Water-based liquid

Abstract

To provide a formulation technique pertaining to an aqueous liquid formulation that contains brimonidine and / or salts thereof.SOLUTION: An aqueous liquid formulation containing brimonidine and / or salts thereof, a buffering agent and a metal chloride is capable of inhibiting adsorption of brimonidine and / or salts thereof to a filter when passed through the filter, and is capable of inhibiting decrease in the content of brimonidine and / or salts thereof in the aqueous liquid formulation even when contained in a container with a filter or when subjected to a sterilization step through filtering during production.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an aqueous liquid preparation containing brimonidine and / or a salt thereof, in which the adsorption of brimonidine and / or a salt thereof to a filter is suppressed. [Background technology]

[0002] Aqueous liquid preparations such as eye drops and eyewashes usually contain preservatives such as benzalkonium chloride and methylparaben to prevent the growth of microorganisms. Such aqueous liquid preparations are usually subjected to a sterilization process by filtration during production.

[0003] While preservatives can prevent bacterial growth, they have been reported to be irritating and cytotoxic (see Non-Patent Document 1). Therefore, in order to avoid the adverse effects of preservatives, preservative-free aqueous liquid preparations have been developed. Multi-dose containers containing preservative-free aqueous liquid preparations have a structure that aseptically isolates the inside and outside of the container to prevent bacteria from entering the container during use, and containers with a filter attached to the nozzle (filter-equipped containers) are widely used (see Patent Documents 1 and 2).

[0004] On the other hand, brimonidine and its salts are known as adrenergic α2 receptor agonists, which have the effect of reducing intraocular pressure by inhibiting aqueous humor production and promoting the outflow of aqueous humor via the uveoscleral outflow pathway, and have traditionally been used to treat glaucoma and ocular hypertension. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Japanese Ophthalmology, Vol. 58, No. 10, pp. 945-950, 1987 [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Laid-Open No. 2004-51170 [Patent Document 2] Japanese Patent Application Laid-Open No. 2002-80055 Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide a formulation technology relating to an aqueous liquid preparation containing brimonidine and / or a salt thereof. [Means for solving the problem]

[0008] The present inventors have found that an aqueous liquid preparation comprising brimonidine and / or a salt thereof, a buffer, and a metal chloride can be prevented from adsorbing brimonidine and / or a salt thereof to a filter even when the aqueous liquid preparation is passed through a filter, and that a decrease in the content of brimonidine and / or a salt thereof in the aqueous liquid preparation can be prevented even when the aqueous liquid preparation is placed in a container with a filter or subjected to a sterilization process using a filter during production.

[0009] Furthermore, the present inventors have found that an aqueous liquid preparation comprising brimonidine and / or a salt thereof, a buffer, and a specific preservative (at least one selected from the group consisting of chlorhexidine and a salt thereof, benzalkonium chloride, and polyhexanide and a salt thereof) can suppress adsorption of brimonidine and / or a salt thereof to a filter even when passed through a filter, and can suppress a decrease in the content of brimonidine and / or a salt thereof in the aqueous liquid preparation even when subjected to a sterilization process by filter treatment during production.

[0010] The present invention was completed based on these findings and through further investigation.

[0011] That is, the present invention provides pharmaceutical products of the following aspects. Item 1-1. A pharmaceutical product comprising an aqueous liquid preparation containing brimonidine and / or a salt thereof, a buffer, and a metal chloride, which is contained in a container with a filter. Item 1-2. The pharmaceutical product according to Item 1-1, wherein the brimonidine and / or a salt thereof is brimonidine tartrate. Item 1-3. The pharmaceutical product according to Item 1-1 or 1-2, wherein the concentration of the brimonidine and / or a salt thereof is 0.05 to 0.2 w / v %. Item 1-4. The pharmaceutical product according to any one of Items 1-1 to 1-3, wherein the buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, Tris buffer, and citrate buffer. Item 1-5. The pharmaceutical product according to any one of Items 1-1 to 1-4, wherein the buffer is a borate buffer. Item 1-6. The pharmaceutical product according to any one of Items 1-1 to 1-5, wherein the buffer is a borate buffer, and the concentration of the borate buffer is 0.01 to 10 w / v %. Item 1-7. The pharmaceutical product according to any one of Items 1-1 to 1-4, wherein the buffer is a phosphate buffer having a concentration of 0.01 to 5 w / v %. Item 1-8. The pharmaceutical product according to any one of Items 1-1 to 1-4, wherein the buffer is a Tris acid buffer, and the concentration of the Tris acid buffer is 0.01 to 5 w / v %. Item 1-9. The pharmaceutical product according to any one of Items 1-1 to 1-4, wherein the buffer is a citrate buffer having a concentration of 0.01 to 5 w / v %. Item 1-10: The pharmaceutical product according to any one of Items 1-1 to 1-9, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride. Item 1-11: The pharmaceutical product according to any one of Items 1-1 to 1-10, wherein the metal chloride is sodium chloride. Item 1-12. The pharmaceutical product according to any one of Items 1-1 to 1-11, wherein the concentration of the metal chloride is 0.01 to 5 w / v %. Item 1-13. The pharmaceutical product according to any one of Items 1-1 to 1-12, wherein the aqueous liquid preparation is substantially free of preservatives. Item 1-14. The pharmaceutical product according to any one of Items 1-1 to 1-13, wherein the aqueous liquid preparation is an eye drop. Item 1-15. The pharmaceutical product according to any one of Items 1-1 to 1-14, wherein the filter is made of polyethersulfone or polyvinylidene fluoride. Item 1-16: The pharmaceutical product according to any one of Items 1-1 to 1-15, wherein the filter-equipped container is a multi-dose container. Item 1-17. The pharmaceutical product according to any one of Items 1-1 to 1-16, which is used to treat glaucoma. Item 1-18. A pharmaceutical product comprising an aqueous liquid preparation containing brimonidine and / or a salt thereof, a buffer, and a metal chloride contained in a container with a filter, Brimonidine and / or a salt thereof is brimonidine tartrate; the concentration of brimonidine and / or a salt thereof is 0.05 to 0.2 w / v%, the buffer is a borate buffer; the aqueous liquid preparation is an eye drop; The filter material is polyethersulfone, The drug recovery rate, calculated by dividing the brimonidine content in the aqueous solution after passing through the filter by the brimonidine content in the aqueous solution before passing through the filter, is 95% or more, and A pharmaceutical product, wherein the container with a filter is a multi-dose container. Item 1-19. A pharmaceutical product comprising an aqueous liquid preparation containing brimonidine and / or a salt thereof, a buffer, and a metal chloride contained in a container with a filter, Brimonidine and / or a salt thereof is brimonidine tartrate; the concentration of brimonidine and / or a salt thereof is 0.05 to 0.2 w / v%, the buffer is a borate buffer; the aqueous liquid preparation is an eye drop; The filter material is polyvinylidene fluoride. The drug recovery rate, calculated by dividing the brimonidine content in the aqueous solution after passing through the filter by the brimonidine content in the aqueous solution before passing through the filter, is 90% or more, and A pharmaceutical product, wherein the container with a filter is a multi-dose container.

