Compositions comprising maropitant base, and uses thereof

Abstract

The present invention relates to a sustained-release injectable composition comprising maropitant base and at least one acceptable veterinary excipient. 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 cat or dog.

Description

[0001] COMPOSITIONS INCLUDING MAROPITANT BASE AND THEIR

[0002] USES

[0003] Object of the invention

[0004] The present invention relates to the veterinary field, and more particularly to injectable compositions comprising prolonged-release maropitant base 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 novel, long-acting injectable compositions comprising maropitant base and at least one veterinary-acceptable excipient. The compositions according to the invention have the particular advantage of improving the pharmacokinetic parameters of maropitant in its base form compared to the maropitant citrate monohydrate salt formulated in Cerenia® products, specifically by extending its half-life, thus ensuring better bioavailability and a prolonged biological effect. Furthermore, the inventors have advantageously demonstrated that the 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 a prolonged-release injectable composition comprising maropitant base and at least one veterinaryly acceptable excipient.

[0014] According to a particular embodiment of the invention, the maropitant base 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), and even more preferably about 2 or 4% (% w / v). According to another particular embodiment of the invention, the composition is an oily, aqueous, or in situ gel composition.

[0015] One embodiment of the invention is an injectable, extended-release oily composition further comprising an oily vehicle.

[0016] Another embodiment of the invention is an aqueous, long-release injectable composition further comprising a preservative, a viscosifying agent, a surfactant, and water.

[0017] Another embodiment of the invention is an injectable, extended-release in situ gel composition further comprising an in situ gelling compound, and a solvent.

[0018] An object of the invention is a composition as defined in this application intended for use as a medicinal product.

[0019] 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 supportive measures, such as dietary control and fluid therapy.

[0020] According to a preferred mode of the invention, the non-human mammal is a dog or a cat.

[0021] According to a preferred embodiment of the invention, the prolonged-release injectable composition is administered only once. Figure legend

[0022] [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.

[0023] [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.

[0024] [FIGURE 3] 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 composition A2 at a dose of 4 mg / kg.

[0025] [FIGURE 4] 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 composition A3 at a dose of 4 mg / kg.

[0026] Detailed description of the invention

[0027] The present invention provides a prolonged-release injectable composition comprising maropitant base and at least one veterinaryly acceptable excipient.

[0028] The term "w / v %" or "% w / v" means "weight by volume percentage" and expresses the concentration of an ingredient in a composition. 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, a prolonged-release injectable composition containing 4% (% w / v) of maropitant base means that there are 4 grams of maropitant base in 100 milliliters, or 40 mg / mL. Similarly, a prolonged-release injectable composition containing 2% (% w / v) of maropitant base means that there are 2 grams of maropitant base in 100 milliliters, or 20 mg / mL.

[0029] 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.

[0030] According to a particular embodiment of the invention, the maropitant 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).

[0031] The compositions according to the invention and described in this application comprise maropitant base as the active ingredient for its anti-vomiting and anti-nausea effects. In the context of the invention, the terms "maropitant base" or "maropitant base" include only the base form of maropitant. For example, this term does not include pharmaceutically acceptable salts of maropitant, such as maropitant citrate monohydrate.

[0032] By "extended-release composition" or "controlled-release composition" is meant a composition formulated to allow for the slow and controlled release of maropitant base into the body over a prolonged period. Unlike immediate-release drugs, which release their active substance rapidly after ingestion, extended-release drugs are designed to maintain stable plasma concentrations for longer periods, thus reducing the frequency of dosing. In particular, an extended-release composition according to the invention maintains a stable plasma concentration of maropitant base for at least two days, for at least three days, for at least four days, and for at least five days. Preferably, an extended-release composition according to the invention maintains a stable plasma concentration of maropitant base for at least five days.In all cases, a prolonged-release composition according to the invention maintains a stable plasma concentration of maropitant base for a longer duration than the Cerenia® composition comprising maropitant citrate monohydrate salt.

[0033] The term "veterinary acceptable excipient" means any ingredient present in the compositions according to the invention that does not have a direct therapeutic effect or a toxic effect on non-human mammals but may play a role in the stability, bioavailability, and efficacy of the compositions. Without limitation, examples of veterinary acceptable excipients include solvents, co-solvents, oily vehicles, antioxidants, preservatives, thickening agents, surfactants, antifoaming agents, osmotic agents, and in situ gel compounds such as those described below.

[0034] In particular, the prolonged-release injectable compositions as described in this application are oily, aqueous, or in situ gel compositions.

[0035] According to one embodiment of the invention, a prolonged-release injectable composition is an oily composition.

[0036] One object of the invention is an oily composition comprising a maropitant base and an oily vehicle.

[0037] According to a particular embodiment of the invention, the oily composition comprises maropitant, a co-solvent, and an oily vehicle.

[0038] 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 base maropitant in the oily vehicle. Examples of co-solvents include polar solvents, such as alcohols, esters, and ethers, and esterified fatty acids. Among these co-solvents, the following may be cited, in a non-exhaustive manner: N-methylpyrrolidone, 2-pyrrolidone, glycerol formaldehyde, ethanol, dimethyl sulfoxide, benzyl alcohol, oleic alcohol, isopropyl alcohol, benzyl benzoate, glycofurol, solketal, oleic acid, linoleic acid, and glyceryl caprylate / caprate.Examples of co-solvents can also include lipophilic surfactants, particularly non-ionic surfactants or mixtures of non-ionic surfactants. Specifically, these non-ionic surfactants or mixtures of non-ionic surfactants have an HLB of less than 10. Among this type of co-solvent, the following can be cited, but not exhaustively: 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 fatty acid amide, and polyoxyethylene of polyoxypropylene glycol.Also mentioned are polyalcoholic type surfactants, such as fatty acid and glycerol esters, fatty acid and pentaerythritol esters, fatty acid and sorbitan esters, disaccharide fatty acid esters, alkyl polyglycoside, and alkanolamide fatty acids.

[0039] 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 mode, the co-solvent is a mixture of benzyl alcohol and benzyl benzoate. According to another preferred mode, the co-solvent is dimethyl sulfoxide.

