JP7269425B2 - aqueous solution - Google Patents

Description

TECHNICAL FIELD The present invention relates to an aqueous liquid preparation containing brimonidine and/or a salt thereof and having suppressed adsorption of brimonidine and/or a salt thereof on a filter.

Preservatives such as benzalkonium chloride and methylparaben are usually added to aqueous solutions such as eye drops and eye washes to prevent the growth of microorganisms. Such aqueous solutions are usually subjected to a sterilization step by filtering during production.

While preservatives can prevent the growth of bacteria, they have been reported to exhibit irritation and cytotoxicity (see Non-Patent Document 1). Therefore, in order to avoid the adverse effects of preservatives, preservative-free aqueous solutions have been developed. A multi-dose container that contains a preservative-free aqueous solution has a structure that aseptically separates the inside and outside of the container to prevent bacteria from entering the container during use, and a filter is attached to the nozzle. (filter-equipped container) is often used (see Patent Documents 1 and 2).

On the other hand, brimonidine and its salts are known as adrenergic 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 a laxative effect and has traditionally been used to treat glaucoma and ocular hypertension.

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

Japanese Patent Application Laid-Open No. 2004-51170 JP-A-2002-80055

An object of the present invention is to provide formulation techniques for aqueous solutions containing brimonidine and/or salts thereof.

The present inventors have found that an aqueous solution containing brimonidine and/or a salt thereof, a buffer, and a metal chloride can suppress adsorption of brimonidine and/or a salt thereof to the filter even when passed through a filter. The present inventors have found that the reduction in the content of brimonidine and/or a salt thereof in the aqueous liquid preparation can be suppressed even when the preparation is stored in a container with a container or subjected to a sterilization step by filtering during production.

Furthermore, the present inventors have found that brimonidine and/or its salts, buffering agents, and specific preservatives (at least one selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts) can suppress the adsorption of brimonidine and/or a salt thereof to the filter even if it is passed through a filter, and even if it is subjected to a sterilization process by filtering during production, brimonidine and/or its salt in the aqueous solution can be suppressed. It was found that the decrease in salt content can be suppressed.

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

That is, the present invention provides pharmaceutical products 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. The pharmaceutical product according to Item 1-1, wherein the brimonidine and/or its salt is brimonidine tartrate.
Item 1-3. The pharmaceutical product according to item 1-1 or 1-2, wherein the concentration of said brimonidine and/or its salt is 0.05 to 0.2 w/v%.
Item 1-4. The buffer 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. pharmaceutical products.
Item 1-5. The pharmaceutical product according to any one of Items 1-1 to 1-4, wherein the buffer is a borate buffer.
Item 1-6. The pharmaceutical product according to any one of Items 1-1 to 1-5, wherein the buffer is a borate buffer, and the borate buffer has a concentration of 0.01 to 10 w/v%.
Item 1-7. The pharmaceutical product according to any one of Items 1-1 to 1-4, wherein the buffer is a phosphate buffer, and the concentration of the phosphate buffer is 0.01 to 5 w/v%.
Item 1-8. The pharmaceutical product according to any one of Items 1-1 to 1-4, wherein the buffer is a trisate buffer, and the concentration of the trisate buffer is 0.01 to 5 w/v%.
Item 1-9. The pharmaceutical product according to any one of Items 1-1 to 1-4, wherein the buffer is a citrate buffer, 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. The pharmaceutical product according to any one of Items 1-1 to 1-10, wherein the metal chloride is sodium chloride.
Item 1-12. The pharmaceutical product according to any one of Items 1-1 to 1-11, wherein the concentration of said metal chloride is 0.01 to 5 w/v%.
Item 1-13. The pharmaceutical product according to any one of Items 1-1 to 1-12, wherein said aqueous solution is substantially free of preservatives.
Item 1-14. The pharmaceutical product according to any one of Items 1-1 to 1-13, wherein the aqueous solution is eye drops.
Item 1-15. The pharmaceutical product according to any one of Items 1-1 to 1-14, wherein the filter material 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 filter is a multi-dose container.
Item 1-17. A 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 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,
Brimonidine and/or a salt thereof is brimonidine tartrate,
The concentration of brimonidine and/or its salt is 0.05 to 0.2 w/v%,
the buffering agent is a borate buffer;
the aqueous solution is an eye drop,
The filter material 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 filter is a multi-dose container. product.
Item 1-19. 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,
Brimonidine and/or a salt thereof is brimonidine tartrate,
The concentration of brimonidine and/or its salt is 0.05 to 0.2 w/v%,
the buffering agent is a borate buffer;
the aqueous solution is an eye drop,
The material of the filter is polyvinylidene fluoride,
A drug, wherein 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 filter is a multi-dose container. product.