[0012] The present invention also provides an adsorption suppression method according to the following embodiment. Item 2-1. A method for inhibiting adsorption of brimonidine and / or a salt thereof to a filter, comprising adding brimonidine and / or a salt thereof, a buffer, and a metal chloride to an aqueous liquid preparation to be passed through a filter. Item 2-2. The adsorption inhibiting method according to Item 2-1, wherein the brimonidine and / or a salt thereof is brimonidine tartrate. Item 2-3. The adsorption inhibiting method according to Item 2-1 or 2-2, wherein the concentration of brimonidine and / or a salt thereof in the aqueous liquid preparation is 0.05 to 0.2 w / v %. Item 2-4. The adsorption suppression method according to any one of Items 2-1 to 2-3, wherein the buffer is at least one selected from the group consisting of borate buffers, phosphate buffers, Tris buffers, and citrate buffers. Item 2-5. The adsorption suppression method according to any one of Items 2-1 to 2-4, wherein the buffer is a borate buffer. Item 2-6. The adsorption suppression method according to any one of Items 2-1 to 2-5, wherein the buffer is a borate buffer, and the concentration of the borate buffer in the aqueous liquid preparation is 0.01 to 10 w / v %. Item 2-7. The adsorption suppression method according to any one of Items 2-1 to 2-4, wherein the buffer is a phosphate buffer, and the concentration of the phosphate buffer in the aqueous liquid preparation is 0.01 to 5 w / v %. Item 2-8. The adsorption suppression method according to any one of Items 2-1 to 2-4, wherein the buffer is a Tris acid buffer, and the concentration of the Tris acid buffer in the aqueous liquid preparation is 0.01 to 5 w / v %. Item 2-9. The adsorption suppression method according to any one of Items 2-1 to 2-4, wherein the buffer is a citrate buffer, and the concentration of the citrate buffer in the aqueous liquid preparation is 0.01 to 5 w / v %. Item 2-10. The adsorption suppression method according to any one of Items 2-1 to 2-9, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride. Item 2-11. The adsorption suppression method according to any one of Items 2-1 to 2-10, wherein the metal chloride is sodium chloride. Item 2-12. The adsorption suppression method according to any one of Items 2-1 to 2-11, wherein the concentration of the metal chloride in the aqueous liquid preparation is 0.01 to 5 w / v %. Item 2-13. The adsorption suppression method according to any one of Items 2-1 to 2-12, wherein the aqueous liquid preparation is substantially free of preservatives. Item 2-14. The adsorption suppression method according to any one of Items 2-1 to 2-13, wherein the aqueous liquid preparation is an eye drop. Item 2-15. The adsorption suppression method according to any one of Items 2-1 to 2-14, wherein the material of the filter is polyethersulfone or polyvinylidene fluoride. Item 2-16. The adsorption suppression method according to any one of Items 2-1 to 2-15, wherein the filter is a filter in a container with a filter. Item 2-17. The adsorption suppression method according to any one of Items 2-1 to 2-15, wherein the filter is a filter used in a filtration sterilization step.

[0013] The present invention also provides the following manufacturing methods. Item 3-1. A step of preparing an aqueous liquid preparation containing brimonidine and / or a salt thereof, a buffer, and a metal chloride; and a step of subjecting the aqueous liquid preparation obtained in the above step to a filtration sterilization step using a filter; A method for producing an aqueous liquid preparation, comprising: Item 3-2. The method according to Item 3-1, wherein the brimonidine and / or a salt thereof is brimonidine tartrate. Item 3-3. The method according to Item 3-1 or 3-2, wherein the concentration of brimonidine and / or a salt thereof in the aqueous liquid preparation is 0.05 to 0.2 w / v %. Item 3-4. The production method according to any one of Items 3-1 to 3-3, wherein the buffer is at least one selected from the group consisting of a borate buffer, a phosphate buffer, a Tris buffer, and a citrate buffer. Item 3-5. The production method according to any one of Items 3-1 to 3-4, wherein the buffer is a borate buffer. Item 3-6. The production method according to any one of Items 3-1 to 3-5, wherein the buffer is a borate buffer, and the concentration of the borate buffer in the aqueous liquid preparation is 0.01 to 10 w / v %. Item 3-7. The method according to any one of Items 3-1 to 3-4, wherein the buffer is a phosphate buffer, and the concentration of the phosphate buffer in the aqueous liquid preparation is 0.01 to 5 w / v %. Item 3-8. The method according to any one of Items 3-1 to 3-4, wherein the buffer is a Tris acid buffer, and the concentration of the Tris acid buffer in the aqueous liquid preparation is 0.01 to 5 w / v %. Item 3-9. The method according to any one of Items 3-1 to 3-4, wherein the buffer is a citrate buffer, and the concentration of the citrate buffer in the aqueous liquid preparation is 0.01 to 5 w / v%. Manufacturing method. Item 3-10. The production method according to any one of Items 3-1 to 3-9, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride. Item 3-11. The production method according to any one of Items 3-1 to 3-10, wherein the metal chloride is sodium chloride. Item 3-12. The method according to any one of Items 3-1 to 3-11, wherein the concentration of the metal chloride in the aqueous liquid preparation is 0.01 to 5 w / v %. Item 3-13. The method according to any one of Items 3-1 to 3-12, wherein the aqueous liquid preparation is substantially free of preservatives. Item 3-14. The method according to any one of Items 3-1 to 3-13, wherein the aqueous liquid preparation is an eye drop. Item 3-15. The manufacturing method according to any one of Items 3-1 to 3-14, wherein the material of the filter is polyethersulfone or polyvinylidene fluoride.

[0014] The present invention also provides an adsorption suppression method according to the following embodiment. Item 4-1. For aqueous liquids that pass through the filter, Brimonidine and / or a salt thereof, A buffering agent; At least one preservative selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts; A method for inhibiting adsorption of brimonidine and / or a salt thereof to a filter, comprising: Item 4-2. The adsorption inhibiting method according to Item 4-1, wherein the brimonidine and / or a salt thereof is brimonidine tartrate. Item 4-3. The adsorption inhibiting method according to Item 4-1 or 4-2, wherein the concentration of brimonidine and / or a salt thereof in the aqueous liquid preparation is 0.05 to 0.2 w / v %. Item 4-4. The adsorption suppression method according to any one of Items 4-1 to 4-3, wherein the buffer is at least one selected from the group consisting of borate buffers, phosphate buffers, Tris buffers, and citrate buffers. Item 4-5. The adsorption suppression method according to any one of Items 4-1 to 4-4, wherein the buffer is a borate buffer. Item 4-6. The adsorption suppression method according to any one of Items 4-1 to 4-5, wherein the buffer is a borate buffer, and the concentration of the borate buffer in the aqueous liquid preparation is 0.01 to 10 w / v %. Item 4-7. The adsorption suppression method according to any one of Items 4-1 to 4-4, wherein the buffer is a phosphate buffer, and the concentration of the phosphate buffer in the aqueous liquid preparation is 0.01 to 5 w / v %. Item 4-8. The adsorption suppression method according to any one of Items 4-1 to 4-4, wherein the buffer is a Tris acid buffer, and the concentration of the Tris acid buffer in the aqueous liquid preparation is 0.01 to 5 w / v %. Item 4-9. The adsorption suppression method according to any one of Items 4-1 to 4-4, wherein the buffer is a citrate buffer, and the concentration of the citrate buffer in the aqueous liquid preparation is 0.01 to 5 w / v %. Item 4-10. The adsorption suppression method according to any one of Items 4-1 to 4-9, wherein the preservative is at least one selected from the group consisting of chlorhexidine gluconate, benzalkonium chloride, and polyhexanide hydrochloride. Item 4-11. The adsorption suppression method according to any one of Items 4-1 to 4-10, wherein the preservative is chlorhexidine and / or a salt thereof, and the concentration of chlorhexidine and / or a salt thereof in the aqueous liquid preparation is 0.0001 to 0.1 w / v %. Item 4-12. The adsorption suppression method according to any one of Items 4-1 to 4-10, wherein the preservative is benzalkonium chloride, and the concentration of benzalkonium chloride in the aqueous liquid preparation is 0.0001 to 0.1 w / v %. Item 4-13. The adsorption suppression method according to any one of Items 4-1 to 4-10, wherein the preservative is polyhexanide and / or a salt thereof, and the concentration of polyhexanide and / or a salt thereof in the aqueous liquid preparation is 0.00001 to 0.1 w / v %. Item 4-14. The adsorption suppression method according to any one of Items 4-1 to 4-13, wherein the aqueous liquid preparation does not contain a thickening agent. Item 4-15. The adsorption suppression method according to any one of Items 4-1 to 4-14, wherein the aqueous liquid preparation is an eye drop. Item 4-16. The adsorption suppression method according to any one of Items 4-1 to 4-15, wherein the material of the filter is polyethersulfone or polyvinylidene fluoride. Item 4-17. The adsorption suppression method according to any one of Items 4-1 to 4-16, wherein the filter is a filter used in a filtration sterilization step. Item 4-18. The adsorption suppression method according to any one of Items 4-1 to 4-17, wherein the aqueous liquid preparation is passed through a filter in a filtration sterilization step during production, and is provided in a multi-dose container not equipped with a filter after the filtration sterilization step. Item 4-19. The adsorption suppression method according to any one of Items 4-1 to 4-16, wherein the filter is a filter in a container with a filter.

