Compositions that have improved voluntary acceptance

Abstract

The present invention relates to the field of pharmaceutical compositions suitable for oral administration of active substances to animals. In particular, the present invention relates to a liquid drug-containing formulation and its use. The present invention further relates to the use of a liquid formulation auxiliary composition comprising at least one natural oil derived from herb in a liquid drug-containing formulation to improve the acceptance or voluntary acceptance of drug intake in animals.

Description

[Technical Field]

[0001] The present invention relates to the field of pharmaceutical compositions suitable for oral administration of active substances in animals. In particular, the present invention relates to a liquid drug-containing formulation comprising at least one drug which is a hypoxia-inducible factor prolyl hydroxylase inhibitor and at least one natural oil derived from a herb. The present invention further relates to the use of a liquid formulation adjuvant composition comprising at least one natural oil derived from a herb and / or an animal in the liquid drug-containing formulation to improve the acceptance or voluntary acceptance of drug ingestion in animals.

[0002] Certain diseases require routine and long-term medication in veterinary medicine, which usually needs to be administered at home by untrained owners. These medications are often administered orally, which can be difficult, especially in cats and dogs, if the product has an undesirable flavor. Animals tend to refuse to take the medication, which can be dangerous for the animal's owner. Furthermore, complete administration of the required medication cannot be ensured. These difficulties become even more severe when the medication needs to be administered daily over a long period.

[0003] One example of the need for daily long-term administration is the treatment and / or prevention of diseases associated with the hypoxia-inducible factor prolyl hydroxylase enzyme. Such diseases may include cardiovascular disease, heart failure, anemia, chronic kidney disease, or renal failure, particularly anemia associated with chronic kidney disease. For example, WO2008 / 067871 describes certain substituted dihydroparazolones thought to have the aforementioned activity, and WO2012 / 065967 describes substituted sodium-1H-pyrazole-5-oleate.

[0004] Most commercially available oral drug formulations are aqueous-based solutions or suspensions.

[0005] US5756474 relates to a non-aqueous oral medication composition for treating parasitic diseases in mammals. Aqueous formulations are generally disclosed to have a better taste.

[0006] US20120141546 relates to an oily preparation for the control of parasitic protozoa and endoparasites in animals. The focus is on single-dose administration.

[0007] Therefore, in order to ensure the safety and compliance of individuals administered drug-containing formulations, there is a continuing need for formulations for oral medicines for animals that have high acceptance or voluntary acceptance of each drug. In this regard, an object of the present invention is to provide a drug-containing formulation that has high acceptance or voluntary acceptance. Furthermore, an object of the present invention is to provide convenient drug administration for animals. In particular, an object of the present invention is to provide improved intake of a drug-containing formulation comprising at least one hypoxia-inducible factor prolyl hydroxylase inhibitor. Furthermore, an object of the present invention is to provide a liquid formulation adjuvant composition for improving drug intake in animals.

[0008] Furthermore, it is desirable that the formulations exhibit good bioavailability for each drug.

[0009] Surprisingly, it has been found that at least one of these objectives can be achieved by the liquid drug-containing formulations and / or liquid formulation aid compositions according to the present invention.

[0010] In the first aspect, the present invention comprises the following components A) At least one drug that is a hypoxia-inducible factor prolyl hydroxylase inhibitor, B) Natural oil derived from at least one herb, C) Optionally, at least one natural oil of animal origin, D) The present invention relates to a liquid drug-containing formulation that optionally includes at least one thickening agent.

[0011] The following describes preferred embodiments of the components of the above formulation in more detail. It should be understood that each preferred embodiment is relevant both in itself and in combination with other preferred embodiments.

[0012] In a preferred embodiment A1 of the first aspect, the hypoxia-inducible factor prolyl hydroxylase inhibitor is a compound of formula (I). [ka] Or it is a salt thereof, a stereoisomer, a tautomer, or an N-oxide.

[0013] In a preferred embodiment A2 of the first aspect, the hypoxia-inducible factor prolyl hydroxylase inhibitor is a compound of formula (I), which is in the form of a salt having formula (II), [ka] During the ceremony, M is selected from the group consisting of lithium, sodium, potassium, calcium, magnesium, barium, manganese, copper, silver, zinc, iron, ammonium, and substituted ammonium, and 1 to 4 of its hydrogen atoms are replaced by C1 to C4 alkyl groups, preferably M is sodium. m represents the positive charge of each cation, and is 1, 2, or 3, preferably 1. n represents the stoichiometric amount of each counteranion, which is 1, 2, or 3, preferably 1, and n is equal to m so that the salt having formula (II) is not charged.

[0014] In a preferred embodiment A3 of the first aspect, the natural oil derived from at least one herb is selected from the group consisting of almond oil, apricot kernel oil, canola oil, castor oil, coconut oil, cottonseed oil, flaxseed oil, grape oil, hemp oil, corn oil, olive oil, coconut oil, peanut oil, sesame oil, soybean oil, sunflower oil, thistle oil, rapeseed oil, rice bran oil, and wheat germ oil.

[0015] In the preferred embodiment A4 of the first aspect, at least one natural oil derived from herbs is selected from the group consisting of modified almond oil, modified apricot kernel oil, modified canola oil, modified castor oil, modified coconut oil, modified cottonseed oil, modified linseed oil, modified grape seed oil, modified hemp oil, modified corn oil, modified olive oil, modified palm oil, modified peanut oil, modified sesame oil, modified soybean oil, modified sunflower oil, modified safflower oil, modified rapeseed oil, modified rice bran oil, and modified wheat germ oil, and the modification is preferably obtained by alcoholysis with glycerol, propylene glycol, or low molecular weight polyethylene glycol.

[0016] In the preferred embodiment A5 of the first aspect, at least one natural oil derived from animals is present, which is selected from the group consisting of fish oil and salmon oil.

[0017] In the preferred embodiment A6 of the first aspect, at least one natural oil derived from herbs is soybean oil or sunflower oil, and at least one natural oil derived from animals is present, which is fish oil.

[0018] In the preferred embodiment A7 of the first aspect, at least one natural oil derived from herbs is modified corn oil.

[0019] In the preferred embodiment A8 of the first aspect, at least one thickener is present, which is a glycerol ester, preferably a glycerol ester having C 12 ~C 24 fatty acids, and / or a monoester, diester, triester, or a mixture thereof.

[0020] In the preferred embodiment A9 of the first aspect, at least one thickener is present, which is glycerol dibehenate.

[0021] In the preferred embodiment A10 of the first aspect, the liquid drug-containing formulation defined herein is the component E) At least one antioxidant selected from the group consisting of ascorbyl palmitate, butylhydroxytoluene, butylhydroxyanisole, citric acid, lecithin, propyl gallate, tocopherol, and combinations thereof, and / or F) At least one preservative selected from the group consisting of ethanol, propylene glycol, butanol, chlorobutanol, benzoic acid, sorbic acid, para-hydroxybenzoic acid esters, and / or combinations thereof, and / or G) Optionally, further comprising at least one surfactant.

[0022] In a preferred embodiment A11 of the first aspect, the liquid drug-containing formulation as defined herein is: A) Based on the total weight of the liquid drug-containing preparation, an amount of 0.1 to 20% by weight, preferably 0.5 to 10% by weight, of a hypoxia-inducible factor prolyl hydroxylase inhibitor. B) Based on the total weight of the liquid drug-containing preparation, 50 to 99.8% by weight, preferably 70 to 98.97% by weight, of natural oil derived from at least one herb. C) Optionally, based on the total weight of the liquid drug-containing formulation, an amount of at least one natural oil of animal origin of 0.01 to 5% by weight, preferably 0.01 to 1.5% by weight, D) Optionally, at least one thickener in an amount of 0.1 to 10% by weight, preferably 0.5 to 5% by weight, based on the total weight of the liquid drug-containing formulation. E) Optionally, based on the total weight of the liquid drug-containing formulation, at least one antioxidant in an amount of 0.01 to 2% by weight, preferably 0.01 to 1.5% by weight, and F) Optionally, the liquid drug-containing formulation may contain at least one preservative in an amount of 0.01 to 2% by weight, preferably 0.01 to 1.5% by weight, based on the total weight of the formulation.

