CN114845734A - Aqueous composition - Google Patents
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- CN114845734A CN114845734A CN202080088973.9A CN202080088973A CN114845734A CN 114845734 A CN114845734 A CN 114845734A CN 202080088973 A CN202080088973 A CN 202080088973A CN 114845734 A CN114845734 A CN 114845734A
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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
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- 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
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- 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
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- 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
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- 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
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- 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
Abstract
The invention relates to an aqueous composition containing a bisexkinase inhibitor and a biguanide preservative.
Description
Technical Field
The present invention relates to an aqueous composition.
Background
Janus kinases (JAKs) are non-receptor tyrosine kinases that play an important role in the transduction of immune activation signals in cells, and it is expected that autoimmune diseases or allergic diseases can be ameliorated by inhibiting the excessive activation of immune response by a drug having a Janus kinase inhibitory activity (hereinafter also referred to as "Janus kinase inhibitor"). Examples of compounds having a bishydrokinase inhibitory activity include 3- [ (3S,4R) -3-methyl-6- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 6-diazaspiro [3.4] octan-1-yl ] -3-oxopropanenitrile (trivial name: digoxinib), 3- { (3S,4R) -4-methyl-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] piperidin-1-yl } -3-oxopropanenitrile (trivial name: Tofacitinib)) and the like (for example, patent documents 1 and 2).
Documents of the prior art
Patent document
Patent document 1: international publication No. 2017/006968
Patent document 2: international publication No. 02/096909
Disclosure of Invention
Technical problems to be solved by the invention
Although aqueous preparations such as eye drops are required to have a certain storage efficiency, the storage efficiency of aqueous preparations containing a janus kinase inhibitor as an active ingredient has not been known at all.
The purpose of the present invention is to provide an aqueous composition containing a bisexkinase inhibitor, which has excellent storage efficiency.
Means for solving the problems
The inventors of the present application have conducted earnest studies to solve the above-mentioned problems, and as a result, have found that when a biguanide preservative is blended in an aqueous composition containing a biseskinase inhibitor, the storage efficacy is significantly enhanced. The present invention has been completed based on this finding, and further provides the following inventions.
[1] An aqueous composition comprising 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 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 digoxitinib.
[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 used in ophthalmology.
Effects of the invention
According to the present invention, an aqueous composition containing a biseskinase inhibitor and having excellent storage efficiency can be provided.
Detailed Description
The following describes in detail the embodiments for carrying out the present invention. However, the present invention is not limited to the following embodiments.
The aqueous composition of the present embodiment contains a bisexkinase inhibitor and a biguanide preservative.
[ Janus kinase inhibitor ]
The janus kinase inhibitor can be used without any particular limitation as long as it is a drug 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(TYK 2). As commercially available or under development janus kinase inhibitors, for example, compounds having a nitrogen-containing condensed heterocycle (preferably, a pyrrolopyrimidine ring, pyrrolopyridine ring, imidazopyrrole ring, or triazolopyridine ring) as a partial structure shown below or salts thereof are known, and these are 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 a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable salt thereof. Specific examples of such salts include salts with inorganic acids (for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like), salts with organic acids (for example, salts with 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 the like), salts with inorganic bases (for example, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, ammonium salts), salts with organic bases (for example, salts with diethylamine, diethanolamine, meglumine, N-dibenzylethylenediamine, and the like), salts with acidic amino acids or basic amino acids (for example, salts with aspartic acid, glutamic acid, arginine, lysine, ornithine, and the like), and the like.
(1) Digatinib
Didotinib is a well-known compound also known as 3- [ (3S,4R) -3-methyl-6- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 6-diazaspiro [3.4] octan-1-yl ] -3-oxopropanenitrile, represented by the following formula.
[ chemical formula 1]
The digoxitinib or a salt thereof can be produced, for example, by the methods described in international publication No. 2017/006968 and international publication No. 2018/117151.
