TW202333742A - Liquid pharmaceutical composition containing fosaprepitant, preparation method and application - Google Patents

Abstract

The present disclosure discloses a liquid pharmaceutical composition containing fosaprepitant, preparation method and application. The present disclosure discloses a liquid pharmaceutical composition containing fosaprepitant, including an active pharmaceutical ingredient, a chelating agent, a stabilizer and a pH regulation, the active pharmaceutical ingredient described is selected from the group consisting of fosaprepitant, a pharmaceutically acceptable salt, hydrate, or solvate thereof; the described liquid pharmaceutical composition containing fosaprepitant does not contain polysorbate 80 and lactose. The present liquid pharmaceutical composition containing fosaprepitant, which has the advantages of simple preparation process, good physical and chemical stability, convenient clinical use without reconstitution, low risk of microbial contamination in the formulation process, and suitability for industrial production.

Description

Liquid pharmaceutical composition containing fosaprepitant, its preparation method and use

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

The present invention claims the benefit of the prior application submitted to the State Intellectual Property Office of China on November 2, 2021, with the patent application number 202111286261.0 and titled "Liquid pharmaceutical composition containing fosaprepitant, preparation method and application thereof" Priority interests. The entire text of the prior application is incorporated into the present application by reference.

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 delay or sometimes even refuse chemotherapy plans because of CINV. treatment. The emetogenic reaction may be acute (within 24 hours after chemotherapy) or delayed (after 24 hours after chemotherapy). The mechanisms underlying acute and delayed emesis are thought to be different. Current treatments include serotonin HT3 receptor antagonists such as ondansetron, tropisetron, and granisetron, and the dopamine receptor antagonist metoclopramide. These compounds are sufficiently effective against acute CINV but not against 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, which is rapidly converted to aprepitant in the body after intravenous (IV) administration. Aprepitant is a human substance P neurokinin 1 (NK1) receptor antagonist. Therefore, the pharmacological activities and antiemetic effects of fosaprepitant mirror those of its parent compound, aprepitant.

Because in aqueous environments and high temperatures, fosaprepitant (or its salts) will be hydrolyzed into water-insoluble aprepitant, even in the solid state, such as in freeze-dried preparations, when the moisture control is not good, fosaprepitant will Saprepitant can still be hydrolytically degraded to form aprepitant. Therefore, in order to prevent potential hydrolytic degradation of fosaprepitant to form aprepitant during the shelf life of the product, resulting in crystallization and precipitation, the formulation of fosaprepitant dimeglumine for injection contains polysorbate 80, As a solubilizer of aprepitant; and the moisture control is very strict.

However, polysorbate 80 (a nonionic surfactant often used as a solubilizer for low-solubility products) can cause a variety of adverse reactions, including severe infusion site reactions and potentially life-threatening allergic reactions; lactose, as a freeze-drying protectant, Possible protein residues in excipients can lead to allergies, which poses a higher risk; freeze-dried products require strict moisture control, which makes freeze-drying technically difficult and consumes a lot of energy.

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

Therefore, finding a fosaprepitant dosage form with good physical and chemical stability, simple preparation technology, and suitable for industrial production is an urgent technical problem that needs to be solved.

The invention provides a liquid pharmaceutical composition containing fosaprepitant, which contains: a pharmaceutical active ingredient, a chelating agent, a stabilizer and a pH regulator. The pharmaceutical active ingredient is fosaprepitant, which is pharmaceutically acceptable. salt, hydrate or solvate; the fosaprepitant-containing liquid pharmaceutical composition does not contain polysorbate 80 and lactose.

