JP7447072B2 - aqueous liquid - Google Patents

Description

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

Aqueous solutions such as eye drops and eye washes 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 filter treatment during manufacture.

It has been reported that while preservatives can prevent the proliferation of bacteria, they are irritating and cytotoxic (see Non-Patent Document 1). Therefore, in order to avoid the adverse effects of preservatives, aqueous liquid preparations that do not contain preservatives have been developed. Multi-dose containers that contain aqueous solutions that do not contain preservatives have a structure that aseptically isolates the inside and outside of the container to prevent bacteria from entering the container during use, and a filter is installed in the nozzle. Containers equipped with filters (containers with filters) are often used (see Patent Documents 1 and 2).

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

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

Japanese Patent Application Publication No. 2004-51170 Japanese Patent Application Publication No. 2002-80055

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

The present inventor has discovered that even when an aqueous solution containing brimonidine and/or its salt, a buffer, and a metal chloride is passed through a filter, adsorption of brimonidine and/or its salt to the filter can be suppressed; It has been found that the decrease in the content of brimonidine and/or its salt in an aqueous liquid preparation can be suppressed even when the aqueous liquid preparation is housed in a container or subjected to a sterilization process by filter treatment during production.

Furthermore, the present inventor has prepared brimonidine and/or a salt thereof, a buffer, and a specific preservative (at least one selected from the group consisting of chlorhexidine and its salt, benzalkonium chloride, and polyhexanide and its salt). Even if an aqueous solution containing brimonidine and/or its salt is passed through a filter, adsorption of brimonidine and/or its salt to the filter can be suppressed, and even if it is subjected to a sterilization process by filter treatment during manufacturing, the adsorption of brimonidine and/or its salt in the aqueous solution can be suppressed. It has been found that the decrease in salt content can be suppressed.

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

That is, the present invention provides a pharmaceutical product according to the following aspects.
Section 1-1. A pharmaceutical product comprising an aqueous solution containing brimonidine and/or a salt thereof, a buffer, and a metal chloride in a container equipped with a filter.
Section 1-2. The pharmaceutical product according to item 1-1, wherein the brimonidine and/or its salt is brimonidine tartrate.
Section 1-3. The pharmaceutical product according to item 1-1 or 1-2, wherein the concentration of the brimonidine and/or its salt is 0.05 to 0.2 w/v%.
Section 1-4. According to any one of Items 1-1 to 1-3, the buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, Tris buffer, and citrate buffer. pharmaceutical products.
Section 1-5. The pharmaceutical product according to any one of Items 1-1 to 1-4, wherein the buffer is a borate buffer.
Section 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%.
Section 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%.
Section 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%.
Section 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%.
Section 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.
Section 1-11. The pharmaceutical product according to any one of Items 1-1 to 1-10, wherein the metal chloride is sodium chloride.
Section 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%.
Section 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.
Section 1-14. The pharmaceutical product according to any one of Items 1-1 to 1-13, wherein the aqueous solution is an eye drop.
Section 1-15. 15. The pharmaceutical product according to any one of Items 1-1 to 1-14, wherein the filter material is polyether sulfone or polyvinylidene fluoride.
Section 1-16. 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.
Section 1-17. The pharmaceutical product according to any one of Items 1-1 to 1-16, which is used for the treatment of glaucoma.
Section 1-18. A pharmaceutical product comprising an aqueous solution containing brimonidine and/or a salt thereof, a buffer, and a metal chloride in a container with a filter,
Brimonidine and/or its salt is Brimonidine tartrate,
The concentration of brimonidine and/or its salt is 0.05 to 0.2 w/v%,
the buffer is a borate buffer;
The aqueous solution is an eye drop,
The material of the filter is polyether sulfone,
A drug whose drug recovery rate, determined by dividing the brimonidine content in the aqueous solution after passing through the filter by the brimonidine content in the aqueous solution before passing through the filter, is 95% or more, and the container with the filter is a multi-dose container. product.
Section 1-19. A pharmaceutical product comprising an aqueous solution containing brimonidine and/or a salt thereof, a buffer, and a metal chloride in a container with a filter,
Brimonidine and/or its salt is Brimonidine tartrate,
The concentration of brimonidine and/or its salt is 0.05 to 0.2 w/v%,
the buffer is a borate buffer;
The aqueous solution is an eye drop,
The material of the filter is polyvinylidene fluoride,
A drug whose drug recovery rate, determined by dividing the brimonidine content in the aqueous solution after passing through the filter by the brimonidine content in the aqueous solution before passing through the filter, is 90% or more, and the container with the filter is a multi-dose container. product.

