WO2019167183A1 - Préparation pharmaceutique - Google Patents

Préparation pharmaceutique Download PDF

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Publication number
WO2019167183A1
WO2019167183A1 PCT/JP2018/007584 JP2018007584W WO2019167183A1 WO 2019167183 A1 WO2019167183 A1 WO 2019167183A1 JP 2018007584 W JP2018007584 W JP 2018007584W WO 2019167183 A1 WO2019167183 A1 WO 2019167183A1
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Prior art keywords
compound represented
group
aqueous composition
general formula
container
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PCT/JP2018/007584
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English (en)
Japanese (ja)
Inventor
佳央 山北
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興和株式会社
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Priority to PCT/JP2018/007584 priority Critical patent/WO2019167183A1/fr
Priority to JP2020503175A priority patent/JP7165185B2/ja
Publication of WO2019167183A1 publication Critical patent/WO2019167183A1/fr
Priority to JP2022166447A priority patent/JP7464675B2/ja

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D1/00—Containers having bodies formed in one piece, e.g. by casting metallic material, by moulding plastics, by blowing vitreous material, by throwing ceramic material, by moulding pulped fibrous material, by deep-drawing operations performed on sheet material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D65/00—Wrappers or flexible covers; Packaging materials of special type or form
    • B65D65/02—Wrappers or flexible covers
    • B65D65/16—Wrappers or flexible covers with provision for excluding or admitting light
    • B65D65/20—Wrappers or flexible covers with provision for excluding or admitting light with provision for excluding light of a particular wavelength

Definitions

  • the present invention relates to pharmaceutical preparations and the like.
  • network may also be referred to as AR-13324, which has pharmacological actions such as Rho kinase inhibitory action and norepinephrine transporter inhibitory action, such as ocular hypertension and glaucoma. It is reported to be useful for the prevention and treatment of eye diseases (for example, Patent Document 1, Non-Patent Documents 1 and 2).
  • verosil may also be referred to as AR-12286, which has a Rho kinase inhibitory action and is used for the prevention and treatment of ocular diseases such as ocular hypertension. It is reported to be useful (for example, Patent Document 2, Non-Patent Documents 1 and 3). Therefore, it is extremely useful to establish a technique for stably formulating these isoquinoline-6-amino derivatives as, for example, ophthalmic agents.
  • Patent Document 3 describes that a composition containing netersil or velosil was prepared in a 150 mL plastic container.
  • each composition is prepared for use in a pharmacological test, and there is no description about the stability of netersil or velosil in the composition. There is no mention of any materials or properties.
  • An ophthalmic agent or the like is usually a composition containing water (aqueous composition). Accordingly, the present inventor prepared an aqueous composition containing an isoquinoline-6-amino derivative such as netersudil, and placed the container in a container to confirm its preservability. However, surprisingly, it was revealed that when stored at a high temperature, the aqueous composition becomes cloudy over time and the clarity is lowered. A decrease in clarity due to white turbidity of an aqueous composition not only means a decrease in quality, but also makes it difficult to confirm the presence or absence of foreign matter in the aqueous composition, which can be a major problem in quality control during production. . Accordingly, an object of the present invention is to provide a pharmaceutical preparation that is stable even at high temperatures, even though it is a preparation of an aqueous composition containing an isoquinoline-6-amino derivative such as netersil or velosil.
  • an aqueous composition containing an isoquinoline-6-amino derivative is contained in a container of a specific material such as a polyolefin resin container or a polyester resin container, a decrease in clarity during high temperature storage is suppressed. If the container is made transparent, it is possible to confirm the presence or absence of foreign matter in the aqueous composition by observation with the naked eye from the outside of the container, and a pharmaceutical preparation capable of quality control with improved stability at high temperatures. As a result, the present invention was completed.
  • R 1 and R 2 each independently represent a hydrogen atom or a C 1 -C 4 alkyl group
  • R 3 represents a hydrogen atom or a hydroxy group
  • A is —CH (R 4 ) — or —CH 2 —CH (R 4 ) —
  • R 4 may have a C 6 -C 10 aryl group which may have a substituent, or may have a substituent).
  • the tautomer is also contained in Formula (1).
  • An aqueous composition containing a compound represented by the formula (1) or a salt thereof, or a solvate thereof, is housed in a transparent container made of one or more resins selected from the group consisting of polyolefin resins and polyester resins, A pharmaceutical preparation is provided.
  • the stability at high temperature of an aqueous composition containing an isoquinoline-6-amino derivative typified by Netersudil can be improved.
  • FIG. 10 is a graph showing light transmittance (%) in a wavelength range of 270 to 800 nm of a transparent container for eye drops made of polypropylene kneaded with a benzotriazole-based ultraviolet absorber used in Test Example 8.
  • the transparent container for the eye drop made of polypropylene provided with the shrink film containing the ultraviolet light scattering agent used in Test Example 9 in the wavelength range of 270 to 800 nm on the side of the container (the part around which the shrink film is wound). It is a graph which shows the transmittance
  • R 1 and R 2 each independently represent a hydrogen atom or a C 1 -C 4 alkyl group
  • R 3 represents a hydrogen atom or a hydroxy group
  • A is —CH (R 4 ) — or —CH 2 —CH (R 4 ) —
  • R 4 may have a C 6 -C 10 aryl group which may have a substituent, or may have a substituent).
  • the tautomer is also contained in Formula (1).
  • a salt or a solvate thereof is also included in the compound represented by the formula (1) or a salt thereof or a solvate thereof.
  • the salt of the compound represented by the general formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt, and specifically, for example, hydrochloride, sulfate, nitrate, hydrofluoric acid.
  • Inorganic acid salts such as salt and hydrobromide; acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfone
  • Organic acid salts such as acid salts, toluene sulfonates, naphthalene sulfonates, camphor sulfonates, and the like can be mentioned, and hydrochlorides and methane sulfonates are preferred.
  • Examples of the solvate of the compound represented by the general formula (1) or a salt thereof include hydrates and alcohol solvates.
  • various stereoisomers may exist, but as the compound represented by the general formula (1),
  • the configuration is not particularly limited, and may be a single stereoisomer or a mixture of various stereoisomers in any ratio.
  • a compound represented by various formulas has an asymmetric carbon in its chemical structure, such a formula is represented by various stereoisomers alone and those unless otherwise specified. Includes all mixtures in any proportion. Therefore, the compound represented by the formula that does not particularly specify the configuration may be a single stereoisomer or a mixture of various stereoisomers in an arbitrary ratio.
  • the general formula (1) includes not only the compound directly represented by the general formula (1) but also tautomers thereof. Specifically, for example, in the case of the following general formula (1a) in which R 3 is a hydroxy group, its tautomer (general formula (1b)) may be produced. In addition to the compound represented by the following general formula (1a), a compound represented by the general formula (1b) is also included in the “compound”.
