JP4963359B2 - Ophthalmic topical preparation - Google Patents

Description

  The present invention relates to a preparation for topical ocular application such as eye drops and eye wash.

  In topical ophthalmic preparations such as eye drops and eyewashes that are applied to the ocular mucosa, the drug on the ocular mucosa and cooling are used to enhance the bioavailability of the drug and maintain the refreshing feeling of the cooling components. It is necessary to improve the retention of components. In the formulation design of general topical ophthalmic preparations, a composition comprising a cellulosic polymer compound such as hydroxyethylcellulose or hydroxypropylmethylcellulose or a vinyl polymer compound such as polyvinylpyrrolidone or polyvinyl alcohol as a thickening agent. Formulation design has been performed in which drug retention is improved by imparting viscosity to.

  By the way, the eye drops are accommodated in a container provided with an extraction port for facilitating the dropping of the liquid into the eye. Further, the eye wash is contained in a container provided with an easy-to-pour extraction port in order to facilitate injection of the liquid into an eye wash cup used for eye washing. Therefore, in a liquid agent containing a cellulose-based polymer compound or a vinyl-based polymer compound and imparted with a viscosity, liquid drainage at the spout is not sufficient and liquid dripping tends to occur. Furthermore, the cellulose-based polymer compound and the vinyl-based polymer compound have a problem that white solids are likely to be precipitated at the spout, the periphery thereof, and the inside of the container cap. There is a problem in terms of safety because the deposits in the spout and its surroundings are likely to enter the eye or into the container when instilled.

  In addition, when we apply eyelashes to liquids containing cellulosic polymer compounds and vinyl polymer compounds, wetting the eyelashes causes white solids to adhere to the eyelashes after the solution is dried. It was also a problem. In order to solve such a problem, conventionally, in the composition for contact lenses and the composition for eyewash, (A) 0.01-10 w / v% of a cellulose-based polymer compound having a weight average molecular weight of 50,000 to 1,000,000, (B) A composition having no precipitation of components even after storage after use, characterized by containing 0.1 to 10 w / v% of a liquid polyhydric alcohol is known (Patent Document 1: Japanese Patent Application Laid-Open No. 2003-2003). No. 107416).

  Therefore, the present invention relates to a cellulosic polymer compound or a vinyl polymer in a topical ophthalmic preparation containing a cellulosic polymer compound such as hydroxyethylcellulose or hydroxypropylmethylcellulose, or a vinyl polymer compound such as polyvinylpyrrolidone or polyvinyl alcohol. It is an object to prevent solid compounds from being precipitated.

  As a result of diligent studies for solving the problems, the present inventors have made topical ophthalmic applications containing at least one selected from a) alginic acid or a salt thereof, and b) a cellulose polymer compound or a vinyl polymer compound. It was found that in the preparation, crystal precipitation of a cellulose polymer compound or a vinyl polymer compound can be prevented or suppressed.

The present invention has been developed based on such knowledge.
That is, the present invention includes the following inventions:
(1) ophthalmic topical preparation containing at least one selected from a) alginic acid or a salt thereof, and b) a cellulosic polymer compound or a vinyl polymer compound,
(2) Alginic acid or a salt thereof, and b) a topical preparation for eye application in which a liquid agent containing at least one selected from a cellulose polymer compound or a vinyl polymer compound is contained in a container provided with a spout. ,
(3) a) Alginic acid or a salt thereof 0.001 (w / v)% to 5 (w / v)%, and b) at least one compound selected from a cellulose polymer compound or a vinyl polymer compound 0.001 (w / v)% to 10 (w / v)% of the preparation for topical ophthalmic application according to (1) or (2),
(4) a) Alginic acid or a salt thereof per 1 part by weight, b) At least one selected from cellulose-based polymer compounds or vinyl-based polymer compounds in a total amount of 0.0001 to 100 parts by weight The ophthalmic topical preparation according to any one of (1) to (3),
(5) The ophthalmic topical preparation according to any one of (1) to (4), which is an eye drop, an eye wash, and a contact lens mounting solution,
(6) At least one compound selected from a cellulose polymer compound or a vinyl polymer compound is methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose, or a salt thereof. The ophthalmic topical preparation according to any one of (1) to (5), which is at least one selected from
(7) a) alginate or a salt thereof, and b) a method for suppressing precipitation by containing in the preparation at least one compound selected from a cellulose polymer compound or a vinyl polymer compound,
(8) A method for increasing the viscosity of a preparation by containing at least one compound selected from a) alginic acid or a salt thereof, and b) a cellulosic polymer compound or a vinyl polymer compound in the preparation. ,
In the present specification, unless otherwise specified,% means w / v%. Further, in the present specification, the contact lens is meant to include all types of contact lenses such as hard, oxygen permeable hard, soft, and color.