[0023] In a second aspect, the present invention relates to a liquid drug-containing formulation, as defined herein, for use in the treatment and / or prevention of diseases related to the hypoxia-inducible factor prolyl hydroxylase enzyme, preferably the disease being cardiovascular disease, heart failure, anemia, chronic kidney disease, or renal failure, particularly for use in the treatment of anemia associated with chronic kidney disease.

[0024] In the preferred embodiment B1 of the second aspect, the liquid drug-containing formulation can be administered for a period of at least two weeks without causing problems with acceptance or voluntary acceptance.

[0025] In a preferred embodiment B2 of the second aspect, the liquid drug-containing formulation is administered to cats and dogs, preferably cats.

[0026] In a third aspect, the present invention relates to the use of a liquid formulation aid composition comprising at least one herb and / or animal-derived natural oil, preferably at least one herb-derived natural oil, and optionally at least one thickener, in a liquid drug-containing formulation for improving the acceptance or voluntary acceptance of drug ingestion in animals. Preferably, according to a third aspect, the present invention relates to the use of a liquid formulation aid composition comprising at least one herb-derived natural oil, and optionally at least one thickener, in a liquid drug-containing formulation for improving the acceptance or voluntary acceptance of drug ingestion in animals.

[0027] In a preferred embodiment C1 of the third aspect, the liquid drug-containing formulation comprises at least 50% by weight of the liquid formulation aid composition based on the total weight of the liquid drug-containing formulation.

[0028] In a preferred embodiment C2 of the third aspect, drug ingestion or voluntary acceptance is improved in cats and dogs, preferably in cats.

[0029] In a preferred embodiment C3 of the third aspect, acceptance or voluntary acceptance of the drug is improved over a period of at least two weeks.

[0030] In a preferred embodiment C4 of the third aspect, the material includes at least one natural oil derived from herbs, which is selected from the group consisting of almond oil, apricot kernel oil, canola oil, castor oil, coconut oil, cottonseed oil, flaxseed oil, grape oil, hemp oil, corn oil, olive oil, coconut oil, peanut oil, sesame oil, soybean oil, sunflower oil, thistle oil, rapeseed oil, rice bran oil, and wheat germ oil, and is preferably soybean oil or sunflower oil.

[0031] In a preferred embodiment C5 of the third aspect, the natural oil derived from at least one herb is selected from the group consisting of modified almond oil, modified apricot kernel oil, modified canola oil, modified castor oil, modified coconut oil, modified cottonseed oil, modified flaxseed oil, modified grape oil, modified hemp oil, modified corn oil, modified olive oil, modified coconut oil, modified peanut oil, modified sesame oil, modified soybean oil, modified sunflower oil, modified thistle oil, modified rapeseed oil, modified rice bran oil, and modified wheat germ oil, and is preferably modified corn oil, and the modification is preferably obtained by alcohol decomposition with glycerol, propylene glycol, or low molecular weight polyethylene glycol.

[0032] In a preferred embodiment C6 of the third aspect, the liquid formulation aid composition comprises at least one natural oil of animal origin, which is preferably selected from the group consisting of fish oil and salmon oil, and is particularly fish oil.

[0033] In a preferred embodiment C7 of the third aspect, there is at least one thickening agent, which is a glycerol ester, preferably C 12 ~C 24 It is a glycerol ester containing a fatty acid, and / or a monoester, diester, triester, or a mixture thereof.

[0034] In a preferred embodiment C8 of the third aspect, at least one thickening agent is present, which is glycerol dibehenate.

[0035] In a preferred embodiment C9 of the third aspect, the liquid formulation aid composition is At least one antioxidant selected from the group consisting of ascorbyl palmitate, butylhydroxytoluene, butylhydroxyanisole, citric acid, lecithin, propyl gallate, tocopherol, and combinations thereof, and / or At least one preservative selected from the group consisting of ethanol, propylene glycol, butanol, chlorobutanol, benzoic acid, sorbic acid, para-hydroxybenzoic acid esters, and / or combinations thereof, and / or Optionally, it further includes at least one surfactant.

[0036] In a preferred embodiment C10 of the third aspect, at least one natural oil derived from herbs is present in the liquid formulation additive composition in an amount of at least 90% by weight, based on the total weight of the liquid formulation additive composition. [Modes for carrying out the invention]

[0037] Before describing exemplary embodiments of the present invention in detail, we will provide some important definitions necessary for understanding the invention.

[0038] Where used herein and in the appended claims, the singular forms of “a” and “an” also include their respective plural forms unless the context explicitly indicates otherwise. In the context of the present invention, the terms “about” and “approximately” indicate intervals of precision that a person skilled in the art would understand in order to still ensure the technical effect of the feature in question. These terms typically indicate a deviation from the stated number of ±20%, preferably ±15%, more preferably ±10%, and even more preferably ±5%. It should be understood that the term “including” is not limiting. For the purposes of the present invention, the term “consisting of” is considered a preferred embodiment of the term “comprising of.” Where a group is defined below as including at least a certain number of embodiments, this also means that it preferably includes a group consisting only of these embodiments. Furthermore, terms such as “first,” “second,” “third,” or “(a),” “(b),” “(c),” “(d)” in the description and claims are used to distinguish similar elements and are not necessarily used to describe order or chronology. It should be understood that the terms used herein are interchangeable under appropriate circumstances, and that the embodiments of the invention described herein may operate in an order other than those described or illustrated herein. Where terms such as “first,” “second,” “third,” or “(a),” “(b),” “(c),” “(d),” “i,” “ii” relate to steps of a method, use, or assay, there is no consistency in time or time intervals between steps; that is, steps may be performed simultaneously, or there may be time intervals of seconds, minutes, hours, days, weeks, months, or even years between such steps unless otherwise indicated in the applications described herein above or below. It should be understood that the invention is not limited to the specific methodologies, protocols, reagents, etc. described herein, as these may vary. It should also be understood that the terms used herein are solely for the purpose of describing specific embodiments and are not intended to limit the scope of the invention, which will only be limited by the appended claims.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art.

[0039] The term “compound of formula (I)” includes the compounds as defined herein, as well as their stereoisomers, salts, or tautomers.

[0040] Depending on the substitution pattern, the compounds according to the present invention may have one or more chirality centers. The present invention provides both single pure enantiomers or pure diastereomers of the compounds according to the present invention, and mixtures thereof, as well as the use of the pure enantiomers or pure diastereomers or mixtures thereof of the compounds according to the present invention. Suitable compounds according to the present invention also include all possible geometric stereoisomers (cis / trans isomers or E / Z isomers) and mixtures thereof. Cis / trans isomers may exist, for example, with respect to an amide group. The term “stereoisomer” encompasses both optical isomers such as enantiomers or diastereomers, the latter being present because there is more than one chirality center in the molecule, and similarly encompasses geometric isomers (cis / trans isomers). The present invention relates to all possible stereoisomers of the compound of formula (I), i.e., single enantiomers or diastereomers, and mixtures thereof.

[0041] In the context of this invention, terms such as "active substance," "activator," and "drug" refer to any suitable activator in any pharmaceutically acceptable chemical and morphological form, as well as in any physical state.

[0042] The compound of formula (I) may be amorphous, or may exist in one or more different crystalline states (polymorphs) that may have different macroscopic properties such as stability, or exhibit different biological properties such as activity. The present invention relates to amorphous and crystalline compounds of formula (I), mixtures of different crystalline states of each compound of formula (I), and amorphous or crystalline salts thereof.

[0043] Salts of the compound of formula (I) may be pharmaceutically acceptable salts, such as those containing counterions present in drug products listed in the U.S. FDA Orange Book database. These can be formed by conventional methods, for example, by reacting the compound with the acid of the anion in question if the compound of formula (I) has a basic functional group, or by reacting the acidic compound according to the present invention with a suitable base.

