JP6797992B1 - Aqueous solution - Google Patents

Abstract

An object of the present invention is to provide a formulation technique for an aqueous solution containing brimonidine and / or a salt thereof. An aqueous solution containing brimonidine and / or a salt thereof, a buffering agent, and a metal chloride can suppress the adsorption of brimonidine and / or a salt thereof to the filter even if it is passed through a filter, and has a filter. Even if it is contained in a container or subjected to a sterilization step by filtering at the time of production, it is possible to suppress a decrease in the content of brimonidine and / or a salt thereof in the aqueous solution. [Selection diagram] None

Description

The present invention relates to an aqueous liquid agent containing brimonidine and / or a salt thereof, in which the adsorption of brimonidine and / or a salt thereof is suppressed.

Aqueous solutions such as eye drops and eyewashes usually contain preservatives such as benzalkonium chloride and methylparaben in order to prevent the growth of microorganisms. Such an aqueous solution is usually subjected to a sterilization step by filtering at the time of manufacture.

Preservatives have been reported to be irritating and cytotoxic while being able to prevent bacterial growth (see Non-Patent Document 1). Therefore, conventionally, in order to avoid the adverse effect of the preservative, an aqueous solution containing no preservative has been developed. The multi-dose container that contains an aqueous liquid agent that does not contain a preservative has a structure that aseptically separates the inside of the container from the outside of the container to prevent bacteria from entering the inside of the container during use, and a filter is applied to the nozzle. (Containers with filters) are often used (see Patent Documents 1 and 2).

On the other hand, brimonidine and its salts are known as adrenaline α2 receptor agonists and reduce intraocular pressure by suppressing the production of aqueous humor and promoting the outflow of aqueous humor through the uveoscleral outflow tract. It has the effect of causing glaucoma and has been conventionally used for the treatment of glaucoma and ocular hypertension.

Japanese Ophthalmology, Vol. 58, No. 10, pp. 945-950, 1987

Japanese Unexamined Patent Publication No. 2004-51170 JP-A-2002-80055

An object of the present invention is to provide a formulation technique for an aqueous solution containing brimonidine and / or a salt thereof.

The present inventor can suppress the adsorption of brimonidine and / or its salt on the filter even if the aqueous solution containing brimonidine and / or its salt, the buffer, and the metal chloride is passed through the filter, and the filter. It has been found that a decrease in the content of brimonidine and / or a salt thereof in the aqueous solution can be suppressed even when the brimonidine is contained in a buffer or subjected to a sterilization step by filtering at the time of production.

Furthermore, the present inventor presents the present invention as a brimonidine and / or a salt thereof, a buffer, and a specific preservative (at least one selected from the group consisting of chlorhexidine and its salt, benzalkonium chloride, and polyhexanide and its salt). The aqueous solution containing and can suppress the adsorption of brimonidin and / or its salt to the filter even if it is passed through the filter, and even if it is subjected to a sterilization step by filtering at the time of production, the brimonidin and / or its salt in the aqueous solution is used. It was found that the decrease in salt content can be suppressed.

The present invention has been completed by further studies based on these findings.

That is, the present invention provides a pharmaceutical product in the following aspects.
Item 1-1. A pharmaceutical product comprising an aqueous solution containing brimonidine and / or a salt thereof, a buffering agent, and a metal chloride contained in a container with a filter.
Item 1-2. Item 2. The pharmaceutical product according to Item 1-1, wherein the brimonidine and / or a salt thereof is brimonidine tartrate.
Item 1-3. Item 2. The pharmaceutical product according to Item 1-1 or 1-2, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.2 w / v%.
Item 1-4. Item 2. The item according to any one of Items 1-1 to 1-3, wherein the buffer is at least one selected from the group consisting of a boric acid buffer, a phosphate buffer, a Tris buffer, and a citric acid buffer. Pharmaceutical products.
Item 1-5. Item 4. The pharmaceutical product according to any one of Items 1-1 to 1-4, wherein the buffer is a boric acid buffer.
Item 1-6. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-5, wherein the buffering agent is a boric acid buffering agent, and the concentration of the boric acid buffering agent is 0.01 to 10 w / v%.
Item 1-7. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-4, wherein the buffering agent is a phosphate buffering agent, and the concentration of the phosphate buffering agent is 0.01 to 5 w / v%.
Item 1-8. Item 4. The pharmaceutical product according to any one of Items 1-1 to 1-4, wherein the buffer is a trisic acid buffer, and the concentration of the trisic acid buffer is 0.01 to 5 w / v%.
Item 1-9. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-4, wherein the buffering agent is a citric acid buffering agent, and the concentration of the citric acid buffering agent is 0.01 to 5 w / v%.
Item 1-10. Item 2. 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. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-10, wherein the metal chloride is sodium chloride.
Item 1-12. Item 2. 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. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-12, wherein the aqueous solution contains substantially no preservative.
Item 1-14. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-13, wherein the aqueous solution is an eye drop.
Item 1-15. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-14, wherein the material of the filter is polyether sulfone or polyvinylidene fluoride.
Item 1-16. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-15, wherein the container with a filter is a multi-dose type 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 in which an aqueous solution containing brimonidine and / or a salt thereof, a buffering agent, and a metal chloride is 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 boric acid buffer,
The aqueous solution is eye drops,
The material of the filter is polyether sulfone,
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 the filter is a multidose type container. Product.
Item 1-19. A pharmaceutical product in which an aqueous solution containing brimonidine and / or a salt thereof, a buffering agent, and a metal chloride is 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 boric acid buffer,
The aqueous solution is eye drops,
The material of the filter is polyvinylidene fluoride,
A drug in which 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 the filter is a multidose type container. Product.

The present invention also provides a method for suppressing adsorption according to the following aspects.
Item 2-1. A method for suppressing adsorption of brimonidine and / or its salt to a filter, which comprises a brimonidine and / or a salt thereof, a buffer, and a metal chloride in an aqueous liquid agent to be passed through a filter.
Item 2-2. Item 2. The method for suppressing adsorption according to Item 2-1. The brimonidine and / or a salt thereof is brimonidine tartrate.
Item 2-3. Item 2. The adsorption suppression method according to Item 2-1 or 2-2, wherein the concentration of brimonidine and / or a salt thereof in the aqueous solution is 0.05 to 0.2 w / v%.
Item 2-4. Item 2. The item 2-1 to 2-3, wherein the buffer is at least one selected from the group consisting of a boric acid buffer, a phosphate buffer, a Tris buffer, and a citrate buffer. Adsorption suppression method.
Item 2-5. Item 2. The adsorption suppression method according to any one of Items 2-1 to 2-4, wherein the buffer is a boric acid buffer.
Item 2-6. Item 2. 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. Item 2. 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. Item 2. 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. Item 2. The adsorption suppression method according to any one of Items 2-1 to 2-4, wherein the buffering agent is a citric acid buffering agent, and the concentration of the citric acid buffering agent in the aqueous solution is 0.01 to 5 w / v%. ..
Item 2-10. Item 2. The method for suppressing adsorption 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. Item 2. The method for suppressing adsorption according to any one of Items 2-1 to 2-10, wherein the metal chloride is sodium chloride.
Item 2-12. Item 2. The method for suppressing adsorption 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. Item 2. The adsorption suppression method according to any one of Items 2-1 to 2-12, wherein the aqueous solution does not substantially contain a preservative.
Item 2-14. Item 8. The adsorption suppression method according to any one of Items 2-1 to 2-13, wherein the aqueous solution is an eye drop.
Item 2-15. Item 2. The method for suppressing adsorption according to any one of Items 2-1 to 2-14, wherein the material of the filter is polyether sulfone or polyvinylidene fluoride.
Item 2-16. Item 2. The adsorption suppression method according to any one of Items 2-1 to 2-15, wherein the filter is a filter for a container with a filter.
Item 2-17. Item 2. 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.

