JP6177594B2 - 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 having a reduced defoaming time and suppressed white turbidity.

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

  It is known that an aqueous composition containing a surfactant is likely to foam, and foam is generated by applying vibration or impact during production or distribution. In general, in order to apply an aqueous ophthalmic composition to the eye safely, emphasis is placed on confirmation of dissolution during production. In addition, foreign substances in the manufacturing process are indispensable for pharmaceuticals such as eye drops and eye wash agents among aqueous ophthalmic compositions. However, when bubbles are generated in the aqueous ophthalmic composition being manufactured and the rate at which the bubbles disappear is slow, it is difficult to distinguish between the blended components or the foreign material and the foam. In other words, the current situation is that manufacturing cannot be performed efficiently.

  Moreover, in an aqueous composition, it is important to ensure the stability in a manufacturing process, a market distribution process, and long-term stability after opening. For this reason, the influence which the cloudiness of a clear solution has on quality cannot be ignored. Therefore, a method for stably storing a solution for a long period of time without forming cloudiness is desired.

  On the other hand, imidazoline-based vasoconstrictors are blended in eye drops and nasal drops for the purpose of removing ocular hyperemia and reducing nasal congestion. Neostigmine is blended in an ophthalmic composition for the purpose of imparting an effect of improving the focus adjustment function of the pupil. Polyoxyethylene / polyoxypropylene block copolymers have a surface active action and have been used in ophthalmic compositions for the purpose of assisting dissolution of medicinal ingredients, and chlorobutanol is used as an antiseptic in ophthalmic compositions. It is used.

  However, when these components are added to an aqueous ophthalmic composition, the effects on the defoaming time and the occurrence of white turbidity have not been clarified so far. In particular, when these components and a specific surfactant are contained in an aqueous ophthalmic composition, it is currently difficult to predict what effect will be exerted on the aqueous ophthalmic composition. is there.

JP 2005-298448 A

  Due to the importance of the steps of dissolution confirmation and foreign substance inspection in the aqueous ophthalmic composition as described above, it is an important problem to shorten the defoaming time in the aqueous ophthalmic composition. The present invention has been made in view of the state of the art as described above, and its main purpose is an aqueous ophthalmic composition, particularly an aqueous ophthalmic composition that is easy to foam, in which a solubilizing agent such as a surfactant is blended. An object of the present invention is to provide an aqueous ophthalmic composition having a reduced defoaming time even if bubbles are generated by vibration or impact, and a method for reducing the defoaming time in the aqueous ophthalmic composition.

  Further, the present inventors have conducted various studies on an aqueous ophthalmic composition containing polyoxyethylene castor oil, which is a nonionic surfactant among the surfactants. The aqueous ophthalmic composition contained may become clouded when stored in a heated state. In particular, the aqueous ophthalmic composition containing polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 is cloudy. Has been found to occur easily. The occurrence of white turbidity in the aqueous ophthalmic composition causes a reduction in quality including safety and a reduction in commercial value. Therefore, it is extremely important to suppress this.

  Accordingly, another object of the present invention is to provide an aqueous ophthalmic composition in which white turbidity is suppressed, and to provide a method capable of suppressing white turbidity in the aqueous ophthalmic composition.

  The present inventors have conducted intensive studies to solve the above problems. As a result, an aqueous ophthalmic composition containing polyoxyethylene castor oil (hereinafter sometimes referred to as component (A)) as a nonionic surfactant was added to an imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxy When foam is generated by vibration or impact by adding at least one selected from the group consisting of ethylene / polyoxypropylene block copolymer and chlorobutanol (hereinafter also referred to as component (B)), It was found that the foaming time can be shortened remarkably, and dissolution confirmation, foreign matter confirmation, etc. can be performed in a short time. In addition, aqueous ophthalmic compositions such as eye drops in the state where bubbles are generated have a large variation in the amount of dripping each time when used, especially in eye drops and contact lens mounting liquids where the amount used per time is relatively small. It is difficult for the user himself to control the amount of each use, and inconveniences such as difficulty in handling occur. In particular, when the aqueous ophthalmic composition is a pharmaceutical, there is a possibility that it may lead to a decrease in compliance. According to the present invention, as a result of shortening the defoaming time, variations in the amount of dripping in the aqueous ophthalmic composition can be suppressed.

  As a result of further investigations, the present inventors have formulated an aqueous ophthalmic composition containing polyoxyethylene castor oil by blending component (B) with an aqueous ophthalmic composition containing polyoxyethylene castor oil, in particular, It has been found that the occurrence of white turbidity in an aqueous ophthalmic composition containing polyoxyethylene castor oil having an average added mole number of ethylene oxide that is likely to be white turbid can be suppressed.

