TWI605836B - Aqueous liquid - Google Patents

Description

Aqueous liquid Field of invention

The present invention relates to an aqueous liquid preparation which, although containing hydroxypropylmethylcellulose (Hypromellose) and/or hydroxyethylcellulose, can suppress a decrease in temporal viscosity.

Background of the invention

Conventionally, in an aqueous liquid preparation such as an eye drop or a nasal drop, it is known that the viscosity is imparted by blending a cellulose-based adhesive, and the feeling of use, the moist feeling or the cooling feeling can be maintained. As a result of the improvement of the drug retention and the enhancement of the drug effect (refer to Patent Document 1), various aqueous liquid preparations in which a cellulose-based adhesive is blended have been put into practical use today.

However, when a cellulose-based viscous agent such as hydroxypropylmethylcellulose or hydroxyethylcellulose is blended in an aqueous liquid preparation, there is a problem that the viscosity stability is inferior and the viscosity of the liquid agent is lowered with time. . The formulation design or quality of the aqueous liquid preparation (especially eye drops) in which the cellulose-based adhesive is blended is such that the viscosity is lowered, or the feeling of use is impaired, or the desired effect is not exhibited. On the guarantee, it is important to suppress the decrease in the viscosity over time. In particular, eye drops are used to maintain the wettability of the keratoconjunctiva, prevent dryness, and act as an eyelid during eye movement by setting the viscosity to the same level as tears. The effect of the lubricating oil between the eyeballs, etc., or adjustment to the eye drops is not uncomfortable. If the viscosity of the eye drops is reduced, it will cause the weakening of these functions, so it is important to improve the viscosity stability of the eye drops.

Conventionally, in the presence of hydroxypropyl methylcellulose or hydroxyethyl fibers A formulation technique for inhibiting the decrease in viscosity over time in an aqueous liquid preparation such as a cellulose-based adhesive has been reported. For example, Patent Document 2 discloses that by using a polyol such as mannitol, glycerin or polyvinyl alcohol, it is possible to prevent the aqueous liquid preparation containing the cellulose-based adhesive from having a reduced viscosity over time. Further, Patent Document 3 discloses that the viscosity of the aqueous liquid preparation containing the cellulose-based adhesive and the nonionic surfactant can be stabilized by using a specific vegetable oil such as sesame oil.

However, in recent years, it has been in the field of eye drops or nasal drops. The development of the formulation of the agent is endless. The formulation techniques of Patent Documents 2 and 3 are not applicable to the formulation of the formulation developed in recent years due to the restriction of the formulation design. There is a need to establish a new formulation technique for inhibiting the viscosity reduction of aqueous liquid preparations containing hydroxypropylmethylcellulose and/or hydroxyethylcellulose.

On the other hand, it has been reported that nonionic surfactants have been reported. In order to reduce the viscosity of the aqueous liquid containing a cellulose-based adhesive (refer to paragraph [0005] of Patent Document 3), according to the prior art, the nonionic surfactant is not considered to inhibit the inclusion of hydroxypropyl groups. The time-dependent viscosity of the aqueous liquid preparation of methyl cellulose and/or hydroxyethyl cellulose is lowered, but the current state of the art is believed to contribute to the reduction of viscosity over time.

Advanced technical literature Patent literature

Patent Document 1: Japanese Laid-Open Patent Publication No. 2007-16024

Patent Document 2: Japanese Laid-Open Patent Publication No. Hei 11-71478

Patent Document 3: Japanese Laid-Open Patent Publication No. 2005-206598

Summary of invention

SUMMARY OF THE INVENTION An object of the present invention is to provide a formulation technique for inhibiting a decrease in viscosity over time in an aqueous liquid preparation containing hydroxypropylmethylcellulose and/or hydroxyethylcellulose.

The inventors of the present invention have carefully studied to solve the above problems, and have obtained the following findings. That is, the nonionic surfactant is not limited to the prior art and is believed to promote the decrease in the viscosity of the aqueous solution containing the cellulose-based adhesive, and the polyoxyethylene hydrogenated castor oil is selected from the nonionic surfactant. And/or polyoxyethylene stearate, and combining the predetermined amounts with hydroxypropylmethylcellulose and/or hydroxyethylcellulose, blended in an aqueous liquid, and found in the aqueous liquid The agent can effectively inhibit the decrease of the viscosity over time. The present invention is based on this finding and is accomplished by a more cautious discussion.

That is, the present invention provides the invention of the following aspects.

An aqueous liquid preparation comprising: at least one cellulose-based adhesive selected from the group consisting of (A) hydroxypropylmethylcellulose and hydroxyethylcellulose; B) Polyoxyethylene hydrogenated castor oil and polyoxyethylene stearic acid At least one nonionic surfactant of the group consisting of esters.

2. The aqueous liquid preparation according to item 1, wherein the polyoxyethylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil 60.

3. The aqueous liquid according to item 1 or 2, wherein the polyoxyethylene stearate is polyoxyethylene stearate 40.

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

5. The aqueous liquid according to any one of items 1 to 4, which comprises the polyoxyethylene hydrogenated castor oil at a concentration of 0.01 to 0.2 w/v%.

