Molidustat Formulations and Methods of Use for the Treatment of Anemia in Cats

Abstract

A pharmaceutical composition comprising molidustat and an oil for the treatment of anemia in cats and an associated method of use are described.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This patent application is an international patent application claiming priority to U.S. Provisional Application No. 63 / 301,881, filed January 21, 2022, the disclosure of which is incorporated herein in its entirety. FIELD OF THE ART

[0002] Anemia associated with chronic kidney disease (CKD) in cats is primarily caused by decreased erythropoietin (EPO) production in the kidney. The production of EPO is controlled by hypoxia-inducible factor (HIF). High levels of HIF increase EPO production, which occurs in hypoxic conditions. In CKD, reduced metabolic activity of the defective kidney leads to relative renal hyperoxia and thus reduced EPO production, despite preserved EPO control mechanisms. Thus, cats with chronic kidney disease (CKD) are unable to produce enough EPO to maintain normal red blood cell levels. Thus, renal anemia is a common and severe complication of CKD that worsens with disease progression. There remains a need for compounds that stimulate EPO production and methods for treating or managing anemia due to CKD. There remains a need for stable formulations that are palatable and provide improved delivery to cats. Summary of the Invention

[0003] The present disclosure provides various compositions comprising hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors (e.g., molidustat or a salt thereof) that increase endogenous erythropoietin production, as well as methods of preparing and using such compositions.

[0004] For example, pharmaceutical compositions are provided herein.

[0005] The compositions (e.g., pharmaceutical compositions) described herein may include a hypoxia-inducible factor prolyl hydroxylase inhibitor and an oil. The hypoxia-inducible factor prolyl hydroxylase inhibitor is a compound of formula (I): [ka] or a salt, stereoisomer, tautomer, or N-oxide thereof.

[0006] The compound of formula I may be in the form of a salt having the formula (II): [ka] In the formula, M is lithium, sodium, potassium, calcium, magnesium, barium, manganese, copper, silver, zinc, iron, ammonium or substituted ammonium, in which one to four of the hydrogen atoms are replaced by C1-C4-alkyl, m represents the respective positive charge of the cation and is 1, 2 or 3, preferably 1, and n represents the respective stoichiometric amount of the counter anion and is 1, 2 or 3, preferably 1, and n is equal to m, such that the salt having formula (II) is uncharged.

[0007] Hypoxia inducible factor prolyl hydroxylase inhibitors may include compounds of formula (IIA). [ka]

[0008] The hypoxia inducible factor prolyl hydroxylase inhibitor may comprise a sodium salt.The hypoxia inducible factor prolyl hydroxylase inhibitor may comprise or consist of molidustat.The hypoxia inducible factor prolyl hydroxylase inhibitor may comprise or consist of molidustat sodium.

[0009] The pharmaceutical composition may include micronized particles comprising a hypoxia inducible factor prolyl hydroxylase inhibitor. The micronized particles may be characterized by a D90 of about 70 μm or less, about 60 μm or less, about 50 μm or less, about 40 μm or less, or about 30 μm or less. The micronized particles may be characterized by a D90 of about 20 μm to about 70 μm, about 20 μm to about 60 μm, about 20 μm to about 50 μm, about 20 μm to about 40 μm, or about 20 μm to about 30 μm. The micronized particles may be characterized by a D10 of about 0.1 μm to about 10 μm, about 0.2 μm to about 10 μm, or about 0.2 to about 5 μm. Micronized particles may be characterized by a D50 that is about 1 μm to about 20 μm, about 1 μm to about 15 μm, about 1 μm to about 10 μm, about 5 μm to about 20 μm, about 5 μm to about 15 μm, about 5 μm to about 10 μm, about 10 to about 20 μm, or about 10 to about 15 μm. Micronized particles may be characterized by a substantially monomodal particle size distribution.

[0010] In the pharmaceutical compositions described herein, the concentration of the hypoxia inducible factor prolyl hydroxylase inhibitor (e.g., molidustat or molidustat sodium) can be about 1.0% to 20% (m / v). The concentration of the hypoxia inducible factor prolyl hydroxylase inhibitor can be about 1.0% to 10% (m / v). The concentration of the hypoxia inducible factor prolyl hydroxylase inhibitor can be about 1.0% to 5.0% (m / v). The concentration of the hypoxia inducible factor prolyl hydroxylase inhibitor can be about 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.50%, 3.75%, 4.0%, 4.25%, 4.50%, 4.75%, or 5.0% (m / v), or any concentration within any of these percentages. The concentration of the hypoxia inducible factor prolyl hydroxylase inhibitor can be about 1.5% to 2.5% (m / v), 2.0% to 4.5% (m / v), 2.0% to 3.0% (m / v), 1.0% to 3.0% (m / v), or 2.0% to 5.0% (m / v). For example, the concentration of the hypoxia inducible factor prolyl hydroxylase inhibitor can be about 2.5% (m / v).

[0011] The pharmaceutical compositions described herein can include an oil that can include at least one selected from the group consisting of almond oil, apricot kernel oil, canola oil, castor oil, coconut oil, cottonseed oil, linseed oil, grape oil, hemp oil, corn oil, olive oil, palm oil, peanut oil, sesame seed oil, soybean oil, sunflower oil, thistle oil, canola oil, rice bran oil, wheat germ oil, and mixtures thereof.

[0012] The pharmaceutical composition described herein can include oils that can include at least one 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 oil, modified hemp oil, modified corn oil, modified olive oil, modified palm oil, modified peanut oil, modified sesame seed oil, modified soybean oil, modified sunflower oil, modified thistle oil, modified rapeseed oil, modified rice bran oil, modified wheat germ oil, and mixtures thereof, and the modification is obtained by alcoholysis, preferably using glycerol, propylene glycol, or low molecular weight polyethylene glycol.The oil can include sunflower oil.The oil can include modified corn oil.

[0013] The pharmaceutical compositions described herein may further comprise fish oil. The compositions may further comprise at least one fish oil selected from the group consisting of salmon oil, cod liver oil, and mixtures thereof. The fish oil may be in an amount of about 0.01% to 5% (w / w). The fish oil may be in an amount of about 0.01% to 1.5% (w / w). The fish oil may be in an amount of 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% (w / w), or at a concentration within any of these percentages.

[0014] The pharmaceutical compositions described herein may further comprise a viscosity enhancing agent. 12 ~C 24The thickener may include glycerol esters with fatty acids. The glycerol esters may be monoesters, diesters, triesters, or mixtures thereof. The thickener may include glycerol dibehenate. The thickener may be in an amount of about 0.1% to 10% (w / w). The thickener may be in an amount of about 0.1% to 8% (w / w). The thickener may be in an amount of about 0.5% to 5% (w / w). The thickener may be in an amount of about 0.5% to 2.5% (w / w). The thickener may be in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (w / w), or a concentration within any of these percentages. The thickening agent may be in an amount of about 1.0% (w / w).

[0015] The pharmaceutical compositions described herein may further comprise an antioxidant. For example, the compositions described herein may further comprise at least one antioxidant selected from the group consisting of ascorbyl palmitate, butylhydroxytoluene, butylhydroxyanisole, citric acid, lecithin, propyl gallate, tocopherol, and combinations thereof. The antioxidant may be in an amount of about 0.01% to 2% (w / w). The antioxidant may be in an amount of about 0.01% to 1.5% (w / w). The antioxidant may be in an amount of 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, or 2% (w / w), or a concentration within any of these percentages.

[0016] The pharmaceutical compositions described herein may further comprise a preservative. For example, the compositions described herein may further comprise 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. The preservative may be in an amount of about 0.01% to 2% (w / w). The preservative may be in an amount of about 0.01% to 1.5% (w / w). Preservatives may be in the amount of 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, or 2% (w / w), or at a concentration within any of these percentages.

[0017] The pharmaceutical composition may comprise a hypoxia inducible factor prolyl hydroxylase inhibitor described herein in an amount of 0.1% to 20%, optionally 0.5% to 10% (w / w), an oil in an amount of 50% to 99.8%, optionally 70% to 98.97% (w / w), optionally a fish oil in an amount of 0.01% to 5%, optionally 0.01% to 1.5% (w / w), optionally a thickening agent in an amount of 0.1% to 10%, optionally 0.5% to 5% (w / w), optionally an antioxidant in an amount of 0.01% to 2%, optionally 0.01% to 1.5% (w / w), and optionally a preservative in an amount of 0.01% to 2%, optionally 0.01% to 1.5% (w / w).

[0018] The pharmaceutical compositions described herein can be formulated for oral administration, sublingual / buccal administration, or a combination thereof. For example, the compositions described herein can be formulated for oral administration.

[0019] The pharmaceutical compositions described herein can be a suspension, emulsion, slurry, dispersion, or solution. For example, the compositions described herein can be a suspension.

[0020] The pharmaceutical compositions described herein may further comprise a pharma- ceutically acceptable carrier, excipient, lubricant, emulsifier, stabilizer, solvent, diluent, buffer, surface active agent, or combinations thereof.

[0021] The pharmaceutical compositions described herein can be used in the manufacture of a medicament for treating anemia (e.g., for use in the manufacture of a medicament for treating anemia associated with chronic kidney disease (CKD)).

[0022] The pharmaceutical composition described herein can be used for treating anemia.The anemia can be non-regenerative anemia.The anemia can be iron deficiency anemia, pernicious anemia, aplastic anemia, chemotherapy-induced anemia (CIA), immune-mediated hemolytic anemia (IMHA) or hemolytic anemia.The anemia can be associated with chronic kidney disease (CKD).

