Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents

Definitions

• the present invention relates to an aqueous composition.
• Janus kinase is a non-receptor tyrosine kinase that plays an important role in intracellular immune activation signal transduction, and drugs with Janus kinase inhibitory activity suppress excessive activation of immune responses. It is expected to improve autoimmune diseases and allergic diseases.
• the ophthalmic preparation containing delgocitinib is required to have a certain degree of stability.
• a new problem has been found that if even a small amount of copper is mixed in the manufacturing stage of an ophthalmic preparation containing delgocitinib, the ophthalmic preparation is colored and its stability is lowered.
• An object of the present invention is to provide an aqueous composition containing delgocitinib or a salt thereof as an active ingredient, which is excellent in stability even when a small amount of copper is mixed.
• the present inventor has added edetonic acid, creatinine or a salt thereof to an aqueous composition containing delgocitinib and a trace amount of copper to stabilize the aqueous composition. It was found that the sex was significantly improved.
• the present invention is based on this finding and provides the following inventions.
• An aqueous composition containing (A) delgocitinib or a salt thereof and (B) at least one selected from the group consisting of edetic acid, creatinine, and salts thereof.
• A delgocitinib or a salt thereof
• B at least one selected from the group consisting of edetic acid, creatinine, and salts thereof.
• an aqueous composition containing delgocitinib or a salt thereof as an active ingredient which is excellent in stability even when a small amount of copper is mixed.
• the aqueous composition according to the present embodiment is at least selected from the group consisting of (A) delgocitinib or a salt thereof (also referred to as “component (A)") and (B) edetic acid, creatinine, and salts thereof. Contains one type (also referred to as “component (B)”).
• Delgocitinib is 3-[(3S, 4R) -3-methyl-6- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1,6-diazaspiro [3.4] octane-1-yl).
• the salt of delgocitinib is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.
• Specific examples of such salts include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with acidic amino acids, salts with basic amino acids, and the like. ..
• Examples of the salt with the inorganic acid include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
• Salts with organic acids include, for example, acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid (mesylic acid), ethanesulfonic acid, p-toluenesulfonic acid. And so on.
• Examples of the salt with the inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt.
• Examples of the salt with an organic base include salts with diethylamine, diethanolamine, meglumine, N, N-dibenzylethylenediamine and the like.
• Examples of the salt with an acidic amino acid include a salt with aspartic acid, glutamic acid and the like.
• Examples of the salt with a basic amino acid include salts with arginine, lysine, ornithine and the like.
• the aqueous composition according to the present embodiment contains dergocitinib or a salt thereof as an active ingredient, and is caused by an endogenous disease such as dry eye (dry eye syndrome), Sjogren's syndrome, Stevens-Johnson syndrome, etc. It can be used for the treatment of conjunctival epithelial disorder or keratoconjunctival epithelial disorder caused by postoperative, drug-induced, traumatic, extrinsic diseases such as wearing contact lenses.
• the aqueous composition according to the present embodiment can be used for improving dry eye because it promotes the secretion of tears by containing delgocitinib or a salt thereof.
• the dry eye may be a dry eye caused by an autoimmune disease such as Sjogren's syndrome, or may be a dry eye caused by a factor other than the autoimmune disease.
• the content of the component (A) in the aqueous composition according to the present embodiment is not particularly limited, and is appropriately set according to the type and content of other compounding components, the formulation form, and the like.
• the content of the component (A) from the viewpoint of exerting the effect of the present invention more remarkably, for example, the total content of the component (A) is 0. 003% by mass to 3% by mass, 0.005% by mass to 1% by mass, 0.01% by mass to 0.5% by mass, 0.015% by mass to 0.4% by mass, or 0.03% by mass to 0 It may be 3% by mass.
• [(B) component] (B)
• the components edetic acid, creatinine, and salts thereof are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.
• Edetoic acid also referred to as ethylenediaminetetraacetic acid (EDTA)
• EDTA ethylenediaminetetraacetic acid
• Examples of the salt of edetonic acid include alkali metal salts such as sodium edetate, disodium edetate, and tetrasodium edetate.
• alkali metal salts such as sodium edetate, disodium edetate, and tetrasodium edetate.
• disodium edetate is preferable.
• Edetonic acid and a salt thereof may be a hydrate or an anhydrate.
• the edetic acid or a salt thereof may be used alone or in combination of two or more.
