WO2023078171A1 - Fosaprepitant-containing liquid pharmaceutical composition, preparation method therefor, and use thereof - Google Patents

Abstract

A Fosaprepitant-containing liquid pharmaceutical composition, a preparation method therefor, and a use thereof. The Fosaprepitant-containing liquid pharmaceutical composition comprises an active pharmaceutical ingredient, a chelating agent, a stabilizer, and a pH regulator. The active pharmaceutical ingredient comprises Fosaprepitant, and a pharmaceutically acceptable salt, hydrate or solvate of the Fosaprepitant-containing liquid pharmaceutical composition. The Fosaprepitant-containing liquid pharmaceutical composition does not contain polysorbate 80 and lactose. The Fosaprepitant-containing liquid pharmaceutical composition has the advantages of simple preparation process, good physical and chemical stability, convenience in clinical use, no need of redissolution, low microbial pollution risk in the preparation process, suitability for industrial production and the like.

Description

Liquid pharmaceutical composition containing fosaprepitant, its preparation method and application

This application claims to be entitled to the prior application of the patent application number 202111286261.0 submitted to the State Intellectual Property Office of China on November 2, 2021, and the title of the invention is "liquid pharmaceutical composition containing fosaprepitant, its preparation method and application". priority interest. The entirety of said prior application is incorporated by reference into this application.

technical field

The invention relates to a liquid pharmaceutical composition containing fosaprepitant, its preparation method and application.

Background technique

Nausea and vomiting (CINV) is a common adverse reaction during or after cancer chemotherapy. This syndrome can have a significant impact on patients' functional status and quality of life, and patients may postpone chemotherapy plans and sometimes even refuse treatment because of CINV . Emetogenic reactions may be acute (within 24 hours after chemotherapy) or delayed (after 24 hours after chemotherapy). The underlying mechanisms of acute and delayed emesis are thought to be different. Current therapies include serotonin HT3 receptor antagonists such as ondansetron, tropisetron, and granisetron, and the dopamine receptor antagonist metoclopramide. These compounds had sufficient effect on acute CINV but not on delayed CINV.

Fosaprepitant dimeglumine is an active pharmaceutical ingredient for injection marketed by Merck Sharp & Dohme Corp. Fosaprepitant is a water-soluble phosphorylated prodrug of aprepitant that is rapidly converted to aprepitant in vivo after intravenous (IV) administration. Aprepitant is an antagonist of the human substance P neurokinin 1 (NK1) receptor. Thus, the pharmacological activity and antiemetic effects of fosaprepitant mirror those of its parent compound, aprepitant.

Since fosaprepitant (or its salt) will be hydrolyzed into water-insoluble aprepitant under aqueous environment and high temperature conditions, even in solid state, such as in freeze-dried preparations, when the moisture control is not good, fusapitant Saprepitant remains hydrolytically degraded to form aprepitant. Therefore, in order to prevent crystallization and precipitation caused by aprepitant formed by the hydrolytic degradation of potential fosaprepitant during the shelf life of the product, the formulation of fosaprepitant dipglumine for injection contains polysorbate 80, as Solubilizer of aprepitant; and moisture control is very strict.

However, polysorbate 80 (a nonionic surfactant often used as a solubilizer for low-solubility products) can cause various adverse reactions, including severe infusion site reactions and potentially life-threatening allergic reactions; The possible protein residues in excipients and excipients will cause allergies, and the risk is high; the moisture control of freeze-dried products is strict, which makes the freeze-drying process difficult and consumes a lot of energy.

Currently published patent documents are basically the freeze-drying process of fosaprepitant. However, the freeze-drying process is time-consuming, energy-consuming, and costly, and the product has very strict moisture control; and when it is used clinically, it needs to be reconstituted first, which increases the operation and has the risk of bacterial contamination.

Therefore, finding fosaprepitant dosage forms with good physical and chemical stability, simple preparation process and suitable for industrial production is a technical problem urgently to be solved at present.

Contents of the invention

The invention provides a liquid pharmaceutical composition containing fosaprepitant, which comprises: a pharmaceutical active ingredient, a chelating agent, a stabilizer and a pH regulator, and the pharmaceutical active ingredient is fosaprepitant, which can be used pharmaceutically Accepted salt, hydrate or solvate; said liquid pharmaceutical composition containing fosaprepitant does not contain polysorbate 80 and lactose.