[0023] As described, various methods of use are also provided herein. For example, a method for increasing erythropoietin can include administering a pharmaceutical composition described herein to a subject in need thereof. Furthermore, a method for treating anemia can include administering a pharmaceutical composition described herein to a subject in need thereof. As described, anemia can be non-regenerative anemia. Anemia can be iron deficiency anemia, pernicious anemia, aplastic anemia, chemotherapy-induced anemia (CIA), immune-mediated hemolytic anemia (IMHA), or hemolytic anemia. Anemia can be associated with chronic kidney disease (CKD).

[0024] In the method described herein, the pharmaceutical composition can be administered once a day. The pharmaceutical composition can be administered once a day for at least 28 consecutive days. The pharmaceutical composition can be administered intermittently once a day after 28 consecutive days of administration. The pharmaceutical composition is not administered at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, or at least 14 days after 28 consecutive days of administration.

[0025] In the methods described herein, the subject in need thereof can be a mammal. Further, the subject can be a cat.

[0026] In the methods described herein, the pharmaceutical composition may be administered orally. The pharmaceutical composition described herein may be administered at a dose sufficient to provide a maximum plasma concentration (Cmax) of the hypoxia-inducible factor prolyl hydroxylase inhibitor of about 0.5 mg / L or more, about 1 mg / L or more, 1.5 mg / L or more, 2 mg / L or more, 2.5 mg / L or more, 3 mg / L or more, or about 0.5 mg / L to about 5 mg / L. [Brief description of the drawings]

[0027] [Figure 1] Figure 1 shows the effect of different doses and formulations of molidustat sodium on plasma hematocrit values, with mean (± standard deviation) hematocrit (HCT) over a follow-up period of 98 days. Treatment was stopped at SD15 (group treated with 10% suspension) and SD23 (group treated with 5% suspension), respectively. [Diagram 2] Figure 2 shows the effect of different doses and formulations of molidustat sodium on plasma hematocrit values. The time course of group mean ± SD hematocrit is presented over 28 days. [Diagram 3] Figure 3 shows the mean (± standard deviation) plasma concentrations of erythropoietin on study day 0 and study day 7. Molidustat sodium oil suspension was administered daily. [Figure 4] FIG. 4 shows a particle size distribution histogram of molidustat sodium oil suspension formulated with micronized molidustat. [Diagram 5] FIG. 5 shows a particle size distribution histogram of a molidustat sodium oil suspension formulated with non-micronized molidustat. [Figure 6] FIG. 6 shows a graph of the sedimentation analysis of micronized (circles) and non-micronized (triangles) formulations over a 48 hour period. Detailed Description of the Invention

[0028] Before the subject disclosure is further described, it should be understood that the present disclosure is not limited to the specific embodiments of the present disclosure described below, since variations of the specific embodiments can be made and still fall within the scope of the appended claims. It should also be understood that the terminology used is for the purpose of describing the specific embodiments and is not intended to be limiting. Instead, the scope of the present disclosure is established by the appended claims.

[0029] In this specification and the appended claims, the singular form includes the plural form unless the context clearly dictates otherwise.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.Although preferred methods and compositions are described, any methods and compositions similar or equivalent to those described herein can be used to carry out or test the present invention.

[0030] Treatment of anemia with hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) Anemia, optionally associated with chronic kidney disease, can be treated by administration of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI). These inhibitors are members of a class of drugs that act by inhibiting prolyl hydroxylase, a determinant in the degradation of hypoxia-inducible factor (HIF) under normoxic conditions. Hypoxia-inducible factor prolyl hydroxylase inhibitors or pharmaceutical compositions containing inhibitors may be used to treat cats suffering from non-regenerative anemia associated with chronic kidney disease (CKD). For example, hypoxia-inducible factor prolyl hydroxylase inhibitors, optionally as sodium salts, may be formulated in a 2.5% (m / v) oil suspension and used for oral administration once a day at a rate of 5 mg HIF-PHI per kg body weight for the treatment of anemia in cats (e.g., anemia associated with CKD).

[0031] The hypoxia inducible factor prolyl hydroxylase inhibitor is preferably a compound of formula (I) [ka] or a salt, stereoisomer, tautomer, or N-oxide thereof. The compound of formula (I) is also known as Molidustat.

[0032] The hypoxia inducible factor prolyl hydroxylase inhibitor may be a compound of formula (I) in the form of a salt having the 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, in which one to four of the hydrogen atoms are replaced by C1-C4-alkyl, preferably M is sodium; m represents the respective positive charge of the cation and is 1, 2, or 3, preferably 1; n indicates the respective stoichiometric amount of counteranion and is 1, 2, or 3, preferably 1, and n is equal to m, such that the salt having formula (II) is uncharged.

[0033] The hypoxia inducible factor prolyl hydroxylase inhibitor may be in the form of a sodium salt having the formula (IIA): [ka] It is also known as sodium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazole-5-oleate.

[0034] The hypoxia inducible factor prolyl hydroxylase inhibitor may be in the form of a potassium or ammonium salt of formula (II), which is also known as potassium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazole-5-olate or ammonium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazole-5-olate.

[0035] The hypoxia-inducible factor prolyl hydroxylase inhibitor may be molidustat.For example, molidustat may be formulated as sodium salt in 2.5% (m / v) oil suspension and used for once-daily oral administration at a rate of 5 mg molidustat sodium per kg body weight for the treatment of anemia in cats.Moldustat, 2-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-2,3-dihydro-1H-pyrazol-3-one, may be used in the method of treating anemia associated with chronic kidney disease in cats described herein.

[0036] Treatment method The present disclosure further provides a method for treating or preventing anemia. The method comprises administering to a mammal a pharmaceutical composition comprising an effective amount of a hypoxia-inducible factor prolyl hydroxylase inhibitor, either therapeutically or prophylactically. The anemia to be treated or prevented may be associated with chronic kidney disease.

[0037] Methods for treating or preventing anemia, optionally associated with chronic kidney disease, may include administering to the mammal a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a hypoxia-inducible factor prolyl hydroxylase inhibitor (e.g., molidustat or a salt thereof, e.g., molidustat sodium). As used herein, "therapeutically effective amount" refers broadly to an amount of a compound disclosed herein that is effective to prevent, ameliorate, treat, or delay the onset of a disease or condition. The phrase "prophylactically effective amount" refers to an amount of a compound disclosed herein that is effective to inhibit the onset or progression of a disorder.

[0038] The method for treating anemia optionally associated with chronic kidney disease may comprise administering to the mammal a pharmaceutical composition comprising an effective amount of a hypoxia inducible factor prolyl hydroxylase inhibitor.

[0039] A method for treating or preventing anemia, optionally non-regenerative anemia, may comprise administering to the mammal a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a hypoxia-inducible factor prolyl hydroxylase inhibitor.

[0040] A method for treating anemia, optionally non-regenerative anemia, may comprise administering to the mammal a pharmaceutical composition comprising an effective amount of a hypoxia-inducible factor prolyl hydroxylase inhibitor.

[0041] The anemia may be non-regenerative anemia.The anemia may be iron deficiency anemia, pernicious anemia, aplastic anemia, hemolytic anemia, anemia associated with inflammatory disease, chemotherapy-induced anemia (CIA) or immune-mediated hemolytic anemia (IMHA).The anemia may be associated with chronic kidney disease (CKD).

[0042] Methods for increasing erythropoietin can include administering to a subject in need thereof a pharmaceutical composition described herein.

[0043] The pharmaceutical compositions described herein may be administered once daily. The pharmaceutical compositions described herein may be administered once daily for at least 28 consecutive days. The pharmaceutical compositions described herein may be administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days. The pharmaceutical compositions described herein may be administered once daily for about 1-28 days. The pharmaceutical compositions described herein may be administered once daily for about 1-7 days, 1-14 days, 1-21 days, 3-21 days, 16-28 days, or 14-21 days.

[0044] The subject may be a mammal, for example, the mammal may be a cat.

[0045] The pharmaceutical compositions described herein may be administered orally.

[0046] The effective amount of the hypoxia inducible factor prolyl hydroxylase inhibitor may be about 5 mg per kg of body weight. For example, the effective amount of the hypoxia inducible factor prolyl hydroxylase inhibitor may be about 1 to 10 mg per kg of body weight. The effective amount of the hypoxia inducible factor prolyl hydroxylase inhibitor may be about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg per kg of body weight.

[0047] The hypoxia inducible factor prolyl hydroxylase inhibitor may be present in the pharmaceutical composition in an amount of about 1.0% to 5.0% (m / v). The hypoxia inducible factor prolyl hydroxylase inhibitor may be present in an amount of about 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.50%, 3.75%, 4.0%, 4.25%, 4.50%, 4.75%, or 5.0% (m / v), or at a concentration within any of these percentages. The hypoxia inducible factor prolyl hydroxylase inhibitor may be in an amount of about 1.5%-2.5% (m / v), 2.0%-4.5% (m / v), 2.0%-3.0% (m / v), 1.0%-3.0% (m / v), or 2.0%-5.0% (m / v). The hypoxia inducible factor prolyl hydroxylase inhibitor may be in an amount of about 2.5%. The hypoxia inducible factor prolyl hydroxylase inhibitor may be molidustat. The hypoxia inducible factor prolyl hydroxylase inhibitor may be a compound having formula (I), formula (II), formula (IIA), or a combination thereof.

[0048] The pharmaceutical composition may be formulated as a suspension, emulsion, slurry, dispersion or solution. The pharmaceutical composition may be a suspension.