(2) Tofacitinib
Tofacitinib is a well known compound also known as 3- { (3S,4R) -4-methyl-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] piperidin-1-yl } -3-oxopropanenitrile, represented by the following formula.
[ chemical formula 2]
Tofacitinib or a salt thereof can be prepared, for example, by the method described in international publication No. 01/42246. Tofacitinib citrate is preferably used as tofacitinib or a salt thereof.
(3) Upatinib (Upadacitinib)
Ipatinib is a well-known compound represented by the following formula, also known as (3S,4R) -3-ethyl-4- (3H-imidazo [1,2-a ] pyrrolo [2,3-e ] pyrazin-8-yl) -N- (2,2, 2-trifluoroethyl) pyrrolidine-1-amide.
[ chemical formula 3]
The preferred urotropinib or salt thereof is urotropinib tartrate.
(4) Oratinib (Octacitinib)
Olatinib is a well-known compound also known as N-methyl-1- [ trans-4- (methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-ylamino) cyclohexyl ] methanesulfonamide and represented by the following formula.
[ chemical formula 4]
As the olatinib or a salt thereof, preferred is olatinib maleate.
(5) Pefitinib (Pefitinib)
Pefitinib is a well known compound also known as 4- { [ (1R,2S,3S,5S,7S) -5-hydroxyadamantan-2-yl ] amino } -1H-pyrrolo [2,3-b ] pyridine-5-amide, represented by the following formula.
[ chemical formula 5]
Pefitinib or a salt thereof is preferably pefitinib hydrobromide.
(6) Baricitinib (Baricitinib)
Baricitinib is a well-known compound represented by the following formula, also known as {1- (ethylsulfonyl) -3- [4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl ] azetidin-3-yl } acetonitrile.
[ chemical formula 6]
(7) Non-gautinib (Filgotinib)
Non-golitinib is a well-known compound also known as N- (5- (4- ((1, 1-dioxothiomorpholino) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) cyclopropylamide, represented by the following formula.
[ chemical formula 7]
Among these janus kinase inhibitors, digoxitinib, tofacitinib or a citrate thereof is preferable, and digoxitinib is more preferable, from the viewpoint of more significantly exerting the effects of the present invention.
The aqueous composition of the present embodiment contains a bisexkinase inhibitor as an active ingredient, and can be used for the treatment of keratoconjunctival epithelial injury caused by endogenous diseases such as dry eye (xerophthalmia syndrome), sjogren's syndrome, Stevens-Johnson syndrome, and the like, or keratoconjunctival epithelial injury caused by exogenous diseases such as postoperative, drug-induced, traumatic, and contact lens wearing.
The content of the janus kinase inhibitor in the aqueous composition of the present embodiment is not particularly limited, and may be appropriately set according to the kind and content of other blending components, the use and formulation form of the aqueous composition, and the like. From the viewpoint of more significantly exerting the effect of the present invention and from the viewpoint of appropriately expressing the drug effect of the janus kinase inhibitor, the total content of the janus kinase inhibitor is preferably 0.001 to 5% by mass, more preferably 0.003 to 3% by mass, even more preferably 0.005 to 1% by mass, even more preferably 0.01 to 0.5% by mass, particularly preferably 0.015 to 0.4% by mass, and particularly preferably 0.02 to 0.3% by mass, based on the total amount of the aqueous composition of the present embodiment, for example.
[ biguanide preservatives ]
The biguanide preservative is a compound having a preservative effect and containing a biguanide shown below in a molecule.
[ chemical formula 8]
Examples of the biguanide preservative include chlorhexidine or a salt thereof, Alexidine (Alexidine) or a salt thereof, and polyhexamethylene guanidine (Polyhexanide) or a salt thereof.
Chlorhexidine is a well-known compound also known as 1,1' -hexamethylene-bis [5- (4-chlorophenyl) biguanide ]. Alexidine is a known compound also called 1,1' -hexamethylene-bis [5- (2-ethylhexyl) biguanide ].
