WO2014050301A1 - Médicament liquide aqueux - Google Patents

Médicament liquide aqueux Download PDF

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Publication number
WO2014050301A1
WO2014050301A1 PCT/JP2013/070765 JP2013070765W WO2014050301A1 WO 2014050301 A1 WO2014050301 A1 WO 2014050301A1 JP 2013070765 W JP2013070765 W JP 2013070765W WO 2014050301 A1 WO2014050301 A1 WO 2014050301A1
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WO
WIPO (PCT)
Prior art keywords
aqueous liquid
liquid preparation
viscosity
castor oil
hydrogenated castor
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PCT/JP2013/070765
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English (en)
Japanese (ja)
Inventor
律子 中村
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千寿製薬株式会社
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Application filed by 千寿製薬株式会社 filed Critical 千寿製薬株式会社
Priority to JP2014538250A priority Critical patent/JP6353365B2/ja
Priority to CN201380049935.2A priority patent/CN104661682B/zh
Publication of WO2014050301A1 publication Critical patent/WO2014050301A1/fr
Priority to HK15111329.2A priority patent/HK1210589A1/xx

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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
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61P27/04—Artificial tears; Irrigation solutions

Definitions

  • the present invention relates to an aqueous liquid agent that can suppress a decrease in viscosity over time while containing hypromellose and / or hydroxyethyl cellulose.
  • Patent Document 2 discloses that by using a polyhydric alcohol such as mannitol, glycerin, or polyvinyl alcohol, it is possible to prevent a decrease in viscosity over time of an aqueous liquid preparation containing a cellulose-based viscous agent.
  • Patent Document 3 discloses that by using a specific vegetable oil such as sesame oil, the viscosity of an aqueous liquid preparation containing a cellulose-based viscous agent and a nonionic surfactant can be stabilized.
  • nonionic surfactants have been a factor in reducing the viscosity of aqueous liquid preparations containing cellulosic viscosity agents (see paragraph 0005 of Patent Document 3).
  • the non-ionic surfactant is considered to promote the decrease in viscosity over time rather than suppressing the decrease in viscosity over time of the aqueous liquid preparation containing hypromellose and / or hydroxyethyl cellulose.
  • JP 2007-16024 A Japanese Patent Laid-Open No. 11-71478 JP 2005-206598 A
  • An object of the present invention is to provide a preparation technique capable of suppressing a decrease in viscosity over time in an aqueous liquid preparation containing hypromellose and / or hydroxyethyl cellulose.
  • the present inventor conducted intensive studies to solve the above problems, and obtained the following knowledge. That is, in the prior art, a nonionic surfactant was considered to promote a decrease in viscosity over time of an aqueous liquid preparation containing a cellulose-based viscous agent, but a polyionic surfactant was selected from among nonionic surfactants. It has been found that an aqueous liquid preparation in which oxyethylene hydrogenated castor oil and / or polyoxyl stearate is selected and these predetermined amounts are combined with hypromellose and / or hydroxyethyl cellulose can effectively suppress a decrease in viscosity over time. . The present invention has been completed by further studies based on this finding.
  • Item 1 (A) at least one cellulose-based viscosity agent selected from the group consisting of hypromellose and hydroxyethyl cellulose; and (B) at least one non-ion selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyl stearate.
  • Item 2. Item 2. The aqueous liquid preparation according to Item 1, wherein the polyoxyethylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil 60.
  • Item 3. Item 3. The aqueous liquid preparation according to Item 1 or 2, wherein the polyoxyl stearate is polyoxyl 40 stearate.
  • Item 4. Item 4.
  • Item 8. The aqueous solution according to any one of Items 1 to 7, further comprising (C) at least one selected from the group consisting of panthenol, tetrahydrozoline, pyridoxine, pranoprofen, and pharmaceutically acceptable salts thereof. .
  • Item 9. Item 9. The aqueous liquid preparation according to any one of Items 1 to 8, further comprising (D) a terpenoid.