  • the “C 1 -C 4 alkyl group” means a linear, branched or cyclic alkyl group having 1 to 4 carbon atoms. Specific examples of the “C 1 -C 4 alkyl group” include methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, t-butyl group, isobutyl group and the like. And a methyl group is preferable.
  • the “C 6 -C 10 aryl group” means an aryl group having 6 to 10 carbon atoms. Specific examples of the “C 6 -C 10 aryl group” include a phenyl group and a naphthyl group, and a phenyl group is preferable.
  • the “5- to 10-membered heteroaryl group” refers to a 5- to 10-membered monocyclic group containing 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as ring constituent atoms. Means a polycyclic or fused-ring aromatic heterocyclic group.
  • “5- to 10-membered heteroaryl group” include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl Group, triazolyl group, tetrazolyl group, pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, benzofuranyl group, isobenzofuranyl group, benzothienyl group, indolyl group, isoindolyl group, indazolyl group, benzimidazolyl group, benzoxazolyl group , Benzoisoxazolyl group, benzothiazolyl group, benzoisothiazolyl group, benzoxiadiazolyl group, benzothiadiazolyl group, benzotriazolyl
  • the “substituent” in the “optionally substituted C 6 -C 10 aryl group” and the “optionally substituted 5- to 10-membered heteroaryl group” includes Specifically, for example, a halogen atom, —CH 2 —OC ( ⁇ O) —R 5 (wherein R 5 is C 1 -C 4 alkyl group optionally having 1 to 3 C 1 -C 4 alkyl groups).
  • 6 ⁇ C 10 aryl group e.g., 2,4-dimethylphenyl group
  • a chlorine atom, 2,4-dimethylphenyl carboxymethyl group is preferred.
  • the “optionally substituted C 6 -C 10 aryl group” is preferably a 4-chlorophenyl group or a 4- (2,4-dimethylphenylcarboxymethyl) phenyl group.
  • the “optionally substituted 5- to 10-membered heteroaryl group” is preferably a 3-thienyl group.
  • R 3 is a hydroxy group, the substitution position of R 3 is not limited as long as it is on the isoquinoline ring, but the 1-position of the isoquinoline ring is preferable.
  • a compound represented by the formula (Netersil) (chemical name: ⁇ 4-[(2S) -3-amino-1- (isoquinolin-6-ylamino) -1-oxopropan-2-yl] phenyl ⁇ methyl 2,4- Dimethylbenzoate ([4-[(2S) -3-amino-1- (isoquinolin-6-ylamino) -1-oxopropan-2-yl] phenyl] methyl 2,4-dimethylbenzoate), international general name: netarsudil) or The salt or solvate thereof is more preferable, and the following formula (4):
  • Monohydrochloride of the compound represented by the above formula (6) (chemical name: rac- (2R) -2- (dimethylamino) -N- (1-oxo-1,2-dihydroisoquinoline- 6-yl) -2- (thiophen-3-yl) acetamide monohydrochloride (rac- (2R) -2- (dimethylamino) -N- (1-oxo-1,2-dihydroisoquinolin-6-yl) -2 -(thiophen-3-yl) acetamide monohydrochloride) (hereinafter sometimes referred to as “velosil monohydrochloride” in the present specification) is particularly preferable.
  • the compound represented by the general formula (1) or a salt thereof or a solvate thereof is known and can be produced by a known method. Specifically, for example, it can be produced with reference to the methods described in Patent Documents 1 to 3 and the method described in Non-Patent Document 2. The contents of these documents are incorporated herein by reference. Moreover, the compound represented by General formula (1), its salt, or those solvates are marketed, and these commercial products may be used.
  • commercially available products include, for example, netarsudil dimesylate (compound represented by formula (4)) manufactured by Medchemexpress and Chemscene LLS, and netarsudil monohydrochloride manufactured by Shanghai biopharmaleader (formula Monohydrochloride of the compound represented by (3)), velosil (free form of the compound represented by formula (6)) manufactured by MedKoo biosciences, and the like.
  • the content of the compound represented by the general formula (1) or a salt thereof or a solvate thereof in the aqueous composition is not particularly limited, and is appropriately determined according to the disease applied, the sex, age, symptoms, etc. of the patient.
  • the compound represented by the general formula (1) is converted into a free form in an amount of 0.0001 to 5 w / v% with respect to the total volume of the aqueous composition. It is preferably contained, more preferably 0.001 to 3 w / v%, even more preferably 0.005 to 2 w / v%, and particularly preferably 0.01 to 1 w / v%. .
  • netersil is converted into a free form with respect to the total volume of the aqueous composition to be 0.0001. It is preferably contained in an amount of ⁇ 1 w / v%, more preferably 0.001 to 0.5 w / v%, further preferably 0.005 to 0.1 w / v%, more preferably 0.01 to 0 It is particularly preferable to contain 0.04 w / v%.
  • velosil when used as the compound represented by the general formula (1), from the viewpoint of obtaining an excellent pharmacological action, velosil is converted to a free form with respect to the total volume of the aqueous composition to 0.01. Is preferably contained in an amount of about 3.5 to 3.5 w / v%, more preferably 0.1 to 2.5 w / v%, still more preferably 0.2 to 1.5 w / v%, It is particularly preferred to contain ⁇ 0.8 w / v%.
  • the formula (8) Is preferably contained in a free form in an amount of 0.0001 to 3 w / v%, more preferably 0.001 to 2 w / v%, and more preferably 0.005 to 1 w / v%. It is more preferably contained, and particularly preferably 0.01 to 0.5 w / v%.
  • the “aqueous composition” means a composition containing at least water, and its properties are not particularly limited as long as it can be accommodated in a container described later. Or suspension) and semi-solid (ointment).
  • a transparent container it is preferably clear to the extent that foreign matter contamination can be confirmed by observation with the naked eye from the outside of the container, for example, as defined in the 17th revision Japanese Pharmacopoeia What is judged to be clear when the insoluble foreign matter inspection method for eye drops is performed is preferable.
  • water in a composition purified water, water for injection, sterilized purified water, etc. can be used, for example.
  • the content of water contained in the aqueous composition is not particularly limited, but is preferably 5% by mass or more, more preferably 20% by mass or more, further preferably 50% by mass or more, still more preferably 90% by mass or more, and more preferably 90 to 99.99 mass% is particularly preferable.
  • the aqueous composition may further optionally contain acids.
  • the aqueous composition containing the compound represented by the general formula (1) or a salt thereof or a solvate thereof is further added with acids, and this is converted into a polyolefin-based polymer. It became clear that the fall of the clarity at the time of preserve
  • the “acids” are not particularly limited, and may be organic acids or inorganic acids. “Acids” include “boric acids”, “phosphoric acids”, and “fats” from the viewpoint of suppressing a decrease in clarity of an aqueous composition containing the compound represented by the general formula (1) during high-temperature storage. One or more selected from the group consisting of “aromatic carboxylic acids” is preferable, and “boric acids” and “aliphatic carboxylic acids” are particularly preferable.