Examples of the salt of chlorhexidine, alexidine, polyhexamethylene guanidine, or a salt thereof include an inorganic acid salt, an organic acid salt, and a sulfonate salt. 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 sulfonate include salts with methanesulfonic acid, isethionic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
From the viewpoint of more remarkably exerting the effect of the present invention, chlorhexidine or a salt thereof is preferable, and chlorhexidine gluconate is more preferable as the biguanide preservative.
The content of the biguanide preservative in the aqueous composition of the present embodiment is not particularly limited, and may be appropriately set according to the kind and content of other blending components, the use and formulation form of the aqueous composition, and the like. The content of the biguanide preservative is, for example, preferably 0.00001 to 2 mass%, more preferably 0.00005 to 1 mass%, and particularly preferably 0.00008 to 0.5 mass% in total based on the total amount of the aqueous composition of the present embodiment, from the viewpoint of more remarkably exhibiting the effect of the present invention. Further, a preferable content is 0.00005 to 0.1% by mass, and 0.0001 to 0.01% by mass.
The content ratio of the biguanide preservative to the janus kinase inhibitor in the aqueous composition of the present embodiment is not particularly limited, and can be appropriately set according to the type of janus kinase inhibitor and the biguanide preservative, the type and content of other blending components, the use and the formulation form of the aqueous composition, and the like. From the viewpoint of further improving the effect of the present invention, the content ratio of the biguanide preservatives to the janus kinase inhibitor is, for example, preferably 0.00003 to 100 parts by mass, and more preferably 0.0001 to 50 parts by mass, based on 1 part by mass of the total janus kinase inhibitor contained in the eye drop of the present embodiment. The preferable content ratio is 0.0001 to 5 parts by mass, and 0.0003 to 0.5 part by mass.
[ buffering agent ]
The aqueous composition of this embodiment may further contain a buffer. By further including a buffer in the aqueous composition, the effects of the present invention can be more remarkably exhibited. The buffer is not particularly limited as long as it is a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable buffer.
Examples of the buffer include a boric acid buffer (e.g., boric acid, a combination of boric acid and borax, etc.). The buffer may be a commercially available product. One kind of the buffer may be used alone, or two or more kinds may be used in combination. Boric acid is preferred as the buffering agent.
The content of the buffer in the aqueous composition of the present embodiment is not particularly limited, and may be appropriately set according to the kind of the buffer, the kinds and contents of other blending components, the use and preparation form of the aqueous composition, and the like. The content of the buffer agent is, for example, preferably 0.01 to 10% by mass, more preferably 0.05 to 5% by mass, and still more preferably 0.1 to 3% by mass in total based on the total amount of the aqueous composition, from the viewpoint of more remarkably exerting the effect of the present invention.
The content ratio of the buffer to the janus kinase inhibitor in the aqueous composition of the present embodiment is not particularly limited, and is appropriately set depending on the types of janus kinase inhibitor and buffer, the types and contents of other blending components, the use and preparation form of the aqueous composition, and the like. From the viewpoint of further improving the effect of the present invention, the content ratio of the buffer to the janus kinase inhibitor is, for example, preferably 0.03 to 500 parts by mass, more preferably 0.1 to 250 parts by mass, and still more preferably 0.3 to 150 parts by mass, based on 1 part by mass of the total content of the janus kinase inhibitor contained in the aqueous composition of the present embodiment.
[ inorganic salts ]
The aqueous composition of the present embodiment may further contain an inorganic salt. The effect of the present invention can be more remarkably exhibited by further containing an inorganic salt in the aqueous composition. The inorganic salt is not particularly limited as long as it is a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable inorganic salt.
Examples of the inorganic salts include chloride salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. Commercially available inorganic salts can be used. One kind of the inorganic salt may be used alone, or two or more kinds may be used in combination. As the inorganic salt, sodium chloride and potassium chloride are preferable.
