Compositions that have improved voluntary acceptance

Abstract

This invention provides a pharmaceutical composition suitable for oral administration of an active substance to animals, and its use. [Solution] A liquid drug-containing formulation is provided, comprising A) at least one drug which is a hypoxia-inducible factor prolyl hydroxylase inhibitor, B) at least one natural oil derived from herbs, C) optionally at least one natural oil derived from animals, and D) optionally at least one thickener. Furthermore, the use of a liquid formulation aid composition is provided, comprising at least one natural oil derived from herbs and / or animals, preferably at least one natural oil derived from herbs, and optionally at least one thickener, in the liquid drug-containing formulation to improve the acceptance or voluntary acceptance of drug ingestion in animals.

Description

[Technical Field]

[0001] The present invention relates to the field of pharmaceutical compositions suitable for oral administration of active substances to animals. The present invention relates to at least one hypoxia-inducible factor prolyl hydroxylase inhibitor. This invention relates to a liquid drug-containing formulation comprising a drug and a natural oil derived from at least one herb. The present invention further provides for improving the acceptance or voluntary acceptance of drug administration in animals. Liquid drug formulation aids containing at least one herb and / or animal-derived natural oil in the liquid drug formulation. Regarding the use of the drug composition.

[0002] Certain diseases require routine and long-term medication in veterinary medicine, which is usually, It needs to be administered at home by an untrained pet owner. This drug is often It is administered orally, and it is especially important in cats and dogs if the product has an undesirable flavor. This is difficult. Animals tend to refuse to take medication. This is a challenge for pet owners. It can be dangerous. Furthermore, complete intake of necessary medications cannot be ensured. These difficulties Furthermore, the situation becomes even more challenging when medication needs to be administered daily over a long period.

[0003] One example of the need for daily long-term administration is the hypoxia-inducible factor prolyl hydroxylase enzyme. The treatment and / or prevention of related diseases, such as cardiovascular disease, heart failure, and anemia. This could be chronic kidney disease or renal failure, particularly anemia associated with chronic kidney disease. For example, WO2 008 / 067871 is a specific substituted dihydropara that is thought to possess the aforementioned activity. Dihydroparazolone is described in WO2012 / 065967. This describes the substituted sodium-1H-pyrazole-5-oleate.

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

[0005] US5756474 is a non-aqueous oral medication for the treatment of parasitic diseases in mammals. Regarding compositions, aqueous formulations are generally disclosed to have a better taste.

[0006] US20120141546 is used to eradicate parasitic protozoa and endoparasites in animals. This relates to an oily preparation for that purpose. The focus is on single-dose administration.

[0007] Therefore, in order to ensure the safety and compliance of individuals receiving drug-containing preparations Therefore, for oral medicines for animals, which have a high acceptance or voluntary acceptance rate for each drug. There is a continuous need for the formulation. In this regard, the object of the present invention is to achieve high acceptance or self The objective of the present invention is to provide a drug-containing formulation that has primary acceptance. Furthermore, the objective of the present invention is to provide an animal The objective of the present invention is to provide convenient drug administration for at least one Improved intake of drug-containing preparations containing hypoxia-inducible factor prolyl hydroxylase inhibitors The objective of the present invention is to provide a solution for improving drug uptake in animals. The objective is to provide a liquid formulation aid composition.

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

[0009] Surprisingly, at least one of these purposes is the liquid drug-containing method according to the present invention. It has been found that it can be achieved by a pharmaceutical preparation and / or a liquid pharmaceutical adjuvant composition.

[0010] In a first aspect, the present invention relates to a liquid pharmaceutical composition containing the following components A) at least one drug which is a hypoxia-inducible factor prolyl hydroxylase inhibitor, B) at least one natural oil derived from herbs, C) optionally, at least one natural oil derived from animals, D) optionally, at least one thickener.

[0011] Hereinafter, preferred embodiments of the components of the above preparation will be described in more detail. It should be understood that each preferred embodiment is relevant in itself and in combination with other preferred embodiments. It is to be understood that each preferred embodiment is relevant in itself and in combination with other preferred embodiments. Desirable.

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

[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) wherein [Chemical formula] wherein M is selected from the group consisting of lithium, sodium, potassium, calcium, magnesium, barium, manganese, copper, silver, zinc, iron, ammonium and substituted ammonium, and One to four of the hydrogen atoms are replaced by C1-C4 alkyl groups, preferably M is na It is thorium, m represents the positive charge of each cation, and is 1, 2, or 3, preferably 1. n represents the stoichiometric amount of each counteranion, and is 1, 2, or 3, preferably. The value is 1, and n is equal to m such that the salt having equation (II) is not charged.

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

[0015] In a preferred embodiment A4 of the first aspect, at least one natural oil derived from herbs is modified. Modified almond oil, modified apricot kernel oil, modified canola oil, modified castor oil, modified coconut oil, modified Cottonseed oil, modified linseed oil, modified grape oil, modified hemp oil, modified corn oil, modified olive oil Oil, modified coconut oil, modified peanut oil, modified sesame oil, modified soybean oil, modified sunflower oil, modified Selected from the group consisting of thistle oil, modified rapeseed oil, modified rice bran oil, and modified wheat germ oil, The properties are preferably glycerol, propylene glycol, or low molecular weight polyethylene glycol. It is obtained by the decomposition of alcohol by a fertilizer.

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

[0017] In a preferred embodiment A6 of the first aspect, at least one natural oil derived from herbs is used. It is either sorghum oil or sunflower oil, and contains at least one natural oil of animal origin, which is fish. It is oil.

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

[0019] In a preferred embodiment A8 of the first aspect, there is at least one thickening agent, which is, It is a glycerol ester, preferably C 12 ~C 24 Glycerol containing fatty acids It is a ster, and / or a monoester, diester, triester, or a mixture thereof. It is an object.

[0020] In a preferred embodiment A9 of the first aspect, there is at least one thickening agent, which is, It is glycerol dibehenate.

[0021] In a preferred embodiment A10 of the first aspect, the liquid drug-containing formulation as defined herein is ,component E) Ascorbyl palmitate, butylhydroxytoluene, butylhydroxyanisole , citric acid, lecithin, propyl gallate, tocopherol, and their antioxidants At least one antioxidant selected from the group consisting of combinations, and / or F) Ethanol, propylene glycol, butanol, chlorobutanol, benzoic acid, so From rubic acid, para-hydroxybenzoic acid esters, and / or combinations thereof At least one preservative selected from the group, 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, 0.1 to 20% by weight, preferably 0.5 to 1 0% by weight of a hypoxia-inducible factor prolyl hydroxylase inhibitor, B) Based on the total weight of the liquid drug-containing formulation, 50-99.8% by weight, preferably 70-9%. 8.97% by weight of natural oil derived from at least one herb, C) Optionally, based on the total weight of the liquid drug-containing preparation, 0.01 to 5% by weight, preferably This includes 0.01 to 1.5% by weight of at least one natural oil of animal origin. D) Optionally, based on the total weight of the liquid drug-containing preparation, 0.1 to 10% by weight, preferably This includes at least one thickening agent in an amount of 0.5 to 5% by weight. E) Optionally, based on the total weight of the liquid drug-containing preparation, 0.01 to 2% by weight, preferably This includes at least one antioxidant in an amount of 0.01 to 1.5% by weight, and F) Optionally, based on the total weight of the liquid drug-containing preparation, 0.01 to 2% by weight, preferably It contains at least one preservative in an amount of 0.01 to 1.5% by weight.