[0044] Suitable cationic counterions include alkali metals, preferably lithium, sodium, and potassium ions; alkaline earth metals, preferably calcium, magnesium, and barium ions; and transition metals, preferably aluminum, manganese, copper, silver, zinc, and iron ions; as well as ammonium (NH4) ions. + These are substituted ammonium ions in which 1 to 4 of the hydrogen atoms are replaced by C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, (C1-C4-alkoxy)-(C1-C4-alkyl), hydroxy-(C1-C4-alkoxy)-(C1-C4-alkyl), phenyl, or benzyl. Examples of substituted ammonium ions include methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trimethylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxyethylammonium, 2-(2-hydroxyethoxy)ethylammonium, bis(2-hydroxyethyl)ammonium, benzyltrimethylammonium, and benzyltriethylammonium, and further include cations of 1,4-piperazine, meglumine, benzathine, and lysine. Preferred cations are lithium, sodium, potassium, calcium, magnesium, barium, manganese, copper, silver, zinc, iron, ammonium, and substituted ammonium in which 1 to 4 of the hydrogen atoms are replaced by C1-C4 alkyl groups, particularly sodium.

[0045] Suitable anionic counterions include, in particular, anions of chlorides, bromides, bisulfates, sulfates, dihydrogen phosphates, hydrogen phosphates, phosphates, nitrates, bicarbonates, carbonates, hexafluorosilicates, hexafluorophosphates, benzoates, and C1-C4 alkanates, preferably formate, acetate, trifluoroacetate, propionate, and butyrate, as well as lactate and gluconate anions, and polyacid anions such as succinate, oxalate, maleate, fumarate, malate, tartrate, and citrate, as well as sulfonate, besilate (benzenesulfonate), tosilate (p-toluenesulfonate), napsilate (naphthalene-2-sulfonate), mesilate (methanesulfonate), esylate (ethanesulfonate), and ethanedisulfonate sulfonate. These can be formed by reacting the compounds according to the present invention, which have a basic functional group, with the acid of the corresponding anion. A preferred salt of the compound of formula (I) is a chloride salt.

[0046] When substituents are present in the compound of formula (I), tautomers may be formed, which enables the formation of tautomers such as keto-enol tautomers.

[0047] The organic part mentioned in the above definition of a variable is a general term for the individual list of individual group members, like the term halogen. The prefix C n ~C m This indicates the possible number of carbon atoms in the group in each case.

[0048] As used herein, the term "alkyl" refers in each case to a linear or branched alkyl group having typically 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, and tert-butyl. Methyl, ethyl, n-propyl, isopropyl, and isobutyl are particularly preferred.

[0049] As used herein and in the appended claims, the term “acceptance” means “forced administration” or “forced induction” of the formulation by an animal, where the formulation is administered directly into the animal’s mouth. It should be understood that the formulation is acceptable if the animal is not reacting violently (e.g., biting) or experiencing adverse effects (e.g., convulsions).

[0050] As used herein and in the appended claims, the term “voluntary acceptance” refers to the voluntary ingestion of an oral formulation by an animal. The formulation is administered in a bowl, and voluntary and autonomous ingestion by the animal is assessed over a maximum serving time of 3 minutes. Generally, the procedure for assessing voluntary acceptance in an animal can be as follows: The test samples are offered daily in a food bowl for 3 minutes. Voluntary intake of different formulations is evaluated and recorded using a Visual Analog Scale (VAS), where 0 cm represents the worst possible voluntary intake and 10 cm represents the best possible voluntary intake.

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[0051] In the worst possible intake (0 cm), the animals show no interest and do not ingest the test sample. In the best possible intake (10 cm), the animals ingest the entire test sample.

[0052] The evaluator marks vertically on the line based on the animal's behavior (e.g., no intake / shows interest, smells the test product / partially consumes the test product / requests more). All voluntary intake evaluations for a single treatment day are performed by the same individual.

[0053] Preferred embodiments relating to the liquid drug-containing formulations according to the present invention, and to the use of said liquid drug-containing formulations in the treatment and / or prevention of diseases, are described below. It should be understood that the preferred embodiments of the present invention are preferred individually or in combination with each other. Furthermore, preferred embodiments relating to the use of the liquid formulation adjuvant compositions according to the present invention for improving the acceptance or voluntary acceptance of drug ingestion in animals are described below.

[0054] As described above, in one embodiment, the present invention comprises the following components A) At least one drug that is a hypoxia-inducible factor prolyl hydroxylase inhibitor, B) Natural oil derived from at least one herb, C) Optionally, at least one natural oil of animal origin, D) The present invention relates to a liquid drug-containing formulation that optionally includes at least one thickening agent.

[0055] Preferred embodiments relating to the components of a liquid drug-containing formulation suitable for all aspects of the present invention are defined below.

[0056] According to the present invention, a liquid drug-containing formulation comprises at least one drug that is a hypoxia-inducible factor prolyl hydroxylase inhibitor (also known as HIF-PHI). These inhibitors are members of a class of drugs that act by inhibiting prolyl hydroxylase, which is responsible for the breakdown of hypoxia-inducible factors (HIF) under normal oxygen conditions. These inhibitors are associated with diseases such as anemia, chronic kidney disease, and cancer. Examples of HIF prolyl hydroxylase inhibitors are daprodostat, moridustat, roxadustat, vadadustat, and desidustat. Therefore, in one embodiment of the present invention, the hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor is selected from the group consisting of daprodostat, moridustat, roxadustat, vadadustat, and desidustat, and is particularly moridustat.

[0057] Preferably, the liquid drug-containing formulation according to the present invention contains a hypoxia-inducible factor prolyl hydroxylase inhibitor in an amount of 0.1 to 20% by weight, more preferably 0.5 to 10% by weight, even more preferably 1 to 8% by weight, and particularly 1 to 5% by weight, based on the total weight of the liquid drug-containing formulation.

[0058] In one embodiment of the present invention, the HIF prolyl hydroxylase inhibitor is a compound of formula (I). [ka] Or it is a salt thereof, a stereoisomer, a tautomer, or an N-oxide.

[0059] In one embodiment, the HIF prolyl hydroxylase inhibitor is a compound of formula (I) in the form of a salt having formula (II), [ka] During the ceremony, M is selected from the group consisting of lithium, sodium, potassium, calcium, magnesium, barium, manganese, copper, silver, zinc, iron, ammonium, and substituted ammonium, and 1 to 4 of its hydrogen atoms are replaced by C1 to C4 alkyl groups, preferably M is sodium. m represents the positive charge of each cation, and is 1, 2, or 3, preferably 1. n represents the stoichiometric amount of each counteranion, which is 1, 2, or 3, preferably 1, and n is equal to m so that the salt having formula (II) is not charged.

[0060] In a preferred embodiment of the present invention, the HIF prolyl hydroxylase inhibitor is in the form of the sodium salt of formula (IIa), [ka] This is also known as sodium 1-[6-(morpholin-4-yl)pyrimidine-4-yl]-4-(1H-1,2,3-triazole-1-yl)-1H-pyrazole-5-oleate.

[0061] In another preferred embodiment of the present invention, the HIF prolyl hydroxylase inhibitor is in the form of a potassium salt or ammonium salt of formula (II), which is also known as potassium 1-[6-(morpholin-4-yl)pyrimidine-4-yl]-4-(1H-1,2,3-triazole-1-yl)-1H-pyrazole-5-oleate or ammonium 1-[6-(morpholin-4-yl)pyrimidine-4-yl]-4-(1H-1,2,3-triazole-1-yl)-1H-pyrazole-5-oleate.

[0062] According to the present invention, the liquid drug-containing formulation contains a natural oil derived from at least one herb. It should be understood that, in the sense of the present invention, the term "herb" is interchangeable with "plant-based." Preferably, the liquid drug-containing formulation contains a natural oil derived from at least one herb in an amount of at least 50% by weight, preferably 50-99.8% by weight, more preferably 70-98.97% by weight, and even more preferably 80-98.9% by weight, based on the total weight of the liquid drug-containing formulation.