[0049] dose The pharmaceutical compositions described herein are administered to a subject in a manner known in the art. The dose administered will depend on the age, health, and weight of the recipient, type of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

[0050] Hypoxia-inducible factor prolyl hydroxylase inhibitors can be present in any suitable amount in the pharmaceutical compositions described herein.Those skilled in the art can easily determine the suitable concentration of compound to be included in pharmaceutical compositions, depending on various factors, including dosage and route of administration.The pharmaceutical compositions useful in the present invention can contain an amount of hypoxia-inducible factor prolyl hydroxylase inhibitor that is effective for treating or preventing the condition, disorder or disease of the subject being treated.

[0051] The hypoxia inducible factor prolyl hydroxylase inhibitor may be present in the pharmaceutical composition in an amount of about 1.0% to 5.0% (m / v). The hypoxia inducible factor prolyl hydroxylase inhibitor may be present in an amount of about 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.50%, 3.75%, 4.0%, 4.25%, 4.50%, 4.75%, or 5.0% (m / v), or at a concentration within any of these percentages. The hypoxia inducible factor prolyl hydroxylase inhibitor may be in an amount of about 1.5%-2.5% (m / v), 2.0%-4.5% (m / v), 2.0%-3.0% (m / v), 1.0%-3.0% (m / v), or 2.0%-5.0% (m / v). The hypoxia inducible factor prolyl hydroxylase inhibitor may be in an amount of about 2.5%.

[0052] The pharmaceutical compositions described herein may be administered in a single dose per day, or the total daily dose may be administered in divided doses, two, three, or four times per day.Doses may be administered over the course of a week, a month, or several months, three, six, nine, or twelve months, or over intervals known in the art and determined to be clinically relevant.Doses may be continued throughout the subject's life, or discontinued when clinical judgment requires.

[0053] The daily dose of the pharmaceutical compositions described herein may vary over a wide range of about 1 to about 10 mg per subject per day. The subject may be an animal. The subject may be a mammal. The subject may be a feline. The range may be about 1 mg to 10 mg per kg of body weight per day. Further, the dose may be about 0.5 to 20 mg / kg per day, about 1 to 10 mg / kg per day, about 2.5 to 10 mg / kg per day, about 5 to 10 mg / kg per day, or about 2.5 to 7.5 mg / kg per day. The daily dose of the pharmaceutical compositions described herein may be about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / kg per subject per day. For other animals, the dose calculated for 1 kg may be administered.

[0054] As a non-limiting example, animal treatments can be from 0.0001 to about 1,000 mg per subject per day as a single dose or periodic dose of the pharmaceutical compositions described herein. The ranges can be more specifically from about 0.001 mg / kg to 10 mg / kg of body weight per subject per day, from about 0.1 to 100 mg per day, from about 1.0 to 50 mg, or from about 1.0 to 20 mg. Additionally, doses can be from about 0.5 to 10 mg / kg per day, from about 1.0 to 5.0 mg / kg per day, or from 5.0 to 10 mg / kg per day.

[0055] The dose may also be an amount that achieves a serum concentration.

[0056] The pharmaceutical composition of the present invention may be administered at least once a week for several weeks. The pharmaceutical composition may be administered at least once a week for several weeks to several months. The pharmaceutical composition may be administered once a week for 4 to 8 weeks. The pharmaceutical composition may be administered once a week for 4 weeks. The pharmaceutical composition may be administered once a day.

[0057] Route of administration Routes of administration and dosages of effective amounts of pharmaceutical compositions containing the compounds are also disclosed. The compounds of the present invention can be administered in combination with other pharmaceutical agents in various protocols for the effective treatment of diseases.

[0058] The pharmaceutical compositions disclosed herein may be administered by routes including, but not limited to, oral, parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraperitoneal, intracapsular, intrachondral, intrasinus, intracavity, intracerebellar, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, intravaginal, rectal, buccal, sublingual, intranasal, iontophoretic, or transdermal. The pharmaceutical compositions disclosed herein may be administered by injection. The pharmaceutical compositions disclosed herein may be administered orally.

[0059] subject The pharmaceutical compositions described herein can be administered to any animal that can experience the beneficial effects of hypoxia-inducible factor prolyl hydroxylase inhibitors.Such animals include humans and non-humans such as pets and livestock.Animals can include, but are not limited to, humans, cats, dogs, mice, rats, guinea pigs, horses, donkeys, mules, sheep, cows, goats, llamas, and hamsters.Animals can be cats.

[0060] Pharmaceutical Compositions As mentioned above, the pharmaceutical composition comprises at least one hypoxia-inducible factor prolyl hydroxylase inhibitor, in particular comprising molidustat (i.e., compound of formula (I)) as described herein, or its salt, stereoisomer, tautomer, or N-oxide.Moldustat can be formulated as a salt.For example, molidustat can be formulated as a sodium salt.

[0061] The pharmaceutical compositions described herein may further comprise at least one of any suitable auxiliary agent, including but not limited to diluents, binders, stabilizers, buffers, thickeners, antioxidants, salts, lipophilic solvents, surfactants, preservatives, adjuvants, or combinations thereof. Examples and methods for preparing such sterile solutions are well known in the art and can be found in well-known texts, including but not limited to REMINGTON'S PHARMACEUTICAL SCIENCES (Gennaro, Ed., 18th Edition, Mack Publishing Co. (1990)). A pharmaceutically acceptable carrier suitable for the method of administration, solubility, and / or stability of the compound can be routinely selected. As used herein, "pharmaceutically acceptable carrier" refers broadly to any solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic and absorption delaying agents for pharmaceutically active substances well known in the art. Except insofar as any conventional media or agent is incompatible with the compound, its use in the therapeutic compositions is contemplated. Supplementary compounds can also be incorporated into the compositions.

[0062] The pharmaceutical composition may contain a surfactant. Suitable surfactants are amphiphilic compounds. Polyoxyethylated compounds such as mono-, di- or tri-esters of sorbitan with fatty acids, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives and poloxamers may be used as surfactants. Polyoxyethylated compounds, also called polyethoxylated compounds, are prepared, for example, by reaction with ethylene oxide. They have one or more linking units of the formula -[O-CH2-CH2]-. Polyoxyethylated compounds that may be mentioned in particular are non-ionic amphiphilic polyoxyethylated compounds, for example: - poloxamer, preferably having a molar mass between 100 and 5000 g / mol, particularly preferably having a molar mass between 1000 and 3500 g / mol. Poloxamer is the international generic name for block copolymers of ethylene oxide and methyloxirane, polyoxyethylene fatty acid glycerides, also called non-ionic emulsifiers, preferably glycerol polyethylene glycol ricinoleate, polyoxyethylene sorbitan fatty acid esters, preferably polyoxyethylene 20 sorbitan monooleate, - polyoxyethylene fatty acids such as macrogol 15 hydroxystearic acid (=Solutol HS15, which can be obtained by reacting 15 mol of ethylene oxide and 1 mol of 12-hydroxystearic acid), -hydroxypolyethoxydodecane and other polyoxyethylene fatty alcohols.

[0063] Fatty acids or fatty alcohols in particular refer to the corresponding compounds having at least 6 carbon atoms, and usually not more than 30 carbon atoms.

[0064] The pharmaceutical composition may include a thickening agent. The thickening agent may be in an amount of 0.1% to 10% (w / w), 0.1% to 8% (w / w), 0.5% to 5% (w / w), or 0.5% to 2.5% (w / w). The pharmaceutical composition may include a thickening agent in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (w / w), or a concentration within any of these percentages. The pharmaceutical composition may include a thickening agent in an amount of about 1.0% (w / w).

[0065] Suitable thickening agents include cellulose derivatives, such as methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, microcrystalline cellulose, bentonite, kaolin, pectin, starch, modified starch, wax, agar, paraffin, gelatin, alginates, polyvinylpyrrolidone, crospovidone, cetyl alcohol, stearates, such as magnesium stearate, zinc stearate or glyceryl stearate, saturated or unsaturated long chain fatty acids (C8-C 24, high molecular weight polyethylene glycols (e.g., polyethylene glycol 2000), glycerol esters, and combinations thereof.

[0066] The thickening agent may be a glycerol ester, preferably 12 -C 24 It is a glycerol ester with fatty acids and / or is a monoester, diester, triester, or mixtures thereof. The thickener may be glycerol dibehenate, also known as glyceryl dibehenate or glycerin dibehenate.

[0067] The pharmaceutical composition may include an antioxidant. The antioxidant may be in an amount of 0.01%-2% (w / w), 0.01%-1.5% (w / w), 0.5-2% by weight, 0.01%-1.5% (w / w), 0.001%-1% (w / w), or 0.01%-0.3% (w / w). The pharmaceutical compositions described herein may include an antioxidant in an amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, or 2% (w / w), or at a concentration within any of these percentages.

[0068] Suitable antioxidants include, but are not limited to, 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 may be selected from the group consisting of ascorbyl palmitate, butylated hydroxytoluene, butylated hydroxyanisole, citric acid, lecithin, propyl gallate, and tocopherol.

[0069] The pharmaceutical composition may include an antioxidant selected from the group consisting of ascorbyl palmitate, butylated hydroxytoluene, butylated hydroxyanisole, citric acid, lecithin, propyl gallate, tocopherol, or combinations thereof.

