JP6868595B2 - Aqueous ophthalmic composition - Google Patents

Description

The present invention relates to an aqueous ophthalmic composition. More specifically, the present invention relates to an aqueous ophthalmic composition to which white turbidity is suppressed, photostability is improved, and an action of improving corneal epithelial barrier function is imparted.

In the field of ophthalmology, lysis aids are incorporated into many formulations. In particular, in an aqueous ophthalmic composition, various dissolution aids have been devised for the purpose of assisting the dissolution of physiologically active ingredients and additives having relatively low water solubility. One of the solubilizing agents used in the field of ophthalmology is a surfactant. Polyoxyethylene castor oil is a kind of nonionic surfactant, and is known to be blended in an aqueous ophthalmic composition for the purpose of assisting dissolution of other blending components (Patent Document 1).

Further, in the aqueous composition, it is important to ensure the stability in the manufacturing process and the market distribution process, and the long-term stability after opening. Therefore, the influence on the quality of the white turbidity of the clear solution and the decomposition of the contained components that occur when exposed to light cannot be ignored. Therefore, a method of preventing cloudiness and photodecomposition and stably storing the solution for a long period of time is desired.

In addition, the corneal epithelium functions as a barrier between the outside world and the stroma of the cornea, and stimulants from the outside such as allergens, substances present in tears, and pathogens permeate from the corneal epithelium to the stroma of the cornea. By controlling this, the homeostasis of the cornea is maintained. Therefore, once the barrier function of the corneal epithelium is reduced, a vicious cycle of increased permeability of inflammatory mediators, activation of corneal parenchymal cells, expression and secretion of inflammation-related molecules, and promotion of inflammation in the cornea occurs. Therefore, in an ophthalmic composition, having an action of improving the corneal epithelial barrier function is important from the viewpoint of suppressing the onset of ophthalmic symptoms.

On the other hand, cellulosic thickeners are widely used in ophthalmic compositions as thickeners for improving drug retention to enhance bioavailability and water retention effect. In addition, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxine, etc. promote energy metabolism, promote metabolism and cellular respiration to relieve eye strain, or replenish tear components. It has been conventionally added to ophthalmic compositions for the purpose of exerting an anti-inflammatory effect.

However, when an aqueous ophthalmic composition containing polyoxyethylene castor oil contains components such as a cellulosic thickener, epsilon-aminocaproic acid, aspartic acid, aminoethyl sulfonic acid, and pyridoxine, these components are used. It is not known how they will affect each other.

Japanese Unexamined Patent Publication No. 2005-298448

The present inventors have conducted various studies on an aqueous ophthalmic composition containing polyoxyethylene castor oil. As a result, it was found that white turbidity is likely to occur when an aqueous ophthalmic composition containing polyoxyethylene castor oil is stored. In particular, when the aqueous ophthalmic composition is stored in a heated state, the occurrence of cloudiness is remarkable. In addition to polyoxyethylene castor oil, the aqueous ophthalmic composition contains various pharmacologically active ingredients, physiologically active ingredients, and the like, and some of these ingredients are easily decomposed by exposure to light. May contain ingredients. According to the research by the present inventors, among the components contained in the aqueous ophthalmic composition of the present invention described later, polyoxyethylene castor oil and pyridoxine hydrochloride are easily decomposed when exposed to light. It was confirmed that. The occurrence of cloudiness in the aqueous ophthalmic composition and the photodecomposition of the contained components lead to a decrease in quality including safety and a decrease in commercial value, and further prevent the contained components from exhibiting their original performances. It is an extremely important issue to suppress the phenomenon of.

Further, as described above, imparting an action of improving the corneal epithelial barrier function to an aqueous ophthalmic composition is an important issue from the viewpoint of suppressing the onset of ophthalmic symptoms.

Therefore, a main object of the present invention is to provide an aqueous ophthalmic composition having an action of suppressing white turbidity, improving photostability, and further improving the corneal epithelial barrier function, and an aqueous ophthalmic composition. On the other hand, it is an object of the present invention to provide a method capable of suppressing cloudiness, improving photostability, and further imparting an action of improving the corneal epithelial barrier function.

The present inventors have conducted intensive research to solve the above problems. As a result, an aqueous ophthalmic composition containing polyoxyethylene castor oil (hereinafter, may be referred to as "component (A)") contains a cellulose-based thickening agent, epsilon-aminocaproic acid, aspartic acid, and aminoethyl sulfonic acid. , Pyridoxin and at least one selected from the group consisting of salts thereof (hereinafter, may be referred to as "component (B)"), thereby causing cloudiness in the aqueous ophthalmic composition containing the polyoxyethylene castor oil. It was found that the occurrence of can be suppressed. Further, by blending the above-mentioned components (A) and (B) in the aqueous ophthalmic composition, the photodecomposition of the component (A) contained in the aqueous ophthalmic composition can be suppressed, and the photostability is improved. Found to be done. Furthermore, by blending the above-mentioned components (A) and (B) in the aqueous ophthalmic composition, photodecomposition of pyridoxine hydrochloride, which is a component that easily causes photodecomposition, is suppressed and photostability is improved. I found. Furthermore, it has been found that by blending the above-mentioned components (A) and (B) in an aqueous ophthalmic composition, it is possible to impart an action of improving the corneal epithelial barrier function to the ophthalmic composition.

The present invention has been completed as a result of further research based on these findings.

That is, the present invention provides an aqueous ophthalmic composition according to the following aspects.
Item 1-1. Aqueous containing (A) polyoxyethylene castor oil and (B) at least one selected from the group consisting of cellulosic thickener, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxine and salts thereof. Ophthalmic composition.
Item 1-2. Item 2. The aqueous ophthalmic composition according to Item 1-1, wherein the component (A) is polyoxyethylene castor oil having an average addition mole number of ethylene oxide of 2 to 30.
Item 1-3. Item 2. The aqueous ophthalmic composition according to Item 1-1 or 1-2, wherein the cellulosic thickener is at least one selected from the group consisting of hydroxypropylmethyl cellulose and hydroxyethyl cellulose.
Item 1-4. Item 2. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-3, wherein the total content of the component (A) is 0.0005 to 5 w / v% based on the total amount of the aqueous ophthalmic composition.
Item 1-5. Item 2. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-4, wherein the total content of the component (B) is 0.0005 to 20 w / v% based on the total amount of the aqueous ophthalmic composition.
Item 1-6. Item 2. Aqueous ophthalmology according to any one of Items 1-1 to 1-5, wherein the total content of the component (B) is 0.0001 to 50,000 parts by weight with respect to 1 part by weight of the total content of the component (A). Composition.
Item 1-7. Item 2. Aqueous ophthalmology according to any one of Items 1-1 to 1-6, wherein the total content of the component (B) is 0.02 to 5000 parts by weight with respect to 1 part by weight of the total content of the component (A). Composition.
Item 1-8. Item 2. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-7, which further contains a buffer.
Item 1-9. Item 2. The aqueous ophthalmic composition according to Item 1-8, wherein the buffer is a boric acid buffer.
Item 1-10. Item 2. The aqueous ophthalmic composition according to Item 1-8 or 1-9, wherein the total content of the buffer is 0.01 to 15 w / v% based on the total amount of the aqueous ophthalmic composition.
Item 1-11. Item 2. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-10, further containing a surfactant and / or an isotonic agent other than the component (A).
Item 1-12. Item 2. The aqueous ophthalmic composition according to Item 1-11, wherein the surfactant other than the component (A) is a nonionic surfactant, and the tonicity agent is a polyhydric alcohol or an inorganic salt.
Item 1-13. Item 2. The aqueous solution according to Item 1-11 or 1-12, wherein the total content of the nonionic surfactant other than the component (A) is 0.001 to 3 w / v% based on the total amount of the aqueous ophthalmic composition. Ophthalmic composition.
Item 1-14. Item 2. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-13, which is filled in a polyethylene terephthalate container.
Item 1-15. Item 2. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-14, which is filled in a container equipped with a polyethylene nozzle.
Item 1-16. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-15, which is an eye drop.
Item 1-17. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-15, which is an eye wash.
Item 1-18. Item 8. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-15, which is a contact lens mounting solution.
Item 1-19. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-15, which is a contact lens care agent.

