JP5847211B2 - Mucosal composition - Google Patents

Description

  The present invention relates to a composition for applying to mucous membrane and the like in which wetting of eyes and contact lenses is improved by containing sodium carboxymethylcellulose and a terpenoid.

  In order to wear a contact lens accurately and safely on the cornea that is always wet with tear fluid and to make wearing for a long time comfortable, it is desirable that the material of the contact lens is hydrophilic and the surface is easily wetted. However, hard contact lenses and oxygen permeable hard contact lenses are essentially hard to wet because they are based on hydrophobic polymethyl methacrylate and polysiloxanyl methacrylate, respectively. In the case of soft contact lenses, a hydrophilic material with high moisture content is used, so that it is easy to get wet, but adsorption of proteins and lipids is remarkable, and these substances adhere with the use of contact lenses. As it accumulates, the wettability of the soft contact lens surface deteriorates. As described above, any type of contact lens has a problem that the wettability of the surface of the contact lens is deteriorated due to the properties of the material and adhering matter, and the eye tissue is damaged during wearing and wearing. . In order to solve this problem, it is desirable to apply a composition having a sufficient water-wetting effect regardless of the material of the contact lens, and further to apply a composition that maintains the water-wetting effect.

  In addition, keratoconjunctival epithelial disorder caused by dry eye, that is, qualitative or quantitative abnormality of tears is a problem regardless of whether or not a contact lens is worn. Contact lens wearers in particular are prone to severe corneal epithelial damage. Therefore, for the treatment of dry eye, it is important that the corneal surface of the eye is in a state where it can be easily wetted and can maintain moisture.

  Polyoxyethylene polyoxypropylene glycol and polyoxyethylene polyoxypropylene-substituted ethylenediamine are already known as ophthalmically safe surfactants that have no adverse effects such as accumulation in contact lenses, and use their washing and wetting effects. A contact lens cleaning agent is disclosed (Patent Document 1: JP-A-4-313721). Further, a method for enhancing water wettability of a soft contact lens containing terpenoid as an active ingredient and an ophthalmic composition thereof are known (Patent Document 2: JP-A-11-130667). Furthermore, in the ophthalmic composition with adjusted viscosity, which contains polyoxyethylene polyoxypropylene glycol and a thickening agent and has a viscosity at 20 degrees of 1 cps or more and 8 cps or less, It is known that the contact lens is excellent in the effect of improving water resistance and has a continuous water-wetting effect on the contact lens (Patent Document 3: WO 97/28827).

  By the way, 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. The thickening agent may also be used as a wetting agent for corneal surfaces and contact lens surfaces that are easily dried by exposure to the external environment. For example, sodium carboxymethyl cellulose having a water retaining action, dry eye It has been found that there is an effect of treating a corneal epithelial cell disorder caused by dryness of a representative ocular mucosa (Patent Document 2: Japanese Patent Application No. 2004-233874).

Therefore, the present invention improves the wetness of the corneal surface and contact lenses, and can keep the eyes and contact lenses moist, and thus has excellent preventive and therapeutic effects on keratoconjunctive disorders that can occur due to dryness typified by dry eyes. It is an object of the present invention to provide a composition for applying to mucosa.

  As a result of intensive studies for solving the problems, the present inventors have found that the inclusion of a terpenoid together with sodium carboxymethylcellulose can improve the wetting of eyes and contact lenses, and have completed the present invention. .

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 (13).
(1) Mucosal application composition containing sodium carboxymethylcellulose and a terpenoid,
(2) The mucosa-applied composition according to (1), which is used for improving wetting,
(3) The composition for applying to mucosa according to (1) or (2), which is used for prevention or improvement of dry eye,
(4) The composition for applying to mucosa according to any one of (1) to (3), which is for contact lenses, (5) nasal drops, eye drops, eye ointments, contact lens mounting solutions, eye wash or contact lenses A composition for applying to mucosa according to any one of (1) to (4), which is a care agent;
(6) The composition for applying to mucosa according to (1) to (5), wherein a viscosity at 20 ° C. is 1.5 mPa · s or more and 300 mPa · s or less,
(7) The composition for applying to mucosa according to (1) to (6), wherein the viscosity of sodium carboxymethylcellulose at 25 ° C. and a 2% (w / v) aqueous solution is 20 mPa · s to 8000 mPa · s,
(8) The composition for applying to mucosa according to (1) to (7), wherein the etherification degree of sodium carboxymethylcellulose is 0.6 to 1.0,
(9) The composition for applying to mucosa according to (1) to (8), wherein the terpenoid is at least one selected from menthol, camphor, borneol or geraniol,
(10) Further, a nonionic surfactant is contained at 0.001 to 5% (w / v) (1)
Thru | or the mucosa application composition as described in (9),
(11) The composition for applying to mucosa according to (10), wherein the nonionic surfactant is at least one selected from poloxamer, poloxamine, polyoxyethylene sorbitan fatty acid esters or polyoxyethylene hydrogenated castor oil,
(12) Further, an ethylenediamineacetic acid derivative or a salt thereof is added in an amount of 0.0001 to 1% (w /
v) The composition for applying to mucosa according to (1) to (11),
(13) The composition for applying to mucosa according to (1) to (12), further comprising an inorganic salt or / and a buffering agent,
Furthermore, the present invention is the method described in the following (14):
(14) A method for improving the wettability of a contact lens by blending sodium carboxymethylcellulose and a terpenoid in the composition.
In addition, when it only describes with% in this specification, it shall mean% (w / v).

