HK1210589A1

HK1210589A1 - Aqueous liquid medicine

Info

Publication number: HK1210589A1
Application number: HK15111329.2A
Authority: HK
Inventors: 中村律子
Original assignee: 千寿制药株式会社
Priority date: 2012-09-27
Filing date: 2013-07-31
Publication date: 2016-04-29
Also published as: JP6538920B2; TWI605836B; JP6832390B2; TW201818922A; JP2018111730A; JPWO2014050301A1; JP6353365B2; JP2019142979A; CN104661682A; CN104661682B; WO2014050301A1; TW201412343A

Abstract

The purpose of the present invention is to provide formulation technology with which it is possible to prevent a reduction over time in the kinematic viscosity of an aqueous liquid medicine containing hypromellose and/or hydroxyethyl cellulose. It is possible to prevent a reduction over time in the viscosity of an aqueous liquid medicine compounded by combining hypromellose and/or hydroxyethyl cellulose and polyoxyethylene-hydrogenated castor oil and/or polyoxyl stearate.

Description

Aqueous liquid formulation

Technical Field

The present invention relates to an aqueous liquid formulation containing hypromellose and/or hydroxyethyl cellulose and capable of suppressing a decrease in viscosity with time.

Background

Conventionally, it has been known that various aqueous liquids containing a cellulose-based viscous agent are put into practical use today, in order to improve the feeling of use, maintain the moist feeling and cool feeling, improve the retention of a drug, enhance the drug effect, and the like by adding a cellulose-based viscous agent to an aqueous liquid such as an eye drop or a nose drop to impart viscosity (see patent document 1).

However, when a cellulose-based viscosity agent such as hypromellose or hydroxyethyl cellulose is added to an aqueous liquid formulation, there is a problem that viscosity stability is low and viscosity of the liquid formulation is lowered with time. Such a decrease in viscosity impairs the feeling of use or prevents the desired drug effect from being exhibited, and therefore, it is important to suppress the decrease in viscosity with time in the formulation and quality assurance of such an aqueous liquid preparation (particularly, an eye drop) containing a cellulose-based viscous agent. In particular, in the case of eye drops, the viscosity is set to be about the same as that of tear fluid, thereby imparting retention of wettability of the cornea, prevention of dryness, action as lubricant between the eyelid and the eyeball during movement of the eyeball, or the like, or adjusting to eliminate discomfort at the time of eye drop. Therefore, if the viscosity of the eye drops is lowered, these functions are weakened, and therefore, it is particularly important to improve the viscosity stability of the eye drops.

Conventionally, there have been reported techniques for preparing an aqueous liquid preparation containing a cellulose-based viscous agent such as hypromellose or hydroxyethyl cellulose, which suppresses a decrease in viscosity with time. For example, patent document 2 discloses that the use of a polyhydric alcohol such as mannitol, glycerol, or polyvinyl alcohol can prevent the viscosity of an aqueous solution containing a cellulose-based viscosity agent from decreasing with time. Patent document 3 discloses that the viscosity of an aqueous liquid containing a cellulose-based viscosity agent and a nonionic surfactant can be stabilized by using a specific vegetable oil such as sesame oil.

However, in recent years, the development of a formulation in the field of eye drops, nasal drops, and the like is not exhaustive, and in the formulation techniques of patent documents 2 and 3, due to restrictions on formulation design, the formulation cannot be applied to a formulation developed in recent years in some cases. Therefore, it is required to establish a new formulation technique for suppressing the decrease in viscosity of an aqueous liquid formulation containing hypromellose and/or hydroxyethyl cellulose.

On the other hand, conventionally, it has been reported that a nonionic surfactant causes a decrease in viscosity of an aqueous liquid containing a cellulose-based viscous agent (see paragraph 0005 and the like of patent document 3), and according to the prior art, a nonionic surfactant is considered to contribute to a decrease in viscosity with time rather than to a suppression of a decrease in viscosity with time of an aqueous liquid containing hypromellose and/or hydroxyethyl cellulose, which is the present situation.

Documents of the prior art

Patent document

Patent document 1: japanese laid-open patent publication No. 2007-16024

Patent document 2: japanese laid-open patent publication No. 11-71478

Patent document 3: japanese patent laid-open publication No. 2005-206598

Disclosure of Invention

Problems to be solved by the invention

The purpose of the present invention is to provide a formulation technique capable of suppressing a decrease in viscosity with time in an aqueous liquid formulation containing hypromellose and/or hydroxyethyl cellulose.

Means for solving the problems

The present inventors have conducted intensive studies to solve the above problems, and as a result, have obtained the following findings. That is, although it is considered that the nonionic surfactant contributes to the reduction in viscosity of the aqueous liquid formulation containing the cellulose-based viscosity agent with time in the prior art, the aqueous liquid formulation can be obtained by selecting polyoxyethylene hydrogenated castor oil and/or polyoxyl stearate among the nonionic surfactants and combining a predetermined amount of these with hypromellose and/or hydroxyethyl cellulose. The present invention has been completed by further repeated studies based on such findings.

That is, the present invention provides the following embodiments.