  • Item 10. Item 10. The aqueous liquid preparation according to any one of Items 1 to 9, which is an eye drop.
  • Item 11. Item 11. The aqueous liquid preparation according to any one of Items 1 to 10, wherein the kinematic viscosity at 20 ° C.
  • aqueous liquid preparation In the aqueous liquid preparation, (A) at least one cellulose-based viscous agent selected from the group consisting of hypromellose and hydroxyethyl cellulose; and (B) at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyl stearate. A method for suppressing a decrease in the viscosity of an aqueous liquid preparation containing the cellulose-based viscosity agent, which coexists with a nonionic surfactant. Item 13.
  • An aqueous liquid preparation comprising at least one cellulose-based viscous agent selected from the group consisting of hypromellose and hydroxyethyl cellulose, wherein the active ingredient is at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyl stearate Viscosity reduction inhibitor.
  • the active ingredient is at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyl stearate Viscosity reduction inhibitor.
  • Item 15 At least one selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyl stearate for suppressing a decrease in viscosity with respect to an a
  • polyoxyethylene hydrogenated castor oil and polyoxyl stearate for the manufacture of a viscosity reduction inhibitor for an aqueous liquid comprising at least one cellulosic viscosity selected from the group consisting of hypromellose and hydroxyethylcellulose. At least one use.
  • Item 16 Polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate used for inhibiting a decrease in viscosity of an aqueous solution containing at least one cellulose-based viscous agent selected from the group consisting of hypromellose and hydroxyethyl cellulose.
  • the aqueous liquid preparation of the present invention contains hypromellose and / or hydroxyethyl cellulose, it can suppress a decrease in viscosity over time, so that it improves the feeling of use, maintains a moist feeling and a refreshing feeling, improves the retention of drugs, has a medicinal effect.
  • the effects imparted by these cellulosic viscosity agents, such as enhancement of the viscosity, can be maintained for a long time.
  • the aqueous liquid preparation of the present invention can be adjusted to a viscosity close to tears by setting the concentration of hypromellose and / or hydroxyethyl cellulose within a predetermined range. Therefore, when using the aqueous liquid preparation of the present invention as an eye drop, it is possible to eliminate the uncomfortable feeling at the time of eye drop, and further, the function of tears (for example, retention of wetness of keratoconjunctiva, prevention of drying, And the like as a lubricating oil between the eyelid and the eyeball in eye movement), and these functions can be maintained for a long time.
  • Aqueous Solution The aqueous solution of the present invention comprises (A) at least one cellulose-based viscosity agent selected from the group consisting of hypromellose and hydroxyethyl cellulose, and (B) a group consisting of polyoxyethylene hydrogenated castor oil and polyoxyl stearate. It contains at least one selected.
  • a cellulose-based viscosity agent selected from the group consisting of hypromellose and hydroxyethyl cellulose
  • B a group consisting of polyoxyethylene hydrogenated castor oil and polyoxyl stearate. It contains at least one selected.
  • the aqueous liquid preparation is a preparation containing water as a base and exhibiting a liquid state.
  • the unit of concentration “w / v%” of each component indicates a mass-to-volume percentage in the 16th revised Japanese Pharmacopoeia and is synonymous with g / 100 mL.
  • the suppression of the decrease in viscosity over time refers to the time-lapse as compared with an aqueous solution containing hypromellose and / or hydroxyethyl cellulose and not containing polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate. It shows that the decrease in kinematic viscosity is improved.
  • the aqueous liquid preparation of the present invention contains hypromellose and / or hydroxyethyl cellulose (hereinafter also referred to as component (A)) as a cellulose-based viscosity agent.
  • component (A) either hypromellose or hydroxyethyl cellulose may be used alone, or a combination thereof may be used.
  • hypromellose is preferable.
  • substitution degree type of hypromellose used as the component (A) is not particularly limited, and may be any of 1828, 2208, 2906, and 2910, preferably a substitution degree type of 2906.
