JP2006131580A - Composition for mucosa application - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a composition for mucosa application, which suppresses reduction in viscosity. <P>SOLUTION: The composition suppresses reduction in viscosity by including sodium carboxymethyl cellulose and 2-aminoethanesulfonic acid. The composition suppresses adhesion of protein to ocular tissue and in its turn prevents various keratoconjunctivites. The composition suppresses adhesion of protein to contact lenses in the case of wearing contact lenses. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a composition for applying to mucosa in which a decrease in viscosity of a composition containing sodium carboxymethylcellulose is suppressed and protein adhesion to a tissue is suppressed.

  In a mucosa-applied composition applied to the ocular mucosa, nasal mucosa, intraoral mucosa, etc., it is necessary to improve the retention of the composition in the mucosa in order to increase the bioavailability of the components. Then, the formulation design which mix | blends thickeners, such as carboxymethylcellulose sodium, and improves a retention property is performed. Such mucosal retention is attributed to the viscosity imparted to the composition by containing sodium carboxymethylcellulose. Therefore, in the composition for applying to mucosa containing sodium carboxymethylcellulose, it was important to set an appropriate viscosity and stably maintain a desired set viscosity for a long period of time.

  Cellulose polymers are known to undergo partial decomposition by heat and a decrease in viscosity. To date, polymers that are bioadhesives or viscosity enhancing agents, such as polyacrylic acids, acrylate copolymers, cross-linked polyacrylic acids, cellulose, cellulose derivatives, dextran, hyaluronic acid have been degraded. Reduced free metal ions by using phosphonic acids or phosphonates, chelating agents that are promoted by metal ions in solutions and slurries but have a greater ability to complex with free ions than EDTA. It has been found that the viscosity of a polymer composition can be disrupted, reducing the rate of degradation, degradation or other inactivation (US Pat. However, it has not been sufficient as a technique for practical application of a mucosa-applied composition containing sodium carboxymethylcellulose.

Moreover, in the composition applied to mucosa, it is necessary to consider the influence on the applied mucosal tissue. Taking the ocular mucosa as an example, keratoconjunctival diseases such as hay fever, giant papillary conjunctivitis and stye are known as the most common ocular mucosal diseases. When foreign proteins such as pollen and bacteria, and endogenous proteins such as altered self-proteins adhere to tissues such as the keratoconjunctiva, or stick to or adsorb further, the proteins are recognized by inflammatory cells, and then the inflammatory reaction proceeds and horns. It is said to lead to conjunctival disease. In recent years, contact lenses, particularly soft contact lenses with a high water content, have been regarded as problematic because they tend to adhere or adhere to proteins and cause keratoconjunctival diseases.
Therefore, a mucosa-applied composition capable of suppressing the adhesion of protein to tissues and contact lenses has been desired.

  As a method of physically washing the attached protein with a water flow, an eyewash or a nasal washing solution is used. However, since the cleaning is performed using a relatively large amount of aqueous solution, the usage scene is limited, and the mucous membrane may be damaged due to excessive cleaning. Further, although a certain degree of protein cleaning effect can be obtained by blending a surfactant in the composition for applying to mucosa, blending a large amount of the surfactant has a problem in terms of safety and irritation.

  By the way, it is known that sodium carboxymethylcellulose has a water retention effect and has an effect of treating corneal epithelial cell damage caused by dryness of ocular mucosa represented by dry eye (Patent Document 2). On the other hand, 2-aminoethanesulfonic acid is a component widely used in eye drops for the purpose of improving fatigue eyes because of its metabolism promoting action. An eye drop for repairing corneal injury containing inorganic salts having a therapeutic effect on corneal epithelial injury and 2-aminoethanesulfonic acid is also known (Patent Document 3 WO96 / 08244).

Japanese National Patent Publication No. 11-510480 Japanese Patent Application No. 2004-233874 WO96 / 08244

  Then, this invention makes it a subject to provide the composition applied to a mucous membrane in which the fall of the viscosity by sodium carboxymethylcellulose was suppressed. It is another object of the present invention to provide a composition for applying to mucosa in which protein adhesion is suppressed to mucosal tissue and contact lenses.