In addition, the present invention provides a method for suppressing adsorption according to the following aspects.
Item 2-1. A method for suppressing adsorption of brimonidine and/or a salt thereof to a filter, comprising adding brimonidine and/or a salt thereof, a buffer, and a metal chloride to an aqueous solution to be passed through the filter.
Item 2-2. The adsorption suppression method according to Item 2-1, wherein the brimonidine and/or its salt is brimonidine tartrate.
Item 2-3. 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. The buffer according to any one of Items 2-1 to 2-3, wherein the buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, Tris buffer, and citrate buffer. adsorption suppression method.
Item 2-5. The adsorption suppression method according to any one of Items 2-1 to 2-4, wherein the buffer is a borate buffer.
Item 2-6. The adsorption suppression method according to any one of Items 2-1 to 2-5, wherein the buffer is a borate buffer, and the concentration of the borate buffer in the aqueous 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 trisate buffer, and the concentration of the trisate buffer in the aqueous solution is 0.01 to 5 w/v%. .
Item 2-9. The adsorption suppression method according to any one of Items 2-1 to 2-4, wherein the buffer is a citrate buffer, and the concentration of the citrate buffer in the aqueous solution is 0.01 to 5 w/v%. .
Item 2-10. The adsorption suppression method according to any one of Items 2-1 to 2-9, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
Item 2-11. The adsorption suppression method according to any one of Items 2-1 to 2-10, wherein the metal chloride is sodium chloride.
Item 2-12. The method for inhibiting adsorption according to any one of Items 2-1 to 2-11, wherein the aqueous solution has a metal chloride concentration of 0.01 to 5 w/v%.
Item 2-13. The method for inhibiting adsorption according to any one of Items 2-1 to 2-12, wherein the aqueous liquid preparation does not substantially contain a preservative.
Item 2-14. The method for inhibiting adsorption according to any one of Items 2-1 to 2-13, wherein the aqueous solution is eye drops.
Item 2-15. The adsorption suppression method according to any one of Items 2-1 to 2-14, wherein the material of the filter is polyethersulfone or polyvinylidene fluoride.
Item 2-16. The method for inhibiting adsorption 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. 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.

Moreover, this invention provides the manufacturing method of the aspect hung up below.
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 solution, comprising:
Item 3-2. Item 3-1, wherein the brimonidine and/or salt thereof is brimonidine tartrate.
Item 3-3. 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. The buffer according to any one of Items 3-1 to 3-3, wherein the buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, Tris buffer, and citrate buffer. manufacturing method.
Item 3-5. The production method according to any one of Items 3-1 to 3-4, wherein the buffer is a borate buffer.
Item 3-6. The production method according to any one of Items 3-1 to 3-5, wherein the buffer is a borate buffer, and the concentration of the borate buffer in the aqueous solution is 0.01 to 10 w/v%.
Item 3-7. 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. The production method according to any one of Items 3-1 to 3-4, wherein the buffer is a trisate buffer, and the concentration of the trisate buffer in the aqueous solution is 0.01 to 5 w/v%.
Item 3-9. Item 3-1 to 3-4, 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%. manufacturing method.
Item 3-10. The production method according to any one of Items 3-1 to 3-9, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
Item 3-11. The production method according to any one of Items 3-1 to 3-10, wherein the metal chloride is sodium chloride.
Item 3-12. The production method according to any one of Items 3-1 to 3-11, wherein the aqueous solution has a metal chloride concentration of 0.01 to 5 w/v%.
Item 3-13. The production method according to any one of Items 3-1 to 3-12, wherein the aqueous liquid preparation is substantially free of preservatives.
Item 3-14. The manufacturing method according to any one of Items 3-1 to 3-13, wherein the aqueous solution is an eye drop.
Item 3-15. The manufacturing method according to any one of Items 3-1 to 3-14, wherein the filter material is polyethersulfone or polyvinylidene fluoride.

In addition, the present invention provides a method for suppressing adsorption according to the following aspects.
Item 4-1. For the aqueous liquid agent to pass through the filter,
brimonidine and/or a salt thereof;
a buffer;
A method for suppressing adsorption of brimonidine and/or its salts to a filter, comprising adding at least one preservative selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts.
Item 4-2. The adsorption suppression method according to Item 4-1, wherein the brimonidine and/or its salt is brimonidine tartrate.
Item 4-3. 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. Any one of Items 4-1 to 4-3, wherein the buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, Tris buffer, and citrate buffer. adsorption suppression method.
Item 4-5. The adsorption suppression method according to any one of Items 4-1 to 4-4, wherein the buffer is a borate buffer.
Item 4-6. The adsorption suppression method according to any one of Items 4-1 to 4-5, wherein the buffer is a borate buffer, and the concentration of the borate buffer in the aqueous 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 trisate buffer, and the concentration of the trisate 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 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 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%. The adsorption suppression method described in .
Item 4-12. The 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 one of Items 4-1 to 4-10, wherein the preservative is polyhexanide and/or a salt thereof, and the concentration of polyhexanide and/or a salt thereof in the aqueous solution is 0.00001 to 0.1 w/v%. The adsorption suppression method described in .
Item 4-14. The adsorption suppression method according to any one of Items 4-1 to 4-13, wherein the aqueous liquid agent does not contain a thickening agent.
Item 4-15. The method for inhibiting adsorption according to any one of Items 4-1 to 4-14, wherein the aqueous solution is eye drops.
Item 4-16. The adsorption suppression method according to any one of Items 4-1 to 4-15, wherein the filter material is polyethersulfone or polyvinylidene fluoride.
Item 4-17. The adsorption suppression method according to any one of Items 4-1 to 4-16, wherein the filter is a filter used in a filtration sterilization step.
Item 4-18. Sections 4-1 to 4-17, wherein the aqueous liquid preparation is an aqueous liquid preparation that is passed through a filter in the sterilization step during manufacture, and is provided in a multi-dose container that does not have a filter after the sterilization step. The method for suppressing adsorption according to any one of the above.
Item 4-19. The method for inhibiting adsorption according to any one of Items 4-1 to 4-16, wherein the filter is a filter for a container with a filter.