The content of the inorganic salt in the aqueous composition of the present embodiment is not particularly limited, and may be appropriately set according to the kind of the inorganic salt, the kinds and contents of other blending components, the use and preparation form of the aqueous composition, and the like. The content of the inorganic salts is, for example, preferably 0.00001 to 3% by mass, more preferably 0.0001 to 2% by mass, and still more preferably 0.001 to 1.5% by mass in total based on the total amount of the aqueous composition, from the viewpoint of more remarkably exerting the effect of the present invention.
The pH of the aqueous composition of 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 of the present embodiment may be, for example, 5.0 to 6.5, preferably 5.0 to 6.0. The pH of the aqueous composition of the present embodiment may be, for example, 4.0 to 6.5, 4.0 to 6.0, or 4.5 to 6.0.
The osmotic pressure ratio of the aqueous composition of the present embodiment can be adjusted within a range allowed by the living body as needed. The appropriate osmotic pressure ratio can be appropriately set according to the use, preparation form, use method, and the like of the aqueous composition, and for example, the osmotic pressure ratio can be set to 0.4 to 5.0, preferably 0.6 to 3.0, more preferably 0.8 to 2.2, and further preferably 0.8 to 2.0. According to the seventeenth modification of the Japanese pharmacopoeia, the osmotic pressure ratio is defined as the ratio of the osmotic pressure of a sample to 286mOsm (the osmotic pressure of a 0.9 w/v% aqueous sodium chloride solution), and the osmotic pressure is measured by an osmotic pressure measurement method (freezing point depression method) described in the Japanese pharmacopoeia. The standard solution for measuring osmotic pressure ratio (0.9 w/v% aqueous sodium chloride solution) may be used by drying sodium chloride (standard reagent for Japanese pharmacopoeia) at 500 to 650 ℃ for 40 to 50 minutes, then cooling it naturally in a dryer (silica gel), and accurately weighing 0.900g of the sodium chloride and dissolving it in pure water to accurately prepare 100mL, or a commercially available standard solution for measuring osmotic pressure ratio (0.9 w/v% aqueous sodium chloride solution) may be used.
The viscosity of the aqueous composition of 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 of the present embodiment is preferably 0.5 to 10 mPas, more preferably 1 to 5 mPas, and still more preferably 1 to 3 mPas, as measured at 20 ℃ with a rotational viscometer (RE550 type viscometer, TOKI SANGYO CO., LTD., spindle; 1 ℃ 34' × R24).
The aqueous composition of the present embodiment can be prepared, for example, by adding and mixing the janus kinase inhibitor, the biguanide preservative, and other contained components as necessary at a desired content. Specifically, for example, the composition can be prepared by dissolving or suspending the above components in pure water, adjusting the pH and osmotic pressure to predetermined values, and further performing sterilization treatment such as filtration sterilization.
The aqueous composition of the present embodiment can be prepared into various dosage forms according to the purpose, and examples thereof include a solution, a gel, and a semisolid agent (e.g., ointment).
The aqueous composition of the present embodiment is useful for ophthalmology. In addition, the aqueous composition of the present embodiment is useful, for example, as eye drops (also referred to as eye drops or eye drops; in addition, eye drops include artificial tears, eye drops that can be dropped into the eye while wearing contact lenses).
When the aqueous composition of the present embodiment is an eye drop, the method of use and the amount of use are not particularly limited as long as they are effective and have little side effects, and examples thereof include a method of 4 drops and 1 drop or 1 to 2 drops for 1 day and a method of 5 to 6 drops and 1 drop or 1 to 2 drops for 1 day in the case of an adult (15 years or older) and a child aged 7 years or older.