[0015] The present invention also provides the following manufacturing methods. Item 5-1. Brimonidine and / or a salt thereof, a buffer, and chlorhexidine and a salt thereof, preparing an aqueous solution comprising benzalkonium chloride and at least one preservative selected from the group consisting of polyhexanide and salts thereof; a step of subjecting the aqueous liquid preparation obtained in the above step to a filtration sterilization step using a filter; A method for producing an aqueous liquid preparation, comprising: Item 5-2. The method according to Item 5-1, wherein the brimonidine and / or a salt thereof is brimonidine tartrate. Item 5-3. The method according to Item 5-1 or 5-2, wherein the concentration of brimonidine and / or a salt thereof in the aqueous liquid preparation is 0.05 to 0.2 w / v %. Item 5-4. The production method according to any one of Items 5-1 to 5-3, wherein the buffer is at least one selected from the group consisting of a borate buffer, a phosphate buffer, a Tris buffer, and a citrate buffer. Item 5-5. The production method according to any one of Items 5-1 to 5-4, wherein the buffer is a borate buffer. Item 5-6. The production method according to any one of Items 5-1 to 5-5, wherein the buffer is a borate buffer, and the concentration of the borate buffer in the aqueous liquid preparation is 0.01 to 10 w / v %. Item 5-7. The method according to any one of Items 5-1 to 5-4, wherein the buffer is a phosphate buffer, and the concentration of the phosphate buffer in the aqueous liquid preparation is 0.01 to 5 w / v %. Item 5-8. The method according to any one of Items 5-1 to 5-4, wherein the buffer is a Tris acid buffer, and the concentration of the Tris acid buffer in the aqueous liquid preparation is 0.01 to 5 w / v %. Item 5-9. The production method according to any one of Items 5-1 to 5-4, wherein the buffer is a citrate buffer, and the concentration of the citrate buffer in the aqueous liquid preparation is 0.01 to 5 w / v %. Item 5-10. The adsorption suppression method according to any one of Items 5-1 to 5-9, wherein the preservative is at least one selected from the group consisting of chlorhexidine gluconate, benzalkonium chloride, and polyhexanide hydrochloride. Item 5-11. The adsorption suppression method according to any one of Items 5-1 to 4-10, wherein the preservative is chlorhexidine and / or a salt thereof, and the concentration of chlorhexidine and / or a salt thereof in the aqueous liquid preparation is 0.0001 to 0.1 w / v %. Item 5-12. The adsorption suppression method according to any one of Items 5-1 to 5-10, wherein the preservative is benzalkonium chloride, and the concentration of benzalkonium chloride in the aqueous liquid preparation is 0.0001 to 0.1 w / v %. Item 5-13. The adsorption suppression method according to any one of Items 5-1 to 5-10, wherein the preservative is polyhexanide and / or a salt thereof, and the concentration of polyhexanide and / or a salt thereof in the aqueous liquid preparation is 0.00001 to 0.1 w / v %. Item 5-14. The method according to any one of Items 5-1 to 5-13, wherein the aqueous liquid preparation does not contain a thickening agent. Item 5-15. The method according to any one of Items 5-1 to 5-14, wherein the aqueous liquid preparation is an eye drop. Item 5-16. The manufacturing method according to any one of Items 5-1 to 5-15, wherein the material of the filter is polyethersulfone or polyvinylidene fluoride. Item 5-17. The production method according to any one of Items 5-1 to 5-16, wherein the aqueous liquid preparation is provided in a multi-dose container without a filter after the filtration sterilization step. [Effects of the Invention]

[0016] According to the present invention, by adding a buffer and a metal chloride to an aqueous liquid preparation containing brimonidine and / or a salt thereof, it is possible to suppress adsorption of brimonidine and / or a salt thereof to a filter, and to suppress a decrease in the content of brimonidine and / or a salt thereof in the aqueous liquid preparation after passing through the filter. Therefore, in one aspect of the present invention, even if an aqueous liquid preparation containing brimonidine and / or a salt thereof is contained in a container with a filter, it is possible to suppress a decrease in the content of brimonidine and / or a salt thereof in the aqueous liquid preparation that passes through the filter and is poured out of the container during use. In another aspect of the present invention, even if an aqueous liquid preparation containing brimonidine and / or a salt thereof is subjected to a sterilization process by filter treatment during production, it is possible to suppress a decrease in the content of brimonidine and / or a salt thereof in the aqueous liquid preparation after filtration sterilization.

[0017] Furthermore, according to the present invention, by adding a buffer and a specific preservative (at least one selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts) to an aqueous liquid preparation containing brimonidine and / or a salt thereof, it is possible to suppress adsorption of brimonidine and / or a salt thereof to a filter, and to suppress a decrease in the content of brimonidine and / or a salt thereof in the aqueous liquid preparation after passing through the filter. Therefore, in one aspect of the present invention, even if an aqueous liquid preparation containing brimonidine and / or a salt thereof is subjected to a sterilization step by filter treatment during production, it is possible to suppress a decrease in the content of brimonidine and / or a salt thereof in the aqueous liquid preparation after filtration sterilization. DETAILED DESCRIPTION OF THE INVENTION

[0018] 1.Definition It should be understood that the terms used herein are used in the sense commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0019] As used herein, the term "aqueous liquid preparation" refers to a preparation that contains water as a base and is in a liquid form.

[0020] As used herein, the term "pharmaceutical product" refers to a product in which an aqueous liquid formulation is contained in any container.

[0021] As used herein, "brimonidine" refers to 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine, a compound known as an adrenergic α2 receptor agonist.

[0022] As used herein, the term "buffer" refers to a compound or mixture that acts to moderate fluctuations in the hydrogen ion concentration (pH) of an aqueous liquid preparation.

[0023] In this specification, the term "metal chloride" refers to a compound in which a metal ion and a chloride ion are ionic bonded.

[0024] As used herein, "chlorhexidine" refers to a compound known as a preservative, 1-[amino-[6-[amino-[amino-(4-chlorophenyl)amino-methylidene]amino-methylidene]aminohexyrimino]methyl]imino-N-(4-chlorophenyl)-methanediamine.

[0025] As used herein, "benzalkonium chloride" is a compound known as a preservative, and refers to the chloride of alkyl (C8 to C18)benzyldimethylammonium.

[0026] In this specification, "polyhexanide" refers to a compound known as a preservative, which is a compound represented by the following general formula (1), and is a guanidine derivative also known as polyhexamethylene biguanidine (PHMB). [ka] [In general formula (1), R 1 and R 2are the same or different and each represents an amino group or a group represented by the following general formula (2): In general formula (1), n ​​represents an integer of 1 to 500. [ka]

[0027] As used herein, the term "preservative" refers to a compound or mixture that has sufficient bactericidal activity against bacteria and fungi and has preservative effect, and is formulated for the purpose of preventing microbial contamination. However, in the present invention, the term "preservative" does not include boric acid and its salts.

[0028] In this specification, "substantially free of preservatives" refers to a concentration of preservatives at which the preservative alone is unable to exert its preservative effect, and specifically refers to a concentration of preservatives at which, when an aqueous solution containing only the preservative is prepared, the aqueous solution is "compliant" based on the criteria set forth in Category "IC" in the Reference Information for "Preservative Effectiveness Testing Methods" in the 17th Edition of the Japanese Pharmacopoeia.

[0029] As used herein, the term "filter" refers to a porous membrane that allows an aqueous liquid preparation to pass through but does not allow bacteria or fungi to pass through. The pore size of the filter is usually 5 μm or less, preferably 0.1 to 2.5 μm, and more preferably 0.2 to 1 μm.

[0030] In this specification, the term "filter-equipped container" refers to a container that stores an aqueous liquid formulation, in which the inside and outside of the container are separated by a filter, and in which the aqueous liquid formulation inside the container passes through the filter and is poured out of the container during use. One embodiment of a filter-equipped container includes a container that has a container body with an opening and a nozzle provided with a flow path for pouring the aqueous liquid formulation out of the container, the nozzle being attached to the opening of the container body, and a filter being provided to block the flow path of the nozzle (e.g., Patent Documents 1 and 2, etc.).

[0031] In this specification, the term "multi-dose container" refers to a container that is filled with an amount of aqueous liquid preparation sufficient for multiple uses and can be used repeatedly.

[0032] As used herein, the term "unit-dose container" refers to a container filled with a single dose of aqueous liquid preparation and used up after one instillation.