The present invention also provides a manufacturing method according to the following aspects.
Item 3-1. A step of preparing an aqueous solution containing brimonidine and / or a salt thereof, a buffer, and a metal chloride, and a step of subjecting the aqueous solution obtained in the above step to a filtration sterilization step using a filter.
A method for producing an aqueous liquid preparation, including.
Item 3-2. Item 3. The production method according to Item 3-1. The brimonidine and / or a salt thereof is brimonidine tartrate.
Item 3-3. Item 3. The production method according to Item 3-1 or 3-2, wherein the concentration of brimonidine and / or a salt thereof in the aqueous solution is 0.05 to 0.2 w / v%.
Item 3-4. Item 2. The item 3-1 to 3-3, wherein the buffer is at least one selected from the group consisting of boric acid buffer, phosphate buffer, Tris buffer, and citric acid buffer. Manufacturing method.
Item 3-5. Item 8. The production method according to any one of Items 3-1 to 3-4, wherein the buffer is a boric acid buffer.
Item 3-6. Item 8. The production method according to any one of Items 3-1 to 3-5, 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 3-7. Item 8. The production 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 solution is 0.01 to 5 w / v%.
Item 3-8. Item 8. The production method according to any one of Items 3-1 to 3-4, wherein the buffering agent is a trisic acid buffer, and the concentration of the trisic acid buffering agent in the aqueous solution is 0.01 to 5 w / v%.
Item 3-9. Item 2. The item according to any one of Items 3-1 to 3-4, wherein the buffer is a citric acid buffer, and the concentration of the citric acid buffer in the aqueous solution is 0.01 to 5 w / v%. Manufacturing method.
Item 3-10. Item 6. 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. Item 8. The production method according to any one of Items 3-1 to 3-10, wherein the metal chloride is sodium chloride.
Item 3-12. Item 8. The production 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. Item 8. The production method according to any one of Items 3-1 to 3-12, wherein the aqueous solution does not substantially contain a preservative.
Item 3-14. Item 8. The production method according to any one of Items 3-1 to 3-13, wherein the aqueous solution is an eye drop.
Item 3-15. Item 8. The production method according to any one of Items 3-1 to 3-14, wherein the material of the filter is polyether sulfone or polyvinylidene fluoride.

The present invention also provides a method for suppressing adsorption according to the following aspects.
Item 4-1. For aqueous liquids that pass through the filter
With brimonidine and / or its salt,
Buffering agent and
A method for suppressing adsorption of brimonidine and / or a salt thereof to a filter, which comprises chlorhexidine and a salt thereof, benzalkonium chloride, and at least one preservative selected from the group consisting of polyhexanide and a salt thereof.
Item 4-2. Item 4. The method for suppressing adsorption according to Item 4-1. The brimonidine and / or a salt thereof is brimonidine tartrate.
Item 4-3. Item 4. The adsorption suppression method according to Item 4-1 or 4-2, wherein the concentration of brimonidine and / or a salt thereof in the aqueous solution is 0.05 to 0.2 w / v%.
Item 4-4. Item 2. The item 4-1 to 4-3, wherein the buffer is at least one selected from the group consisting of a boric acid buffer, a phosphate buffer, a Tris buffer, and a citrate buffer. Adsorption suppression method.
Item 4-5. Item 4. The adsorption suppression method according to any one of Items 4-1 to 4-4, wherein the buffer is a boric acid buffer.
Item 4-6. Item 2. 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. Item 2. 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. Item 4. 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. Item 4. The adsorption suppression method according to any one of Items 4-1 to 4-4, wherein the buffer is a citric acid buffer, and the concentration of the citric acid buffer in the aqueous solution is 0.01 to 5 w / v%. ..
Item 4-10. Item 2. 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. Any 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%. The adsorption suppression method according to.
Item 4-12. Item 2. Adsorption 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%. Suppression method.
Item 4-13. Any 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 solution is 0.00001 to 0.1 w / v%. The adsorption suppression method according to.
Item 4-14. Item 4. The adsorption suppression method according to any one of Items 4-1 to 4-13, wherein the aqueous solution does not contain a viscous agent.
Item 4-15. Item 8. The adsorption suppression method according to any one of Items 4-1 to 4-14, wherein the aqueous solution is an eye drop.
Item 4-16. Item 4. The method for suppressing adsorption according to any one of Items 4-1 to 4-15, wherein the material of the filter is polyether sulfone or polyvinylidene fluoride.
Item 4-17. Item 4. 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. Item 4-1 to 4-17, wherein the aqueous liquid agent is an aqueous liquid agent that is passed through a filter in a filtration sterilization step at the time of manufacture, and is provided by being housed in a multi-dose type container not provided with a filter after the filtration sterilization step. The adsorption suppression method according to any one of.
Item 4-19. Item 4. The adsorption suppression method according to any one of Items 4-1 to 4-16, wherein the filter is a filter for a container with a filter.

The present invention also provides a manufacturing method according to the following aspects.
Item 5-1. A step of preparing an aqueous solution containing brimonidine and / or a salt thereof, a buffer, and at least one preservative selected from the group consisting of chlorhexidine and its salt, benzalkonium chloride, and polyhexanide and its salt. In addition, a step of subjecting the aqueous liquid agent obtained in the above step to a filtration sterilization step using a filter,
A method for producing an aqueous liquid preparation, including.
Item 5-2. Item 5. The production method according to Item 5-1. The brimonidine and / or a salt thereof is brimonidine tartrate.
Item 5-3. Item 2. The production method according to Item 5-1 or 5-2, wherein the concentration of brimonidine and / or a salt thereof in the aqueous solution is 0.05 to 0.2 w / v%.
Item 5-4. Item 5. The item 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 citric acid buffer. Manufacturing method.
Item 5-5. Item 8. The production method according to any one of Items 5-1 to 5-4, wherein the buffer is a boric acid buffer.
Item 5-6. Item 2. The production method according to any one of Items 5-1 to 5-5, 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 5-7. Item 8. The production 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 solution is 0.01 to 5 w / v%.
Item 5-8. Item 8. The production 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. Item 5. The item according to any one of Items 5-1 to 5-4, wherein the buffer is a citric acid buffer, and the concentration of the citric acid buffer in the aqueous solution is 0.01 to 5 w / v%. Manufacturing method.
Item 5-10. Item 2. 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. Any 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%. The adsorption suppression method according to.
Item 5-12. Item 2. Adsorption 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%. Suppression method.
Item 5-13. Any 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 solution is 0.00001 to 0.1 w / v%. The adsorption suppression method according to.
Item 5-14. Item 8. The production method according to any one of Items 5-1 to 5-13, wherein the aqueous solution does not contain a thickener.
Item 5-15. Item 8. The production method according to any one of Items 5-1 to 5-14, wherein the aqueous solution is an eye drop.
Item 5-16. Item 8. The production method according to any one of Items 5-1 to 5-15, wherein the material of the filter is polyether sulfone or polyvinylidene fluoride.
Item 5-17. Item 2. The production method according to any one of Items 5-1 to 5-16, wherein the aqueous solution is provided in a multi-dose container not provided with a filter after the filtration sterilization step.

