JP2024052871A - Water-based liquid - Google Patents

Abstract

[Problem] The object of the present invention is to provide a formulation technology for an aqueous liquid preparation containing brimonidine and/or a salt thereof. [Solution] An aqueous liquid preparation containing brimonidine and/or a salt thereof, a buffer, and a metal chloride can suppress the adsorption of brimonidine and/or a salt thereof to the filter even when passed through a filter, and can suppress the decrease in the content of brimonidine and/or a salt thereof in the aqueous liquid preparation even when stored in a container with a filter or subjected to a sterilization process by filter treatment during production. [Selected Figure] None

Description

The present invention relates to an aqueous liquid preparation that contains brimonidine and/or a salt thereof and in which the adsorption of brimonidine and/or a salt thereof to a filter is suppressed.

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

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

On the other hand, brimonidine and its salts are known as adrenergic α2 receptor agonists, which act to reduce intraocular pressure by inhibiting aqueous humor production and promoting the outflow of aqueous humor via the uveoscleral outflow pathway, and have traditionally been used to treat glaucoma and ocular hypertension.

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

JP 2004-51170 A JP 2002-80055 A

The object of the present invention is to provide a formulation technology for an aqueous liquid preparation containing brimonidine and/or a salt thereof.

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

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

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

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

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

The present invention also provides a production method having 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 formulation comprising the steps of:
Item 3-2: The method according to Item 3-1, wherein the brimonidine and/or a salt thereof is brimonidine tartrate.
Item 3-3. The method according to Item 3-1 or 3-2, wherein the concentration of brimonidine and/or a salt thereof in the aqueous liquid preparation is 0.05 to 0.2 w/v %.
Item 3-4. The method according to any one of Items 3-1 to 3-3, wherein the buffer is at least one selected from the group consisting of a borate buffer, a phosphate buffer, a Tris buffer, and a citrate buffer.
Item 3-5: The method according to any one of Items 3-1 to 3-4, wherein the buffer is a borate buffer.
Item 3-6. The method according to any one of Items 3-1 to 3-5, wherein the buffer is a borate buffer, and the concentration of the borate buffer in the aqueous liquid preparation is 0.01 to 10 w/v %.
Item 3-7. The method according to any one of Items 3-1 to 3-4, wherein the buffer is a phosphate buffer, and the concentration of the phosphate buffer in the aqueous liquid preparation is 0.01 to 5 w/v %.
Item 3-8. The method according to any one of Items 3-1 to 3-4, wherein the buffer is a Tris acid buffer, and the concentration of the Tris acid buffer in the aqueous liquid preparation is 0.01 to 5 w/v %.
Item 3-9. The method according to any one of Items 3-1 to 3-4, wherein the buffer is a citrate buffer, and the concentration of the citrate buffer in the aqueous liquid preparation is 0.01 to 5 w/v %.
Item 3-10. The 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 method according to any one of Items 3-1 to 3-10, wherein the metal chloride is sodium chloride.
Item 3-12. The method according to any one of Items 3-1 to 3-11, wherein the concentration of the metal chloride in the aqueous liquid is 0.01 to 5 w/v %.
Item 3-13. The method according to any one of Items 3-1 to 3-12, wherein the aqueous liquid preparation is substantially free of a preservative.
Item 3-14. The method according to any one of Items 3-1 to 3-13, wherein the aqueous liquid preparation is an eye drop.
Item 3-15. The method according to any one of Items 3-1 to 3-14, wherein the material of the filter is polyethersulfone or polyvinylidene fluoride.