[0033] As used herein, the term "method for inhibiting adsorption of brimonidine and / or salts thereof to a filter" refers to a method for inhibiting the adsorption of brimonidine and / or salts thereof to a filter, thereby inhibiting a decrease in the content of brimonidine and / or salts thereof in an aqueous solution that has passed through a filter. The effect of inhibiting adsorption of brimonidine and / or salts thereof to a filter is evaluated using the drug recovery rate, which is calculated by dividing the brimonidine content in the aqueous solution after passing through the filter by the brimonidine content in the aqueous solution before passing through the filter (calculation formula: {brimonidine content in the aqueous solution after passing through the filter / brimonidine content in the aqueous solution before passing through the filter} × 100), as an index. When the drug recovery rate of an aqueous solution containing a metal chloride (or preservative) is higher than the drug recovery rate of an aqueous solution that is the same as the aqueous solution except that it does not contain a metal chloride (or preservative), it can be said that the method has an effect of inhibiting adsorption of brimonidine and / or salts thereof to a filter. In this specification, the "method for inhibiting adsorption of brimonidine and / or a salt thereof to a filter" may also be simply referred to as the "method for inhibiting adsorption."

[0034] 2. Description of the Preferred Embodiment Although the following description of preferred embodiments is given, it should be understood that these embodiments are merely examples of the present invention and that the scope of the present invention is not limited to such preferred embodiments. It should also be understood that those skilled in the art can easily make modifications, changes, etc. within the scope of the present invention by referring to the following preferred examples. Those skilled in the art can combine any of these embodiments as appropriate.

[0035] 3. Pharmaceutical products For aqueous liquid preparations contained in a container with a filter, if the drug is adsorbed to the filter of the container, the drug content in the aqueous liquid preparation dispensed from the container will decrease, leading to the inability to achieve the expected effect. Therefore, aqueous liquid preparations contained in a container with a filter are required to be designed so that the drug will not be adsorbed to the filter.

[0036] The present inventors have conducted various studies on pharmaceutical products in which an aqueous liquid preparation containing brimonidine and / or a salt thereof is contained in a container with a filter, and have found that brimonidine and / or a salt thereof is adsorbed to the filter of the container, resulting in a decrease in the content of brimonidine and / or a salt thereof in the aqueous liquid preparation dispensed from the container. Therefore, the present inventors have conducted extensive studies and have found that an aqueous liquid preparation containing brimonidine and / or a salt thereof, a buffer, and a metal chloride can be prevented from being adsorbed to the filter, even when contained in a container with a filter, and a decrease in the content of brimonidine and / or a salt thereof in the aqueous liquid preparation dispensed from the container can be prevented.

[0037] In one aspect, the present invention provides a pharmaceutical product comprising an aqueous liquid formulation containing brimonidine and / or a salt thereof, a buffer, and a metal chloride, the aqueous liquid formulation being contained in a container equipped with a filter. The pharmaceutical product of the present invention is described in detail below.

[0038] In the pharmaceutical product of the present invention, the aqueous liquid contains brimonidine and / or its salt. Brimonidine salts are not particularly limited as long as they are pharmaceutically acceptable, and specific examples include organic acid salts such as tartrate and acetate; inorganic acid salts such as hydrochloride. Brimonidine or its salts may also be in the form of a solvate such as a hydrate. Among brimonidine and its salts, brimonidine tartrate is preferred.

[0039] In the aqueous liquid preparation used in the present invention, either brimonidine or a salt thereof may be used alone, or these may be used in combination.

[0040] In the aqueous liquid preparation used in the present invention, the concentration of brimonidine and / or a salt thereof is not particularly limited and may be appropriately determined depending on the intended use of the aqueous liquid preparation, the severity of symptoms in the patient to be treated, the amount administered per administration, etc., and may be, for example, 0.05 to 0.2 w / v%, preferably 0.1 to 0.2 w / v%, and particularly preferably 0.1 w / v%. In this specification, the concentration of brimonidine and / or a salt thereof is the concentration converted into brimonidine tartrate.

[0041] In the pharmaceutical product of the present invention, the aqueous liquid formulation further contains a buffer. The buffer is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include borate buffer, phosphate buffer, Tris buffer, citrate buffer, tartrate buffer, acetate buffer, amino acid buffer, etc.

[0042] Specific examples of boric acid buffers include boric acid and / or salts thereof. Boric acid is not particularly limited as long as it is pharmaceutically acceptable, but examples include orthoboric acid, metaboric acid, and tetraboric acid. Among these boric acids, orthoboric acid and tetraboric acid are preferred. These boric acids may be used alone or in combination of two or more. Salts of boric acid are not particularly limited as long as they are pharmaceutically acceptable, but examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; and organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, and pyrrolidine. Boric acid and / or its salts may also be in the form of a hydrate, such as borax.

[0043] As the boric acid buffer, one selected from boric acid and its salts may be used alone or in combination of two or more. Among boric acid and its salts, from the viewpoint of further improving the effect of suppressing adsorption of brimonidine and / or its salts to the filter, at least one of boric acid and borax is preferred, and at least one of orthoboric acid and borax is more preferred.

[0044] In addition, a preferred embodiment of the boric acid buffer is a combination of boric acid and borax. By using boric acid and borax in combination in this way, it is possible to further improve the effect of suppressing the adsorption of brimonidine and / or its salts to the filter. When using boric acid and borax in combination, the ratio thereof is not particularly limited, but for example, 0 to 100 parts by mass of borax per 100 parts by mass of boric acid, preferably 20 to 80 parts by mass, more preferably 40 to 60 parts by mass.

[0045] The concentration of the borate buffer is, from the viewpoint of buffering action, usually 0.01 to 10 w / v%, more preferably 0.1 to 5 w / v%, even more preferably 0.1 to 2 w / v%, and particularly preferably 0.1 to 1 w / v%. In this specification, the concentration of the borate buffer is the concentration of boric acid. This is the converted concentration.

[0046] Specific examples of phosphate buffers include phosphoric acid and / or salts thereof. Phosphate salts are not particularly limited as long as they are pharmaceutically acceptable, and examples include dialkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; alkali metal dihydrogen phosphates such as sodium dihydrogen phosphate and potassium dihydrogen phosphate; and trialkali metal phosphates such as trisodium phosphate and tripotassium phosphate. Phosphate salts may also be in the form of solvates such as hydrates, for example, disodium hydrogen phosphate may be in the form of a dodecahydrate, and sodium dihydrogen phosphate may be in the form of a dihydrate.

[0047] The phosphate buffer may be one selected from phosphoric acid and its salts and used alone, or two or more may be used in combination. Among phosphoric acid and its salts, from the viewpoint of further improving the effect of inhibiting adsorption of brimonidine and / or its salts to the filter, preferred is a phosphate, more preferred is at least one of dialkali metal hydrogen phosphate and alkali metal dihydrogen phosphate, and particularly preferred is at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate.

[0048] Another preferred embodiment of the phosphate buffer is a combination of a dialkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate. Using a combination of a dialkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate in this manner can further improve the effect of inhibiting adsorption of brimonidine and / or its salts to the filter. When a combination of a dialkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate is used, the ratio between them is not particularly limited, but may be, for example, 1 to 120 parts by mass, preferably 5 to 80 parts by mass, and more preferably 10 to 40 parts by mass of the alkali metal dihydrogen phosphate per 100 parts by mass of the dialkali metal hydrogen phosphate.

[0049] From the viewpoint of buffering action, the concentration of the phosphate buffer is usually 0.01 to 5 w / v%, preferably 0.1 to 3 w / v%, and more preferably 0.1 to 2 w / v%. In this specification, the concentration of the phosphate buffer is the concentration converted into phosphoric acid.

[0050] Specific examples of Tris buffers include trometamol and / or its salts. The salts of trometamol are not particularly limited as long as they are pharmaceutically acceptable, and examples include organic acid salts such as acetate salts, and organic acid salts such as hydrochloride and sulfonate salts.

[0051] As the Tris acid buffer, one selected from trometamol and its salts may be used alone or in combination of two or more. Among trometamol and its salts, trometamol is preferred from the viewpoint of further improving the effect of suppressing adsorption of brimonidine and / or its salts to the filter.

[0052] From the viewpoint of buffering action, the concentration of the Tris buffer is usually 0.01 to 5 w / v%, preferably 0.1 to 3 w / v%, and more preferably 0.1 to 2 w / v%. In this specification, the concentration of the Tris buffer is the concentration converted to trometamol.

