JP6802943B2 - Aqueous solution - Google Patents

Description

The present invention relates to an aqueous liquid agent containing a water-soluble polymer and brimonidine and / or a salt thereof, which can suppress a decrease in viscosity over time and a decrease in the content of brimonidine and / or a salt thereof over time.

Brimonidine is a selective adrenergic α2 receptor agonist that suppresses the production of aqueous humor and promotes the outflow of aqueous humor through the uveoscleral outflow tract, thereby reducing intraocular pressure. Shown. For this reason, brimonidine and its salts are used in the treatment of glaucoma.

In order to enhance the bioavailability of the pharmacological component contained in the aqueous solution, the retention of the component in the ocular mucosa has been improved. For example, it is known that the retention of pharmacological components contained in the aqueous solution can be improved by blending a water-soluble polymer as a thickener or a thickener in the aqueous solution. Therefore, various techniques for formulating aqueous liquid preparations containing a water-soluble polymer have been studied (see, for example, Patent Documents 1 and 2).

Japanese Unexamined Patent Publication No. 2006-104114 International Publication No. 2008/0507776

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

According to the present inventor, an aqueous solution containing a water-soluble polymer, brimonidine and / or a salt thereof, and polyhexanide and / or a salt thereof can suppress a decrease in viscosity over time, and brimonidine and / or a salt thereof over time. It has been found that the decrease in the content of Brimonidine can be suppressed and excellent formulation stability can be provided. The present inventor has also found that an aqueous solution containing brimonidine and / or a salt thereof, and polyhexanide and / or a salt thereof can suppress a decrease in the content of brimonidine and / or a salt thereof over time. The present invention has been completed by further studies based on such findings.

As one embodiment of the present invention, the following aqueous liquid preparations are provided.
Item 1-1. An aqueous solution containing a water-soluble polymer, brimonidine and / or a salt thereof, and polyhexanide and / or a salt thereof.
Item 1-2. Item 2. The aqueous solution according to Item 1-1, wherein the water-soluble polymer contains at least one selected from a cellulosic polymer compound, a polyvinyl polymer compound and a polysaccharide.
Item 1-3. Item 2. The aqueous solution according to Item 1-2, wherein the cellulosic polymer compound contains carboxymethyl cellulose and / or a salt thereof.
Item 1-4. Item 3. The aqueous solution according to Item 1-3, wherein the 2% aqueous solution of carboxymethyl cellulose and / or a salt thereof has a viscosity of 25 to 35 Pa · s at 25 ° C.
Item 1-5. Item 3. The aqueous solution according to Item 1-3, wherein the 2% aqueous solution of carboxymethyl cellulose and / or a salt thereof has a viscosity of 300 to 400 Pa · s at 25 ° C.
Item 1-6. The degree of etherification of carboxymethyl cellulose and / or a salt thereof is 0.70 to 0
Item 2. The aqueous solution according to any one of Items 1-3 to 1-5, which is 0.85.
Item 1-7. The degree of etherification of carboxymethyl cellulose and / or a salt thereof is 0.79 to
Item 2. The aqueous solution according to any one of Items 1-3 to 1-6, which is 0.85.
Item 1-8. Item 2. The aqueous solution according to any one of Items 1-1 to 1-7, wherein the concentration of the water-soluble polymer is 0.1 to 2.0 w / v%.
Item 1-9. Brimonidine and / or a salt thereof is brimonidine tartrate, items 1-1 to 1-8.
The aqueous solution according to any one of.
Item 1-10. Item 2. The aqueous solution according to any one of Items 1-1 to 1-9, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.5 w / v%.
Item 1-11. Item 2. The aqueous solution according to any one of Items 1-1 to 1-10, wherein brimonidine and / or a salt thereof is 2.5 to 500 parts by mass per 100 parts by mass of the water-soluble polymer.
Item 1-12. Item 2. The aqueous solution according to any one of Items 1-1 to 1-11, wherein the polyhexanide and / or a salt thereof is polyhexanide hydrochloride.
Item 1-13. Item 2. The aqueous solution according to any one of Items 1-1 to 1-12, wherein the concentration of polyhexanide and / or a salt thereof is 0.01 to 30 ppm.
Item 1-14. Item 2. The aqueous solution according to any one of Items 1-1 to 1-13, wherein the amount of polyhexanide and / or a salt thereof is 0.0005 to 30 μg per 1 mg of the water-soluble polymer.
Item 1-15. The concentration of the water-soluble polymer is 0.1 to 2.0 w / v%, the concentration of brimonidine and / or its salt is 0.05 to 0.5 w / v%, and the concentration of polyhexanide and / or its salt. Item 2. The aqueous solution according to any one of Items 1-1 to 1-14, which has a concentration of 0.01 to 30 ppm.
Item 1-16. The water-soluble polymer is carboxymethyl cellulose and / or a salt thereof, brimonidine and / or a salt thereof is brimonidine tartrate, polyhexanide and / or a salt thereof is polyhexanide hydrochloride, and carboxymethyl cellulose and / or a salt thereof. Items 1-1 to 1-15, wherein the salt concentration is 0.5 w / v%, the brimonidine tartrate concentration is 0.1 w / v%, and the polyhexanide hydrochloride concentration is 0.1 to 10 ppm. The aqueous solution according to any one.
Item 1-17. Item 2. The aqueous solution according to Item 1-2, wherein the cellulosic polymer compound contains hydroxyethyl cellulose.
Item 1-18. Item 2. The aqueous solution according to Item 1-2, wherein the cellulosic polymer compound contains methyl cellulose.
Item 1-19. Item 2. The aqueous solution according to Item 1-2, wherein the polyvinyl-based polymer compound contains polyvinylpyrrolidone.
Item 1-20. Item 2. The aqueous solution according to Item 1-2, wherein the polysaccharide comprises hyaluronic acid and / or a salt thereof.
Item 1-21. Item 2. The aqueous solution according to Item 1-2, wherein the polysaccharide comprises xanthan gum and / or a salt thereof.
Item 1-22. When the aqueous liquid is stored at 60 ° C. for 2 weeks under light-shielding conditions immediately after preparation, the viscosity retention rate obtained from the viscosity of the aqueous liquid at 25 ° C. before and after storage is 90% or more, Item 1-1 to The aqueous liquid agent according to any one of 1-21.
Item 1-23. The brimonidine content retention rate obtained from the brimonidine content in the aqueous solution before and after storage when the aqueous solution is stored at 60 ° C. for 2 weeks under light-shielding conditions immediately after preparation is 97% or more, Item 1-1 to The aqueous solution according to any one of 1-22.
Item 1-24. Item 2. The aqueous solution according to any one of Items 1-1 to 1-23, which is a pharmaceutical composition.
Item 1-25. Item 2. The aqueous solution according to Item 1-1 to 1-24, which is an ophthalmic composition.
Item 1-26. Item 2. The aqueous solution according to Item 1-25, which is an eye drop.
Item 1-27. Item 2. The aqueous solution according to Item 1-26, which is used for the treatment of glaucoma.