[0040] 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).

[0041] 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.

[0042] 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.

[0043] 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.

[0044] According to one embodiment, the oil composition further comprises an antioxidant and / or a preservative. 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).

[0045] In particular, the antioxidant is chosen from butyl hydroxyanisole (BHA), butyl hydroxytoluene (BHT), vitamin E, and a mixture of these.

[0046] 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).

[0047] By "preservative" or "preservative agent" we mean a compound, ingredient, or substance that helps prevent the growth of microorganisms and microbial contamination, thus ensuring the stability and effectiveness of an active ingredient formulated in a pharmaceutical or veterinary product.

[0048] Examples of preservatives include benzyl alcohol, benzoic acid, phenol, boric acid, chlorocresol, cresol, metacresol, sorbic acid, monothioglycerol, potassium sorbate, chlorobutanol, thiomersal, benzalkonium chloride, phenoxyethanol, monothioglycerol, and parabens.

[0049] In particular, the preservative is chosen from benzyl alcohol, benzalkonium chloride, chlorocresol, and sorbic acid.

[0050] 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).

[0051] 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.

[0052] A preferred object of the invention is an oily composition comprising:

[0053] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0054] - between 1 and 5% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0055] - between 5 and 20% (w / v%), preferably about 15% (w / v) of benzyl benzoate, and

[0056] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0057] Another preferred object of the invention is an oily composition comprising:

[0058] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0059] - between 1 and 10% (w / v%), preferably about 6% (w / v) of benzyl alcohol, and

[0060] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0061] Another preferred object of the invention is an oily composition comprising:

[0062] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0063] - between 1 and 5% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0064] - between 2 and 30% (% w / v), preferably about 10 or 15% (% w / v) of oleic acid,

[0065] - and propylene glycol dicaprylocaprate Qs 100%.

[0066] Another preferred object of the invention is an oily composition comprising:

[0067] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0068] - between 1 and 5% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0069] - between 2 and 30% (w / v%), preferably about 10% (w / v) of glyceryl capryl ate / caprate,

[0070] - and propylene glycol dicaprylocaprate Qs 100%.

[0071] Another preferred object of the invention is an oily composition comprising:

[0072] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0073] - between 1 and 5% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0074] - between 2 and 30% (% w / v), preferably about 5% (% w / v) of oleic alcohol, - and propylene glycol dicaprylocaprate Qs 100%.

[0075] Another preferred object of the invention is an oily composition comprising:

[0076] - approximately 2% (% w / v) of maropitant base,

[0077] - and propylene glycol dicaprylocaprate Qs 100%.

[0078] Another preferred object of the invention is an oily composition comprising:

[0079] - approximately 2% (% w / v) of maropitant base,

[0080] - and medium chain triglycerides Qs 100%.

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

[0082] - approximately 2% (% w / v) of maropitant base,

[0083] - and isopropyl myristate Qs 100%.

[0084] Another preferred object of the invention is an oily composition comprising:

[0085] - approximately 2% (% w / v) of maropitant base,

[0086] - and ethyl oleate Qs 100%.

[0087] Another preferred object of the invention is an oily composition comprising:

[0088] - approximately 2% (% w / v) of maropitant base,

[0089] - approximately 1% (w / v) of benzyl alcohol,

[0090] - and propylene glycol dicaprylocaprate Qs 100%.

[0091] Another preferred object of the invention is an oily composition comprising:

[0092] - approximately 2% (% w / v) of maropitant base,

[0093] - approximately 1% (w / v) of benzyl alcohol,

[0094] - approximately 0.03% (w / v) of butyl hydroxytoluene,

[0095] - and propylene glycol dicaprylocaprate Qs 100%.

[0096] Another preferred object of the invention is an oily composition comprising:

[0097] - approximately 2% (% w / v) of maropitant base,

[0098] - about 2% (% w / v) of benzyl alcohol, - and propylene glycol dicaprylocaprate Qs 100%.

[0099] Another preferred object of the invention is an oily composition comprising:

[0100] - approximately 2% (% w / v) of maropitant base,

[0101] - approximately 2% (w / v) benzyl alcohol,

[0102] - approximately 0.01% (w / v) of benzalkonium chloride,

[0103] - approximately 0.03% (w / v) of butyl hydroxytoluene,

[0104] - and propylene glycol dicaprylocaprate Qs 100%.

[0105] Another preferred object of the invention is an oily composition comprising:

[0106] - approximately 2% (% w / v) of maropitant base,

[0107] - approximately 2% (w / v) dimethyl sulfoxide,

[0108] - approximately 0.01% (w / v) of benzalkonium chloride,

[0109] - approximately 0.03% (w / v) of butyl hydroxytoluene,

[0110] - and propylene glycol dicaprylocaprate Qs 100%.

[0111] Another preferred object of the invention is an oily composition comprising:

[0112] - approximately 2% (% w / v) of maropitant base,

[0113] - approximately 2% (w / v) dimethyl sulfoxide,

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

[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 0.03% (w / v) of butyl hydroxytoluene,

[0120] - and propylene glycol dicaprylocaprate Qs 100%.

[0121] Another preferred object of the invention is an oily composition comprising:

[0122] - approximately 2% (% w / v) of maropitant base,

[0123] - approximately 2% (w / v) dimethyl sulfoxide,

[0124] - about 1% (% w / v) of vitamin E, - 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] - approximately 1% (w / v) of vitamin E,

[0130] - and propylene glycol dicaprylocaprate Qs 100%.

[0131] Another preferred object of the invention is an oily composition comprising:

[0132] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0133] - between 1 and 5% (w / v), preferably about 1.5% (w / v) of benzyl alcohol,

[0134] - between 5 and 20% (w / v%), preferably about 15% (w / v) of benzyl benzoate,

[0135] - approximately 0.01% (w / v) of benzalkonium chloride, and

[0136] - propylene glycol dicaprylocaprate Qs 100%.

