JP2015067607A - Eye-drops containing two or more components - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide eye-drops, in which the precipitation generation under cold conditions and the stability of allantoin are improved, containing tetrahydrozoline or a salt thereof, neostigmine or a salt thereof, allantoin, glycyrrhizinic acid or a salt thereof, zinc sulfate hydrate, chlorpheniramine or a salt thereof, vitamin B12, vitamin B6 or a salt thereof, panthenol, L-aspartic acid or a salt thereof, taurine and chondroitin sulfate ester or a salt thereof.SOLUTION: The invention provides eye-drops containing tetrahydrozoline or a salt thereof, neostigmine or a salt thereof, allantoin, glycyrrhizinic acid or a salt thereof, zinc sulfate hydrate, chlorpheniramine or a salt thereof, vitamin B12, vitamin B6 or a salt thereof, panthenol, L-aspartic acid or a salt thereof, taurine, chondroitin sulfate ester or a salt thereof, and a surfactant, controlling pH of 4.0-5.7. As the surfactant, polysorbate 80 is preferable.

Description

  The present invention relates to tetrahydrozoline or a salt thereof, neostigmine or a salt thereof, allantoin, crityllithic acid or a salt thereof, zinc sulfate hydrate, chlorpheniramine or a salt thereof, vitamin B12, vitamin B6 or a salt thereof, panthenol, L-asparagine The present invention relates to an eye drop containing an acid or a salt thereof, taurine and chondroitin sulfate or a salt thereof, which is improved in precipitation and allantoin stability under low temperature conditions.

  In the 16th revision Japanese Pharmacopoeia, an eye drop is defined as “a liquid sterile liquid preparation applied to an eye tissue such as conjunctival sac or a solid aseptic preparation used upon suspension or suspension upon use”. The eye drops are required to have a preservative effect due to the property of being a sterile preparation to be used multiple times, except for single-use type preparations. Furthermore, since the eyes are sensitive tissues, they are comfortable (use feeling). Is also sought. For this reason, when manufacturing eye drops, a plurality of additives are added in consideration of storage efficacy and comfort.

  The prescription drug manufacturing (import) approval standard (hereinafter, abbreviated as approval standard) prescribes the formulation rules for the manufacture of over-the-counter drugs. Among these, “general eye drops” classified as eye drops (ophthalmic drugs) are one type from the A column of the decongestant component, one type from the B column, and three types or less from the C column of the anti-inflammatory / astringent component. One from the D column of the histamine component, 3 or less from the E column of vitamins, and 3 or less from the F column of amino acids can be arbitrarily selected and blended, and up to 12 components can be blended. Because “general eye drops” contain multiple ingredients with different mechanisms of action, the effects are “eye fatigue, conjunctival hyperemia, eye disease prevention (after swimming, when dust or sweat enters the eyes, etc.) , Uvitis caused by UV rays or other rays (such as snow eyes), blepharitis (eyelid sores), discomfort when wearing hard contact lens, itchy eyes, blurred eyes (such as when there are many eyes) And a wide variety. Due to the diversification of consumer needs in recent years, many consumers are seeking “general eye drops” with a wide range of efficacy, and there are actually many products featuring multi-component formulations and high compounding amounts that are expected to have higher effects. Has been.

  Even components that are within the acceptance criteria may cause problems in the formulation of eye drops. For example, it has been pointed out that tetrahydrozoline in the approval standard “general eye drops” column A causes a decrease in content when stored for a long time in a neutral region (pH 6 to 8) (see Patent Document 1). Furthermore, pyridoxine in the approval standard “general eye drops” column E has a decreased photostability when combined with flavin adenine dinucleotide (see Patent Document 2), and lysozyme in the approval standard “general eye drops” column C is boric acid. It has also been pointed out that the feeling of pointing is worsened by blending with (see Patent Document 3). Thus, in the manufacture of eye drops, the pH of the liquid and the combination of components including additives must be taken into account, and eye drops with more compounding components are more difficult to manufacture.

  In fact, the present inventors also made tetrahydrozoline hydrochloride, neostigmine methyl sulfate, allantoin, dipotassium glycyrrhizinate, zinc sulfate hydrate, chlorpheniramine maleate, cyanocobalamin, pyridoxine hydrochloride, panthenol, magnesium L-aspartate・ As a result of manufacturing eye drops containing potassium, taurine, and sodium chondroitin sulfate, there was no suspension or precipitation at the time of manufacture, but precipitation occurred when stored under low temperature conditions, and this precipitation was changed to room temperature storage. But it did not disappear. Furthermore, there was a problem that the content of allantoin was lowered due to the stability evaluation over time.

