Aqueous liquid

Abstract

The object of the present invention is to provide a formulation technology relating to an aqueous solution containing brimonidine and / or a salt thereof. [Solution] An aqueous solution containing brimonidine and / or its salt, a buffer, and a metal chloride can suppress the adsorption of brimonidine and / or its salt onto a filter even when passed through a filter, and can suppress the decrease in the content of brimonidine and / or its salt in the aqueous solution even when stored in a filtered container or subjected to a sterilization process by filtering during manufacturing.

Description

[Technical Field]

[0001] The present invention relates to an aqueous solution comprising brimonidine and / or a salt thereof, wherein the adsorption of brimonidine and / or a salt thereof to a filter is suppressed. [Background technology]

[0002] Aqueous solutions such as eye drops and eye washes typically contain preservatives such as benzalkonium chloride and methylparaben to prevent microbial growth. These aqueous solutions are usually subjected to a sterilization process using filters during manufacturing.

[0003] While preservatives can prevent bacterial growth, they have been reported to exhibit irritation and cytotoxicity (see Non-Patent Document 1). Therefore, conventionally, aqueous solutions without preservatives have been developed to avoid the adverse effects of preservatives. Multi-dose containers that contain preservative-free aqueous solutions have a structure that aseptically isolates the inside and outside of the container to prevent bacteria from entering the container during use, and containers equipped with filters in the nozzle (filtered 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 and work by suppressing aqueous humor production and promoting aqueous humor outflow via the uveoscleral outflow pathway, thereby lowering intraocular pressure. They have traditionally been used to treat glaucoma and ocular hypertension. [Prior art documents] [Non-patent literature]

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

[0006] [Patent Document 1] Japanese Patent Publication No. 2004-51170 [Patent Document 2] Japanese Patent Publication No. 2002-80055 [Overview of the Initiative] [Problems that the invention aims to solve]

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

[0008] The inventors have found that an aqueous solution containing brimonidine and / or a salt thereof, a buffer, and a metal chloride can suppress the adsorption of brimonidine and / or a salt thereof onto a filter even when passed through a filter, and that it can suppress the decrease in the content of brimonidine and / or a salt thereof in the aqueous solution even when stored in a filtered container or subjected to a sterilization process by filtering during manufacturing.

[0009] Furthermore, the inventors have found that an aqueous solution containing brimonidine and / or its salt, a buffer, and a specific preservative (at least one selected from the group consisting of chlorhexidine and its salt, benzalkonium chloride, and polyhexanides and their salts) can suppress the adsorption of brimonidine and / or its salt onto a filter even when passed through a filter, and can suppress the decrease in the content of brimonidine and / or its salt in the aqueous solution even when subjected to a sterilization process by filtration during manufacturing.

[0010] This invention was completed by further investigation based on these findings.

[0011] In other words, the present invention provides pharmaceutical products in the following embodiments. Item 1-1. A pharmaceutical product comprising an aqueous solution containing brimonidine and / or a salt thereof, a buffer, and a metal chloride, housed in a filtered container. Item 1-2. The pharmaceutical product according to item 1-1, wherein the brimonidine and / or salt thereof is brimonidine tartrate. Item 1-3. The pharmaceutical product according to item 1-1 or 1-2, wherein the concentration of brimonidine and / or its salt 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. A pharmaceutical product according to any one of items 1-1 to 1-4, wherein the buffering agent is a boric acid buffering agent. Item 1-6. A pharmaceutical product according to any one of items 1-1 to 1-5, wherein the buffer is a boric acid buffer and the concentration of the boric acid buffer is 0.01 to 10 w / v%. Item 1-7. A pharmaceutical product according to any one of items 1-1 to 1-4, wherein the buffer is a phosphate buffer and the concentration of the phosphate buffer is 0.01 to 5 w / v%. Item 1-8. A pharmaceutical product according to any one of items 1-1 to 1-4, wherein the buffer is a trisate buffer and the concentration of the trisate buffer is 0.01 to 5 w / v%. Item 1-9. A pharmaceutical product according to any one of items 1-1 to 1-4, wherein the buffer is a citrate buffer and the concentration of the citrate buffer is 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. A pharmaceutical product according to any one of items 1-1 to 1-10, wherein the metal chloride is sodium chloride. Item 1-12. A 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. A pharmaceutical product according to any one of items 1-1 to 1-12, wherein the aqueous solution substantially contains no preservatives. Item 1-14. A pharmaceutical product according to any one of items 1-1 to 1-13, wherein the aqueous solution is an eye drop solution. Item 1-15. The pharmaceutical product according to any one of Items 1-1 to 1-14, wherein the material of the filter is polyethersulfone or polyvinylidene fluoride. Item 1-16. The pharmaceutical product according to any one of Items 1-1 to 1-15, wherein the container with a filter 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 for the treatment of glaucoma. Item 1-18. A pharmaceutical product, wherein an aqueous solution containing brimonidine and / or its salt, a buffering agent, and a metal chloride is contained in a container with a filter, where brimonidine and / or its salt is brimonidine tartrate, the concentration of brimonidine and / or its salt is 0.05 - 0.2 w / v%, the buffering agent is a boric acid buffering agent, the aqueous solution is an eye drop, the material of the filter is polyethersulfone, the drug recovery rate obtained 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 the container with a filter is a multi-dose container. Item 1-19. A pharmaceutical product, wherein an aqueous solution containing brimonidine and / or its salt, a buffering agent, and a metal chloride is contained in a container with a filter, where brimonidine and / or its salt is brimonidine tartrate, the concentration of brimonidine and / or its salt is 0.05 - 0.2 w / v%, the buffering agent is a boric acid buffering agent, the aqueous solution is an eye drop, the material of the filter is polyvinylidene fluoride, the drug recovery rate obtained 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 the container with a filter is a multi-dose container.