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

That is, this invention provides the aqueous ophthalmic composition of the aspect hung up below.
Item 1-1. (A) polyoxyethylene castor oil and (B) an imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and at least one selected from the group consisting of chlorobutanol, Aqueous ophthalmic composition.
Item 1-2. Item 11. 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 70 mol.
Item 1-3. The aqueous ophthalmic composition according to Item 1-1 or Item 1-2, wherein the component (A) is polyoxyethylene castor oil having an average addition mole number of ethylene oxide of 2 to 35 moles.
Item 1-4. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-3, wherein the component (A) is polyoxyethylene castor oil having an average addition mole number of ethylene oxide of 2 to 30 mol object.
Item 1-5. The aqueous solution according to any one of Items 1-1 to 1-4, wherein the imidazoline-based vasoconstrictor is at least one selected from the group consisting of naphazoline, tetrahydrozoline, oxymetazoline, and salts thereof. Ophthalmic composition.
Item 1-6. Item 6. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-5, 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 1-7. Item 7. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-6, wherein the total content of the component (B) is 0.0001 to 10 w / v% based on the total amount of the aqueous ophthalmic composition.
Item 1-8. The aqueous ophthalmologist according to any one of Items 1-1 to 1-7, wherein the total content of the component (B) is 0.00002 to 20000 parts by weight with respect to 1 part by weight of the total content of the component (A) Composition.
Item 1-9. The total content of component (B) is 0.002 to 100 with respect to 1 part by weight of the total content of component (A).
Item 9. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-8, which is part by weight.
Item 1-10. Item 10. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-9, further comprising a buffer.
Item 1-11. Item 11. The aqueous ophthalmic composition according to Item 1-10, wherein the buffer is a borate buffer.
Item 1-12. Item 11. The aqueous ophthalmic composition according to Item 1-10 or 1-11, 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 1-13. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-12, which further contains a surfactant and / or an isotonic agent other than the component (A).
Item 1-14. Item 14. The surfactant according to Item 1-13, wherein the surfactant other than the component (A) is a nonionic surfactant, and the tonicity agent is at least one selected from the group consisting of polyhydric alcohols and inorganic salts. Aqueous ophthalmic composition.
Item 1-15. The aqueous composition according to Item 1-13 or 1-14, 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 1-16. Item 15. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-15, which is filled in a polyethylene terephthalate container.
Item 1-17. Item 15. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-16, which is filled in a container equipped with a polyethylene nozzle.
Item 1-18. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-17, which is an eye drop.
Item 1-19. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-17, which is an eye wash.
Item 1-20. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-17, which is a contact lens mounting liquid.
Item 1-21. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-17, which is a contact lens care agent.

Moreover, this invention provides the shortening method of the defoaming time in the aqueous | water-based ophthalmic composition of the aspect hung up below, and the variation suppression method of the dripping amount at the time of use.
Item 2. (A) at least one selected from the group consisting of polyoxyethylene castor oil and (B) imidazoline-based vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and chlorobutanol, A method for shortening the defoaming time in the aqueous ophthalmic composition, comprising blending the ophthalmic composition.
Item 3. (A) An aqueous ophthalmic composition containing polyoxyethylene castor oil is selected from the group consisting of (B) imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and chlorobutanol The method of shortening the defoaming time in this aqueous | water-based ophthalmic composition including mix | blending at least 1 type | mold made.
Item 4. (A) at least one selected from the group consisting of polyoxyethylene castor oil and (B) imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and chlorobutanol, The method to suppress the variation in the amount of dripping at the time of use in this aqueous | water-based ophthalmic composition including mix | blending with an ophthalmic composition.

Moreover, this invention provides the method of suppressing white turbidity in the aqueous | water-based ophthalmic composition of the aspect hung up below.
Item 5. (A) An aqueous ophthalmic composition containing polyoxyethylene castor oil is selected from the group consisting of (B) imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and chlorobutanol The method of suppressing the cloudiness in this aqueous | water-based ophthalmic composition including mix | blending at least 1 type.
Item 6. (A) polyoxyethylene castor oil, and (B) at least one selected from the group consisting of imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and chlorobutanol is aqueous. A method for suppressing white turbidity in the aqueous ophthalmic composition, comprising blending in the ophthalmic composition.
Item 7. Item 7. The method for suppressing white turbidity in an aqueous ophthalmic composition according to any one of Items 4 to 6, wherein the component (A) is polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 mol.

Furthermore, the present invention also provides the use of the following aspects.
Item 8. (A) Polyoxyethylene castor oil and (B) imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and chloro for the production of an aqueous ophthalmic composition At least one use selected from the group consisting of butanol;
Item 9. Item 9. The use according to Item 8, wherein the aqueous ophthalmic composition is the composition according to any one of Items 1-1 to 1-21.

Furthermore, the present invention also provides the use of the embodiments listed below.
Item 10. As an aqueous ophthalmic composition, comprising (A) polyoxyethylene castor oil and (B) imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and chlorobutanol Use of a composition comprising at least one selected from the group.
Item 11. The use according to Item 10, wherein the composition is the composition according to any one of Items 1-1 to 1-21.

Furthermore, this invention also provides the composition of the aspect hung up below.
Item 12. For use as an aqueous ophthalmic composition, (A) polyoxyethylene castor oil, and (B) an imidazoline vasoconstrictor, neostigmine, a salt of neostigmine, a polyoxyethylene-polyoxypropylene block copolymer, and A composition comprising at least one selected from the group consisting of chlorobutanol.
Item 13. The composition according to Item 12, which is described in any one of Items 1-1 to 1-21.

Furthermore, this invention also provides the manufacturing method of the aqueous ophthalmic composition of the aspect hung up below.
Item 14. A group comprising (A) a polyoxyethylene castor oil and (B) an imidazoline vasoconstrictor, neostigmine, a salt of neostigmine, a polyoxyethylene / polyoxypropylene block copolymer, and chlorobutanol as a carrier containing water A method for producing an aqueous ophthalmic composition, comprising adding at least one selected from more.
Item 15. The production method according to Item 14, wherein the aqueous ophthalmic composition is the composition according to any one of Items 1-1 to 1-21.

According to the present invention, the following various effects are exhibited.
(1) According to the present invention, the defoaming time in an aqueous ophthalmic composition containing polyoxyethylene castor oil can be shortened. As a result, it is possible to perform dissolution confirmation or foreign matter confirmation during the production of the aqueous ophthalmic composition in a short time, and the production efficiency can be improved. Furthermore, variation in the amount of dripping can be suppressed by reducing the defoaming time.
(2) According to the aqueous ophthalmic composition of the present invention, white turbidity that is likely to occur during storage of an aqueous ophthalmic composition containing polyoxyethylene castor oil can be suppressed. Therefore, the aqueous ophthalmic composition of the present invention can stably exhibit the excellent performance of the contained components for a long period of time without deteriorating safety and quality.