[0070] The pharmaceutical compositions described herein may contain a preservative. Suitable preservatives include, but are not limited to, carboxylic acids (sorbic acid, propionic acid, benzoic acid, lactic acid), phenols (cresol, p-hydroxybenzoic acid esters such as methylparaben, propylparaben), aliphatic alcohols (benzyl alcohol, ethanol, butanol), and quaternary ammonium compounds (benzalkonium chloride, cetylpyridinium chloride). Preferably, the preservative may be ethanol, propylene glycol, butanol, chlorobutanol, benzoic acid, sorbic acid, and para-hydroxybenzoic acid esters. Methyl 4-hydroxybenzoate, ethyl 4-hydroxybenzoate, and propyl 4-hydroxybenzoate are also known as preferred para-hydroxybenzoic acid esters.

[0071] The pharmaceutical compositions may contain a preservative selected from the group consisting of ethanol, propylene glycol, butanol, chlorobutanol, benzoic acid, sorbic acid, para-hydroxybenzoic acid esters, and combinations thereof.

[0072] Pharmaceutical excipients and additives useful in the present invention also include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., saccharides including monosaccharides, disaccharides, trisaccharides, terasaccharides, and oligosaccharides, derivatized saccharides such as alditols, aldonic acids, esterified saccharides, and polysaccharides or sugar polymers), which may be present alone or in combinations ranging from 1 to 99.99% by weight or volume. Exemplary protein excipients include serum albumins such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, etc. Representative amino acid components that may also function in a buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and combinations thereof.

[0073] Carbohydrate excipients suitable for use in the present invention include monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, disaccharides such as lactose, sucrose, trehalose, cellobiose, polysaccharides such as raffinose, melezitose, maltodextrin, dextran, starch, and alditols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), myo-inositol, and combinations thereof.

[0074] The pharmaceutical compositions described herein may further comprise a colorant, an emulsifier, a surfactant, a thickening agent, a suspending agent, ethanol, a chelating agent (e.g., EDTA), a buffer (e.g., a citrate buffer), a flavoring agent, water, or a combination thereof.

[0075] Chelating agents such as EDTA and EGTA can be optionally added to the pharmaceutical composition to reduce aggregation.These additives are particularly useful when the pharmaceutical composition is administered using a pump or plastic container.The presence of a pharma-ceutically acceptable surfactant reduces the tendency of the composition to aggregate.

[0076] The pharmaceutical compositions described herein may contain emulsifiers, including, but not limited to, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0077] Additionally, the pharmaceutical compositions described herein may include polymeric excipients / additives such as polyvinylpyrrolidone, Ficoll (polymeric sugars), dextrates (e.g., cyclodextrins, e.g., hydroxypropyl-β-cyclodextrin), polyethylene glycol, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates such as "Tween® 20" and "Tween® 80", lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA or EGTA). These and additional known pharmaceutical excipients and / or additives suitable for use in the pharmaceutical compositions described herein are known, e.g., those described in REMINGTON: The SCIENCE & PRACTICE OF PHARMACY (19th ed., Williams & Williams (1995)) and PHYSICBMS's DESK REFERENCE (52nd ed., Medical Economics (1998)).

[0078] The present disclosure provides stable pharmaceutical compositions, as well as storage solutions and formulations containing a preservative, and multi-use storage formulations suitable for pharmaceutical or veterinary use, comprising at least one compound disclosed herein in a pharma- ceutically acceptable formulation.

[0079] The compounds disclosed herein can also be administered in the form of liposomes. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present composition in liposome form can contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients, or combinations thereof. The preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art (Prescott, ed., METH. CELL BIOL. 14:33 (1976)). Liposomes, methods of making, and methods of use are described in U.S. Patent Nos. 4,089,8091 (process for preparation of liposomes), 4,233,871 (method for biologically active substances in lipid vesicles), 4,438,052 (process for producing mixed micelles), 4,485,054 (large multilamellar vesicles), 4,532,089 (giant size liposomes and methods thereof), 4,897,269 (liposomal drug delivery systems), and 5,820,880 (liposomal formulations).

[0080] The hypoxia inducible factor prolyl hydroxylase inhibitor can be solubilized or suspended in the preconcentrate (before dilution with diluent), added to the preconcentrate before dilution, added to the diluted preconcentrate, or added to the diluent before mixing with the preconcentrate.The hypoxia inducible factor prolyl hydroxylase inhibitor can also be co-administered as part of an independent dosage form for therapeutic effect.Optionally, the hypoxia inducible factor prolyl hydroxylase inhibitor can be present in a first solubilized amount and a second non-solubilized (suspended) amount.

[0081] The pharmaceutical compositions described herein can be presented in unit-dose or multi-dose containers, sealed ampoules, and vials and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, water for injection, immediately prior to use. Extemporaneous suspensions can be prepared from sterile powders, granules, and tablets.

[0082] Acceptable liquid carriers for use in pharmaceutical compositions include, but are not limited to, vegetable oils, such as peanut oil, cottonseed oil, sesame oil, or combinations thereof. Pharmaceutical compositions can be prepared by dissolving or suspending a hypoxia-inducible factor prolyl hydroxylase inhibitor in a liquid carrier such that the final formulation contains about 0.5% to 5.0% (m / v).

[0083] For oral administration in the form of tablet or capsule, hypoxia inducible factor prolyl hydroxylase inhibitors can be combined with oral and non-toxic pharma- ceutically acceptable inert carriers such as ethanol, glycerol, water, or combinations thereof.In addition, if desired or necessary, suitable binders, lubricants, disintegrants, and colorants can also be incorporated into the pharmaceutical composition.Suitable binders include, but are not limited to, starch, gelatin, natural sugars including glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, wax, or combinations thereof.Lubricants used in these dosage forms include, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, or combinations thereof.Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, or combinations thereof.

[0084] For oral administration, the pharmaceutical composition may be free of sweeteners.Sweeteners include, but are not limited to, sucrose, fructose, sodium saccharin, sucralose (SPLENDA®), sorbitol, mannitol, aspartame, sodium cyclamate, and combinations thereof.The pharmaceutical composition described herein may be substantially free of sweeteners.The pharmaceutical composition described herein may be free of flavorings, such as vanilla, anise, honey flavor, or combinations thereof.

[0085] The pharmaceutical compositions described herein formulated for oral administration can be combined with diluents such as water, glycerin, and various combinations, as well as colorants, such as dyes, natural colors, or pigments. Methods for preparing such pharmaceutical compositions can incorporate other suitable pharmaceutical excipients and their formulations described in REMINGTON's PHARMACEUTICAL SCIENCES, Martin, EW, ed., Mack Publishing Company, 19th ed. (1995).

[0086] Micronization The composition may include micronized particles comprising a hypoxia inducible factor prolyl hydroxylase inhibitor. The micronized particles may be characterized by a D90 of about 70 μm or less, about 60 μm or less, about 50 μm or less, about 40 μm or less, or about 30 μm or less. The micronized particles may be characterized by a D90 of about 20 μm to about 70 μm, about 20 μm to about 60 μm, about 20 μm to about 50 μm, about 20 μm to about 40 μm, or about 20 μm to about 30 μm. The micronized particles may be characterized by a D10 of about 0.1 μm to about 10 μm, about 0.2 μm to about 10 μm, or about 0.2 to about 5 μm. Micronized particles may be characterized by a D50 that is about 1 μm to about 20 μm, about 1 μm to about 15 μm, about 1 μm to about 10 μm, about 5 μm to about 20 μm, about 5 μm to about 15 μm, about 5 μm to about 10 μm, about 10 to about 20 μm, or about 10 to about 15 μm. Micronized particles may be characterized by a substantially monomodal particle size distribution.

[0087] The terms "D10" and "Dx10" describe the diameter of particles measured where 10% of the distribution by volume has a smaller particle size and 90% has a larger particle size. The terms "D50" and "Dx50" describe the diameter of particles where 50% of the distribution by volume has a smaller particle size and 50% has a larger particle size. The terms "D90" and "Dx90" describe the diameter of particles where 90% of the distribution by volume has a smaller particle size and 10% has a larger particle size.

[0088] Micronization of hypoxia-inducible factor prolyl hydroxylase inhibitor allows greater suspension properties in oil.Micronization of hypoxia-inducible factor prolyl hydroxylase inhibitor particles has been found to beneficially prevent aggregation, so that particles remain loosely aggregated in suspension, reducing sedimentation rate and allowing easy rehomogenization throughout the shelf life of the product.For example, micronized hypoxia-inducible factor prolyl hydroxylase inhibitor particles remain in suspension longer than non-micronized particles, for example, for 6 hours compared to less than 1 hour.Surprisingly, it has been found that micronized particles can remain in suspension for 48 hours without significant sedimentation.Therefore, micronization of hypoxia-inducible factor prolyl hydroxylase inhibitor provides more consistent and predictable administration of hypoxia-inducible factor prolyl hydroxylase inhibitor.

