Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
  • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
• • 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
  • 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

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 the immune response. It is expected to improve autoimmune diseases and allergic diseases.
• the ophthalmic preparation containing dergocitinib is required to have a certain degree of stability.
• An object of the present invention is to provide an aqueous composition containing dergocitinib or a salt thereof as an active ingredient, which has excellent stability.
• the present inventor has found that the stability of the aqueous composition is remarkably improved by setting the pH of the aqueous composition containing dergocitinib to a specific range. It was.
• the present invention is based on this finding and provides the following inventions.
• an aqueous composition containing dergocitinib or a salt thereof as an active ingredient which has excellent stability.
• the aqueous composition according to this embodiment contains dergocitinib or a salt thereof.
• Delgocitinib is 3-[(3S, 4R) -3-methyl-6- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1,6-diazaspiro [3.4] octane-1- Il] -3-oxopropanenitrile, also known as the following formula: It is a known compound represented by. Delgocitinib or a salt thereof can be produced, for example, by the method described in International Publication No. 2017/006968 and International Publication No. 2018/117151.
• the salt of dergocitinib 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 salt can be mentioned.
• 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 a salt 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 intrinsic 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 exogenous diseases such as drug-induced, traumatic, and contact lens wearing after surgery.
• the aqueous composition according to the present embodiment can be used for improving dry eye because it promotes tear secretion by containing dergocitinib 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 dergocitinib or a salt thereof 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 ingredients, the formulation form, and the like.
• the total content of dergocitinib or a salt thereof is 0, based on the total amount of the aqueous composition according to the present embodiment. It is preferably 001% by mass to 5% by mass, more preferably 0.003% by mass to 3% by mass, further preferably 0.005% by mass to 1% by mass, and 0.01% by mass. It is even more preferably ⁇ 0.5% by mass, particularly preferably 0.015% by mass to 0.4% by mass, and particularly preferably 0.02% by mass to 0.3% by mass. ..
• the aqueous composition according to this embodiment may further contain a buffer.
• a buffer When the aqueous composition further contains a buffer, the effect according to the present invention is more prominently exhibited.
• the buffer is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.
• the buffer examples include a boric acid buffer (for example, boric acid, a combination of boric acid and borax, etc.).
• a boric acid buffer for example, boric acid, a combination of boric acid and borax, etc.
• 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 buffer in the aqueous composition according to the present embodiment is not particularly limited, and is appropriately set according to the type of the buffer, the type and content of other compounding ingredients, 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 based on the total amount of the aqueous composition. It is more preferable, it is more preferably 0.05% by mass to 5% by mass, and further preferably 0.1% by mass to 3% by mass.
• the content ratio of the buffer to dergocitinib or a salt thereof in the aqueous composition according to the present embodiment is not particularly limited, and the type of buffer, the type and content of other compounding ingredients, the use and formulation form of the aqueous composition, etc. It is set appropriately according to.
• Regarding the content ratio of the buffer to dergocitinib or a salt thereof from the viewpoint of further enhancing the effect of the present invention, for example, with respect to 1 part by mass of the total content of dergocitinib or a salt thereof contained in the aqueous composition according to the present embodiment.
• the total content of the buffer is preferably 0.03 parts by mass to 500 parts by mass, more preferably 0.1 parts by mass to 250 parts by mass, and 0.3 parts by mass to 150 parts by mass. Is more preferable.
• the aqueous composition according to this embodiment may further contain inorganic salts.
• the aqueous composition further contains inorganic salts, the effect according to the present invention is more prominently exhibited.
• 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. Commercially available inorganic salts may be used. As the inorganic salts, one type may be used alone, or two or more types may be used in combination. As the inorganic salts, 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 based on the total amount of the aqueous composition. It is more preferable, it is more preferably 0.0001% by mass to 2% by mass, and further preferably 0.001% by mass to 1.5% by mass.
• the pH of the aqueous composition according to this embodiment is 4.0 to 6.5.
• the stability of the aqueous composition containing dergocitinib or a salt thereof as an active ingredient is remarkably improved.
• the pH of the aqueous composition is preferably 4.5 to 6.5, 4.5 to 6.0 or 5.0 to 6.5. , 5.0 to 6.0, more preferably.
• 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 0.9 w / 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 (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes and then in a desiccator (silica gel). Allow to cool, weigh accurately 0.900 g, dissolve in purified water to prepare exactly 100 mL, or use a commercially available standard solution for measuring osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution).
• 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 rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1 ° 34'x 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 dergocitinib or a salt thereof and, if necessary, other contained components so as to have a desired content. 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.
• the aqueous composition according to the present embodiment is, for example, as an eye drop (also referred to as an eye drop or an eye drop; the eye drop includes an artificial tear solution and an eye drop that can be instilled while wearing contact lenses). Can be used.
• the aqueous composition according to the present embodiment is provided by being housed in a container (also simply referred to as "polyolefin resin container") in which a part or all of the portion in contact with the aqueous composition is made of a polyolefin resin.
• the polyolefin-based resin container may be a package having a portion in contact with the aqueous composition, for example, a container main body portion for accommodating the aqueous composition, a portion including a discharge portion of the container (for example, a nozzle, an inner plug), and the like. It may be composed of a suction tube, a cap, or the like.