The present invention also provides a method for suppressing adsorption in the following aspects.
Section 2-1. A method for suppressing adsorption of brimonidine and/or its salt to a filter, which comprises containing brimonidine and/or its salt, a buffer, and a metal chloride in an aqueous solution that is passed through the filter.
Section 2-2. The method for suppressing adsorption according to item 2-1, wherein the brimonidine and/or its salt is brimonidine tartrate.
Section 2-3. The method for suppressing adsorption according to item 2-1 or 2-2, wherein the concentration of brimonidine and/or its salt in the aqueous liquid is 0.05 to 0.2 w/v%.
Section 2-4. According to any one of Items 2-1 to 2-3, the buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, Tris buffer, and citrate buffer. adsorption suppression method.
Section 2-5. The method for suppressing adsorption according to any one of Items 2-1 to 2-4, wherein the buffer is a boric acid buffer.
Section 2-6. The method for suppressing adsorption according to any one of Items 2-1 to 2-5, wherein the buffer is a borate buffer, and the concentration of the borate buffer in the aqueous solution is 0.01 to 10 w/v%. .
Section 2-7. The method for suppressing adsorption 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 is 0.01 to 5 w/v%. .
Section 2-8. The method for suppressing adsorption 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 solution is 0.01 to 5 w/v%. .
Section 2-9. The method for suppressing adsorption 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 is 0.01 to 5 w/v%. .
Section 2-10. The method for suppressing adsorption according to any one of Items 2-1 to 2-9, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
Section 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.
Section 2-12. The method for suppressing adsorption according to any one of Items 2-1 to 2-11, wherein the concentration of metal chloride in the aqueous liquid is 0.01 to 5 w/v%.
Section 2-13. Item 2-13. The method for suppressing adsorption according to any one of Items 2-1 to 2-12, wherein the aqueous liquid preparation does not substantially contain a preservative.
Section 2-14. Item 2-14. The method for suppressing adsorption according to any one of Items 2-1 to 2-13, wherein the aqueous solution is an eye drop.
Section 2-15. Item 2-15. The method for suppressing adsorption according to any one of Items 2-1 to 2-14, wherein the filter material is polyether sulfone or polyvinylidene fluoride.
Section 2-16. Item 2-16. The method for suppressing adsorption according to any one of Items 2-1 to 2-15, wherein the filter is a filter for a container with a filter.
Section 2-17. Item 2-16. 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 process.

Further, the present invention provides a manufacturing method according to the following aspects.
Section 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 step to a filtration sterilization step using a filter,
A method for producing an aqueous liquid formulation, including:
Section 3-2. The manufacturing method according to item 3-1, wherein the brimonidine and/or its salt is brimonidine tartrate.
Section 3-3. Item 3-1 or 3-2, wherein the concentration of brimonidine and/or its salt in the aqueous solution is 0.05 to 0.2 w/v%.
Section 3-4. According to any one of Items 3-1 to 3-3, the buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, Tris buffer, and citrate buffer. manufacturing method.
Section 3-5. The manufacturing method according to any one of Items 3-1 to 3-4, wherein the buffer is a borate buffer.
Section 3-6. The manufacturing method according to any one of Items 3-1 to 3-5, wherein the buffer is a borate buffer, and the concentration of the borate buffer in the aqueous solution is 0.01 to 10 w/v%.
Section 3-7. The manufacturing method according to any one of Items 3-1 to 3-4, wherein the buffer is a phosphate buffer, and the concentration of the phosphate buffer in the aqueous solution is 0.01 to 5 w/v%.
Section 3-8. The manufacturing 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 solution is 0.01 to 5 w/v%.
Section 3-9. 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 solution is 0.01 to 5 w/v%. manufacturing method.
Section 3-10. The manufacturing method according to any one of Items 3-1 to 3-9, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
Section 3-11. The manufacturing method according to any one of Items 3-1 to 3-10, wherein the metal chloride is sodium chloride.
Section 3-12. The manufacturing method according to any one of Items 3-1 to 3-11, wherein the concentration of the metal chloride in the aqueous solution is 0.01 to 5 w/v%.
Section 3-13. Item 3-13. The manufacturing method according to any one of Items 3-1 to 3-12, wherein the aqueous liquid preparation does not substantially contain a preservative.
Section 3-14. Item 3-14. The manufacturing method according to any one of Items 3-1 to 3-13, wherein the aqueous solution is an eye drop.
Section 3-15. The manufacturing method according to any one of Items 3-1 to 3-14, wherein the filter material is polyether sulfone or polyvinylidene fluoride.

The present invention also provides a method for suppressing adsorption in the following aspects.
Section 4-1. For the aqueous liquid that passes through the filter,
Brimonidine and/or its salt;
A buffer and
A method for suppressing adsorption of brimonidine and/or its salt to a filter, which comprises containing at least one preservative selected from the group consisting of chlorhexidine and its salt, benzalkonium chloride, and polyhexanide and its salt.
Section 4-2. Item 4-1. The adsorption suppression method according to item 4-1, wherein the brimonidine and/or its salt is brimonidine tartrate.
Section 4-3. The method for suppressing adsorption according to item 4-1 or 4-2, wherein the concentration of brimonidine and/or its salt in the aqueous solution is 0.05 to 0.2 w/v%.
Section 4-4. According to any one of Items 4-1 to 4-3, the buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, Tris buffer, and citrate buffer. adsorption suppression method.
Section 4-5. The method for suppressing adsorption according to any one of Items 4-1 to 4-4, wherein the buffer is a boric acid buffer.
Section 4-6. The method for suppressing adsorption according to any one of Items 4-1 to 4-5, wherein the buffer is a borate buffer, and the concentration of the borate buffer in the aqueous solution is 0.01 to 10 w/v%. .
Section 4-7. The method for suppressing adsorption 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 is 0.01 to 5 w/v%. .
Section 4-8. The method for suppressing adsorption 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 solution is 0.01 to 5 w/v%. .
Section 4-9. The method for suppressing adsorption 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 is 0.01 to 5 w/v%. .
Section 4-10. The method for suppressing 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.
Section 4-11. Any one of Items 4-1 to 4-10, wherein the preservative is chlorhexidine and/or a salt thereof, and the concentration of chlorhexidine and/or a salt thereof in the aqueous solution is 0.0001 to 0.1 w/v%. The adsorption suppression method described in .
Section 4-12. The adsorption according to any one of Items 4-1 to 4-10, wherein the preservative is benzalkonium chloride, and the concentration of benzalkonium chloride in the aqueous solution is 0.0001 to 0.1 w/v%. Suppression method.
Section 4-13. Any one of Items 4-1 to 4-10, wherein the preservative is polyhexanide and/or a salt thereof, and the concentration of the polyhexanide and/or salt thereof in the aqueous solution is 0.00001 to 0.1 w/v%. The adsorption suppression method described in .
Section 4-14. The method for suppressing adsorption according to any one of Items 4-1 to 4-13, wherein the aqueous liquid does not contain a thickening agent.
Section 4-15. Item 4-15. The method for suppressing adsorption according to any one of Items 4-1 to 4-14, wherein the aqueous solution is an eye drop.
Section 4-16. Item 4-15. The method for suppressing adsorption according to any one of Items 4-1 to 4-15, wherein the filter material is polyether sulfone or polyvinylidene fluoride.
Section 4-17. 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 process.
Section 4-18. 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 manufacturing, and is provided in a multi-dose type container that is not equipped with a filter after the filtration sterilization step. The method for suppressing adsorption according to any one of the above.
Section 4-19. 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 for a container with a filter.