  The aqueous ophthalmic composition of the present invention has the above-described various excellent effects, and can be used safely and comfortably over a long period of time.

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

  In the present specification, unless otherwise specified, the abbreviation “POE” means polyoxyethylene.

  In this specification, unless otherwise specified, the abbreviation “POP” means polyoxypropylene.

  In the present specification, unless otherwise specified, the contact lens is 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 (component (B)) selected from the group consisting of an imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and chlorobutanol, which will be described later. The above-described excellent effects of the present invention are exhibited.

  Polyoxyethylene castor oil is a known compound obtained by addition polymerization of ethylene oxide to castor oil, and several types having different average added mole numbers of ethylene oxide are known. In the present invention, the average added mole number of ethylene oxide in the polyoxyethylene castor oil used as the component (A) is not particularly limited, but is, for example, about 2 to 70 moles. Specifically, polyoxyethylene castor oil 3 having an average addition mole number of ethylene oxide of 3, polyoxyethylene castor oil 4 having an average addition mole number of ethylene oxide of 4, and an average addition mole number of ethylene oxide of 6 Polyoxyethylene castor oil 6, polyoxyethylene castor oil 7 with an average addition mole number of ethylene oxide of 7, polyoxyethylene castor oil 10 with an average addition mole number of ethylene oxide of 10, an average addition of ethylene oxide Polyoxyethylene castor oil 13.5 having a mole number of 13.5, polyoxyethylene castor oil 17 having an average addition mole number of ethylene oxide of 17, polyoxyethylene castor oil having an average addition mole number of ethylene oxide of 20 Oil 20, polyoxyethylene castor oil 25 having an average added mole number of ethylene oxide of 25, ethylene oxide Polyoxyethylene castor oil 30 having an average addition mole number of 30, polyoxyethylene castor oil 35 having an average addition mole number of ethylene oxide of 35, polyoxyethylene castor oil 40 having an average addition mole number of ethylene oxide of 40 Polyoxyethylene castor oil 50 having an average addition mole number of ethylene oxide of 50, polyoxyethylene castor oil 60 having an average addition mole number of ethylene oxide of 60, and polyoxyethylene having an average addition mole number of ethylene oxide of 70 Ethylene castor oil 70 etc. are mentioned.

  Among these, as an example of polyoxyethylene castor oil capable of suitably exhibiting the effects of the present invention, the average added mole number of ethylene oxide is 2 to 35, preferably 2 to 30, more preferably 2 to 20, particularly preferably. May include 2 to 12 moles of polyoxyethylene castor oil.

  In addition, the aqueous ophthalmic composition containing polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 has a large tendency to become cloudy during storage. In the aqueous ophthalmic composition, this is referred to as component (B). By using together, the cloudiness of the aqueous ophthalmic composition containing polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 can also be suppressed.

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

  In the aqueous ophthalmic composition of the present invention, the content of the component (A) is not particularly limited, the type of the component (A), the type and content of the component (B) to be used in combination, the use and formulation of the aqueous ophthalmic composition It is appropriately set according to the form, usage method, and the like. For example, based on the total amount of the aqueous ophthalmic composition, the total content of the component (A) is 0.0005 to 5 w / v%, preferably 0.001 to 3 w / v%, more preferably 0.002 to 2 w. / v%, more preferably 0.005 to 1 w / v%, particularly preferably 0.01 to 0.5 w / v%.

  The content of the component (A) is suitable from the viewpoint of further enhancing the action of shortening the defoaming time and the action of suppressing white turbidity in the aqueous ophthalmic composition.

  The aqueous ophthalmic composition of the present invention is selected from the group consisting of an imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and chlorobutanol in addition to the component (A). It is necessary to contain at least one (component (B)). Thus, by using the component (A) and the component (B) in combination, the effects described above, that is, effects such as shortening the defoaming time and suppressing white turbidity are exhibited.

  An imidazoline-based vasoconstrictor is a drug having an imidazoline skeleton, and a vasoconstrictor contracts the expanded peripheral blood vessels, relieves conjunctival hyperemia in the ophthalmic region, and congested nasal mucosa It is a drug used to relieve nasal congestion that accompanies nasal congestion.

  The imidazoline vasoconstrictor used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Specifically, naphazoline, tetrahydrozoline, Examples thereof include oxymetazoline and salts thereof. Examples of the salt of the above compound include inorganic acid salts such as hydrochloride and nitrate. Among these salts, tetrahydrozoline hydrochloride and naphazoline hydrochloride are preferable. Further, the above compound and its salt may be in the form of a hydrate. Furthermore, the compound may be any of d-form, l-form, and dl-form. In the present invention, the imidazoline-based vasoconstrictor may be selected from one of these and used alone, or two or more may be used in any combination.

  Neostigmine is a compound also called N-(-3-dimethylcarbamoyloxyphenyl) -N, N, N-trimethylammonium. Neostigmine and neostigmine salt are known compounds as eye focus control function improving agents, and may be synthesized by a known method or obtained as a commercial product.

  The neostigmine salt used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, methylsulfate (methylsulfate) Neostigmine), bromide salts (neostigmine bromide) and the like. Among these salts, preferably, neostigmine methyl sulfate is used. In the present invention, neostigmine and neostigmine salts may be used alone or in combination of two or more thereof.

  The polyoxyethylene / polyoxypropylene block copolymer is a block copolymer of a polyoxyethylene group and a polyoxypropylene group, and may be a POE-POP block copolymer adduct of ethylenediamine. These are known compounds as nonionic surfactants.