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

According to the embodiment of the present invention, the drug loading capacity of the active pharmaceutical ingredient is 1 mg/ml~400 mg/ml, and more preferably 3 mg/ml~200 mg/ml. The drug loading capacity refers to The ratio of the weight of fosaprepitant 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 pharmaceutically acceptable salts thereof; in one embodiment, the chelating agent The mixture is disodium ethylenediaminetetraacetate. Preferably, the weight ratio of the chelating agent to the active pharmaceutical ingredient is 1:8~1:56 (w/w), such as 1:50, 1:45, 1:40, 1:30, The weight of the active pharmaceutical ingredient is based on the weight 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 oleic acid , one or more of 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 can be selected from one or two 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 the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, glutamic acid, aspartic acid, sodium hydroxide, tromethamine, arginine, lysine, and histidine. , one or more of meglumine.

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

In some embodiments, the dosage of the stabilizer is 0.5~20% (W/V), such as 1~20% (W/V), such as 1~10% (W/V). It refers to the percentage of the weight of the stabilizer (g) to the total volume (mL) of the fosaprepitant-containing liquid pharmaceutical composition;

In some embodiments, when the stabilizer is selected from oleic acid and/or sodium oleate, the dosage of oleic acid and/or sodium oleate is preferably 0.5~10% (W/V); In some embodiments, the dosage 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 The dosage of one or more of citrate, tartrate and borate is preferably 0.5~10% (W/V); in some embodiments, the acetate, carbonate, phosphate, citric acid The dosage of one or more of salt, 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-containing liquid pharmaceutical composition can be selected from any one of the following formulas:

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

Formula 2: 12.265% (W/V) fosaprepitant dimeglumine, 0.27% (W/V) EDTA-2Na, 2.88% (W/V) oleic acid, 3% (W/V) dihydrogen phosphate Sodium, and adjust the pH with 1.0 M NaOH to pH 8.0~9.5.

The present invention also provides the use of the fosaprepitant-containing liquid pharmaceutical composition in preparing pharmaceutical preparations.

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

According to an embodiment of the present invention, the pharmaceutical preparation is administered parenterally, such as by injection.

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, dilute it with normal saline. The dilution ratio of the physiological saline is preferably 25 times to 500 times, and further 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. The plastic is selected from PVC (polyvinyl chloride), PP (polypropylene), PE (polyethylene), COP (cyclic olefin polymer), COC (cyclic olefin copolymer) and Aclar (chlorotrifluoroethylene). One or more of copolymers and homopolymers).

According to an embodiment of the present invention, the pharmaceutical preparation is used to treat diseases caused by NK-1 receptors, including but not limited to vomiting.

The invention also provides the use of the fosaprepitant-containing liquid pharmaceutical composition in the preparation of NK-1 receptor antagonists.

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

The beneficial effects of the present invention are: the fosaprepitant-containing liquid pharmaceutical composition of the present invention has simple preparation technology, good physical and chemical stability, is convenient for clinical use and does not require reconstitution, has low risk of microbial contamination during the preparation process, and is suitable for Industrial production and other advantages.

It solves the problem that the freeze-drying technology of fosaprepitant in the existing technology is time-consuming, energy-consuming, costly, has very strict moisture control, and needs to be reconstituted before clinical use, which increases the number of operations and may lead to bacterial contamination. Risks and other shortcomings.

Definitions and explanations of terms

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

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

The term "therapeutically effective amount" refers to an amount of a pharmaceutically active ingredient of the present invention sufficient to achieve the intended use, including but not limited to the treatment of disease as defined below. The therapeutically effective amount may vary depending on factors such as the intended application (in vitro or in vivo), or the subject and 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. It can be easily determined by a person with ordinary knowledge in the technical field. The specific dosage will vary depending on the specific active ingredient selected, the dosing regimen followed, whether administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system upon which it is administered. .

Detailed implementation

The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following examples are only illustrative and explain the present invention and should not be construed as limiting the scope of the present invention. All technologies implemented based on the above contents of the present invention are covered by 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. Experimental methods that do not indicate specific conditions in the following examples should be selected according to conventional methods and conditions, or according to product specifications.