  The composition for applying to mucosa of the present invention can improve the wettability of the contact lens surface and the corneal surface by containing a terpenoid together with sodium carboxymethylcellulose. That is, in combination with the excellent water retention effect of carboxymethylcellulose, wetting can be maintained and moisture can be maintained. In addition, the composition of the present invention is a composition for applying to mucous membranes that is excellent in use feeling and has an excellent effect in preventing and improving diseases and symptoms in which dry mucous membranes such as dry eye, dry nose and dry mouse are dry.

It is a figure which shows the method of the measurement by the conical one plate type rotational viscometer used in the test example.

  Sodium carboxymethyl cellulose used in the composition for applying to mucosa of the present invention is a known polymer compound. As sodium carboxymethylcellulose, those usually used by those skilled in the art for compositions applied to mucous membranes can be used without limitation, but preferably those having a viscosity of 25 m, 2% aqueous solution of 20 mPa · s to 8000 mPa · s, more It is preferably 20 mPa · s to 6000 mPa · s, particularly preferably 20 mPa · s to 3000 mPa · s. Further, the degree of etherification of sodium carboxymethylcellulose may be usually in the range of 0.1 to 3.0, but for the composition applied to mucosa of the present invention, preferably 0.6 to 1.0, more preferably It is 0.6 to 0.9, particularly preferably 0.7 to 0.9.

  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 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) Viscosity of 300 mPa · s to 400 mPa · s, degree of etherification 0.70 to 0.85), AG gum M (viscosity of 2% aqueous solution at 25 ° C., 900 mPa · s to 1500 mPa · s, degree of etherification 0.70 to 0.85), P− 815C (25 ° C., 1% aqueous solution has a viscosity of 1000 mPa · s to 2000 mPa · s, degree of etherification 0.70 to 0.85), etc. are sold by Daicel Chemical Industries, Ltd. CMC Daicel series and Sunrose F series sold by Nippon Paper Chemicals Co., Ltd. can be used.

  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%.

  Examples of terpenoids used in the composition for applying to mucosa of the present invention include monoterpenes such as menthol, borneol, camphor, geraniol, cineol, anethole, limonene, eugenol, sesquiterpenes such as farnesol and nerolidol, diterpenes such as phytol and semblene, and the like. These terpenoids may be used alone or in combination of two or more. Of these, at least one terpenoid selected from menthol, borneol, geraniol or camphor is preferred. These terpenoids may be any of d-form, l-form, and dl-form, and can also be blended as essential oils (peppermint oil, eucalyptus oil, bergamot oil, rose oil, etc.) containing these terpenoids.

  The content of the terpenoid used in the present invention in the composition applied to mucosa varies depending on the type and dosage form, and thus cannot be defined unconditionally. However, the concentration in the composition applied to mucosa is usually 0.0001 to 10%, preferably 0.0005 to 5%, more preferably 0.001 to 3%, still more preferably 0.001 to 1%, and particularly preferably about 0.005 to 1%. The terpenoid is preferably 0.001 to 10 parts by weight, more preferably 0.01 to 5 parts by weight, still more preferably 0.02 to 3 parts by weight, particularly preferably 1 part by weight of sodium carboxymethylcellulose. About 0.05 to 2 parts by weight can be used.

