WO2013008716A1

WO2013008716A1 - Aqueous ophthalmic composition

Info

Publication number: WO2013008716A1
Application number: PCT/JP2012/067195
Authority: WO
Inventors: 温子中田
Original assignee: ロート製薬株式会社
Priority date: 2011-07-08
Filing date: 2012-07-05
Publication date: 2013-01-17

Abstract

Defoaming time is shortened by means of this aqueous ophthalmic composition containing (A) polyoxyethylene castor oil with a 2-30 added moles of ethylene oxide and (B) at least one item selected from a group consisting of sesame oil and vitamin A.

Description

Aqueous ophthalmic composition

The present invention relates to an aqueous ophthalmic composition. More particularly, the present invention relates to an aqueous ophthalmic composition with reduced defoaming time.

In the field of ophthalmology, solubilizing agents are blended in many prescriptions. 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).

An aqueous composition containing a surfactant is known to easily 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.

On the other hand, in order to improve the physical properties of the aqueous ophthalmic composition, blending of various components has been attempted. For example, Patent Document 2 discloses a mucosa-applied composition containing castor oil as a method for stabilizing the viscosity of the composition. In addition, vitamins A have been previously incorporated into ophthalmic compositions for the purpose of promoting eye cell metabolism and cell respiration to relieve eye fatigue and exert anti-inflammatory effects. (Patent Document 3).

However, the effects on the defoaming time when these components are added to the aqueous ophthalmic composition 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 JP 2006-117656 A JP 2009-173638 A

Due to the importance of the dissolution confirmation and foreign substance inspection processes 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. An aqueous ophthalmic composition, particularly an aqueous ophthalmic composition that is easily foamed with a solubilizing agent such as a surfactant, is vibrated or An object of the present invention is to provide an aqueous ophthalmic composition having a reduced defoaming time even when bubbles are generated by impact, and a method for reducing the defoaming time 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 also simply referred to as “component (A)”) having 2 to 30 moles of added ethylene oxide as a nonionic surfactant. When at least one selected from the group consisting of castor oil and vitamin A (hereinafter also referred to as “component (B)”) is added to the product, when bubbles are generated by vibration or impact, It was found that the defoaming time in the aqueous ophthalmic composition can be remarkably shortened, 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, it is possible to suppress variations in the amount of dripping in the aqueous ophthalmic composition.

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. An aqueous ophthalmic composition comprising (A) polyoxyethylene castor oil having an addition mole number of ethylene oxide of 2 to 30, and (B) at least one selected from the group consisting of castor oil and vitamin A.
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 12.
Item 1-3. Item 11. The aqueous ophthalmic composition according to Item 1-1 or 1-2, wherein the total content of component (A) is 0.0005 to 5 w / v% based on the total amount of the aqueous ophthalmic composition.
Item 1-4. Item 4. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-3, wherein the total content of the component (B) is 0.0001 to 5 w / v% based on the total amount of the aqueous ophthalmic composition.
Item 1-5. Item 5. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-4, wherein the total content of vitamin A is 200 to 5000000 IU / 100 mL based on the total amount of the aqueous ophthalmic composition.
Item 1-6. The aqueous ophthalmologist according to any one of Items 1-1 to 1-5, wherein the total content of the component (B) is 0.00002 to 10,000 parts by weight with respect to 1 part by weight of the total content of the component (A) Composition.
Item 1-7. Any one of Items 1-1 to 1-6, further comprising at least one selected from the group consisting of boric acid and salts thereof (hereinafter also referred to as “component (C)”) An aqueous ophthalmic composition according to claim 1.
Item 1-8. Item 8. The aqueous ophthalmic composition according to Item 1-7, wherein the total content of component (C) is 0.01 to 10 w / v% based on the total amount of the aqueous ophthalmic composition.
Item 1-9. Item 9. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-8, further comprising a buffer.
Item 1-10. Item 10. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-9, further comprising a nonionic surfactant other than the component (A).
Item 1-11. The nonionic surfactant other than the component (A) is polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil having an added mole number of ethylene oxide exceeding 30. Item 11. The aqueous ophthalmic composition according to Item 1-10, which is at least one selected from the group consisting of polyoxyethylene / polyoxypropylene / block copolymers.
Item 1-12. Item 11. The aqueous solution according to item 1-10 or 1-11, wherein the total content of nonionic surfactants other than component (A) is 0.001 to 3 w / v% based on the total amount of the aqueous ophthalmic composition Ophthalmic composition.
Item 1-13. The aqueous ophthalmic composition according to any one of Items 1-1 to 1-12, further comprising an isotonic agent.
Item 1-14. The aqueous ophthalmologic according to Item 1-13, wherein the tonicity agent is at least one selected from the group consisting of glycerin, propylene glycol, glucose, sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. Composition.
Item 1-15. The aqueous ophthalmic composition according to Item 1-13 or 1-14, wherein the total content of tonicity agents is 0.005 to 10 w / v% based on the total amount of the aqueous 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) adding at least one selected from the group consisting of polyoxyethylene castor oil having an added mole number of ethylene oxide of 2 to 30 and (B) castor oil and vitamin A to the aqueous ophthalmic composition. A method for shortening the defoaming time in the aqueous ophthalmic composition.
Item 3. (A) The aqueous ophthalmic composition containing polyoxyethylene castor oil having 2 to 30 moles of added ethylene oxide is blended with at least one selected from the group consisting of (B) castor oil and vitamin A A method for reducing the defoaming time in the aqueous ophthalmic composition.
Item 4. (A) adding at least one selected from the group consisting of polyoxyethylene castor oil having an added mole number of ethylene oxide of 2 to 30 and (B) castor oil and vitamin A to the aqueous ophthalmic composition. A method for suppressing variation in dripping amount during use in the aqueous ophthalmic composition.