[0023] In a second aspect, the present invention is for use in the treatment of anemia particularly associated with chronic kidney disease, Diseases related to the hypoxia-inducible factor prolyl hydroxylase enzyme, preferably, The disease in question is a cardiovascular disease, heart failure, anemia, chronic kidney disease, or kidney failure, and the treatment of the disease. This relates to formulations containing liquid drugs as defined herein, for use in and / or prevention.

[0024] In the preferred embodiment B1 of the second aspect, the liquid drug-containing preparation is accepted or voluntarily accepted It can be administered for at least two weeks without causing any problems.

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

[0026] In a third aspect, the present invention improves the acceptance or voluntary acceptance of drug ingestion in animals. To do so, at least one natural oil of herb and / or animal origin, preferably at least A liquid drug containing a natural oil derived from one herb, and optionally, at least one thickening agent. This invention relates to the use of liquid formulation aid compositions contained in formulations. Preferably, the present invention relates to a third aspect. According to this, in order to improve the acceptance or voluntary acceptance of drug administration in animals, at least A liquid drug-containing natural oil derived from one herb, and optionally, at least one thickening agent. This relates to the use of liquid formulation aid compositions contained in a drug.

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

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

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

[0030] In a preferred embodiment C4 of the third aspect, at least one natural oil derived from herbs is included. This is 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, goat oil A group consisting of sesame oil, soybean oil, sunflower oil, thistle oil, rapeseed oil, rice bran oil, and wheat germ oil. The oil is selected from among and is preferably soybean oil or sunflower oil.

[0031] In a preferred embodiment C5 of the third aspect, at least one natural oil derived from herbs is modified. Modified almond oil, modified apricot kernel oil, modified canola oil, modified castor oil, modified coconut oil, modified Cottonseed oil, modified linseed oil, modified grape oil, modified hemp oil, modified corn oil, modified olive oil Oil, modified coconut oil, modified peanut oil, modified sesame oil, modified soybean oil, modified sunflower oil, modified Selected from the group consisting of thistle oil, modified rapeseed oil, modified rice bran oil, and modified wheat germ oil, The oil is modified corn oil, and the modification is preferably glycerol, propylene glycol It is obtained by alcohol decomposition with coal 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 movable It contains natural oils derived from substances, which are preferably selected from the group consisting of fish oil and salmon oil, It is fish oil.

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

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

[0035] In a preferred embodiment C9 of the third aspect, the liquid formulation aid composition is Ascorbyl palmitate, butylhydroxytoluene, butylhydroxyanisole, A combination of citric acid, lecithin, propyl gallate, tocopherol, and their antioxidants. At least one antioxidant selected from the group consisting of combinations, and / or Ethanol, propylene glycol, butanol, chlorobutanol, benzoic acid, sorbitan Consists of benzoic acid, para-hydroxybenzoic acid esters, and / or combinations thereof. At least one preservative selected from the group, 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 used. Based on the total weight of the liquid formulation additive composition, at least 90% by weight of the liquid formulation additive composition It exists within an object. [Modes for carrying out the invention]

[0037] Before describing exemplary embodiments of the present invention in detail, we must first define some important definitions necessary for understanding the invention. Give.

[0038] As used herein and in the appended claims, the singular forms of "a" and "an" are , including their plural forms unless the context explicitly indicates otherwise. In the context of this invention The terms "about" and "approximately" are used to still ensure the technical effect of the characteristics of the problem. Therefore, it indicates an accuracy interval that a person skilled in the art would understand. This term typically refers to ±20 The indicated percentages are preferably ±15%, more preferably ±10%, and even more preferably ±5%. This indicates a deviation from the specified value. Please understand that the term "includes" is not limited. For the purpose of the invention, the term "consisting of" is not used. This is considered a preferred embodiment of the term "comprising of". If a group is defined below as including at least a certain number of embodiments, then this is Furthermore, it preferably means to include only these embodiments. The terms “first,” “second,” “third,” or “(a)” in the description and claims, Terms such as "(b)", "(c)", and "(d)" are used to distinguish similar elements. It is not necessarily used to describe order or chronological order. The terms used are interchangeable under appropriate circumstances, and the embodiments of the present invention described herein are, Please understand that the components can be operated in an order other than that described or illustrated in this specification. "of", "second of", "third of", or "(a)", "(b)", "(c)", "(d)" When terms such as "i" and "ii" relate to a method, use, or assay step, There is no consistency in time or time intervals between steps; that is, the steps are performed simultaneously. Alternatively, or otherwise indicated in the application described above or below in this specification. Unless otherwise indicated, such steps are not measured in seconds, minutes, hours, days, weeks, months, or even years. Intervals may exist. The present invention relates to specific methodologies, protocols, and reagents described herein. Please understand that this is not limited to these, as these can change. The terminology used in this document is solely for the purpose of describing specific embodiments, and the attached claims It is not intended to limit the scope of the present invention, which would be limited only by the range of the present invention. Please also understand that, unless otherwise defined, all technical terms and scientific terms used herein refer to all technical and scientific terms. The terms have the same meaning as those generally understood by those skilled in the art.

[0039] The term "compound of formula (I)" refers to the compound as defined herein, as well as its stereoisomers. Includes derivatives, 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 relates to a single pure enantiomer or pure diastere of the compound according to the present invention. Both omers and mixtures thereof, as well as pure enantiomers of the compounds according to the present invention. Alternatively, the present invention provides for the use of pure diastereomers or mixtures thereof. Suitable compounds according to the present invention include all possible geometric stereoisomers (cis / trans isomers). This also includes isomers (or E / Z isomers) and mixtures thereof. Cis / trans isomers are, for example, , may exist with respect to the amide group. The term "stereoisomer" is used for enantiomers or dia. It encompasses both optical isomers such as stereomers, and the latter has one chiral center within the molecule. It exists to exceed one isomer, and similarly includes geometric isomers (cis / trans isomers). The clearing is that all possible stereoisomers of the compound of formula (I), i.e., a single enantiomer, The invention relates to diastereomers, or mixtures thereof.

[0041] In the meaning of this invention, terms such as "active substance," "activator," and "drug" refer to any pharmaceutical... This refers to any suitable activator in a chemically and morphologically acceptable form, as well as in a physical state. .

[0042] The compound of formula (I) may be amorphous or may have different macroscopic properties such as stability. It may be possible, or one or more different crystalline states that can exhibit different biological properties such as activity. The present invention relates to amorphous and crystalline compounds of formula (I), and the same of formula (I). This invention relates to mixtures of compounds in different crystalline states, as well as their amorphous or crystalline salts.