[0053] Specific examples of citrate buffers include citric acid and / or salts thereof. The salts of citric acid are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and the like. Citric acid and its salts may also be in the form of solvates such as hydrates.

[0054] The citrate buffer may be selected from citric acid and its salts and used alone or in combination of two or more thereof. Among citric acid and its salts, citric acid is preferred from the viewpoint of further improving the effect of inhibiting adsorption of brimonidine and / or its salts to the filter.

[0055] From the viewpoint of buffering action, the concentration of the citrate buffer is usually 0.01 to 5 w / v%, preferably 0.05 to 3.5 w / v%, and more preferably 0.1 to 1 w / v%. In this specification, the concentration of the citrate buffer is the concentration converted into citric acid.

[0056] Specific examples of tartaric acid buffers include tartaric acid and / or salts thereof. Salts of tartaric acid are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and the like. Furthermore, the salts of tartaric acid may be in the form of solvates such as hydrates. As the tartaric acid buffer, one selected from tartaric acid and its salts may be used alone, or two or more may be used in combination.

[0057] Specific examples of acetate buffers include acetic acid and / or salts thereof. The salts of acetic acid are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and ammonium salts. Furthermore, the salts of acetic acid may be in the form of a solvate such as a hydrate. As the acetate buffer, one selected from acetic acid and its salts may be used alone, or two or more may be used in combination.

[0058] Specific examples of the amino acid buffer include acidic amino acids and / or their salts. Specific examples of the acidic amino acids include aspartic acid and glutamic acid. The salts of acidic amino acids are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts. As the amino acid buffer, one selected from acidic amino acids and salts thereof may be used alone, or two or more may be used in combination.

[0059] These buffers may be used alone or in combination of two or more.

[0060] Among these buffers, from the viewpoint of further improving the effect of inhibiting adsorption of brimonidine and / or its salts to the filter, preferred are borate buffer, phosphate buffer, Tris buffer, and citrate buffer, and more preferred is borate buffer.

[0061] In the pharmaceutical product of the present invention, the aqueous liquid formulation further contains a metal chloride. The metal chloride is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include chlorides of alkali metals such as sodium chloride and potassium chloride, chlorides of alkaline earth metals such as magnesium chloride and calcium chloride, zinc chloride, iron chloride, etc.

[0062] These metal chlorides may be used alone or in combination of two or more. Among these metal chlorides, from the viewpoint of further improving the effect of inhibiting adsorption of brimonidine and / or its salts to the filter, preferred are sodium chloride, potassium chloride, magnesium chloride, and calcium chloride, and more preferred is sodium chloride.

[0063] The concentration of the metal chloride in the aqueous liquid preparation used in the present invention is usually 0.01 to 5 w / v%. From the viewpoint of further improving the effect of inhibiting adsorption of brimonidine and / or a salt thereof to the filter, the concentration of the metal chloride in the aqueous liquid preparation used in the present invention is preferably 0.05 to 2.5 w / v%, more preferably 0.1 to 2 w / v%, particularly preferably 0.2 to 1 w / v%, and even more preferably 0.4 to 1 w / v%.

[0064] In the pharmaceutical product of the present invention, the aqueous liquid formulation is contained in a container with a filter, preventing bacteria from entering the aqueous liquid formulation during use or storage. Therefore, the aqueous liquid formulation can have storage stability even if it is substantially free of preservatives. Furthermore, preservatives can have adverse effects such as irritation and cytotoxicity, and if the aqueous liquid formulation is substantially free of preservatives, such adverse effects can be avoided. Therefore, one preferred embodiment of the aqueous liquid formulation used in the present invention is that it is substantially free of preservatives.

[0065] Specific examples of preservatives include chlorites such as sodium chlorite; quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride; sorbic acid and its salts such as sorbic acid and potassium sorbate; parahydroxybenzoic acid esters such as methylparaben and propyl parahydroxybenzoate; benzoic acid and its salts; chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, chlorobutanol, chlorhexidine, polyhexanide, polyquatrium, etc.

[0066] In an embodiment in which the aqueous liquid preparation used in the present invention is substantially free of preservatives, the acceptable concentration of the preservative varies depending on the type of preservation, etc., but specifically includes less than 0.00001 w / v%, preferably 0.000005 w / v% or less, particularly preferably 0.000001 w / v% or less, and even more preferably 0 w / v%.

[0067] In addition to the above-mentioned components, the aqueous liquid preparation used in the present invention may contain additives such as an isotonic agent (other than a metal chloride), a surfactant, a thickening agent, a chelating agent, a cooling agent, a stabilizer, and a pH adjuster, as needed.

[0068] The tonicity agent (other than metal chlorides) is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, and polyethylene glycol; metal salts such as sodium acetate, potassium acetate, sodium hydrogen sulfite, sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate; etc. These tonicity agents may be used alone or in combination of two or more.

[0069] The surfactant is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include nonionic surfactants such as tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxynol, etc.; amphoteric surfactants such as alkyldiaminoethylglycine, lauryldimethylaminoacetic acid betaine, etc.; anionic surfactants such as alkyl sulfates, N-acyltaurine salts, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates, etc.; cationic surfactants such as alkylpyridinium salts, alkylamine salts, etc. These surfactants may be used alone or in combination of two or more.

[0070] The thickening agent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include water-soluble polymers such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate; celluloses such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and sodium carboxymethyl cellulose. These thickening agents may be used alone or in combination of two or more.

[0071] The chelating agent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include edetic acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, polyphosphoric acid, metaphosphoric acid, hexametaphosphoric acid, phytic acid, thiosulfuric acid, and salts thereof. The salt form is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts. These chelating agents may be used alone or in combination of two or more.

[0072] The cooling agent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include 1-menthol, borneol, camphor, eucalyptus oil, etc. These cooling agents may be used alone or in combination of two or more.

[0073] The stabilizer is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include polyvinylpyrrolidone, sulfite, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol, dibutylhydroxytoluene, etc. These stabilizers may be used alone or in combination of two or more.

[0074] The pH adjuster is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, and epsilon-aminocaproic acid; alkalis such as sodium hydroxide, potassium hydroxide, borax, triethanolamine, monoethanolamine, sodium bicarbonate, and sodium carbonate. These pH adjusters may be used alone or in combination of two or more.

[0075] The concentrations of these additives may be appropriately set depending on the types of additives used and the properties to be imparted to the aqueous liquid preparation.

[0076] Furthermore, the aqueous liquid preparation used in the present invention may contain, in addition to brimonidine and / or a salt thereof, a pharmacological ingredient that exhibits a therapeutic effect on glaucoma or ocular hypertension, as necessary, within a range that does not impair the effects of the present invention.

[0077] Examples of such pharmacological ingredients include prostaglandins such as tafluprost, latanoprost, isopropyl unoprostone, etc.; parasympathomimetics such as pilocarpine hydrochloride, etc.; anticholinesterase agents such as distigmine bromide, etc.; sympathomimetics such as dipivefrine hydrochloride, etc.; β1-blockers such as betaxolol hydrochloride, etc.; β-blockers such as timolol maleate, etc.; α1-β-blockers such as nipradilol, levobunolol hydrochloride, etc.; α1-blockers such as bunazosin hydrochloride, etc. These pharmacological ingredients may be used alone or in combination of two or more.

[0078] The concentrations of these pharmacological ingredients may be appropriately determined depending on the type of pharmacological ingredient used, the medicinal effect to be imparted, and the like.

[0079] The pH of the aqueous liquid preparation used in the present invention is not particularly limited, but may be, for example, pH 6 to 8, preferably pH 7 to 8, and more preferably pH 7.

[0080] The osmotic pressure ratio of the aqueous liquid preparation used in the present invention is not particularly limited, and may be, for example, 0.5 to 4, preferably 0.7 to 1.3, and more preferably 0.9 to 1.1. The osmotic pressure ratio is the ratio to the osmotic pressure of a 0.9 w / v% aqueous sodium chloride solution, and the osmotic pressure is measured in accordance with the "osmotic pressure method (osmolality measurement method)" specified in the 17th Edition of the Japanese Pharmacopoeia.

[0081] The formulation form of the aqueous liquid preparation used in the present invention is not particularly limited, and may be any of an aqueous solution, an emulsion, etc., but is preferably an aqueous solution.

