Oily compositions comprising maropitant and uses thereof

Abstract

The present invention relates to an oily composition comprising maropitant and an oily carrier. The invention also relates to the use of such a composition in the treatment and prevention of nausea and vomiting in a non-human mammal, in particular a dog or cat.

Description

[0001] OILY COMPOSITIONS INCLUDING MAROPITANT AND THEIR

[0002] USES

[0003] Object of the invention

[0004] The present invention relates to the veterinary field, and more particularly to compositions comprising prolonged-release maropitant and their use to treat and / or prevent nausea and vomiting in non-human mammals, preferably in cats and dogs.

[0005] Technological background of the invention

[0006] Maropitant, with the chemical name (2S,3S)-N-(5-tert-butyl-2-methoxybenzyl)-2-(diphenylmethyl)-l-azabicyclo[2.2.2]octan-3-amine (or (2S,3S)-N-(5-tert-butyl-2-methoxyphenyl)methyl-2-(diphenylmethyl)-l-azabicyclo[2.2.2]octan-3-amine; IUP AC name: (2S,3S)-2-benzhydryl-N-[(5-tert-butyl-2-methoxyphenyl)methyl]-l-azabicyclo[2.2.2]octan-3-amine), is an antiemetic that acts as an NK-1 neurokinin receptor antagonist. It is indicated for the treatment of vomiting, particularly that induced by cancer chemotherapy. It has been marketed for dogs since 2007 and for cats since 2012.

[0007] In particular, Zoetis markets the Cerenia® product range, one of which is an oral formulation (tablet) containing maropitant in the form of a monohydrate citrate salt, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sunset yellow FCF (El 10) dye, for dogs to prevent nausea and vomiting, particularly induced by chemotherapy or motion sickness (Cerenia® Product Characteristics Summary).

[0008] A product from the Cerenia® range can also be used as a 10 mg / mL injectable solution in dogs and cats. This injectable solution contains maropitant in the form of a monohydrate citrate salt, sulfobutyl ether P-cyclodextrin, metacresol, and water.

[0009] However, the effects of Cerenia® products last approximately 24 hours and must be administered once a day, either in tablet or injectable form, for a maximum of 5 days to avoid any toxic side effects for the animal.

[0010] There therefore remains a need to develop new compositions and formulations based on maropitant allowing prolonged release of the active ingredient while minimizing side effects for non-human mammals, particularly in the case of parenteral administration by injection.

[0011] Summary of the invention

[0012] In this context, the inventors have provided new oily compositions of maropitant, preferably in its base form, comprising an oily vehicle. The oily compositions according to the invention have the particular advantage of improving the pharmacokinetic parameters of maropitant compared to the maropitant formulated in Cerenia® products, especially by prolonging its half-life, thus ensuring better bioavailability and a prolonged biological effect. Furthermore, the inventors have advantageously demonstrated that the oily compositions according to the invention do not exhibit any side effects or toxicity in animals upon administration, particularly when administered by injection, unlike the Cerenia® product.

[0013] The present invention therefore relates to an oily composition comprising maropitant, and an oily vehicle.

[0014] In particular, the oily composition further comprises a co-solvent. Specifically, the co-solvent is selected from benzyl alcohol, benzyl benzoate, oleic acid, oleic alcohol, glyceryl caprylate / caprate, dimethyl sulfoxide, and a mixture thereof.

[0015] Specifically, the oily vehicle is selected from propylene glycol dicapryl locaprate, medium-chain triglycerides, isopropyl myristate, ethyl oleate, and mixtures thereof. Preferably, the oily vehicle is propylene glycol dicapryl locaprate.

[0016] According to one embodiment, the composition further includes an antioxidant and / or a preservative.

[0017] Preferably, the maropitant is in basic form.

[0018] According to a particular embodiment of the invention, the maropitant in the composition has a concentration by weight by volume (w / v) of between 1 and 5% (% w / v), preferably between 2 and 5% (% w / v), even more preferably of about 2 or 4% (% w / v).

[0019] According to another particular embodiment of the invention, the co-solvent has a concentration by weight by volume (w / v) of between 0.5 and 40% (% w / v), preferably between 1 and 30% (% w / v), and even more preferably between 2 and 25% (% w / v).

[0020] A preferred object of the invention is an oily composition comprising:

[0021] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0022] - between 1 and 5% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0023] - between 5 and 20% (w / v%), preferably about 15% (w / v) of benzyl benzoate, and

[0024] - propylene glycol dicaprylocaprate Qs 100%.

[0025] Another preferred object of the invention is an oily composition comprising:

[0026] - approximately 2% (% w / v) of maropitant base,

[0027] - approximately 2% (w / v) benzyl alcohol, - approximately 0.01% (w / v) benzalkonium chloride,

[0028] - approximately 0.03% butyl hydroxytoluene,

[0029] - and propylene glycol dicaprylocaprate Qs 100%.

[0030] Another preferred object of the invention is an oily composition comprising:

[0031] - approximately 2% (% w / v) of maropitant base,

[0032] - approximately 2% (w / v) dimethyl sulfoxide,

[0033] - approximately 0.01% (w / v) of benzalkonium chloride,

[0034] - approximately 0.03% (w / v) of butyl hydroxytoluene,

[0035] - and propylene glycol dicaprylocaprate Qs 100%.

[0036] In one particular embodiment, the composition according to the invention is a solution. In a more particular embodiment, the composition according to the invention is a sterile solution.

[0037] An object of the invention is a composition as defined in this application intended for use as a medicinal product.

