JP7783403B2 - Stabilized preparation of fosnetupitant or a pharmaceutically acceptable salt thereof and method for producing the same - Google Patents

Description

CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority based on Japanese Patent Application No. 2022-047580, filed on March 23, 2022, the entire disclosure of which is incorporated herein by reference.
The present invention relates to chemically stable injectable formulations of fosnetupitant or pharmaceutically acceptable salts thereof that are suitable for mixing with neutral and/or acidic formulations, and methods for preparing the same.

Netupitant, a substance developed for the treatment of diseases mediated by the NK1 receptor, including antineoplastic agent-induced nausea and vomiting, is a drug primarily administered orally. Fosnetupitant is a substance in which phosphonooxymethyl is added to netupitant to improve water solubility. Upon administration, the phosphonooxymethyl moiety is removed, resulting in the active compound netupitant, which exerts its pharmacological effects. Netupitant is primarily administered intravenously. In the United States, a lyophilized formulation containing fosnetupitant chloride hydrochloride and palonosetron hydrochloride was approved and marketed in 2018 as AKYNZEO For Injection (Non-Patent Document 1).

In clinical practice, NK1 receptor inhibitors, including fosnetupitant and fosaprepitant, are rarely used as single agents, and are often administered in combination with 5- _HT3 receptor antagonists, such as palonosetron and granisetron, other antiemetics such as dexamethasone, and even other medications.

As an injectable formulation of fosnetupitant, a formulation containing fosnetupitant, sodium hydroxide, disodium edetate, and mannitol has been disclosed, and a formulation further containing palonosetron has also been disclosed (Patent Document 2).
However, in general, formulations prepared by converting prodrugs into phosphoric acid are prone to hydrolysis in aqueous solutions and are difficult to stabilize.

Furthermore, the stability of the formulation described in Patent Document 2, which contains only fosnetupitant or a pharmaceutically acceptable salt thereof as the active ingredient, when mixed with pharmaceutical formulations containing other active ingredients is unknown.

Patent Document 3 discloses a solution formulation of fosaprepitant, which is a phosphorylated prodrug, and netupitant. However, the purpose of Patent Document 3 is to develop a combination drug of fosaprepitant and another 5- _HT3 receptor antagonist, and there is no disclosure of fosnetupitant, which is a phosphonooxymethylated version of netupitant, nor is there any description as to whether fosnetupitant can be mixed with other commercially available preparations.

Patent document 3 discloses the formulation of a solution formulation of fosaprepitant, but only provides stability data up to six months, and does not state whether the formulation is stable for the period required for a pharmaceutical formulation.

International Publication No. 2013/082102 Patent No. 6936817 US 2019/0358249

AKYNZEO US Product Insert April 2018 Edition

The problem to be solved by the present invention is to provide an injectable formulation containing fosnetupitant or a pharmaceutically acceptable salt thereof that is stable as a pharmaceutical, and a method for producing such a formulation. A further object of the present invention is to provide an injectable formulation containing stable fosnetupitant that is more compatible with infusions and/or other injectable formulations than conventional fosnetupitant formulations.

The inventors have completed a highly stable injectable formulation by investigating the combinations and blending ratios of fosnetupitant or a pharmaceutically acceptable salt thereof with various additives. In other words, in one embodiment, the present invention provides a formulation containing fosnetupitant or a pharmaceutically acceptable salt thereof, trehalose, and a nonionic surfactant.

As another embodiment, the following is provided.
[1]
a) fosnetupitant or a pharmaceutically acceptable salt thereof;
An injectable formulation comprising b) trehalose, and c) a non-ionic surfactant.
[2]
a) The formulation according to [1], which contains 50 to 500 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, calculated as a fosnetupitant equivalent amount.
[3]
a) The formulation according to [2], containing 235 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, calculated as a fosnetupitant equivalent amount.
[4]
a) The formulation according to [2] or [3], wherein fosnetupitant or a pharmaceutically acceptable salt thereof is fosnetupitant chloride hydrochloride.
[5]
b) The formulation according to [1], which is injectable and contains 0.7 to 8.1 mg of trehalose, calculated as an anhydrous trehalose amount, per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof.
[6]
b) The formulation according to [5], which is injectable and contains 1.5 to 8.1 mg of trehalose, calculated as an anhydrous trehalose amount, per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof.
[7]
b) The injectable formulation according to [5] or [6], which contains trehalose in an amount of 4.0 to 5.0 mg, calculated as an anhydrous trehalose amount, per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof.
[8]
b) The injectable formulation according to any one of [5] to [7], wherein the trehalose is trehalose hydrate.
[9]
c) The formulation according to [1], comprising 0.2 to 2.5 mg of a nonionic surfactant per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof in terms of fosnetupitant.
[10]
c) The formulation according to [9], comprising 0.7 to 1.5 mg of a nonionic surfactant per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof in terms of fosnetupitant.
[11]
c) The formulation according to [9] or [10], comprising 1.0 to 1.5 mg of a nonionic surfactant per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof in terms of fosnetupitant.
[12]
c) The formulation according to any one of [9] to [11], wherein the nonionic surfactant is at least one selected from the group consisting of polyoxyethylene fatty acid esters and polyoxyethylene sorbitan fatty acid esters.
[13]
c) The formulation according to any one of [9] to [12], wherein the nonionic surfactant is polysorbate 80.
[14]
The formulation according to [1], further comprising d) a surfactant.
[15]
d) The formulation according to [14], wherein the surfactant is contained in an amount of 0.004 to 8.6 mg per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof in terms of fosnetupitant.
[16]
d) The formulation according to [14] or [15], wherein the surfactant is contained in an amount of 0.02 to 0.43 mg per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof in terms of fosnetupitant.
[17]
d) The formulation according to any one of [14] to [16], wherein the surfactant co-activator is contained in an amount of 0.03 to 0.06 mg per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof in terms of fosnetupitant.
[18]
d) The formulation according to any one of [14] to [17], wherein the surfactant is propylene glycol.
[19]
The formulation according to [1], further comprising e) a pH adjuster.
[20]
e) The formulation according to [19], wherein the pH adjuster is one or more of sodium hydroxide, hydrochloric acid, meglumine, L-arginine, and Tris.
[21]
e) The formulation according to [19] or [20], wherein the pH adjuster is sodium hydroxide or hydrochloric acid.
[22]
f) The formulation according to [1], wherein the pH is 6.5 to 11.0.
[23]
f) The formulation according to [22], wherein the pH is 7.5 to 9.5.
[24]
The formulation according to any one of [1] to [23], which does not contain EDTA, a chelating agent, or an antioxidant.
[25]
The formulation according to any one of [1] to [24], which is a liquid formulation.
[26]
The formulation according to [25], which is a liquid formulation in which a) fosnetupitant or a pharmaceutically acceptable salt thereof, b) trehalose, and c) a nonionic surfactant are dissolved in a solvent comprising water, ethanol, or a water/ethanol mixture.
[27]
The formulation according to [25] or [26], which is a liquid formulation dissolved in water as a solvent.
[28]
Per 10 mL,
a) containing 235 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, in terms of fosnetupitant;
b) containing 1085.7 mg of trehalose in terms of anhydrous trehalose;
c) A liquid formulation dissolved in a solvent containing 300 mg of a nonionic surfactant;
The formulation according to any one of [25] to [27].
[29]
The formulation according to any one of [1] to [24], which is a freeze-dried formulation.
[30]
The formulation according to [29], which is a lyophilized formulation to be used by mixing with at least one solvent selected from the group consisting of water, infusion solutions, and other injectable formulations.
[31]
The formulation according to [29] or [30], which is a freeze-dried formulation for use in combination with an infusion solution.
[32]
a) containing 235 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, in terms of fosnetupitant;
b) containing 1085.7 mg of trehalose in terms of anhydrous trehalose;
c) containing 300 mg of a nonionic surfactant;
A freeze-dried formulation that can be dissolved in a solvent.
The formulation according to any one of [29] to [31].
[33]
a) containing 235 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, in terms of fosnetupitant;
b) containing 1085.7 mg of trehalose in terms of anhydrous trehalose;
c) containing 300 mg of polysorbate 80;
d) 10 mg of propylene glycol;
e) containing sodium hydroxide and hydrochloric acid;
Injectable formulation.
[34]
The formulation according to any one of [1] to [33], which is mixable with at least one selected from the group consisting of infusion solutions and other injectable formulations.
[35]
The formulation according to [34], wherein the injectable formulation containing another active ingredient is at least one selected from the group consisting of antiemetics and adrenal hormones.
[36]
The formulation according to [35], wherein the antiemetic is palonosetron hydrochloride.
[37]
The formulation according to [35] or [36], wherein the adrenal hormone is dexamethasone.
[38]
The formulation according to any one of [1] to [37], which is used for the treatment of gastrointestinal symptoms.
[39]
The formulation according to any one of [1] to [38], which is used for administration by mixing with 50 to 500 mL of an infusion solution.
[40]
The formulation according to any one of [1] to [39], which is used for intravenous administration over 30 minutes.
[41]
[42] The formulation according to [40], which is stored in a dark place.
The formulation according to [40], which is stable at 25°C for 6 months or more.
[43]
The formulation according to [40], which is stable at 5°C for 12 months or more.
[44]
The formulation according to [40], which is stable at 5°C for 36 months or more.
[45]
A method for treating a gastrointestinal symptom, comprising administering the injectable formulation according to any one of [1] to [44].
[46]
Use of the formulation according to any one of [1] to [44] for the manufacture of a pharmaceutical for treating a gastrointestinal symptom.