[0089] The inventors have discovered that the formulation of micronized hypoxia inducible factor prolyl hydroxylase inhibitor particles in sunflower oil using glyceryl dibehenate as a thickening agent resulted in an unexpected improvement of the suspension. Without wishing to be bound by a particular theory, the inventors have found that the micronized hypoxia inducible factor prolyl hydroxylase inhibitor particles are formulated into an oleogel-like structure formed by sunflower oil and glyceryl dibehenate. The gelling concept follows that of disordered structure. The thickening agent, glyceryl dibehenate, is a polar fat that is solid at room temperature but plasticizes in sunflower oil (vegetable oils in general) at temperatures above 40°C. Above this temperature, the binary system sunflower oil and glyceryl dibehenate forms a clear oily liquid. Upon cooling, glyceryl dibehenate begins to recrystallize into small crystalline particles that form a network-like structure in sunflower oil. This situation is comparable to the bentonite structuring mechanism in aqueous systems. When the concentration of glyceryl dibehenate is high enough, an organogel is formed, and a three-dimensional network of partially aggregated crystals occupies the entire volume of the vehicle. When the concentration is low, the particles form a loose structure, floating in the sunflower oil and slowly settling over time. This settling structure then provides support for the micronized hypoxia-inducible factor prolyl hydroxylase inhibitor particles that settle in the glyceryl dibehenate network in a card house-like structure. The co-sedimentation of the micronized hypoxia-inducible factor prolyl hydroxylase inhibitor particles and glyceryl dibehenate is then easy to redisperse. The versatility of these irregular particulate organogels lies in the fact that they do not require a specific physicochemical interaction between the thickener and the supported micronized hypoxia-inducible factor prolyl hydroxylase inhibitor particles.

[0090] Pharmacokinetic data derived for molidustat sodium oil suspension 2.5% show high and almost complete bioavailability (approximately 80%) following oral administration in the target animal cat.

[0091] Oily suspension Pharmaceutical compositions can be formulated as oil suspension.Oil can be almond oil, apricot kernel oil, canola oil, castor oil, coconut oil, cottonseed oil, linseed oil, grape oil, hemp oil, corn oil, olive oil, palm oil, peanut oil, sesame seed oil, soybean oil, sunflower oil, thistle oil, canola oil, rice bran oil, wheat germ oil and mixtures thereof.Oil can be sunflower oil.

[0092] Maize oil (corn oil) may be obtained from corn seeds after pressing or extraction with optional refining. Preferably, the corn oil contains, based on the total amount of fatty acids, 8.6% to 16.5% (w / w) palmitic acid, up to 3.3% (w / w) stearic acid, 20% to 42.2% (w / w) oleic acid, 39.4% to 65.6% (w / w) linoleic acid, 0.5% to 1.5% (w / w) arachidic acid, up to 0.5% (w / w) eicosenoic acid, and up to 0.5% (w / w) behenic acid.

[0093] Sunflower oil may be obtained from sunflower seeds after mechanical pressing or extraction with optional refining. Preferably, the sunflower oil contains 4% to 9% (w / w) palmitic acid, 1% to 7% (w / w) stearic acid, 14% to 40% (w / w) oleic acid, and 48% to 74% (w / w) linoleic acid, based on the total amount of fatty acids.

[0094] Thistle oil (safflower oil) may be obtained from safflower seeds (type I) or from safflower hybrid seeds (type II) with optional refining after expression and / or extraction. Preferably, thistle oil obtained from the type I fraction has a C 2 O 4 content based on the total amount of fatty acids. 14Preferably, the thistle oil obtained from the type II fraction contains a maximum of 0.2% (w / w) saturated fatty acids of chain length less than 1000, a maximum of 0.2% (w / w) myristic acid, 4% to 10% (w / w) palmitic acid, 1% to 5% (w / w) stearic acid, 8% to 21% (w / w) oleic acid, 68% to 83% (w / w) linoleic acid, a maximum of 0.5% (w / w) linolenic acid, a maximum of 0.5% (w / w) arachidic acid, a maximum of 0.5% (w / w) eicosenoic acid, and a maximum of 1% behenic acid, based on the total amount of fatty acids. 14 Preferably, it contains up to 0.2% (w / w) saturated fatty acids of chain length less than 100 nm, up to 0.2% (w / w) myristic acid, 3.6% to 6% (w / w) palmitic acid, 1% to 5% (w / w) stearic acid, 70% to 84% (w / w) oleic acid, 7% to 23% (w / w) linoleic acid, up to 0.5% (w / w) linolenic acid, up to 1% (w / w) arachidic acid, up to 1% (w / w) eicosenoic acid, and up to 1.2% behenic acid.

[0095] The pharmaceutical composition may also contain modified oils, the modification being obtained by alcoholysis, preferably with glycerol, propylene glycol or low molecular weight polyethylene glycols. In this context, it should be understood that low molecular weight polyethylene glycols are defined as follows: H-(O-CH2-CH2) n- OH, where n is selected from 1 to 5, preferably 1 to 4, and optionally 1 to 3 or 1 to 2.

[0096] The modified oil may include oils that may include at least one 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 oil, modified hemp oil, modified corn oil, modified olive oil, modified palm oil, modified peanut oil, modified sesame seed oil, modified soybean oil, modified sunflower oil, modified thistle oil, modified rapeseed oil, modified rice bran oil, modified wheat germ oil, or mixtures thereof, and the modification may be alcoholysis, preferably glycerol, propylene glycol, or low molecular weight polyethylene glycol.In this context, it should be understood that low molecular weight polyethylene glycol is defined as follows.H-(O-CH2-CH2) n- OH, where n is selected from 1 to 5, preferably 1 to 4, and optionally 1 to 3 or 1 to 2.

[0097] Alcoholysis is an example of a solvation reaction, in which triglycerides are reacted with an alcohol, such as methanol or ethanol, to obtain methyl or ethyl esters of fatty acids. Optionally, glycerol may be used as the alcohol. This reaction is also known as transesterification by exchange of alcohol fragments. The alcoholysis reaction is preferably followed by a winterization process to remove certain saturated mono-, di-, and triglycerides.

[0098] For example, Maisine® CC is an exemplary modified corn oil. It is obtained by alcoholysis of corn oil and subsequent winterization of the corn oil. The product contains monoglycerides, diglycerides, and triglycerides, with the monoester fraction consisting of 32% to 52% (w / w), the diester fraction consisting of 40% to 60% (w / w), and the triester fraction consisting of 5% to 20% (w / w) based on the total amount of monoglycerides, diglycerides, and triglycerides.

[0099] Pharmaceutical compositions may include sesame seed oil, soybean oil, sunflower oil, thistle oil, and corn oil, with modification obtained by alcoholysis, preferably with glycerol, propylene glycol, or low molecular weight polyethylene glycols.

[0100] The pharmaceutical composition may include sunflower oil.

[0101] The pharmaceutical composition may include soybean oil.

[0102] The pharmaceutical composition may include modified corn oil.

[0103] The pharmaceutical composition may include a mixture of modified and unmodified oils.

[0104] The pharmaceutical composition may include fish oil. The fish oil may be cod liver oil, salmon oil, or a mixture thereof.

[0105] The fish oil can be obtained from fish of the families Engraulidae, Carangidae, Clupeidae, Scombridae (excluding Thunnus and Bonito), and Sandlanceidae (Type I), or from Thunnus and Bonito belonging to the Scombridae (Type II).The fish oil may contain omega-3 acids such as alpha-linolenic acid (C18:3 n-3), moroctic 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). The fish oil obtained from type I preferably contains at least 28% (w / w) of omega-3 acids in total, expressed as triglycerides. The fish oil obtained from type I preferably contains at least 13% (w / w) of EPA and at least 9% (w / w) of DHA, expressed as triglycerides. The fish oil obtained from type II preferably contains at least 28% (w / w) of omega-3 acids in total, expressed as triglycerides. The fish oil obtained from type II preferably contains 4-12% (w / w) of EPA and at least 20% (w / w) of DHA, expressed as triglycerides.

[0106] Cod liver oil may be obtained from the fresh liver of cod (Gadus morhua L.) and other species of the Gadidae family, and solid material is removed by cooling and filtration. Cod liver oil may contain omega-3 acids such as alpha-linolenic acid (C18:3 n-3), moroctic 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). Cod liver oil preferably contains 10% to 28% (w / w) EPA and DHA expressed as triglycerides. Cod liver oil may further contain 3% to 11% (w / w) linoleic acid, based on the total amount of fatty acids.

[0107] The salmon oil may be obtained from Atlantic salmon (Salmo salar). The positional distribution (β(2)-acyl) is 60-70% for cervonic (docosahexaenoic) acid (C22:6 n-3; DHA), 25%-35% (w / w) for thymnodontic (eicosapentaenoic) acid (C20:5 n-3; EPA), and 40%-55% (w / w) for moroctic acid (C18:4 n-3). The salmon oil preferably contains 10%-28% (w / w) EPA and DHA expressed as triglycerides.

[0108] The pharmaceutical composition may include sunflower oil and fish oil.

[0109] The pharmaceutical compositions may include modified corn oil and fish oil.

[0110] For example, the pharmaceutical compositions described herein include (A) a hypoxia-inducible factor prolyl hydroxylase inhibitor as described herein in an amount of 0.1% to 20%, preferably 0.5% to 10% (w / w); (B) oil in an amount of 50% to 99.8%, preferably 70% to 98.97% (w / w); (C) optionally, fish oil in an amount of 0.01% to 5%, preferably 0.01% to 1.5% (w / w); (D) optionally a thickening agent in an amount of 0.1% to 10%, preferably 0.5% to 5% (w / w); (E) optionally an antioxidant in an amount of 0.01% to 2%, preferably 0.01% to 1.5% (w / w); (F) optionally a preservative in an amount of 0.01% to 2%, preferably 0.01% to 1.5% (w / w);

[0111] The pharmaceutical composition may be free of flavorings. For example, the pharmaceutical composition may be free of flavoring agents. The pharmaceutical compositions described herein may be free of flavoring agents, such as vanilla flavoring agents, anise, honey flavoring agents, or combinations thereof.