[0082] The aqueous solution used in the present invention can be used as an ophthalmic preparation such as eye drops, eyewash, etc. In particular, the aqueous solution used in the present invention can reduce intraocular pressure by the action of brimonidine and / or a salt thereof, and therefore is provided as eye drops and can be suitably used for treating glaucoma or ocular hypertension.

[0083] The aqueous liquid preparations used in the present invention may be prepared according to known preparation methods depending on the intended use, for example, by the method described in the General Provisions for Preparations in the 17th Edition of the Japanese Pharmacopoeia.

[0084] In the pharmaceutical product of the present invention, a filter-equipped container is used as the container for containing the aqueous liquid preparation. The structure of a filter-equipped container is publicly known (Patent Documents 1 and 2, etc.), and a publicly known filter-equipped container can be used in the present invention. Furthermore, the filter-equipped container may be an eye dropper, an eyewash container, or the like, depending on the intended use of the aqueous liquid preparation.

[0085] The material of the filter in the filter-equipped container used in the present invention is not particularly limited, and examples thereof include polyethersulfone, polyvinylidene fluoride, polycarbonate, polytetrafluoroethylene, mixed cellulose esters, nylon, polyamide, etc. Among these materials, from the viewpoint of further improving the effect of inhibiting adsorption of brimonidine and / or a salt thereof to the filter, preferred are polyethersulfone and polyvinylidene fluoride, and more preferred are polyethersulfone.

[0086] The filter-equipped container used in the present invention is preferably a multi-dose container, since it has the function of preventing the intrusion of bacteria by the filter.

[0087] The pharmaceutical product of the present invention is produced by preparing the aqueous liquid preparation, subjecting it to a sterilization treatment such as filtration sterilization, and then filling it into the filter-equipped container.

[0088] In one embodiment of the use of a container with a polyethersulfone filter in the pharmaceutical product of the present invention, a polyethersulfone filter (e.g., STERIVEX-GP 0.22 μm / Merck Millipore (pore size: 0.22 μm, height: 67 mm, diameter: 10 cm)) is used. 2The drug recovery rate, calculated by dividing the brimonidine content in the aqueous liquid formulation after passing through the filter (the first 0.6 g that has passed through the filter) by the brimonidine content in the aqueous liquid formulation before passing through the filter, is 95% or more. In addition, in one embodiment where a container with a polyvinylidene fluoride filter is used in the pharmaceutical product of the present invention, a polyvinylidene fluoride filter (e.g., STERIVEX-GV 0.22 μm / Merck Millipore (pore size: 0.22 μm, height: 67 mm, diameter: 10 cm) is used. 2 The drug recovery rate, calculated by dividing the brimonidine content in the aqueous liquid formulation after passing through the filter (the first 1.0 g that passes through the filter) by the brimonidine content in the aqueous liquid formulation before passing through the filter, is 90% or more.

[0089] 4. Adsorption suppression method (1) As described above, in the prior art, when an aqueous liquid preparation containing brimonidine and / or a salt thereof is placed in a container with a filter, there is a problem that brimonidine and / or a salt thereof is adsorbed to the filter of the container. This problem also occurs in the filtration sterilization step using a filter in the production of an aqueous liquid preparation containing brimonidine and / or a salt thereof. That is, when an aqueous liquid preparation containing brimonidine and / or a salt thereof is placed in a container with a filter and used, or when a filtration sterilization step using a filter is performed, there is a problem that brimonidine and / or a salt thereof is adsorbed to the filter.

[0090] In contrast, by containing a buffer and a metal chloride in addition to brimonidine and / or a salt thereof in the aqueous liquid preparation, adsorption of brimonidine and / or a salt thereof to the filter can be suppressed even when the aqueous liquid preparation is passed through a filter, and it is possible to suppress a decrease in the content of brimonidine and / or a salt thereof in the aqueous liquid preparation after passing through the filter.

[0091] Therefore, in one aspect, the present invention provides a method for inhibiting adsorption of brimonidine and / or a salt thereof to a filter, in which brimonidine and / or a salt thereof, a buffer, and a metal chloride are contained in an aqueous liquid preparation to be passed through a filter.

[0092] The types and concentrations of brimonidine and / or its salts, buffers, and metal chlorides used in the adsorption suppression method of the present invention are as described above in the section "3. Pharmaceutical products." In addition, the types of other components that can be incorporated into the aqueous liquid preparation, the pH, osmotic pressure ratio, dosage form, etc. of the aqueous liquid preparation in the adsorption suppression method of the present invention are also as described above in the section "3. Pharmaceutical products."

[0093] The filter used in the present invention may be a filter in a filter-equipped container, or may be a filter used in a filtration sterilization step. That is, the aqueous liquid preparation to be passed through the filter may be an aqueous liquid preparation contained in a filter-equipped container and passed through the filter of the container before use and poured out of the container, or may be an aqueous liquid preparation to be passed through the filter during a filtration sterilization step during the production of the aqueous liquid preparation. The type of filter-equipped container and the filter material are as described in the above section "3. Pharmaceutical Products." Furthermore, the material of the filter used in the filtration sterilization step during production is the same as the material of the filter in the filter-equipped container described in the above section "3. Pharmaceutical Products."

[0094] In the adsorption suppression method of the present invention, when the aqueous liquid preparation passed through a filter is contained in a container with a filter, the aqueous liquid preparation does not necessarily require preservative effect, and therefore preferably does not contain substantially any preservative. Also, in the adsorption suppression method of the present invention, even when the aqueous liquid preparation passed through a filter is an aqueous liquid preparation passed through a filter in a filtration sterilization step and is provided in a unit-dose container after the filtration sterilization step, the aqueous liquid preparation does not necessarily require preservative effect, and therefore preferably does not contain substantially any preservative.

[0095] On the other hand, in the adsorption suppression method of the present invention, when the aqueous liquid preparation passed through a filter is an aqueous liquid preparation passed through a filter in a sterilization step and is provided in a multi-dose container without a filter after the sterilization step, the aqueous liquid preparation preferably contains a preservative to ensure the desired preservative effect. The types of preservatives are as described in the above section "3. Pharmaceutical Products." Furthermore, when a preservative is contained in the aqueous liquid preparation, the concentration of the preservative in the aqueous liquid preparation may be appropriately set within a range that ensures the desired preservative effect, and may be, for example, 0.00001 to 0.01 w / v%, preferably 0.00005 to 0.01 w / v%, and more preferably 0.001 to 0.01 w / v%.

[0096] 5. Method for producing aqueous liquid preparation (1) As described above, when an aqueous liquid preparation containing brimonidine and / or a salt thereof is produced by a filtration sterilization step using a filter, there is a problem that brimonidine and / or a salt thereof is adsorbed onto the filter, resulting in a decrease in the content of brimonidine and / or a salt thereof in the aqueous liquid preparation that has passed through the filter.

[0097] In contrast, by subjecting an aqueous liquid preparation containing brimonidine and / or a salt thereof, a buffer, and a metal chloride to a filtration sterilization process using a filter, it is possible to suppress adsorption of brimonidine and / or a salt thereof to the filter, and to suppress a decrease in the content of brimonidine and / or a salt thereof in the aqueous liquid preparation after filtration sterilization.

[0098] Therefore, in one aspect, the present invention provides a method for producing an aqueous liquid preparation, comprising the steps of preparing an aqueous liquid preparation containing brimonidine and / or a salt thereof, a buffer, and a metal chloride, and subjecting the aqueous liquid preparation obtained in the above step to a filtration sterilization step using a filter.

[0099] In the production method of the present invention, the types and concentrations of brimonidine and / or its salts, buffers, and metal chlorides are as described in the above section "3. Pharmaceutical Products." Furthermore, in the production method of the present invention, the types of other components that can be incorporated into the aqueous liquid, the pH, osmotic pressure ratio, and dosage form of the aqueous liquid are also as described in the above section "3. Pharmaceutical Products." Furthermore, in the production method of the present invention, the material of the filter used in the filtration sterilization step is the same as the material of the filter in the filter-equipped container described in the above section "3. Pharmaceutical Products."

[0100] The aqueous liquid preparation obtained by the production method of the present invention may be provided in a container equipped with a filter, or in a multi-dose or unit-dose container not equipped with a filter.

[0101] When the aqueous liquid preparation obtained by the production method of the present invention is provided in a container with a filter or a unit dose container, the aqueous liquid preparation itself does not necessarily need to have preservative effectiveness, and therefore it is preferable that the aqueous liquid preparation is substantially free of preservatives.

