JP7001454B2 - Pharmaceutical product containing fosaprepitant - Google Patents

Description

The present invention relates to a pharmaceutical preparation containing fosaprepitant or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to a pharmaceutical preparation containing fosaprepitant or a pharmaceutically acceptable salt thereof as an active ingredient, which suppresses the production of related substances and has excellent stability.

Fosaprepitant is a phosphorylated prodrug with improved water solubility of the non-peptide selective substance P / neurokinin 1 (NK1) receptor antagonist aprepitant. Currently, the dimeglumin salt of fosaprepitant is used as a therapeutic agent for gastrointestinal symptoms (nausea and vomiting) (including late onset) associated with administration of antineoplastic agents (cisplatin, etc.). The pharmaceutical formulations of fosaprepitant meglumine used clinically include the active ingredient fosaprepitant meglumine and sodium edetate hydrate as a chelating agent, polysorbate 80 as a solubilizer, anhydrous lactose as an excipient, and a pH adjuster. It is a lyophilized preparation containing hydrochloric acid and sodium hydroxide, and is provided as a preparation for intravenous drip infusion of fosaprepitant meglumine (PROEMEND registered trademark). The pharmaceutical product is dissolved in 5 mL of physiological saline and then diluted with physiological saline so that the final volume is 100 to 250 mL (final concentration is 0.6 to 1.5 mg / mL) and intravenously infused.

Fosaprepitant, which is a phosphorylated prodrug of aprepitant, is known to be susceptible to hydrolysis and have unstable physical properties. Therefore, when preparing a pharmaceutical preparation containing fosaprepitant or a pharmaceutically acceptable salt thereof as an active ingredient, it is necessary to take measures to improve the stability against hydrolysis and heat.
Non-Patent Document 1 describes a pharmaceutical preparation containing fosaprepitant meglumine as an active ingredient, which is currently on the market. The formulation is prepared as a lyophilized formulation in consideration of stability, and the storage method is storage in a cold place (2 to 8 ° C.).
Examples of Patent Document 1 disclose a non-aqueous composition containing fosaprepitant, polyethylene glycol, ethanol, D-sorbitol, and sodium hydroxide as an injectable composition for improving the stability of fosaprepitant. ing.
As described above, a pharmaceutical preparation having excellent storage stability of a pharmaceutical preparation containing fosaprepitant and a pharmaceutically acceptable salt thereof as an active ingredient is desired.

International release WO2016 / 059587 Pharmaceutical Interview Form Selective NK1 Receptor Antagonist Antiemetic Agent Proimend 150 mg March 2016 (8th Edition)

An object of the present invention is to provide a pharmaceutical preparation containing fosaprepitant or a pharmaceutically acceptable salt thereof as an active ingredient and suppressing the production of related substances.

The present inventor has found that a pharmaceutical preparation containing fosaprepitant or a pharmaceutically acceptable salt thereof and a pyridine derivative can provide a pharmaceutical preparation in which the production of a related substance of fosaprepitant or a pharmaceutically acceptable salt thereof is suppressed. rice field. The present application is based on the inventions described in the following [1] to [4].

[1] A pharmaceutical preparation containing fosaprepitant or a pharmaceutically acceptable salt thereof and a pyridine derivative.
[2] The pharmaceutical preparation according to [1], wherein the pyridine derivative is nicotinamide.
[3] The pharmaceutical preparation according to [1], which contains a pyridine derivative in an amount of 0.005 part by mass or more and 8 parts by mass or less with respect to 1 part by mass of fosaprepitant or a pharmaceutically acceptable salt thereof.
[4] The pharmaceutical product according to [1] to [3], wherein the pharmaceutical product is a lyophilized product or a liquid preparation for injection.