6. The aqueous liquid according to any one of items 1 to 4, which comprises the polyoxyethylene stearate at a concentration of 0.01 to 0.4 w/v%.

7. The aqueous liquid according to any one of items 1 to 6, which is substantially free of a nonionic surfactant other than polyoxyethylene hydrogenated castor oil and polyoxyethylene stearate.

8. The aqueous liquid according to any one of items 1 to 7, which further comprises a pharmaceutically acceptable one selected from the group consisting of (C) panthenol, tetrahydrozoline, pyridoxine, pranoprofen, and the like. At least one of the groups formed by the salt.

9. The aqueous liquid according to any one of items 1 to 8, which further comprises (D) terpenoid.

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

The aqueous liquid according to any one of items 1 to 10, which has an kinetic viscosity at 20 ° C of 1.1 to 50.0 mm ² /s as measured by an Ubbelohde viscometer.

A method for suppressing a decrease in viscosity of an aqueous liquid preparation, wherein the aqueous liquid preparation contains a cellulose-based adhesive, and the method is selected from the aqueous liquid preparation to be selected from the group consisting of At least one cellulose-based adhesive in the group consisting of (A) hydroxypropylmethylcellulose and hydroxyethylcellulose, and selected from (B) polyoxyethylene hydrogenated castor oil and poly At least one nonionic surfactant in the group consisting of oxyethylene stearate coexists.

A viscosity reducing inhibitor for inhibiting viscosity reduction of an aqueous liquid agent containing at least one cellulose-based adhesive selected from the group consisting of hydroxypropylmethylcellulose and hydroxyethylcellulose The viscosity reduction inhibitor is selected from at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyethylene stearate as an active ingredient.

14. Use of at least one compound selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyethylene stearate for use in a mixture selected from the group consisting of hydroxypropyl methylcellulose The aqueous liquid preparation of at least one cellulose-based adhesive agent in the group consisting of hydroxyethyl cellulose suppresses viscosity reduction.

15. The use of at least one compound selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyethylene stearate for use in the manufacture of a viscosity reducing inhibitor An aqueous liquid preparation of at least one cellulose-based adhesive agent in the group consisting of hydroxypropylmethylcellulose and hydroxyethylcellulose suppresses a decrease in viscosity.

A polyoxyethylene hydrogenated castor oil and a polyoxyethylene stearate for use in at least one fiber selected from the group consisting of hydroxypropylmethylcellulose and hydroxyethylcellulose The aqueous liquid agent of the viscous agent inhibits the viscosity reduction.

The aqueous liquid preparation of the invention contains hydroxypropyl methylcellulose and / or hydroxyethyl cellulose, can still inhibit the decrease in viscosity over time, so it can maintain the following effects imparted by the cellulose-based adhesive for a long time: the use of the feeling of improvement, the moist feeling or the cooling sensation, Increased drug retention and enhanced drug efficacy.

Further, the aqueous liquid preparation of the present invention, by using hydroxypropyl methyl fiber The concentration of the ketone and/or hydroxyethyl cellulose is set to a predetermined range and can be adjusted to a viscosity close to that of the tear. Therefore, when the aqueous liquid preparation of the present invention is used as an eye drop, the discomfort during eye drops can be eliminated, and the function of serving as a tear liquid can be further provided (for example, the retention of the wettability of the cornea and conjunctiva, the prevention of drying, and the eyeball) It acts as a lubricant between the eyelids and the eyeball during exercise, etc., and can maintain these functions for a long time.

Used to implement the type of invention

1. Aqueous liquid agent

The aqueous liquid preparation of the present invention is characterized in that it contains at least one cellulose-based adhesive selected from the group consisting of (A) hydroxypropylmethylcellulose and hydroxyethylcellulose, and is selected from the group consisting of (B) At least one selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyethylene stearate. Hereinafter, the aqueous liquid preparation of the present invention will be described in detail.

In the present invention, the aqueous liquid preparation system contains a preparation in which water is used as a base and which is in a liquid form. In addition, in the present specification, the "w/v%" of each component concentration unit indicates the mass-to-capacity percentage in the 16th edition of the Japanese Pharmacopoeia. Synonymous with g/100mL.

Further, in the present invention, the inhibition of the decrease in the viscosity with time is expressed as follows: compared with hydroxypropylmethylcellulose and/or hydroxyethylcellulose, and does not contain polyoxyethylene hydrogenated castor oil and/or The aqueous liquid preparation of polyoxyethylene stearate has been improved by the reduction of the dynamic viscosity over time.

The aqueous liquid preparation of the present invention contains hydroxypropyl methylcellulose and/or Hydroxyethyl cellulose (hereinafter also referred to as component (A)) is used as a cellulose-based adhesive. In the aqueous liquid preparation of the present invention, one of hydroxypropylmethylcellulose or hydroxyethylcellulose may be used alone as the component (A), or these may be used in combination. Among the components (A), hydroxypropylmethylcellulose is preferred.

About the use of hydroxypropyl methylcellulose as component (A) The type of generation is not particularly limited. Any one of 1828, 2208, 2906, and 2910 is acceptable, but it is preferable to use the type of substitution of 2906. Further, the molecular weight of the hydroxypropylmethylcellulose to be used in the present invention is not particularly limited. For example, the weight average molecular weight may be from 10,000 to 500,000, and from 100,000 to 500,000, preferably 300,000. 500,000 is better.