  • molecular weight of hypromellose used in the present invention is not particularly limited, and examples thereof include a weight average molecular weight of 10,000 to 500,000, preferably 100,000 to 500,000, and more preferably 300,000 to 500,000. .
  • the molar substitution degree of hydroxyethoxy groups of hydroxyethyl cellulose used as component (A) is not particularly limited.
  • the degree of molar substitution of the hydroxyethoxy group may be, for example, about 1.5 to 3.0, preferably 2.5.
  • the molecular weight of hydroxyethyl cellulose used in the present invention is not particularly limited. Examples of the molecular weight include a weight average molecular weight of 10,000 to 1,000,000, preferably 100,000 to 1,000,000, and more preferably 600,000 to 800,000.
  • the concentration of the component (A) in the aqueous liquid preparation of the present invention may be in a range where a desired viscosity can be imparted to the aqueous liquid preparation.
  • the total amount of component (A) is 0.01 to 2 w / v%, preferably 0.02 to 0.5 w / v%, more preferably 0.05 to 0.2 w / v%, and most preferably 0. 1 w / v%.
  • the aqueous liquid preparation of the present invention contains polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate (hereinafter also referred to as component (B)) in addition to the component (A).
  • component (B) polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate
  • the average added mole number of ethylene oxide of the polyoxyethylene hydrogenated castor oil used as the component (B) is not particularly limited as long as it is within a pharmaceutically acceptable range.
  • Specific examples of the polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, and the like.
  • polyoxyethylene hydrogenated castor oils polyoxyethylene hydrogenated castor oil 60 is preferably used from the viewpoint of more effectively suppressing a decrease in viscosity over time.
  • these polyoxyethylene hydrogenated castor oils may be used singly or in combination of two or more.
  • the average added mole number of ethylene oxide is not particularly limited and may be within a pharmaceutically acceptable range.
  • examples of polyoxyl stearate include polyoxyl stearate 40, polyoxyl stearate 45, polyoxyl stearate 55, and the like.
  • polyoxyl 40 stearate is preferably used from the viewpoint of more effectively suppressing the decrease in viscosity over time.
  • these polyoxyl stearates may be used alone or in combination of two or more.
  • polyoxyethylene hydrogenated castor oil or polyoxyl stearate may be used alone, or a combination thereof may be used.
  • the concentration of the component (B) in the aqueous liquid preparation of the present invention is, for example, 0.005 to 0.45 w / v%, preferably 0.01 to 0.4 w / v%, based on the total amount of the component (B). More preferred is 0.01 to 0.2 w / v%.
  • the viscosity reduction with time of the aqueous liquid preparation is more effective.
  • concentrations are preferably exemplified.
  • polyoxyethylene hydrogenated castor oil preferably 0.01 to 0.2 w / v%, more preferably 0.05 to 0.2 w / v%, still more preferably 0.1 to 0.2 w / v %.
  • polyoxyl stearate is used: preferably 0.01 to 0.4 w / v%, more preferably 0.05 to 0.4 w / v%, still more preferably 0.1 to 0.2 w / v%.
  • the aqueous liquid preparation of the present invention is optionally at least one selected from the group consisting of panthenol, tetrahydrozoline, pyridoxine, pranoprofen, and pharmaceutically acceptable salts thereof (hereinafter referred to as (C ) May be described as a component).
  • component (C ) By containing the component (C) in the aqueous liquid preparation of the present invention, the effect of suppressing the decrease in viscosity over time can be further enhanced, and a more stable aqueous liquid preparation can be obtained.
  • the pharmaceutically acceptable salt used as the component (C) may be any one according to the type of the compound forming the salt.
  • specific examples of the pharmaceutically acceptable salt of tetrahydrozoline include inorganic acid salts such as hydrochloride and nitrate.
  • Specific examples of the pharmaceutically acceptable salt of pyridoxine include inorganic acid salts such as hydrochloride and phosphate.