The pharmaceutical preparation of the present invention can suppress the production of related substances associated with the decomposition of fosaprepitant or a pharmaceutically acceptable salt thereof, and is a pharmaceutical preparation of fosaprepitant or a pharmaceutically acceptable salt thereof having excellent stability. Can be provided. In particular, it is possible to provide a pharmaceutical preparation of fosaprepitant having excellent stability or a pharmaceutically acceptable salt thereof by suppressing the production of aprepitant by hydrolysis of fosaprepitant.
Therefore, it is possible to provide a pharmaceutical preparation that retains the efficacy and safety of fosaprepitant or a pharmaceutically acceptable salt thereof for a long period of time.

The present invention is a pharmaceutical preparation containing fosaprepitant or a pharmaceutically acceptable salt thereof as an active ingredient and further containing a pyridine derivative. The details will be described below.

The pharmaceutical composition of the present invention is characterized by containing fosaprepitant or a pharmaceutically acceptable salt thereof as an active ingredient. Fosaprepitant or a pharmaceutically acceptable salt thereof is an antiemetic agent having selective NK1 receptor antagonistic activity. Japanese Patent No. 3073770 describes that fosaprepitant can form salts with various inorganic and organic acids as well as bases. Examples of such acid addition salts are acetates, adipates, benzoates, benzenesulfonates, bicarbonates, butyrates, citrates, sulphates, sulphates, ethanesulfonates. , Fumalate, hemisulfate, heptaneate, hexaxate, hydrochloride, hydrobromide, hydroiodide, methanesulfonate, lactate, maleate, methanesulfonate, 2 -Naphthalene sulfonate, oxalate, pamoate, persulfate, picrate, pivalate, propionate, citrate, succinate, tosylate and undecanoate are listed and base salts. Are alkali metal salts such as ammonium salts, sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine. (Meglumin) and salts with amino acids such as arginine, lysine, ornithine and the like are mentioned. Fosaprepitant or a pharmaceutically acceptable salt thereof is a morpholintachykinin receptor antagonist and is available by the method described in Japanese Patent No. 3073770.
Fosaprepitant or a pharmaceutically acceptable salt thereof is preferably of a quality level that can be used as an active ingredient for pharmaceutical products.

It is preferable to use fosaprepitant meglumine in the pharmaceutical preparation of the present invention. Fosaprepitant meglumine is disclosed in Japanese Patent No. 3073770 and is available by the method described therein.

As used herein, the main relatives include aprepitants produced by the hydrolysis of fosaprepitants. The pharmaceutical preparation of the present invention can suppress the hydrolysis of fosaprepitant.

The pharmaceutical preparation of the present invention is characterized by containing a pyridine derivative. Examples of the pyridine derivative include nicotine, nicotinic acid, nicotinic acid amide, pyridoxine, pyridoxal, pyridoxamine and the like. Preferred examples include nicotinic acid and nicotinic acid amide. More preferably, it is nicotinamide. Among various pyridine derivatives, the use of nicotinamide can suppress the production of related substances of pharmaceutical preparations containing fosaprepitant or a pharmaceutically acceptable salt thereof as an active ingredient. More specifically, it is possible to prevent fosaprepitant from producing low-water-soluble aprepitant by hydrolysis. It is particularly preferable to use nicotinamide in the pharmaceutical preparation of the present invention.

In the pharmaceutical preparation of the present invention, the amount of the pyridine derivative applied to fosaprepitant or a pharmaceutically acceptable salt thereof is 0.005 to 8 to 8 parts by mass of fosaprepitant or a pharmaceutically acceptable salt thereof. It preferably contains parts by mass, more preferably 0.01 to 4 parts by mass, and even more preferably 0.05 to 2 parts by mass. When the pyridine derivative is in this range with respect to 1 part by mass of fosaprepitant or a pharmaceutically acceptable salt thereof, it is possible to suppress the production of a related substance of fosaprepitant or a pharmaceutically acceptable salt thereof. That is, a pharmaceutical preparation capable of suppressing the production of low-water-soluble aprepitant by hydrolysis of fosaprepitant, maintaining the stability of fosaprepitant, and maintaining the safety as a pharmaceutical preparation for a long period of time. Can be provided.