The present invention can provide a pharmaceutical preparation that is an injectable preparation and has high storage stability.
Furthermore, the preparation of the present invention does not cause precipitation or the like even when mixed with other injectable preparations, and is therefore an injectable preparation that can be used clinically.
Such formulations offer increased versatility in clinical practice.

The pharmaceutical composition and method for producing the same according to the present invention are described below. However, the pharmaceutical composition and method for producing the same according to the present invention should not be construed as being limited to the description of the following embodiments and examples.

One embodiment of the present invention is an injectable formulation comprising: a) fosnetupitant or a pharmaceutically acceptable salt thereof; b) trehalose; and c) a non-ionic surfactant.
The formulation (pharmaceutical composition) of the present invention contains fosnetupitant or a pharmaceutically acceptable salt thereof as an active ingredient, and may contain other additives (antioxidants, etc.) as long as the effects of the present invention are achieved.

Fosnetupitant is a neurokinin-1 (NK-1) antagonist developed by Helsinn Healthcare SA, and is a phosphonooxymethylated prodrug of netupitant. When fosnetupitant or a pharmaceutically acceptable salt thereof is administered to the body, the phosphate moiety is rapidly removed, and the compound is converted to the active compound, netupitant, thereby exerting its medicinal effects. Netupitant exhibits selective antagonistic activity against the NK-1 receptor.
The structure of fosnetupitant is shown below, and there exist equilibrium relationships shown in (i) and (ii).

Fosnetupitant that can be used in the present invention may be in the form of a salt, such as a salt formed from a cation in the quaternary ammonium of fosnetupitant and its counter anion, an acid addition salt formed at the basic moiety of fosnetupitant, or a base addition salt formed at the acidic moiety of fosnetupitant.
Examples of the anion in the "salt formed from a cation in a quaternary ammonium salt and its counter anion" of fosnetupitant include halide ions (fluoride ion, chloride ion, bromide ion, iodide ion, etc.), hydroxide ion, inorganic acid ions (phosphate, metaphosphate, nitrate, carbonate, sulfonic acid, sulfuric acid, etc.), and organic acid ions (acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, trifluoromethanesulfonic acid, succinic acid, toluenesulfonic acid, tartaric acid, trifluoroacetic acid, etc.), among which halide ions are preferred, and chloride ions are more preferred.
Examples of "acid addition salts that add to the basic moiety" of fosnetupitant include inorganic acid salts of hydrohalic acids (e.g., hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid), boric acid, fluoroboric acid, phosphoric acid, metaphosphoric acid, nitric acid, carbonic acid, and sulfuric acid, as well as acetic acid, trifluoroacetic acid, formic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, digluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, panthenol, benzoic acid ... Examples of suitable salts include organic acid salts such as tothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, alginic acid, β-hydroxybutyric acid, galactaric acid, galacturonic acid, adipic acid, butyric acid, camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid, dodecylsulfuric acid, glycoheptanoic acid, glycerophosphate, heptanoic acid, hexanoic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, palmoic acid, pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid, thiocyanic acid, tosylic acid, and undecanoic acid. However, inorganic acid salts are preferred, hydrohalide salts are more preferred, and hydrochloride salts are particularly preferred.
The "base addition salts which add to the acidic moiety" of fosnetupitant include inorganic bases of alkali metals (such as sodium and potassium) and alkaline earth metals (such as calcium, magnesium and cesium), as well as organic bases such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
In the "fosnetupitant or a pharmaceutically acceptable salt thereof" of the present invention, fosnetupitant halide is preferred, fosnetupitant chloride is more preferred, fosnetupitant chloride hydrohalide is even more preferred, and fosnetupitant chloride hydrochloride is particularly preferred.

Fosnetupitant chloride hydrochloride is 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium chloride hydrochloride (molecular weight: 761.52) and has the following structure:
In this specification, unless otherwise specified, the amount equivalent to fosnetupitant refers to the amount equivalent to fosnetupitant having a molecular weight of 688.61 shown in (i).