The aqueous composition of the present embodiment is preferably provided in a container (also referred to simply as "polyolefin-based resin container") in which part or all of the part of the container that comes into contact with the aqueous composition is formed of a polyolefin-based resin. The polyolefin-based resin container may be any package having a portion in contact with the aqueous composition, and may be constituted by, for example, a container main body portion for containing the aqueous composition, a portion including a container discharge portion (e.g., a nozzle, an inner plug), a straw, a cap, or the like.
The polyolefin-based resin may be any of a polymer obtained by polymerizing a single olefin and a polymer obtained by copolymerizing two or more olefins. These polymers may contain other polymerizable monomers as constituent components. Specific examples of the polyolefin-based resin include polyethylene (including low-density polyethylene, medium-density polyethylene, high-density polyethylene, and the like), polypropylene (including isotactic polypropylene, syndiotactic polypropylene, and atactic polypropylene), an ethylene-propylene copolymer, and polymethylpentene. Among them, polyethylene and polypropylene are preferable, and polyethylene is more preferable.
Examples
The present invention will be specifically described below with reference to test examples, but the present invention is not limited thereto. The units of the components in the tables are w/v% unless otherwise specified.
[ test example 1: storage Effect test (1)
Aqueous compositions were prepared according to conventional methods with the compositions shown in table 1. Each of the aqueous compositions thus prepared was filtered and sterilized by a 0.2 μm membrane filter. Then, the aqueous composition was filled in an eye drop bottle (material: polyethylene, volume: 5mL), and stored at 50 ℃ for 2 months in the dark. The storage potency of each aqueous composition after storage at 50 ℃ for 2 months was evaluated according to the storage potency test method defined in the seventeenth modification of the Japanese pharmacopoeia. Specifically, Pseudomonas aeruginosa (Pseudomonas aeruginosa) was inoculated on the surface of a soybean-casein-digest agar medium and cultured at 30 to 35 ℃ for 24 hours. The cultured cells were aseptically collected using platinum loop and suspended in an appropriate amount of sterilized physiological saline to prepare a composition containing about 1X 10 7 CFU/mL of a bacterial suspension of viable bacteria. The bacterial suspension was added at about 1X 10 5 Adding the mixture into each preparation in a CFU/mL mode, and standing for 7 days at the temperature of 20-25 ℃. Then, the bacteria were recovered by membrane filtration, and after standing at 30 to 35 ℃ for 2 to 3 days on the surface of a soybean, casein, digest agar medium, the number of viable bacteria per 1mL of each aqueous composition was measured, and the Log reduction ratio (Log reduction) was calculated from the value. The results are shown in table 1.
[ test example 2: evaluation of stability of Chlorhexidine gluconate
Each of the aqueous compositions prepared in test example 1 was filtered and sterilized by a 0.2 μm membrane filter. Then, the aqueous composition was filled in an eye drop bottle (material: polyethylene, volume: 5mL), and stored at 50 ℃ for 2 months in the dark. The content of chlorhexidine gluconate contained in each aqueous composition immediately after preparation and each aqueous composition after storage at 50 ℃ for 2 months was quantitatively measured by HPLC (measurement conditions are described below), and the reduction improvement rate of the chlorhexidine gluconate concentration was calculated according to the following (formula 1) and (formula 2). The results are shown in table 1.
(formula 1) Chlorhexidine gluconate reduced concentration (mg/100mL) — Chlorhexidine gluconate concentration immediately after completion of production-Chlorhexidine gluconate concentration after 2 months of storage at 50 ℃
(formula 2) the rate of improvement in decrease (%) in chlorhexidine gluconate concentration { (decreased concentration in comparative example 2 — decreased concentration in each example)/decreased concentration in comparative example 2 } × 100
(conditions for HPLC measurement)
A detector: ultraviolet absorption photometer (measuring wavelength: 254nm)
A chromatographic column: inertsil ODS-2 (inner diameter 4.6mm, length 150mm, particle size 5 μm)
Temperature of the column: constant temperature of about 40 DEG C
Mobile phase: a solution obtained by dissolving 1.50g of sodium lauryl sulfate in 1000mL of a mixed solution (7: 3) of acetonitrile/dilute acetic acid (100) (1 → 60)
Flow rate: 0.9 mL/min
[ Table 1]
Comparative example 1, in which chlorhexidine gluconate was not added to the aqueous composition containing digoxitinib, had an extremely weak storage effect. On the other hand, it was confirmed that the storage efficiency of examples 1 and 2 in which chlorhexidine gluconate was blended in the aqueous composition containing digoxitinib was significantly enhanced as compared with comparative example 1 or comparative example 2 in which only chlorhexidine gluconate was blended.
