JP7792540B2 - Water-based liquid - Google Patents

Description

The present invention relates to an aqueous liquid preparation containing brimonidine and/or a salt thereof, in which 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 using filtration during manufacturing.

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

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

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

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

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 inventors have discovered that an aqueous liquid preparation containing brimonidine and/or a salt thereof, a buffer, and a metal chloride can be passed through a filter without adsorption of brimonidine and/or a salt thereof to the filter, and that the decrease in the content of brimonidine and/or a salt thereof in the aqueous liquid preparation can be suppressed even when the aqueous liquid preparation is stored in a container with a filter or subjected to a sterilization process using a filter during production.

Furthermore, the present inventors have discovered 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 adsorption of brimonidine and/or a salt thereof to a filter even when passed through a filter, and can suppress a decrease in the content of brimonidine and/or a salt thereof in the aqueous liquid preparation even when subjected to a sterilization process using a filter during production.

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

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

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

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

The present invention also provides an adsorption suppression method according to the following embodiment.
Section 4-1. The aqueous liquid to be passed through the filter
Brimonidine and/or a salt thereof,
A buffering agent;
A method for inhibiting adsorption of brimonidine and/or its salts onto 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 inhibiting method according to Item 4-1, wherein the brimonidine and/or a salt thereof 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 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 adsorption suppression method according to any one of Items 4-1 to 4-9, wherein the preservative is at least one selected from the group consisting of chlorhexidine gluconate, benzalkonium chloride, and polyhexanide hydrochloride.
Item 4-11. The adsorption suppression method according to any one of Items 4-1 to 4-10, wherein the preservative is chlorhexidine and/or a salt thereof, and the concentration of chlorhexidine and/or a salt thereof in the aqueous liquid preparation is 0.0001 to 0.1 w/v %.
Item 4-12. The adsorption suppression method according to any one of Items 4-1 to 4-10, wherein the preservative is benzalkonium chloride, and the concentration of benzalkonium chloride in the aqueous liquid preparation is 0.0001 to 0.1 w/v %.
Item 4-13. The adsorption suppression method according to any one of Items 4-1 to 4-10, wherein the preservative is polyhexanide and/or a salt thereof, and the concentration of polyhexanide and/or a salt thereof in the aqueous liquid preparation is 0.00001 to 0.1 w/v %.
Item 4-14. The adsorption suppression method according to any one of Items 4-1 to 4-13, wherein the aqueous liquid preparation does not contain a thickening agent.
Item 4-15: The adsorption suppression method according to any one of Items 4-1 to 4-14, wherein the aqueous liquid preparation is an eye drop.
Item 4-16: The adsorption suppression method according to any one of Items 4-1 to 4-15, wherein the filter is made of polyethersulfone or polyvinylidene fluoride.
Item 4-17: The adsorption suppression method according to any one of Items 4-1 to 4-16, wherein the filter is a filter used in a filtration sterilization step.
Item 4-18. The adsorption suppression method according to any one of Items 4-1 to 4-17, wherein the aqueous liquid preparation is passed through a filter in a filtration sterilization step during production, and is provided in a multi-dose container not equipped with a filter after the filtration sterilization step.
Item 4-19: The adsorption suppression method according to any one of Items 4-1 to 4-16, wherein the filter is a filter in a container with a filter.

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

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

Furthermore, according to the present invention, by adding a buffer and a specific preservative (at least one selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts) to an aqueous liquid preparation containing brimonidine and/or its salts, adsorption of brimonidine and/or its salts to the filter can be suppressed, and the decrease in the content of brimonidine and/or its salts in the aqueous liquid preparation after passing through the filter can be suppressed. 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, the decrease in the content of brimonidine and/or its salts in the aqueous liquid preparation after filtration sterilization can be suppressed.

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 one of ordinary skill in the art to which this invention belongs.

As used herein, an "aqueous liquid" refers to a preparation that contains water as a base and is liquid.