It is more preferable to add a buffering agent to the composition for applying to mucosa of the present 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%. Moreover, in a contact lens cleaning agent, it is 0.001-15% normally, Preferably it is 0.001-10%, More preferably, it is used at about 0.001-7%. 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 more preferable to add inorganic salts to the composition for applying to mucosa 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 more 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 copolymer (for example, poloxamer 407, poloxamer 235, poloxamer 188, etc.); POE-POP block copolymer adduct of ethylenediamine such as poloxamine; POE (20) sorbitan monolaurate (
POE sorbitan fatty acid esters such as polysorbate 20), monooleic 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 hydrogenated castor oil 20, POE hydrogenated castor oil 40, PO
POE-hardened castor oils such as E-hardened castor oil 50, POE-hardened castor oil 60, POE-hardened castor oil 100; POE alkyl ethers such as POE (9) lauryl ether; POE (20) POP (4) cetyl ether, etc. POE / POP alkyl ethers; POE alkylphenyl ethers such as POE (10) nonylphenyl ether. The numbers in parentheses indicate the number of added moles.

  Among these, nonionic surfactants selected from poloxamer, poloxamine, POE sorbitan fatty acid esters or POE hydrogenated castor oil are preferable, and poloxamer, poloxamine, polysorbate 80, POE hydrogenated castor oil 60 are particularly preferable. .

  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%.

More preferably, the composition for applying to mucosa of the present invention is blended with an ethylenediamineacetic acid derivative or a salt thereof. 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 use application of the mucosa of the present invention is not specified as long as it utilizes the effects of the invention, and in various fields such as pharmaceuticals, quasi-drugs, miscellaneous goods, ophthalmic compositions, otolaryngological compositions. It can be used for compositions applied to mucous membranes, such as products, oral compositions, and pharyngeal compositions. Examples of ophthalmic compositions include eye drops (agents) (including eye drops that can be used even while wearing contact lenses, and also eye drops), eye wash (agents) (contact lenses). Contains eye wash that can be used even during wearing, also called eye wash), eye ointment, contact lens mounting solution, contact lens care agent (cleaning solution, preservative solution, bactericidal solution, multipurpose solution, etc.) ), Otolaryngological compositions include nasal drops, nasal washings, and oral compositions include oral preparations, oral cleaning agents, and the like. Preferably, they are nasal drops, eye drops, eye ointments, contact lens mounting liquids, eye wash or contact lens care agents, and particularly preferably useful for nasal drops, eye drops, eye wash, contact lens mounting liquids. It is. In addition, from the viewpoint of improving the wettability of contact lenses, it is further useful for eye drops and facial cleansing agents, contact lens care agents, and contact lens mounting solutions for contact lenses.
In the present specification, contact lenses include all types of contact lenses such as hard, soft, oxygen permeable hard, and color.

  The composition for applying to mucosa of the present invention is preferably used for contact lenses. Among contact lenses, it is particularly preferable to use for soft contact lenses. Soft contact lenses generally cause water dehydration due to increased evaporation of tears and changes in osmotic pressure gradients than hard contact lenses and oxygen-permeable hard contact lenses, resulting in dehydration. For this reason, it is said that the eyes are easy to dry even when the water wetting of the lens does not decrease, and that dry eyes are easily induced. Furthermore, the composition of the present invention is excellent in usability as well as being kept wet.

  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 and the like.
Amino acids: for example, aminoethylsulfonic acid (taurine), 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, 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 Or a pharmacologically acceptable salt thereof.
Sugars: for example, glucose, cyclodextrin and the like.
Polysaccharides: For example, chondroitin sulfate, chondroitin polysulfate, hyaluronic acid, heparin, heparan sulfate, keratosulfuric acid or salts thereof.
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 antibacterial agents: 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.), Glow Kill (manufactured by 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.
Stabilizer: Dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, etc.

  The viscosity of the composition for applying to mucosa of the present invention has a great influence on the improvement of wetting, the feeling of use, the prevention or improvement effect of diseases such as dry eye, etc., so it is important to set the viscosity. The ophthalmic composition is preferably designed with the viscosity at 20 ° C. kept at 1.5 mPa · s or more, 1.5 to 300 mPa · s, preferably 2 to 200 mPa · s, particularly preferably 4 to 100 mPa · s. s, more preferably about 4 to 80 mPa · s. More specifically, the ophthalmic composition is about 1.5 to 200 mPa · s for eye drops, more preferably about 1.5 to 100 mPa · s, and about 1.5 to 70 mPa · s for eyewashes. In the case of a contact lens mounting solution, it is more preferable to design at about 1.5 to 200 mPa · s, and for a contact lens preparation, about 1.5 to 50 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 applied 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 also includes the method of improving the wetness of a corneal surface or a contact lens by mix | blending sodium carboxymethylcellulose and a terpenoid in a composition. In addition, about sodium carboxymethylcellulose and terpenoid, it follows the above-mentioned description regarding the mucosa applicable 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 the viscosity, a commercially available viscometer such as an E-type viscometer [TOKIM (TOKIM
EC), sold by Toki Sangyo (Japan)], Synchronic PC type (Brookfield, USA), Ferranti Shirley (Feranti, UK), Rot Visco R (Haake, Germany), IGK Heischer Rheometer (Ishida Giken, Japan), Shimadzu Rheometer R (Shimazu Seisakusho, Japan), Weissenberg Greogoniometer (Sangamo, UK), Mechanical Spectrometer (Rheometrics, USA), 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, 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: 20 rpm for Test Examples 1, 2, 4, 5, 7, and 9 and 100 rpm for Test Solutions 1, 6, 8, and 8 of Test Example 1. Test Example 2 The test samples 1 to 3 were set to 100 rpm, and the test example 2 test samples 4 and 5 were set to 10 rpm. It was set to 100 rpm for Examples 1, 3 to 5, 7 to 8, 5 rpm for Example 6, and 50 rpm for Examples 2 and 9.
Measurement time: The viscosity after 3 minutes was taken as the measured value.

