JP2010229159A - Liquid composition applicable to mucous membrane - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a liquid composition applicable to mucous membranes, containing hyaluronic acids and having high viscosity stability. <P>SOLUTION: The liquid composition applicable to mucous membranes comprises (A) hyaluronic acids, (B) a nonionic surfactant and (C) at least one kind of compounds selected from the group consisting of vitamin Es and their derivatives, wherein the composition comprises, per total amount of composition, (A) the hyaluronic acids with concentration of 0.0001-0.01 (w/v)%, (B) the nonionic surfactant with concentration of 0.001-10 (w/v)%, and (C) the vitamin Es and their derivatives with concentration of 0.00005-0.1 (w/v)%. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a liquid composition applied to mucous membranes in which a decrease in viscosity is suppressed, and more specifically, a method for suppressing molecular weight reduction or decomposition of hyaluronic acid in a composition containing a surfactant and hyaluronic acid, and the method It is related with the liquid composition applied to mucosa obtained by this.

  Hyaluronic acid is a polymer composed of glucuronic acid and N-acetylglucosamine, is a mucopolysaccharide that exhibits high viscoelasticity in aqueous solution and is widely distributed mainly in connective tissues in vivo. Due to its high viscosity and safety to the living body, it is widely used in the medical field. For example, in the ophthalmology region, it has high viscoelasticity, and it has been generated by dry eye and contact lens wearing because it has a corneal wound healing promoting action and a corneal epithelial extension promoting action as a surgical aid during eye surgery. It is one of the substances useful as a component of various ophthalmic compositions such as a therapeutic agent for corneal epithelial disorder.

  In recent years, with the spread of personal computers and the increase in the population of wearing contact lenses, an increasing number of people suffer from so-called dry eye symptoms. In order to alleviate such symptoms, topical preparations such as eye drops (or eye drops) are often used. In order to effectively relieve dryness of the eyes, these preparations are formulated with a thickening agent for the purpose of improving the retention at the application site, or have a therapeutic effect on corneal epithelial disorders caused by dry eye. Although there are many occasions when a high drug is blended, sodium hyaluronate is often used as a substance having these effects.

  Since hyaluronic acid is easily decomposed in aqueous solution, it is formulated in the form of a salt (for example, sodium salt) that is more difficult to decompose when blended in a preparation. However, even such salts are unstable in aqueous solution. is there. Known factors that affect the stability of hyaluronic acids include pH, free radicals, metals, and surfactants. In liquid preparations for application to mucous membranes such as ophthalmic compositions, surfactants are often added as solubilizers for the purpose of increasing the solubility of various components to be mixed. Is decomposed over time, and the molecular weight decreases. As a result, the viscosity of the preparation may decrease, and the high viscoelasticity of the preparation tends to be impaired. In this case, the molecular weight reduction usually does not reach a plateau (Patent Document 1, Patent Document 2). When hyaluronic acids are decomposed and reduced in molecular weight, sufficient pharmacological effects of hyaluronic acids at the application site cannot be obtained, or the high viscoelasticity of the composition decreases or disappears, resulting in deterioration of the retention of the preparation at the application site, It causes inconvenience not only in terms of medicinal properties but also in terms of functionality. Thus, the decomposition of hyaluronic acids in a hyaluronic acid-containing composition is a problem that cannot be ignored from the viewpoint of quality control, and a method for stabilizing hyaluronic acids is strongly demanded.

  Conventionally, a method of adding an iodine-containing reducing agent and / or a sulfur-containing reducing agent has been proposed to suppress a decrease in the molecular weight of sodium hyaluronate in an aqueous solution (Patent Document 3). However, sulfur compounds cause white turbidity and yellowing due to changes over time, and iodine is not suitable as a component of ophthalmic compositions because it has eye irritation. In order to increase the viscosity of the sodium hyaluronate solution in the aqueous solution, a method of blending boric acid into the hyaluronic acid aqueous solution as a thickener has been proposed (Patent Document 4). However, according to the method of Patent Document 4, only the initial viscosity value of the hyaluronic acid aqueous solution is increased, and the viscosity decreasing tendency itself is not affected.

JP-A-9-227385 JP-A-10-72376 JP-A-10-212303 JP-A-11-43446

An object of the present invention is to stably maintain the viscosity of a liquid composition for mucosa containing a surfactant and hyaluronic acids.
Specifically, an object of the present invention is to provide a mucosa-applied liquid composition in which the degradation of hyaluronic acids in the presence of a surfactant is suppressed.
Another object of the present invention is to provide a method for stabilizing hyaluronic acids in a liquid composition for mucosa in which a surfactant and hyaluronic acids are blended.