  Japanese Patent Laid-Open No. 9-169642   JP-A-8-104636   JP 2008-156268 A

  Accordingly, the object of the present invention is to provide tetrahydrozoline or a salt thereof, neostigmine or a salt thereof, allantoin, glycyrrhizic acid or a salt thereof, zinc sulfate hydrate, chlorpheniramine or a salt thereof, vitamin B12, vitamin B6 or a salt thereof, panthenol, The ophthalmic solution containing L-aspartic acid or a salt thereof, taurine and chondroitin sulfate ester or a salt thereof is provided which has improved precipitation under low temperature conditions and allantoin stability.

  The present inventors have intensively studied for the above purpose. Tetrahydrozoline or its salt, neostigmine or its salt, allantoin, glycyrrhizic acid or its salt, zinc sulfate hydrate, chlorpheniramine or its salt, vitamin B12, vitamin B6 or its salt, panthenol, L-aspartic acid or its salt , Taurine and chondroitin sulfate or its salts containing ophthalmic solution and a surfactant as an additive, and the pH was set to 4.0-5.7, resulting in improved precipitation under low temperature conditions In addition, the present inventors have found that an ophthalmic solution with improved allantoin stability can be obtained, thereby completing the present invention.

  According to the present invention, tetrahydrozoline or a salt thereof, neostigmine or a salt thereof, allantoin, glycyrrhizic acid or a salt thereof, zinc sulfate hydrate, chlorpheniramine or a salt thereof, vitamin B12, vitamin B6 or a salt thereof, panthenol, L-asparagine It is possible to produce an ophthalmic solution containing a multi-component blended with an acid or a salt thereof, taurine and chondroitin sulfate or a salt thereof.

  In the present specification, the “salt” means a pharmacologically or physiologically acceptable salt.

  Examples of tetrazoline or a salt thereof used in the present invention include tetrahydrozoline hydrochloride. The content of tetrahydrozoline or a salt thereof is preferably 0.01 to 0.05% from the pharmacological viewpoint.

  Examples of neostigmine or a salt thereof used in the present invention include neostigmine methyl sulfate. The content of neostigmine or a salt thereof is preferably 0.001 to 0.005% from the pharmacological viewpoint.

  The content of allantoin is preferably 0.06 to 0.3% from the pharmacological viewpoint.

  Examples of glycyrrhizic acid or a salt thereof used in the present invention include dipotassium glycyrrhizinate. The content of glycyrrhizic acid or a salt thereof is preferably 0.05 to 0.25% from the pharmacological viewpoint.

  The content of zinc sulfate hydrate is preferably 0.05 to 0.25% from the pharmacological viewpoint.

  Examples of chlorpheniramine or a salt thereof used in the present invention include chlorpheniramine maleate. The content of chlorpheniramine or a salt thereof is preferably 0.006 to 0.03% from the pharmacological viewpoint.

  Examples of vitamin B12 used in the present invention include cyanocobalamin and the like. The content of vitamin B12 is preferably 0.004 to 0.02% from the pharmacological viewpoint.

  Examples of vitamin B6 or a salt thereof used in the present invention include pyridoxine hydrochloride. The content of vitamin B6 or a salt thereof is preferably 0.01 to 0.1% from the pharmacological viewpoint.

  The content of panthenol is preferably 0.01 to 0.1% from the pharmacological viewpoint.

  Examples of L-aspartic acid or a salt thereof used in the present invention include potassium L-aspartate, magnesium L-aspartate, and magnesium / potassium L-aspartate (equal mixture). The content of L-aspartic acid or a salt thereof is preferably 0.2 to 2% from the pharmacological viewpoint.

  The taurine content is preferably 0.1 to 1% from the pharmacological viewpoint.

  Examples of chondroitin sulfate or a salt thereof used in the present invention include sodium chondroitin sulfate. The content of chondroitin sulfate or a salt thereof is preferably 0.05 to 0.5% from the pharmacological viewpoint.

  Examples of the surfactant used in the present invention include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and polyoxyl 40 stearate. Polysorbate 80 is particularly preferable. These contents are preferably 0.001 to 0.5 w / v% in the composition, but it is particularly preferable that the blending amount is as small as possible for eye irritation.

  In addition to the above components, the ophthalmic solution of the present invention contains various additives such as thickeners, sugars, pH adjusters, buffers, isotonic agents, stabilizers, fragrances or refreshing agents, preservatives, It can contain in the range which does not impair the effect of this invention.

  Examples of the thickener include carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, alginic acid, polyvinyl alcohol, polyvinyl pyrrolidone, macrogol and the like.

  Examples of the saccharide include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like.

  Examples of the pH adjuster include sodium hydroxide, potassium hydroxide, hydrochloric acid and the like.