According to an embodiment of the present invention, the pharmaceutically acceptable salt of fosaprepitant is preferably fosaprepitant dipeglumine salt.

According to an embodiment of the present invention, the drug loading of the active ingredient of the drug is 1 mg/ml to 400 mg/ml, more preferably 3 mg/ml to 200 mg/ml, and the drug loading refers to that of fosaprepitant The ratio of the mass to the volume of the liquid pharmaceutical composition containing fosaprepitant.

According to an embodiment of the present invention, the chelating agent is selected from one or more of citric acid, tartaric acid, gluconic acid and ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof; in one embodiment, The chelating agent is disodium edetate. Preferably, the mass ratio of the chelating agent to the active pharmaceutical ingredient is 1:8 to 1:56 (w/w), such as 1:50, 1:45, 1:40, 1:30, so The quality of the above-mentioned pharmaceutical active ingredients is based on the mass of fosaprepitant.

According to an embodiment of the present invention, the stabilizer is selected from one or more of oleic acid, sodium oleate, acetate, carbonate, phosphate, citrate, tartrate and borate , preferably one or more of oleic acid, sodium oleate and phosphate.

In some embodiments, the stabilizer is selected from oleic acid and/or sodium oleate.

In some embodiments, the stabilizer is selected from one or more of acetate, carbonate, phosphate, citrate, tartrate and borate, preferably phosphate.

In some embodiments, the stabilizer is selected from a mixture of oleic acid and phosphate, or a mixture of sodium oleate and phosphate.

In some embodiments, the phosphate may be selected from one or both of disodium hydrogen phosphate and sodium dihydrogen phosphate, preferably disodium hydrogen phosphate.

According to an embodiment of the present invention, the pH regulator is selected from hydrochloric acid, sulfuric acid, phosphoric acid, glutamic acid, aspartic acid, sodium hydroxide, tromethamine, arginine, lysine, histidine , one or more of meglumine.

According to an embodiment of the present invention, the pH value of the liquid pharmaceutical composition containing fosaprepitant is in the range of 7.0-10.0, more preferably 7.5-9.5, such as 8.0, 8.5, 8.8, 9.0.

In some embodiments, the amount of the stabilizer is 0.5-20% (W/V), such as 1-20% (W/V), such as 1-10% (W/V), the amount Refer to the percentage of the mass (g) of stabilizer and the total volume (mL) of the liquid pharmaceutical composition containing fosaprepitant;

In some embodiments, when the stabilizer is selected from oleic acid and/or sodium oleate, the amount of oleic acid and/or sodium oleate is preferably 0.5-10% (W/V); In some embodiments, the amount of oleic acid and/or sodium oleate is 1-5% (W/V), such as 1.44% (W/V), 2% (W/V), 2.11% ( W/V), 2.88% (W/V), 4.23% (W/V);

In some embodiments, when the stabilizer is selected from one or more of acetate, carbonate, phosphate, citrate, tartrate and borate, the acetate , carbonate, phosphate, citrate, tartrate and borate in an amount of one or more is preferably 0.5 to 10% (W/V); In some embodiments, the acetic acid The amount of one or more of salt, carbonate, phosphate, citrate, tartrate and borate is 1-5% (W/V), such as 1.6% (W/V), 2 %(W/V), 3%(W/V), 4%(W/V).

According to an embodiment of the present invention, the fosaprepitant liquid pharmaceutical composition can be selected from any one of the following formulations:

Formulation 1: 12.265% (W/V) fosaprepitant dimeglumine, 0.27% (W/V) EDTA-2Na, 1.44% (W/V) oleic acid, and adjust the pH with 0.1M/1.0M NaOH , pH 8.5～9.5.

Formulation 2: 12.265% (W/V) Fosaprepitant Diglumine, 0.27% (W/V) EDTA-2Na, 2.88% (W/V) Oleic Acid, 3% (W/V) Dihydrogen Phosphate Sodium, and adjust the pH with 1.0M NaOH, pH 8.0-9.5.

The present invention also provides the application of the liquid pharmaceutical composition containing fosaprepitant in the preparation of pharmaceutical preparations.