The pharmaceutical preparation of the present invention preferably contains an excipient. Excipients include, for example, sucrose, trehalose, maltose, lactose, D-mannitol, inositol, glucose, fructose, gluconic acid or a salt thereof, tartrate acid or a salt thereof, citric acid or a salt thereof, macrogol, cyclodextrin, glycerin. And so on. In the present invention, the excipient is preferably sucrose, trehalose, maltose, lactose, or D-mannitol, and more preferably maltose, lactose, or trehalose.

In the pharmaceutical preparation of the present invention, the amount of the excipient applied to fosaprepitant or a pharmaceutically acceptable salt thereof is 0.5 with respect to 1 part by mass of fosaprepitant or a pharmaceutically acceptable salt thereof. It is preferably contained in an amount of up to 20 parts by mass, more preferably 1 to 15 parts by mass, and even more preferably 1.5 to 10 parts by mass.

The pharmaceutical preparation of the present invention preferably contains a pH adjuster. A pharmaceutical product having a pH of 6 to 11 in the aqueous solution of the pharmaceutical product of the present invention containing a pH adjuster and having a concentration of fosaprepitant as an active ingredient or a pharmaceutically acceptable salt thereof of 0.6 to 50 mg / mL. It is preferably a preparation. It is preferable that the aqueous solution is a pharmaceutical preparation having a pH of 6.5 to 10, and it is particularly preferable to adjust the pH to the range of 7.0 to 9.0.
Examples of the pH adjusting agent include acidic agents such as inorganic acids such as hydrochloric acid, phosphoric acid, boric acid and carbonic acid, and organic acids such as ascorbic acid and acetic acid. In addition, alkali metals such as sodium hydroxide, potassium hydroxide and lithium hydroxide or hydroxides of alkaline earth metals, inorganic acids such as sodium dihydrogen phosphate, disodium monohydrogen phosphate, sodium carbonate and sodium hydrogen carbonate. Alkaline agents such as alkaline earth metal salts of the above can be mentioned. Further, a buffer agent having a pH adjusted by mixing the acidic agent and the alkaline agent may be used. In the present invention, it is preferable to use an alkaline agent as the pH adjuster, and it is more preferable to use sodium hydroxide.
The amount of the pH adjuster used can be adjusted as appropriate to adjust to the above pH range.

The pharmaceutical preparation of the present invention preferably contains a surfactant. Examples of the surfactant include polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene (160) polyoxypropylene (30) glycol, and sucrose fatty acid ester. , Nonionic surfactants such as sorbitan fatty acid ester, anionic surfactants such as sodium desoxycholate, sodium ursodesoxycholate, sodium lauryl sulfate, cationic surfactants such as benzethonium chloride, lecithin, etc. These may be used alone or as a mixed solvent of two or more kinds. In the present invention, it is preferable to use a nonionic surfactant as the surfactant, more preferably polysorbate 80 or polysorbate 20, and further preferably polysorbate 80.

In the pharmaceutical preparation of the present invention, the amount of the surfactant applied to fosaprepitant or a pharmaceutically acceptable salt thereof is 0 for 1 part by mass of fosaprepitant or a pharmaceutically acceptable salt thereof. It preferably contains 0.01 to 1 part by mass, more preferably 0.05 to 0.8 part by mass, and even more preferably 0.1 to 0.6 part by mass.

The pharmaceutical preparation of the present invention preferably contains a stabilizer. Stabilizers include ascorbic acid or a salt thereof, aspartic acid or a salt thereof, acetyltryptophan or a salt thereof, arginine or a salt thereof, sodium hydrogen sulfite, sodium sulfite, inositol, edetonic acid or a salt thereof, erythorbic acid or a salt thereof, Sodium chloride, fructose, xylitol, citric acid or its salt, glycine, glycerin, gluconic acid or its salt, glutamic acid or its salt, creatinine, acetic acid or its salt, cyclodextrin, cysteine or its salt, tartrate's acid or its salt, sorbitol, Thioglycolic acid or its salt, thiosulfate or its salt, tromethamole, lactic acid or its salt, urea, sucrose, histidine or its salt, pyrosulfite or its salt, glucose, propylene glycol, macrogol, methionine, lysine or its salt, Examples thereof include phosphoric acid or a salt thereof, leucine and the like. In the pharmaceutical preparation of the present invention, it is preferable to use edetic acid or a salt thereof, and the edetic acid or a salt thereof includes edetic acid, monosodium edetate, disodium edetate, tetrasodium edetate, disodium calcium edetate and the like. It is more preferable to use disodium edetate, and disodium edetate dihydrate (sodium edetate hydrate) is further preferable.