In the present invention, fosnetupitant synthesized by the method described in Patent Document 1 or a known method can be used. The amount of fosnetupitant or a pharmaceutically acceptable salt thereof is not particularly limited as long as the antiemetic effect is exhibited, but for example, 50 to 500 mg, preferably 100 to 300 mg, more preferably 100 to 250 mg, even more preferably 200 to 250 mg, and particularly preferably 235 mg, can be used per day in terms of the equivalent amount of fosnetupitant.
In the present invention, 50 to 500 mg of fosnetupitant or a pharmaceutically acceptable salt thereof can be used per 10 mL of injectable formulation, preferably 100 to 300 mg, more preferably 100 to 250 mg, even more preferably 200 to 250 mg, and particularly preferably 235 mg, in terms of fosnetupitant equivalent. When dissolving a lyophilized formulation, a solvent can be used to achieve a similar concentration as described above. The terms "per 10 mL of injectable formulation" and "per 10 mL of the formulation of the present invention" refer to concentrations. For example, "50 to 500 mg of fosnetupitant equivalent is used per 10 mL of injectable formulation" is synonymous with "5 to 50 mg of fosnetupitant equivalent is used per 1 mL of injectable formulation."

In the present invention, trehalose protects and stabilizes antibodies and polymers in solution from degradation, and also acts as a protective agent when lyophilized. Therefore, trehalose's ability to inhibit degradation of polymers and other substances is expected to contribute to the stability of the formulations of the present invention. Trehalose is a non-reducing disaccharide, and can be produced by known methods or commercially available. In the present invention, trehalose includes both hydrates and anhydrous forms, but trehalose hydrate (e.g., dihydrate) is preferred.

In the present invention, the amount of trehalose is not particularly limited as long as it does not affect the medicinal efficacy. Furthermore, there is no particular upper limit on the amount of trehalose, as long as it is an acceptable amount from the perspective of solubility. Unless otherwise specified, the "anhydrous trehalose equivalent amount" refers to the amount equivalent to anhydrous trehalose. For example, per 10 mL of an injectable formulation containing fosnetupitant or a pharmaceutically acceptable salt thereof, 180 to 1900 mg of trehalose can be used in anhydrous trehalose equivalent amounts, preferably 200 to 1750 mg, more preferably 300 to 1600 mg, even more preferably 360 to 1400 mg, even more preferably 720 to 1100 mg, particularly preferably 1000 to 1100 mg, and most preferably 1085.7 mg. Trehalose can be used in an amount of 0.7 to 8.1 mg, preferably 0.85 to 7.4 mg, more preferably 1.2 to 6.8 mg, even more preferably 1.5 to 6.0 mg, still more preferably 3.0 to 5.0 mg, particularly preferably 4.0 to 5.0 mg, and most preferably 4.6 mg, per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, calculated as an equivalent amount of fosnetupitant.

In the present invention, the dissolution of fosnetupitant or a pharmaceutically acceptable salt thereof can be promoted by the use of a nonionic surfactant. Although the solubility of fosnetupitant or a pharmaceutically acceptable salt thereof increases under basic conditions compared to neutral conditions, precipitation may occur due to a decrease in pH when mixed with other acidic and/or neutral infusion solutions and other injectable formulations. To avoid this, it is preferable to add a nonionic surfactant to the formulation of the present invention. Examples of nonionic surfactants that can be used include ester-type nonionic surfactants in which a polyhydric alcohol such as glycerin or sorbitol is ester-bonded to a fatty acid, and ether-type nonionic surfactants in which ethylene oxide or the like is added to the hydroxyl group of a higher alcohol, etc. Examples of ester-type nonionic surfactants include polyoxyethylene fatty acid esters (e.g., polyoxyethylene castor oil), sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 60, polysorbate 65, polysorbate 80, etc.). Examples of the ether-type nonionic surfactant include polyoxyethylene alkyl ether, polyoxyethylene alkylaryl ether, and polyoxyethylene propylene glycol.
In the present invention, examples of the nonionic surfactant include the surfactants described above, preferably an ester-type nonionic surfactant, more preferably a polyoxyethylene fatty acid ester or a polyoxyethylene sorbitan fatty acid ester, even more preferably polyoxyethylene castor oil or polysorbate 80, and particularly preferably polysorbate 80. These nonionic surfactants may be produced by known methods or commercially available products. These nonionic surfactants may be used alone or in combination of two or more.

The amount of nonionic surfactant is not particularly limited as long as it is capable of dissolving fosnetupitant or a pharmaceutically acceptable salt thereof. For example, 100 to 500 mg of nonionic surfactant can be used per 10 mL of the formulation of the present invention. Preferably, it is 150 to 500 mg, more preferably 300 to 500 mg, and most preferably 300 mg. Furthermore, the amount of nonionic surfactant per 1 mg of fosnetupitant equivalent is 0.2 to 2.5 mg, preferably 0.35 to 2.0 mg, even more preferably 0.5 to 1.75 mg, even more preferably 0.7 to 1.5 mg, even more preferably 1.0 to 1.5 mg, and particularly preferably 1.2 to 1.3 mg. When polysorbate 80 is used as the nonionic surfactant, the above amounts are listed per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, but 1.3 mg is most preferred.

Furthermore, in the present invention, trehalose, due to its role as a protective agent as described above, is also expected to protect polymers such as surfactants from hydrolysis in aqueous solutions. Because surfactants consist of hydrophilic and hydrophobic portions, they may be hydrolyzed under the influence of temperature and pH. If the surfactant decomposes under acidic or alkaline conditions, there is a risk that dissolved substances may precipitate due to the surfactant's action. Therefore, to reduce this risk and ensure efficacy and/or safety as a pharmaceutical, it is preferable to increase the amount of surfactant in anticipation of a decrease. On the other hand, due to the nature of pharmaceuticals, it is preferable to keep the amount of additives added as low as possible. As long as these requirements can be met, the ratio of trehalose to nonionic surfactant is not particularly limited, but for example, 0.8 to 10 mg of trehalose, calculated as anhydrous trehalose, can be used per 1 mg of nonionic surfactant, preferably 1.0 to 8.0 mg, more preferably 1.0 to 7.0 mg, even more preferably 1.0 to 6.0 mg, still more preferably 1.4 to 5.5 mg, particularly preferably 2.4 to 4.5 mg, especially more preferably 3.5 to 4.0 mg, and most preferably 3.6 mg.

The solubility of fosnetupitant or its pharmaceutically acceptable salts varies depending on the pH of the solution, with solubility increasing under basic conditions. Therefore, solubility can be controlled by appropriately adjusting the pH using a pH adjuster. Furthermore, the use of a buffer can suppress fluctuations in solubility due to extreme pH fluctuations when mixed with other formulations.

As long as the pH can be adjusted, there are no particular limitations on the pH adjuster, but examples include sodium carbonate, calcium carbonate, citric acid, sodium citrate, sodium dihydrogen citrate, disodium citrate, succinic acid, disodium succinate, acetic acid, sodium acetate, tartaric acid, sodium tartrate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium bicarbonate, monoethanolamine, hydrochloric acid, meglumine, L-arginine, and trishydroxymethylaminomethane (Tris). Sodium hydroxide and/or hydrochloric acid are preferred. These pH adjusters can be used alone or in combination of two or more.

