Oral liquid formulations of netupitant and palonosetron

Abstract

An oral liquid formulation of netupitant and palonosetron that is effective, chemically stable, and has a physiological balance of safety and efficacy.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present disclosure relates to liquid formulations for oral administration of netupitant and palonosetron that are effective, chemically stable, and physiologically balanced in terms of safety and efficacy. [Background technology]

[0002] Background of the Invention Although drug solutions and suspensions are widely used in the pharmaceutical industry as dosage forms for various routes of administration, including oral, parenteral, and inhalation, they are generally considered to be different dosage forms, and the techniques required to produce homogeneous, readily dispensable suspensions of drugs differ from those required to produce pharmaceutically acceptable solutions / suspensions. For a detailed review of these techniques and other related issues, see, e.g., Remington, The Science and Practice of Pharmacy (latest edition).

[0003] The preparation of liquid formulations and suspensions generally involves several considerations on the part of the manufacturer, including the purpose of the drug, whether it is for oral or topical use, the solubility and concentration of the drug, the choice of liquid vehicle, the physical and chemical stability of the drug and any excipients, preservation of the dosage form, and the use of appropriate excipients (e.g., buffers, solubility enhancers, suspending agents, emulsifiers, viscosity modifiers, colorants, flavoring agents). The viscosity of the product must also be considered to ensure adequate mouthfeel in the case of oral formulations and adequate suspension properties in the case of emulsions or suspensions.

[0004] Bioavailability is also an important consideration, and in liquid formulations, bioavailability is greatly influenced by factors such as drug concentration, volume of liquid administered, pH, ionic strength, buffering capacity, surface tension, specific gravity, viscosity, and additives. The bioavailability of emulsions and suspensions can be affected by other factors, including surfactants, type of viscosity modifier, particle size, particle size distribution, polymorphism, and the solubility of the drug in the oil-phase emulsion.

[0005] Administrability is also an important consideration. When administering from unit dosage forms such as vials or stick packs, it is important to find packaging materials that maintain the stability of the formulation and yet allow nearly 100% of the contained formulation to be administered to the patient.

[0006] Combination dosage forms of netupitant and palonosetron are known. For example, WO / 2013 / 057554 discloses a fixed-dose combination of palonosetron hydrochloride and netupitant in an oral capsule for the prevention of chemotherapy-induced nausea and vomiting ("CINV"). However, WO / 2013 / 057554 does not describe a liquid formulation suitable for oral administration. Furthermore, WO2013 / 057554 and other prior art do not disclose a liquid formulation suitable for oral administration containing netupitant or a pharmaceutically acceptable salt thereof and palonosetron or a pharmaceutically acceptable salt thereof together in a single unit dosage form.

[0007] The purpose of this disclosure is to define liquid oral dosage forms of netupitant and palonosetron and prophylaxis regimens for CINV using such dosage forms, including in pediatric patients. Summary of the Invention

[0008] In one embodiment, the present disclosure provides an antiemetic composition for oral administration in a suspension / solution mixed solvent system comprising palonosetron or a pharmaceutically acceptable salt thereof and netupitant or a pharmaceutically acceptable salt thereof together in a liquid unit dosage form.

[0009] In one embodiment, the present disclosure provides an antiemetic composition for oral administration in a suspension / solution mixed solvent system, comprising palonosetron or a pharmaceutically acceptable salt thereof and netupitant or a pharmaceutically acceptable salt thereof in a solid suspension together in a dissolved state in a liquid unit dosage form.

[0010] In another embodiment, the present disclosure provides an antiemetic composition for oral administration in a suspension / solution mixed solvent system, the composition comprising: (a) 0.01-0.2 mg / mL of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a dissolved state and 10-100 mg / mL of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a solid suspension, preferably wherein the netupitant or a pharmaceutically acceptable salt thereof has a particle size distribution defined by a d(50) of 1-8 μm and a d(90) of 24 μm or less, or a d(50) of 2-4 μm and a d(90) of 12 μm or less; and (b) A solvent system in which netupitant or a pharmaceutically acceptable salt thereof is insoluble but uniformly suspended, and palonosetron or a pharmaceutically acceptable salt thereof is soluble. In another embodiment, the solvent system comprises water, one or more miscible humectants, one or more miscible suspending agents, one or more miscible pH adjusting agents, optionally one or more miscible sweetening agents, and optionally one or more miscible preservatives.

[0011] In one embodiment particularly suitable for administration to adults, the formulation is present in a unit dose package containing 300 mg of netupitant or a pharmaceutically acceptable salt thereof at a concentration of 30 mg / mL and 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof at a concentration of 0.05 mg / mL, where the doses and concentrations are based on the free forms of netupitant and palonosetron. Thus, if the formulation contains palonosetron hydrochloride, 0.56 mg of palonosetron hydrochloride will be present at a concentration of 0.056 mg / mL.

[0012] In one embodiment particularly suitable for administration to adults, the formulation is present in a unit dose package containing about 300 mg of netupitant or a pharmaceutically acceptable salt thereof at a concentration of 60 mg / mL and about 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof, preferably at a concentration of about 0.1 mg, where the doses and concentrations are based on the free forms of netupitant and palonosetron. Thus, if the formulation contains palonosetron hydrochloride, 0.56 mg of palonosetron hydrochloride will be present at a concentration of 0.112 mg / mL.

[0013] In one embodiment particularly suitable for pediatric administration, the formulation is present in a unit dose package containing 300 mg of netupitant or a pharmaceutically acceptable salt thereof, preferably at a concentration of 30 mg / mL, and 1.5 mg of palonosetron or a pharmaceutically acceptable salt thereof, preferably at a concentration of 0.15 mg / mL, where the doses and concentrations are based on the free forms of netupitant and palonosetron. Thus, if the formulation contains palonosetron hydrochloride, the 1.68 mg of palonosetron hydrochloride will be present at a concentration of 0.168 mg / mL.

[0014] In another embodiment, palonosetron is palonosetron hydrochloride.

[0015] In one embodiment, the one or more pH adjusting agents help ensure the stability of palonosetron or a pharmaceutically acceptable salt thereof and provide good uniformity of the liquid formulation that also includes netupitant or a pharmaceutically acceptable salt thereof.

[0016] In another embodiment, the one or more miscible suspending agents, such as xanthan gum, provide that the composition does not exhibit settling and / or separation during storage. In another embodiment, the one or more miscible suspending agents, such as xanthan gum, increase viscosity, thereby reducing or avoiding settling.

