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

Abstract

The present invention addresses the problem of providing: an injectable formulation that contains fosnetupitant or a pharmaceutically acceptable salt in a stable form as a medicinal product; and a method for producing the same. The present invention provides an injectable formulation containing a) fosnetupitant or a pharmaceutically acceptable salt thereof, b) trehalose, and c) a nonionic surfactant.

Description

[Technical Field]

[0001] [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. [Background technology]

[0002] Netupitant, a substance developed for the treatment of NK1 receptor-mediated diseases, including antineoplastic agent-induced nausea and vomiting, is a drug primarily administered orally. Fosnetupitant is a compound in which phosphonooxymethyl groups have been added to netupitant to improve its water solubility. Upon administration, the phosphonooxymethyl group is removed, resulting in the active compound, netupitant, which exerts its pharmacological effects. It is primarily administered intravenously. In the United States, a lyophilized formulation containing fosnetupitant chloride hydrochloride and palonosetron hydrochloride, known as AKYNZEO For Injection, was approved and marketed in 2018 (Non-Patent Document 1).

[0003] In clinical practice, NK1 receptor inhibitors, including fosnetupitant and fosaprepitant, are rarely used as monotherapy, 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.

[0004] 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.

[0005] Furthermore, with regard to the formulation described in Patent Document 2, which contains only fosnetupitant or a pharmaceutically acceptable salt thereof as an active ingredient, the stability when mixed with pharmaceutical formulations containing other active ingredients is unknown.

[0006] 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 other 5-HT3 receptor antagonists, 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.

[0007] Patent Document 3 discloses the formulation of a solution formulation of fosaprepitant, but only describes stability data up to 6 months, and does not describe whether the formulation is stable for the period required for a pharmaceutical formulation. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2013 / 082102 [Patent Document 2] Patent No. 6936817 [Patent Document 3] US 2019 / 0358249 [Non-patent literature]

[0009] [Non-Patent Document 1] AKYNZEO US Product Insert April 2018 Edition Summary of the Invention [Problem to be solved by the invention]

[0010] The present invention aims to provide an injectable formulation containing fosnetupitant or a pharmaceutically acceptable salt thereof that is stable as a pharmaceutical product, and a method for producing such a formulation. Another object of the present invention is to provide an injectable formulation containing fosnetupitant that is more stable than conventional fosnetupitant formulations and that can be mixed with infusion solutions and / or other injectable formulations. [Means for solving the problem]

[0011] The present inventors have investigated the combinations and blending ratios of fosnetupitant or a pharmaceutically acceptable salt thereof with various additives, thereby completing a highly stable injectable formulation. That is, in one embodiment, the present invention provides a formulation containing fosnetupitant or a pharmaceutically acceptable salt thereof, trehalose, and a nonionic surfactant.

[0012] As another embodiment, the following is provided. [1] a) fosnetupitant or a pharmaceutically acceptable salt thereof, b) trehalose, and c) Nonionic surfactants 1. An injectable formulation comprising: [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 described in [2], which contains 235 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, in terms of fosnetupitant equivalent. [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 in terms of anhydrous trehalose per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof in terms of fosnetupitant. [6] b) The formulation according to [5], which is injectable and contains 1.5 to 8.1 mg of trehalose in terms of anhydrous trehalose per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof in terms of fosnetupitant. [7] b) An 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 equivalent, 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], which contains 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], which contains 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] , which contains 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] , comprising 0.004 to 8.6 mg of a surfactant co-agent per 1 mg of fosnetupitant equivalent amount of fosnetupitant or a pharmaceutically acceptable salt thereof.

[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] , which contains 0.03 to 0.06 mg of a surfactant co-agent per 1 mg of fosnetupitant equivalent amount of fosnetupitant or a pharmaceutically acceptable salt thereof.

[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 described in

[19] , wherein the pH adjuster is one or more of sodium hydroxide, hydrochloric acid, meglumine, L-arginine, and Tris. [twenty one] e) The formulation according to

[19] or

[20] , wherein the pH adjuster is sodium hydroxide or hydrochloric acid. [twenty two] f) The formulation according to [1], wherein the pH is 6.5 to 11.0. [twenty three] f) The formulation according to

[22] , wherein the pH is 7.5 to 9.5. [twenty four] The formulation according to any one of [1] to

[23] , which does not contain EDTA, a chelating agent, or an antioxidant. [twenty five] 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 10mL, a) Contains 235 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, calculated as fosnetupitant; b) Contains 1085.7 mg of trehalose in terms of anhydrous trehalose, c) Contains 300 mg of nonionic surfactant A liquid formulation dissolved in a solvent, 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 freeze-dried formulation for use 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) Contains 235 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, calculated as fosnetupitant; b) Contains 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) Contains 235 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, calculated as fosnetupitant; b) Contains 1085.7 mg of trehalose in terms of anhydrous trehalose, c) Contains 300 mg of polysorbate 80; d) Contains 10 mg of propylene glycol; e) containing sodium hydroxide and hydrochloric acid; Injectable formulation.

