and the properties of solution B in step S2 were recorded, and the results are shown in table 3.
TABLE 3
Figure BDA0003297034170000151
As can be seen from table 3, the dissolution time of the active ingredient of comparative example 1 was significantly higher than that of examples 1 to 4 and comparative example 2, and the solution B obtained in comparative example 1 had visible foreign matter, and the active ingredient was not completely dissolved.
The active ingredient of comparative example 2 has the shortest dissolution time, and thus it is known that the solubility of the active ingredient increases as the pH of the water for injection decreases.
Experimental example 2 stability of the injection solutions prepared in examples 1 to 4 and comparative examples 2 to 4 was examined
Test materials: injection solutions prepared in examples 1 to 4 and comparative examples 2 to 4.
The test method comprises the following steps: the injections were placed in a constant temperature incubator at 40 ℃. + -. 2 ℃ and 75%. + -. 10% relative humidity, and the active ingredient content and the content of the relevant substances (active ingredient content was calculated as 12mg/mL as 100%) in each injection were measured at 0 month and 6 months.
The content is detected by high performance liquid chromatography (refer to general rules of the four parts of the 2020 edition of Chinese pharmacopoeia 0512), and the result is shown in Table 4 by calculating peak area according to an external standard method.
TABLE 4
Figure BDA0003297034170000161
As can be seen from table 4, the active ingredient content of the injections prepared in examples 1 to 4 is in the range of 95 to 105%, the total impurity content is low, the drug solutions are colorless and clear, the requirements of the drugs are met, after 6 months, the active ingredient content and the total impurity content do not change obviously, and the injections have high stability.
The injection prepared in the comparative example 2 has low content of active ingredients and high total impurities, and after 6 months, the content of the active ingredients and the content of the total impurities are changed obviously, and the stability of the injection is low.
The microporous filter cores used in comparative examples 3 and 4 have obvious adsorption effect on active ingredients, so that the content of the active ingredients is obviously reduced, and the microporous filter cores do not meet the relevant regulations of medicines.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (9)

1. An injection having a JAK kinase inhibitory activity, comprising per 1000ml of the injection having a JAK kinase inhibitory activity:
10-20 g of active ingredients;
5-10 g of osmotic pressure regulator;
adding 1000mL of water for injection;
adjusting the pH of the injection having JAK kinase inhibitory activity with a pH adjusting agent;
the pH value of the injection with JAK kinase inhibitory activity is 6.2-6.7;
the active ingredient is a compound having the structure of formula I:
Figure FDA0004020544760000011
in the formula, R 1 Represents hydrogen, carbonyl, substituted or unsubstituted C1-C5 alkyl; r 2 Represents a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkylcarbonyl group; wherein when said R is 1 When represents a substituted C1-C5 alkyl group, the substituent is fluorine; when said R is 1 When represents an unsubstituted C1-C5 alkyl group, the R 1 Selected from one of the following structures:
Figure FDA0004020544760000012
when said R is 2 When represents a substituted C1-C6 alkyl group, the substituent is cyano or fluorine;
when said R is 2 When represents a substituted C1-C6 alkylcarbonyl group, the substituent is fluorine, amino, phenyl or pyridyl;
the injection is prepared by the following steps:
s1, dissolving the osmotic pressure regulator with the prescription amount in 60-90% of the injection water with the prescription amount to obtain a solution A;
s2, adding the active ingredient with the prescription amount into the solution A, adjusting the pH value of the solution A by using the pH regulator, and controlling the pH value of the solution A to be 6.0-6.6 to obtain a solution B;
s3, adding the water for injection into the solution B to a prescribed amount to obtain a solution C;
and S4, sterilizing and filtering the solution C by using a 0.45-micrometer microporous filter element and a 0.22-micrometer microporous filter element to obtain filtrate, subpackaging the filtrate, filling nitrogen, plugging and capping to obtain a filling liquid, and then sterilizing to obtain the injection with JAK kinase inhibitory activity, wherein the microporous filter element is a polyether sulfone microporous filter element.
2. The injection having JAK kinase inhibitory activity according to claim 1, wherein the active ingredient is at least one of the compounds represented by formulae (1) to (28):
Figure FDA0004020544760000021
/>
Figure FDA0004020544760000031
3. the injection having JAK kinase inhibitory activity according to claim 1, wherein the tonicity modifier is at least one of sodium chloride, glucose, mannitol, sorbitol, glycerol.
4. The injection having JAK kinase inhibitory activity according to claim 1, wherein the pH adjusting agent is at least one of hydrochloric acid, acetic acid, citric acid.
5. The method for producing an injection having a JAK kinase inhibitory activity according to any one of claims 1 to 4, comprising the steps of:
s1, dissolving the osmotic pressure regulator with the prescription amount in 60-90% of the injection water with the prescription amount to obtain a solution A;
s2, adding the active ingredient with the prescription amount into the solution A, adjusting the pH value of the solution A by using the pH regulator, and controlling the pH value of the solution A to be 6.0-6.6 to obtain a solution B;
s3, adding the water for injection into the solution B to a prescribed amount to obtain a solution C;
and S4, sterilizing and filtering the solution C by using a 0.45-micrometer microporous filter element and a 0.22-micrometer microporous filter element to obtain filtrate, subpackaging the filtrate, filling nitrogen, plugging and capping to obtain a filling liquid, and then sterilizing to obtain the injection with JAK kinase inhibitory activity, wherein the microporous filter element is a polyether sulfone microporous filter element.
6. The method for preparing an injection having JAK kinase inhibitory activity according to claim 5, further comprising, prior to said dissolving a prescribed amount of said osmolality adjusting agent in 60% to 90% of a prescribed amount of said water for injection:
weighing 60-90% of the injection water according to the prescription amount, filling nitrogen below the liquid level, and controlling the dissolved oxygen amount in the injection water to be less than 2mg/L.
7. The method for producing an injection having a JAK kinase inhibitory activity according to claim 5, wherein in step S1:
the temperature of the water for injection is 20-40 ℃.
8. The method for producing an injection having a JAK kinase inhibitory activity according to claim 5, wherein in step S4:
and the sterilization step is to place the filling liquid in a water bath sterilization cabinet, and sterilize for 15min at the temperature of 121 ℃.
9. Use of an injection having JAK kinase inhibitory activity according to any one of claims 1 to 4 as a JAK inhibitor for the preparation of a medicament for the prevention and/or treatment of a neoplastic disease associated with JAK abnormalities.
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