[0012] Furthermore, the present invention provides an adsorption suppression method in the following embodiments. Section 2-1. A method for suppressing the adsorption of brimonidine and / or its salts onto a filter, comprising containing brimonidine and / or its salts, a buffer, and a metal chloride in an aqueous solution passed through the filter. Item 2-2. The adsorption inhibition method according to Item 2-1, wherein the brimonidine and / or salt thereof is brimonidine tartrate. Item 2-3. The adsorption inhibition method according to Item 2-1 or 2-2, wherein the concentration of brimonidine and / or its salt in the aqueous solution is 0.05 to 0.2 w / v%. Item 2-4. The adsorption inhibition method according to any one of items 2-1 to 2-3, wherein the buffering agent is at least one selected from the group consisting of boric acid buffering agent, phosphate buffering agent, Tris buffering agent, and citrate buffering agent. Section 2-5. The adsorption inhibition method according to any one of Sections 2-1 to 2-4, wherein the buffer is a boric acid buffer. Item 2-6. The adsorption suppression method according to any one of items 2-1 to 2-5, wherein the buffer is a boric acid buffer and the concentration of the boric acid buffer in the aqueous solution 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 solution 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 trisic acid buffer and the concentration of the trisic acid buffer in the aqueous solution is 0.01 to 5 w / v%. Item 2-9. The adsorption inhibition 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 solution is 0.01 to 5 w / v%. Item 2-10. The adsorption inhibition 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 solution is 0.01 to 5 w / v%. Item 2-13. The adsorption inhibition method according to any one of items 2-1 to 2-12, wherein the aqueous solution substantially contains no preservatives. Item 2-14. The adsorption inhibition method according to any one of items 2-1 to 2-13, wherein the aqueous solution is an eye drop solution. Section 2-15. The adsorption suppression method according to any one of Sections 2-1 to 2-14, wherein the material of the filter is polyethersulfone or polyvinylidene fluoride. Section 2-16. The adsorption suppression method according to any one of Sections 2-1 to 2-15, wherein the filter is a filter for a filter-equipped container. Section 2-17. The adsorption suppression method according to any one of Sections 2-1 to 2-15, wherein the filter is a filter used in a filtration sterilization process.

[0013] Furthermore, the present invention provides a manufacturing method in the following embodiments. Item 3-1. A step of preparing an aqueous solution containing brimonidine and / or a salt thereof, a buffer, and a metal chloride, and The aqueous solution obtained in the above step is subjected to a filtration sterilization step using a filter. A method for producing an aqueous solution containing [the specified ingredient]. Item 3-2. The method for producing the product according to Item 3-1, wherein the brimonidine and / or salt thereof is brimonidine tartrate. Item 3-3. The manufacturing method according to item 3-1 or 3-2, wherein the concentration of brimonidine and / or its salt in the aqueous solution is 0.05 to 0.2 w / v%. Item 3-4. The manufacturing method according to any one of items 3-1 to 3-3, wherein the buffering agent is at least one selected from the group consisting of boric acid buffering agent, phosphate buffering agent, Tris buffering agent, and citrate buffering agent. Item 3-5. The manufacturing method according to any one of items 3-1 to 3-4, wherein the buffering agent is a boric acid buffering agent. Item 3-6. The manufacturing method according to any one of items 3-1 to 3-5, wherein the buffer is a boric acid buffer and the concentration of the boric acid buffer in the aqueous solution is 0.01 to 10 w / v%. Item 3-7. The manufacturing method according to any one of items 3-1 to 3-4, wherein the buffering agent is a phosphate buffering agent, and the concentration of the phosphate buffering agent in the aqueous solution is 0.01 to 5 w / v%. Item 3-8. The manufacturing method according to any one of items 3-1 to 3-4, wherein the buffering agent is a trisic acid buffering agent, and the concentration of the trisic acid buffering agent in the aqueous solution is 0.01 to 5 w / v%. Item 3-9. The manufacturing method according to any one of items 3-1 to 3-4, wherein the buffering agent is a citrate buffering agent, and the concentration of the citrate buffering agent in the aqueous solution is 0.01 to 5 w / v%. Item 3-10. The manufacturing 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 manufacturing method according to any one of items 3-1 to 3-10, wherein the metal chloride is sodium chloride. Item 3-12. The manufacturing method according to any one of items 3-1 to 3-11, wherein the concentration of the metal chloride in the aqueous solution is 0.01 to 5 w / v%. Item 3-13. The manufacturing method according to any one of items 3-1 to 3-12, wherein the aqueous solution is substantially free of preservatives. Item 3-14. The manufacturing method according to any one of items 3-1 to 3-13, wherein the aqueous solution is an eye drop solution. 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] Furthermore, the present invention provides an adsorption suppression method in the following embodiments. Section 4-1. The aqueous solution to be passed through the filter, Brimonidine and / or its salts, Cushioning material, At least one preservative selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanides and their salts. A method for inhibiting the adsorption of brimonidine and / or its salts onto a filter, wherein the filter contains the following. Item 4-2. The adsorption inhibition method according to Item 4-1, wherein the brimonidine and / or salt thereof is brimonidine tartrate. Item 4-3. The adsorption inhibition method according to Item 4-1 or 4-2, wherein the concentration of brimonidine and / or its salt in the aqueous solution is 0.05 to 0.2 w / v%. Item 4-4. The adsorption inhibition 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 boric acid buffer, phosphate buffer, Tris buffer, and citrate buffer. Section 4-5. The adsorption inhibition method according to any one of Sections 4-1 to 4-4, wherein the buffer is a boric acid buffer. Item 4-6. The adsorption suppression method according to any one of items 4-1 to 4-5, wherein the buffer is a boric acid buffer and the concentration of the boric acid buffer in the aqueous solution 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 solution 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 trisic acid buffer and the concentration of the trisic acid buffer in the aqueous solution 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 solution is 0.01 to 5 w / v%. Item 4-10. The adsorption inhibition 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 inhibition 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 solution is 0.0001 to 0.1 w / v%. Item 4-12. The adsorption inhibition 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 solution is 0.0001 to 0.1 w / v%. Item 4-13. The adsorption inhibition method according to any one of items 4-1 to 4-10, wherein the preservative is a polyhexanide and / or a salt thereof, and the concentration of the polyhexanide and / or salt thereof in the aqueous solution is 0.00001 to 0.1 w / v%. Section 4-14. The adsorption inhibition method according to any one of sections 4-1 to 4-13, wherein the aqueous solution does not contain a viscosity agent. Section 4-15. The adsorption inhibition method according to any one of Sections 4-1 to 4-14, wherein the aqueous solution is an eye drop solution. Section 4-16. The adsorption suppression method according to any one of Sections 4-1 to 4-15, wherein the material of the filter is polyethersulfone or polyvinylidene fluoride. Section 4-17. The adsorption suppression method according to any one of Sections 4-1 to 4-16, wherein the filter is a filter used in a filtration sterilization process. Item 4-18. The adsorption suppression method according to any one of items 4-1 to 4-17, wherein the aqueous solution is an aqueous solution that is passed through a filter in a filtration sterilization step during manufacturing, and is provided in a multi-dose container without a filter after the filtration sterilization step. Section 4-19. The adsorption suppression method according to any one of sections 4-1 to 4-16, wherein the filter is a filter for a filter-equipped container.