The present invention also provides a method for suppressing cloudiness in an aqueous ophthalmic composition according to the following aspects.
Item 2. Aqueous ophthalmic composition containing (A) polyoxyethylene castor oil, (B) cellulose-based thickening agent, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxine, epsilon-aminocaproic acid and salts thereof. A method for suppressing cloudiness in the aqueous ophthalmic composition, which comprises blending at least one selected from the group consisting of.
Item 3. Aqueous ophthalmology at least one selected from the group consisting of (A) polyoxyethylene castor oil and (B) cellulosic thickener, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxin and salts thereof. A method for suppressing cloudiness in the aqueous ophthalmic composition, which comprises blending into the composition.

The present invention also provides a method for improving photostability in an aqueous ophthalmic composition according to the following aspects.
Item 4. Selected from the group consisting of (A) an aqueous ophthalmic composition containing polyoxyethylene castor oil, (B) a cellulosic thickener, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxin and salts thereof. A method for improving photostability in an aqueous ophthalmic composition, comprising blending at least one of the following.
Item 5. Aqueous ophthalmology at least one selected from the group consisting of (A) polyoxyethylene castor oil and (B) cellulosic thickener, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxin and salts thereof. A method for improving photostability in an aqueous ophthalmic composition, which comprises blending into the composition.

The present invention also provides a method for imparting an action of improving the corneal epithelial barrier function to an aqueous ophthalmic composition according to the following aspects.
Item 6. Aqueous ophthalmology at least one selected from the group consisting of (A) polyoxyethylene castor oil and (B) cellulose-based thickening agent, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxine and salts thereof. A method for imparting a corneal epithelial barrier function improving effect to the aqueous ophthalmic composition, which comprises blending with the composition.
Item 7. Item 6. The use according to Item 6, wherein the aqueous ophthalmic composition is the composition according to any one of Items 1-1 to 1-19 above.

Furthermore, the present invention also provides the use of the following aspects.
Item 8. Consists of (A) polyoxyethylene castor oil and (B) cellulosic thickener, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxine and salts thereof for the production of aqueous ophthalmic compositions. At least one use selected from the group.
Item 9. Item 2. The use according to Item 8, wherein the aqueous ophthalmic composition is the composition according to any one of Items 1-1 to 1-19 above.

Furthermore, the present invention also provides the use of the following aspects.
Item 10. Selected from the group consisting of (A) polyoxyethylene castor oil and (B) cellulosic thickener, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxine and salts thereof as an aqueous ophthalmic composition. Use of compositions containing at least one to be made.
Item 11. Item 2. The use according to Item 10, wherein the composition is the composition according to any one of Items 1-1 to 1-19 above.

Furthermore, the present invention also provides compositions of the following aspects.
Item 12. From (A) polyoxyethylene castor oil and (B) cellulosic thickeners, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxine and salts thereof for use as aqueous ophthalmic compositions. A composition comprising at least one selected from the group.
Item 13. Item 12. The composition according to Item 12, which is the one according to any one of Items 1-1 to 1-19.

Furthermore, the present invention also provides a method for producing an aqueous ophthalmic composition according to the following aspects.
Item 14. Selected from the group consisting of (A) polyoxyethylene castor oil and (B) cellulosic thickener, epsilon-aminocaproic acid, aspartic acid, aminoethyl sulfonic acid, pyridoxine and salts thereof in a carrier containing water. A method for producing an aqueous ophthalmic composition, which comprises adding at least one of these.
Item 15. Item 3. The production method according to Item 14, wherein the aqueous ophthalmic composition is the composition according to any one of Items 1-1 to 1-19 above.

According to the present invention, it is selected from the group consisting of polyoxyethylene castor oil (component (A)), a cellulosic thickener, epsilon-aminocaproic acid, aspartic acid, aminoethyl sulfonic acid, pyridoxine and salts thereof. By using at least one of them (component (B)) in combination, it is possible to suppress white turbidity that tends to occur during storage of the aqueous ophthalmic composition. Further, by using the component (A) and the component (B) in combination in the aqueous ophthalmic composition, polyoxyethylene castor oil and hydrochloric acid, which are components that are likely to cause photodecomposition among the components contained in the aqueous ophthalmic composition. It is possible to suppress the photodegradation of pyridoxin and improve the photostability.

Therefore, the aqueous ophthalmic composition of the present invention is an aqueous ophthalmic composition having excellent quality and stability, which is less likely to cause cloudiness and photodecomposition and can stably exhibit the performance of the contained components for a long period of time. Is.

Furthermore, by using the component (A) and the component (B) in combination in the aqueous ophthalmic composition, it is possible to impart an action of improving the corneal epithelial barrier function to the aqueous ophthalmic composition.

Therefore, the aqueous ophthalmic composition of the present invention is useful for suppressing various ophthalmic symptoms, and in particular, can be suitably used for suppressing eye allergic symptoms caused by pollen, house dust (indoor dust), and the like.

A photograph showing the state of each aqueous ophthalmic composition used in Test Example 2 after 14 days of storage.

In the present specification, the unit of content "%" means "w / v%" and is synonymous with "g / 100 mL".

Unless otherwise stated, the abbreviation "POE" in the present specification means polyoxyethylene.

Unless otherwise stated, the abbreviation "POP" in the present specification means polyoxypropylene.

Unless otherwise stated, in the present specification, contact lenses are meant to include all types of contact lenses such as hard, oxygen permeable hard, soft (including silicone hydrogel lenses), and color.

Hereinafter, the present invention will be specifically described.

[1. Aqueous ophthalmic composition]
The aqueous ophthalmic composition of the present invention contains polyoxyethylene castor oil (component (A)). By using this in combination with at least one selected from the group consisting of a cellulosic thickening agent, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxine, and salts thereof, which will be described later, the present invention described above. The excellent effect of.

Polyoxyethylene castor oil is a known compound obtained by addition polymerization of ethylene oxide to castor oil, and several types are known in which the average number of moles of ethylene oxide added is different. In the present invention, the average number of moles of ethylene oxide added in the polyoxyethylene castor oil used as the component (A) is not particularly determined, but is, for example, about 2 to 70 moles. Specifically, polyoxyethylene castor oil having an average addition molar number of 3 is 3, polyoxyethylene castor oil having an average addition molar number of 4 is 4, and ethylene oxide having an average addition molar number of 6 is 6. A certain polyoxyethylene castor oil 6, polyoxyethylene castor oil 7 having an average addition mole of ethylene oxide 7, polyoxyethylene castor oil 10 having an average addition mole number of ethylene oxide 10, and an average addition mole of ethylene oxide. Polyoxyethylene castor oil having a number of 13.5 is 13.5, polyoxyethylene castor oil having an average addition molar number of 17 is 17, and polyoxyethylene castor oil having an average addition mole number of 20. 20, polyoxyethylene castor oil 25 having an average added mole number of ethylene oxide 25, polyoxyethylene castor oil 30 having an average added mole number of ethylene oxide 30, and poly having an average added mole number of ethylene oxide of 35. Oxyethylene castor oil 35, polyoxyethylene castor oil 40 having an average addition molar number of 40 ethylene oxide, polyoxyethylene castor oil 50 having an average addition mole number of ethylene oxide 50, and average addition mole number of ethylene oxide 60 polyoxyethylene glycol oil 60, polyoxyethylene glycol oil 70 having an average addition molar number of 70, and the like can be used.

Among these polyoxyethylene castor oils, as an example of a component capable of exerting the effect of the present invention particularly well, the average number of moles of ethylene oxide added is 2 to 35, preferably 2 to 30, and more preferably 2 to 20. Particularly preferably, 2 to 12 mol of polyoxyethylene castor oil can be mentioned.

In the present invention, these polyoxyethylene castor oils may be used alone or in any combination of two or more. The polyoxyethylene castor oil used in the present invention is a compound different from the polyoxyethylene hydrogenated castor oil obtained by addition polymerization of ethylene oxide to the cured castor oil, and is distinguished from this.