Test Example 1 Contact Lens Wetting Duration Test A solution according to the formulation shown in Table 1 was prepared as a test solution. Specifically, the preparation method of the test solution 4 is shown. 0.05 g of polysorbate 80 was weighed out into a beaker, 0.02 g of 1-menthol was further weighed, dissolved by stirring, and an appropriate amount of purified water was added to make 50 mL (hereinafter, menthol solution). Furthermore, 30 mL of 0.40 g sodium carboxymethylcellulose (trade name “Serogen AG Gum M”, Daiichi Kogyo Co., Ltd.) and purified water were added and dissolved by stirring. To this, 50 mL of menthol solution was added, and an appropriate amount of purified water was further added to make a total of 100 mL. The other test solutions also became test solution 4.
Each test solution was put in a petri dish, and an oxygen-permeable hard contact lens (Bochrom Japan Co., Ltd., trade name “Bochrom EX-O ₂ ”) immersed in physiological saline all day and night was immersed in each test solution. Next, the test solution was sucked off and exposed from the apex of the contact lens to half the radius in the air. Thereafter, the time until the lens surface was dried was measured while observing the exposed portion of the contact lens with a stereomicroscope (n = 6). The results are shown in Table 1.

  As a result of the test, terpenoids are known to enhance the wettability by reducing the contact angle between the liquid and the contact lens (see JP-A-11-130667). In some cases, the duration of wetting was shortened. Moreover, even with sodium carboxymethylcellulose, which has a known water retention effect, the duration of wetting is not sufficient, and there is no synergistic enhancement effect on wetting even when carboxymethylcellulose sodium is combined with a nonionic surfactant. It was. On the other hand, when carboxymethylcellulose sodium and terpenoid were combined, wetting was confirmed to be synergistically sustained, and it was shown that the composition of the present invention has an excellent wetting improvement effect.

Test Example 2 Friction Feeling Test A test sample was prepared according to the formulation in Table 2. In addition, a polyhydroxy 2-hydroxyethyl methacrylate (hereinafter, pHEMA) gel having a water content of 38% was prepared for use in the test, and a 2 cm × 5 cm rectangular block was cut out and immersed in physiological saline for 2 days. The soaked pHEMA gel was taken out of the physiological saline and gently wiped off the water, and then placed on a petri dish fixed on the sample table, and the MIU value was measured quickly 5 times to obtain an average value (this is a basic value). . Next, the pHEMA gel soaked in the same manner was taken out and lightly wiped off, and 1 mL of a test sample was dropped and the MIU value was measured 5 times continuously. The reduction rate was calculated as (MIU basic value of pHEMA gel−MIU value of pHEMA gel dropped for each test sample) ÷ MIU basic value of pHEMA gel, and measurement was performed 5 times with 3 PHEMA gels for each test sample. The average MIU reduction rate was calculated. It shows that the pHEMA gel surface became slippery as the MIU value decreased.
In addition, the friction feeling tester KES-SE (Kato Tech Co., Ltd.) was used for the measurement of MIU value. Each time the PHEMA gel was replaced, the friction element was cleaned with ethanol under the measurement conditions of the friction tester, sensitivity H (20 g / v), load 50 (gf), SPEED 10 mm / sec.