[0038] Another object of the invention is a composition as defined in this application intended for use in the treatment and prevention of nausea and vomiting in a non-human mammal, in particular in the treatment and prevention of chemotherapy-induced nausea and vomiting or perioperative nausea and vomiting, and in the treatment and prevention of nausea and vomiting in association with other accompanying measures, such as dietary control and fluid therapy.

[0039] According to a preferred embodiment of the invention, the composition is administered parenterally, preferably by injection, and even more preferably by subcutaneous injection.

[0040] According to a preferred embodiment of the invention, the non-human mammal is a dog or a cat. Key to figures

[0041] [FIGURE 1] represents the mean (ng / mL) and time-dependent (h) plasma concentration profiles of maropitant observed in cats after subcutaneous administration of Cerenia® at a dose of 1 mg / kg and of composition Al at a dose of 4 mg / kg.

[0042] [FIGURE 2] represents the mean (ng / mL) and time-dependent (h) plasma concentration profiles of maropitant observed in dogs after subcutaneous administration of Cerenia® at a dose of 1 mg / kg and of composition Al at a dose of 4 mg / kg.

[0043] Detailed description of the invention

[0044] The present invention provides an oily composition comprising maropitant, and an oily vehicle.

[0045] According to a particular embodiment of the invention, the oily composition comprises maropitant, a co-solvent, and an oily vehicle.

[0046] The term "w / v %" or "% w / v" means "weight by volume percentage" and expresses the concentration of an ingredient in a composition, particularly a solution. It corresponds to the number of grams of solute dissolved in 100 milliliters of the composition. For example, a 5% w / v solution of a substance means that 5 grams of that substance are dissolved in 100 milliliters of the total composition. Thus, an oily composition containing 4% (% w / v) of maropitant means that there are 4 grams of maropitant in 100 milliliters, or 40 mg / mL. Similarly, an oily composition containing 2% (% w / v) of maropitant means that there are 2 grams of maropitant in 100 milliliters, or 20 mg / mL.

[0047] The terms "approximately" and "around" will be understood by a person skilled in the art and may vary to some extent depending on the context in which they are used. If some uses of these terms are not clear to a person skilled in the art depending on the context, "approximately" or "around" means plus or minus 20%, preferably plus or minus 10% of the particular term.

[0048] According to a particular embodiment of the invention, the maropitant, preferably in base form, has a concentration by weight by volume (w / v) of between 1 and 5% (% w / v), preferably between 2 and 5% (% w / v), between 2.5 and 4.5% (% w / v), and even more preferably of about 2 or 4% (% w / v).

[0049] The term "co-solvent" refers to a solvent used in combination with another vehicle to improve the solubility of a substance or active ingredient in the formulation. In particular, the co-solvent in the oily compositions of the invention improves the solubility of the maropitant in the oily vehicle.

[0050] Examples of co-solvents include polar solvents, such as alcohols, esters, and ethers, and esterified fatty acids. Other examples of co-solvents include, but are not limited to, N-methylpyrrolidone, 2-pyrrolidone, glycerol formaldehyde, ethanol, dimethyl sulfoxide, benzyl alcohol, oleyl alcohol, isopropyl alcohol, benzyl benzoate, glycofurol, solketal, oleic acid, linoleic acid, and glyceryl caprylate / caprate. Lipophilic surfactants, particularly nonionic surfactants or mixtures of nonionic surfactants, are also examples of co-solvents. In particular, these non-ionic surfactants or mixtures of non-ionic surfactants have an HLB of less than 10.Among these types of co-solvents, the following may be mentioned, but not limited to: polyethylene glycol-type surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene phenyl alkyl ethers, polyoxyethylene fatty acid esters, polyoxyethylene fatty acid esters of polyhydric alcohol, polyoxyethylene alkylamine, polyoxyethylene of fatty acid amide, and polyoxyethylene of polyoxypropylene glycol. Also included are polyalcoholic-type surfactants, such as fatty acid esters of glycerol, fatty acid esters of pentaerythritol, fatty acid esters of sorbitan and sorbitol, disaccharide fatty acid esters, alkyl polyglycosides, and alkanolamide fatty acids.Specifically, the co-solvent for the oily composition is selected from benzyl alcohol, benzyl benzoate, oleic acid, oleic alcohol, glyceryl caprylate / caprate, dimethyl sulfoxide, and mixtures thereof. In one particular method, the co-solvent is a mixture of benzyl alcohol and benzyl benzoate. In another particular method, the co-solvent is benzyl alcohol. In another particular method, the co-solvent is a mixture of benzyl alcohol and oleic acid. In another particular method, the co-solvent is a mixture of benzyl alcohol and glyceryl caprylate / caprate. In another particular method, the co-solvent is a mixture of benzyl alcohol and oleic alcohol. In another particular method, the co-solvent is dimethyl sulfoxide. In a particular method, the co-solvent is a mixture of benzyl benzoate and dimethyl sulfoxide. In another particular method, the co-solvent is a mixture of benzyl alcohol and dimethyl sulfoxide.According to one preferred method, the co-solvent is a mixture of benzyl alcohol and benzyl benzoate. According to another preferred method, the co-solvent is dimethyl sulfoxide.

[0051] According to a particular embodiment of the invention, the co-solvent has a weight-by-volume (w / v) concentration of between 0.5 and 40% (% w / v), between 1 and 35% (% w / v), preferably between 1 and 30% (% w / v), and even more preferably between 2 and 25% (% w / v). According to another particular embodiment of the invention, the co-solvent has a weight-by-volume (w / v) concentration of between 0.5 and 10% (% w / v), between 1 and 10% (% w / v), between 1 and 5% (% w / v), preferably between 1.5 and 4% (% w / v), and even more preferably about 1 or 2% (% w / v).