The content of the component (A) in the aqueous ophthalmic composition of the present invention is not particularly limited, and the type of the component (A), the type and content of the component (B) to be used in combination, the use and preparation of the aqueous ophthalmic composition. It is appropriately set according to the form, usage, and the like. For example, based on the total amount of the aqueous ophthalmic composition of the present invention, the total content of the component (A) is 0.0005 to 5 w / v%, preferably 0.001 to 3 w / v%, and more preferably 0. It is 002 to 1.5 w / v%, more preferably 0.005 to 0.8 w / v%, and particularly preferably 0.01 to 0.5 w / v%.

The content of the component (A) is preferable from the viewpoint of the effect of suppressing cloudiness, improving photostability, and imparting an action of improving the corneal epithelial barrier function in the aqueous ophthalmic composition.

The aqueous ophthalmic composition of the present invention is selected from the group consisting of a cellulosic thickener, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxine and salts thereof, in addition to the above component (A). It is necessary to contain at least one kind (component (B)). As described above, by using the component (A) and the component (B) in combination in the aqueous ophthalmic composition, the cloudiness of the aqueous ophthalmic composition containing the component (A) can be suppressed, and further, the component (A) is contained in the composition. It can suppress the photodegradation of polyoxyethylene castor oil and pyridoxine hydrochloride, improve photostability, and further improve the corneal epithelial barrier function.

The cellulosic thickening agent is a cellulosic derivative obtained by replacing the hydroxyl group of cellulose with a polar group or a non-polar group, and is a compound capable of imparting viscosity to an aqueous composition.

Examples of the functional group for substituting the hydroxyl group of cellulose used in the present invention include a methoxyl group, an ethoxyl group, a hydroxyethoxyl group and a hydroxypropoxyl group. Examples of cellulose derivatives include methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromellose), carboxymethyl cellulose, carboxyethyl cellulose, and pharmacologically acceptable salts thereof. Here, examples of the pharmacologically acceptable salt include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and salts with metals such as aluminum.

Of these, at least one selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, and salts thereof is preferable. In particular, from the viewpoint of the effect of imparting an action of improving the corneal epithelial barrier function, it is preferably at least one selected from the group consisting of hydroxyethyl cellulose and hydroxypropyl methyl cellulose. Further, from the viewpoint of the effect of suppressing white turbidity and improving photostability, hydroxypropylmethyl cellulose is particularly preferable.

The type of hydroxypropylmethylcellulose used in the present invention is not particularly limited, and examples thereof include hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, and hydroxypropylmethylcellulose 2910. Particularly preferred are hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910 and the like.

The cellulosic thickener used in the present invention is not limited in the degree of substitution of the substituent and the molecular weight, but for example, the weight average molecular weight is 5,000 to 1,000,000, preferably 10,000 to 500,000, and further. Preferably, about 10,000 to 300,000 can be used. Moreover, as these cellulosic thickeners, commercially available ones can be used. In the present invention, the cellulosic thickener and a salt thereof may be used alone or in combination of two or more of these compounds.

Epsilon-aminocaproic acid is a compound known as a neutral amino acid, also called 6-aminocaproic acid.

The salt of epsilon-aminocaproic acid used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of the salt of epsilon-aminocaproic acid include organic acid salts [for example, monocarboxylates (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylates. (Fumarate, maleate, succinate, malonate, etc.), oxycarboxylate (lactate, tartrate, citrate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, etc.) , Tosilate, etc.)], inorganic acid salts (eg, hydrochlorides, sulfates, nitrates, hydrobromates, phosphates, etc.), salts with organic bases (eg, methylamine, triethylamine, triethanol) Acids with organic amines such as amines, morpholins, piperazins, pyrrolidines, tripyridines, picolins, etc.), salts with inorganic bases [eg, ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.) ), Salts with metals such as aluminum] and the like. Of these, epsilon-aminocaproic acid is preferred. In the present invention, epsilon-aminocaproic acid and a salt thereof may be used alone or in any combination of two or more.

Aspartic acid is a compound known as an acidic amino acid, also called 2-aminobutanedioic acid. Aspartic acid may be L-form, D-form, or DL-form, but is preferably L-form.

The salt of aspartic acid used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, salts with organic bases (eg, salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazin, pyrrolidine, tripyridine, picolin, etc.), salts with inorganic bases [eg, ammonium Salts; alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), salts with metals such as aluminum, etc.] and the like. Among these salts, preferably a salt of aspartic acid with an inorganic base, more preferably an alkali metal salt and an alkaline earth metal salt, further preferably potassium aspartate, magnesium aspartate, and magnesium aspartate-potassium aspartate, in particular. It is preferably potassium aspartate. In the present invention, aspartic acid and a salt thereof may be used alone or in combination of two or more.

Aminoethyl sulfonic acid is a known compound also called taurine.

The salt of aminoethyl sulfonic acid used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of the salt of aminoethyl sulfonic acid include those having the same form as the salt that can be taken by aspartic acid. Among these, aminoethyl sulfonic acid is preferable. In the present invention, aminoethyl sulfonic acid and a salt thereof may be used alone or in combination of two or more.

Pyridoxine is a compound known as vitamin B6, a water-soluble vitamin.

The salt of pyridoxine used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, organic acid salts (eg, lactate, acetate, butyrate, trifluoroacetate, fumarate, maleate, tartrate, citrate, succinate, malonate, methanesulfone). Acid salts, toluenesulfonates, tosylates, palmitates, stearate, etc.); Inorganic acid salts (eg, hydrochlorides, sulfates, nitrates, hydrobromates, phosphates, etc.), etc. Be done. Among these pyridoxine salts, an inorganic acid salt is preferable, and a hydrochloride salt (pyridoxine hydrochloride) is more preferable. In the present invention, pyridoxine and a salt thereof may be used alone or in combination of two or more.

The content of the component (B) in the aqueous ophthalmic composition of the present invention is not particularly limited, and the type of the component (B), the type and content of the component (A) to be used in combination, the use and preparation of the aqueous ophthalmic composition. It is appropriately set according to the form, usage, and the like. For example, based on the total amount of the aqueous ophthalmic composition of the present invention, the total content of the component (B) is 0.0005 to 20 w / v%, preferably 0.005 to 15 w / v%, and more preferably 0. It is 02 to 10 w / v%, particularly preferably 0.1 to 5 w / v%.

The content of the cellulosic thickener and its salt is, for example, 0.0005 to 3 w / as the total content of the cellulosic thickener and its salt based on the total amount of the aqueous ophthalmic composition of the present invention. It is v%, preferably 0.005 to 1 w / v%, and more preferably 0.05 to 0.5 w / v%.

The content of epsilon-aminocaproic acid and its salt is preferably 0.01 to 10 w / v% as the total content of epsilon-aminocaproic acid and its salt, based on, for example, the total amount of the aqueous ophthalmic composition of the present invention. Is 0.05 to 8 w / v%, more preferably 0.1 to 5 w / v%.

The content of aspartic acid, aminoethyl sulfonic acid and their salts is, for example, 0. as the total content of aspartic acid, aminoethyl sulfonic acid and their salts, based on the total amount of the aqueous ophthalmic composition of the present invention. It is 001 to 5 w / v%, preferably 0.01 to 2 w / v%, and more preferably 0.1 to 1 w / v%.

The content of pyridoxine and its salt is, for example, 0.0005 to 1 w / v%, preferably 0.001 to 0, as the total content of pyridoxine and its salt based on the total amount of the aqueous ophthalmic composition of the present invention. It is .5 w / v%, more preferably 0.01 to 0.1 w / v%.

The content of the component (B) is preferable from the viewpoint of further enhancing the effect of the present invention.