[0137] Another preferred object of the invention is an oily composition comprising:

[0138] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0139] - between 5 and 20% (w / v%), preferably about 15% (w / v) of benzyl benzoate,

[0140] - between 1 and 5% (w / v%), preferably about 2% (w / v) of dimethyl sulfoxide, and

[0141] - propylene glycol dicaprylocaprate Qs 100%.

[0142] Another preferred object of the invention is an oily composition comprising:

[0143] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0144] - between 1 and 5% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0145] - between 5 and 20% (w / v%), preferably about 15% (w / v) of benzyl benzoate,

[0146] - approximately 0.1% (w / v) of chlorocresol, and

[0147] - propylene glycol dicaprylocaprate Qs 100%.

[0148] Another preferred object of the invention is an oily composition comprising:

[0149] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0150] - between 1 and 10% (w / v), preferably about 6% (w / v) of benzyl alcohol, - between 1 and 5% (w / v), preferably about 2% (w / v) of dimethyl sulfoxide, and

[0151] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0152] Another preferred object of the invention is an oily composition comprising:

[0153] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0154] - between 1 and 10% (w / v%), preferably about 6% (w / v) of benzyl alcohol,

[0155] - approximately 0.01% (w / v) of benzalkonium chloride, and

[0156] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0157] Another preferred object of the invention is an oily composition comprising:

[0158] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0159] - between 1 and 10% (w / v%), preferably about 6% (w / v) of benzyl alcohol,

[0160] - approximately 0.05% (w / v) of vitamin E, and

[0161] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0162] Another preferred object of the invention is an oily composition comprising:

[0163] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0164] - between 1 and 10% (w / v%), preferably about 6% (w / v) of benzyl alcohol,

[0165] - approximately 0.03% (w / v) of butyl hydroxytoluene, and

[0166] - approximately 0.8% (w / v) sorbic acid,

[0167] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0168] Another preferred object of the invention is an oily composition comprising:

[0169] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0170] - between 1 and 10% (w / v%), preferably about 6% (w / v) of benzyl alcohol,

[0171] - between 1 and 5% (w / v%), preferably about 2% (w / v) of dimethyl sulfoxide,

[0172] - approximately 0.03% (w / v) of butyl hydroxytoluene, and

[0173] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0174] Another preferred object of the invention is an oily composition comprising:

[0175] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0176] - between 5 and 20% (w / v%), preferably about 15% (w / v) of benzyl benzoate, - between 1 and 5% (w / v), preferably about 2% (w / v) of dimethyl sulfoxide,

[0177] - approximately 0.03% (w / v) of butyl hydroxytoluene, and

[0178] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0179] Another preferred object of the invention is an oily composition comprising:

[0180] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0181] - between 1 and 10% (w / v%), preferably about 6% (w / v) of benzyl alcohol,

[0182] - between 1 and 5% (w / v%), preferably about 2% (w / v) of dimethyl sulfoxide,

[0183] - approximately 0.03% (w / v) of butyl hydroxyanisole, and

[0184] - of dicapryl ocaprate of propylene glycol Qs 100%.

[0185] In particular, 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 this application, formulated as a solution, preferably a sterile solution. Another particular embodiment of the invention is a composition as described in this application administered parenterally, preferably by injection, and even more preferably by subcutaneous injection.

[0186] 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 then 100% of the oily vehicle is added. The composition is then recovered after sterile filtration.

[0187] According to one embodiment of the invention, a prolonged-release injectable composition is an aqueous composition.

[0188] One object of the invention is an aqueous composition comprising a maropitant base, a preservative, a thickening agent, a surfactant, and water. The term "preservative" or "preservative agent" refers to 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.

[0189] Examples of preservatives include benzyl alcohol, benzoic acid, phenol, boric acid, chlorocresol, cresol, metacresol, sorbic acid, monothioglycerol, potassium sorbate, chlorobutanol, thiomersal, benzalkonium chloride, phenoxyethanol, monothioglycerol, and parabens.

[0190] Specifically, the preservative is chosen from among benzyl alcohol, benzalkonium chloride, chlorocresol, and sorbic acid. Preferably, the preservative is benzyl alcohol.

[0191] In particular, the preservative in the aqueous composition as described in this application has a weight-by-volume (w / v) concentration of between 0.01 and 5% (w / v), 0.1 and 5% (w / v), 0.5 and 3% (w / v), 1 and 2% (w / v), and approximately 1.5% (w / v). In a more particular manner, the preservative has a weight-by-volume (w / v) concentration of between 0.01 and 5% (w / v), between 0.1 and 5% (w / v), preferably between 0.5 and 3% (w / v), and even more preferably approximately 1.5% (w / v).

[0192] A "viscoating agent" is a compound, ingredient, or substance that increases the viscosity of a composition or formulation and / or limits sedimentation within that composition or formulation. The terms "viscoating agent" and "viscosity agent" are interchangeable and may also be referred to as "thickening agent."

[0193] Examples of viscosifying agents include natural gums, such as xanthan gum, guar gum, and gum arabic; modified starches; synthetic polymers, such as carbomers, polyvinylpyrrolidone (PVP), polyacrylates, and poloxamers; natural thickeners; cellulose and its derivatives, such as hydroxypropylmethylcellulose, methylcellulose, and carboxymethylcellulose; protein gelling agents, such as gelatin and collagen; polysaccharides, such as alginate and carrageenan; and silica (or silicon dioxide). In particular, the viscosifying agent is chosen from sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, guar gum, xanthan gum, polyacrylic acid, silica, and a poloxamer.Preferably, the viscosifying agent is sodium carboxymethylcellulose or silica dioxide, advantageously carboxymethylcellulose.

[0194] In particular, the thickening agent in the aqueous composition as described in this application has a weight-by-volume (w / v) concentration of between 0.01 and 5% (% w / v), 0.05 and 3% (% w / v), 0.05 and 2% (% w / v), 0.05 and 1% (% w / v), 0.1 and 1% (% w / v), 0.1 and 0.5% (% w / v), and approximately 0.2% (% w / v). In a more particular manner, the thickening agent has a weight-by-volume (w / v) concentration of between 0.01 and 5% (% w / v), preferably between 0.05 and 3% (% w / v), and even more preferably of approximately 0.2%, 0.3%, 1.0%, or 2% (% w / v).