[0052] An "oil-based vehicle" is an oil-based liquid used to dissolve or suspend an active ingredient in a formulation. Specifically, an oil-based vehicle is one suitable for injection into an animal.

[0053] Examples of oily vehicles include natural or refined vegetable oils, mineral oils, synthetic oils such as medium-chain triglycerides (MCTs), and essential oils. Other examples include, but are not limited to, soybean oil, sesame oil, cottonseed oil, corn oil, semi-synthetic vegetable oils, caprylic, capric, linoleic, or succinic acid triglycerides (marketed under the names Miglyol® 810, 812, 818, 820, 829), esters of propylene glycol and fatty acids derived from vegetable oils (Miglyol® 840), isopropyl myristate, isopropyl palmitate, ethyl oleate, and glyceryl triacetate.

[0054] Specifically, the oily vehicle for the oily composition is selected from propylene glycol dicaprylocaprate, medium-chain triglycerides, isopropyl myristate, and ethyl oleate. Preferably, the oily vehicle is propylene glycol dicaprylocaprate.

[0055] According to one embodiment, the composition further includes an antioxidant and / or a preservative.

[0056] Examples of antioxidants include tocopherol, butyl hydroxyanisole (BHA), butyl hydroxytoluene (BHT), vitamin E and its derivatives, citric acid, propyl gallate, ascorbyl palmitate, acetylcysteine, and ethyl-1-enediaminetetraacetic acid (EDTA).

[0057] In particular, the antioxidant is chosen from butyl hydroxyanisole (BHA), butyl hydroxytoluene (BHT), vitamin E, and a mixture of these.

[0058] According to another particular embodiment of the invention, the antioxidant has a concentration by weight by volume (w / v) of between 0.01 and 2% (% w / v), between 0.02 and 1.5% (% w / v), preferably between 0.03 and 1.03% (% w / v), and even more preferably about 0.03 or 1 or 1.03% (% w / v).

[0059] A preservative is a compound, ingredient, or substance that prevents the growth of microorganisms and microbial contamination, thereby ensuring the stability and efficacy of an active ingredient formulated in a pharmaceutical or veterinary product. Examples of preservatives include benzyl alcohol, benzoic acid, phenol, boric acid, chlorocresol, cresol, metacresol, sorbic acid, monothioglycerol, potassium sorbate, chlorobutanol, thiomersal, benzalkonium chloride, phenoxyethanol, and parabens.

[0060] In particular, the preservative is chosen from benzyl alcohol, benzalkonium chloride, chlorocresol, and sorbic acid.

[0061] In particular, the preservative in the oily composition as described in this application has a weight-by-volume (w / v) concentration of between 0.01 and 5% (% w / v), 0.01 and 1% (% w / v), and about 0.01 or 0.8% (% w / v).

[0062] It is understood by those skilled in the art that certain ingredients, such as those described in this application, may have multiple functions due to their nature and inherent properties. For example, benzyl alcohol can act as both a co-solvent and a preservative.

[0063] A preferred object of the invention is an oily composition comprising:

[0064] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0065] - between 1 and 5% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0066] - between 5 and 20% (w / v%), preferably about 15% (w / v) of benzyl benzoate, and

[0067] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0068] Another preferred object of the invention is an oily composition comprising:

[0069] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0070] - between 1 and 10% (w / v%), preferably about 6% (w / v) of benzyl alcohol, and

[0071] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0072] Another preferred object of the invention is an oily composition comprising:

[0073] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0074] - between 1 and 5% (w / v), preferably about 1.5% (w / v) of benzyl alcohol, - between 2 and 30% (w / v), preferably about 10 or 15% (w / v) of oleic acid,

[0075] - and propylene glycol dicaprylocaprate Qs 100%.

[0076] Another preferred object of the invention is an oily composition comprising:

[0077] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0078] - between 1 and 5% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0079] - between 2 and 30% (w / v%), preferably about 10% (w / v) of glyceryl capryl ate / caprate,

[0080] - and propylene glycol dicaprylocaprate Qs 100%.

[0081] Another preferred object of the invention is an oily composition comprising:

[0082] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0083] - between 1 and 5% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0084] - between 2 and 30% (% w / v), preferably around 5% (% w / v) of oleic alcohol,

[0085] - and propylene glycol dicaprylocaprate Qs 100%.

[0086] Another preferred object of the invention is an oily composition comprising:

[0087] - approximately 2% (% w / v) of maropitant base,

[0088] - and propylene glycol dicaprylocaprate Qs 100%.

[0089] Another preferred object of the invention is an oily composition comprising:

[0090] - approximately 2% (% w / v) of maropitant base,

[0091] - and medium chain triglycerides Qs 100%.

[0092] Another preferred object of the invention is an oily composition comprising:

[0093] - approximately 2% (% w / v) of maropitant base,

[0094] - and isopropyl myristate Qs 100%.

[0095] Another preferred object of the invention is an oily composition comprising:

[0096] - approximately 2% (% w / v) of maropitant base,

[0097] - and ethyl oleate Qs 100%. Another preferred object of the invention is an oily composition comprising:

[0098] - approximately 2% (% w / v) of maropitant base,

[0099] - approximately 1% (w / v) of benzyl alcohol,

[0100] - and propylene glycol dicaprylocaprate Qs 100%.