  The ratio of the polyoxyethylene group to the polyoxypropylene group in the polyoxyethylene / polyoxypropylene block copolymer used in the present invention is not particularly limited. The oxypropylene group is 1-1000, preferably 1-300, more preferably 1-100, and particularly preferably 1-50. Further, the molecular weight of the polyoxyethylene / polyoxypropylene block copolymer used in the present invention is not particularly limited, and examples thereof include 1000 to 30000, preferably 4000 to 20000, and more preferably 8000 to 15000. . The molecular weight is a value measured by a size exclusion chromatography method.

  Specific examples of the polyoxyethylene / polyoxypropylene block copolymer used in the present invention include POE (3) POP (17) glycol (Pluronic L31), POE (20) POP (20) glycol (Pluronic L44), POE (24) POP (20) Glycol (Poloxamer 124, Pluronic L44), POE (25) POP (30) Glycol (Pluronic L64), POE (35) POP (40) Glycol (Pluronic P84), POE (42) POP (67) Glycol (Poloxamer 403, Pluronic P123), POE (54) POP (39) Glycol (Poloxamer 235, Pluronic P85), POE (105) POP (5) Glycol, POE (120) POP (40) Glycol (Poloxamer) 237, Pluronic F87), POE (160) POP (30) Glycol (Poloxamer 188, Pluronic F68), PO Poloxamers such as E (196) POP (67) glycol (Poloxamer 407, Pluronic F127), POE (200) POP (70) glycol; Tetronic (registered trademark) 707, Tetronic (registered trademark) 908, Tetronic ( Examples include poloxamines such as (registered trademark) 909, Tetronic (registered trademark) 1107, Tetronic (registered trademark) 1508 (BASF). Among these, preferably poloxamers, more preferably POE (42) POP (67) glycol (poloxamer 403, pluronic P123), POE (54) POP (39) glycol (poloxamer 235, pluronic P85), POE (160 ) POP (30) glycol (poloxamer 188, pluronic F68), POE (196) POP (67) glycol (poloxamer 407, pluronic F127), particularly preferably POE (196) POP (67) glycol (poloxamer 407, pluronic F127) Is mentioned. In the present invention, the polyoxyethylene / polyoxypropylene block copolymer may be used alone or in any combination of two or more thereof. In the compounds exemplified above, the numbers in parentheses indicate the number of added moles.

  Chlorobutanol is a known compound also called 1,1,1, -trichloro-2-methyl-2-propanol, and may be synthesized by a known method or obtained as a commercial product.

  In the aqueous ophthalmic composition of the present invention, the content of the component (B) is not particularly limited, the type of the component (B), the type and content of the component (A) to be used together, the use of the aqueous ophthalmic composition, It is appropriately set according to the formulation form, usage method 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 0.0001 to 10 w / v%, preferably 0.0005 to 5 w / v%, more preferably 0.00. 001 to 2 w / v%, particularly preferably 0.005 to 0.5 w / v%.

  The content of the imidazoline-based vasoconstrictor is, for example, 0.0005 to 0.5 w / v%, preferably 0 as the total content of the imidazoline-based vasoconstrictor, based on the total amount of the aqueous ophthalmic composition of the present invention. 0.001 to 0.1 w / v%, more preferably 0.002 to 0.05 w / v%.

  The content of neostigmine and the neostigmine salt is, for example, 0.0001 to 0.02 w / v%, preferably 0 as the total content of neostigmine and the salt of neostigmine, based on the total amount of the aqueous ophthalmic composition of the present invention. .0005 to 0.01 w / v%, more preferably 0.001 to 0.005 w / v%.

  The content of the polyoxyethylene / polyoxypropylene block copolymer is, for example, 0.001 to 5 w /% as the total content of the polyoxyethylene / polyoxypropylene block copolymer based on the total amount of the aqueous ophthalmic composition of the present invention. v%, preferably 0.005 to 1 w / v%, more preferably 0.01 to 0.5 w / v%.

  The content of chlorobutanol is, for example, 0.001 to 2 w / v%, preferably 0.005 to 0.5 w / v as the total content of chlorobutanol, based on the total amount of the aqueous ophthalmic composition of the present invention. %, More preferably 0.02 to 0.2 w / v%.

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

  Further, the content ratio of the component (B) to the component (A) in the aqueous ophthalmic composition is not particularly limited, the types of the components (A) and (B), the use of the aqueous ophthalmic composition, the formulation form, It is set as appropriate according to the method of use. For example, with respect to 1 part by weight of the total content of component (A) contained in the aqueous ophthalmic composition of the present invention, the total content of component (B) is 0.00002 to 20000 parts by weight, preferably 0.0001. ˜2000 parts by weight, more preferably 0.0005 to 500 parts by weight, particularly preferably 0.002 to 100 parts by weight.

  The content ratio of the imidazoline vasoconstrictor to the component (A) is, for example, the total content of the imidazoline vasoconstrictor 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. The amount is 0.0001 to 1000 parts by weight, preferably 0.0005 to 100 parts by weight, more preferably 0.001 to 20 parts by weight, and particularly preferably 0.005 to 5 parts by weight.

  The content ratio of neostigmine and neostigmine salt to component (A) is, for example, the total content of neostigmine and neostigmine salt relative to 1 part by weight of the total content of component (A) contained in the aqueous ophthalmic composition of the present invention. The amount is 0.00002 to 50 parts by weight, preferably 0.0001 to 10 parts by weight, more preferably 0.0005 to 2 parts by weight, and particularly preferably 0.002 to 0.5 parts by weight.

The content ratio of the polyoxyethylene / polyoxypropylene block copolymer to the component (A) is, for example, relative to 1 part by weight of the total content of the component (A) contained in the aqueous ophthalmic composition of the present invention. The total content of the polyoxypropylene block copolymer is 0.0002 to 10,000 parts by weight, more preferably 0.001 to 1000 parts by weight, still more preferably 0.005 to 200 parts by weight, and particularly preferably 0.02 to 50 parts by weight. Part. The content ratio of the chlorobutanol to the component (A) is, for example, 0.
The amount is 0002 to 5000 parts by weight, preferably 0.002 to 500 parts by weight, more preferably 0.01 to 100 parts by weight, and particularly preferably 0.05 to 20 parts by weight.