[0195] A surfactant is a compound, ingredient, or substance that modifies the surface tension between two surfaces. Surfactants are amphiphilic molecules with two parts of opposite polarity: a lipophilic part and a hydrophilic part. They allow the solubilization of two immiscible phases by interacting with the nonpolar phase (with its lipophilic part) and the polar phase (with its hydrophilic part). Surfactants may also be called surfactants or surfactant agents.

[0196] Examples of surfactants include anionic surfactants, such as sodium lauryl sulfate (SLS), linear alkylbenzene sulfonate (LAS), and sodium docusate; cationic surfactants, such as cetyltrimethylammonium chloride and benzalkonium bromide; nonionic surfactants, such as ethoxylated fatty alcohols, e.g. hydrogenated castor oil polyethylene glycol, poloxamers, and polysorbates (Tween); and amphoteric (or zwitterionic) surfactants, such as phospholipids, betaine, and cocoamidopropyl betaine. In particular, the surfactant is chosen from a polysorbate, a phospholipid, such as soy phosphatidylcholine, hydrogenated castor oil polyethylene glycol, ethoxylated hydrogenated castor oil, a poloxamer, Triton X100, and sodium docusate, and a mixture of these.Preferably, the surfactant is a polysorbate, in particular polysorbate 80 (Tween 80) or a mixture of polysorbate and soy phosphatidylcholine.

[0197] In particular, the surfactant in the aqueous composition as described in this application has a weight-by-volume (w / v) concentration of between 0.05 and 2% (w / v), 0.1 and 2% (w / v), 0.5 and 1.5% (w / v), 0.7 and 1.3% (w / v), 0.9 and 1.1% (w / v), and approximately 1% (w / v). In a more particular manner, the surfactant has a weight-by-volume (w / v) concentration of between 0.05 and 2% (w / v), preferably between 0.5 and 1.5% (w / v), and even more preferably of approximately 1% or 1.5% (w / v).

[0198] Depending on the specific aspect, the composition also includes at least one additional excipient. This may be an antifoaming agent or an osmotic agent.

[0199] The term "antifoaming agent" means a compound, ingredient, or substance that reduces or eliminates foam formation. Examples of antifoaming agents include mineral oils, vegetable oils, silicones, polymer-based antifoams, and solid-particle-based antifoams. Preferably, the antifoaming agent is a silicone, and advantageously, simethicone. In a particular manner, the antifoaming agent has a weight-by-volume (w / v) concentration of between 0.05 and 1% (% w / v), preferably between 0.1 and 1% (% w / v), and even more preferably about 0.5% (% w / v).

[0200] An "osmotic agent" is understood to be a compound, ingredient, or substance that creates osmotic pressure in a system. Examples include, but are not limited to, natural osmotic agents such as salts, particularly sodium chloride, sugars, particularly glucose and sucrose, and glycerol, and synthetic osmotic agents such as polyethylene glycol, mannitol, and dextran. Preferably, the osmotic agent is natural, particularly a salt, and advantageously, sodium chloride. In a particular manner, the osmotic agent has a concentration by weight per volume (w / v) of between 0.05 and 1% (% w / v), preferably between 0.1 and 1% (% w / v), and even more preferably about 0.5% (% w / v).

[0201] A preferred object of the invention is an aqueous composition comprising:

[0202] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0203] - between 0.5 and 3% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0204] - between 0.05 and 1% (w / v%), preferably about 0.2% (w / v) of sodium carboxymethylcellulose,

[0205] - between 0.5 and 1.5% (w / v%), preferably about 1% (w / v) of polysorbate 80, and

[0206] - water Qs 100%.

[0207] Another preferred object of the invention is an aqueous composition comprising:

[0208] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0209] - between 0.5 and 3% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0210] - between 0.05 and 1% (w / v%), preferably about 0.2% (w / v) of sodium carboxymethylcellulose,

[0211] - between 0.5 and 1.5% (% w / v), preferably about 1% (% w / v) of polysorbate 80,

[0212] - between 0.05 and 1% (w / v%), preferably about 0.5% (w / v) of simethicone,

[0213] - between 0.05 and 1% (w / v%), preferably about 0.5% (w / v) of sodium chloride, and

[0214] - water Qs 100%.

[0215] Another preferred object of the invention is an aqueous composition comprising:

[0216] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0217] - between 0.5 and 3% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0218] - between 0.05 and 3% (w / v%), preferably about 1% (w / v) of silica dioxide,

[0219] - between 0.5 and 1.5% (% w / v), preferably about 1% (% w / v) of polysorbate 80,

[0220] - between 0.05 and 1% (w / v%), preferably about 0.2% (w / v) of simethicone, and

[0221] - water Qs 100%. Another preferred object of the invention is an aqueous composition comprising:

[0222] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0223] - between 0.5 and 3% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0224] - between 0.05 and 3% (% w / v), preferably about 2% (% w / v) of silica dioxide,

[0225] - between 0.5 and 1.5% (% w / v), preferably about 1% (% w / v) of polysorbate 80,

[0226] - between 0.05 and 1% (w / v%), preferably about 0.5% (w / v) of simethicone, and

[0227] - water Qs 100%.

[0228] Another preferred object of the invention is an aqueous composition comprising:

[0229] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0230] - between 0.5 and 3% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0231] - between 0.05 and 1% (% w / v), preferably about 0.3% (% w / v) of sodium carboxymethylcellulose,

[0232] - between 0.5 and 1.5% (% w / v), preferably about 1% (% w / v) of polysorbate 80,

[0233] - between 0.05 and 1% (w / v%), preferably about 0.5% (w / v) of simethicone,

[0234] - approximately 0.5% (w / v) of soy phosphatidylcholine, and

[0235] - water Qs 100%.