According to the present invention, by adding a buffer and a metal chloride in an aqueous solution containing brimonidine and / or a salt thereof, adsorption of brimonidine and / or a salt thereof to the filter can be suppressed, and after passing through the filter. In the aqueous solution, a decrease in the content of brimonidine and / or a salt thereof can be suppressed. Therefore, in one aspect of the present invention, even if an aqueous solution containing brimonidine and / or a salt thereof is contained in a container with a filter, brimonidine and / or the aqueous solution in the aqueous solution that has passed through the filter and is poured out of the container during use. It is possible to suppress a decrease in the salt content. In another aspect of the present invention, even if the aqueous liquid preparation containing brimonidine and / or a salt thereof is subjected to a sterilization step by filtering during the production, the content of brimonidine and / or a salt thereof in the aqueous liquid preparation after filtration sterilization is reduced. It can be suppressed.

Further, according to the present invention, in an aqueous solution containing brimonidine and / or a salt thereof, it is selected from the group consisting of a buffer and a specific preservative (chlorhexidine and its salt, benzalkonium chloride, and polyhexanide and its salt). By containing at least one of these), the adsorption of brimonidine and / or its salt to the filter can be suppressed, and the decrease in the content of brimonidine and / or its salt can be suppressed in the aqueous solution after passing through the filter. .. Therefore, in one aspect of the present invention, even if the aqueous liquid preparation containing brimonidine and / or a salt thereof is subjected to a sterilization step by filtering during production, the content of brimonidine and / or a salt thereof in the aqueous liquid preparation after filtration sterilization can be reduced. It can be suppressed.

1. 1. Definitions It should be understood that the terms used herein are used in the meaning commonly used in the art unless otherwise noted. Thus, unless otherwise defined, all terminology and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.

In the present specification, the "aqueous solution" is a preparation containing water as a base and exhibiting a liquid state.

As used herein, the term "pharmaceutical product" refers to a product in which an aqueous solution is contained in an arbitrary container.

As used herein, "brimonidine" is a compound known as an adrenergic α2 receptor agonist, and is 5-bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxaline-6-amine. Point to.

As used herein, the term "buffering agent" refers to a compound or mixture that has the effect of alleviating fluctuations in the hydrogen ion concentration (pH) of an aqueous solution.

As used herein, the term "metal chloride" refers to a compound in which a metal ion and a chloride ion are ionically bonded.

As used herein, "chlorhexidine" is a compound known as a preservative, and is 1- [amino- [6- [amino- [amino- (4-chlorophenyl) amino-methylidene] amino-methylidene] aminohexidine. Mino] Methyl] Imino-N- (4-chlorophenyl) -Methanediamine.

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

［一般式（１）中、Ｒ¹及びＲ²は、同一又は異なって、アミノ基又は下記一般式（２）に示される基である。一般式（１）中、ｎは、１〜５００の整数を示す。］

In the present specification, "polyhexanide" is a compound known as a preservative, a compound represented by the following general formula (1), and a guanidine derivative also referred to as polyhexamethylene biguanidine (PHMB).

[In the 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). In the general formula (1), n represents an integer of 1 to 500. ]

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

In the present specification, "substantially free of preservatives" means that the concentration of the preservative is a concentration at which the preservative alone cannot exert the preservative effect, and specifically, only the preservative. In the case of an aqueous solution containing, the aqueous solution is more than the minimum concentration of the preservative that is "conforming" based on the criteria specified in the category "IC" in the 17th revised Japanese Pharmacopoeia Reference Information "Preservation Efficacy Test Method". Refers to less.

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

In the present specification, the "container with a filter" is a container for containing an aqueous liquid agent, and the inside of the container and the outside of the container are separated by a filter, and the aqueous liquid agent inside the container passes through the filter during use. Refers to a container that has a structure that is poured out to the outside. As one aspect of the container with a filter, it has a container body having an opening and a nozzle provided with a flow path for pouring the aqueous liquid agent to the outside of the container, and the nozzle is attached to the opening of the container body. Examples thereof include containers provided with a filter so as to block the flow path of the nozzle (for example, Patent Documents 1 and 2 and the like).

As used herein, the term "multi-dose container" refers to a container filled with a plurality of doses of an aqueous liquid agent and used repeatedly.

As used herein, the term "unit-dose type container" refers to a container filled with a single dose of an aqueous solution and used after one instillation.

As used herein, the term "method for suppressing the adsorption of brimonidine and / or its salt on a filter" refers to brimonidine and / or its salt in an aqueous solution that has passed through a filter by suppressing the adsorption of brimonidine and / or its salt on a filter. / Or refers to a method of suppressing a decrease in the salt content thereof. The effect of suppressing the adsorption of brimonidine and / or its salt on the filter is the drug recovery rate (calculation formula: {filter) 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. The brimonidine content in the aqueous solution after passing / brimonidine content in the aqueous solution before passing through the filter} × 100) was evaluated as an index, and the drug recovery rate of the aqueous solution containing metal chloride (or preservative) was determined by the metal chloride (or preservative). Or, when it is higher than the drug recovery rate of the same aqueous solution as the aqueous solution except that it does not contain a preservative), it can be said that there is an effect of suppressing the adsorption of brimonidine and / or its salt on the filter. In the present specification, "a method for suppressing adsorption of brimonidine and / or a salt thereof to a filter" may be simply referred to as "method for suppressing adsorption".

2. 2. Description of Preferred Embodiments Although description of preferred embodiments will be given below, it should be understood that this embodiment is an example of the present invention and the scope of the present invention is not limited to such preferred embodiments. .. It should be understood that those skilled in the art can also easily make modifications, changes, etc. within the scope of the present invention with reference to the following preferred embodiments. For these embodiments, those skilled in the art may combine any of the embodiments as appropriate.

3. 3. Regarding aqueous liquids contained in containers with pharmaceutical product filters, if the drug is adsorbed on the filter of the container, the content of the drug in the aqueous liquid dispensed from the container will decrease, and the desired effect will not be achieved. Connect. Therefore, the aqueous liquid agent contained in the container with a filter is required to be designed so that the drug is not adsorbed on the filter.

The present inventor conducted various studies on a pharmaceutical product containing an aqueous solution containing brimonidine and / or a salt thereof in a container with a filter. As a result, brimonidine and / or a salt thereof was adsorbed on the filter of the container and poured out from the container. It was found that the content of brimonidine and / or a salt thereof in the aqueous solution was reduced. Therefore, the present inventor conducted a diligent study and found that even if the aqueous solution containing brimonidine and / or a salt thereof, a buffer, and a metal chloride was contained in a container with a filter, brimonidine and / or a salt thereof could be contained in the filter. It has been found that the adsorption of / or its salt can be suppressed, and the decrease in the content of brimonidine and / or its salt in the aqueous solution poured out from the container can be suppressed.