Further, the content ratio of the component (B) to the component (A) in the aqueous ophthalmic composition of the present invention is not particularly limited, and the types of the component (A) and the component (B), the uses and formulations of the aqueous ophthalmic composition. It is appropriately set according to the form, usage, and the like. For example, the total content of the component (B) is 0.0001 to 50,000 parts by weight, preferably 0.001 with respect to 1 part by weight of the total content of the component (A) contained in the aqueous ophthalmic composition of the present invention. It is ~ 20000 parts by weight, more preferably 0.005 to 10000 parts by weight, and particularly preferably 0.02 to 5000 parts by weight.

The content ratio of the cellulosic thickener and its salt to the component (A) is, for example, the cellulosic thickener with respect to 1 part by weight of the total amount of the component (A) contained in the aqueous ophthalmic composition of the present invention. And the total content of the salt thereof is 0.001 to 1000 parts by weight, preferably 0.01 to 200 parts by weight, more preferably 0.05 to 50 parts by weight, and particularly preferably 0.3 to 20 parts by weight. ..

The content ratio of epsilon-aminocaproic acid and its salt to the component (A) is, for example, the content ratio of epsilon-aminocaproic acid and its salt to 1 part by weight of the total amount of the component (A) contained in the aqueous ophthalmic composition of the present invention. The total content is 0.01 to 5000 parts by weight, preferably 0.1 to 1000 parts by weight, more preferably 1 to 500 parts by weight, and particularly preferably 10 to 200 parts by weight.

The content ratio of aspartic acid, aminoethyl sulfonic acid and salts thereof to the component (A) is, for example, aspartic acid with respect to 1 part by weight of the total content of the component (A) contained in the aqueous ophthalmic composition of the present invention. , Aminoethyl sulfonic acid and salts thereof as a total content of 0.002 to 2000 parts by weight, preferably 0.01 to 500 parts by weight, more preferably 0.05 to 100 parts by weight, particularly preferably 0.3. ~ 50 parts by weight.

The content ratio of pyridoxine and its salt to the component (A) is, for example, as the total content of pyridoxine and its salt with respect to 1 part by weight of the total content of the component (A) contained in the aqueous ophthalmic composition of the present invention. , 0.001 to 500 parts by weight, preferably 0.005 to 100 parts by weight, more preferably 0.05 to 50 parts by weight, and particularly preferably 0.3 to 20 parts by weight.

The content ratio of the component (B) to the component (A) is suitable from the viewpoint of further enhancing the effect of the present invention.

As will be described later, the aqueous ophthalmic composition of the present invention may contain various pharmacologically active ingredients, physiologically active ingredients, and the like, and may also contain various additives, depending on the purpose of use thereof. .. In this case, in order to improve the solubility of the physiologically active ingredient, the additive and the like, other surfactants can be further added as the dissolution aid in addition to the ingredient (A).

The surfactant other than the component (A) that can be blended in the aqueous ophthalmic composition of the present invention is particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. However, it may be any of a nonionic surfactant, an amphoteric surfactant, an anionic surfactant, and a cationic surfactant.

Specific examples of the nonionic surfactant other than the component (A) that can be blended in the aqueous ophthalmic composition of the present invention include monolauric acid POE (20) sorbitan (polysolvate 20) and monopalmitate POE (20). POE sorbitan fatty acid esters such as sorbitan (polysorbate 40), monostearate POE (20) sorbitan (polysorbate 60), tristearate POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80) POE hardened bean oil such as POE (40) hardened bean oil (polyoxyethylene hydrogenated bean oil 40), POE (60) hardened bean oil (polyoxyethylene hydrogenated bean oil 60); POE (9) POE such as lauryl ether Alkyl ether; POE-POP alkyl ether such as POE (20) POP (4) cetyl ether; poly such as POE (196) POP (67) glycol (Poroxummer 407, Pluronic F127), POE (200) POP (70) glycol Oxyethylene / polyoxypropylene block copolymer; average addition of ethylene oxide such as polyoxyethylene glycol oil 35, polyoxyethylene glycol oil 40, polyoxyethylene glycol oil 50, polyoxyethylene glycol oil 60, polyoxyethylene glycol oil 70, etc. Examples thereof include polyoxyethylene glycol oil having a molar number exceeding 30. In the compounds exemplified above, the numbers in parentheses indicate the number of added moles.

Specific examples of the amphoteric tenside agent that can be blended in the aqueous ophthalmic composition of the present invention include alkyldiaminoethylglycine or a salt thereof (for example, hydrochloride, etc.).

Specific examples of the cationic surfactant that can be blended in the aqueous ophthalmic composition of the present invention include benzalkonium chloride and benzethonium chloride.

Specific examples of the anionic surfactant that can be blended in the aqueous ophthalmic composition of the present invention include alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, and aliphatic α-sulfomethyl ester. , Α-Olefin sulfonic acid and the like are exemplified.

As a surfactant other than the component (A) that can be blended in the aqueous ophthalmic composition of the present invention, it is preferably a nonionic surfactant, and more preferably POE sorbitan fatty acid ester, POE cured castor oil, POE. It is a POP block copolymer, and particularly preferably polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and poloxamer 407.

In the aqueous ophthalmic composition of the present invention, the surfactants other than the above component (A) may be used alone or in combination of two or more.

When a surfactant other than the above component (A) is blended in the aqueous ophthalmic composition of the present invention, the content thereof includes the type of the surfactant, the type and content of other blended components, and the aqueous ophthalmic composition. It is appropriately set according to the intended use, formulation form, usage method, etc. For example, based on the total amount of the aqueous ophthalmic composition of the present invention, the total content of the surfactant other than the component (A) is 0.001 to 3 w / v%, preferably 0.005 to 2 w / v%. It is more preferably 0.01 to 1 w / v%, and particularly preferably 0.05 to 1 w / v%.

The aqueous ophthalmic composition of the present invention can further contain a buffer. Thereby, the pH of the aqueous ophthalmic composition of the present invention can be adjusted. The buffer that can be blended in the aqueous ophthalmic composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such a buffer include borate buffer, phosphate buffer, carbonic acid buffer, citric acid buffer, acetate buffer, Tris buffer and the like. These buffers may be used alone or in any combination of two or more. Examples of the boric acid buffer include borate, and borates such as an alkali metal boric acid salt and an alkaline earth metal boric acid salt. Examples of the phosphoric acid buffer include phosphates, or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonic acid buffer include carbonic acid, or carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Examples of the citric acid buffer include citric acid, an alkali metal citrate salt, and an alkaline earth metal citrate salt. Moreover, borate or phosphate hydrate may be used as a borate buffer or a phosphate buffer. As a more specific example, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, boar sand, etc.) as a borate buffer; phosphoric acid or a salt thereof as a phosphate buffer. Salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); Or a salt thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); as a citrate buffer, citric acid or a salt thereof (sodium citrate, potassium citrate, citrus) Calcium acid, sodium dihydrogen citrate, disodium citrate, etc.); Examples of the acetate buffer include acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.). Among these buffers, boric acid buffer (particularly a combination of boric acid and boric acid) and phosphate buffer (particularly a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate) are preferable, and boric acid buffering is preferable. Agents are particularly preferred.

When a buffer is added to the aqueous ophthalmic composition of the present invention, the content thereof includes the type of the buffer, the type and content of other ingredients, the use, formulation form, usage method, etc. of the aqueous ophthalmic composition. It is set appropriately according to. For example, based on the total amount of the aqueous ophthalmic composition of the present invention, the total content of the buffer is 0.01 to 15 w / v%, preferably 0.05 to 10 w / v%, and more preferably 0. It is 1 to 7.5 w / v%, particularly preferably 0.5 to 5 w / v%.

In addition, the aqueous ophthalmic composition of the present invention may further contain an isotonic agent. The tonicity agent that can be blended in the aqueous ophthalmic composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such isotonic agents include disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, and magnesium chloride. , Potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, polyethylene glycol, glucose, mannitol, sorbitol and the like. Among these isotonic agents, preferred are polyhydric alcohols such as glycerin, propylene glycol and polyethylene glycol, and inorganic salts such as sodium chloride, potassium chloride, calcium chloride and magnesium chloride, and more preferably sodium chloride. , Potassium chloride, propylene glycol and glycerin, and particularly preferably glycerin. These isotonic agents may be used alone or in any combination of two or more.