  • Specific examples of pharmaceutically acceptable salts of pranoprofen include metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt, and aluminum salt; triethylamine salt, diethylamine salt, morpholine salt, piperazine salt, and the like. And organic base salts thereof.
  • components (C) may be used alone or in combination of two or more. From the viewpoint of further improving the enhancing effect of the effect of suppressing the decrease in viscosity over time, when polyoxyethylene hydrogenated castor oil is included as component (B), pyridoxine and / or its pharmaceuticals as component (C) The salts that are acceptable are preferred. In addition, when polyoxyl stearate is included as component (B), pyridoxine and / or a pharmaceutically acceptable salt thereof is preferable as component (C).
  • the concentration thereof is not particularly limited, and is appropriately set according to the type of the component (C) to be used.
  • the total amount of component (C) is 0.001 to 1 w / v%, preferably 0.01 to 0.2 w / v%. More specifically, the following concentrations are preferably exemplified for each type of component (C) from the viewpoint of effectively exerting an enhancing effect of the effect of suppressing the decrease in viscosity over time.
  • panthenol preferably 0.001 to 1 w / v%, more preferably 0.005 to 0.5 w / v%, still more preferably 0.01 to 0.2 w / v%.
  • tetrahydrozoline and / or a pharmaceutically acceptable salt thereof is used: preferably 0.001 to 1 w / v%, more preferably 0.005 to 0.5 w / v%, still more preferably 0.01 to 0 .1 w / v%.
  • pyridoxine and / or a pharmaceutically acceptable salt thereof is used: preferably 0.001 to 1 w / v%, more preferably 0.005 to 0.5 w / v%, still more preferably 0.01 to 0 .2w / v%.
  • pranoprofen and / or a pharmaceutically acceptable salt thereof preferably 0.001-1 w / v%, more preferably 0.005-0.5 w / v%, still more preferably 0.01 ⁇ 0.1 w / v%.
  • the aqueous liquid preparation of the present invention may contain a terpenoid (hereinafter also referred to as the component (D)) for the purpose of imparting a refreshing feeling, if necessary, in addition to the components described above.
  • a terpenoid hereinafter also referred to as the component (D)
  • the retention property of the terpenoid on the mucous membrane is improved by the action of hypromellose and / or hydroxyethylcellulose contained in the aqueous liquid preparation of the present invention, so that an aqueous liquid preparation that continuously exhibits a refreshing feeling is provided. Can do.
  • terpenoids used as component (D) include monoterpenes such as menthol, menthone, camphor, borneol, geraniol, cineol, limonene, eugenol, citral, pinene, linalool, fentil alcohol, and terpinene. It is done. Among these, preferably menthol, menthone, camphor, and more preferably menthol. These terpenoids may be used individually by 1 type, and may be used in combination of 2 or more type. In addition, these terpenoids do not necessarily have to be in a purified state, and essential oils containing these terpenoids may be used. Examples of essential oils containing menthol include peppermint oil, spearmint oil, peppermint oil, and the like.
  • the concentration thereof is not particularly limited and is appropriately set according to the type of the component (D) to be used, the degree of refreshing feeling to be imparted, and the like.
  • 0.0001 to 0.1 w / v%, preferably 0.0001 to 0.05 w / v% can be mentioned.
  • the aqueous liquid preparation of the present invention contains hypromellose and / or hydroxyethyl cellulose and polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate, so that a decrease in viscosity over time is suppressed.
  • the aqueous liquid preferably contains substantially no polysorbate 80, more preferably contains substantially no polysorbate, (B) It is particularly preferred that substantially no nonionic surfactant other than the components is contained.
  • each of the nonionic surfactants is substantially not included means that the effect of suppressing the decrease in viscosity over time in the aqueous liquid preparation of the present invention is within a range that is not impaired.
  • the concentration of each nonionic surfactant is less than 0.0001 w / v%, preferably 0 w / v%.
  • the aqueous liquid preparation of the present invention preferably contains substantially no oil agent.