[0063] In one embodiment of the present invention, the natural oil derived from at least one herb is selected from the group consisting of almond oil, apricot kernel oil, canola oil, castor oil, coconut oil, cottonseed oil, flaxseed oil, grape oil, hemp oil, corn oil, olive oil, coconut oil, peanut oil, sesame oil, soybean oil, sunflower oil, thistle oil, rapeseed oil, rice bran oil, and wheat germ oil.

[0064] According to the present invention, natural oils derived from herbs are obtained from natural products. According to the present invention, natural oils derived from herbs contain at least 5% by weight, preferably at least 8% by weight, of unsaturated fatty acids, based on the total amount of fatty acids in the natural oil derived from herbs. Generally, natural oils derived from herbs can be obtained by mechanical pressing or by extraction of the respective herbs (e.g., sunflower oil from Helianthus annuus), followed by optional refining. Suitable antioxidants may be added.

[0065] The following provides an illustrative description of natural oils derived from herbs according to the present invention.

[0066] Corn oil, also known as maize oil, can be obtained from the seeds of Zea mays L. by pressing or extraction, followed by optional refining. Preferably, the maize oil contains, based on the total amount of fatty acids, 8.6–16.5% by weight of palmitic acid, up to 3.3% by weight of stearic acid, 20–42.2% by weight of oleic acid, 39.4–65.6% by weight of linoleic acid, 0.5–1.5% by weight of arachidic acid, up to 0.5% by weight of eicosenoic acid, and up to 0.5% by weight of behenic acid.

[0067] Sunflower oil can be obtained from the seeds of Helianthus anus by mechanical pressing or extraction followed by optional refining. Preferably, the sunflower oil contains, based on the total amount of fatty acids, 4-9% by weight of palmitic acid, 1-7% by weight of stearic acid, 14-40% by weight of oleic acid, and 48-74% by weight of linoleic acid.

[0068] Thistle oil, also known as safflower oil, can be obtained from the seeds of Carthamus tinctorius L. (Type I) or hybrid seeds of Carthamus tinctorius L. (Type II) by pressing and / or extraction, followed by optional purification. Preferably, thistle oil obtained from the Type I fraction contains, based on the total amount of fatty acids, up to 0.2% by weight of saturated fatty acids with a chain length of less than C14, up to 0.2% by weight of myristic acid, 4-10% by weight of palmitic acid, 1-5% by weight of stearic acid, 8-21% by weight of oleic acid, 68-83% by weight of linoleic acid, up to 0.5% by weight of linolenic acid, up to 0.5% by weight of arachidonic acid, up to 0.5% by weight of eicosenoic acid, and up to 1% by weight of behenic acid. Preferably, the thistle oil obtained from the Type II fraction contains, based on the total amount of fatty acids, up to 0.2% by weight of saturated fatty acids with a chain length of less than C14, including up to 0.2% by weight of myristic acid, 3.6-6% by weight of palmitic acid, 1-5% by weight of stearic acid, 70-84% by weight of oleic acid, 7-23% by weight of linoleic acid, up to 0.5% by weight of linolenic acid, up to 1% by weight of arachidic acid, up to 1% by weight of eicosenoic acid, and up to 1.2% by weight of behenic acid.

[0069] In general, it should be understood that the natural oils derived from herbs according to the present invention can be obtained from each herb by pressing and / or extraction, followed by optional refining.

[0070] It should be understood that, according to the present invention, the herb-derived natural oils may be any suitable herb-derived natural oils known in the art as defined above and obtainable as described above. In one embodiment of the present invention, these herb-derived natural oils may be further modified.

[0071] In one embodiment of the present invention, the at least one herb-derived natural oil is selected from the group consisting of modified almond oil, modified apricot kernel oil, modified canola oil, modified castor oil, modified coconut oil, modified cottonseed oil, modified linseed oil, modified grape seed oil, modified hemp oil, modified corn oil, modified olive oil, modified palm oil, modified peanut oil, modified sesame oil, modified soybean oil, modified sunflower oil, modified safflower oil, modified rapeseed oil, modified rice bran oil, and modified wheat germ oil, and the modification is preferably obtained by alcoholysis with glycerol, propylene glycol, or low molecular weight polyethylene glycol. In this regard, it should be understood that the low molecular weight polyethylene glycol is defined as follows: H-(O-CH 2- CH2) n- OH, where n is selected from 1 to 5, preferably 1 to 4, particularly 1 to 3, or 1 to 2, H-(O-CH 2- CH2) n- OH.

[0072] Generally, alcoholysis is an example of a solvation reaction, and triglycerides react with an alcohol such as methanol or ethanol to obtain methyl or ethyl esters of fatty acids. In particular, glycerol can be used as the alcohol. This reaction is also known as a transesterification reaction resulting from the exchange of alcohol fragments.

[0073] After the alcoholysis reaction, preferably, a dewaxing process for removing certain saturated mono-, di-, and triglycerides follows.

[0074] Maisine® CC can be named as an exemplary modified corn oil. It is obtained by alcoholysis of corn oil and subsequent dewaxing of the corn oil. The product contains mono-, di-, and triglycerides, and the monoester fraction contains 32 to 52% by weight based on the total amount of mono-, di-, and triglycerides, the diester fraction contains 40 to 60% by weight, and the triester fraction contains 5 to 20% by weight.

[0075] In certain embodiments of the present invention, the natural oil derived from at least one herb is selected from the group consisting of sesame oil, soybean oil, sunflower oil, thistle oil, and modified corn oil, and the modification is preferably obtained by alcohol decomposition with glycerol, propylene glycol, or low molecular weight polyethylene glycol.

[0076] According to one particular embodiment, the formulations or compositions described herein contain sunflower oil.

[0077] According to further specific embodiments, the formulations or compositions described herein contain soybean oil.

[0078] According to further specific embodiments, the formulations or compositions described herein contain modified corn oil.

[0079] According to one embodiment of the present invention, a liquid drug-containing formulation comprises a mixture of natural oil derived from modified herbs and natural oil derived from unmodified herbs.

[0080] According to one embodiment of the present invention, the liquid drug-containing formulation further comprises at least one natural oil of animal origin. Preferably, the liquid drug-containing formulation comprises 0.01 to 5% by weight, more preferably 0.01 to 2.5% by weight, even more preferably 0.01 to 1.5% by weight, and particularly 0.01 to 1% by weight of at least one natural oil of animal origin, based on the total weight of the liquid drug-containing formulation.

[0081] It should be understood that, according to the present invention, the natural oil of animal origin may be any suitable natural oil of animal origin known in the art, for example, fish oil, particularly cod liver oil, and salmon oil. According to the present invention, the natural oil of animal origin is obtained from natural products. Illustrative descriptions of natural oil of animal origin according to the present invention are given below.

[0082] Fish oil may be obtained from fish of the Engraulidae, Carangidae, Clupeidae, Osmeridae, Scombridae (excluding the genera Thunnus and Sarda), and Ammodytidae (Type I), or from the genera Thunnus and Sarda of Scombridae (Type II). Fish oil may contain omega-3 acids such as alpha-linolenic acid (C18:3 n-3), molocinic acid (C18:4 n-3), eicosatetraenoic acid (C20:4 n-3), timnodonic acid (eicosapentaenoic acid) (C20:5 n-3; EPA), heneicosapentaenoic acid (C21:5 n-3), clupanodonic acid (C22:5 n-3), and cervonic acid (docosahexaenoic acid) (C22:6 n-3; DHA). Preferably, the fish oil obtained from type I contains at least 28% by weight of omega-3 acids in total, expressed as triglycerides. In particular, the fish oil obtained from type I contains at least 13% by weight of EPA and at least 9% by weight of DHA in total, expressed as triglycerides. Preferably, the fish oil obtained from type II contains at least 28% by weight of omega-3 acids in total, expressed as triglycerides. In particular, the fish oil obtained from type II contains 4-12% by weight of EPA and at least 20% by weight of DHA in total, expressed as triglycerides.