Further, the present invention provides a manufacturing method according to the following aspects.
Section 5-1. preparing an aqueous solution comprising brimonidine and/or a salt thereof, a buffer, and at least one preservative selected from the group consisting of chlorhexidine and its salt, benzalkonium chloride, and polyhexanide and its salt; 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, including:
Section 5-2. The manufacturing method according to item 5-1, wherein the brimonidine and/or its salt is brimonidine tartrate.
Section 5-3. Item 5-1 or 5-2, wherein the concentration of brimonidine and/or its salt in the aqueous solution is 0.05 to 0.2 w/v%.
Section 5-4. According to any one of Items 5-1 to 5-3, the buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, Tris buffer, and citrate buffer. manufacturing method.
Section 5-5. The manufacturing method according to any one of Items 5-1 to 5-4, wherein the buffer is a borate buffer.
Section 5-6. The manufacturing method according to any one of Items 5-1 to 5-5, wherein the buffer is a borate buffer, and the concentration of the borate buffer in the aqueous solution is 0.01 to 10 w/v%.
Section 5-7. The manufacturing method according to any one of Items 5-1 to 5-4, wherein the buffer is a phosphate buffer, and the concentration of the phosphate buffer in the aqueous solution is 0.01 to 5 w/v%.
Section 5-8. The manufacturing 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 solution is 0.01 to 5 w/v%.
Section 5-9. 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 solution is 0.01 to 5 w/v%. manufacturing method.
Section 5-10. The method for suppressing 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.
Section 5-11. Any one of Items 5-1 to 4-10, wherein the preservative is chlorhexidine and/or a salt thereof, and the concentration of chlorhexidine and/or a salt thereof in the aqueous solution is 0.0001 to 0.1 w/v%. The adsorption suppression method described in .
Section 5-12. The adsorption according to any one of Items 5-1 to 5-10, wherein the preservative is benzalkonium chloride, and the concentration of benzalkonium chloride in the aqueous solution is 0.0001 to 0.1 w/v%. Suppression method.
Section 5-13. Any one of Items 5-1 to 5-10, wherein the preservative is polyhexanide and/or a salt thereof, and the concentration of the polyhexanide and/or salt thereof in the aqueous solution is 0.00001 to 0.1 w/v%. The adsorption suppression method described in .
Section 5-14. The manufacturing method according to any one of Items 5-1 to 5-13, wherein the aqueous liquid preparation does not contain a thickening agent.
Section 5-15. Item 5-15. The manufacturing method according to any one of Items 5-1 to 5-14, wherein the aqueous solution is an eye drop.
Section 5-16. The manufacturing method according to any one of Items 5-1 to 5-15, wherein the filter material is polyether sulfone or polyvinylidene fluoride.
Section 5-17. 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 type container without a filter after the filtration sterilization step.

According to the present invention, by containing a buffer and a metal chloride in an aqueous solution containing brimonidine and/or its salt, adsorption of brimonidine and/or its salt to the filter can be suppressed, and after passing through the filter, the adsorption of brimonidine and/or its salt can be suppressed. In an aqueous liquid preparation, a decrease in the content of brimonidine and/or its salt can be suppressed. Therefore, in one aspect of the present invention, even if an aqueous solution containing brimonidine and/or its salt is stored in a container with a filter, brimonidine and/or The decrease in the salt content can be suppressed. In another aspect of the present invention, even if the aqueous solution containing brimonidine and/or its salt is subjected to a sterilization step by filter treatment during production, the content of brimonidine and/or its salt does not decrease in the aqueous solution after filtration sterilization. Can be suppressed.

Further, according to the present invention, in an aqueous solution containing brimonidine and/or a salt thereof, a buffering agent and a specific preservative (selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts) are provided. By containing at least one type of brimonidine and/or its salt, adsorption of brimonidine and/or its salt to the filter can be suppressed, and a decrease in the content of brimonidine and/or its salt in the aqueous solution after passing through the filter can be suppressed. . Therefore, in one aspect of the present invention, even if an aqueous solution containing brimonidine and/or its salt is subjected to a sterilization process by filter treatment during production, the content of brimonidine and/or its salt in the aqueous solution after filtration sterilization is not reduced. Can be suppressed.

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

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

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

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

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

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

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

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

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

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

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

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

As used herein, the term "substantially free of preservatives" refers to a concentration of preservatives that is such that the preservatives alone cannot exert the preservative effect. When an aqueous solution containing a preservative is made, the concentration of the preservative is higher than the minimum concentration of the preservative that the aqueous solution meets the criteria specified in the category "IC" in the Reference Information "Preservative Efficacy Test Methods" of the 17th Edition of the Japanese Pharmacopoeia. Refers to less.