  • boric acid refers to boric acid and salts thereof (for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt; ammonium salt and the like) and solvates thereof. Means one or more selected from the group consisting of substances (hydrates, etc.). Specific examples of the boric acids include boric acid, ammonium borate, and borax. In the present specification, “boric acids” are composed of boric acid and salts thereof from the viewpoint of suppressing a decrease in clarity during high-temperature storage of an aqueous composition containing the compound represented by the general formula (1). One or more selected from the group is preferred, and boric acid is particularly preferred. These boric acids are all known and may be produced by a known method, or commercially available products may be used.
  • phosphoric acids refers to phosphoric acid and salts thereof (for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts; ammonium salts) and solvates thereof. Means one or more selected from the group consisting of substances (hydrates, etc.). Specific examples of such phosphoric acids include, for example, the following components listed in the Pharmaceutical Additives Dictionary 2016 (published by Yakuji Nippo Co., Ltd.): phosphoric acid, calcium monohydrogen phosphate, sodium monohydrogen phosphate.
  • phosphoric acid, sodium hydrogenphosphate hydrate, diphosphoric acid phosphate are used from the viewpoint of suppressing a decrease in clarity of the aqueous composition containing the compound represented by the general formula (1) during high-temperature storage.
  • One or more selected from the group consisting of potassium hydrogen, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, crystalline sodium dihydrogen phosphate, anhydrous sodium monohydrogen phosphate, and anhydrous sodium dihydrogen phosphate are preferred.
  • all of these phosphoric acids are well-known, may be manufactured by a well-known method, and may use a commercial item.
  • aliphatic carboxylic acids refers to aliphatic carboxylic acids and salts thereof (for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt) Etc.) and their solvates (hydrates, etc.).
  • the number of carbon atoms in the aliphatic carboxylic acid is not particularly limited, but from the viewpoint of suppressing a decrease in clarity during high-temperature storage of the aqueous composition containing the compound represented by the general formula (1), 2 to 20 4 to 18 is more preferable, and 6 to 16 is particularly preferable.
  • the carbon chain may be linear or branched, saturated or unsaturated, and a tertiary amino group between carbon-carbon atoms. Etc. may be included.
  • the number of carboxyl groups in the aliphatic carboxylic acid is not particularly limited, but from the viewpoint of suppressing a decrease in clarity during high-temperature storage of the aqueous composition containing the compound represented by the general formula (1), 1 to Four are preferable, and 2 to 4 are particularly preferable.
  • the “aliphatic carboxylic acids” may be a carboxylic acid (amino acid) having an amino group as a substituent and a carboxylic acid (oxycarboxylic acid) having a hydroxy group as a substituent.
  • the number of substituents is not particularly limited. However, from the viewpoint of suppressing a decrease in clarity during high-temperature storage of the aqueous composition containing the compound represented by the general formula (1), the number of substituents may be 1 to 3. It is preferable that it is 1 or 2 and particularly preferable.
  • aliphatic carboxylic acids include aspartic acid such as sodium L-aspartate, potassium L-aspartate, magnesium L-aspartate or a salt thereof or a solvate thereof; DL-alanine Alanine such as L-alanine or a salt thereof or a solvate thereof; arginine or a salt thereof such as L-arginine or L-arginine hydrochloride or a solvate thereof; epsilon-aminocaproic acid; disodium calcium edetate; Edetic acid sodium hydrate, edetic acid tetrasodium or the like, or a salt thereof, or a solvate thereof; calcium citrate, citric acid hydrate, sodium citrate hydrate (trisodium citrate dihydrate) ), Sodium dihydrogen citrate, disodium citrate, none Citric acid such as citric acid and anhydrous sodium citrate or a salt thereof or a solvate thereof; glycine or a salt
  • aliphatic carboxylic acids examples include aliphatic carboxylic acids having 2 to 4 carboxyl groups from the viewpoint of suppressing a decrease in clarity of the aqueous composition containing the compound represented by the general formula (1) during high-temperature storage.
  • a salt thereof or a solvate thereof is preferable, and edetic acid, citric acid, tartaric acid, a salt thereof, or a solvate thereof is particularly preferable.
  • all of these aliphatic carboxylic acids are publicly known, and may be manufactured by a publicly known method, and a commercial item may be used.
  • the content of the acids in the aqueous composition is not particularly limited and may be determined by appropriate examination.
  • the clarity of the aqueous composition containing the compound represented by the general formula (1) during storage at high temperature is deteriorated.
  • it is preferably contained in an amount of 0.0001 to 4 w / v%, more preferably 0.001 to 3 w / v%, more preferably 0.002 to 2. It is particularly preferable to contain 5 w / v%.
  • the content of boric acids is not particularly limited and may be determined by appropriate examination.
  • an aqueous composition containing the compound represented by the general formula (1) From the viewpoint of suppressing a decrease in clarity during high-temperature storage, the content is preferably 0.003 to 2 w / v%, and preferably 0.01 to 1 w / v%, based on the total volume of the aqueous composition. More preferably, the content is 0.03 to 0.5 w / v%.
  • the content of the aliphatic carboxylic acids is not particularly limited and may be determined by appropriate examination, but contains the compound represented by the general formula (1).
  • the aqueous composition when stored at a high temperature, it is preferably contained in an amount of 0.001 to 3.5 w / v% based on the total volume of the aqueous composition, and 0.003 to 2.
  • the content is more preferably 5 w / v%, particularly preferably 0.005 to 1 w / v%.
  • the content mass ratio of the compound represented by the general formula (1) or a salt thereof or a solvate thereof and acids in the aqueous composition is not particularly limited, but is an aqueous solution containing the compound represented by the general formula (1). From the viewpoint of suppressing a decrease in clarity during high-temperature storage of the composition, the compound represented by the general formula (1) or a salt thereof, or a solvate thereof is used in a free form with respect to 1 part by mass of acids.
  • the content is preferably 0003 to 200 parts by mass, more preferably 0.003 to 80 parts by mass, and particularly preferably 0.02 to 30 parts by mass.
  • the content ratio of boric acids is not particularly limited, but the clarity of the aqueous composition containing the compound represented by the general formula (1) is reduced when stored at high temperature.
  • the content ratio of the aliphatic carboxylic acids is not particularly limited, but the aqueous composition containing the compound represented by the general formula (1) can be stored at high temperature. From the viewpoint of suppressing the decrease in clarity, 0.05 to 150 parts by mass of an aliphatic carboxylic acid is used per 1 part by mass of the compound represented by the general formula (1) or a salt thereof or a solvate thereof as a free form.
  • the content is preferably 0.1 to 100 parts by mass, more preferably 0.3 to 75 parts by mass.
  • netarsudil as the compound represented by the general formula (1) and using boric acid as the acid
  • the content is particularly preferably 20 to 20 parts by mass.