About hydroxyethyl oxyhydroxide used as the component (A) The molar substitution rate (the average number of moles added to the hydroxyethoxy group per unit of anhydroglucose) is not particularly limited. The molar substitution degree of the hydroxyethoxy group is, for example, about 1.5 to 3.0, but it is preferably 2.5. Further, the molecular weight of the hydroxyethyl cellulose used in the present invention is not particularly limited. The molecular weight is, for example, 10,000 to 1,000,000 as the average molecular weight, and preferably 100,000 to 1,000,000, and more preferably 600,000 to 800,000.

Further, as the concentration of the component (A) in the aqueous liquid preparation of the present invention, If the aqueous liquid agent can give a desired viscosity range. For example, based on the total amount of the component (A), it may be 0.01 to 2 w/v%, and preferably 0.02 to 0.5 w/v%, preferably 0.05 to 0.2 w/v%, more preferably 0.1 w/v%. .

Further, the aqueous liquid preparation of the present invention contains the above-mentioned (A) component, plus The polyoxyethylene hydrogenated castor oil and/or polyoxyethylene stearate (hereinafter also referred to as component (B)) is contained. Thus, by allowing hydroxypropylmethylcellulose and/or hydroxyethylcellulose to coexist with polyoxyethylene hydrogenated castor oil and/or polyoxyethylene stearate, the viscosity stability of the aqueous liquid agent can be improved. It inhibits the decrease of the viscosity over time.

About polyoxyethylene hydrogenated castor oil used as component (B), The average addition mole number of the ethylene oxide is not particularly limited, and may be 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 suppressing the deterioration of the viscosity with time. In the aqueous liquid preparation of the present invention, these polyoxyethylene hydrogenated castor oils may be used alone or in combination of two or more.

Further, regarding the polyoxyethylene stearic acid used as the component (B) The ester, the average addition molar number of ethylene oxide is not particularly limited, and may be in a pharmaceutically acceptable range. Examples of the polyoxyethylene stearate include polyoxyethylene stearate 40, polyoxyethylene stearate 45, and polyoxyethylene stearate 55. Among these polyoxyethylene stearates, from the viewpoint of the so-called more effective inhibition of the change in viscosity over time, it is possible to use polyoxyethylene hard. Fatty acid ester 40 is preferred. In the aqueous liquid preparation of the present invention, these polyoxyethylene stearates may be used singly or in combination of two or more kinds.

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

Further, 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%, and preferably 0.01 to 0.4 w/v%, based on the total amount of the component (B). , 0.01~0.2w/v% is better.

Further, in the aqueous liquid preparation of the present invention, when one of polyoxyethylene hydrogenated castor oil and polyoxyethylene stearate is used as the component (B), the so-called more effective aqueous liquid inhibiting agent is used. From the standpoint of the decrease in the temporal viscosity, the following suitable concentrations are exemplified.

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

When polyoxyethylene stearate is used, 0.01 to 0.4 w/v% is preferred, and 0.05 to 0.4 w/v% is preferred, and 0.1 to 0.2 w/v% is more preferred.

Furthermore, the aqueous liquid preparation of the present invention may further contain a group selected from the group consisting of panthenol, tetrahydrozoline, pyridoxine, pranoprofen, and the pharmaceutically acceptable salts thereof. At least one of them (hereinafter also referred to as 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 to be used as the component (C) may be any type corresponding to the compound forming the salt. For example, as the pharmaceutically acceptable salt of the tetrahydrozoline, an inorganic salt such as a chlorate or a nitrate can be specifically mentioned. Specific examples of the pharmaceutically acceptable salt of pranoprofen include metal salts such as a sodium salt, a potassium salt, a calcium salt, a magnesium salt and an aluminum salt; a triethylamine salt and a diethylamine salt; Petrone salt An organic salt or the like such as a salt.

These (C) ingredients may also be used alone or in combination of two It can also be used in combination. From the viewpoint of enhancing the effect of suppressing the effect of reducing the viscosity over time, when polyoxyethylene hydrogenated castor oil is contained as the component (B), as the component (C), pyridoxine and/or Pharmaceutically acceptable salts are preferred. Further, when polyoxyethylene stearate is contained as the component (B), pyridoxine and/or a pharmaceutically acceptable salt thereof is preferably used as the component (C).

When the component (C) is contained in the aqueous liquid preparation of the present invention, The concentration is not particularly limited, and may be appropriately set depending on the type of the component (C) to be used. For example, the total amount of the component (C) may be 0.001 to 1 w/v%, and preferably 0.01 to 0.2 w/v%. More specifically, from the viewpoint of effectively enhancing the effect of suppressing the so-called chronological viscosity reduction effect, the following concentrations can be appropriately exemplified depending on the various types of the component (C).

When using panthenol: 0.001~1w/v% is preferred, and 0.005~0.5w/v% is preferred, and 0.01~0.2w/v% is more preferable.

When tetrahydrozoline and/or a pharmaceutically acceptable salt thereof is used, it is preferably 0.001 to 1 w/v%, more preferably 0.005 to 0.5 w/v%, more preferably 0.01 to 0.1 w/v%.