An aqueous liquid formulation comprising: (A) at least 1 cellulose-based viscosity agent selected from hypromellose and hydroxyethyl cellulose, and (B) at least 1 nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyl stearate.

Item 2. the aqueous liquid formulation of item 1, wherein the polyoxyethylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil 60.

Item 3 the aqueous liquid formulation of item 1 or 2, wherein the polyoxyl stearate is polyoxyl stearate 40.

The aqueous liquid according to any one of items 1 to 3, wherein the component (A) is contained at a concentration of 0.01 to 2 w/v%.

The aqueous liquid preparation according to any one of items 1 to 4, wherein the polyoxyethylene hydrogenated castor oil is contained at a concentration of 0.01 to 0.2 w/v%.

The aqueous liquid preparation according to any one of claims 1 to 4, wherein the polyoxyl stearate is contained at a concentration of 0.01 to 0.4 w/v%.

The aqueous liquid preparation according to any one of claims 1 to 6, wherein the aqueous liquid preparation substantially contains no nonionic surfactant other than polyoxyethylene hydrogenated castor oil and polyoxyl stearate.

The aqueous liquid preparation according to any one of claims 1 to 7, further comprising (C) at least 1 selected from the group consisting of panthenol, tetrahydrozoline, pyridoxine, pranoprofen, and pharmaceutically acceptable salts thereof.

The aqueous liquid according to any one of claims 1 to 8, further comprising a terpenoid (D).

The aqueous liquid according to any one of claims 1 to 9, which is an eye drop.

The aqueous liquid according to any one of items 1 to 10, wherein the kinematic viscosity at 20 ℃ measured with an Ubbelohde viscometer is 1.1 to 50.0mm²/s。

Item 12 is a method for suppressing a decrease in viscosity of the aqueous liquid formulation containing a cellulose-based viscosity agent, wherein (a) at least 1 cellulose-based viscosity agent selected from hypromellose and hydroxyethyl cellulose and (B) at least 1 nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyl stearate are allowed to coexist in the aqueous liquid formulation.

Item 13. a viscosity-lowering inhibitor for an aqueous liquid formulation containing a cellulose-based viscosity-imparting agent selected from at least 1 of hypromellose and hydroxyethyl cellulose, wherein the aqueous liquid formulation contains at least 1 selected from polyoxyethylene hydrogenated castor oil and polyoxyl stearate as an active ingredient.

Item 14. use of at least 1 selected from polyoxyethylene hydrogenated castor oil and polyoxyl stearate for suppressing a decrease in viscosity of an aqueous liquid formulation containing a cellulose-based viscosity agent selected from at least 1 selected from hypromellose and hydroxyethyl cellulose.

Item 15 use of at least 1 selected from polyoxyethylene hydrogenated castor oil and polyoxyl stearate in the manufacture of a viscosity reduction inhibitor for an aqueous liquor containing a cellulosic viscosity agent selected from at least 1 of hypromellose and hydroxyethyl cellulose.

Item 16. polyoxyethylene hydrogenated castor oil and/or polyoxyl stearate used for suppressing the decrease in viscosity of an aqueous liquid formulation containing a cellulose-based viscosity agent selected from at least 1 of hypromellose and hydroxyethyl cellulose.

ADVANTAGEOUS EFFECTS OF INVENTION

The aqueous liquid formulation of the present invention contains hypromellose and/or hydroxyethyl cellulose, and can suppress a decrease in viscosity with time, and therefore, can maintain the effects imparted by these cellulose-based viscous agents, such as an improvement in feeling of use, a continuation of moist feeling or refreshing feeling, an improvement in retention of a drug, and an enhancement in drug efficacy, for a long period of time.

The aqueous liquid formulation of the present invention can be adjusted to a viscosity close to that of tear fluid by setting the concentration of hypromellose and/or hydroxyethyl cellulose within a predetermined range. Therefore, when the aqueous liquid preparation of the present invention is used as an eye drop, it is possible to eliminate discomfort at the time of eye drop, and further, to provide functions (for example, retention of wettability of the keratoconjunctiva, prevention of dryness, function as a lubricant between the eyelid and the eyeball during movement of the eyeball) borne by tears, and to maintain these functions for a long period of time.

Detailed Description

1. Aqueous liquid formulation

The aqueous liquid formulation of the present invention is characterized by containing (A) at least 1 cellulose-based viscous agent selected from hypromellose and hydroxyethyl cellulose, and (B) at least 1 cellulose-based viscous agent selected from polyoxyethylene hydrogenated castor oil and polyoxyl stearate. The aqueous liquid of the present invention will be described in detail below.

In the present invention, the aqueous liquid is a liquid preparation containing water as a base. In the present specification, the unit "w/v%" of the concentration of each component represents the mass-to-volume percentage in the sixteenth revised japanese pharmacopoeia, and has the same meaning as g/100 mL.

In the present invention, the suppression of the decrease in viscosity with time means that the decrease in kinematic viscosity with time is improved as compared with an aqueous solution containing hypromellose and/or hydroxyethyl cellulose and not containing polyoxyethylene hydrogenated castor oil and/or polyoxyl stearate.