The lower limit of the pH is not particularly limited, but should be 6.0 or higher, preferably 6.5 or higher, more preferably 7.0 or higher, and even more preferably 7.5 or higher. The pH is preferably basic, i.e., 8.0 or higher, even more preferably 8.5 or higher, and even more preferably 9.0 or higher. The upper limit of the pH is not particularly limited, but is preferably 12.0 or lower, even more preferably 11.0 or lower, even more preferably 10.0 or lower, and even more preferably 9.5 or lower. Therefore, the pH is not particularly limited, but examples include 6.0 to 12.0. Preferably, it is 6.5 to 12.0, more preferably 6.5 to 11.0, even more preferably 7.0 to 11.0, even more preferably 7.0 to 10.0, even more preferably 7.5 to 10.0, and even more preferably 7.5 to 9.5.

If the pH is 9.0 or higher, the amount of nonionic surfactant can be reduced, while if the pH is less than 9.0, a larger amount of nonionic surfactant is required compared to a pH of 9.0 or higher. The relationship between pH and the amount of nonionic surfactant can be considered in the present invention to prevent precipitation of fosnetupitant or a pharmaceutically acceptable salt thereof due to the influence of the pH or additives of the mixture when mixed with an infusion solution and/or other injectable formulation. Therefore, if the pH is less than 9.0, for example, a 10 mL formulation containing 235 mg of fosnetupitant or a pharmaceutically acceptable salt thereof in fosnetupitant equivalent amounts requires more than 150 mg of polysorbate 80. The amount is preferably 175 mg to 500 mg, more preferably 200 mg to 500 mg, even more preferably 250 mg to 500 mg, and particularly preferably 300 mg. Furthermore, when the pH is less than 9.0, the amount of polysorbate 80 contained may be more than 0.64 mg per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof converted into fosnetupitant. The amount is preferably 0.74 to 2.2 mg, more preferably 0.85 to 2.2 mg, even more preferably 1.0 to 2.2 mg, and particularly preferably 1.3 mg. By containing polysorbate 80 in this proportion or more, mixing with other formulations becomes possible. The upper limit can be determined based on the track record of use in pharmaceuticals and acceptable safety.

In the present invention, a surfactant (a solubilizer for surfactants; also referred to as a cosurfactant) can be used. Using a surfactant in combination with a nonionic surfactant allows for a reduction in the amount of nonionic surfactant added, and therefore, the surfactant can be added appropriately, taking into consideration factors such as the safety of the formulation. In the present invention, there are no limitations on the type of surfactant used, as long as it can be used in combination with a nonionic surfactant. For example, alcohols such as ethanol, glycerin, propylene glycol, and trometamol, salts such as potassium dihydrogen phosphate, sodium acetate, and zinc sulfate, glycine, boric acid, etc. can be used. Alcohols are preferred as surfactants, with ethanol, glycerin, propylene glycol, and trometamol being more preferred, and propylene glycol being even more preferred. These surfactants can be produced by known methods or commercially available products. These surfactants can be used alone or in combination of two or more. The amount of surfactant is not particularly limited as long as it does not affect the efficacy, but examples include 1 to 2,000 mg per 10 mL of the formulation of the present invention. Preferably, the amount is 1 to 1500 mg, more preferably 1 to 1000 mg, even more preferably 1 to 500 mg, even more preferably 1 to 200 mg, and even more preferably 1 to 100 mg. 0.004 to 8.6 mg can be used per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof equivalent to fosnetupitant. Preferably, the amount is 0.004 to 6.4 mg, more preferably 0.004 to 4.3 mg, even more preferably 0.004 to 2.2 mg, more preferably 0.004 to 0.86 mg, even more preferably 0.004 to 0.43 mg, and particularly preferably 0.02 to 0.43 mg. In a preferred embodiment, when propylene glycol is used as a surfactant, the amount is most preferably 7.5 to 12.5 mg per 10 mL of the formulation of the present invention. The amount of propylene glycol is most preferably 0.03 to 0.06 mg per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof in terms of fosnetupitant.
When used in combination with a nonionic surfactant such as polysorbate or polyoxyethylene castor oil, the most preferred amount of propylene glycol is 7.5 to 12.5 mg, and the most preferred amount of propylene glycol is 0.03 to 0.06 mg per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof in terms of fosnetupitant.
In the lyophilized formulation, the amount of propylene glycol may be less than the amount of propylene glycol used in the liquid formulation, and may be 5 to 20 mg, or preferably 0.02 to 0.09 mg per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof equivalent to fosnetupitant.

Additives other than those mentioned above can be added to the present invention as needed. Examples include antioxidants (ethylenediaminetetraacetic acid (EDTA) or its salts, tocopherol, ascorbic acid, etc.) and soothing agents (chlorobutanol, benzyl alcohol, etc.). Preferably, the formulation does not contain antioxidants and/or soothing agents.

Because the content of fosnetupitant or a pharmaceutically acceptable salt thereof is important in the formulation of the present invention, the total volume of the formulation does not necessarily have to be 10 mL; it may be less than 10 mL (e.g., 5 mL) or more than 10 mL (e.g., 100 mL). There are no particular limitations on the containers used for the formulation of the present invention, as long as they are used for injectable formulations, such as vials, ampoules, bags, and syringes. The volume of the container used for distribution of injectable formulations is also not limited, but may be, for example, 2 to 500 mL, preferably 2 to 250 mL, more preferably 2 to 100 mL, even more preferably 2 to 50 mL, even more preferably 5 to 20 mL, and particularly preferably 10 mL. Furthermore, the formulation of the present invention can also be prepared as a lyophilized product to achieve the above-mentioned volume.

It has been suggested that the active ingredient, fosnetupitant, may be decomposed by light in the injectable formulation of the present invention, so it is preferable to store it in a light-shielded state. Any known means that can block light may be used, but examples include paper boxes, plastic bags with a light-shielding agent kneaded into them, black plastic bags, shrink wrap with light-shielding properties, and amber vials.

As used herein, "injectable" formulations include those that can be administered by injection as is, or those that can be mixed or diluted with a solvent or infusion solution as needed and then administered by injection. If suitable, the injectable formulations of the present invention containing fosnetupitant or a pharmaceutically acceptable salt thereof may be liquid, lyophilized, or other formulations, with liquid formulations being preferred.

The injectable formulation of the present invention is a formulation in which the active ingredient, fosnetupitant or a pharmaceutically acceptable salt thereof, is stable. In other words, the properties, pH, content (of fosnetupitant or a pharmaceutically acceptable salt thereof), related substances (of fosnetupitant or a pharmaceutically acceptable salt thereof), insoluble particulates, and other characteristics remain largely unchanged since manufacture, making it stable as a pharmaceutical.

The liquid formulation of the present invention is stable when stored at 5°C for preferably 6 months or more, more preferably 12 months or more, and even more preferably 36 months or more.
Furthermore, the liquid formulation of the present invention is stable when stored at 25°C for 6 months or more, more preferably for 12 months or more, and even more preferably for 36 months or more.