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

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

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

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.

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

In this specification, "polyhexanide" refers to a compound known as a preservative, which is a compound represented by the following general formula (1), and is a guanidine derivative also known as polyhexamethylene biguanidine (PHMB).
[In general formula (1), ^R1 and ^R2 are the same or different and each represent 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.]

As used herein, the term "preservative" refers to a compound or mixture that has sufficient bactericidal activity against bacteria and fungi and has preservative properties, and is formulated to prevent microbial contamination. However, in this invention, the term "preservative" does not include boric acid and its salts.

As used herein, "substantially free of preservatives" refers to a concentration of preservatives at which the preservative alone is ineffective; specifically, when made into an aqueous solution containing only the preservative, the concentration of preservative is lower than the minimum concentration required for the solution to be "compliant" based on the criteria set forth in Category "IC" in the "Preservative Effectiveness Test Method" in the Reference Information for the Japanese Pharmacopoeia, 17th Edition.

In this specification, the term "filter" refers to a porous membrane that allows aqueous liquid preparations to pass through but blocks bacteria and fungi. The pore size of the filter is generally 5 μm or less, preferably 0.1 to 2.5 μm, and more preferably 0.2 to 1 μm.

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

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

As used herein, the term "unit-dose container" refers to a container filled with a single dose of aqueous liquid preparation that can be used up after one instillation.

As used herein, the term "method for inhibiting adsorption of brimonidine and/or its salts to a filter" refers to a method for inhibiting the adsorption of brimonidine and/or its salts to a filter, thereby inhibiting a decrease in the brimonidine and/or its salt content in an aqueous liquid formulation that has passed through a filter. The effectiveness of inhibiting adsorption of brimonidine and/or its salts to a filter is evaluated using the drug recovery rate, which is calculated by dividing the brimonidine content in the aqueous liquid formulation after passing through the filter by the brimonidine content in the aqueous liquid formulation before passing through the filter (calculation formula: {brimonidine content in aqueous liquid formulation after passing through the filter / brimonidine content in aqueous liquid formulation before passing through the filter} × 100). When the drug recovery rate of an aqueous liquid formulation containing a metal chloride (or preservative) is higher than the drug recovery rate of an aqueous liquid formulation that is identical to the aqueous liquid formulation but does not contain the metal chloride (or preservative), it can be said that the method is effective in inhibiting adsorption of brimonidine and/or its salts to a filter. In this specification, the "method for inhibiting adsorption of brimonidine and/or a salt thereof to a filter" may also 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, changes, etc. within the scope of the present invention by referring to the following preferred examples. Those skilled in the art can combine any of these embodiments as appropriate.

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

The present inventors conducted extensive research into pharmaceutical products in which an aqueous liquid preparation containing brimonidine and/or its salts is contained in a container with a filter, and found that brimonidine and/or its salts are adsorbed to the filter of the container, resulting in a decrease in the content of brimonidine and/or its salts in the aqueous liquid preparation dispensed from the container. Consequently, the present inventors conducted extensive research and found that, even when an aqueous liquid preparation containing brimonidine and/or its salts, a buffer, and a metal chloride is contained in a container with a filter, adsorption of brimonidine and/or its salts to the filter can be suppressed, and a decrease in the content of brimonidine and/or its salts in the aqueous liquid preparation dispensed from the container can be suppressed.

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, 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, brimonidine and/or a salt thereof is contained in the aqueous liquid formulation. Brimonidine salts are not particularly limited as long as they are pharmaceutically acceptable, but specific examples include organic acid salts such as tartrate and acetate; and inorganic acid salts such as hydrochloride. Brimonidine or a salt thereof may also be in the form of a solvate such as a hydrate. Among brimonidine and its salts, brimonidine tartrate is preferred.