  • the oil agent causes stickiness at the time of instillation in an eye drop, a factor of lens contamination in an eye drop for contact lenses, and the like, and it is possible to prevent these problems by substantially not containing the oil agent.
  • the oil agent is a component composed of vegetable oil, animal oil, and / or mineral oil, triglyceryl ester of fatty acid and glycerin (that is, triglyceride), aliphatic hydrocarbon, fatty acid, monoalkyl ester of fatty acid, higher grade.
  • the main component is at least one of non-volatile hydrophobic substances such as alcohol. Therefore, the oil does not include essential oil that is volatile.
  • the phrase “substantially not containing an oil agent” specifically means that the oil agent concentration is less than 0.00001 w / v%, preferably 0 w / v%.
  • the aqueous liquid preparation of the present invention can contain a pharmacological component in addition to the above components as long as the effects of the present invention are not impaired.
  • pharmacological ingredients that can be incorporated include dipotassium glycyrrhizinate, allantoin, epsilon aminocaproic acid, bromfenac, ketorolac tromethamine, nepafenac, berberine chloride, berberine sulfate, sodium azulenesulfonate, zinc sulfate, zinc lactate, lysozyme hydrochloride Anti-histamines such as chlorpheniramine maleate and diphenhydramine hydrochloride; antiallergic agents such as cromoglycate sodium, ketotifen fumarate, acitazanolast, amlexanox, pemirolast potassium, tranilast, ibudilast; , Ofloxacin, lomefloxacin, levoflox
  • the aqueous liquid preparation of the present invention contains a buffering agent, an isotonic agent, a solubilizing agent, a viscous base, a chelating agent, a pH adjusting agent, a preservative, a stabilizer, a nonionic surfactant as necessary. You may contain additives, such as surfactant other than.
  • buffer examples include phosphate buffer, borate buffer, citrate buffer, tartaric acid buffer, acetate buffer, Tris buffer, amino acid, and the like.
  • isotonic agent examples include saccharides such as sorbitol, glucose and mannitol; polyhydric alcohols such as glycerin and propylene glycol; salts such as sodium chloride; boric acid and the like.
  • solubilizers examples include polyhydric alcohols such as glycerin and macrogol.
  • viscous base examples include water-soluble polymers such as polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, and carboxyvinyl polymer.
  • chelating agents examples include sodium edetate and citric acid.
  • Examples of the pH adjuster include alkalis such as sodium hydroxide and potassium hydroxide; acids such as acetic acid, citric acid, hydrochloric acid, phosphoric acid and tartaric acid.
  • preservatives include sorbic acid, potassium sorbate, sodium benzoate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, chlorohexidine gluconate, boric acid, dehydroacetic acid, dehydro
  • examples thereof include sodium acetate, benzethonium chloride, benzyl alcohol, zinc chloride, parachlormetaxylenol, chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal and the like.
  • the stabilizer examples include polyvinylpyrrolidone, sodium sulfite, monoethanolamine, glycerin, propylene glycol, cyclodextrin, dextran, ascorbic acid, sodium edetate, taurine, tocopherol and the like.
  • surfactants other than nonionic surfactants include amphoteric surfactants such as alkyldiaminoethylglycine and lauryldimethylaminoacetic acid betaine; alkyl sulfates, N-acyl taurine salts, polyoxyethylene alkyl ether phosphates Anionic surfactants such as salts and polyoxyethylene alkyl ether sulfates; and cationic surfactants such as alkylpyridinium salts and alkylamine salts.
  • the kinematic viscosity of the aqueous liquid preparation of the present invention is appropriately set according to the use of the aqueous liquid preparation.
  • the kinematic viscosity at 20 ° C. is 1.1 to 50.0 mm 2 / s, preferably 1.1. To 35.0 mm 2 / s, more preferably 1.2 to 28 mm 2 / s.
  • the aqueous liquid preparation of the present invention when used as an ophthalmic preparation, it preferably has a viscosity comparable to that of tears.
  • the kinematic viscosity at 20 ° C. is preferably 1.1. ⁇ 3.0 mm 2 / s, more preferably 1.5 to 2.5 mm 2 / s.
