JP2822058B2 - Stable eye drops - Google Patents

Description

The present invention relates to flavin adenine dinucleotide by simultaneously mixing sodium or cyanocobalamin flavin adenine dinucleotide and a nonionic surfactant and further mixing a polyhydric alcohol. The present invention relates to an eye drop containing sodium or cyanocobalamin stably.

[Problems to be Solved by the Prior Art and the Invention] Sodium flavin adenine dinucleotide is a component that is contained in the corneal epithelium in a relatively large amount and is a component that remarkably increases the oxygen consumption ability of the cornea and enhances respiratory metabolism. It is formulated in eye drops for the purpose of maintaining tissue function. Also,
Cyanocobalamin has an anti-anemic effect and promotes corneal epithelial regeneration for the eyes and activates the optic nerve function.
It is incorporated into eye drops for the purpose of improving fine movement control in accommodative asthenopia.

On the other hand, nonionic surfactants such as polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are fat-soluble vitamins such as vitamin E and vitamin A.
In addition to its use as a solubilizing agent when adding fat-soluble components such as menthol and borneol to ophthalmic solutions, it is widely used as a component for preventing generation of sedimentation of the ophthalmic solution over time. However, these nonionic surfactants significantly degrade the component stability of sodium flavin adenine dinucleotide and cyanocobalamin, and are conventionally combined with sodium flavin adenine dinucleotide and cyanocobalamin and a nonionic surfactant to form a stable eye drop. It was difficult to do. The present invention stabilizes flavin adenine dinucleotide sodium or cyanocobalamin in an eye drop containing sodium flavin adenine dinucleotide or cyanocobalamin and a nonionic surfactant at the same time, enabling a combination formulation that has been conventionally difficult, and enables stable eye drops. It is intended to provide an agent.

[Means for Solving the Problems] The present inventors have conducted intensive studies on means for achieving the above-mentioned objects, and as a result, have found that eye drops containing sodium flavin adenine dinucleotide or cyanocobalamin and a nonionic surfactant simultaneously. Of the present invention succeeded in obtaining stable eye drops of flavin adenine dinucleotide sodium and cyanocobalamin by blending polyhydric alcohols. That is, in the case of eye drops containing sodium flavin adenine dinucleotide or cyanocobalamin and a nonionic surfactant at the same time, the component stability of sodium flavin adenine dinucleotide and cyanocobalamin is very poor, whereas a polyhydric alcohol is used. This greatly differs from the prior art in that the stability of sodium flavin adenine dinucleotide and cyanocobalamin is improved and provided as useful eye drops, which is a major feature of the present invention. Among the nonionic surfactants used in the present invention, polyoxyethylene hydrogenated castor oils include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60 and polyoxyethylene hydrogenated castor oil 80, polyethylene glycol As fatty acid esters, polyethylene glycol monostearate 25, polyethylene glycol monostearate 40 and polyethylene glycol monostearate 45,
Polyoxyethylene sorbitan fatty acid esters include polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan triolate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene monostearate, and polyoxyethylene And sorbitan tristearate. The polyhydric alcohols used in the present invention include propylene glycol and glycerin.

The eye drops of the present invention can be obtained, for example, by dissolving a nonionic surfactant and a polyhydric alcohol together with sodium flavin adenine dinucleotide or cyanocobalamin in purified water.

The ophthalmic solution of the present invention contains 0.01 to 0.05 w / v% of sodium flavin adenine dinucleotide and 0.004 to 0.02 w / v% of cyanocobalamin, whereas 0.01 to 0.5 w / v of nonionic surfactant is used. %, And the polyhydric alcohol is preferably blended at a rate of 0.01 to 5 w / v%.

The ophthalmic solution thus obtained is stable without degradation of sodium flavin adenine dinucleotide and cyanocobalamin over time.