Example 1

Table 1 Formula of Example 1 Name Recipe 1 Recipe 2 Recipe 3 Fosaprepitant dimeglumine (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 0.1 mol/L NaOH (ml) 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 a stable fosaprepitant composition in formulas 1 to 3 is described here: after adding the formula amount of EDTA-2Na, oleic acid, and 0.1 M sodium hydroxide solution, add 1 M sodium hydroxide solution until stirred and dissolved, then add API (fosaprepitant dimeglumine), and adjust to the target pH value with 1 M NaOH/20% HCl diluent. The prepared medicinal liquid is pre-filtered with a 0.45 µm filter element, filled and sealed to obtain the final product.

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

Stability of simulated clinical dilution samples: samples stored 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, sampled at 5 hours and 24 hours, and filtered with 0.45 µm PES. After filtration, temporarily store it in a refrigerator at 2~8°C, observe the appearance of the unfiltered sample, and detect the content of the filtered liquid. The test results are shown in Table 3.

Table 2 Test results of the formula in Example 1 Recipe No. condition Appearance *Aprepitant(%) Before refrigeration After refrigeration 1 60℃ 0h Clarity and transparency Clarity and transparency 0.18 60℃ 4h Clarity and transparency Clarity and transparency 0.63 60℃ 8h Clarity and transparency Clarity and transparency 1.45 60℃ 24h Clarity and transparency Clarity and transparency 4.33 2 60℃ 0h Clarity and transparency Clarity and transparency 0.17 60℃ 4h Clarity and transparency Clarity and transparency 0.65 60℃ 8h Clarity and transparency Clarity and transparency 1.36 60℃ 24h Clarity and transparency Clarity and transparency 4.01 3 60℃ 0h Clarity and transparency Clarity and transparency 0.17 60℃ 4h Clarity and transparency Clarity and transparency 0.6 60℃ 8h Clarity and transparency Clarity and transparency 1.26 60℃ 24h Clarity and transparency Clarity and transparency 3.82 *Aprepitant results are calculated as area normalized.

The results show that formulas 1 to 3 are clear and transparent under each condition, and no foreign matter precipitates. Although the content of aprepitant (active ingredient) in the relevant substances has increased, there is no risk of precipitation under high or low temperature conditions.

Table 3 Test results of the diluted formula in Example 1 Recipe No. condition Appearance API mg/ml 1 2~8℃-5h Clarity and transparency 1.08 2~8℃-24h Clarity and transparency 1.10 2 2~8℃-5h Clarity and transparency 1.04 2~8℃-24h Clarity and transparency 1.05 3 2~8℃-5h Clarity and transparency 1.09 2~8℃-24h Clarity and transparency 1.10

The results show that for formulas 1 to 3, samples placed at 60°C for 24 hours were diluted 100 times and placed at 2 to 8°C for 24 hours. The samples were all clear and transparent, and no foreign matter precipitated. Moreover, the API content at 5 h and 24 h was basically the same, indicating that insoluble aprepitant would not precipitate under low temperature conditions.

Example 2

Test the effect of different dosages of oleic acid on the stability of the product.

Table 4 Formula of Example 2 Name Recipe 4 Recipe 5 Recipe 6 Recipe 7 Recipe 8 Recipe 9 Fosaprepitant dimeglumine (mg) 245.3 245.3 245.3 245.3 245.3 245.3 EDTA-2Na (mg) 5.4 5.4 5.4 5.4 5.4 5.4 Oleic acid (mg) 28.8 57.6 84.6 28.8 57.6 84.6 1 M sodium hydroxide to pH 8.43 8.55 8.58 8.52 8.55 8.58 Dilute to ml 2 2 2 4 4 4

An exemplary preparation method of the fosaprepitant composition used to form formulas 4 to 9 is described here: in the formula amount of 60 to 70% water for injection, add the formula amount of EDTA-2Na, oleic acid, API (fosaprepitant Tansimeglumine), stir evenly, add 1 M sodium hydroxide, stir until the solution is clear, and check the pH value; use 1 M NaOH / 20% HCl to adjust the pH value to 8.5 ± 0.1, and check the pH value after diluting the volume. The prepared medicinal liquid 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 h respectively. The results are shown in Table 5.