The present inventors have found that the addition of a certain antioxidant to an aqueous solution containing hyaluronic acids and a surfactant suppresses the tendency to lower the molecular weight of hyaluronic acids, leading to the completion of the present invention. It was. In the present specification, suppression of the tendency to lower the molecular weight (decomposition) of hyaluronates is judged by using a decrease in the viscosity of the solution as an index.
That is, the present invention
[1] Mucosal application, comprising A) hyaluronic acid, B) nonionic surfactant, and C) at least one compound selected from the group consisting of vitamin E and derivatives thereof A liquid composition per total amount of the composition,
A) The concentration of hyaluronic acid is 0.0001 to 0.01 (w / v)%,
B) The concentration of the nonionic surfactant is 0.001 to 10 (w / v)%,
C) Mucosa-applied liquid composition in which the concentration of vitamins E and derivatives thereof is 0.00005 to 0.1 (w / v)%,
[2] The liquid composition for mucosa according to the above [1], wherein the nonionic surfactant comprises polyoxyethylene sorbitan fatty acid esters,
[3] The liquid composition applied to mucosa according to the above [1] or [2], which is an ophthalmic composition,
[4] Mucosa-applied liquid composition according to the above [3], which is any of eye drops, eyewashes, and contact lens mounting liquids,
And so on.

  According to the present invention, the hyaluronic acid can be prevented from lowering or decomposing in the liquid composition for mucous membranes containing hyaluronic acid and a surfactant, and the viscosity of the composition can be prevented from decreasing. The medicinal effect and functionality of the liquid composition for mucous membranes containing can be maintained well for a long period of time. Accordingly, it is possible to supply a liquid composition having a higher quality applied to mucosa.

1 is a schematic diagram showing the basic structure of a cone-plate rotational viscometer for viscosity measurement.

  The present invention relates to a liquid composition for application to mucosa in which the molecular weight reduction or degradation of hyaluronic acid is suppressed. In the present specification, “the molecular weight reduction or degradation of hyaluronic acid is suppressed” and “hyaluronic acid is The terms “stabilized, viscosity reduction of the liquid composition applied to mucosa is suppressed, viscosity reduction rate is reduced, or viscosity reduction curve reaches a plateau state” are used interchangeably.

  The mucous membrane to which the liquid composition for mucosa application in the present invention is applied includes, for example, ocular mucosa such as cornea and conjunctiva, nasal mucosa, gums, tongue, lips, oral mucosa, pharyngeal mucosa, anal mucosa, rectal mucosa, Includes vulva mucosa, vaginal mucosa and the like. Among these, the present composition is suitable for use in preparations applied to ocular mucosa such as cornea and conjunctiva, nasal mucosa, pharyngeal mucosa, particularly ocular mucosa.

  In the liquid composition for mucosa application of the present invention (hereinafter simply referred to as “the composition of the present invention”), any hyaluronic acid generally used in preparations for mucosa application in ophthalmic areas and the like can be used. Examples of such hyaluronic acids include hyaluronic acid or derivatives thereof or pharmaceutically and physiologically acceptable salts thereof. In addition, origin (chicken origin, microorganism origin, etc.) and molecular weight are not particularly limited, but specific examples include hyaluronic acid, sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate and the like. Sodium acid is preferred. The molecular weight of the hyaluronic acid used in the present invention is preferably an average molecular weight in the range of 500,000 to 5,000,000, more preferably 600 to 4,000,000, particularly preferably 600 to 2,500,000.

  The blending amount of hyaluronic acids in the composition of the present invention varies depending on the use of the composition, the intended viscosity, the molecular weight of the hyaluronic acid used, and the like. For example, when the liquid composition applied to mucosa is an ophthalmic composition such as eye drops The range is usually 0.0001 to 10% by weight, more preferably 0.001 to 1% by weight, and particularly preferably 0.005 to 0.5% by weight. Note that if the concentration falls outside this concentration range, viscosity is not imparted to the preparation, and it is difficult to obtain a sufficient effect in terms of pharmacology. There is a risk of hindering the filtration operation.

  In the composition of the present invention, any surfactant generally used in mucosal preparations such as nonionic surfactants, anionic surfactants, amphoteric surfactants, and cationic surfactants can be used. . However, since the hyaluronic acid stabilization method of the present invention has an excellent effect particularly in the case of a liquid composition for mucosa containing a nonionic surfactant, a nonionic surfactant is preferred.

  Nonionic surfactants include polyoxyethylene (hereinafter referred to as “POE”)-polyoxypropylene (hereinafter referred to as “POP”) block copolymers (poloxamers), POE sorbitan fatty acid esters (polysorbates) POE hydrogenated castor oil such as POE (60) hydrogenated castor oil, POE alkyl ethers such as POE (9) lauryl ether, POE / POP alkyl ethers such as POE (20) POP (4) cetyl ether, POE ( 10) POE alkylphenyl ethers such as nonylphenyl ether, POE castor oil, and the like.

Specifically, examples of the poloxamers include poloxamer 407, poloxamer 235, poloxamer 188, and the like, among which poloxamer 407 is preferable.
Examples of the POE sorbitan fatty acid esters include monolauric acid POE (20) sorbitan (polysorbate 20), monooleic acid POE (20) sorbitan (polysorbate 80), and polysorbate 80 is particularly preferable. (The number in parentheses represents the number of moles added).
Examples of POE alkylphenyl ethers include polyoxyethylene hydrogenated castor oil 5, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60 and the like. Castor oil 60 is preferred. (The number in parentheses represents the number of moles added).

