Use of polyether compounds

Abstract

The present disclosure provides the use of a polyether compound. In one embodiment, the present disclosure relates to improvement of the stability of a polyether compound that uses a polyether compound and improvement of the solubility of a sparingly soluble compound. In one embodiment, the present disclosure relates to a composition that includes a chelating compound, the composition being for stabilizing a polyether compound. In one embodiment, the present disclosure relates to a composition for improving the solubility of a sparingly soluble compound, the composition including at least one of a hydrophobic polyoxyaliphatic moiety-containing polyether compound and a hydrating compound, by combining a hydrophobic polyoxyaliphatic moiety-containing polyether compound and a hydrating compound. In one embodiment, regarding the present disclosure, regarding the polyether compound, the polyether compound includes a poloxamer and polyethylene glycol.

Description

[Technical Field]

[0001] The present disclosure relates to the use of polyether-based compounds, and more particularly to improving the stability of polyether-based compounds and improving the solubility of poorly soluble compounds. [Background technology]

[0002] Polyether compounds such as poloxamers and polyethylene glycols are often used in the formulation of pharmaceuticals and the like (Patent Document 1). Polyether compounds can be oxidatively decomposed by oxygen radicals or light (e.g., UV) in environments such as aqueous solutions. Decomposition of polyether compounds can produce acidic compounds such as acetic acid and formic acid, which can cause a decrease in pH and viscosity. Therefore, it is desirable to improve the stability of polyether compounds.

[0003] Furthermore, many drugs have low solubility in water. For example, solubility in water is a very important factor in the preparation of eye drops, and developing an aqueous formulation of a drug with low solubility can be difficult. When a drug is soluble in oil, an emulsion may be selected as the dosage form, but it is often prepared as a suspension. Suspensions are more difficult to formulate and industrialize than aqueous formulations, and their development takes time. Furthermore, the intraocular penetration of drugs in suspensions is often inferior to that of aqueous formulations, so suspensions require a higher drug concentration, and aqueous formulations are desirable from a safety perspective. Therefore, improving the solubility of poorly soluble compounds is desirable for the preparation of aqueous formulations. [Prior art documents] [Non-patent literature]

[0004] [Patent Document 1] Special Publication No. 9-510712 Summary of the Invention [Means for solving the problem]

[0005] The present inventors have found that combining a polyether-based compound with a chelating compound stabilizes the polyether-based compound. The present inventors have also found that the solubility of poorly soluble compounds can be improved by using a polyether-based compound. The present disclosure provides a formulation that stabilizes a polyether-based compound, and a formulation of a polyether-based compound that improves the solubility of poorly soluble compounds, as well as uses thereof.

[0006] Thus, the present invention provides the following: (Item 1) A composition for stabilizing a polyether-based compound, comprising a chelating compound. (Item 2) A composition comprising a polyether compound and a chelating compound. (Item 3) The composition of any of the preceding items, wherein the polyether-based compound comprises poloxamer and polyethylene glycol. (Item 4) The composition of any of the preceding items, wherein the chelating compound is selected from the group consisting of thiosulfate, ethylenediaminetetraacetic acid (EDTA) or a salt or ion thereof, and citric acid or a salt or ion thereof. (Item 5) The composition of any of the preceding items, wherein the chelating compound comprises a thiosulfate. (Item 6) The composition of any preceding item, wherein the composition further comprises at least one of mannitol and dibutylhydroxytoluene (BHT). (Item 7) The composition of any of the preceding items, wherein the poloxamer has an average molecular weight of about 1,000 to 15,000. (Item 8) The composition of any of the preceding items, wherein the poloxamer contains 10 to 90% by weight of polyoxyethylene per molecule. (Item 9) The composition of any of the preceding items, wherein the poloxamer has polyoxypropylene with an average molecular weight of about 900 to 4000 per molecule. (Item 10) The composition of any of the preceding items, wherein the polyethylene glycol has an average molecular weight of about 200 to 50,000. (Item 11) The composition of any of the preceding items, wherein when prepared at a pH of about 7.5 and stored at 60°C and 1 atm for 4 weeks, the pH change before and after storage is within 0.5. (Item 12) The composition of any of the preceding items, wherein when prepared at a pH of about 7.5 and stored at 60°C and 1 atm for 4 weeks, the viscosity measured with a rotational viscometer at 25°C and 100 rpm decreases by 20% or less before and after storage. (Item 13) A composition for improving the solubility of a poorly soluble compound by combining a hydrophobic polyoxyaliphatic moiety-containing polyether compound and a hydratable compound, the composition comprising at least one of a hydrophobic polyoxyaliphatic moiety-containing polyether compound and a hydratable compound. (Item 14) A composition comprising a sparingly soluble compound, a hydrophobic polyoxyaliphatic moiety-containing polyether-based compound, and a hydratable compound. (Item 15) The composition of any of the preceding items, wherein the hydrophobic polyoxyaliphatic moiety-containing polyether-based compound is a polyoxypropylene-containing polyether-based compound. (Item 16) The composition of any of the preceding items, wherein the hydrophobic polyoxyaliphatic moiety-containing polyether-based compound comprises a poloxamer. (Item 17) The composition of any of the preceding items, wherein the poloxamer has an average molecular weight of about 1,000 to 15,000. (Item 18) The composition of any of the preceding items, wherein the poloxamer contains 10 to 90% by weight of polyoxyethylene per molecule. (Item 19) The composition of any of the preceding items, wherein the poloxamer has polyoxypropylene with an average molecular weight of about 900 to 4000 per molecule. (Item 20) The composition of any of the preceding items, wherein the hydratable compound comprises polyethylene glycol. (Item 21) The composition of any of the preceding items, wherein the polyethylene glycol has an average molecular weight of about 200 to 50,000. (Item 22) The composition of any of the preceding items, wherein the poorly soluble compound has a LogP of 0.5 to 8. (Item 23) The composition of any of the preceding items, wherein the poorly soluble compound has a LogP of 0.5 to 8 at the pH of the composition. (Item 24) The composition according to any of the preceding items, wherein the solubility of the poorly soluble compound is improved by 1.1 times or more by adding the hydratable compound to the hydrophobic polyoxyaliphatic moiety-containing polyether compound under conditions of 25°C and 1 atm atmospheric pressure. (Item 25) The composition of any of the preceding items, wherein the solubility of the poorly soluble compound is improved by 1.5 times or more by adding the hydratable compound to the hydrophobic polyoxyaliphatic moiety-containing polyether compound under conditions of 15°C and 1 atm atmospheric pressure. (Item 26) The composition of any of the preceding items, wherein the solubility of the poorly soluble compound is improved by two times or more by adding the hydratable compound to the hydrophobic polyoxyaliphatic moiety-containing polyether compound under conditions of 5°C and 1 atm atmospheric pressure. (Item 27) The composition of any of the preceding items, comprising a cyclodextrin or a water-soluble polymer. (Item 28) The composition of any preceding item, comprising at least one of sulfobutylether-β-cyclodextrin and carboxymethylcellulose. (Item 29) The composition of any of the preceding items, which is the composition of any one of items 1 to 10. (Item 30) The composition of any of the preceding items, including a buffering agent. (Item 30A) The composition of any of the preceding items, which is an internal preparation, an external preparation, or an injection. (Item 30B) The composition of any of the preceding items, which is for intravenous, intramuscular, subcutaneous, or intravitreal administration. (Item 30C) The composition of any preceding item, wherein the composition is for administration selected from the group consisting of dermal, nasal, ocular, mucosal, rectal, and inhalation administration. (Item 31) The composition of any preceding item for application to the eye. (Item 32) The composition of any of the preceding items, further comprising a pharmaceutically acceptable excipient. (Item 33) The composition of any preceding item which is a pharmaceutical composition. (Item 34) An eye drop comprising the composition of any of the preceding items. (Item 35) A pharmaceutical composition comprising the composition of any of the preceding items and an active ingredient. (Item 36) An ophthalmic pharmaceutical composition comprising the composition of any of the preceding items and an active ingredient. (Item 37) A composition for improving the solubility of a pharmaceutical containing a hydratable compound and a poorly soluble compound, comprising a hydrophobic polyoxyaliphatic moiety-containing polyether compound. (Item 38) A composition for improving the solubility of a pharmaceutical, comprising a hydrophobic polyoxyaliphatic moiety-containing polyether compound, including a hydratable compound, and a poorly soluble compound. (Item 39) A chelating compound for stabilizing polyether compounds. (Item 40) The chelating compound of any preceding item, wherein the polyether compound comprises poloxamer and polyethylene glycol. (Item 41) The chelating compound of any of the preceding items is selected from the group consisting of thiosulfate, ethylenediaminetetraacetic acid (EDTA) or a salt or ion thereof, and citric acid or a salt or ion thereof. (Item 42) Chelating compounds of any of the preceding items, including thiosulfates. (Item 43) The chelating compound of any of the preceding items for use in combination with at least one of mannitol and dibutylhydroxytoluene (BHT). (Item 44) The chelating compound of any of the preceding items, wherein the poloxamer has an average molecular weight of about 1,000 to 15,000. (Item 45) The chelating compound according to any one of the preceding items, wherein the poloxamer contains 10 to 90% by weight of polyoxyethylene in one molecule. (Item 46) The chelating compound according to any one of the preceding items, wherein the poloxamer has polyoxypropylene with an average molecular weight of about 900 to 4000 per molecule. (Item 47) The chelate compound of any of the preceding items, wherein the polyethylene glycol has an average molecular weight of about 200 to 50,000. (Item 48) A chelate compound according to any of the preceding items for preparing a composition which, when prepared at a pH of about 7.5 and stored at 60°C and 1 atm for 4 weeks, shows a change in pH of no more than 0.5 before and after storage. (Item 49) A chelate compound according to any of the preceding items for preparing a composition which, when prepared at a pH of about 7.5 and stored at 60°C and 1 atm for 4 weeks, shows a decrease in viscosity of 20% or less before and after storage as measured with a rotational viscometer at 25°C and 100 rpm. (Item 50) A hydrophobic polyoxyaliphatic moiety-containing polyether compound or a hydratable compound for improving the solubility of a poorly soluble compound by the combination of the hydrophobic polyoxyaliphatic moiety-containing polyether compound and the hydratable compound. (Item 51) The hydrophobic polyoxyaliphatic moiety-containing polyether compound or hydratable compound according to any of the preceding items, wherein the hydrophobic polyoxyaliphatic moiety-containing polyether compound is a polyoxypropylene-containing polyether compound. (Item 52) The hydrophobic polyoxyaliphatic moiety-containing polyether compound or hydratable compound of any preceding item, wherein the hydrophobic polyoxyaliphatic moiety-containing polyether compound comprises a poloxamer. (Item 53) The hydrophobic polyoxyaliphatic moiety-containing polyether compound or hydratable compound of any of the preceding items, wherein the poloxamer has an average molecular weight of about 1,000 to 15,000. (Item 54) The hydrophobic polyoxyaliphatic moiety-containing polyether compound or hydratable compound according to any one of the preceding items, wherein the poloxamer contains 10 to 90% by weight of polyoxyethylene per molecule. (Item 55) The hydrophobic polyoxyaliphatic moiety-containing polyether compound or hydratable compound according to any of the preceding items, wherein the poloxamer has polyoxypropylene with an average molecular weight of about 900 to 4000 per molecule. (Item 56) The hydrophobic polyoxyaliphatic moiety-containing polyether compound or hydratable compound of any preceding item, wherein the hydratable compound comprises polyethylene glycol. (Item 57) The hydrophobic polyoxyaliphatic moiety-containing polyether compound or hydratable compound of any of the preceding items, wherein the polyethylene glycol has an average molecular weight of about 200 to 50,000. (Item 58) The hydrophobic polyoxyaliphatic moiety-containing polyether compound or hydratable compound according to any one of the preceding items, wherein the poorly soluble compound has a LogP of 0.5 to 8. (Item 59) The hydrophobic polyoxyaliphatic moiety-containing polyether compound or hydratable compound according to any of the preceding items, for preparing a composition in which the poorly soluble compound has a LogP of 0.5 to 8 at the pH of the composition. (Item 60) The hydrophobic polyoxyaliphatic moiety-containing polyether compound or hydratable compound according to any one of the preceding items is used to prepare a composition in which the solubility of the poorly soluble compound is improved by 1.1 times or more by adding the hydratable compound to the hydrophobic polyoxyaliphatic moiety-containing polyether compound under conditions of 25°C and 1 atm atmospheric pressure. (Item 61) The hydrophobic polyoxyaliphatic moiety-containing polyether compound or hydratable compound according to any one of the preceding items is used to prepare a composition in which the solubility of the poorly soluble compound is improved by 1.5 times or more by adding the hydratable compound to the hydrophobic polyoxyaliphatic moiety-containing polyether compound under conditions of 15°C and 1 atm atmospheric pressure. (Item 62) The hydrophobic polyoxyaliphatic moiety-containing polyether compound or hydratable compound according to any one of the preceding items is used to prepare a composition in which the solubility of the poorly soluble compound is improved by two times or more by adding the hydratable compound to the hydrophobic polyoxyaliphatic moiety-containing polyether compound under conditions of 5°C and 1 atm atmospheric pressure. (Item 63) The hydrophobic polyoxyaliphatic moiety-containing polyether compound or hydratable compound of any of the preceding items, including cyclodextrin or a water-soluble polymer. (Item 64) The hydrophobic polyoxyaliphatic moiety-containing polyether or hydratable compound of any of the preceding items for use in combination with at least one of sulfobutylether-β-cyclodextrin and carboxymethylcellulose. (Item 65) A chelating compound, a hydrophobic polyoxyaliphatic moiety-containing polyether compound, or a hydratable compound of any of the preceding items for use in combination with a buffering agent. (Item 65A) A chelating compound, a hydrophobic polyoxyaliphatic moiety-containing polyether compound, or a hydratable compound according to any of the preceding items for use in an internal preparation, an external preparation, or an injection. (Item 65B) The chelating compound, hydrophobic polyoxyaliphatic moiety-containing polyether compound or hydratable compound of any of the preceding items for intravenous, intramuscular, subcutaneous or intravitreal administration. (Item 65C) The chelating compound, hydrophobic polyoxyaliphatic moiety-containing polyether compound, or hydratable compound of any of the preceding items for administration selected from the group consisting of dermal administration, nasal administration, ocular administration, mucosal administration, rectal administration, and inhalation administration. (Item 66) A chelating compound, a hydrophobic polyoxyaliphatic moiety-containing polyether-based compound or a hydratable compound of any of the preceding items for application to the eye. (Item 67) The chelating compound, hydrophobic polyoxyaliphatic moiety-containing polyether compound or hydratable compound of any of the preceding items for use in an eye drop. (Item 68) A method for treating a subject in need thereof, comprising administering to the subject a composition comprising a therapeutically effective amount of an active ingredient, a chelating compound, and a polyether-based compound. (Item 69) The method of any preceding item, wherein the polyether-based compound comprises poloxamer and polyethylene glycol. (Item 70) The method of any preceding item, wherein the chelating compound is selected from the group consisting of thiosulfate, ethylenediaminetetraacetic acid (EDTA) or a salt or ion thereof, and citric acid or a salt or ion thereof. (Item 71) The method of any preceding item, wherein the chelating compound comprises a thiosulfate. (Item 72) The method of any preceding item, wherein the composition comprises at least one of mannitol and dibutylhydroxytoluene (BHT). (Item 73) The method of any of the preceding items, wherein the poloxamer has an average molecular weight of about 1,000 to 15,000. (Item 74) The method according to any of the preceding items, wherein the poloxamer contains 10 to 90% by weight of polyoxyethylene per molecule. (Item 75) The method according to any of the preceding items, wherein the poloxamer has polyoxypropylene with an average molecular weight of about 900 to 4000 per molecule. (Item 76) The method of any of the preceding items, wherein the polyethylene glycol has an average molecular weight of about 200 to 50,000. (Item 77) The method of any of the preceding items, wherein the composition, when prepared at a pH of about 7.5 and stored at 60° C. and 1 atm for 4 weeks, exhibits a pH change of no more than 0.5 before and after storage. (Item 78) The method of any of the preceding items, wherein the composition, when prepared at a pH of about 7.5 and stored at 60°C and 1 atm for 4 weeks, exhibits a viscosity decrease of 20% or less before and after storage as measured with a rotational viscometer at 25°C and 100 rpm. (Item 79) A method for treating a subject in need of treatment, comprising administering to the subject an effective amount of a composition comprising a poorly soluble compound, a hydrophobic polyoxyaliphatic moiety-containing polyether compound, and a hydratable compound. (Item 80) The method of any of the preceding items, wherein the hydrophobic polyoxyaliphatic moiety-containing polyether-based compound is a polyoxypropylene-containing polyether-based compound. (Item 81) The method of any of the preceding items, wherein the hydrophobic polyoxyaliphatic moiety-containing polyether-based compound comprises a poloxamer. (Item 82) The method of any of the preceding items, wherein the poloxamer has an average molecular weight of about 1,000 to 15,000. (Item 83) The method according to any of the preceding items, wherein the poloxamer contains 10 to 90% by weight of polyoxyethylene per molecule. (Item 84) The method according to any of the preceding items, wherein the poloxamer has polyoxypropylene with an average molecular weight of about 900 to 4000 per molecule. (Item 85) The method of any preceding item, wherein the hydratable compound comprises polyethylene glycol. (Item 86) The method of any of the preceding items, wherein the polyethylene glycol has an average molecular weight of about 200 to 50,000. (Item 87) The method of any of the preceding items, wherein the poorly soluble compound has a LogP of 0.5 to 8. (Item 88) The method of any of the preceding items, wherein the poorly soluble compound has a LogP of 0.5 to 8 at the pH of the composition. (Item 89) The method according to any of the preceding items, wherein the composition exhibits an improvement in solubility of the poorly soluble compound by 1.1 times or more when the hydratable compound is added to the hydrophobic polyoxyaliphatic moiety-containing polyether compound under conditions of 25°C and 1 atm atmospheric pressure. (Item 90) The method according to any of the preceding items, wherein the composition exhibits an improvement in solubility of the poorly soluble compound by 1.5 times or more when the hydratable compound is added to the hydrophobic polyoxyaliphatic moiety-containing polyether compound under conditions of 15°C and 1 atm atmospheric pressure. (Item 91) The method according to any of the preceding items, wherein the composition exhibits an improvement in solubility of the poorly soluble compound by adding the hydratable compound to the hydrophobic polyoxyaliphatic moiety-containing polyether compound at 5°C and 1 atm atmospheric pressure, which is at least two times greater. (Item 92) The method of any preceding item, wherein the composition comprises a cyclodextrin or a water-soluble polymer. (Item 93) The method of any preceding item, wherein the composition comprises at least one of sulfobutylether-β-cyclodextrin and carboxymethylcellulose. (Item 94) The method of any preceding item, wherein the composition comprises a buffer. (Item 94A) The method of any preceding item, wherein the administering step comprises administering to the subject intravenously, intramuscularly, subcutaneously, or intravitreally. (Item 94B) The method of any preceding item, wherein the administering step comprises administering to the subject dermally, nasally, ocularly, mucosally, rectally, or by inhalation. (Item 95) The method of any preceding item, wherein the administering step comprises administering to the eye of the subject. (Item 96) 1. Use of a chelating compound to stabilize a polyether-based compound in the manufacture of a medicament for treating a subject in need of treatment with an active ingredient. (Item 97) The use of any of the preceding items, wherein the polyether-based compound comprises poloxamer and polyethylene glycol. (Item 98) The use of any of the preceding items, wherein the chelating compound is selected from the group consisting of thiosulfate, ethylenediaminetetraacetic acid (EDTA) or a salt or ion thereof, and citric acid or a salt or ion thereof. (Item 99) The use of any of the preceding items, wherein the chelating compound comprises a thiosulfate. (Item 100) The use of any of the preceding items, wherein at least one of mannitol and dibutylhydroxytoluene (BHT) is further used. (Item 101) The use of any of the preceding items, wherein the poloxamer has an average molecular weight of about 1,000 to 15,000. (Item 102) The use of any of the preceding items, wherein the poloxamer contains 10 to 90% by weight of polyoxyethylene per molecule. (Item 103) The use of any of the preceding items, wherein the poloxamer has polyoxypropylene with an average molecular weight of about 900 to 4000 per molecule. (Item 104) The use of any of the preceding items, wherein the polyethylene glycol has an average molecular weight of about 200 to 50,000. (Item 105) 2. Use of any of the preceding items to prepare a pharmaceutical product which, when prepared at a pH of about 7.5 and stored at 60°C and 1 atm for 4 weeks, exhibits a pH change of no more than 0.5 before and after storage. (Item 106) Use of any of the preceding items to prepare a pharmaceutical product which, when prepared at a pH of about 7.5 and stored at 60°C and 1 atm for 4 weeks, shows a decrease in viscosity of not more than 20% before and after storage as measured with a rotational viscometer at 25°C and 100 rpm. (Item 106) Use of at least one of a hydrophobic polyoxyaliphatic moiety-containing polyether compound and a hydratable compound in the manufacture of a medicament for treating a subject in need of treatment with a poorly soluble compound, to improve the solubility of the poorly soluble compound by the combination of the hydrophobic polyoxyaliphatic moiety-containing polyether compound and the hydratable compound. (Item 107) The use of any of the preceding items, wherein the hydrophobic polyoxyaliphatic moiety-containing polyether-based compound is a polyoxypropylene-containing polyether-based compound. (Item 108) The use of any of the preceding items, wherein the hydrophobic polyoxyaliphatic moiety-containing polyether-based compound comprises a poloxamer. (Item 109) The use of any of the preceding items, wherein the poloxamer has an average molecular weight of about 1,000 to 15,000. (Item 110) The use of any of the preceding items, wherein the poloxamer contains 10 to 90% by weight of polyoxyethylene per molecule. (Item 111) The use of any of the preceding items, wherein the poloxamer has polyoxypropylene with an average molecular weight of about 900 to 4000 per molecule. (Item 112) The use of any of the preceding items, wherein the hydratable compound comprises polyethylene glycol. (Item 113) The use of any of the preceding items, wherein the polyethylene glycol has an average molecular weight of about 200 to 50,000. (Item 114) 3. The use of any of the preceding items, wherein the poorly soluble compound has a LogP of 0.5 to 8. (Item 115) 2. Use of any of the preceding items for the preparation of a composition, wherein the poorly soluble compound has a LogP of 0.5 to 8 at the pH of the composition. (Item 116) Use of any of the preceding items for preparing a composition in which the solubility of the poorly soluble compound is improved by 1.1 times or more by adding the hydratable compound to the hydrophobic polyoxyaliphatic moiety-containing polyether compound under conditions of 25°C and 1 atm atmospheric pressure. (Item 117) Use of any of the preceding items for the preparation of a pharmaceutical, in which the solubility of the poorly soluble compound is improved by 1.5 times or more by adding the hydratable compound to the hydrophobic polyoxyaliphatic moiety-containing polyether compound under conditions of 15°C and 1 atm atmospheric pressure. (Item 118) Use of any of the preceding items for the preparation of a pharmaceutical, in which the solubility of the poorly soluble compound is improved by 2-fold or more by adding the hydratable compound to the hydrophobic polyoxyaliphatic moiety-containing polyether compound under conditions of 5°C and 1 atm atmospheric pressure. (Item 119) The use of any of the preceding items, wherein a cyclodextrin or a water-soluble polymer is further used. (Item 120) The use of any of the preceding items, wherein at least one of sulfobutylether-β-cyclodextrin and carboxymethylcellulose is further used. (Item 121) The use of any of the preceding items wherein a buffering agent is further used. (Item 121A) The use of any of the preceding items, wherein the medicine is an internal medicine, an external medicine, or an injection. (Item 121B) The use of any of the preceding items, wherein the medicament is for intravenous, intramuscular, subcutaneous or intravitreal administration. (Item 121C) The use of any of the preceding items, wherein the medicament is for dermal, nasal, ocular, mucosal, rectal, or inhalation administration. (Item 122) The use of any of the preceding items, wherein the medicament is for application to the eye. (Item 123) The use of any of the preceding items, wherein the medicament is an eye drop.