[0017] In one embodiment, the present disclosure provides an antiemetic composition for oral administration in which palonosetron or a pharmaceutically acceptable salt thereof and netupitant or a pharmaceutically acceptable salt thereof are contained together in a single stable combination in a liquid formulation despite having different solubility characteristics. Thus, palonosetron or a pharmaceutically acceptable salt thereof is contained in a dissolved state, and netupitant or a pharmaceutically acceptable salt thereof is contained in a solid suspended state, and both are present together in a suspension / solution mixed solvent system. In a preferred embodiment, the antiemetic composition for oral administration is an oral suspension. Surprisingly, it has been found that palonosetron or a pharmaceutically acceptable salt thereof and netupitant or a pharmaceutically acceptable salt thereof formulated according to the suspension / solution mixed solvent system of the present disclosure remain stable in the liquid formulation without precipitation.

[0018] In one embodiment, having palonosetron or a pharmaceutically acceptable salt thereof dissolved in solution ensures uniformity even at low doses of the active ingredient.

[0019] In another embodiment, the present disclosure provides a unit dose packaged composition, the composition comprising: (a) a unit dose package selected from a pouch (e.g., a stick pack or sachet), a plastic vial, a plastic tube, and a glass vial; (b) 0.01 to 0.2 mg / mL of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a dissolved state, and 10 to 100 mg / mL of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a solid suspension, preferably wherein the netupitant or a pharmaceutically acceptable salt thereof has a particle size distribution defined by a d(50) of 1 to 8 μm and a d(90) of 24 μm or less, or a d(50) of 2 to 4 μm and a d(90) of 12 μm or less; and (c) A solvent system in which netupitant or a pharmaceutically acceptable salt thereof is insoluble and palonosetron or a pharmaceutically acceptable salt thereof is soluble, the solvent system comprising water, one or more miscible humectants, one or more miscible suspending agents, one or more pH adjusting agents, optionally one or more miscible sweetening agents, and optionally one or more miscible preservatives.

[0020] Another embodiment provides a method for preventing chemotherapy-induced nausea and vomiting in a human patient in need thereof, comprising orally administering to the patient an antiemetic composition comprising palonosetron or a pharmaceutically acceptable salt thereof and netupitant or a pharmaceutically acceptable salt thereof, together in a single liquid dosage form, in a suspension / solution mixed solvent system.

[0021] Another embodiment provides a method for preventing chemotherapy-induced nausea and vomiting in a human patient in need thereof, comprising orally administering to the patient about 300 mg of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) and about 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) from a composition of the present disclosure.

[0022] Another embodiment provides a method for preventing chemotherapy-induced nausea and vomiting in a pediatric human patient in need thereof, comprising orally administering to the patient about 300 mg of netupitant or a pharmaceutically acceptable salt thereof and about 1.5 mg of palonosetron or a pharmaceutically acceptable salt thereof from a composition of the present disclosure.

[0023] In another embodiment, the present invention provides a method for preparing an antiemetic composition for oral administration in a suspension / solution mixed solvent system, the method comprising the steps of: (a) preparing a bulk formulation comprising 0.01 to 0.2 mg / mL of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a dissolved state and 10 to 100 mg / mL of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a solid suspension; and (b) Filling the bulk formulation into multiple unit dose packages while continuously agitating the formulation to minimize or prevent foaming.

[0024] Another embodiment provides palonosetron as palonosetron hydrochloride.

[0025] Additional advantages of the present disclosure will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned in part by practice of the present disclosure. The advantages of the present disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure as claimed.

[0026] Detailed Description Definitions and Use of Terms Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this disclosure pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material discussed in the sentence in which the reference is relied upon.

[0027] As used in the specification and claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. For example, the term "a pharmaceutical excipient" refers to one or more pharmaceutical excipients used in the formulations and methods of the present disclosure.

[0028] When a range is expressed by separately specifying a lower and upper limit of the range, it is understood that the range can be defined by combining any one of the lower limit variables with any one of the upper limit variables in any combination that is mathematically possible.

[0029] As used herein, the term "about" is used to allow for variations accepted in the pharmaceutical industry, such as differences in product strength due to manufacturing variability and product degradation over time, as well as variations inherent in pharmaceuticals. In one embodiment, the term allows for any variation that would allow pharmaceutical practice to consider the product being evaluated to be pharmaceutically equivalent or bioequivalent to the stated strength. In another embodiment, the term allows for any variation within 5% of the stated strength or concentration of the formulation.

[0030] "Pharmaceutically acceptable" means something that is useful in preparing pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and includes something that is acceptable for veterinary as well as human pharmaceutical use.

[0031] "Pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable as defined above and that possesses the desired pharmacological activity. It is understood that salts dissociate into ion / counterion pairs in a liquid medium, but still constitute "salts" as the term is used herein according to industry practice.

[0032] Exemplary salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or with acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, Included are acid addition salts formed with organic acids such as p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0033] Furthermore, when the acidic protons present can react with inorganic or organic bases, pharmaceutically acceptable salts may be formed. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.

[0034] When the weight of an active ingredient is given without reference to the free base or salt of the active ingredient, it is understood that the weight can refer to the weight of the free base or the weight of the total salt. Similarly, when a molecule exists as a hydrate and the weight of the molecule is given, it is understood that the weight can refer to the weight of the hydrate or the weight of the molecule excluding the water of hydration.

[0035] When ingredients are expressed based on a percentage (e.g., sorbitol 70%, nc), it is understood that this refers to any combination of sorbitol and water that produces 70% sorbitol. Thus, if a formulation includes sorbitol (70%, nc), it is understood that 7 parts anhydrous sorbitol (100%) can be mixed with 3 parts water in the formulation to produce sorbitol (70%, nc).

[0036] "Edetate disodium" or "EDTA" refers to either anhydrous edetate disodium or its hydrate. In one embodiment, the compositions of the present disclosure do not include EDTA.

[0037] The term "liquid formulation" or "liquid solution" or "liquid suspension" or similar terms refer to a liquid formulation suitable for therapeutic administration. The formulation may be manufactured and packaged as a liquid.

[0038] "Netupitant" refers to 2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethyl-N-(6-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridin-3-yl)propanamide. This compound has the following chemical structure: [ka]

[0039] Netupitant is preferably micronized, preferably having a particle size d(50) of 2-4 μm and a d(90) of 12 μm or less, as measured by laser diffraction.

[0040] "Palonosetron" refers to (3aS)-2-[(S)-1-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1H-benz[de]isoquinoline (molecular weight 296.407). Its hydrochloride salt has a molecular weight of 332.87 and the following chemical structure: [ka]

[0041] Thus, a formulation containing 0.5 mg of palonosetron hydrochloride based on the weight of palonosetron in free form would contain 0.56 mg of palonosetron hydrochloride.