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

As used herein, the term "container with a filter" refers to a container containing an aqueous liquid drug, in which the inside of the container and the outside of the container are separated by a filter, and when in use, the aqueous liquid drug inside the container passes through the filter. Refers to a container designed to be poured outside. One embodiment of a container with a filter includes a container main body having an opening and a nozzle provided with a flow path for pouring an aqueous liquid to the outside of the container, and the nozzle is attached to the opening of the container main body. Examples include containers in which a filter is provided to block the flow path of the nozzle (for example, Patent Documents 1 and 2).

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

As used herein, the term "unit-dose container" refers to a container that is filled with a single dose of aqueous liquid and used after one eye drop.

As used herein, "a method for suppressing adsorption of brimonidine and/or its salt to a filter" refers to brimonidine and/or its salt in an aqueous solution that has passed through a filter by suppressing adsorption of brimonidine and/or its salt to a filter. / or refers to a method of suppressing a decrease in the content of its salts. The effect of suppressing the adsorption of brimonidine and/or its salts on the filter is determined 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. Brimonidine content in the aqueous solution after passing through / Brimonidine content in the aqueous solution before passing through the filter} x 100) is evaluated as an index. When the drug recovery rate is higher than that of an aqueous solution that is the same as the above-mentioned aqueous solution except that it does not contain brimonidine and/or a preservative, it can be said that there is an effect of suppressing adsorption of brimonidine and/or its salt to the filter. In this specification, "method for suppressing adsorption of brimonidine and/or its salt onto a filter" may be simply referred to as "method for suppressing adsorption."

2. DESCRIPTION OF PREFERRED EMBODIMENTS A description of a preferred embodiment is provided below, but it should be understood that this embodiment is an illustration of the present invention and that the scope of the present invention is not limited to such preferred embodiment. . It should also be understood that those skilled in the art can readily make modifications, changes, etc. that fall within the scope of the invention with reference to the preferred embodiments described below. Those skilled in the art can combine any of these embodiments as appropriate.

3. For aqueous liquid medicines stored in containers with filters for pharmaceutical products , if the drug is adsorbed to the filter of the container, the content of the drug in the aqueous liquid medicine dispensed from the container will decrease and the intended effect may no longer be achieved. Connect. Therefore, the aqueous liquid medicine contained in a container with a filter is required to be designed so that the drug does not adsorb to the filter.

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

In one embodiment, the present invention provides a pharmaceutical product, wherein an aqueous solution containing brimonidine and/or a salt thereof, a buffer, and a metal chloride is housed in a filter-equipped container. The pharmaceutical product of the present invention will be described in detail below.

In the pharmaceutical product of the present invention, the aqueous solution contains brimonidine and/or a salt thereof. The salt of brimonidine is not particularly limited as long as it is pharmaceutically acceptable, but specific examples thereof include organic acid salts such as tartrate and acetate; inorganic acid salts such as hydrochloride. Further, brimonidine or a salt thereof may be in the form of a solvate such as a hydrate. Among brimonidine and 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 solution used in the present invention, the concentration of brimonidine and/or its salt is not particularly limited and depends on the use of the aqueous solution, the severity of symptoms of the patient to whom it is applied, the amount applied per time, etc. It may be set as appropriate, for example, 0.05 to 0.2 w/v%, preferably 0.1 to 0.2 w/v%, particularly preferably 0.1 w/v%. In this specification, the concentration of brimonidine and/or its salt is the concentration converted to brimonidine tartrate.

In the pharmaceutical product of the present invention, the aqueous solution further includes a buffer. Buffers are not particularly limited as long as they are pharmaceutically acceptable, but include, for example, borate buffers, phosphate buffers, Tris buffers, citrate buffers, tartrate buffers, acetate buffers, and amino acids. Examples include buffering agents.

Specific examples of the boric acid buffer include boric acid and/or its salts. The boric acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include orthoboric acid, metaboric acid, tetraboric acid, and the like. Among these boric acids, orthoboric acid and tetraboric acid are preferred. These boric acids may be used alone or in combination of two or more. Examples of boric acid salts include, but are not particularly limited to, as long as they are pharmaceutically acceptable; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; Examples include organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, and pyrrolidine. Further, boric acid/or its salt 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, preferably at least one of boric acid and borax, more preferably orthoboric acid and borax, from the viewpoint of further improving the effect of suppressing adsorption of brimonidine and/or its salts to the filter. At least one of the following is mentioned.

Further, a preferred embodiment of the boric acid buffer includes a combination of boric acid and borax. By using boric acid and borax in combination in this way, it becomes possible to further improve the effect of suppressing adsorption of brimonidine and/or its salt to the filter. When boric acid and borax are used in combination, their ratio is not particularly limited, but for example, borax is preferably 0 to 100 parts by mass, preferably 20 to 80 parts by mass, and more preferably 20 to 80 parts by mass, per 100 parts by mass of boric acid. is 40 to 60 parts by mass.

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

Specific examples of the phosphate buffer include phosphoric acid and/or its salts. Phosphoric acid salts are not particularly limited as long as they are pharmaceutically acceptable, but examples include dialkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; sodium dihydrogen phosphate; , alkali metal salts of dihydrogen phosphate such as potassium dihydrogen phosphate; and trialkali metal salts of phosphate such as trisodium phosphate and tripotassium phosphate. In addition, the salt of phosphoric acid may be in the form of a solvate such as a hydrate; for example, in the case of disodium hydrogen phosphate, it is in the form of a dodecahydrate; If necessary, it may be in the form of a dihydrate.