[0101] Another preferred object of the invention is an oily composition comprising:

[0102] - approximately 2% (% w / v) of maropitant base,

[0103] - approximately 1% (w / v) of benzyl alcohol,

[0104] - approximately 0.03% (w / v) of butyl hydroxytoluene,

[0105] - and propylene glycol dicaprylocaprate Qs 100%.

[0106] Another preferred object of the invention is an oily composition comprising:

[0107] - approximately 2% (% w / v) of maropitant base,

[0108] - approximately 2% (w / v) benzyl alcohol,

[0109] - and propylene glycol dicaprylocaprate Qs 100%.

[0110] Another preferred object of the invention is an oily composition comprising:

[0111] - approximately 2% (% w / v) of maropitant base,

[0112] - approximately 2% (w / v) benzyl alcohol,

[0113] - approximately 0.01% (w / v) of benzalkonium chloride,

[0114] - approximately 0.03% (w / v) of butyl hydroxytoluene,

[0115] - and propylene glycol dicaprylocaprate Qs 100%.

[0116] Another preferred object of the invention is an oily composition comprising:

[0117] - approximately 2% (% w / v) of maropitant base,

[0118] - approximately 2% (w / v) dimethyl sulfoxide,

[0119] - approximately 0.01% (w / v) of benzalkonium chloride,

[0120] - approximately 0.03% (w / v) of butyl hydroxytoluene,

[0121] - and propylene glycol dicaprylocaprate Qs 100%.

[0122] Another preferred object of the invention is an oily composition comprising: - approximately 2% (w / v) of maropitant base, - approximately 2% (w / v) of dimethyl sulfoxide,

[0123] - approximately 0.03% (w / v) of butyl hydroxyanisole,

[0124] - and propylene glycol dicaprylocaprate Qs 100%.

[0125] Another preferred object of the invention is an oily composition comprising:

[0126] - approximately 2% (% w / v) of maropitant base,

[0127] - approximately 2% (w / v) dimethyl sulfoxide,

[0128] - approximately 0.03% (w / v) of butyl hydroxytoluene,

[0129] - and propylene glycol dicaprylocaprate Qs 100%.

[0130] Another preferred object of the invention is an oily composition comprising:

[0131] - approximately 2% (% w / v) of maropitant base,

[0132] - approximately 2% (w / v) dimethyl sulfoxide,

[0133] - approximately 1% (w / v) of vitamin E,

[0134] - and propylene glycol dicaprylocaprate Qs 100%.

[0135] Another preferred object of the invention is an oily composition comprising:

[0136] - approximately 2% (% w / v) of maropitant base,

[0137] - approximately 2% (w / v) dimethyl sulfoxide,

[0138] - approximately 0.03% (w / v) of butyl hydroxytoluene,

[0139] - approximately 1% (w / v) of vitamin E,

[0140] - and propylene glycol dicaprylocaprate Qs 100%.

[0141] Another preferred object of the invention is an oily composition comprising:

[0142] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0143] - between 1 and 5% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0144] - between 5 and 20% (w / v%), preferably about 15% (w / v) of benzyl benzoate,

[0145] - approximately 0.01% (w / v) of benzalkonium chloride, and

[0146] - propylene glycol dicaprylocaprate Qs 100%.

[0147] Another preferred object of the invention is an oily composition comprising: - between 2 and 5% (w / v%), preferably about 4% (w / v) of maropitant base, - between 5 and 20% (w / v), preferably about 15% (w / v) of benzyl benzoate,

[0148] - between 1 and 5% (w / v%), preferably about 2% (w / v) of dimethyl sulfoxide, and

[0149] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0150] Another preferred object of the invention is an oily composition comprising:

[0151] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0152] - between 1 and 5% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0153] - between 5 and 20% (w / v%), preferably about 15% (w / v) of benzyl benzoate,

[0154] - approximately 0.1% (w / v) of chlorocresol, and

[0155] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0156] Another preferred object of the invention is an oily composition comprising:

[0157] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0158] - between 1 and 10% (w / v%), preferably about 6% (w / v) of benzyl alcohol,

[0159] - between 1 and 5% (w / v%), preferably about 2% (w / v) of dimethyl sulfoxide, and

[0160] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0161] Another preferred object of the invention is an oily composition comprising:

[0162] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0163] - between 1 and 10% (w / v%), preferably about 6% (w / v) of benzyl alcohol,

[0164] - approximately 0.01% (w / v) of benzalkonium chloride, and

[0165] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0166] Another preferred object of the invention is an oily composition comprising:

[0167] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0168] - between 1 and 10% (w / v%), preferably about 6% (w / v) of benzyl alcohol,

[0169] - approximately 0.05% (% w / v) of vitamin E, and

[0170] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0171] Another preferred object of the invention is an oily composition comprising:

[0172] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0173] - between 1 and 10% (w / v), preferably about 6% (w / v) of benzyl alcohol, - about 0.03% (w / v) of butylhydroxytoluene, and

[0174] - approximately 0.8% (w / v) sorbic acid,

[0175] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0176] Another preferred object of the invention is an oily composition comprising:

[0177] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0178] - between 1 and 10% (w / v%), preferably about 6% (w / v) of benzyl alcohol,

[0179] - between 1 and 5% (w / v%), preferably about 2% (w / v) of dimethyl sulfoxide,

[0180] - approximately 0.03% (w / v) of butyl hydroxytoluene, and

[0181] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0182] Another preferred object of the invention is an oily composition comprising:

[0183] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0184] - between 5 and 20% (w / v%), preferably about 15% (w / v) of benzyl benzoate,

[0185] - between 1 and 5% (w / v%), preferably about 2% (w / v) of dimethyl sulfoxide,