[0007] It is contemplated that one or more of the above features may be provided in combinations other than those explicitly stated. Still further embodiments and advantages of the present invention will be recognized by those skilled in the art upon reading and understanding the following detailed description, if necessary. [Effects of the Invention]

[0008] The present disclosure provides various formulations that can facilitate and improve the handling of pharmaceuticals, such as drugs. [Brief explanation of the drawings]

[0009] [Figure 1] Figure 1 shows mebendazole solubility at 5°C, 15°C, and 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows mebendazole solubility (%). The horizontal axis shows the polyethylene glycol concentration (%) used. The poloxamer concentration (%) used (in the graph) and the corresponding results are indicated by the same marker. [Figure 2] Figure 2 shows the dexamethasone solubility at 5°C, 15°C, and 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the dexamethasone solubility (%). The horizontal axis shows the polyethylene glycol concentration (%) used. The poloxamer concentration (%) used (in the graph) and the corresponding results are indicated by the same marker. [Figure 3] Figure 3 shows the solubility of triamcinolone acetonide at 5°C, 15°C, or 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the solubility of triamcinolone acetonide (%). The horizontal axis shows the concentration of polyethylene glycol (%) used. The poloxamer concentration (%) used (in the graph) and the corresponding results are indicated by the same marker. [Figure 4] Figure 4 shows the solubility of fluocinolone acetonide at 5°C, 15°C, or 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows fluocinolone acetonide solubility (%). The horizontal axis shows the polyethylene glycol concentration (%) used. The poloxamer concentration (%) used (in the graph) and the corresponding results are indicated by the same marker. [Figure 5]Figure 5 shows the desonide solubility at 5°C, 15°C, or 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows desonide solubility (%). The horizontal axis shows the polyethylene glycol concentration (%) used. The poloxamer concentration (%) used (in the graph) and the corresponding results are indicated by the same marker. [Figure 6] Figure 6 shows the flubendazole solubility at 5°C, 15°C, and 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows flubendazole solubility (%). The horizontal axis shows the polyethylene glycol concentration (%) used. The poloxamer concentration (%) used (in the graph) and the corresponding results are indicated by the same marker. [Figure 7] Figure 7 shows the cilostazol solubility at 5°C, 15°C, and 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the cilostazol solubility (%). The horizontal axis shows the polyethylene glycol concentration (%) used. The poloxamer concentration (%) used (in the graph) and the corresponding results are indicated by the same marker. [Figure 8] Figure 8 shows the itraconazole solubility at 5°C, 15°C, and 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the itraconazole solubility (%). The horizontal axis shows the polyethylene glycol concentration (%) used. The poloxamer concentration (%) used (in the graph) and the corresponding results are indicated by the same marker. [Figure 9] Figure 9 shows the sorafenib solubility at 5°C, 15°C, and 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows sorafenib solubility (%). The horizontal axis shows the polyethylene glycol concentration (%) used. The poloxamer concentration (%) used (in the graph) and the corresponding results are indicated by the same marker symbols. [Figure 10] Figure 10 shows the solubility of regorafenib at 5°C, 15°C, or 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the solubility of regorafenib (%). The horizontal axis shows the concentration (%) of polyethylene glycol used. The concentration (%) of poloxamer used (in the graph) and the corresponding results are indicated by the same marker symbols. [Figure 11] Figure 11 shows the solubility of telmisartan at 5°C, 15°C, and 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the solubility of telmisartan (%). The horizontal axis shows the concentration of polyethylene glycol (%) used. The concentration of poloxamer (%) used (in the graph) and the corresponding results are indicated by the same marker. [Figure 12] Figure 12 shows the solubility of cabozantinib at 5°C, 15°C, or 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the solubility of cabozantinib (%). The horizontal axis shows the concentration of polyethylene glycol (%) used. The concentration of poloxamer (%) used (in the graph) and the corresponding results are indicated by the same marker symbols. [Figure 13] Figure 13 shows the solubility of nilotinib at 5°C, 15°C, or 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the solubility of nilotinib (%). The horizontal axis shows the concentration of polyethylene glycol (%) used. The concentration of poloxamer (%) used (in the graph) and the corresponding results are indicated by the same marker. [Figure 14]Figure 14 shows the aprepitant solubility at 5°C, 15°C, and 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the aprepitant solubility (%). The horizontal axis shows the polyethylene glycol concentration (%) used. The poloxamer concentration (%) used (in the graph) and the corresponding results are indicated by the same marker symbols. [Figure 15] Figure 15 shows the rotenone solubility at 5°C, 15°C, or 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows rotenone solubility (%). The horizontal axis shows the polyethylene glycol concentration (%) used. The poloxamer concentration (%) used (in the graph) and the corresponding results are indicated by the same marker. [Figure 16] Figure 16 shows the griseofulvin solubility at 5°C, 15°C, or 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the griseofulvin solubility (%). The horizontal axis shows the polyethylene glycol concentration (%) used. The poloxamer concentration (%) used (in the graph) and the corresponding results are indicated by the same marker symbols. [Figure 17] Figure 17 shows the solubility of osthole at 5°C, 15°C, or 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the solubility of osthole (%). The horizontal axis shows the concentration of polyethylene glycol (%) used. The concentration of poloxamer (%) used (in the graph) and the corresponding results are indicated by the same marker. [Figure 18] Figure 18 shows the solubility of 4-bromodibenzofuran at 5°C, 15°C, or 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the solubility of 4-bromodibenzofuran (%). The horizontal axis shows the concentration of polyethylene glycol (%) used. The poloxamer concentration (%) used (in the graph) and the corresponding results are indicated by the same marker. [Figure 19] Figure 19 shows the solubility of simvastatin at 5°C, 15°C, or 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows simvastatin solubility (%). The horizontal axis shows the polyethylene glycol concentration (%) used. The poloxamer concentration (%) used (in the graph) and the corresponding results are indicated by the same marker symbols. [Figure 20] Figure 20 shows the solubility of efavirenz at 5°C, 15°C, or 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the solubility of efavirenz (%). The horizontal axis shows the concentration of polyethylene glycol (%) used. The concentration of poloxamer (%) used (in the graph) and the corresponding results are indicated by the same marker. [Figure 21] Figure 21 shows the solubility of rebamipide at 5°C, 15°C, and 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the solubility of rebamipide (%). The horizontal axis shows the concentration of polyethylene glycol (%) used. The poloxamer concentration (%) used (in the graph) and the corresponding results are indicated by the same marker. [Figure 22] Figure 22 shows the solubility of celecoxib at 5°C, 15°C, or 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows celecoxib solubility (%). The horizontal axis shows the polyethylene glycol concentration (%) used. The poloxamer concentration (%) used (in the graph) and the corresponding results are indicated by the same marker. [Figure 23]Figure 23 shows the solubility of celecoxib in the presence of 0.5% CMC at 5°C, 15°C, or 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the solubility (%) of celecoxib in the presence of 0.5% CMC. The horizontal axis shows the concentration (%) of polyethylene glycol used. The concentration (%) of poloxamer used (in the graph) and the corresponding results are indicated by the same marker. [Figure 24] Figure 24 shows the solubility of celecoxib in the presence of 5% SBE-β-CD at 5°C, 15°C, or 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the solubility (%) of celecoxib in the presence of 5% SBE-β-CD. The horizontal axis shows the concentration (%) of polyethylene glycol used. The concentration (%) of poloxamer used (in the graph) and the corresponding results are indicated by the same marker symbols. [Figure 25] Figure 25 shows the solubility of celecoxib in the presence of 5% HP-β-CD at 5°C, 15°C, or 25°C under each additive condition. The top panel shows the results at 5°C, the middle panel shows the results at 15°C, and the bottom panel shows the results at 25°C. The vertical axis shows the solubility (%) of celecoxib in the presence of 5% HP-β-CD. The horizontal axis shows the concentration (%) of polyethylene glycol used. The concentration (%) of poloxamer used (in the graph) and the corresponding results are indicated by the same marker. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present disclosure will now be described, illustrating the best mode thereof. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Thus, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to have the meaning commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0011] The following provides definitions of terms particularly used in this specification and / or explains basic technical content as appropriate.

[0012] As used herein, the term "polyether compound" refers to a compound containing a repeating partial structure having an ether bond, such as a polyoxypropylene chain (-CH-CH(CH)-O-) or a polyoxyethylene chain (-CH-CH-O-). Examples of polyether compounds include poloxamer, polyethylene glycol, polypropylene glycol, and polybutylene glycol.

[0013] As used herein, the term "hydrophobic polyoxyaliphatic moiety" refers to a repeating moiety of -O- (an aliphatic group having 3 or more carbon atoms) in a compound, and the term "hydrophobic polyoxyaliphatic moiety-containing polyether compound" refers to a polyether compound containing a hydrophobic polyoxyaliphatic moiety.

[0014] As used herein, "poloxamer" (also referred to as "poloxamer") refers to a type of polyether compound, a block copolymer containing a polyoxypropylene chain (POP) flanked by polyoxyethylene chains (POE). Poloxamers can be characterized by their molecular weight (average molecular weight), the weight percent of polyoxyethylene, the molecular weight of polyoxypropylene per molecule, and the presence and / or type of modification. Poloxamers herein include those having the structure of Formula I: [ka] (Formula I) (wherein x, y, and z are each independently selected integers of 0 or greater). The term "poloxamer" as used herein includes molecules having the formula (I), but also includes modified molecules thereof. For example, the term "poloxamer" as used herein includes compounds in which the total molecular weight of the partial structures represented by the repeating units -CH2-CH2-O- and -CH2-CH(CH3)-O- accounts for 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the molecular weight of the entire compound. Examples of poloxamer modifications include the following modifications in the structure of Formula I: branching modifications in which one or more hydrogen atoms in the molecule are replaced by -H (-CH2-CH2-O- and / or -CH2-CH(CH3)-O- repeat units); One or more of the repeating units of -CH2-CH2-O- or -CH2-CH(CH3)-O- may be independently replaced by -R 2 -O-, -R 2 -S-, -R 2 - and -R 2 -N(R 1 )-, one or more -OH groups, independently, -NR 1 2, -OR 1 , -SR 1 and -R 1 a modification in which the group is replaced with a group selected from the group consisting of Modifications that replace one or more hydrogen atoms in the molecule with halogen or methyl groups, any combination of the above modifications, (In the formula, R 1 may be substituted C 1~10 Aliphatic group, or its C 1~10 a group in which any carbon atom in an aliphatic group is replaced with an optionally substituted 5- to 7-membered cyclic group, R 2 may be substituted C 1~10 Aliphatic group, or its C 1~10 Any carbon atom in the aliphatic group is replaced with an optionally substituted 5- to 7-membered cyclic group. Examples include, but are not limited to, a poloxamer having a molecular weight of about 4000 in the polyoxypropylene moiety and a polyoxyethylene chain ratio of about 70% is commonly referred to as Poloxamer 407, a poloxamer having a molecular weight of about 1800 in the polyoxypropylene moiety and a polyoxyethylene chain ratio of about 40% is commonly referred to as Poloxamer 184, etc. The relationship between the common name of a poloxamer and its structure is commonly understood by those skilled in the art.