Moreover, this invention provides the manufacturing method of the aspect hung up below.
Item 5-1. preparing an aqueous solution comprising brimonidine and/or salts thereof, a buffering agent, and at least one preservative selected from the group consisting of chlorhexidine and salts thereof, benzalkonium chloride, and polyhexanide and salts thereof; 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 solution, comprising:
Item 5-2. The production method according to Item 5-1, wherein the brimonidine and/or salt thereof is brimonidine tartrate.
Item 5-3. 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. According to any one of Items 5-1 to 5-3, wherein the buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, Tris buffer, and citrate buffer. manufacturing method.
Item 5-5. The production method according to any one of Items 5-1 to 5-4, wherein the buffer is a borate buffer.
Item 5-6. The production method according to any one of Items 5-1 to 5-5, wherein the buffer is a borate buffer, and the concentration of the borate buffer in the aqueous solution is 0.01 to 10 w/v%.
Item 5-7. 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. The production method according to any one of Items 5-1 to 5-4, wherein the buffer is a trisate buffer, and the concentration of the trisate buffer in the aqueous solution is 0.01 to 5 w/v%.
Item 5-9. Item 5-1 to 5-4, 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%. manufacturing method.
Item 5-10. The adsorption suppression method according to any one of Items 5-1 to 5-9, wherein the preservative is at least one selected from the group consisting of chlorhexidine gluconate, benzalkonium chloride, and polyhexanide hydrochloride.
Item 5-11. 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%. The adsorption suppression method described in .
Item 5-12. The 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 one of Items 5-1 to 5-10, wherein the preservative is polyhexanide and/or a salt thereof, and the concentration of polyhexanide and/or a salt thereof in the aqueous solution is 0.00001 to 0.1 w/v%. The adsorption suppression method described in .
Item 5-14. The production method according to any one of Items 5-1 to 5-13, wherein the aqueous liquid formulation does not contain a thickening agent.
Item 5-15. 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. The manufacturing method according to any one of Items 5-1 to 5-15, wherein the filter material is polyethersulfone or polyvinylidene fluoride.
Item 5-17. The production method according to any one of Items 5-1 to 5-16, wherein the aqueous liquid preparation is provided in a filter-free multi-dose container after the step of filter sterilization.

According to the present invention, an aqueous liquid preparation containing brimonidine and/or a salt thereof contains a buffer and a metal chloride, thereby suppressing adsorption of brimonidine and/or a salt thereof to the filter. Aqueous solution WHEREIN: The fall of the content of brimonidine and/or its salt can be suppressed. Therefore, in one aspect of the present invention, even if an aqueous solution containing brimonidine and / or a salt thereof is stored in a container with a filter, brimonidine and / or A decrease in the salt content can be suppressed. In another aspect of the present invention, even if an aqueous solution containing brimonidine and/or a salt thereof is subjected to a sterilization step by filtration during the production of the aqueous solution, the content of brimonidine and/or a salt thereof in the aqueous solution after filter sterilization is reduced. can be suppressed.

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

1. Definitions Unless otherwise specified, the terms used herein should be understood to have the meanings commonly used in the art. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used herein, the term "aqueous liquid formulation" refers to a formulation that contains water as a base and exhibits a liquid state.

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

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

As used herein, the term "buffer" refers to a compound or mixture that has the effect of buffering 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 ionic bonded.

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

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

［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。］

As used herein, "polyhexanide" is a compound known as a preservative, a compound represented by the following general formula (1), and a guanidine derivative also called polyhexamethylenebiguanidine (PHMB).

[In the general formula (1), R ¹ and R ² are the same or different and represent an amino group or a group represented by the following general formula (2). In general formula (1), n represents an integer of 1-500. ]

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

As used herein, the term "substantially free of preservatives" refers to a concentration of preservatives at which the preservative alone cannot exhibit preservative efficacy. When an aqueous solution containing means less.

As used herein, "filter" refers to a porous membrane that allows passage of aqueous solutions but impermeability of bacteria and fungi. The pore size of the filter is usually 5 μm or less, preferably 0.1 to 2.5 μm, more preferably 0.2 to 1 μm.

As used herein, the term “container with a filter” refers to a container 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 inside the container passes through the filter during use. Refers to a container that is designed to be poured 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 out the aqueous solution to the outside of the container, and the nozzle is attached to the opening of the container body. and a container provided with a filter so as to close the flow path of the nozzle (for example, Patent Documents 1 and 2).

As used herein, the term "multi-dose type container" refers to a container that is filled with multiple doses of an aqueous solution and is used repeatedly.

As used herein, the term "unit-dose type container" refers to a container filled with a single-use amount of an aqueous liquid preparation, which can be used up with a single eye drop.

As used herein, the term "method for suppressing adsorption of brimonidine and/or a salt thereof to a filter" refers to a method for suppressing adsorption of brimonidine and/or a salt thereof to a filter, thereby suppressing adsorption of brimonidine and/or a salt thereof in an aqueous liquid agent that has passed through the filter. / Or refers to a method for suppressing a decrease in the content of the salt. The effect of suppressing the adsorption of brimonidine and/or its salts to the filter is the drug recovery rate (calculation formula: {filter The brimonidine content in the aqueous solution after passing/the brimonidine content in the aqueous solution before passing through the filter}×100) was used as an indicator, and the drug recovery rate of the aqueous solution containing the metal chloride (or preservative) was the metal chloride ( or a preservative), it can be said that there is an effect of suppressing adsorption of brimonidine and/or a salt thereof to the filter when the drug recovery rate is higher than that of the same aqueous solution as the aqueous solution. 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 "a method for suppressing adsorption".

2. Description of Preferred Embodiments A description of a preferred embodiment is set forth below, but it should be understood that this embodiment is illustrative of the invention and the scope of the invention is not limited to such preferred embodiment. . It should also be understood that those skilled in the art can easily make alterations, changes, etc. within the scope of the present invention with reference to the following preferred examples. Those skilled in the art can combine any of these embodiments as appropriate.