[0083] Cod liver oil can be obtained from the fresh livers of cod, Gadus morhua L., and other species of Gadidae, with solid matter removed by cooling and filtration. Cod liver oil may contain omega-3 acids such as alpha-linolenic acid (C18:3 n-3), molocinic acid (C18:4 n-3), eicosatetraenoic acid (C20:4 n-3), timnodonic acid (eicosapentaenoic acid) (C20:5 n-3; EPA), heneicosapentaenoic acid (C21:5 n-3), clupanodonic acid (C22:5 n-3), and ceruvonic acid (docosahexaenoic acid) (C22:6 n-3; DHA). Preferably, cod liver oil contains 10-28% by weight of EPA and DHA, expressed as triglycerides. Cod liver oil may contain an additional 3-11% by weight of linoleic acid, based on the total amount of fatty acids.

[0084] Salmon oil can be obtained from Salmo salar. The positional distribution (β(2)-acyl) is 60-70% ceruvonic acid (docosahexaenoic acid) (C22:6 n-3; DHA), 25-35% timnodonic acid (eicosapentaenoic acid) (C20:5 n-3; EPA), and 40-55% moloctic acid (C18:4 n-3). Preferably, salmon oil contains 10-28% by weight of EPA and DHA expressed as triglycerides.

[0085] In one embodiment of the present invention, there is at least one natural oil of animal origin, which is selected from the group consisting of fish oil and salmon oil.

[0086] In one embodiment of the present invention, at least one herb-derived natural oil is soybean oil or sunflower oil, and at least one animal-derived natural oil is present, which is fish oil. In a preferred embodiment of the present invention, at least one herb-derived natural oil is sunflower oil, and at least one animal-derived natural oil is present, which is fish oil.

[0087] In another embodiment of the present invention, at least one herb-derived natural oil is modified corn oil, and at least one animal-derived natural oil is present, which is fish oil.

[0088] According to one embodiment of the present invention, the liquid drug-containing formulation further comprises at least one thickening agent. Preferably, the liquid drug-containing formulation as defined herein comprises at least one thickening agent in an amount of 0.1 to 10% by weight, preferably 0.1 to 8% by weight, more preferably 0.5 to 5% by weight, and even more preferably 0.5 to 2.5% by weight, based on the total weight of the liquid drug-containing formulation.

[0089] Suitable cellulose derivatives as thickeners include, for example, methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, microcrystalline cellulose, bentonite, kaolin, pectin, starch, modified starch, wax, agar, paraffin, gelatin, alginate, polyvinylpyrrolidone, crospovidone, cetyl alcohol, stearate, for example, magnesium stearate, zinc stearate, or glyceryl stearate, saturated or unsaturated long-chain fatty acids (C8-C24), high molecular weight polyethylene glycol (e.g., polyethylene glycol 2000), glycerol esters, and silica.

[0090] In one embodiment of the present invention, at least one thickening agent is a glycerol ester, preferably C 12 ~C 24 It is a glycerol ester containing a fatty acid, and / or a monoester, diester, triester, or a mixture thereof.

[0091] In preferred embodiments of the present invention, at least one thickening agent is glycerol dibehenate. Glycerol dibehenate may also be known as glyceryl dibehenate or glycerin dibehenate.

[0092] According to one embodiment of the present invention, a liquid drug-containing formulation comprises the following components E) At least one antioxidant, and / or F) At least one preservative, and / or G) Optionally, further comprising at least one surfactant.

[0093] Preferably, the liquid drug-containing formulation contains, based on the total weight of the liquid drug-containing formulation, at least one antioxidant in an amount of 0.01 to 2% by weight, preferably 0.01 to 1.5% by weight, and / or at least one preservative in an amount of 0.01 to 2% by weight, preferably 0.01 to 1.5% by weight, and / or at least one surfactant in an amount of 0.001 to 1% by weight, preferably 0.01 to 0.3% by weight, based on the total weight of the liquid drug-containing formulation.

[0094] Suitable antioxidants include ascorbyl palmitate, butylated hydroxytoluene, butylated hydroxyanisole, lecithin, sulfites (sodium sulfite, sodium metabisulfite), organic sulfides (cystine, cysteine, cysteamine, methionine, thioglycerol, thioglycolic acid, thiolactic acid), phenols (tocopherol, and vitamin E and vitamin E DPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate)), butylated hydroxyanisole, butylated hydroxytoluene, gallic acid (propyl, octyl, propyl gallate, and dodecyl gallate), organic acids (ascorbic acid, citric acid, tartaric acid, lactic acid), and their salts and esters. Preferably, the antioxidant can be selected from the group consisting of ascorbyl palmitate, butylated hydroxytoluene, butylated hydroxyanisole, citric acid, lecithin, propyl gallate, and tocopherol.

[0095] Suitable preservatives include carboxylic acids (sorbic acid, propionic acid, benzoic acid, lactic acid), phenols (cresol, p-hydroxybenzoic acid esters, e.g., methylparaben, propylparaben), aliphatic alcohols (benzyl alcohol, ethanol, butanol, etc.), and quaternary ammonium compounds (benzalkonium chloride, cetylpyridinium chloride). Preferably, the preservative can be selected from the group consisting of ethanol, propylene glycol, butanol, chlorobutanol, benzoic acid, sorbic acid, and p-hydroxybenzoic acid esters. In this regard, methyl 4-hydroxybenzoic acid, ethyl 4-hydroxybenzoic acid, and propyl 4-hydroxybenzoate may be named as preferred p-hydroxybenzoic acid esters.

[0096] Suitable surfactants are amphiphilic compounds. Examples include mono, di, or triesters of sorbitan having fatty acids, polyoxyethylated compounds such as polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, and poloxamers. Polyoxyethylated compounds, also called polyethoxylated compounds, are prepared, for example, by reaction with ethylene oxide. They are represented by the formula -[O-CH 2- It has one or more linked units of CH2]-. Polyoxyethylated compounds that can be particularly mentioned are nonionic amphiphilic polyoxyethylated compounds, for example, -A poloxamer having a molar mass of preferably 100 to 5000 g / mol, and particularly preferably 1000 to 3500 g / mol. Poloxamer is the international general name for block copolymers of ethylene oxide and methyloxirane. -Polyoxyethylene fatty acid glycerides, also called nonionic emulsifiers, preferably, for example, glycerol polyethylene glycol ricinoleate. -Polyoxyethylene sorbitan fatty acid ester, preferably, for example, polyoxyethylene 20-sorbitan monooleate, -Polyoxyethylene fatty acids such as macrogol 15-hydroxystearate (=Solutol HS15, obtained by reacting 15 mol of ethylene oxide with 1 mol of 12-hydroxystearic acid), -Polyoxyethylene aliphatic alcohols such as hydroxypolyethoxide dodecane.

[0097] Fatty acids or fatty alcohols refer, in particular, to the corresponding compounds having at least six carbon atoms and usually 30 or fewer carbon atoms.

[0098] According to one embodiment of the present invention, a liquid drug-containing formulation comprises the following components E) At least one antioxidant selected from the group consisting of ascorbyl palmitate, butylhydroxytoluene, butylhydroxyanisole, citric acid, lecithin, propyl gallate, tocopherol, and combinations thereof, and / or F) At least one preservative selected from the group consisting of ethanol, propylene glycol, butanol, chlorobutanol, benzoic acid, sorbic acid, para-hydroxybenzoic acid esters, and / or combinations thereof, and / or G) Optionally, further comprising at least one surfactant.