Furthermore, the present invention also provides the use of the embodiments listed below.
Item 5. Selected from the group consisting of (A) polyoxyethylene castor oil in which the number of moles of ethylene oxide added is 2 to 30 and (B) castor oil and vitamin A for the production of an aqueous ophthalmic composition Use of a composition comprising at least one.
Item 6. The use according to Item 5, wherein the aqueous ophthalmic composition is the composition according to any one of Items 1-1 to 1-21.
Item 7. As an aqueous ophthalmic composition, (A) polyoxyethylene castor oil in which the number of moles of ethylene oxide added is 2 to 30, and (B) at least one selected from the group consisting of castor oil and vitamin A Use of a composition comprising.
Item 8. The use according to Item 7, 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 9. For use as an aqueous ophthalmic composition, selected from the group consisting of (A) polyoxyethylene castor oil in which the number of moles of ethylene oxide added is 2 to 30, and (B) castor oil and vitamin A A composition comprising at least one of the above.
Item 10. The composition according to Item 9, 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 11. To a carrier containing water, (A) polyoxyethylene castor oil having 2 to 30 moles of added ethylene oxide, and (B) at least one selected from the group consisting of castor oil and vitamin A is added A method for producing an aqueous ophthalmic composition.
Item 12. The production method according to Item 11, 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 defoaming time in an aqueous ophthalmic composition containing polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 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.

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

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

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

Unless otherwise specified, in this specification, the contact lens is meant to include all types of contact lenses such as hard, oxygen permeable hard, soft (including silicone hydrogel lens), 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)) having an average addition mole number of ethylene oxide of 2 to 30. By using this together with at least one selected from the group consisting of castor oil and vitamin A, which will be described later, the excellent effects of the present invention described above 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 addition mole numbers of ethylene oxide are known. In the present invention, polyoxyethylene castor oil having an average addition mole number of ethylene oxide of 2 to 30 mol is used as the component (A). 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. A certain polyoxyethylene castor oil 6, polyoxyethylene castor oil 7 having an average addition mole number of ethylene oxide of 7, polyoxyethylene castor oil 10 having an average addition mole number of ethylene oxide of 10, an average addition mole of ethylene oxide Polyoxyethylene castor oil 13.5 having a 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 20. Polyoxyethylene castor oil 25 having an average added mole number of ethylene oxide of 25, Molar number of addition can be used as the polyoxyethylene castor oil 30, 30.