In the pharmaceutical preparation of the present invention, the amount of edetonic acid or a salt thereof applied to phosapphetant or a pharmaceutically acceptable salt thereof is such that edetic acid or a salt thereof is added to 1 part by mass of phosparepitant or a pharmaceutically acceptable salt thereof. The salt preferably contains 0.001 to 2 parts by mass, more preferably 0.005 to 1 part by mass, and even more preferably 0.01 to 0.5 part by mass.

In the pharmaceutical preparation of the present invention, usually, as an optional additive component other than fosaprepitant or a pharmaceutically acceptable salt thereof, a pyridine derivative, an excipient, a pH adjuster, a surfactant, and a stabilizer, an tonicity agent or the like is used. It may contain other additives used in the pharmaceutical formulation of.
Examples of the tonicity agent include sodium chloride, lactose, sucrose, inositol, fructose, glucose, glycine, glycerin, sorbitol, xylitol, nicotinic acid amide, macrogol, propylene glycol, pyrophosphate or a salt thereof.
As the optional additive component thereof, an additive used in a usual pharmaceutical preparation may be used as long as the stability of the fosaprepitant of the pharmaceutical preparation according to the present invention or a pharmaceutically acceptable salt thereof is maintained, and the applied amount thereof. May be set as appropriate. The content of other additives is appropriately set in an appropriate amount in consideration of the stability of fosaprepitant or a pharmaceutically acceptable salt thereof, and the active ingredient fosaprepitant or its pharmaceutically acceptable salt is used. It is preferable to add 30 parts by mass or less to each 1 part by mass of the salt. More preferably, the applied amount is 15 parts by mass or less with respect to 1 part by mass of fosaprepitant or a pharmaceutically acceptable salt thereof.

In the pharmaceutical preparation of the present invention, 0.005 to 8 parts by mass of a pyridine derivative, 0.5 to 20 parts by mass of an excipient, and a surfactant with respect to 1 part by mass of phosapphetant or a pharmaceutically acceptable salt thereof. The pharmaceutical product of the present invention contains 0.01 to 1 part by mass of the stabilizer and 0.001 to 2 parts by mass of the stabilizer, and the concentration of the phosapphetant or a pharmaceutically acceptable salt thereof is 0.6 to 50 mg / mL. It is preferable to include a pH adjuster having a pH of 6 to 11 in the aqueous product solution.

Since the pharmaceutical preparation of the present invention is provided as an antiemetic agent by intravenous administration in the form of an injection, a pharmaceutical product containing phosapphetant or a pharmaceutically acceptable salt thereof as an active ingredient is provided as an antiemetic agent. Is also preferably an injectable product. That is, it is preferably in the form of a lyophilized preparation or an injection liquid preparation. The pharmaceutical preparation of the present invention is more preferably a freeze-dried preparation.

For the pharmaceutical preparation of the present invention, a solution containing fosaprepitant or a pharmaceutically acceptable salt thereof and additives other than the pyridine derivative and the pyridine derivative is prepared, filtered through a membrane filter, and dispensed into a glass vial. Can be prepared by In the case of an injectable solution, it can be prepared by aseptically sealing it, and in the case of a lyophilized product, the vial to which the solution is dispensed may be freeze-dried and aseptically sealed.
The solvent for preparing a solution containing the above-mentioned component fosaprepitant or a pharmaceutically acceptable salt thereof and an additive other than the pyridine derivative and the pyridine derivative may be a solvent capable of dissolving these components and pharmaceutically acceptable. However, the present invention is not particularly limited, and an appropriate solvent may be used by appropriately selecting the solvent. For example, water, tert-butanol and the like can be mentioned, and these may be used alone or as a mixed solvent of two kinds, and it is preferable to use only water.