[0015] Furthermore, the present invention provides a manufacturing method in the following embodiments. Item 5-1. A step of preparing an aqueous solution comprising brimonidine and / or a salt thereof, a buffer, and at least one preservative selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanides and their salts, and The aqueous solution obtained in the above step is subjected to a filtration sterilization step using a filter. A method for producing an aqueous solution containing [the specified ingredient]. Item 5-2. The method for producing the product according to item 5-1, wherein the brimonidine and / or salt thereof is brimonidine tartrate. Item 5-3. The manufacturing method according to item 5-1 or 5-2, wherein the concentration of brimonidine and / or its salt in the aqueous solution is 0.05 to 0.2 w / v%. Item 5-4. The manufacturing 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 boric acid buffer, phosphate buffer, Tris buffer, and citrate buffer. Item 5-5. The manufacturing method according to any one of items 5-1 to 5-4, wherein the buffering agent is a boric acid buffering agent. Item 5-6. The manufacturing method according to any one of items 5-1 to 5-5, wherein the buffering agent is a boric acid buffering agent, and the concentration of the boric acid buffering agent in the aqueous solution is 0.01 to 10 w / v%. Item 5-7. The manufacturing method according to any one of items 5-1 to 5-4, wherein the buffering agent is a phosphate buffering agent, and the concentration of the phosphate buffering agent in the aqueous solution is 0.01 to 5 w / v%. Item 5-8. The manufacturing method according to any one of items 5-1 to 5-4, wherein the buffer is a trisic acid buffer and the concentration of the trisic acid buffer in the aqueous solution is 0.01 to 5 w / v%. Item 5-9. The manufacturing method according to any one of items 5-1 to 5-4, wherein the buffering agent is a citrate buffering agent, and the concentration of the citrate buffering agent in the aqueous solution is 0.01 to 5 w / v%. Item 5-10. The adsorption inhibition 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 inhibition 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 solution is 0.0001 to 0.1 w / v%. Item 5-12. The adsorption inhibition 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 solution is 0.0001 to 0.1 w / v%. Item 5-13. The adsorption inhibition method according to any one of items 5-1 to 5-10, wherein the preservative is a polyhexanide and / or a salt thereof, and the concentration of the polyhexanide and / or salt thereof in the aqueous solution is 0.00001 to 0.1 w / v%. Item 5-14. The manufacturing method according to any one of items 5-1 to 5-13, wherein the aqueous solution does not contain a viscous agent. Item 5-15. The manufacturing method according to any one of items 5-1 to 5-14, wherein the aqueous solution is an eye drop solution. 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 manufacturing method according to any one of items 5-1 to 5-16, wherein the aqueous solution is provided in a multi-dose container without a filter after a filtration sterilization step. [Effects of the Invention]

[0016] According to the present invention, by including a buffer and a metal chloride in an aqueous solution containing brimonidine and / or its salt, the adsorption of brimonidine and / or its salt onto the filter can be suppressed, and the decrease in the content of brimonidine and / or its salt in the aqueous solution after passing through the filter can be suppressed. Therefore, in one aspect of the present invention, even if the aqueous solution containing brimonidine and / or its salt is contained in a filter-equipped container, the decrease in the content of brimonidine and / or its salt in the aqueous solution that passes through the filter and is dispensed outside the container during use can be suppressed. In another aspect of the present invention, even if the aqueous solution containing brimonidine and / or its salt is subjected to a sterilization process by filtration during manufacturing, the decrease in the content of brimonidine and / or its salt in the aqueous solution after filtration sterilization can be suppressed.

[0017] Furthermore, according to the present invention, by including a buffer and a specific preservative (at least one selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanides and their salts) in an aqueous solution containing brimonidine and / or its salt, the adsorption of brimonidine and / or its salt onto the filter can be suppressed, and the decrease in the content of brimonidine and / or its salt in the aqueous solution after passing through the filter can be suppressed. Therefore, in one aspect of the present invention, even if the aqueous solution containing brimonidine and / or its salt is subjected to a sterilization process by filtration during production, the decrease in the content of brimonidine and / or its salt in the aqueous solution after filtration sterilization can be suppressed. [Modes for carrying out the invention]

[0018] 1.Definition Terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains.

[0019] In this specification, "aqueous solution" refers to a formulation that contains water as a base and exhibits a liquid state.

[0020] In this specification, "pharmaceutical product" refers to a product in which an aqueous liquid is contained in any container.

[0021] In this specification, "brimonidine" refers to a compound known as an adrenergic α2 receptor agonist, and specifically to 5-bromo-N-(4,5-dihydro-1H-imidazole-2-yl)quinoxaline-6-amine.

[0022] In this specification, "buffering agent" refers to a compound or mixture that has the effect of mitigating fluctuations in the hydrogen ion concentration (pH) of an aqueous solution.

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

[0024] In this specification, "chlorhexidine" refers to a compound known as a preservative, specifically 1-[amino-[6-[amino-[amino-(4-chlorophenyl)amino-methylidene]amino-methylidene]aminohexylimino]methyl]imino-N-(4-chlorophenyl)-methanediamine.

[0025] In this specification, "benzalkonium chloride" refers to a compound known as a preservative, specifically the chloride of alkyl(C8-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 2 These are, either identical or different, an amino group or a group represented by the general formula (2) below. In general formula (1), n ​​represents an integer from 1 to 500. [ka]

[0027] In this specification, "preservative" refers to a compound or mixture that has sufficient bactericidal activity against bacteria and fungi and possesses preservative properties, and is formulated for the purpose of preventing microbial contamination. However, in this invention, boric acid and its salts are not included as preservatives.