  • Velosil or a salt thereof or a solvate thereof is preferably contained in an amount of 0.001 to 5 parts by mass, more preferably 0.01 to 1 part by mass with respect to 1 part by mass of the free form. 0.05 to 0.5 parts by mass is particularly preferable.
  • the aqueous solution containing the compound represented by the formula (8) is added in an amount of 0.1% to 1 part by mass of the compound represented by the formula (8) or a salt thereof or a solvate thereof as a free form.
  • the content is preferably 01 to 80 parts by mass, more preferably 0.05 to 40 parts by mass, and particularly preferably 0.1 to 20 parts by mass.
  • netterzil is used as the compound represented by the general formula (1) and an aliphatic carboxylic acid is used as the acid
  • the deterioration of the clarity during storage at high temperature of the aqueous composition containing netarthil is suppressed.
  • velosil is used as the compound represented by the general formula (1) and aliphatic carboxylic acids are used as the acids, the deterioration of the clarity of the aqueous composition containing velosil during high-temperature storage is suppressed.
  • the compound represented by the formula (8) is contained.
  • the compound represented by the formula (8) or a salt thereof or a solvate thereof is used as a free form with respect to 1 part by mass of an aliphatic carboxylic acid.
  • the acid content is preferably 0.1 to 180 parts by mass, more preferably 1 to 130 parts by mass, and particularly preferably 3 to 80 parts by mass.
  • the aqueous composition may contain additives used in pharmaceuticals, quasi drugs, etc., depending on the dosage form.
  • additives include, for example, inorganic salts, isotonic agents, chelating agents, stabilizers, pH adjusters, preservatives, antioxidants, thickeners, surfactants, solubilizers, suspensions.
  • examples include turbidizers, cooling agents, dispersants, preservatives, oily bases, emulsion bases, water-soluble bases, and the like.
  • additives include sodium bisulfite, benzyl benzoate, fennel oil, ethanol, ethylene / vinyl acetate copolymer, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, and alkyl hydrochloride.
  • Diaminoethylglycine solution carboxyvinyl polymer, dry sodium sulfite, dry sodium carbonate, d-camphor, dl-camphor, xylitol, glycerin, creatinine, chlorobutanol, geraniol, sodium chondroitin sulfate, titanium oxide, gellan gum, dibutylhydroxytoluene, odor Potassium bromide, benzododecinium bromide, sodium hydroxide, polyoxyl 45 stearate, purified lanolin, D-sorbitol, sorbitol solution, taurine, sodium bicarbonate, Sodium hydrate, sodium thiosulfate hydrate, thimerosal, tyloxapol, sodium dehydroacetate, trometamol, concentrated glycerin, concentrated mixed tocopherol, white petrolatum, mint water, mint oil, concentrated benzalkonium chloride solution 50, paraoxybenzoic acid Ethyl
  • additives include potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, glycerin, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate, concentrated glycerin, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, Povidone, polysorbate 80, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyvinyl alcohol (partially saponified product), macrogol 4000, macrogol 6000, methylcellulose, monoethanolamine, glucose, l-menthol and the like are preferable.
  • the aqueous composition may further contain other medicinal ingredients depending on the disease to be applied.
  • medicinal ingredients include ⁇ 1 receptor blockers including bunazosin such as bunazosin hydrochloride or a salt thereof or a solvate thereof; brimonidine or a salt thereof such as brimonidine tartrate or an solvate thereof; ⁇ 2 receptor agonist containing clonidine or a salt thereof or a solvate thereof; carteolol or a salt thereof such as carteolol hydrochloride or a solvate thereof, nipradilol or a salt thereof or a solvate thereof, timolol maleic acid Timolol such as a salt or a salt thereof, or a solvate thereof, betaxolol or a salt thereof such as betaxolol hydrochloride or a solvate thereof, levobanolol or a salt thereof such as levobanolol hydrochloride or a solvate thereof,
  • the aqueous composition may not contain the above prostaglandins and derivatives thereof.
  • the aqueous composition of one embodiment is preferably one other than the following ⁇ A-1> to ⁇ A-10>.
  • ⁇ A-1> (rac) -2- (Dimethylamino) -N- (1-hydroxyisoquinolin-6-yl) -2- (thiophen-3-yl) acetamide hydrochloride, travoprost, boric acid, D- A composition comprising mannitol, benzalkonium chloride, polyoxyl 40 stearate, polyethylene glycol 400, EDTA, and purified water.
  • ⁇ A-2> (rac) -2- (Dimethylamino) -N- (1-hydroxyisoquinolin-6-yl) -2- (thiophen-3-yl) acetamide hydrochloride, travoprost, boric acid, D- A composition comprising mannitol, benzalkonium chloride, Cremophor RH40, polyethylene glycol 400, EDTA, and purified water.
  • ⁇ A-3> (rac) -2- (Dimethylamino) -N- (1-hydroxyisoquinolin-6-yl) -2- (thiophen-3-yl) acetamide hydrochloride, travoprost, boric acid, D- A composition comprising mannitol, polyoxyl 40 stearate, polyethylene glycol 400, EDTA, and purified water.
  • ⁇ A-4> (rac) -2- (Dimethylamino) -N- (1-hydroxyisoquinolin-6-yl) -2- (thiophen-3-yl) acetamide hydrochloride, latanoprost, monobasic sodium phosphate , A composition comprising dibasic sodium phosphate, benzalkonium chloride, sodium chloride, EDTA, and purified water.
  • ⁇ A-5> (rac) -2- (Dimethylamino) -N- (1-hydroxyisoquinolin-6-yl) -2- (thiophen-3-yl) acetamide hydrochloride, latanoprost, boric acid, D-mannitol , Benzalkonium chloride, EDTA, and purified water.
  • ⁇ A-6> (rac) -2- (Dimethylamino) -N- (1-hydroxyisoquinolin-6-yl) -2- (thiophen-3-yl) acetamide hydrochloride, bimatoprost, monobasic sodium phosphate , A composition comprising dibasic sodium phosphate, benzalkonium chloride, sodium chloride, EDTA, and purified water.
  • ⁇ A-7> (rac) -2- (Dimethylamino) -N- (1-hydroxyisoquinolin-6-yl) -2- (thiophen-3-yl) acetamide hydrochloride, bimatoprost, monobasic sodium phosphate , A composition comprising dibasic sodium phosphate, benzalkonium chloride, sodium chloride, EDTA, and purified water.
  • ⁇ A-8> (rac) -2- (Dimethylamino) -N- (1-hydroxyisoquinolin-6-yl) -2- (thiophen-3-yl) acetamide hydrochloride, bimatoprost, boric acid, D-mannitol And a composition comprising purified water.
  • the pH (25 ° C.) of the aqueous composition is not particularly limited, but is preferably 3 to 9, more preferably 3.5 to 8, further preferably 4 to 7, and particularly preferably 5 to 6.