When pyridoxine and/or a pharmaceutically acceptable salt thereof is used, it is preferably 0.001 to 1 w/v%, more preferably 0.005 to 0.5 w/v%, more preferably 0.01 to 0.2 w/v%.

When using pranoprofen and/or its pharmaceutically acceptable salt: 0.001~1w/v% Preferably, 0.005~0.5w/v% is better, and 0.01~0.1w/v% is better.

Furthermore, the aqueous liquid preparation of the present invention comprises, in addition to the aforementioned components, It may contain a terpenoid (hereinafter also referred to as a component (D)) for the purpose of imparting a cooling sensation or the like as needed. If it is made to contain a terpenoid, the retention of the terpenoid on the mucosa can be improved by the action of hydroxypropylmethylcellulose and/or hydroxyethylcellulose contained in the aqueous liquid preparation of the present invention. An aqueous liquid that continuously exerts a cooling sensation.

As the aspect of the use of the component (D), specifically, mint can be mentioned. Alcohol, menthone, camphor, borneol, geraniol, eucalyptol, limonene, eugenol, citral, terpene, linalool, decyl alcohol, decene and the like. Among these, menthol, menthone, and camphor are preferable, and menthol is more preferable. These may be used alone or in combination of two or more. Moreover, such sputum may also be an essential oil containing such hydrazines, which may not necessarily be purified. Examples of the essential oil containing menthol include peppermint oil, spearmint oil, peppermint oil, and the like.

When the component (D) is contained in the aqueous liquid preparation of the present invention, The concentration is not particularly limited, and the type of the component (D) to be used can be appropriately set depending on the degree of cooling imparted. For example, it is preferably 0.0001 to 0.1 w/v%, and preferably 0.0001 to 0.05 w/v%.

The aqueous liquid preparation of the present invention, comprising hydroxypropyl methylcellulose And / or hydroxyethyl cellulose, and polyoxyethylene hydrogenated castor oil and / or polyoxyethylene stearate, can be inhibited by a decrease in viscosity. In order to make such a viscosity-inhibiting effect more effective, the aqueous liquid preparation is preferably substantially free of polysorbate 80, and substantially free of polysorbate, substantially not A nonionic interface agent other than the component (B) is particularly preferred. Here, the term "substantially not containing the above-mentioned nonionic interfacial agent" means that the aqueous liquid preparation of the present invention does not impair the effect of suppressing the effect of reducing the viscosity over time, specifically, the above-mentioned nonionic properties. The concentration of the interface agent may be less than 0.0001 w/v%, and is preferably 0 w/v%.

Furthermore, the aqueous liquid preparation of the present invention is substantially free of oil The agent is suitable. The oil agent can be used as a cause of stickiness in eye drops in eye drops, or as a cause of contamination of lenses in eye drops for contact lenses, etc., and such loss can be prevented by substantially not containing an oil agent. Herein, the oil agent is a component consisting of vegetable oil, animal oil and/or mineral oil, a triglyceride of fatty acid and glycerin (ie, triglyceride), an aliphatic hydrocarbon, a fatty acid, a monoalkyl ester of a fatty acid, and a high grade. At least one of the nonvolatile hydrophobic materials such as alcohol is a main component. Therefore, the oil does not contain volatile essential oils. Further, the substance is substantially free of an oil agent, and specifically, the concentration of the oil agent is preferably less than 0.00001 w/v%, and preferably 0 w/v%.

The aqueous liquid preparation of the present invention may contain a pharmacological ingredient as long as it does not impair the effects of the present invention, in addition to the above components. As a pharmacological component which can be blended, for example, dipotassium glycyrrhizinate, allantoin, ε-hexylamine, bromfenac, triptolide, dextromethorphan, berberine chloride, bismuth sulfate Anti-inflammatory agents such as alkali, sodium sulfonate, zinc sulfate, zinc lactate, lysozyme chlorate; antihistamines such as chlorpheniramine and diphenhydramine hydrochloride; sodium cromoglycate and fumarate Anti-allergic agents such as fen, acitazanolast, Amlexanox, Pemirolast potassium, Tranilast, Ibudilast, etc. Antibacterial agents such as Norfloxacin, Ofloxacin, Lomefloxacin, Levofloxacin, Gentamicin, Gatifloxacin; Ascorbic acid, Vitamins such as flavin adenine dinucleotide sodium, vitamin B12, tocopherol ethyl acetate, vitamin A ethyl acetate, vitamin A palmitate, calcium pantothenate, sodium pantothenate; aspartic acid, taurine, cartilage Amino acids such as sodium sulphate; anticholinergic esterases such as neostigmine Methylsulfate ; vasopressin such as naphazoline, adrenaline, ephedrine, norepinephrine, racemic methyl ephedrine; therapeutic agent for isotonic conjunctival epithelial damage of sodium hyaluronate; sulfadiazine, sulfonamide Isoxazole, sulfamethazine, sulfadimethoxine, sulfamethoxazole Sulfonamide, sulfamethoxazole, Sulfamethomidine, sulfaphenazole, sulfaguanidine, sulfamethoxazole, sulfamethoxazole amber and other sulfonamides. The compounds exemplified herein have the pharmaceutically acceptable content as the bottom limit, and may also be in the form of a salt or in the form of other salts.