[0015] As used herein, "polyethylene glycol" or "PEG" refers to a type of polyether compound, a copolymer containing polyoxyethylene chains (POE). Polyethylene glycol can be characterized by its molecular weight (average molecular weight), the presence and / or type of modifications. Polyethylene glycols herein typically have the structure of Formula II: HO-(CH2-CH2-O) n -H (formula II) (wherein n is an integer of 0 or more) The term "polyethylene glycol" as used herein includes molecules having the following structure, but also includes modified molecules thereof. For example, polyethylene glycol as used herein can refer to a compound in which the total molecular weight of the partial structure represented by the repeating unit -CH2-CH2-O- accounts for 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the molecular weight of the entire molecule. The following modifications in the structure of Formula II: branching modifications in which one or more hydrogen atoms in the molecule are replaced by -(-CH2-CH2-O- repeat units)-H; One or more of the repeating units of -CH2-CH2-O- may be independently replaced by -R 2 -O-, -R 2 -S-, -R 2 - and -R 2 -N(R 1 )-, one or more -OH groups, independently, -NR 1 2, -OR 1 , -SR 1 and -R 1 a modification in which the group is replaced with a group selected from the group consisting of Modifications that replace one or more hydrogen atoms in the molecule with halogen or methyl groups; any combination of the above modifications, (In the formula, R 1 may be substituted C 1~10 Aliphatic group, or its C 1~10 a group in which any carbon atom in an aliphatic group is replaced with an optionally substituted 5- to 7-membered cyclic group, R 2 may be substituted C 1~10 Aliphatic group, or its C 1~10 Any carbon atom in the aliphatic group is replaced with an optionally substituted 5- to 7-membered cyclic group. Examples include, but are not limited to, those skilled in the art. For example, those skilled in the art will understand that PEG400 has an average molecular weight of 380 to 420, PEG2000 has an average molecular weight of 1800 to 2200, PEG4000 has an average molecular weight of 2600 to 3800, PEG6000 has an average molecular weight of 7300 to 9300, and PEG20000 has an average molecular weight of 15000 to 25000. Furthermore, those skilled in the art will understand that in PEGs represented with a small number, such as PEG-4, the number represents the number of polyoxyethylene repeating units in the molecule. Those skilled in the art will clearly understand the structure and composition of polyethylene glycols with specific names (e.g., PEG2000).

[0016] As used herein, "polypropylene glycol" refers to a copolymer containing a polyoxypropylene chain, and "polybutylene glycol" refers to a copolymer containing a polyoxybutylene chain (POE), both of which are types of polyether compounds. Polypropylene glycol and polybutylene glycol can be characterized by their molecular weight (average molecular weight), the presence and / or type of modification. Polypropylene glycol and polybutylene glycol as used herein typically have the structures of Formula III and Formula IV, respectively: HO-(CH2-CH(CH3)-O) n -H (formula III) HO-(CH2-CH2-CH(CH3)-O) n -H (formula IV) (wherein n is an integer of 0 or more) The term "polypropylene glycol" and "polybutylene glycol" as used herein refers to compounds in which the total molecular weight of the partial structures represented by the repeating units -CH2-CH(CH3)-O- and -CH2-CH2-CH(CH3)-O-, respectively, is 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the molecular weight of the entire molecule. The following modifications in the structures of Formula III and Formula IV: branched modifications in which one or more hydrogen atoms in the molecule are replaced by -(-CH2-CH(CH3)-O- or -CH2-CH2-CH(CH3)-O- repeat units)-H, One or more of the repeating units of -CH2-CH(CH3)-O- or -CH2-CH2-CH(CH3)-O- may be independently replaced by -R 2 -O-, -R 2 -S-, -R 2 - and -R 2 -N(R 1 )-, one or more -OH groups, independently, -NR 1 2, -OR 1 , -SR 1 and -R 1 a modification in which the group is replaced with a group selected from the group consisting of Modifications that replace one or more hydrogen atoms in the molecule with halogen or methyl groups; any combination of the above modifications, (In the formula, R 1 may be substituted C 1~10 Aliphatic group, or its C 1~10 a group in which any carbon atom in an aliphatic group is replaced with an optionally substituted 5- to 7-membered cyclic group, R 2 may be substituted C 1~10 Aliphatic group, or its C 1~10 Any carbon atom in the aliphatic group is replaced with an optionally substituted 5- to 7-membered cyclic group. These include, but are not limited to:

[0017] As used herein, "molecular weight" in reference to polymeric substances (e.g., poloxamers, polyethylene glycols, etc.) refers to average molecular weight, unless otherwise specified, and refers to experimentally determined average molecular weight, unless otherwise specified.

[0018] As used herein, "average molecular weight" refers to "number average molecular weight" unless otherwise specified. However, when specifically mentioned, "weight average molecular weight," "viscosity average molecular weight," or other experimentally determined average molecular weights may also be used. However, it should be noted that in the examples and other sections of this specification, the average molecular weight of PEG (e.g., PEG 4000) typically refers to the number average molecular weight, and the average molecular weight of poloxamer (e.g., poloxamer 407) typically refers to the weight average molecular weight. Experimentally measured average molecular weights can be determined by those skilled in the art, for example, by diluting a test solution containing the polymer whose average molecular weight is to be measured, as necessary, and measuring the osmotic pressure, boiling point elevation, or freezing point depression, and these are used as the weight average molecular weight, number average molecular weight, etc., depending on the method.

[0019] As used herein, the term "hydratable compound" refers to a compound that has a strong tendency to become hydrated in solution.

[0020] As used herein, the term "poorly soluble compound" generally refers to a compound that is poorly soluble in aqueous solvents. Poorly soluble compounds are described in more detail elsewhere in this specification, but in addition to being evaluated based on the LogP value, they can also be evaluated based on the solubility ratio in aqueous and non-aqueous solvents, or based on the structural characteristics of the compound.

[0021] As used herein, the "LogP" of a compound refers to Log(Co / Cw) of the compound at 25°C and 1 atm atmospheric pressure (where Co is the compound concentration in n-octanol, and Cw is the compound concentration in water). However, as used herein, the LogP of a compound at a specific pH refers to the partition coefficient obtained when a minimum amount of an acid or base (e.g., hydrochloric acid or sodium hydroxide) that does not decompose the test compound is added to a mixture of octanol, water, and the test compound during an experiment to derive the octanol / water partition coefficient, and the pH of the aqueous layer of the mixture is adjusted to this specific pH.

[0022] As used herein, the term "substituent" refers to an atom or functional group that replaces one chemical group with another in the chemical structure of a compound.

[0023] When a group, moiety, or compound is "substituted," at least one hydrogen atom in the group, moiety, or compound is replaced with a group (substituent) other than hydrogen, and the number of the substituents is not particularly limited as long as it is substitutable, and may be one or more. Unless otherwise specified, the description of each group also applies when the group is a part or substituent of another group. For example, C 1~6 When an alkyl group is substituted with a substituent, the number of carbon atoms of the substituent is not included in the number of carbon atoms of the alkyl group. The same applies to other groups.

[0024] "C 1~6 " means that the number of carbon atoms is 1 to 6. The same applies to other numbers, for example, "C 1~4 " means that the number of carbon atoms is 1 to 4. 1~6 The term "alkyl group" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms.

[0025] As used herein, the term "optionally substituted" means that a group may or may not be substituted with a substituent.

[0026] As used herein, "alkyl group" refers to a straight or branched chain saturated hydrocarbyl group having carbon atoms. 1~3 Examples of alkyl groups include methyl, ethyl, propyl, and isopropyl groups. 1~4 Examples of alkyl groups include the aforementioned C 1~3 Examples include alkyl groups, as well as butyl, isobutyl, sec-butyl, and tert-butyl groups. 1~6 Examples of alkyl groups include the aforementioned C 1~4 Examples include alkyl groups, as well as pentyl groups, isopentyl groups, neopentyl groups, and hexyl groups.

[0027] As used herein, an "alkylene group" is a divalent group formed by removing one additional hydrogen from an "alkyl group." Specific examples of alkylene groups include, but are not limited to, -CH-, -CHCH-, -(CH)-, -CHCH(CH)-, -(CH)-, -CHCHCH(CH)-, and -CHCH(CH)CH-.

[0028] As used herein, "alkenyl group" refers to a straight-chain or branched-chain hydrocarbyl group having carbon atoms and one or more carbon-carbon double bonds. The one or more carbon-carbon double bonds may be internal (e.g., the double bonds in 2-butenyl) or terminal (e.g., the double bonds in 1-butenyl). 2~4 Examples of alkenyl groups include ethenyl (vinyl), 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and butadienyl groups. 2~6 Examples of alkenyl groups include the aforementioned C 2~4 Examples include an alkenyl group, as well as a pentenyl group, a pentadienyl group, a hexenyl group, and the like.

[0029] As used herein, an "alkenylene group" is a divalent group formed by removing one additional hydrogen atom from an "alkenyl group." Specific examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CH-CH2-, -CH=CH-(CH2)2-, -CH2-CH=CH-CH2-, -CH=C(CH3)-CH2-, -CH=CH-CH=CH-, -CH=CH-(CH2)3-, and the like.

[0030] As used herein, an "alkoxyl group" is a monovalent group of -O-alkyl. Examples of alkoxyl groups include C 1~6 Alkoxyl groups (i.e., C 1~6 Alkyl-O-), C 1~4 Alkoxyl groups (i.e., C 1~4 alkyl-O-) and the like.

[0031] As used herein, "aliphatic group" refers to alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene groups, and does not include cyclic hydrocarbon groups. For example, C 1~5 Illustrative examples of aliphatic groups include, but are not limited to, -CH3, -CH2-, -CH2CH2-, -CH2CH3, -CH=CH-, -CH=CH2, -C≡CH, -C≡C-, -CH2CH2CH3, -CH2CH2CH2-, -CH=CHCH3, -C≡CCH3, -CH2CH=CH2, -CH2C≡CH, -CH2CH(CH3)-, and -CH2CH(CH3)CH3.

[0032] As used herein, "halo" or "halogen" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).

[0033] As used herein, the term "aryl group" refers to a single aromatic ring or a fused polycyclic ring system in which at least one of the rings is aromatic and all ring atoms are carbon. Aryl groups include phenyl groups. Aryl groups also include fused polycyclic ring systems (e.g., ring systems containing 2, 3, or 4 rings) in which at least one ring is aromatic and the other rings may or may not be aromatic. The rings of a fused polycyclic ring system may be connected to each other via fused, spiro, and bridged bonds, if valence requirements permit. Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthryl, pyrenyl, and the like.

[0034] As used herein, the term "heteroaryl group" refers to a single aromatic ring or fused polycyclic ring system having at least one heteroatom in the ring, the heteroatom being selected from the group consisting of oxygen, nitrogen, and sulfur. Heteroaryl groups include single aromatic rings having about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. Such rings include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, furyl, and the like. The sulfur and nitrogen atoms may also be present in oxidized form if the ring is aromatic. Heteroaryl groups also include fused polycyclic ring systems (e.g., ring systems containing 2, 3, or 4 rings) in which the heteroaryl groups defined above can be fused with one or more rings selected from heteroaryl (e.g., to form naphthyridinyl, e.g., 1,8-naphthyridinyl), heterocycle (e.g., to form 1,2,3,4-tetrahydronaphthyridinyl, e.g., 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (e.g., to form 5,6,7,8-tetrahydroquinolyl), and aryl (e.g., to form indazolyl) to form a fused polycyclic ring system. It is also understood that the point of attachment of the fused polycyclic ring system can be at any position of the fused polycyclic ring system, including the heteroaryl, heterocycle, aryl, or carbocyclic portion of the fused polycyclic ring system, and at any suitable atom of the fused polycyclic ring system, including carbon atoms and heteroatoms (e.g., nitrogen). Exemplary heteroaryl groups include, but are not limited to, quinolyl, benzothiazolyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, isoquinolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinylbenzofuranyl, benzimidazolyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole.

[0035] As used herein, a "carbocycle" or "carbocyclic group," alone or as part of another group, refers to a monocyclic, bicyclic, tricyclic or higher polycyclic hydrocarbon group that is fully saturated or contains one or more units of unsaturation, but is not aromatic. In one embodiment, a carbocyclic group is a monocyclic C 3~9 Hydrocarbon group, bicyclic C 8~12 Hydrocarbon group or tricyclic C 10~16 It may be a hydrocarbon group. Any individual ring in the carbocyclic group may have 3 to 7 ring atoms. Examples of carbocyclic groups include, but are not limited to, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl; cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and cyclononenyl; and cycloalkynyl groups such as cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl, cycloheptynyl, cyclooctynyl, and cyclononyl; and adamantyl groups. In a carbocyclic group, any ring atom may be attached to the remainder of the molecule, if possible.

[0036] As used herein, a "heterocycle," "heterocyclic group," or "heterocyclic group," alone or as part of another group, refers to a monocyclic, bicyclic, tricyclic, or higher polycyclic ring system in which at least one ring in the ring system contains one or more heteroatoms, which may be the same or different, and is either fully saturated or contains one or more units of unsaturation, but is not aromatic. In some embodiments, a "heterocycle" or "heterocyclic group" has 3 to 14 ring atoms, where one or more ring atoms is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the ring system contains 3 to 8 ring atoms.

[0037] Examples of heterocyclic groups include a 2-tetrahydrofuranyl group, a 3-tetrahydrofuranyl group, a 2-tetrahydrothiophenyl group, a 3-tetrahydrothiophenyl group, a 2-morpholino group, a 3-morpholino group, a 4-morpholino group, a 2-thiomorpholino group, a 3-thiomorpholino group, a 4-thiomorpholino group, a 1-pyrrolidinyl group, a 2-pyrrolidinyl group, a 3-pyrrolidinyl group, a 1-tetrahydropiperazinyl group, a 2-tetrahydropiperazinyl group, a 3-tetrahydropiperazinyl group, a 1-piperidinyl group, a 2-piperidinyl group, a 3-piperidinyl group, a 1-pyrazolinyl group, a 3-pyrazolinyl group, a 4-pyrazolinyl group, and a 5-pyrazolinyl group. Examples of heterocyclic groups include, but are not limited to, monocyclic rings such as 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, and 5-imidazolidinyl groups, and bicyclic rings such as 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and 1,3-dihydro-imidazol-2-one groups. In heterocyclic groups, any ring atom may be attached to the remainder of the molecule, if possible.

[0038] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0039] As used herein, the term "cyclic group" refers to an aryl group, an arylene group, a monovalent or divalent carbocyclic group, a monovalent or divalent heterocyclic group, a heteroaryl group, or a heteroarylene group. Specific examples of 5- to 7-membered cyclic groups include, but are not limited to, phenyl, phenylene, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, cyclohexynyl, adamantyl, quinolyl, benzothiazolyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, imidazolyl, tetrahydrofuranyl, morpholino, pyrrolidinyl, piperidinyl, and thiazolidinyl groups.

[0040] When a "heterocycle", "heterocyclic group" or "heteroaryl group" is substituted, it may have a substituent on the heteroatom, if substitutable.

[0041] As used herein, the term "means" refers to any tool that can achieve a certain purpose (e.g., detection, treatment), and in particular, as used herein, "means for selectively recognizing (detecting)" refers to a means that can recognize (detect) a certain object differently from others.

[0042] As used herein, the term "pharmaceutical ingredient" refers to any component that can constitute a pharmaceutical, and examples thereof include active ingredients (components that themselves exhibit medicinal effects), additive ingredients (components that are not expected to have medicinal effects themselves, but are expected to play a certain role when included in a pharmaceutical (e.g., excipient, lubricant, surfactant, etc.)), and adjuvants (components that enhance the medicinal effects of active ingredients). A pharmaceutical ingredient may be a single substance, or a combination of multiple substances or agents. It may also include any combination, such as a combination of an active ingredient and an additive ingredient, or a combination of an adjuvant and an active ingredient.

[0043] As used herein, the term "active ingredient" refers to an ingredient that exerts an intended medicinal effect, and may refer to a single ingredient or multiple ingredients.

[0044] As used herein, the term "additive component" refers to any component that is not expected to have a medicinal effect but that plays a certain role when included in a pharmaceutical, and examples thereof include pharmaceutically acceptable carriers, stabilizers, (co)adjuvants, solubility improvers, solubilizers, diluents, excipients, buffers, binders, blasting agents, diluents, flavorings, and lubricants.

[0045] As used herein, the term "subject" refers to a subject that is the target of treatment or the like (including living organisms such as humans, as well as cells, blood, and serum extracted therefrom).

[0046] As used herein, the terms "drug," "agent," or "factor" (all of which correspond to the English term "agent") are used interchangeably in a broad sense and may refer to any substance or other element (e.g., energy such as light, radioactivity, heat, or electricity) that can achieve the intended purpose. Examples of such substances include, but are not limited to, proteins, polypeptides, oligopeptides, peptides, polynucleotides, oligonucleotides, nucleotides, nucleic acids (e.g., DNA such as cDNA and genomic DNA, and RNA such as mRNA), polysaccharides, oligosaccharides, lipids, small organic molecules (e.g., hormones, ligands, signaling substances, small organic molecules, molecules synthesized by combinatorial chemistry, small molecules that can be used as pharmaceuticals (e.g., small molecule ligands), etc.), and composite molecules thereof.

[0047] As used herein, the term "therapeutic agent" broadly refers to any drug capable of treating a target condition. In one embodiment of the present disclosure, the "therapeutic agent" may be a pharmaceutical composition containing an active ingredient and one or more pharmacologically acceptable carriers. The pharmaceutical composition can be prepared, for example, by mixing the active ingredient with the carrier(s) using any method known in the technical field of pharmaceuticals.

[0048] As used herein, the term "prophylactic agent" broadly refers to any agent that can prevent a target condition.

[0049] As used herein, the term "kit" refers to a unit in which the components to be provided (e.g., detection agent, therapeutic agent, preventive agent, instructions, etc.) are provided, usually separated into two or more compartments. This kit form is preferred when the purpose is to provide a composition that should not be provided in a mixed state for reasons of stability, etc., but is preferably mixed immediately before use. Such a kit advantageously includes instructions or instructions describing how to use the provided components or how to handle the reagents. When the kit is used herein as a reagent kit, the kit usually includes instructions describing how to use the detection agent, therapeutic agent, preventive agent, etc.

[0050] As used herein, "instructions" refer to written instructions for a physician or other user on how to use the present disclosure. The instructions contain language directing administration of the medicament or the like of the present disclosure. The instructions may also contain language directing the mode of administration. The instructions are prepared in accordance with a format specified by the regulatory agency of the country in which the present disclosure is implemented (e.g., the Ministry of Health, Labor and Welfare in Japan, or the Food and Drug Administration (FDA) in the United States), and clearly state that they have been approved by the regulatory agency. The instructions are what is known as a package insert, and are usually provided in paper form, but are not limited thereto and may also be provided in the form of electronic media (e.g., a homepage provided on the Internet, email, etc.).