In one embodiment, the present invention provides a pharmaceutical product comprising brimonidine and / or a salt thereof, a buffer, and an aqueous solution containing a metal chloride, which is contained in a container with a filter. Hereinafter, the pharmaceutical product of the present invention will be described in detail.

In the pharmaceutical product of the present invention, the aqueous solution contains brimonidine and / or a salt thereof. The salt of brimonidine is not particularly limited as long as it is pharmaceutically acceptable, and specific examples thereof include organic acid salts such as tartrate and acetate; and inorganic acid salts such as hydrochloride. Further, brimonidine or a salt thereof may be in the form of a solvate such as a hydrate. Among brimonidine and salts thereof, brimonidine tartrate is preferable.

In the aqueous solution used in the present invention, either brimonidine or a salt thereof may be used alone, or these may be used in combination.

In the aqueous solution used in the present invention, the concentration of brimonidine and / or a salt thereof is not particularly limited, and depends on the use of the aqueous solution, the degree of symptoms of the patient to be applied, the amount applied per application, and the like. It may be appropriately set, and examples thereof include 0.05 to 0.2 w / v%, preferably 0.1 to 0.2 w / v%, and particularly preferably 0.1 w / v%. As used herein, the concentration of brimonidine and / or a salt thereof is the concentration converted to brimonidine tartrate.

In the pharmaceutical product of the present invention, the aqueous solution further contains a buffer. The buffer is not particularly limited as long as it is pharmaceutically acceptable, and for example, borate buffer, phosphate buffer, Tris buffer, citric acid buffer, tartaric acid buffer, acetate buffer, amino acid. Buffering agents and the like can be mentioned.

Specific examples of the boric acid buffer include boric acid and / or a salt thereof. The boric acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include orthoboric acid, metaboric acid, and tetraboric acid. Among these boric acids, orthoboric acid and tetraboric acid are preferable. These boric acids may be used alone or in combination of two or more. The salt of boric acid is not particularly limited as long as it is pharmaceutically acceptable, but is an alkali metal salt such as sodium salt and potassium salt; an alkaline earth metal salt such as calcium salt and magnesium salt; an aluminum salt; Examples thereof include organic amine salts such as triethylamine, triethanolamine, morpholin, piperazine and pyrrolidine. Further, boric acid / or a salt thereof may be in the form of a hydrate, such as borax.

As the boric acid buffer, one type may be selected from boric acid and a salt thereof and used alone, or two or more types may be used in combination. Among boric acid and its salts, at least one of boric acid and borax is preferable, and more preferably orthoboric acid and borax, from the viewpoint of further improving the effect of suppressing the adsorption of brimonidine and / or its salt on the filter. At least one of.

In addition, a preferred embodiment of the boric acid buffering agent is a combination of boric acid and borax. By using boric acid and borax in combination in this way, it becomes possible to further improve the effect of suppressing the adsorption of brimonidine and / or a salt thereof on the filter. When boric acid and borax are used in combination, these ratios are not particularly limited, but for example, boric acid is 0 to 100 parts by mass, preferably 20 to 80 parts by mass, and more preferably 20 to 80 parts by mass per 100 parts by mass of boric acid. 40 to 60 parts by mass.

The concentration of the boric acid buffer is usually 0.01 to 10 w / v%, more preferably 0.1 to 5 w / v%, still more preferably 0.1 to 2 w / v%, particularly from the viewpoint of buffering action. Preferably 0.1 to 1 w / v%. In the present specification, the concentration of boric acid buffer is a concentration converted to boric acid.

Specific examples of the phosphoric acid buffer include phosphoric acid and / or a salt thereof. The salt of phosphate is not particularly limited as long as it is pharmaceutically acceptable, and for example, a dialkali metal phosphate of hydrogen phosphate such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; sodium dihydrogen phosphate. , Disodium dihydrogen phosphate alkali metal salt such as potassium dihydrogen phosphate; trisodium phosphate trialkali metal salt such as trisodium phosphate and tripotassium phosphate. The salt of phosphoric acid may be in the form of a solvate such as a hydrate. For example, in the case of disodium hydrogen phosphate, the salt of phosphoric acid may be in the form of dihydrate, sodium dihydrogen phosphate. In some cases, it may be in the form of dihydrate or the like.

As the phosphoric acid buffer, one type may be selected from phosphoric acid and a salt thereof and used alone, or two or more types may be used in combination. Among the phosphates and salts thereof, from the viewpoint of further improving the effect of suppressing the adsorption of brimonidin and / or its salts on the filter, a phosphate is preferable, and a dialkali metal phosphate and disodium phosphate are more preferable. At least one kind of hydrogen alkali metal salt, particularly preferably at least one kind of disodium hydrogen phosphate and sodium dihydrogen phosphate.

Further, as a preferable aspect of the phosphoric acid buffer, a combination of a disodium hydrogen phosphate metal salt and a dihydrogen phosphate metal salt can be mentioned. By using the disodium hydrogen phosphate metal salt and the disodium dihydrogen phosphate metal salt in combination in this way, it is possible to further improve the effect of suppressing the adsorption of brimonidine and / or its salt on the filter. When the hydrogen dihydrogen phosphate metal salt and the dihydrogen phosphate metal salt are used in combination, the ratio thereof is not particularly limited, but for example, diiodium phosphate per 100 parts by mass of the dialkali metal phosphate salt. The hydrogen alkali metal salt is 1 to 120 parts by mass, preferably 5 to 80 parts by mass, and more preferably 10 to 40 parts by mass.

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% from the viewpoint of buffering action. .. In the present specification, the concentration of the phosphoric acid buffer is a concentration converted into phosphoric acid.

Specific examples of the Tris buffer include tromethamole and / or a salt thereof. The salt of tromethamole is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include organic acid salts such as acetate; and organic acid salts such as hydrochloride and sulfonate.

As the trisic acid buffering agent, one type may be selected from tromethamole and a salt thereof and used alone, or two or more types may be used in combination. Among the tromethamole and its salt, tromethamole is preferably mentioned from the viewpoint of further improving the effect of suppressing the adsorption of brimonidine and / or its salt on the filter.

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%. As used herein, the concentration of Tris buffer is the concentration converted to tromethamole.

Specific examples of the citric acid buffer include citric acid and / or a salt thereof. The citric acid salt is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as calcium salt and magnesium salt. Be done. Further, citric acid and a salt thereof may be in the form of a solvate such as a hydrate.

As the citric acid buffering agent, one type may be selected from citric acid and a salt thereof and used alone, or two or more types may be used in combination. Among the citric acid and its salt, citric acid is preferably mentioned from the viewpoint of further improving the effect of suppressing the adsorption of brimonidine and / or its salt on the filter.

The concentration of the citric acid 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% from the viewpoint of buffering action. Can be mentioned. In the present specification, the concentration of the citric acid buffering agent is the concentration converted into citric acid.

Specific examples of the tartaric acid buffer include tartaric acid and / or a salt thereof. The salt of tartrate is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as calcium salt and magnesium salt. .. Further, the salt of tartaric acid may be in the form of a solvate such as hydrate. As the tartaric acid buffering agent, one type may be selected from tartaric acid and a salt thereof and used alone, or two or more types may be used in combination.