The stable eye drops of the present invention include naphazoline hydrochloride, decongestant components such as tetrahydrozoline hydrochloride, dipotassium glycyrrhizinate, ε-aminocaproic acid, anti-inflammatory astringent components such as berberine chloride, and tocopherol acetate, retinol acetate, pyridoxine hydrochloride and the like. Pharmaceutical ingredients often used in eye drops such as itamines, and isotonicity of boric acid, borax, sodium hydrogen phosphate, citric acid, sodium citrate and other buffer salts, potassium chloride, sodium chloride, glucose, etc. Additives such as preservatives such as benzalkonium chloride, chlorobutanol and alkylparaben, and refreshing agents such as menthol, borneol and peppermint oil can also be added.

The present invention will be described in detail with reference to the following Examples, but it should not be construed that the invention is limited thereto. Further, Comparative Examples show production examples of conventional eye drops of sodium flavin adenine dinucleotide and cyanocobalamin.

Example 1 L-menthol (10 mg) was dissolved in polyoxyethylene hydrogenated castor oil (60 200 mg) while heating, this mixture was dissolved in purified water, and flavin adenine dinucleotide sodium (30 mg) and propylene glycol (1 g) were dissolved therein. 0.1 ml of a 10% aqueous solution of benzalkonium chloride was added. To this, 1 g of boric acid was dissolved, and an appropriate amount of borax was added to adjust the pH to 6.0. This aqueous solution was made up to 100 ml with purified water and 0.22μ
After filtration through an m-membrane filter, the mixture was aseptically filled in a 10 ml ophthalmic container and stoppered to obtain an ophthalmic solution.

Example 2 30 mg of tocopherol acetate was dissolved in 300 mg of polyoxyethylene sorbitan monooleate while heating, and this mixture was dissolved in purified water, and 10 mg of cyanocobalamin was added thereto.
After dissolving 2 g of glycerin, benzalkonium chloride 10%
0.1 ml of an aqueous solution was added. Dissolve 1.0 g of boric acid in this,
An appropriate amount of borax was added to adjust the pH to 6.0. Hereinafter, Example 1
An eye drop was prepared in the same manner as described above.

Example 3 20 mg of tocopherol acetate was dissolved in 200 mg of polyoxyethylene hydrogenated castor oil while heating, and this mixture was dissolved in purified water. To this was added 50 mg of sodium flavin adenine dinucleotide, 2 g of glycerin, 100 mg of dipotassium glycyrrhizinate, 200 mg of chlorobutanol was dissolved. To this, 1.0 g of boric acid was dissolved, and an appropriate amount of borax was added to adjust the pH to 6.0. Hereinafter, the same operation as in Example 1 was performed to obtain an eye drop.

Example 4 20 mg of L-menthol was dissolved in 350 mg of polyoxyethylene sorbitan monooleate while heating, this mixture was dissolved in purified water, and 20 mg of cyanocobalamin, 1 g of propylene glycol, and 2 mg of naphazoline hydrochloride were dissolved in the solution. 0.1 ml of a 10% aqueous solution of benzalkonium was added. To this, dissolve 1.0 g of boric acid and add an appropriate amount of borax
The pH was adjusted to 6.0. Hereinafter, the same operation as in Example 1 was performed to obtain an eye drop.

Example 5 10 mg of retinol acetate was dissolved in 200 mg of polyethylene glycol monostearate while heating, and this mixture was dissolved in purified water, and 30 mg of sodium flavin adenine dinucleotide, 1 g of propylene glycol, 1 g of ε-aminocaproic acid, And 200 mg of chlorobutanol were dissolved. Dissolve 1.0 g of boric acid in this, add an appropriate amount of borax, and add
Adjusted to 6.0. Hereinafter, the same operation as in Example 1 was performed to obtain an eye drop.