  • the kinematic viscosity at 20 ° C. is measured in accordance with “General Test Method 2.53 Viscosity Test Method 1. First Method Capillary Viscometer Method” stipulated in the 16th revision Japanese Pharmacy using an Ubbelohde viscometer. The value to be measured. Moreover, according to the viscosity range to be measured, the inner diameter of the capillary of the Ubbelohde viscometer used and the sphere B used are as shown in Table 1 in the column of Examples.
  • the pH of the aqueous liquid preparation of the present invention is not particularly limited, and examples thereof include 5.5 to 8.0, preferably 6.5 to 7.5.
  • the preparation form of the aqueous liquid preparation of the present invention is not particularly limited and may be any of aqueous solution, suspension, emulsion, etc., preferably an aqueous solution.
  • the aqueous liquid preparation of the present invention comprises ophthalmic preparations such as eye drops (including eye drops for soft contact lenses) and eyewashes; otolaryngological preparations such as nasal drops and ear drops; contact lens mounting liquids and contact lenses It can be used as a contact lens care product such as a multi-purpose solution.
  • An eye drop for a soft contact lens is an eye drop that can be applied even while wearing a soft contact lens. Among these, an ophthalmic preparation is preferable, and an eye drop is more preferable.
  • aqueous liquid preparation of the present invention may be produced according to a method known per se according to its use, for example, using the method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations.
  • Viscosity reduction inhibiting method and viscosity reduction inhibiting agent In the aqueous liquid preparation , (A) hypromellose and / or hydroxyethyl cellulose and (B) polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate coexist. A method for suppressing a decrease in viscosity of an aqueous liquid preparation containing the component A) is also provided. In this method, the type of component (A), the type of component (B), the types of other components that can be blended, the concentration thereof, the type of aqueous liquid, and the like are as described in “1. Aqueous liquid”. It is.
  • the present invention further provides a viscosity reduction inhibitor for an aqueous solution containing hypromellose and / or hydroxyethyl cellulose, comprising polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate as an active ingredient.
  • the said viscosity fall inhibitor is used as an additive mix
  • the viscosity reduction inhibitor includes panthenol, tetrahydrozoline, pyridoxine, pranoprofen, and pharmaceutically acceptable products thereof, as necessary. It may contain at least one selected from the group consisting of salts. By containing these components, it is possible to further enhance the viscosity reduction inhibitory effect of the viscosity reduction inhibitor. The types and amounts used of these components are also as described in “1. Aqueous solution”.
  • the aqueous liquid agent to be applied and the types and concentrations of hypromellose and / or hydroxyethyl cellulose contained therein are also as described in “1. Aqueous liquid agent”.
  • hypromellose is trade name “METOLOSE 65SH-4000” (substitution degree type 2906, weight average molecular weight 350,000, manufactured by Shin-Etsu Chemical Co., Ltd.), and hydroxyethyl cellulose is trade name “NATROSOL 250M PHARM”.
  • hydroxypropyl cellulose is trade name “HPC-H” (manufactured by Nippon Soda Co., Ltd.)
  • carmellose sodium is trade name “Serogen PR-S Nichipo” (Daiichi Kogyo Seiyaku) Co., Ltd.)
  • Alginic acid is trade name "Alginic acid” (Kimika Co., Ltd.)
  • Xanthan gum is trade name "Echo Gum T” (DSP Gokyo Food & Chemical Co., Ltd.)