[0028] In this specification, "substantially free of preservatives" means that the concentration of preservatives is such that the preservatives alone cannot exert their preservative effect. Specifically, this means that, when an aqueous solution containing only preservatives is prepared, the concentration of the aqueous solution is less than the minimum concentration of preservatives that would be considered "compliant" under the criteria defined for category "IC" in the Reference Information "Preservative Efficacy Test Method" of the 17th edition of the Japanese Pharmacopoeia.

[0029] In this specification, "filter" refers to a porous membrane that allows aqueous solutions to pass through but prevents bacteria and fungi from passing through. The pore size of the filter is usually 5 μm or less, but preferably 0.1 to 2.5 μm, and more preferably 0.2 to 1 μm.

[0030] In this specification, "filtered container" refers to a container for containing an aqueous liquid agent, wherein the inside of the container and the outside of the container are separated by a filter, and the aqueous liquid agent inside the container is poured out to the outside of the container after passing through the filter when used. One embodiment of a filtered container is a container having a container body with an opening and a nozzle provided with a flow path for pouring the aqueous liquid agent to the outside of the container, wherein the nozzle is attached to the opening of the container body and a filter is provided so as to block the flow path of the nozzle (for example, Patent Documents 1 and 2, etc.).

[0031] In this specification, "multi-dose container" refers to a container filled with an aqueous solution for multiple uses and intended for repeated use.

[0032] In this specification, "unit dose container" refers to a container filled with a single dose of aqueous solution, which is used up in one application.

[0033] In this specification, "method for inhibiting the adsorption of brimonidine and / or its salts onto a filter" refers to a method for inhibiting the decrease in the content of brimonidine and / or its salts in an aqueous solution that has passed through a filter by inhibiting the adsorption of brimonidine and / or its salts onto a filter. The effect of inhibiting the adsorption of brimonidine and / or its salts onto a filter is evaluated using the drug recovery rate (calculation formula: {brimonidine content in aqueous solution after filter / brimonidine content in aqueous solution before filter} × 100), which is obtained by dividing the brimonidine content in the aqueous solution after filter passage by the brimonidine content in the aqueous solution before filter passage. If the drug recovery rate of an aqueous solution containing metal chlorides (or preservatives) is higher than that of an aqueous solution that is the same as the aforementioned aqueous solution except that it does not contain metal chlorides (or preservatives), then it can be said that there is an effect of inhibiting the adsorption of brimonidine and / or its salts onto a filter. In this specification, the "method for inhibiting the adsorption of brimonidine and / or its salts onto a filter" may also be simply referred to as the "adsorption inhibition method."

[0034] 2. Description of Preferred Embodiments The following describes preferred embodiments, but it should be understood that these embodiments are illustrative of the present invention and the scope of the invention is not limited to such preferred embodiments. Those skilled in the art should also understand that modifications, changes, etc., within the scope of the invention can be easily made by referring to the following preferred embodiments. Those skilled in the art may combine any of these embodiments as appropriate.

[0035] 3. Pharmaceutical products For aqueous solutions contained in filtered containers, if the drug is adsorbed onto the filter, the drug content in the aqueous solution dispensed from the container decreases, leading to a failure to achieve the intended effect. Therefore, aqueous solutions contained in filtered containers must be designed so that the drug is not adsorbed onto the filter.

[0036] The inventors conducted various studies on pharmaceutical products containing an aqueous solution of brimonidine and / or its salt in a filtered container and found that brimonidine and / or its salt was adsorbed onto the filter of the container, reducing the content of brimonidine and / or its salt in the aqueous solution dispensed from the container. Therefore, the inventors conducted further studies and found that an aqueous solution containing brimonidine and / or its salt, a buffer, and a metal chloride can suppress the adsorption of brimonidine and / or its salt onto the filter, even when contained in a filtered container, thereby suppressing the reduction in the content of brimonidine and / or its salt in the aqueous solution dispensed from the container.

[0037] In one embodiment, the present invention provides a pharmaceutical product comprising an aqueous solution containing brimonidine and / or a salt thereof, a buffer, and a metal chloride, housed in a filtered container. The pharmaceutical product of the present invention will be described in detail below.

[0038] The pharmaceutical product of the present invention contains brimonidine and / or a salt thereof in an aqueous solution. The salt of brimonidine is not particularly limited to the extent that it is pharmaceutically acceptable, but specifically, examples include organic salts such as tartrates and acetates; and inorganic salts such as hydrochlorides. Brimonidine or a salt thereof 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 solution used in the present invention, either brimonidine or a salt thereof may be used alone, or they may be used in combination.

[0040] In the aqueous solution used in the present invention, the concentration of brimonidine and / or its salt is not particularly limited and can be set appropriately according to the use of the aqueous solution, the severity of symptoms in the target patient, the amount applied per dose, etc., but 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 its salt is the concentration converted to brimonidine tartrate.

[0041] The pharmaceutical product of the present invention further contains a buffering agent in the aqueous solution. The buffering agent is not particularly limited as long as it is pharmaceutically acceptable, but examples include borate buffers, phosphate buffers, Tris buffers, citrate buffers, tartaric acid buffers, acetate buffers, amino acid buffers, and the like.

[0042] Specific examples of boric acid buffers include boric acid and / or its salts. The 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 individually or in combination of two or more. The boric acid salts 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. Furthermore, boric acid / or its salts may be in hydrate form, such as borax.

[0043] As a boric acid buffer, one type may be selected from boric acid and its salts and used alone, or two or more types may be used in combination. Among boric acid and its salts, from the viewpoint of further improving the effect of suppressing the 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] Another preferred embodiment of the boric acid buffer is a combination of boric acid and borax. By using boric acid and borax in this combination, it is possible to further improve the effect of suppressing the adsorption of brimonidine and / or its salts onto the filter. When using boric acid and borax in combination, there are no particular restrictions on the ratio of these materials, but for example, 0 to 100 parts by mass, preferably 20 to 80 parts by mass, and more preferably 40 to 60 parts by mass of borax per 100 parts by mass of boric acid.

[0045] Regarding the concentration of the boric acid buffer, from the viewpoint of buffering effect, it is 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 boric acid buffer is the concentration converted to boric acid.