[0043] Salts of the compound of formula (I) are listed in the U.S. FDA Orange Book database as drugs. It may also be a pharmaceutically acceptable salt, such as one containing counterions present in the product. These are, for example, when the compound of formula (I) has a basic functional group, the acid of the anion in question and By reacting the compounds, or by reacting the acidic compound according to the present invention with a suitable base It can be formed in a conventional manner by doing so.

[0044] Suitable cationic counterions include alkali metals, preferably lithium and sodium. and potassium ions, alkaline earth metals, preferably calcium, magnesium and b Ions of lium, and transition metals, preferably aluminum, manganese, copper, silver, zinc, and Iron ions, and ammonium (NH4) + ), and 1 to 4 of the hydrogen atoms are C1 ~C4-alkyl, C1~C4-hydroxyalkyl, C1~C4-alkoxy, (C1 ~C4-alkoxy)-(C1~C4-alkyl), hydroxy-(C1~C4-alkoxy) The position is replaced by xy)-(C1~C4-alkyl), phenyl, or benzyl. It is a substituted ammonium ion. An example of a substituted ammonium ion is methylammonium. Isopropylammonium, dimethylammonium, diisopropylammonium, tri Methylammonium, tetramethylammonium, tetraethylammonium, tetrab Tylammonium, 2-hydroxyethylammonium, 2-(2-hydroxyethoxy ) Ethyl-ammonium, bis(2-hydroxyethyl)ammonium, benzyl trim It contains ammonium trimethylammonium and benzyltriethylammonium, and further, 1,4-piper It contains cations of din, meglumine, benzathine, and lysine. Preferred cations are lysine. Thium, sodium, potassium, calcium, magnesium, barium, manganese, copper, Silver, zinc, iron, ammonium, and 1 to 4 of the hydrogen atoms are converted to C1-C4 alkyl groups. Therefore, the substituted ammonium compounds are, in particular, sodium.

[0045] Suitable anionic counterions include, in particular, chlorides, bromides, bisulfates, sulfates, and diphosphates. Hydrogen salts, hydrogen phosphates, phosphates, nitrates, bicarbonates, carbonates, hexafluorosilicates , hexafluorophosphate, benzoate, and C1-C4-alkanoic acid, preferably glycan Salts, acetates, trifluoroacetates, propionates, and butyrates, as well as lactates, gluten Conate anions, as well as succinates, oxalates, maleates, fumarates, and phosphorus. Polyacid anions such as cecalates, tartrates, and citrates, as well as sulfonates and besyl Salts (benzenesulfonate), tosylates (p-toluenesulfonate), napsylic acid Salt (naphthalene-2-sulfonate), mesylate (methanesulfonate), esylate It is the sulfonate anion of (ethanesulfonate) and ethanedisulfonate. They react the compound according to the present invention, which has a basic functional group, with the acid of the corresponding anion. It can be formed by the following. The 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, thereby keto - This enables the formation of tautomers such as enol tautomers.

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

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

[0049] As used herein and in the appended claims, the term “acceptance” means “animal This refers to "forced administration" or "forced induction of a drug," in which the drug is administered directly into the animal's mouth. The animal is not reacting violently (e.g., biting) or causing harm. Please understand that if the patient is experiencing symptoms such as convulsions, the administration of the medication may be acceptable.

[0050] As used herein and in the appended claims, the term “voluntary acceptance” is used in this specification. This refers to the voluntary oral administration of the preparation by animals. The preparation is administered in a bowl, and the animals voluntarily and voluntarily take it. Voluntary intake is evaluated over a maximum serving time of 3 minutes. Generally, voluntary acceptance in animals This evaluation procedure can be evaluated as follows: The test samples are offered daily in a food bowl for 3 minutes. Voluntary intake of different formulations is visually analyzed. Evaluated and recorded using a logarithmic scale (VAS), where 0 (cm) represents the worst possible voluntary intake. The indicated measurement is 10 cm, which represents the best possible voluntary intake.

number

[0051] In the worst-case scenario of possible intake (0 cm), the animals show no interest and do not ingest the test sample. In the case of a suitable intake (10 cm), the animal will completely ingest the test sample.

[0052] The evaluator places vertical marks on the line based on the animal's behavior (e.g., not ingesting). (Show interest, smell the test product, partially consume the test formulation, request more). All voluntary intake assessments for each day are conducted by the same individual.

[0053] Liquid drug-containing formulations according to the present invention, and the liquid drug in the treatment and / or prevention of disease Preferred embodiments relating to the use of the substance-containing formulation are described below. Preferred embodiment of the present invention It should be understood that these states are preferable individually or in combination with each other. Furthermore, in animals Liquid formulation aid composition according to the present invention for improving the acceptance or voluntary acceptance of drug intake. Preferred embodiments for the use of 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 Defined below.

[0056] According to the present invention, a liquid drug-containing formulation inhibits the hypoxia-inducible factor prolyl hydroxylase inhibitor. It contains at least one drug that is a harmful agent (also known as HIF-PHI). The inhibitor is prolyl, which causes the breakdown of hypoxia-inducible factor (HIF) in normal oxygen conditions. It is a member of a class of drugs that act by inhibiting hydroxylase. These inhibitors are associated with diseases such as anemia, chronic kidney disease, and cancer. Examples of droxylase inhibitors include daprodustat, moridustat, and roxadusta. These are desidustat, badadustad, and desidustad. However, in one embodiment of the present invention, hypoxia-inducible factor (HIF) prolyl hydroxylase The inhibitors are daprodostat, moridustat, roxadustat, and vadadustat. A selection is made from the group consisting of t and decidustat, and is particularly molydustat.

[0057] Preferably, the liquid drug-containing formulation according to the present invention is based on the total weight of the liquid drug-containing formulation. 0.1 to 20% by weight, more preferably 0.5 to 10% by weight, even more preferably 1 to 8% by weight Contains a hypoxia-inducible factor prolyl hydroxylase inhibitor in an amount of % by weight, particularly 1-5% by weight. nothing.

[0058] In one embodiment of the present invention, the HIF prolyl hydroxylase inhibitor is a compound of formula (I) thing [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 salt having formula (II) It is a compound of the form of formula (I), [ka] During the ceremony, M stands for lithium, sodium, potassium, calcium, magnesium, barium, manganese. Selected from the group consisting of ammonium, copper, silver, zinc, iron, ammonium, and substituted ammonium, One to four of the hydrogen atoms are replaced by C1-C4 alkyl groups, preferably M is na It is thorium, m represents the positive charge of each cation, and is 1, 2, or 3, preferably 1. n represents the stoichiometric amount of each counteranion, and is 1, 2, or 3, preferably. The value is 1, and n is equal to m such that the salt having equation (II) is not charged.

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

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

[0062] According to the present invention, the liquid drug-containing formulation contains at least one natural oil derived from herbs. According to the meaning of this invention, the term "herb" is interchangeable with "plant-based". Please understand. Preferably, the liquid drug-containing formulation is based on the total weight of the liquid drug-containing formulation. At least 50% by weight, preferably 50-99.8% by weight, more preferably 70-98% by weight. At least one herb in an amount of 97% by weight, more preferably 80-98.9% by weight Contains natural oils.