Furthermore, the aqueous liquid preparation of the present invention may further contain as needed Additives such as buffers, isotonic agents, solubilizers, viscous bases, chelating agents, pH adjusters, preservatives, stabilizers, and surfactants other than nonionic surfactants.

As a buffer, for example, a phosphate buffer or a boric acid buffer can be mentioned. Agent, citric acid buffer, tartaric acid buffer, acetic acid buffer, Tris buffer, amino acid, and the like.

As an isotonic agent, sorbitol, glucose, mannitol Such as sugars; polyvalent alcohols such as glycerin and propylene glycol; salts such as sodium chloride; boric acid Wait.

Examples of the co-solvent include polyhydric alcohols such as glycerin and macrogol.

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

Examples of the chelating agent include sodium edetate, citric acid, and the like.

Examples of the pH adjuster include a base such as sodium hydroxide or potassium hydroxide; and an acid such as acetic acid, citric acid, hydrochloric acid, phosphoric acid or tartaric acid.

Examples of the preservative include sorbic acid, potassium sorbate, sodium benzoate, methyl paraben, ethyl p-oxybenzoate, propyl paraben, chlorobutanol, chlorhexidine gluconate, and boric acid. , dehydroacetic acid, sodium dehydroacetate, benzyl ammonium chloride, benzyl alcohol, zinc chloride, p-chloro-m-xylenol, chlorocresol, phenylethyl alcohol, paclichlorouronium, thimerosal, and the like.

Examples of the stabilizer include polyvinylpyrrolidone, sodium sulfite, monoethanolamine, glycerin, propylene glycol, cyclodextrin, dextrin, ascorbic acid, sodium ethylenediaminetetraacetate, taurine, tocopherol, and the like.

Examples of the surfactant other than the nonionic surfactant include an amphoteric surfactant such as an alkyldiamine ethylglycine or a lauryl dimethylamine acetic acid betaine; an alkyl sulfate or a thioglycol An anionic surfactant such as a sulfonate, a polyoxyethylene alkyl ether phosphate or a polyoxyethylene alkyl ether sulfate; a cationic surfactant such as an alkylpyridine cation salt or an alkylamine salt.

The dynamic viscosity of the aqueous liquid preparation of the present invention can be appropriately set according to the use of the aqueous liquid preparation, for example, the dynamic viscosity at 20 ° C, which can be 1.1 to 50.0 mm ² /s, and 1.1 to 35.0 mm. ² / s is better, 1.2 ~ 28mm ² / s is better. In particular, when the aqueous liquid preparation of the present invention is used as an ophthalmic preparation, it is preferable to have the same viscosity as the tear liquid, and specifically, the dynamic viscosity at 20 ° C is 1.1 to 3.0 mm ^{2 .} /s is suitable, 1.5~2.5mm ² /s is better. Here, the dynamic viscosity at 20 ° C is measured using a Ubbel-type viscometer according to the "General Test Method 2.53 Viscosity Test Method 1. Method 1 capillary viscosity meter method" prescribed in the 16th edition of the Japanese Pharmacopoeia. Further, depending on the measured viscosity range, the inner diameter of the capillary of the Ubbel-type viscometer used and the ball B used are as shown in Table 1 of the examples.

The pH of the aqueous liquid preparation of the present invention is not particularly limited, and may be, for example, 5.5 to 8.0, and preferably 6.5 to 7.5.

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

The aqueous liquid preparation of the present invention can be used as an ophthalmic preparation such as an eye drop (including an eye drop for a soft contact lens) or an eye wash; an oto nose preparation such as a nasal drop or an ear drop; a contact lens dressing liquid, a contact lens Contact lens care products such as multi-purpose solutions. The eye drop for soft contact lenses is an eye drop that can be dripped even when wearing a soft contact lens. Among them, an ophthalmic preparation is preferred, and an eye drop is preferred.

The aqueous liquid preparation of the present invention may be produced according to the use of a known preparation method, and may be produced, for example, by the method described in the General Provisions of the Japanese Pharmacopoeia, 16th Edition.

2. Viscosity reduction inhibition method and viscosity reduction inhibitor The present invention also provides a method for inhibiting the viscosity reduction of an aqueous liquid preparation comprising the following component (A), which is (A) hydroxypropylmethylcellulose and/or hydroxyethylcellulose, Coexisting with (B) polyoxyethylene hydrogenated castor oil and/or polyoxyethylene stearate. In the method, the type of the component (A), the type of the component (B), the type of the other compoundable component, the concentration of the component, the type of the aqueous liquid agent, and the like are as described in the above "1. Aqueous liquid agent". Recorded.

Moreover, the present invention further provides a viscosity reduction inhibition The agent is an aqueous liquid preparation containing hydroxypropylmethylcellulose and/or hydroxyethylcellulose, and the viscosity reduction inhibitor is made of polyoxyethylene hydrogenated castor oil and/or polyoxyethylene stearate as an active ingredient. . The viscosity-reducing inhibitor is blended and used as an additive for the purpose of suppressing the decrease in the temporal viscosity of the aqueous liquid preparation containing hydroxypropylmethylcellulose and/or hydroxyethylcellulose. The type or amount of polyoxyethylene hydrogenated castor oil and/or polyoxyethylene stearate which is an active ingredient of the viscosity reduction inhibitor is described in the above "1. Aqueous liquid preparation".