[0112] Methods of Making Pharmaceutical Compositions The method of preparing pharmaceutical compositions described herein is prepared in a known manner, including conventional mixing, dissolving or lyophilization process.Therefore, liquid pharmaceutical preparations can be obtained by combining active compound with solid excipient, optionally grinding the mixture obtained, and processing the mixture of granules after adding suitable auxiliary agent if desired or necessary.

[0113] Although preferred embodiments have been shown and described in detail herein, it will be apparent to those skilled in the art that various modifications, additions, and substitutions can be made without departing from the spirit of the invention. These are therefore deemed to be within the scope of the invention as defined in the following claims. Moreover, to the extent not yet indicated, it will be understood by those skilled in the art that any one of the various embodiments described and illustrated herein can be further modified to incorporate features shown in any of the other embodiments disclosed herein.

[0114] The description of the embodiments of the present disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. Although specific embodiments and examples of the present disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the present disclosure, as those skilled in the relevant art will recognize. For example, while steps or functions of a method are presented in a given order, alternative embodiments may perform the functions in a different order or perform the functions substantially simultaneously. The teachings of the present disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the present disclosure can be modified, as appropriate, to adopt compositions, functions, and concepts of the above references and applications to provide still further embodiments of the present disclosure.

[0115] Particular elements of any of the foregoing embodiments may be combined with or substituted for elements of other embodiments. Additionally, although advantages associated with particular embodiments of the present disclosure have been described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments necessarily need to exhibit such advantages in order to fall within the scope of the present disclosure.

[0116] The following examples illustrate some embodiments and aspects of the present invention. It will be apparent to those skilled in the art that various modifications, additions, substitutions, etc. can be made without changing the spirit or scope of the present invention, and such modifications and variations are encompassed within the scope of the present invention as defined in the following claims. The following examples do not limit the present invention in any way. EXAMPLES

[0117] [Example 1] Preparation and analysis of oil suspensions An oil suspension of molidustat sodium was prepared by combining the specified amounts of ingredients as shown in Table 1 below. [Table 1]

[0118] The formulations were analyzed to evaluate the effect of active ingredient particle size on the particle size distribution (PSD) of the final dose. A Malvern laser diffraction instrument was used to measure particle size in suspension. The average particle size measurements are provided in Table 2 below for each formulation. Figures 4 and 5 show the particle size distribution histograms for each formulation. [Table 2]

[0119] A sedimentation analysis comparing the micronized formulation with the non-micronized formulation was performed using a TURBISCAN device (optical principles, light transmittance and backscattering). The results of the analysis are shown in Figure 6. The results show that sedimentation of the non-micronized formulation starts within 1 hour after (re)homogenization, while the micronized formulation remains stable for at least 6 hours and shows only slight sedimentation within 48 hours. The results of this experiment demonstrate that the micronized formulation offers superior quality control for homogeneity, (re)suspendability, and slow sedimentation, which is important for later administration by the user. [Example 2]

[0120] Plasma pharmacokinetic study after oral administration This was a plasma pharmacokinetic study designed to develop the plasma pharmacokinetic profile of molidustat following a single oral (po) dose of its sodium salt (micronized) formulated according to Example 1 to fasted and fed cats. Four adult, healthy, female European Shorthair cats were selected for the study. On the day prior to treatment, food was withheld to ensure a fasted state for oral treatment.

[0121] The pharmacokinetic profile of HIF-PHI was determined in plasma from three adult, female, healthy European shorthair cats with a mean body weight of 3.5 kg (StD = 0.41 kg). One animal was excluded from the study due to difficulties in handling.

[0122] Animals were treated in the fasted state with the test article at a single oral dose rate of 3.0 mg / kg. After a 14-day washout period, animals were treated with the test article at the same dose rate and same route of administration, but in the fed state. Frequent blood samples at fixed intervals were taken over a 48-hour period after each treatment.

[0123] Plasma samples were analyzed for their concentrations of molidustat and its metabolites by HPLC using a tandem mass spectrometry detector (AB Sciex API 4000).

[0124] Pharmacokinetics (PK) from the individual plasma concentration-time profiles obtained were derived using non-compartmental analysis. The mean plasma pharmacokinetics of molidustat are shown in Table 3. [Table 3]

[0125] The peak and extent of plasma exposure of molidustat was higher when administered orally as the sodium salt to cats in the fasted state compared to the fed state. The amount of metabolized molidustat was approximately 60% of the total exposure, regardless of dietary state. The compound was clinically well tolerated without clinical signs of intolerance after two oral treatments at a dose rate of 3.0 mg / kg in cats. Erythropoietin (EPO) concentrations were found to be highly increased after both treatments, i.e., 6 hours after oral administration to fed or fasted cats. The inventors found that oil administration of molidustat in an oil suspension rapidly increased EPO levels without the need for intravenous administration. [Example 3]

[0126] Pharmacodynamic effects on blood parameters This study evaluated the effect of molidustat on red blood cell parameters in healthy adult cats using different formulations of molidustat sodium administered daily via the oral route at different doses. Hematocrit, erythropoietin (EPO), and molidustat plasma concentrations during the treatment phase were considered, with hematocrit representing the primary outcome parameter.

[0127] The study had two phases: a treatment phase, in which an increase in hematocrit was achieved, and an observation phase, in which hematocrit decreased to levels comparable to placebo and within the reference range after cessation of treatment. The study design is outlined in Table 4 below. [Table 4]

[0128] Twenty-two adult cats were randomized into three treatment groups and one control group with 5 and 6 cats per group (3 (2) males / 3 females), respectively. After a 2-week baseline phase, cats were orally dosed once daily in a fasted state. Four different IVP suspensions were administered: placebo oil suspension vehicle, molidustat sodium (micronized) 5% oil suspension, molidustat sodium (micronized) 10% oil suspension, and molidustat sodium (micronized) 10% aqueous suspension. The oil suspensions followed the oil suspensions described in Example 1.

[0129] To maintain a consistent application amount per kg body weight (BW) for each animal, an oil suspension of molidustat was made available in two different concentrations (5% and 10%), such that each cat was treated with 0.1 mL / kg BW of the respective formulation.

[0130] For the evaluation of hematological parameters, blood samples were taken at fixed intervals before, during, and after the treatment phase. In addition, plasma samples were collected before and after treatment on study days (SD) 0, SD 7, and SD 23 and analyzed for EPO and molidustat concentrations.

[0131] All animals receiving molidustat sodium showed an increase in hematocrit above the reference range for up to 42 days after treatment. Hematocrit values ​​met criteria for treatment discontinuation due to exaggerated pharmacodynamic effects already at SD14 in most cats in groups 3 and 4, and at SD21 in cats in group 2. As a result, treatment was omitted in all cats in the respective groups.

[0132] Statistical analysis applied to the treatment phase data resulted in significantly higher mean hematocrit plasma values ​​in the group already treated with 10 mg / kg at SD7 and in the group treated with 5 mg / kg at SD14 compared to placebo. Mean hematocrit values ​​remained significantly higher throughout the treatment period in all groups. Of note, similar results were seen for mean hemoglobin values.

[0133] The mean hematocrit values ​​in the molidustat sodium treatment group returned to levels within the reference range by SD56 and were comparable to those in the placebo group from SD70 onwards. See Figures 1 and 2.

[0134] EPO concentrations were highest in cats in group 4 at 6 hours post-treatment on SD0 and highest in cats in group 3 at 6 hours post-treatment on SD7, consistent with analysis of molidustat plasma concentrations. EPO concentrations (6 hours post-treatment) were significantly different in all molidustat sodium treatment groups compared with the placebo group on all study days measured.

[0135] Plasma EPO concentrations in cats receiving placebo (Group 1) remained at endogenous levels throughout the study.

[0136] Six hours after administration of SD0 and SD7, the mean EPO concentrations peaked in all treatment groups. Six hours after administration of SD0, EPO concentrations were highest in cats in group 4, then group 3, then group 2. However, for SD7, the mean EPO concentrations were highest in cats in groups 3 and 4, then group 2 at 6 hours after administration. Twenty-four hours after treatment with SD1, the mean EPO concentrations were approximately 55 mU / mL in groups 3 and 4, and nearly returned to pretreatment values ​​in group 2. Twenty-four hours after treatment with SD8, the concentrations of EPO in plasma nearly returned to pretreatment values ​​for all groups. See FIG. 3.

[0137] At SD0 and SD7, EPO concentrations in all treatment groups were significantly different from the placebo group. At SD23, EPO concentrations in group 2 (still treatment) were also significantly different from the placebo group.

[0138] Treatment with molidustat sodium was well tolerated and safe in all study groups. Treatment did not affect the body weight of the cats. None of the findings observed during physical examination or general health observations were assessed as adversely affecting the outcome of the study. The most frequently observed finding was vomiting of small amounts of liquid. This adverse event related to treatment (within 4 hours after treatment) was observed across all groups. Adverse events were seen in groups 1-3 at mild doses of less than 10% (group 1: 0.7%, group 2: 3.5%, group 3: 8.8%) and in group 4 at moderate doses of 20%, indicating that administration of the aqueous suspension was less well tolerated than administration of the oily suspension. [Example 4]

[0139] Efficacy in cats with chronic kidney disease (CKD) anemia The objective of this study was to evaluate the safety and efficacy of molidustat for managing anemia associated with chronic kidney disease (CKD) in cats.

[0140] This study was a multicenter, global randomized, blinded, placebo (vehicle)-controlled field study designed to evaluate the efficacy and safety of use of molidustat (micronized) oral suspension according to Example 1 in cats with anemia associated with CKD.