3. Regarding aqueous liquid preparations contained in pharmaceutical product filters, if the drug is adsorbed on the filter of the container, the content of the drug in the aqueous liquid preparations poured out from the container will decrease and the desired effect will not be achieved. Connect. Therefore, it is required that the aqueous liquid medicine contained in the filter-equipped container be designed so that the drug does not adsorb to the filter.

The present inventor conducted various studies on pharmaceutical products containing an aqueous liquid preparation containing brimonidine and/or its salt in a container with a filter, and found that brimonidine and/or its salt was adsorbed on the filter of the container and poured out from the container. It has been found that the content of brimonidine and/or its salt in the aqueous liquid preparation that is used is reduced. Therefore, the present inventors conducted intensive studies and found that even if an aqueous solution containing brimonidine and/or a salt thereof, a buffer, and a metal chloride is stored in a container with a filter, brimonidine and The present inventors have found that adsorption of salts thereof can be suppressed, and reduction in the content of brimonidine and/or salts thereof in the aqueous liquid preparation poured out from the container can be suppressed.

In one aspect, the present invention provides a pharmaceutical product comprising an aqueous solution comprising brimonidine and/or a salt thereof, a buffering agent, and a metal chloride contained in a filtered container. The pharmaceutical product of the present invention is described in detail below.

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

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.

In the aqueous solution used in the present invention, the concentration of brimonidine and/or its salt is not particularly limited, depending on the use of the aqueous solution, the degree of symptoms of the patient to be applied, the dosage per application, etc. For example, 0.05 to 0.2 w/v%, preferably 0.1 to 0.2 w/v%, particularly preferably 0.1 w/v%. In the present specification, the concentration of brimonidine and/or its salt is the concentration converted to brimonidine tartrate.

The pharmaceutical product of the present invention further includes a buffering agent in the aqueous solution. The buffer is not particularly limited as long as it is pharmaceutically acceptable. Examples include borate buffer, phosphate buffer, Tris buffer, citrate buffer, tartarate buffer, acetate buffer, amino acids Buffering agents and the like.

Borate buffers specifically include boric acid and/or salts thereof. Boric acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include orthoboric acid, metaboric acid, tetraboric acid and the like. Among these boric acids, orthoboric acid and tetraboric acid are preferred. These boric acids may be used singly or in combination of two or more. The salt of boric acid is not particularly limited as long as it is pharmaceutically acceptable. Alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; Examples include organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine and the like. Also, boric acid/or its salt may be in the form of a hydrate, such as borax.

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

A preferred embodiment of the borate buffer is a combination of boric acid and borax. By using boric acid and borax in combination in this way, it is possible to further improve the effect of suppressing adsorption of brimonidine and/or its salt to the filter. When boric acid and borax are used in combination, their ratio is not particularly limited. is 40 to 60 parts by mass.

The concentration of the borate buffer is usually 0.01 to 10 w/v%, more preferably 0.1 to 5 w/v%, more preferably 0.1 to 2 w/v%, especially from the viewpoint of buffering action. 0.1 to 1 w/v% is preferred. As used herein, the concentration of the borate buffer is the concentration converted to boric acid.

Specific examples of phosphate buffers include phosphoric acid and/or salts thereof. The salt of phosphoric acid is not particularly limited as long as it is pharmaceutically acceptable. For example, dialkali metal salts of hydrogen phosphate such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; , alkali metal dihydrogen phosphate such as potassium dihydrogen phosphate; and tri-alkali metal phosphate such as tri-sodium phosphate and tripotassium phosphate. In addition, 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 form of dodecahydrate, In some cases, it may be in the form of a dihydrate or the like.

As the phosphate buffer, one of phosphoric acid and salts thereof may be selected and used alone, or two or more thereof may be used in combination. Among phosphoric acids and salts thereof, from the viewpoint of further improving the effect of suppressing adsorption of brimonidine and/or salts thereof to filters, phosphates are preferable, and dialkali metal hydrogen phosphate and diphosphate diphosphate are more preferable. At least one alkali metal hydrogen salt, particularly preferably at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate is mentioned.

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

The concentration of the phosphate buffer is usually 0.01 to 5 w/v%, preferably 0.1 to 3 w/v%, more preferably 0.1 to 2 w/v%, from the viewpoint of buffering action. . As used herein, the concentration of the phosphate buffer is the concentration converted to phosphoric acid.

Tris buffers specifically include trometamol and/or salts thereof. The salt of trometamol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include organic acid salts such as acetate; organic acid salts such as hydrochloride and sulfonate.

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

The concentration of the Tris buffer is usually 0.01 to 5 w/v%, preferably 0.1 to 3 w/v%, more preferably 0.1 to 2 w/v%, from the viewpoint of buffering action. As used herein, the concentration of Tris buffer is the concentration converted to trometamol.

Citric acid buffers specifically include citric acid and/or salts thereof. The salt of citric acid is not particularly limited as long as it is pharmaceutically acceptable. Examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; be done. Citric acid and its salts may also be in the form of solvates such as hydrates.

As the citric acid buffer, one of citric acid and salts thereof may be selected and used alone, or two or more thereof may be used in combination. Among citric acid and salts thereof, citric acid is preferred from the viewpoint of further improving the effect of suppressing adsorption of brimonidine and/or salts thereof to a filter.

The concentration of the citrate buffer is usually 0.01 to 5 w/v%, from the viewpoint of buffering action.
Preferably 0.05 to 3.5 w/v%, more preferably 0.1 to 1 w/v%. As used herein, the concentration of the citrate buffer is the concentration converted to citric acid.

Tartaric acid buffers specifically include tartaric acid and/or salts thereof. Salts of tartaric acid are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; . Also, the salt of tartaric acid may be in the form of a solvate such as a hydrate. As the tartaric acid buffer, one of tartaric acid and salts thereof may be selected and used alone, or two or more thereof may be used in combination.