When an isotonic agent is blended in the aqueous ophthalmic composition of the present invention, the content thereof is the type of the isotonic agent, the type and content of other compounding ingredients, the use of the aqueous ophthalmic composition, and the formulation form. , It is set appropriately according to the usage method. For example, based on the total amount of the aqueous ophthalmic composition of the present invention, the total content of the tonicity agent is 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, and more preferably 0. .1 to 3 w / v%.

The pH of the aqueous ophthalmic composition of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range. An example of the pH of the aqueous ophthalmic composition of the present invention is in the range of 4.0 to 9.5, preferably 5.0 to 9.0, and more preferably 5.5 to 8.5.

The osmotic pressure of the aqueous ophthalmic composition of the present invention is not particularly limited as long as it is within the range acceptable to the living body. As an example of the osmotic pressure ratio of the aqueous ophthalmic composition of the present invention, 0.5 to 5.0, preferably 0.6 to 3.0, still more preferably 0.7 to 2.0, particularly preferably 0.9 to 0.9. It is 1.55. The osmotic pressure can be adjusted by a method known in the art using inorganic salts, polyhydric alcohols, sugar alcohols, sugars and the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacy, and the osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacy. Measure with reference to (freezing point descent method). For the standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution), sodium chloride (standard reagent of the Japanese Pharmacopoeia) is dried at 500 to 650 ° C. for 40 to 50 minutes, and then in a desiccator (silica). Then, 0.900 g thereof may be accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for measuring osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) may be used.

The viscosity of the aqueous ophthalmic composition of the present invention is not particularly limited as long as it is within the range acceptable to the living body. For example, the viscosity at 25 ° C. measured with a rotary viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34'x24) is 0.01 to 1000 mPa · s, preferably 0.05 to 100 mPa · s. s, more preferably 0.1 to 10 mPa · s.

The aqueous ophthalmic composition of the present invention may contain various pharmacologically active ingredients and / or physiologically active ingredients in an appropriate amount alone or in combination as long as the effects of the present invention are exhibited. Such components are not particularly limited, and specific examples of the components used in ophthalmic drugs include the following components.

Antihistamines or antiallergic agents: for example, iproheptine, diphenhydramine hydrochloride, chlorpheniramine maleate, ketotifen fumarate, potassium pemirolast and the like.

Decongestant: for example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride and the like.

Eye muscle regulators: For example, cholinesterase inhibitors having an active center similar to acetylcholine, specifically neostigmine methylsulfate, tropicamide, atropine heleniensulfate, and the like.

Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinyl acetate, retinol palmitate, panthenol, calcium pantothenate, tocopherol acetate and the like.

Anti-inflammatory agents: For example, zinc sulfate, zinc lactate, sodium bromphenac, dipotassium glycyrrhizinate, planoprofen, allantoin, azulene, sodium azulene sulfonate, guaiazulene, berberine chloride, berberine sulfate, lysozyme chloride, licorice, etc.

Others: For example, sodium cromoglycate, sodium chondroitin sulfate, sodium hyaluronate, sulfamethoxazole, sodium sulfamethoxazole, etc.

In addition, for the aqueous ophthalmic composition of the present invention, as long as the effects of the invention are exhibited, various additives are appropriately selected according to a conventional method according to the use, formulation form, etc. A suitable amount may be contained in combination of more than that. The following additives can be mentioned as typical components.

Carrier: An aqueous carrier such as water or hydrous ethanol.

Sugar: For example, cyclodextrin and the like.
Sugar alcohols: for example, xylitol, sorbitol, mannitol, etc. These may be d-form, l-form or dl-form.

Preservatives, disinfectants or antibacterial agents: for example, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexanide hydrochloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, chlorhexidine gluconate, chlorobutanol. , Sorbic acid, potassium sorbate, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, glokill (trade name, Rhodia) , Polyhexanide hydrochloride, etc.

Thickening agent or thickener: gum arabic powder, sodium alginate, propylene glycol alginate, sodium chondroitin sulfate, sorbitol, dextran 70, tragant powder, carboxyvinyl polymer, polyvinyl alcohol, polyvinylpyrrolidone, macrogol 4000 and the like.

Oils: Sesame oil, castor oil, etc.

Fragrances or refreshing agents: menthol, anethole, eugenol, camphor, geraniol, cineole, borneol, limonene, ryunou, etc. These may be d-form, l-form or dl-form, and are blended as essential oils (mint oil, cool mint oil, spare mint oil, peppermint oil, uikyo oil, kehi oil, bergamot oil, eucalyptus oil, rose oil, etc.). You may.

Others: Ethanol, dibutylhydroxytoluene, sodium edetate, etc.

The aqueous ophthalmic composition of the present invention is prepared by adding a desired amount of the above-mentioned components (A) and (B), and if necessary, other compounding components to the carrier at a desired concentration. For example, in the case of eye drops, contact lens wearing liquids, eye wash agents or contact lens care agents, the components are dissolved or suspended in purified water, adjusted to a predetermined pH and osmotic pressure, and sterilized by filtration sterilization or the like. Can be prepared by Regarding the dissolution of the above-mentioned components (A) and (B) and other highly hydrophobic components, the mixture is previously stirred together with a component having a dissolution assisting action such as a surfactant, and then purified water is further added. May be dissolved or suspended.

Therefore, from another point of view, the present invention comprises (A) polyoxyethylene castor oil having an average addition molar number of ethylene oxide of 2 to 30 mol, and (B) a cellulose-based thickening agent on a carrier containing water. , Epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxin and salts thereof, which comprises adding at least one selected from the group.

In the present invention, the aqueous ophthalmic composition means an ophthalmic composition having a water content of 85 w / v% or more based on the total amount of the aqueous ophthalmic composition. The content of water in the aqueous ophthalmic composition is preferably 90 w / v% or more, more preferably 92 w / v% or more, still more preferably 94 w / v% or more, and particularly preferably 96 w / v% or more. As the water used in the aqueous ophthalmic composition of the present invention, pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable water may be used, and as such water, specifically, Examples thereof include distilled water, normal water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like. The dosage form of the aqueous ophthalmic composition in the present invention is not particularly limited as long as it can be used in the field of ophthalmology, but a liquid is preferable. These definitions are based on the 16th revised Japanese Pharmacopoeia.

The aqueous ophthalmic composition of the present invention can be used as a preparation for pharmaceuticals, non-pharmaceutical products, etc., and includes eye drops [however, eye drops include eye drops that can be instilled while wearing contact lenses], artificial tears, and eye washing. Agents [However, eye drops include eye drops that can be washed while wearing contact lenses], composition for contact lenses [contact lens wearing solution, composition for contact lens care (contact lens disinfectant, preservative for contact lenses) , Contact lens cleaning agents, contact lens cleaning preservatives), etc.] and the like are included. Preferable examples of the aqueous ophthalmic composition of the present invention include eye drops, artificial tears, eye wash, and contact lens wearing solution, and particularly suitable examples include eye drops and artificial tears. When used as a composition for contact lenses, it can be applied to all contact lenses including hard contact lenses and soft contact lenses.

As the container for accommodating the aqueous ophthalmic composition of the present invention, a container usually used as a container for accommodating the aqueous ophthalmic composition can be used, and it may be made of glass or plastic. When a plastic container is used as a container for accommodating the aqueous ophthalmic composition of the present invention, the constituent material of the plastic container is not particularly limited, but for example, polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene, polyethylene and the like. Examples thereof include any one type of polyimide, a copolymer thereof, or a mixture of two or more types. The copolymer mainly contains any one of ethylene-2,6-naphthalate unit, allylate unit, ethylene terephthalate unit, propylene unit, ethylene unit and imide unit, and other polyester unit, imide unit and the like. Examples thereof include copolymers containing. When the container is described as, for example, a polyethylene terephthalate container in the present invention, it means that the polyethylene terephthalate is 50 w / w% or more with respect to the total weight of the constituent materials of the container.