The pharmaceutical preparation of the present invention is preferably prepared using a pH adjuster. The pH adjuster may be added to the solvent before dissolving fosaprepitant or a pharmaceutically acceptable salt thereof in the solvent, or may be added after dissolving fosaprepitant or a pharmaceutically acceptable salt thereof in the solvent. Preferably, fosaprepitant or a pharmaceutically acceptable salt thereof may be added both before and after dissolution in the solvent.

In the pharmaceutical preparation of the present invention, after dissolving the surfactant in a solvent, a stabilizer, an excipient, and a pyridine derivative are dissolved, a pH adjuster is added, and phosapphetant or a pharmaceutically acceptable salt thereof is dissolved. It can be prepared by adding a pH adjuster, optionally, filtering the solution with a solvent filter, and dispensing the solution into a glass vial. In the case of an injectable solution, it can be prepared by aseptically sealing it, and in the case of a lyophilized product, the vial to which the solution is dispensed may be freeze-dried and aseptically sealed.

The pharmaceutical preparation of the present invention can be used as a medicine containing fosaprepitant or a pharmaceutically acceptable salt thereof as an active ingredient. Fosaprepitant or a pharmaceutically acceptable salt preparation thereof is used to control gastrointestinal symptoms (nausea and vomiting) (including delayed onset) associated with administration of antineoplastic agents (cisplatin, etc.) based on selective NK1 receptor antagonistic activity. It can be applied as a vomiting agent.

Hereinafter, the present invention will be further described with reference to Examples. However, the present invention is not limited to these examples.

[Example 1]
Polysorbate 80 75.0 mg, sodium edetate hydrate 5.4 mg, anhydrous lactose 375 mg, and nicotinic acid amide 150 mg were dissolved in 4 mL of water for injection, and an appropriate amount of 0.5 M sodium hydroxide solution was added to adjust the pH to about 10. To the solution, 245.3 mg of phosapprepitan tomeglumin was added and dissolved. Water for injection was added to this aqueous solution to make the total volume 5 mL. The solution had a pH of 8.7.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, the vial was filled with the filtered solution, and freeze-dried to prepare the freeze-dried preparation according to Example 1.

[Example 2]
A solution prepared by dissolving 75.0 mg of polysorbate, 5.4 mg of sodium edetate hydrate, 375 mg of maltose, and 150 mg of nicotinic acid amide in 4 mL of water for injection, and adding an appropriate amount of 0.5 M sodium hydroxide solution to adjust the pH to about 10. To, 245.3 mg of fosaprepitant meglumine was added and dissolved. Water for injection was added to this aqueous solution to make the total volume 5 mL. The solution had a pH of 8.7.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, the vial was filled with the filtered solution, and freeze-dried to prepare the freeze-dried preparation according to Example 2.

[Example 3]
A solution prepared by dissolving 75.0 mg of polysorbate, 5.4 mg of sodium edetate hydrate, 375 mg of trehalose, and 150 mg of nicotinic acid amide in 4 mL of water for injection, and adding an appropriate amount of 0.5 M sodium hydroxide solution to adjust the pH to about 10. To, 245.3 mg of fosaprepitant tomeglumin was added and dissolved. Water for injection was added to this aqueous solution to make the total volume 5 mL. The solution had a pH of 8.7.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, the vial was filled with the filtered solution, and lyophilized to prepare the lyophilized preparation according to Example 3.