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

The present invention also provides a production method having the following aspects.
Item 5-1. A step of preparing an aqueous liquid preparation containing brimonidine and/or a salt thereof, a buffer, and at least one preservative selected from the group consisting of chlorhexidine and a salt thereof, benzalkonium chloride, and polyhexanide and a salt thereof, and a step of subjecting the aqueous liquid preparation obtained in the above step to a filtration sterilization step using a filter;
A method for producing an aqueous liquid formulation comprising the steps of:
Item 5-2: The method according to Item 5-1, wherein the brimonidine and/or a salt thereof is brimonidine tartrate.
Item 5-3. The method according to item 5-1 or 5-2, wherein the concentration of brimonidine and/or a salt thereof in the aqueous liquid preparation is 0.05 to 0.2 w/v %.
Item 5-4. The method according to any one of Items 5-1 to 5-3, wherein the buffer is at least one selected from the group consisting of a borate buffer, a phosphate buffer, a Tris buffer, and a citrate buffer.
Item 5-5: The method according to any one of Items 5-1 to 5-4, wherein the buffer is a borate buffer.
Item 5-6. The method according to any one of Items 5-1 to 5-5, wherein the buffer is a borate buffer, and the concentration of the borate buffer in the aqueous liquid preparation is 0.01 to 10 w/v %.
Item 5-7. The method according to any one of Items 5-1 to 5-4, wherein the buffer is a phosphate buffer, and the concentration of the phosphate buffer in the aqueous liquid preparation is 0.01 to 5 w/v %.
Item 5-8. The method according to any one of Items 5-1 to 5-4, wherein the buffer is a Tris acid buffer, and the concentration of the Tris acid buffer in the aqueous liquid preparation is 0.01 to 5 w/v %.
Item 5-9. The method according to any one of Items 5-1 to 5-4, wherein the buffer is a citrate buffer, and the concentration of the citrate buffer in the aqueous liquid preparation is 0.01 to 5 w/v %.
Item 5-10. The method for inhibiting adsorption according to any one of Items 5-1 to 5-9, wherein the preservative is at least one selected from the group consisting of chlorhexidine gluconate, benzalkonium chloride, and polyhexanide hydrochloride.
Item 5-11. The adsorption suppression method according to any one of Items 5-1 to 4-10, wherein the preservative is chlorhexidine and/or a salt thereof, and the concentration of chlorhexidine and/or a salt thereof in the aqueous liquid preparation is 0.0001 to 0.1 w/v %.
Item 5-12. The adsorption suppression method according to any one of Items 5-1 to 5-10, wherein the preservative is benzalkonium chloride, and the concentration of benzalkonium chloride in the aqueous liquid preparation is 0.0001 to 0.1 w/v %.
Item 5-13. The adsorption suppression method according to any one of Items 5-1 to 5-10, wherein the preservative is polyhexanide and/or a salt thereof, and the concentration of polyhexanide and/or a salt thereof in the aqueous liquid preparation is 0.00001 to 0.1 w/v %.
Item 5-14. The method according to any one of Items 5-1 to 5-13, wherein the aqueous liquid preparation does not contain a thickening agent.
Item 5-15. The method according to any one of Items 5-1 to 5-14, wherein the aqueous liquid preparation is an eye drop.
Item 5-16. The method according to any one of Items 5-1 to 5-15, wherein the material of the filter is polyethersulfone or polyvinylidene fluoride.
Item 5-17. The method according to any one of Items 5-1 to 5-16, wherein the aqueous liquid preparation is provided in a multi-dose container not equipped with a filter after the filtration sterilization step.

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

In addition, according to the present invention, by incorporating a buffer and a specific preservative (at least one selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts) in an aqueous liquid preparation containing brimonidine and/or its salts, it is possible to suppress adsorption of brimonidine and/or its salts to the filter, and to suppress a decrease in the content of brimonidine and/or its salts in the aqueous liquid preparation after passing through the filter. Therefore, in one aspect of the present invention, even if an aqueous liquid preparation containing brimonidine and/or its salts is subjected to a sterilization process by filter treatment during production, it is possible to suppress a decrease in the content of brimonidine and/or its salts in the aqueous liquid preparation after filtration sterilization.

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

In this specification, an "aqueous liquid preparation" is a preparation that contains water as a base and is liquid.

In this specification, the term "pharmaceutical product" refers to a product in which an aqueous liquid formulation is contained in any container.

In this specification, "brimonidine" refers to a compound known as an adrenergic α2 receptor agonist, 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine.