Acetate buffers specifically include acetic acid and/or salts thereof. The salt of acetic acid is not particularly limited as long as it is pharmaceutically acceptable. Examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts, etc. is mentioned. Also, the acetic acid salt may be in the form of a solvate such as a hydrate. As the acetate buffer, one of acetic acid and salts thereof may be selected and used alone, or two or more thereof may be used in combination.

Amino acid buffers specifically include acidic amino acids and/or salts thereof. Specific 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, and examples thereof include alkali metal salts such as sodium salts and potassium salts. As the amino acid buffer, one selected from acidic amino acids and salts thereof may be used alone, or two or more thereof may be used in combination.

These buffering agents may be used individually by 1 type, and may be used in combination of 2 or more type.

Among these buffers, preferably borate buffer, phosphate buffer, Tris buffer, citrate buffer, A borate buffer is more preferred.

The pharmaceutical product of the present invention further includes a metal chloride in the aqueous solution. The metal chloride is not particularly limited as long as it is pharmaceutically acceptable. 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 and the like.

These metal chlorides may be used singly 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 suppressing adsorption of brimonidine and/or salts thereof to filters. mentioned.

The concentration of the metal chloride in the aqueous solution used in the present invention is usually 0.01 to 5 w/v%. From the viewpoint of further improving the effect of suppressing adsorption of brimonidine and/or a salt thereof to a filter, the concentration of the 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%, 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 entering the aqueous solution during use and storage, so the aqueous solution is substantially free of preservatives. Both can have storage stability. In addition, preservatives may exert adverse effects such as irritation and cytotoxicity, and such adverse effects can be avoided when the aqueous solution is substantially free of preservatives. Therefore, one preferable aspect of the aqueous liquid preparation used in the present invention is that it does not substantially contain a preservative.

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

In embodiments 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 preservation, but specifically, it is 0.00001 w/v. %, preferably 0.000005 w/v% or less, particularly preferably 0.000001 w/v% or less, more preferably 0 w/v%.

In addition to the above ingredients, the aqueous solution used in the present invention may optionally contain a tonicity agent (other than metal chlorides), a surfactant, a thickening agent, a chelating agent, a cooling agent, and a stabilizing agent. It may contain additives such as agents and pH adjusters.

Tonicity agents (other than metal chlorides) are not particularly limited as long as they are pharmaceutically acceptable. Examples include polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, and polyethylene glycol; sodium acetate, acetic acid; Metal salts such as potassium, sodium hydrogen sulfite, sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate and sodium dihydrogen phosphate are included. These isotonizing agents may be used singly or in combination of two or more.

The surfactant is not particularly limited as long as it is pharmaceutically acceptable, and examples include tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxy nonionic surfactants such as Nol; amphoteric surfactants such as alkyldiaminoethylglycine and betaine lauryldimethylaminoacetate; alkyl sulfates, N-acyl taurates, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl Examples include anionic surfactants such as ether sulfates; cationic surfactants such as alkylpyridinium salts and alkylamine salts. These surfactants may be used singly or in combination of two or more.

The thickening agent is not particularly limited as long as it is pharmaceutically acceptable. Molecules: Celluloses such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and the like. These thickening agents may be used singly or in combination of two or more.

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

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

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

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

The concentrations of these additives may be appropriately set according to the types of additives to be used, the properties to be imparted to the aqueous liquid agent, and the like.

Furthermore, in addition to brimonidine and/or a salt thereof, the aqueous liquid preparation used in the present invention may, if necessary, contain pharmacological agents exhibiting therapeutic effects on glaucoma and ocular hypertension within a range that does not interfere with the effects of the present invention. ingredients may be included.

Examples of such pharmacological components include prostaglandins such as tafluprost, latanoprost, and isopropyl unoprostone; parasympathomimetic agents such as pilocarpine hydrochloride; anticholinesterase agents such as distigmine bromide; stimulants; _β1 blockers such as betaxolol hydrochloride; β blockers such as timolol maleate; α1 _{/ β} blockers such as nipradilol and levonolol hydrochloride; . These pharmacological ingredients may be used singly or in combination of two or more.

The concentrations of these pharmacological ingredients may be appropriately set according to the types of pharmacological ingredients to be used, the efficacy to be imparted, and the like.

Although the pH of the aqueous solution used in the present invention is not particularly limited, it may be pH 6-8, preferably 7-8, more preferably pH 7.

The osmotic pressure ratio of the aqueous solution used in the present invention is not particularly limited, but is, for example, 0.5 to 4, preferably 0.7 to 1.3, more preferably 0.9 to 1.1. . The 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 determined according to the "osmotic pressure method (osmolality measurement method)" specified in the 17th revision of the Japanese Pharmacopoeia. measured.

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

The aqueous solution used in the present invention can be used as ophthalmic preparations such as eye drops and eye washes. In particular, the aqueous solution used in the present invention can reduce intraocular pressure by the action of brimonidine and/or salts thereof, so it is provided as an eye drop and is suitably used for the treatment of glaucoma or ocular hypertension. can.

The aqueous solution used in the present invention may be produced according to a known preparation method according to its use, for example, it can be produced using the method described in the Japanese Pharmacopoeia 17th Edition, General Rules for Pharmaceutical Preparations. .

In the pharmaceutical product of the present invention, a filter-equipped container is used as the container containing the aqueous solution. The structure of the filter-equipped container is known (Patent Documents 1 and 2, etc.), and a known filter-equipped container can be used in the present invention. Moreover, the container with a filter may be an eyedropper container, an eyewash container, or the like, depending on the application of the aqueous solution.