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

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

[0048] Furthermore, a preferred embodiment of the phosphate buffer is a combination of a dialkali metal hydrogen phosphate and a dialkali metal dihydrogen phosphate. By using a combination of a dialkali metal hydrogen phosphate and a dialkali metal dihydrogen phosphate 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 a combination of a dialkali metal hydrogen phosphate and a dialkali metal dihydrogen phosphate, there are no particular restrictions on their ratio, but 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 dialkali metal dihydrogen phosphate are used per 100 parts by mass of the dialkali metal hydrogen phosphate.

[0049] Regarding the concentration of the phosphate buffer, from the viewpoint of buffering effect, it 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 expressed as the concentration converted to phosphoric acid.

[0050] Examples of Tris buffering agents include trometamol and / or its salts. While there are no particular restrictions on trometamol salts, provided they are pharmaceutically acceptable, examples include organic acid salts such as acetate; and organic acid salts such as hydrochloride and sulfonate.

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

[0052] Regarding the concentration of the Tris buffer, from the viewpoint of buffering effect, it 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 expressed as the concentration converted to trometamol.

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

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

[0055] Regarding the concentration of the citrate buffer, from the viewpoint of buffering effect, it 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 expressed as the concentration converted to citric acid.

[0056] Specific examples of tartaric acid buffers include tartaric acid and / or its salts. The salts of tartaric acid are not particularly limited as long as they are pharmaceutically acceptable, but examples include alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as calcium salt and magnesium salt. The salts of tartaric acid may also be in the form of solvates such as hydrates. One of tartaric acid and its salts may be selected and used alone as a tartaric acid buffer, or two or more may be used in combination.

[0057] Specific examples of acetic acid buffers include acetic acid and / or its salts. The salts of acetic 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; and ammonium salts. The salts of acetic acid may also be in the form of solvates such as hydrates. One of acetic acid and its salts may be selected and used alone as an acetic acid buffer, or two or more may be used in combination.

[0058] Examples of amino acid buffers include acidic amino acids and / or their salts. Examples of acidic amino acids include aspartic acid and glutamic acid. Salts of acidic amino acids are not particularly limited as long as they are pharmaceutically acceptable, but examples include alkali metal salts such as sodium salts and potassium salts. One type of acidic amino acid and its salt may be selected and used alone as an amino acid buffer, or two or more types may be used in combination.

[0059] These cushioning materials may be used individually or in combination of two or more types.

[0060] Among these buffers, from the viewpoint of further improving the effect of suppressing the adsorption of brimonidine and / or its salts onto the filter, boric acid buffers, phosphate buffers, Tris buffers, citrate buffers, and more preferably boric acid buffers are used.

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

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

[0063] The concentration of metal chloride in the aqueous solution used in the present invention is typically 0.01 to 5 w / v%. From the viewpoint of further improving the effect of suppressing the adsorption of brimonidine and / or its salts to the filter, the concentration of metal chloride in the aqueous solution 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 solution is contained in a filtered container, preventing bacteria from entering the aqueous solution during use or storage. Therefore, even if the aqueous solution substantially contains no preservatives, it can still possess storage stability. Furthermore, preservatives can have adverse effects such as irritation and cytotoxicity, and such adverse effects can be avoided if the aqueous solution substantially contains no preservatives. For this reason, one preferred embodiment of the aqueous solution used in the present invention is that it is substantially free of preservatives.

[0065] 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, polyhexanides, and polyquatrium.

[0066] In embodiments of the present invention in which the aqueous solution used is substantially free of preservatives, the permissible concentration of preservatives varies depending on the type of preservation, but specifically, it is 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 solution used in the present invention may optionally contain additives such as isotonic agents (other than metal chlorides), surfactants, viscosity enhancers, chelating agents, cooling agents, stabilizers, and pH adjusters.

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

[0069] The surfactants are not particularly limited as long as they are pharmaceutically acceptable, but examples include nonionic surfactants such as tyroxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, and octoxynol; amphoteric surfactants such as alkyldiaminoethylglycine and lauryldimethylaminoacetic acid betaine; anionic surfactants such as alkyl sulfates, N-acyl taurine salts, polyoxyethylene alkyl ether phosphates, and polyoxyethylene alkyl ether sulfates; and cationic surfactants such as alkylpyridinium salts and alkylamine salts. These surfactants may be used individually or in combination of two or more.

[0070] The viscosity agent is not particularly limited to the extent that it is pharmaceutically acceptable, but examples include water-soluble polymers such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate; and celluloses such as hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose. These viscosity agents may be used individually or in combination of two or more.

[0071] The chelating agents are not particularly limited to those that are pharmaceutically acceptable, but examples include edetate, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, polyphosphate, metaphosphate, hexametaphosphate, phytic acid, thiosulfate, and their salts. The form of the salts is not particularly limited to those that are pharmaceutically acceptable, but examples include alkali metal salts such as sodium salts and potassium salts. These chelating agents may be used individually or in combination of two or more.

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

[0073] The stabilizers are not particularly limited as long as they are pharmaceutically acceptable, but examples include polyvinylpyrrolidone, sulfites, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol, and dibutylhydroxytoluene. These stabilizers may be used individually or in combination of two or more.

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

[0075] The concentrations of these additives should be set appropriately according to the type of additive used and the characteristics that should be imparted to the aqueous solution.

[0076] Furthermore, the aqueous solution used in the present invention may, in addition to brimonidine and / or its salts, optionally contain pharmacological components that exhibit therapeutic effects against glaucoma and ocular hypertension, to the extent that they do not interfere with the effects of the present invention.

[0077] Examples of such pharmacological components include prostaglandins such as tafluprost, latanoprost, and isopropyl unoprostone; parasympathetic stimulants such as pilocarpine hydrochloride; anticholinesterases such as distigmine bromide; sympathetic stimulants such as dipivefrin hydrochloride; β1 blockers such as betaxolol hydrochloride; β-blockers such as timolol maleate; α1 and β-blockers such as nipradilol and levovunol hydrochloride; and α1 blockers such as bunazosin hydrochloride. Examples include drugs, etc. These pharmacological components may be used individually or in combination of two or more.

[0078] The concentrations of these pharmacological components should be set appropriately according to the type of pharmacological component used and the therapeutic effect to be imparted.

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

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

[0081] The formulation form of the aqueous solution used in the present invention is not particularly limited and may be in the form of an aqueous solution, an emulsion, or any other form, but an aqueous solution is preferred.