[Example 4]
Dissolve 75.0 mg of polysorbate, 5.4 mg of sodium edetate hydrate, 375 mg of D-mannitol, and 150 mg of nicotinic acid amide in 4 mL of water for injection, and add an appropriate amount of 0.5 M sodium hydroxide solution to adjust the pH to about 10. 245.3 mg of fosaprepitant meglumine was added to the solution to dissolve it. Water for injection was added to this aqueous solution to make the total volume 5 mL. The solution had a pH of 8.7.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, the vial was filled with the filtered solution, and freeze-dried to prepare the freeze-dried preparation according to Example 4.

[Example 5]
A solution prepared by dissolving 75.0 mg of polysorbate, 5.4 mg of sodium edetate hydrate, 375 mg of maltose, and 15 mg of nicotinic acid amide in 4 mL of water for injection, and adding an appropriate amount of 0.5 M sodium hydroxide solution to adjust the pH to about 10. To, 245.3 mg of fosaprepitant meglumine was added and dissolved. Water for injection was added to this aqueous solution to make the total volume 5 mL. The solution had a pH of 8.8.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, the vial was filled with the filtered solution, and lyophilized to prepare the lyophilized preparation according to Example 5.

[Example 6]
A solution prepared by dissolving 75.0 mg of polysorbate, 5.4 mg of sodium edetate hydrate, 375 mg of maltose, and 50 mg of nicotinic acid amide in 4 mL of water for injection, and adding an appropriate amount of 0.5 M sodium hydroxide solution to adjust the pH to about 10. To, 245.3 mg of fosaprepitant meglumine was added and dissolved. Water for injection was added to this aqueous solution to make the total volume 5 mL. The solution had a pH of 8.8.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, the vial was filled with the filtered solution, and freeze-dried to prepare the freeze-dried preparation according to Example 6.

[Example 7]
A solution prepared by dissolving 75.0 mg of polysorbate, 5.4 mg of sodium edetate hydrate, 375 mg of maltose, and 250 mg of nicotinic acid amide in 4 mL of water for injection, and adding an appropriate amount of 0.5 M sodium hydroxide solution to adjust the pH to about 10. To, 245.3 mg of fosaprepitant meglumine was added and dissolved. Water for injection was added to this aqueous solution to make the total volume 5 mL. The solution had a pH of 8.8.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, the vial was filled with the filtered solution, and lyophilized to prepare the lyophilized preparation according to Example 7.

[Comparative Example 1]
80 75.0 mg of polysorbate, 5.4 mg of sodium edetate hydrate, and 375 mg of anhydrous lactose were dissolved in 4 mL of water for injection, and an appropriate amount of 0.5 M sodium hydroxide solution was added to a solution having a pH of about 10, and phosapprepitant was added. 245.3 mg of meglumin was added and dissolved. Water for injection was added to this aqueous solution to make the total volume 5 mL. The solution had a pH of 8.7.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, the vial was filled with the filtered solution, and freeze-dried to prepare the freeze-dried preparation according to Comparative Example 1.

[Comparative Example 2]
Dissolve 75.0 mg of polysorbate, 5.4 mg of sodium edetate hydrate, and 375 mg of maltose in 4 mL of water for injection, add an appropriate amount of 0.5 M sodium hydroxide solution to a solution with a pH of about 10, and add fosaprepitant meglumine. Was added and dissolved in 245.3 mg. Water for injection was added to this aqueous solution to make the total volume 5 mL. The solution had a pH of 8.7.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, the vial was filled with the filtered solution, and freeze-dried to prepare the freeze-dried preparation according to Comparative Example 2.

[Comparative Example 3]
Dissolve 75.0 mg of polysorbate 80 75.0 mg of sodium edetate hydrate and 375 mg of trehalose in 4 mL of water for injection, add an appropriate amount of 0.5 M sodium hydroxide solution to a solution with a pH of about 10, and add fosaprepitant tomeglumin. Was added and dissolved in 245.3 mg. Water for injection was added to this aqueous solution to make the total volume 5 mL. The solution had a pH of 8.3.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, the vial was filled with the filtered solution, and freeze-dried to prepare the freeze-dried preparation according to Comparative Example 3.