The present invention also provides a pharmaceutical preparation, which contains the above-mentioned liquid pharmaceutical composition containing fosaprepitant.

According to an embodiment of the present invention, the administration of the pharmaceutical preparation is parenteral administration, such as injection administration.

According to the embodiment of the present invention, the pharmaceutical preparation can be an injection; clinically, intravenous infusion can be used. If intravenous infusion is used, it can be diluted with normal saline. The dilution factor of the physiological saline is preferably 25 times to 500 times, more preferably 50 times to 125 times.

According to an embodiment of the present invention, the pharmaceutical preparation may include a packaging material, and the packaging material may be plastic, borosilicate glass or coated borosilicate glass. Described plastic is selected from PVC (polyvinyl chloride), PP (polypropylene), PE (polyethylene), COP (cyclic olefin polymer), COC (cyclic olefin copolymer) and Aclar (Aclar, chlorotrifluoroethylene) One or more of copolymers and homopolymers).

According to an embodiment of the present invention, the pharmaceutical preparation is used for treating diseases caused by NK-1 receptors, and the diseases caused by NK-1 receptors include but not limited to emesis.

The present invention also provides the application of the liquid pharmaceutical composition containing fosaprepitant in the preparation of NK-1 receptor antagonist.

The present invention also provides a method for treating diseases caused by NK-1 receptors, which is to take an effective dose of the fosaprepitant-containing liquid pharmaceutical composition or the pharmaceutical preparation to a patient in need. The diseases caused by NK-1 receptor include but not limited to vomiting.

The beneficial effects of the present invention are: the liquid pharmaceutical composition containing fosaprepitant of the present invention has simple preparation process, good physical and chemical stability, convenient clinical use without reconstitution, low risk of microbial contamination in the preparation process, and is suitable for Advantages of industrial production.

It solves the time-consuming, energy-consuming, high-cost, and very strict control of moisture in the fosaprepitant freeze-drying process in the prior art, and it needs to be reconstituted first when it is used clinically, and the operation is increased, and there will be bacterial contamination risks and other defects.

Definition and Explanation of Terms

Unless otherwise stated, the definitions of terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, specific definitions in the embodiments, etc., can be combined and combined with each other in any way . Such combinations and combinations should fall within the scope of the description of the present application.

The above "% (W/V)" refers to the percentage of the mass (g) of the component to the total volume (mL) of the liquid pharmaceutical composition containing fosaprepitant.

The term "therapeutically effective amount" refers to an amount of a pharmaceutically active ingredient of the invention sufficient to achieve the intended use, including but not limited to the treatment of diseases as defined below. A therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and the disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending upon the particular active ingredient chosen, the dosing regimen upon which it is administered, whether it is administered in combination with other compounds, the timing of administration, the tissue administered and the physical delivery system employed .

Detailed ways

The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies realized based on the above content of the present invention are covered within the scope of protection intended by the present invention.

Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

Example 1

The prescription of table 1 embodiment 1

name	Prescription 1	Prescription 2	Prescription 3
Fosaprepitant Diglumine mg	245.3	245.3	245.3
EDTA-2Na mg	5.4	5.4	5.4
Oleic acid mg	28.8	28.8	28.8
0.1mol/LNaOHml	1	1	1
pH regulator	qs pH 8.79	qs pH 9.00	qs pH 9.29
Dilute to ml	2	2	2

An exemplary preparation method for forming stable fosaprepitant compositions of prescriptions 1 to 3 is described here: after adding prescription amounts of EDTA-2Na, oleic acid, and 0.1M sodium hydroxide solution, according to the dissolution of the solution, add 1M Sodium hydroxide solution, until stirring and dissolving, then add API (fosaprepitant dimeglumine), and adjust to the target pH value with 1M NaOH/20% HCl diluent. The prepared medicinal solution is pre-filtered with a 0.45 μm filter element, filled and sealed to obtain the final product.

Stability of simulated stability lofting: place at 60°C for 24 hours, and temporarily store in a refrigerator at 2-8°C. Observe the appearance of stability samples before and after refrigeration, and detect related substances after refrigeration. The test results are shown in Table 2.