[34] The preparation 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 preparations.

[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 administered 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] The formulation according to

[40] , which is stored in a dark place.

[42] The formulation described in

[40] , which is stable for at least 6 months at 25°C.

[43] The formulation described in

[40] , which is stable at 5°C for 12 months or more.

[44] The formulation described in

[40] , which is stable for 36 months or more at 5°C.

[45] A method for treating a digestive 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. [Effects of the Invention]

[0013] The present invention can provide an injectable pharmaceutical preparation that 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. DETAILED DESCRIPTION OF THE INVENTION

[0014] The pharmaceutical composition and its manufacturing method according to the present invention will be described below. However, the pharmaceutical composition and its manufacturing method according to the present invention should not be construed as being limited to the description of the following embodiments and examples.

[0015] 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.

[0016] Fosnetupitant is a neurokinin-1 (NK-1) antagonist developed by Helsinn Healthcare SA. It is a phosphonooxymethylated prodrug of netupitant. When fosnetupitant or its pharmaceutically acceptable salts are administered to the body, the phosphate moiety is rapidly removed, converting it to the active compound, netupitant, and exerting its medicinal effects. Netupitant exhibits selective antagonistic activity against the NK-1 receptor. The structure of fosnetupitant is as follows, and there exists an equilibrium relationship shown in (i) and (ii). [ka]

[0017] 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 of 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.), with halide ions being preferred, and chloride ions being 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 of 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, but 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.

[0018] 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: [ka] In this specification, unless otherwise specified, the term "equivalent amount of fosnetupitant" refers to the amount equivalent to fosnetupitant having a molecular weight of 688.61 shown in (i).

[0019] 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 it exerts an antiemetic effect, 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 fosnetupitant equivalent amount. In the present invention, fosnetupitant or a pharmaceutically acceptable salt thereof can be used in an amount of 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, per 10 mL of injectable preparation. When dissolving a lyophilized preparation, a solvent can be used to achieve a similar concentration as above. The terms "per 10 mL of injectable preparation" and "per 10 mL of the preparation of the present invention" refer to concentrations. For example, "50 to 500 mg of fosnetupitant is used per 10 mL of injectable preparation" is synonymous with "5 to 50 mg of fosnetupitant is used per 1 mL of injectable preparation."

[0020] In the present invention, trehalose has the effect of protecting and stabilizing antibodies and polymers in solution from degradation, or acts as a protective agent when preparing lyophilized formulations. 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 is preferably a trehalose hydrate (e.g., dihydrate).

[0021] In the present invention, the amount of trehalose is not particularly limited as long as it does not affect the efficacy of the drug. Furthermore, the upper limit of trehalose is not particularly limited as long as it is an amount acceptable from the viewpoint of solubility. Unless otherwise specified, the term "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 an amount equivalent to anhydrous trehalose, preferably 200 to 1750 mg, more preferably 300 to 1600 mg, even more preferably 360 to 1400 mg, still 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 trehalose anhydrate.

[0022] 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 or 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 or the like. 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 ester-type nonionic surfactants, more preferably polyoxyethylene fatty acid esters or polyoxyethylene sorbitan fatty acid esters, 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.

[0023] The amount of nonionic surfactant is not particularly limited as long as it can dissolve 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 amount of nonionic surfactant per 1 mg of fosnetupitant equivalent of fosnetupitant or a pharmaceutically acceptable salt thereof is as described above, but 1.3 mg is most preferred.

[0024] Furthermore, in the present invention, trehalose is expected to protect polymers such as surfactants from hydrolysis in aqueous solutions due to its role as a protective agent as described above. Because surfactants consist of hydrophilic and hydrophobic moieties, 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 in the amount. 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 are 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.

[0025] The solubility of fosnetupitant or a pharmaceutically acceptable salt thereof varies depending on the pH of the solution, with its solubility increasing under basic conditions. Therefore, the solubility can be controlled by appropriately controlling the pH using a pH adjuster. Furthermore, the use of a buffer can suppress changes in solubility due to extreme pH fluctuations when mixed with other formulations.