[0236] In particular, aqueous compositions are in the form of a suspension, 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 this application, formulated as an aqueous suspension, preferably a sterile aqueous suspension. Another particular embodiment of the invention is a composition as described in this application administered parenterally, preferably by injection, and even more preferably by subcutaneous injection.

[0237] The aqueous compositions according to the invention can be prepared using a simple, economical process, and are therefore well-suited to industrial scale. For example, the surfactant is added to water and the mixture is homogenized using a deflocculator. Next, the optional osmotic agent, if present in the composition, and the preservative are added, and the composition is homogenized again using a deflocculator. The thickening agent is then added, and the composition is vigorously agitated with a deflocculator to solubilize the thickening agent. The base maropitant is then added before homogenization with a deflocculator. Finally, the suspension is homogenized, the final volume is adjusted, and the composition is homogenized with a magnetic stirrer before being collected.

[0238] According to one embodiment of the invention, a prolonged-release injectable composition is an in situ gel composition.

[0239] An object of the invention is an in situ gel composition comprising maropitant base, an in situ gelling compound, and a solvent.

[0240] The term "gel or in situ gelling composition" refers to a composition that changes from a liquid to a gel state after being introduced into a given environment. More specifically, the composition as described in this application is in liquid form before administration and transforms into a gel either immediately or after administration to a subject such as a non-human mammal.

[0241] An "in situ gelling or gelling compound" is defined as a compound, ingredient, or substance that aids and promotes the transition of a composition or formulation from a liquid to a gel state. This change of state can be triggered by various factors, such as temperature, pH, the presence of ions, and various environmental conditions, particularly when the composition or formulation is administered to a subject.

[0242] Examples of "in situ gelling compounds" include natural polymers such as chitosan, alginate or alginic acid, gelatin, pectin, and agarose. "In situ gelling compounds" also include synthetic polymers such as poly(N-isopropylacrylamide), polylactic acid, poly(lactic-co-glycolic acid), polycaprolactone, poloxamer, methyl polyacrylate, polyacrylic acid, a hydrophilic acrylic acid polymer, and polyethylene glycol. In a more specific aspect, "in situ gelling compounds" are sugars or sugar derivatives.According to a preferred embodiment of the invention, the in situ gelling compound is sucrose acetate isobutyrate (SAIB), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), a poloxamer, methyl polyacrylate (PMA), polyacrylic acid (PAA), poly(N-isopropylacrylamide) (NIPAAM), a hydrophilic polymer of acrylic acid (Carbopol®), alginic acid, and pectin. Preferably, the in situ gelling compound is sucrose acetate isobutyrate.

[0243] In particular, the in situ gelling compound in the composition as described in this application has a weight-by-volume (w / v) concentration of between 20 and 60% (% w / v), 25 and 55% (% w / v), 30 and 55% (% w / v), 35 and 50% or 40 and 50% (% w / v), for example about 38%, 38.4%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, and 50% (% w / v). In a more specific manner, the in situ gelling compound has a weight-by-volume (w / v) concentration of between 20 and 60% (% w / v), preferably between 30 and 55% (% w / v), and even more preferably between 40 and 50% (% w / v). In yet another specific manner, the in situ gelling compound has a weight-by-volume (w / v) concentration of approximately 38.4%, approximately 40%, or approximately 48% (% w / v).

[0244] The term "solvent" refers to a vehicle designed to improve the solubility of a compound, ingredient, substance, or active ingredient in a composition or formulation. In particular, the solvent in the in situ gel compositions of the invention improves the solubility of the maropitant. The solvent also improves the solubility and reduces the viscosity of the in situ gelling compound, such as sucrose acetate isobutyrate, for improved administration to a patient, particularly by parenteral injection.

[0245] Examples of solvents include polar solvents, such as alcohols, esters, and ethers. Specifically, the solvent for the in situ gel composition is selected from glycerol formal, benzyl benzoate, ethanol, isopropanol, dimethyl sulfoxide, 2-pyrrolidone, ethyl benzoate, triacetin, propylene carbonate, and N-methylpyrrolidone, and mixtures thereof. In one particular method, the solvent is glycerol formal. In another particular method, the solvent is benzyl benzoate. In yet another particular method, the solvent is a mixture of glycerol formal and benzyl benzoate. Preferably, the solvent is glycerol formal.

[0246] According to one aspect of the invention, the in situ gel composition further comprises a cosolvent.

[0247] The term "co-solvent" means a solvent used with another vehicle, which may be a solvent, to improve the solubility of the maropitant in compositions as described in this application. An example of a co-solvent is a solvent as described above. Benzyl benzoate is a preferred co-solvent.

[0248] In particular, the co-solvent in the composition as described in this application has a weight-by-volume (w / v) concentration of between 10 and 60% (w / v), preferably between 15 and 40% (w / v), and even more preferably between 20 and 30% (w / v). Preferably, the co-solvent in the composition as described in this application has a weight-by-volume (w / v) concentration of about 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 28.8%, 29%, and 30% (w / v). In an even more preferred manner, the co-solvent in the composition as described in this application has a weight-by-volume (w / v) concentration of about 24%, 25%, and 28.8%, and advantageously about 25% (w / v).

[0249] According to one aspect of the invention, the in situ gel composition further comprises a preservative.

[0250] A preservative is a compound, ingredient, or substance that inhibits 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. Specifically, the preservative is chosen from among benzyl alcohol, benzalkonium chloride, chlorocresol, and sorbic acid. Preferably, the preservative is benzyl alcohol.

[0251] In particular, the preservative in the in situ gel composition as described in this application has a weight-by-volume (w / v) concentration of between 0.01 and 5% (w / v), 0.1 and 5% (w / v), 0.5 and 3% (w / v), 1 and 2% (w / v), and approximately 1.5% (w / v). In a more particular manner, the preservative has a weight-by-volume (w / v) concentration of between 0.01 and 5% (w / v), between 0.1 and 5% (w / v), preferably between 0.5 and 3% (w / v), and even more preferably approximately 1.5% (w / v).

