WO2021132609A1 - Aqueous composition - Google Patents

Aqueous composition Download PDF

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Publication number
WO2021132609A1
WO2021132609A1 PCT/JP2020/048855 JP2020048855W WO2021132609A1 WO 2021132609 A1 WO2021132609 A1 WO 2021132609A1 JP 2020048855 W JP2020048855 W JP 2020048855W WO 2021132609 A1 WO2021132609 A1 WO 2021132609A1
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Prior art keywords
aqueous composition
mass
acid
janus kinase
present
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PCT/JP2020/048855
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French (fr)
Japanese (ja)
Inventor
明功 西本
奈穂子 掛樋
紗衣子 林
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ロート製薬株式会社
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Priority to JP2021567697A priority Critical patent/JPWO2021132609A1/ja
Priority to CN202080088973.9A priority patent/CN114845734A/en
Publication of WO2021132609A1 publication Critical patent/WO2021132609A1/en

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    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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 having Janus kinase inhibitory activity (hereinafter, also referred to as "Janus kinase inhibitor”) are immune. It is expected to improve autoimmune diseases and allergic diseases by suppressing excessive activation of the reaction. Examples of compounds having an inhibitory effect on yanus kinase include 3-[(3S, 4R) -3-methyl-6- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1,6-diazaspiro.
  • An object of the present invention is to provide an aqueous composition containing a Janus kinase inhibitor, which has an excellent preservative effect.
  • the present inventor has found that the preservative effect is remarkably enhanced when a biguanide-based preservative is added to an aqueous composition containing a Janus kinase inhibitor.
  • the present invention is based on this finding and provides the following inventions.
  • An aqueous composition containing a Janus kinase inhibitor and a biguanide preservative [2] The aqueous composition according to [1], wherein the content of the Janus kinase inhibitor is 0.001% by mass to 5% by mass based on the total amount of the aqueous composition. [3] The aqueous composition according to [1] or [2], wherein the Janus kinase inhibitor is dergocitinib. [4] The aqueous composition according to any one of [1] to [3], wherein the biguanide preservative is chlorhexidine or a salt thereof. [5] The aqueous composition according to any one of [1] to [4], which has a pH of 4.0 to 6.5. [6] The aqueous composition according to any one of [1] to [5], which is for ophthalmology.
  • aqueous composition containing a Janus kinase inhibitor which has an excellent preservative effect.
  • the aqueous composition according to this embodiment contains a Janus kinase inhibitor and a biguanide-based preservative.
  • the Janus kinase inhibitor can be any agent that inhibits at least one selected from the group consisting of Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). It can be used without particular limitation.
  • a commercially available or developing Janus kinase inhibitor for example, a compound having the following nitrogen-containing fused heterocycle (preferably a pyrolopyrimidine ring, a pyrolopyridine ring, an imidazolopyrazine ring, or a triazolopyridine ring) as a partial structure.
  • salts thereof are known, and these can be suitably used as Janus kinase inhibitors.
  • the salt of the compound having a nitrogen-containing condensed heterocycle as a partial structure 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 (eg, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitrate, phosphoric acid, etc.) and salts with organic acids (eg, acetic acid, succinic acid, etc.).
  • inorganic bases for example, Alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium
  • Delgocitinib is 3-[(3S, 4R) -3-methyl-6- (7H-pyrrolo [2,3-d] pyrimidine-4-yl) -1,6-diazaspiro [3.4].
  • Octane-1-yl] -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.
  • Tofacitinib is 3- ⁇ (3S, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidine-1-yl ⁇ - Also called 3-oxopropanenitrile, it has the following formula: It is a known compound represented by. Tofacitinib or a salt thereof can be produced, for example, by the method described in International Publication No. 01/42246. As tofacitinib or a salt thereof, tofacitinib citrate is preferable.
  • Upadacitinib is (3S, 4R) -3-ethyl-4- (3H-imidazole [1,2-a] pyrrolidine [2,3-e] pyrazine-8-yl) -N- (2, 2,2-Trifluoroethyl) Also called pyrrolidine-1-carboxamide, the following formula: It is a known compound represented by. As upadacitinib or a salt thereof, upadacitinib tartrate is preferable.
  • Oclacitinib is also referred to as N-methyl-1- [trans-4- (methyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) cyclohexyl] methanesulfonamide, and has the following formula: It is a known compound represented by. As the okracitinib or a salt thereof, okracitinib maleate is preferable.
  • Peficitinib is 4- ⁇ [(1R, 2s, 3S, 5s, 7s) -5-hydroxyadamantan-2-yl] amino ⁇ -1H-pyrrolo [2,3-b] pyridine-5-carboxamide. Also known as the following formula: It is a known compound represented by. As peficitinib or a salt thereof, peficitinib hydrobromide is preferable.
  • Baricitinib is ⁇ 1- (ethylsulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] azetidine-3- Il ⁇ Also called acetonitrile, the following formula: It is a known compound represented by.
  • Filgotinib is N- (5-(4-((1,1-dioxidethiomorpholino) methyl) phenyl)-[1,2,4] triazolo [1,5-a] pyridine-2- Il) Also called cyclopropanecarboxamide, the following formula: It is a known compound represented by.
  • dergocitinib is preferable, and dergocitinib is more preferable, from the viewpoint of exerting the effect of the present invention more remarkably.
  • the aqueous composition according to the present embodiment contains a Janus kinase inhibitor 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.
  • 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 content of the Janus kinase inhibitor 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 use of the aqueous composition, the formulation form, and the like.
  • the content of the Janus kinase inhibitor is, for example, based on the total amount of the aqueous composition according to the present embodiment from the viewpoint of exerting the effect of the present invention more remarkably and appropriately exhibiting the medicinal effect of the Janus kinase inhibitor.
  • the total content of the Janus kinase inhibitor is preferably 0.001% by mass to 5% by mass, more preferably 0.003% by mass to 3% by mass, and 0.005% by mass to 1% by mass. %, More preferably 0.01% by mass to 0.5% by mass, particularly preferably 0.015% by mass to 0.4% by mass, 0.02% by mass. It is particularly more preferably about 0.3% by mass.
  • Biguanide preservatives are listed below. Means a compound that contains the above in the molecule and has an antiseptic effect. Examples of the biguanide-based preservative include chlorhexidine or a salt thereof, alexidine or a salt thereof, polyhexanide or a salt thereof.
  • Chlorhexidine is a known compound also called 1,1'-hexamethylene-bis- [5- (4-chlorophenyl) biguanide].
  • Alexidine is also a known compound also referred to as 1,1'-hexamethylene-bis- [5- (2-ethylhexyl) biguanide].
  • Examples of the salt of chlorhexidine, the salt of alexidine, polyhexanide or a salt thereof include inorganic acid salts, organic acid salts and sulfonates.
  • Examples of the inorganic acid salt include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, boric acid, phosphoric acid and nitric acid.
  • Examples of the organic acid salt include salts with acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid and citric acid.
  • Examples of the sulfonic acid salt include salts with methanesulfonic acid, isethionic acid, benzenesulfonic acid and p-toluenesulfonic acid.
  • chlorhexidine or a salt thereof is preferable, and chlorhexidine gluconate is more preferable, from the viewpoint of exerting the effect of the present invention more remarkably.
  • the content of the biguanide-based preservative 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 use of the aqueous composition, the formulation form, and the like.
  • the total content of the biganide-based preservative is 0. It is preferably 0.0001% by mass to 2% by mass, more preferably 0.00005% by mass to 1% by mass, and particularly preferably 0.00008% by mass to 0.5% by mass.
  • 0.00005% by mass to 0.1% by mass and 0.0001% by mass to 0.01% by mass can also be presented as preferable contents.