[0099] According to one embodiment of the present invention, a liquid drug-containing formulation as defined herein is A) Based on the total weight of the liquid drug-containing preparation, an amount of 0.1 to 20% by weight, preferably 0.5 to 10% by weight, of a hypoxia-inducible factor prolyl hydroxylase inhibitor. B) Based on the total weight of the liquid drug-containing preparation, 50 to 99.8% by weight, preferably 70 to 98.97% by weight, of natural oil derived from at least one herb. C) Optionally, based on the total weight of the liquid drug-containing formulation, an amount of at least one natural oil of animal origin of 0.01 to 5% by weight, preferably 0.01 to 1.5% by weight, D) Optionally, at least one thickener in an amount of 0.1 to 10% by weight, preferably 0.5 to 5% by weight, based on the total weight of the liquid drug-containing formulation. E) Optionally, based on the total weight of the liquid drug-containing formulation, at least one antioxidant in an amount of 0.01 to 2% by weight, preferably 0.01 to 1.5% by weight, and F) Optionally, the liquid drug-containing formulation may contain at least one preservative in an amount of 0.01 to 2% by weight, preferably 0.01 to 1.5% by weight, based on the total weight of the formulation.

[0100] According to one embodiment of the present invention, the liquid drug-containing formulation as defined herein does not contain additional flavoring agents such as vanilla, anise, or honey flavoring.

[0101] According to one embodiment of the present invention, the present invention relates to a liquid drug-containing formulation, as defined herein, for use in the treatment and / or prevention of diseases related to the hypoxia-inducible factor prolyl hydroxylase enzyme, preferably, the disease being cardiovascular disease, heart failure, anemia, chronic kidney disease, or renal failure, particularly for use in the treatment of anemia associated with chronic kidney disease.

[0102] According to one embodiment, the present invention relates to a liquid drug-containing formulation as defined herein for the control (or management) of secondary non-regenerative anemia resulting from chronic kidney disease in animals, preferably cats and dogs, and particularly in cats.

[0103] According to one embodiment of the present invention, a liquid drug-containing formulation can be administered for a period of at least one week without causing problems of acceptance or voluntary acceptance.

[0104] According to one embodiment of the present invention, a liquid drug-containing formulation can be administered for a period of at least two weeks without causing problems of acceptance or voluntary acceptance.

[0105] According to one embodiment of the present invention, a liquid drug-containing formulation is administered to cats and dogs, preferably to cats.

[0106] According to one embodiment of the present invention, a liquid drug-containing formulation can be administered to cats for a period of at least two weeks without causing problems with acceptance or voluntary acceptance. According to a particular embodiment of the present invention, a liquid drug-containing formulation can be administered to cats for a period of at least four weeks without causing problems with voluntary acceptance.

[0107] According to another embodiment of the present invention, a liquid drug-containing formulation can be administered to dogs for a period of at least two weeks, and particularly at least four weeks, without causing problems of voluntary acceptance.

[0108] It should be understood that, according to the present invention, the liquid drug-containing formulation as defined herein is administered orally to animals.

[0109] According to the present invention, the voluntary acceptance of the liquid drug-containing formulation according to the present invention is determined to be at least 7, preferably at least 8, as defined herein.

[0110] As described above, the present invention further relates to the use of a liquid formulation adjuvant composition comprising at least one natural oil derived from a herb for improving the acceptance or voluntary acceptance of drug ingestion.

[0111] As described above, the present invention further relates to the use of a liquid formulation aid composition comprising at least one animal-derived natural oil for improving the acceptance or voluntary acceptance of drug ingestion.

[0112] In one embodiment of the present invention, the liquid formulation aid composition comprises at least one natural oil derived from herbs and at least one natural oil derived from animals.

[0113] In one embodiment of the present invention, the liquid drug-containing formulation comprises a liquid formulation aid composition in an amount of at least 20% by weight, preferably at least 40% by weight, more preferably at least 50% by weight, even more preferably at least 70% by weight, and particularly at least 80% by weight, based on the total weight of the liquid drug-containing formulation.

[0114] In one embodiment of the present invention, acceptance or voluntary acceptance of drug ingestion is improved in cats and dogs, preferably in cats.

[0115] In one embodiment of the present invention, acceptance or voluntary acceptance of drug administration is improved over a period of at least one week.

[0116] In one embodiment of the present invention, acceptance or voluntary acceptance of drug administration is improved over a period of at least two weeks.

[0117] In certain embodiments of the present invention, acceptance or voluntary acceptance of drug administration is improved over a period of at least four weeks.

[0118] It should be understood that the natural oil derived from at least one herb contained in the liquid formulation additive composition is defined as outlined in more detail above.

[0119] One embodiment of the present invention includes at least one natural oil derived from herbs, which is selected from the group consisting of almond oil, apricot kernel oil, canola oil, castor oil, coconut oil, cottonseed oil, flaxseed oil, grape oil, hemp oil, corn oil, olive oil, coconut oil, peanut oil, sesame oil, soybean oil, sunflower oil, thistle oil, rapeseed oil, rice bran oil, and wheat germ oil, and is preferably soybean oil or sunflower oil.

[0120] It should be understood that, according to the present invention, the herb-derived natural oil contained in the liquid formulation additive composition may be any suitable herb-derived natural oil known in the art as defined above and obtainable as described above. These herb-derived natural oils may be further modified.

[0121] In another embodiment of the present invention, the oil comprises at least one natural oil derived from herbs, which is selected from the group consisting of modified almond oil, modified apricot kernel oil, modified canola oil, modified castor oil, modified coconut oil, modified cottonseed oil, modified flaxseed oil, modified grape oil, modified hemp oil, modified corn oil, modified olive oil, modified coconut oil, modified peanut oil, modified sesame oil, modified soybean oil, modified sunflower oil, modified thistle oil, modified rapeseed oil, modified rice bran oil, and modified wheat germ oil, preferably modified corn oil, and the modification is preferably obtained by alcohol decomposition with glycerol, propylene glycol, or low molecular weight polyethylene glycol.

[0122] In certain embodiments of the present invention, the present invention includes at least one natural oil derived from herbs, which is selected from the group consisting of sesame oil, soybean oil, sunflower oil, thistle oil, and modified corn oil, and modification is preferably achieved by alcohol decomposition with glycerol, propylene glycol, or low molecular weight polyethylene glycol.

[0123] In one embodiment of the present invention, the liquid formulation aid composition comprises at least one natural oil of animal origin, which is preferably selected from the group consisting of fish oil and salmon oil, and is particularly fish oil.

[0124] In one embodiment of the present invention, at least one thickening agent is preferably present in the liquid formulation aid composition, which is a glycerol ester, preferably C 12 ~C 24 It is a glycerol ester containing a fatty acid, and / or a monoester, diester, triester, or a mixture thereof.

[0125] In one embodiment of the present invention, at least one thickening agent is preferably present in the liquid formulation aid composition, and this is glycerol dibehenate.

[0126] In one embodiment of the present invention, a liquid formulation aid composition, At least one antioxidant selected from the group consisting of ascorbyl palmitate, butylhydroxytoluene, butylhydroxyanisole, citric acid, lecithin, propyl gallate, tocopherol, and combinations thereof, and / or At least one preservative selected from the group consisting of ethanol, propylene glycol, butanol, chlorobutanol, benzoic acid, sorbic acid, para-hydroxybenzoic acid esters, and / or combinations thereof, and / or Optionally, it further includes at least one surfactant.

[0127] In one embodiment of the present invention, a natural oil derived from at least one herb is present in the liquid formulation aid composition in an amount of at least 50% by weight, preferably at least 70% by weight, more preferably at least 90% by weight, even more preferably at least 93% by weight, and particularly at least 95% by weight, based on the total weight of the liquid formulation aid composition.

[0128] In another embodiment of the present invention, at least one animal-derived natural oil is present in the liquid formulation aid composition in an amount of at least 50% by weight, preferably at least 70% by weight, more preferably at least 90% by weight, even more preferably at least 93% by weight, and particularly at least 95% by weight, based on the total weight of the liquid formulation aid composition.

[0129] It should be further understood that the at least one animal-derived natural oil, at least one thickener, at least one antioxidant, at least one preservative, and at least one surfactant that may be included in the liquid formulation additive composition are defined as outlined in more detail above.

[0130] According to one embodiment of the present invention, the liquid formulation aid composition defined herein does not contain additional flavoring agents such as vanilla, anise, or honey flavoring.