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

Further, a preferred embodiment of the phosphate buffer includes a combination of a dialkali metal hydrogen phosphate salt and an alkali metal dihydrogen phosphate salt. By using the dialkali metal salt of hydrogen phosphate in combination with the alkali metal salt of dihydrogen phosphate in this way, it becomes possible to further improve the effect of suppressing adsorption of brimonidine and/or its salt to the filter. When using a combination of a di-alkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate, the ratio is not particularly limited; The hydrogen alkali metal salt may be used in an amount of 1 to 120 parts by weight, preferably 5 to 80 parts by weight, and more preferably 10 to 40 parts by weight.

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

Specific examples of the Tris buffer include trometamol and/or its salts. Salts of trometamol are not particularly limited as long as they are pharmaceutically acceptable, and include, for example, organic acid salts such as acetate; organic acid salts such as hydrochloride and sulfonate.

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

From the viewpoint of buffering effect, the concentration of the Tris buffer is usually 0.01 to 5 w/v%, preferably 0.1 to 3 w/v%, and more preferably 0.1 to 2 w/v%. As used herein, the concentration of Tris buffer is the concentration in terms of trometamol.

Specific examples of the citric acid buffer include citric acid and/or its salts. Salts of citric 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. It will be done. Moreover, citric acid and its salt may be in the form of a solvate such as a hydrate.

As the citric acid 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 suppressing adsorption of brimonidine and/or its salts to the filter.

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% from the viewpoint of buffering effect. Can be mentioned. As used herein, the concentration of citrate buffer is the concentration converted to citric acid.

Specific examples of the tartaric acid buffer include tartaric acid and/or its salts. Salts of tartaric acid are not particularly limited as long as they are pharmaceutically acceptable, and include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts. . Moreover, the salt of tartaric acid may be in the form of a solvate such as a hydrate. As the tartaric acid buffer, one type may be selected from tartaric acid and its salts and used alone, or two or more types may be used in combination.

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

Specific examples of the amino acid buffer include acidic amino acids and/or salts thereof. Specific examples of 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 include, for example, alkali metal salts such as sodium salts and potassium salts. As the 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, boric acid buffers, phosphate buffers, Tris buffers, citrate buffers, and More preferred is a boric acid buffer.

The pharmaceutical product of the invention further includes a metal chloride in the aqueous solution. Metal chlorides are not particularly limited as long as they are pharmaceutically acceptable, but include, for example, alkali metal chlorides such as sodium chloride and potassium chloride; alkaline earth metal chlorides such as magnesium chloride and calcium chloride. ; Examples include zinc chloride and iron chloride.

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

The concentration of 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 salt to the filter, the concentration of 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%, still more preferably 0.4 to 1 w/v%.

In the pharmaceutical product of the present invention, the aqueous solution is housed in a container with a filter to prevent bacteria from entering the aqueous solution during use and storage, so the aqueous solution does not substantially contain preservatives. Both can have storage stability. Furthermore, preservatives can have adverse effects such as irritation and cytotoxicity, and such adverse effects can be avoided if the aqueous solution is substantially free of preservatives. Therefore, one preferred aspect of the aqueous liquid preparation used in the present invention is that it does not substantially contain a preservative.

Preservatives include, specifically, 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, polydronium chloride, thimerosal, chlorobutanol, chlorhexidine, polyhexanide, polyquatrium, and the like.

In the embodiment in which the aqueous liquid preparation used in the present invention does not substantially contain a preservative, the allowable concentration of the preservative varies depending on the type of storage, etc., but specifically, it is 0.00001w/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 optionally include isotonic agents (other than metal chlorides), surfactants, thickening agents, chelating agents, cooling agents, and stabilizing agents. It may also contain additives such as agents and pH adjusters.

Isotonic agents (other than metal chlorides) are not particularly limited as long as they are pharmaceutically acceptable, but include, for example, polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, and polyethylene glycol; sodium acetate, acetic acid. Examples include metal salts such as potassium, sodium hydrogen sulfite, sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. These tonicity 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, but examples include tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxy Non-ionic surfactants such as alcohol; amphoteric surfactants such as alkyldiaminoethylglycine, lauryldimethylaminoacetic acid betaine; alkyl sulfates, N-acyl taurine salts, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl Examples include anionic surfactants such as ether sulfates; cationic surfactants such as alkylpyridinium salts and alkylamine salts. These surfactants may be used alone or in combination of two or more.

The thickening agent is not particularly limited as long as it is pharmaceutically acceptable, but examples include highly water-soluble thickeners such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate. Molecules: Examples include celluloses such as hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose. These thickeners may be used alone or in combination of two or more.

The chelating agent is not particularly limited as long as it is pharmaceutically acceptable, but examples include edetic acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, and 1-hydroxyethane-1,1-diphosphonic acid. Examples include acids, polyphosphoric acid, metaphosphoric acid, hexametaphosphoric acid, phytic acid, thiosulfuric acid, salts thereof, and the like. The form of the salt is not particularly limited as long as it is pharmaceutically acceptable, and 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, and examples thereof include l-menthol, borneol, camphor, eucalyptus oil, and the like. These refreshing 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, and the like. Can be mentioned. These stabilizers may be used alone or in combination of two or more.

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

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

Furthermore, in addition to brimonidine and/or its salt, the aqueous liquid preparation used in the present invention may contain, as necessary, pharmacological substances that have a therapeutic effect on glaucoma and ocular hypertension to the extent that they do not interfere with the effects of the present invention. Components may be included.