  As a result of intensive studies for solving the problems, the present inventors have found that by containing 2-aminoethanesulfonic acid together with sodium carboxymethylcellulose, it is possible to suppress a decrease in the viscosity of the composition and complete the present invention. It came to.

The present inventor has been developed based on such knowledge.
That is, this invention is a composition applied to mucous membranes listed in the following (1) to (8).
(1) A mucosa-applied composition containing sodium carboxymethylcellulose and 2-aminoethanesulfonic acid,
(2) The composition applied to mucosa according to (1), wherein the viscosity at 20 ° C. is 1.5 mPa · s or more and 100,000 mPa · s or less.
(3) The composition for applying to mucosa according to (1) or (2), wherein the viscosity of sodium carboxymethylcellulose at 25 ° C. and a 2% aqueous solution has a viscosity of 20 mPa · s to 8000 mPa · s,
(4) The composition for applying to mucosa according to (1) to (3), wherein the degree of etherification of sodium carboxymethylcellulose is 0.6 to 1.0,
(5) The composition for applying to mucosa according to any one of (1) to (4), further comprising an inorganic salt or / and a buffering agent,
(6) The composition for applying to mucosa according to (1) to (5), further comprising 0.001 to 5% (w / v) of a nonionic surfactant,
(7) The composition for applying to mucosa according to (1) to (6), further containing 0.0001 to 1% (w / v) of an ethylenediamineacetic acid derivative or a salt thereof,
(8) The mucosa-applied composition according to any one of (1) to (7), wherein the mucosa-applied composition is a nasal drop, an eye drop, a contact lens mounting solution, an eye wash, a nasal wash, or a contact lens care agent.
Furthermore, the present invention is the method described in the following (9):
(9) A method of stabilizing the viscosity of the composition by blending sodium carboxymethylcellulose and 2-aminoethanesulfonic acid into the composition.
In the present specification, unless otherwise specified,% means w / v%.

The composition for applying to mucous membranes of the present invention contains 2-aminoethanesulfonic acid together with sodium carboxymethylcellulose, thereby suppressing a decrease in viscosity of the composition. Being able to maintain the composition at a desired viscosity eventually suppresses fluctuations in performance such as the feeling of use and drug retention of the composition applied to mucosa.
Moreover, the mucosa-applied composition of the present invention can suppress protein adhesion to mucosal tissues and contact lenses. That is, the protein can be prevented from adhering or the adhering protein can be removed. Therefore, various diseases and disorders can be prevented or suppressed, and further, an effect of preventing deterioration can be achieved, and the contact lens can be kept clean. Usually, when a composition is applied to the mucosa, immediately after the application, the immune barrier such as mucus and tears which play the main role in mucosal immunity is disturbed, and a part of the immune barrier is replaced with the composition. Therefore, it is expected that such a composition for applying to mucosa has a function of preventing protein adhesion to a tissue to play an auxiliary role for mucosal immunity of a living body.

  Sodium carboxymethyl cellulose used in the composition for applying to mucosa of the present invention is a known polymer compound. Sodium carboxymethylcellulose usually used for mucosa-applied compositions by those skilled in the art can be used without particular limitation. However, in the present invention, preferably a 25%, 2% aqueous solution has a viscosity of 20 mPa · s to 8000 mPa · s. More preferably, sodium carboxymethylcellulose of 20 mPa · s to 6000 mPa · s, particularly preferably 20 mPa · s to 3000 mPa · s is used. In addition, the degree of etherification of sodium carboxymethylcellulose can usually be in the range of 0.1 to 3.0, but is preferably 0.6 to 1.0, more preferably for the composition applied to mucosa of the present invention. Is 0.6 to 0.9, particularly preferably 0.7 to 0.9.