[0131] According to the present invention, the liquid formulation aid composition improves the voluntary acceptance of liquid drug-containing formulations in that it is determined to be at least 7, preferably at least 8, as defined herein.

[0132] The present invention is further illustrated by the following embodiments.

[0133] Materials used Compritol® 888ATO is a glyceryl dibehenate purchased from Gattefosse. It is obtained by esterifying glycerol with behenic acid (a C22 fatty acid) followed by spraying. The product contains mono, di, and triglycerides of behenic acid, with the diester fraction making up 40-60% by weight.

[0134] Maisine® CC, purchased from Gattefosse, is a modified corn oil. It is obtained by the alcoholic decomposition of corn oil and subsequent dewaxing. The product contains mono, di, and triglycerides, with the monoester fraction comprising 32–52% by weight, the diester fraction comprising 40–60% by weight, and the triester fraction comprising 5–20% by weight.

[0135] More specifically, Maisine(registered trademark) CC mainly consists of mono, di, and triglycerides of linoleic acid (C18:2) and oleic acid (C18:1), with the diester fraction being the most prominent component.

[0136] Maisine® CC is also known as corn oil mono, di, and triglycerides, glycerol / glyceryl monolinoleate (EP, USP-NF), or corn glycerides (FDA IID).

[0137] Miglyol® 810, purchased from IOI Oleo GmbH, is a mixture of decanoyl glyceride and octanoyl glyceride. It is also known as caprylic / capric triglyceride or medium-chain triglyceride.

[0138] Miglyol® 812, purchased from IOI Oleo GmbH, is a mixture of decanoyl glyceride and octanoyl glyceride. It is also known as caprylic / capric triglyceride or medium-chain triglyceride.

[0139] Miglyol® 840, purchased from IOI Oleo GmbH, is a mixture of glycol monoesters and diesters of caprylic acid (C8H16O2) and capric acid (C10H20O2), with the diester fraction being the dominant component.

[0140] I bought Solbrol P from Fluka.

[0141] I bought Solbrol M from Fluka.

[0142] I purchased Tween20 from Croda GmbH.

[0143] I purchased the Tween80 from Croda GmbH.

[0144] I purchased an Avicel CL611 from FMC Corporation.

[0145] I purchased natural oils derived from herbs and animals from Fluka.

[0146] Compound A can be accessed, for example, by following the synthesis disclosed in WO2013 / 167552A1, and is sodium 1-[6-(morpholine-4-yl)pyrimidine-4-yl]-4-(1H-1,2,3-triazole-1-yl)-1H-pyrazole-5-oleate having formula (IIa). [ka]

[0147] The following describes the general procedure for evaluating voluntary acceptance in cats.

[0148] The test samples were offered daily in a food bowl for 3 minutes. Voluntary intake of different formulations was evaluated and recorded using a visual analog scale (VAS), where 0 cm represented the worst possible voluntary intake and 10 cm represented the best possible voluntary intake.

number

[0149] In the worst possible intake (0 cm), the cat showed no interest and did not ingest the test sample. In the best possible intake (10 cm), the cat completely ingested the test sample.

[0150] The evaluators placed vertical marks on a line based on the cats' behavior (e.g., did not ingest / showed interest, smelled the test product / partially consumed the test product / wanted more). All voluntary intake evaluations for a single treatment day were performed by the same individual.

[0151] Example 1 In the following, we tested the voluntary acceptance of several natural oils derived from herbs and animals (Examples 1.1 to 1.8). Furthermore, we tested the voluntary acceptance of a mixture of natural oil derived from herbs and triglycerides (Example 1.9).

[0152] For the voluntary acceptance trial, eight cats were tested according to the general procedure described above for evaluation over a period of 4 or 7 days (compare Tables 1.a and 1.b). Each cat was provided with 0.5 ml of the respective oil.

[0153] Each result was obtained through the following exemplary procedure. Mean values ​​are shown in Tables 1.a and 1.b, and more detailed results are shown in Table 1.c.

[0154] Two test groups were applied, each containing eight cats. In one voluntary acceptance trial phase (7 days), only one formulation was tested.

[0155] To accustom the cats to the procedure of licking fluids from a bowl, the cats were provided with water and / or milk for three days, one animal at a time, to establish a baseline phase value. Following the baseline phase, they were provided with natural oils of their respective herbs or animals, or a mixture containing natural oils of herbs and triglycerides.

[0156] Test group 1 (cats 1-9) was provided with natural oils derived from herbs according to Examples 1.1, 1.2, 1.3, 1.6, and 1.7.

[0157] Test group 2 (cats 10-17) was provided with natural oils derived from herbs or animals according to Examples 1.4, 1.5, 1.8, and 1.9, or a mixture containing natural oils derived from herbs and triglycerides.

[0158] Detailed results of the voluntary acceptance program are shown in Table 1.c.

[0159] Preparation of a mixture containing sunflower oil and triglycerides according to Example 1.9: Sunflower oil was placed in a flask. Miglyol 810 and Miglyol 812 were added under stirring, and the mixture was stirred for a further 10 minutes. [Table 1] [Table 2] [Table 3]

[0160] Sunflower oil, soybean oil, and modified corn oil demonstrate the best voluntary acceptance.

[0161] Example 2 In the following, voluntary acceptance testing of liquid placebo formulations was conducted according to Examples 2.1 to 2.4.

[0162] For the voluntary acceptance trials, eight cats were tested according to the general procedure described above for evaluation over periods of 8, 23, and 28 days (compare Tables 2.a and 2.b). In this regard, please note that the evaluation of the formulation according to Example 2.4 was stopped after 8 days due to poor uptake. A liquid placebo formulation of 0.2 ml / kg body weight (cat body weight) was provided.

[0163] Each result was obtained through the following exemplary procedure. Average values ​​are shown in Tables 2.a and 2.b, and more detailed results for Examples 2.1 to 2.4 are shown in Table 2.c.

[0164] Two test groups were applied, each containing eight cats. In one voluntary acceptance trial phase (23 or 28 days), only one formulation was tested.

[0165] To accustom the cats to the procedure of licking fluids from a bowl, the cats were provided with water and / or milk for 4 days, one animal at a time, to provide baseline phase values. Following the baseline phase, each liquid placebo formulation was tested.

[0166] Test group 1 (cats 18-25) was provided with liquid placebo formulations, Examples 2.1 and 2.2.

[0167] Test group 2 (cats 26-33) was provided with liquid placebo formulations, Examples 2.3 and 2.4.

[0168] Detailed results of the voluntary acceptance program are shown in Table 2.c.

[0169] Preparation of liquid placebo formulations according to Examples 2.1 to 2.4: Examples 2.1 and 2.2: Sunflower oil was placed in a flask. Fish oil was added, and the mixture was heated to 70°C. Butylhydroxytoluene, sorbic acid, and Compritol were added under stirring, and the mixture was stirred for a further 10 minutes, after which the mixture was cooled to room temperature.

[0170] Example 2.3: Miglyol was placed in a flask and heated to 75°C. Butylhydroxytoluene, sorbic acid, and Compritol were added under stirring, and the mixture was stirred for a further 10 minutes, after which the mixture was cooled to room temperature.

[0171] Example 2.4: Water was placed in a flask. Sodium citrate was added to obtain a pH of 8.37, citric acid was added to obtain a pH of 6.03, Solbrol M and Solbrol P were added under stirring, the mixture was heated to 40°C and stirred until the parabens dissolved, and then the mixture was cooled to room temperature. Sorbitol, propylene glycol, vanilla flavor, Tween 20, Tween 80, and Avicel were added under stirring. The final citric acid was added to obtain a pH of 5.52, and the mixture was stirred for a further 10 minutes. [Table 4] [Table 5] [Table 6]

[0172] The best voluntary acceptance is demonstrated by a liquid placebo formulation containing sunflower oil.

[0173] Example 3 In the following, we tested the voluntary acceptance of liquid drug-containing formulations 3.1 to 3.6.