[0063] In one embodiment of the present invention, the natural oil derived from at least one herb is almond oil, apricot oil. Seed 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, It is selected from the group consisting of 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 are at least 5 based on the total amount of fatty acids in the natural oils derived from the herbs. It contains, preferably at least 8% by weight, unsaturated fatty acids. Generally, it is derived from herbs. Natural oils are produced by mechanical pressing or by extraction of each herb (for example, sunflower oil). Helianthus annuus, followed by any purification This can be obtained. 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, is produced by pressing or extracting, followed by optional refining. It can be obtained from the seeds of Zea mays L. Preferably, corn oil This is based on the total amount of fatty acids, with 8.6-16.5% by weight of palmitic acid, up to a maximum of 3.3 by weight. % stearic acid, 20-42.2% by weight oleic acid, 39.4-65.6% by weight Nolic acid, 0.5-1.5% by weight of arachidic acid, up to 0.5% by weight of eicosenoic acid, and It contains up to 0.5% by weight of behenic acid.

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

[0068] Thistle oil, also known as safflower oil, is extracted by pressing and / or extraction, followed by any extraction. Depending on the preparation, the seeds may be those of Carthamus tinctorius L. (Type I), or C It can be obtained from the hybrid seeds of arthamus tinctorius L. (Type II). Preferably, the thistle oil obtained from the Type I fraction is, based on the total amount of fatty acids, up to 0 0.2% by weight of saturated fatty acids with chain length less than C14, up to 0.2% by weight of myristic acid, 4-1 0% by weight palmitic acid, 1-5% by weight stearic acid, 8-21% by weight 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 linoleic acid The lacidic acid contains up to 0.5% by weight of eicosenoic acid and up to 1% by weight of behenic acid. Furthermore, thistle oil obtained from the Type II fraction is up to 0.2 times the total amount of fatty acids. Amount % of saturated fatty acids with chain lengths less than C14, up to 0.2 wt% myristic acid, 3.6-6 Palmitic acid by weight, 1-5% by weight stearic acid, 70-84% by weight oleic acid, 7-23% by weight linoleic acid, up to 0.5% by weight linolenic acid, up to 1% by weight arachid It contains eicosenoic acid, up to 1% by weight, and behenic acid, up to 1.2% by weight.

[0069] Generally, the natural oils derived from herbs according to the present invention are extracted and / or pressed, followed by any refining. Please understand what can be obtained from each herb.

[0070] According to the present invention, natural oils derived from herbs are known in the art as defined above. , which may be any suitable natural oil derived from herbs that can be obtained as described above. It should be understood that. In one embodiment of the present invention, these natural oils derived from herbs are additional can be modified.

[0071] In one embodiment of the present invention, at least one natural oil derived from herbs is modified almond oil , modified apricot kernel oil, modified canola oil, modified castor oil, modified coconut oil, modified cottonseed oil, modified linseed oil, modified grape 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 CH2) OH, where 2- CH2) n- OH, and 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 triglyceride reacts with an alcohol such as methanol or ethanol to obtain a methyl or ethyl ester of a fatty acid. 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. After the alcoholysis reaction, preferably, a dewaxing process for removing certain saturated mono-, di-, and triglycerides follows.

[0073] ​​

[0074] Maisine(registered trademark) CC is named as an exemplary modified corn oil. This can be done. This involves the alcohol decomposition of corn oil, and the subsequent decomposition of corn oil. It is obtained by wax. The products include mono, di, and triglycerides, and monoesters. The fraction contains 32-52% by weight, based on the total amount of mono, di, and triglycerides. The ester fraction contains 40-60% by weight, and the triester fraction contains 5-20% by weight. ru.

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

[0076] According to one particular embodiment, the formulation or composition described herein is sunflower oil It contains.

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

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

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

[0080] According to one embodiment of the present invention, a liquid drug-containing formulation is a natural drug derived from at least one animal. It further contains oil. Preferably, the liquid drug-containing formulation is based on the total weight of the liquid drug-containing formulation. 0.01 to 5% by weight, more preferably 0.01 to 2.5% by weight, even more preferably 0 0.01-1.5% by weight, especially 0.01-1% by weight, of at least one natural oil of animal origin include.

[0081] According to the present invention, natural oils of animal origin are any suitable animal-derived oils known in the art. It may be a natural oil, for example, fish oil, especially cod liver oil, and salmon oil. Please understand. According to the present invention, natural oils of animal origin are obtained from natural products. An exemplary description of natural oils of animal origin according to the present invention is given.

[0082] Fish oil is produced by Engraulidae, Carangidae, Clupeidae, and Os. Meridae, Scombridae (excluding the genera Thunnus and Sarda), and from fish of Ammodytidae (Type I), or Scombridae (Type II) It may be obtained from the genera Thunnus and Sarda. Fish oil is alpha-linolenic acid. Acid (C18:3 n-3), molocinic acid (C18:4 n-3), eicosatetraene Acid (C20:4 n-3), timnodonic acid (eicosapentaenoic acid) (C20:5 n -3;EPA), heneicosapentaenoic acid (C21:5 n-3), culpanodonic acid (C 22:5 n-3), and cervic acid (docosahexaenoic acid) (C22:6 n-3;D It may contain omega-3 acids such as HA. Preferably, the fish oil obtained from type I contains at least In total, it contains 28% by weight of omega-3 acids expressed as triglycerides. In particular, type I or The fish oil obtained contains at least 13% by weight of EPA, expressed as triglycerides, and It contains at least 9% by weight of DHA. Preferably, the fish oil obtained from type II is at least In total, it contains 28% by weight of omega-3 acids expressed as triglycerides. In particular, II The fish oil obtained from the mold contains 4-12% by weight of EPA, expressed as triglycerides, and a small amount It contains at least 20% by weight of DHA.

[0083] Cod liver oil is derived from cod, Gadus morhua L., and other species of Gadidae. It can be obtained from fresh liver, and solid matter is removed by cooling and filtration. Cod liver oil is , alpha-linolenic acid (C18:3 n-3), molocinic acid (C18:4 n-3) , eicosatetraenoic acid (C20:4 n-3), timnodonic acid (eicosapentaene Acid (C20:5 n-3; EPA), Heneicosapentaenoic acid (C21:5 n-3) , crupanodonic acid (C22:5 n-3), and cervonic acid (docosahexaenoic acid) (C It may contain omega-3 acids such as 22:6 n-3 (DHA). Preferably, cod liver oil is It contains 10-28% by weight of EPA and DHA, expressed as ligcerides. Cod liver oil is Based on the total amount of fatty acids, it may further contain 3-11% by weight of linoleic acid.

[0084] Salmon oil can be obtained from Salmo salar. Positional distribution (β(2)-Ash (L) contains 60-7% cerubonic acid (docosahexaenoic acid) (C22:6 n-3; DHA). 0%, timnodonic acid (eicosapentaenoic acid) (C20:5 n-3; EPA) is 25% ~35%, and molocinic acid (C18:4 n-3) is 40-55%. Preferably, Ke 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 fish oil. Selected from the group consisting of and salmon oil.