[0026] The pH adjuster is not particularly limited as long as it can adjust the pH, but examples thereof 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, trishydroxymethylaminomethane (Tris), etc. Sodium hydroxide and / or hydrochloric acid are preferred. These pH adjusters can be used alone or in combination of two or more.

[0027] The lower limit of the pH is not particularly limited, but is sufficient as long as it is 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, being 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 may be, for example, 6.0 to 12.0. It is preferably 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.

[0028] At a pH of 9.0 or higher, the amount of nonionic surfactant can be reduced, whereas at a pH of less than 9.0, a larger amount of nonionic surfactant is required compared to a pH of 9.0 or higher. In the present invention, the relationship between pH and the amount of nonionic surfactant can be considered 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, for example, at a pH of less than 9.0, more than 150 mg of polysorbate 80 is required for a 10 mL formulation containing 235 mg of fosnetupitant or a pharmaceutically acceptable salt thereof in terms of fosnetupitant equivalent. The amount of polysorbate 80 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.

[0029] In the present invention, a surfactant (a solubilizer for surfactants; also referred to as a cosurfactant) can be used. By using a surfactant in combination with a nonionic surfactant, the amount of nonionic surfactant added can be reduced. Therefore, the surfactant can be added appropriately, taking into consideration 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. The surfactant is preferably an alcohol, more preferably ethanol, glycerin, propylene glycol, or trometamol, and even more preferably propylene glycol. 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 pharmaceutical efficacy, and can be, for example, 1 to 2,000 mg per 10 mL of the formulation of the present invention. The amount is preferably 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. The amount is preferably 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 amount of propylene glycol is most preferably 7.5 to 12.5 mg, and most preferably 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.

[0030] In the present invention, additives other than those mentioned above can be added as needed. For example, antioxidants (ethylenediaminetetraacetic acid (EDTA) or its salts, tocopherol, ascorbic acid, etc.) and soothing agents (chlorobutanol, benzyl alcohol, etc.) are included. Preferably, the formulation does not contain antioxidants and / or soothing agents.

[0031] Since the content of fosnetupitant or a pharmaceutically acceptable salt thereof is important for 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). The container used for the formulation of the present invention is not particularly limited as long as it is one used for injectable formulations, such as a vial, ampule, bag, or syringe. The volume of the container used for distributing the injectable formulation is also not particularly 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, still more preferably 5 to 20 mL, and particularly preferably 10 mL. The formulation of the present invention can also be prepared as a lyophilized product to have the above-mentioned volume.

[0032] Since it has been suggested that the active ingredient fosnetupitant may be decomposed by light, the injectable formulation of the present invention is preferably stored in a light-shielded state. Any known means capable of blocking light may be used, such as a paper box, a plastic bag containing a light-shielding agent, a black plastic bag, a shrink wrap with a light-shielding function, or an amber vial.

[0033] In the present invention, the term "injectable" includes formulations that can be administered by injection as is, or those that can be administered by injection after mixing or diluting with a solvent or infusion solution as necessary. If suitable, the injectable formulation containing fosnetupitant or a pharmaceutically acceptable salt thereof of the present invention may be a liquid formulation, a lyophilized formulation, or other formulation, preferably a liquid formulation.

[0034] The injectable formulation of the present invention is a formulation in which the active ingredient, fosnetupitant or a pharmaceutically acceptable salt thereof, is stable, i.e., the properties such as appearance, pH, content (of fosnetupitant or a pharmaceutically acceptable salt thereof), related substances (of fosnetupitant or a pharmaceutically acceptable salt thereof), and insoluble particulates remain unchanged from the time of manufacture, and the formulation is stable as a pharmaceutical.

[0035] 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.

[0036] 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.

[0037] 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 storage stability tests at room temperature can be used as accelerated tests for storage stability in a cold place. That is, if a drug 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.

[0038] The injectable formulation of the present invention may be stored under any 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 to 8°C).

[0039] 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 thereof. 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 reconstituted from a powder state to a liquid state using a solvent, but the solvent used to reconstitute the powder state is not particularly limited. For example, water for injection, physiological saline, other infusion solutions, and even other injectable formulations can be used.

[0040] The injectable formulation of the present invention can be prepared by the following procedure.

[0041] 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 prepare 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. A pH adjuster is added to the mixture 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.