Further, it was confirmed that the decrease in chlorhexidine gluconate was improved depending on the concentration of digotinib (examples 1 and 2), and that digotinib could improve the stability of chlorhexidine gluconate.
[ test example 3: storage Effect test (2)
Aqueous compositions were prepared according to conventional methods with the compositions shown in table 2. Each of the aqueous compositions thus prepared was filtered and sterilized by a 0.2 μm membrane filter, and the storage efficiency of each of the aqueous compositions was evaluated according to the storage efficiency test method defined in the seventeenth modification of the Japanese pharmacopoeia. Specifically, Pseudomonas aeruginosa (Pseudomonas aeruginosa) was inoculated on the surface of a soybean-casein-digest agar medium and cultured at 30 to 35 ℃ for 24 hours. The cultured cells were aseptically collected using platinum loop and suspended in an appropriate amount of sterilized physiological saline to prepare a composition containing about 3X 10 7 CFU/mL of a bacterial suspension of viable bacteria. The bacterial suspension was added at about 3X 10 5 Adding the mixture into each preparation in a CFU/mL mode, and standing for 7 days at the temperature of 20-25 ℃. Then, the bacteria were recovered by membrane filtration, and after standing at 30 to 35 ℃ for 1 day on the surface of a soybean, casein, digest agar medium, the number of viable bacteria per 1mL of each aqueous composition was measured, and the Log removal rate (Log reduction) was calculated from the value. The results are shown in table 2.
[ Table 2]
| Test example 1 | Test example 2 | Test example 3 | Test example 4 | |
| Digatinib | - | 0.3 | - | 0.02 |
| Chlorhexidine gluconate | 0.00094 | 0.00094 | - | - |
| Polyhexamethylene biguanide hydrochloride | - | - | 0.00002 | 0.00002 |
| Boric acid | 0.5 | 0.5 | 0.5 | 0.5 |
| Sodium chloride | 0.4 | 0.4 | 0.4 | 0.4 |
| Potassium chloride | 0.1 | 0.1 | 0.1 | 0.1 |
| Hydrochloric acid | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Sodium hydroxide | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Pure water | Residual amount of | Residual amount of | Residual amount of | Residual amount of |
| pH | 4.5 | 4.5 | 5.5 | 5.5 |
| Preservation efficacy (Log removal Rate) | 2.7 | 3.6 | 2.5 | 3.2 |
[ test example 4: storage Effect test (3)
Aqueous compositions were prepared according to conventional methods with the compositions shown in table 3. Each of the aqueous compositions thus prepared was filtered and sterilized by a 0.2 μm membrane filter. Then, the aqueous composition was filled in an eye drop bottle (material: polyethylene, volume: 5mL), and stored at 60 ℃ for 3 weeks in the dark. According to the seventeenth modification of the Japanese pharmacopoeiaThe storage efficiency test method (2) is a method of evaluating the storage efficiency of each aqueous composition. Specifically, Pseudomonas aeruginosa (Pseudomonas aeruginosa) was inoculated on the surface of a soybean casein digest agar medium and cultured at 30 to 35 ℃ for 24 hours. The cultured cells were aseptically collected using platinum loop and suspended in an appropriate amount of sterilized physiological saline to prepare a composition containing about 3X 10 7 CFU/mL of a bacterial suspension of viable bacteria. The bacterial suspension was added at about 3X 10 5 Adding the mixture into each preparation in a CFU/mL mode, and standing for 14 days at 20-25 ℃. Then, the bacteria were recovered by membrane filtration, and after standing at 30 to 35 ℃ for 1 day on the surface of a soybean, casein, digest agar medium, the number of viable bacteria per 1mL of each aqueous composition was measured, and the Log removal rate (Log reduction) was calculated from the value. The results are shown in table 3.