  A commercially available sodium carboxymethyl cellulose can be used, for example, Serogen (registered trademark) series PR-S (25 ° C., 2% aqueous solution having a viscosity of 20 mPa · s to 40 mPa, sold by Daiichi Kogyo Seiyaku Co., Ltd.). S, degree of etherification 0.70 to 0.85), P-715A (viscosity of 2% aqueous solution at 25 ° C., 80 mPa · s to 140 mPa · s, degree of etherification 0.60 to 0.70), F-SC (25 ° C., 2% aqueous solution) Daicel with a viscosity of 300 mPa · s to 400 mPa · s, an etherification degree of 0.70 to 0.85), AG-GUM (25 ° C., 2% aqueous solution has a viscosity of 900 mPa · s to 1500 mPa · s, an etherification degree of 0.70 to 0.85), etc. The CMC Daicel series sold by Chemical Industry Co., Ltd. and the Sunrose F series sold by Nippon Paper Chemicals Co., Ltd. are available. That.

  In the present invention, the content of sodium carboxymethylcellulose in the composition applied to mucosa is preferably 0.001 to 10%, more preferably 0.005 to 5%, and particularly preferably about 0.01 to 3%.

2-Aminoethanesulfonic acid used in the composition for applying to mucosa of the present invention is a known compound of sulfur-containing amino acids existing in the living body, and is also referred to as aminoethylsulfonic acid. The content of 2-aminoethanesulfonic acid used in the present invention in the composition applied to mucosa is usually 0.0001 to 10%, preferably 0.005 to 5%, more preferably 0.005 to 3%, particularly preferably. Can be used at about 0.005 to 2%.
More specifically, for example, the concentration in eye drops or nasal drops is 0.001 to 10%, preferably 0.005 to 5%, more preferably 0.005 to 3%, and particularly preferably 0.00. It can be used at about 005 to 1%. The concentration in the eyewash or nasal wash is 0.0001 to 10%, preferably 0.001 to 5%, more preferably 0.005 to 3%, and particularly preferably about 0.005 to 1%. it can. The concentration in the contact lens preparation may be 0.001 to 10%, preferably 0.005 to 5%, more preferably 0.005 to 3%, and particularly preferably about 0.005 to 2%. .

It is preferable to mix | blend a buffering agent with the composition applied to mucosa of this invention. Examples of the buffer used in the present invention include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, HEPES buffer, and MOPS buffer. More specifically, boric acid, sodium borate, potassium tetraborate, potassium metaborate, etc., phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, carbonic acid, sodium hydrogen carbonate, sodium carbonate , Citric acid, sodium citrate, potassium citrate, acetic acid, sodium acetate, HEPES, MOPS, and a combination of two or more compounds selected from these groups.
Preferred buffering agents are borate buffer, phosphate buffer, carbonate buffer and citrate buffer.
Particularly preferred buffering agents are borate buffers or phosphate buffers.
Particularly preferred buffering agents include, more specifically, boric acid buffering agents such as boric acid, boric acid salts such as alkali metal borates and alkaline earth metal borates, and combinations of boric acid and borates. It is done. 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.

  In the composition for applying to mucosa of the present invention, the content of the buffering agent varies depending on the type of the buffering agent, and thus cannot be defined unconditionally. However, the total amount of the compound used as the buffering agent is usually 0.001 to 5%, preferably 0. 001 to 3%, more preferably about 0.005 to 1.5%. In contact lens cleaning agents, it is usually used in an amount of 0.001 to 15%, preferably 0.001 to 10%, more preferably about 0.001 to 7%. The pH of the composition may be adjusted to pH 4.0 to 10.0, preferably 5.0 to 9.0, particularly preferably 5.5 to 8.5 with a buffer.

  It is preferable to add inorganic salts to the mucosa-applied composition of the present invention. Inorganic salts include potassium chloride and / or sodium chloride.

  In the composition for applying to mucous membranes of the present invention, the content of inorganic salts varies depending on the kind of inorganic salts and the like, and thus cannot be specified unconditionally, but is usually 0.001 to 5%, preferably 0.001 to 1%, more preferably 0. Used at about 0.005 to 0.5%.