  • the osmotic pressure ratio with respect to physiological saline is not particularly limited, but is preferably 0.6 to 3, particularly preferably 0.6 to 2.
  • the pharmaceutical preparation of the present invention uses a transparent container made of polyolefin resin or a transparent container made of polyester resin.
  • the “container” means a container that directly contains the aqueous composition.
  • Container is a concept encompassing any of “sealed container”, “airtight container”, and “sealed container” defined in the 17th revised Japanese Pharmacopoeia.
  • the “transparent container” means a container having a portion having transparency (internal visibility) such that the inside thereof can be observed with the naked eye.
  • an aqueous composition containing an isoquinoline-6-amino derivative in a transparent container it is possible to confirm the presence or absence of foreign matter in the aqueous composition by observation with the naked eye from the outside of the container. Appropriate quality control becomes possible at the time of manufacturing.
  • the transparent container does not prevent the transparency of the transparent container from being impaired by applying a label or a shrink film on the surface of the transparent container. .
  • the transparent part is not contained in the transparent container by the user. It is preferable that the aqueous composition is secured to such an extent that it can be observed with the naked eye.
  • the degree of transparency is not particularly limited as long as the inside of the container is observable with the naked eye.
  • the transparency is sufficient to perform the “inspection method for insoluble foreign substances in eye drops” prescribed in the 17th revision Japanese Pharmacopoeia. I just need it.
  • the average value of the light transmittance in the visible light region (400 to 750 nm) in the transparent container in the transparent portion is about 10% or more (more preferably about 20% or more, More preferably about 30% or more, still more preferably about 40% or more, and particularly preferably about 50% or more), but it is not limited thereto.
  • the measurement of the average value of the transmittance of light in a specific wavelength range was performed by measuring the transmittance of light in a container in air every 5 nm within the range using a spectrophotometer. Thereafter, it can be measured by calculating the average value.
  • a spectrophotometer is U-3900 (Hitachi High-Technologies Corporation).
  • the transparent part of the transparent container may be a part or the whole of the container. If transparency is ensured in at least a part of the container, the aqueous composition contained in the container can be observed from the part.
  • a transparent container it is preferable that 10% or more of the total area of the outer surface is transparent with respect to the outer surface, and 30% or more of the transparent container is transparent. It is more preferable that the portion is provided, and it is particularly preferable that 50% or more of the portion is provided with transparency.
  • the form of the transparent container is not particularly limited as long as it can contain the aqueous composition, and may be appropriately selected and set according to the dosage form, the use of the pharmaceutical preparation, and the like.
  • Specific examples of such a container include, for example, an injection container, an inhaler container, a spray container, a bottle container, a tube container, an eye drop container, a nasal drop container, Examples include ear container, bag container and the like.
  • the container is preferably an eye drop container from the viewpoint of advantageously utilizing the pharmacological action of the compound represented by the general formula (1).
  • the “transparent container made of polyolefin resin” means a transparent container in which at least a portion in contact with the aqueous composition is “made of polyolefin resin”. Therefore, for example, a transparent container in which a polyolefin-based resin layer is provided on the inner layer in contact with the aqueous composition and a resin of another material is laminated on the outer side also corresponds to the “transparent container made of polyolefin-based resin”.
  • the polyolefin-based resin is not particularly limited, and may be a polymer (homopolymer) of a single type of monomer or a copolymer (copolymer) of a plurality of types of monomers.
  • the polymerization mode is not particularly limited, and may be random polymerization or block polymerization. Furthermore, the stereoregularity (tacticity) is not particularly limited. Specific examples of such polyolefin resins include polyethylene (more specifically, for example, low density polyethylene (including linear low density polyethylene), high density polyethylene, medium density polyethylene, etc.), polypropylene, and cyclic polyolefin.
  • Poly (4-methylpentene), polytetrafluoroethylene, ethylene / propylene copolymer, ethylene / ⁇ -olefin copolymer, ethylene / acrylic acid copolymer, ethylene / methacrylic acid copolymer, ethylene / vinyl acetate Copolymers, ethylene / ethyl acrylate copolymers and the like can be mentioned, and one or more of these can be used in combination.
  • polyethylene, polypropylene, and cyclic polyolefin are preferable from the viewpoint of suppressing a decrease in clarity during high-temperature storage of the aqueous composition containing the compound represented by the general formula (1), low-density polyethylene, Medium density polyethylene, high density polyethylene and polypropylene are more preferred, low density polyethylene, high density polyethylene and polypropylene are even more preferred, and low density polyethylene is particularly preferred.
  • “made of polyolefin resin” means that at least a part of the material contains a polyolefin resin, for example, two or more of a polyolefin resin and another resin. A resin mixture (polymer alloy) is also included in the “made of polyolefin resin”.
  • the “transparent container made of polyester resin” means a transparent container in which at least a portion in contact with the aqueous composition is “made of polyester resin”. Therefore, for example, a transparent container in which a polyester-based resin layer is provided on the inner layer in contact with the aqueous composition and a resin of another material is laminated on the outer side also corresponds to the “polyester-based resin transparent container”.
  • the dicarboxylic acid and diol constituting the polyester resin are not particularly limited. Examples of the dicarboxylic acid include phthalic acid, terephthalic acid, and 2,6-naphthalenedicarboxylic acid. Examples of the diol include ethylene glycol and 1,3.
  • the polymerization mode is not particularly limited, and may be random polymerization or block polymerization.
  • the stereoregularity (tacticity) is not particularly limited.
  • polyester resins include polyalkylene terephthalate (eg, polyethylene terephthalate, polybutylene terephthalate, etc.), polyalkylene naphthalate (eg, polyethylene naphthalate, polybutylene naphthalate, etc.), polycyclohexane, and the like.
  • Homopolyesters such as alkylene terephthalate (for example, poly (1,4-cyclohexylenedimethylene terephthalate)), polyarylate (for example, resin composed of bisphenol and phthalic acid), and the main component of these homopolyester units And a copolymer of the above-mentioned homopolyester. These may be used alone or in combination of two or more.
  • polyester-based resin polyethylene terephthalate is preferable from the viewpoint of suppressing a decrease in clarity during high-temperature storage of the aqueous composition containing the compound represented by the general formula (1).
  • “made of polyester resin” means that at least a part of the material contains a polyester resin, for example, two or more of a polyester resin and another resin.
  • a resin mixture (polymer alloy) is also included in the “made of polyester resin”.
  • a transparent container made of a polyolefin resin or a transparent container made of a polyester resin may block light in a specific wavelength range as long as the container is transparent.
  • an aqueous composition containing the compound represented by the general formula (1) or a salt thereof or a solvate thereof is applied to a transparent container that blocks light having a wavelength of 320 to 380 nm. It became clear by containing that the fall of the content by exposure of the compound represented by General formula (1) in an aqueous composition was further suppressed.