[0051] The term "about" refers to the indicated value plus or minus 10%. When "about" is used in reference to temperature, it refers to the indicated temperature plus or minus 5°C, and when "about" is used in reference to pH, it refers to the indicated pH plus or minus 0.5.

[0052] (Preferred embodiment) Preferred embodiments of the present disclosure will be described below. The embodiments provided below are provided for a better understanding of the present disclosure, and it is understood that the scope of the present disclosure should not be limited to the following description. Therefore, it is clear that those skilled in the art can make appropriate modifications within the scope of the present disclosure in light of the description herein. It is also understood that the following embodiments can be used alone or in combination.

[0053] In one aspect, the present disclosure provides improved stability of polyether compounds and / or improved solubility (e.g., aqueous solubility) of poorly soluble compounds. Any means for achieving this are contemplated as falling within the scope of the present disclosure. For example, even if not explicitly stated, a description of a method for using a certain component also contemplates embodiments reflecting other means, such as a composition containing the component, the use of the component, and the component for use in the method. In this specification, the present disclosure is described primarily in terms of composition embodiments, but a description of a composition containing a certain component for a certain use also contemplates embodiments reflecting other means, such as a method for the use of the component and the use of the component.

[0054] (Stability-enhancing composition) In one aspect, the present disclosure provides a composition for stabilizing a polyether-based compound, comprising one or more chelating compounds, and in one embodiment, a composition comprising a polyether-based compound that utilizes this effect.

[0055] In one embodiment, the polyether-based compound to be stabilized is -R 2 -O-(wherein, R 2 may be substituted C 1~10 Aliphatic group, or its C 1~10 A group in which any carbon atom in an aliphatic group is replaced with an optionally substituted 5- to 7-membered cyclic group, where "optionally substituted" means that one or more hydrogen atoms are each independently substituted with a monovalent C 1~5 Aliphatic groups, halogens, -OH, -O-(monovalent C 1~5Aliphatic groups), -COOH, -CO- (monovalent C 1~5 Aliphatic group), -CO-NH2, -CO-NH-(monovalent C 1~5 Aliphatic groups), -COH, -SH, -S- (monovalent C 1~5 Aliphatic group), -NH2, -NH-(monovalent C 1~5 Aliphatic group), -N-(monovalent C 1~5 The polyether-based compound to be stabilized may contain repeating units of the aliphatic group (meaning that the repeating units may be replaced by an aliphatic group, -NO, -POH, -SOH, -CN, or a monovalent 5- to 7-membered cyclic group). In one embodiment, the stabilized polyether-based compound may have an average molecular weight of about 200 to 50,000, about 500 to 20,000, about 1,000 to 15,000, about 2,000 to 10,000, about 500 to 20,000, about 500 to 10,000, about 500 to 5,000, about 1,000 to 50,000, about 1,000 to 20,000, about 1,000 to 10,000, about 1,500 to 20,000, or about 1,500 to 15,000. In one embodiment, the stabilized polyether-based compound may include at least one of poloxamer, polyethylene glycol, polypropylene glycol, and polybutylene glycol. In one embodiment, the stabilized polyether-based compound may include poloxamer and polyethylene glycol.

[0056] In one embodiment, the stabilized poloxamer can have an average molecular weight of about 500-20,000, about 1,000-15,000, about 2,000-10,000, about 500-20,000, about 500-10,000, about 500-5,000, about 1,000-50,000, about 1,000-20,000, about 1,000-10,000, about 1,500-20,000, or about 1,500-15,000. In one embodiment, the stabilized composition of the present disclosure can contain about 1-50% by weight, about 1-40% by weight, about 2-30% by weight, about 5-25% by weight, about 10-30% by weight, about 1-20% by weight, about 2-20% by weight, about 5-20% by weight, about 15-30% by weight, or about 15-40% by weight of the poloxamer. In one embodiment, the stabilized poloxamer can include poloxamer 101, poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer 403, or poloxamer 407. In one embodiment, the stabilized poloxamer may include poloxamer 407.

[0057] In one embodiment, the stabilized poloxamer has a molecular weight of about 5 to 95% by weight, about 10 to 95% by weight, about 20 to 95% by weight, about 30 to 95% by weight, about 40 to 95% by weight, about 5 to 90% by weight, about 10 to 90% by weight, about 20 to 90% by weight, about 30 to 90% by weight, about 40 to 90% by weight, about 5 to 80% by weight, about 10 to 80% by weight, about 20 to 80% by weight, about 30 to 8 ... The polyoxyethylene content may be 80% by weight, about 5 to 70% by weight, about 10 to 70% by weight, about 20 to 70% by weight, about 30 to 70% by weight, about 40 to 70% by weight, about 5 to 60% by weight, about 10 to 60% by weight, about 20 to 60% by weight, about 30 to 60% by weight, about 40 to 60% by weight, about 5 to 50% by weight, about 10 to 50% by weight, about 20 to 50% by weight, about 30 to 50% by weight, or about 40 to 50% by weight.

[0058] In one embodiment, the stabilized poloxamer has a ratio of the number of oxyethylene units to the total number of oxyethylene units + oxypropylene units in one molecule of about 5 to 95%, about 10 to 95%, about 15 to 95%, about 20 to 95%, about 30 to 95%, about 40 to 95%, about 50 to 95%, about 5 to 90%, about 10 to 90%, about 15 to 90%, about 20 to 90%, about 30 to 90%, about 40 to 90%, about 50 to 90%, about 5 to 80%, about 10 to 80%, about 15 to 80%, about 16 to 180%, about 18 to 200%, about 20 ... It can be about 20 to 80%, about 30 to 80%, about 40 to 80%, about 50 to 80%, about 5 to 70%, about 10 to 70%, about 15 to 70%, about 20 to 70%, about 30 to 70%, about 40 to 70%, about 50 to 70%, about 5 to 65%, about 10 to 65%, about 15 to 65%, about 20 to 65%, about 30 to 65%, about 40 to 65%, about 50 to 65%, about 5 to 60%, about 10 to 60%, about 15 to 60%, about 20 to 60%, about 30 to 60%, about 40 to 60%, or about 50 to 60%. In one preferred embodiment, the stabilized poloxamer can have a ratio of the number of oxyethylene units to the number of oxyethylene units plus oxypropylene units in one molecule of about 70% or less, about 65% or less, or about 60% or less.

[0059] In one embodiment, the stabilized poloxamer may have a polyoxypropylene average molecular weight of about 500 to 15,000, about 600 to 10,000, about 700 to 7,000, about 900 to 10,000, about 900 to 7,000, about 900 to 4,000, about 1,000 to 10,000, about 1,000 to 7,000, about 1,500 to 7,000, about 2,000 to 7,000, or about 2,500 to 7,000 per molecule.

[0060] In one embodiment, the stabilized poloxamer has the structure of Formula I: [ka] (Formula I) (wherein x, y, and z are each independently selected integers of 0 or greater). or a molecule having the same, modified therefrom. In one embodiment, x = 1 to 1000, y = 1 to 1000, and z = 1 to 1000. In one embodiment, x = 10 to 500, y = 10 to 500, and z = 10 to 500. In one embodiment, x = 50 to 200, y = 50 to 200, and z = 50 to 200. In one embodiment, the stabilized poloxamer may be a compound in which the sum of the molecular weights of the partial structures represented by -CH2-CH2-O- and -CH2-CH(CH3)-O- repeating units is 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the molecular weight of the entire compound.

[0061] In one embodiment, the stabilized poloxamer has the following modifications in the structure of Formula I above: branching modifications in which one or more hydrogen atoms in the molecule are replaced by -H (-CH2-CH2-O- and / or -CH2-CH(CH3)-O- repeat units); One or more of the repeating units of -CH2-CH2-O- or -CH2-CH(CH3)-O- may be independently replaced by -R 2 -O-, -R 2 -S-, -R 2 - and -R 2 -N(R1 )-, one or more -OH groups, independently, -NR 1 2, -OR 1 , -SR 1 and -R 1 a modification in which the group is replaced with a group selected from the group consisting of Modifications that replace one or more hydrogen atoms in the molecule with halogen or methyl groups, any combination of the above modifications, (In the formula, R 1 may be substituted C 1~10 Aliphatic group, or its C 1~10 a group in which any carbon atom in an aliphatic group is replaced with an optionally substituted 5- to 7-membered cyclic group, R 2 may be substituted C 1~10 Aliphatic group, or its C 1~10 a group in which any carbon atom in an aliphatic group is replaced with an optionally substituted 5- to 7-membered cyclic group, "Optionally substituted" means that one or more hydrogen atoms are each independently substituted with a monovalent C 1~5 Aliphatic groups, halogens, -OH, -O-(monovalent C 1~5 Aliphatic groups), -COOH, -CO- (monovalent C 1~5 Aliphatic group), -CO-NH2, -CO-NH-(monovalent C 1~5 Aliphatic groups), -COH, -SH, -S- (monovalent C 1~5 Aliphatic group), -NH2, -NH-(monovalent C 1~5 Aliphatic group), -N-(monovalent C 1~5 aliphatic group) means that it may be substituted with 2, -NO2, -PO3H, -SO3H, -CN, or a monovalent 5- to 7-membered cyclic group The compound may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 modifications selected from the group consisting of:

[0062] In one embodiment, the stabilized poloxamer can be a compound containing one, two, three, four, or five branching modifications, replacing one or more hydrogen atoms in the molecule with -(-CH-CH-O- and / or -CH-CH(CH)-O- repeat units)-H. In one embodiment, the stabilized poloxamer can be a propylene glycol-based compound having the structure of Formula I above, where one hydrogen atom in each CH of one, two, or three -CH-CH(CH)-O- repeat units is replaced with -OH or -(-CH-CH-O- and / or -CH-CH(CH)-O- repeat units)-H.

[0063] In one embodiment, the stabilized poloxamer has 1 to 20, 1 to 15, 1 to 10, or 1 to 5, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, of the —CH—CH—O— or —CH—CH(CH)—O— repeat units independently substituted with —R 2 -O-, -R 2 -S-, -R 2 - and -R 2 -N(R 1 )-.

[0064] In one embodiment, the stabilized poloxamer has 1 to 20, 1 to 15, 1 to 10, or 1 to 5, e.g., 1, 2, 3, 4, or 5, —OH groups independently replaced with —NR 1 2, -OR 1 , -SR 1 and -R 1 The compound may include a modification in which the group is replaced with a group selected from the group consisting of:

[0065] In one embodiment, the stabilized poloxamer can be a compound containing a modification in which 1 to 100, 1 to 70, 1 to 50, 1 to 30, 1 to 20, 1 to 15, 1 to 10, or 1 to 5, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, hydrogen atoms in the molecule are replaced with halogen or methyl groups.

[0066] In one embodiment, the stabilized polypropylene glycol or polybutylene glycol can be a compound that exhibits the same average molecular weight and modification range as the stabilized poloxamers described above.

[0067] In one embodiment, the stabilized polyethylene glycol may have an average molecular weight of about 200 to 50,000, about 500 to 20,000, about 1,000 to 15,000, about 2,000 to 10,000, about 500 to 20,000, about 500 to 10,000, about 500 to 5,000, about 1,000 to 50,000, about 1,000 to 20,000, about 1,000 to 10,000, about 1,500 to 20,000, or about 1,500 to 15,000. In one embodiment, the stabilized composition of the present disclosure may contain about 1 to 50 wt%, about 1 to 40 wt%, about 2 to 30 wt%, about 5 to 25 wt%, about 10 to 30 wt%, about 1 to 20 wt%, about 2 to 20 wt%, about 5 to 20 wt%, about 15 to 30 wt%, or about 15 to 40 wt% polyethylene glycol. In one embodiment, the stabilized polyethylene glycol may include PEG200, PEG300, PEG400, PEG600, PEG1000, PEG1500, PEG2000, PEG4000, PEG6000, PEG8000, PEG10000, or PEG20000. In one embodiment, the stabilized polyethylene glycol may include PEG4000.

[0068] In one embodiment, the polyethylene glycol to be stabilized has the structure of Formula II: HO-(CH2-CH2-O) n -H (formula II) (wherein n is an integer of 0 or more) or a modified molecule thereof. In one embodiment, n may be 1 to 1000, n may be 10 to 500, or n may be 50 to 200. In one embodiment, the stabilized polyethylene glycol may be a compound in which the total molecular weight of partial structures represented by repeating units of -CH2-CH2-O- is 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the molecular weight of the entire molecule.

[0069] In one embodiment, the stabilized polyethylene glycol has the following modification in the structure of Formula II above: branching modifications in which one or more hydrogen atoms in the molecule are replaced by -(-CH2-CH2-O- repeat units)-H; One or more of the repeating units of -CH2-CH2-O- may be independently replaced by -R 2 -O-, -R 2 -S-, -R 2 - and -R 2 -N(R 1 )-, one or more -OH groups, independently, -NR 1 2, -OR 1 , -SR 1 and -R 1 a modification in which the group is replaced with a group selected from the group consisting of Modifications that replace one or more hydrogen atoms in the molecule with halogen or methyl groups; any combination of the above modifications, (In the formula, R 1 may be substituted C 1~10 Aliphatic group, or C 1~10 a group in which any carbon atom in an aliphatic group is replaced with an optionally substituted 5- to 7-membered cyclic group, R 2 may be substituted C 1~10 Aliphatic group, or C 1~10 a group in which any carbon atom in an aliphatic group is replaced with an optionally substituted 5- to 7-membered cyclic group; "Optionally substituted" means that one or more hydrogen atoms are each independently substituted with a monovalent C 1~5 Aliphatic groups, halogens, -OH, -O-(monovalent C 1~5 Aliphatic groups), -COOH, -CO- (monovalent C 1~5 Aliphatic group), -CO-NH2, -CO-NH-(monovalent C 1~5 Aliphatic groups), -COH, -SH, -S- (monovalent C 1~5 Aliphatic group), -NH2, -NH-(monovalent C 1~5 Aliphatic group), -N-(monovalent C 1~5 aliphatic group) means that it may be substituted with 2, -NO2, -PO3H, -SO3H, -CN, or a monovalent 5- to 7-membered cyclic group The compound may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 modifications selected from the group consisting of:

[0070] In one embodiment, the stabilized polyethylene glycol can be a compound containing 1, 2, 3, 4, or 5 branched modifications that replace one or more hydrogen atoms in the molecule with -(-CH2-CH2-O- repeating units)-H.

[0071] In one embodiment, the stabilized polyethylene glycol has 1 to 20, 1 to 15, 1 to 10, or 1 to 5, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, of the repeating units of —CH—CH—O— independently substituted with —R 2 -O-, -R 2 -S-, -R 2 - and -R 2 -N(R 1 )-.

[0072] In one embodiment, the stabilized polyethylene glycol has 1 to 20, 1 to 15, 1 to 10, or 1 to 5, e.g., 1, 2, 3, 4, or 5, —OH groups independently substituted with —NR 12, -OR 1 , -SR 1 and -R 1 The compound may include a modification in which the group is replaced with a group selected from the group consisting of:

[0073] In one embodiment, the stabilized polyethylene glycol may be a compound containing a modification in which 1 to 100, 1 to 70, 1 to 50, 1 to 30, 1 to 20, 1 to 15, 1 to 10 or 1 to 5, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, hydrogen atoms in the molecule are replaced with halogen or methyl groups.

[0074] In one embodiment, the chelating compound in the stabilized composition of the present disclosure contains 0.1 ppm of free metal ions (Cu 2+ , Fe 3+ , Zn 2+ , Ca 2+ , Al 3+ , Ag + The chelating compound may have such a chelate-forming ability that when a chelating compound is added at 25°C and 1 atm at the same molar concentration as the free metal ion to an aqueous solution having a pH of about 7.0 containing the free metal ion and left to stand for a sufficient period of time, the concentration of the free metal ion becomes 0.05 ppm or less, 0.02 ppm or less, 0.01 ppm or less, 0.005 ppm or less, 0.002 ppm or less, or 0.001 ppm or less. Examples of chelating compounds that can be added include ethylenediamine, ethylenediaminetetraacetic acid (EDTA), thiosulfuric acid, citric acid, metaphosphoric acid, pyrophosphoric acid, polyphosphoric acid, malic acid, tartaric acid, phytic acid, gluconic acid, lactic acid, and dimercaprol (or salts thereof), and these chelating compounds may be in the form of the corresponding ions in solution.

[0075] In one embodiment, the stabilized composition of the present disclosure comprises a chelating compound selected from the group consisting of thiosulfate, ethylenediaminetetraacetic acid (EDTA), or a salt or ion thereof, and citric acid, or a salt or ion thereof. In one preferred embodiment, the stabilized composition of the present disclosure comprises a chelating compound selected from the group consisting of thiosulfate, ethylenediaminetetraacetic acid (EDTA), or a salt or ion thereof. In one even more preferred embodiment, the stabilized composition of the present disclosure comprises a chelating compound selected from the group consisting of thiosulfate, or a salt or ion thereof. In one embodiment, the stabilized composition of the present disclosure further comprises, in addition to the chelating compound, at least one additional stabilizing component selected from mannitol and dibutylhydroxytoluene (BHT). The additional stabilizing component alone does not stabilize the polyether-based compound, but when added to the chelating compound, such as thiosulfate or EDTA, does not interfere with or can further stabilize the polyether-based compound. Furthermore, since polyether compounds such as poloxamers can be stabilized by adding dibutylhydroxytoluene (BHT) alone, the stabilized composition of the present disclosure may contain dibutylhydroxytoluene (BHT) without containing a chelating compound.