Further, if necessary, remove the poly-reducing inhibitor In addition to oxyethylene hydrogenated castor oil and/or polyoxyethylene stearate, it may also contain a pharmaceutically acceptable salt selected from the group consisting of panthenol, tetrahydrozoline, pyridoxine, pranoprofen, and the like. At least one of the groups consisting of salts. By containing these components, the viscosity-reducing effect by the viscosity-reducing inhibitor can be further enhanced. The type and amount of these components are also described in the above "1. Aqueous liquid agent".

Further, in the viscosity reduction inhibitor, the object to be applied is The type or concentration of the aqueous liquid preparation, hydroxypropylmethylcellulose and/or hydroxyethylcellulose contained therein, and the like are also described in the above "1. Aqueous liquid preparation".

Example

The present invention is specifically illustrated by the following examples, but the invention is not limited thereto.

Further, in the following examples and comparative examples, hydroxypropylmethylcellulose was used as the trade name "METOLOSE 65SH-4000" (substitution degree type 2906, weight average molecular weight 350,000, Shin-Etsu Chemical Co., Ltd.)羟), hydroxyethyl cellulose is trade name "NATROSOL 250M PHARM" (weight average molecular weight: 720,000, Ashland Industries), hydroxypropyl cellulose is trade name "HPC-H" (made by Nippon Soda Co., Ltd.), carboxy Methylcellulose sodium is traded under the trade name "CELLOGEN PR-S Day Bureau" (manufactured by Daiichi Kogyo Co., Ltd.), and alginic acid is traded under the trade name "Alginic Acid" (manufactured by Ximeike Co., Ltd.). Xanthan gum is a commodity. "EKOGAMU T" (manufactured by DSP Co., Ltd., FOOD & CHEMICAL Co., Ltd.), polyoxyethylene hydrogenated castor oil 60 is trade name "NIKKOL HCO-60" (manufactured by Nikko Chemical Co., Ltd.), and polyoxyethylene stearate 40 is Product name "NIKKOL MYS-40V" (manufactured by Nikko Chemical Co., Ltd.), polysorbate 80 is a trade name "polysorbate 80" (manufactured by Nippon Oil Co., Ltd.), and polyoxyethylene oleic acid glyceride is commercially available. Name "NIKKOL TMGO-1 5 (manufactured by Nikko Chemical Co., Ltd.), monooleate polyethylene glycol is a trade name "NIKKOL MYO-10V" (manufactured by Nikko Chemical Co., Ltd.).

Test Example 1: Nonionic surfactant for cellulose The influence of the viscosity of the aqueous liquid agent

Each component shown in Table 2 was mixed by a usual method, and each of the aqueous liquid preparations was prepared by filtration sterilization using a 0.22 μm membrane filter. After measuring the dynamic viscosity of each aqueous liquid agent after the preparation of the instant, 15 mL of each aqueous liquid preparation was filled and sealed in a container of polyethylene terephthalate having a capacity of 15 mL, and stored at 50 ° C in the dark. week. The dynamic viscosity was measured for each aqueous liquid agent after storage, and the dynamic viscosity retention ratio (%) was calculated according to the following formula.

Number 1

Dynamic viscosity retention rate (%) = {(moving viscosity of aqueous liquid agent after storage for 2 weeks at 50 ° C) / (dynamic viscosity of each aqueous liquid agent after modulation)} x100

In addition, the dynamic viscosity of each aqueous liquid is set at 20 ° C, using the Uber-Dod type viscometer (manufactured by Mutual Chemical Co., Ltd.), and the "General Test Method" in accordance with the 16th edition of the Japanese Pharmacopoeia. 2.53 Viscosity Test Method 1. Determination of the first method of capillary viscometer method. The dynamic viscosity was measured twice per sample and the average value thereof was used as a measured value. Further, the measurement of the dynamic viscosity of each aqueous liquid was carried out in each viscosity measurement range, and the Ubbel-type viscometer and the ball B system were each carried out using the materials shown in Table 1.

The results obtained are shown in Table 2. According to this result, an aqueous liquid solution in which hydroxypropylmethylcellulose and polyoxyethylene hydrogenated castor oil 60 are coexisted (Example 1) and an aqueous liquid preparation (Example 2) in which hydroxypropylmethylcellulose and polyoxyethylene stearate 40 are coexisted, and a nonionic interface containing hydroxypropylmethylcellulose The aqueous solution of the active agent (Comparative Example 1) was able to suppress the decrease in viscosity after storage for 2 weeks at 50 °C. On the other hand, together with hydroxypropylmethylcellulose, an aqueous liquid solution in which polysorbate 80, polyoxyethylene oleate or monooleate polyethylene glycol is present (Comparative Examples 2 to 4), Compared with the aqueous liquid preparation of Comparative Example 1, the viscosity decreased after storage at 50 ° C for 2 weeks.