  It is preferable to add a nonionic surfactant to the composition for applying to mucosa of the present invention. As the nonionic surfactant to be used in the present invention, those which can be usually used by those skilled in the art for a composition applied to mucosa can be used. For example, polyoxyethylene (hereinafter also referred to as POE) -polyoxypropylene (hereinafter referred to as POE). Block copolymers (eg, poloxamer 407, poloxamer 235, poloxamer 188, etc.); POE-POP block copolymer adducts of ethylenediamine such as poloxamine; POE (20) sorbitan monolaurate (polysorbate 20), monoolein POE sorbitan fatty acid esters such as acid POE (20) sorbitan (polysorbate 80), POE sorbitan monostearate (polysorbate 60), POE sorbitan tristearate (polysorbate 65); POE hydrogenated castor oil 5, POE hydrogenated castor oil 10, POE curing POE hydrogenated castor oil such as castor oil 20, POE hydrogenated castor oil 40, POE hydrogenated castor oil 60, POE hydrogenated castor oil 60, POE hydrogenated castor oil 100; POE alkyl ethers such as POE (9) lauryl ether; POE ( 20) POE / POP alkyl ethers such as POP (4) cetyl ether; POE alkyl phenyl ethers such as POE (10) nonylphenyl ether. The numbers in parentheses indicate the number of added moles.

  Among these, nonionic surfactants selected from polyoxyethylene-polyoxypropylene block copolymers, POE sorbitan fatty acid esters or POE hydrogenated castor oils are preferable, and poloxamer 407, polysorbate 80, polyoxy is particularly preferable. Ethylene hydrogenated castor oil 60.

  In the composition for applying to mucosa of the present invention, the content of the nonionic surfactant varies depending on the type of the surfactant and the like, and thus cannot be defined unconditionally, but is usually 0.001 to 5%, preferably 0.001 to 1%. More preferably, it is used at about 0.005 to 0.5%.

  The composition for applying to mucosa of the present invention preferably contains an ethylenediamineacetic acid derivative or a salt thereof. More preferably, the ethylenediamineacetic acid derivative or a salt thereof, a nonionic surfactant, an inorganic salt, and a buffer are combined. Examples of such ethylenediamineacetic acid derivatives or salts thereof include edetic acid (ethylenediaminetetraacetic acid, EDTA), ethylenediaminediacetic acid (EDDA), diethylenetriaminepentaacetic acid (DTPA), and N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA). Etc. can be exemplified. These may be used alone or in combination, and may be used as a pharmacologically or physiologically acceptable salt (for example, sodium ethylenediaminetetraacetate). Among them, ethylenediaminetetraacetic acid or a salt thereof is preferable, for example, ethylenediaminetetraacetic acid disodium, ethylenediaminetetraacetic acid disodium dihydrate (hereinafter also referred to as sodium edetate).

  The content of the ethylenediamineacetic acid derivative or a salt thereof in the composition for applying to mucosa of the present invention varies depending on the molecular weight, type, etc., and thus cannot be defined unconditionally, but is preferably 0.0001 to 1%, more preferably 0.0005 to 0.00. 5%, particularly preferably about 0.001 to 0.3%.

  The total amount of these components in the composition for applying to mucosa of the present invention is preferably 0.01 to 5%, particularly preferably about 0.05 to 3%.

As long as the effects of the invention are utilized, the intended use is not specified, and in various fields such as pharmaceuticals, quasi-drugs, miscellaneous goods, ophthalmic compositions, otolaryngological compositions, oral compositions, pharyngeal compositions It can utilize for the composition applied to a mucous membrane, such as a composition. 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) Eyewash, eye ointment, contact lens mounting solution, contact lens care agent (cleaning solution, preservative solution, bactericidal solution, multipurpose solution, etc.), nasal drops, nose A cleaning liquid, an oral preparation, an oral cleaning agent, etc. are mentioned. Preferably, nasal drops, eye drops, eye ointments, contact lens mounting liquid, eye wash, nasal wash or contact lens care agent, particularly preferably nasal drops, eye drops, eye wash, nasal wash, Useful for contact lens mounting fluid.
In the present specification, contact lenses include all types of contact lenses such as hard, soft, oxygen permeable hard, and color.