[0186] - approximately 0.03% (w / v) of butyl hydroxytoluene, and

[0187] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0188] Another preferred object of the invention is an oily composition comprising:

[0189] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0190] - between 1 and 10% (w / v%), preferably about 6% (w / v) of benzyl alcohol,

[0191] - between 1 and 5% (w / v%), preferably about 2% (w / v) of dimethyl sulfoxide,

[0192] - approximately 0.03% (w / v) of butyl hydroxyanisole, and

[0193] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0194] In particular, the oily compositions are in the form of a solution, which is a form particularly well-suited to parenteral administration, especially by injection. A particular embodiment of the invention is therefore a composition as described in the present application, formulated as a solution, preferably a sterile solution. Another particular embodiment of the invention is a composition as described in the present application administered parenterally, preferably by injection, and even more preferably by subcutaneous injection. The oily compositions according to the invention can be prepared using a simple, economical process, and are therefore well-suited to industrial scale. For example, the oily vehicle is heated to 40 °C under nitrogen bubbling, and a co-solvent is optionally added. The maropitant, preferably in base form, is then added to the mixture.The mixture is then cooled to 25°C and 100% of the vehicle oil is added. The composition is then recovered after sterilizing filtration.

[0195] The oily compositions according to the invention and described in this application comprise maropitant as the active ingredient for its anti-vomiting and anti-nausea effects. In the context of the invention, the term "maropitant" includes the basic form of maropitant, as well as all its pharmaceutically acceptable salts, all its crystalline forms, all its hydrated forms, and any other form based on maropitant as the active ingredient. For example, a pharmaceutically acceptable salt of maropitant is the monohydrate citrate salt of maropitant. According to a preferred embodiment of the invention, the maropitant is in its basic form. According to this preferred embodiment, the maropitant may be called "maropitant base" or "maropitant base." A person skilled in the art will readily adjust the amount of the form of maropitant used to achieve the desired weight-by-volume (w / v) concentration of maropitant.

[0196] An object of the invention also relates to a composition as described in the present application intended for use as a medicinal product.

[0197] Another object of the invention relates to a composition as described in this application for use in the treatment and prevention of nausea and vomiting in a non-human mammal. The invention also relates to a composition as described in this application for use in the treatment and prevention of nausea and vomiting in a non-human mammal. In the context of the present invention, the terms "treatment" and "treat" also broadly refer to prophylaxis, prevention, avoidance, prevention, control, and minimization of the risks of nausea and vomiting. In a particular way, these expressions include the curative treatment of nausea and vomiting in non-human mammals. "Curative treatment" means treatment that allows the cessation of nausea and vomiting in the non-human mammal.In another specific sense, these expressions include the "preventive treatment" of non-human mammals against nausea and vomiting. In one sense, preventive treatment refers to treatment administered before a non-human mammal experiences nausea and vomiting. Preventive treatment therefore reduces the risk of the non-human mammal suffering from nausea and vomiting. The terms "treatment" and / or "prevention" can thus also refer to protecting a non-human mammal from nausea and vomiting.

[0198] In particular, the compositions of the invention are veterinary compositions. They are preferably intended for administration to non-human mammals, and especially companion animals, such as cats or dogs. According to a preferred aspect of the invention, the compositions of the invention are intended for administration to cats and dogs.

[0199] One object of the invention relates to the use of a composition as described in this application for the manufacture of a medicinal product for the treatment and prevention of nausea and vomiting in a non-human mammal, in particular in a dog or cat.

[0200] An object of the invention also relates to a method for treating and preventing nausea and vomiting in a non-human mammal, particularly a dog or cat, comprising administering an effective amount of a composition as described in this application. Nausea and vomiting have various causes. They can be induced by motion sickness. They can also be associated with more serious and debilitating conditions, including gastrointestinal obstructions, and can also be induced by chemotherapy or occur during the perioperative phases.

[0201] The invention therefore also relates to a composition as described in the present application intended for use in the treatment and prevention of nausea and vomiting induced by chemotherapy or perioperative nausea and vomiting.

[0202] The invention also relates to a composition as described in this application intended for use in the treatment and prevention of nausea and vomiting in association with other accompanying measures, such as dietary control and fluid therapy.

[0203] In particular, an oily composition according to the invention comprises maropitant at a weight-by-volume (w / v) concentration of between 1 and 5% (% w / v), preferably between 2 and 5% (% w / v), and even more preferably between 2 and 4% (% w / v). Such a concentration (w / v) of 2% corresponds to a maropitant (maropitant base) concentration of 20 mg per mL of composition. Such a concentration (w / v) of 4% corresponds to a maropitant (maropitant base) concentration of 40 mg per mL of composition.

[0204] In particular, an oily composition according to the invention is administered to a non-human mammal, especially a dog or cat, at a dose of maropitant, preferably maropitant base, of between 1 and 5 mg / kg body weight, preferably between 2 and 5 mg / kg body weight, and even more preferably between 2 and 4 mg / kg body weight. Thus, administering 4 mg / kg body weight of maropitant, preferably maropitant base, to a non-human mammal is equivalent to administering 0.1 mL / kg body weight of an oily composition comprising maropitant, preferably maropitant base, at a weight-by-volume (w / v) concentration of 4% or a concentration of 40 mg / mL to that non-human mammal.Similarly, administering 4 mg / kg body weight of maropitant, preferably maropitant base, to a non-human mammal is equivalent to administering 0.2 mL / kg body weight of an oily composition containing maropitant, preferably maropitant base, at a weight-by-volume (w / v) concentration of 2% or a concentration of 20 mg / mL to that non-human mammal. Likewise, administering 2 mg / kg body weight of maropitant, preferably maropitant base, to a non-human mammal is equivalent to administering 0.1 mL / kg body weight of an oily composition containing maropitant, preferably maropitant base, at a weight-by-volume (w / v) concentration of 2% or a concentration of 20 mg / mL to that non-human mammal.