In the aqueous liquid formulation 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 its salts is not particularly limited and may be set appropriately depending on the intended use of the aqueous liquid preparation, the severity of the patient's symptoms, the amount administered per dose, etc., but examples include 0.05 to 0.2 w/v%, preferably 0.1 to 0.2 w/v%, and particularly preferably 0.1 w/v%. In this specification, the concentration of brimonidine and/or its salts is the concentration converted to brimonidine tartrate.

In the pharmaceutical product of the present invention, the aqueous liquid formulation further contains a buffer. There are no particular limitations on the buffer, as long as it is pharmaceutically acceptable, but examples include borate buffer, phosphate buffer, Tris buffer, citrate buffer, tartrate buffer, acetate buffer, amino acid buffer, etc.

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

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, at least one of boric acid and borax is preferred, and at least one of orthoboric acid and borax is more preferred, from the viewpoint of further improving the effect of inhibiting adsorption of brimonidine and/or its salts to the filter.

A preferred embodiment of the boric acid buffer is a combination of boric acid and borax. Using a combination of boric acid and borax in this manner can further improve the effect of inhibiting adsorption of brimonidine and/or its salts to the filter. When using a combination of boric acid and borax, the ratio between them is not particularly limited, but examples include 0 to 100 parts by weight, preferably 20 to 80 parts by weight, and more preferably 40 to 60 parts by weight of borax per 100 parts by weight of boric acid.

From the viewpoint of buffering action, the concentration of the borate buffer is usually 0.01 to 10 w/v%, more preferably 0.1 to 5 w/v%, still more preferably 0.1 to 2 w/v%, and particularly preferably 0.1 to 1 w/v%. In this specification, the concentration of the borate 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 pharmaceutically acceptable, and examples include dialkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; alkali metal dihydrogen phosphates such as sodium dihydrogen phosphate and potassium dihydrogen phosphate; and trialkali metal phosphates such as trisodium phosphate and tripotassium phosphate. Phosphate salts may also be in the form of solvates such as hydrates; for example, disodium hydrogen phosphate may be in the form of a dodecahydrate, and sodium dihydrogen phosphate may be in the form of a dihydrate.

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 inhibiting adsorption of brimonidine and/or its salts to the filter, preferred are phosphate salts, 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.

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

From the viewpoint of buffering action, the concentration of the phosphate buffer is typically 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 its salts. There are no particular limitations on the salts of trometamol, as long as they are pharmaceutically acceptable, but examples include organic acid salts such as acetate salts, and organic acid salts such as hydrochloride and sulfonate salts.

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

From the standpoint of buffering action, the concentration of the Tris buffer is typically 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 its salts. There are no particular limitations on the citric acid salts, as long as they are pharmaceutically acceptable. Examples include alkali metal salts such as sodium salts and potassium salts; and alkaline earth metal salts such as calcium salts and magnesium salts. Citric acid and its salts may also be in the form of solvates, such as hydrates.

As the citrate buffer, one type selected from citric acid and its salts may be 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 standpoint of buffering action, the concentration of the citrate buffer is typically 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 its salts. Salts of tartaric acid are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; and alkaline earth metal salts such as calcium salts and magnesium salts. Tartaric acid salts may also be in the form of solvates such as hydrates. Tartaric acid and its salts may be selected and used alone or in combination as the tartaric acid buffer.

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 pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and ammonium salts. Acetic acid salts may also be in the form of solvates such as hydrates. Acetic acid and its salts may be selected and used alone or in combination as the acetate buffer.

Specific examples of amino acid buffers include acidic amino acids and/or their salts. 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 include alkali metal salts such as sodium salts and potassium salts. As an amino acid buffer, one type may be selected from acidic amino acids and their salts and used alone, or two or more types 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 inhibiting adsorption of brimonidine and/or its salts to the filter, borate buffer, phosphate buffer, Tris buffer, and citrate buffer are preferred, and borate buffer is even more preferred.