Further, as an embodiment of the present invention, the following viscosity stabilizing method is provided.
Item 2-1. A method for stabilizing the viscosity of an aqueous solution containing a water-soluble polymer and brimonidine and / or a salt thereof.
A method for stabilizing viscosity, which comprises a step of coexisting a water-soluble polymer, brimonidine and / or a salt thereof, and polyhexanide and / or a salt thereof in an aqueous solution.

Further, as an embodiment of the present invention, the following viscosity stabilizers are provided.
Item 3-1. A viscosity stabilizer used to stabilize the viscosity of water-soluble polymers and aqueous liquids containing brimonidine and / or salts thereof.
A viscosity stabilizer comprising polyhexanide and / or a salt thereof.

Further, as an embodiment of the present invention, a method for stabilizing the content of brimonidine and / or a salt thereof listed below is provided.
Item 4-1. A method for stabilizing the content of brimonidine and / or a salt thereof in an aqueous solution containing brimonidine and / or a salt thereof.
A method for stabilizing the content of brimonidine and / or a salt thereof, which comprises a step of coexisting brimonidine and / or a salt thereof and polyhexanide and / or a salt thereof in an aqueous solution.
Item 4-2. Item 4. The method for stabilizing the content of brimonidine and / or a salt thereof according to Item 4-1 in which a water-soluble polymer coexists in the aqueous solution.

Further, as an embodiment of the present invention, the following brimonidine and / or a salt content stabilizer thereof is provided.
Item 5-1. A content stabilizer used to stabilize brimonidine and / or a salt thereof in an aqueous solution containing brimonidine and / or a salt thereof.
A content stabilizer for brimonidine and / or a salt thereof, which comprises polyhexanide and / or a salt thereof.
Item 5-2. Item 2. The agent for stabilizing the content of brimonidine and / or a salt thereof according to Item 5-1 in which the aqueous solution further contains a water-soluble polymer.

Further, as an embodiment of the present invention, the following aqueous liquid preparations are provided.
Item 6-1. An aqueous solution containing brimonidine and / or a salt thereof, and polyhexanide and / or a salt thereof.
Item 6-2. Item 2. The aqueous solution according to Item 6-1 which further contains a water-soluble polymer.

Since the aqueous solution of the present invention contains a water-soluble polymer and brimonidine and / or a salt thereof, it can suppress a decrease in viscosity over time, so that the retention of the drug can be maintained and the desired pharmacological effect can be obtained for a long period of time. Can be maintained.

Further, since the aqueous solution of the present invention can suppress a decrease in the content of brimonidine and / or a salt thereof over time, the content of brimonidine and / or a salt thereof can be stabilized, and a desired one based on brimonidine and / or a salt thereof is desired. The pharmacological effect can be maintained for a long period of time.

1. 1. Definitions It should be understood that the terms used herein are used in the meaning commonly used in the art unless otherwise noted. Thus, unless otherwise defined, all terminology and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In case of conflict, this specification (including definitions) takes precedence.

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

As used herein, the term "water-soluble polymer" refers to a polymer that is soluble in water.

As used herein, the term "cellulosic polymer compound" refers to a type of water-soluble polymer, which is a cellulosic derivative in which the hydroxyl group of cellulose is partially converted into another substituent.

In the present specification, "carboxymethyl cellulose" (hereinafter, also referred to as "CMC") is a kind of cellulosic polymer compound, and is a part of the hydroxyl group of glucose contained as a constituent unit of cellulose. Refers to a cellulose derivative in which a carboxymethyl group is ether-bonded.

In the present specification, the "viscosity of the CMC 2% aqueous solution" is the viscosity of the CMC 2% aqueous solution measured using a BM type viscometer at 25 ° C. When the viscosity of the CMC 2% aqueous solution is 25 to 35 mPa · s, the rotor No. When the viscosity of the CMC 2% aqueous solution is 300 to 400 mPa · s as measured using No. 1, the rotor No. 1 is measured at a rotation speed of 30 rpm. Measured using 2. The viscosity of the CMC 2% aqueous solution can be measured using a BM type viscometer manufactured by Toki Sangyo Co., Ltd. and its accessories. The "CMC 2% aqueous solution" is an aqueous solution in which CMC and / or a salt thereof is dissolved in purified water so as to be 2% by weight.

As used herein, the "weight average molecular weight of CMC and / or a salt thereof" is a value determined by a gel permeation chromatography (GPC) method using polystyrene as a standard substance. Specifically, it can be measured by a gel permeation chromatography (GPC) -differential refractive index detector (RI) system. The weight average molecular weight is a value calculated as a numerical value in terms of PEG.
(Operating conditions)
Eluent: 0.1M NaNO ₃
Flow velocity: 1 ml / min
Sample: 0.02-0.3% by weight
Solvent: 0.1M NaNO ₃
Injection volume: 200 μl
(apparatus)
Liquid transfer pump: Shodex DS-4 (manufactured by Showa Denko)
Degasser: ERC3115 (manufactured by ERC)
Column: Shodex SB-806MHQ (manufactured by Showa Denko)
Differential Refractometer: Shodex RI-71 (Showa Denko)

In the present specification, the "degree of etherification of CMC and / or its salt" is an index indicating the degree to which the OH group in anhydrous glucose in CMC and / or its salt is replaced with a carboxymethyl group, and is described below. It is a value obtained according to the method.
<Method of measuring the degree of etherification of CMC and / or its salt>
Weigh 0.5 to 0.7 g of the sample (anhydride) precisely, wrap it in filter paper, and incinerate it in a magnetic crucible. After cooling, this is transferred to a 500 mL beaker, 250 mL of water and 35 ml of 0.05 mol / L sulfuric acid are added, and the mixture is boiled for 30 minutes. This is cooled, a phenolphthalein indicator is added, excess acid is back titrated with 0.1 mol / L potassium hydroxide, and the degree of etherification is calculated according to the following formula.

The used to calculate degree of etherification "alkalinity" or "acidity", the alkali component contained the sample (anhydrous) 2 g in an aqueous solution dissolved in water _{^{200ml (OH -, CO 3 2-}} , HCO 3 ^It indicates the total amount of anions such as ⁻ ) or acids (cations such as H ⁺ ), and is a value obtained according to the following method.
<Measurement method of alkalinity or acidity>
Weigh 1 g of the sample (anhydride) precisely into a 300 ml Erlenmeyer flask, and add 200 ml of water to dissolve it. Add 5 ml of 0.05 mol / l sulfuric acid with a pipette, boil for 10 minutes, cool, add a phenolphthalein indicator, and titrate with 0.1 mol / l potassium hydroxide (S ml). At the same time, perform a blank test (B ml) and calculate by the following formula.

As used herein, the term "polyvinyl-based polymer compound" refers to a type of water-soluble polymer, which is a polymer compound obtained by homopolymerizing or copolymerizing a monomer having a vinyl group.

As used herein, the term "polysaccharide" refers to a type of water-soluble polymer, which is a natural polymer in which a monosaccharide is polymerized by a glycosidic bond.