  • the content ratio of the biguanide-based preservative to the Janus kinase inhibitor in the aqueous composition according to the present embodiment is not particularly limited, and the types of the Janus kinase inhibitor and the biguanide-based preservative, the types and contents of other compounding components, and the like. It is appropriately set according to the use of the aqueous composition, the form of the formulation, and the like.
  • the content ratio of the biguanide-based preservative to the Janus kinase inhibitor is, for example, 1 part by mass of the total content of the Janus kinase inhibitor contained in the eye drops according to the present embodiment from the viewpoint of further enhancing the effect of the present invention.
  • the total content of the biguanide-based preservative is preferably 0.00003 parts by mass to 100 parts by mass, and more preferably 0.0001 parts by mass to 50 parts by mass.
  • 0.0001 parts by mass to 5 parts by mass and 0.0003 parts by mass to 0.5 parts by mass can also be presented as preferable content ratios.
  • 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 the Janus kinase inhibitor in the aqueous composition according to the present embodiment is not particularly limited, and the type of the Janus kinase inhibitor and the buffer, 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 content ratio of the buffer to the Janus kinase inhibitor is determined 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 the Janus kinase inhibitor 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 the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range.
  • the pH of the aqueous composition according to the present embodiment may be, for example, 5.0 to 6.5, preferably 5.0 to 6.0.
  • the pH of the aqueous composition according to the present embodiment may be, for example, 4.0 to 6.5, 4.0 to 6.0, or 4.5 to 6.0.
  • 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 a Janus kinase inhibitor, a biguanide-based preservative, and, if necessary, other contained components so as to have a desired content. it can. Specifically, for example, it can be prepared by dissolving or suspending the above components in purified water, adjusting the pH and osmotic pressure to a predetermined value, 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 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. ..
  • 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.
  • 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 storage efficacy of each aqueous composition after storage at 50 ° C. for 2 months was evaluated according to the storage efficacy test method specified in the 17th revised Japanese Pharmacopoeia.
  • Pseudomonas aeruginosa was inoculated on the surface of soybean casein digest canten medium and cultured at 30 to 35 ° C. for 24 hours.
  • the cultured cells were aseptically harvested a platinum loop, and suspended in an appropriate amount of sterilized physiological saline to prepare a bacteria suspension containing viable bacteria of approximately 1 ⁇ 10 7 CFU / mL.
  • the bacterial suspension after addition to be about 1 ⁇ 10 5 CFU / mL in each formulation was allowed to stand at 20 ⁇ 25 ° C. 7 days.
  • the bacteria were collected according to the membrane filter method, allowed to stand on the surface of the soybean casein digest canten medium at 30 to 35 ° C. for 2 to 3 days, and then the viable cell count per 1 mL of each aqueous composition was measured. Then, the Log reduction was calculated based on the value. The results are shown in Table 1.
  • Test Example 2 Evaluation of stability of chlorhexidine gluconate
  • Each aqueous composition prepared in Test Example 1 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 chlorhexidine gluconate contained in each aqueous composition immediately after preparation and after storage at 50 ° C. for 2 months was quantified by HPLC (measurement conditions are described below), and the following (Formula 1) was used. And (Equation 2), it was calculated as the reduction improvement rate of the chlorhexidine gluconate concentration. The results are shown in Table 1.
  • Detector Ultraviolet absorptiometer (measurement wavelength: 254 nm)
  • 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, and the preservation efficacy of each aqueous composition was evaluated according to the preservation efficacy test method specified in the 17th revised Japanese Pharmacopoeia. Specifically, Pseudomonas aeruginosa was inoculated on the surface of soybean casein digest canten medium and cultured at 30 to 35 ° C. for 24 hours.
  • the cultured cells were aseptically harvested a platinum loop, and suspended in an appropriate amount of sterilized physiological saline to prepare a bacteria suspension containing live bacteria of approximately 3 ⁇ 10 7 CFU / mL.
  • the bacterial suspension after addition to be about 3 ⁇ 10 5 CFU / mL in each formulation was allowed to stand at 20 ⁇ 25 ° C. 7 days.
  • the bacteria were collected according to the membrane filter method, allowed to stand on the surface of the soybean casein digest canten medium at 30 to 35 ° C. for 1 day, and then the viable cell count per 1 mL of each aqueous composition was measured. The Log reduction was calculated based on the value. 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, the aqueous composition was filled in an eye drop bottle (material: polyethylene, volume: 5 mL) and stored at 60 ° C. for 3 weeks under light-shielding conditions. The preservation efficacy of each aqueous composition was evaluated according to the preservation efficacy test method specified in the 17th revised Japanese Pharmacopoeia.
  • Pseudomonas aeruginosa was inoculated on the surface of soybean casein digest canten medium and cultured at 30 to 35 ° C. for 24 hours.
  • the cultured cells were aseptically harvested a platinum loop, and suspended in an appropriate amount of sterilized physiological saline to prepare a bacteria suspension containing live bacteria of approximately 3 ⁇ 10 7 CFU / mL.
  • the bacterial suspension after addition to be about 3 ⁇ 10 5 CFU / mL in each formulation was allowed to stand at 20 ⁇ 25 ° C. 14 days.
  • the bacteria were collected according to the membrane filter method, allowed to stand on the surface of the soybean casein digest canten medium at 30 to 35 ° C. for 1 day, and then the viable cell count per 1 mL of each aqueous composition was measured. The Log reduction was calculated based on the value. The results are shown in Table 3.

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Abstract

The present invention pertains to an aqueous composition containing a janus kinase inhibitor and a biguanide-based preservative.

Description

水性組成物Aqueous composition
　本発明は、水性組成物に関する。 The present invention relates to an aqueous composition.
　ヤヌスキナーゼ（ＪＡＫ）は、細胞内の免疫活性化シグナル伝達に重要な役割を果たす非受容体型チロシンキナーゼであり、ヤヌスキナーゼ阻害活性を有する薬剤（以下、「ヤヌスキナーゼ阻害剤」ともいう）は免疫反応の過剰な活性化を抑制することで、自己免疫疾患やアレルギー性疾患を改善することが期待されている。ヤヌスキナーゼの阻害作用を有する化合物として、例えば、３－［（３Ｓ，４Ｒ）－３－メチル－６－（７Ｈ－ピロロ［２，３－ｄ］ピリミジン－４－イル）－１，６－ジアザスピロ［３．４］オクタン－１－イル］－３－オキソプロパンニトリル（一般名：デルゴシチニブ）、３－｛（３Ｓ，４Ｒ）－４－メチル－３－［メチル（７Ｈ－ピロロ［２，３－ｄ］ピリミジン－４－イル）アミノ］ピペリジン－１－イル｝－３－オキソプロパンニトリル（一般名：トファシチニブ）などが知られている（例えば、特許文献１及び２）。 Janus kinase (JAK) is a non-receptor tyrosine kinase that plays an important role in intracellular immune activation signal transduction, and drugs having Janus kinase inhibitory activity (hereinafter, also referred to as "Janus kinase inhibitor") are immune. It is expected to improve autoimmune diseases and allergic diseases by suppressing excessive activation of the reaction. Examples of compounds having an inhibitory effect on yanus kinase include 3-[(3S, 4R) -3-methyl-6- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1,6-diazaspiro. [3.4] Octane-1-yl] -3-oxopropanenitrile (generic name: dergocitinib), 3-{(3S, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2,3-] d] Pyrimidine-4-yl) amino] piperidine-1-yl} -3-oxopropanenitrile (generic name: tofacitinib) and the like are known (for example, Patent Documents 1 and 2).