• the polyolefin-based resin may be any of a polymer obtained by polymerizing one type of olefin alone and a polymer obtained by copolymerizing two or more types of olefins. These polymers may contain other polymerizable monomers as constituents.
• Specific examples of the polyolefin resin include polyethylene (including low-density polyethylene, medium-density polyethylene, high-density polyethylene, etc.), polypropylene (including isotactic polypropylene, syndiotactic polypropylene, and atactic polypropylene), and ethylene-. Examples thereof include propylene copolymer and polymethylpentene. Among these, polyethylene and polypropylene are preferable, and polyethylene is more preferable.
• the polyolefin-based resin container that houses the aqueous composition may be a container generally used in the field of ophthalmology, and specifically, for example, an eye drop container or an eyewash container.
• the type of container is preferably an eye drop container.
• the polyolefin-based resin container according to the present embodiment is made of a polyolefin-based resin in part or all of the portion in contact with the aqueous composition.
• the portion in contact with the aqueous composition is, for example, an accommodating portion (in the case where the container has a structure consisting of a plurality of layers, the innermost layer), an inner plug, and a hole.
• the inner plug is mentioned.
• the accommodating portion of the aqueous composition other than the perforated inner plug may be formed of the polyolefin-based resin, and the entire container may be made of the polyolefin-based resin. It may be made of resin.
• a part of the portion in contact with the aqueous composition may be formed of the polyolefin-based resin, but from the viewpoint of exerting the effect of the present invention more remarkably, the accommodating portion is provided. It is preferably formed of a polyolefin resin.
• the shape and capacity of the polyolefin-based resin container according to this embodiment are not particularly limited, and may be appropriately set according to the intended use.
• the volume may be 0.3 mL or more and 25 mL or less, preferably 1 mL or more and 10 mL or less, and 2 mL or more and 7 mL or less. More preferred.
• the polyolefin-based resin container according to the present embodiment may be a multi-dose type that accommodates a plurality of uses, or may be a unit-dose type that accommodates a single use.
• the volume may be 0.1 mL or more and 1 mL or less, and preferably 0.2 mL or more and 0.5 mL or less.
• aqueous composition was prepared according to a conventional method with the compositions shown in Table 1. Each of the prepared aqueous compositions was filtered through a 0.2 ⁇ m membrane filter and sterilized. Then, the aqueous composition was filled in an eye drop bottle (material: polyethylene, volume: 5 mL) and stored at 50 ° C. for 2 months under light-shielding conditions. The content of dergocitinib contained in the preparation immediately after preparation and the preparation after storage is quantified by the HPLC method (measurement conditions are described below, using either measurement condition 1 or 2), and according to the following (formula 1). Calculated as the residual rate of dergocitinib. The results are shown in Table 1.
• Delgocitinib residual rate (%) (content of delgocitinib after storage at 50 ° C. for 2 months / content of delgocitinib immediately after preparation ⁇ 100) -moisture permeability
• Moisture permeability (%) (Weight of filled product immediately after preparation-Weight of filled product after storage at -50 ° C for 2 months) / (Weight of filled product immediately after preparation-Empty weight of eye drop bottle) x 100 (HPLC measurement condition 1) Detector: Ultraviolet absorptiometer (measurement wavelength: 254 nm) Column: Inertsil ODS-2 (inner diameter 4.6 mm, length 150 mm, particle size 5 ⁇ m) Column temperature: Constant temperature around 40 ° C.
• Mobile phase Solution of 1.50 g of sodium lauryl sulfate dissolved in 1000 mL of acetonitrile / diluted acetic acid (100) (1 ⁇ 60) mixture (7: 3) Flow rate: 0.9 mL / min (HPLC measurement condition 2) Detector: Ultraviolet absorptiometer (measurement wavelength: 283 nm) Column: Inertsil Ph-3 (inner diameter 4.6 mm, length 150 mm, particle size 5 ⁇ m) Column temperature: Constant temperature around 40 ° C. Mobile phase: Ammonium acetate 3.9 g and acetic acid (100) 12.5 mL were added to make 1000 mL of water / acetonitrile mixed solution (4: 1). Flow velocity: Approximately 0.8 mL / min
• aqueous composition was prepared according to a conventional method with the compositions shown in Table 2. Each of the prepared aqueous compositions was filtered through a 0.2 ⁇ m membrane filter and sterilized. Then, the aqueous composition was filled in an eye drop bottle (material: polyethylene, volume: 5 mL) and stored at 40 ° C. for 5 months under light-shielding conditions. The content of dergocitinib contained in the preparation immediately after preparation and the preparation after storage was quantified by the HPLC method (measurement conditions are the same as in Test Example 1), and calculated as the residual rate of dergocitinib according to the following (Formula 3). The results are shown in Table 2.
• aqueous composition was prepared according to a conventional method with the compositions shown in Table 3. Each of the prepared aqueous compositions was filtered through a 0.2 ⁇ m membrane filter and sterilized. Then, 5 mL of the aqueous composition was injected into a centrifuge tube (material: polypropylene, volume: 15 mL) and stored at 50 ° C. for 1 month under light-shielding conditions. The content of dergocitinib contained in the preparation immediately after preparation and the preparation after storage was quantified by the HPLC method (measurement conditions are the same as in Test Example 1), and calculated as the residual rate of dergocitinib according to the following (Formula 5).

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• 2020
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