As used herein, "brimonidine" is a compound known as an adrenergic α2 receptor agonist, and is 5-bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxaline-6-amine. Point to. Further, in the present specification, the concentration of brimonidine and / or a salt thereof is the concentration converted to brimonidine tartrate unless otherwise specified.

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

In the present specification, "polyhexanide" is a compound represented by the following general formula (1), and is a guanidine derivative also referred to as polyhexamethylene biguanidine (PHMB). Further, in the present specification, the concentration of polyhexanide and / or a salt thereof is a concentration converted to polyhexanide hydrochloride unless otherwise specified.

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

In the present specification, the "viscosity" of the aqueous solution is referred to as "2. Second method rotational viscometer method" of "2.53 Viscosity measurement method" specified in the general test method of the 17th revised Japanese Pharmacopoeia. 1.3. Conical-plate type rotational viscometer (cone plate type viscometer) ”(25 ° C, rotation speed 50 rpm, cone-plate type rotational viscometer, cone rotor used: 0.8 ° × R24) .. Specifically, the viscosity of the aqueous liquid agent can be measured using a viscometer TV-25 type (model: TVE-25L) manufactured by Toki Sangyo Co., Ltd. The viscosity of the aqueous liquid agent is appropriately set according to the purpose of use.

In the present specification, the "viscosity retention rate" is the ratio of the viscosity of the aqueous liquid agent immediately after preparation to the viscosity of the aqueous liquid agent after storage at 60 ° C. for 2 weeks under light-shielding conditions immediately after preparation, and is calculated by the following formula. Refers to the value obtained according to.

In the present specification, the notation such as "decrease in viscosity with time" means that the viscosity of the aqueous liquid agent decreases by storage for a certain period of time. For example, when the viscosity retention rate is less than 90%, " It can be said that "decrease in viscosity over time" is observed.

In the present specification, the notation such as "suppressing the decrease in viscosity over time" means that the decrease in viscosity of the aqueous solution after storage for a certain period of time can be suppressed as compared with the aqueous solution before storage. That is, it means that the viscosity retention rate of the aqueous liquid agent containing polyhexanide and / or its salt is higher than the viscosity maintenance rate of the aqueous liquid agent containing polyhexanide and / or its salt. Specifically, when the viscosity maintenance rate is 90% or more, it can be said that "the decrease in viscosity with time is suppressed".

In the present specification, the notation such as "stabilization of viscosity" means that the decrease in viscosity of the aqueous liquid agent over time due to storage for a certain period of time is suppressed and the viscosity is maintained. Specifically, when the viscosity retention rate is 90% or more, it can be said that "viscosity stabilization" is achieved.

In the present specification, the "brimonidine content retention rate" is the ratio of the brimonidine content in the aqueous solution immediately after preparation to the brimonidine content in the aqueous solution immediately after preparation and stored at 60 ° C. for 2 weeks under light-shielding conditions. Yes, it refers to the value obtained according to the following formula.

In the present specification, the notation such as "decrease in the content of brimonidine and / or its salt over time" means that the brimonidine content in the aqueous solution decreases after storage for a certain period of time, for example, the brimonidine content retention rate If it is less than 97%, it can be said that "decrease in the content of brimonidine and / or its salt over time" is observed.

In the present specification, the notation such as "suppressing the decrease in the content of brimonidine and / or its salt over time" means that the content of the brimonidine in the aqueous solution after storage for a certain period of time is lower than that in the aqueous solution before storage. It means that can be suppressed. That is, it means that the brimonidine content retention rate of the aqueous liquid preparation containing polyhexanide and / or its salt is higher than the brimonidine content maintenance rate of the aqueous liquid preparation containing polyhexanide and / or its salt. Specifically, when the brimonidine content maintenance rate is 97% or more, it can be said that "the decrease in the content of brimonidine and / or its salt over time is suppressed".

In the present specification, the notation such as "stabilization of the content of brimonidine and / or its salt" suppresses the decrease in the content of brimonidine and / or its salt over time in the aqueous solution, and the content of brimonidine and / or its salt thereof. Indicates that is maintained stable. Specifically, when the brimonidine content retention rate is 97% or more, it can be said that "the content of brimonidine and / or a salt thereof is stabilized".

As used herein, the term "formulation stability" refers to the degree to which the viscosity of an aqueous solution and the content of brimonidine and / or a salt thereof are maintained by storage for a certain period of time, and "stabilization of viscosity" and When "stabilizing the content of brimonidine and / or a salt thereof" is achieved, it can be said that the product has excellent "formulation stability".

As used herein, the term "viscosity stabilizing method" means a method used to suppress a decrease in viscosity of an aqueous solution containing a water-soluble polymer and brimonidine and / or a salt thereof, and to maintain a stable viscosity. ..

In the present specification, the "viscosity stabilizer" is added to suppress a decrease in viscosity of an aqueous liquid containing a water-soluble polymer and brimonidine and / or a salt thereof over time and maintain the viscosity stably. Means an agent. Examples of the "viscosity stabilizer" include a composition containing polyhexanide and / or a salt thereof or a polyhexanide and / or a salt thereof.

As used herein, the term "method for stabilizing the content of brimonidine and / or a salt thereof" means that the content of brimonidine and / or a salt thereof decreases with time in an aqueous solution containing a water-soluble polymer and brimonidine and / or a salt thereof. It means a method performed to suppress and maintain a stable content of brimonidine and / or a salt thereof.

As used herein, the term "brimonidine and / or its salt content stabilizer" means that the content of brimonidine and / or its salt decreases over time in an aqueous solution containing a water-soluble polymer and brimonidine and / or its salt. It means an agent added to suppress and maintain a stable content of brimonidine and / or a salt thereof. Examples of the "content stabilizer for brimonidine and / or a salt thereof" include a composition containing polyhexanide and / or a salt thereof itself or polyhexanide and / or a salt thereof.

In the present specification, "osmotic pressure of aqueous solution" is measured according to the method specified in "30. Osmotic pressure measurement method (osmolality measurement method)" of "General test method" of the 17th revised Japanese Pharmacopoeia. Is the value to be.

In the present specification, the "osmotic pressure ratio of the aqueous solution" refers to the ratio of the osmotic pressure of the aqueous solution to the osmotic pressure of the physiological saline solution (0.9 w / v% sodium chloride aqueous solution).

As used herein, the term "glaucoma" as used herein refers to the functional of the eye, which has characteristic changes in the optic nerve and visual field and can usually improve or suppress optic nerve damage by sufficiently lowering intraocular pressure. It means a disease characterized by structural abnormalities. In addition, "treatment" means alleviation, alleviation, or decrease in the rate of progression of a disease or symptom.