  • the wavelength range of light blocked by the transparent container is sufficient in the range of 320 to 380 nm (preferably in the range of 320 to 395 nm) in consideration of the normal storage environment of the pharmaceutical preparation.
  • 300 to 380 nm is preferable, and 300 to 395 nm is more preferable. Further, considering use under storage conditions where there is a high risk of exposure to a wavelength of less than 300 nm, 270 to 380 nm is preferable, and 270 to 395 nm is particularly preferable.
  • blocking light in the wavelength range means that the average value of the transmittance of light in the wavelength range is 40% or less. Therefore, for example, “a container that blocks light having a wavelength of 320 to 380 nm” means a container having an average transmittance of light having a wavelength of 320 to 380 nm of 40% or less.
  • the average value of the transmittance of light in the wavelength range of the transparent container is preferably 35% or less, more preferably 30% or less, from the viewpoint of further improving the stability to light. % Or less, more preferably 20% or less, even more preferably 15% or less, even more preferably 10% or less, and particularly preferably 5% or less. preferable.
  • the residual ratio of the compound represented by the general formula (1) in the aqueous composition after irradiation is, for example, 80% or more (preferably 85% or more, more preferably 90% or more, particularly Preferably, it may be 95% or more.
  • the residual ratio of the compound represented by the general formula (1) in the aqueous composition is determined by measuring the concentration of the compound in the aqueous composition before and after the light irradiation, and from the ratio of the obtained concentrations, It can be calculated by the following formula.
  • Residual rate of compound represented by general formula (1) (%) ⁇ (concentration of compound represented by general formula (1) in aqueous composition after light irradiation) / (aqueous composition before light irradiation) Concentration of the compound represented by the general formula (1) in the inside) ⁇ ⁇ 100
  • Specific means for imparting the transparent container with the characteristic of blocking light in the wavelength range is not particularly limited, but examples include a method using a substance that blocks light in the wavelength range, and more specifically, For example, A method of containing a substance that blocks light in the wavelength range in a transparent container (for example, a method of adding a substance that blocks light in the wavelength range to a polyolefin resin or polyester resin, and molding this into a container shape etc); A method of providing a member (for example, a film or the like) containing a substance that blocks light in the above wavelength range on the surface of the transparent container (at least one of the inside and the outside of the container) (for example, a resin having the above wavelength range) Add a substance that blocks light to form a heat-shrinkable film and wrap it around the outer surface of the container); A method of applying a substance that blocks light in the wavelength range on the surface of the transparent container (at least one of the inside and the outside of the container); Etc.
  • the substance that blocks light in the wavelength range is not particularly limited, but a substance that blocks the transmission of ultraviolet rays, such as an ultraviolet absorber and an ultraviolet scattering agent, is preferable.
  • examples of the ultraviolet light scattering agent include titanium oxide; zinc oxide and the like.
  • ultraviolet absorbers examples include 2- (2H-benzotriazol-2-yl) -p-cresol (for example, Tinuvin P: BASF), 2- (2H-benzotriazol-2-yl) -4,6 -Bis (1-methyl-1-phenylethyl) phenol (eg Tinuvin 234: BASF), 2- (3,5-di-t-butyl-2-hydroxyphenyl) benzotriazole (eg Tinuvin320: BASF) ), 2- [5-chloro (2H) -benzotriazol-2-yl] -4-methyl-6- (tert-butyl) phenol (for example, Tinuvin 326: BASF), 2- (3,5-di -T-butyl-2-hydroxyphenyl) -5-chlorobenzotriazole (eg, Tinuvin327: BASF), 2- (2H-benzotriazol-2-yl) -4,6-di-tert Pentylphenol (for example, Tinu
  • the substance that blocks light in the wavelength range is preferably titanium oxide; a benzotriazole ultraviolet absorber.
  • the blending ratio varies depending on the type of the substance, the material of the container, another member, etc.
  • the content of the member may be 0.001 to 50% by mass, preferably 0.002 to 25% by mass, and particularly preferably about 0.01 to 10% by mass.
  • a container that blocks light includes a case where only a part of the container blocks light.
  • the means for containing the aqueous composition in the container is not particularly limited, and it may be filled by a conventional method according to the form of the container.
  • compositions or aqueous compositions can be made into various dosage forms according to known methods described in, for example, the 17th revised Japanese Pharmacopoeia, General Rules for Preparations.
  • the dosage form include injections, inhalation solutions, eye drops, eye ointments, ear drops, nasal solutions, enemas, external liquids, sprays, ointments, gels, oral solutions, syrups, etc. Is mentioned.
  • an ophthalmic agent specifically an eye drop and an eye ointment are preferable, and an eye drop is particularly preferable. .
  • the applicable disease of the pharmaceutical preparation is not particularly limited, and may be appropriately selected depending on the pharmacological action and the like of the compound represented by the general formula (1). Specifically, for example, it can be used as a preventive or therapeutic agent for ocular hypertension and glaucoma based on the Rho kinase inhibitory action, the norepinephrine transporter inhibitory action and the intraocular pressure reducing action of the compound represented by the general formula (1).
  • glaucoma more specifically, for example, primary open-angle glaucoma, normal-tension glaucoma, excessive aqueous production glaucoma, acute closed-angle glaucoma, chronic closed-angle glaucoma, plateau iris syndrome, mixed glaucoma Steroid glaucoma, capsular glaucoma, pigment glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma and the like.
  • an aqueous composition or pharmaceutical preparation is used as a prophylactic or therapeutic agent for eye diseases (preferably diseases selected from ocular hypertension and glaucoma), for example, about 1 to 3 times a day, an appropriate amount May be administered.
  • eye diseases preferably diseases selected from ocular hypertension and glaucoma
  • R 1 and R 2 each independently represent a hydrogen atom or a C 1 -C 4 alkyl group
  • R 3 represents a hydrogen atom or a hydroxy group
  • A is —CH (R 4 ) — or —CH 2 —CH (R 4 ) —
  • R 4 may have a C 6 -C 10 aryl group which may have a substituent, or may have a substituent).
  • the tautomer is also contained in Formula (1).
  • An aqueous composition containing a compound represented by the formula (1) or a salt thereof, or a solvate thereof, is housed in a transparent container made of one or more resins selected from the group consisting of polyolefin resins and polyester resins, Pharmaceutical formulation.
  • the compound represented by the general formula (1) is represented by the following formula (2), (5), (5 ′) or (8):
  • the container is the following 1) or 2): 1) Substance that obstructs transmission of ultraviolet rays (more preferably, one or more selected from ultraviolet scatterers and ultraviolet absorbers; particularly preferably, one selected from zinc oxide, titanium oxide, and benzotriazole-based ultraviolet absorbers) A container made of polyolefin resin (preferably polypropylene) kneaded (preferably a container whose inside is visible); 2) Substance that obstructs transmission of ultraviolet rays (more preferably, one or more selected from ultraviolet scatterers and ultraviolet absorbers; particularly preferably, one selected from zinc oxide, titanium oxide, and benzotriazole-based ultraviolet absorbers) A container made of polyolefin resin (preferably polypropylene) with a member (preferably heat shrink film (shrink film)) wound around the side (preferably a container whose inside is visible) ; The pharmaceutical preparation according to any one of [1] to [14].