In the pharmaceutical product of the present invention, the aqueous liquid formulation further contains a metal chloride. There are no particular limitations on the metal chloride, provided 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, etc.

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

The concentration of the metal chloride in the aqueous liquid preparation used in the present invention is typically 0.01 to 5 w/v%. From the perspective of further improving the effect of inhibiting adsorption of brimonidine and/or its salts to the filter, the concentration of the metal chloride in the aqueous liquid preparation used in the present invention is preferably 0.05 to 2.5 w/v%, more preferably 0.1 to 2 w/v%, particularly preferably 0.2 to 1 w/v%, and even more preferably 0.4 to 1 w/v%.

In the pharmaceutical product of the present invention, the aqueous liquid formulation is contained in a container equipped with a filter, preventing bacteria from entering the aqueous liquid formulation during use or storage. This means that the aqueous liquid formulation can be stable during storage even if it is substantially free of preservatives. Furthermore, preservatives can have adverse effects such as irritation and cytotoxicity, and these adverse effects can be avoided if the aqueous liquid formulation is substantially free of preservatives. Therefore, one preferred embodiment of the aqueous liquid formulation 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; parahydroxybenzoic acid esters such as methylparaben and propyl parahydroxybenzoate; benzoic acid and its salts; chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, chlorobutanol, chlorhexidine, polyhexanide, polyquatrium, etc.

In embodiments in which the aqueous liquid preparation used in the present invention is substantially free of preservatives, the acceptable concentration of preservatives 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 isotonic agents (other than metal chlorides), surfactants, thickening agents, chelating agents, cooling agents, stabilizers, and pH adjusters, as needed.

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

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

Chelating agents are not particularly limited as long as they are pharmaceutically 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 pharmaceutically 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 pharmaceutically 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.

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

The concentrations of these additives can 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, pharmacological ingredients that exhibit therapeutic effects against glaucoma or ocular hypertension, as needed, to the extent that the effects of the present invention are 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.; _β1- blockers such as betaxolol hydrochloride, etc.; β-blockers such as timolol maleate, etc.; _α1 -β-blockers such as nipradilol, levobunolol hydrochloride, etc.; α1 _- blockers such as bunazosin hydrochloride, etc. These pharmacological ingredients may be used alone or in combination of two or more.

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

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

The osmotic pressure ratio of the aqueous liquid preparation 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. This osmotic pressure ratio is the ratio to the osmotic pressure of a 0.9 w/v% aqueous sodium chloride solution, and the osmotic pressure is measured in accordance with the "osmotic pressure method (osmolality measurement method)" specified in the 17th Edition of the Japanese Pharmacopoeia.

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

The aqueous solution used in the present invention can be used as ophthalmic preparations such as eye drops and eyewashes. In particular, the aqueous solution used in the present invention can reduce intraocular pressure through the action of brimonidine and/or its salts, and therefore is provided as eye drops and is suitable for use in 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, 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 filter-equipped container is used as the container for containing the aqueous liquid formulation. The structure of filter-equipped containers is publicly known (see, for example, Patent Documents 1 and 2), and publicly known filter-equipped containers can be used in the present invention. Furthermore, the filter-equipped container may be an eye dropper container, an eyewash container, or the like, depending on the intended use of the aqueous liquid formulation.

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 inhibiting adsorption of brimonidine and/or its salts to the filter, polyethersulfone and polyvinylidene fluoride are preferred, and polyethersulfone is even more preferred.

The filter-equipped container used in the present invention is preferably a multi-dose container, given that the filter has the function of preventing bacterial entry.

