JP5164967B2 - Solution stabilization method - Google Patents

Description

  The present invention relates to a method for improving the stability of a solution in which zincs and a nonionic surfactant are blended simultaneously, and an ophthalmic solution thus obtained.

Zinc such as zinc sulfate and zinc lactate is widely used as a medicinal component for ophthalmic compositions such as eye drops and eyewashes, as well as pharmaceuticals, quasi drugs and the like because of its anti-inflammatory effect.
On the other hand, surfactants are usually added to eye drops and eyewashes as additives in order to increase the stability and solubility of the ingredients and to improve the feeling of use (functionality).

  However, when zinc is present together with a nonionic surfactant, there is a problem that it becomes cloudy over time and the stability is lowered. In particular, in the case of ophthalmic solutions such as eye drops and eyewashes that are required to contain no insoluble foreign matter, the influence on the quality cannot be ignored even if the solution is slightly cloudy. Therefore, a method for stably storing a solution for a long period of time without forming cloudiness has been desired.

  By the way, ethylenediaminetetraacetic acid (EDTA) or their sodium salts is used to prevent the formation of precipitates when a metallic astringent is added to eye drops containing flavin, adenine, dinucleotide and paraoxybenzoates. Is known, and a method for obtaining a stable eye drop (Patent Document 1) is known. Here, the amount of EDTA required to prevent precipitation that occurs when a metallic astringent is blended is the same mole. It is described as above. However, there is no description regarding precipitation by blending with a nonionic surfactant.

Japanese Patent Laid-Open No. 61-112010 (paragraph number 0004)

  The present invention provides a method for suppressing the occurrence of white turbidity in a solution containing zinc and a nonionic surfactant and obtaining a stable ophthalmic solution. Still another object of the present invention is to provide an ophthalmic solution that is stable and excellent in quality over a long period of time.

As a result of intensive studies to establish a method for suppressing the white turbidity of a solution containing zincs and a nonionic surfactant and maintaining the stability of the composition over a long period of time, the present inventors have obtained edetic acid. It has been found that the addition of salts to the composition suppresses white turbidity, and the present invention has been completed.
That is, this invention is a method hung up to the following (1)-(3).
(1) A method for stabilizing a solution, comprising adding edetate to a solution containing zinc and a nonionic surfactant.
(2) The edetic acid salt is blended in a ratio of 0.02 to 1 part by weight with respect to 1 part by weight of zinc in a solution containing zinc and a nonionic surfactant (1) The stabilization method described in 1.
(3) The stabilization method according to any one of (1) and (2), wherein the pH is further in the range of 4 to 6.5.
Moreover, this invention is an ophthalmic solution listed in the following (4) to (5).
(4) An ophthalmic solution containing zinc and a nonionic surfactant characterized by containing edetate as a stabilizer.
(5) The edetate is blended in a ratio of 0.02 to 1 part by weight with respect to the amount of zinc in a solution containing zinc and a nonionic surfactant. Ophthalmic solution.

  In the stabilization method of the present invention, by blending edetate with a solution containing zinc and a nonionic surfactant, the quality is stabilized without causing a change in appearance such as cloudiness over time, A safe and effective ophthalmic solution can be provided.

  In the present specification, unless otherwise specified,% means w / v%. Further, the term “contact lens (CL)” is used in the meaning of including all types of contact lenses such as hard, oxygen permeable hard, and soft unless otherwise specified. In the present specification, the ophthalmic solution may be simply referred to as “formulation”.

  The zinc that can be used in the ophthalmic solution of the present invention is not particularly limited as long as it is pharmacologically or physiologically acceptable, and examples thereof include zinc sulfate and zinc lactate.

  The concentration of zinc in the ophthalmic solution is, for example, usually in the range of 0.01 to 1.0% by weight, preferably 0.05 to 0.3% by weight in the case of eye drops, and usually in the case of eyewash. The range is 001 to 0.1% by weight, preferably 0.005 to 0.03% by weight.

As the nonionic surfactant of the ophthalmic solution of the present invention, polyoxyethylene (hereinafter referred to as “POE”)-polyoxypropylene (hereinafter referred to as “POP”) block copolymer (poloxamers) or ethylenediamine POE-POP block copolymer adducts (poloxamines), POE sorbitan fatty acid esters (polysorbates), POE hydrogenated castor oils 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, and POE alkylphenyl ethers such as POE (10) nonylphenyl ether. Of these, poloxamers, polysorbates, and POE hydrogenated castor oil are preferable, and poloxamer 407, monooleic acid POE (20) sorbitan (polysorbate 80), and polyoxyethylene hydrogenated castor oil 60 are particularly preferable. (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 concentration of the nonionic surfactant in the ophthalmic composition in the ophthalmic solution of the present invention varies depending on the use and the type of surfactant used, but in the case of eye drops for example, it is usually 0.005 to 5% by weight. The range is preferably 0.01 to 2% by weight.