Stability of simulated clinically diluted samples: samples placed at 60°C for 24 hours were diluted 100 times with 0.9% sodium chloride diluent, the diluted samples were placed in a refrigerator at 2-8°C, samples were taken at 5h and 24h respectively, and filtered with a 0.45μm PES filter head Temporarily store in a refrigerator at 2-8°C, observe the appearance of the unfiltered sample, and detect the content of the filtered medicinal solution. The test results are shown in Table 3.

The detection result of prescription in the embodiment 1 of table 2

*Aprepitant results calculated with area normalization.

The results showed that prescriptions 1 to 3 were clear and transparent under all conditions, and no foreign matter was precipitated. Although the content of aprepitant (active ingredient) in the related substance has increased, there is no risk of precipitation under high or low temperature conditions.

The detection result of prescription after dilution in the embodiment 1 of table 3

The results showed that, for prescriptions 1-3, samples placed at 60°C for 24 hours were diluted 100 times and placed at 2-8°C for 24 hours. The samples were all clear and transparent, and no foreign matter was precipitated. And the API content of 5h and 24h is basically the same, indicating that under low temperature conditions, insoluble aprepitant will not be precipitated.

Example 2

The influence of different amounts of oleic acid on the stability of the product was investigated.

The prescription of table 4 embodiment 2

Describe here the exemplary preparation method that is used to form the fosapredide composition of prescription 4～9: in prescription quantity 60～70% water for injection, add the EDTA-2Na of prescription quantity, oleic acid, API (fosapitant meglumine), stir evenly, add 1M sodium hydroxide, stir until a clear solution, and check the pH value; use 1M NaOH/20% HCl to adjust the pH value to 8.5±0.1, and check the pH value after constant volume. The prepared medicinal solution is pre-filtered with a 0.45 μm filter element, filled and sealed to obtain the final product.

The obtained samples were placed at 60°C for stability investigation, and related substances were detected at 0, 4, 8, and 24 hours respectively. The results are shown in Table 5.

The prescription stability result of table 5 embodiment 2

*Aprepitant results calculated with area normalization.

In the above prescriptions, in the 2ml prescription, when the oleic acid dosage is 28.8mg (1.44W/V%), the maximum aprepitant is 8.07%, and the appearance is clear and transparent; in the 4ml prescription, the oleic acid When the dosage is 28.8mg (0.72W/V%), the maximum amount of aprepitant is 9.24%, and there is precipitation on the appearance after standing.

From the above results, it can be seen that the smaller the concentration of oleic acid, the more aprepitant content, and the greater the risk of precipitation.

Example 3

The influence of different buffer ions on product stability was investigated. The specific prescription is shown in Table 6.

The prescription of table 6 embodiment 3

Describe here the exemplary preparation method that is used to form the fosaprepitant composition of prescription 10～16: in prescription quantity 60～70% water for injection, add the EDTA-2Na of prescription quantity, buffer salt, then add API (Fusapitant After dissolution of sapitant (diglumine), the pH value was checked. Use 1M NaOH/HCl to adjust the pH value to 10.0, and measure the pH value after constant volume. The prepared medicinal solution is pre-filtered with a 0.45 μm filter element, filled and sealed to obtain the final product.

The stability of the obtained product was tested at 60°C, and related substances were detected at 0 and 24 hours respectively. The results are shown in Table 7.

The prescription stability detection result of table 7 embodiment 3

*Aprepitant results calculated with area normalization.

At the same pH level, prescription 14—citrate buffer solution, prescription 15—tartaric acid buffer solution, prescription 16—boric acid buffer solution had higher aprepitant content at 60°C and 0h (most prescriptions were at 0h) The prepitant content is basically 0.2-0.3%), especially the prescription 14,0h aprepitant content is 0.99%, much higher than other prescriptions.

At 60°C and 24 hours, prescription 14-citrate buffer solution and prescription 15-tartrate buffer solution had the highest aprepitant content, exceeding 4%. Among the buffer ion pairs, the slowest increase in aprepitant content was in the prescription 11-phosphate buffer system, and the final aprepitant content was the lowest, which was 3.32%.

When the buffer pair is a phosphate system, the increase of aprepitant is the least, and the system is the most stable.