[0102] On the other hand, when the aqueous liquid preparation obtained by the production method of the present invention is provided in a multi-dose container without a filter, the aqueous liquid preparation preferably contains a preservative so as to have the desired preservative effect. The type of preservative is as described in the above section "3. Pharmaceutical products," and the concentration of the preservative in the aqueous liquid preparation is as described in the above section "4. Method for inhibiting adsorption (1)."

[0103] 6. Adsorption suppression method (2) As described above, when an aqueous liquid preparation containing brimonidine and / or a salt thereof is subjected to a filtration sterilization process using a filter or when it is stored in a container with a filter and used, there is a problem that brimonidine and / or a salt thereof is adsorbed to the filter.

[0104] In contrast, by including a buffer and a specific preservative (at least one selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts) in the aqueous liquid preparation together with brimonidine and / or its salts, it is possible to suppress adsorption of brimonidine and / or its salts to the filter even when the preparation is passed through a filter, and to suppress a decrease in the content of brimonidine and / or its salts in the aqueous liquid preparation after passing through the filter.

[0105] Therefore, in one aspect, the present invention provides a method for inhibiting adsorption of brimonidine and / or a salt thereof onto a filter, comprising comprising an aqueous liquid preparation to be passed through a filter, containing brimonidine and / or a salt thereof, a buffer, and at least one selected from the group consisting of chlorhexidine and a salt thereof, benzalkonium chloride, and polyhexanide and a salt thereof.

[0106] The aqueous liquid formulation used in the present invention contains brimonidine and / or a salt thereof. The type, concentration, etc. of the brimonidine and / or salt thereof are the same as those in "3. Pharmaceutical Products" above.

[0107] The aqueous liquid preparation used in the present invention contains a buffer. The type and concentration of the buffer are the same as those described above in "3. Pharmaceutical Products."

[0108] The aqueous liquid preparation used in the present invention further contains at least one preservative selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts.

[0109] The salt of chlorhexidine used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include inorganic acid salts such as hydrochloride, and organic acid salts such as acetate and gluconate. Chlorhexidine or its salts may also be in the form of a solvate such as a hydrate. Among chlorhexidine and its salts, preferred are chlorhexidine salts, and more preferred are chlorhexidine gluconate.

[0110] Specific examples of polyhexanides used in the present invention include compounds represented by the following general formula (1). [ka]

[0111] In general formula (1), R 1 and R 2 are the same or different and each represents an amino group or a group represented by the following general formula (2): 1 and R 2 Preferably, R 1 is an amino group, and R 2 is an amino group or a group represented by the following general formula (2); more preferably R 1 is an amino group, and R 2 is a group represented by the following general formula (2). [ka]

[0112] In the general formula (1), n ​​represents an integer of 1 to 500. n is preferably an integer of 2 to 200, more preferably an integer of 4 to 100, and particularly preferably an integer of 8 to 20.

[0113] The salt of polyhexanide is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include inorganic acid salts and organic acid salts. Specific examples of inorganic acid salts include hydrochloric acid, hydrogen bromide, sulfuric acid, boric acid, etc. Specific examples of organic acid salts include acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid, citric acid, etc.

[0114] Among polyhexanide and salts thereof, preferred are salts of polyhexanide, more preferred are inorganic acid salts of polyhexanide, and particularly preferred is polyhexanide hydrochloride.

[0115] In the adsorption suppression method of the present invention, one or more of chlorhexidine, chlorhexidine salts, benzalkonium chloride, polyhexanide, and polyhexanide salts may be used, or two or more of these may be used in combination. Among these, from the viewpoint of further improving the effect of suppressing adsorption of brimonidine and / or its salts to the filter, preferred are chlorhexidine salts, benzalkonium chloride, and polyhexanide salts, and more preferred are chlorhexidine salts and polyhexanide salts.

[0116] When chlorhexidine and / or a salt thereof is used, the concentration of chlorhexidine and / or a salt thereof in the aqueous liquid preparation is, for example, 0.001 to 0.01 w / v%, preferably 0.003 to 0.01 w / v%, and more preferably 0.005 to 0.01 w / v%. In this specification, the concentration of chlorhexidine and / or a salt thereof is the concentration converted into chlorhexidine gluconate.

[0117] When benzalkonium chloride is used, the concentration of benzalkonium chloride in the aqueous liquid preparation is, for example, 0.001 to 0.01 w / v%, preferably 0.003 to 0.01 w / v%, and more preferably 0.005 to 0.01 w / v%.

[0118] When polyhexanide and / or a salt thereof is used, the concentration of polyhexanide and / or a salt thereof in the aqueous liquid preparation is, for example, 0.00001 to 0.01 w / v%, preferably 0.00005 to 0.01 w / v%, and more preferably 0.001 to 0.01 w / v%. In this specification, the concentration of polyhexanide and / or a salt thereof is the concentration converted into polyhexanide hydrochloride.

[0119] The aqueous liquid preparation used in the present invention may further contain a metal chloride. The type and concentration of the metal chloride are the same as those in "3. Pharmaceutical Products" above.

[0120] Other ingredients that can be blended into the aqueous liquid preparation used in the present invention are the same as those in "3. Pharmaceutical Products" above, but in one embodiment of the aqueous liquid preparation used in the present invention, the thickening agent is less than 0.05 w / v%, and in a preferred embodiment, no thickening agent is included from the viewpoint of the effect of inhibiting brimonidine adsorption, the stability of brimonidine (the effect of inhibiting a decrease in the brimonidine content in the aqueous liquid preparation), or the filterability of the aqueous liquid preparation. The types of thickening agents are as described in the section "3. Pharmaceutical Products" above.

[0121] In the aqueous liquid preparation used in the present invention, the pH, osmotic pressure ratio, dosage form, etc. of the aqueous liquid preparation are the same as those in "3. Pharmaceutical products" above.

[0122] The filter used in the present invention may be a filter used in a filtration sterilization step, or may be a filter in a filter-equipped container. That is, the aqueous liquid preparation passed through the filter may be an aqueous liquid preparation passed through a filter in a filtration sterilization step during the production of the aqueous liquid preparation, or may be an aqueous liquid preparation contained in a filter-equipped container and passed through the filter of the container before use and poured out of the container. The material of the filter used in the filtration sterilization step during production is the same as the material of the filter in the filter-equipped container described in the "3. Pharmaceutical Products" section above. The type of filter-equipped container and the material of the filter are as described in the "3. Pharmaceutical Products" section above.

[0123] In the adsorption suppression method of the present invention, the aqueous liquid preparation used contains a specific preservative (at least one selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts), which can provide the desired preservative effect. Therefore, one preferred form of the aqueous liquid preparation used in the present invention is an aqueous liquid preparation that is passed through a filter in the filtration sterilization step during production, and is provided in a multi-dose container that is not equipped with a filter after the filtration sterilization step.

[0124] 7. Method for producing aqueous liquid preparations (2) As described above, when an aqueous liquid preparation containing brimonidine and / or a salt thereof is produced by a filtration sterilization step using a filter, there is a problem that brimonidine and / or a salt thereof is adsorbed onto the filter, resulting in a decrease in the content of brimonidine and / or a salt thereof in the aqueous liquid preparation that has passed through the filter.

[0125] In contrast, by subjecting an aqueous liquid preparation containing brimonidine and / or a salt thereof, a buffer, and a specific preservative (at least one selected from the group consisting of chlorhexidine and a salt thereof, benzalkonium chloride, and polyhexanide and a salt thereof) to a filtration sterilization step using a filter, it is possible to suppress adsorption of brimonidine and / or a salt thereof to the filter, and to suppress a decrease in the content of brimonidine and / or a salt thereof in the aqueous liquid preparation after filtration sterilization.

[0126] Thus, in one aspect, the present invention provides a method for producing an aqueous liquid preparation, comprising the steps of: preparing an aqueous liquid preparation containing brimonidine and / or a salt thereof, a buffer, and at least one selected from the group consisting of chlorhexidine and a salt thereof, benzalkonium chloride, and polyhexanide and a salt thereof; and subjecting the aqueous liquid preparation obtained in the above step to a filtration sterilization step using a filter.