  The mucosa-applied composition of the present invention is suitable for containing various components (including pharmacologically active components and physiologically active components) in combination. Examples include decongestants, ophthalmic regulators, anti-inflammatory or astringents, antihistamines or antiallergics, vitamins, amino acids, local anesthetics, steroids, etc. it can. Specifically, the following components can be exemplified.

Decongestant: For example, α-adrenergic agonists, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, naphazoline nitrate. These may be d-form, l-form or dl-form.
Eye muscle modulator component: For example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, atropine sulfate helenien, and the like.
Anti-inflammatory component or astringent component: for example, zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, pranoprofen, sodium azulenesulfonate, dipotassium glycyrrhizinate, diclofenac sodium, bromfena Sodium chloride, berberine chloride, berberine sulfate, etc.
Antihistamine component or antiallergic agent component: for example, acitazanolast, amlexanox, ibudilast, tranilast, diphenhydramine hydrochloride, levocabastine hydrochloride, ketotifen fumarate, sodium cromoglycate, pemirolast potassium, chlorpheniramine maleate and the like.
Vitamins: for example, retinol acetate, retinol palmitate, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, pyridoxal phosphate, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, ascorbic acid, tocopherol acetate, etc.
Amino acids: For example, potassium aspartate, sodium aspartate, magnesium / potassium aspartate, glutamic acid, sodium glutamate and the like.
Local anesthetic ingredients: for example, chlorobutanol, oxybuprocaine hydrochloride, cocaine hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate, piperocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine hydrochloride, hydrochloric acid Lidocaine etc.
Steroid component: for example, dexamethasone, hydrocortisone, fluorometholone, prednisolone, methylprednisolone, hydroxymesterone, hydrocortisone caproate, prednisolone caproate, cortisone acetate, hydrocortisone acetate, prednisolone acetate, sodium dexamethasone metasulfobenzoate, sodium dexamethasone sulfate Dexamethasone sodium phosphate, triamcinolone acetonide, betamethasone sodium phosphate, dexamethasone sodium metasulfobenzoate, methylprednisolone and the like.

  In addition, in the composition applied to mucosa of the present invention, various components and additives are appropriately selected according to conventional methods according to the use and form within a range not impairing the effects of the invention, and one or more are used in combination. May be included. 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, Various additives such as preservatives, bactericides or antibacterial agents, pH adjusting agents, tonicity agents, fragrances or refreshing agents, stabilizers and the like can be mentioned.

Although the typical component used for the mucosa application composition of this invention is illustrated below, it is not limited to these.
Thickener: For example, polyethylene glycol, dextran, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, carboxyvinyl polymer, alginic acid, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyethylcellulose , Hyaluronic acid or a pharmacologically acceptable salt thereof.
Sugars: for example, glucose, cyclodextrin and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like.
Surfactant: For example, in addition to the above-mentioned nonionic surfactants, glycine-type amphoteric surfactants such as alkyldiaminoethylglycine; alkyl quaternary ammonium salts (specifically, benzalkonium chloride, benzethonium chloride, etc.) Cationic surfactants, etc. The numbers in parentheses indicate the number of moles added.
Preservatives, bactericides or antibacterials: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glowyl (product of Rhodia) Name) etc.
pH adjuster: For example, hydrochloric acid, boric acid, epsilon-aminocaproic acid, acetic acid, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, borax, triethanolamine, monoethanolamine and the like.
Isotonizing agents: for example, sodium bisulfite, sodium sulfite, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, dihydrogen phosphate Sodium, potassium dihydrogen phosphate, glycerin, propylene glycol, etc.
Perfume or refreshing agent: For example, geraniol, camphor, fennel oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, rose oil, etc. other than the menthol, camphor and borneol described above. These may be d-form, l-form or dl-form.
Stabilizer: Dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, etc.