  In the present invention, the cellulosic polymer compound or the vinyl polymer compound has the edge of the eye by containing both alginic acid or a salt thereof and at least one selected from the cellulosic polymer compound or the vinyl polymer compound. It is possible to prevent the cosmetic appearance from deteriorating due to precipitation with eyelashes. Further, when a liquid agent containing both alginic acid or a salt thereof and at least one selected from a cellulose-based polymer compound or a vinyl-based polymer compound is contained in a container provided with a spout, Precipitation of the cellulose-based polymer compound or vinyl-based polymer compound in the peripheral portion can be prevented, and the ophthalmic topical preparation can be used safely.

  As the alginic acid or a salt thereof in the present invention, either a natural product or a synthetic product may be used. Typical natural products include Macrocystis on the west coast of the United States, Lessonia in Chile in South America, Ascophyllum in Scandinavia, etc. The extraction method includes an alkali extraction method, but is not particularly defined. In addition, the mannuronic acid / guluronic acid ratio (M / G ratio) of alginic acid or a salt thereof is not particularly specified, and a wide range of alginic acid from M-rich to G-rich can be used. More preferably, it is 3.0 or less, More preferably, it is 2.5 or less, Most preferably, it is 2.0 or less. Commercially available alginic acid can also be used, and is commercially available from Kibun Food Chemifa Co., Ltd., Kimika Co., Ltd., Fuji Chemical Industry Co., Ltd. and the like. Examples of the alginic acid salt in the present invention include alginic acid salts such as sodium salt, potassium salt, and ammonium salt of alginic acid, but are not limited thereto. Of these, sodium alginate and potassium alginate are preferable. Commercially available salts of alginic acid can be used, and are commercially available from Kibun Food Chemifa Co., Ltd., Kimika Co., Ltd., Fuji Chemical Industry Co., Ltd. and the like.

  The content of alginic acid or a salt thereof in the ophthalmic topical preparation of the present invention can be appropriately set according to the molecular weight, composition (M / G ratio) and other components coexisting in the preparation. It is 001-5%, More preferably, it is 0.005-5%, More preferably, it is 0.005-1%, More preferably, it is 0.01-0.5%.

  The ophthalmic topical preparation in the present invention contains at least one selected from a cellulose polymer compound or a vinyl polymer compound. When two or more types are contained in combination, only the cellulose polymer compound, only the vinyl polymer compound, cellulose compound and vinyl polymer compound can be used in combination.

  As the cellulose-based polymer compound, a cellulose-based polymer compound obtained by replacing the hydroxyl group of cellulose with a polar group or a nonpolar group, which can impart viscosity to the aqueous composition is used. it can. Examples of the functional group that substitutes the hydroxyl group of cellulose include a methoxyl group, an ethoxyl group, a hydroxyethoxyl group, and a hydroxypropoxyl group. Examples of the cellulose polymer compound include methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, and pharmacologically acceptable salts thereof. Among these, at least one selected from methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose, or a salt thereof is preferable. Particularly preferred is at least one selected from hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone. Here, examples of the pharmacologically acceptable salt include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and salts with metals such as aluminum.

  The content of the cellulose-based polymer compound or the vinyl-based polymer compound is not limited because it varies depending on the type and molecular weight of the compound, but the total amount of these compounds is usually 0.001 to 25%, preferably It is 0.001 to 10%, more preferably 0.01 to 10%, particularly preferably about 0.05 to 7%, further preferably about 0.05 to 5%. Further, alginic acid or a salt thereof is usually 0.0001 to 100 parts by weight, preferably 0.001 to 100 parts by weight, more preferably 0.01 to 10 parts by weight, based on 1 part by weight of the total amount of these compounds. The content is preferably 0.01 to 5 parts by weight, more preferably 0.1 to 5 parts by weight, and particularly preferably 0.1 to 1.0 parts by weight.