In addition, the material of the filter in the filter-equipped container used in the present invention is not particularly limited, but examples thereof include polyethersulfone, polyvinylidene fluoride, polycarbonate, polytetrafluoroethylene, cellulose mixed ester, nylon, and polyamide. be done. Among these materials, polyethersulfone and polyvinylidene fluoride are preferred, and polyethersulfone is more preferred, from the viewpoint of further improving the effect of suppressing adsorption of brimonidine and/or its salts to the filter.

The filter-equipped container used in the present invention is preferably a multi-dose container in view of the fact that the filter has a function of preventing the invasion of bacteria.

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

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

4. Adsorption suppression method (1)
As described above, in the prior art, when an aqueous solution containing brimonidine and/or its salt is contained in a container with a filter, there is a problem that brimonidine and/or its salt is adsorbed on the filter of the container. Points also occur during the filter sterilization process using filters in the manufacture of aqueous solutions containing brimonidine and/or salts thereof. That is, when an aqueous liquid preparation containing brimonidine and/or a salt thereof is stored in a container with a filter and used, or when a filtration sterilization step using a filter is performed, there is a problem that brimonidine and/or a salt thereof is adsorbed on the filter. be.

In contrast, the adsorption of brimonidine and/or its salt to the filter is suppressed even when the aqueous solution is passed through the filter by including a buffer and a metal chloride together with brimonidine and/or its salt. It is possible to suppress the decrease in the content of brimonidine and/or a salt thereof in the aqueous solution after passing through the filter.

Therefore, in one aspect, the present invention provides an aqueous liquid preparation to be passed through a filter containing brimonidine and/or a salt thereof, a buffering agent, and a metal chloride for adsorption of brimonidine and/or a salt thereof to a filter. A suppression method is provided.

The types and concentrations of brimonidine and/or salts thereof, buffers, and metal chlorides used in the method for inhibiting adsorption of the present invention are as described in the section "3. Pharmaceutical products" above. In addition, in the method for inhibiting adsorption of the present invention, the types of other ingredients that can be blended in the aqueous liquid preparation, the pH of the aqueous liquid preparation, the osmotic pressure ratio, the formulation form, etc. are as described in the above-mentioned "3. Pharmaceutical products". be.

The filter used in the present invention may be a filter for a container with a filter, or may be a filter used in a filter sterilization process. That is, the aqueous liquid preparation to be passed through the filter may be an aqueous liquid preparation that is contained in a container with a filter and is poured out of the container after being passed through the filter of the container at the time of use. It may be an aqueous solution that is passed through a filter in the process. The type of container with a filter, the material of the filter, etc. are as described in the section "3. Pharmaceutical products" above. The material of the filter used in the filter sterilization process during manufacture is the same as the material of the filter in the filter-equipped container described in the section "3. Pharmaceutical products".

In the method for inhibiting adsorption 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 need to have preservative efficacy, and thus substantially contains a preservative. preferably not. In addition, in the method for inhibiting adsorption of the present invention, even if the aqueous liquid agent to be passed through the filter is the aqueous liquid agent to be passed through the filter in the sterilization process and is provided in a unit dose container after the sterilization process, the Aqueous solutions are preferably substantially free of preservatives, as they are not necessarily required to have preservative efficacy.

On the other hand, in the method for suppressing adsorption of the present invention, the aqueous liquid agent to be passed through the filter is the aqueous liquid agent to be passed through the filter in the sterilization step, and is provided after being housed in a multi-dose container having no filter after the sterilization step. When used, the aqueous solution preferably contains a preservative so as to have the desired preservative efficacy. The types of preservatives are as described in the section "3. Pharmaceutical products" above. In addition, when the aqueous solution contains a preservative, the concentration of the preservative in the aqueous solution may be appropriately set within a range in which the desired preservative effect can be obtained. v %, preferably 0.00005 to 0.01 w/v %, more preferably 0.001 to 0.01 w/v %.

5. Method for producing aqueous solution (1)
As described above, when an aqueous liquid preparation containing brimonidine and/or its salt is subjected to a filtration sterilization step using a filter, brimonidine and/or its salt is adsorbed on the filter, and brimonidine and/or in the aqueous liquid preparation that has passed through the filter. / Or there is a problem that the content of the salt is reduced.

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 solution after filtration sterilization can be suppressed.

Therefore, in one aspect, the present invention provides a step of preparing an aqueous solution containing brimonidine and/or a salt thereof, a buffer, and a metal chloride, and filtering the aqueous solution obtained by the step through a filter. Provided is a method for producing an aqueous solution comprising subjecting it to a filtered sterilization step.

In the production method of the present invention, the types and concentrations of brimonidine and/or its salts, buffers, and metal chlorides are as described in the section "3. Pharmaceutical products" above. In addition, in the production method of the present invention, the types of other ingredients that can be blended in the aqueous liquid preparation, the pH of the aqueous liquid preparation, the osmotic pressure ratio, the formulation form, etc. are also as described in the above "3. Pharmaceutical products". . In addition, 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-equipped container described in the section "3. Pharmaceutical products".

The aqueous liquid preparation obtained by the production method of the present invention may be provided in a filter-equipped container, or may be provided in a multi-dose type container or unit dose type container without a filter.

When the aqueous liquid preparation obtained by the production method of the present invention is provided in a container with a filter or a unit dose type container, the aqueous liquid preparation itself does not necessarily need to have a preservative effect. It is preferably substantially free of agents.

On the other hand, when the aqueous liquid preparation obtained by the production method of the present invention is contained in a multi-dose container without a filter and provided, the aqueous liquid preparation should have a desired preservative effect. preferably contains a preservative. The type of preservative is as described in the above "3. Pharmaceutical product" column, and the concentration of the preservative in the aqueous solution is described in the above "4. Adsorption suppression method (1)" column. is as follows.