These nonionic surfactants may be blended singly or in combination of two or more.
The compounding amount of the nonionic surfactant in the composition of the present invention varies depending on the use and the type of the surfactant used. For example, the liquid composition applied to the mucous membrane is an ophthalmic composition such as an eye drop or an eye wash. In this case, it is usually in the range of 0.001 to 10% by weight, preferably 0.01 to 5% by weight, particularly preferably 0.01 to 1% by weight. Note that if the concentration is significantly lower than this concentration range, the dissolving power for other components decreases, while if the concentration is outside the concentration range, eye irritation tends to appear, and the stability of other components is adversely affected. There is also a risk.

  Other surfactants used in the composition of the present invention include amphoteric surfactants such as glycine type such as alkyldiaminoethylglycine, betaine acetate type such as lauryldimethylaminoacetic acid betaine, and imidazoline type; POE (10) lauryl ether phosphorus POE alkyl ether phosphoric acid and salts thereof such as sodium acid, N-acyl amino acid salts such as sodium lauroylmethylalanine, alkyl ether carboxylates, N-acyl taurine salts such as sodium cocoylmethyl taurate, sodium tetradecenesulfonate Sulfonates such as sodium sulfate, alkyl sulfates such as sodium lauryl sulfate, POE (3) POE alkyl ether sulfates such as sodium lauryl ether sulfate, anionic surfactants such as α-olefin sulfonates; alkylamine salts And cationic surfactants such as alkyl quaternary ammonium salts (such as benzalkonium chloride and benzethonium chloride) and alkylpyridinium salts (such as cetylpyridinium chloride and cetylpyridinium bromide). The numbers in parentheses indicate the number of added moles. The amount of these surfactants is also the same as in the case of the nonionic surfactant.

The fat-soluble vitamins and their derivatives used in the composition of the present invention are exemplified below.
Examples of the fat-soluble vitamins include vitamin Es, vitamin As and derivatives thereof.
Examples of vitamin E include tocopherol and derivatives thereof or salts thereof, ubiquinone derivatives or salts thereof, and both natural products and synthetic products can be used. The salt that can be used can be used as a pharmacologically (pharmaceutically) or physiologically acceptable salt. Examples of pharmacologically or physiologically acceptable salts include organic acid salts (lactate, acetate, butyrate, trifluoroacetate, fumarate, maleate, tartrate, citrate, succinate. , Malonate, methanesulfonate, toluenesulfonate, tosylate, palmitate, stearate, etc., inorganic salts (eg hydrochloride, sulfate, nitrate, hydrobromide, phosphoric acid) Salts), salts with organic bases (eg, salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, amino acids, tripyridine, picoline), salts with inorganic bases (eg, Ammonium salts, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, metals such as aluminum , And others such as salts).

Specifically, there are d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, etc. Examples of these derivatives include vitamin E acetate (tocopherol acetate), vitamins, and the like. E nicotinic acid ester, vitamin E succinic acid ester, vitamin E linolenic acid ester and the like. Of these, tocopherol acetate (such as d-α-tocopherol acetate and dl-α-tocopherol acetate) is preferable.
These vitamin E can be used individually by 1 type or in combination of 2 or more types as appropriate.
The amount of vitamin E compounded in the composition of the present invention is usually 0.00005 to 0.5% by weight, preferably 0.0005 to 0.25% by weight, particularly preferably 0.001 to 0.1% by weight. is there. In addition, when it deviates significantly from this concentration range, the hyaluronic acid-containing mucosa-applied liquid composition for mucous membranes of the present invention may not be able to sufficiently exhibit the effect of suppressing the viscosity reduction. On the other hand, if the concentration is too high, there is a tendency to cause inconveniences such as stickiness when used, and it is necessary to increase the amount of surfactant necessary to solubilize vitamin Es. The eye irritation associated with it may appear.

As vitamin A, in addition to vitamin A, a mixture containing vitamin A and a derivative having vitamin A activity can be mentioned, and any of natural products and synthetic products can be used.
Specifically, retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene and pharmacologically acceptable salts thereof (for example, retinol acetate, retinol palmitate, etc.), among which retinol acetate and retinol palmitate are used. preferable.
The compounding amount of vitamin A in the composition of the present invention is usually 0.0010,000 to 200,000 I.D. U. / 100 mL, preferably 10 million to 100,000 IU / 100 mL, particularly preferably in the range of 50,000 to 70,000 IU / 100 mL. In addition, when it deviates significantly from this concentration range, the hyaluronic acid-containing mucosa-applied liquid composition for mucous membranes of the present invention may not be able to sufficiently exhibit the effect of suppressing the viscosity reduction. On the other hand, if the concentration is too high, there is a tendency to cause inconveniences such as stickiness when used, and it is necessary to increase the amount of surfactant necessary to solubilize vitamin As. The eye irritation associated with it may appear.