  The cellulose-based polymer compound or vinyl-based polymer compound used in the present invention is not limited in the degree of substitution and the molecular weight of the substituent. For example, the weight-average molecular weight is 50,000 to 1,000,000, preferably 10,000 to 500,000. More preferably, about 10,000 to 100,000 can be used. Moreover, a commercially available thing can be used for these cellulose polymer compounds, and these compounds may be used alone or in combination of two or more.

  The ophthalmic topical preparation of the present invention contains a liquid agent containing alginic acid or a salt thereof, and b) at least one selected from a cellulose polymer compound or a vinyl polymer compound in a container provided with a spout. The ocular topical preparation is also provided. In a container provided with a spout, if the liquid gap is poor at the outlet of the liquid agent, a cellulose polymer compound or a vinyl polymer compound precipitates in the vicinity of the cap or the spout after drying. In addition, in the case of eye drops, there is a possibility that precipitates generated in the vicinity of the spout may directly enter the eye at the time of use, but this is eliminated in the topical ophthalmic preparation of the present invention.

  In the eye drop container for containing eye drops, the inner diameter of the liquid agent outlet portion of the spout is set to be as thin as about 1.5 mm to 3.0 mm, and further about 1.7 mm to 2.5 mm. In addition, since the eyewash is prepared by putting an eyewash solution in a dedicated small cup, the eyewash is contained in a container provided with a spout to facilitate pouring of the liquid into the small cup. Furthermore, in a thin extraction port, precipitation may occur not only on the outer or outer periphery of the spout, but also on the inner or inner periphery, and the precipitate may enter the container. In the present invention, even when a liquid agent contained in a container having an extraction port is used, it is possible to prevent precipitation of the cellulose polymer compound or vinyl polymer compound at the outlet, which is safe.

  In many cases, the extraction port is mainly composed of a polyester resin such as polypropylene, polyerylene, polystyrene, polyethylene terephthalate, polyethylene naphthalate, etc., but the preparation of the present invention prevents precipitation at the extraction port composed of such a resin. There is an effect. In particular, the effect can be exhibited in the extraction port mainly composed of polyethylene.

  The pH of the ophthalmic topical preparation of the present invention can be adjusted as appropriate, but is usually about 4.5 to 9.5. More preferably, it is 5.5-8.5, More preferably, it is 6.0-8.0, Most preferably, it is 6.5-7.5. It is more desirable to adjust the pH to 5.0 or more, particularly in eye drops and eye drops, especially in eye drops and eye wash. The pH can be adjusted using a buffer, a pH adjuster described later, etc., but it is preferable to adjust using a buffer.

When a buffer is used in the ophthalmic topical preparation of the present invention, borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer and the like can be mentioned. Preferred buffering agents are borate buffer, phosphate buffer, carbonate buffer and citrate buffer. Particularly preferred buffering agents are borate buffers or phosphate buffers. Examples of the boric acid buffer include borates such as boric acid, alkali metal borates, and alkaline earth metal borates, and combinations of boric acid and borates. Examples of the phosphate buffer include phosphates such as phosphoric acid, alkali metal phosphates, and alkaline earth metal phosphates, and combinations of phosphoric acid and phosphates. Moreover, you may use the borate or the hydrate of a phosphate as a borate buffer or a phosphate buffer. More specifically, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, etc.), phosphoric acid or a salt thereof (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.) , Carbonic acid or a salt thereof (sodium bicarbonate, sodium carbonate, etc.), citric acid or a salt thereof (sodium citrate, potassium citrate, etc.). When borate buffer or phosphate buffer is used as the buffer, the concentration of these buffers in the ophthalmic topical preparation of the present invention is, for example, preferably 0.0001 to 10.0%, more preferably 0.001 to 5%, more preferably 0.005 to 5%, and particularly preferably 0.005 to 3%.

  The osmotic pressure of the ocular topical preparation of the present invention can be adjusted as appropriate, and is, for example, 80 to 1000 mOsm. More preferably, it is 100-900 mOsm, More preferably, it is 200-600 mOsm, More preferably, it is 250-600 mOsm, Most preferably, it is 250-500 mOsm. It is more desirable to adjust to 200 to 400 mOsm, especially in the case of eye drops and eye wash, even in preparations for topical ophthalmic application. The osmotic pressure of the preparation is sodium chloride, potassium chloride, sodium bicarbonate, sodium carbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate or potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, sodium thiosulfate, glycerin, propylene It can be adjusted using an isotonic agent such as glycol.