From the above results, it was confirmed that the cellulose-based adhesive was water-based. The time-dependent viscosity of the liquid agent is lowered and can be suppressed by polyoxyethylene hydrogenated castor oil or polyoxyethylene stearate.

Test Example 2: Effect of nonionic surfactant on viscosity of aqueous liquid containing various adhesives

The components shown in Tables 3 and 4 were mixed in a usual manner, and each aqueous liquid preparation was prepared by filtration and sterilization using a 0.22 μm membrane filter, and a modulation transient was obtained for each aqueous liquid agent in the same manner as in Test Example 1 above. After the dynamic viscosity, the dynamic viscosity and the dynamic viscosity retention rate after storage for 2 weeks at 50 °C.

The results obtained are shown in Tables 3 and 4. Confirmed from this result, ie It is an aqueous liquid preparation in which hydroxyethyl cellulose and polyoxyethylene hydrogenated castor oil 60 are coexisted, and the decrease in dynamic viscosity after storage for 2 weeks at 50 ° C can be suppressed. On the other hand, as confirmed from Tables 3 and 4, cellulose-based adhesives other than hydroxypropylmethylcellulose and hydroxyethylcellulose, or aqueous liquids of alginic acid or xanthan gum, even The non-ionic surfactant was not blended at 50 ° C for 2 weeks, and the dynamic viscosity was still not reduced. That is, it has been confirmed that even in the case of the cellulose-based adhesive, the aqueous liquid preparation containing hydroxypropylmethylcellulose and/or hydroxyethylcellulose has a specific problem of reduction in the temporal dynamic viscosity.

Test Example 3: Effect of concentration of nonionic surfactant on viscosity of aqueous liquid containing cellulose-based adhesive

The components shown in Tables 5 and 6 were mixed in a usual manner, and each aqueous liquid preparation was prepared by filtration and sterilization using a 0.22 μm membrane filter, and a modulation transient was obtained for each aqueous liquid agent in the same manner as in Test Example 1 above. After the dynamic viscosity, the dynamic viscosity and the dynamic viscosity retention rate after storage for 2 weeks at 50 °C.

The results obtained are shown in Tables 5 and 6. According to the result, in the aqueous liquid preparation containing hydroxypropyl methylcellulose, by blending polyoxyethylene hydrogenated castor oil 60, 0.01~0.2w/v%, especially 0.1~0.2w/v% concentration It can effectively inhibit the decrease of dynamic viscosity after storage for 2 weeks at 50 °C. Further, in the aqueous liquid preparation containing hydroxypropylmethylcellulose, by blending polyoxyethylene stearin The concentration of the acid ester 40, 0.01~0.4w/v%, especially 0.1~0.4w/v%, can effectively inhibit the decrease of the dynamic viscosity after storage for 2 weeks at 50 °C. On the other hand, in the aqueous liquid preparation containing hydroxypropylmethylcellulose, even if the polysorbate 80 is blended at a concentration of 0.05 to 0.5 w/v%, the dynamic viscosity after 2 weeks of storage at 50 ° C cannot be suppressed. Reduced.

Table 6

Test Example 4: Effect of the concentration of the cellulose-based adhesive on the viscosity of the aqueous liquid containing the cellulose-based adhesive and the nonionic surfactant

The components shown in Tables 7 and 8 were mixed in a usual manner, and each aqueous liquid preparation was prepared by filtration and sterilization using a 0.22 μm membrane filter, and a modulation transient was obtained for each aqueous liquid agent in the same manner as in the above Test Example 1. After the dynamic viscosity, the dynamic viscosity and the dynamic viscosity retention rate after storage for 2 weeks at 50 °C.

The results obtained are shown in Tables 7 and 8. According to this result, in the aqueous liquid preparation containing hydroxypropylmethylcellulose and containing no nonionic interfacial surfactant, when the concentration of hydroxypropylmethylcellulose becomes high, it is stored at 50 ° C for 2 weeks. The decrease in dynamic viscosity has a tendency to become significant (Comparative Examples 11 to 17), but in the case where polyoxyethylene hydrogenated castor oil 60 or polyoxyethylene stearate 40 has been blended, it can be inhibited from being stored at 50 ° C. 2 The decrease in dynamic viscosity after weeks (Examples 18 to 31). On the other hand, from the results of this test, it was confirmed that the polysorbate 80 could not inhibit the dynamic viscosity of the aqueous liquid preparation containing hydroxypropylmethylcellulose after being stored at 50 ° C for 2 weeks (Comparative Examples 18 to 24). .

Table 7

Test Example 5: Effect of oil agent on viscosity of cellulose-based adhesive and nonionic surfactant aqueous liquid preparation

Each of the components shown in Table 9 was mixed in a usual manner, and each aqueous liquid preparation was prepared by filtration and sterilization using a 0.22 μm membrane filter, and a modulation transient was obtained for each aqueous liquid agent in the same manner as in the above Test Example 1. Dynamic viscosity, dynamic viscosity and dynamic viscosity retention after storage for 2 weeks at 50 °C.