In this specification, the term "buffer" refers to a compound or mixture that acts to reduce fluctuations in the hydrogen ion concentration (pH) of an aqueous liquid preparation.

In this specification, "metal chloride" refers to a compound in which a metal ion and a chloride ion are ionic bonded.

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

In this specification, "benzalkonium chloride" refers to a compound known as a preservative, and refers to the chloride of alkyl (C8-C18) benzyldimethylammonium.

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

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

In this specification, "substantially free of preservatives" refers to a concentration of preservative that is such that the preservative alone is unable to exert its preservative effect, and specifically refers to an aqueous solution containing only the preservative that has a lower concentration of preservative than the minimum concentration that is "compliant" based on the criteria set forth in the "Testing Method for Preservative Effectiveness" in the 17th Edition of the Japanese Pharmacopoeia, Reference Information, Category "IC".

In this specification, the term "filter" refers to a porous membrane that allows the passage of an aqueous liquid agent but does not allow the passage of bacteria and fungi. The pore size of the filter is usually 5 μm or less, preferably 0.1 to 2.5 μm, and more preferably 0.2 to 1 μm.

In this specification, a "container with a filter" refers to a container that holds an aqueous liquid agent, in which the inside and outside of the container are separated by a filter, and in which the aqueous liquid agent inside the container passes through the filter and is poured out to the outside of the container during use. One embodiment of a container with a filter includes a container that has a container body with an opening and a nozzle with a flow path for pouring the aqueous liquid agent out of the container, the nozzle is attached to the opening of the container body, and a filter is provided to block the flow path of the nozzle (for example, Patent Documents 1 and 2, etc.).

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

In this specification, the term "unit-dose container" refers to a container filled with a single dose of aqueous liquid preparation and used up after one instillation.

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

2. Description of Preferred Embodiments The following describes preferred embodiments, but it should be understood that these embodiments are merely examples of the present invention and that the scope of the present invention is not limited to such preferred embodiments. It should also be understood that those skilled in the art can easily make modifications and changes within the scope of the present invention by referring to the following preferred examples. Those skilled in the art can combine any of these embodiments as appropriate.

3. For aqueous liquid preparations contained in containers with pharmaceutical filters, if the drug is adsorbed to the filter of the container, the drug content in the aqueous liquid preparation dispensed from the container will decrease, leading to failure to achieve the intended effect. Therefore, aqueous liquid preparations contained in containers with filters are required to be designed so that the drug is not adsorbed to the filter.

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

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

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

In the aqueous liquid preparation 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 liquid preparation used in the present invention, the concentration of brimonidine and/or a salt thereof is not particularly limited and may be appropriately set depending on the application of the aqueous liquid preparation, the severity of symptoms of the patient to whom it is applied, the amount applied per administration, etc., and may be, for example, 0.05 to 0.2 w/v%, preferably 0.1 to 0.2 w/v%, and particularly preferably 0.1 w/v%. In this specification, the concentration of brimonidine and/or a salt thereof is the concentration converted to brimonidine tartrate.

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

Specific examples of boric acid buffers include boric acid and/or salts thereof. As boric acid, there are no particular limitations, provided that it is pharmaceutically acceptable, but examples 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 alone or in combination of two or more. As salts of boric acid, there are no particular limitations, provided that it is pharmaceutically acceptable, but examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; and organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, and pyrrolidine. In addition, boric acid/or its salts 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 its salts and used alone, or two or more types may be used in combination. Among boric acid and its salts, from the viewpoint of further improving the effect of suppressing the adsorption of brimonidine and/or its salts to the filter, at least one type of boric acid and borax is preferable, and at least one type of orthoboric acid and borax is more preferable.

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

From the viewpoint of buffering action, the concentration of the boric acid buffer is usually 0.01 to 10 w/v%, more preferably 0.1 to 5 w/v%, even more preferably 0.1 to 2 w/v%, and particularly preferably 0.1 to 1 w/v%. In this specification, the concentration of the boric acid buffer is the concentration converted into boric acid.