  When setting the viscosity of the ophthalmic topical preparation of the present invention, the viscosity at 20 ° C. is designed to be kept at 1.2 mPa · s or more, preferably 1.2 to 500 mPa · s, more preferably 1. It is designed to be 5 to 100 mPa · s, particularly preferably 1.5 to 80 mPa · s, more preferably about 2 to 70 mPa · s.

In the ophthalmic topical preparation of the present invention, any drug or the like that is applied topically to the eye can be used as appropriate without particular limitation.
For example, decongestant component, ocular regulator component, anti-inflammatory component or astringent component, antihistamine component or antiallergic component, vitamins, amino acids, antibacterial component, bactericidal component, saccharide, local anesthetic component , Steroid components, glaucoma drugs, etc., more specifically,
Decongestant component: for example, ophthalmic muscle modulator component such as naphazoline hydrochloride, naphazoline nitrate, tetrahydrozoline hydrochloride: for example, neostigmine methyl sulfate.
Anti-inflammatory component or astringent component: for example, zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, pranoprofen, sodium azulene sulfonate, dipotassium glycyrrhizinate berberine chloride, berberine sulfate, etc.
Antihistamine component or antiallergic agent component: for example, tranilast, diphenhydramine hydrochloride, ketotifen fumarate, sodium cromoglycate, chlorpheniramine maleate and the like.
Vitamins: for example, retinol acetate, retinol palmitate, pyridoxine hydrochloride, sodium flavin adenine dinucleotide, pyridoxal phosphate, cyanocobalamin, panthenol, sodium pantothenate, tocopherol acetate, etc.
Amino acids: For example, aminoethylsulfonic acid (taurine), glutamic acid, potassium aspartate, sodium glutamate, sodium chondroitin sulfate and the like.
Antibacterial component or bactericidal component: For example, sulfamethoxazole, sulfamethoxazole sodium and the like.
Sugars: glucose, trehalose, sodium hyaluronate, sodium chondroitin sulfate, etc.
Local anesthetic components: for example, oxybuprocaine hydrochloride, dibucaine hydrochloride, procaine hydrochloride, lidocaine hydrochloride, etc.
Steroid component: For example, dexamethasone, hydrocortisone, prednisolone, methylprednisolone and the like.
In addition, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone and the like.
Cooling ingredients: menthol, camphor, borneol, geraniol, cineole, etc.

  The compounding amounts of these components in the ophthalmic topical preparation are appropriately selected according to the type of formulation, the type of active ingredient, and the like, and the compounding amounts of various components are known in the art. For example, it can be selected from the range of about 0.0001 to 30%, preferably about 0.001 to 10% with respect to the whole preparation. More specifically, the following ranges are exemplified.

Decongestant component (vasoconstrictor or sympathomimetic drug): For example, 0.0001 to 0.5%, preferably 0.0005 to 0.3%, more preferably 0.001 to 0.1%.
Eye muscle modulator component: For example, 0.0001 to 0.5%, preferably 0.0005 to 0.1%, more preferably 0.0005 to 0.01%.
Anti-inflammatory component or astringent component: for example, 0.0001-10%, preferably 0.0001-5%.
Antihistamine component or antiallergic agent component: for example, 0.0001 to 10%, preferably 0.001 to 5%.
Vitamins: For example, 0.0001 to 1%, preferably 0.0001 to 0.5%.
Amino acids: For example, 0.0001 to 10%, preferably 0.001 to 3%.
Antibacterial component or bactericidal component: For example, 0.00001 to 10%, preferably 0.0001 to 10%.
Saccharides: For example, 0.0001 to 5%, preferably 0.001 to 5%, more preferably 0.01 to 2%.
Local anesthetic component: For example, 0.001-1%, preferably 0.01-1%.
Steroid component: For example, 0.001 to 1%, preferably 0.01 to 1%.
Cooling component: For example, 0.0001 to 5%, preferably 0.001 to 3%, more preferably 0.005 to 2%, and particularly preferably about 0.01 to 1%.

  The ocular topical preparation of the present invention can be used in various fields such as pharmaceuticals, quasi-drugs, miscellaneous goods, etc., as long as it utilizes the effects of the invention. For example, eye drops (agents) (including eye drops that can be used while wearing contact lenses, also referred to as eye drops), eye wash (agents) (use contact lenses while wearing) And eyewashes), eye ointments, contact lens mounting solutions, and the like. Preferably, it is suitable for eye drops and eye wash that easily cause white residue.