  • Polyoxyethylene hydrogenated castor oil 60 is trade name " NIKKOL HCO-60 ”(manufactured by Nikko Chemicals Co., Ltd.) and polyoxyl 40 stearate are trade names“ NIKKOL MYS-40V ”(Nikko Chemicals Co., Ltd.) )
  • Polysorbate 80 is the trade name “Polysorbate 80" (manufactured by NOF Corporation), polyoxy
  • Test Example 1 Effect of Nonionic Surfactant on Viscosity of Aqueous Solution Containing Cellulosic Viscosity Agents shown in Table 2 were mixed by a conventional method and sterilized by filtration using a 0.22 ⁇ m membrane filter. Thus, each aqueous liquid preparation was prepared. After measuring the kinematic viscosity of each aqueous solution immediately after preparation, 15 mL of each aqueous solution was filled in a 15 mL polyethylene terephthalate container, sealed, and stored at 50 ° C. for 2 weeks under light-shielding conditions. The kinematic viscosity was measured for each aqueous liquid after storage, and the kinematic viscosity retention rate (%) was calculated according to the following formula.
  • the kinematic viscosities of each aqueous liquid preparation are set in the “General Test” defined in the 16th revision Japanese Pharmacy using a Ubbelohde viscometer (manufactured by Mutual Riken Glass Co., Ltd.) at a measurement temperature of 20 ° C.
  • Table 2 shows the results obtained. From this result, the aqueous liquid agent (Example 1) in which hypromellose and polyoxyethylene hydrogenated castor oil 60 coexist and the aqueous liquid agent (Example 2) in which hypromellose and polyoxyl 40 stearate coexist contain hypromellose. Compared with the aqueous liquid agent (Comparative Example 1) which does not contain an ionic surfactant, the viscosity reduction after storage at 50 ° C. for 2 weeks could be suppressed.
  • aqueous solution (Comparative Example 2-4) in which polysorbate 80, polyglyceryl polyoxyethylene oleate or polyethylene glycol monooleate coexisted with hypromellose is stored at 50 ° C. for 2 weeks, compared with the aqueous solution of Comparative Example 1. Later viscosity drop was greater.
  • Test Example 2 Effect of Nonionic Surfactant on Viscosity of Aqueous Solution Containing Various Viscos Agents
  • Each component shown in Tables 3 and 4 is mixed by a conventional method and filtered using a 0.22 ⁇ m membrane filter.
  • Each aqueous solution was prepared by sterilization, and the kinematic viscosity immediately after preparation, kinematic viscosity after storage for 2 weeks at 50 ° C., and kinematic viscosity retention rate were determined for each aqueous solution in the same manner as in Test Example 1 above. .
  • Test Example 3 Effect of concentration of nonionic surfactant on viscosity of aqueous liquid containing cellulose-based viscosity agent Each component shown in Tables 5 and 6 was mixed by a conventional method, and a 0.22 ⁇ m membrane filter was prepared. Each aqueous solution is prepared by sterilizing by filtration and using the same method as in Test Example 1 above, kinematic viscosity immediately after preparation, kinematic viscosity after storage at 50 ° C. for 2 weeks, and kinematic viscosity retention rate for each aqueous solution Asked.
  • Test Example 4 Effect of Cellulose Viscosity Concentration on Viscosity of Aqueous Solution Containing Cellulose Viscosity Agent and Nonionic Surfactant
  • Each component shown in Tables 7 and 8 was mixed by a conventional method.
  • Each aqueous solution was prepared by sterilizing by filtration using a 22 ⁇ m membrane filter, and kinematic viscosity immediately after preparation for each aqueous solution in the same manner as in Test Example 1 above, kinematic viscosity after storage at 50 ° C. for 2 weeks, The kinematic viscosity retention was determined.
  • Test Example 5 Effect of oil on viscosity of aqueous liquid containing cellulosic viscosity agent and nonionic surfactant Each component shown in Table 9 was mixed by a conventional method, and sterilized by filtration using a 0.22 ⁇ m membrane filter. Thus, each aqueous solution was prepared, and the kinematic viscosity immediately after preparation, the kinematic viscosity after storage for 2 weeks at 50 ° C., and the kinematic viscosity retention rate were determined for each aqueous solution in the same manner as in Test Example 1 above.