[0086] In one embodiment of the present invention, at least one natural oil derived from herbs is soybean oil or castor oil. It is a type of oil, and contains at least one natural oil of animal origin, which is fish oil. In a preferred embodiment of the present invention, the natural oil derived from at least one herb is sunflower oil. There is at least one natural oil of animal origin, which is fish oil.

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

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

[0089] Suitable cellulose derivatives as thickeners include, for example, methylcellulose and hydroxypropylcellulose. Pyrylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, Carboxymethylcellulose, microcrystalline cellulose, bentonite, kaolin, pectin, Starch, modified starch, wax, agar, paraffin, gelatin, alginate, po Livinylpyrrolidone, crospovidone, cetyl alcohol, stearate, for example, Magnesium stearate, zinc stearate, or glyceryl stearate, saturated or unsaturated Saturated long-chain fatty acids (C8-C24), high molecular weight polyethylene glycol (e.g., polyethylene Examples include 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 mono It is an ester, diester, triester, or a mixture thereof.

[0091] In a preferred embodiment of the present invention, at least one thickening agent is glycerol dibehenate. It is. Glycerol dibehenate is also called glyceryl dibehenate or glycerin di It may be known under Behenet.

[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 is based on the total weight of the liquid drug-containing formulation, with a concentration of 0.01 to At least one antioxidant in an amount of 2% by weight, preferably 0.01 to 1.5% by weight, and / Alternatively, based on the total weight of the liquid drug-containing preparation, 0.01 to 2% by weight, preferably 0.01 to Based on the total weight of the liquid drug-containing preparation containing at least one preservative in an amount of 1.5% by weight. Therefore, at least 1 in an amount of 0.001 to 1% by weight, preferably 0.01 to 0.3% by weight. Contains two surfactants.

[0094] Suitable antioxidants include ascorbyl palmitate, butylhydroxytoluene, and Tylhydroxyanisole, lecithin, sulfites (sodium sulfite, sodium metabisulfite) (Lium), organic sulfides (cystine, cysteine, cysteamine, methionine, thioglycerides) (Lol, thioglycolic acid, thiolactic acid), phenol (tocopherol, and vitamins) E and Vitamin E DPGS (d-alpha-tocopheryl polyethylene glycol 10 00 succinate, butylated hydroxyanisole, butylated hydroxytoluene, ammonium Food acid (propyl, octyl, propyl gallate, and dodecyl gallate), organic acid (A Examples include scorbic acid, citric acid, tartaric acid, lactic acid, and their salts and esters. Preferably, the antioxidants are ascorbyl palmitate and butylhydroxytoluene. , butylhydroxyanisole, citric acid, lecithin, propyl gallate, and tocopherol It can be selected from a group consisting of rolls.

[0095] Suitable preservatives include carboxylic acids (sorbic acid, propionic acid, benzoic acid, lactic acid), and Enol (cresol, p-hydroxybenzoic acid ester, e.g., methylparaben, p) (e.g., parabens), fatty alcohols (benzyl alcohol, ethanol, butanol) Examples include quaternary ammonium compounds (benzalkonium chloride, cetylpyridinium chloride). It may be possible. Preferably, the preservative is ethanol, propylene glycol, butanol, From chlorobutanol, benzoic acid, sorbic acid, and para-hydroxybenzoic acid esters It can be selected from the following group. In this regard, methyl 4-hydroxybenzoic acid, ethyl 4- Hydroxybenzoic acid and propyl 4-hydroxybenzoate are preferred para-hydroxybenzoic acid. It may also be named as a benzoic acid ester.

[0096] Suitable surfactants are amphiphilic compounds. Mono, di, sorbitan having fatty acids. Alternatively, polyoxyethyl esters such as triesters and polyoxyethylene sorbitan fatty acid esters. Examples include chemical compounds, polyoxyethylene castor oil derivatives, and poloxamers. Polyoxyethylated compounds, also called polyethoxylated compounds, are examples of ethylene ethyl They are prepared by reaction with oxides. They are of the formula -[O-CH 2- CH2]- one or more It has the linked units shown above. Polyoxyethylated compounds that can be specifically mentioned are nonionic. It is a sexually amphiphilic polyoxyethylated compound, for example, - Preferably a molar mass of 100 to 5000 g / mol, particularly preferably 1000 to 3500 Poloxamer has a molar mass of g / mol. Poloxamer is composed of ethylene oxide and methyl This is the international generic name for the block copolymer with luoxirane. -Polyoxyethylene fatty acid glycerides, also known as nonionic emulsifiers, preferably, e.g. For example, glycerol polyethylene glycol ricinoleate, -Polyoxyethylene sorbitan fatty acid ester, preferably, for example, polyoxyethylene Ren20 sorbitan monooleate, -Polyoxyethylene fatty acids such as macrogol-15 hydroxystearate (=Solu tol HS15, 15 mol ethylene oxide and 1 mol 12-hydroxystearate (Obtained by reacting with phosphoric acid), -Polyoxyethylene aliphatic alcohols such as hydroxypolyethoxide dodecane.

[0097] Fatty acids or fatty alcohols, in particular, have at least 6 carbon atoms and usually 30 or fewer. This represents the corresponding compound having a carbon atom.

[0098] According to one embodiment of the present invention, a liquid drug-containing formulation comprises the following components E) Ascorbyl palmitate, butylhydroxytoluene, butylhydroxyanisole , citric acid, lecithin, propyl gallate, tocopherol, and their antioxidants At least one antioxidant selected from the group consisting of combinations, and / or F) Ethanol, propylene glycol, butanol, chlorobutanol, benzoic acid, so From rubic acid, para-hydroxybenzoic acid esters, and / or combinations thereof At least one preservative selected from the group, 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, 0.1 to 20% by weight, preferably 0.5 to 1 0% by weight of a hypoxia-inducible factor prolyl hydroxylase inhibitor, B) Based on the total weight of the liquid drug-containing formulation, 50-99.8% by weight, preferably 70-9%. 8.97% by weight of natural oil derived from at least one herb, C) Optionally, based on the total weight of the liquid drug-containing preparation, 0.01 to 5% by weight, preferably This includes 0.01 to 1.5% by weight of at least one natural oil of animal origin. D) Optionally, based on the total weight of the liquid drug-containing preparation, 0.1 to 10% by weight, preferably This includes at least one thickening agent in an amount of 0.5 to 5% by weight. E) Optionally, based on the total weight of the liquid drug-containing preparation, 0.01 to 2% by weight, preferably This includes at least one antioxidant in an amount of 0.01 to 1.5% by weight, and F) Optionally, based on the total weight of the liquid drug-containing preparation, 0.01 to 2% by weight, preferably It contains at least one preservative in an amount of 0.01 to 1.5% by weight.

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

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

[0102] According to one embodiment, the present invention relates to the treatment of chronic illness in animals, preferably cats and dogs, and particularly cats. For the control (or management) of secondary non-regenerative anemia resulting from nephropathy, as defined herein Regarding liquid drug-containing preparations.

[0103] According to one embodiment of the present invention, a liquid drug-containing formulation addresses the issue of acceptance or voluntary acceptance. It can be administered for at least one week without causing any adverse reactions.