国際公開第２０１７／００６９６８号International Publication No. 2017/006968 国際公開第０２／０９６９０９号International Publication No. 02/096909
　点眼剤などの水性製剤には一定の保存効力が要求されるところ、ヤヌスキナーゼ阻害剤を有効成分として配合した水性製剤における保存効力についてはこれまで全く知られていなかった。 Although a certain preservative effect is required for aqueous preparations such as eye drops, the preservative effect of aqueous preparations containing a Janus kinase inhibitor as an active ingredient has not been known at all.
　本発明は、保存効力に優れた、ヤヌスキナーゼ阻害剤を含有する水性組成物を提供することを目的とする。 An object of the present invention is to provide an aqueous composition containing a Janus kinase inhibitor, which has an excellent preservative effect.
　本発明者は、上記課題を解決すべく鋭意検討を行った結果、ヤヌスキナーゼ阻害剤を含有する水性組成物にビグアニド系防腐剤を配合すると、保存効力が顕著に増強することを見出した。本発明は、この知見に基づくものであり、以下の各発明を提供するものである。 As a result of diligent studies to solve the above problems, the present inventor has found that the preservative effect is remarkably enhanced when a biguanide-based preservative is added to an aqueous composition containing a Janus kinase inhibitor. The present invention is based on this finding and provides the following inventions.
［１］
　ヤヌスキナーゼ阻害剤と、ビグアニド系防腐剤とを含有する、水性組成物。
［２］
　ヤヌスキナーゼ阻害剤の含有量が、水性組成物の総量を基準として、０．００１質量％～５質量％である、［１］に記載の水性組成物。
［３］
　ヤヌスキナーゼ阻害剤がデルゴシチニブである、［１］又は［２］に記載の水性組成物。
［４］
　ビグアニド系防腐剤がクロルヘキシジン又はその塩である、［１］～［３］のいずれかに記載の水性組成物。
［５］
　ｐＨが４．０～６．５である、［１］～［４］のいずれかに記載の水性組成物。
［６］
　眼科用である、［１］～［５］のいずれかに記載の水性組成物。 [1]
An aqueous composition containing a Janus kinase inhibitor and a biguanide preservative.
[2]
The aqueous composition according to [1], wherein the content of the Janus kinase inhibitor is 0.001% by mass to 5% by mass based on the total amount of the aqueous composition.
[3]
The aqueous composition according to [1] or [2], wherein the Janus kinase inhibitor is dergocitinib.
[4]
The aqueous composition according to any one of [1] to [3], wherein the biguanide preservative is chlorhexidine or a salt thereof.
[5]
The aqueous composition according to any one of [1] to [4], which has a pH of 4.0 to 6.5.
[6]
The aqueous composition according to any one of [1] to [5], which is for ophthalmology.
　本発明によれば、保存効力に優れた、ヤヌスキナーゼ阻害剤を含有する水性組成物を提供することができる。 According to the present invention, it is possible to provide an aqueous composition containing a Janus kinase inhibitor, which has an excellent preservative effect.
　以下、本発明を実施するための形態について詳細に説明する。ただし、本発明は以下の実施形態に限定されるものではない。 Hereinafter, a mode for carrying out the present invention will be described in detail. However, the present invention is not limited to the following embodiments.
　本実施形態に係る水性組成物は、ヤヌスキナーゼ阻害剤と、ビグアニド系防腐剤とを含有する。 The aqueous composition according to this embodiment contains a Janus kinase inhibitor and a biguanide-based preservative.
〔ヤヌスキナーゼ阻害剤〕
　ヤヌスキナーゼ阻害剤は、ヤヌスキナーゼ１（ＪＡＫ１）、ヤヌスキナーゼ２（ＪＡＫ２）、ヤヌスキナーゼ３（ＪＡＫ３）、及びチロシンキナーゼ２（ＴＹＫ２）からなる群より選択される少なくとも１つを阻害する薬剤であれば特に制限なく用いることができる。市販又は開発中のヤヌスキナーゼ阻害剤として、例えば、以下に示す含窒素縮合複素環（好ましくは、ピロロピリミジン環、ピロロピリジン環、イミダゾピロロピラジン環、又はトリアゾロピリジン環）を部分構造として有する化合物又はその塩が知られており、これらをヤヌスキナーゼ阻害剤として好適に用いることができる。 [Janus kinase inhibitor]
The Janus kinase inhibitor can be any agent that inhibits at least one selected from the group consisting of Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). It can be used without particular limitation. As a commercially available or developing Janus kinase inhibitor, for example, a compound having the following nitrogen-containing fused heterocycle (preferably a pyrolopyrimidine ring, a pyrolopyridine ring, an imidazolopyrazine ring, or a triazolopyridine ring) as a partial structure. Alternatively, salts thereof are known, and these can be suitably used as Janus kinase inhibitors.
　含窒素縮合複素環を部分構造として有する化合物の塩は、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば、特に制限されない。このような塩として具体的には、無機酸との塩（例えば、塩酸、臭化水素酸、硫酸、硝酸、リン酸などとの塩）、有機酸との塩（例えば、酢酸、コハク酸、フマル酸、マレイン酸、酒石酸、クエン酸、乳酸、ステアリン酸、安息香酸、メタンスルホン酸（メシル酸）、エタンスルホン酸、ｐ－トルエンスルホン酸などとの塩）、無機塩基との塩（例えば、ナトリウム塩、カリウム塩などのアルカリ金属塩、カルシウム塩、マグネシウム塩などのアルカリ土類金属塩、アルミニウム塩、アンモニウム塩）、有機塩基との塩（例えば、ジエチルアミン、ジエタノールアミン、メグルミン、Ｎ，Ｎ－ジベンジルエチレンジアミンなどとの塩）、酸性アミノ酸又は塩基性アミノ酸との塩（例えば、アスパラギン酸、グルタミン酸、アルギニン、リジン、オルニチンなどとの塩）等が挙げられる。 The salt of the compound having a nitrogen-containing condensed heterocycle as a partial structure 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 (eg, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitrate, phosphoric acid, etc.) and salts with organic acids (eg, acetic acid, succinic acid, etc.). Salts with fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid (mesylic acid), ethanesulfonic acid, p-toluenesulfonic acid, etc.), salts with inorganic bases (for example, Alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, ammonium salt) and salts with organic bases (eg, diethylamine, diethanolamine, meglumin, N, N-di). Salts with benzylethylenediamine and the like), salts with acidic or basic amino acids (eg, salts with aspartic acid, glutamate, arginine, lysine, ornithine and the like) and the like.
（１）デルゴシチニブ
　デルゴシチニブは、３－［（３Ｓ，４Ｒ）－３－メチル－６－（７Ｈ－ピロロ［２，３－ｄ］ピリミジン－４－イル）－１，６－ジアザスピロ［３．４］オクタン－１－イル］－３－オキソプロパンニトリルとも称され、以下の式：
Figure JPOXMLDOC01-appb-C000001
 で表される公知の化合物である。デルゴシチニブ又はその塩は、例えば国際公開第２０１７／００６９６８号、国際公開第２０１８／１１７１５１号に記載の方法により製造することができる。 (1) Delgocitinib Delgocitinib is 3-[(3S, 4R) -3-methyl-6- (7H-pyrrolo [2,3-d] pyrimidine-4-yl) -1,6-diazaspiro [3.4]. Octane-1-yl] -3-oxopropanenitrile, also known as the following formula:
Figure JPOXMLDOC01-appb-C000001
 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.