Table 5 Formula stability results of Example 2 Recipe NO. condition Appearance *Aprepitant% 4 60℃ 0h Clarity and transparency 0.31 60℃ 4h Clarity and transparency 1.16 60℃ 8h Clarity and transparency 2.65 60℃ 24h Clarity and transparency 8.07 5 60℃ 0h Clarity and transparency 0.31 60℃ 4h Clarity and transparency 1.00 60℃ 8h Clarity and transparency 2.26 60℃ 24h Clarity and transparency 6.51 6 60℃ 0h Clarity and transparency 0.34 60℃ 4h Clarity and transparency 0.90 60℃ 8h Clarity and transparency 2.01 60℃ 24h Clarity and transparency 5.77 7 60℃ 0h Clarity and transparency 0.32 60℃ 4h Clarity and transparency 1.41 60℃ 8h Clarity and transparency 3.27 60℃ 24h There is precipitation 9.24 8 60℃ 0h Clarity and transparency 0.35 60℃ 4h Clarity and transparency 1.32 60℃ 8h Clarity and transparency 3.12 60℃ 24h Clarity and transparency 9.24 9 60℃ 0h Clarity and transparency 0.41 60℃ 4h Clarity and transparency 1.29 60℃ 8h Clarity and transparency 2.92 60℃ 24h Clarity and transparency 8.39 *Aprepitant results are calculated as area normalized.

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

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

Example 3

Test the effect of different buffer ions on product stability. The specific formula is shown in Table 6.

Table 6 Formula of Example 3 Name Recipe 10 Recipe 11 Recipe 12 Recipe 13 Recipe 14 Recipe 15 Recipe 16 Fosaprepitant dimeglumine (mg) 245.3 245.3 245.3 245.3 245.3 245.3 245.3 EDTA-2Na (mg) 5.4 5.4 5.4 5.4 5.4 5.4 5.4 Anhydrous sodium dihydrogen phosphate (mg) NA 32 NA NA NA NA NA Sodium acetate trihydrate (mg) NA NA 4 NA NA NA NA Potassium carbonate (mg) NA NA NA 12.2 NA NA NA Citric acid monohydrate (mg) NA NA NA NA 32 NA NA Tartaric acid (mg) NA NA NA NA NA 10 NA Boric acid (mg) NA NA NA NA NA NA 6.4 Sodium hydroxide or hydrochloric acid/to pH 10.10 10.15 10.26 10.08 10.11 10.09 10.08 Dilute to ml 2 2 2 2 2 2 2

An exemplary preparation method of the fosaprepitant composition used to form formulas 10 to 16 is described here: in the formula amount of 60 to 70% water for injection, add the formula amount of EDTA-2Na and buffer salt, and then add API (Fosaprepitant After sapitant and dimeglumine) is dissolved, check the pH value. Use 1 M NaOH/HCl to adjust the pH to 10.0, and then check the pH after diluting to volume. The prepared medicinal liquid is pre-filtered with a 0.45 µm filter element, filled and sealed to obtain the final product.

The obtained product was stored at 60°C to test its stability, and related substances were tested at 0 and 24 h respectively. The results are shown in Table 7.

Table 7 Formula stability test results of Example 3 Name Appearance *Aprepitant% 0h 24 hours 0 h 24h Recipe 10 Clarity and transparency Clarity and transparency 0.20 3.71 Recipe 11 Clarity and transparency Clarity and transparency 0.30 3.32 Recipe 12 Clarity and transparency Clarity and transparency 0.21 3.83 Recipe 13 Clarity and transparency Clarity and transparency 0.17 3.82 Recipe 14 Clarity and transparency Clarity and transparency 0.99 4.22 Recipe 15 Clarity and transparency Clarity and transparency 0.68 4.15 Recipe 16 Clarity and transparency Clarity and transparency 0.56 3.89 *Aprepitant results are calculated as area normalized.