  The composition of the present invention is selected from vitamin Es, fat-soluble vitamins including vitamin A and derivatives thereof (hereinafter, these may be collectively referred to as “fat-soluble vitamins etc.”). At least one compound can be contained. When the composition of the present invention contains one or more compounds, they may be selected from the same type or from two or more types. When it contains 2 or more types, the compounding quantity in a composition is suitably determined according to the compounding quantity of each compound. The compound to be used may vary depending on the application, the type of coexisting surfactant, etc., but vitamin A and vitamin E are more preferable, and vitamin E specifically shown above is particularly preferable.

  In the present invention, when vitamins or the like according to the above definition are added to a liquid composition for mucous membranes containing a surfactant and hyaluronic acids, the molecular weight of the hyaluronic acids is suppressed and compared with the case where no vitamins are present. Therefore, it is based on the knowledge that the viscosity reduction of the composition can be prevented. That is, in the composition of the present invention, since the molecular weight reduction of hyaluronic acids is suppressed, a decrease in the viscosity of the composition can be suppressed and a suitable viscosity can be stably maintained. Therefore, the composition of the present invention has a characteristic that the viscosity reduction rate is small as compared with the case where vitamins and the like are not contained.

  The viscosity value of the liquid composition for mucous membranes of the present invention varies depending on the preparation. For example, when the composition is an ophthalmic composition, sterilization is necessary, and the relationship with the workability of the filtration process. Therefore, it is desirable that the absolute viscosity value measured at 20 ° C. is in the range of 200 mPa · s or less. On the other hand, for the purpose of imparting viscosity, it is desirable that the absolute viscosity value measured at 20 ° C. is 1.2 mPa · s, preferably 2 mPa · s, more preferably 5 mPa · s or more.

  The viscosity of the liquid composition for mucosa of the present invention can be measured by any method used in the art. In the present specification, a viscosity measuring method using a known cone-disk rotational viscometer (general test method, 45. viscosity measuring method, second method rotating viscometer method described in the 14th revised Japanese pharmacy method, It is based on the measured value by the method described in “(3) Cone-Plate type rotational viscometer”.

  In addition, the present invention provides a method for producing a liquid composition for application to mucosa that suppresses the lowering of the molecular weight of hyaluronic acid in a solution containing hyaluronic acid and a surfactant and is excellent in viscosity stability. That is, the present invention relates to a method for stabilizing hyaluronic acid, and the stabilization method of the present invention includes at least one selected from the aforementioned fat-soluble vitamins and derivatives thereof in a solution containing hyaluronic acid and a surfactant. This can be achieved by compounding the compounds. Therefore, the aforementioned fat-soluble vitamins and their derivatives can be said to be hyaluronic acid stabilizers. The types, blending ratios, blending methods, and the like of hyaluronic acids, surfactants, fat-soluble vitamins, etc. used in the stabilization method of the present invention should be carried out according to the description of the liquid composition applied to mucosa in the present specification. Can do.

  The composition of the present invention includes various components (including pharmacologically active components and physiologically active components) in addition to the hyaluronic acids, surfactants and fat-soluble vitamins defined above, unless they are contrary to the object of the present invention. Can be blended. Examples of ingredients that can be added include, for example, a decongestant component, an anti-inflammatory component, an antihistamine component, an astringent component, a bactericidal component, an antineoplastic component, hormones, proteins or peptides, other vitamins, amino acids Can be used. Furthermore, an ocular muscle modifier component, a saccharide, a local anesthetic component, a steroid component, cellulose or a derivative thereof or a salt thereof, a polysaccharide or a derivative thereof may be contained. Specifically, the following components can be exemplified.

  Decongestant: epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine and their salts.

  Eye muscle modulator component: cholinesterase inhibitor having an active center similar to acetylcholine, for example, quaternary ammonium compounds such as neostigmine methyl sulfate and salts thereof.

  Anti-inflammatory components: Celecoxib, rofecoxib, indomethacin, diclofenac, pranoprofen, piroxicam, meloxicam, epsilon-aminocaproic acid, berberine, azulene, glycyrrhizic acid, zinc, lysozyme, salicylic acid methyl Allantoin and pharmacologically acceptable salts (for example, berberine chloride, berberine sulfate, diclofenac sodium, azulene, guaiazulene, kamaazulene, sodium guaiazulenesulfonate, sodium azulenesulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, chloride) Lysozyme, etc.).

  Antihistamine components: for example, diphenhydramine, chlorpheniramine, iproheptin, ketotifen, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglycic acid, tranilast, amlexanox, mequitazine, loratadine (loratadine) cetirizine), ibudilast, suplatast, pemirolast, and pharmacologically acceptable salts (eg, diphenhydramine hydrochloride, chlorpheniramine maleate, iproheptin hydrochloride, ketotifen fumarate, emedastine fumarate, clemastine fumarate, azelastine hydrochloride, levocaustine hydrochloride) Olopatadine hydrochloride, sodium cromoglycate, etc.).