（２）トファシチニブ
　トファシチニブは、３－｛（３Ｓ，４Ｒ）－４－メチル－３－［メチル（７Ｈ－ピロロ［２，３－ｄ］ピリミジン－４－イル）アミノ］ピペリジン－１－イル｝－３－オキソプロパンニトリルとも称され、以下の式：
Figure JPOXMLDOC01-appb-C000002
 で表される公知の化合物である。トファシチニブ又はその塩は、例えば国際公開第０１／４２２４６号に記載の方法により製造することができる。トファシチニブ又はその塩としては、トファシチニブクエン酸塩が好ましい。 (2) Tofacitinib Tofacitinib is 3-{(3S, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidine-1-yl}- Also called 3-oxopropanenitrile, it has the following formula:
Figure JPOXMLDOC01-appb-C000002
 It is a known compound represented by. Tofacitinib or a salt thereof can be produced, for example, by the method described in International Publication No. 01/42246. As tofacitinib or a salt thereof, tofacitinib citrate is preferable.
（３）ウパダシチニブ
　ウパダシチニブは、（３Ｓ，４Ｒ）－３－エチル－４－（３Ｈ－イミダゾ［１，２－ａ］ピロロ［２，３－ｅ］ピラジン－８－イル）－Ｎ－（２，２，２－トリフルオロエチル）ピロリジン－１－カルボキサミドとも称され、以下の式：
Figure JPOXMLDOC01-appb-C000003
 で表される公知の化合物である。ウパダシチニブ又はその塩としては、ウパダシチニブ酒石酸塩が好ましい。 (3) Upadacitinib Upadacitinib is (3S, 4R) -3-ethyl-4- (3H-imidazole [1,2-a] pyrrolidine [2,3-e] pyrazine-8-yl) -N- (2, 2,2-Trifluoroethyl) Also called pyrrolidine-1-carboxamide, the following formula:
Figure JPOXMLDOC01-appb-C000003
 It is a known compound represented by. As upadacitinib or a salt thereof, upadacitinib tartrate is preferable.
（４）オクラシチニブ
　オクラシチニブは、Ｎ－メチル－１－［トランス－４－（メチル－７Ｈ－ピロロ［２，３－ｄ］ピリミジン－４－イルアミノ）シクロヘキシル］メタンスルホンアミドとも称され、以下の式：
Figure JPOXMLDOC01-appb-C000004
 で表される公知の化合物である。オクラシチニブ又はその塩としては、オクラシチニブマレイン酸塩が好ましい。 (4) Oclacitinib Oclacitinib is also referred to as N-methyl-1- [trans-4- (methyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) cyclohexyl] methanesulfonamide, and has the following formula:
Figure JPOXMLDOC01-appb-C000004
 It is a known compound represented by. As the okracitinib or a salt thereof, okracitinib maleate is preferable.
（５）ペフィシチニブ
　ペフィシチニブは、４－｛［（１Ｒ，２ｓ、３Ｓ，５ｓ，７ｓ）－５－ヒドロキシアダマンタン－２－イル］アミノ｝－１Ｈ－ピロロ［２，３－ｂ］ピリジン－５－カルボキサミドとも称され、以下の式：
Figure JPOXMLDOC01-appb-C000005
 で表される公知の化合物である。ペフィシチニブ又はその塩としては、ペフィシチニブ臭化水素酸塩が好ましい。 (5) Peficitinib Peficitinib is 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxyadamantan-2-yl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide. Also known as the following formula:
Figure JPOXMLDOC01-appb-C000005
 It is a known compound represented by. As peficitinib or a salt thereof, peficitinib hydrobromide is preferable.
（６）バリシチニブ
　バリシチニブは、｛１－（エチルスルホニル）－３－［４－（７Ｈ－ピロロ［２，３－ｄ］ピリミジン－４－イル）－１Ｈ－ピラゾール－１－イル］アゼチジン－３－イル｝アセトニトリルとも称され、以下の式：
Figure JPOXMLDOC01-appb-C000006
 で表される公知の化合物である。 (6) Baricitinib Baricitinib is {1- (ethylsulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] azetidine-3- Il} Also called acetonitrile, the following formula:
Figure JPOXMLDOC01-appb-C000006
 It is a known compound represented by.
（７）フィルゴチニブ
　フィルゴチニブは、Ｎ－（５－（４－（（１，１－ジオキシドチオモルホリノ）メチル）フェニル）－［１，２，４］トリアゾロ［１，５－ａ］ピリジン－２－イル）シクロプロパンカルボキサミドとも称され、以下の式：
Figure JPOXMLDOC01-appb-C000007
 で表される公知の化合物である。 (7) Filgotinib Filgotinib is N- (5-(4-((1,1-dioxidethiomorpholino) methyl) phenyl)-[1,2,4] triazolo [1,5-a] pyridine-2- Il) Also called cyclopropanecarboxamide, the following formula:
Figure JPOXMLDOC01-appb-C000007
 It is a known compound represented by.
　これらのヤヌスキナーゼ阻害剤の中でも、本発明による効果をより顕著に奏する観点から、デルゴシチニブ、トファシチニブ又はそのクエン酸塩が好ましく、デルゴシチニブがより好ましい。 Among these Janus kinase inhibitors, dergocitinib, tofacitinib or a citrate thereof is preferable, and dergocitinib is more preferable, from the viewpoint of exerting the effect of the present invention more remarkably.
　本実施形態に係る水性組成物は、ヤヌスキナーゼ阻害剤を有効成分として含有しており、例えば、ドライアイ（眼球乾燥症候群）、シェーグレン症候群、スティーブンス・ジョンソン症候群等の内因性疾患に起因する角結膜上皮障害、又は術後、薬剤性、外傷、コンタクトレンズ装用等による外因性疾患に起因する角結膜上皮障害の治療のために用いることができる。 The aqueous composition according to the present embodiment contains a Janus kinase inhibitor 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.
　本実施形態に係る水性組成物におけるヤヌスキナーゼ阻害剤の含有量は特に限定されず、他の配合成分の種類及び含有量、水性組成物の用途及び製剤形態等に応じて適宜設定される。ヤヌスキナーゼ阻害剤の含有量としては、本発明による効果をより顕著に奏する観点、ヤヌスキナーゼ阻害剤による薬効を適切に発現する観点から、例えば、本実施形態に係る水性組成物の総量を基準として、ヤヌスキナーゼ阻害剤の総含有量が、０．００１質量％～５質量％であることが好ましく、０．００３質量％～３質量％であることがより好ましく、０．００５質量％～１質量％であることがさらに好ましく、０．０１質量％～０．５質量％であることがさらにより好ましく、０．０１５質量％～０．４質量％であることが特に好ましく、０．０２質量％～０．３質量％であることが特により好ましい。 The content of the Janus kinase inhibitor 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 use of the aqueous composition, the formulation form, and the like. The content of the Janus kinase inhibitor is, for example, based on the total amount of the aqueous composition according to the present embodiment from the viewpoint of exerting the effect of the present invention more remarkably and appropriately exhibiting the medicinal effect of the Janus kinase inhibitor. , The total content of the Janus kinase inhibitor is preferably 0.001% by mass to 5% by mass, more preferably 0.003% by mass to 3% by mass, and 0.005% by mass to 1% by mass. %, More preferably 0.01% by mass to 0.5% by mass, particularly preferably 0.015% by mass to 0.4% by mass, 0.02% by mass. It is particularly more preferably about 0.3% by mass.
〔ビグアニド系防腐剤〕
　ビグアニド系防腐剤は、以下に示すビグアニド：
Figure JPOXMLDOC01-appb-C000008
 を分子内に含む化合物であって、かつ防腐作用を有する化合物を意味する。ビグアニド系防腐剤としては、例えば、クロルヘキシジン又はその塩、アレキシジン又はその塩、ポリヘキサニド又はその塩が挙げられる。 [Biguanide preservatives]
Biguanide-based preservatives are listed below.
Figure JPOXMLDOC01-appb-C000008
 Means a compound that contains the above in the molecule and has an antiseptic effect. Examples of the biguanide-based preservative include chlorhexidine or a salt thereof, alexidine or a salt thereof, polyhexanide or a salt thereof.