[0252] A preferred object of the invention is an in situ gel composition comprising:

[0253] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0254] - between 0.5 and 3% (w / v%), preferably about 1.5% (w / v) of benzyl alcohol,

[0255] - between 15 and 40% (w / v%), preferably about 25% (w / v) of benzyl benzoate,

[0256] - between 30 and 55% (w / v%), preferably about 40% (w / v) of sucrose acetate isobutyrate, and

[0257] - of glycerol formai Qs 100%.

[0258] Another preferred object of the invention is an in situ gel composition comprising:

[0259] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0260] - between 15 and 40% (w / v%), preferably about 24% (w / v) of benzyl benzoate,

[0261] - between 30 and 55% (w / v%), preferably about 48% (w / v) of sucrose acetate isobutyrate, and

[0262] - of glycerol formai Qs 100%.

[0263] Another preferred object of the invention is an in situ gel composition comprising: - between 2 and 5% (% w / v), preferably about 4% (% w / v) of maropitant base,

[0264] - between 30 and 55% (w / v%), preferably about 48% (w / v) of sucrose acetate isobutyrate, and

[0265] - benzyl benzoate Qs 100%.

[0266] Another preferred object of the invention is an in situ gel composition comprising:

[0267] - between 2 and 5% (% w / v), preferably around 4% (% w / v) of maropitant base,

[0268] - between 15 and 40% (% w / v), preferably about 28.8% (% w / v) of benzyl benzoate,

[0269] - between 30 and 55% (w / v%), preferably about 38.4% (w / v) of sucrose acetate isobutyrate, and

[0270] - of glycerol formai Qs 100%.

[0271] In particular, in situ gel compositions are in liquid form, which is particularly well-suited for parenteral administration, especially by injection. A particular embodiment of the invention is therefore a composition as described in this application, formulated in liquid form, preferably a sterile liquid form. Another particular embodiment of the invention is a composition as described in this application administered parenterally, preferably by injection, and even more preferably by subcutaneous injection.

[0272] The in situ gel compositions according to the invention can be prepared using a simple, economical process, and are therefore well-suited to industrial scale. For example, the solvent and any optional co-solvent, if present in the composition, are mixed with the in situ gelling compound, and then the composition is homogenized using a magnetic stirrer. The maropitant is then added, and the composition is mixed again using the magnetic stirrer until the active ingredient is completely dissolved and then collected.

[0273] One object of the invention also relates to a composition as described in this application for use as a medicament. Another object of the invention relates to a prolonged-release injectable 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 prolonged-release injectable composition as described in this application for use in the treatment and prevention of nausea and vomiting in a non-human mammal.

[0274] 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 one particular sense, these expressions include the curative treatment of nausea and vomiting in non-human mammals. "Curative treatment" is understood to mean treatment that stops nausea and vomiting in non-human mammals. In another particular sense, these expressions include the "preventive treatment" of nausea and vomiting in non-human mammals. In one aspect, preventive treatment means treatment administered before the non-human mammal experiences nausea and vomiting. Preventive treatment therefore reduces the risk of nausea and vomiting in non-human mammals.The terms "treatment" and / or "prevention" can therefore also refer to the protection of a non-human mammal against nausea and vomiting.

[0275] 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.

[0276] One aspect 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 a dog or cat. Another aspect of the invention relates to a method for treating and preventing nausea and vomiting in a non-human mammal, in particular a dog or cat, comprising administering an effective amount of a composition as described in this application.

[0277] Nausea and vomiting have various causes. They can be caused 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.

[0278] 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.

[0279] 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.

[0280] In particular, a prolonged-release injectable composition according to the invention comprises maropitant base 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.

[0281] In particular, a prolonged-release injectable composition according to the invention is administered to a non-human mammal, especially a dog or cat, at a dose of maropitant base of between 1 and 5 mg / kg body weight, preferably between 2 and 5 mg / kg body weight, and even more preferably 2 or 4 mg / kg body weight. Thus, administering 4 mg / kg body weight of maropitant base to a non-human mammal is equivalent to administering 0.1 mL / kg body weight of a prolonged-release injectable composition comprising maropitant base to that non-human mammal at a weight-by-volume (w / v) concentration of 4% or a concentration of 40 mg / mL.Similarly, administering 4 mg / kg body weight of maropitant base to a non-human mammal is equivalent to administering 0.2 mL / kg body weight of a prolonged-release injectable composition containing maropitant base to that non-human mammal at a weight-by-volume (w / v) concentration of 2% or a concentration of 20 mg / mL. Likewise, administering 2 mg / kg body weight of maropitant base to a non-human mammal is equivalent to administering 0.1 mL / kg body weight of a prolonged-release injectable composition containing maropitant base to that non-human mammal at a weight-by-volume (w / v) concentration of 2% or a concentration of 20 mg / mL.

[0282] Specifically, the prolonged-release injectable compositions according to the invention comprising maropitant base 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 a prolonged-release injectable composition according to the invention is recommended in view of the plasma profile shown in Figures 1 to 4, demonstrating an effect lasting beyond 5 days.

[0283] Other aspects and advantages of the invention will become apparent from the following examples, which should be considered illustrative and not limiting.

[0284] Examples

[0285] 1. Preparation of prolonged-release injectable compositions according to the invention

[0286] 1.1. Oily compositions. The compositions are prepared by the following general process:

[0287] A quantity of the 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 dissolved. The mixture was then cooled to 25 °C, and the final volume was adjusted with 100% of the oily vehicle. The final composition of the invention was obtained after sterile filtration through a 0.2 µm filter.

[0288] Examples of oily compositions: 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.

[0289] [Table 1]

[0290] [Table 2] [Table 3]

[0291] [Table 4] [Table 5] [Table 6]

[0292] 1.2. Aqueous compositions

[0293] The compositions are prepared using the following general procedure: A quantity of surfactant was mixed with 70% pure water for injection (PFI) and then homogenized using a deflocculator. A quantity of osmotic agent was then added and homogenized with the deflocculator. A quantity of preservative was added to the mixture and then homogenized with the deflocculator. A quantity of thickening agent was added to the mixture, which was then vigorously stirred using the deflocculator to dissolve it. Maropitant was added to the mixture and then homogenized with the deflocculator to disperse it. The resulting suspension was then homogenized under high shear conditions using an ultra-turrax and a rod at 10,000 rpm for 5 minutes. The final volume was then adjusted with 100% PFI. The final composition was obtained after homogenization with a magnetic stirrer.