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

In the aqueous ophthalmic composition of the present invention, as described later, various pharmacologically active ingredients, physiologically active ingredients and the like can be blended according to the purpose of use, and various additives can be blended. . In this case, in order to improve the solubility of physiologically active ingredients and additives, in addition to the component (A), other surfactants can be further blended as a solubilizing agent. When such a surfactant is blended, foaming usually increases.According to the present invention, the aqueous ophthalmic composition that is easily foamed by blending a surfactant other than the component (A) is also (A By adding the component (B) and the component (B), the defoaming time can be shortened, the production efficiency can be improved, and the variation in the dripping amount can be suppressed.

  The surfactant other than the component (A) 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. However, any of nonionic surfactants, amphoteric surfactants, anionic surfactants, and cationic surfactants may be used.

  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 (polysorbate 20) and monopalmitic acid POE (20). POE sorbitan fatty acid esters such as sorbitan (polysorbate 40), monostearic acid POE (20) sorbitan (polysorbate 60), tristearic acid POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80) ; POE (40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40), POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60), etc .; POE (9) POE such as lauryl ether; Alkyl ethers; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether and the like. In the compounds exemplified above, the numbers in parentheses indicate the number of added moles.

  Specific examples of the amphoteric surfactant that can be incorporated into the aqueous ophthalmic composition of the present invention include alkyldiaminoethylglycine or a salt thereof (for example, hydrochloride).

  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 incorporated into the aqueous ophthalmic composition of the present invention include alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, and aliphatic α-sulfomethyl ester. And α-olefin sulfonic acid.

  As a surfactant other than the component (A) that can be blended in the aqueous ophthalmic composition of the present invention, preferably a nonionic surfactant, more preferably a POE sorbitan fatty acid ester, a POE hydrogenated castor oil, Particularly preferred are polysorbate 80 and polyoxyethylene hydrogenated castor oil 60.

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

  When a surfactant other than the component (A) is blended in the aqueous ophthalmic composition of the present invention, the content thereof is the type of the surfactant, the type and content of other blended components, the aqueous ophthalmic composition. Is appropriately set according to the use, formulation form, method of use and the like. For example, based on the total amount of the aqueous ophthalmic composition of the present invention, the total content of surfactants other than the component (A) is 0.001 to 3 w / v%, preferably 0.01 to 2 w / v%, More preferably, it is 0.05-1 w / v%, Most preferably, it is 0.1-1 w / v%.

  The aqueous ophthalmic composition of the present invention can further contain a buffer. Thereby, pH of the aqueous ophthalmic composition of this invention can be adjusted. The buffer that can be incorporated into 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 buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, Tris buffer, aspartic acid, aspartate and the like. These buffering agents may be used alone or in any combination of two or more. Examples of the boric acid buffer include boric acid or boric acid salts such as alkali metal borate and alkaline earth metal borate. Examples of the phosphate buffer include phosphoric acid or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonate buffer include carbonates or carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Examples of the citrate buffer include citric acid, alkali metal citrate, and alkaline earth metal citrate. Moreover, you may use the borate or the hydrate of a phosphate 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, borax, etc.); as a phosphate buffer, phosphoric acid or a salt thereof Salt (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 bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.); citric acid or a salt thereof (sodium citrate, potassium citrate, citric acid, etc.) Calcium acetate, sodium dihydrogen citrate, disodium citrate, etc.); with acetate buffer Examples thereof include acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); aspartic acid or a salt thereof (sodium aspartate, magnesium aspartate, potassium aspartate, etc.). Among these buffering agents, boric acid buffering agents (particularly a combination of boric acid and borax) and phosphoric acid buffering agents (particularly a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate) are preferable.

  When a buffering agent is blended in the aqueous ophthalmic composition of the present invention, the content thereof includes the type of the buffering agent, the type and content of other blending components, the use of the aqueous ophthalmic composition, the formulation form, the method of use, etc. 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%, more preferably 0.1. -7.5 w / v%, particularly preferably 0.5-5 w / v%.

  The aqueous ophthalmic composition of the present invention may further contain an isotonic agent. The isotonic agent that can be incorporated into 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, for example, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride Potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, polyethylene glycol, glucose, mannitol, sorbitol and the like. Among these isotonic agents, polyhydric alcohols such as glycerin, propylene glycol, and polyethylene glycol, and inorganic salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride are preferable, and sodium chloride is more preferable. , Potassium chloride, propylene glycol or glycerin, 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 includes the type of tonicity agent, the type and content of other compounding ingredients, the use of the aqueous ophthalmic composition, and the formulation form. It is set as appropriate according to the method of use. 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%, more preferably 0. .1-3 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 includes a range of 4.0 to 9.5, preferably 5.0 to 9.0, and more preferably 5.5 to 8.5. .

  In addition, the osmotic pressure of the aqueous ophthalmic composition of the present invention is not particularly limited as long as it is within a range acceptable for a 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, more preferably 0.7 to 2.0, and particularly preferably 0.9 to 1.55. The adjustment of the osmotic pressure can be performed by a method known in the art using an inorganic salt, a polyhydric alcohol, a sugar alcohol, a sugar or the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopeia. Measured with reference to the method (freezing point depression method). In addition, about the standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution), after drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650 degreeC for 40-50 minutes, it is a desiccator (silica gel). It is allowed to cool, and 0.900 g is accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (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 a range acceptable for a living body. For example, the viscosity at 25 ° C. measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34 ′ × 24) 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 an appropriate amount of various pharmacologically active ingredients and / or physiologically active ingredients in addition to the above ingredients, as long as the effects of the present invention are exhibited. Such components are not particularly limited, and specific examples of components used in ophthalmic drugs include the following components.