At the same pH value, Formula 14—Citric Acid Buffer, Formula 15—Tartaric Acid Buffer, and Formula 16—Boric Acid Buffer have higher aprepitant content at 60°C and 0 h (most formulas at 0 h The aprepitant content is basically 0.2~0.3%), especially in formula 14, the aprepitant content at 0 h is 0.99%, which is much higher than other formulas.

At 60°C and 24 h, the aprepitant content of Formula 14—Citric Acid Buffer and Formula 15—Tartaric Acid Buffer was the highest, exceeding 4%. Among the buffer ion pairs, the slowest increase in aprepitant content was found in Formula 11—phosphate buffer system, and the final aprepitant content was the lowest at 3.32%.

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

Example 4

Table 8 Formula of Example 4 Name Recipe 4 Recipe 17 Recipe 18 Recipe 19 Recipe 20 Fosaprepitant dimeglumine (mg) 245.3 245.3 245.3 245.3 245.3 EDTA-2Na (mg) 5.4 5.4 5.4 5.4 5.4 Disodium hydrogen phosphate (mg) 0 20 40 60 80 Oleic acid(mg) 28.8 28.8 28.8 28.8 28.8 1 M sodium hydroxide/20% hydrochloric acid to pH 8.43 8.51 8.53 8.54 8.50 Dilute to ml 2 2 2 2 2

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

Table 9 Formula stability results of Example 4 Recipe NO. condition Appearance *Aprepitant% 4 60℃ 0h Clarity and transparency 0.31 60℃ 4h Clarity and transparency 1.16 60℃ 8h Clarity and transparency 2.65 60℃ 24h Clarity and transparency 8.07 17 60℃ 0h Clarity and transparency 0.32 60℃ 4h Clarity and transparency 0.94 60℃ 8h Clarity and transparency 1.62 60℃ 24h Clarity and transparency 4.69 18 60℃ 0h Clarity and transparency 0.31 60℃ 4h Clarity and transparency 0.83 60℃ 8h Clarity and transparency 1.47 60℃ 24h Clarity and transparency 4.15 19 60℃ 0h Clarity and transparency 0.30 60℃ 4h Clarity and transparency 0.77 60℃ 8h Clarity and transparency 1.35 60℃ 24h Clarity and transparency 3.78 20 60℃ 0h Clarity and transparency 0.31 60℃ 4h Clarity and transparency 0.79 60℃ 8h Clarity and transparency 1.36 60℃ 24h Clarity and transparency 3.77 *Aprepitant results are calculated as area normalized.

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

Example 5

Table 10 Formula of Example 5 Name Recipe 21 Fosaprepitant dimeglumine (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 product prepared with the above formula according to the preparation method in Example 2 was placed upside down at high temperatures of 25°C and 40°C to detect stability. At the same time, the marketed preparation (trade name EMEND, licensee: MERCK SHARP & DOHME CORP., manufacturer Patheon Manufacturing Services LLC, batch number: T037941) was used for comparison. The data is shown in Table 11.

Table 11 Comparison of stability results between the formulation of Example 5 and the marketed preparation sample condition Appearance Aprepitant% *% of total impurities Recipe 21 0 days Colorless, clear and transparent 0.33 0.09 40℃ 5 days Colorless, clear and transparent 1.42 0.25 40℃ 10 days Colorless, clear and transparent 2.54 0.33 25℃ January Colorless, clear and transparent 0.92 0.22 25℃ March Colorless, clear and transparent 1.93 0.34 25℃ June Light yellow, clear and transparent 4.13 0.15 Marketed preparations 0 days white fluffy solid 0.29 0.25 40℃ 10 days white fluffy solid 0.67 0.22 25℃ January white fluffy solid 0.42 0.21 25℃ February white fluffy solid 0.50 0.22 25℃ March white fluffy solid 0.58 0.26 25℃ June white fluffy solid 0.77 0.25 *Aprepitant is the active ingredient and is calculated based on area normalization and is not included in the calculation of total impurities.