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

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

[0106] According to one embodiment of the present invention, a liquid drug-containing formulation addresses the issue of acceptance or voluntary acceptance. It can be administered to cats for at least two weeks without causing any adverse reactions. According to a specific embodiment of the present invention, a liquid drug-containing formulation may cause problems with voluntary acceptance. In any case, it can be administered to cats for a period of at least 4 weeks.

[0107] According to another embodiment of the present invention, a liquid drug-containing formulation causes the problem of voluntary acceptance. Administer to dogs for at least two weeks, and especially at least four weeks, without interruption. It is possible.

[0108] According to the present invention, a liquid drug-containing formulation as defined herein is administered orally to an animal. Please understand this.

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

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

[0111] As described above, the present invention further provides for improving the acceptance or voluntary acceptance of drug intake, This relates to the use of a liquid pharmaceutical additive composition containing at least one natural oil of animal origin.

[0112] In one embodiment of the present invention, the liquid formulation aid composition is a natural compound derived from at least one herb. It contains oil and at least one natural oil of animal origin.

[0113] In one embodiment of the present invention, a liquid drug-containing formulation is based on the total weight of the liquid drug-containing formulation. , at least 20% by weight, preferably at least 40% by weight, more preferably at least 50% by weight, more preferably at least 70% by weight, and especially at least 80% by weight It contains a liquid formulation aid composition.

[0114] In one embodiment of the present invention, acceptance or voluntary acceptance of drug administration is performed by cats and dogs, and is preferred Or, it is improved in cats.

[0115] In one embodiment of the present invention, acceptance or voluntary acceptance of drug use lasts for at least one week. Improvement is observed throughout the duration of treatment.

[0116] In one embodiment of the present invention, acceptance or voluntary acceptance of drug administration lasts for at least two weeks. Improvement is observed throughout the duration of treatment.

[0117] In certain embodiments of the present invention, acceptance or voluntary acceptance of drug intake lasts for at least 4 weeks. Improvement is observed over the intervening treatment period.

[0118] At least one natural oil derived from herbs contained in the liquid formulation aid composition is more detailed than described above. Please understand that it is defined as outlined in detail.

[0119] One embodiment of the present invention includes a natural oil derived from at least one herb, which is a Almond oil, apricot kernel oil, canola oil, castor oil, coconut oil, cottonseed oil, linseed oil, bud Cow oil, hemp oil, corn oil, olive oil, coconut oil, peanut oil, sesame oil, soybean oil, hi Selected from the group consisting of castor oil, safflower oil, rapeseed oil, rice bran oil, and wheat germ oil, preferably is soybean oil or sunflower oil.

[0120] According to the present invention, the natural herb-derived oil contained in the liquid formulation adjuvant composition is known in the art as defined above and can be any suitable natural herb-derived oil that can be obtained as described above. It should be understood that these natural herb-derived oils can be additionally modified. In another embodiment of the present invention, at least one natural herb-derived oil is included, which is modified almond oil, modified apricot kernel oil, modified canola oil, modified castor oil, modified coconut oil,

[0121] modified cottonseed oil, modified linseed oil, modified grape 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, selected from the group consisting of preferably modified corn oil, and the modification is preferably obtained by alcoholysis with glycerol, propylene glycol, or low molecular weight polyethylene glycol. In a specific embodiment of the present invention, at least one natural herb-derived oil is included, which is selected from the group consisting of sesame oil, soybean oil, sunflower oil, safflower oil, and modified corn oil, and the modification is preferably obtained by alcoholysis with glycerol, propylene glycol, or low molecular weight polyethylene glycol.

[0122] In one embodiment of the present invention, the liquid formulation adjuvant composition comprises at least one natural animal-derived oil selected from the group consisting of and the modification is preferably obtained by alcoholysis with glycerol, propylene glycol, or low molecular weight polyethylene glycol.

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

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

[0125] In one embodiment of the present invention, at least one thickener is preferably present in the liquid formulation aid composition which is glycerol dibehenate.

[0126] In one embodiment of the present invention, the liquid formulation aid composition is ascorbyl palmitate, butylated hydroxytoluene, butylated hydroxyanisole, citric acid, lecithin, propyl gallate, tocopherol, and at least one antioxidant selected from the group consisting of combinations of these antioxidants, and / or ethanol, propylene glycol, butanol, chlorobutanol, benzoic acid, sorbic acid, para-hydroxybenzoic acid ester, and / or at least one preservative selected from the group consisting of combinations thereof, and / or

[0127] optionally further comprising at least one surfactant. In one embodiment of the present invention, at least one herb-derived natural oil is 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, particularly at least

[0128] It is present in the liquid pharmaceutical additive composition in an amount of at least 95% by weight.

[0128] In another embodiment of the present invention, at least one animal-derived natural oil is used in the composition of a liquid formulation aid. Based on the total weight of the object, at least 50% by weight, preferably at least 70% by weight, more Preferably at least 90% by weight, more preferably at least 93% by weight, especially less It is present in the liquid pharmaceutical additive composition in an amount of at least 95% by weight.

[0129] A liquid formulation additive composition may contain at least one natural oil of animal origin, at least one One thickener, at least one antioxidant, at least one preservative, and at least one It is further understood that the two surfactants are defined as outlined in more detail above. stomach.

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

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

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

[0133] Materials used Compritol(registered trademark) 888ATO was purchased from Gattefosse. It is glyceryl dibehenate. Glycerol is esterified with behenic acid (C22 fatty acid). The product is obtained by subsequently spraying. The product is mono, di, and triglycerides of behenic acid. It contains reserid, and the diester fraction is contained at 40 - 60% by weight.

[0134] Maisine® CC was purchased from Gattefosse and is a modified corn oil. It is obtained by the alcoholysis of corn oil and subsequent dewaxing. The product contains mono, di, and triglycerides. The monoester fraction is contained at 32 - 5 2% by weight, the diester fraction is contained at 40 - 60% by weight, and the triester fraction is contained at 5 - 20% by weight.

[0135] More specifically, Maisine® CC mainly consists of mono, di, and triglycerides of linoleic acid (C18:2) and oleic acid (C18:1), and the diester fraction is the main one.

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

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

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

[0139] Miglyol(registered trademark) 840 was purchased from IOI Oleo GmbH and is a captive-grade product. Glycol monoester of lylic acid (C8H16O2) and capric acid (C10H20O2) It is a mixture of esters and diesters, with the diester fraction being the main 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 synthesized according to the synthesis disclosed in WO2013 / 167552A1, for example. It can be set, and sodium 1-[6-(morpholine-4-I) having formula (IIa) [Pyrimidine-4-yl]-4-(1H-1,2,3-triazole-1-yl)-1 It is H-pyrazole-5-oleate. [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 monitored visually. Evaluate and record using a logarithmic scale (VAS), where 0 (cm) represents the worst possible voluntary intake. This indicates that 10 cm represents the best possible voluntary intake.

number

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

[0150] The evaluators placed vertical marks on the line based on the cat's behavior (e.g., did not ingest). (Show interest, smell the test product, partially consume the test formulation, request more). All voluntary intake evaluations were conducted by the same individual.