  Antihistamine or antiallergic agent: for example, iproheptin, diphenhydramine hydrochloride, chlorpheniramine maleate, ketotifen fumarate, pemirolast potassium and the like.

  Decongestant: For example, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, etc.

  Vitamins: for example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, tocopherol acetate, etc.

  Amino acids: for example, potassium aspartate, magnesium aspartate, aminoethylsulfonic acid, epsilon-aminocaproic acid and the like.

  Anti-inflammatory agents: for example, zinc sulfate, zinc lactate, bromfenac sodium, dipotassium glycyrrhizinate, pranoprofen, allantoin, azulene, sodium azulenesulfonate, guaiazulene, berberine chloride, berberine sulfate, lysozyme chloride, licorice, etc.

  Other: For example, sodium cromoglycate, sodium chondroitin sulfate, sodium hyaluronate, sulfamethoxazole, sodium sulfamethoxazole and the like.

  Further, in the aqueous ophthalmic composition of the present invention, various additives are appropriately selected according to conventional methods depending on the use, formulation form, etc., as long as the effects of the invention are exerted, and one type or An appropriate amount may be added in combination. Typical additives include the following additives.

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

  Sugar: For example, cyclodextrin and the like.

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

  Preservatives, bactericides or antibacterials: for example, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexanide hydrochloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, chlorhexidine gluconate, sorbic acid , Potassium sorbate, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, glowkill (trade name, Rhodia), polyhexanide hydrochloride etc.

  Thickener or thickener: gum arabic powder, sodium alginate, propylene glycol alginate, sodium chondroitin sulfate, sorbitol, dextran 70, tragacanth powder, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, polyvinyl Alcohol, polyvinyl pyrrolidone, macrogol 4000, etc.

  Perfume or refreshing agent: menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, ryuno and the like. These may be either d-form, l-form or dl-form, and are formulated as essential oils such as peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, rose oil, etc. May be.

  Others: ethanol, dibutylhydroxytoluene, sodium edetate, etc.

  Oils: sesame oil, castor oil, etc.

  The aqueous ophthalmic composition of the present invention is prepared by adding a desired amount of the above components (A) and (B) and, if necessary, other blending components to a desired concentration. For example, in the case of eye drops, contact lens mounting solution, eye wash or contact lens care agent, the above 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. Regarding the dissolution of the above component (A) and component (B) and other highly hydrophobic components, stir in advance with a component having a solubilizing action such as a surfactant, and then add purified water. It may be dissolved or suspended.

  Therefore, the present invention, from another point of view, the carrier containing water, (A) polyoxyethylene castor oil, (B) imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene polyoxypropylene block The present invention provides a method for producing an aqueous ophthalmic composition, comprising adding at least one selected from the group consisting of a copolymer and chlorobutanol.

  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 water content 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 water used in the aqueous ophthalmic composition of the present invention, water that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable may be used, and as such water, specifically, Examples include distilled water, ordinary water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like. In addition, 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 ophthalmic field, but a liquid form is preferable. These definitions are based on the 16th revised Japanese Pharmacopoeia.

  Specific examples of the aqueous ophthalmic composition of the present invention include eye drops (also referred to as eye drops or eye drops) [however, eye drops include eye drops that can be applied while wearing contact lenses], eye wash (eye wash or eye drops) (It is also called eye wash) [However, eye wash includes eye wash that can be washed while wearing contact lenses], contact lens mounting solution, contact lens care products (contact lens disinfectant, contact lens preservative, contact lens use) Cleaning agents, contact lens cleaning preservatives, contact lens disinfecting / preserving / cleaning agents (multipurpose solutions for contact lenses)) and the like. The aqueous ophthalmic composition of the present invention has a shorter defoaming time and less variation in the amount of dripping during use, so that the amount of use at one time is particularly small compared to other dosage forms. It is suitably used for liquids. Eye drops are particularly preferable.

  As a container for containing the aqueous ophthalmic composition of the present invention, a container usually used as a container for containing the aqueous ophthalmic composition can be used, and it may be made of glass or plastic. When the plastic container is used as the container for storing the aqueous ophthalmic composition of the present invention, the constituent material of the plastic container is not particularly limited. For example, polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene, polyethylene, Any one of polyimides, a copolymer thereof, or a mixture of two or more types can be given. In addition, as the copolymer, ethylene-2,6-naphthalate unit, arylate unit, ethylene terephthalate unit, propylene unit, ethylene unit, imide unit is mainly used, and other polyester units and imide units are included. Examples of the copolymer include. In the present invention, for example, a container made of polyethylene terephthalate means that the polyethylene terephthalate is 50 w / w% or more based on the weight of the entire material constituting the container.

  In addition, the structure, constituent materials, and the like of the peripheral portion of the container inlet such as a nozzle provided in the container for storing the aqueous ophthalmic composition of the present invention are not particularly limited. The structure around the container inlet such as a nozzle may be a structure generally employed as a spout (for example, a nozzle) of a container for an ophthalmic composition (for example, an eye drop 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 or the spout (for example, nozzle), for example, the same material as that of the plastic container is exemplified.

  In particular, from the viewpoint of further improving the flexibility, cost, and / or the effect of suppressing variation in the amount of dripping, a spout containing polyethylene or polypropylene as a constituent material is suitable. Examples of the type of polyethylene include high-density polyethylene and low-density polyethylene. Among these, spouts containing low-density polyethylene as a constituent material are suitable. Moreover, as a spout, the nozzle used for an eye drop container is suitable.