Specific examples of phosphate buffers include phosphoric acid and/or salts thereof. Phosphate salts are not particularly limited as long as they are pharma- ceutically acceptable, but examples include dialkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; alkali metal dihydrogen phosphates such as sodium dihydrogen phosphate and potassium dihydrogen phosphate; and trialkali metal phosphates such as trisodium phosphate and tripotassium phosphate. Phosphate salts may be in the form of a solvate such as a hydrate, for example, in the case of disodium hydrogen phosphate, it may be in the form of a dodecahydrate, and in the case of sodium dihydrogen phosphate, it may be in the form of a dihydrate.

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

In addition, a suitable embodiment of the phosphate buffer is a combination of a dialkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate. By using a combination of a dialkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate in this manner, it is possible to further improve the effect of inhibiting adsorption of brimonidine and/or its salts to the filter. When a combination of a dialkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate is used, the ratio between them is not particularly limited, but for example, the amount of the alkali metal dihydrogen phosphate per 100 parts by weight of the dialkali metal hydrogen phosphate is 1 to 120 parts by weight, preferably 5 to 80 parts by weight, and more preferably 10 to 40 parts by weight.

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

Specific examples of tris buffers include trometamol and/or salts thereof. Salts of trometamol are not particularly limited as long as they are pharma- ceutically acceptable, but examples include organic acid salts such as acetate salts; and organic acid salts such as hydrochloride salts and sulfonate salts.

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

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

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

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

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

Specific examples of tartaric acid buffers include tartaric acid and/or salts thereof. Salts of tartaric acid are not particularly limited as long as they are pharma- ceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; and alkaline earth metal salts such as calcium salts and magnesium salts. The salts of tartaric acid may also be in the form of solvates such as hydrates. As the tartaric acid buffer, one of tartaric acid and its salts may be selected and used alone, or two or more of them may be used in combination.

Specific examples of acetate buffers include acetic acid and/or salts thereof. Salts of acetic acid are not particularly limited as long as they are pharma- ceutically acceptable, but examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and ammonium salts. Salts of acetic acid may also be in the form of solvates such as hydrates. As acetate buffers, one of acetic acid and its salts may be selected and used alone, or two or more of them may be used in combination.

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

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

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

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

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

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 its salts to the 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%, and even more preferably 0.4 to 1 w/v%.

In the pharmaceutical product of the present invention, the aqueous liquid is contained in a container with a filter, and bacteria are prevented from entering the aqueous liquid during use or storage, so that the aqueous liquid can have storage stability even if it does not substantially contain a preservative. In addition, preservatives can have adverse effects such as irritation and cytotoxicity, and such adverse effects can be avoided if the aqueous liquid is substantially free of preservatives. Therefore, one preferred embodiment of the aqueous liquid used in the present invention is one that is substantially free of preservatives.

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

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

In addition to the above-mentioned components, the aqueous liquid preparation used in the present invention may contain additives such as isotonicity agents (other than metal chlorides), surfactants, thickening agents, chelating agents, cooling agents, stabilizers, and pH adjusters, as necessary.

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

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

Thickening agents are not particularly limited as long as they are pharma- ceutically acceptable, but examples include water-soluble polymers such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate; and celluloses such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose. These thickening agents may be used alone or in combination of two or more.

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

The cooling agent is not particularly limited as long as it is pharma- ceutically acceptable, but examples include l-menthol, borneol, camphor, eucalyptus oil, etc. These cooling agents may be used alone or in combination of two or more.

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

There are no particular limitations on the pH adjuster, so long as it is pharma- ceutically acceptable. Examples of the pH adjuster include acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, and epsilon-aminocaproic acid; and alkalis such as sodium hydroxide, potassium hydroxide, borax, triethanolamine, monoethanolamine, sodium bicarbonate, and sodium carbonate. These pH adjusters may be used alone or in combination of two or more.

The concentrations of these additives may be set appropriately depending on the type of additive used and the properties to be imparted to the aqueous liquid.