The aqueous liquid formulation of the present invention contains hypromellose and/or hydroxyethyl cellulose (hereinafter, sometimes referred to as component (a)) as a cellulose-based viscous agent. In the aqueous liquid formulation of the present invention, as the component (a), either hypromellose or hydroxyethyl cellulose may be used alone, or a combination thereof may be used. (A) Among the components, hypromellose is preferably used.

The substitution degree of hypromellose used as component (a) is not particularly limited, and may be any of 1828, 2208, 2906, and 2910, and preferably 2906. The molecular weight of hypromellose used in the present invention is not particularly limited, and for example, the weight average molecular weight is 1 ten thousand to 50 ten thousand, preferably 10 ten thousand to 50 ten thousand, and more preferably 30 ten thousand to 50 ten thousand.

The molar substitution degree of the hydroxyethoxy group (the average number of moles of hydroxyethoxy groups added per unit of anhydrous glucose) of the hydroxyethylcellulose used as component (a) is not particularly limited. The molar substitution degree of the hydroxyethoxy group may be, for example, about 1.5 to 3.0, and preferably 2.5. The molecular weight of the hydroxyethyl cellulose used in the present invention is also not particularly limited. The molecular weight is, for example, 1 to 100 ten thousand, preferably 10 to 100 ten thousand, and more preferably 60 to 80 ten thousand.

The concentration of the component (a) in the aqueous liquid of the present invention may be in a range that can impart a desired viscosity to the aqueous liquid. For example, the amount of the 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 formulation of the present invention contains polyoxyethylene hydrogenated castor oil and/or polyoxyl stearate (hereinafter, sometimes referred to as component (B)) in addition to component (a). In this way, by allowing hypromellose and/or hydroxyethyl cellulose to coexist with polyoxyethylene hydrogenated castor oil and/or polyoxyl stearate, the viscosity stability of the aqueous liquid formulation can be improved, and the viscosity decrease with time can be suppressed.

The polyoxyethylene hydrogenated castor oil used as the component (B) is not particularly limited as long as it has an average addition mole number of ethylene oxide groups within a pharmaceutically acceptable range. Specific examples of the polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60. Among these polyoxyethylene hydrogenated castor oils, polyoxyethylene hydrogenated castor oil 60 is preferred from the viewpoint of more effectively suppressing the decrease in viscosity with time. In the aqueous liquid of the present invention, these polyoxyethylene hydrogenated castor oils may be used alone in 1 kind, or may be used in combination in 2 or more kinds.

In addition, the average molar number of addition of the oxyethylene group of the polyoxyalkoxy stearate used as the component (B) is not particularly limited as long as it is within a pharmaceutically acceptable range. Examples of the polyoxyl stearate include polyoxyl stearate 40, polyoxyl stearate 45, and polyoxyl stearate 55. Among these polyoxy stearate esters, polyoxy stearate 40 is preferred from the viewpoint of more effectively suppressing the decrease in viscosity with time. In the aqueous liquid of the present invention, these polyoxyl stearate may be used alone in 1 kind, or may be used in combination in 2 or more kinds.

The aqueous liquid of the present invention may be used alone or in combination as component (B) in one of polyoxyethylene hydrogenated castor oil and polyoxyl stearate.

The concentration of the component (B) in the aqueous liquid formulation of the present invention is, for example, 0.005 to 0.45 w/v%, preferably 0.01 to 0.4 w/v%, and more preferably 0.01 to 0.2 w/v% based on the total amount of the component (B).

In the aqueous liquid of the present invention, when any one of polyoxyethylene hydrogenated castor oil and polyoxyl stearate is used as the component (B), the following concentrations are preferably exemplified from the viewpoint of more effectively suppressing the decrease in viscosity of the aqueous liquid with time.

When polyoxyethylene hydrogenated castor oil is used: preferably 0.01 to 0.2 w/v%, more preferably 0.05 to 0.2 w/v%, and still more preferably 0.1 to 0.2 w/v%.

When polyoxyl stearate is used: preferably 0.01 to 0.4 w/v%, more preferably 0.05 to 0.4 w/v%, and still more preferably 0.1 to 0.2 w/v%.

The aqueous liquid of the present invention may contain, if necessary, at least 1 selected from the group consisting of panthenol, tetrahydrozoline, pyridoxine, pranoprofen, and pharmaceutically acceptable salts thereof (hereinafter, also referred to as component (C)). By containing the component (C) in the aqueous liquid of the present invention, the effect of suppressing the viscosity reduction with time can be further enhanced, and a more stable aqueous liquid can be obtained.

The pharmaceutically acceptable salt used as component (C) may be any salt corresponding to the type of the compound forming the salt. For example, as the pharmaceutically acceptable salt of tetrahydrooxazoline, inorganic acid salts such as hydrochloride and nitrate are specifically mentioned. Specific examples of the pharmaceutically acceptable salt of pyridoxine include inorganic acid salts such as hydrochloride and phosphate. Examples of the pharmaceutically acceptable salt of pranoprofen include metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt, and aluminum salt; and organic base salts such as triethylamine salt, diethylamine salt, morpholine salt, and piperazine salt.