6. Adsorption suppression method (2)
As described above, when an aqueous liquid preparation containing brimonidine and/or its salt is subjected to a filtration sterilization step using a filter or is used in a container with a filter, brimonidine and/or its salt is said to be adsorbed on the filter. I have a problem.

On the other hand, in the aqueous solution, together with brimonidine and/or its salts, a buffer and a specific preservative (at least one selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts) By containing brimonidine and/or a salt thereof, adsorption of brimonidine and/or a salt thereof to the filter can be suppressed even after passing through the filter, and a decrease in the content of brimonidine and/or a salt thereof in the aqueous solution after passing through the filter can be prevented. can be suppressed.

Thus, in one aspect, the present invention provides an aqueous liquid preparation to be passed through a filter from the group consisting of brimonidine and/or its salts, a buffering agent, chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts. A method for suppressing adsorption of brimonidine and/or a salt thereof to a filter, comprising at least one selected.

Brimonidine and/or salts thereof are included in the aqueous solutions used in the present invention. The type, concentration, etc. of brimonidine and/or its salt are the same as in the case of "3. Pharmaceutical products".

A buffering agent is blended in the aqueous solution used in the present invention. The type and concentration of the buffering agent are the same as in the above "3. Pharmaceutical products".

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

The salt of chlorhexidine used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. Specific examples include inorganic acid salts such as hydrochloride; organic acids such as acetate and gluconate; Salt etc. are mentioned. Chlorhexidine or a salt thereof may also be in the form of a solvate such as a hydrate. Among chlorhexidine and salts thereof, chlorhexidine salts are preferred, and chlorhexidine gluconate is more preferred.

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

In general formula (1), R ¹ and R ² are the same or different and represent an amino group or a group represented by general formula (2) below. 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 general formula (1), n represents an integer of 1-500. n is preferably an integer of 2-200, more preferably an integer of 4-100, particularly preferably an integer of 8-20.

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

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

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

When chlorhexidine and/or its salt is used, the concentration of chlorhexidine and/or its salt 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%. In the present specification, the concentration of chlorhexidine and/or its salt 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. is 0.005 to 0.01 w/v%.

When using polyhexanide and/or a salt thereof, 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 its salt is the concentration converted to polyhexanide hydrochloride.

The aqueous solution used in the present invention may further contain a metal chloride. The type, concentration, etc. of the metal chloride are the same as in the above "3. Pharmaceutical products".

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

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

The filter used in the present invention may be a filter used in a filtration sterilization process, or may be a filter of a container with a filter. That is, the aqueous liquid preparation to be passed through the filter may be an aqueous liquid preparation to be passed through the filter in the filter sterilization process during the production of the aqueous liquid preparation, or may be stored in a container with a filter and allowed to pass through the filter of the container at the time of use. It may be an aqueous solution that is poured out of the container. 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 the section "3. Pharmaceutical products". In addition, the types of containers with filters, the materials of the filters, etc. are as described in the section "3. Pharmaceutical products" above.

In the method for inhibiting adsorption of the present invention, the aqueous solution used contains a specific preservative (at least one selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts). As a preferred form of the aqueous liquid preparation used in the present invention, an aqueous liquid preparation that is passed through a filter in the sterilization process during manufacture, and does not have a filter after the sterilization process. Examples include those provided in a multi-dose type container.

7. Method for producing aqueous solution (2)
As described above, when an aqueous liquid preparation containing brimonidine and/or its salt is subjected to a filtration sterilization step using a filter, brimonidine and/or its salt is adsorbed on the filter, and brimonidine and/or in the aqueous liquid preparation that has passed through the filter. / Or there is a problem that the content of the salt is reduced.

On the other hand, brimonidine and/or its salts, a buffer, and a specific preservative (at least one selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts) By subjecting the aqueous liquid preparation containing to a filtration sterilization step using a filter, the adsorption of brimonidine and / or a salt thereof to the filter can be suppressed, and the content of brimonidine and / or a salt thereof in the aqueous liquid preparation after filtration sterilization can be reduced. can be suppressed.

Therefore, in one aspect, the present invention comprises 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 polyhexanide and its salts. and a step of subjecting the aqueous liquid preparation obtained in the above step to a filtration sterilization step using a filter.

In the production method of the present invention, the types and concentrations of brimonidine and/or salts thereof and buffering agents used are as described in the section "3. Pharmaceutical products".

In the production method of the present invention, the types and concentrations of brimonidine and/or its salts, buffering agent, chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts used in the above "6. Adsorption Suppression method (2)".

In the production method of the present invention, the aqueous solution may further contain a metal chloride. The type, concentration, etc. of the metal chloride are the same as in the above "3. Pharmaceutical products".

In addition, in the production method of the present invention, the types of other ingredients that can be blended in the aqueous liquid preparation, the pH of the aqueous liquid preparation, the osmotic pressure ratio, the formulation form, etc. are also as described in the above "3. Pharmaceutical products". . In addition, 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-equipped container described in the section "3. Pharmaceutical products".

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

EXAMPLES The present invention will be specifically described below with reference to Examples, but the present invention is not limited to these. In the following test examples, boric acid used was orthoboric acid.

Test Example 1: Evaluation of Suppression of Drug Adsorption to Filters (Examination of Effects of Buffers and Metal Chlorides)
An aqueous solution having the composition shown in Table 1 was prepared. The prepared aqueous solution was filtered using a filter with a pore size of 0.22 μm (polyethersulfone membrane; PES membrane), and 0.6 g of the first filtrate that passed through the filter was collected. Separately, the prepared aqueous solution was filtered using a filter with a pore size of 0.22 μm (polyvinylidene fluoride membrane; PVDF membrane), and 1.0 g of the first filtrate that passed through the filter was collected. The PES membrane 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 membrane is STERIVEX
- GV 0.22 μm/Merck Millipore (pore size: 0.22 μm, height: 67 mm, diameter: 10 cm ² , catalog number: SVGV010RS) was used.