Furthermore, the aqueous liquid preparation used in the present invention may contain, in addition to brimonidine and/or its salt, a pharmacological ingredient that exhibits a therapeutic effect against glaucoma or ocular hypertension, if necessary, to the extent that the effect of the present invention is not impaired.

Examples of such pharmacological ingredients include prostaglandins such as tafluprost, latanoprost, isopropyl unoprostone, etc.; parasympathomimetics such as pilocarpine hydrochloride, etc.; anticholinesterase drugs such as distigmine bromide, etc.; sympathomimetics such as dipivefrine hydrochloride, etc.; β ₁ blockers such as betaxolol hydrochloride, etc.; β blockers such as timolol maleate, etc.; α ₁ /β blockers such as nipradilol, levobunolol hydrochloride, etc.; α ₁ blockers such as bunazosin hydrochloride, etc. These pharmacological ingredients may be used alone or in combination of two or more.

The concentrations of these pharmacological ingredients can be set appropriately depending on the type of pharmacological ingredient used and the medicinal effect to be imparted.

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

The osmotic pressure ratio of the aqueous liquid formulation used in the present invention is not particularly limited, but may be, for example, 0.5 to 4, preferably 0.7 to 1.3, and more preferably 0.9 to 1.1. The osmotic pressure ratio is the ratio to the osmotic pressure of a 0.9 w/v% aqueous sodium chloride solution, and the osmotic pressure is measured according to the "osmotic pressure method (osmolarity measurement method)" specified in the 17th revised edition of the Japanese Pharmacopoeia.

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

The aqueous solution used in the present invention can be used as an ophthalmic preparation such as eye drops or eye wash. In particular, the aqueous solution used in the present invention can reduce intraocular pressure by the action of brimonidine and/or its salt, and therefore is provided as an eye drop and can be suitably used for the treatment of glaucoma or ocular hypertension.

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

In the pharmaceutical product of the present invention, a container with a filter is used as the container for storing the aqueous liquid preparation. The structure of a container with a filter is publicly known (Patent Documents 1 and 2, etc.), and a publicly known container with a filter can be used in the present invention. In addition, the container with a filter may be an eye drop container, an eyewash container, etc., depending on the application of the aqueous liquid preparation.

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

The container with a filter used in the present invention is preferably a multi-dose container, since the filter has the function of preventing the intrusion of bacteria.

The pharmaceutical product of the present invention is manufactured by preparing the aqueous liquid formulation, subjecting it to a sterilization process such as filtration sterilization, and then filling it into the filter-equipped container.

In one embodiment of the case where a polyethersulfone filter-equipped container is used in the pharmaceutical product of the present invention, the drug recovery rate, calculated by dividing the brimonidine content in the aqueous liquid preparation after passing through a polyethersulfone filter (e.g., STERIVEX-GP 0.22 μm/Merck Millipore (pore size: 0.22 μm, height: 67 mm, diameter: ¹⁰ cm2, catalog number: SVGP01050)) (the first 0.6 g that passes through the filter) by the brimonidine content in the aqueous liquid preparation before passing through the filter, is 95% or more. In one embodiment of the pharmaceutical product of the present invention when a polyvinylidene fluoride filter-equipped container is used, the drug recovery rate, calculated by dividing the brimonidine content in the aqueous liquid preparation after passing through a polyvinylidene fluoride filter (e.g., STERIVEX-GV 0.22 μm/Merck Millipore (pore size: 0.22 μm, height: 67 mm, diameter: ¹⁰ cm2, catalog number: SVGV010RS)) (the first 1.0 g that passes through the filter) by the brimonidine content in the aqueous liquid preparation before passing through the filter, is 90% or more.

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

In response to this, by including a buffer and a metal chloride in the aqueous liquid formulation together with brimonidine and/or a salt thereof, it is possible to suppress the adsorption of brimonidine and/or a salt thereof to the filter even when the formulation is passed through the filter, and it is possible to suppress the decrease in the content of brimonidine and/or a salt thereof in the aqueous liquid formulation after passing through the filter.