  • An aqueous composition containing the compound represented by the general formula (1) or a salt thereof or a solvate thereof is made of one or more resins selected from the group consisting of polyolefin resins and polyester resins.
  • a method for improving the thermal stability of the compound represented by the general formula (1) or a salt thereof, or a solvate thereof in an aqueous composition which comprises a step of containing in a transparent container of “Method of improving stability” means a method of suppressing a decrease in clarity when stored at a high temperature. For example, as compared with a case where the same aqueous composition is contained in a glass container.
  • Clarity test 1 The presence or absence of clearness of the aqueous composition containing netarsudil after storage at high temperature (presence of cloudiness) was evaluated by measuring the transmittance of light at a wavelength of 500 nm of the aqueous composition and also visually evaluated. . That is, an aqueous composition having a formulation shown in Table 1 was prepared by a conventional method. In addition, the aqueous composition was clear at the time of preparation, and cloudiness etc. were not confirmed by observation with the naked eye. Then, it put into the transparent container made from the following polypropylene (PP), and was set as the pharmaceutical formulation of Example 1.
  • PP polypropylene
  • aqueous composition was placed in the following glass transparent container to obtain a pharmaceutical preparation of Comparative Example 1.
  • Each obtained pharmaceutical preparation was stored at 80 ° C. for 1 week.
  • the aqueous composition was taken out from each transparent container, and then, using a spectrophotometer (U-3900: Hitachi High-Technologies), 500 nm The transmittance of light having a wavelength of was measured.
  • the presence or absence of cloudiness of the aqueous composition in each pharmaceutical preparation was evaluated according to the following evaluation criteria by observation with the naked eye from the outside of the transparent container. ⁇ Evaluation criteria> ⁇ : The aqueous composition is clear, and even when foreign matter is mixed, it is clearly visible.
  • X White turbidity is generated in the aqueous composition, and it is difficult to visually recognize foreign matters.
  • ⁇ Transparent container made of polypropylene (PP)> A container for eye drops made of polypropylene was used. The container was almost transparent in appearance except for the cap part, and the inside of the container was observable with the naked eye (for example, the transmittance of light in the visible light region (400 to 750 nm) was 70% at all wavelengths. And the average was 80.9%).
  • a spectrophotometer U-3900: Hitachi High-Technologies
  • ⁇ Transparent glass container> A glass container was used. The container was almost transparent in appearance except for the cap part, and the inside of the container was observable with the naked eye (for example, the transmittance of light in the visible light region (400 to 750 nm) was 70% at all wavelengths. The average was 75.1%.)
  • permeability of the light with respect to a container was measured by the method similar to the transparent container made from a polypropylene. The results are shown in Table 2.
  • Clarity test 4 In order to confirm the degree of suppression of the decrease in clarity when the material of the transparent container is changed, the following test was performed. That is, after preparing the aqueous composition of the prescription shown in Table 3 by a conventional method, it puts into the transparent container made from the following low density polyethylene (LDPE), or the transparent container made from a polyethylene terephthalate (PET), and each Example 4 5 pharmaceutical preparations. Each obtained pharmaceutical preparation was tested in the same manner as in Test Example 1.
  • LDPE low density polyethylene
  • PET polyethylene terephthalate
  • LDPE low density polyethylene
  • a container for eye drops made of low density polyethylene was used.
  • the container was almost transparent except for the cap part, and the inside of the container was observable with the naked eye (for example, the transmittance of light in the visible light region (400 to 750 nm) was 30% at all wavelengths. And the average was 52.0%).
  • the light transmittance was measured by the same method as the transparent container made of polypropylene described in Test Example 1.
  • PET polyethylene terephthalate
  • a container for eye drops made of polyethylene terephthalate was used.
  • the container was almost transparent except for the cap part, and the inside of the container was observable with the naked eye (for example, the transmittance of light in the visible light region (400 to 750 nm) was 75% at all wavelengths. And the average was 80.5%.)
  • the light transmittance was measured by the same method as the transparent container made of polypropylene described in Test Example 1.
  • an aqueous composition containing the compound represented by the general formula (1) represented by Netersudil or a salt thereof or a solvate thereof was converted into polypropylene or low-density polyethylene.
  • a transparent container made of a polyolefin resin represented by a polyester resin transparent container represented by a representative polyolefin resin and polyethylene terephthalate By housing in a transparent container made of a polyolefin resin represented by a polyester resin transparent container represented by a representative polyolefin resin and polyethylene terephthalate, a decrease in clarity when stored under high temperature conditions is relatively low, It was confirmed that contamination could be confirmed by observation with the naked eye from the outside of the container even if foreign matter was mixed.
  • the concentration of netarsudil in the aqueous composition before and after exposure was measured.
  • the concentration of netersudil in the aqueous composition was calculated by measuring the ratio of the peak area in the aqueous composition to the peak area of the netarsudil solution having a known concentration using HPLC. And from the density
  • Residual rate (%) [(concentration of netarsudil in aqueous composition after exposure) / (concentration of netarsudil in aqueous composition before exposure)] ⁇ 100
  • Test Example 7 Light stability test 2 About the decrease in content due to exposure of netasil in the aqueous composition confirmed in Test Example 6, the wavelength of the light beam causing the loss was irradiated with light having a wavelength in a specific range, and the presence or absence of the decrease in content due to exposure was evaluated. It was confirmed by doing. That is, the aqueous composition of the prescription shown in Table 9 was prepared, and this was accommodated in the glass transparent container, and the pharmaceutical formulation was obtained.
  • spectral unit HSU-100S, light source: MAX-302FBD, all of which is Asahi Spectroscopy Co., Ltd.
  • an optical filter approximately 270 to 335 nm, 320 to 395 nm, 380 to 410 nm, 430
  • the irradiation energy was set to about 200 W ⁇ h / m 2 for light of any wavelength.
  • Test Example 8 Light stability test 3 Based on the results obtained in Test Example 7, an attempt was made to stabilize the aqueous composition containing netersil by containing it in a transparent container containing an ultraviolet absorber. That is, the aqueous composition of the prescription shown in Table 9 was prepared, and this was accommodated in the transparent container for eye drops made of polypropylene containing the following ultraviolet absorber, to obtain a pharmaceutical preparation.
  • the photostability test apparatus LT-120A: Nagano Science Co., Ltd.
  • the obtained pharmaceutical preparation was irradiated with 4000 lux of light at a temperature of 25 ° C. with a D65 fluorescent lamp as a light source and an integrated irradiation dose of 1,200,000. Irradiation was performed for 300 hours so as to be lux ⁇ hr.