Example 4

The prescription of table 8 embodiment 4

The above prescription was prepared according to the preparation method in Implementation 2, and the obtained product was placed at 60°C to investigate the stability, and the related substances were detected at 0, 4, 8, and 24 hours respectively. The results are shown in Table 9.

The prescription stability result of table 9 embodiment 4

*Aprepitant results calculated with area normalization.

As can be seen from the above data, the prescription (prescription 4) of oleic acid alone has a clear and transparent appearance and good physical stability. After combined use of phosphate, the stability was further improved, and the growth rate of aprepitant was significantly reduced. It shows that the phosphate root system has a certain stabilizing effect on the stability of the product, and the greater the concentration, the more stable the system.

Example 5

The prescription of table 10 embodiment 5

name	Prescription 21
Fosaprepitant Diglumine mg	245.3
EDTA-2Na mg	5.4
Disodium hydrogen phosphate mg	60
Oleic acid mg	57.6
pH regulator	Adjust pH 8.5
Dilute to ml	2

The above prescription was prepared according to the preparation method in Implementation 2. The product was placed upside down and placed at high temperatures of 25°C and 40°C to test its stability. At the same time, it is compared with the marketed preparation (trade name EMEND, licensee: MERCK SHARP&DOHME CORP., manufacturer Patheon Manufacturing Services LLC, batch number: T037941). The data are shown in Table 11.

The prescription of table 11 embodiment 5 is compared with the stability result of listed preparations

*Aprepitant is the active ingredient, calculated by area normalization and not included in the total miscellaneous calculation.

The appearance of the samples at each time point of prescription 21 was clear and transparent. Although aprepitant had an increasing trend, it did not precipitate, and the system was stable. It shows that the stability of prescription 21 is equivalent to that of the marketed preparation.

Sample stability of simulated clinical dilution: use the above 40°C-10 day prescription 21 samples, dilute 75 times with 0.9% sodium chloride, place at 25°C, take samples at 0, 4, 8, and 24 hours respectively, and observe the diluted samples The appearance of the diluted drug solution was detected to detect the fosaprepitant content and related substances.

Table 12 Prescription 21 Stability 40°C-10 days sample dilution stability

*Aprepitant is the active ingredient, calculated by area normalization and not included in the total miscellaneous calculation.

The test results of the stability of the diluent showed that the content of API was stable, the aprepitant remained basically unchanged, the growth of total impurities was small, and the stability of the diluent was good.

Example 6

After Prescription 21 is placed at a high temperature of 80°C for 4 hours, observe the appearance and detect related substances. Simulate the stability of the clinically diluted sample, dilute it 75 times with 0.9% sodium chloride, place it at 25°C, take samples at 0, 14, and 24 hours respectively, observe the appearance of the diluted sample, and detect the related substances of the diluted medicinal solution. At the same time, the commercial preparation (trade name EMEND, licensee: MERCK SHARP&DOHME CORP., manufacturer Patheon Manufacturing Services LLC, batch number: T037941) was used for comparison.

Table 13 Prescription 21 stability 80°C-4h sample and market preparation dilution stability comparison

*Aprepitant is the active ingredient, calculated by area normalization and not included in the total miscellaneous calculation.

The results showed that the aprepitant increased to 5.68% after prescription 21 high temperature 80℃-4h, the appearance was still clear and transparent, and the total impurities were equivalent to the marketed preparations; and other impurities have no significant change, and the total impurity level is comparable to that of the listed preparation, indicating that the stability is good.

The liquid pharmaceutical composition containing fosaprepitant provided by the present invention has a simple preparation process, although the active ingredient aprepitant is increased, the physical and chemical stability is still good, and the physical and chemical stability of the administered sample after simulating clinical dilution is simple. Both chemical stability was good.