In one embodiment, the present invention provides a method for inhibiting adsorption of brimonidine and/or a salt thereof to a filter, comprising containing brimonidine and/or a salt thereof, a buffer, and a metal chloride in an aqueous liquid preparation that is passed through a filter.

In the adsorption suppression method of the present invention, the types and concentrations of brimonidine and/or its salts, buffers, and metal chlorides used are as described in the above section "3. Pharmaceutical products." In addition, in the adsorption suppression method of the present invention, the types of other components 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 section "3. Pharmaceutical products."

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 process. That is, the aqueous liquid to be passed through the filter may be an aqueous liquid that is contained in a container with a filter and is poured out of the container by passing through the filter of the container when used, or may be an aqueous liquid to be passed through the filter in a filtration sterilization process during the production of the aqueous liquid. The type of container with a filter and the material of the filter are as described in the above section "3. Pharmaceutical products". The material of the filter used in the filtration sterilization process during production is the same as the material of the filter in the container with a filter described in the above section "3. Pharmaceutical products".

In the adsorption suppression method of the present invention, when the aqueous liquid preparation passed through the filter is contained in a container with a filter, the aqueous liquid preparation does not necessarily need to have a preservative effect, and therefore it is preferable that the aqueous liquid preparation does not substantially contain a preservative. Also, in the adsorption suppression method of the present invention, even if the aqueous liquid preparation passed through the filter is an aqueous liquid preparation passed through a filter in a filtration sterilization process and is contained in a unit-dose container after the filtration sterilization process and provided, the aqueous liquid preparation does not necessarily need to have a preservative effect, and therefore it is preferable that the aqueous liquid preparation does not substantially contain a preservative.

On the other hand, in the adsorption suppression method of the present invention, when the aqueous liquid preparation passed through the filter is an aqueous liquid preparation passed through the filter in a filtration sterilization step and is provided in a multi-dose container not equipped with a filter after the filtration sterilization step, the aqueous liquid preparation preferably contains a preservative so as to have the desired preservative effect. The types of preservatives are as described in the above section "3. Pharmaceutical Products". When the aqueous liquid preparation contains a preservative, the concentration of the preservative in the aqueous liquid preparation may be appropriately set within a range that provides the desired preservative effect, for example, 0.00001 to 0.01 w/v%, preferably 0.00005 to 0.01 w/v%, and more preferably 0.001 to 0.01 w/v%.

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

In response to this, by subjecting an aqueous solution containing brimonidine and/or a salt thereof, a buffer, and a metal chloride to a filtration sterilization process using a filter, it is possible to suppress the adsorption of brimonidine and/or a salt thereof to the filter, and to suppress a decrease in the content of brimonidine and/or a salt thereof in the aqueous solution after filtration sterilization.

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

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

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

When the aqueous liquid preparation obtained by the manufacturing 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, so it is preferable that the aqueous liquid preparation does not substantially contain a preservative.

On the other hand, when the aqueous liquid preparation obtained by the manufacturing method of the present invention is provided in a multi-dose container that does not have a filter, it is preferable that the aqueous liquid preparation contains a preservative so that the aqueous liquid preparation has the desired preservative effect. The type of preservative is as described in the above section "3. Pharmaceutical products," and the concentration of the preservative in the aqueous liquid preparation is as described in the above section "4. Method for inhibiting adsorption (1)."

6. Adsorption suppression method (2)
As described above, when an aqueous liquid preparation containing brimonidine and/or a salt thereof is subjected to a filtration sterilization process using a filter or when the aqueous liquid preparation is stored in a container equipped with a filter and used, brimonidine and/or a salt thereof may be adsorbed onto the filter. There are challenges.

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

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

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

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

The aqueous liquid formulation 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 pharma- ceutically acceptable, but specific examples include inorganic acid salts such as hydrochloride; and organic acid salts such as acetate and gluconate. Chlorhexidine or its salts may also be in the form of a solvate such as a hydrate. Among chlorhexidine and its salts, preferred are chlorhexidine salts, and more preferred are chlorhexidine gluconate.