[0294] Examples of aqueous compositions:

[0295] [Table 7]

[0296] 1.3. In situ gel compositions

[0297] The compositions are prepared using the following general process:

[0298] The desired amount of solvent and optional co-solvent was mixed using a magnetic stirrer. Sucrose acetate isobutyrate (SAIB) was added to the mixture and then mixed with the magnetic stirrer. Maropitant was then added to the mixture and homogenized using a magnetic stirrer. The final volume of the solution was then adjusted with the solvent and / or co-solvent. The final composition was obtained after mixing with the magnetic stirrer.

[0299] Examples of in situ gel compositions:

[0300] [Table 8] 2. Clinical study in cats - Tolerance and pharmacokinetics

[0301] 2.1. Materials and methods

[0302] 2.1.1. Experimental design - Administration Eighteen animals were divided into three groups (two cats in each group for phase 1 and four cats in each group for phase 2).

[0303] The compositions were administered according to the following procedure:

[0304] 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)

[0305] 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)

[0306] Group 1: 1 mg / kg (reference product Cerenia®).

[0307] 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.

[0308] The volume to be administered was calculated from the individual body weights recorded prior to administration.

[0309] The injection sites were not massaged / manipulated after administration (except for the assessment of pain intensity and heat).

[0310] This experimental plan was reproduced with compositions A2 and A3.

[0311] The experimental design of this study is detailed in the following table 9:

[0312] [Table 9]

[0313] 2.1.2. Clinical observations

[0314] 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.

[0315] 2.1.3. Reactions during injection

[0316] Reactions were assessed during injection and for 5 minutes after injection.

[0317] - Movement of the head and / or neck

[0318] Scraping of the injection site

[0319] Injection-specific vocalization

[0320] - Defensive reaction

[0321] Duration of discomfort (min)

[0322] Any other abnormal reaction / behavior

[0323] - Licking at the injection site (number and duration)

[0324] 2.1.4. Local tolerance at the injection site

[0325] The local reaction at the injection site was assessed before administration (on the day of treatment) and approximately 1 hour, 4 hours, and 9 hours after, then daily until 120 hours after administration. 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

[0326] Mild pain: reaction to slight pressure = 1

[0327] Moderate pain: defensive reaction to slight pressure = 2

[0328] Severe pain: defensive reaction without pressure = 3

[0329] Swelling :

[0330] No = 0

[0331] Yes = 1 (if yes, measure length x width x height)

[0332] Heat

[0333] None = 0

[0334] Heat perceived during palpation = 1

[0335] Excoriation (yes / no)

[0336] Crusts (yes / no)

[0337] 2.2. Results

[0338] 2.2.1. Local tolerance

[0339] Reaction during injection and for 5 minutes after injection

[0340] The number of cats observed during and 5 minutes after injection is detailed in Tables 10 to 12 below.

[0341] [Table 10] 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®.

[0342] [Table 11]

[0343] No injection reactions were reported for composition A2, unlike with Cerenia®. Also, fewer reactions, particularly fewer defensive reactions, discomfort, or abnormal behaviors, were reported within 5 minutes of injection of composition A2 compared to Cerenia®.

[0344] [Table 12]

[0345] At injection, fewer reactions were reported for composition A3 compared to Cerenia®, particularly with regard to defensive reactions. Also, in general, fewer reactions, especially less licking at the injection site, were reported within 5 minutes of injection of composition A3 compared to Cerenia®.

[0346] Swelling and pain

[0347] The number of cats observed to have swelling and pain at the injection site is detailed in Table 13 below. [Table 13]

[0348] No swelling or pain was observed within 5 days of administration of the Al or NI compositions and Cerenia®.

[0349] Other observations around the injection site

[0350] No heat, excoriation, or crusting was observed around the injection site after injection of composition A3 and Cerenia®.

[0351] These observations are all the more surprising given that the Al or NI, A2, and A3 compositions include a maropitant concentration (dose) four times higher than the maropitant concentration in the Cerenia® product.

[0352] 2.2.2. Pharmacokinetic results

[0353] Figures 1, 3, and 4 show the mean plasma concentration-time profile of maropitant observed in cats after subcutaneous administration of Cerenia® at a dose of 1 mg / kg, composition A1 at a dose of 4 mg / kg, composition A2 at a dose of 4 mg / kg, and composition A3 at a dose of 4 mg / kg. Table 14 below reports the evaluation of pharmacokinetic parameters after administration of Cerenia® and compositions A1, A2, and A3.

[0354] [Table 14]

[0355] Figures 1, 3, and 4 and the inspection of the mean terminal half-life, TL z, in Table 14 showed that the extended-release Al, A2, A3 compositions had a longer terminal half-life than Cerenia®.

[0356] 3. Clinical study in dogs - Tolerance and pharmacokinetics

[0357] 3.1. Materials and methods

[0358] 3.1.1. Experimental Plan - Administration

[0359] Twenty-four animals were divided into three groups of eight animals (four males and four females in each group).

[0360] The compositions were administered according to the following procedure:

[0361] 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)

[0362] 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)

[0363] 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.

[0364] The volume to be administered was calculated from the individual body weights recorded prior to administration.

[0365] The injection sites were not massaged / manipulated after administration (except for the assessment of pain intensity and heat).

[0366] The experimental design of this study is detailed in Table 15 below:

[0367] [Table 15]

[0368] 3.1.2. Clinical observations

[0369] 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.

[0370] 3.1.3. Reactions during injection

[0371] Reactions were assessed during injection and for 5 minutes after injection.

[0372] - Movement of the head and / or neck

[0373] Scraping of the injection site

[0374] Injection-specific vocalization

[0375] - Defensive reaction

[0376] - Licking at the injection site (number and duration)

[0377] Local muscle contraction 3.1.4. Local tolerance at the injection site

[0378] 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.