These (C) components can be used alone in 1 kind, in addition to the combination of 2 or more. When polyoxyethylene hydrogenated castor oil is contained as component (B), pyridoxine and/or a pharmaceutically acceptable salt thereof is preferred as component (C) from the viewpoint of further improving the enhancing effect of the effect of suppressing the viscosity decrease with time. When the component (B) contains polyoxyl stearate, the component (C) is preferably pyridoxine and/or a pharmaceutically acceptable salt thereof.

When the aqueous liquid of the present invention contains the component (C), the concentration thereof is not particularly limited, and is appropriately set according to the type of the component (C) to be used. For example, the amount of the component (C) is 0.001 to 1 w/v%, preferably 0.01 to 0.2 w/v%. More specifically, from the viewpoint of effectively exerting the enhancing action of the effect of suppressing the viscosity reduction with time, the following concentrations are suitable for each type of the component (C).

When panthenol is used: preferably 0.001 to 1 w/v%, more preferably 0.005 to 0.5 w/v%, and still more preferably 0.01 to 0.2 w/v%.

When 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%, and still more preferably 0.01 to 0.1 w/v%.

When 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%, and still more preferably 0.01 to 0.2 w/v%.

When pranoprofen 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%, and still more preferably 0.01 to 0.1 w/v%.

The aqueous liquid of the present invention may contain terpenoids (hereinafter, sometimes referred to as component (D)) in addition to the above components, as necessary for the purpose of providing a cool feeling or the like. When a terpenoid is contained, the retention of the terpenoid on mucous membranes is improved by the action of hypromellose and/or hydroxyethyl cellulose contained in the aqueous liquid formulation of the present invention, and thus an aqueous liquid formulation which can continuously exert a refreshing feeling can be provided.

Specific examples of the terpenoids used as component (D) include monoterpenes such as menthol, menthone, camphor, borneol, citronellol, eucalyptol, limonene, eugenol, citral, pinene, linalool, anisyl alcohol, and terpinene. Of these, menthol, menthone and camphor are preferred, and menthol is more preferred. These terpenoids may be used alone in 1 kind, or in combination of 2 or more kinds. These terpenoids may not necessarily be in a purified state, and essential oils containing these terpenoids may also be used. Examples of the menthol-containing essential oil include peppermint oil, spearmint oil, and peppermint oil.

When the aqueous liquid of the present invention contains the component (D), the concentration thereof is not particularly limited, and is appropriately set according to the type of the component (D) used, the degree of the refreshing feeling to be imparted, and the like. For example, the concentration is 0.0001 to 0.1 w/v%, preferably 0.0001 to 0.05 w/v%.

The aqueous liquid formulation of the present invention contains hypromellose and/or hydroxyethyl cellulose, and polyoxyethylene hydrogenated castor oil and/or polyoxyl stearate, thereby suppressing a decrease in viscosity with time. In order to more effectively exhibit such a viscosity reduction-suppressing effect, it is preferable that the aqueous liquid formulation contains substantially no polysorbate 80, more preferably substantially no polysorbate, and particularly preferably substantially no nonionic surfactant other than the component (B). The term "substantially not containing each nonionic surfactant" means a range in which the effect of suppressing the decrease in viscosity with time is not impaired in the aqueous liquid formulation of the present invention, and specifically, the concentration of each nonionic surfactant is less than 0.0001 w/v%, preferably 0 w/v%.

Furthermore, the aqueous liquor of the present invention is preferably substantially free of oil agents. Since the oil agent causes stickiness of the eye drops at the time of eye dropping, causes contamination of lenses of the eye drops for contact lenses, and the like, these problems can be prevented by substantially containing no oil. Here, the oil agent is a component containing vegetable oil, animal oil and/or mineral oil, and contains at least 1 of nonvolatile hydrophobic substances such as triglycerides (i.e., triglycerides) of fatty acids and glycerol, aliphatic hydrocarbons, fatty acids, monoalkyl esters of fatty acids, and higher alcohols as a main component. Therefore, the oil agent does not contain volatile essential oil. The oil-containing composition is substantially free of oil agents, and specifically, the concentration of the oil agent is less than 0.00001 w/v%, preferably 0 w/v%.

The aqueous liquid of the present invention may contain a pharmacological component in addition to the above components as long as the effect of the present invention is not impaired. Examples of the pharmacologically acceptable components that can be blended include anti-inflammatory agents such as dipotassium glycyrrhizinate, allantoin, -aminocaproic acid, bromfenac, ketorolac tromethamine, nepafenac, berberine chloride, berberine sulfate, sodium azulene sulfonate, zinc sulfate, zinc lactate, and lysozyme hydrochloride; antihistamines such as chlorpyrifos maleate salt and diphenhydramine hydrochloride; antiallergic agents such as cromolyn sodium, ketotifen fumarate, azakast (Acitazanolast), Amlexanox (Amlexanox), Pemirolast potassium (Pemirolast potassium), Tranilast (Tranilast), Ibudilast (Ibudilast), and the like; antibacterial agents such as norfloxacin, ofloxacin, lomefloxacin, levofloxacin, gentamicin, gatifloxacin, etc.; vitamins such as ascorbic acid, flavin adenine dinucleotide sodium, cyanocobalamin, tocopherol acetate, retinol palmitate, calcium pantothenate, and sodium pantothenate; anticholinesterase agents such as amino acids including aspartic acid, taurine and sodium chondroitin sulfate, and neostigmine methylsulfate; vasoconstrictors such as naphazoline, epinephrine, ephedrine, phenylephrine, dl-methylephedrine, etc.; therapeutic agents for keratoconjunctival epithelial disorders such as sodium hyaluronate; sulfadiazine such as sulfadiazine, sulfisoxazole, sulfamethazine, sulfamethoxypyridazine, sulfamethoxazole, sulfamethazole, sulfamethoxydiazine, sulfamtopyrazole, sulfaguanidine, phthalylsulfathiazole, succinylsulfathiazole, etc. The compounds exemplified herein may be in the form of a salt or in the form of another salt to the extent that they are pharmaceutically acceptable.