  • ⁇ Transparent container made of polypropylene containing UV absorber> A polypropylene eye drop container containing a benzotriazole UV absorber was used.
  • the average value of the light transmittance of the container is 18.6% at 320 to 380 nm (note that the average is 18.2% at 300 to 380 nm; the average is 21.5% at 270 to 380 nm; the average is 23.3% at 320 to 395 nm. 7%; average from 300 to 395 nm, 22.3%; average from 270 to 395 nm, 24.3%).
  • the container was almost transparent in appearance, and the inside of the container was observable with the naked eye (for example, the transmittance of light in the visible light region (400 to 750 nm) exceeded 60% at all wavelengths, The average was 80.5%.)
  • the light transmittance was measured by using a spectrophotometer (U-3900: Hitachi High-Technologies), cutting the container into a plate-like piece, and setting it on the optical path so that the light was incident substantially perpendicularly. In addition, it measured every 5 nm.
  • the average value of the light transmittance was calculated as the average value of the light transmittance for each 5 nm within a predetermined wavelength range.
  • a graph showing the relationship between the wavelength of light and the transmittance (%) in the range of 270 nm to 800 nm in the container is shown in FIG.
  • test results (results of Test Example 6) using polypropylene eye drop containers containing no ultraviolet absorber (average value of transmittance of light of 320 to 380 nm: 68.4%) and Display side by side.
  • the content of netersil in the aqueous composition was obtained by placing the aqueous composition containing netarsudil in a transparent container having an average value of light transmittance at 320 to 380 nm of 18.6%. It was revealed that the decrease was remarkably suppressed and the photostability was improved.
  • Test Example 9 Light stability test 4 Similar to Test Example 8, an attempt was made to stabilize the aqueous composition containing netersil by containing it in a polypropylene container containing an ultraviolet scattering agent. That is, the test was carried out in the same manner as in Test Example 8, except that a transparent container made of polypropylene having a shrink film containing the following UV scattering agent was used instead of the transparent container made of polypropylene containing the UV absorber. Carried out.
  • a white shrink film heat-shrink film
  • titanium oxide as an ultraviolet scattering agent.
  • those wound in accordance with a conventional method were used.
  • the average value of the light transmittance of the shrink film containing titanium oxide is 0% at 320 to 380 nm (300 to 380 nm, 270 to 380 nm, 320 to 395 nm, 300 to 395 nm, and 270 to 395 nm are all average 0) %)Met.
  • the shrink film Since the shrink film is not transparent, the contents were not visible from the side of the container. For this reason, a slit having a width of about 5 mm was provided in the lower half of the side surface of the container so that the inside of the container could be observed with the naked eye (in this portion, the light beam could not be blocked). In addition, since the shrink film is not wrapped around the bottom of the container, the inside of the container can be observed with the naked eye from the bottom (transmission of light rays in the visible light region (400 to 750 nm) at the slit and bottom).
  • FIG. 2 is a graph showing the relationship between the wavelength of light on the side surface of the container (portion where the shrink film is wound) and the transmittance (%) in the range of 270 nm to 800 nm.
  • the aqueous composition containing netarsudil is contained in a transparent container made of polypropylene having an average value of light transmittance at 320 to 380 nm of 0%. It was revealed that the decrease in content was almost completely suppressed and the photostability was further improved.
  • the aqueous composition containing the compound represented by the general formula (1) represented by Netersudil or a salt thereof, or a solvate thereof blocks light having a wavelength of 320 to 380 nm. It was confirmed that the photostability of the compound represented by the general formula (1) in the aqueous composition was improved by accommodating it in a polyolefin resin container.
  • Production Examples 37 to 72 In Production Examples 1 to 36, the pharmaceutical preparations of Production Examples 37 to 72 can be produced using transparent containers for eye drops made of high density polyethylene instead of low density polyethylene.
  • Production Examples 73 to 108 In Production Examples 1-36, the pharmaceutical preparations of Production Examples 73-108 can be produced using transparent containers for eye drops made of polypropylene instead of low density polyethylene.
  • Production Examples 109 to 144 In Production Examples 1 to 36, the pharmaceutical preparations of Production Examples 109 to 144 can be produced using transparent containers for eye drops made of polyethylene terephthalate instead of low density polyethylene.
  • Production Examples 145 to 288 In Production Examples 1 to 144, 0.5 g of velosil monohydrochloride as a free form can be produced in the usual manner as the pharmaceutical preparations of Production Examples 145 to 288 instead of Netersudil dimesylate.
  • Production Examples 289 to 432 In Production Examples 1 to 144, 0.7 g of velosidyl monohydrochloride as a free form can be produced in the usual manner as the pharmaceutical preparations of Production Examples 289 to 432 instead of Netersudil dimesylate.
  • Production Examples 433 to 576 In Production Examples 1 to 144, 0.02 g of the compound represented by the formula (8) can be produced in the usual manner as the pharmaceutical preparations of Production Examples 433 to 576 instead of Netersudil dimesylate. .
  • a pharmaceutical preparation excellent in stability can be provided and can be suitably used in the pharmaceutical industry and the like.

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  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Mechanical Engineering (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Ceramic Engineering (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une préparation pharmaceutique qui contient une composition aqueuse contenant un dérivé d'isoquinoléine-6-amine tel que le nétarsudil ou le vérosudil, mais qui est, néanmoins, stable même à température élevée. Cette préparation pharmaceutique est obtenue en introduisant, dans un récipient transparent constitué d'au moins une résine choisie dans le groupe constitué des résines polyoléfine et des résines polyester, une composition aqueuse contenant un composé représenté par la formule générale (1) (dans la formule, R1 et R2 représentent chacun indépendamment un atome d'hydrogène ou un groupe alkyle en C1-C4, R3 représente un atome d'hydrogène ou un groupe hydroxy, A représente -CH(R4)- ou -CH2-CH(R4)- (où R4 représente un groupe aryle en C6-C10 éventuellement substitué ou un groupe hétéroaryle à 5 à 10 chaînons éventuellement substitué), et dans la formule (1), un tautomère du composé est également inclus) ou un sel de celui-ci, ou un solvate de celui-ci.
PCT/JP2018/007584 2018-02-28 2018-02-28 Préparation pharmaceutique WO2019167183A1 (fr)

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PCT/JP2018/007584 WO2019167183A1 (fr) 2018-02-28 2018-02-28 Préparation pharmaceutique
JP2020503175A JP7165185B2 (ja) 2018-02-28 2018-02-28 医薬品製剤
JP2022166447A JP7464675B2 (ja) 2018-02-28 2022-10-17 医薬品製剤（２）

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JP7464675B2 (ja) 2024-04-09
JP2022186821A (ja) 2022-12-15
JP7165185B2 (ja) 2022-11-02

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