[0379] 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

[0380] Mild pain: reaction to slight pressure = 1

[0381] Moderate pain: defensive reaction to slight pressure = 2

[0382] Severe pain: defensive reaction without pressure = 3

[0383] Heat

[0384] None = 0

[0385] Heat perceived during palpation = 1

[0386] Swelling :

[0387] No = 0

[0388] Yes = 1 (if yes, measure length x width x height)

[0389] Erythema:

[0390] No erythema = 0

[0391] Mild erythema (slight redness barely visible) = 1

[0392] Moderate erythema (clearly visible redness) = 2

[0393] Severe erythema (beetroot red) with slight sores (deep lesions) = 3

[0394] Excoriation (yes / no)

[0395] Crusts (yes / no)

[0396] Ulceration (yes / no)

[0397] Abscess (yes / no)

[0398] Any other abnormal observation 3.2. Results

[0399] 3.2.1. Local tolerance

[0400] Reaction during injection and for 5 minutes after injection

[0401] The number of dogs observed during and 5 minutes after injection is detailed in Table 16 below.

[0402] [Table 16]

[0403] 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.

[0404] Other observations around the injection site

[0405] These additional observations are described in Table 17 below.

[0406] [Table 17]

[0407] No further observations were reported for dogs that received composition Al or composition NI.

[0408] After administration of Cerenia®, one dog presented with local heat at T1h, and another dog presented with local erythema at T4h.

[0409] No pain, excoriation, ulceration, abscess, or other adverse reactions were observed at the injection site, regardless of the product administered. 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. 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 the Cerenia® product.

[0410] 3.2.2. Pharmacokinetic results

[0411] 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 18 below reports the evaluation of pharmacokinetic parameters after administration of Cerenia® and the AL composition.

[0412] [Table 18] Figure 2 and inspection of the mean terminal half-life, TL z, in Table 18 showed that the extended-release Al composition had a longer terminal half-life than Cerenia®.

[0413] 4. Clinical efficacy study in dogs

[0414] 4.1. Materials and methods

[0415] 4.1.1. Experimental Plan - Administration

[0416] Thirty-five dogs were divided into 5 groups, and the compositions were administered according to the following procedure:

[0417] Group V: Placebo

[0418] Group IV: Single subcutaneous injection (midline of the neck between the shoulder blades) of 0.1 ml / kg, which corresponds to a dose of 2 mg / kg (NI Composition) three days before the induction of vomiting by subcutaneous administration of apomorphine at a dose of 0.05 mg / kg.

[0419] Group III: Single subcutaneous injection (midline of the neck between the shoulder blades) of 0.15 ml / kg, which corresponds to a dose of 3 mg / kg (NI Composition) three days before the induction of vomiting by subcutaneous administration of apomorphine at a dose of 0.05 mg / kg.

[0420] 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 apomorphine at a dose of 0.05 mg / kg.

[0421] Group 1: 1 mg / kg (reference product Cerenia®) one day before induction of vomiting by subcutaneous administration of apomorphine at a dose of 0.05 mg / kg as indicated in the product's SmPC.

[0422] The volume to be administered was calculated from the individual body weights recorded prior to administration.

[0423] The experimental design of this study is detailed in the following Table 19: [Table 19]

[0424] 4.1.2. Clinical observations Each dog was observed to determine the occurrence of emetic events (retching and / or vomiting) for one hour after induction via apomorphine.

[0425] Subcutaneous administration of the NI composition at a dose of 2, 3, or 4 mg / kg was well tolerated by the dogs. No pain at the injection site and no local reactions were observed after administration. 4.2. Results

[0426] The results are detailed in Table 20 below.

[0427] [Table 20]

[0428] 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®.

[0429] 5. Clinical efficacy study in cats

[0430] 5.1. Materials and methods

[0431] 5.1.1. Experimental Plan - Administration

[0432] Eighteen cats were divided into 3 groups, and the compositions were administered to them according to the following procedure:

[0433] Group III: Placebo

[0434] 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.

[0435] Group 1: 1 mg / kg (reference product Cerenia®) one day before inducing vomiting by subcutaneous administration of xylazine at a dose of 0.44 mg / kg. The volume to be administered was calculated from individual body weights recorded before administration.

[0436] The experimental design of this study is detailed in the following Table 21:

[0437] [Table 21]

[0438] 4.1.2. Clinical observations

[0439] Each cat was observed to determine the occurrence of emetic events (retching and / or vomiting) for one hour after induction via xylazine.

[0440] 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.

[0441] 4.2. Results

[0442] The results are detailed in Table 22 below. [Table 22]

[0443] 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®.

[0444] 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

48 DEMANDS 1. Injectable composition with prolonged release comprising maropitant base and at least one veterinaryly acceptable excipient.

2. Injectable composition with prolonged release according to claim 1, wherein the maropitant base has 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 of about 2 or 4% (% w / v).

3. Injectable composition with prolonged release according to claim 1 or 2, wherein the composition is an oily, aqueous, or in situ gel composition.

4. Injectable composition with prolonged release according to any one of claims 1 to 3, wherein the composition is an oily composition further comprising an oily vehicle.

5. Injectable composition with prolonged release according to any one of claims 1 to 3, wherein the composition is an aqueous composition further comprising a preservative, a viscosifying agent, a surfactant, and water.

6. Injectable composition with prolonged release according to any one of claims 1 to 3, wherein the composition is an in situ gel composition further comprising an in situ gelling compound, and a solvent.

7. Injectable composition with prolonged release according to any one of claims 1 to 6, intended for use in the treatment and prevention of nausea and vomiting in a non-human mammal.

8. Delayed-release injectable composition for use according to claim 7, 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 supportive measures, such as dietary control and fluid therapy.

9. Injectable composition with prolonged release intended for use according to claim 7 or 8, wherein the non-human mammal is a dog or a cat.

10. Delayed-release injectable composition for use according to any one of claims 7 to 9, wherein the composition is administered only once.

Images