Further, the structure, constituent materials, and the like of the peripheral portion of the container spout such as the nozzle provided in the container containing the aqueous ophthalmic composition of the present invention are not particularly limited. The structure around the spout of the container such as a nozzle may be a structure generally adopted as a spout (for example, a nozzle) of a container for an ophthalmic composition (for example, an ophthalmic agent container), and is integrated with the container body. It may be molded or may be molded separately from the container body. As the constituent material of the spout peripheral portion and the spout (for example, the nozzle), for example, the same material as the constituent material of the plastic container is exemplified.

From another point of view, the present invention comprises (A) polyoxyethylene castor oil having an average addition molar number of ethylene oxide of 2 to 30 and (B) cellulosic viscosity for the production of an aqueous ophthalmic composition. Also provided is the use of at least one selected from the group consisting of thickeners, epsilon-aminocaproic acid, aspartic acid, aminoethyl sulfonic acid, pyridoxin and salts thereof.

Further, from another point of view, the present invention comprises (A) polyoxyethylene castor oil having an average addition molar number of ethylene oxide of 2 to 30, and (B) a cellulosic thickening agent as an aqueous ophthalmic composition. Also provided are the use of compositions comprising, at least one selected from the group consisting of epsilon-aminocaproic acid, aspartic acid, aminoethyl sulfonic acid, pyridoxin and salts thereof.

Further, from another point of view, the present invention comprises (A) polyoxyethylene castor oil having an average addition molar number of 2 to 30 of ethylene oxide for use as an aqueous ophthalmic composition, and (B) a cellulosic acid. A composition comprising at least one selected from the group consisting of a thickening agent, epsilon-aminocaproic acid, aspartic acid, aminoethyl sulfonic acid, pyridoxin and salts thereof is provided.

[2. How to suppress cloudiness]
As described above, from (A) polyoxyethylene castor oil, (B) cellulose-based thickener, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxine and salts thereof in an aqueous ophthalmic composition. By blending at least one selected from the above group, it is possible to suppress cloudiness that tends to occur when the aqueous ophthalmic composition containing the component (A) is stored in a heated state.

Therefore, the present invention comprises (A) an aqueous ophthalmic composition containing polyoxyethylene castor oil, (B) a cellulosic thickener, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxin and theirs. It provides a method of suppressing cloudiness in the aqueous ophthalmic composition, which comprises blending at least one selected from the group consisting of salts.

The present invention is also selected from the group consisting of (A) polyoxyethylene castor oil and (B) cellulosic thickener, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxine and salts thereof. To provide a method for suppressing cloudiness in an aqueous ophthalmic composition, which comprises blending at least one of the above into an aqueous ophthalmic composition.

In the above method, as long as the component (A) and the component (B) coexist in the aqueous ophthalmic composition, the order of addition thereof is not particularly limited. Regarding the components (A) and (B), the type and content of each component, the type and content of other components to be blended, the formulation form of the composition, and the like are described in "1. Aqueous" of the present invention. It is the same as "ophthalmic composition".

In this specification, whether or not cloudiness in the aqueous ophthalmic composition is suppressed can be determined by the method described in Examples described later.

[3. Light stabilization method]
As described above, in an aqueous ophthalmic composition, with (A) polyoxyethylene castor oil, (B) from a cellulose-based thickener, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxine and salts thereof. By blending at least one selected from the above group, the photodecomposition of polyoxyethylene castor oil and pyridoxine hydrochloride contained in the aqueous ophthalmic composition can be suppressed.

Therefore, the present invention comprises (A) an aqueous ophthalmic composition containing polyoxyethylene castor oil, (B) a cellulosic thickener, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxin and theirs. It provides a method of improving photostability in the aqueous ophthalmic composition, which comprises blending at least one selected from the group consisting of salts.

The present invention also presents in (A) polyoxyethylene castor oil, and (B) cellulose-based thickeners, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxine and theirs in aqueous ophthalmic compositions. It provides a method of improving photostability in the aqueous ophthalmic composition, which comprises blending at least one selected from the group consisting of salts.

In the above method, as long as the component (A) and the component (B) coexist in the aqueous ophthalmic composition, the order of addition thereof is not particularly limited. Regarding the components (A) and (B), the type and content of each component, the type and content of other components to be blended, the formulation form of the composition, and the like are described in "1. Aqueous" of the present invention. It is the same as "ophthalmic composition".

In this specification, whether or not the photostability of the aqueous ophthalmic composition is improved can be determined by the method described in Examples described later.
[4. Method of imparting action to improve corneal epithelial barrier function]
As described above, in an aqueous ophthalmic composition, with (A) polyoxyethylene castor oil, (B) from a cellulose-based thickener, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxine and salts thereof. By blending at least one selected from the above group, the aqueous ophthalmic composition can be imparted with an action of improving the corneal epithelial barrier function.

Therefore, the present invention presents in (A) polyoxyethylene castor oil and (B) cellulose-based thickeners, epsilon-aminocaproic acid, aspartic acid, aminoethylsulfonic acid, pyridoxine and theirs in aqueous ophthalmic compositions. It provides a method for imparting a corneal epithelial barrier function improving effect to the aqueous ophthalmic composition, which comprises blending at least one selected from the group consisting of salts.

In the above method, as long as the component (A) and the component (B) coexist in the aqueous ophthalmic composition, the order of addition thereof is not particularly limited. Regarding the components (A) and (B), the type and content of each component, the type and content of other components to be blended, the formulation form of the composition, and the like are described in "1. Aqueous" of the present invention. It is the same as "ophthalmic composition".

In the present specification, it is possible to determine whether or not the aqueous ophthalmic composition is imparted with the action of improving the corneal epithelial barrier function by the method described in Examples described later.

Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but the present invention is not limited to these Examples and the like.

[ Test Example 1 Test on cloudiness (1) ]
The aqueous ophthalmic compositions shown in Table 1 below were prepared by a conventional method, and the state of white turbidity during storage was evaluated. As the polyoxyethylene castor oil 10, those conforming to the standard of polyoxyethylene castor oil of the pharmaceutical additive standard 2003 and having an average number of moles of ethylene oxide added of 10 were used. As hydroxypropylmethylcellulose and epsilon-aminocaproic acid, those conforming to the standards of the 16th revised Japanese Pharmacopoeia were used.

Next, the prepared aqueous ophthalmic composition was filled in a glass headspace vial having a capacity of 10 mL by 5 mL each, and stored in an incubator at 70 ° C. under shading. After storage for 14 days, the white turbidity in each aqueous ophthalmic composition was observed and evaluated by the following indexes. The evaluation results are also shown in Table 1.

White turbidity-: Clear
+: If you look closely, it becomes cloudy
++: To the extent that cloudiness can be recognized at a glance
+++: White turbidity that blocks the background

As shown in Table 1, the aqueous ophthalmic composition containing polyoxyethylene castor oil 10 was found to be cloudy when stored at 70 ° C. (Comparative Example 1). On the other hand, in the aqueous ophthalmic composition containing hydroxypropylmethylcellulose or epsilon-aminocaproic acid together with polyoxyethylene castor oil 10, no cloudiness is observed even after storage at 70 ° C. for 14 days, and clarity can be maintained. Was confirmed (Examples 1 and 2).

[ Test Example 2 Test on cloudiness (2) ]
The aqueous ophthalmic compositions shown in Table 2 below were prepared by a conventional method, and the state of white turbidity during storage was evaluated. As the polyoxyethylene castor oil 10, the same oil as in Test Example 1 was used. As the potassium L-aspartate, aminoethyl sulfonic acid, and pyridoxine hydrochloride, those conforming to the standards of the 16th revised Japanese Pharmacopoeia were used.

These aqueous ophthalmic compositions were stored in the same manner as in Test Example 1, and the white turbidity was evaluated by the following index. The results of the evaluation 14 days after storage are also shown in Table 2. In addition, a photograph showing the state of each of the aqueous ophthalmic compositions of Comparative Examples and Examples after 14 days of storage is shown in FIG.