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

In general formula (1), ^R1 and ^R2 are the same or different and each is an amino group or a group represented by the following general formula (2). As ^R1 and ^R2 , preferably, ^R1 is an amino group and ^R2 is an amino group or a group represented by the following general formula (2); more preferably, ^R1 is an amino group and ^R2 is a group represented by the following general formula (2).

In general formula (1), n is an integer from 1 to 500. n is preferably an integer from 2 to 200, more preferably an integer from 4 to 100, and particularly preferably an integer from 8 to 20.

Salts of polyhexanide are not particularly limited, so long as they are pharma- ceutically acceptable, and examples of such salts 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 its salts, salts of polyhexanide 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, salts of chlorhexidine, benzalkonium chloride, polyhexanide, and salts of polyhexanide may be used, or two or more of these may be used in combination. Among these, from the viewpoint of further improving the effect of suppressing the adsorption of brimonidine and/or its salts to the filter, preferred are salts of chlorhexidine, benzalkonium chloride, and salts of polyhexanide, and more preferred are salts of chlorhexidine and salts of polyhexanide.

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

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

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

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

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

The pH, osmotic pressure ratio, formulation form, etc. of the aqueous liquid used in the present invention are the same as those in "3. Pharmaceutical products" above.

The filter used in the present invention may be a filter used in a filtration sterilization process, or may be a filter in a container with a filter. That is, the aqueous liquid to be passed through the filter may be an aqueous liquid to be passed through a filter in a filtration sterilization process during the production of the aqueous liquid, or may be an aqueous liquid contained in a container with a filter and passed through the filter of the container when used and poured out of the container. The material of the filter used in the filtration sterilization process during production is the same as the material of the filter in the container with a filter described in the above section "3. Pharmaceutical products". The type of container with a filter and the material of the filter are as described in the above section "3. Pharmaceutical products".

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

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

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

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

In the manufacturing method of the present invention, the type and concentration of brimonidine and/or its salt, and the buffering agent used are as described in the above section "3. Pharmaceutical Products."

In the manufacturing method of the present invention, the types and concentrations of brimonidine and/or its salts, buffer, chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts used are as described in the above section "6. Method for suppressing adsorption (2)".

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

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

The aqueous liquid preparation obtained by the manufacturing method of the present invention may be provided in a container with a filter, or in a multi-dose or unit-dose container without a filter. The aqueous liquid preparation obtained by the manufacturing 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) and can therefore have the desired preservative effect, so it is preferable to provide it in a multi-dose container without a filter.

The present invention will be specifically explained below with reference to examples, but the present invention is not limited to these in any way. In the following test examples, orthoboric acid was used as the boric acid.

Test Example 1: Evaluation of the suppression of drug adsorption to the filter (examination of the effects of buffers and metal chlorides)
An aqueous solution having the composition shown in Table 1 was prepared. The aqueous solution after preparation was filtered using a filter (polyethersulfone membrane; PES membrane) with a pore size of 0.22 μm, and 0.6 g of the first filtrate that passed through the filter was collected. Separately, the aqueous solution after preparation was filtered using a filter (polyvinylidene fluoride membrane; PVDF membrane) with a pore size of 0.22 μm, and 1.0 g of the first filtrate that passed through the filter was collected. The PES membrane used was STERIVEX-GP 0.22 μm/Merck Millipore (pore size: 0.22 μm, height: 67 mm, diameter: ¹⁰ cm2, catalog number: SVGP01050), and the PVDF membrane used was STERIVEX-GV 0.22 μm/Merck Millipore (pore size: 0.22 μm, height: 67 mm, diameter: ¹⁰ cm2, catalog number: SVGV010RS).