[ Table 3]
| Test example 5 | Test example 6 | |
| Tofacitinib | - | 0.01 |
| Polyhexamethylene biguanide hydrochloride | 0.00002 | 0.00002 |
| Boric acid | 0.5 | 0.5 |
| Sodium chloride | 0.4 | 0.4 |
| Potassium chloride | 0.1 | 0.1 |
| Hydrochloric acid | Proper amount of | Proper amount of |
| Sodium hydroxide | Proper amount of | Proper amount of |
| Pure water | Residual amount of | Residual amount of |
| pH | 5.5 | 5.0 |
| Preservation efficacy (Log removal Rate) | 0.9 | 1.6 |
Claims (5)
1. An ophthalmic aqueous composition contains a bisexual nerve kinase inhibitor and a biguanide preservative.
2. The ophthalmic aqueous composition according to claim 1, wherein the janus kinase inhibitor is contained in an amount of 0.001 to 5% by mass based on the total amount of the ophthalmic aqueous composition.
3. An ophthalmic aqueous composition according to claim 1 or 2, wherein the janus kinase inhibitor is degatinib.
4. An ophthalmic aqueous composition according to any one of claims 1 to 3, wherein the biguanide preservative is chlorhexidine or a salt thereof.
5. The ophthalmic aqueous composition according to any one of claims 1 to 4, which has a pH of 4.0 to 6.5.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2019239600 | 2019-12-27 | ||
| JP2019-239600 | 2019-12-27 | ||
| PCT/JP2020/048855 WO2021132609A1 (en) | 2019-12-27 | 2020-12-25 | Aqueous composition |
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| Publication Number | Publication Date |
|---|---|
| CN114845734A true CN114845734A (en) | 2022-08-02 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN202080088973.9A Pending CN114845734A (en) | 2019-12-27 | 2020-12-25 | Aqueous composition |
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| Country | Link |
|---|---|
| JP (1) | JPWO2021132609A1 (en) |
| CN (1) | CN114845734A (en) |
| TW (1) | TW202135822A (en) |
| WO (1) | WO2021132609A1 (en) |
Families Citing this family (2)
| 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 |
| CN114867480A (en) * | 2019-12-27 | 2022-08-05 | 乐敦制药株式会社 | Aqueous composition |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101743009A (en) * | 2007-07-11 | 2010-06-16 | 辉瑞大药厂 | Pharmaceutical compositions and methods of treating dry eye disorders |
| JP2016166195A (en) * | 2015-03-06 | 2016-09-15 | 参天製薬株式会社 | Ophthalmic composition |
Family Cites Families (2)
| 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 |
-
2020
- 2020-12-25 JP JP2021567697A patent/JPWO2021132609A1/ja active Pending
- 2020-12-25 CN CN202080088973.9A patent/CN114845734A/en active Pending
- 2020-12-25 TW TW109146302A patent/TW202135822A/en unknown
- 2020-12-25 WO PCT/JP2020/048855 patent/WO2021132609A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101743009A (en) * | 2007-07-11 | 2010-06-16 | 辉瑞大药厂 | Pharmaceutical compositions and methods of treating dry eye disorders |
| JP2016166195A (en) * | 2015-03-06 | 2016-09-15 | 参天製薬株式会社 | Ophthalmic composition |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2021132609A1 (en) | 2021-07-01 |
| TW202135822A (en) | 2021-10-01 |
| JPWO2021132609A1 (en) | 2021-07-01 |
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