[0076] Polyether compounds are generally less stable and more difficult to stabilize than thickeners such as cellulose-based polymers (e.g., hydroxypropyl cellulose). For example, the glycosidic bonds of cellulose-based polymers may be more stable than the ether bonds of polyether compounds. However, the present inventors have unexpectedly discovered that polyether compounds can be efficiently stabilized (in small amounts) by chelating compounds. While not wishing to be bound by any theory, it is hypothesized that chelating compounds, particularly sulfate-based compounds such as thiosulfate, not only indirectly protect other compounds from oxidation by preferentially oxidizing themselves, but also directly protect the oxygen atoms in the ether moieties of polyether compounds (which can form hydrogen bonds with molecules in solvents such as water) by hydrogen bonding, thereby stabilizing the polyether compounds.

[0077] In one embodiment, the stabilized composition of the present disclosure contains a chelating compound in an amount of about 0.001 to 5 wt%, about 0.005 to 2 wt%, about 0.005 to 1 wt%, about 0.005 to 0.5 wt%, about 0.005 to 0.2 wt%, about 0.01 to 5 wt%, about 0.01 to 1 wt%, about 0.01 to 0.5 wt%, about 0.01 to 0.2 wt%, about 0.01 to 0.1 %, about 0.02 to 1 wt%, about 0.02 to 0.5 wt%, about 0.02 to 0.2 wt%, about 0.02 to 0.1 wt%, about 0.05 to 2 wt%, about 0.05 to 1 wt%, about 0.05 to 0.5 wt%, about 0.05 to 0.2 wt%, about 0.1 to 5 wt%, about 0.1 to 2 wt%, about 0.1 to 1 wt%, or about 0.1 to 0.5 wt%.

[0078] In one embodiment, the stabilized composition of the present disclosure has a polyether-based compound content of about 0.1 to 1000 mol%, about 0.1 to 100 mol%, about 0.1 to 50 mol%, about 0.2 to 1000 mol%, about 0.2 to 100 mol%, about 0.2 to 50 mol%, about 0.5 to 1000 mol%, about 0.5 to 1000 mol%, about 0.5 to 100 mol%, about 0.5 to 50 mol%, about 0.5 to 20 mol%, about 0.5 to 10 mol%, about 1 to 1000 mol%, about 1 to 100 mol%, about 1 to 50 mol%, about 1 to 10 mol%, about 2 to 1000 mol%, about 2 to 100 mol%, about 2 to 50 mol%, about 2 to 200 mol%, about 2 to 100 mol%, about 2 to 50 mol%, about 5 to 1000 mol%, about 10 to 500 mol%, about 20 to 200 mol%, about 10 to 500 mol%, about 10 to 200 mol%, about 10 to 100 mol%, about 20 to 1000 mol%, about 20 to 500 mol%, or about 20 to 200 mol% of the chelating compound.

[0079] In one embodiment, the stabilized composition of the present disclosure may contain about 0.001 to 5 wt%, about 0.005 to 2 wt%, about 0.01 to 1 wt%, about 0.02 to 0.5 wt%, about 0.05 to 0.2 wt%, about 0.01 to 5 wt%, about 0.01 to 0.5 wt%, about 0.01 to 0.2 wt%, about 0.01 to 0.1 wt%, about 0.02 to 1 wt%, about 0.02 to 0.5 wt%, about 0.02 to 0.2 wt%, about 0.05 to 2 wt%, about 0.05 to 1 wt%, about 0.05 to 0.5 wt%, about 0.1 to 5 wt%, about 0.1 to 2 wt%, or about 0.1 to 1 wt% of at least one stabilizing component selected from mannitol and dibutylhydroxytoluene (BHT).

[0080] In one embodiment, the stabilized composition of the present disclosure has a polyether-based compound content of about 0.01 to 1000 mol%, about 0.01 to 100 mol%, about 0.01 to 10 mol%, about 0.02 to 1000 mol%, about 0.02 to 1000 mol%, about 0.02 to 100 mol%, about 0.02 to 10 mol%, about 0.05 to 1000 mol%, about 0.05 to 100 mol%, about 0.05 to 10 mol%, about 0.1 to 1000 mol%, about 0.1 to 100 mol%, about 0.1 to 50 mol%, about 0.2 to 1000 mol%, about 0.2 to 100 mol%, about 0.2 to 50 mol%, about 0.5 to 1000 mol%, about 0. The stabilizing component may be contained in an amount of 5 to 100 mol%, about 0.5 to 50 mol%, about 0.5 to 20 mol%, about 0.5 to 10 mol%, about 1 to 1000 mol%, about 1 to 100 mol%, about 1 to 50 mol%, about 1 to 10 mol%, about 2 to 1000 mol%, about 2 to 100 mol%, about 2 to 50 mol%, about 2 to 200 mol%, about 2 to 100 mol%, about 2 to 50 mol%, about 5 to 1000 mol%, about 10 to 500 mol%, about 20 to 200 mol%, about 10 to 500 mol%, about 10 to 200 mol%, about 10 to 100 mol%, about 20 to 1000 mol%, about 20 to 500 mol%, or about 20 to 200 mol%.

[0081] In one embodiment, the stabilized composition of the present disclosure may be stable such that when adjusted to a predetermined initial pH (e.g., about 4.0, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, or about 8.0), transferred to a storage container, and then stored in an environment at 60°C and 1 atm for 4 weeks, the pH changes by 0.5 or less, 1.0 or less, or 1.5 or less compared to the pH immediately after transfer to the storage container. In one embodiment, the stabilized composition of the present disclosure may be stable such that when adjusted to a predetermined initial pH (e.g., about 4.0, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, or about 8.0), transferred to a storage container, and then stored in an environment at 60°C and 1 atm for 4 weeks, the pH changes by 0.5 or less, 1.0 or less, or 1.5 or less compared to the pH immediately after transfer to the storage container. Since the pH of a liquid preparation such as a pharmaceutical product at the time of preparation may differ from the pH immediately after transfer to a storage container or the pH when the product is shipped from the factory, the above test may be performed taking into account a difference of about 0.5 between the pH at preparation or the pH immediately after transfer to a storage container relative to the pH of the product liquid. Furthermore, the above test does not necessarily have to be performed on the liquid preparation immediately after preparation; the test may be performed on the product immediately after shipping from the factory, after adjusting the pH to a predetermined value as necessary. For example, the product immediately after shipping from the factory may be transferred to a pH-adjusting container, the pH may be adjusted in this container, and then the product may be transferred to a storage container for testing.

[0082] In one embodiment, the stabilized composition of the present disclosure may have a stability such that, after adjustment to a predetermined initial pH (e.g., about 4.0, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, or about 8.0), storage at 60°C and 1 atm for 4 weeks results in a decrease in viscosity, as measured with a rotational viscometer at 25°C and 100 rpm, of 5% or less, 10% or less, 15% or less, 20% or less, 25% or less, 30% or less, 35% or less, 40% or less, 45% or less, or 50% or less.

[0083] In this aspect of the disclosure, there is no limitation on the medicinal ingredients or active ingredients that may be used together, and any may be used.Examples of such drugs include docetaxel, paclitaxel, capecitabine, oxaliplatin, geftinat, doxorubicin, irinotecan, gemcitabine, pemetrexed, temozolomide, imatinib, vinorelbine, letrozole, teniposide, etoposide, podophyllotoxin, camptothecin, topotecan, vinblastine, vincristine, vindesine, vinflunine, vinpocetine, norcantharidin, silybin, propofol, florfenicol, mitiglinide, artemisinin, dihydroartemisinin, and tacrolimus. , sirolimus, ibuprofen, nitrendipine, nicardipine, nimodipine, gliclazide, propulsid, nifedipine, felodipine, glibenclamide, acyclovir, oleanolic acid, breviscapine, ferulic acid, paracetamol, palmitoylrhizoxin, penclomedine, vitamin A, tamoxifen, navelbine, valproic acid, cyclosporine A, amphotericin B, ketoconazole, domperidone, sulpiride, fenofibrate, bezafibrate, itraconazole, miconazole, latanoprost, brinzola amide, erythromycin, roxithromycin, rifaximin, cisapride, diclofenac acid, terfenadine, theophylline, ketoprofen, furosemide, spironolactone, dipyridamole, piroxicam, mefenamic acid, trichlorothiazide, pindolol, acemetacin, indomethacin, diflunisal, naproxen, triamcinolone, triamcinolone acetonide, fluorometholone, dexamethasone, hydrocortisone, prednisolone, cisplatin, enoxacin, norfloxacin, clofibrate, protease inhibitor These include, but are not limited to, cholangiocin, simvastatin, reserpine, verapamil hydrochloride, atenolol, digitoxin, digoxin, diazepam, nitrazepam, haloperidol, droperidol, triazolam, phenytoin, phenobarbital, cimetidine, famotidine, omeprazole, lansoprazole, oxethazaine, sucralfate, gefarnate, metoclopramide, tranilast, tolbutamide, mebendazole, albendazole, fenbendazole, cilostazol, phenylbutazone, and celecoxib.

[0084] (Composition for improving the solubility of poorly soluble compounds) In another aspect, the present disclosure provides a composition that improves the solubility (e.g., aqueous solubility) of a poorly soluble compound, and in one embodiment, provides a poorly soluble compound-containing composition utilizing this effect. In one embodiment, the solubility-improved composition of the present disclosure may have any of the characteristics of the stability-improved composition of the present disclosure.

[0085] In one embodiment, the present disclosure provides a composition for improving the solubility of a poorly soluble compound by combining a hydrophobic polyoxyaliphatic moiety-containing polyether compound and a hydratable compound, the composition comprising at least one of a hydrophobic polyoxyaliphatic moiety-containing polyether compound and a hydratable compound. The hydrophobic polyoxyaliphatic moiety-containing polyether compound functions as a surfactant by virtue of its hydrophobic and hydrophilic moieties, and is thought to improve the solubility (solubilizing power) of a poorly soluble compound. When the hydrophobic moiety of the hydrophobic polyoxyaliphatic moiety-containing polyether compound becomes hydrophilic (e.g., upon exposure to low temperature conditions), the surfactant activity of the hydrophobic polyoxyaliphatic moiety-containing polyether compound decreases, resulting in a decrease in the solubilizing power. Without wishing to be bound by theory, it is thought that when the hydrophobic polyoxyaliphatic moiety-containing polyether compound is combined with a hydratable compound, the hydratable compound attracts many water molecules, thereby preventing the water molecules from hydrating the hydrophobic polyoxyaliphatic moiety-containing polyether compound, thereby improving the solubilizing power of the hydrophobic polyoxyaliphatic moiety-containing polyether compound and preventing a decrease in the solubilizing power of the hydrophobic polyoxyaliphatic moiety-containing polyether compound.

[0086] In one embodiment, the hydrophobic polyoxyaliphatic moiety-containing polyether-based compound is —O—(C 3~20 aliphatic group), -O-(C 3~15 aliphatic group), -O-(C 3~10 aliphatic group), -O-(C 3~7 aliphatic group)-O-(C 3~5 aliphatic group), -O-(C 3~4The hydrophobic polyoxyaliphatic moiety-containing polyether compound may contain repeating units of -O-(C3 aliphatic group) or -O-(C3 aliphatic group). In one embodiment, the hydrophobic polyoxyaliphatic moiety-containing polyether compound may have an average molecular weight of about 500-20,000, about 1,000-15,000, about 2,000-10,000, about 500-20,000, about 500-10,000, about 500-5,000, about 1,000-50,000, about 1,000-20,000, about 1,000-10,000, about 1,500-20,000, or about 1,500-15,000. In one embodiment, the hydrophobic polyoxyaliphatic moiety-containing polyether compound may be a poloxamer, polypropylene glycol, or polybutylene glycol. In one embodiment, the hydrophobic polyoxyaliphatic moiety-containing polyether compound may be a poloxamer.

[0087] In one embodiment, the hydratable compound may be polyethylene glycol, propylene glycol, glycerin, or an ionic salt. In one embodiment, the ionic salt may include, but is not limited to, a salt formed by the reaction of a metal element such as sodium, potassium, calcium, or magnesium with a strong acid such as hydrochloric acid, nitric acid, or sulfuric acid (e.g., sodium chloride, potassium sulfate, etc.). In one embodiment, the hydratable compound may be polyethylene glycol.

[0088] In one embodiment, the solubility-enhancing composition of the present disclosure may contain a total of 10% by weight or more, 12% by weight or more, 15% by weight or more, 25% by weight or more, 30% by weight or more, 35% by weight or more, 40% by weight or more, 45% by weight or more, or 50% by weight or more of a hydrophobic polyoxyaliphatic moiety-containing polyether-based compound (e.g., poloxamer) and a hydratable compound (e.g., polyethylene glycol). The appropriate amounts of the hydrophobic polyoxyaliphatic moiety-containing polyether-based compound (e.g., poloxamer) and a hydratable compound (e.g., polyethylene glycol) in the solubility-enhancing composition of the present disclosure may vary depending on the type of poorly soluble compound.

[0089] In one embodiment, the poloxamer for solubility enhancement may have an average molecular weight of about 500-20,000, about 1,000-15,000, about 2,000-10,000, about 500-20,000, about 500-10,000, about 500-5,000, about 1,000-50,000, about 1,000-20,000, about 1,000-10,000, about 1,500-20,000, or about 1,500-15,000. In one embodiment, the solubility-enhancing composition of the present disclosure may contain about 1-40% by weight, about 1-40% by weight, about 2-30% by weight, about 5-25% by weight, about 10-30% by weight, about 1-20% by weight, about 2-20% by weight, about 5-20% by weight, about 15-30% by weight, or about 15-40% by weight. In one embodiment, the poloxamer for solubility enhancement can include poloxamer 101, poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer 403, or poloxamer 407. In one embodiment, the poloxamer for solubility enhancement may include poloxamer 407.

[0090] In one embodiment, the poloxamer for improving solubility may contain about 5 to 95% by weight, about 10 to 90% by weight, about 20 to 80% by weight, about 30 to 75% by weight, about 30 to 95% by weight, about 30 to 90% by weight, about 30 to 80% by weight, about 30 to 75% by weight, about 30 to 70% by weight, about 30 to 60% by weight, about 50 to 90% by weight, about 50 to 80% by weight, about 50 to 75% by weight, or about 50 to 70% by weight of polyoxyethylene per molecule.

[0091] In one embodiment, the poloxamer for improving solubility may have a polyoxypropylene with an average molecular weight of about 500 to 15,000, about 600 to 10,000, about 700 to 7,000, about 900 to 10,000, about 900 to 7,000, about 900 to 4,000, about 1,000 to 10,000, about 1,000 to 7,000, about 1,500 to 7,000, about 2,000 to 7,000, or about 2,500 to 7,000 per molecule.

[0092] In one embodiment, the poloxamer used for solubility enhancement can have a hydrophilic-lipophilic balance (HLB) of about 0 to 30, about 1 to 25, about 1 to 20, about 1 to 15, about 1 to 10, about 5 to 30, about 5 to 25, about 5 to 20, about 5 to 15, about 10 to 30, about 10 to 25, about 10 to 20, about 15 to 30, about 15 to 25, or greater than about 25. For information on HLB values, see Colloids and Surfaces A: Physicochemical and Engineering Aspects, Volume 96, Issues 1-2, 10 March 1995, Pages 1-46.

[0093] In one embodiment, the poloxamer for solubility enhancement has the structure of Formula I: [ka] (Formula I) (wherein x, y, and z are each independently selected integers of 0 or greater). or a molecule having the same, modified therefrom. In one embodiment, x may be 1 to 1,000, y may be 1 to 1,000, and z may be 1 to 1,000. In one embodiment, x may be 10 to 500, y may be 10 to 500, and z may be 10 to 500. In one embodiment, x may be 50 to 200, y may be 50 to 200, and z may be 50 to 200. In one embodiment, the poloxamer for improving solubility may be a compound in which the total molecular weight of the partial structures represented by the repeating units -CH2-CH2-O- and -CH2-CH(CH3)-O- accounts for 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the molecular weight of the entire compound.

[0094] In one embodiment, the poloxamer for solubility enhancement has the following modifications in the structure of Formula I above: branching modifications in which one or more hydrogen atoms in the molecule are replaced by -H (-CH2-CH2-O- and / or -CH2-CH(CH3)-O- repeat units); One or more of the repeating units of -CH2-CH2-O- or -CH2-CH(CH3)-O- may be independently replaced by -R 2 -O-, -R 2 -S-, -R 2 - and -R 2 -N(R 1 )-, one or more -OH groups, independently, -NR 1 2, -OR 1 , -SR 1 and -R 1 a modification in which the group is replaced with a group selected from the group consisting of Modifications that replace one or more hydrogen atoms in the molecule with halogen or methyl groups, any combination of the above modifications, (In the formula, R 1 may be substituted C 1~10 Aliphatic group, or its C 1~10 a group in which any carbon atom in an aliphatic group is replaced with an optionally substituted 5- to 7-membered cyclic group, R 2 may be substituted C 1~10 Aliphatic group, or its C 1~10 a group in which any carbon atom in an aliphatic group is replaced with an optionally substituted 5- to 7-membered cyclic group, "Optionally substituted" means that one or more hydrogen atoms are each independently substituted with a monovalent C 1~5 Aliphatic groups, halogens, -OH, -O-(monovalent C 1~5 Aliphatic groups), -COOH, -CO- (monovalent C 1~5 Aliphatic group), -CO-NH2, -CO-NH-(monovalent C 1~5 Aliphatic groups), -COH, -SH, -S- (monovalent C 1~5 Aliphatic group), -NH2, -NH-(monovalent C 1~5 Aliphatic group), -N-(monovalent C 1~5 aliphatic group) means that it may be substituted with 2, -NO2, -PO3H, -SO3H, -CN, or a monovalent 5- to 7-membered cyclic group The compound may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 modifications selected from the group consisting of:

[0095] In one embodiment, a poloxamer for improving solubility can be a compound containing one, two, three, four, or five branching modifications, replacing one or more hydrogen atoms in the molecule with -(-CH-CH-O- and / or -CH-CH(CH)-O- repeat units)-H. In one embodiment, a poloxamer for improving solubility can be a propylene glycol-based compound with the structure of Formula I above, where one hydrogen atom in each CH of one, two, or three -CH-CH(CH)-O- repeat units is replaced with -OH or -(-CH-CH-O- and / or -CH-CH(CH)-O- repeat units)-H.