[0042] The lyophilized preparation of the present invention can be produced by a commonly known method. For example, a liquid preparation can be prepared, sterilized by filtration, filled into a container such as a vial, and lyophilized by a known method to produce a lyophilized preparation. The production conditions for the lyophilized preparation can be appropriately changed depending on the amount and type of additives contained in the formulation.

[0043] The formulation of the present invention can be used to treat gastrointestinal symptoms (nausea and vomiting) (including delayed symptoms) associated with the administration of antineoplastic agents (e.g., cisplatin, ifosfamide, epirubicin, cyclophosphamide, streptozocin, dacarbazine, doxorubicin, carboplatin, actinomycin D, azacitidine, irinotecan, epirubicin, oxaliplatin, busulfan, bendamustine, miriplatin, methotrexate, etc.). Furthermore, the administration of the formulation of the present invention can be completed before the administration of the antineoplastic agent. The formulation of the present invention is also a formulation to be administered intravenously by intravenous 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 intravenously over 30 minutes.

[0044] 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 infusion solutions for the purpose of nutritional supplementation. 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 with 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 formulation of the present invention is 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.

[0045] Examples of infusion fluids include 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 infusion fluids such as 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.

[0046] 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.

[0047] 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.

[0048] 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 surfactant co-agent. Preferably, the infusion solution and / or other injectable formulation is a 5-HT3 receptor antagonist and / or a corticosteroid.

[0049] Another embodiment of the present invention is a light-protected injectable formulation comprising: a) fosnetupitant or a pharmaceutically acceptable salt thereof; b) trehalose; c) a non-ionic surfactant; and d) a co-surfactant.

[0050] In typical embodiments, the formulations of the invention are administered to a subject in need thereof by injection. Thus, in preferred embodiments, the invention provides each of the above formulations for administration by injection.

[0051] 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 clinical practice 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) Nonionic surfactants 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-described 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-described steps. [Example]

[0052] [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 until complete dissolution was confirmed by visual inspection. Subsequently, the pH was adjusted to the desired level 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 using the same procedure, lyophilized using a lyophilizer (Kyowa Vacuum Triomaster II, A-04), and then sealed to prepare lyophilized samples.

[0053] Unless otherwise specified, the evaluation methods for stability testing of formulations below were performed 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 of evaluation methods include HPLC (high-performance liquid chromatography) or UPLC (ultra-performance liquid chromatography) for measuring content and the amount of related substances, and evaluation methods for appearance (presence of coloration, insoluble particles, turbidity, precipitation, etc.).

[0054] [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.

[0055] [Table 1]

[0056] [Table 2]

[0057] 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 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 saline can be suppressed by adding a nonionic surfactant.

[0058] [Test Example 2] Evaluation of compatibility with excipients To select excipients for freeze-dried formulations, three excipients (D-mannitol, trehalose dihydrate, and lactose hydrate) were used to evaluate their compatibility. 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 using HPLC.

[0059] The results are shown in Table 4. In the case of D-mannitol (Formulation 10), the reconstituted solution became cloudy and the pH clearly decreased after storage. In the case of lactose hydrate (Formulation 12), the color of the freeze-dried cake and the reconstituted solution changed during storage. However, in the case of trehalose dihydrate (Formulation 11), no change in the appearance of the freeze-dried cake or the reconstituted solution was observed, and the pH and content of the reconstituted solution also showed the smallest changes. Therefore, trehalose was superior in terms of stability.

[0060] [Table 3]

[0061] [Table 4]

[0062] [Test Example 3] Evaluation of the usefulness of propylene glycol in liquid formulations 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, to achieve a formulation design with a near-neutral pH while reducing the amount of polysorbate 80, we created formulations containing surfactants (Formulations 13-18) as shown in Table 5, hoping to increase the solubility of fosnetupitant chloride hydrochloride. Then, 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.

[0063] [Table 5]

[0064] [Table 6]

[0065] At pH 9.0 or higher, the amount of nonionic surfactant used is not specified, but at pH 8.5, when 100 mg of nonionic surfactant was mixed with 80 mL of another injectable formulation and stored at room temperature for 16 hours, the mixture became cloudy, but 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.

[0066] [Test Example 4] Investigation of the amount of trehalose dihydrate in freeze-dried preparations The stability of the sample stored at 5°C for the formulation in Table 7 was compared based on the change in the amount of related substances, with the initial value being used, and the sample stored as a lyophilized formulation at 40°C for 2 weeks being used as the post-storage value. Related substances were measured using HPLC.