  As a result of the test, it was confirmed that by further containing menthol in the composition containing carboxymethylcellulose, there was an effect of reducing friction on the pHEMA gel. This effect was confirmed both in the low-viscosity composition and in the high-viscosity composition. pHEMA gel is a material commonly used for contact lenses, and friction reduction on such a gel is achieved by the present invention between the contact lens and the eyelid conjunctiva, between the contact lens and the cornea surface, or between the eyelid conjunctiva and the cornea surface. By reducing the friction generated in the eye, it is shown that it has the effect of improving the feeling of use by reducing the risk of irritation to the eye by reducing the sensation of blinking or by contact lenses. Further, when used when wearing a contact lens, it shows that the discomfort such as a foreign object feeling when wearing the contact lens is remarkably reduced.

Examples Each Example 1-9 in the table shall be described as 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, wetting was improved and the usability was improved.

Claims (16)

A mucosa-applied composition containing sodium carboxymethylcellulose and a terpenoid for preventing and / or improving dry eye (where the mucosa-applied composition has the formula (1) [in formula (1), R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom or an optionally substituted alkyl group] and a pharmacologically acceptable salt thereof. Except for ophthalmic compositions containing at least one compound) .

  The mucosa-applied composition according to claim 1, wherein the amount of terpenoid relative to 1 part by weight of sodium carboxymethylcellulose is 0.01 to 5 parts by weight.   The mucosa-applied composition according to claim 1 or 2, wherein the content of sodium carboxymethylcellulose is 0.05 to 0.6% (w / v).   The mucosa-applied composition according to any one of claims 1 to 3, wherein the viscosity at 20 ° C is 1.5 mPa · s to 80 mPa · s.   The mucosa-applied composition according to any one of claims 1 to 4, wherein the terpenoid is at least one selected from menthol, camphor, borneol, and geraniol.   The composition according to any one of claims 1 to 5, which is used for contact lenses.   The mucosa-applied composition according to any one of claims 1 to 6, which is an eye drop, an eye ointment, a contact lens mounting solution, an eye wash, or a contact lens care agent.   The mucosa-applied composition according to any one of claims 1 to 7, wherein the viscosity of sodium carboxymethylcellulose at 25 ° C and a 2% (w / v) aqueous solution is 20 mPa · s to 8000 mPa · s.   The composition for mucosal application according to any one of claims 1 to 8, wherein the degree of etherification of carboxymethylcellulose sodium is 0.6 to 1.0.   Furthermore, the composition applied to mucosa according to any one of claims 1 to 9, further comprising a nonionic surfactant.   Furthermore, the composition applied to mucosa according to any one of claims 1 to 10, further comprising at least one selected from ethylenediamineacetic acid derivatives or salts thereof, inorganic salts, and buffering agents. Mucosal composition containing sodium carboxymethylcellulose and terpenoid for maintaining the corneal surface and / or contact lens (however, the composition applied to mucosa is R ^{1 in} Formula (1) [ ^1] , R ² and R ³ may be the same or different and each represents a hydrogen atom or an optionally substituted alkyl group] and pharmacologically acceptable salts thereof. Except when the composition is an ophthalmic composition containing at least one selected compound) .

A mucosa-applied composition containing sodium carboxymethylcellulose and a terpenoid for improving discomfort at the time of wearing a contact lens (however, the mucosa-applied composition has the formula (1) [in formula (1), R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom or an optionally substituted alkyl group] and a pharmacologically acceptable salt thereof. Except for ophthalmic compositions containing at least one compound) .

Mucosal composition containing sodium carboxymethylcellulose and terpenoid for preventing and / or improving dry eye (however, the mucosa-applied composition is selected from limonene, terpinene, ferrandrene, pinene) In the case of an ophthalmic composition containing a monocyclic monoterpene ketone selected from monoterpene hydrocarbons, menthone, isomenton, carvone, piperiton, plegon, monocyclic monoterpene ketone selected from cineol, And represented by the formula (1) [in the formula (1), R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom or an optionally substituted alkyl group]. An ophthalmic composition comprising at least one compound selected from a compound and a pharmacologically acceptable salt thereof Except in the case of

A method for imparting a wetting improvement effect on a corneal surface and / or a contact lens to a composition applied to a mucosa by blending sodium carboxymethylcellulose and a terpenoid in the composition applied to a mucosa (provided that the composition applied to a mucosa has the formula ( 1) [In the formula (1), R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom or an optionally substituted alkyl group] and these compounds Except in the case of an ophthalmic composition containing at least one compound selected from pharmacologically acceptable salts) .

A method for imparting a friction reducing action to a mucosa-applied composition by incorporating sodium carboxymethylcellulose and a terpenoid in the mucosa-applied composition (however, the mucosa-applied composition has the formula (1) [in formula (1) , R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom or an optionally substituted alkyl group] and pharmacologically acceptable salts thereof Except in the case of an ophthalmic composition containing at least one compound selected from among the above) .

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