  As the edetate used in the ophthalmic solution of the present invention, edetic acid or a pharmacologically or physiologically acceptable salt thereof can be used. Examples of pharmacologically or physiologically acceptable salts include disodium ethylenediaminetetraacetate (sodium edetate), tetrasodium ethylenediaminetetraacetate, barium ethylenediaminetetraacetate, calcium ethylenediaminetetraacetate, cobalt ethylenediaminetetraacetate and ethylenediaminetetraacetate copper. , Ethylenediaminetetraacetate diammonium, ethylenediaminetetraacetate dipotassium, ethylenediaminetetraacetate iron, ethylenediaminetetraacetate iron, ethylenediaminetetraacetate magnesium, ethylenediaminetetraacetate magnesium, ethylenediaminetetraacetate manganese, ethylenediaminetetraacetate nickel, ethylenediaminetetraacetate tripotassium, ethylenediaminetetraacetate Examples thereof include trisodium acetate and zinc ethylenediaminetetraacetate. Among these, ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, ethylenediaminetetraacetic acid tetrasodium, ethylenediaminetetraacetic acid dipotassium, ethylenediaminetetraacetic acid tripotassium, ethylenediaminetetraacetic acid trisodium, etc. are preferred, ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid disodium, ethylenediaminetetraacetic acid, etc. Tetrasodium acetate is particularly preferred.

  The blending amount of edetates in the ophthalmic solution of the present invention is suitably in the range of 0.0005 to 0.5%, preferably in the range of 0.001 to 0.1%. If it is less than 0.0005%, the stabilizing effect in the present invention is difficult to obtain, and if it exceeds 0.5%, eye irritation may occur, which is not preferable.

  Moreover, the usage-amount of the edetate salt in this invention shall be 0.02-1 weight part with respect to 1 weight part of zinc, Preferably it is 0.02-0.5 weight part. This corresponds to a molar ratio of 0.01 to 0.8, preferably 0.01 to 0.4, with respect to zinc. In addition, if it deviates significantly from this range, the effect obtained by the present invention tends to be reduced.

  Further, the pH of the ophthalmic solution in the present invention is preferably from weakly acidic to near neutral, considering the stability of the blended components, and particularly preferably around 4 to 6.5.

  Further, the stabilization method in the present invention is a composition having improved stability by using as a raw material a composition obtained by blending edetate with a solution containing zinc and a nonionic surfactant. It can also be defined as a method of manufacturing. On the other hand, the stabilization method in the present invention suppresses the occurrence of white turbidity that occurs over time in a solution containing zinc and a nonionic surfactant, and improves the storage stability of the solution. In other words, the edetate salt compounded to suppress white turbidity can also be defined as a white turbidity inhibitor.

  The ophthalmic solution of the present invention can contain a combination of various components other than zincs and nonionic surfactants as long as the object of the present invention is not adversely affected. Examples of components that can be combined include, for example, a decongestant component, other anti-inflammatory component, other antihistamine component, bactericidal component, antitumor component, hormones, proteins or peptides, vitamins, amino acids Etc. can be used. As a component which can be mix | blended with this invention liquid agent, the following components can be illustrated, for example.

  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 ingredients: celecoxib, rofecoxib, indomethacin, diclofenac, pranoprofen, piroxicam, meloxicam, epsilon-aminocaproic acid, berberine, azulenesulfonic acid, lysozyme, methyl salicylate, glycyrrhizic acid And pharmacologically acceptable salts (for example, berberine chloride, berberine sulfate, diclofenac sodium, sodium azulenesulfonate, dipotassium glycyrrhizinate, lysozyme chloride, etc.).

  Antihistamine components: for example, chlorpheniramine, diphenhydramine, iproheptin, ketotifen, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglycic acid, amlexanox, mequitazine, loratadine, exofenadine (fine) , Ibudilast, suplatast, pemirolast, and pharmacologically acceptable salts (for example, diphenhydramine hydrochloride, iproheptin hydrochloride, ketotifen fumarate, emedastine fumarate, clemastine fumarate, azelastine hydrochloride, levocabastine 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.), alkylpolyaminoethyl Glycine, new quinolone (lomefloxacin, levofloxacin, ciprofloxacin hydrochloride, ofloxacin, norfloxacin, etc.)