[0067] The results are shown in Table 8. The amount of trehalose dihydrate in formulations 19 to 23 decreased, but the lower the amount, the greater the increase in the total amount of related substances. Since the inclusion of nonionic surfactants increases the amount of related substances, increasing the amount of trehalose dihydrate reduces contact between fosnetupitant chloride hydrochloride and nonionic surfactants in the lyophilized formulation, improving the stability of fosnetupitant chloride hydrochloride. However, there was little difference in stability between formulations containing 600 mg or more of trehalose dihydrate.

[0068] [Table 7]

[0069] [Table 8]

[0070] Nonionic surfactants contribute to preventing 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 the contact between fosnetupitant chloride hydrochloride and nonionic surfactants, thereby enhancing the stability of fosnetupitant chloride hydrochloride. Therefore, the addition of trehalose was found to be essential for the coexistence of fosnetupitant chloride hydrochloride and polysorbate 80 in the formulation.

[0071] [Test Example 5] Optimization of the amount of polysorbate 80 in a liquid formulation In order to optimize the amount of polysorbate 80 in a formulation containing 260 mg of fosnetupitant chloride hydrochloride, formulations 24 to 27, which contain different amounts of polysorbate 80 as shown in Table 9, were mixed with palonosetron (Aloxi (registered trademark) intravenous injection 0.75 mg) to prepare solutions. The solutions were stored at room temperature and the precipitation of insoluble particles was evaluated over time.

[0072] As a result, precipitation was observed within 1 hour in formulation 24. No precipitation was observed in formulations 25, 26, and 27. When combined with the results of formulation 17, it was thought that the critical amount of polysorbate 80 to be incorporated was 150 mg when the pH was 8.5. [Table 9]

[0073] [Test Example 6] Optimization of the amount of trehalose dihydrate As shown in Table 10, formulations 28 to 30, each containing 300 mg of polysorbate 80 and varying amounts of trehalose dihydrate (800 to 1200 mg), were used. Each lyophilized formulation was stored at 40°C / 75% RH for 3 months, and the chemical stability was evaluated. The amount of related substances was measured using HPLC.

[0074] 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 higher amount of trehalose dihydrate was considered preferable from the standpoint of stability.

[0075] [Table 10]

[0076] [Table 11]

[0077] [Test Example 7] A formulation without added propylene glycol was also prepared to examine whether it could be mixed with other injectable formulations.

[0078] 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. [Table 12]

[0079] [Test Example 8] Evaluation of Formulation 34 As shown in Table 13, trehalose dihydrate was used as the excipient, polysorbate 80 as the nonionic surfactant, propylene glycol as the 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.

[0080] [Table 13]

[0081] [Table 14]

[0082] Formulation 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 Formulation 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 the same bag, and its stability was confirmed at room temperature. The content was measured using HPLC.

[0083] 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 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 freeze-dried 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 freeze-dried 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® IV infusion bag 0.75 mg). When stored at room temperature, cloudiness occurred and precipitation occurred within 1 hour.

[0084] [Table 15]

[0085] [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 a fosnetupitant aqueous solution (pH 9.0), which was then lyophilized to obtain a formulation of Formulation 36. A stability test was conducted.

[0086] 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, confirming that the product was stable for 24 months. [Table 16]

[0087] Compatibility with palonosetron and dexamethasone The compatibility of the above formulation with concomitant medications was evaluated from the standpoint of stability. One vial of formulation 36 was reconstituted by withdrawing 10 mL from a 100 mL saline bag and then injected 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 same bag to prepare the administration solution. The solution was stored at room temperature under diffuse light conditions (approximately 400 lx).

[0088] The results are shown in Table 18. Up to 24 hours after preparation, the solution remained clear and colorless, 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.

[0089] [Table 17]

[0090] [Table 18]

[0091] Compatibility with granisetron preparations As in the previous study, one vial of the reconstituted solution for Formulation 36 and 4 mL of granisetron were added to a 100 mL saline bag to mimic the administration method used in clinical trials, and the administration solution was evaluated for stability. The solution was stored at room temperature under scattered light conditions.

[0092] The results are shown in Table 19. Up to 24 hours after preparation, the solution remained colorless and clear, 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 are no problems with the stability of the administration solution under typical clinical usage conditions.

[0093] [Table 19]

[0094] [Test Example 10] Evaluation of Formulation 37 Formulation 37 in Table 17 was prepared, and this formulation was used to conduct a long-term storage test (5°C), an accelerated test (25°C 60% RH), and a stress test (heat and light).