  Bactericidal component: for example, sulfonamides (eg, sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisomidine sodium, etc.)) , Acrinol, quaternary ammonium compounds (eg benzalkonium, benzethonium, cetylpyridinium and pharmacologically acceptable salts (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, etc.)), alkyl Polyaminoethylglycine, new quinolone (lomefloxacin, levofloxacin, ciprofloxacin hydrochloride, ofloxacin, norfloxacin, etc.), etc.

  Vitamins: For example, vitamin Bs (for example, thiamine, bisthiamine, thiamine disulfide, dicetiamine, octothiamine, chicotiamine, bisibutamine, bisbenchamine, prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine Dinucleotide, pyridoxine, pyridoxal, hydroxocobalamin, cyanocobalamin, methylcobalamin, deoxyadenocobalamin, folic acid, tetrahydrofolic acid, dihydrofolic acid, nicotinic acid, nicotinic amide, nicotinic alcohol, pantothenic acid, panthenol, biotin, choline, inositol and Their pharmacologically acceptable salts (eg thiamine hydrochloride, thiamine nitrate, discetiamine hydrochloride, fursultiamine hydrochloride, riboflavybutyrate) Flavin adenine dinucleotide sodium, pyridoxine hydrochloride, pyridoxal phosphate phosphate, calcium pyridoxal phosphate, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, calcium pantothenate, sodium pantothenate, etc.)) and other vitamin Ds (eg, ergocalciferol, Other vitamins such as calciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotaxosterol and pharmacologically acceptable salts thereof (eg carnitine, ferulic acid, γ-oryzanol, orotic acid, cyanocobalamin) , Rutin, eriocitrin, hesperidin and pharmacologically acceptable salts thereof (such as carnitine chloride).

  Amino acids: for example, leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, asparagine, aspartic acid, serine, glutamine, glutamic acid, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, hydroxy Lysine, glycylglycine, aminoethylsulfonic acid (taurine) and pharmacologically acceptable salts thereof (for example, potassium aspartate, magnesium aspartate, cysteine hydrochloride, etc.) and the like.

  Sugars: monosaccharides (eg glucose), disaccharides (eg trehalose, lactose, fructose etc.), oligosaccharides (eg lactulose, raffinose, pullulan etc.), cellulose or derivatives thereof (eg methylcellulose, ethylcellulose, hydroxyethylcellulose) , Hydroxypropylcellulose, carboxymethylcellulose, carboxyethylcellulose, nitrocellulose, etc.), high-molecular sugars (eg chondroitin sulfate) and pharmacologically acceptable salts thereof (eg sodium chondroitin sulfate)), sugar alcohols (eg Mannitol, xylitol, sorbitol, etc.).

Antipruritic ingredients (such as crotamiton, ictamol, moctamol or thymol acid).
Other components: polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, etc.

  The content of these components can be selected according to the type of preparation, the type of active ingredient, etc., for example, from 0.0001 to 30%, preferably from about 0.001 to 10% with respect to the whole preparation. You can choose. More specifically, each component can be contained in the liquid composition for mucosa of the present invention in the amounts exemplified below.

Decongestant component: for example, 0.0001 to 2%, preferably 0.0005 to 1.0%.
Eye muscle modulator component: For example, 0.0001 to 0.5%, preferably 0.0002 to 0.1%.
Anti-inflammatory component or astringent component: for example 0.001-10%, preferably 0.002-5%.
Antihistamine or antiallergic ingredient: for example 0.0001-10%, preferably 0.001-5%.
Bactericidal component: for example 0.001 to 10%, preferably 0.01 to 5%
Vitamins: For example, 0.0001 to 1%, preferably 0.001 to 0.5%.
Amino acids: For example, 0.0001 to 10%, preferably 0.001 to 3%.

  The mucosa-applied liquid composition of the present invention is prepared by arbitrarily selecting and using various ingredients and additives used in pharmaceuticals, quasi drugs, etc., as long as the effects of the present invention are not impaired. It is possible to Although a specific example is given below, it is not limited to this.

  Sugars: for example, glucose, fructose, galactose, mannose, ribose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, lactose, pullulan, lactulose, raffinose, maltitol and the like Acceptable salts.

  Thickeners: gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac gum, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, carrageenan, gelatin, collagen, Pectin, starch, polygalacturonic acid, chitin and derivatives thereof, chitosan and derivatives thereof, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, chondroitin sulfate, ceramide, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Carboxymethylcellulose, carboxyethylcellulose, cellulose, nitrocellulose, poly Vinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, macrogol, polyvinyl methacrylate, polyacrylic acid, carboxyvinyl polymer, polyethyleneimine, ribonucleic acid, deoxyribonucleic acid, carboxyvinyl polymer, etc., and pharmacologically acceptable Salt etc.