　クロルヘキシジンは、１，１’－ヘキサメチレン－ビス－［５－（４－クロロフェニル）ビグアニド］とも称される公知の化合物である。また、アレキシジンは、１，１’－ヘキサメチレン－ビス－［５－（２－エチルヘキシル）ビグアニド］とも称される公知の化合物である。 Chlorhexidine is a known compound also called 1,1'-hexamethylene-bis- [5- (4-chlorophenyl) biguanide]. Alexidine is also a known compound also referred to as 1,1'-hexamethylene-bis- [5- (2-ethylhexyl) biguanide].
　クロルヘキシジンの塩、アレキシジンの塩、ポリヘキサニド又はその塩としては、例えば、無機酸塩、有機酸塩及びスルホン酸塩が挙げられる。無機酸塩としては、例えば、塩酸、臭化水素酸、硫酸、ホウ酸、リン酸及び硝酸との塩が挙げられる。有機酸塩としては、例えば、酢酸、グルコン酸、マレイン酸、アスコルビン酸、ステアリン酸、酒石酸及びクエン酸との塩が挙げられる。スルホン酸塩としては、例えば、メタンスルホン酸、イセチオン酸、ベンゼンスルホン酸及びｐ－トルエンスルホン酸との塩が挙げられる。 Examples of the salt of chlorhexidine, the salt of alexidine, polyhexanide or a salt thereof include inorganic acid salts, organic acid salts and sulfonates. Examples of the inorganic acid salt include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, boric acid, phosphoric acid and nitric acid. Examples of the organic acid salt include salts with acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid and citric acid. Examples of the sulfonic acid salt include salts with methanesulfonic acid, isethionic acid, benzenesulfonic acid and p-toluenesulfonic acid.
　ビグアニド系防腐剤としては、本発明による効果をより顕著に奏する観点から、クロルヘキシジン又はその塩が好ましく、クロルヘキシジングルコン酸塩がより好ましい。 As the biguanide-based preservative, chlorhexidine or a salt thereof is preferable, and chlorhexidine gluconate is more preferable, from the viewpoint of exerting the effect of the present invention more remarkably.
　本実施形態に係る水性組成物におけるビグアニド系防腐剤の含有量は特に限定されず、他の配合成分の種類及び含有量、水性組成物の用途及び製剤形態等に応じて適宜設定される。ビグアニド系防腐剤の含有量としては、本発明による効果をより顕著に奏する観点から、例えば、本実施形態に係る水性組成物の総量を基準として、ビグアニド系防腐剤の総含有量が、０．００００１質量％～２質量％であることが好ましく、０．００００５質量％～１質量％であることがより好ましく、０．００００８質量％～０．５質量％含有することが特に好ましい。ほかに、０．００００５質量％～０．１質量％、０．０００１質量％～０．０１質量％も好ましい含有量として提示することができる。 The content of the biguanide-based preservative 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 use of the aqueous composition, the formulation form, and the like. Regarding the content of the biguanide-based preservative, from the viewpoint of exerting the effect of the present invention more remarkably, for example, the total content of the biganide-based preservative is 0. It is preferably 0.0001% by mass to 2% by mass, more preferably 0.00005% by mass to 1% by mass, and particularly preferably 0.00008% by mass to 0.5% by mass. In addition, 0.00005% by mass to 0.1% by mass and 0.0001% by mass to 0.01% by mass can also be presented as preferable contents.
　本実施形態に係る水性組成物における、ヤヌスキナーゼ阻害剤に対するビグアニド系防腐剤の含有比率は特に限定されず、ヤヌスキナーゼ阻害剤及びビグアニド系防腐剤の種類、他の配合成分の種類及び含有量、水性組成物の用途及び製剤形態等に応じて適宜設定される。ヤヌスキナーゼ阻害剤に対するビグアニド系防腐剤の含有比率としては、本発明による効果をより一層高める観点から、例えば、本実施形態に係る点眼剤に含まれるヤヌスキナーゼ阻害剤の総含有量１質量部に対して、ビグアニド系防腐剤の総含有量が、０．００００３質量部～１００質量部であることが好ましく、０．０００１質量部～５０質量部であることがより好ましい。ほかに、０．０００１質量部～５質量部、０．０００３質量部～０．５質量部も好ましい含有比率として提示することができる。 The content ratio of the biguanide-based preservative to the Janus kinase inhibitor in the aqueous composition according to the present embodiment is not particularly limited, and the types of the Janus kinase inhibitor and the biguanide-based preservative, the types and contents of other compounding components, and the like. It is appropriately set according to the use of the aqueous composition, the form of the formulation, and the like. The content ratio of the biguanide-based preservative to the Janus kinase inhibitor is, for example, 1 part by mass of the total content of the Janus kinase inhibitor contained in the eye drops according to the present embodiment from the viewpoint of further enhancing the effect of the present invention. On the other hand, the total content of the biguanide-based preservative is preferably 0.00003 parts by mass to 100 parts by mass, and more preferably 0.0001 parts by mass to 50 parts by mass. In addition, 0.0001 parts by mass to 5 parts by mass and 0.0003 parts by mass to 0.5 parts by mass can also be presented as preferable content ratios.
〔緩衝剤〕
　本実施形態に係る水性組成物は、緩衝剤を更に含有してもよい。水性組成物が緩衝剤を更に含有することで、本発明による効果がより顕著に奏される。緩衝剤は、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば、特に制限されない。 [Buffering agent]
The aqueous composition according to this embodiment may further contain 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.
　緩衝剤としては、例えば、ホウ酸緩衝剤（例えば、ホウ酸、ホウ酸とホウ砂の組み合わせ等）が挙げられる。緩衝剤は、市販されているものを使用してもよい。緩衝剤は、１種を単独で使用してもよく、又は２種以上を組み合わせて使用してもよい。緩衝剤としては、ホウ酸が好ましい。 Examples of the buffer include a boric acid buffer (for example, boric acid, a combination of boric acid and borax, etc.). As 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.
　本実施形態に係る水性組成物における緩衝剤の含有量は特に限定されず、緩衝剤の種類、他の配合成分の種類及び含有量、水性組成物の用途及び製剤形態等に応じて適宜設定される。緩衝剤の含有量としては、本発明による効果をより顕著に奏する観点から、例えば、水性組成物の総量を基準として、緩衝剤の総含有量が、０．０１質量％～１０質量％であることが好ましく、０．０５質量％～５質量％であることがより好ましく、０．１質量％～３質量％であることがさらに好ましい。 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. To. Regarding the content of the buffer, from the viewpoint of exerting the effect of the present invention more remarkably, for example, 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.
　本実施形態に係る水性組成物における、ヤヌスキナーゼ阻害剤に対する緩衝剤の含有比率は特に限定されず、ヤヌスキナーゼ阻害剤及び緩衝剤の種類、他の配合成分の種類及び含有量、水性組成物の用途及び製剤形態等に応じて適宜設定される。ヤヌスキナーゼ阻害剤に対する緩衝剤の含有比率としては、本発明による効果をより一層高める観点から、例えば、本実施形態に係る水性組成物に含まれるヤヌスキナーゼ阻害剤の総含有量１質量部に対して、緩衝剤の総含有量が、０．０３質量部～５００質量部であることが好ましく、０．１質量部～２５０質量部であることがより好ましく、０．３質量部～１５０質量部であることがさらに好ましい。 The content ratio of the buffer to the Janus kinase inhibitor in the aqueous composition according to the present embodiment is not particularly limited, and the type of the Janus kinase inhibitor and the buffer, 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 content ratio of the buffer to the Janus kinase inhibitor is determined 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 the Janus kinase inhibitor 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.