[0042] The term "child" refers to subjects under the age of 18, including subjects under the ages of 12, 8, and 6, as well as subjects between the ages of 3 and 12 and between the ages of 3 and 18.

[0043] "Suspension / solution mixed solvent system" refers to a liquid formulation in which one drug is present in a dissolved state and another drug is present in a suspended state within the same formulation.

[0044] For clarity, it is understood that for regulatory or marketing purposes, a suspension / solution mixed solvent system may be classified and / or marketed simply as a "suspension." It is also understood that a formulation marketed as a "suspension" may still qualify as a "suspension / solution mixed solvent system" as long as one drug is present in solution and another drug is present in suspension within the same formulation.

[0045] As used herein, the terms "reducing sugars" and "total sugars" have the meanings defined in the United States Pharmacopeia USP37-NF32 and commonly understood by those skilled in the art.

[0046] Consideration In one embodiment, the present disclosure provides an antiemetic composition for oral administration in a suspension / solution mixed solvent system comprising palonosetron or a pharmaceutically acceptable salt thereof and netupitant or a pharmaceutically acceptable salt thereof in a single liquid dosage form.

[0047] In another embodiment, the present disclosure provides an antiemetic composition for oral administration in a suspension / solution mixed solvent system, the composition comprising: (a) 0.01 to 0.2 mg / mL of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a dissolved state and 10 to 100 mg / mL of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a solid suspension, preferably wherein the netupitant or a pharmaceutically acceptable salt thereof has a particle size distribution defined by a d(50) of 1 to 8 μm and a d(90) of 24 μm or less, or a d(50) of 2 to 4 μm and a d(90) of 12 μm or less; and (b) A solvent system in which netupitant or a pharmaceutically acceptable salt thereof is insoluble but uniformly suspended, and palonosetron or a pharmaceutically acceptable salt thereof is soluble. In another embodiment, the solvent system of point (b) comprises water, one or more miscible wetting agents, one or more miscible suspending agents, one or more miscible pH adjusting agents, optionally one or more miscible sweetening agents, and optionally one or more miscible preservatives. In one embodiment, palonosetron is palonosetron hydrochloride.

[0048] In another embodiment, the present disclosure provides a unit dose packaged composition comprising: (a) a unit dose package selected from a pouch (e.g., a stick pack or sachet), a plastic vial, a plastic tube, and a glass vial; (b) 0.01 to 0.2 mg / mL of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a dissolved state and 10 to 100 mg / mL of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a solid suspension, preferably wherein the netupitant or a pharmaceutically acceptable salt thereof has a particle size distribution defined by a d(50) of 1 to 8 μm and a d(90) of 24 μm or less, or a d(50) of 2 to 4 μm and a d(90) of 12 μm or less; and (c) a solvent system in which netupitant or a pharmaceutically acceptable salt thereof is insoluble and palonosetron or a pharmaceutically acceptable salt thereof is soluble. In another embodiment, the solvent system of (c) above comprises water, one or more miscible humectants, one or more miscible suspending agents, one or more pH adjusting agents, optionally one or more miscible sweetening agents, and optionally one or more miscible preservatives.

[0049] Another embodiment provides a method for preventing chemotherapy-induced nausea and vomiting in a human patient in need thereof, comprising orally administering to the patient an antiemetic composition in a suspension / solution mixed solvent system comprising palonosetron or a pharmaceutically acceptable salt thereof and netupitant or a pharmaceutically acceptable salt thereof, together in a single liquid dosage form.

[0050] Another embodiment provides a method for preventing chemotherapy-induced nausea and vomiting in a human patient in need thereof, comprising orally administering to the patient about 300 mg of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) and about 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) from a composition of the present disclosure.

[0051] Another embodiment provides a method for preventing chemotherapy-induced nausea and vomiting in a pediatric human patient in need thereof, comprising orally administering to the patient about 300 mg of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) and about 1.5 mg of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) from a composition of the present disclosure.

[0052] In one embodiment, palonosetron is present as palonosetron hydrochloride and netupitant is present as the free base. In another embodiment, netupitant is present as the free base and has a particle size distribution defined by a d(50) of 2-4 μm and a d(90) of 12 μm or less.

[0053] In one embodiment, the compositions of the present disclosure have a pH of 4 to 7. In another embodiment, the compositions of the present disclosure have a pH of 5 to 6. In one embodiment, these pH values, and preferably a pH in the range of 5 to 6, impart a thixotropic rheological profile to the compositions of the present disclosure, avoiding settling and / or separation of the compositions during storage.

[0054] In some embodiments, the density of the formulation is 1.1 to 1.3 mg / mL. In one embodiment, the density is 1.15 to 1.28 mg / mL. In another embodiment, the density is 1.18 to 1.26 mg / mL.

[0055] The formulation is preferably an aqueous formulation in which the ingredients are mixed and dissolved in water. The formulation may be isotonic or non-isotonic. The formulation may optionally be in 5 mL or 10 mL volumes for administration to adults or children.

[0056] In one embodiment particularly well suited for a 10 mL adult formulation, the composition of the present disclosure comprises 30 mg / mL netupitant free base and 0.056 mg / mL palonosetron hydrochloride. In another embodiment particularly well suited for a 5 mL adult formulation, the composition of the present disclosure comprises 60 mg / mL netupitant free base and 0.112 mg / mL palonosetron hydrochloride. In another embodiment particularly well suited for a 10 mL pediatric formulation, the composition of the present disclosure comprises 30 mg / mL netupitant free base and 0.168 mg / mL palonosetron hydrochloride.

[0057] Formulations can also be defined based on the concentration ranges of netupitant and palonosetron, or pharmaceutically acceptable salts thereof, in the formulation. In one embodiment particularly suitable for adults (particularly when the unit dose is 10 mL), the composition comprises: (a) 20-40 mg / mL, 25-35 mg / mL, or 30 mg / mL of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base); and (b) 0.02-0.08 mg / mL, 0.03-0.07 mg / mL, or 0.05 mg / mL of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base). In another embodiment particularly suitable for adults (particularly when the unit dose is 5 mL), the composition comprises: (a) 40-80 mg / mL, 50-70 mg / mL, or 60 mg / mL of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base); and (b) 0.05-0.15 mg / mL, 0.075-0.125 mg / mL, or 0.1 mg / mL of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base). In another embodiment particularly suitable for pediatric use (particularly when the unit dose is 10 mL), the formulations of the present disclosure contain 20-40 mg / mL, 25-35 mg / mL, or 30 mg / mL of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) and 0.1-0.2 mg / mL, 0.125-0.175 mg / mL, or 0.15 mg / mL of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base).