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

3. 3. Aqueous solution (1)
An aqueous liquid preparation containing a water-soluble polymer may have a problem that the viscosity of the liquid preparation decreases with time. Such a decrease in viscosity impairs the feeling of use and makes it impossible to exhibit the desired medicinal effect. Therefore, in the formulation design and quality assurance of aqueous liquid preparations (particularly eye drops) containing these water-soluble polymers. It is important to suppress the decrease in viscosity over time. Further, in the ophthalmic solution, the drug retention is maintained by keeping the viscosity constant, and the amount of the drug transferred to the treatment site is adjusted. Therefore, when the viscosity of the ophthalmic solution decreases, the amount of the drug transferred to the treatment site changes, so that effective treatment may not be possible. Since long-term administration of a drug is required for the treatment of glaucoma, it is particularly important to suppress the decrease in viscosity over time in the eye drops used for the treatment of glaucoma.

Conventionally, there have been reports on formulation techniques for suppressing a decrease in viscosity over time in an aqueous solution containing a water-soluble polymer. For example, Patent Document 1 reports that a decrease in viscosity can be suppressed by adding aspartic acid or a salt thereof to a mucosal application composition containing carboxymethyl cellulose. Further, Patent Document 2 reports that the stability of viscosity can be enhanced by blending gluconic acid or a metal salt thereof with an aqueous solution for ophthalmology containing hyaluronic acid. However, it is not known what effect polyhexanide and / or its salt has on the decrease in viscosity of the water-soluble polymer and the aqueous liquid containing brimonidine and / or its salt over time.

In addition, the present inventor states that in an aqueous solution containing a water-soluble polymer and brimonidine and / or a salt thereof, not only the viscosity decreases with time but also the content of brimonidine and / or a salt thereof decreases with time. I got to know. Such a decrease in the content of brimonidine and / or a salt thereof will reduce the efficacy of brimonidine and / or a salt thereof. Therefore, it is also extremely important to develop a formulation technology that suppresses a decrease in the content of brimonidine and / or its salt in the aqueous solution and maintains the content of brimonidine and / or its salt in a stable manner. However, it is known what effect polyhexanide and / or its salt has on the decrease in the content of brimonidine and / or its salt over time in aqueous solutions containing water-soluble polymers and brimonidine and / or its salt. Not done.

Under such circumstances, the present inventor found that an aqueous solution containing a water-soluble polymer, brimonidine and / or a salt thereof, and polyhexanide and / or a salt thereof can suppress a decrease in viscosity over time and over time. It has been found that a decrease in the content of brimonidine and / or a salt thereof can be suppressed, and excellent formulation stability can be provided.

That is, in one embodiment, the present invention provides an aqueous solution containing a water-soluble polymer, brimonidine and / or a salt thereof, and polyhexanide and / or a salt thereof. One aspect of the aqueous solution of the present invention solves the problem that the viscosity of the aqueous solution containing the water-soluble polymer and brimonidine and / or a salt thereof decreases with time. Further, in another aspect of the aqueous liquid preparation of the present invention, the problem that the content of brimonidine and / or its salt decreases with time in the water-soluble polymer and the aqueous liquid preparation containing brimonidine and / or its salt is solved. To. Hereinafter, the aqueous solution will be described.

[Water-soluble polymer]
The aqueous solution of the present invention contains a water-soluble polymer. The type of the water-soluble polymer used in the present invention is not particularly limited as long as it can impart a desired viscosity to the aqueous solution, and is not particularly limited as long as it is pharmaceutically acceptable. For example, a thickener. Alternatively, a water-soluble polymer used as a thickener can be mentioned. Specific examples of such a water-soluble polymer include cellulose-based polymer compounds, polyvinyl-based polymer compounds, and polysaccharides.

Among the water-soluble polymers, the cellulosic polymer compound includes, for example, carboxymethyl cellulose (hereinafter, may be referred to as "CMC"), hydroxyethyl cellulose (hereinafter, may be referred to as "HEC"), and methyl cellulose. (Hereinafter, it may be referred to as "MC"), hydroxypropyl cellulose, hydroxypropyl methyl cellulose, salts thereof and the like. These cellulosic polymer compounds may be used alone or in combination of two or more. Among these cellulosic polymer compounds, it is preferable from the viewpoint of more effectively suppressing the decrease in viscosity with time, or more effectively suppressing the decrease in the content of brimonidine and / or its salt with time. Can be CMC and / or a salt thereof, HEC, MC, or hydroxypropyl methylcellulose, more preferably CMC and / or a salt thereof. The cellulosic polymer compound in the form of a salt may be, for example, an alkali metal salt in the case of CMC. Examples of the alkali metal salt include CMC sodium and CMC potassium. From the viewpoint of more effectively suppressing the decrease in viscosity over time, or more effectively suppressing the decrease in the content of brimonidine and / or its salt over time, the alkali metal salt of CMC is preferably sodium CMC. Is good.

The weight average molecular weight of the CMC and / or a salt thereof used in the present invention is not particularly limited, and examples thereof include a weight average molecular weight of 20,000 to 700,000. As the molecular weight of CMC and / or its salt increases, the viscosity of the aqueous solution obtained by dissolving the CMC and / or its salt in purified water increases. From the viewpoint of more effectively suppressing the decrease in viscosity of the aqueous liquid agent of the present invention over time, the weight average molecular weight is preferably 30,000 to 100,000, more preferably 35,000 to 85,000. .. A preferred embodiment of the CMC and / or a salt thereof used in the present invention includes a weight average molecular weight of 35,000 to 42,000 from the viewpoint of more effectively suppressing a decrease in viscosity over time. .. In addition, the weight average molecular weight of another suitable embodiment of CMC and / or a salt thereof used in the present invention includes 75,000 to 85,000.

The viscosity characteristics of the CMC and / or a salt thereof used in the present invention are not particularly limited, and examples thereof include the viscosity of a 2% aqueous solution of CMC of about 25 to 400 mPa · s. As one aspect of the CMC and / or a salt thereof used in the present invention, there is a CMC and / or a salt thereof having a viscosity of a 2% aqueous solution of CMC of about 25 to 35 mPa · s. In addition, as another aspect of CMC and / or a salt thereof used in the present invention, CMC and / or a salt thereof having a viscosity of a 2% aqueous solution of CMC of about 300 to 400 mPa · s can be mentioned. From the viewpoint of more effectively suppressing the decrease in viscosity with time, CMC and / or a salt thereof having a CMC 2% aqueous solution viscosity of about 25 to 35 mPa · s is preferable.

The degree of etherification of the CMC and / or a salt thereof used in the present invention is not particularly limited, and examples thereof include 0.6 to 1.5. The degree of etherification of CMC and / or a salt thereof is preferably 0.70 to 0.85, more preferably 0.79 to 0.85, from the viewpoint of further stabilizing the viscosity of the aqueous liquid agent. ..

As one aspect of the CMC and / or its salt used in the present invention, the CMC and / or its salt having a viscosity of a 2% aqueous solution of CMC of 300 to 400 mPa · s and a degree of etherification of 0.70 to 0.85. Salt is mentioned. Further, as another aspect of CMC and / or a salt thereof used in the present invention, the viscosity of the CMC 2% aqueous solution is about 25 to 35 mPa · s, and the degree of etherification is 0.79 to 0.85. Examples include CMC and / or salts thereof. From the viewpoint of more effectively suppressing the decrease in viscosity over time, the CMC having a viscosity of about 25 to 35 mPa · s and an etherification degree of 0.79 to 0.85 is preferably used. / Or its salt.