• Creatinine also referred to as 2-amino-1-methyl-2-imidazolin-4-one or 2-imino-1-methylimidazolidine- 4 - one, is a known compound represented by C4H7N3O . be.
• creatinine examples include inorganic acid salts such as creatinine hydrochloride. As creatinine or a salt thereof, creatinine is preferable. Creatinine and its salt may be hydrated or anhydrous. Creatinine or a salt thereof may be used alone or in combination of two or more.
• the content of the component (B) in the aqueous composition according to the present embodiment is not particularly limited, and is appropriately set according to the type and content of other compounding components, the formulation form, and the like.
• the total content of the component (B) is 0, based on the total amount of the aqueous composition according to the present embodiment. It may be 0.001% by mass or more, 0.00005% by mass or more, 0.0001% by mass or more, 0.0005% by mass or more, 0.05% by mass or less, 0.04% by mass or less, 0.03% by mass.
• it may be 0.02% by mass or less.
• 0.000001% by mass to 10% by mass 0.00001% by mass to 1% by mass, 0.0001% by mass to 0.1% by mass, 0.0005% by mass to 0.05% by mass, 0.0001% by mass. It may be% to 0.05% by mass, 0.00001% by mass to 0.1% by mass, or 0.00001% by mass to 0.05% by mass.
• the content ratio of the component (B) to the component (A) in the aqueous composition according to the present embodiment is not particularly limited, and depends on the type of the component (B), the type and content of other compounding components, the formulation form, and the like. Is set as appropriate.
• the total content of the component (B) contained in the aqueous composition according to the present embodiment is 1 part by mass.
• the total content of the component (B) is 0.0000003 parts by mass to 4000 parts by mass, 0.00001 parts by mass to 200 parts by mass, 0.0002 parts by mass to 10 parts by mass, or 0.001 to 4 parts. It may be a mass part.
• the aqueous composition according to this embodiment may further contain a buffer.
• a buffer When the aqueous composition further contains a buffer, the effect of the present invention is more pronounced.
• the buffer is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.
• the buffer is not limited, but is, for example, a boric acid buffer (for example, boric acid, a combination of boric acid and boric acid, etc.), a carbon dioxide buffer, an acetate buffer, a tris buffer, aspartic acid, and aspartate. And so on.
• a boric acid buffer for example, boric acid, a combination of boric acid and boric acid, etc.
• carbon dioxide buffer for example, an acetate buffer, a tris buffer, aspartic acid, and aspartate.
• the buffering agent a commercially available one may be used.
• the buffer may be used alone or in combination of two or more. Boric acid is preferred as the buffer.
• the content ratio of the buffering agent to the component (A) in the aqueous composition according to the present embodiment is not particularly limited, and the type of the component (B) and the buffering agent, the type and content of other compounding components, and the aqueous composition. It is appropriately set according to the intended use, the form of the formulation, and the like.
• the total content of the buffer may be 0.03 parts by mass to 500 parts by mass, 0.1 parts by mass to 250 parts by mass, or 0.3 parts by mass to 150 parts by mass.
• the content ratio of the buffer to the component (B) in the aqueous composition according to the present embodiment is not particularly limited, and the type of the buffer, the type and content of other compounding components, the use and the formulation form of the aqueous composition, etc. It is set appropriately according to.
• the total content of the buffer may be 0.01 parts by mass to 1,000,000 parts by mass, 0.5 parts by mass to 50,000 parts by mass, or 2 parts by mass to 6000 parts by mass.
• the aqueous composition according to this embodiment may further contain inorganic salts.
• the aqueous composition further contains inorganic salts, the effect of the present invention is more remarkable.
• the inorganic salts are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.
• inorganic salts examples include chloride salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.
• chloride salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.
• the inorganic salts commercially available ones may be used.
• the inorganic salts one kind may be used alone, or two or more kinds may be used in combination.
• sodium chloride and potassium chloride are preferable.
• the content of the inorganic salt in the aqueous composition according to the present embodiment is not particularly limited, and is appropriately set according to the type of the inorganic salt, the type and content of other compounding components, the use of the aqueous composition, the formulation form, and the like.
• the total content of the inorganic salts is 0.00001% by mass to 3% by mass, 0, based on the total amount of the aqueous composition. It may be .0001% by mass to 2% by mass, or 0.001% by mass to 1.5% by mass.