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 pharmaceutical product of the present invention, when a polyethersulfone filter-equipped container is used, the drug recovery rate, calculated by dividing the brimonidine content in the aqueous liquid preparation (the first 0.6 g that passes through the filter) 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 cm ² , catalog number: SVGP01050)), 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 container equipped with a polyvinylidene fluoride filter is used, the drug recovery rate, calculated by dividing the brimonidine content in the aqueous liquid preparation (the first 1.0 g that passes through the filter) 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 cm ² , catalog number: SVGV010RS)) 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. This problem also occurs in the filtration sterilization step using a filter in the production of an aqueous liquid preparation containing brimonidine and/or a salt thereof. That is, when an aqueous liquid preparation containing brimonidine and/or a salt thereof is placed in a container with a filter and used, or when a filtration sterilization step using a filter is performed, there is a problem that brimonidine and/or a salt thereof is adsorbed to the filter.

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

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

The types and concentrations of brimonidine and/or its salts, buffers, and metal chlorides used in the adsorption inhibition method of the present invention are as described above in the section "3. Pharmaceutical Products." Furthermore, the types of other ingredients that can be incorporated into the aqueous liquid formulation, the pH, osmotic pressure ratio, and formulation form of the aqueous liquid formulation in the adsorption inhibition method of the present invention are also as described above in the section "3. Pharmaceutical Products."

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

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

On the other hand, in the adsorption suppression method of the present invention, if the aqueous liquid preparation passed through a filter is an aqueous liquid preparation passed through a filter in a sterilization filtration process and is provided in a multi-dose container without a filter after the sterilization filtration process, the aqueous liquid preparation preferably contains a preservative to ensure the desired preservative effect. The types of preservatives are as described in the above section "3. Pharmaceutical Products." Furthermore, if a preservative is contained in the aqueous liquid preparation, the concentration of the preservative in the aqueous liquid preparation may be appropriately set within a range that ensures the desired preservative effect, and examples include 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 carried out during the production of an aqueous liquid preparation containing brimonidine and/or a salt thereof, there is a problem in 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 contrast, by subjecting an aqueous liquid preparation containing brimonidine and/or a salt thereof, a buffer, and a metal chloride to a filtration sterilization process using a filter, adsorption of brimonidine and/or a salt thereof to the filter can be suppressed, and a decrease in the content of brimonidine and/or a salt thereof in the aqueous liquid preparation after filtration sterilization can be suppressed.

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

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 above in "3. Pharmaceutical Products." Furthermore, in the manufacturing method of the present invention, the types of other ingredients that can be incorporated into the aqueous liquid, the pH, osmotic pressure ratio, and dosage form of the aqueous liquid are also as described above in "3. Pharmaceutical Products." Furthermore, in the manufacturing method of the present invention, the material of the filter used in the filtration sterilization step is the same as the material of the filter in the filter-equipped container described above in "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 without 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 container, the aqueous liquid preparation itself does not necessarily need to have preservative effectiveness, so it is preferable that it is substantially free of preservatives.

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 without a filter, it is preferable that the aqueous liquid preparation contain a preservative to provide the desired preservative effect. The type of preservative is as described above in "3. Pharmaceutical Products," and the concentration of the preservative in the aqueous liquid is as described above in "4. Adsorption Suppression Method (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 it is stored in a container with a filter and used, there is a problem that brimonidine and/or a salt thereof is adsorbed to the filter.

In response to this, by including a buffer and a specific preservative (at least one selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts) in the aqueous liquid formulation along with brimonidine and/or its salts, adsorption of brimonidine and/or its salts to the filter can be suppressed even when the formulation passes through a filter, and the decrease in the content of brimonidine and/or its salts in the aqueous liquid formulation after passing through the filter can be suppressed.

In one aspect, 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 at least one selected from the group consisting of chlorhexidine and a salt thereof, benzalkonium chloride, and polyhexanide and a salt thereof in an aqueous liquid preparation to be passed through a filter.

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

The aqueous liquid formulations used in the present invention contain a buffer. The type and concentration of the buffer are the same as those described above in "3. Pharmaceutical Products."