The aqueous liquid of the present invention may contain additives such as a buffer, an isotonic agent, a solubilizing agent, a viscous base, a chelating agent, a pH adjuster, a preservative, a stabilizer, and a surfactant other than a nonionic surfactant, if necessary.

Examples of the buffer include a phosphate buffer, a borate buffer, a citrate buffer, a tartrate buffer, an acetate buffer, a Tris buffer, and an amino acid.

Examples of the isotonic agent include sugars such as sorbitol, glucose, and mannitol; polyhydric alcohols such as glycerin and propylene glycol; salts such as sodium chloride; boric acid, and the like.

Examples of the cosolvent include polyhydric alcohols such as glycerin and polyethylene glycol.

Examples of the viscous matrix include water-soluble polymers such as polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, and carboxyvinyl polymer.

Examples of the chelating agent include disodium ethylenediaminetetraacetate and citric acid.

Examples of the pH adjuster include bases such as sodium hydroxide and potassium hydroxide; acetic acid, citric acid, hydrochloric acid, phosphoric acid, tartaric acid, etc.

Examples of the preservative include sorbic acid, potassium sorbate, sodium benzoate, methyl paraben, ethyl paraben, propyl paraben, chlorobutanol, chlorhexidine gluconate, boric acid, dehydroacetic acid, sodium dehydroacetate, tolyloxyethylamine chloride, benzyl alcohol, zinc chloride, p-chloroxylenol, chlorocresol, phenethyl alcohol, polonium chloride, and thimerosal.

Examples of the stabilizer include polyvinylpyrrolidone, sodium sulfite, monoethanolamine, glycerol, propylene glycol, cyclodextrin, dextran, ascorbic acid, disodium ethylenediaminetetraacetate, taurine, and tocopherol.

Examples of the surfactant other than the nonionic surfactant include amphoteric surfactants such as alkyldiaminoethylglycine and lauryl dimethylaminoacetic acid betaine; anionic surfactants such as alkyl sulfates, N-acyl taurates, polyoxyethylene alkyl ether phosphates, and polyoxyethylene alkyl ether sulfates; and cationic surfactants such as alkylpyridinium salts and alkylamine salts.

The kinematic viscosity of the aqueous liquid of the present invention is appropriately set according to the use of the aqueous liquid, and for example, the kinematic viscosity at 20 ℃ is 1.1 to 50.0mm²A preferred range is 1.1 to 35.0mm²More preferably 1.2 to 28mm in terms of the total mass of the particles²And s. Particularly, when the aqueous liquid of the present invention is used as an ophthalmic preparation, it is preferable that the aqueous liquid has a viscosity of about the same level as that of lacrimal fluid, specifically, a kinematic viscosity at 20 ℃ is preferably 1.1 to 3.0mm²More preferably 1.5 to 2.5mm in terms of the total mass of the particles²And s. The kinematic viscosity at 20 ℃ is a value measured by using a Ubbelohde viscometer in accordance with "general test method 2.53 viscosity test method 1. method 1 capillary viscometer method" prescribed in the sixteenth revised Japanese pharmacopoeia. Further, from the measured viscosity range, the inner diameter of the capillary of the Ubbelohde viscometer to be used and the ball B to be used are as shown in Table 1 in the examples section.

The pH of the aqueous liquid of the present invention is not particularly limited, and examples thereof include 5.5 to 8.0, preferably 6.5 to 7.5.

The form of the aqueous liquid preparation of the present invention is not particularly limited, and may be any form such as an aqueous solution, a suspension, and an emulsion, and preferably an aqueous solution is exemplified.

The aqueous liquid of the present invention can be used as ophthalmic preparations such as eye drops (including eye drops for soft contact lenses) and eye washes; preparations for otorhinology such as nasal drops and ear drops; contact lens care products such as contact lens wearing solutions and multifunctional care solutions for contact lenses are used. The soft contact lens eye drops are eye drops which can be dropped even when the soft contact lens is worn. Among these, ophthalmic preparations are preferred, and eye drops are more preferred.

The aqueous liquid of the present invention may be produced according to a production method known per se depending on the use thereof, and for example, it can be produced by a method described in the sixteenth revised japanese pharmacopoeia general guidelines.