〔無機塩類〕
　本実施形態に係る水性組成物は、無機塩類を更に含有してもよい。水性組成物が無機塩類を更に含有することで、本発明による効果がより顕著に奏される。無機塩類は、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば、特に制限されない。 [Inorganic salts]
The aqueous composition according to this embodiment may further contain inorganic salts. When 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.
　無機塩類としては、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム等の塩化物塩が挙げられる。無機塩類は、市販されているものを使用してもよい。無機塩類は、１種を単独で使用してもよく、又は２種以上を組み合わせて使用してもよい。無機塩類としては、塩化ナトリウム、塩化カリウムが好ましい。 Examples of inorganic salts 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.
　本実施形態に係る水性組成物における無機塩類の含有量は特に限定されず、無機塩類の種類、他の配合成分の種類及び含有量、水性組成物の用途及び製剤形態等に応じて適宜設定される。無機塩類の含有量としては、本発明による効果をより顕著に奏する観点から、例えば、水性組成物の総量を基準として、無機塩類の総含有量が、０．００００１質量％～３質量％であることが好ましく、０．０００１質量％～２質量％であることがより好ましく、０．００１質量％～１．５質量％であることがさらに好ましい。 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. To. Regarding the content of the inorganic salts, from the viewpoint of exerting the effect of the present invention more remarkably, for example, 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.
　本実施形態に係る水性組成物のｐＨは、医薬上、薬理学的に（製薬上）又は生理学的に許容される範囲内であれば特に限定されるものではない。本実施形態に係る水性組成物のｐＨとしては、例えば、５．０～６．５であってよく、５．０～６．０であることが好ましい。また、本実施形態に係る水性組成物のｐＨとしては、例えば、４．０～６．５、４．０～６．０、又は４．５～６．０であってもよい。 The pH 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 pH of the aqueous composition according to the present embodiment may be, for example, 5.0 to 6.5, preferably 5.0 to 6.0. The pH of the aqueous composition according to the present embodiment may be, for example, 4.0 to 6.5, 4.0 to 6.0, or 4.5 to 6.0.
　本実施形態に係る水性組成物は、必要に応じて、生体に許容される範囲内の浸透圧比に調節することができる。適切な浸透圧比は、水性組成物の用途、製剤形態、使用方法等に応じて適宜設定され得るが、例えば、０．４～５．０とすることができ、０．６～３．０とすることが好ましく、０．８～２．２とすることがより好ましく、０．８～２．０とすることが更に好ましい。浸透圧比は、第十七改正日本薬局方に基づき、２８６ｍＯｓｍ（０．９ｗ／ｖ％塩化ナトリウム水溶液の浸透圧）に対する試料の浸透圧の比とし、浸透圧は日本薬局方記載の浸透圧測定法（凝固点降下法）を参考にして測定する。なお、浸透圧比測定用標準液（０．９ｗ／ｖ％塩化ナトリウム水溶液）は、塩化ナトリウム（日本薬局方標準試薬）を５００～６５０℃で４０～５０分間乾燥した後、デシケーター（シリカゲル）中で放冷し、その０．９００ｇを正確に量り、精製水に溶かし正確に１００ｍＬとして調製するか、市販の浸透圧比測定用標準液（０．９ｗ／ｖ％塩化ナトリウム水溶液）を用いることができる。 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).
　本実施形態に係る水性組成物の粘度は、医薬上、薬理学的に（製薬上）又は生理学的に許容される範囲内であれば、特に限定されるものではない。本実施形態に係る水性組成物の粘度としては、例えば、回転粘度計（ＲＥ５５０型粘度計、東機産業社製、ローター；１°３４’×Ｒ２４）で測定した２０℃における粘度が０．５～１０ｍＰａ・ｓであることが好ましく、１～５ｍＰａ・ｓであることがより好ましく、１～３ｍＰａ・ｓであることが更に好ましい。 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. As 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.
　本実施形態に係る水性組成物は、例えば、ヤヌスキナーゼ阻害剤、ビグアニド系防腐剤、及び必要に応じて他の含有成分を所望の含有量となるように添加及び混和することにより調製することができる。具体的には、例えば、精製水で上記成分を溶解又は懸濁させ、所定のｐＨ及び浸透圧に調整し、濾過滅菌等により滅菌処理することで調製できる。 The aqueous composition according to the present embodiment can be prepared, for example, by adding and mixing a Janus kinase inhibitor, a biguanide-based preservative, and, if necessary, other contained components so as to have a desired content. it can. Specifically, for example, it can be prepared by dissolving or suspending the above components in purified water, adjusting the pH and osmotic pressure to a predetermined value, and sterilizing by filtration sterilization or the like.
　本実施形態に係る水性組成物は、目的に応じて種々の剤型をとることができ、例えば、液剤、ゲル剤、半固形剤（軟膏等）等が挙げられる。 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.
　本実施形態に係る水性組成物は、眼科用として用いることができる。また、本実施形態に係る水性組成物は、例えば、点眼剤（点眼液又は点眼薬ともいう。また、点眼剤には人工涙液、コンタクトレンズ装用中に点眼可能な点眼剤を含む。）として用いることができる。 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 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.
　本実施形態に係る水性組成物が点眼剤である場合、その用法・用量としては、効果を奏し、副作用の少ない用法・用量であれば特に限定されないが、例えば成人（１５歳以上）及び７歳以上の小児の場合、１回１滴又は１～２滴を１日４回点眼して用いる方法、１回１滴又は１～２滴を１日５～６回点眼して用いる方法を例示できる。 When the aqueous composition according to the present embodiment is an eye drop, 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. In the case of the above-mentioned children, 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. ..
　本実施形態に係る水性組成物は、該水性組成物と接する部分の一部又は全部がポリオレフィン系樹脂で形成された容器（単に「ポリオレフィン系樹脂容器」とも表記する。）に収容して提供されることが好ましい。ポリオレフィン系樹脂容器は、水性組成物と接触する部分を有する包装体であればよく、例えば、水性組成物を収容する容器本体部分、容器の吐出部を含む部分（例えば、ノズル、中栓）、吸い上げチューブ、キャップ等で構成されていてもよい。 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. Is preferable. 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.
　ポリオレフィン系樹脂は、１種単独のオレフィンを重合させたポリマー、２種以上のオレフィンを共重合させたポリマーのいずれであってもよい。これらのポリマーには、構成成分として重合可能な他のモノマーが含まれていてもよい。ポリオレフィン系樹脂の具体例としては、ポリエチレン（低密度ポリエチレン、中密度ポリエチレン、高密度ポリエチレン等を含む。）、ポリプロピレン（アイソタクチックポリプロピレン、シンジオタクチックポリプロピレン、アタクチックポリプロピレンを含む。）、エチレン－プロピレン共重合体、ポリメチルペンテン等が挙げられる。これらの中でも、ポリエチレン及びポリプロピレンが好ましく、ポリエチレンがより好ましい。 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.
　以下、試験例に基づいて本発明を具体的に説明するが、本発明はこれらに限定されるものではない。また、特に記載がない限り、表中の各成分の単位はｗ／ｖ％である。 Hereinafter, the present invention will be specifically described based on test examples, but the present invention is not limited thereto. Unless otherwise specified, the unit of each component in the table is w / v%.