[0096] In one embodiment, the solubility-enhancing poloxamer is a poloxamer in which 1 to 20, 1 to 15, 1 to 10, or 1 to 5, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, of the -CH-CH-O- or -CH-CH(CH)-O- repeating units are independently selected from the group consisting of -R 2 -O-, -R 2 -S-, -R 2 - and -R 2 -N(R 1 )-.

[0097] In one embodiment, the solubility-enhancing poloxamer has 1 to 20, 1 to 15, 1 to 10, or 1 to 5, e.g., 1, 2, 3, 4, or 5, —OH groups independently substituted with —NR 1 2, -OR 1 , -SR 1 and -R 1 The compound may include a modification in which the group is replaced with a group selected from the group consisting of:

[0098] In one embodiment, the poloxamer for solubility enhancement can be a compound containing a modification in which 1 to 100, 1 to 70, 1 to 50, 1 to 30, 1 to 20, 1 to 15, 1 to 10, or 1 to 5, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, hydrogen atoms in the molecule are replaced with halogen or methyl groups.

[0099] In one embodiment, the polypropylene glycol or polybutylene glycol for solubility enhancement may be a compound having the same average molecular weight, range of modification, and HLB value as the poloxamer for solubility enhancement described above.

[0100] In one embodiment, the polyethylene glycol as the hydratable compound may have an average molecular weight of about 200 to 50,000, about 500 to 20,000, about 1,000 to 15,000, about 2,000 to 10,000, about 500 to 20,000, about 500 to 10,000, about 500 to 5,000, about 1,000 to 50,000, about 1,000 to 20,000, about 1,000 to 10,000, about 1,500 to 20,000, or about 1,500 to 15,000. In one embodiment, the solubility-enhancing composition of the present disclosure may comprise polyethylene glycol in an amount of about 1-40 wt%, about 1-40 wt%, about 2-30 wt%, about 5-25 wt%, about 10-30 wt%, about 1-20 wt%, about 2-20 wt%, about 5-20 wt%, about 15-30 wt%, or about 15-40 wt%. In one embodiment, the polyethylene glycol as the hydratable compound may include PEG200, PEG300, PEG400, PEG600, PEG1000, PEG1500, PEG2000, PEG4000, PEG6000, PEG8000, PEG10000, or PEG20000. In one embodiment, the polyethylene glycol as the hydratable compound may include PEG4000.

[0101] In one embodiment, the hydratable compound polyethylene glycol has the structure of Formula II: HO-(CH2-CH2-O) n -H (formula II) (wherein n is an integer of 0 or more) or a modified molecule thereof. In one embodiment, n may be 1 to 1000, n may be 10 to 500, or n may be 50 to 200. In one embodiment, the hydratable compound polyethylene glycol may be a compound in which the total molecular weight of partial structures represented by repeating units of -CH2-CH2-O- accounts for 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the molecular weight of the entire molecule.

[0102] In one embodiment, the polyethylene glycol as the hydratable compound has the following modification in the structure of formula II above: branching modifications in which one or more hydrogen atoms in the molecule are replaced by -(-CH2-CH2-O- repeat units)-H; One or more of the repeating units of -CH2-CH2-O- may be independently replaced by -R 2 -O-, -R 2 -S-, -R 2 - and -R 2 -N(R 1 )-, one or more -OH groups, independently, -NR 1 2, -OR 1 , -SR 1 and -R 1 a modification in which the group is replaced with a group selected from the group consisting of Modifications that replace one or more hydrogen atoms in the molecule with halogen or methyl groups; any combination of the above modifications, (In the formula, R 1 may be substituted C 1~10 Aliphatic group, or C 1~10 a group in which any carbon atom in an aliphatic group is replaced with an optionally substituted 5- to 7-membered cyclic group, R 2 may be substituted C 1~10 Aliphatic group, or C 1~10 a group in which any carbon atom in an aliphatic group is replaced with an optionally substituted 5- to 7-membered cyclic group; "Optionally substituted" means that one or more hydrogen atoms are each independently substituted with a monovalent C 1~5 Aliphatic groups, halogens, -OH, -O-(monovalent C 1~5 Aliphatic groups), -COOH, -CO- (monovalent C 1~5 Aliphatic group), -CO-NH2, -CO-NH-(monovalent C 1~5 Aliphatic groups), -COH, -SH, -S- (monovalent C 1~5 Aliphatic group), -NH2, -NH-(monovalent C 1~5 Aliphatic group), -N-(monovalent C 1~5aliphatic group) means that it may be substituted with 2, -NO2, -PO3H, -SO3H, -CN, or a monovalent 5- to 7-membered cyclic group The compound may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 modifications selected from the group consisting of:

[0103] In one embodiment, the hydratable compound polyethylene glycol can be a compound containing 1, 2, 3, 4, or 5 branched modifications that replace one or more hydrogen atoms in the molecule with -(-CH2-CH2-O- repeating units)-H.

[0104] In one embodiment, the polyethylene glycol as the hydratable compound has 1 to 20, 1 to 15, 1 to 10, or 1 to 5, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, of the repeating units of —CH—CH—O— independently replaced by —R 2 -O-, -R 2 -S-, -R 2 - and -R 2 -N(R 1 )-.

[0105] In one embodiment, the hydratable compound polyethylene glycol has 1 to 20, 1 to 15, 1 to 10, or 1 to 5, e.g., 1, 2, 3, 4, or 5, —OH groups independently substituted with —NR 1 2, -OR 1 , -SR 1 and -R 1 The compound may include a modification in which the group is replaced with a group selected from the group consisting of:

[0106] In one embodiment, the polyethylene glycol as the hydratable compound may be a compound containing a modification in which 1 to 100, 1 to 70, 1 to 50, 1 to 30, 1 to 20, 1 to 15, 1 to 10 or 1 to 5, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, hydrogen atoms in the molecule are replaced with halogen or methyl groups.

[0107] In one embodiment, the solubility-improved composition of the present disclosure has a viscosity of about 1 to 1000 mPa·s, about 1 to 500 mPa·s, about 1 to 200 mPa·s, about 1 to 100 mPa·s, about 1 to 50 mPa·s, about 1 to 20 mPa·s, about 1 to 10 mPa·s, about 2 to 1000 mPa·s, about 2 to 500 mPa·s, about 2 to 200 mPa·s, about 2 to 100 mPa·s, about 2 to 50 mPa·s, about 2 to 50 mPa·s, or about 2 to 50 mPa·s when measured using a rotational viscometer at 25°C and 100 rpm. The viscosity may be 20 mPa·s, about 5 to 1000 mPa·s, about 5 to 500 mPa·s, about 5 to 200 mPa·s, about 5 to 100 mPa·s, about 5 to 50 mPa·s, about 10 to 1000 mPa·s, about 10 to 500 mPa·s, about 10 to 200 mPa·s, about 10 to 100 mPa·s, about 20 to 1000 mPa·s, about 20 to 500 mPa·s, about 20 to 200 mPa·s, about 50 to 1000 mPa·s, or about 50 to 500 mPa·s.

[0108] In one embodiment, the solubility-enhancing composition of the present disclosure has a solubility of about 0.01 to 1000 mOsm / kg, about 0.01 to 500 mOsm / kg, about 0.01 to 200 mOsm / kg, about 0.01 to 100 mOsm / kg, about 0.01 to 50 mOsm / kg, about 0.01 to 20 mOsm / kg, about 0.01 to 10 mOsm / kg, about 0.01 to 5 mOsm / kg, about 0.0 2~1000mOsm / kg, approximately 0.02~500mOsm / kg, approximately 0.02~200mOsm / kg, approximately 0.02~100mOsm / kg, approximately 0.02~50mOsm / kg, approximately 0. 02~20mOsm / kg, approx. 0.02~10mOsm / kg, approx. 0.05~1000mOsm / kg, approx. 0.05~500mOsm / kg, approx. 0.05~200mOsm / kg, approx. 0. 05~100mOsm / kg, approx. 0.05~50mOsm / kg, approx. 0.05~20mOsm / kg, approx. 0.05~10mOsm / kg, approx. 0.1~1000mOsm / kg, approx. 0.1 ~500mOsm / kg, approximately 0.1~200mOsm / kg, approximately 0.1~100mOsm / kg, approximately 0.1~50mOsm / kg, approximately 0.1~20mOsm / kg, approximately 0.1~10mOs m / kg, approximately 0.2~1000mOsm / kg, approximately 0.2~500mOsm / kg, approximately 0.2~200mOsm / kg, approximately 0.2~100mOsm / kg, approximately 0.2~50mOsm / kg , about 0.5~1000mOsm / kg, about 0.5~500mOsm / kg, about 0.5~200mOsm / kg, about 0.5~100mOsm / kg, about 0.5~50mOsm / kg, about 0.5~20mOsm / kg, approx. 1~1000mOsm / kg, approx. 1~500mOsm / kg, approx. 1~200mOsm / kg, approx. 1~100mOsm / kg, approx. 1~50mOsm / kg, approx. 2~1000mOsm / kg, Approx. 2~500mOsm / kg, approx. 2~200mOsm / kg, approx. 2~100mOsm / kg, approx. 2~50mOsm / kg, approx. 5~1000mOsm / kg, approx. 5~500mOsm / kg, approx. 5~200mOsm / kg The compositions of the present disclosure may have an osmolality of about 5-100 mOsm / kg, about 5-50 mOsm / kg, about 10-1000 mOsm / kg, about 10-500 mOsm / kg, about 10-200 mOsm / kg, about 10-100 mOsm / kg, about 20-1000 mOsm / kg, about 20-500 mOsm / kg, about 20-200 mOsm / kg, about 50-1000 mOsm / kg, about 50-500 mOsm / kg, or about 100-1000 mOsm / kg. Direct measurement of the osmolality of compositions of the present disclosure, which may contain high concentrations of polyether compounds, can be difficult. However, the osmolality can be determined by, for example, estimating the osmolality of the original composition from the osmolality measurement results of diluted compositions. Furthermore, when preparing solutions, the osmolality can also be calculated from the amount of each solute. .

[0109] In one embodiment, the poorly soluble compound may have a LogP of about 0.2 to 7, about 0.3 to 4, about 0.4 to 4, about 0.5 to 4, about 0.7 to 4, about 1 to 4, about 1.5 to 4, about 0.5 to 7, about 0.5 to 6, about 0.5 to 5, about 0.5 to 3.5, about 0.5 to 3, or about 0.5 to 2.5. In one embodiment, the LogP of the poorly soluble compound at the pH of the solubility-enhancing composition of the present disclosure may be about 0.2 to 7, about 0.3 to 4, about 0.4 to 4, about 0.5 to 4, about 0.7 to 4, about 1 to 4, about 1.5 to 4, about 0.5 to 7, about 0.5 to 6, about 0.5 to 5, about 0.5 to 3.5, about 0.5 to 3, or about 0.5 to 2.5.

[0110] The poor solubility of a compound can be evaluated by LogP as described above, but can also be evaluated by measuring the solubility in aqueous and non-aqueous solvents independently. In one embodiment, the poorly soluble compound of the present disclosure may be a compound that is poorly soluble in aqueous solvents but whose solubility is improved in non-aqueous solvents (ethanol, PEG400, propylene glycol, etc.). It is preferable to avoid the use of non-aqueous solvents in compositions to be applied to animals such as humans, but the solubility-improved composition of the present disclosure, which can use aqueous solvents, can also be suitably used for compounds whose solubility is improved in non-aqueous solvents. In one embodiment, a poorly soluble compound that can be suitably used in the solubility-enhanced composition of the present disclosure can be a compound whose solubility at 25°C in ethanol, PEG400, and / or propylene glycol is improved by about 10 times or more, about 20 times or more, about 50 times or more, about 70 times or more, about 100 times or more, about 150 times or more, about 200 times or more, about 300 times or more, about 400 times or more, about 500 times or more, about 700 times or more, or about 1000 times or more compared to its solubility at 25°C in a buffer solution adjusted to pH 7.0 (e.g., an aqueous solution of 0.2% sodium hydrogen phosphate hydrate and 0.3% sodium dihydrogen phosphate hydrate). Compounds whose solubility is improved by about 100 times or more are considered to be particularly effective.

[0111] In one embodiment, the poorly soluble compound has the following characteristics: (1) Does not contain easily ionizable groups (acidic groups (carboxyl groups, tetrazole groups, sulfate groups, phosphate groups, etc.), basic groups (amine groups, etc.)) or ionic groups thereof; (2) having a fluorine atom (and, if necessary, having neither a hydroxyl group nor an amino group at the vicinal position of the fluorine atom); (3) No hydroxyl groups (4) Contains 2, 3, 4, 5, 6, 7, 8, 9, 10, or more rings (e.g., aromatic rings) (wherein fused or spiro rings are not counted as a single ring, but the total number of closed rings is counted). In one embodiment, the poorly soluble compound has a pyridyl-substituted imidazole structure and / or has about 5 rings (e.g., aromatic rings).

[0112] In this aspect of the present disclosure, the poorly soluble compound used may be any compound as long as it has the above characteristics. The poorly soluble compound used may have any combination of the above characteristics, such as a combination of the above characteristics of the solubility ratio in a non-aqueous solvent compared to an aqueous solvent with other characteristics. Examples of poorly soluble compounds may or may not be pharmaceutical ingredients or active ingredients.Examples of such drugs include docetaxel, paclitaxel, capecitabine, oxaliplatin, geftinat, doxorubicin, irinotecan, gemcitabine, pemetrexed, temozolomide, imatinib, vinorelbine, letrozole, teniposide, etoposide, podophyllotoxin, camptothecin, topotecan, vinblastine, vincristine, vindesine, vinflunine, vinpocetine, norcantharidin, silybin, propofol, florfenicol, mitiglinide, artemisinin, dihydroartemisinin, and tacrolimus. , sirolimus, ibuprofen, nitrendipine, nicardipine, nimodipine, gliclazide, propulsid, nifedipine, felodipine, glibenclamide, acyclovir, oleanolic acid, breviscapine, ferulic acid, paracetamol, palmitoylrhizoxin, penclomedine, vitamin A, tamoxifen, navelbine, valproic acid, cyclosporine A, amphotericin B, ketoconazole, domperidone, sulpiride, fenofibrate, bezafibrate, itraconazole, miconazole, latanoprost, brinzola amide, erythromycin, roxithromycin, rifaximin, cisapride, diclofenac acid, terfenadine, theophylline, ketoprofen, furosemide, spironolactone, dipyridamole, piroxicam, mefenamic acid, trichlorothiazide, pindolol, acemetacin, indomethacin, diflunisal, naproxen, triamcinolone, triamcinolone acetonide, fluorometholone, dexamethasone, hydrocortisone, prednisolone, cisplatin, enoxacin, norfloxacin, clofibrate, protease inhibitor These include, but are not limited to, cholangiocin, simvastatin, reserpine, verapamil hydrochloride, atenolol, digitoxin, digoxin, diazepam, nitrazepam, haloperidol, droperidol, triazolam, phenytoin, phenobarbital, cimetidine, famotidine, omeprazole, lansoprazole, oxethazaine, sucralfate, gefarnate, metoclopramide, tranilast, tolbutamide, mebendazole, albendazole, fenbendazole, cilostazol, phenylbutazone, and celecoxib.

[0113] In one embodiment, the solubility-enhancing composition of the present disclosure may contain cyclodextrin or a water-soluble polymer. Examples of cyclodextrins include α-cyclodextrin, hydroxypropyl-α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, γ-cyclodextrin, and hydroxypropyl-γ-cyclodextrin. Examples of water-soluble polymers include methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylcellulose, xanthan gum, carrageenan, gum arabic, locust bean gum, gellan gum, tamarind gum, alginic acid, hyaluronic acid, chondroitin sulfate, carboxyvinyl polymer, polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP). In one embodiment, the solubility-enhancing composition of the present disclosure may include at least one of sulfobutylether-β-cyclodextrin and carboxymethylcellulose. In one embodiment, the addition of these cyclodextrins or water-soluble polymers may further improve the solubility of poorly soluble compounds.In one embodiment, the solubility-enhancing composition of the present disclosure contains these cyclodextrins or water-soluble polymers in an amount of about 0.001 to 20% by weight, about 0.001 to 10% by weight, about 0.005 to 20% by weight, about 0.005 to 10% by weight, about 0.005 to 5% by weight, about 0.01 to 20% by weight, about 0.01 to 10% by weight, about 0.01 to 5% by weight, about 0.02 to 20% by weight, about 0.02 to 10% by weight, about 0.02 to 5% by weight, about 0.05 to 20% by weight, about 0.05 to 10% by weight, about 0.05 to 5% by weight, or about It may contain 0.001 to 5% by weight, about 0.005 to 2% by weight, about 0.01 to 1% by weight, about 0.02 to 0.5% by weight, about 0.05 to 0.2% by weight, about 0.01 to 5% by weight, about 0.01 to 0.5% by weight, about 0.01 to 0.2% by weight, about 0.01 to 0.1% by weight, about 0.02 to 1% by weight, about 0.02 to 0.5% by weight, about 0.02 to 0.2% by weight, about 0.05 to 2% by weight, about 0.05 to 1% by weight, about 0.05 to 0.5% by weight, about 0.1 to 5% by weight, about 0.1 to 2% by weight, or about 0.1 to 1% by weight.