Commercially available CMC and / or salts thereof used in the present invention can be used. Commercially available products of CMC sodium include, for example, cellogen (registered trademark) series PR-S (25 ° C., 2% aqueous solution having a viscosity of 25 mPa · s to 3) sold by Dai-ichi Kogyo Seiyaku Co., Ltd.
5 mPa · s, etherification degree 0.79 to 0.85), P-715A (25 ° C, 2% aqueous solution viscosity 80 mPa · s to 140 mPa · s, etherification degree 0.60 to 0.70), F -SC (25 ° C, 2% aqueous solution viscosity 300 mPa · s ~ 400 mPa · s, etherification degree 0.70 to 0.85), AG-GUM (25 ° C, 2% aqueous solution viscosity 900 mPa · s ~ 1500 mPa) -S, etherification degree 0.70 to 0.85), etc., CMC Daicel series sold by Daicel Chemical Industry Co., Ltd., Sunrose F series sold by Nippon Paper Chemicals Co., Ltd., etc. can be mentioned.

Among the water-soluble polymers, examples of the polyvinyl-based polymer compound include polyvinylpyrrolidone (hereinafter, may be referred to as “PVP”), polyvinyl alcohol, carboxyvinyl polymer (crosslinked polyacrylic acid polymer, etc.) and the like. Be done. These polyvinyl-based polymer compounds may be used alone or in combination of two or more. Among these polyvinyl-based polymer compounds, it is preferable from the viewpoint of more effectively suppressing the decrease in viscosity with time, or more effectively suppressing the decrease in the content of brimonidine and / or its salt with time. Examples include PVP, polyvinyl alcohol and / or carboxyvinyl polymer (crosslinked polyacrylic acid polymer, etc.), and more preferably PVP and / or polyvinyl alcohol.

Among the water-soluble polymers, examples of the polysaccharide include xanthan gum, chondroitin sulfate, hyaluronic acid (hereinafter, may be referred to as “HA”), alginic acid and the like. These polysaccharides may be in the form of salts. Examples of the polysaccharide in the form of a salt include alkali metal salts such as sodium chondroitin sulfate, sodium HA, and sodium alginate. These polysaccharides may be used alone or in combination of two or more. Among these polysaccharides, xanthan gum and xanthan gum are preferable from the viewpoint of more effectively suppressing the decrease in viscosity over time, or more effectively suppressing the decrease in the content of brimonidine and / or its salt over time. / Or HA sodium, more preferably HA sodium.

These water-soluble polymers may be used alone or in combination of two or more.

Among these water-soluble polymers, it is preferable from the viewpoint of more effectively suppressing the decrease in viscosity over time, or more effectively suppressing the decrease in the content of brimonidine and / or its salt over time. , Cellulose-based polymer compounds, and / or polyvinyl-based polymer compounds, more preferably cellulosic polymer compounds.

As one aspect of the aqueous liquid preparation of the present invention, the water-soluble polymer contains at least one selected from the group consisting of cellulosic polymers, polyvinyl-based polymer compounds, and polysaccharides, and substantially other additions. Examples include a mode that does not contain a viscous agent or a viscous agent. Further, as one aspect of the aqueous liquid preparation of the present invention, there is an embodiment in which the water-soluble polymer contains a cellulosic polymer and does not contain another thickener or a thickening agent. Further, as one aspect of the aqueous liquid preparation of the present invention, there is an aspect in which the water-soluble polymer contains a polyvinyl-based polymer and does not contain another thickener or thickener.

The concentration of the water-soluble polymer in the aqueous solution of the present invention may be appropriately set according to the type of the water-soluble polymer used, the viscosity to be imparted, and the like. For example, 0.1 to 2.0 / v. %. From the viewpoint of more effectively suppressing the decrease in viscosity over time, more effectively suppressing the decrease in the concentration of brimonidine and / or its salt over time, or maintaining the feeling of use, the water-soluble polymer The concentration is preferably 0.1 w / v% to 1.0 w / v%, more preferably 0.2 w / v% to 0.7 w / v%, and particularly preferably 0.3 to 0.6 w / v%. Can be mentioned.

[Brimonidine and / or its salt]
The aqueous solution of the present invention contains brimonidine and / or a salt thereof. The salt of brimonidine used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include organic acid salts and inorganic acid salts. Examples of the organic acid salt include tartrate salt and acetate. Examples of the inorganic acid salt include hydrochloride and the like. Further, brimonidine or a salt thereof may be in the form of a solvate such as a hydrate. Among brimonidine or salts thereof, brimonidine tartrate is preferably used because it is marketed as a pharmaceutical product and its safety has been established.

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

Examples of the concentration of brimonidine and / or a salt thereof in the aqueous solution of the present invention include 0.05 to 0.5 w / v%. From the viewpoint of more effectively suppressing the decrease in viscosity over time, more effectively suppressing the decrease in the concentration of brimonidine and / or its salt over time, or completely dissolving brimonidine and / or its salt. , Brimonidine and / or a salt thereof is preferably 0.1 w / v%, more preferably 0.1 w / v%.

In the aqueous solution of the present invention, the ratio of brimonidine and / or a salt thereof to the water-soluble polymer is not particularly limited, but for example, brimonidine and / or a salt thereof is 2.5 to 100 parts by mass of the water-soluble polymer. It is 500 parts by mass. From the viewpoint of improving the viscosity maintenance rate of the aqueous liquid agent or the brimonidine content maintenance rate of the aqueous liquid agent, 16.7 to 66.7 parts by mass is preferable, and 20 to 40 parts by mass is more preferable.

[Polyhexanide and / or its salt]
The aqueous solution of the present invention contains polyhexanide and / or a salt thereof. By containing polyhexanide and / or a salt thereof in an aqueous solution containing a water-soluble polymer and brimonidine and / or a salt thereof, a decrease in viscosity of the aqueous solution over time can be suppressed, and brimonidine in the aqueous solution can be further suppressed. And / or its salt content can be suppressed from decreasing over time.

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

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

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

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

In the aqueous solution of the present invention, one of polyhexanide and a salt thereof may be selected and used alone, or two or more of these may be used in combination.

Among the polyhexanide and its salts, preferably a salt of polyhexanide, more preferably an inorganic acid salt of polyhexanide, particularly preferably polyhexanide hydrochloride, from the viewpoint of more effectively suppressing the decrease in viscosity of the aqueous solution with time. Be done.

Examples of the concentration of polyhexanide and / or a salt thereof in the aqueous solution of the present invention include 0.01 to 30 ppm. The concentration of polyhexanide and / or its salt is preferable from the viewpoint of more effectively suppressing the decrease in viscosity over time, or more effectively suppressing the decrease in the content of brimonidine and / or its salt over time. Is 0.1 to 10 ppm, more preferably 0.5 to 10 ppm, and particularly preferably 1 to 10 ppm.