[0058] In one embodiment, a unit dose package for adult administration contains 300 mg of netupitant or a pharmaceutically acceptable salt thereof in a concentration of 30 mg / mL and 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof in a concentration of 0.05 mg / mL, wherein the doses and concentrations are based on the free forms of netupitant and palonosetron.

[0059] In one embodiment, a unit dose package for adult administration contains 300 mg of netupitant or a pharmaceutically acceptable salt thereof in a concentration of 60 mg / mL and 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof in a concentration of 0.1 mg / mL, wherein the doses and concentrations are based on the free forms of netupitant and palonosetron.

[0060] In another embodiment, a unit dose package for pediatric administration contains 300 mg of netupitant or a pharmaceutically acceptable salt thereof in a concentration of 30 mg / mL and 1.5 mg of palonosetron or a pharmaceutically acceptable salt thereof in a concentration of 0.15 mg / mL, wherein the doses and concentrations are based on the free forms of netupitant and palonosetron.

[0061] The formulations of the present disclosure can be further defined in terms of inactive ingredients. In some embodiments, the humectant used in the formulations of the present disclosure is selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, ethanol, and combinations thereof.

[0062] In some embodiments, the humectant is glycerin and the formulation comprises 25-100 mg / mL, 35-75 mg / mL, or 50 mg / mL of glycerin.

[0063] In some embodiments, the suspending agent is selected from the group consisting of cellulose derivatives, acacia, xanthan gum, and combinations thereof. In some embodiments, the suspending agent includes xanthan gum, and the formulation includes xanthan gum in an amount of 2.5 to 3.5 mg / mL, 2.75 to 3.25 mg / mL, or 3 mg / mL. Xanthan gum, as a suspending agent, is more viscous than formulations containing other thickening agents, but this characteristic does not affect the administration process. Formulations containing xanthan gum are physically most stable. According to the present disclosure, formulations containing xanthan gum as a suspending agent are characterized by rapid and complete hydration of the polymer, which enables a fast and simple manufacturing process. On the other hand, for example, cellulose used as a suspending agent exhibits separation (sedimentation) after approximately 30 days of storage, while formulations containing carboxymethylcellulose exhibit separation after 20 days. Formulations of the present disclosure containing xanthan gum are stable after 30 days of storage at room temperature, with no precipitation observed, demonstrating the desired stability.

[0064] In some embodiments, the formulations of the present disclosure contain a sweetener, which is a monosaccharide selected from the group consisting of glucose, fructose, galactose, and combinations thereof, or a sugar alcohol selected from the group consisting of ethylene glycol and / or propylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetriitol, polyglycitol, and combinations thereof. In some embodiments, the formulations of the present disclosure contain sorbitol as a sweetener. Sorbitol exhibits better stability in the formulations of the present disclosure than, for example, sucrose syrup, which has a wider viscosity range and lower stability.

[0065] In some embodiments, the formulation comprises 800 mg / mL to 950 mg / mL, 850 to 900 mg / mL, or 886.333 mg / mL of sorbitol syrup (70%, nc). The sorbitol is, in one embodiment, of the amorphous type.

[0066] When sorbitol syrup or other forms of sorbitol are used in the formulation, various embodiments can be defined based on the ratio of water to sorbitol in the overall formulation, or the ratio of water to sorbitol to netupitant in the overall formulation. That is, in various embodiments, the formulation contains 20-60% by weight water and 30-70% by weight sorbitol, or 30-50% by weight water and 40-60% by weight sorbitol. In other embodiments, the formulation contains 20-60% by weight water, 30-70% by weight sorbitol, and 1.5-4.0% netupitant, or 30-50% by weight water, 40-60% by weight sorbitol, and 2.0-3.0% netupitant.

[0067] Of course, it should be understood that sorbitol is only one of many sweetening agents that can be used in the formulations of the present invention. That is, in some embodiments, the formulations include one or more sweetening agents, preferably monosaccharides selected from the group consisting of glucose, fructose, galactose, and combinations thereof, and / or sugar alcohols selected from the group consisting of ethylene glycol and / or propylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetritoitol, polyglycitol, and combinations thereof.

[0068] The sweeteners described above may contain reducing sugars as residual substances remaining from the synthesis process. These reducing sugars and / or their degradation products carry the risk of being classified as "unknown" impurities in drug product analysis. To avoid structural evaluation and toxicity assessment of the impurities, the upper limit of their content can be set at 0.2% or less (Not More Than (NMT)). That is, in another embodiment, the formulation contains 0.2% or less reducing sugars based on the total weight of the sweetener.

[0069] Sorbitol is considered one of the most widely used sweetening agents. The permitted levels of reducing sugars in sorbitol are reported in the USP and Ph.Eur. as 0.3% and 0.2%, respectively, although these amounts could all be detected as "unknown" impurities, i.e., the same reducing sugar or one of its degradation products. Thus, in another embodiment, the formulation contains no more than 0.3% or 0.2% sorbitol reducing sugars based on the weight of sorbitol.

[0070] To avoid or minimize the presence of these impurities, in one embodiment, the sweetener (particularly sorbitol) contains very little reducing sugars compared to the allowable amounts reported in the USP and Ph.Eur., and in one embodiment, the sweetener (particularly sorbitol) contains no more than 0.05% reducing sugars and no more than 0.25% total sugars based on the weight of sucrose.

[0071] In some embodiments, the compositions of the present disclosure include a preservative selected from the group consisting of parabens, alcohol, glycerin, propylene glycol, sorbates, and combinations thereof. In other embodiments, the compositions of the present disclosure include potassium sorbate at a concentration of 0.5-1.5 mg / mL, 0.75-1.25 mg / mL, or 1 mg / mL.

[0072] In some embodiments, the compositions of the present disclosure comprise a pH adjuster selected from the group consisting of anhydrous citric acid and trisodium citrate, and combinations thereof.

[0073] In one embodiment, the present disclosure provides a formulation comprising a combination of inert excipients including: (a) 25-100 mg / mL, 35-75 mg / mL, or 50 mg / mL of glycerin; and (b) 2-4 mg / mL, 2.5-3.5 mg / mL, or 3 mg / mL of xanthan gum.

[0074] In other embodiments, the present disclosure provides formulations comprising a combination of inert excipients including 2-4 mg / mL, 2.5-3.5 mg / mL, or 3 mg / mL xanthan gum, 800 mg / mL-950 mg / mL, 850-900 mg / mL, or 886.333 mg / mL sorbitol syrup (70%, nc), and 0.5-1.5 mg / mL, 0.75-1.25 mg / mL, or 1 mg / mL potassium sorbate.