[0174] For the voluntary acceptance trials, eight cats were tested according to the general procedure described above for evaluation over a period of 3 or 7 days. They were provided with a liquid drug formulation at a dose of 0.2 ml / kg body weight (cat body weight). For animal welfare reasons, healthy cats were not provided with the liquid drug formulation over a 28-day period.

[0175] Each result was obtained through the following exemplary procedure. Average values ​​are shown in Tables 3.a and 3.b, and more detailed results for Examples 3.1 and 3.2 are shown in Table 3.c.

[0176] Two test groups were applied, each containing eight cats. In one voluntary acceptance trial phase (3 or 7 days), only one formulation was tested.

[0177] To accustom the cats to the procedure of licking fluids from a bowl, the cats were provided with water and / or milk for 4 days, one animal at a time, to provide baseline phase values. Following the baseline phase, each liquid drug-containing formulation was tested.

[0178] Test group 1 (cats 18-25) was provided with the liquid drug-containing formulation Example 3.1.

[0179] Test group 2 (cats 26-33) was provided with liquid drug-containing formulation Example 3.2.

[0180] Detailed results of the voluntary acceptance program are shown in Table 3.c.

[0181] Accordingly, results for liquid drug-containing formulations were obtained according to Examples 3.3 to 3.6.

[0182] Preparation of liquid drug-containing formulations according to Examples 3.1 to 3.6: Examples 3.1 and 3.4: Sunflower oil was placed in a flask. Fish oil was added, and the mixtures were heated to 70°C (Example 3.1) and 75°C (Example 3.4), respectively. Butylhydroxytoluene, sorbic acid, and Compritol were added under stirring, and the mixtures were stirred for a further 10 minutes, after which the mixtures were cooled to room temperature. Compound A was added under stirring, and the mixtures were stirred for a further 10 minutes.

[0183] Example 3.2: Water was placed in a flask. Sodium citrate was added to obtain a pH of 8.27, citric acid was added to obtain a pH of 6.01, Solbrol M and Solbrol P were added under stirring, the mixture was heated to 40°C and stirred until the parabens dissolved, and then the mixture was cooled to room temperature. Sorbitol, propylene glycol, vanilla flavor, Tween 20, Tween 80, and Avicel were added under stirring. Citric acid was added to obtain a pH of 5.50, and compound A was added. A final amount of citric acid was added to obtain a pH of 5.5.0 again, and the mixture was stirred for a further 10 minutes.

[0184] Example 3.3: Sunflower oil was placed in a flask and heated to 75°C. Sorbic acid, butylhydroxytoluene, and Compritol were added while stirring. After the mixture cooled to room temperature, compound A was added and the mixture was stirred for a further 10 minutes.

[0185] Example 3.5: Miglyol 840 was placed in a flask and heated to 75°C. Sorbic acid, butylhydroxytoluene, and Compritol were added while stirring. The mixture was cooled to room temperature, compound A was added while stirring, and the mixture was stirred for a further 10 minutes.

[0186] Example 3.6: Miglyol 840 was placed in a flask. Fish oil was added, and the mixture was heated to 75°C. Sorbic acid, butylhydroxytoluene, and Compritol were added while stirring. The mixture was cooled to room temperature, compound A was added while stirring, and the mixture was stirred for a further 10 minutes. [Table 7] [Table 8] [Table 9]

[0187] The best voluntary acceptance is demonstrated by a liquid drug-containing formulation containing sunflower oil.

Claims

1. The following ingredients A) At least one drug that is a hypoxia-inducible factor prolyl hydroxylase inhibitor, B) A natural oil derived from at least one herb, wherein the natural oil derived from the herb is sunflower oil. C) At least one natural oil of animal origin, wherein the natural oil of animal origin is fish oil. D) At least one thickening agent, wherein the thickening agent is glyceryl dibehenate. Includes, The hypoxia-inducible factor prolyl hydroxylase inhibitor is a compound of formula (I). 【Chemistry 1】 or its salt, stereoisomer, tautomer, or N-oxide, Liquid drug-containing preparation.

2. The compound of formula (I) is in the form of a salt having formula (II), 【Chemistry 2】 During the ceremony, M is selected from the group consisting of lithium, sodium, potassium, calcium, magnesium, barium, manganese, copper, silver, zinc, iron, ammonium, and substituted ammonium, and 1 to 4 of the hydrogen atoms are C １ ~C ４ Replaced with alkyl, m represents the positive charge of each cation, and is 1, 2, or 3. The liquid drug-containing formulation according to claim 1, wherein n represents the stoichiometric amount of each counteranion and is 1, 2, or 3, and n is equal to m such that the salt having formula (II) is not charged.

3. The liquid drug-containing formulation according to claim 1 or 2, wherein the natural oil derived from at least one herb is modified, and the modification is obtained by alcohol decomposition.

4. The liquid drug-containing formulation according to claim 1 or 2, wherein the fish oil is salmon oil or cod liver oil.

5. E) At least one antioxidant selected from the group consisting of ascorbyl palmitate, butylhydroxytoluene, butylhydroxyanisole, citric acid, lecithin, propyl gallate, tocopherol, and combinations thereof, and / or F) At least one preservative selected from the group consisting of ethanol, propylene glycol, butanol, chlorobutanol, benzoic acid, sorbic acid, para-hydroxybenzoic acid esters, and combinations thereof, and / or G) further comprising at least one surfactant, A liquid drug-containing formulation according to claim 1 or 2.

6. A) A hypoxia-inducible factor prolyl hydroxylase inhibitor in an amount of 0.1 to 20% by weight, B) A natural oil derived from at least one of the above herbs in an amount of 50 to 99.8% by weight, C) A natural oil of at least one animal in an amount of 0.01 to 5% by weight, D) At least one of the thickeners in an amount of 0.1 to 10% by weight, E) At least one antioxidant in an amount of 0.01 to 2% by weight, F) A liquid drug-containing formulation according to claim 5, comprising 0.01 to 2% by weight of at least one preservative.

7. A liquid drug-containing preparation according to any one of claims 1 to 6, for use in the treatment and / or prevention of a disease that is related to the hypoxia-inducible factor prolyl hydroxylase enzyme.

8. The liquid drug-containing formulation for use according to claim 7, wherein the liquid drug-containing formulation can be administered for a period of at least two weeks without causing problems in acceptance or voluntary acceptance.

9. The liquid drug-containing formulation for use according to claim 7 or 8, wherein the liquid drug-containing formulation is administered to cats and dogs.

10. The liquid drug-containing formulation according to claim 2, wherein M is sodium.

11. The liquid drug-containing formulation according to claim 2, wherein m represents the positive charge of each cation and is 1.

12. The liquid drug-containing formulation according to claim 2, wherein n represents the stoichiometric amount of each counter anion and is 1.

13. The liquid drug-containing formulation according to claim 3, wherein the modification is obtained by alcohol decomposition with glycerol, propylene glycol, or low molecular weight polyethylene glycol.

14. A liquid drug-containing formulation according to claim 6, A) Based on the total weight of the liquid drug-containing preparation, 0.5 ～ 10% by weight of a hypoxia-inducible factor prolyl hydroxylase inhibitor, B) Based on the total weight of the liquid drug-containing preparation, 70 ～ 98.97% by weight of natural oil derived from at least one herb, C) Based on the total weight of the liquid drug-containing preparation, 0.01 ～ 1.5% by weight of at least one natural oil of animal origin, D) Based on the total weight of the liquid drug-containing preparation, 0.5 ～ At least one thickening agent in an amount of 5% by weight, E) Based on the total weight of the liquid drug-containing preparation, 0.01 ～ 1. At least one antioxidant in an amount of 1.5% by weight, and F) Based on the total weight of the liquid drug-containing preparation, 0.01 ～ 1. At least one preservative in an amount of 1.5% by weight A liquid drug-containing preparation, including [specific drug].

15. A liquid drug-containing preparation according to any one of claims 1 to 6, for use in the treatment of anemia associated with chronic kidney disease in cats.

16. A liquid drug-containing formulation for use according to claim 9, which is a formulation for administration to cats.

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