[0151] Example 1 In the following, several natural oils derived from herbs and animals (Examples 1.1 to 1.8) were used. The primary acceptance was tested. Furthermore, a mixture of natural oils derived from herbs and triglycerides (Examples) We tested the voluntary acceptance described in 1.9).

[0152] For voluntary acceptance tests, the above general criteria apply to evaluations conducted over a period of 4 or 7 days. Eight cats were tested according to the procedure (compare Tables 1.a and 1.b). Each cat received 0.5 ml They provided each of the oils.

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

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

[0155] To get a cat used to the procedure of licking liquid from a bowl, give the cat three days, one animal at a time. Water and / or milk were provided, and baseline phase values ​​were provided. Baseline phase Next, natural oils derived from each herb or animal, or natural oils derived from herbs and birds A mixture containing glycerides was provided.

[0156] Test group 1 (cats 1-9) included examples 1.1, 1.2, 1.3, 1.6, and 1.7. We provided natural oils derived from herbs.

[0157] Test group 2 (cats 10-17) was subjected to the following treatments according to Examples 1.4, 1.5, 1.8 and 1.9. A mixture containing natural oils derived from herbs or animals, or natural oils derived from herbs, and triglycerides. I provided the item.

[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 stirred. The mixture was added below and stirred for another 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. did.

[0162] Regarding the voluntary acceptance examination, evaluation will take place over the period of the 8th, 23rd, and 28th. Eight cats were tested according to the general procedure described above (compare Tables 2.a and 2.b). Furthermore, the evaluation of the formulation according to Example 2.4 was discontinued after 8 days due to poor intake. Please note: A liquid placebo formulation was provided at a dose of 0.2 ml / kg body weight (cat's body weight).

[0163] Each result was obtained through the following exemplary procedure. The mean values ​​are shown in Tables 2.a and 2.b. The results are shown in the table below, 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 8 cats. One voluntary acceptance trial phase (2 In the 3-day or 28-day trials, only one formulation was tested.

[0165] To get a cat used to the procedure of licking liquid from a bowl, give the cat a 4-day period, one animal at a time. Water and / or milk were provided, and baseline phase values ​​were established. Following the baseline phase... Then, each liquid placebo formulation was tested.

[0166] Test group 1 (cats 18-25) received liquid placebo formulations Example 2.1 and Example 2.2 They provided it.

[0167] Test group 2 (cats 26-33) received liquid placebo formulations Examples 2.3 and 2.4 They provided it.

[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. The mixture was heated to °C. Butylhydroxytoluene, sorbic acid, and Compritol were stirred. The mixture was added below, stirred for a further 10 minutes, and then cooled to room temperature.

[0170] Example 2.3: Miglyol was placed in a flask and heated to 75°C. Butylhydrox Add citoluene, sorbic acid, and Compritol under stirring, and further mix the mixture for 10 minutes. After stirring for 1 minute, the mixture was cooled to room temperature.

[0171] Example 2.4: Water was placed in a flask. Sodium citrate was added to adjust the pH to 8.37. To obtain the desired result, citric acid was added to obtain a pH of 6.03, and Solbrol M and Solbrol Add P under stirring, heat the mixture to 40°C, and stir until the parabens dissolve, The mixture was cooled to room temperature. Sorbitol, propylene glycol, vanilla flavor, Tweed n20, Tween80, and Avicel were added under stirring. The final citric acid was added. The mixture was then stirred for a further 10 minutes to obtain a pH of 5.52. [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 voluntary acceptance tests, the above general criteria apply to evaluations conducted over a period of 3 or 7 days. Eight cats were tested according to the procedure. Each cat received 0.2 ml / kg body weight (cat's body weight) of liquid drug. A formulation was provided. For animal welfare reasons, healthy cats were given liquid medication over a period of 28 days. We did not provide a formulation containing the substance.

[0175] Each result was obtained through the following exemplary procedure. The mean values ​​were shown in Tables 3.a and 3.b. The results are shown in the table below, 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 8 cats. One voluntary acceptance trial phase (3 In the 7-day trial, only one formulation was tested.

[0177] To get a cat used to the procedure of licking liquid from a bowl, give the cat a 4-day period, one animal at a time. Water and / or milk were provided, and baseline phase values ​​were provided. Baseline phase Following that, 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, the results for liquid drug-containing formulations in Examples 3.3 to 3.6 were obtained. .

[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 mixture was then... These were heated to 70°C (Example 3.1) and 75°C (Example 3.4), respectively. Add toluene, sorbic acid, and Compritol under stirring, and let the mixture steep for another 10 minutes. After stirring, the mixture was cooled to room temperature. Compound A was added under stirring, and the mixture was further stirred for 10 minutes. Stirred for 1 minute.

[0183] Example 3.2: Water was placed in a flask. Sodium citrate was added to adjust the pH to 8.27. To obtain the desired result, citric acid was added to obtain a pH of 6.01, and Solbrol M and Solbrol Add P under stirring, heat the mixture to 40°C, and stir until the parabens dissolve, The mixture was cooled to room temperature. Sorbitol, propylene glycol, vanilla flavor, Tweed n20, Tween80, and Avicel were added under stirring. Citric acid was added, A pH of 5.50 was obtained, and compound A was added. Finally, citric acid was added, and the pH was again 5.5. A pH of 0 was obtained, 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, butyl Hydroxytoluene and Compritol were added under stirring. The mixture was cooled to room temperature. Afterward, compound A was added and the mixture was stirred for another 10 minutes.

[0185] Example 3.5: Miglyol 840 was placed in a flask and heated to 75°C. Acid, butylhydroxytoluene, and Compritol were added under stirring. The mixture was then mixed. The mixture was cooled to room temperature, compound A was added under 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 7. The mixture was heated to 5°C. Sorbic acid, butylhydroxytoluene, and Compritol were stirred. It was added under stirring. The mixture was cooled to room temperature, compound A was added under stirring, and the mixture was further mixed for 10 minutes. Stirred for 1 minute. [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. and, B) A natural oil derived from at least one herb, C) Optionally, at least one natural oil of animal origin, D) A liquid drug-containing formulation comprising, optionally, at least one thickening agent.

2. The hypoxia-inducible factor prolyl hydroxylase inhibitor is a compound of formula (I). 【Chemistry 1】 The claim 1, or a salt thereof, stereoisomer, tautomer, or N-oxide thereof. A liquid drug-containing preparation.

3. The compound of formula (I) is in the form of a salt having formula (II), 【Chemistry 2】 During the ceremony, M stands for lithium, sodium, potassium, calcium, magnesium, barium, man. Selected from the group consisting of ammonium, copper, silver, zinc, iron, ammonium, and substituted ammonium , 1 to 4 of the hydrogen atoms are C １ ~C ４ Replaced with alkyl, preferably M is It 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, and is preferably 1, 2, or 3. is 1, and n is equal to m such that the salt having formula (II) is not charged. A liquid drug-containing preparation as described in item 2.