[0205] Specifically, the oily compositions according to the invention comprising maropitant are administered to a non-human mammal at the doses specified in this application once, once every two days, once every three days, once every four days, or once every five days, preferably once, i.e., a single dose. A single administration of an oily composition according to the invention is recommended in view of the plasma profile in Figure 1, demonstrating an effect lasting beyond 5 days. The oily compositions according to the invention thus correspond to controlled-release or extended-release compositions of maropitant in a non-human mammal.

[0206] Other aspects and advantages of the invention will become apparent from the following examples, which should be considered illustrative and not limiting.

[0207] Examples

[0208] 1. Preparation of oily compositions according to the invention

[0209] The compositions of the invention are prepared by the following general process: A quantity of vehicle was heated to 40 °C under nitrogen bubbling. Optionally, a desired quantity of co-solvent was then added to the mixture. Next, a desired quantity of maropitant base was also added to the mixture and then dissolved. The mixture was then cooled to 25 °C, and the final volume was adjusted with 100% oily vehicle. The final composition of the invention was obtained after sterile filtration through a 0.2 µm filter. Examples of compositions:

[0210] Examples of compositions including maropitant base 4.0% (% w / v) and maropitant base 2.0% (% w / v) are detailed respectively in Tables 1 to 6 below.

[0211] [Table 1]

[0212] [Table 2] [Table 3]

[0213] [Table 4] [Table 5] [Table 6]

[0214] 2. Clinical study in cats - Tolerance and pharmacokinetics 2.1. Materials and methods

[0215] 2.1.1. Experimental Plan - Administration

[0216] Eighteen animals were divided into three groups (two cats in each group for phase 1 and four cats in each group for phase 2).

[0217] The compositions were administered according to the following procedure:

[0218] Group III: Single subcutaneous injection (midline of the neck between the shoulder blades) of 0.2 ml / kg, which corresponds to a dose of 4 mg / kg (NI Composition)

[0219] Group II: Single subcutaneous injection (midline of the neck between the shoulder blades) of 0.1 ml / kg, which corresponds to a dose of 4 mg / kg (Composition Al)

[0220] Group 1: 1 mg / kg (reference product Cerenia®). Within three days prior to treatment, the hair at the administration site was cut using an electric clipper, taking care to avoid any skin trauma.

[0221] The volume to be administered was calculated from the individual body weights recorded prior to administration.

[0222] The injection sites were not massaged / manipulated after administration (except for the assessment of pain intensity and heat).

[0223] The experimental design of this study is detailed in the following Table 7: [Table 7] 2.1.2. Clinical observations

[0224] General clinical observation was assessed approximately 1 hour, 4 hours and 9 hours after injection, and then daily for up to 5 days after administration.

[0225] 2.1.3. Reactions during injection

[0226] Reactions were assessed during injection and for 5 minutes after injection.

[0227] - Movement of the head and / or neck

[0228] Scraping of the injection site

[0229] Injection-specific vocalization

[0230] - Defensive reaction

[0231] Duration of discomfort (min)

[0232] Any other abnormal reaction / behavior

[0233] - Licking at the injection site (number and duration)

[0234] 2.1.4. Local tolerance at the injection site

[0235] The local reaction at the injection site was assessed before administration (on the day of treatment) and approximately 1h, 4h, and 9h after, then daily up to 120h after administration.

[0236] Pain intensity (assessed by gentle pressure of the palm of the hand on the injection site; manipulation of the injection site should be strictly avoided): No pain = 0

[0237] Mild pain: reaction to slight pressure = 1

[0238] Moderate pain: defensive reaction to slight pressure = 2

[0239] Severe pain: defensive reaction without pressure = 3

[0240] Swelling :

[0241] No = 0

[0242] Yes = 1 (if yes, measure the length x width x height) 2.2. Results

[0243] 2.2.1. Local tolerance

[0244] Reaction during injection and for 5 minutes after injection

[0245] The number of cats observed during and 5 minutes after injection is detailed in Table 8 below.

[0246] [Table 8]

[0247] No injection reactions were reported for the Al or Ni compositions, unlike with Cerenia®. Also, fewer observations were reported within 5 minutes of injection of the Al or Ni compositions compared to Cerenia®.

[0248] Swelling and pain

[0249] The number of cats that were observed to have swelling and pain at the injection site is detailed in Table 9 below.

[0250] [Table 9]

[0251] No swelling or pain was observed within 5 days following administration of the Al or NI compositions and Cerenia®. These observations regarding local tolerance are all the more surprising given that the Al and NI compositions contain a maropitant concentration (dose) four times higher than the maropitant concentration in Cerenia®. 2.2.2. Pharmacokinetic Results

[0252] Figure 1 shows the mean plasma concentration-time profile of maropitant observed in cats after subcutaneous administration of Cerenia® at a dose of 1 mg / kg and of the Al composition at a dose of 4 mg / kg. Table 10 below reports the evaluation of pharmacokinetic parameters after administration of Cerenia® and the AL composition.