Among these polyoxyethylene castor oils, an example of a component that can exhibit the effects of the present invention particularly well is polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 12 mols.

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 of the present invention, the total content of the component (A) is 0.0005 to 5 w / v%, preferably 0.001 to 4 w / v%, more preferably 0.00. 002 to 3 w / v%, more preferably 0.005 to 2 w / v%, particularly preferably 0.01 to 1 w / v%.

The content of the component (A) is preferable from the viewpoint of further enhancing the action of shortening the defoaming time in the aqueous ophthalmic composition.

The aqueous ophthalmic composition of the present invention needs to contain at least one (component (B)) selected from the group consisting of castor oil and vitamin A in addition to the component (A). Thus, the combined use of the component (A) and the component (B) provides an effect of shortening the defoaming time.

Castor oil refers to a vegetable oil obtained from the seeds of plants belonging to the genus Euphorbiaceae (Ricinus communis Linne (EuforbiAceAe), etc.). *

The castor oil used in the aqueous ophthalmic composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Those obtained from seeds using a purification method or those commercially available can be used.

Vitamin A is a kind of fat-soluble vitamin and is an essential nutrient for the human body. Vitamin A is a substance having vitamin A activity, and both natural and synthetic products can be used.

Vitamin A used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable, and specifically, retinol, retinal, retinoic acid, these Derivatives, salts and the like.

Examples of vitamin A in the form of derivatives include retinol palmitate, retinol acetate, retinol butyrate, retinol propionate, retinol octylate, retinol laurate, retinol oleate, retinol linolenate, retinal, retinoic acid, methyl retinoic acid, retinoin Examples thereof include ethyl acid, retinoic acid retinol, δ-tocopheryl retinoate, α-tocopheryl retinoate, β-tocopheryl retinoate and the like.

The vitamin A in the salt form is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and specifically, an organic acid salt [for example, monocarboxylic acid] Acid salt (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, maleate, succinate, malonate, etc.), oxycarboxyl Acid salt (lactate, tartrate, citrate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic acid salt (eg, hydrochloride, sulfate, Nitrates, hydrobromides, phosphates, etc.) and salts with organic bases (eg methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.) Salts, etc.), salts with inorganic bases [for example, ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), salts with metals such as aluminum, etc.] and the like.

Vitamin A may be either isolated from natural products such as animal materials or chemically synthesized. Vitamin A can also be used as vitamin A oil in the form of vitamin A dissolved in oil. Vitamin A oil may be natural oil extracted and purified from animals, or may be vitamin A dissolved in vegetable oil or the like.

These vitamin A may be used alone or in any combination of two or more. Among these vitamin A, from the viewpoint of further enhancing the action of shortening the defoaming time, preferably, retinol acetate, retinol palmitate, and vitamin A oil are used.

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, and 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 component (B) is 0.0001 to 5 w / v%, preferably 0.0002 to 1 w / v%, more preferably 0. 0005 to 0.5 w / v%, particularly preferably 0.001 to 0. 1w / v%.

As can be generally understood by those skilled in the art, IU is known as an international unit for the amount of vitamin A. For example, in the case of retinol, 1 IU corresponds to about 0.30 μg of retinol, in the case of retinol acetate, 1 IU = corresponds to about 0.34 μg of retinol acetate, and in the case of retinol palmitate, 1 IU = about 0.1. It is well known to correspond to 55 μg retinol palmitate.

When the content of vitamin A is represented by IU, for example, based on the total amount of the aqueous ophthalmic composition of the present invention, the total content of vitamin A is 200 to 5000000 IU / 100 mL, preferably 500 to 1000000 IU / 100 mL, More preferably, it is 1,000 to 500,000 IU / 100 mL, and particularly preferably 2000 to 100,000 IU / 100 mL.

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

In the aqueous ophthalmic composition of the present invention, the content ratio of the (B) component to the (A) component is not particularly limited, the types of the (A) component and the (B) component, the use of the aqueous ophthalmic composition, and 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 the component (A) contained in the aqueous ophthalmic composition of the present invention, the total content of the component (B) is 0.00002 to 10,000 parts by weight, preferably 0.0001. It is ˜1000 parts by weight, more preferably 0.0002 to 200 parts by weight, still more preferably 0.0005 to 50 parts by weight, and particularly preferably 0.001 to 10 parts by weight.