The results obtained are shown in Table 9. According to the results, when the polysorbate 80 was added to the aqueous solution containing hydroxypropylmethylcellulose, the dynamic viscosity after storage at 50 ° C for 2 weeks was lowered (Comparative Example 2), but further addition of hydrazine was carried out. Sesame oil, the decrease in dynamic viscosity is suppressed (Ref. 14). On the other hand, even if castor oil was further added to an aqueous solution containing hydroxypropylmethylcellulose and polyoxyethylene hydrogenated castor oil 60, the effect of suppressing the decrease in dynamic viscosity was not observed (Example 32). The polyoxyethylene hydrogenated castor oil 60 was replaced by polyoxyethylene stearate 40 (Example 33).

Test Example 6: Ubiquinol, tetrahydrozoline bismuth ruthenate, pyridoxine citrate Effects of bismuth and pranoprofen on the inhibition of viscosity reduction

Each of the components shown in Table 10 was mixed by a usual method, and each aqueous liquid preparation was prepared by filtration and sterilization using a 0.22 μm membrane filter, and a modulation transient was obtained for each aqueous liquid agent in the same manner as in the above Test Example 1. Dynamic viscosity, dynamic viscosity and dynamic viscosity retention after storage for 2 weeks at 50 °C.

The results obtained are shown in Table 10. From this result, it is confirmed that In the aqueous liquid preparation of hydroxypropylmethylcellulose, polyoxyethylene hydrogenated castor oil 60 or polyoxyethylene stearate 40, if further blended with panthenol, tetrahydrozoline chlorate or pyridinium Alcohol chlorate, or pranoprofen, stored at 50 ° C The inhibition of the decrease in dynamic viscosity after 2 weeks was reluctant. In particular, it has also been confirmed that when panthenol is blended in an aqueous liquid preparation containing hydroxypropylmethylcellulose and polyoxyethylene stearate 40, and hydrogenated with hydroxypropylmethylcellulose and polyoxyethylene When the pyridoxine chlorate was added to the aqueous liquid of castor oil 60 or polyoxyethylene stearate 40, the inhibition of the decrease in the dynamic viscosity after storage at 50 ° C for 2 weeks was more pronounced. On the other hand, when an aqueous liquid preparation containing hydroxypropylmethylcellulose, polyoxyethylene hydrogenated castor oil 60 or polyoxyethylene stearate 40 is added to several other pharmacological components other than the above, it is found that The effect of suppressing the decrease in dynamic viscosity is not affected. That is, it was confirmed that the strong effect of suppressing the dynamic viscosity reduction effect shown in the test example is to select panthenol, tetrahydrozoline chlorate, pyridoxine chlorate, and/or pranoprofen as a more preferable effect. The unique effects obtained by the further addition of the pharmacological ingredients.

Claims (6)

An aqueous liquid preparation comprising: (A) 0.1w/v% of hydroxypropyl methylcellulose having a degree of substitution of 2906; (B) 0.1w/v% of polyoxyethylene hydrogenated castor oil 60; 0.55w/v % sodium chloride, 0.15 w/v% potassium chloride, 0.005 w/v% glucose, 1-menthol and boric acid buffer; substantially free of nonionic interface other than polyoxyethylene hydrogenated castor oil 60 The active agent and the oil agent; and the dynamic viscosity at 20 ° C measured by an Ubbelode type viscometer is 1.5 to 2.5 mm ² /s, and the pH is 6.5 to 7.5. An aqueous liquid preparation according to claim 1, which further comprises a group selected from the group consisting of (C) panthenol, tetrahydrozoline, pyridoxine, pranoprofen and the pharmaceutically acceptable salts thereof. At least one of them. An aqueous liquid preparation according to claim 1 or 2 which further contains (D) anthraquinone. An aqueous liquid preparation according to claim 1 or 2 which is an eye drop. A method for inhibiting a decrease in viscosity of an aqueous liquid preparation, the aqueous liquid preparation comprising hydroxypropyl methylcellulose having a degree of substitution of 2906, the method being based on the aqueous liquid preparation, wherein (A) 0.1 w/v% of the foregoing Hydroxypropyl methylcellulose, (B) 0.1 w/v% polyoxyethylene hydrogenated castor oil 60, 0.55 w/v% sodium chloride, 0.15 w/v% potassium chloride, 0.005 w/v% Glucose, 1-menthol and boric acid buffer coexist; substantially free of nonionic surfactant other than polyoxyethylene hydrogenated castor oil 60, and oil; and measured by an Ubbelode type viscometer The dynamic viscosity at 20 ° C is 1.5 to 2.5 mm ² /s, and the pH is 6.5 to 7.5. A viscosity reducing inhibitor for inhibiting viscosity reduction of an aqueous liquid preparation containing hydroxypropylmethylcellulose containing 0.1w/v% of hydroxypropylmethylcellulose having a degree of substitution of 2906, 0.55w /v% sodium chloride, 0.15 w/v% potassium chloride, 0.005 w/v% glucose, 1-menthol and boric acid buffer; substantially free of polyionics other than polyoxyethylene hydrogenated castor oil 60 a surfactant, and an oil agent; and the dynamic viscosity at 20 ° C measured by an Ubbelode type viscometer is 1.5 to 2.5 mm ² /s, and the pH is 6.5 to 7.5; the viscosity reduction inhibitor system 0.1 w/v% of polyoxyethylene hydrogenated castor oil 60 was used as an active ingredient.