Such pharmacological ingredients include, for example, prostaglandins such as tafluprost, latanoprost, and isopropyl unoprostone; parasympathomimetic agents such as pilocarpine hydrochloride; anticholinesterase agents such as distigmine bromide; and sympathetic nerve agents such as dipivefrin hydrochloride. Stimulants; β ₁ blockers such as betaxolol hydrochloride; β blockers such as timolol maleate; α ₁ and β blockers such as nipradilol and levobunolol hydrochloride; α ₁ blockers such as bunazosin hydrochloride, etc. . These pharmacological ingredients may be used alone or in combination of two or more.

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

The pH of the aqueous liquid preparation used in the present invention is not particularly limited, but includes, for example, pH 6 to 8, preferably pH 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 examples include 0.5 to 4, preferably 0.7 to 1.3, and more preferably 0.9 to 1.1. . The osmotic pressure ratio is the ratio to the osmotic pressure of a 0.9 w/v% sodium chloride aqueous solution, and the osmotic pressure is determined according to the "osmotic pressure method (osmolality measurement method)" specified in the 17th edition of the Japanese Pharmacopoeia. be measured.

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

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

The aqueous liquid preparation used in the present invention may be manufactured according to a known preparation method depending on its intended use; for example, it can be manufactured using the method described in the 17th revised Japanese Pharmacopoeia, General Rules for Preparations. .

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

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

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

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

In one aspect of using a container with a filter made of polyethersulfone in the pharmaceutical product of the present invention, a filter made of polyethersulfone (for example, STERIVEX-GP 0.22 μm/Merck Millipore (pore diameter: 0.22 μm, height : 67 mm, diameter: 10 cm ² , catalog number: SVGP01050 The recovery rate is 95% or more. Further, as an embodiment of the case where a container with a filter made of polyvinylidene fluoride is used in the pharmaceutical product of the present invention, a filter made of polyvinylidene fluoride (for example, STERIVEX-GV 0.22 μm/Merck Millipore (pore diameter: 0.22 μm, Height: 67 mm, diameter: 10 cm ² , catalog number: SVGV010RS The drug recovery rate is 90% or more.

4. Adsorption suppression method (1)
As mentioned above, in the prior art, when an aqueous liquid preparation containing brimonidine and/or its salt is stored in a container with a filter, there is a problem that brimonidine and/or its salt is adsorbed to the filter of the container. This problem also occurs during the filtration sterilization process using a filter in the production of aqueous liquid preparations containing brimonidine and/or its salts. That is, when an aqueous liquid preparation containing brimonidine and/or its salt is stored in a container with a filter and used, or when a filter sterilization process is performed using a filter, there is a problem that brimonidine and/or its salt is adsorbed to the filter. be.

On the other hand, by containing a buffer and a metal chloride together with brimonidine and/or its salt in the aqueous solution, adsorption of brimonidine and/or its salt to the filter can be suppressed even when the aqueous solution is passed through the filter. This makes it possible to suppress a decrease in the content of brimonidine and/or its salt in the aqueous liquid preparation after passing through the filter.

Therefore, in one embodiment, the present invention provides an aqueous solution that is allowed to pass through a filter and contains brimonidine and/or a salt thereof, a buffer, and a metal chloride. Provide a method of suppression.

In the method for suppressing adsorption of the present invention, the types, concentrations, etc. of brimonidine and/or its salt, buffer, and metal chloride used are as described in the column of "3. Pharmaceutical products" above. In addition, in the adsorption suppression method of the present invention, the types of other components that can be incorporated into the aqueous solution, the pH of the aqueous solution, the osmotic pressure ratio, the formulation form, etc. are as described in the column of "3. Pharmaceutical products" above. be.

The filter used in the present invention may be a filter of a container equipped with a filter, or a filter used in a filtration sterilization process. That is, the aqueous solution to be passed through the filter may be an aqueous solution that is stored in a container with a filter and is poured out of the container after passing through the filter of the container during use. It may also be an aqueous solution that is passed through a filter during the process. The type of container with a filter, the material of the filter, etc. are as described in the column of "3. Pharmaceutical products" above. Further, the material of the filter used in the filtration sterilization step during manufacturing is the same as the material of the filter in the filter-equipped container described in the section "3. Pharmaceutical products" above.

In the method for suppressing adsorption of the present invention, when the aqueous liquid to be passed through the filter is stored in a container equipped with a filter, the aqueous liquid does not necessarily contain a preservative and therefore does not necessarily contain a preservative. Preferably not. In addition, in the adsorption suppression method of the present invention, even if the aqueous liquid formulation that is passed through the filter is an aqueous liquid formulation that is passed through the filter in the filtration sterilization process and is provided in a unit dose type container after the filtration sterilization process, the Since the aqueous solution is not necessarily required to have preservative effect, it is preferable that the aqueous solution does not substantially contain a preservative.

On the other hand, in the adsorption suppression method of the present invention, the aqueous liquid formulation that is passed through the filter is an aqueous liquid formulation that is passed through the filter in the filtration sterilization process, and is provided after being housed in a multi-dose type container that is not equipped with a filter. In this case, the aqueous solution preferably contains a preservative so that it can have the desired preservative effect. The type of preservative is as described in the section "3. Pharmaceutical products" above. In addition, when a preservative is included in an aqueous solution, the concentration of the preservative in the aqueous solution may be appropriately set within a range that provides the desired preservative effect, but for example, 0.00001 to 0.01w/ v%, preferably 0.00005 to 0.01 w/v%, more preferably 0.001 to 0.01 w/v%.

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

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

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

In the production method of the present invention, the types, concentrations, etc. of brimonidine and/or its salt, buffer, and metal chloride are as described in the column of "3. Pharmaceutical products" above. In addition, in the manufacturing method of the present invention, the types of other ingredients that can be blended into the aqueous solution, the pH of the aqueous solution, the osmotic pressure ratio, the formulation form, etc. are also as described in the column of "3. Pharmaceutical products" above. . 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 section "3. Pharmaceutical products" above.