Specific examples of the acetic acid buffer include acetic acid and / or a salt thereof. The salt of acetic acid is not particularly limited as long as it is pharmaceutically acceptable, but for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt and the like. Can be mentioned. Further, the salt of acetic acid may be in the form of a solvate such as hydrate. As the acetic acid buffer, one type may be selected from acetic acid and a salt thereof and used alone, or two or more types may be used in combination.

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

These buffering agents may be used alone or in combination of two or more.

Among these buffers, boric acid buffers, phosphate buffers, Tris buffers, citric acid buffers are preferable from the viewpoint of further improving the effect of suppressing the adsorption of brimonidine and / or a salt thereof on the filter. More preferably, a boric acid buffer is used.

In the pharmaceutical product of the present invention, the aqueous solution further contains a metal chloride. The metal chloride is not particularly limited as long as it is pharmaceutically acceptable, but for example, 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 and the like can be mentioned.

One of these metal chlorides may be used alone, or two or more thereof may be used in combination. Among these metal chlorides, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, and more preferably sodium chloride are preferable from the viewpoint of further improving the effect of suppressing the adsorption of brimonidine and / or a salt thereof on the filter. Can be mentioned.

The concentration of the metal chloride in the aqueous solution used in the present invention is usually 0.01 to 5 w / v%. The concentration of metal chloride in the aqueous solution used in the present invention is preferably 0.05 to 2.5 w / v% from the viewpoint of further improving the effect of suppressing the adsorption of brimonidine and / or a salt thereof on the filter. , More preferably 0.1 to 2 w / v%, particularly preferably 0.2 to 1 w / v%, still more preferably 0.4 to 1 w / v%.

In the pharmaceutical product of the present invention, the aqueous solution is contained in a container with a filter to prevent bacteria from invading the aqueous solution during use and storage, so that the aqueous solution does not substantially contain the preservative. Both may have storage stability. In addition, the preservative may have adverse effects such as irritation and cytotoxicity, and such adverse effects can be avoided when the aqueous solution does not substantially contain the preservative. Therefore, a preferred embodiment of the aqueous liquid agent used in the present invention is that it does not substantially contain a preservative.

Specific examples of the preservative include chlorites such as sodium chlorite; quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride; sorbic acid such as sorbic acid and potassium sorbate and salts thereof; Paraoxybenzoic acid esters such as methylparaben and propyl paraoxybenzoate; benzoic acid and salts thereof; chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, chlorobutanol, chlorhexidine, polyhexanide, polyquatrium and the like are applicable.

In the embodiment in which the aqueous solution used in the present invention does not substantially contain a preservative, the permissible concentration of the preservative varies depending on the type of storage and the like, but specifically, 0.00001 w / v. %, Preferably 0.000005w / v% or less, particularly preferably 0.000001w / v% or less, still more preferably 0w / v%.

In addition to the above-mentioned components, the aqueous liquid agent used in the present invention includes, if necessary, an tonicity agent (other than metal chloride), a surfactant, a viscous agent, a chelating agent, a cooling agent, and a stabilizing agent. Additives such as agents and pH adjusters may be contained.

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

The surfactant is not particularly limited as long as it is pharmaceutically acceptable, and for example, tyroxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxy. Nonionic surfactants such as Nol; Amphoteric surfactants such as alkyldiaminoethylglycine, betaine lauryldimethylaminoacetate; alkyl sulfates, N-acyltaurine salts, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl Anionic surfactants such as ether sulfate; cationic surfactants such as alkylpyridinium salt and alkylamine salt can be mentioned. These surfactants may be used alone or in combination of two or more.

The viscous agent is not particularly limited as long as it is pharmaceutically acceptable, and is highly water-soluble, for example, carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, sodium hyaluronate and the like. Polymers: Cellulose such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and the like can be mentioned. These thickeners may be used alone or in combination of two or more.

The chelating agent is not particularly limited as long as it is pharmaceutically acceptable, and for example, edetonic acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphon. Examples thereof include acids, polyphosphoric acid, metaphosphoric acid, hexametaphosphate, phytic acid, thiosulfuric acid, and salts thereof. The form of the salt is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt. These chelating agents may be used alone or in combination of two or more.

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

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

The pH adjuster is not particularly limited as long as it is pharmaceutically acceptable, but for example, acids such as hydrochloric acid, acetic acid, boric acid, aminoethyl sulfonic acid, epsilon-aminocaproic acid; sodium hydroxide, potassium hydroxide , Hosand, triethanolamine, monoethanolamine, sodium hydrogen carbonate, sodium carbonate and other alkalis. These pH adjusters may be used alone or in combination of two or more.

The concentration of these additives may be appropriately set according to the type of additive to be used, the characteristics to be imparted to the aqueous solution, and the like.

Further, the aqueous solution used in the present invention includes, in addition to brimonidine and / or a salt thereof, a pharmacology that exhibits a therapeutic effect on glaucoma and ocular hypertension as necessary within a range that does not interfere with the effect of the present invention. Ingredients may be included.

Examples of such pharmacological components include prostaglandins such as tafluprost, latanoprost, and isopropylunoprost; parasympathomimetic agents such as pilocarpine hydrochloride; anticholineresterase agents such as distigmine bromide; and sympathetic nerves such as dipivefrine hydrochloride. Stimulants; β ₁ blockers such as betaxolol hydrochloride; β blockers such as timolol maleate; α ₁ / β blockers such as nipradirol and levobnorol hydrochloride; α ₁ blockers such as bunazosin hydrochloride. .. These pharmacological components may be used alone or in combination of two or more.

The concentration of these pharmacological components may be appropriately set according to the type of the pharmacological component used, the medicinal effect to be imparted, and the like.

The pH of the aqueous liquid agent used in the present invention is not particularly limited, and examples thereof include pH 6 to 8, preferably 7 to 8, and more preferably pH 7.

The osmotic pressure ratio of the aqueous liquid agent used in the present invention is not particularly limited, and examples thereof include 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 of the 0.9 w / v% sodium chloride aqueous solution to the osmotic pressure, and the osmotic pressure is in accordance with the "osmotic pressure method (osmolal concentration measurement method)" specified in the 17th revised Japanese Pharmacy Law. Be measured.

The formulation form of the aqueous liquid agent used in the present invention is not particularly limited and may be in the form of an aqueous solution, an emulsion, or the like, but an aqueous solution is preferable.

The aqueous solution used in the present invention can be used as an ophthalmic preparation such as an eye drop or an eye wash. 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 is therefore provided as an eye drop and is suitably used for the treatment of glaucoma or ocular hypertension. it can.

The aqueous solution used in the present invention may be produced according to a known preparation method according to its use, and can be produced, for example, by using the method described in the 17th revised Japanese Pharmacopoeia General Regulations for Formulation. ..

In the pharmaceutical product of the present invention, a container with a filter is used as a container for containing the aqueous solution. The structure of the container with a filter is known (Patent Documents 1 and 2, etc.), and in the present invention, a known container with a filter can be used. The container with a filter may be an eye drop container, an eye wash container, or the like, depending on the use of the aqueous liquid agent.

The material of the filter in the container with a filter used in the present invention is not particularly limited, and examples thereof include polyether sulfone, polyvinylidene fluoride, polycarbonate, polytetrafluoroethylene, cellulose mixed ester, nylon, and polyamide. Be done. Among these materials, polyether sulfone, polyvinylidene fluoride, and more preferably polyether sulfone are preferable from the viewpoint of further improving the effect of suppressing the adsorption of brimonidine and / or a salt thereof on the filter.