  Antiseptic / antibacterial / bactericidal agents: for example, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, acrinol, methyl rosaniline chloride, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide , Chlorhexidine, polyhexamethylene biguanide, alkylpolyaminoethylglycine, benzyl alcohol, phenethyl alcohol, chlorobutanol, isopropanol, ethanol, phenoxyethanol, silver phosphate silver support, thimerosal, povidone iodine, dehydroacetic acid, chlorxylenol, chlorophene , Phenol, resorcin, orthophenylphenol, isopropylmethylphenol, thymol, hinokitio Sulfamine, lysozyme, lactoferrin, triclosan, 8-hydroxyquinoline, undecylenic acid, caprylic acid, propionic acid, benzoic acid, propionic acid, sorbic acid, triclocarban sorbate, halocarban, thiabendazole, polymyxin B, 5-chloro- 2-methyl-4-isothiazolin-3-one, 2-methyl-4-isothiazolin-3-one, polylysine, hydrogen peroxide, quaternary ammonium polymers (polydronium chloride (polyquarterium-1), Glokill (product) Name, manufactured by Rhodia), Unisense CP (trade name, poly (diallyldimethylammonium chloride), manufactured by Senca), WSCP (trade name, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio) etrange chloride] About 60 weight Content, manufactured by Bachman Laboratories)), biguanide compounds (Cosmocil CQ (trade name, polyhexamethylene biguanide hydrochloride about 20% by weight, manufactured by Avicia)), and pharmacologically acceptable salts thereof Etc.

  pH adjuster: for example, hydrochloric acid, sulfuric acid, lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid, fumaric acid, propionic acid, acetic acid, aspartic acid, epsilon aminocaproic acid, glutamic acid, aminoethyl Sulfonic acid, phosphoric acid, polyphosphoric acid, boric acid, gluconolactone, ammonium acetate, sodium bicarbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, monoethanolamine, triethanolamine, Diisopropanolamine, triisopropanolamine, lysine, borax, etc., and pharmacologically acceptable salts thereof.

  Isotonizing agents: For example, polyhydric alcohols such as glycerin and propylene glycol, saccharides such as butter sugar, mannitol and sorbitol.

  Chelating agents: for example, edetic acid, citric acid, polyphosphoric acid, hexametaphosphoric acid, metaphosphoric acid, ascorbic acid, succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, and the like Pharmacologically acceptable salts and the like.

  Water-soluble polymer substances: for example, gelatin, polyacrylic acid and its salts, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, methylvinylether / anhydrous Maleic acid copolymer, sodium alginate, polyethylene oxide, gum arabic, xanthan gum, gum tragacanth and the like.

  Polyhydric alcohol: For example, glycerin, sorbitol, propylene glycol, polyethylene glycol, 1,3-butylene glycol, ethylene glycol and the like.

Cross-linking agent: For example, polyhydric metal compounds such as aluminum hydroxide, magnesium aluminum hydroxide, aluminum glycinate, dihydroxyaluminum aminoacetate, and synthetic leather hydrotalcite.
Swelling agent: For example, kaolin, bentonite, titanium oxide, silicic anhydride, etc.

  Inorganic salts: For example, sodium chloride, potassium chloride, sodium carbonate, sodium hydrogen carbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium thiosulfate, sodium acetate and the like.

Furthermore, a fragrance | flavor or a cooling agent, a local anesthetic, etc. can be added as needed.
A fragrance | flavor or a refreshing agent: For example, menthol, camphor, borneol, geraniol, cineol, anethole, limonene, eugenol, menthone etc. are mentioned. These may be any of d-form, l-form, or dl-form. From the viewpoints of sensory and safety such as refreshing feeling and fragrance, 1-menthol, d-menthol, dl-menthol, d-camphor, dl-camphor , D-borneol, dl-borneol and geraniol are preferred. Moreover, l-menthol, d-camphor and d-borneol are particularly preferred. The monoterpene can also be used in the state of being contained in essential oils. Preferred essential oils are eucalyptus oil, bergamot oil, fennel oil, mint oil, cinnamon oil, rose oil, peppermint oil, cool mint oil, spearmint oil. These monoterpenes can be used alone or in combination of two or more.
Local anesthetics: For example, lidocaine, lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.

The liquid composition for mucosal application of the present invention can be formulated into any aqueous or non-aqueous dosage form prepared in a certain viscosity range, and such a preparation includes an ophthalmic therapeutic agent (eye drops, Eyewash, ophthalmic perfusate, contact lens mounting solution, ophthalmic solutions such as contact lens agents), otolaryngological drugs (including nasal and nasal solutions such as nasal wash), dental oral medicine (Including throat liquids such as oropharyngeal drugs and dental liquids such as stomatitis drugs). In particular, it is preferably in the form of an ophthalmic therapeutic agent.
As an administration method, instillation such as instillation and instillation, spray administration and the like are preferable, but not particularly limited. The “contact lens agent” is a composition for storing, cleaning and disinfecting contact lenses. The preparation of the present invention is preferably an ophthalmic therapeutic agent, and is particularly preferably in the form of eye drops or eye wash. For the purposes of the present invention, it is preferably aqueous.
Unless otherwise stated, the term contact lens (CL) is used to encompass all types of contact lenses, such as hard, oxygen permeable hard, and soft.