2. Method for suppressing viscosity reduction and viscosity reduction suppressor

The present invention also provides a method for suppressing a decrease in viscosity of an aqueous liquid formulation containing the component (a) described above, wherein the aqueous liquid formulation contains (a) hypromellose and/or hydroxyethyl cellulose and (B) polyoxyethylene hydrogenated castor oil and/or polyoxyl stearate in a co-presence manner. In this method, the types of the component (A), the component (B), other components that can be blended, their concentrations, and the type of the aqueous liquid are as described in the above-mentioned "1. aqueous liquid".

The present invention also provides a viscosity-lowering inhibitor for an aqueous liquid formulation containing hypromellose and/or hydroxyethyl cellulose, which contains polyoxyethylene hydrogenated castor oil and/or polyoxyl stearate as an active ingredient. The viscosity-lowering inhibitor is used as an additive to be added for the purpose of suppressing lowering of the viscosity of an aqueous liquid formulation containing hypromellose and/or hydroxyethyl cellulose with time. The kind and amount of polyoxyethylene hydrogenated castor oil and/or polyoxyl stearate as the active ingredient of the viscosity-lowering inhibitor are as described in the above "1. aqueous solution".

The viscosity-lowering inhibitor may further contain, as necessary, at least 1 selected from the group consisting of panthenol, tetrahydrozoline, pyridoxine, pranoprofen, and pharmaceutically acceptable salts thereof, in addition to the polyoxyethylene hydrogenated castor oil and/or polyoxyl stearate. By containing these components, the viscosity-lowering suppressing effect of the viscosity-lowering suppressor can be further enhanced. The types, amounts, and the like of these components are also as described in the above "1. aqueous liquid".

The viscosity-lowering inhibitor is also applicable to an aqueous liquid formulation, and the type, concentration, etc. of hypromellose and/or hydroxyethylcellulose contained therein, as described in the above "1. aqueous liquid formulation".

Examples

The present invention will be described in detail with reference to examples, but the present invention is not limited to these.

In the following examples and comparative examples, hypromellose is used under the trade name "METOLOSE 65 SH-4000" (substitution type 2906, weight average molecular weight 35 million available from shin-Etsu chemical Co., Ltd.), hydroxyethylcellulose is used under the trade name "NATROSOL 250 MPHARM" (weight average molecular weight 72 million available from Ashland Industries), hydroxypropylcellulose is used under the trade name "HPC-H" (available from Nippon Kao Co., Ltd.), carboxymethylcellulose sodium is used under the trade name "Serrogen PR-S Nissan" (available from first Industrial pharmaceutical Co., Ltd.), Alginic Acid is used under the trade name "Alginic Acid" (available from KIMICA Co., Ltd.), xanthan gum is used under the trade name "エコーガム T" (available from DSP GOKYO food & chemical Co., Ltd.), polyoxyethylene hydrogenated castor oil 60 is used under the trade name "KKNIOL HCO-60" (available from Nikko chemical Co., Ltd.), and polyoxyl stearate 40 is used under the trade name "NIKKOL HCO-40V" (available from Nikko chemical Co., Ltd.), polysorbate 80 is available under the trade name "Polysorbate 80" (manufactured by Nikko Chemicals), polyoxyethylene glyceryl oleate is available under the trade name "NIKKOL MAGO-15" (manufactured by Nikko Chemicals), and polyethylene glycol monooleate is available under the trade name "NIKKOL MYO-10V" (manufactured by Nikko Chemicals).

Test example 1: nonionic surfactant for aqueous liquid containing cellulose viscous agent Influence of viscosity of

Each aqueous solution was prepared by mixing the components shown in table 2 according to a conventional method and subjecting the mixture to filtration sterilization using a 0.22 μm membrane filter. After measuring the kinematic viscosity of each aqueous solution immediately after preparation, 15mL of each aqueous solution was filled in a container made of polyethylene terephthalate having a volume of 15mL and sealed, and stored at 50 ℃ for 2 weeks under a light-shielding condition. The kinematic viscosity of each aqueous liquid after storage was measured, and the kinematic viscosity retention (%) was calculated according to the following formula.

Kinematic viscosity retention (%)

{ (kinematic viscosity of aqueous liquid after storage at 50 ℃ for 2 weeks)/(kinematic viscosity of aqueous liquid immediately after preparation) } × 100

The kinematic viscosity of each aqueous liquid was measured by setting the measurement temperature at 20 ℃ and using a Ubbelohde viscometer (manufactured by Nippon Kagaku K.K.) according to "general test method 2.53 viscosity test method 1. method 1 capillary viscometer method" prescribed in the sixteenth revised Japanese pharmacopoeia. The kinematic viscosity was measured 2 times for each sample, and the average value thereof was taken as a measured value. In addition, in the measurement of the kinematic viscosity of each aqueous liquid, the ubberlohde viscometer and the ball B shown in table 1 were used for each viscosity measurement range.

[ Table 1]

The results obtained are shown in table 2. From the results, it is understood that in the aqueous liquid formulation in which hypromellose and polyoxyethylene hydrogenated castor oil 60 were coexistent (example 1) and the aqueous liquid formulation in which hypromellose and polyoxyl stearate 40 were coexistent (example 2), the viscosity was suppressed from decreasing after storage at 50 ℃ for 2 weeks, as compared with the aqueous liquid formulation containing hypromellose and containing no nonionic surfactant (comparative example 1). On the other hand, in the aqueous liquid formulation (comparative examples 2 to 4) in which polysorbate 80, polyoxyethylene glyceryl oleate or polyethylene glycol monooleate and hypromellose were coexistent, the viscosity decrease after storage at 50 ℃ for 2 weeks was large as compared with the aqueous liquid formulation of comparative example 1.