The embodiments of the present invention have been described above. However, the present invention is not limited to the above-mentioned embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims (10)

1. A kind of liquid medicine composition containing fosaprepitant, it is characterized in that it comprises: pharmaceutical active ingredient, chelating agent, stabilizer and pH regulator, described pharmaceutical active ingredient is fosaprepitant, its pharmaceutically acceptable salt, hydrate or solvate; the liquid pharmaceutical composition containing fosaprepitant does not contain polysorbate 80 and lactose.
2. The liquid pharmaceutical composition containing fosaprepitant as claimed in claim 1, characterized in that: the pharmaceutically acceptable salt of fosaprepitant is fosaprepitant dipeglumine salt;

   and / or,

   The drug loading of the active ingredient of the drug is 1 mg/ml to 400 mg/ml, and the drug loading refers to the ratio of the mass of fosaprepitant to the volume of the liquid pharmaceutical composition containing fosaprepitant;

   Preferably, the drug loading of the active pharmaceutical ingredient is 3 mg/ml to 200 mg/ml, and the drug loading refers to the ratio of the mass of fosaprepitant to the volume of the liquid pharmaceutical composition containing fosaprepitant .
3. The liquid pharmaceutical composition containing fosaprepitant as claimed in claim 1 or 2, is characterized in that: described chelating agent is selected from citric acid, tartaric acid, gluconic acid and ethylenediaminetetraacetic acid or its pharmaceutically acceptable one or more of the salts;

   and / or,

   The weight ratio of the chelating agent to the active pharmaceutical ingredient is 1:8 to 1:56, and the mass of the active pharmaceutical ingredient is based on the mass of fosaprepitant.
4. The liquid pharmaceutical composition containing fosaprepitant as described in any one of claim 1-3, it is characterized in that: described stabilizing agent is selected from acetate, carbonate, phosphate, citrate, tartaric acid One or more of salt, borate, oleic acid and sodium oleate;

   Preferably, the pH regulator is selected from hydrochloric acid, sulfuric acid, phosphoric acid, glutamic acid, aspartic acid, sodium hydroxide, tromethamine, arginine, lysine, histidine, meglumine one or more of.
5. The liquid pharmaceutical composition containing fosaprepitant according to any one of claims 1-4, characterized in that: the pH value of the liquid composition containing fosaprepitant is in the range of 7.0 to 10.0, preferably 7.5 ~9.5.
6. The liquid pharmaceutical composition containing fosaprepitant according to any one of claims 1-5, characterized in that: the amount of the stabilizer is 0.5-20% (W/V), such as 1-20% (W/V), described consumption refers to the percentage of the quality (g) of stabilizing agent and fosaprepitant liquid pharmaceutical composition total volume (mL);

   When described stabilizing agent adopts oleic acid and/or sodium oleate, the consumption of described oleic acid and/or sodium oleate is preferably 0.5～10% (W/V); When described stabilizing agent adopts vinegar When one or more of salts, carbonates, phosphates, citrates, tartrates and borates, the acetate, carbonates, phosphates, citrates, tartrates and The amount of one or more borates used is preferably 0.5-10% (W/V).
7. The fosaprepitant-containing liquid pharmaceutical composition as described in any one of claims 1-6, is characterized in that: described fosaprepitant liquid pharmaceutical composition can be any of the following formulations:

   Formulation 1: 12.265% (W/V) fosaprepitant dimeglumine, 0.27% (W/V) EDTA-2Na, 1.44% (W/V) oleic acid, and adjust the pH with 0.1M/1.0M NaOH , pH 8.5～9.5;

   Formulation 2: 12.265% (W/V) Fosaprepitant Diglumine, 0.27% (W/V) EDTA-2Na, 2.88% (W/V) Oleic Acid, 3% (W/V) Dihydrogen Phosphate Sodium, and adjust the pH with 1.0M NaOH, pH 8.0-9.5.
8. The liquid pharmaceutical composition containing fosaprepitant according to any one of claims 1-7, characterized in that: the liquid composition containing fosaprepitant is a liquid composition for parenteral administration.
9. Use of the fosaprepitant-containing liquid pharmaceutical composition according to any one of claims 1-8 in the preparation of NK-1 receptor antagonists.
10. Use of the fosaprepitant-containing liquid pharmaceutical composition as described in any one of claims 1-8 in the preparation of a pharmaceutical preparation; the pharmaceutical preparation can be an injection;

    Preferably, the pharmaceutical preparation comprises a packaging material, and the packaging material is plastic, borosilicate glass or coated borosilicate glass;

    Preferably, the plastic is selected from one or more of polyvinyl chloride, polypropylene, polyethylene, cycloolefin polymer, cycloolefin copolymer and Accra.