  The mucosa-applied composition of the present invention can be initially set to an appropriate viscosity to obtain a desired effect, and can maintain the set viscosity stably for a long period of time. The viscosity of the ophthalmic composition has a great effect on the comfort (use feeling), drug retention, and treatment of diseases such as dry eye when applied to the ocular mucosa. It is important that the designed viscosity is kept stable over the long term. In the case of setting an appropriate viscosity, for example, an ophthalmic composition is preferably designed with a viscosity at 20 ° C. maintained at 1.5 mPa · s or more, usually 1.5 to 300 mPa · s, preferably 2 to It can be designed to 200 mPa · s, particularly preferably 5 to 100 mPa · s, more preferably about 10 to 80 mPa · s. The nasal composition is preferably designed by keeping the viscosity at 20 ° C. at 2 mPa · s or more, usually 2 to 100,000 mPa · s, preferably 50 to 10,000 mPa · s, particularly preferably 100 to It can be designed to about 5000 mPa · s.

  The mucosa-applied composition of the present invention is used after adjusting to an osmotic pressure within a range acceptable for a living body, if necessary. The osmotic pressure is about 100 to 1200 mOsm, preferably about 100 to 600 mOsm, particularly preferably about 150 to 400 mOsm, and the osmotic pressure ratio with respect to physiological saline is usually 0.4 to 4.1, preferably 0.3 to 2. 1, particularly preferably about 0.5 to 1.4.

  The mucosa-applied composition of the present invention is used after adjusting to a pH within a range applicable to a living body, if necessary. The pH is usually pH 4.0 to 10.0, preferably 5.0 to 9.0, particularly preferably 5.5 to 8.5. Adjustment of pH can be performed using the said buffer, a pH adjuster, etc.

  The composition for applying to mucosa of the present invention can be produced by a known method, and if necessary, a filtration sterilization treatment step, a filling step into a container, and the like can be added.

  Moreover, this invention is a method of stabilizing the viscosity of a composition by mix | blending carboxymethylcellulose sodium and 2-aminoethanesulfonic acid in a composition. Moreover, this invention is a method of suppressing protein adhesion to a structure | tissue by applying the mucosa application composition which mix | blended sodium carboxymethylcellulose and 2-aminoethanesulfonic acid to the mucous membrane. In addition, about carboxymethylcellulose sodium and 2-aminoethanesulfonic acid, it can carry out according to the above-mentioned description regarding the composition of this invention.

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.
Viscosity measurement method 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 revised Japanese pharmacy method, "( 3) The method described in the section “Cone-plate 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), Rot Bisco R (Haake, Germany), IGK Hischer Rheometer (Ishida Giken, Japan), Shimadzu Rheometer R (Shimadzu, Japan), Weissenberg Greogoniometer (Sangamo, UK), Mechanical Spectro Meters (rheometrics, rice), 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)

The viscosity of each comparative example and each example in this test is a TVE-20L type viscometer cone plate type (manufactured by TOKIMEC, Toki Sangyo (Japan)), which is a type of E-type viscometer. Measurement was performed under the following measurement conditions.
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, use a petroleum-based hydrocarbon oil (Newtonian fluid) stipulated by JIS Z 8809 as the standard solution for calibration before measuring the test sample, 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.
Rotor used: Standard rotor (1 ° 34 ', R = 2.4cm)
Rotation speed: 5rpm
Sample volume: 1 ml
Measurement temperature: 20 ° C
Time: Viscosity after 3 minutes was taken as a measured value.

Test Example 1 Viscosity stability test The test examples were prepared according to the formulation shown in Table 1. Specifically, the preparation method of Test Example 4 or 5 is shown. 2-Aminoethanesulfonic acid, sodium chloride, potassium chloride, potassium sorbate and boric acid were stirred and dissolved in 50 ml of purified water, and further 0.2 g of sodium carboxymethylcellulose (CMC in the table. Serogen PR-S "or trade name" AG-GUM "was added and dissolved by stirring, and borax was added with stirring and dissolution to adjust the pH, and then an appropriate amount of purified water was added to make a total of 100 ml. As a result, the viscosity was measured.
Thereafter, 10 mL of a transparent glass bottle was filled and sealed, and stored for 2 weeks in a 60 ° C. thermostat (CH20-11M manufactured by Nagano Scientific Machine Works). The viscosity was measured again after storage for 2 weeks. From the measured viscosity values before and after the heat treatment, the viscosity reduction inhibition rate (%) was calculated by the following formula 1. The results are shown in Table 1.