  In addition, in the ophthalmic topical preparation of the present invention, various components and additives are appropriately selected according to conventional methods according to the use and form as long as the effects of the invention are not impaired. May be used in combination. As those components or additives, for example, carriers (water, aqueous solvents, aqueous or oily bases, etc.) commonly used in the preparation of semi-solids and liquids, thickeners, sugars, surfactants, Examples thereof include various additives such as nonionic surfactants, preservatives, bactericides or antibacterial agents, pH adjusters, isotonic agents, and fragrances.

  The ocular topical preparation of the present invention can be produced by a known method. Semi-solid and liquid preparations can be prepared by mixing the base and each component. Furthermore, if necessary, a filtration sterilization treatment process, a container filling process, and the like can be added.

  Hereinafter, the present invention will be described in detail based on test examples and examples, but the present invention is not limited to these examples.

Test Example 1 Precipitation Inhibition Test 100 μl of each test preparation having the formulation shown in Table 1 was dropped on a slide glass and a polyethylene resin plate, and the precipitate was visually observed after standing overnight, according to the following evaluation criteria. The results are shown in Table 1.
Evaluation criteria ○: No white solid was deposited Δ: A very small amount of white solid was deposited ×: White solid was deposited

  As a result of the test, in the test preparation containing alginic acid, precipitation of white solids of polyvinyl alcohol, which is a vinyl polymer compound, hydroxyethyl cellulose, which is a cellulose polymer compound, and hydroxypropyl methyl cellulose, was not observed. In carboxymethylcellulose sodium, although a very small amount of white solid was precipitated, the precipitation was remarkably suppressed. It was shown that precipitation of solids was suppressed by alginic acid. In addition, crystal precipitation was suppressed on the polyethylene resin plate as well as on the slide glass.

Test example 2
Each viscosity of the formulations shown in Tables 2 and 3 was measured. The following method was used for measuring the viscosity.
Viscosity measurement method is a method using a cone-and-plate rotational viscometer (General test method, 45. Viscosity measurement method, Second method rotational viscometer method described in the 14th revision Japanese Pharmacopoeia method, “(3) Cones − The method described in the section “Plate type rotational viscometer” was followed. Specifically, the measurement was performed using a commercially available cone-plate type rotational viscometer and an appropriately selected rotor.
In measuring viscosity, commercially available viscometers such as E-type viscometers (manufactured by TOKIMEC, sold by Toki Sangyo (Japan)), Synchronic PC type (Brookfield, USA), Ferranti Shirley (Feranti, UK), Rotobisco R (Haake, Germany), etc. can be used. Then, by appropriately selecting these commercially available viscometers and rotors, by appropriately adjusting the petroleum-based hydrocarbon oil (Newtonian fluid) defined by JIS Z8809 for each test sample measurement as a calibration standard solution, The viscosity at 20 ° C. can be measured.

Specifically, a sample is put in a gap of an angle α between a cone and a flat disc, and the cone or the flat disc is rotated at a constant angular velocity ω or torque T, and the flat disc when a steady state is reached. Alternatively, the torque or angular velocity received by the cone was measured, and the viscosity was measured by calculating the viscosity η of the sample by the following equation.
η = 100 × (3α / 2πR ³ ) · (T / ω)
η: Viscosity of sample (mPa · s) (Pa · s = 10 ³ mPa · s)
α: Angle between the flat disk and the cone (rad)
π: Circumference ratio R: Conical radius (cm)
T: Torque acting on a flat disk or a conical surface (10 ⁻⁷ N · m)
ω: Angular velocity (rad / s)

Viscosity is measured using the TVE-20L type viscometer cone plate type (TOKIMEC, Toki Sangyo (Japan)), which is a type of E-type viscometer, under the following measurement conditions. went.
Measurement condition:
Standard scale cone rotor attached to the TVE-20L viscometer cone plate type (corresponding to cone 1 in Fig. 1) (angle between flat disc and cone = 1 ° 34 ', radius (R) = 2.4cm) full scale・ Rotate with a motor through a spring of torque 673.7 × 10 ^-7 Nm. During measurement, the viscometer is installed so that the rotation axis is perpendicular to the horizontal plane.
Place 1 ml of the test sample on a predetermined position (flat disk) of the cone rotor and leave it until the temperature reaches 20.0 ° C. Next, the apparatus is rotated at a rotational speed corresponding to the viscosity of the test sample, and the displayed viscosity is read. In order to obtain highly accurate measurement results, before measurement of the test sample, petroleum-based hydrocarbon oil (Newtonian fluid) specified by JIS Z 8809 is used as the calibration standard solution, and the measured value is the viscosity of the standard solution. Adjust to match. The same result can be obtained by using a commercially available model other than the TVE-20L viscometer cone plate type, selecting a cone rotor in the same manner as described above, and performing calibration appropriately.
The measurement conditions in the test examples and examples of the present specification are as follows.
Rotor used: Standard rotor (1 ° 34 ', R = 2.4cm)
Rotational speed: 100 rpm for test samples 1, 2, 4, 6, 7
50 rpm for test samples 3, 5 and 8;
20 rpm for the test sample 9,
The test sample 10 was set to 10 rpm.
Time: Viscosity after 3 minutes was taken as a measured value.