  Examples of the buffer include boric acid or a salt thereof (borax, etc.), citric acid or a salt thereof (sodium citrate, etc.), phosphoric acid or a salt thereof (sodium monohydrogen phosphate, etc.), tartaric acid or a salt thereof (sodium tartrate). Etc.), gluconic acid or a salt thereof (sodium gluconate, etc.), acetic acid or a salt thereof (sodium acetate, etc.), carbonic acid or a salt thereof (sodium hydrogencarbonate, etc.), boric acid or a salt thereof, citric acid or a salt thereof Salts are preferred. These contents are preferably 0.01 to 3 w / v% in the composition.

  Examples of the isotonic agent include sodium chloride and potassium chloride.

  Examples of the stabilizer include sodium edetate, cyclodextrin, sulfite, citric acid or a salt thereof, and dibutylhydroxytoluene. Sodium edetate is particularly preferable, and the content is preferably 0.001 to 0.5 w / v% in the composition.

  Examples of the fragrance or the refreshing agent include camphor, geraniol, borneol, menthol, leopard, fennel oil, cool mint oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil and the like. .

  Examples of the preservative include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and the like. These contents are preferably as little as possible in order to stimulate the eyes.

  The ophthalmic solution of the present invention preferably has a pH of 4.0 to 5.7, more preferably 5.0 to 5.7. The ophthalmic solution of the present invention is mixed with a pH adjusting agent or a buffering agent as necessary so as to maintain the pH in the above range.

  The osmotic pressure of the ophthalmic solution of the present invention is not particularly limited as long as it is within a range acceptable as a pharmaceutical product, and is usually 0.1 to 5 pressure ratio, more preferably 0.2 to 2 pressure ratio. The ophthalmic solution of the present invention is blended with an isotonic agent as necessary so that the osmotic pressure is in the above range.

  The ophthalmic solution of the present invention can be used as an ophthalmic solution including use when wearing a contact lens. Note that the contact lens includes all types of contact lenses such as a soft contact lens, a hard contact lens, and an oxygen-permeable hard contact lens.

  EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated further in detail, this invention is not limited to these.

<Example 1 and Comparative Examples 1-3>
Ophthalmic solutions were prepared with the compositions shown in Table 1 and filled with ampoules. The evaluation of precipitation was performed visually at the time of filling, after completion of storage at 100 ° C. for 6 hours, after completion of storage at 60 ° C. for 2 weeks, and after completion of each low-temperature storage (about 2 ° C., 1 day). The allantoin stability over time was determined by measuring the allantoin content of a product that had been stored at 50 ° C. for 2 weeks and calculating the residual rate. The results are shown in Table 1.

<Examples 2 to 7 and Comparative Example 4>
Eye drops were prepared with the composition shown in Table 2 and filled into ampoules. Precipitation was evaluated visually at the time of filling, after completion of storage at 100 ° C. for 6 hours, and after completion of low-temperature storage (about 2 ° C., 1 day). The results are shown in Table 2.

  As is clear from Table 1, precipitation does not occur in Comparative Example 3 where the pH is high, but a decrease in allantoin content occurs. On the other hand, in Comparative Example 1 where the pH is low, the decrease in allantoin content is suppressed but precipitation occurs. . In Example 1 which is the eye drop of the present invention, the decrease in the content of allantoin was suppressed, and precipitation did not occur in any of the cryopreserved products.

  As is apparent from Table 2, precipitation occurred in Comparative Example 4 in which 160 mg of polysorbate 80 was blended in 100 mL, but in Examples 2 to 5 which are eye drops of the present invention, precipitation occurred in any cryopreserved product. There wasn't. Further, in Examples 6 and 7, precipitation did not occur even when polysorbate 80 was replaced with polyoxyethylene hydrogenated castor oil and polyoxyl 40 stearate, which are different surfactants.

Claims (4)

Tetrahydrozoline or its salt, neostigmine or its salt, allantoin, glycyrrhizic acid or its salt, zinc sulfate hydrate, chlorpheniramine or its salt, vitamin B12, vitamin B6 or its salt, panthenol, L-aspartic acid or its salt An eye drop containing taurine, chondroitin sulfate or a salt thereof, and a surfactant. The eye drop according to claim 1, wherein the surfactant is polysorbate 80. 0.01-0.05% tetrahydrozoline or a salt thereof, 0.001-0.005% neostigmine or a salt thereof, 0.06-0.3% allantoin, 0.05-0.25% glycyrrhizic acid Or a salt thereof, 0.05 to 0.25% zinc sulfate hydrate, 0.006 to 0.03% chlorpheniramine or a salt thereof, 0.004 to 0.02% vitamin B12, 0.01 -0.1% vitamin B6 or a salt thereof, 0.01-0.1% panthenol, 0.2-2% L-aspartic acid or a salt thereof, 0.1-1% taurine; An eye drop containing 05 to 0.5% chondroitin sulfate or a salt thereof and 0.2 to 1% polysorbate 80. The ophthalmic solution according to any one of claims 1 to 3, wherein the pH is in the range of 4.0 to 5.7.