〔試験例１：保存効力試験（１）〕
　表１に示す組成で、常法に従い水性組成物を調製した。調製した各水性組成物を、０．２μｍメンブランフィルターでろ過し滅菌した。その後、水性組成物を点眼瓶（材質：ポリエチレン、容量：５ｍＬ）に充填し、遮光条件下にて５０℃で２か月間保管した。第十七改正日本薬局方に定める保存効力試験法に準じて、５０℃で２か月間保管後の各水性組成物の保存効力を評価した。具体的には、Ｐｓｅｕｄｏｍｏｎａｓ　ａｅｒｕｇｉｎｏｓａを、ソイビーン・カゼイン・ダイジェストカンテン培地の表面に接種して、３０～３５℃で２４時間培養を行った。培養菌体を白金耳で無菌的に採取し、適量の滅菌生理食塩水に浮遊させて、約１×１０７ＣＦＵ／ｍＬの生菌を含む細菌浮遊液を調製した。この細菌浮遊液を、各製剤に約１×１０５ＣＦＵ／ｍＬとなるように添加した後に、２０～２５℃で７日間静置した。その後、メンブランフィルター法に準じて菌を回収し、ソイビーン・カゼイン・ダイジェストカンテン培地の表面上で、３０～３５℃で２～３日間静置した後に各水性組成物１ｍＬ当たりの生菌数を測定し、その値を基に、Ｌｏｇ　ｒｅｄｕｃｔｉｏｎを算出した。結果を表１に示す。 [Test Example 1: Preservation efficacy test (1)]
An 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 μm 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 storage efficacy of each aqueous composition after storage at 50 ° C. for 2 months was evaluated according to the storage efficacy test method specified in the 17th revised Japanese Pharmacopoeia. Specifically, Pseudomonas aeruginosa was inoculated on the surface of soybean casein digest canten medium and cultured at 30 to 35 ° C. for 24 hours. The cultured cells were aseptically harvested a platinum loop, and suspended in an appropriate amount of sterilized physiological saline to prepare a bacteria suspension containing viable bacteria of approximately 1 × 10 7 CFU / mL. The bacterial suspension, after addition to be about 1 × 10 5 CFU / mL in each formulation was allowed to stand at 20 ~ 25 ° C. 7 days. Then, the bacteria were collected according to the membrane filter method, allowed to stand on the surface of the soybean casein digest canten medium at 30 to 35 ° C. for 2 to 3 days, and then the viable cell count per 1 mL of each aqueous composition was measured. Then, the Log reduction was calculated based on the value. The results are shown in Table 1.
〔試験例２：クロルヘキシジングルコン酸塩の安定性評価〕
　試験例１において調製した各水性組成物を、０．２μｍメンブランフィルターでろ過し滅菌した。その後、水性組成物を点眼瓶（材質：ポリエチレン、容量：５ｍＬ）に充填し、遮光条件下にて５０℃で２か月間保管した。調製直後の各水性組成物と５０℃で２か月間保管後の各水性組成物に含まれるクロルヘキシジングルコン酸塩の含有量をＨＰＬＣ（測定条件は下記に記載）によって定量し、下記（式１）及び（式２）に従いクロルヘキシジングルコン酸塩濃度の低下改善率として算出した。結果を表１に示す。
（式１）クロルヘキシジングルコン酸塩低下濃度（ｍｇ／１００ｍＬ）＝製造直後のクロルヘキシジングルコン酸塩濃度－５０℃で２か月保管後のクロルヘキシジングルコン酸塩濃度
（式２）クロルヘキシジングルコン酸塩濃度の低下改善率（%）＝｛（比較例２の低下濃度－各実施例の低下濃度）／比較例２の低下濃度｝×１００
（ＨＰＬＣの測定条件）
検出器：紫外吸光光度計（測定波長：２５４ｎｍ）
カラム：Ｉｎｅｒｔｓｉｌ　ＯＤＳ－２（内径４．６ｍｍ、長さ１５０ｍｍ、粒子径５μｍ）
カラム温度：４０℃付近の一定温度
移動相：ラウリル硫酸ナトリウム１．５０gをアセトニトリル／薄めた酢酸（１００）（１→６０）混液（７：３）１０００ｍＬに溶かした溶液
流速：０．９ｍＬ／ｍｉｎ [Test Example 2: Evaluation of stability of chlorhexidine gluconate]
Each aqueous composition prepared in Test Example 1 was filtered through a 0.2 μm 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 chlorhexidine gluconate contained in each aqueous composition immediately after preparation and after storage at 50 ° C. for 2 months was quantified by HPLC (measurement conditions are described below), and the following (Formula 1) was used. And (Equation 2), it was calculated as the reduction improvement rate of the chlorhexidine gluconate concentration. The results are shown in Table 1.
(Formula 1) Chlorhexidine gluconate reduction concentration (mg / 100mL) = Chlorhexidine gluconate concentration immediately after production-Chlorhexidine gluconate concentration after storage at -50 ° C for 2 months (Formula 2) Chlorhexidine gluconate reduction concentration Improvement rate (%) = {(Reduced concentration of Comparative Example 2-Reduced concentration of each example) / Reduced concentration of Comparative Example 2} x 100
(HPLC measurement conditions)
Detector: Ultraviolet absorptiometer (measurement wavelength: 254 nm)
Column: Inertsil ODS-2 (inner diameter 4.6 mm, length 150 mm, particle size 5 μm)
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
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
　デルゴシチニブを含有する水性組成物にクロルヘキシジングルコン酸塩を配合しない比較例１では保存効力が極めて弱かった。一方、デルゴシチニブを含有する水性組成物にクロルヘキシジングルコン酸塩を配合した実施例１及び２では、比較例１やクロルヘキシジングルコン酸塩のみを配合した比較例２と比較して、保存効力が顕著に増強することが確認された。
　また、デルゴシチニブの濃度依存的にクロルヘキシジングルコン酸塩の低下が改善され（実施例１及び２）、デルゴシチニブがクロルヘキシジングルコン酸塩の安定性を高めていることが確認された。 In Comparative Example 1 in which chlorhexidine gluconate was not added to the aqueous composition containing dergocitinib, the preservation effect was extremely weak. On the other hand, in Examples 1 and 2 in which chlorhexidine gluconate was added to the aqueous composition containing dergocitinib, the preservation effect was significantly enhanced as compared with Comparative Example 1 and Comparative Example 2 in which only chlorhexidine gluconate was added. It was confirmed that
In addition, it was confirmed that the decrease in chlorhexidine gluconate was improved in a concentration-dependent manner (Examples 1 and 2), and that delgocitinib enhanced the stability of chlorhexidine gluconate.
〔試験例３：保存効力試験（２）〕
　表２に示す組成で、常法に従い水性組成物を調製した。調製した各水性組成物を、０．２μｍメンブランフィルターでろ過し滅菌し、第十七改正日本薬局方に定める保存効力試験法に準じて、各水性組成物の保存効力を評価した。具体的には、Ｐｓｅｕｄｏｍｏｎａｓ　ａｅｒｕｇｉｎｏｓａを、ソイビーン・カゼイン・ダイジェストカンテン培地の表面に接種して、３０～３５℃で２４時間培養を行った。培養菌体を白金耳で無菌的に採取し、適量の滅菌生理食塩水に浮遊させて、約３×１０７ＣＦＵ／ｍＬの生菌を含む細菌浮遊液を調製した。この細菌浮遊液を、各製剤に約３×１０５ＣＦＵ／ｍＬとなるように添加した後に、２０～２５℃で７日間静置した。その後、メンブランフィルター法に準じて菌を回収し、ソイビーン・カゼイン・ダイジェストカンテン培地の表面上で、３０～３５℃で１日間静置した後に各水性組成物１ｍＬ当たりの生菌数を測定し、その値を基に、Ｌｏｇ　ｒｅｄｕｃｔｉｏｎを算出した。結果を表２に示す。 [Test Example 3: Preservation Efficacy Test (2)]
An 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 μm membrane filter and sterilized, and the preservation efficacy of each aqueous composition was evaluated according to the preservation efficacy test method specified in the 17th revised Japanese Pharmacopoeia. Specifically, Pseudomonas aeruginosa was inoculated on the surface of soybean casein digest canten medium and cultured at 30 to 35 ° C. for 24 hours. The cultured cells were aseptically harvested a platinum loop, and suspended in an appropriate amount of sterilized physiological saline to prepare a bacteria suspension containing live bacteria of approximately 3 × 10 7 CFU / mL. The bacterial suspension, after addition to be about 3 × 10 5 CFU / mL in each formulation was allowed to stand at 20 ~ 25 ° C. 7 days. Then, the bacteria were collected according to the membrane filter method, allowed to stand on the surface of the soybean casein digest canten medium at 30 to 35 ° C. for 1 day, and then the viable cell count per 1 mL of each aqueous composition was measured. The Log reduction was calculated based on the value. The results are shown in Table 2.