  Vitamin: for example, vitamin A (for example, retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene and pharmacologically acceptable salts thereof (for example, retinol acetate, retinol palmitate, etc.)), vitamin B (E.g. thiamine, thiamine disulfide, dicetiamine, octothiamine, chicotiamine, bisbutiamine, bisbenchamine, prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, hydroxocobalamin, Cyanocobalamin, methylcobalamin, deoxyadenocobalamin, folic acid, tetrahydrofolic acid, dihydrofolic acid, nicotinic acid, nicotinamide, nicotinic alcohol, pantothenic acid, bread Nord, biotin, choline, inositol and pharmacologically acceptable salts thereof (for example, thiamine hydrochloride, thiamine nitrate, dicetiamine hydrochloride, fursultiamine hydrochloride, riboflavin butyrate, sodium flavin adenine dinucleotide, pyridoxine hydrochloride, phosphate) Pyridoxal, pyridoxal calcium phosphate, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, calcium pantothenate, sodium pantothenate, etc.), vitamin Cs (ascorbic acid and derivatives thereof, erythorbic acid and derivatives thereof and pharmacologically acceptable Salts such as sodium ascorbate and sodium erythorbate, etc. and vitamin Ds such as ergocalciferol, cholecalciferol, hydroxycholecalcifero Vitamin Es (for example, tocopherol and derivatives thereof, ubiquinone derivatives and pharmacologically acceptable salts thereof, such as tocopherol acetate, dihydroxycholecalciferol, dihydrotaxosterol and pharmacologically acceptable salts thereof) Tocopherol nicotinate, tocopherol succinate, tocopherol calcium succinate, etc.)) and other vitamins (eg carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, hesperidin and their pharmacologically acceptable Salts (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, hyaluronic acid) and pharmacologically acceptable salts thereof (eg, sodium chondroitin sulfate, sodium hyaluronate) ), Sugar alcohols (eg, mannitol, xylitol, sorbitol, etc.), antipruritic ingredients (crotamiton, ictamol, moctamol, thymol acid, etc.), etc.

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, in the ophthalmic solution of the present invention, preferable contents of each component are, for example, as follows.
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 0.002-3%.
Antihistamine component: For example, 0.0001 to 10%, preferably 0.001 to 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 0.3%.
Amino acids: For example, 0.0001 to 10%, preferably 0.001 to 3%.

The ophthalmic solution of the present invention is formulated by arbitrarily selecting and using various components and additives used for pharmaceuticals, quasi-drugs, etc., as necessary, within a range not impairing the effects of the present invention. It is possible. 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 And acceptable salts.

  Thickeners: for example, polysaccharides or derivatives thereof (gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guayac fat, 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 its derivatives, chitosan and its derivatives, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate, etc., ceramide, cellulose derivative (methylcellulose) , Ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose Carboxyethyl cellulose, cellulose, etc.), polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, macrogol, polyvinyl methacrylate, polyacrylic acid, carboxyvinyl polymer, polyethyleneimine, ribonucleic acid, deoxyribonucleic acid, etc., and their pharmacology And salts which are acceptable.

  Surfactant: Amphoteric surfactant such as glycine type such as alkyldiaminoethylglycine, betaine acetate type such as lauryldimethylaminoacetic acid betaine, imidazoline type, POE alkyl ether phosphoric acid such as POE (10) sodium lauryl ether phosphate And salts thereof, N-acyl amino acid salts such as sodium lauroylmethylalanine, alkyl ether carboxylates, N-acyl taurine salts such as N-cocoylmethyl taurine sodium, sulfonates such as sodium tetradecenesulfonate, sodium lauryl sulfate Alkyl sulfates such as POE (3) POE alkyl ether sulfates such as sodium lauryl ether sulfate, and anionic surfactants such as α-olefin sulfonates. POE is an abbreviation for polyoxyethylene and POP is an abbreviation for polyoxypropylene. The number in parentheses indicates the number of added moles.

  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, dehydroacetic acid, chlorxylenol, chlorophene, resorcinol , Thymol, hinokitiol, sulfamine, lysozyme, lactoferrin, triclosan, 8-hydroxyquinoline Undecylenic acid, caprylic acid, propionic acid, benzoic acid, propionic acid, sorbic acid or a salt thereof (sorbic acid, potassium sorbate, sodium sorbate, triclocarban sorbate, etc.), 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 ( Trade name, manufactured by Rhodia), Unisense CP (trade name, poly (diallyldimethylammonium chloride), manufactured by Senka), WSCP (trade name, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio) etrange chloride] ] About 60% by weight, back Nigbo Laboratories)), biguanide compounds (Cosmocil CQ (trade name, containing about 20% by weight of polyhexamethylene biguanide hydrochloride, manufactured by Avicia)), and pharmacologically acceptable salts thereof It is done.

  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, Examples thereof include diisopropanolamine, triisopropanolamine, lysine, borax, and pharmacologically acceptable salts thereof.

  Isotonizing agents: Examples include polyhydric alcohols such as glycerin and propylene glycol, and sugars such as butter sugar, mannitol, and sorbitol.