[0141] The study was conducted using a single protocol in the United States (US, n = 23 clinics) and Europe (EU, n = 11 clinics) over a 10-month period. Blood was collected from cats eligible for enrollment on study day (SD)-7 (± 2 days) for serum chemistry and hematology testing. After meeting enrollment criteria, cats were orally dosed once daily (SD0 to SD27) for at least 28 consecutive days with either a control product (CP [vehicle]) or molidustat. Molidustat was administered orally at a dose of 5 mg / kg body weight (bw) (0.2 mL / kg bw). Blood was collected to evaluate blood parameters at SD0, 7, 14, 21, and 28 (± 2 days at all time points except SD0). Blood was also collected for serum chemistry evaluation at SD28 (± 2 days) except for creatinine. Hematocrit (HCT) and packed cell volume (PCV, performed at each clinic) were the main blood parameters of interest. Success of individual animal treatment was assessed using three different criteria up to SD28±2 as well as using only SD28 data.

[0142] A total of 65 cats were screened across 11 US and 9 EU sites. Twenty-three cats (13 from 9 US sites and 10 from 9 EU sites), approximately evenly distributed by sex, primarily domestic shorthair breeds, age range 4-17 years, and initial weight 2-6 kg, were randomized to receive one of the two treatments. A total of 21 cats were included in the 28-day efficacy phase.

[0143] Clinical conclusions from the analysis of HCT and PCV results were nearly identical. The weekly mean response of the anemic CKD control group (CP, n=6) varied as expected, and study participation declined throughout the study. Only three CP cats completed the 28-day study. Four of the six CP-treated cats did not show any relevant increase in both of these parameters. The weekly mean response of the treatment groups was an increase of 1.65% to 3.91% compared to the mean baseline. Compared to the CP group, HCT and PCV results were significantly higher at SD21 (p-values ​​<0.01). The increase observed at SD28 approached statistical significance (p<0.061), primarily due to the small number of CP cats providing data for this study day. Compared to the baseline of each treatment group (baseline control analysis), HCT in both SD21 and SD28 was significantly different from the mean baseline of 3.91% and 3.68%, respectively. Additionally, compared to baseline in each treatment group (baseline-controlled analysis), both SD21 and SD28 PCV values ​​were significantly different from the mean baseline of 3.46% and 3.89%, respectively. Also, the increase in HCT in SD14 was a mean of 1.87% compared to baseline (approaching significance, p=0.0643), and the increase in SD14 PCV was a mean of 2.21% compared to baseline (p=0.0167). In contrast, no significant increases in HCT or PCV were observed compared to baseline in the CP group.

[0144] Based on HCT values, depending on the success criteria, individual animal treatment success rates for each treatment group were 40%-60% for the IVP treatment group and 16.7% for the CP group. Treatment success based on PCV results was 33%-67% for the treatment group and 33% for the CP group. An improvement of approximately 20%-40% was observed between the two groups, but due to limited sample sizes (n=15 for the IVP group and n=6 for the CP group, respectively), statistically significant differences were not obtained.

[0145] In the continuation phase, there were three cats from the US and five from the EU. Two cats received 5 mg / kg bw throughout the continuation phase, five cats were treated intermittently with 2.5 mg / kg bw, and one cat was treated with 5 mg / kg bw until SD 49. Overall, HCT and PCV levels in all eight cats were maintained or increased throughout the continuation phase, except for one cat from the EU region (GA03) that had a lower PCV at SD 77; however, its PCV increased to 26% at SD 84. Results of the continuation phase cats showed that acceptable HCT / PCV levels could be maintained or achieved by intermittent treatment and / or by adjusting the dose of molidustat, with no treatment-related adverse events.

[0146] No treatment-related adverse events were observed when cats were administered molidustat or the other concomitant medications used in the study to treat CKD symptoms. Administration of molidustat at 5 mg / kg body weight once daily for 28 days significantly increased PCV / HCT in SD21 and SD28 compared with SD0 in anemic cats. Treatment was well tolerated, and no treatment-related adverse events were observed when molidustat was administered alone or in combination with other medications used to treat CKD symptoms. [Example 5]

[0147] Plasma pharmacokinetics of molidustat after multiple oral doses of 2.5% (M / V) molidustat oil suspension The plasma pharmacokinetic profile of the test article (molidustat sodium (micronized) oil suspension 2.5% (m / v) according to Example 1) was determined after repeated oral dosing once daily at a target dose rate of 5 mg molidustat sodium per kg bw in healthy adult cats.

[0148] Following a single-group design, eight healthy young adult cats (four neutered males and four spayed females) were included in the study. The animals were aged between 14 and 15.5 months and weighed between 3.35 and 4.95 kg at the start of the survival phase.

[0149] The dose rate administered was 4.8 mg of molidustat sodium per kg. Dosing was once daily for six consecutive days, with 24-hour intervals maintained. Dose rate calculations were based on body weight determined on SD-1 for all doses.

[0150] Thirty-one blood samples were taken per animal according to a predefined schedule deemed adequate to describe the pharmacokinetic profile of the active substance contained in the test article following repeated administration to cats.

[0151] The concentrations of the active substance molidustat and its major metabolites in plasma were analyzed by high-performance liquid chromatography / tandem mass spectrometry. The lower limit of quantification was 5 μg / L for each substance.

[0152] Pharmacokinetic evaluation of plasma concentration data was based on observed data using non-compartmental methods and included all PK parameters to adequately describe the absorption, distribution and elimination phases of the active substance and its metabolites after multiple doses of the test article. Table 5 shows a summary of the mean plasma pharmacokinetics of molidustat and its metabolites, presented as derived after multiple once-daily oral doses of the test article. [Table 5]

[0153] Under actual study conditions, plasma pharmacokinetics were characterized by low interindividual variability. Six repeated doses of the test article once daily at the actual dose rate of 4.8 mg molidustat sodium per kg bw resulted in steady-state plasma pharmacokinetics. No clinically significant accumulation occurred after repeated dosing once daily at the intended therapeutic dose rate, with a calculated accumulation index of 1.1.

[0154] No changes or modifications in derived plasma pharmacokinetics occurred after repeated dosing comparing pharmacokinetics after the first and final dose, indicating that repeated once-daily dosing at a dose of 5 mg molidustat sodium per kg does not affect the metabolism or excretion pattern of molidustat in cats. [Example 6]

[0155] Bioavailability of Molidustat In this study, the plasma pharmacokinetic properties of an article (molidustat sodium (micronized) oil suspension 2.5% (m / v) according to Example 1) were determined with particular consideration of oral bioavailability and dose proportionality. The test article was applied as a single oral dose at 2.5 mg / kg and 10 mg / kg to healthy adult cats with an expected target dose rate of 5 mg molidustat sodium per kg body weight (bw). A suitable reference article (molidustat sodium aqueous solution 2.0% (m / v)) was used to apply a single intravenous bolus dose of 5.0 mg / kg for comparison.

[0156] Sixteen healthy adult cats (8 neutered males and 8 spayed females) were included in the study and assigned to four study groups of 8 animals each, following a mixed sequential / crossover design. The animals were aged between 13.7 and 14.7 months and weighed between 3.3 and 6.0 kg at the start of the survival phase.

[0157] The dose rates administered were an average of 2.42 mg / kg, 4.79, and 9.54 mg of molidustat sodium per kg for the 0.5x, 1x, and 2x dose groups, respectively. The reference item was administered at an actual mean dose rate of 5.15 mg / kg. Dose rate calculations were based on body weights determined prior to each study period.

[0158] Fifteen blood samples were taken per animal after oral dosing (16 samples per animal after intravenous dosing) according to a predefined schedule deemed appropriate to describe the pharmacokinetic profile of the active substances contained in the test and reference articles after a single oral or intravenous dose to cats.

[0159] The active substance molidustat and its major plasma concentrations were analyzed by high performance liquid chromatography / tandem mass spectrometry according to method 01469 (Krebber et al., Analytical method for the determination of BAY 85-3934 and its metabolite BAY 116-3348 in plasma by LC-MS / MS, BAG-CS report MR-15 / 109). The lower limit of quantification was 5 μg / L for each substance.

[0160] Pharmacokinetic evaluation of plasma concentration data was based on observed data using non-compartmental methods and included all PK parameters to adequately describe the absorption, distribution and elimination phases of the active substance and its metabolites after oral or intravenous administration with the test or reference items. For pharmacokinetic evaluation, actual individual dose rates were used to take into account small differences between the target and actual dose rates. All animals completed the survival phase according to the schedule. The animals showed good general health throughout the survival phase. A summary of the mean plasma pharmacokinetics is shown in Table 6. [Table 6]

[0161] Following a single oral dose of the test article, molidustat sodium oil suspension 2.5% (m / v), to cats at a dose rate of 5 mg molidustat sodium per kg, oral bioavailability was high, with a geometric mean of 82% and a range of 57% to 110%.

[0162] Oral administration of the test article at dose rates of 2.5 and 10 mg / kg of molidustat sodium, corresponding to 0.5 to 2 times the target therapeutic dose rate, resulted in a dose-proportional degree of plasma exposure. Plasma exposure rates (Cmax) were slightly non-proportional.

[0163] Following a single intravenous bolus dose of 5 mg / kg molidustat sodium in cats, the mean molidustat plasma exposure was 16.35 mg*hr / L. Molidustat was distributed in the body with a volume of 2.69 L / kg. Plasma clearance was 0.31 L / hr / kg. Molidustat was excreted with a half-life of 5.91 hours.