[0127] In the production method of the present invention, the types and concentrations of brimonidine and / or a salt thereof and buffering agents used are as described above in the section "3. Pharmaceutical Products."

[0128] In the manufacturing method of the present invention, the types and concentrations of brimonidine and / or a salt thereof, buffer, chlorhexidine and a salt thereof, benzalkonium chloride, and polyhexanide and a salt thereof used are as described in the section "6. Adsorption suppression method (2)" above.

[0129] In the manufacturing method of the present invention, the aqueous liquid preparation may further contain a metal chloride. The type and concentration of the metal chloride are the same as those in "3. Pharmaceutical Products" above.

[0130] In the production method of the present invention, the types of other ingredients that can be blended in the aqueous liquid preparation, the pH of the aqueous liquid preparation, the osmotic pressure ratio, the dosage form, etc. are also as described in the above section "3. Pharmaceutical products." In addition, in the production method of the present invention, the material of the filter used in the filtration sterilization step is the same as the material of the filter in the filter-equipped container described in the above section "3. Pharmaceutical products."

[0131] The aqueous liquid preparation obtained by the production method of the present invention may be provided in a container with a filter, or in a multi-dose or unit-dose container without a filter. The aqueous liquid preparation obtained by the production method of the present invention contains a specific preservative (at least one selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts), so it can have the desired preservative effect, and is therefore preferably provided in a multi-dose container without a filter. [Example]

[0132] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. In the following test examples, orthoboric acid was used as the boric acid.

[0133] Test Example 1: Evaluation of drug adsorption inhibition to the filter (examination of the effects of buffers and metal chlorides) An aqueous liquid formulation having the composition shown in Table 1 was prepared. The prepared aqueous liquid formulation was filtered using a filter (polyethersulfone membrane; PES membrane) with a pore size of 0.22 μm, and 0.6 g of the first filtrate that passed through the filter was collected. Separately, the prepared aqueous liquid formulation was filtered using a filter (polyvinylidene fluoride membrane; PVDF membrane) with a pore size of 0.22 μm, and 1.0 g of the first filtrate that passed through the filter was collected. The PES membrane was STERIVEX-GP 0.22 μm / Merck Millipore (pore size: 0.22 μm, height: 67 mm, diameter: 10 cm). 2, Catalog number: SVGP01050) and the PVDF membrane was STERIVEX-GV 0.22 μm / Merck Millipore (pore size: 0.22 μm, height: 67 mm, diameter: 10 cm). 2 , Catalog number: SVGV010RS) was used.

[0134] The brimonidine contents in the aqueous liquid preparation before filtration and in the aqueous liquid preparation after filtration (filtrate) were measured by liquid chromatography (Shimadzu Corporation, high performance liquid chromatograph: Prominence) under the following conditions. (Measurement conditions) detector :Ultraviolet absorption photometer (measurement wavelength: 230nm) column Symmetry C18, 4.6 mm ID x 150 mm, 3.5 μm, Waters Column Temperature : Constant temperature around 40℃ Mobile phase A : 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio: 84 / 8 / 8) Mobile phase B : 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio: 40 / 30 / 30) Mobile phase delivery The mixing ratio of mobile phase A and mobile phase B was changed as follows to control the linear concentration gradient. Time after injection (min) Mobile phase A (vol%) Mobile phase B (vol%) 0.0~20.0 100 0 20.0~25.0 100→0 0→100 25.0~30.0 0 100 30.0~30.1 0→100 100→0 30.1~60.0 100 0 flow rate : 1.0 mL / min Autosampler temperature: 5℃

[0135] The drug recovery rate after passing through the filter was calculated from the brimonidine contents in the aqueous liquid preparation before and after passing through the filter according to the following formula.

number

[0136] The results are shown in Table 1. When an aqueous solution containing brimonidine tartrate did not contain a buffer or metal chloride (Comparative Example 1), the drug recovery rate after passing through a PES membrane filter was 94%, and as much as 6% of brimonidine tartrate was adsorbed by filtration through the PES membrane. Furthermore, when an aqueous solution containing brimonidine tartrate and a buffer (borate buffer, phosphate buffer, trometamol, or citrate buffer) did not contain a metal chloride (Comparative Examples 2 and 6 to 8), the drug recovery rate after passing through a PES membrane filter was equivalent to that of Comparative Example 1. Furthermore, when an aqueous solution containing brimonidine tartrate and a borate buffer together with sodium edetate or a water-soluble polymer (carboxymethylcellulose or polyvinylpyrrolidone) did not contain a metal chloride (Comparative Examples 3 to 5), the drug recovery rate after passing through a PES membrane filter was equivalent to that of Comparative Example 1.

[0137] In contrast, in an aqueous liquid preparation containing brimonidine tartrate and a buffer (borate buffer, phosphate buffer, trometamol, or citrate buffer) together with a metal chloride (sodium chloride, potassium chloride, calcium chloride, or magnesium chloride), the drug recovery rate after passage through a PES membrane filter was significantly higher than that in Comparative Example 1, demonstrating that metal chlorides have a drug adsorption inhibitory effect. Furthermore, as is clear from comparisons between Example 3 and Comparative Example 2, Example 9 and Comparative Example 6, Example 11 and Comparative Example 7, and Example 12 and Comparative Example 8, among buffers, the use of a borate buffer had the greatest effect of improving the drug recovery rate after passage through a PES membrane filter.

[0138] Furthermore, when a PVDF membrane was used, a similar tendency to that observed with a PES membrane was observed.

[0139] [Table 1]

[0140] Test Example 2: Evaluation of suppression of drug adsorption to the filter (examination of the effects of surfactants and preservatives) Aqueous liquid preparations having the compositions shown in Table 2 were prepared, and the drug recovery rate after passing through the filter was determined in the same manner as in Test Example 1 above.

[0141] The results are shown in Table 2. For aqueous liquid preparations containing brimonidine tartrate and borate buffer together with a surfactant (polysorbate 80, POE(60) hydrogenated castor oil, tyloxapol, poloxamer 407, or polyethylene glycol monostearate (40EO)) (Comparative Examples 9 to 13), the drug recovery rates after passing through the PES and PVDF membrane filters were equal to or lower than those for aqueous liquid preparations not containing a surfactant (Comparative Examples 1 and 2). Furthermore, for aqueous liquid preparations containing chlorobutanol or sorbic acid used as a preservative together with brimonidine tartrate and borate buffer (Comparative Examples 14 and 15), the drug recovery rates after passing through the PES and PVDF membrane filters were equal to those for Comparative Examples 1 and 2. In contrast, in the aqueous liquid preparations (Examples 13 to 15) containing benzalkonium chloride, chlorhexidine gluconate, or polyhexanide hydrochloride together with brimonidine tartrate and borate buffer, the drug recovery rate after passing through the PES membrane and PVDF membrane filters was improved compared to Comparative Examples 1 and 2, demonstrating the effect of suppressing drug adsorption to the PES membrane and PVDF membrane.

[0142] [Table 2]

Claims

1. preparing an aqueous liquid preparation comprising a pharmacological ingredient, a buffer, a metal chloride, a preservative, a pH adjuster, a chelating agent (excluding citric acid and its salts), and water, the aqueous preparation having a pH of 7 to 8; and filtering and sterilizing the aqueous liquid preparation obtained in the above step using a filter. The pharmacological ingredient contains brimonidine and / or a salt thereof in an amount of 0.1 w / v %; the buffer comprises a citrate buffer; the metal chloride includes at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride; The preservative comprises benzalkonium chloride. A method for producing an aqueous liquid formulation.

2. The method of claim 1, wherein the brimonidine and / or salt thereof is brimonidine tartrate.

3. The method according to claim 1 or 2, wherein the concentration of the citrate buffer in the aqueous liquid preparation is 0.01 to 5 w / v %.

4. The method according to any one of claims 1 to 3, wherein the concentration of benzalkonium chloride in the aqueous liquid preparation is 0.0001 to 0.1 w / v%.

5. The method according to any one of claims 1 to 4, wherein the aqueous liquid preparation has a pH of 7.

6. The method according to any one of claims 1 to 5, wherein the aqueous liquid preparation is an eye drop.

7. The method according to any one of claims 1 to 6, wherein the material of the filter is polyethersulfone or polyvinylidene fluoride.

8. The method according to any one of claims 1 to 7, wherein the aqueous liquid preparation is provided in a multi-dose container without a filter after the filtration sterilization step.

Images