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

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

On the other hand, if the aqueous solution obtained by the production method of the present invention is provided in a multi-dose container without a filter, the aqueous solution may be provided with the desired preservative effect. Preferably, a preservative is included. The type of preservative is as described in the column "3. Pharmaceutical products" above, and the concentration of the preservative in the aqueous solution is described in the column "4. Adsorption suppression method (1)" above. It is as follows.

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

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

Therefore, in one embodiment, the present invention provides an aqueous solution that is made of a group consisting of brimonidine and/or its salt, a buffer, chlorhexidine and its salt, benzalkonium chloride, and polyhexanide and its salt. Provided is a method for suppressing adsorption of brimonidine and/or its salt to a filter, which comprises containing at least one selected brimonidine and/or a salt thereof.

The aqueous solution used in the present invention contains brimonidine and/or a salt thereof. The type, concentration, etc. of brimonidine and/or its salt are the same as in the case of "3. Pharmaceutical products" above.

A buffer is added to the aqueous solution used in the present invention. The type, concentration, etc. of the buffer are the same as in the case of "3. Pharmaceutical products" above.

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

The salts of chlorhexidine used in the present invention are not particularly limited as long as they are pharmaceutically acceptable, but specifically include inorganic acid salts such as hydrochloride; organic acids such as acetate and gluconate. Examples include salt. Moreover, chlorhexidine or its salt may be in the form of a solvate such as a hydrate. Among chlorhexidine and its salts, chlorhexidine salts are preferred, and chlorhexidine gluconate is more preferred.

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

In the general formula (1), R ¹ and R ² are the same or different and are an amino group or a group represented by the following general formula (2). R ¹ and R ² are preferably an amino group, and R ² is an amino group or a group represented by the following general formula (2); more preferably, R ¹ is an amino group, and R ² is an amino group or a group represented by the following general formula ( ² ); 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, particularly preferably an integer of 8 to 20.

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

Among polyhexanides and their salts, preferred are salts of polyhexanide, more preferred are inorganic acid salts of polyhexanide, and particularly preferred are polyhexanide hydrochloride.

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

When using chlorhexidine and/or its salt, the concentration of chlorhexidine and/or its salt in the aqueous solution is, for example, 0.001 to 0.01 w/v%, preferably 0.003 to 0.01 w/v. %, more preferably 0.005 to 0.01 w/v%. In this specification, the concentration of chlorhexidine and/or its salt is the concentration converted to chlorhexidine gluconate.

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

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

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

In the aqueous liquid preparation used in the present invention, other ingredients that can be blended are the same as in the case of "3. Pharmaceutical products" above, but in one embodiment of the aqueous liquid preparation used in the present invention, viscous However, in a preferred embodiment, the adsorption inhibitory effect of brimonidine, the stability of brimonidine (the effect of suppressing the decrease in brimonidine content in an aqueous solution), or the effect of suppressing a decrease in brimonidine content in an aqueous solution is included. From the viewpoint of filterability, it is mentioned that no thickening agent is included. The type of thickening agent is as described in the section "3. Pharmaceutical products" above.

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

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

In the method for suppressing adsorption of the present invention, the aqueous solution used contains a specific preservative (at least one selected from the group consisting of chlorhexidine and its salts, benzalkonium chloride, and polyhexanide and its salts). 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 during the filtration sterilization process during manufacturing, and is not equipped with a filter after the filtration sterilization process. Examples include those provided in multi-dose containers.

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

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

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

In the production method of the present invention, the type and concentration of brimonidine and/or its salt, buffering agent, etc. used are as described in the column of "3. Pharmaceutical products" above.

Regarding the types and concentrations of brimonidine and/or its salt, buffer, chlorhexidine and its salt, benzalkonium chloride, and polyhexanide and its salt, which are used in the production method of the present invention, please refer to "6. Adsorption" above. As described in the column "Suppression method (2)".

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

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

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

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

Test Example 1: Evaluation of suppression of drug adsorption to filter (examination of the effects of buffering agents and metal chlorides)
An aqueous solution having the composition shown in Table 1 was prepared. The prepared aqueous solution was filtered using a filter (polyethersulfone membrane; PES membrane) with a pore size of 0.22 μm, and 0.6 g of the initial filtrate that passed through the filter was collected. Separately, the prepared aqueous solution 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 is STERIVEX-GP 0.22μm/Merck Millipore (pore size: 0.22μm, height: 67mm, diameter: 10cm ² , catalog number: SVGP01050), and the PVDF membrane is STERIVEX-GV 0.22μm. /Merck Millipore (pore diameter: 0.22 μm, height: 67 mm, diameter: 10 cm ² , catalog number: SVGV010RS) was used.

The brimonidine content in the aqueous solution before filtration and the aqueous solution (filtrate) after filtration was measured by liquid chromatography (High Performance Liquid Chromatograph: Prominence, manufactured by Shimadzu Corporation) under the following conditions.
(Measurement condition)
Detector : Ultraviolet absorption photometer (measurement wavelength: 230nm)
Column : Symmetry C18, 4.6 mm I. D. ×150mm, 3.5μm, manufactured by Waters
Column temperature : constant temperature around 40℃
Mobile phase A : Mixture of 4.3mM phosphoric acid aqueous solution/methanol/acetonitrile (volume ratio: 84/8/8)
Mobile phase B : Mixture of 4.3mM phosphoric acid aqueous solution/methanol/acetonitrile (volume ratio: 40/30/30)
Mobile phase delivery : Linear concentration gradient control was performed by changing the mixing ratio of mobile phase A and mobile phase B as follows.
Time after injection (min) Mobile phase A (vol%) Mobile phase B (vol%)
0.0～20.0 100 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 : 1.0mL/min
Temperature inside autosampler: 5℃