The container with a filter used in the present invention is preferably a multi-dose type container in view of having a function of preventing the invasion of bacteria by the filter.

The pharmaceutical product of the present invention is produced by preparing the aqueous solution, subjecting it to sterilization such as filtration sterilization, and then filling the container with the filter.

One aspect of using a container with a filter made of polyether sulfone in the pharmaceutical product of the present invention is a filter made of polyether sulfone (for example, STERIVEX-GP 0.22 μm / Merck Millipore (pore diameter: 0.22 μm, height). : 67 mm, diameter: 10 cm ² , catalog number: SVGP01050)) The drug obtained by dividing the brimonidine content in the aqueous solution after passing through (the first 0.6 g that passed through the filter) by the brimonidine content in the aqueous solution before passing through the filter. The recovery rate is 95% or more. Further, as one aspect of using a container with a filter made of polyvinylidene fluoride in the pharmaceutical product of the present invention, a filter made of polyvinylidene fluoride (for example, STERIVEX-GV 0.22 μm / Merck Millipore (pore diameter: 0.22 μm,). Height: 67 mm, Diameter: 10 cm ² , Catalog number: SVGV010RS)) Obtained by dividing the brimonidine content in the aqueous solution (first 1.0 g passed through the filter) after passing by the brimonidine content in the aqueous solution before passing through the filter. The drug recovery rate is 90% or more.

4. Adsorption suppression method (1)
As described above, in the prior art, when an aqueous solution containing brimonidine and / or a salt thereof is contained in a container with a filter, there is a problem that brimonidine and / or a salt thereof is adsorbed on the filter of the container. The point also occurs in the filtration sterilization step using a filter in the production of an aqueous solution containing brimonidine and / or a salt thereof. That is, there is a problem that brimonidine and / or its salt is adsorbed on the filter when an aqueous solution containing brimonidine and / or its salt is housed in a container with a filter and used, or when a filtration sterilization step using a filter is performed. is there.

On the other hand, by adding a buffer and a metal chloride to the aqueous solution together with brimonidine and / or its salt, the adsorption of brimonidine and / or its salt to the filter is suppressed even if it is passed through the filter. It is possible to suppress a decrease in the content of brimonidine and / or a salt thereof in the aqueous solution after passing through the filter.

Therefore, in one embodiment, the present invention presents the adsorption of brimonidine and / or a salt thereof to a filter, which comprises brimonidine and / or a salt thereof, a buffer, and a metal chloride in an aqueous solution passing through the filter. Provide a suppression method.

The types and concentrations of brimonidine and / or salts thereof, buffers, and metal chlorides used in the adsorption suppression method of the present invention are as described in the column of "3. Pharmaceutical products" above. In addition, in the adsorption suppression method of the present invention, the types of other components that can be blended in the aqueous solution, the pH of the aqueous solution, the osmotic pressure ratio, the formulation form, etc. are also as described in the column of "3. Pharmaceutical products" above. is there.

The filter used in the present invention may be a filter in a container with a filter, or may be a filter used in a filtration sterilization step. That is, the aqueous liquid agent that passes through the filter may be an aqueous liquid agent that is contained in a container with a filter and is poured out of the container by passing through the filter of the container at the time of use, or is sterilized by filtration during the production of the aqueous liquid agent. It may be an aqueous solution that is passed through a filter in the process. The type of container with filter, the material of the filter, etc. are as described in the column of "3. Pharmaceutical products" above. The material of the filter used in the filtration sterilization step at the time of manufacture is the same as the material of the filter in the container with a filter described in the column of "3. Pharmaceutical products".

In the adsorption suppression method of the present invention, when the aqueous liquid agent to be passed through the filter is contained in a container with a filter, the aqueous liquid agent does not necessarily have to have a preservative effect, and thus substantially contains the preservative. It is preferable that there is no such thing. Further, in the adsorption suppression method of the present invention, even when the aqueous liquid agent that passes through the filter is an aqueous liquid agent that passes through the filter in the filtration sterilization step and is provided in a unit dose type container after the filtration sterilization step. Since the aqueous solution does not necessarily require a preservative effect, it is preferable that the aqueous solution contains substantially no preservative.

On the other hand, in the adsorption suppression method of the present invention, the aqueous liquid agent that passes through the filter is an aqueous liquid agent that passes through the filter in the filtration sterilization step, and is provided by being housed in a multi-dose type container that does not have a filter after the filtration sterilization step. In this case, it is preferable that the aqueous solution contains a preservative so as to have a desired preservative effect. The types of preservatives are as described in the column of "3. Pharmaceutical products" above. When the aqueous solution contains a preservative, the concentration of the preservative in the aqueous solution may be appropriately set within a range that can provide a desired preservative effect. For example, 0.00001 to 0.01 w /. V%, preferably 0.00005 to 0.01 w / v%, more preferably 0.001 to 0.01 w / v%.

5. Manufacturing method of aqueous liquid agent (1)
As described above, when a filtration sterilization step using a filter is performed during the production of an aqueous solution containing brimonidine and / or a salt thereof, brimonidine and / or its salt is adsorbed on the filter, and the brimonidine and / or its salt in the aqueous solution that has passed through the filter / Or there is a problem that the content of the salt thereof decreases.

On the other hand, by subjecting an aqueous solution containing brimonidine and / or a salt thereof, a buffer, and a metal chloride to a filtration sterilization step using a filter, adsorption of brimonidine and / or a salt thereof to the filter. Can be suppressed, and a decrease in the content of brimonidine and / or a salt thereof in the aqueous liquid preparation after filtration sterilization can be suppressed.

Therefore, in one embodiment, the present invention uses a filter for preparing an aqueous solution containing brimonidine and / or a salt thereof, a buffer, and a metal chloride, and an aqueous solution obtained in the above step. Provided is a method for producing an aqueous solution, which comprises a step of subjecting to a filtration sterilization step.

In the production method of the present invention, the types and concentrations of brimonidine and / or salts thereof, buffers, and metal chlorides are as described in the column of "3. Pharmaceutical products" above. Further, in the production method of the present invention, the types of other components that can be blended in the aqueous solution, the pH of the aqueous solution, the osmotic pressure ratio, the formulation form, etc. are also described in the column of "3. Pharmaceutical products". .. Further, 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 container with a filter described in the column of "3. Pharmaceutical products".

The aqueous liquid agent obtained by the production method of the present invention may be contained in a container with a filter and provided, or may be contained in a multi-dose container or a unit-dose container without a filter and provided.

When the aqueous solution obtained by the production method of the present invention is stored in a container with a filter or a unit dose type container and provided, the aqueous solution itself does not necessarily need to have a preservation effect, and thus is preserved. It is preferable that the agent is substantially free.

On the other hand, when the aqueous solution obtained by the production method of the present invention is stored in a multi-dose container not provided with a filter and provided, the aqueous solution can have a desired storage effect. , Preservatives are preferably included. The type of preservative is as described in the column of "3. Pharmaceutical products", and the concentration of the preservative in the aqueous solution is described in the column of "4. Adsorption suppression method (1)". It is a street.