  As a preferred combination of the container for containing the aqueous ophthalmic composition of the present invention and the peripheral part of the container spout, a combination of a polyethylene terephthalate container and a peripheral part of the polyethylene container spout, more preferably a polyethylene terephthalate eye drop container and a polyethylene nozzle This combination is particularly preferably a combination of a polyethylene terephthalate eye drop container and a low density polyethylene nozzle, and by using such a combination, the effect of suppressing variation in the amount of dripping in the present invention can be exhibited well.

  The aqueous ophthalmic composition of the present invention has a short defoaming time, suppresses variations in the amount of dripping during use, and can be instilled in a certain amount for each use. It is suitable as an eye drop containing a physiologically active ingredient. Uses of such eye drops include eye drops for dry eye, eye drops for removing hyperemia, eye drops for antibacterial use, eye drops for anti-inflammation, eye drops for suppressing itchiness, eye drops for suppressing fatigue eyes, and the like.

  In another aspect, the present invention provides (A) polyoxyethylene castor oil, (B) imidazoline-based vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene There is also provided at least one use selected from the group consisting of a polyoxypropylene block copolymer and chlorobutanol.

  Further, the present invention, from another viewpoint, as an aqueous ophthalmic composition, (A) polyoxyethylene castor oil, and (B) imidazoline vasoconstrictor, neostigmine, a salt of neostigmine, polyoxyethylene polyoxypropylene There is also provided the use of a composition comprising a block copolymer and at least one selected from the group consisting of chlorobutanol.

  Furthermore, the present invention provides, from another viewpoint, (A) polyoxyethylene castor oil, and (B) imidazoline-based vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene for use as an aqueous ophthalmic composition. A composition comprising at least one selected from the group consisting of a polyoxypropylene block copolymer and chlorobutanol is provided.

[2. Method for shortening defoaming time]
As described above, in the aqueous ophthalmic composition of the present invention, the antifoaming time can be shortened in the aqueous ophthalmic composition by containing the component (A) and the component (B). Variations in the amount of dripping can be suppressed.

  Accordingly, the present invention provides, from another viewpoint, (A) polyoxyethylene castor oil, (B) imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and chlorobutanol. There is provided a method for shortening the defoaming time in the aqueous ophthalmic composition, comprising blending at least one selected from the group consisting of:

  The present invention also provides (A) an aqueous ophthalmic composition containing polyoxyethylene castor oil, (B) an imidazoline vasoconstrictor, neostigmine, a neostigmine salt, a polyoxyethylene / polyoxypropylene block copolymer, and a chloroethylene There is also provided a method for shortening the defoaming time in the aqueous ophthalmic composition, which comprises blending at least one selected from the group consisting of butanol.

  Further, the present invention is selected from the group consisting of (A) polyoxyethylene castor oil and (B) imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and chlorobutanol. The method of suppressing the variation in the dripping amount at the time of use in this aqueous | water-based ophthalmic composition including mix | blending at least 1 type with an aqueous | water-based ophthalmic composition is provided.

  In these methods, as long as the component (A) and the component (B) coexist, they may be added simultaneously or separately, and the order thereof is not particularly limited. Types of component (A) and component (B) to be used, their content (or blending amount), ratio thereof, other types of components to be included, content (or blending amount), formulation of aqueous ophthalmic composition About a form, the kind of container, a combination, an implementation method, etc., it is the same as that of the said "1. aqueous ophthalmic composition".

  Among these, these methods are suitably applied when the aqueous ophthalmic composition is an eye drop or a contact lens mounting solution.

  In addition, in this specification, it can be determined by the method as described in the below-mentioned Example whether the defoaming time in an aqueous ophthalmic composition is shortened.

[3. Method for suppressing cloudiness]
As described above, in the aqueous ophthalmic composition, from (A) polyoxyethylene castor oil, (B) imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and chlorobutanol By blending at least one selected from the group, it is possible to suppress the cloudiness that may occur during storage of the aqueous ophthalmic composition containing the component (A).

  Accordingly, the present invention provides an aqueous ophthalmic composition containing (A) polyoxyethylene castor oil, (B) imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and chloroethylene The present invention provides a method for suppressing white turbidity in the aqueous ophthalmic composition, comprising blending at least one selected from the group consisting of butanol.

  Further, the present invention is selected from the group consisting of (A) polyoxyethylene castor oil, and (B) imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and chlorobutanol. A method for suppressing white turbidity in the aqueous ophthalmic composition, comprising blending at least one of the above into the aqueous ophthalmic composition.

  The above-described method is particularly useful as a method for suppressing white turbidity in an aqueous ophthalmic composition containing polyoxyethylene castor oil, in which the average added mole number of ethylene oxide is 2 to 30, which tends to cause white turbidity during storage. It's expensive.

  In the above-described method, the order of addition is not particularly limited as long as the component (A) and the component (B) coexist in the aqueous ophthalmic composition. In addition, regarding the component (A) and the component (B), the type and content of each component, the type and content of other components to be blended, the formulation form of the composition, etc. are described in “1. The same as “ophthalmic composition”.

  In addition, in this specification, it can be determined by the method as described in the below-mentioned Example whether the cloudiness in the aqueous ophthalmic composition is suppressed.

  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 for Antifoaming Time (1) ]
Aqueous ophthalmic compositions having the compositions shown in Table 1 and Table 2 below were prepared by a conventional method, and the defoaming time was evaluated using these. As the polyoxyethylene castor oil 35, one having an average added mole number of ethylene oxide that complies with the standard of polyoxyethylene castor oil of the pharmaceutical additive standard 2003 was used. Tetrahydrozoline hydrochloride and neostigmine methylsulfate are manufactured by WAKO, poloxamer 407 is compliant with the standard of Pharmaceutical Additives 2003, and chlorobutanol is compliant with the 16th revised Japanese Pharmacopoeia. Using.