[Comparative Example 4]
80 75.0 mg of polysorbate, 5.4 mg of sodium edetate hydrate, and 375 mg of D-mannitol were dissolved in 4 mL of water for injection, and an appropriate amount of 0.5 M sodium hydroxide solution was added to the solution to adjust the pH to about 10. 245.3 mg of aprepitant meglumine was added and dissolved. Water for injection was added to this aqueous solution to make the total volume 5 mL. The solution had a pH of 8.3.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, the vial was filled with the filtered solution, and freeze-dried to prepare the freeze-dried preparation according to Comparative Example 4.

Table 1 summarizes the composition of each component of the pharmaceutical product according to Examples 1 to 4 per vial, and Table 3 summarizes the composition of each component of the pharmaceutical product according to Examples 5 to 7 per vial. In addition, Table 2 summarizes the composition of each component per vial of the pharmaceutical formulations according to Comparative Examples 1 to 4.

＊１；生理食塩水で０．６ｍｇ／ｍＬに希釈したときのｐＨ値。

* 1; pH value when diluted to 0.6 mg / mL with physiological saline.

＊１；生理食塩水で０．６ｍｇ／ｍＬに希釈したときのｐＨ値。

* 1; pH value when diluted to 0.6 mg / mL with physiological saline.

＊１；生理食塩水で０．６ｍｇ／ｍＬに希釈したときのｐＨ値。

* 1; pH value when diluted to 0.6 mg / mL with physiological saline.

[Test Example 1] Stability test at 25 ° C (related substance)
The freeze-dried formulations for injection of Example 1 and Comparative Example 1 were lyophilized for 6 months under the condition of 25 ° C., and the lyophilized formulations for injection of Examples 2 to 7 and Comparative Examples 2 to 4 were lyophilized for injection under the condition of 25 ° C. Stored for 1 month in.
For each pharmaceutical product after storage, add 5 mL of physiological saline to 1 vial, dissolve it, and then dilute it with physiological saline to 0.6 mg / mL in terms of fosaprepitant as a sample solution, and use a related substance derived from fosaprepitant for HPLC. Was analyzed. The HPLC analysis conditions for the fosaprepitant relatives are shown below. The analysis results are shown in Tables 5-7.

[Analytical conditions for related substances derived from fosaprepitant]
Related substances derived from the decomposition of fosaprepitant in Examples and Comparative Examples were analyzed under the following liquid chromatography (HPLC) conditions.
Column: C-18 5 μm 4.6 × 250
Column temperature: 20 ° C
Mobile phase A: Water / phosphoric acid mixed solution (1000: 1)
Mobile phase B: Acetonitrile liquid feed rate: 1.5 mL / min.
Wavelength: 215 nm
Mobile phase liquid delivery: Liquid was sent under the conditions shown in Table 4.

Tables 5 to 7 summarize the contents of each related substance in the 25 ° C. storage stability test of the freeze-dried formulations for injection of Examples 1 to 7 and Comparative Examples 1 to 4.

From the results of Test Example 1, it was shown that the pharmaceutical preparation of the present invention suppresses the production of aprepitant by hydrolysis of fosaprepitant to the same extent as in Comparative Example. After the 6-month storage test in Example 1 and the 1-month storage test in Examples 2 to 7 using the pyridine derivative nicotinamide, the production of aprepitant can be suppressed more than in the comparative examples. Shown. That is, the pharmaceutical preparation of the present invention can maintain the stability of fosaprepitant and maintain the safety as a pharmaceutical preparation containing fosaprepitant or a pharmaceutically acceptable salt thereof as an active ingredient for a long period of time. Can be provided.

Claims (2)

A lyophilized preparation containing fosaprepitant or a pharmaceutically acceptable salt thereof, a nicotinic acid amide, and an excipient selected from the group consisting of maltose, lactose and trehalose . The pharmaceutical preparation according to claim 1, which contains nicotinamide in an amount of 0.005 part by mass or more and 8 parts by mass or less with respect to 1 part by mass of fosaprepitant or a pharmaceutically acceptable salt thereof.