6. Adsorption suppression method (2)
As described above, brimonidine and / or its salt is adsorbed on the filter when an aqueous solution containing brimonidine and / or its salt is subjected to a filtration sterilization step using a filter or when it is housed in a container with a filter and used. There are challenges.

On the other hand, in an aqueous solution, at least one selected from the group consisting of a buffer and a specific preservative (chlorhexidine and its salt, benzalkonium chloride, and polyhexanide and its salt) together with brimonidine and / or a salt thereof. By containing (seed), the adsorption of brimonidine and / or its salt to the filter can be suppressed even if it is passed through the filter, and the content of brimonidine and / or its salt in the aqueous solution after passing through the filter can be reduced. It becomes possible to suppress.

Therefore, in one embodiment, the present invention comprises a group consisting of brimonidine and / or a salt thereof, a buffer, chlorhexidine and a salt thereof, benzalkonium chloride, and polyhexanide and a salt thereof in an aqueous liquid preparation passing through a filter. Provided is a method for suppressing adsorption of brimonidine and / or a salt thereof to a filter, which comprises at least one selected.

The aqueous solution used in the present invention includes brimonidine and / or a salt thereof. The type and concentration of brimonidine and / or a salt thereof are the same as in the case of "3. Pharmaceutical product".

A buffering agent is added to the aqueous solution used in the present invention. The type and concentration of the buffering agent are the same as in the case of "3. Pharmaceutical product" described above.

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.

The salt of chlorhexidine used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, but specifically, an inorganic acid salt such as hydrochloride; an organic acid such as acetate or gluconate. Examples include salt. Further, chlorhexidine or a salt thereof may be in the form of a solvate such as a hydrate. Among chlorhexidine and salts thereof, a salt of chlorhexidine is preferable, and chlorhexidine gluconate is more preferable.

Specific examples of the polyhexanide used in the present invention include compounds represented by the following general formula (1).

In the 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).

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.

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 the inorganic acid salt include hydrochloric acid, hydrogen bromide, sulfuric acid, boric acid and the like. Specific examples of the organic acid salt include acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid, and citric acid.

Among the polyhexanide and salts thereof, a salt of polyhexanide is preferable, an inorganic acid salt of polyhexanide is more preferable, and polyhexanide hydrochloride is particularly preferable.

In the adsorption suppression 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. You may. Among these, from the viewpoint of further improving the effect of suppressing the adsorption of brimonidine and / or its salt on the filter, chlorhexidine salt, benzalkonium chloride, polyhexanide salt, and more preferably chlorhexidine salt, polyhexanide are preferable. Salt is mentioned.

When chlorhexidine and / or a salt thereof is used, the concentration of chlorhexidine and / or a salt thereof in the aqueous solution is, for example, 0.001 to 0.01 w / v%, preferably 0.003 to 0.01 w / v. %, More preferably 0.005 to 0.01 w / v%. As used herein, the concentration of chlorhexidine and / or a salt thereof is the concentration converted to chlorhexidine gluconate.

When benzalkonium chloride is used, the concentration of benzalkonium chloride in the aqueous solution is, for example, 0.001 to 0.01 w / v%, preferably 0.003 to 0.01 w / v%, more preferably 0.003 to 0.01 w / v%. Is 0.005 to 0.01 w / v%.

When polyhexanide and / or a salt thereof is used, the concentration of polyhexanide and / or a salt thereof in the aqueous solution is, for example, 0.00001 to 0.01 w / v%, preferably 0.00005 to 0.01 w / v. %, More preferably 0.001 to 0.01 w / v%. In the present specification, the concentration of polyhexanide and / or a salt thereof is the concentration converted to polyhexanide hydrochloride.

The aqueous liquid agent 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" above.

In the aqueous liquid preparation used in the present invention, the other components that can be blended are the same as in the case of "3. Pharmaceutical product", but in one embodiment of the aqueous liquid preparation used in the present invention, it is viscous. The agent may be less than 0.05 w / v%, but in one preferred embodiment, the effect of suppressing the adsorption of brimonidine, the stability of brimonidine (the effect of suppressing the decrease in brimonidine content in the aqueous solution), or the effect of the aqueous solution. From the viewpoint of filterability, it is mentioned that the viscous agent is not contained. The types of thickeners are as described in the column of "3. Pharmaceutical products" above.

In the aqueous liquid preparation used in the present invention, the pH, osmotic pressure ratio, formulation form, etc. of the aqueous liquid preparation are the same as in the case of "3. Pharmaceutical product".

The filter used in the present invention may be a filter used in a filtration sterilization step, or may be a filter in a container with a filter. That is, the aqueous liquid agent that passes through the filter may be an aqueous liquid agent that passes through the filter in the filtration sterilization step during the production of the aqueous liquid agent, or is contained in a container with a filter and passed through the filter of the container at the time of use. It may be an aqueous liquid agent that is poured out of the container. The material of the filter used in the filtration sterilization step at the time of manufacture is the same as the material of the filter in the container with a filter described in the column of "3. Pharmaceutical products". The types of containers with filters, the materials of filters, etc. are as described in the column of "3. Pharmaceutical products" above.

In the adsorption suppression method of the present invention, it is desirable that the aqueous liquid agent to be used contains a specific preservative (chlorhexidine and a salt thereof, benzalkonium chloride, and at least one selected from the group consisting of polyhexanide and a salt thereof). As a preferred form of the aqueous liquid agent used in the present invention, it is an aqueous liquid agent that passes through a filter in the filtration sterilization step at the time of manufacture, and does not have a filter after the filtration sterilization step. Examples include those provided in a multi-dose type container.

7. Manufacturing method of aqueous liquid (2)
As described above, when a filtration sterilization step using a filter is performed during the production of an aqueous solution containing brimonidine and / or a salt thereof, brimonidine and / or its salt is adsorbed on the filter, and the brimonidine and / or its salt in the aqueous solution that has passed through the filter / Or there is a problem that the content of the salt thereof decreases.

In contrast, brimonidin and / or a salt thereof, a buffer, and a specific preservative (at least one selected from the group consisting of chlorhexidine and its salt, benzalkonium chloride, and polyhexanide and its salt). By subjecting the contained aqueous solution to a filtration sterilization step using a filter, the adsorption of brimonidine and / or its salt on the filter can be suppressed, and the content of brimonidine and / or its salt in the aqueous solution after filtration sterilization can be reduced. Can be suppressed.

Therefore, in one embodiment, the present invention comprises brimonidine and / or a salt thereof, a buffer, chlorhexidine and a salt thereof, benzalkonium chloride, and at least one selected from the group consisting of polyhexanide and a salt thereof. Provided is a method for producing an aqueous solution, which comprises a step of preparing an aqueous solution containing the aqueous solution, and a step of subjecting the aqueous solution obtained in the step to a filtration sterilization step using a filter.

The type and concentration of brimonidine and / or a salt thereof used in the production method of the present invention and a buffering agent are as described in the column of "3. Pharmaceutical products" above.

Regarding the type and concentration of brimonidine and / or a salt thereof, a buffer, chlorhexidine and a salt thereof, benzalkonium chloride, and polyhexanide and a salt thereof used in the production method of the present invention, refer to "6. Adsorption". It is as described in the column of "Suppression method (2)".

In the production 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" above.