White turbidity-: Clear
+: If you look closely, it becomes cloudy
++: To the extent that cloudiness can be recognized at a glance
+++: White turbidity that blocks the background

As shown in Table 2 and FIG. 1, in the aqueous ophthalmic composition containing polyoxyethylene castor oil 10, cloudiness was observed after storage at 70 ° C. for 14 days (Comparative Example 1).

On the other hand, in the aqueous ophthalmic composition containing potassium aspartate, aminoethyl sulfonic acid and pyridoxine hydrochloride together with polyoxyethylene castor oil 10, no cloudiness was observed even after storage at 70 ° C. for 14 days, and the composition was clear. It was confirmed that the sex could be maintained (Examples 3 to 5).

[ Test Example 3 Photostability Test (1) ]
An aqueous ophthalmic composition having the composition shown in Table 3 below was prepared by a conventional method, and the photostability was evaluated. The same polyoxyethylene castor oil 10, potassium L-aspartate, aminoethyl sulfonic acid and pyridoxine hydrochloride as in Test Example 1 were used.

The prepared aqueous ophthalmic composition was then filled in 10 mL volume glass headspace vials with 5 mL each. Using a light stability test device (“Light-Tron LT-120 D3CJ type”, manufactured by Nagano Scientific Co., Ltd.), a D65 lamp was used as a light source, and 5000 lux of light was continuously irradiated for 120 hours at room temperature to form an aqueous ophthalmic composition. An object was exposed to light with an integrated irradiation amount of 600,000 lux · hr. After exposure, the content of polyoxyethylene castor oil 10 in the aqueous ophthalmic composition was quantified using HPLC, and the residual rate was calculated according to the following formula.

Residual rate (%) = (10 content of polyoxyethylene castor oil after light irradiation) / (10 content of polyoxyethylene castor oil before light irradiation) × 100
Furthermore, the photostability improvement rate (%) was calculated using the following equation. The calculation results are also shown in Table 3.

Photostability improvement rate (%) = {(Residual rate of each example / Residual rate of Comparative Example 3) -1} × 100

As shown in Table 3, potassium L-aspartate, aminoethylsulfonic acid or pyridoxin hydrochloride were added to the aqueous ophthalmic composition (Comparative Example 2) containing polyoxyethylene castor oil 10 together with polyoxyethylene castor oil 10. In the aqueous ophthalmic composition contained, it was confirmed that the residual rate of the polyoxyethylene castor oil 10 was remarkably improved and the photostability improvement rate of the polyoxyethylene castor oil 10 was increased (Examples 6 to 8). ..

[ Test Example 4 Photostability Test (2) ]
An aqueous ophthalmic composition having the composition shown in Table 4 below was prepared by a conventional method, and the photostability was evaluated. The same polyoxyethylene castor oil 10 and pyridoxine hydrochloride as in Test Example 1 were used.

These aqueous ophthalmic compositions were irradiated with light in the same manner as in Test Example 2 to expose them to light having an integrated irradiation amount of 600,000 lux · hr. After exposure, the content of pyridoxine hydrochloride in the aqueous ophthalmic composition was quantified using HPLC, and the residual rate was calculated according to the following formula.

Residual rate (%) = (pyridoxine hydrochloride content after light irradiation) / (pyridoxine hydrochloride content before light irradiation) x 100
Furthermore, the photostability improvement rate (%) was calculated using the following equation. The calculation results are also shown in Table 4.

Photostability improvement rate (%) = {(residual rate of Example 9 / residual rate of Comparative Example 3) -1} × 100

As shown in Table 4, the residual rate of pyridoxine hydrochloride is remarkable in the aqueous ophthalmic composition containing polyoxyethylene castor oil 10 together with pyridoxine hydrochloride with respect to the aqueous ophthalmic composition containing pyridoxine hydrochloride (Comparative Example 3). It was confirmed that the improvement rate of photostability of pyridoxine hydrochloride was increased (Example 9).

[ Test Example 5 Test on corneal epithelial barrier function (1) ]
An aqueous ophthalmic composition having the composition shown in Table 5 below was prepared by a conventional method, and the effect of improving the corneal epithelial barrier function was evaluated. The same polyoxyethylene castor oil 10, hydroxypropyl methylcellulose, potassium L-aspartate and pyridoxine hydrochloride were used as in Test Examples 1 and 2. As the hydroxyethyl cellulose, those conforming to the standards of the 16th revised Japanese Pharmacopoeia were used.

Then they were seeded at a ratio of human corneal epithelial cell line HCE-T Transwell (24well, Corning ) 1.0 × 10 5 in the insert of cells / well (200μL) (n = 3) . 600 μL of culture medium was placed in the wells, and the cells were cultured at 37 ° C. _{under 5% CO 2} conditions for 24 hours. After culturing, the inserts were transferred to wells containing 600 μL of each aqueous ophthalmic composition and allowed to stand at room temperature for 10 minutes. After the treatment, the insert was transferred to a well containing 600 μL of phosphate buffer, washed once, the culture solution in the insert was removed by suction, and 0.01 wt% sodium fluorescein prepared with phosphate buffer in the insert was removed. 100 μL of the solution was added. The insert was transferred to a well containing 600 μL of phosphate buffer and allowed to stand at room temperature for 20 minutes. 100 μL of the liquid in the well was transferred to a 96-well microplate, and the fluorescence value at an excitation wavelength of 485 nm / an emission wavelength of 527 nm was measured using a fluorescence plate reader (Fluoroskan Ascent CF, manufactured by Labsystems).

Using the fluorescence values in each Comparative Example and Example, the transmission suppression rate was calculated according to the following formula. The higher the permeation inhibition rate, the stronger the barrier between the corneal epithelial cells and the improved the barrier function.

Permeation suppression rate (%) = {1- (fluorescence value of each example and comparative example / fluorescence value of comparative example 4)} × 100

As shown in Table 5, the aqueous ophthalmic composition containing polyoxyethylene castor oil 10 (Comparative Example 5) has a fluorescence value similar to that of the aqueous ophthalmic composition not containing polyoxyethylene castor oil 10 (Comparative Example 4). However, in an aqueous ophthalmic composition containing hydroxypropylmethyl cellulose, hydroxyethyl cellulose, potassium L-aspartate or pyridoxin hydrochloride together with polyoxyethylene castor oil 10, the permeation inhibition rate was slight. It was remarkably improved, and it was confirmed that the corneal epithelial barrier function was improved (Examples 10 to 13).

[ Test Example 6 Test on corneal epithelial barrier function (2) ]
An aqueous ophthalmic composition having the composition shown in Table 6 below was prepared by a conventional method, and the effect of improving the corneal epithelial barrier function was evaluated. As the polyoxyethylene castor oil 35, one conforming to the standard of polyoxyethylene castor oil of the pharmaceutical additive standard 2003 and having an average number of moles of ethylene oxide added of 35 was used. The same hydroxypropylmethyl cellulose, hydroxyethyl cellulose, potassium L-aspartate and pyridoxine hydrochloride as in Test Examples 1, 2 and 5 were used.

Next, the fluorescence value was measured by the same method as in Test Example 5, and the permeation suppression rate was calculated according to the following formula using the fluorescence values in each Comparative Example and Example. The higher the permeation inhibition rate, the stronger the barrier between corneal epithelial cells, which means that the barrier function is improved.

Permeation suppression rate (%) = {1- (fluorescence value of each example and comparative example / fluorescence value of comparative example 6)} × 100

As shown in Table 6, the aqueous ophthalmic composition containing polyoxyethylene castor oil 35 (Comparative Example 7) has a lower permeation inhibition rate with respect to the aqueous ophthalmic composition not containing polyoxyethylene castor oil 10 (Comparative Example 6). On the other hand, in the aqueous ophthalmic composition containing hydroxypropylmethyl cellulose, hydroxyethyl cellulose, potassium L-aspartate or pyridoxin hydrochloride together with polyoxyethylene castor oil 35, the permeation inhibition rate was remarkably improved, and the corneal epithelium was significantly improved. It was confirmed that the epithelial barrier function was improved (Examples 14 to 17).