It was confirmed that the viscosity increased in the preparation containing both hydroxyethyl cellulose (test sample 3) or hydroxypropyl methylcellulose (test sample 5) as compared with the preparation of alginic acid alone (test sample 1).
Furthermore, it was confirmed that the viscosity increased in the preparation containing both sodium alginate or sodium alginate (test sample 6 or 7) together with sodium carboxymethylcellulose (test sample 9 or 10).

  Tables 4 and 5 describe eye drops (Prescription Examples 1 to 13), Table 6 describes eye wash (Prescription Examples 14 to 19), and Examples when the present invention is used as eye drops or eye wash are shown. These examples can be produced according to the Japanese Pharmacopoeia General Rules for Preparation, and can be produced by filling a sterile plastic-sterilized preparation into a plastic container provided with a spout. In the table, polyvinyl alcohol is “GOHSENOL EG05” manufactured by Nippon Synthetic Chemical Co., Ltd., hydroxyethyl cellulose is “CF-V” manufactured by Shin-Etsu Chemical Co., Ltd., and hydroxypropylmethylcellulose is “65SH-” manufactured by Shin-Etsu Chemical Co., Ltd. 4000 ”, polyvinylpyrrolidone,“ Collidon 90 ”manufactured by BASF Corporation, and“ cellogen AG-GUM ”manufactured by Daiichi Kogyo Seiyaku Co., Ltd. were used as sodium carboxymethylcellulose.

Claims (8)

o) topical ophthalmic preparation containing at least one selected from a) alginic acid or a salt thereof, and b) hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and polyvinyl alcohol, provided that it contains a nonionic surfactant; Excluding ophthalmic compositions whose tonicity is 0.5 w / v% or more and less than 0.9 w / v% in terms of sodium chloride) . o) topical application in which a liquid containing at least one selected from a) alginic acid or a salt thereof, and b) hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinyl alcohol is contained in a container provided with a spout. Formulation (excluding ophthalmic compositions containing a nonionic surfactant and having a tonicity of 0.5 w / v% or more and less than 0.9 w / v% in terms of sodium chloride) . a) alginic acid or a salt thereof 0.001 (w / v)% to 5 (w / v)%, and b) at least one compound selected from hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinyl alcohol The ophthalmic topical preparation according to claim 1 or 2, comprising 0.001 (w / v)% to 10 (w / v)%. a) Alginic acid or a salt thereof per 1 part by weight, b) At least one selected from hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinyl alcohol is added in a total amount of 0.0001 to 100 parts by weight. The ophthalmic topical preparation according to any one of claims 1 to 3, which is contained as described above. The ophthalmic topical application according to any one of claims 1 to 4, wherein the pH is 4.5 to 9.5, the osmotic pressure is 80 to 1000 mOsm, and the viscosity at 20 ° C is 1.2 to 500 mPa · s. Formulation. The ophthalmic topical preparation according to any one of claims 1 to 5 , which is an eye drop or an eye wash. By containing at least one compound selected from a) alginic acid or a salt thereof, and b) hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinyl alcohol in the preparation (however, containing a nonionic surfactant) And excluding ophthalmic compositions whose tonicity is 0.5 w / v% or more and less than 0.9 w / v% in terms of sodium chloride) , a method for suppressing precipitation. By containing at least one compound selected from a) alginic acid or a salt thereof, and b) hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinyl alcohol in the preparation (however, containing a nonionic surfactant) And excluding ophthalmic compositions whose tonicity is 0.5 w / v% or more and less than 0.9 w / v% in terms of sodium chloride) , a method for increasing the viscosity of the preparation.