In the aqueous solution of the present invention, the ratio of polyhexanide and / or a salt thereof to the water-soluble polymer is not particularly limited, but for example, 0.0005 to 30 μg of polyhexanide and / or a salt thereof per 1 mg of the water-soluble polymer. The amount is preferably 0.02 to 3.3 μg, more preferably 0.2 to 2 μg.

[Buffering agent]
In one embodiment, the aqueous solution of the present invention may contain a buffer. The buffer used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and for example, a boric acid buffer, a citrate buffer, a phosphate buffer, a tris buffer, and a tartrate buffer. , Acetate buffer, amino acid buffer and the like.

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

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

Specific examples of the phosphoric acid buffer include phosphoric acid and / or a salt thereof. The salt of phosphate is not particularly limited as long as it is pharmaceutically acceptable, and for example, a disodium hydrogen phosphate dialkali metal salt such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; sodium dihydrogen phosphate. , Disodium dihydrogen phosphate alkali metal salt such as potassium dihydrogen phosphate; Examples thereof include trisodium phosphate trialkali metal salt such as trisodium phosphate and tripotassium phosphate. The salt of phosphoric acid may be in the form of a solvate such as a hydrate. For example, in the case of disodium hydrogen phosphate, the salt of phosphoric acid may be in the form of dihydrate, sodium dihydrogen phosphate. In some cases, it may be in the form of dihydrate or the like. As the phosphoric acid buffer, one type may be selected from phosphoric acid and a salt thereof and used alone, or two or more types may be used in combination. Among phosphoric acid and salts thereof, at least one of preferably a phosphate, more preferably a disodium hydrogen phosphate metal salt and a dihydrogen phosphate alkali metal salt, particularly preferably disodium hydrogen phosphate and dihydrogen phosphate. At least one of sodium is mentioned.

Specific examples of the Tris buffer include tromethamole and / or a salt thereof. The salt of tromethamole is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include organic acid salts such as acetate; and inorganic acid salts such as hydrochloride and sulfonate. As the trisic acid buffering agent, one type may be selected from tromethamole and a salt thereof and used alone, or two or more types may be used in combination. Among the trometamole and its salt, tromethamole is preferably mentioned.

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

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

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

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

Among these buffers, boric acid buffers are preferable from the viewpoint of more effectively suppressing the decrease in viscosity with time.

The concentration of the buffering agent in the aqueous solution of the present invention may be appropriately set within a range in which a desired buffering ability can be imparted to the aqueous solution, and examples thereof include 0.01 to 3 w / v%. From the viewpoint of more efficiently suppressing the decrease in viscosity over time or the decrease in brimonidine content over time, preferably 0.05 to 1 w / v%, more preferably 0.1 to 0.5 w / v%. Can be mentioned.

[Other additives]
In one embodiment, the aqueous solution of the present invention is an isotonic agent, a polyhydric alcohol, a surfactant, a chelating agent, a preservative or a preservative, a cooling agent, a stabilizer, a pH adjustment, if necessary. Additives such as agents may be included.

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

The polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include propylene glycol, butylene glycol, polyethylene glycol, and glycerin. These polyhydric alcohols may be used alone or in combination of two or more.

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

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

The preservative or preservative is not particularly limited as long as it is pharmaceutically acceptable, and for example, sorbic acid or a salt thereof, benzoic acid or a salt thereof, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoic acid. Propyl, chlorobutanol, benzalkonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, chlorhexidine acetate, dehydroacetic acid or salts thereof, benzethonium chloride, benzyl alcohol, zinc chloride, parachlormethoxylenol, chlorcresol, phenethyl alcohol, chloride Examples thereof include polydronium, timerosal and dibutylhydroxytoluene. These preservatives or preservatives may be used alone or in combination of two or more.

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

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

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

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

[Other pharmacological components]
In one embodiment, the aqueous solution of the present invention may contain a pharmacological component other than brimonidine and / or a salt thereof, if necessary. Examples of such pharmacological components include prostaglandins such as tafluprost, latanoprost, and isopropylunoprost; parasympathomimetic agents such as pilocarpine hydrochloride; anticholineresterase agents such as distigmine bromide; and sympathetic nerves such as dipivefrine hydrochloride. Stimulants; β ₁ blockers such as betaxolol hydrochloride; β blockers such as timolol maleate; α ₁ / β blockers such as nipradirol and levobnorol hydrochloride; α ₁ blockers such as bunazosin hydrochloride. .. These pharmacological components may be used alone or in combination of two or more. The concentration of these pharmacological components may be appropriately set according to the type of the pharmacological component used, the medicinal effect to be imparted, and the like.

In another embodiment, the aqueous solution of the present invention contains brimonidine and / or a salt thereof as a direct active ingredient for glaucoma, and substantially does not contain other active ingredients.

[Viscosity and viscosity retention rate]
The viscosity of the aqueous liquid agent of the present invention is not particularly limited, and examples thereof include 1.0 to 30 mPa · s as the viscosity immediately after preparation. From the viewpoint of further improving the viscosity retention rate of the aqueous liquid agent, 1.0 to 10 mPa · s is preferable, 1.5 to 8 mPa · s is more preferable, and 2.0 m to 4.0 mPa · s is particularly preferable.

Further, the aqueous solution of the present invention can have a high viscosity retention rate by containing polyhexanide and / or a salt thereof together with a water-soluble polymer and brimonidine and / or a salt thereof. The viscosity retention rate of the aqueous liquid agent of the present invention is not particularly limited, but one embodiment of the aqueous liquid agent of the present invention has a viscosity retention rate of, for example, 90% or more. From the viewpoint of suppressing the decrease in viscosity of the aqueous liquid agent over time, the viscosity retention rate is preferably 91% or more, more preferably 92% or more, particularly preferably 93% or more, still more preferably 94% or more, and most preferably 95. % Or more.

[PH]
The pH of the aqueous liquid preparation of the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include pH 5.0 to 8.0. When the aqueous solution of the present invention is used as an ophthalmic composition, the pH is preferably 6.7 to 7.5, from the viewpoint of further alleviating irritation to the eye applicable to the ophthalmic mucosa. More preferably, it is 6.9 to 7.1, particularly preferably 7.0 to 7.1, and even more preferably 7.0.

[Osmotic pressure / osmotic pressure ratio]
The osmotic pressure of the aqueous liquid agent of the present invention is not particularly limited as long as it can be applied to the intended use. For example, when applied to the ocular mucosa, the osmotic pressure is 250 to 350 mOsm / kg.

Further, the osmotic pressure ratio of the aqueous liquid agent of the present invention is not particularly limited as long as it can be applied to the intended use. For example, when applied to the ocular mucosa, the osmotic pressure ratio is 0.85 to 1.15. From the viewpoint of alleviating eye irritation, 0.9 to 1.1 is preferable, and 1.0 is more preferable.