The brimonidine contents in the aqueous liquid preparation before filtration and in the aqueous liquid preparation after filtration (filtrate) were measured by liquid chromatography (Shimadzu Corporation, high performance liquid chromatograph: Prominence) under the following conditions.
(Measurement condition)
Detector : ultraviolet spectrophotometer (measurement wavelength: 230 nm)
Column : Symmetry C18, 4.6 mm I.D. x 150 mm, 3.5 μm,
Manufactured by Waters
Column temperature : constant temperature around 40°C
Mobile phase A : a mixture of 4.3 mM phosphoric acid aqueous solution/methanol/acetonitrile (volume ratio: 84/8/8)
Mobile phase B : A mixture of 4.3 mM phosphoric acid aqueous solution/methanol/acetonitrile (volume ratio: 40/30/30)
Delivery 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 (min) Mobile phase A (vol%) Mobile phase B (vol%)
0.0～20.0 100 0
20.0～25.0 100→0 0→100
25.0～30.0 0 100
30.0～30.1 0→100 100→0
30.1～60.0 100 0
Flow rate : 1.0 mL/min
Temperature inside the autosampler: 5°C

The drug recovery rate after passing through the filter was calculated from the brimonidine contents in the aqueous solution before and after passing through the filter according to the following formula.

The results are shown in Table 1. In the aqueous solution preparations containing brimonidine tartrate, when no buffer or metal chloride was present (Comparative Example 1), the drug recovery rate after passing through the PES membrane filter was 94%, and as much as 6% of brimonidine tartrate was adsorbed by filtration through the PES membrane. In the aqueous solution preparations containing brimonidine tartrate and a buffer (borate buffer, phosphate buffer, trometamol, or citrate buffer) when no metal chloride was present (Comparative Example 2, Comparative Examples 6 to 8), the drug recovery rate after passing through the PES membrane filter was equivalent to that of Comparative Example 1. Furthermore, in the aqueous solution preparations containing brimonidine tartrate and a borate buffer, as well as sodium edetate or a water-soluble polymer (carboxymethylcellulose or polyvinylpyrrolidone), when no metal chloride was present (Comparative Examples 3 to 5), the drug recovery rate after passing through the PES membrane filter was equivalent to that of Comparative Example 1.

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

In addition, when a PVDF membrane was used, a similar trend was observed as in the case of a PES membrane.

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

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

Claims (14)

A pharmaceutical product comprising an aqueous liquid formulation containing brimonidine and/or a salt thereof, a buffer, and a metal chloride, the aqueous liquid formulation being contained in a container equipped with a filter. The pharmaceutical product according to claim 1, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride. The pharmaceutical product according to claim 1 or 2, wherein the metal chloride is sodium chloride. The pharmaceutical product according to any one of claims 1 to 3, wherein the buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, Tris buffer, and citrate buffer. The pharmaceutical product according to any one of claims 1 to 4, wherein the buffer is a borate buffer. The pharmaceutical product according to any one of claims 1 to 5, wherein the aqueous liquid formulation is an eye drop. The pharmaceutical product according to any one of claims 1 to 6, wherein the filter material is polyethersulfone or polyvinylidene fluoride. The pharmaceutical product according to any one of claims 1 to 7, which is used to treat glaucoma. A method for inhibiting the adsorption of brimonidine and/or its salts to a filter, comprising adding brimonidine and/or its salts, a buffer, and a metal chloride to an aqueous liquid preparation that is passed through a filter. 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 formulation comprising the steps of: A method for inhibiting adsorption of brimonidine and/or its salts to a filter, comprising comprising adding brimonidine and/or its salts, a buffer, and at least one preservative selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts to an aqueous liquid preparation that is passed through a filter. The method for suppressing adsorption according to claim 11, wherein the aqueous liquid does not contain a thickening agent. A method for producing an aqueous liquid preparation, comprising: preparing an aqueous liquid preparation containing brimonidine and/or a salt thereof, a buffer, and at least one preservative selected from the group consisting of chlorhexidine and a salt thereof, benzalkonium chloride, and polyhexanide and a salt thereof; and subjecting the aqueous liquid preparation obtained in the above step to a filtration sterilization step using a filter. The method of claim 13, wherein the aqueous liquid does not contain a thickening agent.