[0075] In another embodiment, the present disclosure provides a formulation comprising a combination of inert excipients including 2-4 mg / mL xanthan gum, 800-950 mg / mL sorbitol syrup (70%, nc), and 0.5-1.5 mg / mL potassium sorbate.

[0076] In another embodiment, the present disclosure provides a formulation comprising a combination of inert excipients including 2.5-3.5 mg / mL xanthan gum, 850-900 mg / mL sorbitol syrup (70%, nc), and 0.75-1.25 mg / mL potassium sorbate.

[0077] Alternatively, the formulation can be described in terms of active and inactive ingredients. That is, in one embodiment particularly suitable for a 10 mL adult formulation, the formulation of the present disclosure comprises 25-35 mg / mL netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base), 0.025-0.075 mg / mL palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base), 2-3 mg / mL xanthan gum, 800-950 mg / mL sorbitol syrup (70%, nc), and 0.5-1.5 mg / mL potassium sorbate.

[0078] In another embodiment particularly suitable for a 10 mL adult formulation, the formulation contains 25-35 mg / mL netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base), 0.025-0.075 mg / mL palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base), 2.5-3.5 mg / mL xanthan gum, 850-900 mg / mL sorbitol syrup (70%, nc), and 0.75-1.25 mg / mL potassium sorbate.

[0079] In one embodiment particularly suitable for a 10 mL adult formulation, the composition comprises: (a) 30 mg / mL netupitant free base; (b) 0.05 mg / mL palonosetron hydrochloride; (c) 50 mg / mL glycerin 98%; (d) 3 mg / mL xanthan gum; (e) 2 mg / mL anhydrous citric acid as a pH adjuster; (f) 13.75 mg / mL trisodium citrate as a pH adjuster; (g) 1 mg / mL potassium sorbate as a preservative; (h) 886.333 mg / mL sorbitol syrup (70%, nc) as a sweetener; and (i) purified water, qs to 1 mL, as a solvent.

[0080] In another embodiment particularly suitable for a 5 mL adult formulation, the formulation contains 50-70 mg / mL netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base), 0.075-0.125 mg / mL palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base), 2-3 mg / mL xanthan gum, 800-950 mg / mL sorbitol syrup (70%, nc), and 0.5-1.5 mg / mL potassium sorbate.

[0081] In another embodiment particularly suitable for a 5 mL adult formulation, the formulation contains 50-70 mg / mL netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base), 0.075-0.125 mg / mL palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base), 2.5-3.5 mg / mL xanthan gum, 850-900 mg / mL sorbitol syrup (70%, nc), and 0.75-1.25 mg / mL potassium sorbate.

[0082] In another embodiment particularly suitable for a 5 mL adult formulation, the formulation contains: (a) 60 mg / mL netupitant free base; (b) 0.1 mg / mL palonosetron hydrochloride; (c) 50 mg / mL glycerin 98%; (d) 3 mg / mL xanthan gum; (e) 2 mg / mL anhydrous citric acid as a pH adjuster; (f) 13.75 mg / mL trisodium citrate as a pH adjuster; (g) 1 mg / mL potassium sorbate as a preservative; (h) 886.333 mg / mL sorbitol syrup (70%, nc) as a sweetener; and (i) purified water, qs to 1 mL, as a solvent.

[0083] In one embodiment particularly suitable for a 10 mL pediatric formulation, the formulation of the present disclosure comprises 25-35 mg / mL netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base), 0.125-0.175 mg / mL palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base), 2-3 mg / mL xanthan gum, 800-950 mg / mL sorbitol syrup (70%, nc), and 0.5-1.5 mg / mL potassium sorbate.

[0084] In another embodiment particularly suitable for a 10 mL pediatric formulation, the formulation contains 25-35 mg / mL netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base), 0.125-0.175 mg / mL palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base), 2.5-3.5 mg / mL xanthan gum, 850-900 mg / mL sorbitol syrup (70%, nc), and 0.75-1.25 mg / mL potassium sorbate.

[0085] In one embodiment particularly suitable for a 10 mL pediatric formulation, the composition comprises: (a) 60 mg / mL netupitant free base; (b) 0.15 mg / mL palonosetron hydrochloride; (c) 50 mg / mL glycerin 98%; (d) 3 mg / mL xanthan gum; (e) 2 mg / mL anhydrous citric acid as a pH adjuster; (f) 13.75 mg / mL trisodium citrate as a pH adjuster; (g) 1 mg / mL potassium sorbate as a preservative; (h) 886.333 mg / mL sorbitol syrup (70%) as a sweetener; and (i) purified water, qs to 1 mL, as a solvent.

[0086] The formulations of the present disclosure are useful for complete administration of the active ingredients to patients. The formulations of the present disclosure, which include palonosetron or a pharmaceutically acceptable salt thereof and netupitant or a pharmaceutically acceptable salt thereof, are contained in a single liquid dosage form in a stable combination that avoids sedimentation effects, and are useful for packaging as described below in this disclosure.

[0087] In another embodiment, the manufacturing process for producing the formulation of the present disclosure is carried out in a manner that reduces the risk of foaming, loss of API uniformity, and dosage errors. In one embodiment, at the end of bulk preparation, the suspension is continuously stirred until and during the filling process to avoid foam separation, which may affect the content uniformity of the final product. The formulation is highly structured, viscous, and prone to entrapment of air during the process. If phase separation occurs, the foam formed will be enriched in palonosetron but not netupitant, potentially resulting in an inaccurate ratio of netupitant to palonosetron in the final filled product. To avoid phase separation, the bulk is continuously stirred at the end of preparation and during the filling process.

[0088] Thus, in another embodiment, the present invention provides a method for preparing an orally administered antiemetic composition in a suspension / solution mixed solvent system, the method comprising the steps of: a) preparing a bulk formulation comprising 0.01-0.2 mg / mL of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a dissolved state and 10-100 mg / mL of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a solid suspension; and b) Filling the bulk formulation into multiple unit dose packages while continuously stirring the formulation to minimize or prevent foaming.

[0089] In one embodiment, the bulk drug formulation comprises a solvent system in which netupitant or a pharmaceutically acceptable salt thereof is insoluble but uniformly suspended, and palonosetron or a pharmaceutically acceptable salt thereof is soluble, water, one or more miscible humectants, one or more miscible suspending agents, one or more pH adjusting agents, optionally one or more miscible sweetening agents, and optionally one or more miscible preservatives.