[Brimonidine content retention rate]
The aqueous solution of the present invention can be provided with a high brimonidine content retention rate by adding polyhexanide and / or a salt thereof to a solution containing a water-soluble polymer and brimonidine and / or a salt thereof. There is. As one aspect of the aqueous liquid preparation of the present invention, the brimonidine content retention rate is, for example, 97% or more. From the viewpoint of more effectively suppressing the decrease in the content of brimonidine and / or a salt thereof over time, the brimonidine content maintenance rate is preferably 98% or more, more preferably 99% or more.

[Formulation form]
The formulation form of the aqueous liquid preparation of the present invention is not particularly limited and may be in the form of an aqueous solution, a suspension, an emulsion or the like, but an aqueous solution is preferable.

The aqueous solution of the present invention is prepared into pharmaceutical compositions for various purposes such as ophthalmology, dentistry, otolaryngology, and dermatology, and is used as a topically administered preparation. As one aspect of the aqueous liquid preparation of the present invention, a composition for ophthalmology, dentistry, otolaryngology, or dermatology can be mentioned, and an ophthalmic composition is preferable.

Specific examples of the ophthalmic composition include eye drops, eyewashes, contact lens preparations, injections and the like. Among these, eye drops are preferably mentioned.

[Use / Dose / Usage]
Brimonidine and / or a salt thereof contained in the aqueous solution of the present invention can suppress the production of aqueous humor and reduce intraocular pressure. Therefore, in one aspect of the aqueous solution of the present invention, as an eye drop. Provided, glaucoma can be suitably used for therapeutic applications.

When the aqueous solution of the present invention is used as an eye drop, one drop may be instilled once or multiple times a day. Further, in one aspect of the aqueous liquid preparation of the present invention, one drop is instilled twice a day.

[container]
The container for containing the aqueous solution of the present invention is not particularly limited, and may be a conventional container containing a pharmaceutical composition. For example, when the aqueous solution of the present invention is an eye drop, the conventional container may be used. The one used as an eye drop container can be used. The material of the container for accommodating the aqueous liquid agent of the present invention is not particularly limited, and may be made of glass or plastic. When a plastic container is used as a container for accommodating the aqueous liquid agent of the present invention, the constituent material of the plastic container is not particularly limited, but for example, polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene, polyethylene, or polyimide. Examples thereof include any one type or two or more types of blended polymers. From the viewpoint of more efficiently suppressing the decrease in brimonidine content over time, the material of the container body (member forming the accommodating portion for accommodating the ophthalmic composition) is preferably polyethylene or polypropylene, more preferably. Polyethylene can be mentioned.

[Production method]
The aqueous solution of the present invention may be produced according to a known preparation method according to the formulation form thereof, and can be produced, for example, by using the method described in the 17th revised Japanese Pharmacopoeia General Regulations for Formulation.

Specifically, in one embodiment, the method for producing an aqueous solution of the present invention comprises a water-soluble polymer, brimonidine and / or a salt thereof, and a polyhexanide and / or a salt thereof in a pharmaceutically acceptable aqueous solution. Includes a step of blending into the medium. The "pharmaceutically acceptable aqueous medium" means a pharmaceutically acceptable aqueous medium, and examples thereof include purified water. Further, in the compounding step, the compounding order of each component is not particularly limited, and may be sequentially compounded in any order, or may be compounded at the same time. Further, after the compounding step, a sterilization process such as filter sterilization, filtration sterilization, dry heat sterilization, electron beam sterilization, and gamma ray sterilization may be performed, if necessary.

4. Viscosity Stabilization Method One embodiment of the present invention is a method for stabilizing the viscosity of a water-soluble polymer and an aqueous solution containing brimonidine and / or a salt thereof, wherein the water-soluble polymer, brimonidine and / Or a method for stabilizing the viscosity, which comprises a step of coexisting a salt thereof and a polyhexanide and / or a salt thereof.

According to the viscosity stabilizing method of the present invention, it is possible to provide an aqueous liquid agent containing a water-soluble polymer and brimonidine and / or a salt thereof, which can suppress a decrease in viscosity with time and can maintain a stable viscosity. Becomes possible.

The method for stabilizing the viscosity of the present invention is carried out, for example, by blending a water-soluble polymer, brimonidine and / or a salt thereof, and polyhexanide and / or a salt thereof in an aqueous medium (for example, purified water). The order of addition of these components is not particularly limited. In addition, each component to be blended may be in a solid state or in a liquid state.

In the viscosity stabilizing method of the present invention, the type and concentration of a water-soluble polymer, the type and concentration of brimonidine and / or a salt thereof, the type and concentration of polyhexanide and / or a salt thereof, and other additives to be added to an aqueous solution. And the types of pharmacological components, viscosity, pH, osmotic pressure, formulation form, use, etc. of the aqueous solution are as described in the column of "3. Aqueous solution (1)".

5. Viscosity Stabilizer As an embodiment of the present invention, there is provided an agent used for stabilizing the viscosity of a water-soluble polymer and an aqueous liquid preparation containing brimonidine and / or a salt thereof. Examples of the viscosity stabilizer include polyhexanide and / or a salt thereof itself, or a composition containing polyhexanide and / or a salt thereof.

According to the viscosity stabilizer of the present invention, an aqueous solution containing a water-soluble polymer and brimonidine and / or a salt thereof can be provided with an effect of suppressing a decrease in viscosity over time, and an aqueous solution capable of maintaining a stable viscosity. It becomes possible to provide a liquid agent.

The viscosity stabilizers of the present invention may be provided in the form of liquids or solids (eg powders or tablets).

The type and concentration of polyhexanide and / or a salt thereof used in the viscosity stabilizer of the present invention are as described in the column of "3. Aqueous solution (1)". Further, in the viscosity stabilizer of the present invention, the type and concentration of the water-soluble polymer contained in the aqueous liquid agent to be applied, the type and concentration of brimonidine and / or a salt thereof, and other additives and pharmacological components to be blended. The type, viscosity, pH, osmotic pressure, formulation form, application, etc. of the aqueous solution are also as described in the column of "3. Aqueous solution (1)".

6. Method for Stabilizing the Content of Brimonidine and / or its Salt As an embodiment of the present invention , a method for stabilizing the content of brimonidine and / or its salt in an aqueous solution containing brimonidine and / or its salt, which is an aqueous solution. Provided is a content stabilization method comprising a step of coexisting a water-soluble polymer, brimonidine and / or a salt thereof, and polyhexanide and / or a salt thereof.

According to the content stabilization method of the present invention, a decrease in the content of brimonidine and / or its salt in an aqueous solution containing brimonidine and / or a salt thereof can be suppressed with time, and brimonidine and / or a salt thereof can be stably maintained. It becomes possible to provide an aqueous liquid preparation that can be produced.

In one embodiment of the content stabilization method of the present invention, the aqueous solution containing brimonidine and / or a salt thereof may further contain a water-soluble polymer.

The content stabilization method of the present invention is carried out, for example, by blending brimonidine and / or a salt thereof, and polyhexanide and / or a salt thereof in an aqueous medium (for example, purified water, etc.), and addition of these components. The order is not particularly limited. In addition, each component to be blended may be in a solid state or in a liquid state.