[0082] The aqueous solution used in the present invention can be used as an ophthalmic preparation such as eye drops or eye wash. In particular, the aqueous solution used in the present invention can lower intraocular pressure through the action of brimonidine and / or its salt, and is therefore suitable for use as an eye drop for the treatment of glaucoma or ocular hypertension.

[0083] The aqueous liquid preparations used in this invention may be manufactured according to known preparation methods, depending on their intended use. For example, they can be manufactured using the methods described in the General Provisions for Preparations of the Seventeenth Revised Japanese Pharmacopoeia.

[0084] In the pharmaceutical product of the present invention, a container with a filter is used to hold the aqueous solution. The structure of a container with a filter is well known (Patent Documents 1 and 2, etc.), and a known container with a filter can be used in the present invention. Furthermore, the container with a filter may be an eye drop container, an eye wash container, etc., depending on the application of the aqueous solution.

[0085] Furthermore, the material of the filter in the filter-equipped container used in the present invention is not particularly limited, but examples include polyethersulfone, polyvinylidene fluoride, polycarbonate, polytetrafluoroethylene, cellulose mixed ester, nylon, polyamide, etc. Among these materials, polyethersulfone, polyvinylidene fluoride, and more preferably polyethersulfone are preferred from the viewpoint of further improving the effect of suppressing the adsorption of brimonidine and / or its salts onto the filter.

[0086] Considering that the filter-equipped container used in the present invention has the function of preventing the entry of bacteria by the filter, it is preferable that it be a multi-dose type container.

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

[0088] In one embodiment of using a container with a polyethersulfone filter in the pharmaceutical product of the present invention, the polyethersulfone filter (for example, STERIVEX-GP 0.22μm / Merck Millipore (pore size: 0.22μm, height: 67mm, diameter: 10cm)) is used. 2 One example is that the drug recovery rate, calculated by dividing the brimonidine content in the aqueous solution after passing through the filter (the first 0.6g after passing through the filter) by the brimonidine content in the aqueous solution before passing through the filter, is 95% or higher. Furthermore, in one embodiment of using a polyvinylidene fluoride filter in the pharmaceutical product of the present invention, a polyvinylidene fluoride filter (for example, STERIVEX-GV 0.22μm / Merck Millipore (pore size: 0.22μm, height: 67mm, diameter: 10cm)) is used. 2One of the characteristics is that the drug recovery rate, calculated by dividing the brimonidine content in the aqueous solution after passing through the filter (the first 1.0 g that has passed through the filter) by the brimonidine content in the aqueous solution before passing through the filter, is 90% or higher. (Catalog number: SVGV010RS)

[0089] 4. Adsorption suppression method (1) As mentioned above, in conventional technology, when an aqueous solution containing brimonidine and / or its salt is placed in a filter-equipped container, the brimonidine and / or its salt is adsorbed onto the filter of the container. This problem also occurs in the filtration sterilization process using a filter during the manufacture of aqueous solutions containing brimonidine and / or its salt. In other words, when an aqueous solution containing brimonidine and / or its salt is placed in a filter-equipped container and used, or when a filtration sterilization process using a filter is performed, there is a problem that the brimonidine and / or its salt is adsorbed onto the filter.

[0090] In contrast, by including a buffer and a metal chloride along with brimonidine and / or its salts in the aqueous solution, the adsorption of brimonidine and / or its salts onto the filter can be suppressed even after passing through the filter, and the decrease in the content of brimonidine and / or its salts in the aqueous solution after passing through the filter can be suppressed.

[0091] Therefore, in one embodiment, the present invention provides a method for suppressing the adsorption of brimonidine and / or its salts onto a filter, wherein the aqueous solution passed through the filter contains brimonidine and / or its salts, a buffer, and a metal chloride.

[0092] In the adsorption inhibition method of the present invention, the types and concentrations of brimonidine and / or its salts, buffers, and metal chlorides used are as described in section 3, "Pharmaceutical Products." Furthermore, in the adsorption inhibition method of the present invention, the types of other components that can be incorporated into the aqueous solution, the pH of the aqueous solution, the osmotic pressure ratio, the formulation form, etc., are as described in section 3, "Pharmaceutical Products."

[0093] The filter used in this invention may be the filter of a filter-equipped container, or it may be the filter used in a filtration sterilization process. That is, the aqueous solution that passes through the filter may be an aqueous solution contained in a filter-equipped container that passes through the filter of the container and is poured out of the container when in use, or it may be an aqueous solution that passes through a filter in a filtration sterilization process during the manufacture of the aqueous solution. The type of filter-equipped container and the material of the filter are as described in section "3. Pharmaceutical Products" above. Furthermore, the material of the filter used in the filtration sterilization process during manufacturing is the same as the material of the filter in the filter-equipped container described in section "3. Pharmaceutical Products" above.

[0094] In the adsorption suppression method of the present invention, when the aqueous solution passed through the filter is contained in a filter-equipped container, it is preferable that the aqueous solution substantially contains no preservatives, as preservative properties are not necessarily required for the aqueous solution. Furthermore, in the adsorption suppression method of the present invention, even when the aqueous solution passed through the filter is an aqueous solution passed through a filter in a filtration sterilization step and provided in a unit dose type container after the filtration sterilization step, it is preferable that the aqueous solution substantially contains no preservatives, as preservative properties are not necessarily required for the aqueous solution.

[0095] On the other hand, in the adsorption suppression method of the present invention, if the aqueous solution that passes through the filter is the same aqueous solution that passes through the filter in the filtration sterilization step, and is provided in a multi-dose container without a filter after the filtration sterilization step, it is preferable that the aqueous solution contains a preservative so that it has the desired preservative effect. The types of preservatives are as described in section "3. Pharmaceutical Products" above. Furthermore, when a preservative is included in the aqueous solution, the concentration of the preservative in the aqueous solution can be appropriately set within a range that provides the desired preservative effect, 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 solutions (1) As mentioned above, when a filter-based sterilization process is performed during the manufacture of an aqueous solution containing brimonidine and / or its salts, brimonidine and / or its salts are adsorbed onto the filter, resulting in a decrease in the content of brimonidine and / or its salts in the aqueous solution that passes through the filter.