  Water-soluble polymer substances: for example, gelatin, methyl vinyl ether / maleic anhydride copolymer, sodium alginate, polyethylene oxide, gum arabic, xanthan gum, tragacanth gum and the like.

  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, etc. Be

  Furthermore, a fragrance | flavor or a refreshing agent (For example, menthol, camphor, borneol, geraniol, cineol, anethole, limonene, eugenol, menthone etc. are mentioned as needed. These may be any of d form, l form, or dl form. However, 1-menthol, d-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, dl-borneol, and geraniol are preferred from the viewpoints of sensory aspects such as refreshment and fragrance and safety. 1-menthol, d-camphor and d-borneol are particularly preferred, and the monoterpene can be used in the state of being contained in essential oils, and preferred essential oils are eucalyptus oil, bergamot oil, fennel oil, peppermint oil. , Keihi Oil, Rose Oil, Peppermint Oil, Cool Mint Oil, Spearmi DOO oil, these monoterpenes can also be used in combination of two or more.), Local anesthetics (e.g., can be added lidocaine, lidocaine hydrochloride, and oxybuprocaine hydrochloride, etc.) and the like.

  In addition, the present invention relates to a solution containing zinc and a nonionic surfactant, which is a method for suppressing the occurrence of white turbidity due to the interaction of these components and obtaining a stable solution. The stabilization method of the present invention can be achieved by blending the aforementioned edetate with a solution containing zinc and a nonionic surfactant. Note that the types, blending ratios, blending methods, and the like of zincs, nonionic surfactants, edetates, etc. used in the stabilization method of the present invention are determined according to the description relating to the ophthalmic composition in the present specification. be able to.

  According to the present invention, the ophthalmic solution is stably maintained without causing a change in physical properties such as cloudiness over a long period of time, so that the quality control of the product is easy. Therefore, the present invention can be applied to ophthalmic solutions in a wide range of fields such as pharmaceuticals and quasi drugs. The ophthalmic solution of the present invention is preferably an eye drop, an eye wash, or a CL preparation. Particularly preferred are eye drops and eye wash. Here, the “agent for CL” includes not only a composition for preserving, cleaning and disinfecting contact lenses, but also a composition used for treating contact lenses including contact lens mounting liquid. is there. The composition of the present invention is adjusted to an osmotic pressure within a range acceptable to a living body, if necessary. The allowable osmotic pressure is 100 to 1200 mOsm, preferably about 100 to 600, particularly preferably about 150 to 400, and the osmotic pressure ratio with respect to physiological saline is usually 0.3 to 4.1, preferably 0.3. Is about 2.1, particularly preferably about 0.5 to 1.6. The adjustment of the osmotic pressure can be performed by a method known in the art using the aforementioned tonicity agents, salts and the like.

  The ophthalmic solution of the present invention can be produced by a known method. For example, using distilled water or purified water, and additives, zinc and nonionic surfactant, and edetate are mixed in the concentration range in this specification to adjust to a predetermined osmotic pressure and pH. It can be produced by subjecting it to filtration sterilization in an aseptic environment and aseptically filling a container that has been washed and sterilized.

  EXAMPLES The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

Test preparations (Examples 1 and 2) were prepared according to the formulations shown in Table 1 below, and ophthalmic preparations (eye drops and eyewashes) (Examples 3 to 10) were prepared according to the formulations shown in Table 2. Similarly, Comparative Examples 1 and 2 were prepared and a stability test at 60 ° C. was performed.
Specifically, the stability test was performed according to the following method.
In addition, about the formulation of an Example and a comparative example, after dissolving each component in purified water and adjusting osmotic pressure and pH. The total amount was 100 mL, sterilized by filtration, sealed in an ampule tube made of brown glass, and stored at 60 ° C. for 7 days.
The sample that had passed the predetermined period was visually observed for the presence or absence of white turbidity.

  From Comparative Example 1 and Comparative Example 2, it can be seen that when a nonionic surfactant is present, the formulation becomes clouded over time. On the other hand, in Examples 1-10 to which sodium edetate was added, cloudiness was suppressed and storage stability was improved.

Claims (3)

In a solution containing zinc selected from the group consisting of zinc sulfate and zinc lactate, and polyoxyethylene hydrogenated castor oil 60, edetic acid or its pharmacologically or physiologically acceptable per 1 part by weight of zinc A method for suppressing white turbidity of a contact lens agent, comprising mixing 0.02 to 1 part by weight of an edetate salt selected from the group consisting of salts. Furthermore, pH is made into the range of 4-6.5, The cloudiness suppression method of Claim 1 characterized by the above-mentioned. The cloudiness suppression method of Claim 1 or 2 whose compounding quantity of the edetate salt in a solution is 0.001-0.1 w / v% .