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

Stability of simulated clinical dilution samples: Use the above 40℃-10 day formula 21 sample, dilute it 75 times with 0.9% sodium chloride, place it at 25℃, take samples at 0, 4, 8, and 24 hours, and observe the dilution The appearance of the sample was examined, and the fosaprepitant content and related substances of the diluted medicinal solution were detected.

Table 12 Stability of Formula 21: Sample dilution stability at 40℃-10 days sample condition Appearance API contentmg/ml Aprepitant% *% of total impurities Recipe 21 25℃-0h Solution, no precipitation 1.52 2.47 0.20 25℃-4h Solution, no precipitation 1.49 2.47 0.23 25℃-8h Solution, no precipitation 1.53 2.48 0.26 25℃-24h Solution, no precipitation 1.56 2.46 0.31 *Aprepitant is the active ingredient and is calculated based on area normalization and is not included in the calculation of total impurities.

The results of the stability investigation of the diluent showed that the API content was stable, aprepitant remained basically unchanged, the total impurities increased slightly, and the stability of the diluent was good.

Example 6

After formula 21 was placed at high temperature of 80°C for 4 hours, the appearance was observed to detect related substances. To simulate the stability of clinically diluted samples, dilute them 75 times with 0.9% sodium chloride, place them at 25°C, and take samples at 0, 14, and 24 hours respectively. Observe the appearance of the diluted samples and detect related substances in the diluted liquid. At the same time, the marketed preparation (trade name EMEND, licensee: MERCK SHARP & DOHME CORP., manufacturer Patheon Manufacturing Services LLC, batch number: T037941) was used for comparison.

Table 13 Comparison of dilution stability between formulation 21 stability 80°C-4 h sample and marketed formulation sample condition Appearance Aprepitant% *% of total impurities Recipe 21 Before dilution 80℃-4h Clear and transparent solution, no precipitation 5.68 0.28 Dilute 75 times 25℃-0h Solution, no precipitation 5.44 0.29 25℃-14h Solution, no precipitation 5.49 0.28 25℃-24h Solution, no precipitation 5.47 0.26 Marketed preparations Before dilution 2~8℃, 19 months white fluffy solid 0.29 0.24 Dilute 75 times 25℃-0h Solution, no precipitation 0.28 0.19 25℃-4h Solution, no precipitation 0.28 0.21 25℃-24h Solution, no precipitation 0.30 0.18 *Aprepitant is the active ingredient and is calculated based on area normalization and is not included in the calculation of total impurities.

The results showed that after formula 21 was heated to 80°C for -4 hours, aprepitant increased to 5.68%, the appearance was still clear and transparent, and the total impurities were equivalent to the marketed preparation; after the original solution was diluted and placed at 25°C for 24 hours, there was no change in appearance. There were no significant changes in pitant and other impurities, and the total impurity content was comparable to that of the marketed formulation, indicating good stability.

The fosaprepitant-containing liquid pharmaceutical composition provided by the invention has simple preparation technology. 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 clinical dilution is simulated. Chemical stability is good.