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

The results are shown in Table 1. When an aqueous solution containing brimonidine tartrate does not contain a buffer and a metal chloride (Comparative Example 1), the drug recovery rate after passing through a filter through a PES membrane is 94%, and 6% after filtration through a PES membrane. Brimonidine tartrate was adsorbed. In addition, even if the aqueous solution contains brimonidine tartrate and a buffer (borate buffer, phosphate buffer, trometamol, or citrate buffer), it does not contain metal chloride (Comparative Example 2, Comparative Examples 6 to 8). ), the drug recovery rate after passing through the filter through the PES membrane was equivalent to Comparative Example 1. Furthermore, even when an aqueous solution containing sodium edetate or a water-soluble polymer (carboxymethylcellulose or polyvinylpyrrolidone) together with brimonidine tartrate and a boric acid buffer does not contain a metal chloride (Comparative Examples 3 to 5), the PES membrane The drug recovery rate after passing through the filter was the same as in Comparative Example 1.

In contrast, it contains metal chlorides (sodium chloride, potassium chloride, calcium chloride, or magnesium chloride) along with brimonidine tartrate and a buffer (borate buffer, phosphate buffer, trometamol, or citrate buffer). In the aqueous solution, the drug recovery rate after passing through the filter through the PES membrane was significantly higher than in Comparative Example 1, indicating that the metal chloride has an effect of suppressing drug adsorption. Furthermore, as is clear from the comparisons between Example 3 and Comparative Example 2, Example 9 and Comparative Example 6, Example 11 and Comparative Example 7, and Example 12 and Comparative Example 8, among the buffering agents, boron When an acid buffer was used, the effect of improving the drug recovery rate after passing through the filter through the PES membrane was the highest.

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

Test Example 2: Evaluation of inhibition of drug adsorption to filter (examination of influence of surfactant and preservative)
An aqueous liquid preparation having the composition shown in Table 2 was 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 aqueous solutions (Comparative Examples 9 to 13) containing a surfactant (polysorbate 80, POE (60) hydrogenated castor oil, tyloxapol, poloxamer 407 or polyethylene glycol monostearate (40EO)) along with brimonidine tartrate and a borate buffer. The recovery rate of the drug after passing through the filters through the PES membrane and the PVDF membrane was equal to or lower than that of the aqueous liquid preparations containing no surfactant (Comparative Examples 1 and 2). In addition, for aqueous solutions containing chlorobutanol or sorbic acid used as preservatives (Comparative Examples 14 and 15) along with brimonidine tartrate and boric acid buffer, the drug recovery rate after passing through the filter through PES membrane and PVDF membrane was as follows: It was equivalent to Comparative Examples 1 and 2. In contrast, in aqueous solutions containing benzalkonium chloride, chlorhexidine gluconate, or polyhexanide hydrochloride (Examples 13 to 15) along with brimonidine tartrate and borate buffer, the drug after passing through the filter through the PES membrane and the PVDF membrane The recovery rate was improved compared to Comparative Examples 1 and 2, and the effect of suppressing drug adsorption to the PES membrane and PVDF membrane was recognized.

Claims (13)

A method for suppressing adsorption of brimonidine and/or its salt to a filter, the method comprising:
The aqueous solution to be passed through the filter contains only brimonidine and/or its salt, citric acid and/or its salt, metal chloride, tonicity agent, buffer, pH adjuster, preservative, and water ,
the metal chloride contains sodium chloride,
the tonicity agent comprises glycerin,
The method for suppressing adsorption , wherein the aqueous solution is provided in a multi-dose container without a filter . The adsorption suppression method according to claim 1, wherein the brimonidine and/or its salt is brimonidine tartrate. The adsorption suppression method according to claim 1 or 2, wherein the concentration of brimonidine and/or its salt in the aqueous liquid is 0.05 to 0.2 w/v%. The method for suppressing adsorption according to any one of claims 1 to 3, wherein the concentration of sodium chloride in the aqueous solution is 0.01 to 5 w/v%. The method for suppressing adsorption according to any one of claims 1 to 4 , wherein the aqueous solution is an eye drop. The method for suppressing adsorption according to any one of claims 1 to 5 , wherein the material of the filter is polyether sulfone or polyvinylidene fluoride. The adsorption suppression method according to any one of claims 1 to 6 , wherein the filter is a filter used in a filtration sterilization process. A method for producing an aqueous liquid drug provided in a multi-dose container without a filter, the method comprising:
Contains only brimonidine and/or a salt thereof, citric acid and/or a salt thereof, a metal chloride, an isotonic agent, a buffer, a pH adjuster, a preservative, and water, the metal chloride comprising sodium chloride, A step of preparing an aqueous solution in which the tonicity agent contains glycerin , and a step of subjecting the aqueous solution obtained in the step to a filtration sterilization step using a filter.
The method for producing the aqueous liquid formulation. The manufacturing method according to claim 8 , wherein the brimonidine and/or its salt is brimonidine tartrate. The manufacturing method according to claim 8 or 9 , wherein the concentration of brimonidine and/or its salt in the aqueous solution is 0.05 to 0.2 w/v%. The manufacturing method according to any one of claims 8 to 10 , wherein the concentration of metal chloride in the aqueous solution is 0.01 to 5 w/v%. The manufacturing method according to any one of claims 8 to 11 , wherein the aqueous solution is an eye drop. The manufacturing method according to any one of claims 8 to 12 , wherein the filter material is polyether sulfone or polyvinylidene fluoride.