• the pH of the aqueous composition according to this embodiment is 5.0 to 6.5.
• the stability of the aqueous composition containing delgocitinib or a salt thereof as an active ingredient is significantly improved.
• the pH of the aqueous composition is preferably 5.0 to 6.0.
• the pH of the aqueous composition may be 4.0 to 6.0, 4.2 to 5.8, 4.3 to 5.7, or 4.5 to 5.5.
• the aqueous composition according to the present embodiment can be adjusted to an osmotic pressure ratio within a range acceptable to the living body, if necessary.
• the appropriate osmotic pressure ratio can be appropriately set depending on the use, formulation form, usage method, etc. of the aqueous composition, and can be, for example, 0.4 to 5.0, and 0.6 to 3.0. It is preferably 0.8 to 2.2, more preferably 0.8 to 2.0.
• the osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9w / v% sodium chloride aqueous solution) based on the 17th revised Japanese Pharmacy, and the osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacy. Measure with reference to (freezing point depression method).
• the standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) is prepared by drying sodium chloride (standard reagent according to the Japanese Pharmacopoeia) at 500 to 650 ° C. for 40 to 50 minutes and then in a desiccator (silica).
• 0.900 g thereof can be accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for measuring osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) can be used.
• the viscosity of the aqueous composition according to the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range.
• the viscosity of the aqueous composition according to the present embodiment for example, the viscosity at 20 ° C. measured with a rotary viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1 ° 34' ⁇ R24) is 0.5. It is preferably about 10 mPa ⁇ s, more preferably 1 to 5 mPa ⁇ s, and even more preferably 1 to 3 mPa ⁇ s.
• the aqueous composition according to the present embodiment can be prepared, for example, by adding and mixing the component (A), the component (B), and, if necessary, other contained components so as to have a desired content.
• can Specifically, for example, it can be prepared by dissolving or suspending the above components in purified water and sterilizing by filtration sterilization or the like.
• the aqueous composition according to the present embodiment can take various dosage forms depending on the purpose, and examples thereof include liquid preparations, gel preparations, semi-solid preparations (ointments, etc.) and the like.
• the aqueous composition according to this embodiment can be used for ophthalmology. Further, the aqueous composition according to the present embodiment is, for example, as an eye drop (also referred to as eye drops or eye drops; the eye drops include artificial tears and eye drops that can be instilled while wearing contact lenses). Can be used.
• eye drops also referred to as eye drops or eye drops; the eye drops include artificial tears and eye drops that can be instilled while wearing contact lenses.
• the dosage and administration thereof is not particularly limited as long as it is effective and has few side effects, but for example, adults (15 years old or older) and 7 years old.
• a method of instilling 1 drop or 1 to 2 drops at a time 4 times a day and a method of using 1 drop or 1 to 2 drops at a time 5 to 6 times a day can be exemplified. ..
• Example 1 Visual stability evaluation
• An aqueous composition was prepared according to a conventional method with the compositions shown in Table 1. Both aqueous compositions were adjusted to pH 5.5 with hydrochloric acid and sodium hydroxide. Each prepared aqueous composition was dispensed into three glass containers by 5 mL each, and copper sulfate pentahydrate was added to each dispensed aqueous composition to a concentration of 4 ppm, and then the temperature was 60 ° C. for 3 weeks. It was left still. Each aqueous composition that had been allowed to stand under the above conditions was subjected to a colorless test tube (inner diameter 15 mm: Lighterbrand Disposable Culture Tubes Borosilicate Glass 16 ⁇ 150 mm (Cat.
• Example 2 Stability evaluation by absorbance measurement
• the aqueous composition was prepared by pouring it into a glass container (Test Examples 9 to 14) and a polyethylene container (Test Examples 15 to 23) according to a conventional method.
• "phosphoric acid” is sodium dihydrogen phosphate
• "edetic acid” is sodium edetate.
• Both aqueous compositions were adjusted to pH 5.5 with hydrochloric acid and sodium hydroxide. Copper sulfate pentahydrate was added to each of the prepared aqueous compositions to a concentration of 4 ppm, and then the mixture was allowed to stand at 60 ° C. for 10 days.

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• 2021
  • 2021-07-30 US US18/018,108 patent/US20230285564A1/en active Pending
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  • 2021-07-30 EP EP21850581.6A patent/EP4176881A4/en active Pending
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