[0253] [Table 10] Figure 1 and the inspection of the mean terminal half-life, TLz, in Table 10 showed that the extended-release Al composition had a longer terminal half-life than Cerenia®. 3. Clinical study in dogs - Tolerance and pharmacokinetics

[0254] 3.1. Materials and methods

[0255] 3.1.1. Experimental Plan - Administration

[0256] Twenty-four animals were divided into three groups of eight animals (four males and four females in each group).

[0257] The compositions were administered according to the following procedure:

[0258] Group III: Single subcutaneous injection (midline of the neck between the shoulder blades) of 0.2 ml / kg, which corresponds to a dose of 4 mg / kg (NI Composition)

[0259] Group II: Single subcutaneous injection (midline of the neck between the shoulder blades) of 0.1 ml / kg, which corresponds to a dose of 4 mg / kg (Composition Al)

[0260] Group 1: 1 mg / kg (reference product Cerenia®).

[0261] In the three days prior to treatment, the hairs at the administration site were trimmed using an electric trimmer, taking care to avoid any skin trauma.

[0262] The volume to be administered was calculated from the individual body weights recorded prior to administration.

[0263] The injection sites were not massaged / manipulated after administration (except for the assessment of pain intensity and heat).

[0264] The experimental design of this study is detailed in the following Table 11:

[0265] [Table 11]

[0266] 3.1.2. Clinical observations

[0267] General clinical observation was assessed approximately 1 hour, 4 hours and 9 hours after injection, and then daily for up to 5 days after administration.

[0268] 3.1.3. Reactions during injection

[0269] Reactions were assessed during injection and for 5 minutes after injection.

[0270] - Movement of the head and / or neck

[0271] Scraping of the injection site

[0272] Injection-specific vocalization

[0273] - Defensive reaction

[0274] - Licking at the injection site (number and duration) Local muscle contraction

[0275] 3.1.4. Local tolerance at the injection site

[0276] The local reaction at the injection site was assessed before administration (on the day of treatment) and approximately 1h, 4h, and 9h after, then daily up to 120h after administration.

[0277] Pain intensity (assessed by gentle pressure of the palm of the hand on the injection site; manipulation of the injection site should be strictly avoided): No pain = 0

[0278] Mild pain: reaction to slight pressure = 1

[0279] Moderate pain: defensive reaction to slight pressure = 2

[0280] Severe pain: defensive reaction without pressure = 3 Heat

[0281] None = 0

[0282] Heat perceived during palpation = 1

[0283] Swelling :

[0284] No = 0

[0285] Yes = 1 (if yes, measure length x width x height)

[0286] Erythema:

[0287] No erythema = 0

[0288] Mild erythema (slight redness barely visible) = 1

[0289] Moderate erythema (clearly visible redness) = 2

[0290] Severe erythema (beetroot red) with slight sores (deep lesions) = 3

[0291] Excoriation (yes / no)

[0292] Crusts (yes / no)

[0293] Ulceration (yes / no)

[0294] Abscess (yes / no)

[0295] Any other abnormal observation

[0296] 3.2. Results

[0297] 3.2.1. Local tolerance

[0298] Reaction during injection and for 5 minutes after injection

[0299] The number of dogs observed during and 5 minutes after injection is detailed in Table 12 below.

[0300] [Table 12] No local muscle contractions were reported within 5 minutes of injection of either the Al or NI composition, unlike with Cerenia®. Specifically, the local muscle contractions observed with Cerenia® in the three dogs occurred within the first five seconds after Cerenia injection.

[0301] Other observations around the injection site

[0302] These additional observations are described in Table 13 below.

[0303] [Table 13]

[0304] No further observations were reported for dogs that received composition Al or composition NI.

[0305] After administration of Cerenia®, one dog presented with local heat at T1h, and another dog presented with local erythema at T4h.

[0306] No pain, abrasion, ulceration, abscess or other was observed at the injection site, regardless of the product administered.

[0307] No other abnormal clinical observations were recorded during the lifetime phase. The general health of all dogs was satisfactory and comparable throughout the lifetime phase.

[0308] These observations on local tolerance are all the more surprising given that the Al and NI compositions include a maropitant concentration (dose) four times higher than the maropitant concentration in the Cerenia® product.

[0309] 3.2.2. Pharmacokinetic results

[0310] Figure 2 shows the mean plasma concentration-time profile of maropitant observed in dogs after subcutaneous administration of Cerenia® at a dose of 1 mg / kg and of the Al composition at a dose of 4 mg / kg. Table 14 below reports the evaluation of pharmacokinetic parameters after administration of Cerenia® and the Al composition.

[0311] [Table 14]

[0312] Figure 2 and the inspection of the mean terminal half-life, TLz, in Table 14 showed that the extended-release Al composition had a longer terminal half-life than Cerenia®. 4. Clinical efficacy study in dogs

[0313] 4.1. Materials and methods

[0314] 4.1.1. Experimental design - Administration Thirty-five dogs were divided into 5 groups, the compositions were administered according to the following procedure:

[0315] Group V: Placebo

[0316] Group IV: A single subcutaneous injection (midline of the neck between the shoulder blades) of 0.1 ml / kg, corresponding to a dose of 2 mg / kg (NI composition), three days prior to induction of vomiting by subcutaneous administration of apomorphine at a dose of 0.05 mg / kg. Group III: A single subcutaneous injection (midline of the neck between the shoulder blades) of 0.15 ml / kg, corresponding to a dose of 3 mg / kg (NI composition), three days prior to induction of vomiting by subcutaneous administration of apomorphine at a dose of 0.05 mg / kg. Group II: A single subcutaneous injection (midline of the neck between the shoulder blades) of 0.2 ml / kg, corresponding to a dose of 4 mg / kg (NI composition), three days prior to induction of vomiting by subcutaneous administration of apomorphine at a dose of 0.05 mg / kg.