[0090] Another embodiment involves filling approximately 10 mL of bulk formulation into each unit dose package containing 300 mg of netupitant or a pharmaceutically acceptable salt thereof at a concentration of 30 mg / mL and 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof at a concentration of 0.05 mg / mL, wherein the doses and concentrations are based on the free forms of netupitant and palonosetron.

[0091] Another embodiment involves filling approximately 5 mL of bulk formulation into each unit dose package containing 300 mg of netupitant or a pharmaceutically acceptable salt thereof at a concentration of 60 mg / mL and 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof at a concentration of 0.1 mg / mL, where the doses and concentrations are based on the free forms of netupitant and palonosetron.

[0092] Another embodiment involves filling approximately 10 mL of bulk formulation into each unit dose package containing 300 mg of netupitant or a pharmaceutically acceptable salt thereof at a concentration of 30 mg / mL and 1.5 mg of palonosetron or a pharmaceutically acceptable salt thereof at a concentration of 0.15 mg / mL, where the doses and concentrations are based on the free forms of netupitant and palonosetron.

[0093] Packaging Exemplary packaging for liquid unit dosage forms includes pouches (e.g., liquid stick packs and sachets), plastic vials, glass vials, and plastic tubes, which can be used as is, diluted with water, or used as is and then a liquid chaser is added. Packaging materials that come into contact with the liquid formulation can be made of any suitable plastic, which provides stability to the formulation and prevents permeation of substances from or into the liquid formulation. Examples of materials suitable for packaging include glass, polyester, polypropylene, polyethylene, and polyethylene terephthalate (PET). In some embodiments, the inner surface of the container comprises glass, polyester, polypropylene, or polyethylene.

[0094] In some embodiments, packaging is performed using a laminate. The material used to construct the laminate sheet can be any material commonly used in the art, such as polyester, polypropylene, polyethylene, and polyethylene terephthalate (PET). In some embodiments, the laminate includes a layer of aluminum foil. Exemplary laminates include PET / ALU / PE 23 / 20 / 50 microns and PET / ALU / PE 12 / 9 / 50 microns.

[0095] The pouch is preferably made from one or two laminate sheets configured to define an internal cavity that is sealed around its perimeter. Examples of suitable pouch designs are described, for example, in US 2015 / 0144518 A1 and US 20030168375 A1. Suitable laminates for pouches or other packaging can also be purchased from companies such as Unette Corporation (Randolph, New Jersey) and Amcor 360 Packaging Solutions (Melbourne, Australia).

[0096] In some embodiments of the present disclosure, the pouch is straight, thereby avoiding the formation of a shoulder at the top, which can cause the formulation to become stuck inside and prevent complete withdrawal of the formulation and complete administration of the drug.

[0097] The packaging of the present disclosure can provide stability to the overall dosage form. In some embodiments, the packaged composition contains less than about 1% or 0.5% total impurities. In another embodiment, the formulation of the present invention contains less than about 1% or 0.5% total impurities after storage at 40°C ± 2°C and 75% RH ± 5% RH for 3 or 6 months. In another embodiment, the formulation of the present invention contains less than about 0.5% total impurities after storage at 25°C ± 2°C and 60% RH ± 5% RH for 9 months.

[0098] The packaging of the present disclosure provides for easier oral administration. In one embodiment, the packaging is a single-dosage unit package that allows for direct administration into the patient's oral cavity.

[0099] Oral liquid antiemetic compositions formulated in this packaged and suspension / solution mixed solvent system improve patient compliance.

[0100] Improved compliance is particularly useful for patients who have difficulty swallowing oral solid dosage forms, such as patients with head and neck tumors, and oncology patients who have dysphagia or difficulty swallowing due to side effects of certain treatments, such as chemotherapy and / or radiation therapy. For example, patients with mouth sores (mucositis) caused by chemotherapy or radiation therapy to the head and neck may experience pain when swallowing, and would be greatly benefited by the easier administration of a liquid composition.

[0101] In another embodiment, the packaging of the present disclosure allows for complete dose recovery and maximizes product dosing, which ensures optimal patient benefit.

[0102] In some other embodiments, the overfill volume can be about 1 mL for a 10 mL dose and about 0.5 mL for a 5 mL dose.

[0103] Treatment method In one embodiment, the present disclosure provides a method for preventing chemotherapy-induced nausea and vomiting in a human patient in need thereof, the method comprising orally administering to the patient an antiemetic composition in a suspension / solution mixed solvent system comprising palonosetron or a pharmaceutically acceptable salt thereof and netupitant or a pharmaceutically acceptable salt thereof, together in a single liquid dosage form.

[0104] In another embodiment, the present disclosure provides a method for preventing chemotherapy-induced nausea and vomiting in a human patient in need thereof, comprising orally administering to the patient about 300 mg of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) and about 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) from any suitable formulation and / or package of the present disclosure.

[0105] In one embodiment, the present disclosure provides a method for preventing chemotherapy-induced nausea and vomiting in a pediatric human patient in need thereof, the method comprising orally administering to the patient an antiemetic composition in a suspension / solution mixed solvent system comprising palonosetron or a pharmaceutically acceptable salt thereof and netupitant or a pharmaceutically acceptable salt thereof, together in a single liquid dosage form.

[0106] In another embodiment, the present disclosure provides a method for preventing chemotherapy-induced nausea and vomiting in a pediatric human patient in need thereof, comprising orally administering to the patient about 300 mg of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) and about 1.5 mg of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) from any suitable formulation and / or package of the present disclosure. Particularly suitable pediatric age ranges include 3 to 18 years and 3 to 12 years.

[0107] In a further embodiment, the method further comprises administering highly emetogenic chemotherapy ("HEC") or moderately emetogenic chemotherapy ("MEC") within two hours after administration of netupitant and palonosetron. For definitions of HEC and MEC, see A Pocket Guide To EMETOGENICITY OF CHEMOTHERAPY REGIMENS Version 2019 published by Helsinn Healthcare SA (https: / / hospitalhealthcare.com / wpcontent / uploads / 2020 / 09 / HEL85_bookletEMESI_UNBRANDED_191219.pdf). [Example]

[0108] In the following examples, efforts have been made to ensure accuracy of numerical values ​​(e.g., amounts, temperatures, etc.), but some errors or deviations are possible. The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of the practice and evaluation of the methods claimed herein, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their invention.