4. The aforementioned natural oil derived from at least one herb is almond oil, apricot kernel oil, canola oil, Castor oil, coconut oil, cottonseed oil, linseed oil, grape oil, hemp oil, corn oil, olive oil Coconut oil, coconut oil, peanut oil, sesame oil, soybean oil, sunflower oil, thistle oil, rapeseed oil, rice A method selected from the group consisting of rice bran oil and wheat germ oil, according to any one of claims 1 to 3. Liquid drug-containing preparation.

5. The aforementioned natural oil derived from at least one herb is modified almond oil, modified apricot kernel oil, modified ki Canola oil, modified castor oil, modified coconut oil, modified cottonseed oil, modified linseed oil, modified grape oil Oils, 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 Selected from the group consisting of , and modified wheat germ oil, wherein the modification is preferably glycerol, By alcohol decomposition with propylene glycol or low molecular weight polyethylene glycol A liquid drug-containing preparation obtained according to any one of claims 1 to 3.

6. At least one animal-derived natural oil is present, and this is a group consisting of fish oil and salmon oil. A liquid drug-containing preparation according to any one of claims 1 to 5, selected from among the above.

7. The aforementioned natural oil derived from at least one herb is soybean oil or sunflower oil, and less In each of the claims 1 to 4 and 6, there is a natural oil of animal origin, and this is fish oil. A liquid drug-containing preparation as described in item one.

8. Claims 1 to 1, wherein the natural oil derived from at least one herb is modified corn oil. A liquid drug-containing preparation as described in any one of paragraphs 3, 5, or 6.

9. At least one thickening agent is present, which is preferably a glycerol ester. is C １２ ~C ２４ A glycerol ester containing a fatty acid, and / or a monoester. any one of claims 1 to 8, which is a diester, triester, or a mixture thereof. A liquid drug-containing preparation as described in item 1.

10. The claim is that at least one thickening agent is present, and this is glycerol dibehenate. A liquid drug-containing preparation as described in any one of items 1 to 9.

11. component E) Ascorbyl palmitate, butylhydroxytoluene, butylhydroxyanisodium Calcium, citric acid, lecithin, propyl gallate, tocopherol, and their antioxidants At least one antioxidant selected from the group consisting of combinations of the following, and / or F) Ethanol, propylene glycol, butanol, chlorobutanol, benzoic acid, A group consisting of sorbic acid, para-hydroxybenzoic acid esters, and combinations thereof. At least one preservative selected from, and / or G) Any of claims 1 to 10, optionally further comprising at least one surfactant. A liquid drug-containing preparation as described in item 1.

12. A) Based on the total weight of the liquid drug-containing preparation, 0.1 to 20% by weight, preferably 0. A 5-10% by weight amount of the 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 This comprises a natural oil derived from at least one of the herbs in an amount of 70 to 98.97% by weight, C) Optionally, 0.01 to 5% by weight based on the total weight of the liquid drug-containing preparation. Preferably, an amount of 0.01 to 1.5% by weight of the above-mentioned natural oil of at least one animal, D) Optionally, 0.1 to 10% by weight based on the total weight of the liquid drug-containing preparation. Preferably, an amount of 0.5 to 5% by weight of at least one of the thickening agents, E) Optionally, 0.01 to 2% by weight based on the total weight of the liquid drug-containing preparation. Preferably, an amount of 0.01 to 1.5% by weight of at least one antioxidant, F) Optionally, 0.01 to 2% by weight based on the total weight of the liquid drug-containing preparation. Preferably comprising 0.01 to 1.5% by weight of the above preservative, A liquid drug-containing preparation as described in any one of the requests 1 to 11.

13. In particular, hypoxia-inducible factor prolirhi, for use in the treatment of anemia associated with chronic kidney disease. Diseases related to the droxylase enzyme, preferably the disease being a cardiovascular disease, heart For use in the treatment and / or prevention of diseases such as organ failure, anemia, chronic kidney disease, or renal failure. The liquid drug-containing preparation according to any one of claims 1 to 12.

14. The aforementioned liquid drug-containing preparation will not cause problems in acceptance or voluntary acceptance, and will be available in small quantities. A liquid drug-containing solution for use according to claim 13, which can be administered for a period of at least two weeks. formulation.

15. Claim 13 or This is a liquid drug-containing preparation for use as described in 14.

16. To improve the acceptance or voluntary acceptance of drug administration in animals, at least one Natural oils derived from herbs and / or animals, preferably at least one natural oil derived from a herb. Furthermore, a liquid formulation aid that optionally includes at least one thickening agent in the liquid drug-containing formulation. Use of the composition.

17. The liquid drug-containing preparation is at least 50 by weight, based on the total weight of the liquid drug-containing preparation. The use according to claim 16, comprising a % amount of the liquid formulation aid composition.

18. The acceptance or voluntary acceptance of the aforementioned drug in cats and dogs, preferably cats, The use described in claim 16 or 17 is improved.

19. The acceptance or voluntary acceptance of the aforementioned drug intake has been maintained for at least two weeks during the administration period. The use described in any one of claims 16 to 18 is provided.

20. The oil contains natural oil derived from at least one of the aforementioned herbs, which may be almond oil or apricot kernel oil. Canola oil, castor oil, coconut oil, cottonseed oil, linseed oil, grape oil, hemp oil, tofu Sorghum oil, olive oil, coconut oil, peanut oil, sesame oil, soybean oil, sunflower oil, bruise Selected from the group consisting of rice oil, rapeseed oil, rice bran oil, and wheat germ oil, preferably soybean oil or The use according to any one of claims 16 to 19, wherein is sunflower oil.

21. The oil contains natural oil derived from at least one of the aforementioned herbs, which is modified almond oil, modified Apricot kernel oil, modified canola oil, modified castor oil, modified coconut oil, modified cottonseed oil, modified flaxseed oil Seed 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 vegetable oil Selected from the group consisting of seed oil, modified rice bran oil, and modified wheat germ oil, preferably modified corn It is rococo oil, and the modification is preferably glycerol, propylene glycol, or low Claims 16-19 obtained by alcohol decomposition with molecular polyethylene glycol Use as described in any one of the items.

22. The liquid formulation aid composition preferably contains at least one natural oil derived from an animal. is selected from the group consisting of fish oil and salmon oil, and is particularly fish oil, any one of claims 16 to 21 Use as described in item 1.

23. At least one thickening agent is present, which is preferably a glycerol ester. is C １２ ~C ２４ A glycerol ester containing a fatty acid, and / or a monoester. Any of claims 16 to 22, which is a diester, triester, or a mixture thereof. Use as described in any one of the items.

24. The claim is that at least one thickening agent is present, and this is glycerol dibehenate. Use as described in any one of paragraphs 16 to 23.

25. The aforementioned liquid formulation aid composition Ascorbyl palmitate, butylhydroxytoluene, butylhydroxyanisole , citric acid, lecithin, propyl gallate, tocopherol, and antioxidants thereof At least one antioxidant selected from the group consisting of combinations, and / or Ethanol, propylene glycol, butanol, chlorobutanol, benzoic acid, sol Select from the group consisting of bic acid, para-hydroxybenzoic acid esters, and combinations thereof. At least one preservative selected, and / or Optionally, any one of claims 16 to 24 further comprises at least one surfactant. Use as described in the section.

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