[0317] Group 1: 1 mg / kg (reference product Cerenia®) one day before inducing vomiting by subcutaneous administration of apomorphine at a dose of 0.05 mg / kg as indicated in the product's SmPC. The volume to be administered was calculated from individual body weights recorded prior to administration.

[0318] The experimental design of this study is detailed in Table 15 below:

[0319] [Table 15]

[0320] 4.1.2. Clinical observations

[0321] Each dog was observed to determine the occurrence of emetic events (retching and / or vomiting) for one hour after induction via apomorphine.

[0322] Subcutaneous administration of the NI composition at a dose of 2, 3, or 4 mg / kg was well tolerated by dogs. No pain at the injection site and no local reactions were observed after administration.

[0323] 4.2. Results

[0324] The results are detailed in Table 16 below. [Table 16]

[0325] Compared to the placebo group, the number of episodes of retching and vomiting was significantly reduced after treatment with the composition according to the invention or with Cerenia®. 5. Clinical efficacy study in cats

[0326] 5.1. Materials and methods

[0327] 5.1.1. Experimental Plan - Administration

[0328] Eighteen cats were divided into 3 groups, and the compositions were administered to them according to the following procedure:

[0329] Group III: Placebo

[0330] Group II: Single subcutaneous injection (midline of the neck between the shoulder blades) of 0.2 ml / kg, which corresponds to a dose of 4 mg / kg (NI Composition) three days before the induction of vomiting by subcutaneous administration of xylazine at a dose of 0.44 mg / kg.

[0331] Group 1: 1 mg / kg (reference product Cerenia®) one day before induction of vomiting by subcutaneous administration of xylazine at a dose of 0.44 mg / kg.

[0332] The volume to be administered was calculated from the individual body weights recorded prior to administration.

[0333] The experimental design of this study is detailed in Table 17 below:

[0334] [Table 17]

[0335] 4.1.2. Clinical observations

[0336] Each cat was observed to determine the occurrence of emetic events (retching and / or vomiting) for one hour after induction via xylazine.

[0337] Subcutaneous administration of the NI composition at a dose of 4 mg / kg was well tolerated by cats. No pain at the injection site and no local reactions were observed after administration.

[0338] 4.2. Results

[0339] The results are detailed in Table 18 below.

[0340] [Table 18]

[0341] Compared to the placebo group, the number of retching and vomiting episodes is significantly reduced after treatment with the composition according to the invention or with Cerenia®.

[0342] Treatment with the composition according to the invention at a concentration of 4 mg / kg significantly reduced vomiting and retching for 3 days in all treated cats.

Claims

35 DEMANDS 1. Oily composition comprising maropitant, and an oily vehicle.

2. Composition according to claim 1, wherein the composition further comprises a co-solvent.

3. Composition according to claim 2, wherein the co-solvent is selected from benzyl alcohol, benzyl benzoate, oleic acid, oleic alcohol, glyceryl capryl ate / caprate, dimethyl sulfoxide, and a mixture thereof.

4. Composition according to any one of claims 1 to 3, wherein the oily vehicle is selected from propylene glycol dicapryl ocaprate, medium chain triglycerides, isopropyl myristate, ethyl oleate, and a mixture thereof, preferably propylene glycol dicapryl ocaprate.

5. Composition according to any one of claims 1 to 4, wherein the composition further comprises an antioxidant and / or a preservative.

6. Composition according to any one of claims 1 to 5, wherein the maropitant is in basic form.

7. Composition according to any one of claims 1 to 6, wherein the maropitant has a concentration by weight by volume (w / v) of between 1 and 5% (% w / v), preferably between 2 and 5% (% w / v), and even more preferably of about 2 or 4% (% w / v).

8. Composition according to any one of claims 2 to 7, wherein the co-solvent has a concentration by weight by volume (w / v) of between 0.5 and 40% (% w / v), preferably between 1 and 30% (% w / v), and even more preferably between 2 and 25% (% w / v). 36 9. Composition according to any one of claims 1 to 8, wherein the composition comprises: - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base, - between 1 and 5% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol, - between 5 and 20% (w / v%), preferably about 15% (w / v) of benzyl benzoate, and - propylene glycol dicaprylocaprate Qs 100%.

10. Composition according to any one of claims 1 to 8, wherein the composition comprises: - approximately 2% (% w / v) of maropitant base, - approximately 2% (w / v) benzyl alcohol, - approximately 0.01% (w / v) of benzalkonium chloride, - approximately 0.03% butyl hydroxytoluene, - and propylene glycol dicaprylocaprate Qs 100%.

11. Composition according to any one of claims 1 to 8, wherein the composition comprises: - approximately 2% (% w / v) of maropitant base, - approximately 2% (w / v) dimethyl sulfoxide, - approximately 0.01% (w / v) of benzalkonium chloride, - approximately 0.03% (w / v) of butyl hydroxytoluene, - and propylene glycol dicaprylocaprate Qs 100%.

12. Composition according to any one of claims 1 to 11, wherein the composition is a solution, preferably a sterile solution.

13. Composition according to any one of claims 1 to 12, intended for use in the treatment and prevention of nausea and vomiting in a non-human mammal.

14. A composition for use according to claim 13, wherein the composition is administered parenterally, preferably by injection, and even more preferably by subcutaneous injection.

15. A composition for use according to claim 13 or 14, wherein the non-human mammal is a dog or a cat.

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