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
  • A61K47/02—Inorganic compounds
• • 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
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • 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 when iron is mixed even in a small amount in the production 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 iron is mixed.
• An aqueous composition containing (A) delgocitinib or a salt thereof, and (B) at least one selected from the group consisting of citric acid, phosphoric acid, and salts thereof.
• A delgocitinib or a salt thereof
• B at least one selected from the group consisting of citric acid, phosphoric acid, 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 iron is mixed.
• the aqueous composition according to the present embodiment is selected from the group consisting of (A) delgocitinib or a salt thereof (also referred to as “component (A)”) and (B) citric acid, phosphoric acid, and salts thereof. It contains at least one kind (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.
• the components (B), citric acid, phosphoric acid, and salts thereof, are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.
• citrate and the phosphate examples include a salt with an inorganic base (for example, an ammonium salt; an alkali metal (sodium, potassium, etc.), an alkaline earth metal (calcium, magnesium, etc.), a salt with a metal such as aluminum, etc.).
• an inorganic base for example, an ammonium salt; an alkali metal (sodium, potassium, etc.), an alkaline earth metal (calcium, magnesium, etc.), a salt with a metal such as aluminum, etc.
• Etc. salts with organic bases (eg, salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholin, piperazine, pyrrolidine, tripyridine, picolin, etc.) and the like.
• citric acid or a salt thereof citric acid and an alkali metal salt of citric acid are preferable, citric acid and sodium citrate are more preferable, and citric acid is further preferable.
• Citric acid and its salt may be hydrated or anhydrous. Citric acid or a salt thereof may be used alone or in combination of two or more.
• phosphoric acid or a salt thereof phosphoric acid and an alkali metal salt of phosphoric acid are preferable, and phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate are more preferable.
• Phosphoric acid is more preferred.
• Phosphoric acid and salts thereof may be hydrates or anhydrides. Phosphoric acid 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 the present embodiment may further contain a buffering agent other than the component (B).
• a buffering agent other than the component (B).
• 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 of the buffering agent in the aqueous composition according to the present embodiment is not particularly limited, and is appropriately set according to the type of the buffering agent, 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 buffer is 0.01% by mass to 10% by mass, 0, based on the total amount of the aqueous composition. It may be 0.05% by mass to 5% by mass, or 0.1% by mass to 3% by mass.
• 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, iron sulfate heptahydrate 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 14 to 21) and a polyethylene container (Test Examples 22 to 32) 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. After adding iron sulfate heptahydrate to a concentration of 4 ppm to each of the prepared aqueous compositions, the mixture was allowed to stand at 60 ° C. for 10 days.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Ophthalmology & Optometry (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Inorganic Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (7)

Applications Claiming Priority (2)

Publications (1)

Family

ID=80036428

Family Applications (1)

Country Status (9)

Families Citing this family (3)

Citations (4)

Family Cites Families (4)

• 2021
  • 2021-07-30 AU AU2021318236A patent/AU2021318236A1/en active Pending
  • 2021-07-30 CA CA3190310A patent/CA3190310A1/en active Pending
  • 2021-07-30 JP JP2022539623A patent/JPWO2022025279A1/ja active Pending
  • 2021-07-30 CN CN202180059005.XA patent/CN116568285A/zh active Pending
  • 2021-07-30 TW TW110128196A patent/TWI908843B/zh active
  • 2021-07-30 EP EP21851495.8A patent/EP4176882A4/en active Pending
  • 2021-07-30 US US18/018,105 patent/US20230285562A1/en active Pending
  • 2021-07-30 KR KR1020237005628A patent/KR20230047400A/ko active Pending
  • 2021-07-30 WO PCT/JP2021/028439 patent/WO2022025279A1/ja not_active Ceased

Patent Citations (4)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events