[0097] In contrast, by subjecting an aqueous solution containing brimonidine and / or its salt, a buffer, and a metal chloride to a filtration sterilization process using a filter, the adsorption of brimonidine and / or its salt onto the filter can be suppressed, and the decrease in the content of brimonidine and / or its salt in the aqueous solution after filtration sterilization can be suppressed.

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

[0099] In the manufacturing method of the present invention, the types and concentrations of brimonidine and / or its salts, buffers, and metal chlorides are as described in section 3, "Pharmaceutical Products." Furthermore, in the manufacturing method of the present invention, the types of other components that can be incorporated into the aqueous solution, the pH of the aqueous solution, the osmotic pressure ratio, the formulation form, etc., are as described in section 3, "Pharmaceutical Products." Furthermore, in the manufacturing 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 section 3, "Pharmaceutical Products."

[0100] The aqueous solution obtained by the manufacturing method of the present invention may be provided in a container with a filter, or in a multi-dose container or a unit-dose container without a filter.

[0101] If the aqueous solution obtained by the manufacturing method of the present invention is provided in a filtered container or a unit-dose container, the aqueous solution itself does not necessarily need to have preservative properties, and therefore it is preferable that it substantially contains no preservatives.

[0102] On the other hand, if the aqueous solution obtained by the manufacturing method of the present invention is provided in a multi-dose container without a filter, it is preferable that the aqueous solution contains a preservative so as to have the desired preservative effect. The type of preservative is as described in section "3. Pharmaceutical Products" above, and the concentration of the preservative in the aqueous solution is as described in section "4. Adsorption Inhibition Method (1)" above.

[0103] 6. Adsorption suppression method (2) As mentioned above, when using an aqueous solution containing brimonidine and / or its salts in a filter-based sterilization process or when using it in a filter-equipped container, there is a problem in that brimonidine and / or its salts are adsorbed onto 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 polyhexanides and their salts) together with brimonidine and / or its salts in the aqueous solution, it is possible to suppress the adsorption of brimonidine and / or its salts onto the filter even after passing through the filter, and to suppress the decrease in the content of brimonidine and / or its salts in the aqueous solution after passing through the filter.

[0105] Therefore, in one embodiment, the present invention provides a method for suppressing the adsorption of brimonidine and / or its salts onto a filter, wherein the aqueous solution passed through the filter contains brimonidine and / or its salts, a buffer, and at least one selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanides and their salts.

[0106] The aqueous solution used in the present invention contains brimonidine and / or its salt. The types, concentrations, etc. of brimonidine and / or its salt are the same as those in the above-mentioned case of "3. Pharmaceutical Products".

[0107] The aqueous solution used in the present invention contains a buffering agent. The types, concentrations, etc. of the buffering agent are the same as those in the above-mentioned case of "3. Pharmaceutical Products".

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

[0109] The salt of chlorhexidine used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. Specifically, inorganic acid salts such as hydrochloride; organic acid salts such as acetate and gluconate can be mentioned. Further, chlorhexidine or its salt may be in the form of a solvate such as a hydrate. Among chlorhexidine and its salts, preferably the salt of chlorhexidine, and more preferably chlorhexidine gluconate can be mentioned.

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

Chemical formula

[0111] In general formula (1), R 1 and R 2 are the same or different and are an amino group or a group represented by the following general formula (2). As R 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 general formula (1), n ​​represents an integer from 1 to 500. Preferably, n is an integer from 2 to 200, more preferably from 4 to 100, and particularly preferably from 8 to 20.

[0113] Furthermore, the salts of polyhexanides are not particularly limited, as long as they are pharmaceutically acceptable, but examples include inorganic salts and organic salts. Specific examples of inorganic salts include hydrochloric acid, hydrogen bromide, sulfuric acid, and boric acid. Specific examples of organic salts include acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid, and citric acid.

[0114] Among polyhexanides and their salts, preferred are salts of polyhexanides, more preferably inorganic salts of polyhexanides, and particularly preferred are polyhexanide hydrochloride.

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

[0116] When using chlorhexidine and / or its salts, the concentration of chlorhexidine and / or its salts in the aqueous solution can be, 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 its salts is expressed as the concentration converted to chlorhexidine gluconate.

[0117] When using benzalkonium chloride, the concentration of benzalkonium chloride in the aqueous solution can be, 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 using polyhexanides and / or their salts, the concentration of polyhexanides and / or their salts in the aqueous solution can 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%. In this specification, the concentration of polyhexanides and / or their salts is the concentration converted to polyhexanide hydrochloride.

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

[0120] In the aqueous solution used in the present invention, other components that can be incorporated are the same as in the case of "3. Pharmaceutical Products" above. However, in one embodiment of the aqueous solution used in the present invention, the viscosity agent is less than 0.05 w / v%, but in a preferred embodiment, the viscosity agent is omitted from the viewpoint of inhibiting the adsorption of brimonidine, the stability of brimonidine (inhibiting the decrease in brimonidine content in the aqueous solution), or the filterability of the aqueous solution. The types of viscosity agents are as described in the section "3. Pharmaceutical Products" above.

[0121] In the aqueous solution used in the present invention, the pH, osmotic pressure ratio, formulation form, etc., of the aqueous solution are the same as in the case of "3. Pharmaceutical Products" described above.

[0122] The filter used in this invention may be a filter used in a filtration sterilization process, or it may be a filter in a filter-equipped container. That is, the aqueous solution that passes through the filter may be an aqueous solution that passes through a filter in a filtration sterilization process during the manufacture of the aqueous solution, or it may be an aqueous solution contained in a filter-equipped container that passes through the filter of the container and is dispensed outside the container when in use. The material of the filter used in the filtration sterilization process during manufacture is the same as the material of the filter in the filter-equipped container described in section "3. Pharmaceutical Products" above. The type of filter-equipped container and the material of the filter are as described in section "3. Pharmaceutical Products" above.

[0123] In the adsorption inhibition method of the present invention, the desired preservative effect can be achieved by including a specific preservative (at least one selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanides and their salts) in the aqueous solution used. A preferred form of the aqueous solution used in the present invention is an aqueous solution that passes through a filter in the filtration sterilization process during manufacturing, and is provided in a multi-dose container without a filter after the filtration sterilization process.