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
〔試験例４：保存効力試験（３）〕
　表３に示す組成で、常法に従い水性組成物を調製した。調製した各水性組成物を、０．２μｍメンブランフィルターでろ過し滅菌した。その後、水性組成物を点眼瓶（材質：ポリエチレン、容量：５ｍＬ）に充填し、遮光条件下にて６０℃で３週間保管した。第十七改正日本薬局方に定める保存効力試験法に準じて、各水性組成物の保存効力を評価した。具体的には、Ｐｓｅｕｄｏｍｏｎａｓ　ａｅｒｕｇｉｎｏｓａを、ソイビーン・カゼイン・ダイジェストカンテン培地の表面に接種して、３０～３５℃で２４時間培養を行った。培養菌体を白金耳で無菌的に採取し、適量の滅菌生理食塩水に浮遊させて、約３×１０７ＣＦＵ／ｍＬの生菌を含む細菌浮遊液を調製した。この細菌浮遊液を、各製剤に約３×１０５ＣＦＵ／ｍＬとなるように添加した後に、２０～２５℃で１４日間静置した。その後、メンブランフィルター法に準じて菌を回収し、ソイビーン・カゼイン・ダイジェストカンテン培地の表面上で、３０～３５℃で１日静置した後に各水性組成物１ｍＬ当たりの生菌数を測定し、その値を基に、Ｌｏｇ　ｒｅｄｕｃｔｉｏｎを算出した。結果を表３に示す。 [Test Example 4: Preservation Efficacy Test (3)]
An 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 μm membrane filter and sterilized. Then, the aqueous composition was filled in an eye drop bottle (material: polyethylene, volume: 5 mL) and stored at 60 ° C. for 3 weeks under light-shielding conditions. The preservation efficacy of each aqueous composition was evaluated according to the preservation efficacy test method specified in the 17th revised Japanese Pharmacopoeia. Specifically, Pseudomonas aeruginosa was inoculated on the surface of soybean casein digest canten medium and cultured at 30 to 35 ° C. for 24 hours. The cultured cells were aseptically harvested a platinum loop, and suspended in an appropriate amount of sterilized physiological saline to prepare a bacteria suspension containing live bacteria of approximately 3 × 10 7 CFU / mL. The bacterial suspension, after addition to be about 3 × 10 5 CFU / mL in each formulation was allowed to stand at 20 ~ 25 ° C. 14 days. Then, the bacteria were collected according to the membrane filter method, allowed to stand on the surface of the soybean casein digest canten medium at 30 to 35 ° C. for 1 day, and then the viable cell count per 1 mL of each aqueous composition was measured. The Log reduction was calculated based on the value. The results are shown in Table 3.
Figure JPOXMLDOC01-appb-T000011
  
Figure JPOXMLDOC01-appb-T000011
  

Claims (5)

  1. 　ヤヌスキナーゼ阻害剤と、ビグアニド系防腐剤とを含有する、眼科用水性組成物。 An aqueous ophthalmic composition containing a Janus kinase inhibitor and a biguanide preservative.
  2. 　ヤヌスキナーゼ阻害剤の含有量が、眼科用水性組成物の総量を基準として、０．００１質量％～５質量％である、請求項１に記載の眼科用水性組成物。 The aqueous ophthalmic composition according to claim 1, wherein the content of the Janus kinase inhibitor is 0.001% by mass to 5% by mass based on the total amount of the aqueous ophthalmic composition.
  3. 　ヤヌスキナーゼ阻害剤がデルゴシチニブである、請求項１又は２に記載の眼科用水性組成物。 The aqueous ophthalmic composition according to claim 1 or 2, wherein the Janus kinase inhibitor is dergocitinib.
  4. 　ビグアニド系防腐剤がクロルヘキシジン又はその塩である、請求項１～３のいずれか一項に記載の眼科用水性組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 3, wherein the biguanide preservative is chlorhexidine or a salt thereof.
  5. 　ｐＨが４．０～６．５である、請求項１～４のいずれか一項に記載の眼科用水性組成物。 The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the pH is 4.0 to 6.5.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4011450A4 (en) * 2019-08-07 2023-08-09 Rohto Pharmaceutical Co., Ltd. Ophthalmic composition for promoting tear secretion
EP4070796A4 (en) * 2019-12-27 2024-01-17 Rohto Pharma Aqueous composition

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0748262A (en) * 1993-06-04 1995-02-21 Senju Pharmaceut Co Ltd Extraocular application composition
JPH115744A (en) * 1997-06-16 1999-01-12 Toa Yakuhin Kk Aqueous solution preparation for external use containing hyaluronic acid
JPH1160505A (en) * 1997-05-20 1999-03-02 Senju Pharmaceut Co Ltd Antiseptic composition
JP2005263792A (en) * 2004-02-19 2005-09-29 Santen Pharmaceut Co Ltd Clear latanoprost eye lotion
JP2009046470A (en) * 2007-07-11 2009-03-05 Pfizer Inc Pharmaceutical composition and method for treating dry eye disorder
JP2016166195A (en) * 2015-03-06 2016-09-15 参天製薬株式会社 Ophthalmic composition

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0748262A (en) * 1993-06-04 1995-02-21 Senju Pharmaceut Co Ltd Extraocular application composition
JPH1160505A (en) * 1997-05-20 1999-03-02 Senju Pharmaceut Co Ltd Antiseptic composition
JPH115744A (en) * 1997-06-16 1999-01-12 Toa Yakuhin Kk Aqueous solution preparation for external use containing hyaluronic acid
JP2005263792A (en) * 2004-02-19 2005-09-29 Santen Pharmaceut Co Ltd Clear latanoprost eye lotion
JP2009046470A (en) * 2007-07-11 2009-03-05 Pfizer Inc Pharmaceutical composition and method for treating dry eye disorder
JP2016166195A (en) * 2015-03-06 2016-09-15 参天製薬株式会社 Ophthalmic composition

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MONTILLA, A.M ET AL.: "Scoping Review on the Use of Drugs Targeting JAK/STAT Pathway in Atopic Dermatitis, Vitiligo, and Alopecia Areata", DERMATOL AND THERAPY, vol. 9, no. 4, 2019, pages 655 - 683, XP055838390, ISSN: 2190-9172, DOI: 10.1007/s13555-019-00329-y *
SAKIMOTO, TOORU ET AL.: "Examination of the effect of eye drops containing a JAK inhibitor on corneal inflammation", JOURNAL OF JAPANESE OPHTHALMOLOGICAL SOCIETY, SPECIAL EXTRA EDITION, vol. 119, pages 255, ISSN: 0029-0203 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4011450A4 (en) * 2019-08-07 2023-08-09 Rohto Pharmaceutical Co., Ltd. Ophthalmic composition for promoting tear secretion
EP4070796A4 (en) * 2019-12-27 2024-01-17 Rohto Pharma Aqueous composition

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