[0114] In one embodiment, the solubility improvement rate of a poorly soluble compound by adding a hydratable compound (e.g., 20 wt%) to a hydrophobic polyoxyaliphatic moiety-containing polyether compound (e.g., 10 wt%) of the solubility-enhancing composition of the present disclosure at a predetermined temperature (e.g., 25°C, 20°C, 15°C, 10°C, 5°C, etc.) and atmospheric pressure of 1 atm can be 1.05 times or more, 1.1 times or more, 1.2 times or more, 1.5 times or more, 1.7 times or more, 2 times or more, 3 times or more, 4 times or more, 5 times or more, 7 times or more, 10 times or more, 15 times or more, 20 times or more, 30 times or more, 40 times or more, 50 times or more, 70 times or more, or 100 times or more. In this specification, the "solubility improvement rate of a poorly soluble compound due to the addition of a hydratable compound to a hydrophobic polyoxyaliphatic moiety-containing polyether compound" of a composition refers to the value calculated by subtracting the solubility of a composition containing a hydrophobic polyoxyaliphatic moiety-containing polyether compound and a hydratable compound from the solubility of the same composition except that it does not contain the hydrophobic polyoxyaliphatic moiety-containing polyether compound, i.e., the solubility (S A+B -S B) is calculated by subtracting the solubility of a composition that does not contain both the hydrophobic polyoxyaliphatic moiety-containing polyether compound and the hydratable compound from the solubility of the same composition except that it does not contain the hydratable compound, i.e., the solubility of the hydrophobic polyoxyaliphatic moiety-containing polyether compound (S A -S0) and is calculated using the following formula: {S A+B -S B} / {S A -S0} (In the formula, S A+B = Solubility of a poorly soluble compound in a composition containing a hydrophobic polyoxyaliphatic moiety-containing polyether compound and a hydratable compound S B = solubility of poorly soluble compounds in compositions that do not contain hydrophobic polyoxyaliphatic moiety-containing polyether compounds and contain hydratable compounds S A = Solubility of a poorly soluble compound in a composition containing a hydrophobic polyoxyaliphatic moiety-containing polyether compound and no hydratable compound S0 = solubility of the poorly soluble compound in a composition that does not contain both a hydrophobic polyoxyaliphatic moiety-containing polyether compound and a hydratable compound Here, all compositions contain the same components other than the hydrophobic polyoxyaliphatic moiety-containing polyether compound and the hydratable compound at the same concentrations, and all measurement conditions (temperature, pressure, etc.) other than the components of the compositions are the same.

[0115] In one embodiment, the solubility improvement rate of a poorly soluble compound by adding a hydratable compound (e.g., 20% by weight) to a hydrophobic polyoxyaliphatic moiety-containing polyether compound (e.g., 10% by weight) of the solubility-enhancing composition of the present disclosure under conditions of 25°C and 1 atm atmospheric pressure can be 1.05 times or more, 1.1 times or more, 1.2 times or more, 1.5 times or more, 1.7 times or more, or 2 times or more.

[0116] In one embodiment, the solubility improvement rate of a poorly soluble compound by adding a hydratable compound (e.g., 20 wt%) to a hydrophobic polyoxyaliphatic moiety-containing polyether compound (e.g., 10 wt%) in the solubility-enhancing composition of the present disclosure under conditions of 15°C and 1 atm atmospheric pressure can be 1.5 times or more, 1.7 times or more, 2 times or more, 3 times or more, 4 times or more, 5 times or more, 7 times or more, 10 times or more, 15 times or more, or 20 times or more.

[0117] In one embodiment, the solubility improvement rate of a poorly soluble compound by adding a hydratable compound (e.g., 20 wt%) to a hydrophobic polyoxyaliphatic moiety-containing polyether compound (e.g., 10 wt%) in the solubility-enhancing composition of the present disclosure under conditions of 5°C and 1 atm atmospheric pressure can be 1.5 times or more, 1.7 times or more, 2 times or more, 3 times or more, 4 times or more, 5 times or more, 7 times or more, 10 times or more, 15 times or more, 20 times or more, 30 times or more, or 40 times or more. In one embodiment, the poorly soluble compound used in combination with the solubility-enhancing composition of the present disclosure is not a compound whose solubility is significantly improved in the presence (e.g., at 5°C and atmospheric pressure of 1 atm) of either a hydrophobic polyoxyaliphatic moiety-containing polyether compound (e.g., poloxamer) (e.g., 10% by weight) or a hydratable compound (e.g., polyethylene glycol) (e.g., 20% by weight) alone, for example, by 5 times or more, 10 times or more, 20 times or more, or 50 times or more, compared to the solubility in a composition that does not contain either a hydrophobic polyoxyaliphatic moiety-containing polyether compound or a hydratable compound.

[0118] For example, while the storage conditions for pharmaceuticals may be specified as 15°C to 25°C, their use is premised on being within this storage temperature range. Therefore, it is preferable that poorly soluble compounds do not precipitate and / or precipitate even at low temperatures, such as 15°C. Therefore, the solubility-improving composition of the present disclosure, which is particularly effective in improving the solubility of poorly soluble compounds at low temperatures, can be preferably used for pharmaceuticals in general that can be stored at low temperatures. Furthermore, pharmaceuticals typically require that their quality, safety, and efficacy be guaranteed within the temperature range specified in the package insert. Quality standards are set in accordance with regulations. In the case of eye drops, foreign matter is controlled by insoluble particle testing in the United States, and insoluble particle testing and insoluble foreign matter testing in Japan. Precipitation of a drug due to insufficient solubility is likely to result in the formation of numerous foreign particles ranging in size from several microns to several hundred microns, which could result in deviation from the standard. Furthermore, when checking the properties of a pharmaceutical product, for example, if foreign matter appears during storage (within the temperature range of the storage conditions) of a product specified as "colorless and clear," it will no longer be clear, which could result in deviation from the standard. Regarding efficacy, for example, precipitation of the drug may reduce the dissolved drug concentration, resulting in a lower-than-expected intraocular delivery rate, which may result in insufficient treatment. Regarding safety, for example, if foreign particles of several hundred micrometers in size are generated, the cornea may be damaged. Thus, the solubility-improving composition of the present disclosure may generally provide benefits for pharmaceuticals that may be exposed to various temperature environments, including low temperatures, such as during storage. Furthermore, the solubility-improving composition of the present disclosure may provide excellent quality stability not only for pharmaceuticals but also for general products that may be exposed to low-temperature environments.

[0119] (Other ingredients) The composition of the present disclosure may be provided in various forms. In one embodiment, the composition of the present disclosure may be an aqueous formulation. In one embodiment, the water content of the composition of the present disclosure may be about 30% by weight or more, about 35% by weight or more, about 40% by weight or more, about 45% by weight or more, about 50% by weight or more, about 55% by weight or more, about 60% by weight or more, about 65% by weight or more, about 70% by weight or more, about 75% by weight or more, about 80% by weight or more, about 85% by weight or more, about 90% by weight or more, or about 95% by weight or more. In one embodiment, the composition of the present disclosure may contain, as a carrier other than water, methanol, ethanol, propanol, propylene glycol, ethyl acetate, or oil (castor oil, peanut oil, soybean oil, mineral oil, sesame oil, olive oil, rapeseed oil, etc.), etc. The pH of any composition of the present disclosure can be about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 11, or a range between any two of these values.

[0120] Any component of the compositions of the present disclosure can be provided as a pharmaceutically acceptable salt, such as salts formed with free carboxyl groups derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, etc.; salts formed with free amine groups such as those derived from isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc.; and salts formed with sodium, potassium, ammonium, calcium, and ferric hydroxide.

[0121] The composition of the present disclosure may contain any additive component, examples of which include a thickener, a solubilizing agent, a suspending agent, a surfactant, an isotonicity adjusting agent, a buffer, a soothing agent, a stabilizer, a preservative, an antioxidant, a pH adjusting agent, a diluent, an adjuvant, a coloring agent, and a flavor.

[0122] In one embodiment, examples of the thickener include polysaccharides, cellulose polymers, synthetic polymers, etc. In one embodiment, examples of the polysaccharide include alginic acid, chondroitin sulfate, hyaluronic acid, xanthan gum, etc. In one embodiment, examples of the cellulose polymer include nonionic cellulose, anionic cellulose, etc. Examples of the nonionic cellulose include methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, etc. Examples of the anionic cellulose include carboxymethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, etc. In one embodiment, examples of the synthetic polymer include carboxyvinyl polymer, polyacrylic acid, polyvinylpyrrolidone, polyvinyl alcohol, etc.

[0123] In one embodiment, the surfactant may be a cationic surfactant, an anionic surfactant, a nonionic surfactant, etc. In one embodiment, the cationic surfactant may be an alkylamine salt, an alkylamine polyoxyethylene adduct, a fatty acid triethanolamine monoester salt, an acylaminoethyl diethylamine salt, a fatty acid polyamine condensate, an alkylimidazoline, a 1-acylaminoethyl-2-alkylimidazoline, a 1-hydroxyethyl-2-alkylimidazoline, etc. In one embodiment, the anionic surfactant may be a phosphate lipid such as lecithin, etc. In one embodiment, examples of the nonionic surfactant include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and polysorbate 65; polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60; polyoxyl castor oils such as polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 castor oil; sucrose fatty acid esters such as sucrose stearate; and tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS).

[0124] In one embodiment, the buffering agent includes boric acid, borax, phosphoric acid, carbonic acid, an organic acid or a salt thereof, etc. In one embodiment, the organic acid includes citric acid, acetic acid, ε-aminocaproic acid, gluconic acid, fumaric acid, lactic acid, ascorbic acid, succinic acid, maleic acid, malic acid, and an amino acid.

[0125] In one embodiment, preservatives include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine, parahydroxybenzoic acid esters, parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, sodium chlorite, and the like.

[0126] In one embodiment, antioxidants include sulfites, ascorbic acid, dibutylhydroxytoluene, α-tocopherol, and the like.

[0127] In one embodiment, the isotonic agent includes sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerin, propylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol, etc. In one embodiment, the soothing agent includes benzyl alcohol, etc.

[0128] In one embodiment, the suspending agent includes surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.

[0129] (Usage / Application) The compositions of the present disclosure can be used in any application that utilizes the effects of improving the stability of the disclosed polyether compounds and / or improving the solubility of poorly soluble compounds. In one embodiment, the compositions of the present disclosure can be used to improve the solubility of a pharmaceutical comprising the disclosed hydrophobic polyoxyaliphatic moiety-containing polyether compounds and / or hydratable compounds and poorly soluble compounds. In one embodiment, the compositions of the present disclosure can be administered intraocularly, ocularly, intravenously, topically, intramuscularly, subcutaneously, intradermally, transdermally, rectally, vaginally, via oral mucosal routes, via pulmonary mucosal routes, via the nose, via the eye, or orally (enterally).

[0130] In one embodiment, the composition of the present disclosure may be a liquid or suspension. In one embodiment, the composition of the present disclosure may be an internal preparation, an external preparation, or an injection. In one embodiment, the composition of the present disclosure may be an eye drop, an injection, a bolus injection, a drip infusion, an oral preparation, an inhalant, or a spray. When the composition of the present disclosure is an injection, its administration route includes, but is not limited to, intravenous administration, intramuscular administration, subcutaneous administration, intravitreal administration, etc. When the composition of the present disclosure is an external preparation, its administration route includes, but is not limited to, dermal administration, nasal administration, ocular administration, mucosal administration, rectal administration, inhalation administration, etc.

[0131] In one embodiment, the present disclosure may be useful for evaluating the efficacy of poorly soluble compounds, and dissolving poorly soluble compounds at high concentrations may simplify or speed up the evaluation of the efficacy (e.g., clinical efficacy) of poorly soluble compounds. In one embodiment, the present disclosure may avoid the use of other solubilizing agents and may eliminate the need to consider developing a suspension agent for poorly soluble compounds that are not soluble in conventional solubilizing agents.

[0132] When the composition of the present disclosure is applied to a subject, the subject is not particularly limited, and may be a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, pig, monkey, human, etc.), bird, reptile, amphibian, arthropod, fish, etc.

[0133] When the compositions of the present disclosure are used as therapeutic, preventative, or detection agents, the amount of the therapeutic agent of the present disclosure effective in treating a particular disorder or condition (e.g., a poorly soluble compound) will vary depending on the nature of the disorder or condition, but can be determined by one of ordinary skill in the art using standard clinical techniques based on the disclosure herein. In addition, in vitro assays may be used in some cases to help identify optimal dosage ranges. The precise dose to be used in the formulation may also vary depending on the route of administration and the severity of the disease or disorder, and should be determined according to the judgment of the attending physician and each patient's circumstances. However, the dosage is not particularly limited, and may be, for example, 0.00001, 0.0001, 0.001, 1, 5, 10, 15, 100, or 1000 mg / kg body weight per administration, or within any two ranges thereof. The administration interval is not particularly limited, and may be, for example, once or twice per 1, 7, 14, 21, or 28 days, or once or twice per range between any two of these values. The dosage, administration interval, and administration method may be appropriately selected depending on the age and weight of the patient, symptoms, target organ, etc.

[0134] The composition of the present disclosure can be provided as a kit. In one embodiment, the present disclosure provides a pharmaceutical pack or kit, comprising one or more containers filled with one or more components that can be added to the composition of the present disclosure. Optionally, such containers can also be associated with information indicating that the manufacture, use, or sale of the product for human administration has been approved by a government agency, as required by the government agency that regulates the manufacture, use, or sale of pharmaceutical or biological products.

[0135] Procedures for formulating the therapeutic agents, prophylactic agents, etc. of the present disclosure as pharmaceuticals and the like are known in the art and are described, for example, in the Japanese Pharmacopoeia, the United States Pharmacopoeia, the Pharmacopoeias of other countries, etc. Therefore, those skilled in the art will be able to determine embodiments such as the amount to be used without undue experimentation, given the description herein.

[0136] In one embodiment, the kit of the present disclosure includes instructions for using the kit of the present disclosure. Suitable containers include, for example, bottles, vials (e.g., dual-chamber vials), syringes (e.g., dual-chamber syringes), test tubes, multi-dose containers, single-use unit-dose containers (unit volume containers), or Preservative-Free Multi-Dose (PFMD) containers. The containers can be formed from a variety of materials, such as glass or plastic.

[0137] In this specification, "or" is used when "at least one or more" of the items listed in the sentence can be employed. The same applies to "alternative." In this specification, when it is specified that "within a range" of "two values," the range includes the two values ​​themselves.

[0138] All references cited herein, including scientific literature, patents, patent applications, and the like, are incorporated by reference in their entirety to the same extent as if each were specifically set forth.

[0139] The present disclosure has been described above by showing preferred embodiments for ease of understanding. The present disclosure will be described below based on examples. However, the above description and the following examples are provided for illustrative purposes only and are not intended to limit the present disclosure. Therefore, the scope of the present disclosure is not limited to the embodiments or examples specifically described herein, but is limited only by the scope of the claims. [Example]

[0140] The reagents used were specifically the products described in the examples, but equivalent products from other manufacturers (Sigma-Aldrich, Fujifilm Wako Pure Chemical Industries, Nakarai, R&D Systems, USCN Life Science INC, etc.) can also be used.

[0141] (Example 1) Stability test Polyether compounds such as poloxamer and polyethylene glycol can be decomposed by light or oxygen radicals, causing a decrease in the pH and viscosity of the solution. Therefore, we tested stabilizers that can be suitably combined with these polyether compounds.

[0142] For aqueous solutions containing poloxamer and / or polyethylene glycol, additional ingredients The viscosity and pH were measured over time under harsh conditions at 60°C for 1 minute. The following poloxamer, polyethylene glycol, and buffer were used. Poloxamer 407 (Corifor P407, BASF, Germany) PEG4000 (Macrogol 4000, NOF Corp., Tokyo) Buffer: Boric acid 0.9%, Borax 0.1%

[0143] Specifically, the buffer, PEG, poloxamer, and additives were weighed into a preparation container, and purified water was added to prepare the desired formulation. The pH was adjusted with hydrochloric acid or sodium hydroxide. Each preparation was filtered through a 0.45 μm pore size filter (Merck, Germany) or a 5 μm pore size filter (GE Healthcare, USA). Five mL of each filtrate was filled into a polyethylene eye dropper bottle and stored in a constant temperature bath at 60°C. The pH and viscosity of the test solution were measured at the time of preparation and after 4 weeks of storage. Viscosity was measured using a rotational viscometer (Toki Sangyo, Osaka, TVE-25 type L viscometer, 25°C, 100 rpm). The pH at the time of preparation was measured in the test solution before transferring it to the eye dropper bottle for storage.

[0144] The pH change was investigated by adding the additives shown in the table below to the basic compositions of 25% PEG4000 only, 10% poloxamer 407 only, and 25% PEG4000 + 10% poloxamer 407. The results are shown in the table below. [Table 1-1] [Table 1-2] [Table 2-1] [Table 2-2] [Table 3-1] [Table 3-2]

[0145] Sodium thiosulfate stabilized PEG 4000 at concentrations as low as 0.01% and poloxamer 407 at concentrations as low as 0.03%. Dibutylhydroxytoluene (BHT) alone stabilized poloxamer 407. Combining sodium thiosulfate with dibutylhydroxytoluene (BHT) stabilized poloxamer 407 (and PEG 4000) even at low concentrations of sodium thiosulfate. EDTA stabilized poloxamer 407 at concentrations as low as 0.01%, but concentrations of 0.1% or higher were required to stabilize PEG 4000. Mannitol, sodium sulfite, and sodium metabisulfite alone failed to stabilize either poloxamer 407 or PEG 4000, but no decrease in stability was observed with the addition of mannitol. Viscosity measurements showed similar results to those of pH measurements.

[0146] Similarly, the results of investigating the change in pH when 0.1% sodium thiosulfate or 0.1% EDTA was used as an additive and various amounts of PEG 4000 and poloxamer 407 were added are shown in the table below. [Table 4] [Table 5] [Table 6]

[0147] Although 0.1% sodium thiosulfate was unable to achieve sufficient stabilization in the presence of a large amount of PEG 4000 (50%), it showed high stabilizing ability for smaller amounts of PEG 4000 and poloxamer 407. 0.1% EDTA was able to stabilize up to approximately 20% PEG 4000 and showed high stabilizing ability for poloxamer 407. Viscosity measurements showed similar results to those of pH measurements.