[0124] 7. Method for producing aqueous solutions (2) As mentioned above, when a filter-based sterilization process is performed during the manufacture of an aqueous solution containing brimonidine and / or its salts, brimonidine and / or its salts are adsorbed onto the filter, resulting in a decrease in the content of brimonidine and / or its salts in the aqueous solution that passes through the filter.

[0125] In contrast, by subjecting an aqueous solution containing brimonidine and / or its salt, a buffer, and a specific preservative (at least one selected from the group consisting of chlorhexidine and its salt, benzalkonium chloride, and polyhexanides and their salts) to a filtration sterilization process using a filter, the adsorption of brimonidine and / or its salt onto the filter can be suppressed, and the decrease in the content of brimonidine and / or its salt in the aqueous solution after filtration sterilization can be suppressed.

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

[0127] The type and concentration of brimonidine and / or its salts, and buffers used in the manufacturing method of the present invention are as described in section 3, "Pharmaceutical Products."

[0128] In the manufacturing method of the present invention, the types and concentrations of brimonidine and / or its salts, buffering agents, chlorhexidine and its salts, benzalkonium chloride, and polyhexanides and their salts used are as described in section "6. Adsorption Inhibition Method (2)" above.

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

[0130] Furthermore, in the manufacturing method of the present invention, the types of other components that can be incorporated into the aqueous solution, the pH of the aqueous solution, the osmotic pressure ratio, the formulation form, etc., are as described in section "3. Pharmaceutical Products" above. Also, in the manufacturing 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 section "3. Pharmaceutical Products" above.

[0131] The aqueous solution obtained by the manufacturing method of the present invention may be provided in a filtered container, or in a multi-dose container or unit-dose container without a filter. Since the aqueous solution obtained by the manufacturing method of the present invention can have desired preservative efficacy by containing a specific preservative (at least one selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanides and their salts), it is preferable to provide it in a multi-dose container without a filter. [Examples]

[0132] The present invention will be specifically described below with reference to examples, but the present invention is not limited in any way by these examples. In the following test examples, orthoboric acid was used in all cases.

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

[0134] The brimonidine content in the aqueous solution before filtration and the aqueous solution after filtration (filtrate) was 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 × 150 mm, 3.5 μm, Waters Corporation Column temperature : A constant temperature around 40℃ Mobile phase A A mixture of 4.3 mM phosphoric acid aqueous solution, methanol, and acetonitrile (volume ratio: 84 / 8 / 8). Mobile phase B A mixture of 4.3 mM phosphoric acid aqueous solution, methanol, and acetonitrile (volume ratio: 40 / 30 / 30). Mobile phase delivery The linear concentration gradient was controlled by varying the mixing ratio of mobile phase A and mobile phase B as follows. Time after injection (minutes) 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 internal temperature: 5℃

[0135] The drug recovery rate after filtration was calculated from the brimonidine content of the aqueous solution before and after filtration, according to the following formula.

number

[0136] The results are shown in Table 1. In the case of aqueous solutions containing brimonidine tartrate, without buffering agents and metal chlorides (Comparative Example 1), the drug recovery rate after filtration with a PES membrane was 94%, indicating that as much as 6% of the brimonidine tartrate was adsorbed by filtration with the PES membrane. Furthermore, in aqueous solutions containing brimonidine tartrate and a buffering agent (boric acid buffer, phosphate buffer, trometamol, or citrate buffer), the drug recovery rate after filtration with a PES membrane was equivalent to that of Comparative Example 1, when metal chlorides were not included (Comparative Examples 2, 6-8). Moreover, in aqueous solutions containing brimonidine tartaric acid and a boric acid buffer along with sodium edetate or a water-soluble polymer (carboxymethylcellulose or polyvinylpyrrolidone), the drug recovery rate after filtration with a PES membrane was equivalent to that of Comparative Example 1, when metal chlorides were not included (Comparative Examples 3-5).

[0137] In contrast, in aqueous solutions containing brimonidine tartaric acid and a buffer (boric acid buffer, phosphate buffer, trometamol, or citrate buffer) along with a metal chloride (sodium chloride, potassium chloride, calcium chloride, or magnesium chloride), the drug recovery rate after passing through the PES membrane filter was significantly higher than in Comparative Example 1, indicating that metal chlorides have a drug adsorption inhibitory effect. Furthermore, as is clear from the 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 the buffers, the use of boric acid buffer showed the greatest effect in improving the drug recovery rate after passing through the PES membrane filter.

[0138] Furthermore, the same trend was observed when using PVDF film as with PES film.

[0139] [Table 1]

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

[0141] The results are shown in Table 2. In aqueous solutions containing brimonidine tartaric acid and a borate buffer along with a surfactant (polysorbate 80, POE(60) hydrogenated castor oil, tyroxapol, poloxamer 407, or polyethylene glycol monostearate (40EO)) (Comparative Examples 9-13), the drug recovery rate after filtration with PES and PVDF membranes was equivalent to or lower than that of aqueous solutions without a surfactant (Comparative Examples 1 and 2). Similarly, in aqueous solutions containing brimonidine tartaric acid and a borate buffer along with chlorobutanol or sorbic acid used as a preservative (Comparative Examples 14 and 15), the drug recovery rate after filtration with PES and PVDF membranes was equivalent to that of Comparative Examples 1 and 2. In contrast, in aqueous solutions containing brimonidine tartaric acid and a borate buffer, along with benzalkonium chloride, chlorhexidine gluconate, or polyhexanide hydrochloride (Examples 13-15), the drug recovery rate after passing through the PES and PVDF membrane filters was improved compared to Comparative Examples 1 and 2, demonstrating an effect of suppressing drug adsorption to the PES and PVDF membranes.

[0142] [Table 2]

Claims

1. A step of preparing an aqueous solution containing brimonidine and / or its salt in an amount of 0.1 w / v%, a citrate buffer, a metal chloride, and benzalkonium chloride, without a viscosity agent, and having a pH of 7 to 8, and A step of sterilizing the aqueous solution obtained in the above step by filtering it using a filter, A method for producing an aqueous solution containing [the specified ingredient].

2. The method for producing the product according to claim 1, wherein the brimonidine and / or salt thereof is brimonidine tartrate.

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

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

5. The manufacturing method according to any one of claims 1 to 4, wherein the pH of the aqueous solution is 7.

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

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

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

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