[0164] Metabolites were assembled in the range of 8.71 mg*hr / L (53% conversion). Plasma clearance was 0.59 L / hr / kg, with an elimination half-life of 5.13 hours. Inter-animal variability was low. Comparison of males and females showed slightly higher plasma clearance (0.33 vs. 0.30 L / hr / kg) and volume of distribution (2.96 vs. 2.36 L / kg) in females, resulting in slightly higher total plasma exposure for both parent and metabolite.

[0165] In conclusion, under real study conditions, the test article, molidustat sodium oil suspension 2.5% (m / v), demonstrated unexpectedly high oral bioavailability (83%) at the target therapeutic dose rate of 5 mg molidustat sodium per kg of cat. Plasma exposure was dose proportional over the tested dose range of 0.5- to 2-fold (2.5-10 mg / kg). There were no relevant gender differences.

[0166] All references cited herein are incorporated by reference as if each reference was specifically and individually indicated to be incorporated by reference. The citation of any reference is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such reference by reason of prior invention.

[0167] Of course, each of the above elements, or two or more together, may find useful application in other types of methods different from those described above. Without further analysis, the foregoing will fully reveal the general outline of the present disclosure, which others may readily adapt to various applications by applying their current knowledge, without omitting features that, in the light of the prior art, fairly constitute essential features of the general or specific aspects of the present disclosure as set forth in the appended claims. The foregoing embodiments are presented by way of example only, and the scope of the present disclosure is limited only by the following claims.

Claims

1. A pharmaceutical composition comprising a hypoxia-inducible factor prolyl hydroxylase inhibitor and an oil.

2. The hypoxia inducible factor prolyl hydroxylase inhibitor is a compound of formula (I) 【Chemical 1】 10. The pharmaceutical composition of claim 1, comprising:

3. wherein the compound of formula I is in the form of a salt having the formula (II): 【Chemistry 2】 In the formula, M is lithium, sodium, potassium, calcium, magnesium, barium, manganese, copper, silver, zinc, iron, ammonium, or substituted ammonium, and one to four of the hydrogen atoms are C １ -C ４ -substituted by alkyl, 3. The pharmaceutical composition of claim 1, wherein m represents the respective positive charge of the cation and is 1, 2, or 3, preferably 1, and n represents the respective stoichiometric amount of the counteranion and is 1, 2, or 3, preferably 1, wherein n is equal to m such that the salt having formula (II) is uncharged.

4. 3. The pharmaceutical composition of claim 1 or 2, wherein the hypoxia-inducible factor prolyl hydroxylase inhibitor comprises a compound of formula (IIA). 【Chemistry 3】

5. 3. The pharmaceutical composition of claim 1, wherein the hypoxia-inducible factor prolyl hydroxylase inhibitor comprises a sodium salt.

6. 3. The pharmaceutical composition of claim 1 or 2, wherein the hypoxia-inducible factor prolyl hydroxylase inhibitor comprises or consists of molidustat, optionally molidustat sodium.

7. 3. The pharmaceutical composition of claim 1, wherein the composition comprises micronized particles comprising a hypoxia-inducible factor prolyl hydroxylase inhibitor, and optionally the micronized particles are characterized by a substantially monomodal particle size distribution.

8. the micronized particles are characterized by a D90 of about 70 μm or less, about 60 μm or less, about 50 μm or less, about 40 μm or less, or about 30 μm or less; and optionally, a D90, wherein the micronized particles are from about 20 μm to about 70 μm, from about 20 μm to about 60 μm, from about 20 μm to about 50 μm, from about 20 μm to about 40 μm, or from about 20 μm to about 30 μm; a D10 of about 0.1 μm to about 10 μm, about 0.2 μm to about 10 μm, or about 0.2 to about 5 μm; and / or 8. The pharmaceutical composition of claim 7, characterized by a D50 of about 1 μm to about 20 μm, about 1 μm to about 15 μm, about 1 μm to about 10 μm, about 5 μm to about 20 μm, about 5 μm to about 15 μm, about 5 μm to about 10 μm, about 10 to about 20 μm, or about 10 to about 15 μm.

9. 3. The pharmaceutical composition of claim 1 or 2, wherein the concentration of the hypoxia-inducible factor prolyl hydroxylase inhibitor is about 1.0% to 20% (m / v), optionally about 1.0% to about 10% (m / v), optionally about 1.0% to about 5.0% (m / v), optionally about 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.50%, 3.75%, 4.0%, 4.25%, 4.50%, 4.75%, or 5.0% (m / v).

10. 3. The pharmaceutical composition of claim 1 or 2, wherein the concentration of the hypoxia-inducible factor prolyl hydroxylase inhibitor is about 1.5% to about 2.5% (m / v), about 2.0% to about 4.5% (m / v), about 2.0% to about 3.0% (m / v), about 1.0% to about 3.0% (m / v), or about 2.0% to about 5.0% (m / v), optionally about 2.5% (m / v).

11. The oil is selected from the group consisting of almond oil, apricot kernel oil, canola oil, castor oil, coconut oil, cottonseed oil, linseed oil, grape oil, hemp oil, corn oil, olive oil, palm oil, peanut oil, sesame seed oil, soybean oil, sunflower oil, thistle oil, canola oil, bran oil, wheat germ oil, 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, corn oil, modified olive oil, modified palm oil, 3. The pharmaceutical composition according to claim 1 or 2, comprising at least one oil selected from the group consisting of modified peanut oil, modified sesame seed oil, modified soybean oil, modified sunflower oil, modified thistle oil, modified rapeseed oil, modified rice bran oil, modified wheat germ oil, and mixtures thereof, wherein the modification is obtained by alcoholysis, preferably using glycerol, propylene glycol, low molecular weight polyethylene glycol, or mixtures thereof, and preferably the oil comprises sunflower oil or modified corn oil.

12. 3. The pharmaceutical composition of claim 1 or 2, wherein the composition further comprises a fish oil, optionally selected from the group consisting of salmon oil, cod liver oil, and mixtures thereof.

13. 13. The pharmaceutical composition of claim 12, wherein the fish oil is in an amount of about 0.01% to about 5% (w / w), optionally wherein the fish oil is in an amount of about 0.01% to about 1.5% (w / w), optionally wherein the fish oil is in an amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% (w / w).

14. 3. The pharmaceutical composition of claim 1, wherein the composition further comprises a thickening agent, optionally comprising a glycerol ester having a C12-C24 fatty acid, optionally wherein the glycerol ester is a monoester, a diester, a triester, or a mixture thereof, and optionally wherein the thickening agent comprises glycerol dibehenate.

15. 15. The pharmaceutical composition of claim 14, wherein the viscosity increasing agent is in an amount of about 0.1% to about 10% (w / w), about 0.1% to about 8% (w / w), or about 0.5% to about 2.5% (w / w), optionally wherein the viscosity increasing agent is in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (w / w).

16. 3. The pharmaceutical composition of claim 1, wherein the composition further comprises an antioxidant, optionally wherein the antioxidant is selected from the group consisting of ascorbyl palmitate, butylhydroxytoluene, butylhydroxyanisole, citric acid, lecithin, propyl gallate, tocopherol, and combinations thereof.

17. 17. The pharmaceutical composition of claim 16, wherein the antioxidant is in an amount of about 0.01% to about 2% (w / w), or about 0.01% to about 1.5% (w / w), optionally wherein the antioxidant is in an amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, or 2% (w / w).

18. 3. The pharmaceutical composition of claim 1, wherein the composition further comprises a preservative, optionally wherein the composition further comprises 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.

19. 19. The pharmaceutical composition of claim 18, wherein the preservative is in an amount of about 0.01% to about 2% (w / w), or about 0.01% to about 1.5% (w / w), optionally wherein the preservative is in an amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, or 2% (w / w).

20. 3. The pharmaceutical composition of claim 1 or 2, wherein the composition further comprises a pharmaceutically acceptable carrier, excipient, lubricant, emulsifier, stabilizer, solvent, diluent, buffer, surfactant, or a combination thereof.

21. 3. The pharmaceutical composition of claim 1 or 2 for use in treating anemia, optionally wherein the anemia is non-regenerative anemia, iron deficiency anemia, pernicious anemia, aplastic anemia, chemotherapy-induced anemia (CIA), immune-mediated hemolytic anemia (IMHA), or hemolytic anemia.

22. 22. The pharmaceutical composition of claim 21, wherein the anemia is associated with chronic kidney disease (CKD).

23. 22. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition is administered once daily.

24. 22. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition is administered once daily for at least 28 consecutive days.

25. 25. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition is administered intermittently once daily after the 28 days of continuous administration.

26. 25. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition is not administered after at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, or at least 14 days after 28 consecutive days of administration.

27. 22. The pharmaceutical composition of claim 21, wherein the subject in need of treatment is a mammal, and optionally, the mammal is a cat.

28. 22. The pharmaceutical composition of claim 21, wherein the composition is formulated for oral administration.

29. 22. The pharmaceutical composition of claim 21, wherein the composition is formulated to be administered at a dose sufficient to provide a maximum plasma concentration (Cmax) of the hypoxia-inducible factor prolyl hydroxylase inhibitor of about 0.5 mg / L or more, about 1 mg / L or more, 1.5 mg / L or more, 2 mg / L or more, 2.5 mg / L or more, 3 mg / L or more, or from about 0.5 mg / L to about 5 mg / L.

30. A pharmaceutical composition according to claim 1 or 2 for use in the treatment of anemia.

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