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

without

Claims (10)

A liquid pharmaceutical composition containing fosaprepitant, which contains: pharmaceutical active ingredients, chelating agent, stabilizer and pH regulator; The active pharmaceutical ingredient is fosaprepitant, its pharmaceutically acceptable salt, hydrate or solvate; the fosaprepitant-containing liquid pharmaceutical composition does not contain polysorbate 80 and lactose. The liquid pharmaceutical composition containing fosaprepitant as described in claim 1, wherein the pharmaceutically acceptable salt of fosaprepitant is fosaprepitant digglumine salt; and / or, The drug loading capacity of the active ingredient of the drug is 1 mg/ml~400 mg/ml. The drug loading capacity refers to the ratio of the weight of fosaprepitant to the volume of the liquid pharmaceutical composition containing fosaprepitant; Preferably, the drug loading capacity of the active pharmaceutical ingredient is 3 mg/ml~200 mg/ml, and the drug loading capacity refers to the ratio of the weight of fosaprepitant to the volume of the liquid pharmaceutical composition containing fosaprepitant. The liquid pharmaceutical composition containing fosaprepitant as described in claim 1 or 2, wherein the chelating agent is selected from the group consisting of citric acid, tartaric acid, gluconic acid and ethylenediaminetetraacetic acid or pharmaceutically acceptable salts thereof one or more; and / or, The weight ratio of the chelating agent to the active ingredient of the drug is 1:8~1:56, and the weight of the active ingredient of the drug is based on the weight of fosaprepitant. The liquid pharmaceutical composition containing fosaprepitant according to any one of claims 1 to 3, wherein the stabilizer is selected from the group consisting of acetate, carbonate, phosphate, citrate, tartrate, borate, oil One or more of acid and sodium oleate; Preferably, the pH adjuster is selected from hydrochloric acid, sulfuric acid, phosphoric acid, glutamic acid, aspartic acid, sodium hydroxide, tromethamine, arginine, lysine, histidine, and meglumine. of one or more. The fosaprepitant-containing liquid pharmaceutical composition according to any one of claims 1 to 4, wherein the pH value of the fosaprepitant-containing liquid pharmaceutical composition ranges from 7.0 to 10.0, preferably from 7.5 to 9.5. . The liquid pharmaceutical composition containing fosaprepitant according to any one of claims 1 to 5, wherein the dosage of the stabilizer is 0.5~20% (W/V), such as 1~20% (W/V) ), the dosage refers to the percentage of the weight of the stabilizer (g) to the total volume (mL) of the fosaprepitant-containing liquid pharmaceutical composition; When the stabilizer uses oleic acid and/or sodium oleate, the dosage of oleic acid and/or sodium oleate is preferably 0.5~10% (W/V); when the stabilizer uses acetate, carbonate, When one or more of phosphate, citrate, tartrate and borate are used, the dosage of one or more of acetate, carbonate, phosphate, citrate, tartrate and borate is preferably 0.5~ 10%(W/V). The fosaprepitant-containing liquid pharmaceutical composition as described in any one of claims 1 to 6, wherein the fosaprepitant-containing liquid pharmaceutical composition can be any of the following formulas: Formula 1: 12.265% (W/V) fosaprepitant dimeglumine, 0.27% (W/V) EDTA-2Na, 1.44% (W/V) oleic acid, and adjust the pH with 0.1 M/1.0 M NaOH , pH 8.5~9.5; Formula 2: 12.265% (W/V) fosaprepitant dimeglumine, 0.27% (W/V) EDTA-2Na, 2.88% (W/V) oleic acid, 3% (W/V) dihydrogen phosphate Sodium, and adjust the pH with 1.0 M NaOH to pH 8.0~9.5. The fosaprepitant-containing liquid pharmaceutical composition according to any one of claims 1 to 7, wherein the fosaprepitant-containing liquid pharmaceutical composition is a liquid composition for parenteral administration. The use of a fosaprepitant-containing liquid pharmaceutical composition as described in any one of claims 1 to 8 in the preparation of an NK-1 receptor antagonist. The use of a fosaprepitant-containing liquid pharmaceutical composition as described in any one of claims 1 to 8 in the preparation of a pharmaceutical preparation; the pharmaceutical preparation can be an injection; Preferably, the pharmaceutical preparation includes 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, cyclic olefin polymers, cyclic olefin copolymers and Accra.