From the above results, it is understood that the decrease in viscosity of the aqueous liquid containing the cellulose-based viscosity agent with time can be suppressed by polyoxyethylene hydrogenated castor oil or polyoxyl stearate.

[ Table 2]

In the table, the unit of the concentration of each compounding ingredient is "w/v%".

The pH of each aqueous solution in the table was 7.

Test example 2: viscosity of nonionic surfactant to various aqueous solutions containing viscous agent Influence of degree

The components shown in tables 3 and 4 were mixed according to a conventional method, and each aqueous liquid was prepared by filtration sterilization using a 0.22 μm membrane filter, and the kinematic viscosity immediately after preparation, the kinematic viscosity after storage at 50 ℃ for 2 weeks, and the kinematic viscosity retention rate were determined for each aqueous liquid in the same manner as in test example 1.

The results obtained are shown in tables 3 and 4. From these results, it was confirmed that even in the case of an aqueous liquid formulation in which hydroxyethyl cellulose and polyoxyethylene hydrogenated castor oil 60 were allowed to coexist, a decrease in kinematic viscosity after storage at 50 ℃ for 2 weeks could be suppressed. On the other hand, as is clear from tables 3 and 4, in the aqueous liquid containing a cellulose-based viscous agent other than hypromellose and hydroxyethylcellulose, or alginic acid or xanthan gum, no decrease in kinematic viscosity was observed even when the liquid was stored at 50 ℃ for 2 weeks without adding a nonionic surfactant. That is, it was found that the decrease in the kinematic viscosity with time is a problem specific to an aqueous liquid containing hypromellose and/or hydroxyethyl cellulose among cellulose-based viscous agents.

[ Table 3]

The pH of each aqueous solution in the table was 7.

[ Table 4]

The pH of each aqueous solution in the table was 7.

Test example 3: concentration of nonionic surfactant to water containing cellulose-based viscosity agent Influence of viscosity of sex liquid

The components shown in tables 5 and 6 were mixed according to a conventional method, and each aqueous liquid was prepared by filtration sterilization using a 0.22 μm membrane filter, and the kinematic viscosity immediately after preparation, the kinematic viscosity after storage at 50 ℃ for 2 weeks, and the kinematic viscosity retention rate were determined for each aqueous liquid in the same manner as in test example 1.

The results obtained are shown in tables 5 and 6. From these results, it is found that by blending polyoxyethylene hydrogenated castor oil 60 in an aqueous solution containing hypromellose at a concentration of 0.01 to 0.2 w/v%, particularly 0.1 to 0.2 w/v%, the decrease in kinematic viscosity after storage at 50 ℃ for 2 weeks can be effectively suppressed. Further, by blending polyoxyl stearate 40 in an aqueous liquid containing hypromellose at a concentration of 0.01 to 0.4 w/v%, particularly 0.1 to 0.4 w/v%, the decrease in kinematic viscosity after storage at 50 ℃ for 2 weeks can be effectively suppressed. On the other hand, when polysorbate 80 is added to an aqueous solution containing hypromellose at a concentration of 0.05 to 0.5 w/v%, the decrease in kinematic viscosity after storage at 50 ℃ for 2 weeks cannot be suppressed.

[ Table 5]

The pH of each aqueous solution in the table was 7.

Test example 4: concentration of cellulose-based viscosity agent Effect of viscosity of aqueous solution of sexual surfactant

The components shown in tables 7 and 8 were mixed according to a conventional method, and each aqueous liquid was prepared by filtration sterilization using a 0.22 μm membrane filter, and the kinematic viscosity immediately after preparation, the kinematic viscosity after storage at 50 ℃ for 2 weeks, and the kinematic viscosity retention rate were determined for each aqueous liquid in the same manner as in test example 1.

The results obtained are shown in tables 7 and 8. From these results, it is clear that in an aqueous liquid formulation containing hypromellose but not containing a nonionic surfactant, the decrease in kinematic viscosity after storage at 50 ℃ for 2 weeks tends to be significant with an increase in the concentration of hypromellose (comparative examples 11 to 17), but when polyoxyethylene hydrogenated castor oil 60 or polyoxyl stearate 40 is added, the decrease in kinematic viscosity after storage at 50 ℃ for 2 weeks can be suppressed (examples 18 to 31). On the other hand, it was confirmed from the test results that polysorbate 80 could not suppress the decrease in kinematic viscosity of the hypromellose-containing aqueous liquid formulation after storage at 50 ℃ for 2 weeks (comparative examples 18 to 24).

Test example 5: oiling agent for water containing cellulose adhesive and nonionic surfactant Influence of viscosity of sex liquid

The components shown in Table 9 were mixed according to a conventional method, and each aqueous liquid was prepared by sterilizing the mixture by filtration using a 0.22 μm membrane filter, and the kinematic viscosity immediately after the preparation, the kinematic viscosity after storage at 50 ℃ for 2 weeks, and the kinematic viscosity retention rate were determined for each aqueous liquid in the same manner as in test example 1.