The content ratio of the component (B) to the component (A) is preferable from the viewpoint of further enhancing the effects 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, an aqueous ophthalmic composition that is easily foamed by blending a surfactant other than the component (A) is By blending the component (B) and the component (B) at the same time, 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; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; POE (196) POP (67) glycol (poloxamer 407, Pluronic F12 ), Polyoxyethylene / polyoxypropylene block copolymers such as POE (200) POP (70) glycol; polyoxyethylene castor oil 35, polyoxyethylene castor oil 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil 60 And polyoxyethylene castor oil having an average added mole number of ethylene oxide exceeding 30 or 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 blended in 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.

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

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 amount of the surfactant other than the component (A) is 0.001 to 3 w / v%, preferably 0.005 to 2 w / v%, more preferably Is 0.01 to 1 w / v%, particularly preferably 0.05 to 1 w / v%.

The aqueous ophthalmic composition of the present invention preferably further contains at least one kind of salt (component (C)) selected from the group consisting of boric acid and salts thereof. By containing at least one selected from the group consisting of boric acid and salts thereof, the effects of the present invention can be further improved.

Boric acid is a general term for oxygen acids generated by hydration of diboron trioxide, and includes orthoboric acid, metaboric acid, tetraboric acid, and the like. Boric acid is a known compound, and may be synthesized by a known method or obtained as a commercial product.

Also, borate salts such as alkali metal borate and alkaline earth metal borate can be cited as boric acid salts. Further, a borate hydrate may be used as the borate. Specific examples of the component (C) include boric acid (orthoboric acid), sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, and borax. Boric acid and its salt can be used alone or in combination of two or more. As a suitable specific example of component (C), a combination of boric acid and its salt; preferably a combination of boric acid and an alkali metal salt and / or alkaline earth metal salt of boric acid; more preferably boric acid and boron Combinations of alkali metal salts of acids; particularly preferably combinations of boric acid and borax.

In the aqueous ophthalmic composition of the present invention, the content of the component (C) is not particularly limited, the type of (C) component, the type and content of other compounding components, the use of the aqueous ophthalmic composition, 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 component (C) is 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, more preferably 0.00. It is 1 to 3 w / v%, particularly preferably 0.2 to 2 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 phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, Tris buffer, aspartic acid, aspartate, epsilon-aminocaproic acid, and the like. These buffering agents may be used alone or in any combination of two or more. 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 hydrate of a phosphate as a phosphate buffer. As a more specific example, as a phosphate buffer, phosphoric acid or a salt thereof (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, monophosphate Calcium hydrogen, calcium dihydrogen phosphate, etc.) Carbonic acid or a salt thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); citrate buffer Citric acid or a salt thereof (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.); acetic acid or a salt thereof (ammonium acetate, potassium acetate, acetic acid) Calcium, sodium acetate, etc.); aspartic acid or a salt thereof (asparagine) Sodium, magnesium aspartate, potassium aspartate, etc.), epsilon - like aminocaproic acid can be exemplified. Among these buffers, a phosphate buffer (in particular, a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate) is preferable.

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 tonicity agents, glycerin, propylene glycol, glucose, sodium chloride, potassium chloride, calcium chloride, and magnesium chloride are preferable. 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 0.005 to 10 w / v%, preferably 0.01 to 5 w / v%, more preferably 0. .05-3w / 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 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, 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 (the osmotic pressure of 0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopoeia. Measured with reference to the method (freezing point depression method). As for the standard solution for measuring the osmotic pressure ratio (0.9% w / v sodium chloride aqueous solution), sodium chloride (Japanese Pharmacopoeia standard reagent) is dried at 500 to 650 ° C. for 40 to 50 minutes, and then 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.

Antihistamines or antiallergic agents: for example, iproheptin, diphenhydramine hydrochloride, chlorpheniramine maleate, ketotifen fumarate, potassium pemirolast, sodium cromoglycate, etc.

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

Vitamin: For example, flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, tocopherol acetate, etc.