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

The salts of chlorhexidine used in the present invention are not particularly limited as long as they are pharmaceutically 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, chlorhexidine salts are preferred, and chlorhexidine gluconate is even 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), ^R1 and ^R2 are the same or different and ^each represent an amino group or a group represented by the following general formula (2): 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 represents an integer of 1 to 500. n is preferably an integer of 2 to 200, more preferably an integer of 4 to 100, and particularly preferably an integer of 8 to 20.

Salts of polyhexanide are not particularly limited, as long as they are pharmaceutically acceptable, and examples 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.

Of 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, chlorhexidine salts, benzalkonium chloride, polyhexanide, and polyhexanide salts may be used, or two or more of these may be used in combination. Of these, from the viewpoint of further improving the effect of suppressing adsorption of brimonidine and/or its salts to the filter, preferred are chlorhexidine salts, benzalkonium chloride, and polyhexanide salts, and more preferred are chlorhexidine salts and polyhexanide salts.

When chlorhexidine and/or its salts are used, the concentration of chlorhexidine and/or its salts in the aqueous solution 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 its salts is the concentration converted into 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 into 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 described above in "3. Pharmaceutical Products."

Other ingredients that can be included in the aqueous liquid formulation used in the present invention are the same as those in "3. Pharmaceutical Products" above. In one embodiment of the aqueous liquid formulation 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 perspective of the effect of inhibiting brimonidine adsorption, brimonidine stability (effect of inhibiting a decrease in the brimonidine content in the aqueous liquid), or the filterability of the aqueous liquid. Types of thickening agents are as described in the section "3. Pharmaceutical Products" above.

The pH, osmotic pressure ratio, formulation, etc. of the aqueous liquid preparation used in the present invention are the same as those described above in "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 in a filter-equipped container. That is, the aqueous liquid formulation passed through the filter may be an aqueous liquid formulation passed through a filter in a filtration sterilization process during the production of the aqueous liquid formulation, or may be an aqueous liquid formulation contained in a filter-equipped container and passed through the filter of the container before being 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 filter-equipped container described above in "3. Pharmaceutical Products." The types of filter-equipped containers and filter materials are as described above in "3. Pharmaceutical Products."

In the adsorption suppression method of the present invention, the aqueous liquid formulation 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 suitable form of the aqueous liquid formulation used in the present invention is an aqueous liquid formulation that is passed through a filter during the filtration sterilization process during production, and is provided in a multi-dose container that does not have a filter after the filtration sterilization process.

7. Method for producing aqueous liquid preparation (2)
As described above, when a filtration sterilization step using a filter is carried out during the production of an aqueous liquid preparation containing brimonidine and/or a salt thereof, there is a problem in 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 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 aspect, the present invention provides a method for producing an aqueous liquid preparation, comprising the steps of: preparing an aqueous liquid preparation containing brimonidine and/or a salt thereof, a buffer, and at least one selected from the group consisting of chlorhexidine and a salt thereof, benzalkonium chloride, and polyhexanide and a salt thereof; and subjecting the aqueous liquid preparation obtained in the above step to a filtration sterilization step using a filter.

The types and concentrations of brimonidine and/or its salts, and buffering agents used in the manufacturing method of the present invention are as described above in the section "3. Pharmaceutical Products."

The types and concentrations of the brimonidine and/or salts thereof, buffer, chlorhexidine and salts thereof, benzalkonium chloride, and polyhexanide and salts thereof used in the manufacturing method of the present invention are as described above in "6. Adsorption Suppression Method (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 described above in "3. Pharmaceutical Products."

In addition, in the manufacturing method of the present invention, the types of other ingredients that can be blended into 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 without a filter. Since 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), it can have the desired preservative effectiveness, and therefore is preferably provided in a multi-dose container without a filter.

The present invention will be explained in detail below using examples, but the present invention is not limited to these examples. In the following test examples, orthoboric acid was used as the boric acid.