[0095] 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 particulates, 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.

[0096] [Table 20]

[0097] [Test Example 11] Effect of formulation pH of Formulation 37 on compatibility with concomitant medications The pH of Formulation 37 was changed, and the resulting solution was 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.

[0098] 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 formulation pH was observed. [Table 21]

[0099] [Test Example 12] Compatibility test of Formulation 37 with other commercially available formulations One vial of Formulation 37 was mixed with other antiemetic agents (palonosetron preparations, corticosteroid preparations) and physiological saline in the amounts shown in Table 22, and the stability was evaluated for up to 24 hours.

[0100] The results are shown in Table 22. It was confirmed that it could be mixed with any of the formulations without any problems. [Table 22]

[0101] [Test Example 13] Dilution stability of Formulation 37 The miscibility of the formulation 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 if necessary, with saline, glucose injection, or ethanol solution, etc., to achieve a total volume actually used in clinical practice (approximately 50 to 1150 mL), and the mixability was evaluated. The infusion solutions listed 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 standards. Storage conditions: Indoor under scattered light (temperature and illuminance: depending), 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 or an increase or decrease in pH was observed immediately after mixing and within 24 hours. △: Precipitation and an increase or decrease in pH were observed depending on the type and amount of other injectable preparations mixed or the solvent used for dilution.

[0102] [Table 23]

[0103] [Table 24]

[0104] [Table 25]

[0105] [Table 26]

[0106] [Table 27]

[0107] [Table 28]

[0108] [Table 29]

[0109] [Table 30]

[0110] [Table 31]

[0111] [Table 32] The results of the mixing test confirmed that it can be mixed with many formulations. In addition, in cases where precipitation or pH fluctuations occurred, precipitation or pH fluctuations were suppressed in some cases by adjusting the additives contained in the commercially available formulation, the pH of the formulation, and the volume (evaluation: △).

[0112] [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 commercially available formulations, provided that the solubility of fosnetupitant was not reduced in terms of additives and pH.

[0113] [Table 33]

[0114] [Table 34]

[0115] [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 removing trehalose dihydrate from Formulation 37.

[0116] The results are shown in Table 35. In Formula 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 reduction in content was not observed in Formula 37. Furthermore, the content of Formula 38 tended to decrease over time during storage, but no reduction was observed in Formula 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. [Table 35]

Claims

1. a) fosnetupitant or a pharmaceutically acceptable salt thereof; b) trehalose, and c) Nonionic surfactants 1. An injectable formulation comprising:

2. a) The formulation according to claim 1, comprising 50 to 500 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, calculated as a fosnetupitant equivalent amount.

3. The formulation according to claim 1, wherein b) trehalose is contained in an amount of 0.7 to 8.1 mg, calculated as an anhydrous trehalose amount, per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, calculated as fosnetupitant.

4. The formulation according to claim 1, wherein c) the nonionic surfactant is contained in an amount of 0.2 to 2.5 mg per 1 mg of fosnetupitant or a pharmaceutically acceptable salt thereof equivalent to fosnetupitant.

5. c) The formulation described in claim 4, wherein the nonionic surfactant is at least one selected from the group consisting of polyoxyethylene fatty acid esters or polyoxyethylene sorbitan fatty acid esters.

6. c) The formulation described in claim 4, wherein the nonionic surfactant is polysorbate 80.

7. The formulation of claim 1 further comprising d) a co-surfactant.

8. d) The formulation described in claim 7, wherein the surfactant aid is propylene glycol.

9. The formulation of claim 1 further comprising: e) a pH adjuster.

10. The formulation of claim 1, wherein f) the pH is 6.5 to 11.

0.

11. 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) Contains 300 mg of a nonionic surfactant A liquid formulation dissolved in a solvent, The formulation of claim 1.

12. a) Contains 235 mg of fosnetupitant or a pharmaceutically acceptable salt thereof, in terms of fosnetupitant equivalent; 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.

13. The formulation according to any one of claims 1 to 12, which is free of EDTA, chelating agents and antioxidants.

14. The formulation according to any one of claims 1 to 12, which is a liquid formulation.

15. The formulation according to any one of claims 1 to 10 and 12, which is a freeze-dried formulation.

16. 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.

17. 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.

18. The formulation according to any one of claims 1 to 12, which is stored protected from light.

19. The formulation according to any one of claims 1 to 12, which is stable at 25°C for 6 months or more.

20. The formulation according to any one of claims 1 to 12, which is stable at 5°C for 12 months or more.

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