The freeze-dried preparation of the present invention is stable when stored at 5°C for preferably 6 months or more, more preferably 12 months or more, and even more preferably 36 months or more.
Furthermore, the freeze-dried preparation of the present invention is stable when stored at 25°C for 6 months or more, more preferably for 12 months or more, and even more preferably for 36 months or more.

Whether the liquid formulation of the present invention is stable for 6 months or more when stored at 5°C or 25°C can be evaluated, for example, by storing it at 5°C or 25°C for 6 months under the conditions described in Test Example 10. Similarly, whether the lyophilized formulation of the present invention is stable for 6 months or more when stored at 5°C or 25°C can be evaluated, for example, by storing it at 5°C or 25°C for 6 months under the conditions described in Test Example 8 or Test Example 9.
The results of the storage stability test at room temperature can be used as an accelerated test for storage stability in a cold place. That is, if a product is stable at room temperature for 6 months or more, it is assumed to be stable in a cold place for 36 months or more.

The injectable formulation of the present invention may be stored under any storage conditions as long as fosnetupitant or a pharmaceutically acceptable salt thereof is stable, but it is preferable to store it in a cool place (2-8°C).

The solvent used in the liquid formulation of the present invention may be water or a non-aqueous solvent such as ethanol, glycerin, or propylene glycol, or a mixture of these may be used. A solvent that does not contain ethanol is preferred, and water is more preferred. The lyophilized formulation of the present invention is used after being converted from a powder state to a liquid state using a solvent, but the solvent used to convert the powder to a liquid state is not particularly limited. For example, water for injection, physiological saline, other infusion solutions, and even other injectable formulations can be used.

The injectable formulation of the present invention can be prepared by the following procedure.

The liquid formulation of the present invention can be produced according to known methods for producing liquid formulations for injection. The order of mixing a) fosnetupitant or a pharmaceutically acceptable salt thereof, b) trehalose, and c) nonionic surfactant, and solvent is not particularly limited. Similarly, the order of mixing the optional d) surfactant co-agent and e) pH adjuster is also not particularly limited. After production, the solution can be sterilized (autoclaved or sterilized by filtration) using known methods to form an injectable formulation.
For example, water for injection, fosnetupitant chloride hydrochloride, and additives are placed in a tank and stirred at 0 to 50°C, preferably at room temperature, for 10 minutes to 24 hours, preferably 30 minutes to 6 hours to dissolve the mixture, to which a pH adjuster is added to adjust the pH, and water for injection is added to adjust the volume to the desired volume and stirred.
After preparing the liquid formulation, it is sterilized by filtration and filled into a container such as a vial to prepare a solution formulation, or after preparing the liquid formulation, it is filled into a container such as a vial and sterilized by high-pressure steam to prepare a solution formulation.

The lyophilized formulation of the present invention can be produced by commonly known methods. For example, a liquid formulation can be prepared, sterilized by filtration, filled into a container such as a vial, and lyophilized by a known method to produce a lyophilized formulation. The production conditions for the lyophilized formulation can be changed as appropriate depending on the amount and type of additives contained in the formulation.

The formulation of the present invention can be used to treat gastrointestinal symptoms (nausea and vomiting) (including delayed symptoms) associated with the administration of anti-cancer agents (e.g., cisplatin, ifosfamide, epirubicin, cyclophosphamide, streptozocin, dacarbazine, doxorubicin, carboplatin, actinomycin D, azacitidine, irinotecan, epirubicin, oxaliplatin, busulfan, bendamustine, miriplatin, methotrexate, etc.). Furthermore, administration of the formulation of the present invention can be terminated before the administration of the anti-cancer agent. Furthermore, the formulation of the present invention is a formulation administered intravenously by infusion. The time required for intravenous infusion is not particularly limited, but can be administered over 30 to 60 minutes, preferably 30 minutes. The formulation of the present invention is preferably mixed with an infusion solution and/or other injectable formulation to a total volume of 10 to 1200 mL, preferably 10 to 800 mL, more preferably 10 to 500 mL, even more preferably 25 to 300 mL, and even more preferably 50 to 250 mL, and is preferably administered in an amount that can be administered by intravenous drip infusion over 30 minutes.

The formulations of the present invention may be mixed with one or more infusion solutions and/or other injectable formulations.
Infusion solutions refer to electrolyte infusions for the purpose of replenishing water and electrolytes, and nutritional infusions for the purpose of replenishing nutrients. Other injectable formulations refer to injectable formulations containing active ingredients used in the treatment of diseases other than fosnetupitant or its pharmaceutically acceptable salts. In the case of lyophilized formulations, they can be reconstituted into a solution using saline, infusion solutions, and/or other injectable formulations, and in the case of liquid formulations, they can be mixed with infusion solutions and/or other injectable formulations as is. The phrase "mixable with infusion solutions and/or other injectable formulations" means that when the formulations of the present invention are mixed with infusion solutions and/or other injectable formulations in a clinical setting, the amount of the active ingredient remains unchanged (within a pharmaceutically acceptable range) for 3 hours after mixing, and administration to patients is possible without precipitation or other adverse events. Preferably, the amount of the active ingredient remains unchanged (within a pharmaceutically acceptable range) for 6 hours, more preferably 12 hours, and even more preferably 24 hours after mixing, and administration to patients is possible without precipitation or other adverse events. The formulations of the present invention are useful because they can be mixed with a wider variety of infusion solutions and/or other injectable formulations than conventional fosnetupitan formulations.

Examples of infusion fluids include physiological saline, glucose-electrolyte solution, total electrolyte infusion, acetated Ringer's solution, and a mixture of vitamin B1, sugar, electrolytes, and amino acids.
Other injectable preparations include infusions such as physiological saline, psychotropic agents, antispasmodics, diuretics, antiulcer agents, antiemetics, adrenal hormone preparations, vitamin B1 preparations, vitamin B preparations, vitamin K preparations, antidotes, alkylating agents, antimetabolites, antitumor antibiotic preparations, antitumor plant ingredient preparations, other antitumor drugs, and antihistamines, with antiemetics and adrenal hormone preparations being preferred.
Antiemetics include 5- _HT3 receptor antagonists, NK1 receptor antagonists, dopamine _D2 receptor antagonists, multi-receptor antipsychotics, phenothiazine antipsychotics, butyrophenone antipsychotics, and propylamine antihistamines, with 5- _HT3 receptor antagonists being preferred. 5- _HT3 receptor antagonists include palonosetron preparations, granisetron preparations, ondansetron preparations, ramosetron preparations, azasetron preparations, and metoclopramide preparations, with palonosetron preparations being preferred.
Examples of adrenal hormone preparations include cortisone preparations, adrenal cortical hormone preparations, and prednisolone preparations, with adrenal cortical hormone preparations being particularly preferred. Examples of adrenal cortical hormone preparations include dexamethasone phosphate preparations, dexamethasone preparations, and betamethasone phosphate preparations, with dexamethasone phosphate preparations being preferred.
In the practice of the present invention, it is most preferred to combine it with an antiemetic and an adrenal hormone.