  The composition of the present invention is adjusted to a pH and / or osmotic pressure within a range acceptable to a living body as necessary. The acceptable pH is usually pH 4.0 to 9.0, preferably 4.5 to 8.5, particularly preferably 4.5 to 8.0. 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 0.3 to 4.1, preferably 0.3 to 2. 1, particularly preferably about 0.5 to 1.4. The adjustment of pH and osmotic pressure can be performed by a method known in the art using the aforementioned pH adjusting agent, tonicity agent, salts and the like.

  The composition of the present invention can be produced by a known method using an aqueous or non-aqueous diluent or the like. For example, examples of the aqueous solution or suspension diluent include distilled water and physiological saline. Non-aqueous diluents or suspensions include vegetable oil, liquid paraffin, mineral oil, propylene glycol, p-octyldodecanol and the like.

  Eye drops and eye washes are prepared by mixing arbitrary additives with the hyaluronic acids, surfactants and vitamins of the present invention in a suitable diluent such as distilled water or purified water, and adjusting the osmotic pressure and pH described above. It can be prepared by adjusting, performing filtration sterilization treatment in an aseptic environment as required, and aseptically filling a container that has been washed and sterilized.

  The container for containing the composition for applying mucosa in the present invention is not particularly defined, but preferably polyesters (polyethylene terephthalate, polyethylene naphthalate, polycyclohexylene / dimethyl terephthalate, U polymer, polybutylene terephthalate, etc. ), Polycarbonates (polycarbonate, etc.), polyolefins (polyethylene, polypropylene, cyclic polyolefins, etc.), ethylene / vinyl alcohol copolymers and the like. Alternatively, a blended product, a copolymer, or a multilayer molded product may be used, and polyolefins, polyesters, polyamides, and polycarbonates may be blended. More preferably, polyethylene and polypropylene are not present in the innermost layer.

EXAMPLES The present invention will be described in more detail with reference to the following examples, but these do not limit the scope of the present invention.
The viscosity was measured in the following examples and test examples by the following method.
The viscosity was measured by a method using a conical one plate type rotational viscometer described in WO97 / 28827, JP-A-2002-265671 and the like. This method is described in the General Test Method, 45. Viscosity Measurement Method, Second Method Rotational Viscometer Method, “(3) Cone-Plate Rotational Viscometer” described in the 14th revised Japanese Pharmacy Law. It is the same as the method. The viscosity can be measured using a commercially available cone-plate rotational viscometer and an appropriately selected rotor. For example, such a viscometer includes an E-type viscometer [TOKIMEC. , Manufactured by Toki Sangyo (Japan)], Synchronic PC type (Brookfield, USA), Ferranti Shirley (Feranti, UK), Rot Visco R (Haake, Germany), IGK High Shear Rheometer ( Ishida Giken, Japan), Shimadzu Rheometer R (Shimazu Seisakusho, Japan), Weissenberg Greogoniometer (Sangamo, UK), Mechanical Spectrometer (Rheometrics, USA), etc. By appropriately selecting these commercially available viscometers and rotors, and appropriately adjusting petroleum hydrocarbon oil (Newtonian fluid) defined by JIS Z8809 as a calibration standard solution for each test sample measurement, Viscosity (unit: mPa · s (Pa · s = 10 ³ mPa · s)) was measured.

Viscosity of each composition described in Examples is a contractor using a TVE-20L viscometer cone plate type [manufactured by TOKIMEC, sold by Toki Sangyo (Japan)], which is one of E type viscometers. The measurement was performed in the same manner as described in WO97 / 28827 and JP2002-265671.
Measurement condition:
Standard cone rotor (corresponding to cone 1 in Fig. 1) (α = 1 ° 34 ', radius (R) = 2.4cm) attached to TVE-20L viscometer cone plate type full scale torque 67.37 × 10 ^-6 Rotate by motor through Nm spring. During measurement, the viscometer is installed so that the rotation axis is perpendicular to the horizontal plane.
1 ml of the test sample is placed on a predetermined position of the cone rotor (plate, corresponding to the flat disk 2 in FIG. 1), and left 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 after 3 minutes, 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. This standard solution is guaranteed with an accuracy of ± 0.1% at 20 ° C, 30 ° C, and 40 ° C. 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.

Test Example 1 Stabilization of Sodium Hyaluronate with Vitamins in Surfactant-Containing Composition Each composition (Comparative Examples 1 and 2 and Examples 1-7) was prepared by mixing the formulations shown in Table 1. Each solution was subjected to an accelerated test at 50 ° C. or 60 ° C., and the change in viscosity for 5 days was examined. The viscosity was measured according to the method described above using a TVE-20L viscometer cone plate type. The results are shown in Table 1 and FIGS. 2-7, with the viscosity (initial value) of the composition at the start of the experiment as 100%, expressed as a percentage (%) with respect to the initial value. In the table, “-” indicates that the corresponding substance does not exist or the viscosity cannot be measured. Moreover, TO-10M means POE (20) sorbitan monooleate, and HCO-60 means POE (60) hydrogenated castor oil. Hyaluronic acid having an average molecular weight of 1,500,000 was used.
Viscosity measurement conditions:
Rotor used: Standard rotor (1 ° 34 ', R = 24mm)
Measurement conditions: 10 rpm
Sample volume: 1 mL
Measurement temperature: 20 ℃
Time: The measured value after 3 minutes was taken as the viscosity.