[0109] Example 1: Tests to obtain a suitable and physicochemically stable suspension A series of studies were designed and conducted to select the optimal suspending agent and wetting agent. In each study, netupitant was buffered with citrate at a concentration of approximately 45 mg / g. The following studies were performed: The appearance and flavor of the suspension Injectability: The bottle stopper and a graduated syringe were used to test whether the required amount of product could be easily withdrawn. Physical stability of the suspension: No sedimentation / cake formation was observed during one week of storage; resuspension was assessed after gentle shaking. The pH was checked to be between 5.0 and 6.0 during storage to ensure that no rheological changes occurred that would adversely affect product performance and maintain flavor. The test compositions are summarized in Table 1. [Table 1]

[0110] All formulations were white, opaque, smooth suspensions without lumps. Dose preparation tests were performed to confirm the actual injectability of the products: all suspensions could be easily withdrawn from the bottles using the appropriate stoppers and graduated syringes. Formulations containing xanthan gum remained stable after 30 days of storage at room temperature, with no precipitation observed. Formulations containing xanthan gum were characterized by rapid and complete hydration of the polymer, allowing for a fast and simple manufacturing process.

[0111] Suspensions were also prepared using carboxymethylcellulose. All of these suspensions exhibited separation (precipitation) after approximately 20–30 days of storage, but could be easily resuspended by gentle shaking. A pH of 5.0–6.0 was obtained using citrate, and this value appeared to be stable during storage (tested after 1 week of storage).

[0112] Example 2: Stability testing of oral suspension Oral formulations were prepared according to the qualitative / quantitative formulations in Table 2, and stability studies were conducted in accordance with ICH Q1A(R2) "Stability Studies of New Drug Substances and New Drug Formulations" (November 2003). The stability test results for 10 mL amber glass vials (Type III) with neutral polymer caps containing 10 mL of oral suspension are shown in Tables 3 and 4. [Table 2] [Table 3] [Table 4]

[0113] Example 3. Other oral suspensions Other formulations are reported in Tables 5 and 6, where Table 5 shows the composition of a typical 10 mL dose and Table 6 reports the composition of a typical 5 mL dose. Results of stability testing of this formulation packaged in a PET / Alu / PE stick pack are reported in Tables 7 and 8 for 25°C / 60% RH and 40°C / 75% RH, respectively. [Table 5] [Table 6] [Table 7] [Table 8]

[0114] Example 4. Stability of xanthan gum [Table 9]

[0115] As can be seen, formulations containing xanthan gum were consistently stable in terms of pH and precipitation.

[0116] Other embodiments Other embodiments and aspects of the present disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

1. An antiemetic composition for oral administration in a suspension / solution mixed solvent system comprising: a) 0.01-0.2 mg / mL of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in solution and 10-100 mg / mL of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in solid suspension; and b) A solvent system in which netupitant or a pharmaceutically acceptable salt thereof is insoluble but uniformly suspended and palonosetron or a pharmaceutically acceptable salt thereof is soluble, the solvent system comprising water, one or more miscible humectants, one or more miscible suspending agents, one or more pH adjusting agents, optionally one or more miscible sweetening agents, and optionally one or more miscible preservatives.

2. 10. The composition of claim 1, wherein the solvent system comprises water, one or more miscible humectants, one or more miscible suspending agents, one or more pH adjusting agents, optionally one or more miscible sweetening agents, and optionally one or more miscible preservatives.

3. 3. The composition of claim 1 or 2, wherein the palonosetron is present as palonosetron hydrochloride and the netupitant is present as the free base.

4. 4. The composition of claim 1, 2, or 3, wherein the netupitant is present as a free base and has a particle size distribution defined by d(50) between 1 and 8 μm and d(90) less than or equal to 24 μm, or d(50) between 2 and 4 μm and d(90) less than or equal to 12 μm.

5. The composition according to any one of claims 1 to 4, which has a pH of 4 to 7 or 5 to 6.

6. The composition of any one of claims 1 to 5, comprising 30 mg / mL netupitant free base and 0.056 mg / mL palonosetron hydrochloride.

7. The composition of any one of claims 1 to 5, comprising 60 mg / mL netupitant free base and 0.112 mg / mL palonosetron hydrochloride.

8. The composition of any one of claims 1 to 5, comprising 30 mg / mL netupitant free base and 0.168 mg / mL palonosetron hydrochloride.

9. 6. The composition of any one of claims 1 to 5, comprising 300 mg of netupitant or a pharmaceutically acceptable salt thereof in a concentration of 30 mg / mL and 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof in a concentration of 0.05 mg / mL, wherein the doses and concentrations are based on the free forms of netupitant and palonosetron.

10. The composition of any one of claims 1 to 5, comprising 300 mg of netupitant or a pharmaceutically acceptable salt thereof in a concentration of 60 mg / mL and 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof in a concentration of 0.1 mg / mL, wherein the doses and concentrations are based on the free forms of netupitant and palonosetron.

11. 6. The composition of any one of claims 1 to 5, comprising 300 mg of netupitant or a pharmaceutically acceptable salt thereof in a concentration of 30 mg / mL and 1.5 mg of palonosetron or a pharmaceutically acceptable salt thereof in a concentration of 0.15 mg / mL, wherein the doses and concentrations are based on the free forms of netupitant and palonosetron.

12. 10. The composition of any preceding claim, wherein the humectant is selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, ethanol, and combinations thereof.

13. 10. The composition of any preceding claim, comprising 25-100 mg / mL, 35-75 mg / mL, or 50 mg / mL glycerin as a humectant.

14. 10. The composition of any preceding claim, wherein the suspending agent is selected from the group consisting of cellulose derivatives, acacia, xanthan gum, and combinations thereof.

15. 10. A composition according to any preceding claim, comprising 2-4 mg / mL, 2.5-3.5 mg / mL, or 3 mg / mL xanthan gum as a suspending agent.

16. 10. The composition according to any of the preceding claims, wherein the sweetening agent is a monosaccharide selected from the group consisting of glucose, fructose, galactose, and combinations thereof, or a sugar alcohol selected from the group consisting of ethylene glycol and / or propylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetritoitol, polyglycitol, and combinations thereof.

17. 10. The composition of any preceding claim, comprising 800 mg / mL to 950 mg / mL, 850 to 900 mg / mL, or 886.333 mg / mL of sorbitol syrup (70%, nc) as a sweetening agent.

18. 10. The composition of any preceding claim, wherein the preservative is selected from the group consisting of parabens, alcohols, glycerin, propylene glycol, sorbates, and combinations thereof.

19. 10. The composition of any preceding claim, comprising 0.5-1.5 mg / mL, 0.75-1.25 mg / mL, or 1 mg / mL potassium sorbate.

20. 10. The composition of any preceding claim, wherein the pH adjuster is selected from the group consisting of anhydrous citric acid and trisodium citrate, and combinations thereof.