Formulation Examples Table 7 and Table 8 prepare eye drops (formulation examples 1 to 8) by a conventional method.

Claims (8)

At least one selected from the group consisting of (A) polyoxyethylene castor oil having an average addition mole number of ethylene oxide of 2 to 35, (B) a cellulosic thickener, aspartic acid, and salts thereof. Aqueous ophthalmic composition comprising
Based on the total amount of the aqueous ophthalmic composition, Ri total content of 0.0005~0.8w / v% der of the component (A),
Based on the total amount of the aqueous ophthalmic composition, the (B) the total content of the component Ru 0.05~2.05w / v% der, aqueous ophthalmic composition (However, the following (1) to (6) except:
(1) Composition for soft contact lenses containing azulene sulfonic acid and / or a salt thereof;
(2) Eye drops containing roflumilast as an active ingredient;
(3) Antazoline, betaxolol, bupivacaine, carbachol, carteolol, chloramphenicol, chlortetracycline, chloramphenicol, dexamethasone, dichlorphenamide, dipibefurin, indomethacin, erythromycin, fluorometallon, indomethacin, ketotiphen, levobnolol. , Lidokine, lignocaine, romefloxacin, medrison, metazolamide, nafazoline, natamaishi, neomycin, noradrenaline, ofloxacin, oxybuprokine, physostigmine, pilocarpine, polymixin B, prednisolone, scopolamine, sorbinyl Aqueous ophthalmic compositions comprising lysine, tropicamide, vidarabin, and their ophthalmatically acceptable salts, and ophthalmic agents selected from mixtures thereof;
(4) Borax oil 2w / v%, polyoxyethylene borax oil 5w / v%, sodium chondroitin sulfate 0.5w / v%, potassium L-aspartate 0.2w / v%, taurine 0.5w / v%, Hypromerose 0.1w / v%, boric acid 1.0w / v%, borax 0.1w / v%, tromethamole 0.05w / v%, sodium chloride 0.6w / v%, sodium edetate 0.1w / v% It contains v%, propylene glycol 1 w / v%, l-menthol 0.005 w / v%, dl-camfur 0.003 w / v%, sodium hydroxide / dilute hydrochloric acid, and purified water, and has a pH of 7.0. Ophthalmic composition;
(5) Himashima oil 1.5 w / v%, polyoxyethylene Himashima oil 3 w / v%, allantoin 0.1 w / v%, potassium L-aspartate 0.1 w / v%, taurine 0.1 w / v%, Hypromerose 0.1w / v%, boric acid 1.0w / v%, boarite 0.1w / v%, tromethamole 0.05w / v%, sodium chloride 0.6w / v%, sodium edetate 0.1w / v% It contains v%, propylene glycol 1 w / v%, l-menthol 0.005 w / v%, dl-camfur 0.003 w / v%, sodium hydroxide / dilute hydrochloric acid, and purified water, and has a pH of 7.0. Ophthalmic composition; and (6) castor oil 1 w / v%, polyoxyethylene castor oil 5 w / v%, retinol palmitate 10,000 units, potassium L-aspartate 0.1 w / v%, taurine 0.1 w / V%, hypromerose 0.1 w / v%, boric acid 1.0 w / v%, boar sand 0.1 w / v%, tromethamole 0.05 w / v%, sodium chloride 0.6 w / v%, sodium edetate 0.1w / v%, dibutylhydroxytoluene 0.005w / v%, propylene glycol 1w / v%, l-menthol 0.008w / v%, dl-camfur 0.003w / v%, sodium hydroxide / dilute hydrochloric acid, And an ophthalmic composition containing purified water and having a pH of 7.0). The aqueous ophthalmic composition according to claim 1, wherein the component (A) is polyoxyethylene castor oil having an average addition mole number of ethylene oxide of 2 to 30. The aqueous ophthalmic composition according to claim 1 or 2, wherein the cellulosic thickener is at least one selected from the group consisting of hydroxypropylmethyl cellulose and hydroxyethyl cellulose. The aqueous ophthalmic composition according to any one of claims 1 to 3, further comprising a surfactant and / or an isotonic agent other than the component (A). The aqueous ophthalmic composition according to any one of claims 1 to 4, further comprising a boric acid buffer. The aqueous ophthalmic composition according to any one of claims 1 to 5, excluding (7) an aqueous ophthalmic composition that can be treated by an autoclave. A group consisting of (A) polyoxyethylene castor oil having an average addition molar number of ethylene oxide of 2 to 35, and (B) a cellulosic thickener, aspartic acid, and salts thereof in an aqueous ophthalmic composition. A method for imparting a corneal epithelial barrier function improving effect to an aqueous ophthalmic composition, which comprises blending at least one selected from the above.
The amount of component (A), based on the total amount of the aqueous ophthalmic composition, Ri 0.0005~0.8w / v% der,
(B) amount of component, based on the total amount of the aqueous ophthalmic composition, Ru 0.05~2.05w / v% der method (however, the aqueous ophthalmic composition is less than (1) - (6 ):
(1) Composition for soft contact lenses containing azulene sulfonic acid and / or a salt thereof;
(2) Eye drops containing roflumilast as an active ingredient;
(3) Antazoline, betaxolol, bupivacaine, carbachol, carteolol, chloramphenicol, chlortetracycline, chloramphenicol, dexamethasone, dichlorphenamide, dipibefurin, indomethacin, erythromycin, fluorometallon, indomethacin, ketotiphen, levobnolol. , Lidokine, lignocaine, romefloxacin, medrison, metazolamide, nafazoline, natamaishi, neomycin, noradrenaline, ofloxacin, oxybuprokine, physostigmine, pilocarpine, polymixin B, prednisolone, scopolamine, sorbinyl Aqueous ophthalmic compositions comprising lysine, tropicamide, vidarabin, and their ophthalmatically acceptable salts, and ophthalmic agents selected from mixtures thereof;
(4) Borax oil 2w / v%, polyoxyethylene borax oil 5w / v%, sodium chondroitin sulfate 0.5w / v%, potassium L-aspartate 0.2w / v%, taurine 0.5w / v%, Hypromerose 0.1w / v%, boric acid 1.0w / v%, borax 0.1w / v%, tromethamole 0.05w / v%, sodium chloride 0.6w / v%, sodium edetate 0.1w / v% It contains v%, propylene glycol 1 w / v%, l-menthol 0.005 w / v%, dl-camfur 0.003 w / v%, sodium hydroxide / dilute hydrochloric acid, and purified water, and has a pH of 7.0. Ophthalmic composition;
(5) Himashima oil 1.5 w / v%, polyoxyethylene Himashima oil 3 w / v%, allantoin 0.1 w / v%, potassium L-aspartate 0.1 w / v%, taurine 0.1 w / v%, Hypromerose 0.1w / v%, boric acid 1.0w / v%, boarite 0.1w / v%, tromethamole 0.05w / v%, sodium chloride 0.6w / v%, sodium edetate 0.1w / v% It contains v%, propylene glycol 1 w / v%, l-menthol 0.005 w / v%, dl-camfur 0.003 w / v%, sodium hydroxide / dilute hydrochloric acid, and purified water, and has a pH of 7.0. Ophthalmic composition; and (6) castor oil 1 w / v%, polyoxyethylene castor oil 5 w / v%, retinol palmitate 10,000 units, potassium L-aspartate 0.1 w / v%, taurine 0.1 w / V%, hypromerose 0.1 w / v%, boric acid 1.0 w / v%, boar sand 0.1 w / v%, tromethamole 0.05 w / v%, sodium chloride 0.6 w / v%, sodium edetate 0.1w / v%, dibutylhydroxytoluene 0.005w / v%, propylene glycol 1w / v%, l-menthol 0.008w / v%, dl-camfur 0.003w / v%, sodium hydroxide / dilute hydrochloric acid, And an ophthalmic composition containing purified water and having a pH of 7.0). The method according to claim 7, except that the aqueous ophthalmic composition is (7) an autoclave-processable aqueous ophthalmic composition.

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