Another embodiment of the present invention is an injectable formulation comprising: a) fosnetupitant or a pharmaceutically acceptable salt thereof; b) trehalose; c) a non-ionic surfactant; d) a co-surfactant; and e) sodium hydroxide.

Another embodiment of the present invention is an injectable formulation administered intravenously over 30 minutes, comprising a) fosnetupitant or a pharmaceutically acceptable salt thereof, b) trehalose, c) a non-ionic surfactant, and d) a co-surfactant.

Another embodiment of the present invention is a formulation that can be mixed with an infusion solution and/or other injectable formulation, comprising: a) fosnetupitant or a pharmaceutically acceptable salt thereof; b) trehalose; c) a non-ionic surfactant; and d) a co-surfactant. Preferably, the infusion solution and/or other injectable formulation is a 5- _HT3 receptor antagonist and/or a corticosteroid.

Another embodiment of the present invention is a light-shielded injectable formulation comprising: a) fosnetupitant or a pharmaceutically acceptable salt thereof; b) trehalose; c) a non-ionic surfactant; and d) a co-surfactant.

In a typical embodiment, the formulations of the present invention are administered by injection to a subject in need thereof. Accordingly, in a preferred embodiment, the present invention provides each of the above-described formulations for administration by injection.

The formulation of the present invention is stable, can be stored for a long period of time, can be widely mixed with infusion solutions and/or other injectable formulations, and is therefore highly versatile, making it extremely useful in medical settings for treating human diseases. Accordingly, in one embodiment, the present invention provides a method for stabilizing fosnetupitant or a pharmaceutically acceptable salt thereof, comprising the steps of mixing the following: a) to c):
a) fosnetupitant or a pharmaceutically acceptable salt thereof;
b) trehalose, and c) a nonionic surfactant. In the present invention, stabilization of fosnetupitant or a pharmaceutically acceptable salt thereof means improving the storage stability of the injectable formulation, which is a medical drug. In this embodiment, each step of the stabilization method can be performed in the same manner as in the above-mentioned method for producing the formulation of the present invention. In a preferred embodiment, the present invention provides a method for suppressing precipitation of fosnetupitant or a pharmaceutically acceptable salt thereof when mixed with another injectable formulation, the method comprising the above-mentioned steps.

[Reference example]
Formulation examples 1 to 38 were prepared. Each formulation is as shown in Tables 1, 3, 5, 7, 9, 10, 12, 13 and 17.
Fosnetupitant chloride hydrochloride and the additives contained in each formulation were added to water for injection and stirred, and it was confirmed by visual inspection that all of them were dissolved. Subsequently, the pH was adjusted to the desired value using sodium hydroxide and hydrochloric acid, and the solution was diluted to the desired volume.
These were synthesized by methods described in patent documents or prepared using commercially available products.
After preparation, liquid preparations were sterile filtered through a 0.22 μm filter as needed to prepare samples. The lyophilized preparations were filled into commercially available vials in the same manner, lyophilized using a lyophilizer (Kyowa Vacuum Triomaster II, A-04), and then sealed to prepare lyophilized samples.

Unless otherwise specified, the evaluation methods for stability testing of formulations below were conducted in accordance with the methods described in the 18th Edition of the Japanese Pharmacopoeia. Specifically, these methods involve evaluation of properties, identification tests, pH, purity tests, related substances, insoluble foreign matter, insoluble particulates, and quantification under various storage conditions (room temperature, cool places, high temperatures, exposure to light, etc.) and usage conditions (dilution, mixing, etc.). Examples include HPLC (high-performance liquid chromatography) or UPLC (ultra-performance liquid chromatography) methods for measuring content and the amount of related substances, and evaluation methods for appearance (presence of coloration, insoluble particles, turbidity, precipitation, etc.).

[Test Example 1]
Chemical stability of liquid formulations
Formulations 1 to 9 were stored at 60°C for 6 days and the amounts of related substances were compared as shown in Table 1. The related substances were measured using HPLC.
The results are shown in Table 2.
Sodium hydroxide was more effective in suppressing the increase of related substances than other pH adjusters.

Precipitation of insoluble particles (upon dilution with saline)
Formulations 1 to 9 were diluted to 2.6 mg/mL with physiological saline and stored at 5° C., and the precipitation of insoluble particles was visually confirmed.
As a result, precipitation was observed overnight in Formulations 1 and 4 to 6, but not in any of the formulations containing polysorbate 80 and polyoxyl 35 castor oil (Formulations 2, 3, and 7 to 9). Therefore, it was confirmed that the precipitation of insoluble particles due to dilution with physiological saline can be suppressed by adding a nonionic surfactant.

[Test Example 2] Evaluation of compatibility with excipients In order to select excipients for freeze-dried preparations, compatibility was evaluated using three excipients (D-mannitol, trehalose dihydrate, and lactose hydrate).
Formulations 10 to 12 were freeze-dried as shown in Table 3 and stored at 60°C for 6 days, and the physicochemical changes before and after storage were compared. The content was measured by HPLC.

The results are shown in Table 4.
In the case of D-mannitol (Formulation 10), the reconstituted solution after storage became cloudy and the pH clearly decreased. In the case of lactose hydrate (Formulation 12), the color of the freeze-dried cake and the reconstituted solution changed upon storage. However, in the case of trehalose dihydrate (Formulation 11), no change was observed in the appearance of the freeze-dried cake and the reconstituted solution, and the pH and content of the reconstituted solution also showed the smallest changes. Therefore, trehalose was superior in terms of stability.

Test Example 3 Evaluation of the usefulness of propylene glycol in liquid preparations From the viewpoint of suppressing the generation of related substances due to the addition of polysorbate, it is preferable to reduce the amount of polysorbate 80 added as much as possible.
Therefore, in order to achieve a formulation design with a near-neutral pH while reducing the amount of polysorbate 80, formulations containing surfactants were prepared as shown in Table 5 (Formulations 13-18) in the hope of increasing the solubility of fosnetupitant chloride hydrochloride. 10 mL of each formulation was mixed with 50 mL of other injectable formulations listed in Table 6 and stored at room temperature for 8 hours. The active ingredient was not added to these other injectable formulations in order to investigate the effects of pH and additives (citric acid). As a result, no precipitation of insoluble particles was observed in any of the mixed solutions.
Next, as a more severe condition, Formulations 17 and 18 were mixed with 80 mL of other injectable formulations and stored at room temperature for 16 hours. In this case, no cloudiness was observed in Formulation 17.

At pH 9.0 or higher, the amount of nonionic surfactant used is not specifically specified. Meanwhile, at pH 8.5, when 100 mg of nonionic surfactant was added to 80 mL of another injectable formulation and stored at room temperature for 16 hours, the mixture became cloudy. However, when 150 mg of nonionic surfactant was used, the mixture remained clear and colorless even under these conditions. These findings suggest that the preferred amount of nonionic surfactant varies depending on the pH.