  • Table 9 shows the obtained results. From this result, when polysorbate 80 was added to an aqueous solution containing hypromellose, the kinematic viscosity after storage for 2 weeks at 50 ° C. decreased (Comparative Example 2), but the decrease in kinematic viscosity was suppressed by further addition of castor oil. (Reference Example 14). On the other hand, even when castor oil was further added to an aqueous solution containing hypromellose and polyoxyethylene hydrogenated castor oil 60, the effect of suppressing the decrease in kinematic viscosity was not observed (Example 32). The same was true when polyoxyethylene hydrogenated castor oil 60 was replaced with polyoxyl 40 stearate (Example 33).
  • Test Example 6 Influence of panthenol, tetrahydrozoline hydrochloride, pyridoxine hydrochloride, and pranoprofen on the viscosity reduction inhibitory effect
  • Each component shown in Table 10 was mixed by a conventional method and filtered using a 0.22 ⁇ m membrane filter.
  • Each aqueous solution was prepared by sterilization, and the kinematic viscosity immediately after preparation, kinematic viscosity after storage for 2 weeks at 50 ° C., and kinematic viscosity retention rate were determined for each aqueous solution in the same manner as in Test Example 1 above. .
  • Table 10 shows the obtained results. From this result, in an aqueous liquid preparation containing hypromellose and polyoxyethylene hydrogenated castor oil 60 or polyoxyl 40 stearate, when panthenol, tetrahydrozoline hydrochloride, pyridoxine hydrochloride, or pranoprofen is further blended, It was clarified that the effect of suppressing the decrease in kinematic viscosity after weekly storage was enhanced.
  • panthenol when panthenol is added to an aqueous solution containing hypromellose and polyoxyl 40 stearate, and when pyridoxine hydrochloride is added to an aqueous solution containing hypromellose and polyoxyethylene hydrogenated castor oil 60 or polyoxyl 40 stearate. It was also confirmed that the effect of suppressing the decrease in kinematic viscosity after storage at 50 ° C. for 2 weeks was remarkably enhanced. On the other hand, in the aqueous liquid preparation containing hypromellose and polyoxyethylene hydrogenated castor oil 60 or polyoxyl 40 stearate, the addition of several pharmacological components other than the above does not affect the effect of suppressing the decrease in kinematic viscosity.
  • the enhancement effect of the kinematic viscosity reduction inhibitory action shown in this test example is peculiar by selecting panthenol, tetrahydrozoline hydrochloride, pyridoxine hydrochloride, and / or pranoprofen as a pharmacological component to be added. It was confirmed that this was the effect.

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Abstract

La présente invention a pour but de proposer une technologie de formulation avec laquelle il est possible de prévenir une réduction au cours du temps de la viscosité cinématique d'un médicament liquide aqueux contenant de l'hypromellose et/ou de l'hydroxyéthyl cellulose. Il est possible de prévenir la réduction au cours du temps de la viscosité d'un médicament liquide aqueux mélangé par la combinaison d'hypromellose et/ou d'hydroxyéthyl cellulose et d'huile de ricin hydrogénée polyoxyéthylénée et/ou de polyoxyl stéarate.
PCT/JP2013/070765 2012-09-27 2013-07-31 Médicament liquide aqueux WO2014050301A1 (fr)

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JP6267394B1 (ja) * 2017-09-07 2018-01-24 参天製薬株式会社 水溶性粘稠化剤を含有する医薬組成物
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JP2019006756A (ja) * 2017-06-23 2019-01-17 参天製薬株式会社 水溶性粘稠化剤を含有する医薬組成物
JP2019174830A (ja) * 2019-06-04 2019-10-10 ロート製薬株式会社 ソフトコンタクトレンズ用組成物
JP2020147557A (ja) * 2019-03-08 2020-09-17 ロート製薬株式会社 刺激感が抑制された眼科組成物

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WO2018235935A1 (fr) * 2017-06-23 2018-12-27 参天製薬株式会社 Composition pharmaceutique comprenant un épaississant hydrosoluble
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JP2019174830A (ja) * 2019-06-04 2019-10-10 ロート製薬株式会社 ソフトコンタクトレンズ用組成物

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