21. A composition according to any of the preceding claims, comprising the following ingredients: a) 25-100 mg / mL, 35-75 mg / mL, or 50 mg / mL glycerin; and b) 2-4 mg / mL, 2.5-3.5 mg / mL, or 3 mg / mL xanthan gum.

22. A composition according to any of the preceding claims, comprising the following ingredients: a) 2-4 mg / mL, 2.5-3.5 mg / mL, or 3 mg / mL xanthan gum; b) sorbitol syrup (70%, nc) at 800 mg / mL to 950 mg / mL, 850 to 900 mg / mL, or 886.333 mg / mL; and c) 0.5-1.5 mg / mL, 0.75-1.25 mg / mL, or 1 mg / mL potassium sorbate.

23. A composition according to any of the preceding claims, comprising the following ingredients: a) 2-4 mg / mL xanthan gum; b) 800-950 mg / mL sorbitol syrup (70%, nc); and c) 0.5-1.5 mg / mL potassium sorbate.

24. A composition according to any of the preceding claims, comprising the following ingredients: a) 2.5-3.5 mg / mL xanthan gum; b) 850-900 mg / mL sorbitol syrup (70%, nc); and c) 0.75 to 1.25 mg / mL potassium sorbate.

25. A composition according to any of the preceding claims, comprising the following ingredients: a) 50 mg / mL glycerin 98%; b) 3 mg / mL xanthan gum; c) 2 mg / mL anhydrous citric acid; d) 13.75 mg / mL trisodium citrate; e) 1 mg / mL potassium sorbate f) 886.333 mg / mL sorbitol syrup (70%, nc); and g) Add an appropriate amount of water to make 1 mL.

26. A unit dose packaged composition comprising: a) a unit dose package selected from a pouch, a plastic vial, and a plastic tube; b) 0.01-0.2 mg / mL of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in solution and 10-100 mg / mL of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in solid suspension; and c) A solvent system in which netupitant or a pharmaceutically acceptable salt thereof is insoluble and palonosetron or a pharmaceutically acceptable salt thereof is soluble, the solvent system comprising water, one or more miscible humectants, one or more miscible suspending agents, one or more miscible pH adjusting agents, one or more miscible sweetening agents, and optionally one or more miscible preservatives.

27. 27. The packaged composition of claim 26 for administration to an adult, comprising 300 mg of netupitant or a pharmaceutically acceptable salt thereof at a concentration of 30 mg / mL and 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof at a concentration of 0.05 mg / mL, wherein the doses and concentrations are based on the free forms of netupitant and palonosetron.

28. 27. The packaged composition of claim 26 for administration to an adult, comprising 300 mg of netupitant or a pharmaceutically acceptable salt thereof at a concentration of 60 mg / mL and 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof at a concentration of 0.1 mg / mL, wherein the doses and concentrations are based on the free forms of netupitant and palonosetron.

29. 27. The packaged composition of claim 26 for pediatric administration, comprising 300 mg of netupitant or a pharmaceutically acceptable salt thereof at a concentration of 30 mg / mL and 1.5 mg of palonosetron or a pharmaceutically acceptable salt thereof at a concentration of 0.15 mg / mL, wherein the doses and concentrations are based on the free forms of netupitant and palonosetron.

30. 30. The packaged composition of any of claims 26-29, wherein the netupitant is present as a free base and has a particle size distribution defined by d(50) between 1 and 8 μm and d(90) equal to or less than 24 μm, or d(50) between 2 and 4 μm and d(90) equal to or less than 12 μm.

31. The packaged composition of any one of claims 26 to 30, wherein the pH is 4 to 7 or 5 to 6.

32. 32. The packaged composition of any one of claims 26 to 31, comprising 2 to 4 mg / mL, 2.5 to 3.5 mg / mL, or 3 mg / mL xanthan gum as a suspending agent.

33. 33. The packaged composition of any of claims 26 to 32, wherein the packaging comprises polyester, polypropylene, polyethylene, or polyethylene terephthalate (PET).

34. 34. A method for preventing chemotherapy-induced nausea and vomiting in a human patient in need thereof, comprising orally administering to the patient 300 mg of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) and 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) from the composition of any of claims 1-28 and 30-33.

35. 35. The method of claim 34, further comprising administering highly emetogenic chemotherapy or moderately emetogenic chemotherapy within 2 hours after administration of netupitant and palonosetron.

36. 31. A method for preventing chemotherapy-induced nausea and vomiting in a pediatric human patient in need thereof, comprising orally administering to the patient 300 mg of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) and 1.5 mg of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) from the composition of any of claims 1-23 and 26-30.

37. 37. The method of claim 36, further comprising administering highly emetogenic chemotherapy or moderately emetogenic chemotherapy within 2 hours after administration of netupitant and palonosetron.

38. A method for preparing an antiemetic composition for oral administration in a suspension / solution mixed solvent system, comprising the steps of: (a) preparing a bulk formulation comprising 0.01-0.2 mg / mL of palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a dissolved state and 10-100 mg / mL of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a solid suspension; and (b) Filling the bulk formulation into multiple unit dose packages while continuously stirring the formulation to minimize or prevent foaming.

39. 39. The method of claim 38, wherein the bulk drug formulation comprises a solvent system in which netupitant or a pharmaceutically acceptable salt thereof is insoluble but uniformly suspended, and palonosetron or a pharmaceutically acceptable salt thereof is soluble, wherein the solvent system comprises water, one or more miscible humectants, one or more miscible suspending agents, one or more pH adjusting agents, optionally one or more miscible sweetening agents, and optionally one or more miscible preservatives.

40. 40. The method of claim 38 or 39, comprising filling approximately 10 mL of bulk formulation into each unit dose package containing 300 mg of netupitant or a pharmaceutically acceptable salt thereof at a concentration of 30 mg / mL and 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof at a concentration of 0.05 mg / mL, wherein the doses and concentrations are based on the free forms of netupitant and palonosetron.

41. 40. The method of claim 38 or 39, comprising filling approximately 5 mL of bulk formulation into each unit dose package containing 300 mg of netupitant or a pharmaceutically acceptable salt thereof at a concentration of 60 mg / mL and 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof at a concentration of 0.1 mg / mL, wherein the doses and concentrations are based on the free forms of netupitant and palonosetron.

42. 40. The method of claim 38 or 39, comprising filling approximately 10 mL of bulk formulation into each unit dose package containing 300 mg of netupitant or a pharmaceutically acceptable salt thereof at a concentration of 30 mg / mL and 1.5 mg of palonosetron or a pharmaceutically acceptable salt thereof at a concentration of 0.15 mg / mL, wherein the doses and concentrations are based on the free forms of netupitant and palonosetron.

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