(Formula 1)
Viscosity reduction inhibition rate (%) = (CMC and 2-aminoethanesulfonic acid aqueous solution viscosity reduction amount after storage at 1-60 ° C. for 2 weeks ÷ CMC-containing aqueous solution viscosity reduction amount after storage at 60 ° C. for 2 weeks) × 100

  As a result of the test, it was confirmed that the viscosity reduction of the composition containing sodium carboxymethylcellulose can be suppressed by containing 2-aminoethanesulfonic acid.

Test Example 2 Preparation of an adsorbed protein removal test test example followed the formulation shown in Table 2. Specifically, about 90 ml of Opeguard (registered trademark, Senju Pharmaceutical Co., Ltd.) having the composition shown in Table 3 is 0.3 g of sodium carboxymethyl cellulose (in the table, CMC. The trade name “Serogen F-SC” is used. And 1.0 g of 2-aminoethanesulfonic acid were dissolved with stirring, and an appropriate amount of Opeguard (registered trademark) was added to make a total of 100 ml.
The cells used for the test were suspended in a rabbit corneal epithelial cell line (SIRC) in Medium 199 (Nippon Invitrogen Corporation) supplemented with 10% (v / v) fetal bovine serum, and then seeded on a 24-well microtiter plate to achieve full growth. Cultured until complete. The cell culture supernatant was removed, and 1 ml of Medium 199 supplemented with 1% (w / v) FITC-labeled bovine serum albumin (FITC-BSA, Sigma-Aldrich) and 10% (v / v) fetal bovine serum was added. After culturing for 24 hours, FITC-BSA was adsorbed on the cell surface. After removing the medium, 1 ml of each test example was added to the well. The 24-well microtiter plate was shaken at a speed of 600 rpm / min. After repeating this operation twice, the test solution was removed, and the fluorescence intensity (Ex. 480 nm, Em. 527 nm) on the bottom of each well was measured. Since the fluorescence intensity of each well is attributable to the remaining FITC-BSA, this was used as an indicator of the amount of remaining protein.

  As a result of the test, in the composition containing both 2-aminoethanesulfonic acid and sodium carboxymethylcellulose (Test Example 7), the amount of FITC-BSA remaining in the cells decreased by 25.2%, and the protein adhering to the corneal epithelial cells was reduced. It was confirmed that there was an effect to remove. Therefore, it was shown that the composition containing 2-aminoethanesulfonic acid and carboxymethyl cellulose can remove or wash the foreign protein adsorbed on the mucosal tissue such as the keratoconjunctiva or the contact lens adhering to the keratoconjunctiva. Furthermore, it is expected to have an excellent preventive effect on ocular mucosal tissue diseases represented by various keratoconjunctivitis.

Examples Each example in the table shall be described in units of g / 100 ml. In the table, “eye drops” refers to eye drops (agents), “eye wash” refers to eye drops (agents), and “artificial points” refers to artificial tears-type eye drops (agents). The “wearing solution” means a contact lens wearing solution, and the “CL agent” means a contact lens care agent. In each of these examples, a decrease in viscosity was suppressed.

Claims (5)

A mucosa-applied composition containing sodium carboxymethylcellulose and 2-aminoethanesulfonic acid. The composition for mucous membrane application according to claim 1, wherein the viscosity at 20 ° C is from 1.5 mPa · s to 100,000 mPa · s. The mucosa-applied composition according to claim 1 or 2, wherein the mucosa-applied composition is a nasal drop, an eye drop, a contact lens mounting solution, an eye wash, a nasal wash, or a contact lens care agent. The method of stabilizing the viscosity of a composition by mix | blending carboxymethylcellulose sodium and 2-aminoethanesulfonic acid in a composition. A method for suppressing protein adhesion to a tissue by applying a mucosa-applied composition containing sodium carboxymethylcellulose and 2-aminoethanesulfonic acid to the mucosa.