Table 1. Viscosity reduction over time of composition in the presence or absence of vitamins (50 ° C and 60 ° C)

When Comparative Example 1 and Examples 1, 2, and 4 are compared with respect to the measurement values on the fifth day, in Comparative Example 1, the initial value is 54% at 50 ° C., and the initial value is 16% at 60 ° C. Although the viscosity decreased, in Examples 1, 2, and 4, the viscosity was maintained at a high viscosity of 70% or more of the initial value at 50 ° C. and almost 50% at 60 ° C.
Further, when Comparative Example 2 and Examples 3 and 5 are compared with respect to the measurement values on the fifth day, in Comparative Example 2, the initial value is 23% at 50 ° C., and the initial value is 4% at 60 ° C. Although the viscosity decreased, in Examples 3 and 5, at 50 ° C., 60% or more of the initial value was maintained, and at 60 ° C., 22% or more of the initial value was maintained.

Comparative Examples 3 and 4 and Examples 6 and 7 show the effect of fat-soluble vitamins on viscosity reduction in compositions containing low concentrations of hyaluronic acids. From these Comparative Examples and Examples, it is clear that the fat-soluble vitamins have an inhibitory effect on the viscosity reduction of the low-concentration hyaluronic acid-containing composition.
The above results show that the use of fat-soluble vitamins suppresses the lowering of molecular weight or decomposition of hyaluronic acids, which is based on the decrease in viscosity of the composition containing hyaluronic acids and a surfactant.

Example 8-29
The liquid composition for mucosa (Examples 8 to 29) of the present invention was prepared according to the formulation shown in Table 2. Subsequently, the viscosity of the obtained composition was measured according to the method described in Test Example 1.
Preparation method:
As described in Example 8, after hyaluronic acid was dissolved in purified water, each component other than hyaluronic acid described in Example 11 was added and dissolved therein, and the osmotic pressure and pH were adjusted to make the total amount 100 mL. . This was sterilized by filtration and then aseptically filled into a plastic container to prepare an eye drop. In the same manner, eye drops of Examples 9-26 and eye wash of 27-29 were prepared.

Table 2 Formula (%) (w / v)

In addition, the following are mentioned as an aspect of this invention.
[1] A mucosa-applied liquid composition comprising A) hyaluronic acid, B) a surfactant, and C) at least one compound selected from fat-soluble vitamins and derivatives thereof.
[2] The above [1], wherein the at least one compound selected from fat-soluble vitamins and derivatives thereof is at least one compound selected from vitamin Es, vitamin As, and derivatives thereof. The liquid composition for mucosa described.
[3] The liquid composition applied to mucosa according to [1] or [2], wherein the surfactant is a nonionic surfactant.
[4] Nonionic surfactant is polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene alkyl ether, polyoxyethylene / polyoxypropylene alkyl ether, polyoxyethylene alkylphenyl ether The liquid composition for mucosa according to any one of [1] to [3], which is at least one selected from the group consisting of polyoxyethylene / polyoxypropylene block copolymers and polyoxyethylene sorbitan fatty acid esters .
[5] The liquid composition applied to mucosa according to any one of [1] to [4], which is an ophthalmic composition.
[6] The liquid composition applied to mucosa according to [5], which is any of eye drops, eyewashes, and contact lens mounting liquids.
[7] A method for stabilizing hyaluronic acids in a liquid composition containing hyaluronic acids and a surfactant, wherein the composition contains at least one compound selected from the group consisting of fat-soluble vitamins and derivatives thereof The method characterized by mix | blending.

Claims (4)

A mucosa-applied liquid composition comprising A) hyaluronic acid, B) nonionic surfactant, and C) at least one compound selected from the group consisting of vitamin E and derivatives thereof Where the total amount of the composition is
A) The concentration of hyaluronic acid is 0.0001 to 0.01 (w / v)%,
B) The concentration of the nonionic surfactant is 0.001 to 10 (w / v)%,
C) Mucosa-applied liquid composition in which the concentration of vitamins E and derivatives thereof is 0.00005 to 0.1 (w / v)%.   The liquid composition for mucous membrane application according to claim 1, wherein the nonionic surfactant comprises polyoxyethylene sorbitan fatty acid esters.   The liquid composition applied to mucosa according to claim 1 or 2, which is an ophthalmic composition. The mucosa-applied liquid composition according to claim 3, wherein the composition is one of an eye drop, an eye wash, and a contact lens mounting liquid.

Images