[0148] Similarly, the pH change was investigated when different types of PEG (addition amount: 25%) and poloxamer (addition amount: 10%) were added using 0.1% sodium thiosulfate or 0.1% EDTA as the additive component. The results are shown in the table below. [Table 7] [Table 8]

[0149] Sodium thiosulfate showed similar stabilizing effects for various PEGs and poloxamers. EDTA showed similar stabilizing effects for various poloxamers, and also for low molecular weight PEG400. Viscosity measurements showed similar results to those for pH measurements.

[0150] The above experiment was carried out under boric acid borax pH 7.5 buffer conditions, but the buffer conditions were set as shown in the table below. The results of investigating the pH change when 0.1% sodium thiosulfate or 0.1% EDTA was added to the basic composition of 25% PEG4000 + 10% poloxamer 407 are shown in the table below. [Table 9] *In the table, "Sodium phosphate" and "borax borate" have the following compositions. Sodium phosphate: Sodium hydrogen phosphate hydrate 0.08%, Sodium dihydrogen phosphate hydrate 0.12% Borax: Boric acid 0.9%, borax 0.1%

[0151] Similar results were obtained when buffering agents and pH were changed. Viscosity measurements showed similar results to those observed with pH measurements. Formulations containing EDTA or sodium thiosulfate may be stable at various pHs (e.g., pH 6).

[0152] (Example 2) Solubility test There are various advantages to preparing poorly soluble compounds as aqueous formulations, so we investigated formulations that can improve the solubility of poorly soluble compounds.

[0153] The solubility of a poorly soluble compound was measured for an aqueous solution of the following basic composition while changing the additive conditions. Sodium hydrogen phosphate hydrate 0.2% Sodium dihydrogen phosphate hydrate 0.3% Sodium hydroxide and hydrochloric acid (adjust to pH 7.0) *Sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate ··Fujifilm Wako Pure Chemical Industries, Ltd.

[0154] Specifically, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate, and additives were weighed into a preparation vessel, and purified water was added to prepare the desired formulation. The poorly soluble compound (mebentazole (Toronto Research Chemicals, Canada), dexamethasone (Tokyo Chemical Industry Co., Ltd., Japan), or triamcinolone acetonide (Tokyo Chemical Industry Co., Ltd., Japan)) was weighed into the preparation solution, and the pH was adjusted to 7.0 with hydrochloric acid or sodium hydroxide. The solution was stirred for several days in storage cabinets at 5°C, 15°C, and 25°C, respectively, and after confirming that the poorly soluble compound was suspended, it was filtered through a 0.45 μm pore size filter (Merck, Germany) in the storage cabinets at each temperature. The content of the poorly soluble compound in the recovered filtrate was measured using liquid chromatography (Shimadzu Corporation, Kyoto, Japan, Prominence high-performance liquid chromatograph) under the following conditions.

[0155] Measurement of sparingly soluble compounds Each filtrate was diluted appropriately with a diluent (30% acetonitrile solution) to prepare a sample solution. A 0.001% standard solution of poorly soluble compounds was prepared by precisely weighing mebentazole standard and dissolving it in diluent (30% acetonitrile solution). Reagents from Fujifilm Wako Pure Chemical Industries (Japan) were used for mebentazole and dexamethasone standards. Reagents from the Pharmaceutical and Medical Device Regulatory Science Foundation (Japan) were used for triamcinolone acetonide standard. 50 μL of the sample solution and standard solution were measured by liquid chromatography under the following conditions, and the peak area of ​​each solution was calculated using the automatic integration method to calculate the content of poorly soluble compounds in the sample solution. Measurement conditions Detector: UV spectrophotometer (measurement wavelength: 235 nm for mebentazole, 239 nm for dexamethasone and triamcinolone acetonide) Column: OSAKA SODA CAPCELL PAK C18 MGII 3 μm, 4.6 × 150 mm Column temperature: constant temperature of about 40°C Mobile phase A: 0.1% trifluoroacetic acid / 10% acetonitrile solution Mobile phase B: 0.1% trifluoroacetic acid / 90% acetonitrile solution Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was changed as follows to control the linear concentration gradient. [Table 10] Cleaning solution: 50% acetonitrile solution Flow rate: 1.0mL / min Autosampler temperature: 5℃ Area measurement range: 45 minutes For mebentazole and dexamethasone, the following calculations were followed: Content of sparingly soluble compounds in standard solution (%) =W F / Capacity (mL) × Pu F / 100×(100-Loss on Drying (%)) / 100×1 / Dilution Ratio / 10 Content of poorly soluble compounds in sample solution (%) =A TF / A SF × Content of poorly soluble compounds in standard solution (%) × Dilution ratio W F :Weighed amount of poorly soluble compound standard product (mg) Pu F : Purity (%) of poorly soluble compound standard A SF : Peak area of ​​poorly soluble compounds in standard solution A TF : Peak area of ​​poorly soluble compounds in sample solution For triamcinolone acetonide, the following calculation was used: Content of sparingly soluble compounds in standard solution (%) =W F / Dilution ratio: 10 Content of poorly soluble compounds in sample solution (%) =A TF / A SF × Content of poorly soluble compounds in standard solution (%) × Dilution ratio W F :Weighed amount of poorly soluble compound standard product (mg) A SF : Peak area of ​​poorly soluble compounds in standard solution A TF : Peak area of ​​poorly soluble compounds in sample solution

[0156] For poorly soluble compounds, the following conditions were tested as additives. [Table 11] Poloxamer 407 (Corifor P407, BASF, Germany) PEG4000 (Macrogol 4000, NOF Corp., Tokyo)

[0157] The results are shown in Figures 1 to 3. The solubility of the composition containing poloxamer 407 and PEG 4000 was subtracted from the solubility of the same composition except that it did not contain poloxamer 407 at temperatures of 5°C, 15°C, and 25°C. This calculated value, i.e., the improved solubility (S A+B -S B ) was calculated by subtracting the solubility of a composition that does not contain either poloxamer 407 or PEG 4000 from the solubility of the same composition except that it does not contain PEG 4000, i.e., the solubility due to poloxamer 407 (S A -S0), and the calculated multiplication factor (called the solubility multiplication factor, calculated using the following formula) is shown below. (S A+B -S B ) / (S A -S0) (In the formula, S A+B = Solubility of poorly soluble compounds in compositions containing poloxamer 407 and PEG 4000 S B = Solubility of a poorly soluble compound in a composition that does not contain poloxamer 407 but contains PEG 4000 S A = Solubility of poorly soluble compounds in compositions containing poloxamer 407 and not containing PEG 4000 SO = solubility of poorly soluble compound in a composition that does not contain both poloxamer 407 and PEG 4000

[0158] Tables 12 to 14 below show the results when mebentazole was used as the poorly soluble compound. [Table 12] [Table 13] [Table 14]

[0159] Tables 15 to 17 below show the results when dexamethasone was used as the poorly soluble compound. [Table 15] [Table 16] [Table 17]

[0160] The following Tables 18 to 20 show the results when triamcinolone acetonide was used as the poorly soluble compound. [Table 18] [Table 19] [Table 20]

[0161] The addition of PEG 4000 improved the solubilization of poorly soluble compounds by poloxamer 407 at all temperatures: 5°C, 15°C, and 25°C. In particular, the solubilization of poorly soluble compounds by PEG 4000 and poloxamer 407 was significantly improved at low temperatures of 5°C and 15°C.

[0162] The solubility of additional compounds in the PEG and poloxamer compositions was measured in the same manner as above. The following compounds were tested (measurement wavelengths in the ultraviolet spectrophotometer are shown in parentheses): fluocinolone acetonide (239 nm), desonide (239 nm), flubendazole (235 nm), cilostazol (254 nm), itraconazole (258 nm), sorafenib (265 nm), regorafenib (260 nm), and telmisartan (295 nm). , cabozantinib (244nm), nilotinib (266nm), aprepitant (215nm), rotenone (295nm), griseofulvin (291nm), osthole (322nm), 4-bromodibenzofuran (281nm), simvastatin (238nm), efavirenz (247nm), rebamipide (254nm), celecoxib (252nm). [ka] [ka]

[0163] Further compounds were obtained from the following sources: [Table 21]

[0164] For cabozantinib and telmisartan, the aqueous solutions with the above basic composition were adjusted to pH 7.4. For repamipide, the aqueous solution with the basic composition was as follows: Sodium hydrogen phosphate hydrate 0.05% Sodium dihydrogen phosphate hydrate 0.45% Sodium hydroxide and hydrochloric acid (adjust to pH 6.0)

[0165] The measurements of other compounds were performed in the same manner as above. Regarding the specific calculation formulas, the same formula as for dexamethasone was applied to itraconazole, telmisartan, cilostazol, and flubendazole, and the same formula as for triamcinolone acetonide was applied to rebamipide, fluocinolone acetonide, and cabozantinib, and the other compounds were as follows (the specific values ​​for the respective fill-up volumes were used). The following calculations were used for desonide, griseofulvin, osthole, rotenone, simvastatin, celecoxib, aprepitant, efavirenz, 4-bromodibenzofuran, and nilotinib. Content of sparingly soluble compounds in standard solution (%) =W F / Capacity (mL) × Pu F / 100×1 / dilution ratio / 10 Content of poorly soluble compounds in sample solution (%) =A TF / A SF × Content of poorly soluble compounds in standard solution (%) × Dilution ratio W F :Weighed amount of poorly soluble compound standard product (mg) Pu F : Purity (%) of poorly soluble compound standard A SF : Peak area of ​​poorly soluble compounds in standard solution A TF : Peak area of ​​poorly soluble compounds in sample solution For regorafenib (hydrate), the following calculation was used: Content of sparingly soluble compounds in standard solution (%) =W F / Capacity (mL) × Pu F / 100 × (molecular weight of regorafenib hydrate - (amount of hydrate × molecular weight of water)) / molecular weight of regorafenib hydrate × 1 / dilution ratio / 10 Content of poorly soluble compounds in sample solution (%) =ATF / A SF × Content of poorly soluble compounds in standard solution (%) × Dilution ratio W F :Weighed amount of poorly soluble compound standard product (mg) Pu F : Purity (%) of poorly soluble compound standard A SF : Peak area of ​​poorly soluble compounds in standard solution A TF : Peak area of ​​poorly soluble compounds in sample solution For sorafenib, the following calculation was used: Content of sparingly soluble compounds in standard solution (%) =W F / Dilution ratio (mL) x (100 - loss on drying (%)) / 100 x 1 / 10 Content of poorly soluble compounds in sample solution (%) =A TF / A SF × Content of poorly soluble compounds in standard solution (%) × Dilution ratio W F :Weighed amount of poorly soluble compound standard product (mg) A SF : Peak area of ​​poorly soluble compounds in standard solution A TF : Peak area of ​​poorly soluble compounds in sample solution

[0166] The solubility results for each compound are shown in Figures 4 to 22. In addition, some of the results of solubility factors calculated in the same manner as above are shown in Table 22 below. Solubility factors under other conditions not specifically described in Table 22 can also be understood based on Figures 4 to 22. Cabozantinib and telmisartan were tested in solutions adjusted to pH 7.4, repamipide was tested in solutions adjusted to pH 6.0, and the other compounds were tested in solutions adjusted to pH 7.0. Efavirenz gelled under 15% poloxamer conditions at 15°C and 25°C, and 4-bromodibenzofuran gelled under 15% poloxamer conditions at 25°C; therefore, the measurement results under these conditions may not be accurate (for these compounds, the experiments were performed by cooling the solution for about 5 minutes before filtration and dilution to obtain reference values). [Table 22]

[0167] For additional compounds, the addition of PEG 4000 similarly improved the solubilization of the compound by poloxamer 407. Rebamipide showed the least degree of solubilization improvement.

[0168] Next, to investigate the compound characteristics that favorably improve solubility in the formulation of the present disclosure, basic solubility in various solvents was tested. Solubility at 25°C was tested in four solvents: ethanol (Fujifilm Wako Pure Chemical Industries, Ltd.), PEG400 (Fujifilm Wako Pure Chemical Industries, Ltd.), propylene glycol (PG) (Fujifilm Wako Pure Chemical Industries, Ltd.), and a buffer solution. Here, the buffer solution had the following composition. Sodium hydrogen phosphate hydrate 0.2% Sodium dihydrogen phosphate hydrate 0.3% Sodium hydroxide and hydrochloric acid (adjust to pH 7.0, except for cabozantinib and telmisartan, adjust to pH 7.4) However, the alternative composition for Repamipide was as follows: Sodium hydrogen phosphate hydrate 0.05% Sodium dihydrogen phosphate hydrate 0.45% Sodium hydroxide and hydrochloric acid (adjust to pH 6.0)

[0169] The measurements for each compound were carried out in the same manner as above. The solubility results in each solvent are shown in Table 23. In the table, the molecular weight and LogP values ​​are literature values ​​(or values ​​calculated from literature values). [Table 23] A Calculated using XLogP3. B Calculated value using CLogP. * pH at the time of LogP measurement: rebamipide (pH 7.0), telmisartan (pH 7.4), cilostazol (pH 7.0), mebendazole (pH 6.0), celecoxib (pH 7), aprepitant (pH 7), cabozantinib (pH 7.4)

[0170] The solubility ratio in non-aqueous solvents (ethanol, PEG400, PG) compared to the buffer solution (aqueous solvent) was calculated as an index of the poor solubility of the compounds. Note that itraconazole was excluded because its solubility in the buffer solution was below the detection limit.

[0171] This solubility ratio, along with selected solubility factors for the PEG / poloxamer formulations determined above, are summarized in Table 24 below. [Table 24]

[0172] The solubility ratio in non-aqueous solvents compared to aqueous solvents was observed to correlate well with the level of solubilization improvement achieved by the PEG / poloxamer formulations of the present disclosure. Note that when repamipide is tested at pH 7.0, the solubility ratio and solubility factor are expected to be similarly low. Similarly, when cabozantinib and telmisartan are tested at pH 7.0, the solubility ratio and solubility factor are expected to be similarly similar to the results above.

[0173] Considering the structure and properties of each compound, it was believed that poorly soluble compounds having the following characteristics tend to be particularly susceptible to solubilization by the formulations of the present disclosure. -Higher solubility ratio in non-aqueous solvents compared to aqueous solvents. -No ionic groups such as carboxyl groups or tetrazole groups. -Contains a fluorine atom (excluding cases where a hydroxyl group or -NH group is present at the vicinal position of the fluorine atom). -No hydroxyl groups. -Molecular weight of 350 or more. -Having two or more rings.

[0174] The solubility of poorly soluble compounds was measured by adding water-soluble polymers. The results showed that sulfobutylether-β-cyclodextrin further improved the solubilization of poorly soluble compounds with poloxamer 407 and PEG 4000. Carboxymethylcellulose also tended to further enhance the solubilization of poorly soluble compounds with poloxamer 407 and PEG 4000.

[0175] More specifically, for celecoxib, solubility measurements were performed in the same PEG / poloxamer compositions as above, with one of the following modifications: PEG / poloxamer formulation with 0.5% carboxymethylcellulose (CMC) PEG / poloxamer formulation with 5% sulfobutyl ether-β-cyclodextrin (SBE-β-CD) PEG / poloxamer formulation with 5% hydroxypropyl-β-cyclodextrin (HP-β-CD) *CMC·Dai-ichi Kogyo Seiyaku *SBE-β-CD··MedChemExpress LLC *HP-β-CD··Fujifilm Wako Pure Chemical Industries, Ltd.

[0176] The solubility results for each compound are shown in Figures 23 to 25. The addition of HP-β-CD did not significantly improve solubility, but the addition of SBE-β-CD or CMC improved solubility overall.

[0177] (Note) As described above, the present disclosure has been illustrated using preferred embodiments of the present disclosure, but it is understood that the scope of the present disclosure should be interpreted only by the claims. It is understood that the patents, patent applications, and literature cited in this specification are incorporated by reference into this specification as if the contents themselves were specifically set forth herein. This application claims priority to Japanese Patent Application No. 2020-16656 filed with the Japan Patent Office on February 3, 2020, and it is understood that the contents themselves are incorporated by reference into this specification as if the contents themselves were specifically set forth herein. [Industrial Applicability]

[0178] The present disclosure can be used to improve ease of handling of drugs (particularly medicines).

Claims

1. A composition comprising a polyether compound and a chelate compound, the polyether compound comprises poloxamer and polyethylene glycol; the chelating compound comprises thiosulfate; The composition comprises 1 to 15% by weight of the poloxamer, 1 to 30% by weight of the polyethylene glycol, and 0.03 to 5% by weight of the thiosulfate.

2. The composition described in claim 1, wherein the composition contains 1 to 15% by weight of the poloxamer, 1 to 30% by weight of the polyethylene glycol, and 0.1 to 1% by weight of the thiosulfate.

3. 3. The composition of claim 1 or 2, wherein the composition further comprises at least one of mannitol and dibutylhydroxytoluene (BHT).

4. 4. The composition of claim 1, wherein the poloxamer has an average molecular weight of about 1,000 to 15,000.

5. The composition according to any one of claims 1 to 4, wherein the poloxamer contains 10 to 90% by weight of polyoxyethylene in one molecule.

6. The composition according to any one of claims 1 to 5, wherein the poloxamer has polyoxypropylene with an average molecular weight of about 900 to 4,000 per molecule.

7. The composition of any one of claims 1 to 6, wherein the polyethylene glycol has an average molecular weight of about 200 to 50,000.

8. The composition according to any one of claims 1 to 7, further comprising a buffering agent.

9. The composition according to any one of claims 1 to 8, which is an internal preparation, an external preparation, or an injection.

10. The composition according to any one of claims 1 to 9, which is for intravenous, intramuscular, subcutaneous or intravitreal administration.

11. 10. The composition of any one of claims 1 to 9, wherein the composition is for administration selected from the group consisting of dermal, nasal, ocular, mucosal, rectal, and inhalation administration.

12. A composition according to any one of claims 1 to 10, for application to the eye.

13. The composition according to any one of claims 1 to 12, which is an eye drop.

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