Further, in the production method of the present invention, the types of other components that can be blended in the aqueous solution, the pH of the aqueous solution, the osmotic pressure ratio, the formulation form, etc. are also described in the column of "3. Pharmaceutical products". .. Further, 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 container with a filter described in the column of "3. Pharmaceutical products".

The aqueous liquid agent obtained by the production method of the present invention may be contained in a container with a filter and provided, or may be contained in a multi-dose container or a unit-dose container without a filter and provided. The aqueous solution obtained by the production method of the present invention contains a specific preservative (chlorhexidine and a salt thereof, benzalkonium chloride, and at least one selected from the group consisting of polyhexanide and a salt thereof). Since it can have a desired storage effect, it is preferable to provide it in a multi-dose container without a filter.

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto. In the following test examples, orthoboric acid was used as the boric acid.

Test Example 1: Evaluation of suppression of drug adsorption on the filter (examination of the effect of buffering agent and metal chloride)
An aqueous solution having the composition shown in Table 1 was prepared. The prepared aqueous solution was filtered using a filter (polyether sulfone membrane; PES membrane) having a pore size of 0.22 μm, and 0.6 g of the first filtrate that passed through the filter was recovered. Separately, the prepared aqueous solution was filtered using a filter (polyvinylidene fluoride membrane; PVDF membrane) having a pore size of 0.22 μm, and 1.0 g of the first filtrate that passed through the filter was recovered. The PES film is STERIVEX-GP 0.22 μm / Merck Millipore (pore diameter: 0.22 μm, height: 67 mm, diameter: 10 cm ² , catalog number: SVGP01050), and the PVDF film is STERIVEX-GV 0.22 μm. / Merck Millipore (pore diameter: 0.22 μm, height: 67 mm, diameter: 10 cm ² , catalog number: SVGV010RS) was used.

The brimonidine content in the aqueous liquid agent before filtration and the aqueous liquid agent (filter solution) after filtration was measured by liquid chromatography (High Performance Liquid Chromatography manufactured by Shimadzu Corporation) under the following conditions.
(Measurement condition)
Detector : Ultraviolet absorptiometer (measurement wavelength: 230 nm)
Column : Symmetry C18, 4.6 mm I. D. × 150 mm, 3.5 μm, manufactured by Waters
Column temperature : Constant temperature around 40 ° C
Mobile phase A : 4.3 mM aqueous phosphoric acid solution / methanol / acetonitrile (volume ratio: 84/8/8) mixed solution
Mobile phase B : A mixed solution of 4.3 mM aqueous phosphoric acid solution / methanol / acetonitrile (volume ratio: 40/30/30)
Liquid transfer of mobile phase: The mixing ratio of mobile phase A and mobile phase B was changed as follows to control the linear concentration gradient.
Time after injection (minutes) Mobile phase A (vol%) Mobile phase B (vol%)
0.0 to 20.0 100 0
20.0 ~ 25.0 100 → 0 0 → 100
25.0 ~ 30.0 0 100
30.0 to 30.1 0 → 100 100 → 0
30.1 to 60.0 100 0
Flow rate : 1.0 mL / min
Temperature inside the autosampler: 5 ° C

From the brimonidine content in the aqueous liquid agent before passing through the filter and the aqueous liquid agent after passing through the filter, the drug recovery rate after passing through the filter was calculated according to the following formula.

The results are shown in Table 1. When the aqueous solution containing brimonidine tartrate does not contain a buffer and metal chloride (Comparative Example 1), the drug recovery rate after passing through the filter by the PES membrane is 94%, and the drug recovery rate after filtering by the PES membrane is 6%. The brimonidine tartrate was adsorbed. Further, even in an aqueous solution containing brimonidine tartrate and a buffer (boric acid buffer, phosphate buffer, tromethamole, or citrate buffer), when metal chloride is not contained (Comparative Example 2, Comparative Examples 6 to 8). ), The drug recovery rate after passing through the filter by the PES membrane was equivalent to that of Comparative Example 1. Further, an aqueous solution containing sodium edetate or a water-soluble polymer (carboxymethyl cellulose or polyvinylpyrrolidone) together with brimonidine tartaric acid and boric acid buffer does not contain metal chloride (Comparative Examples 3 to 5), a PES film. The drug recovery rate after passing through the filter was equivalent to that of Comparative Example 1.

In contrast, it contains metal chloride (sodium chloride, potassium chloride, calcium chloride, or magnesium chloride) along with brimonidine tartrate and buffers (borate buffer, phosphate buffer, tromethamole, or citrate buffer). In the aqueous solution, the drug recovery rate after passing through the filter by the PES film was significantly increased as compared with Comparative Example 1, and it was found that the metal chloride has a drug adsorption suppressing effect. Further, as is clear from the comparison 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 buffering agents, boric acid When an acid buffer was used, the effect of improving the drug recovery rate after passing through the filter by the PES membrane was the highest.

Further, when the PVDF film was used, the same tendency as that of the PES film was observed.

Test Example 2: Evaluation of suppression of drug adsorption on the filter (examination of the effects of surfactants and preservatives)
An aqueous solution having the composition shown in Table 2 was prepared, and the drug recovery rate after passing through the filter was determined by the same method as in Test Example 1.

The results are shown in Table 2. In an aqueous solution (Comparative Examples 9 to 13) containing a surfactant (polysorbate 80, POE (60) hardened castor oil, tyroxapol, poloxamer 407 or polyethylene glycol monostearate (40EO)) together with brimonidine tartrate and borate buffer. The drug recovery rate after passing through the filter by the PES membrane and the PVDF membrane was equal to or less than that of the aqueous liquid preparation containing no surfactant (Comparative Examples 1 and 2). Further, even in an aqueous solution containing chlorobutanol or sorbic acid used as a preservative together with brimonidine tartaric acid and boric acid buffer (Comparative Examples 14 and 15), the drug recovery rate after passing through the filter by the PES membrane and the PVDF membrane is high. It was equivalent to Comparative Examples 1 and 2. On the other hand, in the aqueous solution containing benzalkonium chloride, chlorhexidine gluconate or polyhexanide hydrochloride together with brimonidine tartaric acid and boric acid buffer (Examples 13 to 15), the drug after passing through the filter by the PES membrane and the PVDF membrane. The recovery rate was improved as compared with Comparative Examples 1 and 2, and the effect of suppressing drug adsorption on the PES film and PVDF film was confirmed.

Claims (7)

Includes brimonidine and / or salts thereof, buffers, and at least one metal chloride selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride, substantially free of preservatives. A pharmaceutical product in which an aqueous solution containing only brimonidine and / or a salt thereof as an active ingredient is contained in a container with a filter. Wherein the metal chloride is sodium chloride, pharmaceutical product of claim 1. The pharmaceutical product according to claim 1 or 2 , wherein the buffer is at least one selected from the group consisting of a boric acid buffer, a phosphate buffer, a Tris buffer, and a citrate buffer. The pharmaceutical product according to any one of claims 1 to 3 , wherein the buffering agent is a boric acid buffering agent. The pharmaceutical product according to any one of claims 1 to 4 , wherein the aqueous solution is an eye drop. The pharmaceutical product according to any one of claims 1 to 5 , wherein the material of the filter is polyether sulfone or polyvinylidene fluoride. The pharmaceutical product according to any one of claims 1 to 6 , which is used for the treatment of glaucoma.