The brimonidine content in the aqueous solution before filtration and in the aqueous solution after filtration (filtrate) was measured by liquid chromatography (high performance liquid chromatograph manufactured by Shimadzu Corporation: Prominence) under the following conditions.
(Measurement condition)
Detector : UV absorption photometer (measurement wavelength: 230 nm)
Column : Symmetry C18, 4.6 mm I.D. D. ×150 mm, 3.5 μm, manufactured by Waters
Column temperature : Constant temperature around 40°C
Mobile phase A : mixed solution of 4.3 mM phosphoric acid aqueous solution/methanol/acetonitrile (volume ratio: 84/8/8)
Mobile phase B : mixed solution of 4.3 mM phosphoric acid aqueous solution/methanol/acetonitrile (volume ratio: 40/30/30)
Liquid transfer of mobile phase : Linear concentration gradient control was performed by changing the mixing ratio of mobile phase A and mobile phase B as follows.
Time after injection (min) Mobile phase A (vol%) Mobile phase B (vol%)
0.0 to 20.0 100 0
20.0 to 25.0 100→0 0→100
25.0 to 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
Auto sampler internal temperature: 5°C

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

Table 1 shows the results. When the aqueous solution containing brimonidine tartrate did not contain a buffering agent and metal chloride (Comparative Example 1), the drug recovery rate after passing through the PES membrane filter was 94%, and the drug recovery rate after filtration through the PES membrane was 6%. Brimonidine tartrate was adsorbed. In addition, even aqueous solutions containing brimonidine tartrate and a buffer (borate buffer, phosphate buffer, trometamol, or citrate buffer) do not contain metal chlorides (Comparative Examples 2, 6 to 8). ), the recovery rate of the drug after passing through the PES membrane filter was the same as in Comparative Example 1. Furthermore, even with an aqueous solution containing sodium edetate or a water-soluble polymer (carboxymethylcellulose or polyvinylpyrrolidone) together with brimonidine tartrate and borate buffers, when metal chloride is not contained (Comparative Examples 3 to 5), the PES membrane The recovery rate of the drug after passing through the filter was equivalent to that of Comparative Example 1.

For this, including metal chlorides (sodium chloride, potassium chloride, calcium chloride, or magnesium chloride) with brimonidine tartrate and a buffer (borate buffer, phosphate buffer, trometamol, or citrate buffer). In the aqueous solution, the recovery rate of the drug after passing through the PES membrane filter was significantly higher than that in Comparative Example 1, indicating that the metal chloride has an inhibitory effect on drug adsorption. 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, boron The use of an acid buffer was most effective in improving drug recovery after passage through a PES membrane.

Also, when the PVDF membrane was used, the same tendency as in the case of the PES membrane was observed.

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

Table 2 shows the results. In aqueous solutions containing surfactants (polysorbate 80, POE (60) hydrogenated castor oil, tyloxapol, poloxamer 407 or polyethylene glycol monostearate (40EO)) with brimonidine tartrate and borate buffers (Comparative Examples 9-13) , PES membrane and PVDF membrane, the recovery rate of the drug after passing through the filter was equal to or lower than that of the surfactant-free aqueous solutions (Comparative Examples 1 and 2). In addition, even with aqueous solutions containing chlorobutanol or sorbic acid used as preservatives (Comparative Examples 14 and 15) together with brimonidine tartrate and borate buffers, the drug recovery rate after passing through filters with PES and PVDF membranes was Equivalent to Comparative Examples 1 and 2. In contrast, for aqueous solutions containing benzalkonium chloride, chlorhexidine gluconate, or polyhexanide hydrochloride (Examples 13-15), along with brimonidine tartrate and borate buffers, the drug after filtration through the PES and PVDF membranes The recovery rate was improved compared to Comparative Examples 1 and 2, and the effect of suppressing drug adsorption to the PES membrane and PVDF membrane was recognized.

Claims (8)

Brimonidine and/or a salt thereof in an amount of 0.1 w/v% (provided that crystalline brimonidine having a melting point of 199 to 205°C measured at a temperature elevation rate of 10°C/min using a differential scanning calorimeter) tartrate and amorphous brimonidine tartrate ), a phosphate buffer, benzalkonium chloride, and sodium chloride to form an aqueous solution containing no thickening agent and having a pH of 6 to 7. A step of preparing a liquid formulation, and a step of filtering and sterilizing the aqueous liquid formulation obtained in the above step using a filter,
A method for producing an aqueous solution, comprising: The production method according to claim 1, wherein the brimonidine and/or its salt is brimonidine tartrate. The production method according to claim 1 or 2, wherein the concentration of the phosphate buffer in the aqueous solution is 0.01 to 5 w/v%. The production method according to any one of claims 1 to 3, wherein the phosphate buffer is sodium dihydrogen phosphate. The production method according to any one of claims 1 to 4, wherein the concentration of benzalkonium chloride in the aqueous solution is 0.0001 to 0.1 w/v%. The production method according to any one of claims 1 to 5, wherein the aqueous solution is eye drops. The manufacturing method according to any one of claims 1 to 6, wherein the filter material is polyethersulfone or polyvinylidene fluoride. 8. The production method according to any one of claims 1 to 7, wherein the aqueous liquid preparation is provided in a multi-dose type container without a filter after a filter sterilization step.