Example 6 Mentha oil (10 mg) was dissolved in polyethylene glycol monostearate (40 300 mg) with heating, this mixture was dissolved in purified water, and cyanocobalamin (10 mg) and glycerin were added thereto.
2 g, pyridoxine hydrochloride 500 mg, and methyl paraben 10 mg were dissolved. 1.0 g of boric acid was dissolved therein, and an appropriate amount of borax was added to adjust the pH to 6.0. Hereinafter, the same operation as in Example 1 was performed to obtain an eye drop.

Comparative Example 1 L-menthol (10 mg) was dissolved in polyoxyethylene hydrogenated castor oil (60 200 mg) while heating, this mixture was dissolved in purified water, and flavin adenine dinucleotide sodium (30 mg) was dissolved therein. 0.1 ml of a 10% aqueous solution was added. 1 g of boric acid was dissolved therein, and an appropriate amount of borax was added to adjust the pH to 6.0. Hereinafter, the same operation as in Example 1 was performed to obtain an eye drop.

Comparative Example 2 30 mg of tocopherol acetate was dissolved in 300 mg of polyoxyethylene sorbitan monooleate while heating, this mixture was dissolved in purified water, 10 mg of cyanocobalamin was dissolved therein, and 0.1 ml of a 10% aqueous solution of benzalkonium chloride was added. did. 1.0 g of boric acid was dissolved therein, and an appropriate amount of borax was added to adjust the pH to 6.0. Hereinafter, the same operation as in Example 1 was performed to obtain an eye drop.

[Effect] Wrap the eye drops of Examples and Comparative Examples in a moisture-proof film and
C., 40.degree. C. (75% relative humidity) and room temperature, and flavin adenine dinucleotide sodium and cyanocobalamin were quantified over time to determine the residual ratio. Table 1 shows the results.
6 is shown. In addition, sodium flavin adenine dinucleotide was quantified by reversed-phase partition high performance liquid chromatography, and cyanocobalamin was quantified by absorptiometry (550 nm).

As is clear from each table, in the comparative example, the residual ratio of sodium flavin adenine dinucleotide and cyanocobalamin was remarkably reduced with time, whereas the eye drops of the present invention were stable in the examples.

[Effects of the Invention] The present invention is an ophthalmic solution containing sodium flavin adenine dinucleotide or cyanocobalamin and a nonionic surfactant at the same time, wherein flavin adenine dinucleotide sodium and cyanocobalamin are stabilized, and are extremely useful as eye drops. Useful.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Akira Yino Investigator, Nishigami 2512 Oshikiri, Konan-cho, Osato-gun, Saitama Prefecture Investigator, Central Research Laboratory, Zeria Shinyaku Kogyo Co., Ltd. (A) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 31/68 A61K 31/70 A61K 9/08 A61K 47/10 A61K 47/34 CA (STN)

Claims (7)

(57) [Claims] 1. An ophthalmic solution containing sodium flavin adenine dinucleotide and a nonionic surfactant,
An eye drop characterized by containing a polyhydric alcohol. 2. An ophthalmic solution containing cyanocobalamin and a nonionic surfactant, wherein the polyhydric alcohol is 0.01 to 5 watts.
An eye drop characterized by containing / v%. 3. The nonionic surfactant is one or more selected from polyoxyethylene hydrogenated castor oils, polyethylene glycol fatty acid esters and polyoxyethylene sorbitan fatty acid esters. 2. The eye drop according to 2. 4. The ophthalmic solution according to claim 1, wherein the polyhydric alcohol is one or both of propylene glycol and glycerin. 5. A flavin adenine dinucleotide sodium of 0.01 to 0.05 w / v% and a nonionic surfactant of 0.01 to 0.05 w / v%.
The ophthalmic solution according to claim 1, which is blended at a ratio of 0.5 w / v%. 6. The ophthalmic solution according to claim 2, wherein the ratio of cyanocobalamin is 0.004 to 0.02 w / v% and the ratio of nonionic surfactant is 0.01 to 0.5 w / v%. 7. The ophthalmic solution according to claim 1, wherein a polyhydric alcohol is blended at a ratio of 0.01 to 5 w / v%.