Test Example 1: Evaluation of suppression of drug adsorption to the filter (examination of the effects of buffers and metal chlorides)
Aqueous liquid preparations were prepared with the compositions shown in Table 1. The prepared aqueous liquid preparations were filtered using a filter (polyethersulfone membrane; PES membrane) with a pore size of 0.22 μm, and 0.6 g of the first filtrate that passed through the filter was collected. Separately, the prepared aqueous liquid preparations were 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 cm ² , 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 cm ² , 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 (High Performance Liquid Chromatograph: Prominence, manufactured by Shimadzu Corporation) under the following conditions.
(Measurement conditions)
Detector : ultraviolet absorption photometer (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 aqueous phosphoric acid solution/methanol/acetonitrile (volume ratio: 84/8/8)
Mobile phase B : a mixture of 4.3 mM aqueous phosphoric acid 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 to 20.0 100 0
20.0 to 25.0 100 → 0 0 → 100
25.0-30.0 0 100
30.0 to 30.1 0 → 100 100 → 0
30.1～60.0 100 0
Flow rate : 1.0mL/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 liquid preparation before and after passing through the filter according to the following formula.

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

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

Furthermore, when a PVDF membrane was used, a similar trend to that observed with a PES membrane was observed.

Test Example 2: Evaluation of suppression of drug adsorption onto 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. For aqueous liquid formulations containing brimonidine tartrate and borate buffer together with a surfactant (polysorbate 80, POE (60) hydrogenated castor oil, tyloxapol, poloxamer 407, or polyethylene glycol monostearate (40EO)), (Comparative Examples 9 to 13), the drug recovery rate after passing through the PES and PVDF membrane filters was equal to or lower than that of aqueous liquid formulations not containing a surfactant, (Comparative Examples 1 and 2). Furthermore, for aqueous liquid formulations containing chlorobutanol or sorbic acid, used as a preservative, together with brimonidine tartrate and borate buffer, (Comparative Examples 14 and 15), the drug recovery rate after passing through the PES and PVDF membrane filters was equal to that of Comparative Examples 1 and 2. In contrast, in aqueous liquid preparations (Examples 13-15) containing brimonidine tartrate and borate buffer together with benzalkonium chloride, chlorhexidine gluconate, or polyhexanide hydrochloride, the drug recovery rate after passing through the PES membrane and PVDF membrane was improved compared to Comparative Examples 1 and 2, demonstrating the effectiveness of suppressing drug adsorption to the PES membrane and PVDF membrane.

Claims (8)

preparing an aqueous liquid preparation having a pH of 7 to 8, the aqueous liquid preparation comprising a pharmacological ingredient, a buffer, a metal chloride, a preservative, a pH adjuster, a chelating agent (excluding citric acid and its salts), and water; and filtering and sterilizing the aqueous liquid preparation obtained in the above step using a filter,
The pharmacological ingredient contains brimonidine and/or a salt thereof in an amount of 0.1 w/v %;
the buffer comprises a citrate buffer;
the metal chloride includes at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride;
The preservative comprises benzalkonium chloride.
A method for producing an aqueous liquid formulation. The manufacturing method according to claim 1, wherein the brimonidine and/or a salt thereof is brimonidine tartrate. The manufacturing method described in claim 1 or 2, wherein the concentration of the citrate buffer in the aqueous liquid preparation is 0.01 to 5 w/v%. The manufacturing method described in any one of claims 1 to 3, wherein the concentration of benzalkonium chloride in the aqueous liquid is 0.0001 to 0.1 w/v%. The manufacturing method described in any one of claims 1 to 4, wherein the aqueous liquid has a pH of 7. The manufacturing method according to any one of claims 1 to 5, wherein the aqueous liquid preparation is an eye drop. The manufacturing method described in any one of claims 1 to 6, wherein the filter material is polyethersulfone or polyvinylidene fluoride. The method according to any one of claims 1 to 7, wherein the aqueous liquid preparation is provided in a multi-dose container without a filter after the filtration sterilization step.