The results obtained are shown in table 9. From the results, it is understood that when polysorbate 80 was added to an aqueous solution containing hypromellose, the kinematic viscosity after storage at 50 ℃ for 2 weeks decreased (comparative example 2), but the decrease in kinematic viscosity was suppressed by further adding castor oil (reference example 14). On the other hand, when castor oil was further added to an aqueous solution containing hypromellose and polyoxyethylene hydrogenated castor oil 60, no effect of suppressing a decrease in kinematic viscosity was observed (example 32). The same applies to the replacement of polyoxyethylene hydrogenated castor oil 60 with polyoxyl stearate 40 (example 33).

[ Table 9]

The pH of each aqueous solution in the table was 7.

Test example 6: panthenol, tetrahydrozoline hydrochloride, pyridoxine hydrochloride and pranoprofen viscosity Reducing the influence of the inhibiting effect

The components shown in table 10 were mixed according to a conventional method, and each aqueous liquid was prepared by filtration sterilization using a 0.22 μm membrane filter, and the kinematic viscosity immediately after preparation, the kinematic viscosity after storage at 50 ℃ for 2 weeks, and the kinematic viscosity retention rate were determined for each aqueous liquid in the same manner as in test example 1.

The results obtained are shown in table 10. From these results, it is found that when panthenol, tetrahydrozoline hydrochloride, pyridoxine hydrochloride, or pranoprofen is further added to an aqueous liquid formulation containing hypromellose and polyoxyethylene hydrogenated castor oil 60 or polyoxyl stearate 40, the effect of inhibiting the decrease in kinematic viscosity after storage at 50 ℃ for 2 weeks is enhanced. In particular, when panthenol is added to an aqueous liquid formulation containing hypromellose and polyoxyl stearate 40, and when pyridoxine hydrochloride is added to an aqueous liquid formulation containing hypromellose and polyoxyethylene hydrogenated castor oil 60 or polyoxyl stearate 40, the effect of suppressing the decrease in kinematic viscosity after storage at 50 ℃ for 2 weeks is remarkably enhanced. On the other hand, when a plurality of pharmacological components other than those described above are added to an aqueous liquid containing hypromellose and polyoxyethylene hydrogenated castor oil 60 or polyoxyl stearate 40, the effect of suppressing the decrease in kinematic viscosity is not affected. That is, it was confirmed that the effect of enhancing the effect of inhibiting the decrease in kinematic viscosity shown in the test example is a specific effect of selecting panthenol, tetrahydrozoline hydrochloride, pyridoxine hydrochloride and/or pranoprofen as the pharmacological component to be further added.

Claims

1. An aqueous liquid formulation comprising:

(A) a cellulose-based viscosity agent selected from at least 1 of hypromellose and hydroxyethyl cellulose, and

(B) at least 1 nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyl stearate.

2. Aqueous liquor according to claim 1, characterized in that:

the polyoxyethylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil 60.

3. Aqueous liquor according to claim 1 or 2, characterized in that:

the polyoxyl stearate is polyoxyl stearate 40.

4. The aqueous liquid formulation according to any one of claims 1 to 3, wherein:

the component (A) is contained at a concentration of 0.01 to 2 w/v%.

5. The aqueous liquid formulation according to any one of claims 1 to 4, wherein:

the composition contains polyoxyethylene hydrogenated castor oil at a concentration of 0.01 to 0.2 w/v%.

6. The aqueous liquid formulation according to any one of claims 1 to 4, wherein:

contains polyoxyl stearate in a concentration of 0.01 to 0.4 w/v%.

7. The aqueous liquid formulation according to any one of claims 1 to 6, wherein:

substantially free of nonionic surfactants other than polyoxyethylene hydrogenated castor oil and polyoxyl stearate.

8. The aqueous liquid formulation according to any one of claims 1 to 7, wherein:

further comprises (C) at least 1 selected from the group consisting of panthenol, tetrahydrozoline, pyridoxine, pranoprofen, and pharmaceutically acceptable salts thereof.

9. The aqueous liquid formulation according to any one of claims 1 to 8, wherein:

further contains (D) terpenoids.

10. The aqueous liquid formulation according to any one of claims 1 to 9, wherein:

it is an eye drop.

11. The aqueous liquid formulation according to any one of claims 1 to 10, wherein:

a kinematic viscosity at 20 ℃ of 1.1 to 50.0mm as measured with a Ubbelohde-type viscometer²/s。

12. A method for suppressing a decrease in viscosity of an aqueous liquid containing a cellulose-based viscosity agent, comprising:

in the aqueous liquid formulation, (a) at least 1 cellulose-based viscous agent selected from hypromellose and hydroxyethyl cellulose is made to coexist with (B) at least 1 nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyl stearate.

13. A viscosity-lowering inhibitor for an aqueous liquid formulation containing a cellulose-based viscosity-imparting agent selected from at least 1 of hypromellose and hydroxyethyl cellulose, characterized in that:

the aqueous liquid agent contains at least 1 selected from polyoxyethylene hydrogenated castor oil and polyoxyl stearate as effective component.