Amino acids: For example, potassium aspartate, magnesium aspartate, epsilon-aminocaproic acid, sodium chondroitin sulfate and the like.

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

Other: For example, sodium hyaluronate, sulfamethoxazole, sulfamethoxazole sodium, etc.

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

Carrier: 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 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, glowul (trade name, Rhodia) etc.

Thickening agent 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.
Oils: sesame oil and the like.

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.

Accordingly, the present invention, from another point of view, comprises (A) polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 mol, and (B) castor oil and vitamin A, in a carrier containing water. The present invention provides a method for producing an aqueous ophthalmic composition, which comprises adding at least one selected from the group consisting of:

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. Since the aqueous ophthalmic composition of the present invention has a short defoaming time and less variation in the amount of dripping during use, an ophthalmic solution and a contact lens mounting liquid that require a small amount of use compared to other dosage forms. Is preferably used. Eye drops are particularly preferable.

As the 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. The copolymer is mainly composed of any one of ethylene-2,6-naphthalate units, arylate units, ethylene terephthalate units, propylene units, ethylene units, and imide units, and other polyester units and imide units. 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.

Also, 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.

Particularly, 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 shortens the 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 components. 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 having an average added mole number of ethylene oxide of 2 to 30 mol for the production of an aqueous ophthalmic composition, and (B) castor oil. And at least one use selected from the group consisting of vitamin A.

In another aspect, the present invention provides (A) polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 mol, and (B) castor oil and vitamin A as an aqueous ophthalmic composition. There is also provided the use of a composition comprising at least one selected from the group consisting of:

In another aspect, the present invention provides (A) polyoxyethylene castor oil having an average addition mole number of ethylene oxide of 2 to 30 moles, and (B) castor for use as an aqueous ophthalmic composition. A composition comprising at least one selected from the group consisting of oil and vitamin A 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). Variation in the amount of dripping can be suppressed.

Therefore, the present invention is further selected from the group consisting of (A) polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 mol, and (B) castor oil and vitamin A, from another viewpoint. A method for reducing the defoaming time in the aqueous ophthalmic composition, comprising blending at least one of the above into the aqueous ophthalmic composition.

In the present invention, (A) polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 moles is blended with at least one selected from the group consisting of (B) salmon castor oil and vitamin A. A method for reducing the defoaming time in the aqueous ophthalmic composition is also provided.

The present invention also provides at least one selected from the group consisting of: (A) polyoxyethylene castor oil having an average added mole number of ethylene oxide of 2 to 30 mol; and (B) castor oil and vitamin A. Provided is a method for suppressing variations in dripping amount during use in the aqueous ophthalmic composition, including inclusion in the composition.

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 The form, type of container, combination, method of implementation, and the like are the same as in “1.

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.

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 Tables 1 to 3 below were prepared by a conventional method, and the antifoaming time was evaluated using them. As the polyoxyethylene castor oil 10, 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 is used. As the castor oil, one manufactured by WAKO is used. It was.

Next, 30 mL of each aqueous ophthalmic composition was filled in a 50 mL capacity 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, they were allowed to stand, the volume of the foam portion was measured over time, and the time required until the foam completely disappeared was measured.

Based on the defoaming time of each control and the example, the shortening rate of the defoaming time by castor oil was calculated by the following formula. The larger the shortening rate, the faster the bubble disappears.

Defoaming time shortening rate (%) = (defoaming time of corresponding control−defoaming time of each example) / (defoaming time of corresponding control) × 100
The corresponding controls are specifically control 1 for Examples 1-1 and 1-2, control 2 for Examples 2-1 and 2-2, and control 3 for Example 3-1. Example 4-1 is Control 4. The results are also shown in Tables 1 to 3.

As shown in Tables 1 to 3, castor oil together with each concentration of polyoxyethylene castor oil 10 as compared to the aqueous ophthalmic composition containing polyoxyethylene castor oil 10 and no castor oil (controls 1 to 4) It was confirmed that all of the aqueous ophthalmic compositions containing Examples (Examples 1-1 to 4-1) significantly reduced the defoaming time.