Test Example 4: Investigation of the amount of trehalose dihydrate in freeze-dried preparations. The sample stored at 5°C in the formulation of Table 7 was used as the initial value, and a sample stored as a freeze-dried preparation at 40°C for 2 weeks was used as the post-storage value. The stability was compared based on the change in the amount of related substances. Related substances were measured using HPLC.

The results are shown in Table 8.
The amount of trehalose dihydrate decreased in the order of formulations 19 to 23, but the sample with the lower amount of trehalose dihydrate showed a greater increase in the total amount of related substances. Since the inclusion of a nonionic surfactant increases the amount of related substances, increasing the amount of trehalose dihydrate reduces the contact between fosnetupitant chloride hydrochloride and the nonionic surfactant in the lyophilized formulation, thereby improving the stability of fosnetupitant chloride hydrochloride. On the other hand, there was almost no difference in stability between formulations containing 600 mg or more of trehalose dihydrate.

Nonionic surfactants help prevent precipitation of fosnetupitant in solution, but they also reduce the chemical stability of fosnetupitant chloride hydrochloride in lyophilized formulations. The addition of trehalose dihydrate as an additive reduces contact between fosnetupitant chloride hydrochloride and nonionic surfactants, thereby increasing the stability of fosnetupitant chloride hydrochloride. Therefore, the addition of trehalose was found to be essential for ensuring the coexistence of fosnetupitant chloride hydrochloride and polysorbate 80 in the formulation.

Test Example 5 Optimization of Polysorbate 80 Amount in Liquid Formulations In order to optimize the amount of polysorbate 80 in a formulation containing 260 mg of fosnetupitant chloride hydrochloride, formulations 24 to 27, which have different amounts of polysorbate 80 as shown in Table 9, were mixed with palonosetron (Aloxi (registered trademark) intravenous injection 0.75 mg) to prepare liquids. The liquids were stored at room temperature, and the precipitation of insoluble particles was evaluated over time.

As a result, precipitation was observed in 1 hour in formulation 24. No precipitation was observed in formulations 25, 26 and 27.
When this is combined with the results of formulation 17, it is believed that the critical point for the amount of polysorbate 80 blended is 150 mg when the pH is 8.5.

Test Example 6 Optimization of Trehalose Dihydrate Amount As shown in Table 10, Formulations 28 to 30 containing 300 mg of polysorbate 80 and different amounts of trehalose dihydrate (800 to 1200 mg) were used.
Each freeze-dried preparation was stored at 40°C/75% RH for 3 months to evaluate its chemical stability. The amount of related substances was measured by HPLC.

The results are shown in Table 11.
When comparing the increase in the amount of related substances from the start, no difference in stability was observed among Formulations 28, 29, and 30. Combined with the results of Test Example 4, a larger amount of trehalose dihydrate was considered preferable from the standpoint of stability.

[Test Example 7]
A formulation without added propylene glycol was also prepared to examine whether it could be mixed with other injectable formulations.

10 mL of each of the formulations 31 to 33 in Table 12 was added to 50 mL of other injectable formulations, and stirred with a magnetic stirrer. After mixing, the appearance was visually observed 8 hours later.
As a result, all of the solutions were colorless and clear.

Test Example 8 Evaluation of Formulation 34 As shown in Table 13, trehalose dihydrate was used as an excipient, polysorbate 80 as a nonionic surfactant, propylene glycol as a surfactant aid, and sodium hydroxide and hydrochloric acid as pH adjusters.
The results of storage at 5°C/conventional humidity for up to 36 months are shown in Table 14. Since almost no change was observed in any of the test items under these conditions, it was confirmed that a stable formulation was obtained at 5°C for 36 months.

Formula 34 was used to confirm its usability (compatibility with concomitant medications). 10 mL was withdrawn from a 100 mL saline bag, and one vial of Formula 34 was reconstituted and then injected into the same bag. A solution containing 5 mL of palonosetron (Aloxi® Intravenous Injection 0.75 mg) and 3 mL of dexamethasone (Decadron® Injection) was prepared in this bag, and its stability was confirmed at room temperature. The content was measured using HPLC.

The results are shown in Table 15. Up to 8 hours after preparation, the solution remained colorless and clear, and no precipitation of insoluble particles derived from fosnetupitant was observed. In addition, no change in the content was observed. Therefore, it was determined that co-administration with concomitant medications was possible without any problems.
In contrast, a similar test was performed on a lyophilized formulation using mannitol. 260 mg of fosnetupitant chloride hydrochloride and 780 mg of mannitol were dissolved, and a solution of pH 8.1 was prepared with appropriate amounts of sodium hydroxide and hydrochloric acid. The resulting solution was lyophilized to obtain a formulation (Formulation 35). One vial of Formulation 35 was dissolved in 20 mL of 5% glucose solution and then injected into a 50 mL palonosetron formulation bag (Aloxi® intravenous infusion bag 0.75 mg). When stored at room temperature, the solution became cloudy and precipitated within 1 hour.

[Test Example 9] Evaluation of Formulation 36
Storage stability
A stability test at 25°C was conducted on Formulation 36 in Table 17. Specifically, 260 mg of fosnetupitant chloride hydrochloride, 1200 mg of trehalose, 300 mg of polysorbate 80, 10 mg of propylene glycol, and appropriate amounts of sodium hydroxide and hydrochloric acid were dissolved in water for injection to obtain 10 mL of an aqueous fosnetupitant solution (pH 9.0), which was then lyophilized to obtain a formulation of Formulation 36. A stability test was conducted.

The results are shown in Table 16. The product was stable for 12 months at 25°C. A stability test was also conducted at 5°C, and it was confirmed to be stable for 24 months.

To evaluate the compatibility of the palonosetron formulation with concomitant medications , the above formulations were used to evaluate their compatibility with concomitant medications in terms of stability. One vial of formulation 36 was reconstituted by withdrawing 10 mL from a 100 mL saline bag and then injected back into the same bag. 5 mL of palonosetron (Aloxi® Intravenous Injection 0.75 mg) and 3 mL of dexamethasone (Decadron® Injection) were mixed in the bag to prepare a dosing solution. The solution was stored at room temperature under diffuse light conditions (approximately 400 lx).

The results are shown in Table 18.
The solution remained colorless and clear up to 24 hours after preparation, and no precipitation of insoluble particles derived from fosnetupitant was observed. Furthermore, no change in the content was observed. This formulation was stable even when mixed with concomitant medications.

As in the previous study, the administration method used in clinical trials was simulated by adding one vial of the reconstituted solution of Formulation 36 and 4 mL of granisetron to a 100 mL saline bag to prepare an administration solution, and the stability was evaluated.The solution was stored at room temperature under indoor scattered light conditions.

The results are shown in Table 19.
The solution remained colorless and clear up to 24 hours after preparation, and no precipitation of insoluble particles derived from fosnetupitant was observed. Furthermore, no change in the content was observed. Therefore, it was determined that there is no problem with the stability of the administration solution under typical clinical conditions.