  Next, 30 mL of each aqueous ophthalmic composition was filled in a 50 mL glass centrifuge tube, and they were shaken 1500 times using RECIPAD SHAKER SR-2w (TAITEC). Immediately after the end of shaking, the foam part and the aqueous solution part were visually confirmed, and the volume of the foam part was measured. Next, the time required until the volume of the initial foam was reduced by half was measured as the foam half-life, and the reduction rate of the foam half-life was calculated from the following formula based on the measurement results of the foam half-life of each control and example. . The larger the shortening rate, the faster the bubbles disappear.

Foam half-life shortening rate (%) = (foam half-life of corresponding control−foam half-life of each example) / (foam half-life of corresponding control) × 100
The corresponding controls are specifically control 1 for Examples 1 to 3 and control 2 for Examples 4 to 6. The results are shown in Table 1 and Table 2 together.

  As shown in Tables 1 and 2, as compared with the aqueous ophthalmic composition (Controls 1 and 2) containing polyoxyethylene castor oil 35 and containing none of tetrahydrozoline hydrochloride, neostigmine methyl sulfate, poloxamer 407 and chlorobutanol. Aqueous ophthalmic compositions (Examples 1 to 6) containing tetrahydrozoline hydrochloride, neostigmine methyl sulfate, poloxamer 407, or chlorobutanol together with polyoxyethylene castor oil 35 all have a greatly reduced foam half-life. Was confirmed.

[ Test Example 2 Test for Defoaming Time (2) ]
An aqueous ophthalmic composition having the composition shown in Table 3 below was prepared by a conventional method, and the shortening rate of the foam half-life was determined in the same manner as in Test Example 1.

  The polyoxyethylene castor oil 10 is one having an average added mole number of ethylene oxide that conforms to the standard of polyoxyethylene castor oil of the Pharmaceutical Additives Standard 2003. Tetrahydrozoline hydrochloride, neostigmine methyl sulfate and chlorobutanol The same one as in Test Example 1 was used.

  For Examples 7 and 8, the corresponding control is Control 3. The results are also shown in Table 3.

  As shown in Table 3, poloxamer 407 or polyoxyethylene castor oil 10 is used together with polyoxyethylene castor oil 10 as compared to an aqueous ophthalmic composition (control 3) containing polyoxyethylene castor oil 10 and containing neither poloxamer 407 nor chlorobutanol. In the aqueous ophthalmic composition containing chlorobutanol (Examples 7 and 8), it was confirmed that the foam half-life was significantly shortened.

[ Test Example 3 Test for cloudiness ]
The aqueous ophthalmic composition shown in the following Table 4 was prepared by a conventional method, and the state of occurrence of cloudiness during storage was evaluated. The same polyoxyethylene castor oil 10 as in Test Example 2 was used, and the same tetrahydrozoline hydrochloride and neostigmine methyl sulfate as in Test Example 1 were used.

  Next, the prepared aqueous ophthalmic composition was filled into a 10 mL capacity glass headspace vial by 5 mL, and stored in a thermostat at 70 ° C. under light shielding. After storage for 14 days, the white turbidity in each aqueous ophthalmic composition was observed and evaluated according to the following indices. The evaluation results are also shown in Table 4.

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

  As shown in Table 4, in the aqueous ophthalmic composition containing polyoxyethylene castor oil 10, white turbidity was observed after 14 days of storage (Comparative Example 1). On the other hand, in the aqueous ophthalmic composition containing tetrahydrozoline hydrochloride or neostigmine methyl sulfate together with polyoxyethylene castor oil 10, no cloudiness was observed even after storage at 70 ° C. for 14 days, and it was confirmed that clarity could be maintained. (Examples 9 and 10).

Formulation Examples Eye drops (Formulation Examples 1 to 8) are prepared by a conventional method with the formulations shown in Tables 5 and 6.

Claims (9)

(A) polyoxyethylene castor oil, and (B) an imidazoline-based vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and at least one selected from the group consisting of chlorobutanol, Aqueous ophthalmic composition (however, ketoprofen 0.43 w / w%, medium chain triglycerides 2 w / w%, cremophor EL 1 w / w%, tyloxapol 0.3 w / w%, poloxamer 188 0.01 w / w Excluding oil-in-water emulsions containing w%, glycerin 2.35 w / w%, and benzalkonium chloride 0.02 w / w%) . 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 70 moles. The aqueous ophthalmic composition according to claim 1 or 2 , wherein the imidazoline vasoconstrictor is at least one selected from the group consisting of naphazoline, tetrahydrozoline, oxymetazoline, and salts thereof. The aqueous ophthalmic composition according to any one of claims 1 to 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. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the total content of the component (B) is 0.0001 to 10 w / v% based on the total amount of the aqueous ophthalmic composition. The aqueous ophthalmic composition according to any one of claims 1 to 5, wherein the total content of the component (B) is 0.00002 to 20000 parts by weight with respect to 1 part by weight of the total content of the component (A). object. The aqueous ophthalmic composition according to any one of claims 1 to 6, 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 7 , further comprising a borate buffer. (A) at least one selected from the group consisting of polyoxyethylene castor oil and (B) imidazoline vasoconstrictor, neostigmine, neostigmine salt, polyoxyethylene / polyoxypropylene block copolymer, and chlorobutanol, A method for reducing the defoaming time in the aqueous ophthalmic composition, comprising blending into the ophthalmic composition (provided that the aqueous ophthalmic composition has 0.43 w / w% ketoprofen, 2 w / w% medium chain triglyceride, Contains 1 w / w% Cremophor EL, 0.3 w / w% tyloxapol, 0.01 w / w% poloxamer 188, 2.35 w / w% glycerin, and 0.02 w / w% benzalkonium chloride Except in the case of oil-in-water emulsions) .