[ Test Example 2 Test for Defoaming Time (2) ]
Aqueous ophthalmic compositions having the compositions shown in Tables 4 to 6 below were prepared by a conventional method, and the defoaming time was evaluated. Vitamin A oil contains 55% by weight of retinol palmitate, which is vitamin A, and 45% by weight of sunflower oil. When converted to IU, which is an international unit for the amount of vitamin A, 1 million IU / g A thing was used. The same polyoxyethylene castor oil 10 as in Test Example 1 was used.

Using these aqueous ophthalmic compositions, the shortening rate of the defoaming time with vitamin A oil was calculated by the following formula in the same manner as in Test Example 1. The larger the shortening rate, the shorter the defoaming time.

Defoaming time shortening rate (%) = (defoaming time of corresponding control−defoaming time of each example) / (defoaming time of corresponding control) × 100
The corresponding controls are specifically control 5 for Examples 5-1 and 5-2, control 6 for Examples 6-1 and 6-2, and control 7 for Example 7-1. Examples 8-1 and 8-2 are Control 8, Example 9-1 is Control 9, and Examples 10-1 and 10-2 are Control 10. The results are also shown in Tables 4 to 6.

As shown in Tables 4 to 6, as compared with the aqueous ophthalmic composition (controls 5 to 10) containing polyoxyethylene castor oil 10 and not containing vitamin A oil, vitamins together with polyoxyethylene castor oil 35 of each concentration were used. It was confirmed that all of the aqueous ophthalmic compositions containing oil A (Examples 5-1 to 10-2) significantly shortened the defoaming time.

[ Test Example 3 Test for Defoaming Time (3) ]
Aqueous ophthalmic compositions having the compositions shown in Tables 7 and 8 below were prepared by a conventional method, and the defoaming time was evaluated. 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. The same castor oil as used in Test Example 1 was used, and the same vitamin A oil as used in Test Example 2 was used.

Using these aqueous ophthalmic compositions, the shortening rate of the defoaming time with castor oil and vitamin A oil was calculated by the following formula using the same method as in Test Example 1. In addition, since the defoaming time was longer than Test Examples 1 and 2, the time required until the initial foam was halved was evaluated as the foam half-life, and the shortening rate was calculated by the following formula. The larger the shortening rate, the shorter the defoaming time.

Foam half-life shortening rate (%) = (foam half-life of the corresponding control−foam half-life of each example) / (foam half-life of the corresponding control) × 100
The corresponding controls are specifically control 11 for comparative example 1, 12 for comparative example 2, and control 13 for comparative examples 3 and 4. The results are shown in Table 7 and Table 8.

As shown in Tables 7 and 8, the aqueous ophthalmic composition containing castor oil or vitamin A oil (Comparative Examples 1 to 4) together with polyoxyethylene castor oil 35 of each concentration contains polyoxyethylene castor oil 35. When compared with aqueous ophthalmic compositions containing no castor oil or vitamin A oil (Controls 11 to 13), the foam half-life is comparable or the foam half-life is extended, The effect of shortening time was not recognized.

Formulation Examples Eye drops (Formulation Examples 1-8), eyewashes (Formulation Examples 9 and 10), and eye drops for soft contact lenses (Formulation Example 11) are prepared according to the formulations shown in Table 9 and Table 10. Note that retinol palmitate is vitamin A palmitate (900,000 to 1,050,000 IU / g) manufactured by Wako Pure Chemical Industries, Ltd.

Claims

An aqueous ophthalmic composition comprising (A) polyoxyethylene castor oil having 2 to 30 moles of addition of ethylene oxide and at least one selected from the group consisting of (B) rabbit castor oil and vitamin A.
The aqueous ophthalmic composition according to claim 1, further comprising at least one selected from the group consisting of boric acid and salts thereof.
The aqueous ophthalmic composition according to claim 1 or 2, further comprising a nonionic surfactant or isotonic agent other than the component (A).
(A) adding at least one selected from the group consisting of polyoxyethylene castor oil having an added mole number of ethylene oxide of 2 to 30 and (B) castor oil and vitamin A to the aqueous ophthalmic composition. A method for shortening the defoaming time in the aqueous ophthalmic composition.