Test Example 10 Evaluation of Formulation 37 Formulation 37 in Table 17 was prepared, and a long-term storage test (5°C), an accelerated test (25°C, 60% RH), and a stress test (heat and light) were carried out using this formulation.

The results are shown in Table 20.
When the formulation of the present invention is stored in a light-shielded environment, stability is guaranteed in terms of properties, identification tests, pH, purity tests, related substances, insoluble foreign matter, insoluble fine particles, and quantification methods, even under long-term storage and accelerated test conditions. However, when exposed to light, discoloration and an increase in related substances were observed. Therefore, it is preferable to store the formulation of the present invention in a light-shielded environment, such as by storing the vial in a paper box.

Test Example 11 Effect of Formulation pH on Mixability with Concomitant Medications Formulation 37 was varied in pH and mixed with palonosetron (Aloxi (registered trademark) intravenous injection 0.75 mg) and dexamethasone (Decadron (registered trademark) injection) in a 100 mL bag of physiological saline to prepare a dosage solution. Each dosage solution was then stored at 5°C and 40°C/75% RH, and the appearance and content were evaluated over time.

The results are shown in Table 21. Regardless of the formulation pH, no change in appearance (precipitation of insoluble particles in the administration solution) was observed when mixed with the concomitant medication, and no effect of the formulation pH was observed.

Test Example 12 Compatibility Test of Formulation 37 with Other Commercially Available Formulations One vial of Formulation 37 was mixed with other antiemetics (palonosetron formulation, corticosteroid formulation) and saline in the amounts shown in Table 22, and the stability was evaluated up to 24 hours.

The results are shown in Table 22.
It was confirmed that it could be mixed with any of the formulations without any problems.

Test Example 13: Dilution Stability of Formulation 37 The miscibility with infusion solutions such as saline and other injectable preparations (anticancer drugs, etc.) was also evaluated. Specifically, one vial of Formulation 37 was mixed with the infusion solutions or injectable preparations listed in Tables 23 to 32 below, and optionally with saline, glucose injection, or ethanol solution, to a total volume actually used in clinical practice (approximately 50 to 1150 mL), and the miscibility was evaluated. The infusion solutions in Table 23 were evaluated using commercially available 50 mL to 500 mL products. The storage conditions and evaluation methods were in accordance with the following criteria.
Storage conditions: Under scattered light indoors (temperature and illuminance: as the case may be), exposure time: 24 hours Test method: Appearance, pH and content were measured immediately after mixing, and after 3 hours, 6 hours and 24 hours.
As a result, it was confirmed that it can be mixed with many commercially available formulations.
○: The properties, pH, and residual rate (%) were within the range acceptable for pharmaceuticals from immediately after mixing until 24 hours later.
×: Precipitation and an increase or decrease in pH were observed immediately after mixing and within 24 hours.
Δ: Precipitation and an increase or decrease in pH were observed in some cases depending on the type and amount of other injectable preparations mixed or the solvent used for dilution.

The results of the mixing test confirmed that it can be mixed with many formulations. Furthermore, in cases where precipitation or pH fluctuations occurred, the precipitation or pH fluctuations were suppressed in some cases by adjusting the additives contained in the commercially available formulation, or the pH and volume of the formulation (evaluation: △).

[Test Example 14]
The miscibility with multiple commercially available preparations was also examined in the same manner as in Test Example 13. The experimental method was carried out in the same manner as in Test Example 13, except that the number of preparations to be mixed was increased to two (those listed in the table).
The results are shown in Tables 33 and 34.
The formulation of the present invention was compatible with two or more of many of the commercially available formulations, provided that the solubility of fosnetupitant was not reduced in terms of additives and pH.

Test Example 15 Comparison of the Stability of Nonionic Surfactants with and without Trehalose Dihydrate The protective effect of trehalose on nonionic surfactants was investigated.
Formulations 37 and 38 were prepared, and the polysorbate 80 content was measured by UPLC immediately after preparation and after storage at 60° C. for 1 week or 2 weeks. Formulation 38 is a formulation obtained by omitting trehalose dihydrate from Formulation 37.

The results are shown in Table 35.
In Formulation 38, the polysorbate 80 content immediately after preparation was reduced by approximately 30% from the value blended at the time of preparation. On the other hand, such a large content reduction was not observed in Formulation 37. Furthermore, in Formulation 38, the content tended to decrease over time during storage, but no reduction was observed in Formulation 37.
These results confirmed that trehalose has the effect of suppressing the decomposition of nonionic surfactants in solution, and also indicated that trehalose is suitable for use in combination with nonionic surfactants.

Claims (20)

a) fosnetupitant or a pharmaceutically acceptable salt thereof;
An injectable formulation comprising b) trehalose, and c) a non-ionic surfactant. a) The formulation according to claim 1, containing 50 to 500 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, calculated as a fosnetupitant equivalent amount. b) The formulation of claim 1, containing 0.7 to 8.1 mg of trehalose, calculated as an anhydrous trehalose amount, per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof. c) The formulation of claim 1, containing 0.2 to 2.5 mg of a nonionic surfactant per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof in terms of fosnetupitant equivalent. The formulation according to claim 4, wherein the nonionic surfactant (c) is at least one selected from the group consisting of polyoxyethylene fatty acid esters and polyoxyethylene sorbitan fatty acid esters. 5. The formulation of claim 4, wherein c) the non-ionic surfactant is polysorbate 80. The formulation of claim 1, further comprising d) a surfactant. 8. The formulation of claim 7, wherein d) the co-surfactant is propylene glycol. The formulation of claim 1, further comprising e) a pH adjuster. f) The formulation of claim 1, having a pH of 6.5 to 11.0. Per 10 mL,
a) containing 235 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, in terms of fosnetupitant;
b) 1085.7 mg of trehalose in terms of anhydrous trehalose;
c) Contains 300 mg of a nonionic surfactant
A liquid formulation dissolved in a solvent,
The formulation of claim 1. a) containing 235 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, in terms of fosnetupitant;
b) containing 1085.7 mg of trehalose in terms of anhydrous trehalose;
c) containing 300 mg of polysorbate 80;
d) 10 mg of propylene glycol;
e) containing sodium hydroxide and hydrochloric acid;
Injectable formulation. The formulation according to any one of claims 1 to 12 , which is free of EDTA, chelating agents and antioxidants. The formulation according to any one of claims 1 to 12 , which is a liquid formulation. The formulation according to any one of claims 1 to 10 and 12 , which is a freeze-dried formulation. The preparation according to any one of claims 1 to 12 , which is mixable with at least one selected from the group consisting of infusion solutions and other injectable preparations. The preparation according to any one of claims 1 to 12 , which is administered by mixing with 50 to 500 mL of an infusion preparation. The formulation described in any one of claims 1 to 12, stored in a dark place. The formulation according to any one of claims 1 to 12 , which is stable at 25°C for 6 months or more. The formulation according to any one of claims 1 to 12 , which is stable at 5°C for 12 months or more.