In the content stabilization method of the present invention, the type and concentration of brimonidine and / or a salt thereof, the type and concentration of polyhexanide and / or a salt thereof, are as described in the column of "3. Aqueous solution (1)". Further, in the content stabilization method of the present invention, the type and concentration of the water-soluble polymer used as necessary, the types of other additives and pharmacological components blended in the aqueous solution, the viscosity and pH of the aqueous solution, The osmotic pressure, formulation form, application, etc. are also as described in the column of "3. Aqueous solution (1)".

7. Brimonidine and / or its salt content stabilizer As an embodiment of the present invention, an agent added to stabilize the content of brimonidine and / or its salt in an aqueous solution containing brimonidine and / or its salt is used. provide. Examples of the content stabilizer include polyhexanide and / or a salt thereof itself, or a composition containing polyhexanide and / or a salt thereof.

According to the content stabilizer of the present invention, an aqueous solution containing brimonidine and / or a salt thereof can be given an effect of suppressing a decrease in the content of brimonidine and / or a salt thereof over time, and brimonidine and / or a salt thereof can be imparted. It becomes possible to provide an aqueous liquid preparation capable of stably maintaining the salt content.

In one embodiment of the content stabilizer of the present invention, the aqueous solution to be applied may contain a water-soluble polymer in addition to brimonidine and / or a salt thereof.

The content stabilizers of the present invention may be provided in the form of liquids or solids (eg, powders or tablets).

The types and concentrations of polyhexanide and / or salts thereof used in the content stabilizer of the present invention are as described in the column of "3. Aqueous solution (1)". Further, in the content stabilizer of the present invention, the type and concentration of brimonidine and / or a salt thereof contained in the applicable aqueous liquid preparation, the type and concentration of the water-soluble polymer used as necessary, and the blending are added. The types of other additives and pharmacological components, the viscosity, pH, osmotic pressure, formulation form, use, etc. of the aqueous solution are also as described in the column of "3. Aqueous solution (1)".

8. Aqueous solution (2)
As an embodiment of the present invention, there is provided an aqueous solution containing brimonidine and / or a salt thereof, and polyhexanide and / or a salt thereof. The aqueous solution can suppress a decrease in the content of brimonidine and / or a salt thereof over time. The aqueous solution of such an embodiment may further contain a water-soluble polymer.

In the aqueous solution of such an embodiment, the type and concentration of brimonidine and / or a salt thereof, and the type and concentration of polyhexanide and / or a salt thereof are as described in the column of "3. Aqueous solution (1)". Further, in the aqueous solution of the above embodiment, the type and concentration of the water-soluble polymer to be blended as necessary, the types of other additives and pharmacological components to be blended in the aqueous solution, the viscosity, pH and penetration of the aqueous solution. The pressure, formulation form, application, etc. are also as described in the column of "3. Aqueous solution (1)".

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.

Test Example 1: Evaluation of change in viscosity of aqueous solution [Preparation of aqueous solution]
An aqueous solution was prepared according to the formulation shown in Table 1. Each aqueous solution was isotonic by adding an appropriate amount of sodium chloride, and the pH was adjusted with hydrochloric acid or sodium hydroxide.

[Accelerated deterioration test]
The aqueous solution immediately after preparation was filtered through a 0.22 μm filter, and 5 mL thereof was filled in a 5 mL colorless glass ampoule. Each glass ampoule was placed in a tabletop thermo-hygrostat (NST-80, Nagano Science Co., Ltd.) and stored at 60 ° C. for 2 weeks under light-shielding conditions.

[Viscosity measurement]
The viscosity of the aqueous liquid is determined by "2.1.3. Conical-flat plate" of "2. Second method rotational viscometer method" of "2.53 viscosity measurement method" specified in the 17th revised Japanese Pharmacopoeia general test method. According to the "type rotary viscometer (cone plate type viscometer)", the measurement was performed at 25 ° C. and a rotation speed of 50 rpm using a TVE-25 type viscometer (cone plate) (TVE-25L, Toki Sangyo Co., Ltd.). As the cone rotor, 0.8 ° × R24 (rotor code: 00) was used. Viscosity measurements were performed before and after the accelerated aging test. The viscosity retention rate (%) of the aqueous liquid agent was calculated according to the following formula.

[Test results]
The results obtained are shown in Table 1. The aqueous solution containing CMC sodium and brimonidine tartrate and not containing polyhexanide hydrochloride (Comparative Example 1) had a viscosity retention rate of 88% after storage at 60 ° C. for 2 weeks, which was less than 90%. On the other hand, in the aqueous liquid preparation containing polyhexanide hydrochloride together with CMC sodium and brimonidine tartrate (Examples 1 to 6), the viscosity retention rate was 90% or more, and the viscosity retention rate was improved depending on the concentration of polyhexanide hydrochloride. Was.

Further, in the aqueous solution (Examples 4 to 6) using CMC sodium B having a low viscosity of CMC 2% aqueous solution of 25 to 35 mPa · s as CMC sodium, the viscosity of CMC 2% aqueous solution is as high as 300 to 400 mPa · s. Compared with the case where sodium A was used (Examples 1 to 3), the viscosity retention rate was higher.

Test Example 2: Evaluation of change in brimonidine content in aqueous solution [Preparation of aqueous solution]
An aqueous solution was prepared according to the formulation shown in Table 2. Each aqueous solution was isotonic by adding an appropriate amount of sodium chloride, and the pH was adjusted with hydrochloric acid or sodium hydroxide.

[Accelerated deterioration test]
The aqueous solution immediately after preparation was filtered through a 0.22 μm filter, and 5 mL thereof was filled in a 5 mL colorless glass ampoule. Each glass ampoule was placed in a tabletop thermo-hygrostat (NST-80, Nagano Science Co., Ltd.) and stored at 60 ° C. for 2 weeks under light-shielding conditions.

[Measurement of brimonidine content]
The brimonidine content in the aqueous solution was measured by liquid chromatography (High Performance Liquid Chromatography manufactured by Shimadzu Corporation) under the following conditions.
(Measurement condition)
Detector: Ultraviolet absorptiometer (measurement wavelength: 230 nm)
Column: Symmetry C18, 4.6 mm I. D. × 150 mm, 3.5 μm,
Waters column temperature: constant temperature around 40 ° C Mobile phase: 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile mixed solution gradient flow rate: 1.0 mL / min

In addition, the brimonidine content maintenance rate was calculated according to the following formula.

[Test results]
The results obtained are shown in Table 2. The aqueous liquid preparations containing brimonidine tartrate and not polyhexanide hydrochloride (Comparative Examples 1 and 2) had a brimonidine content retention rate of less than 97% after storage at 60 ° C. for 2 weeks. On the other hand, in the aqueous solution containing brimonidine tartrate and polyhexanide hydrochloride (Examples 1 to 6), the brimonidine content retention rate was 97% or more, and the brimonidine content retention rate improved depending on the concentration of polyhexanide hydrochloride. Was there.

Test Example 3: Evaluation of change in viscosity of aqueous solution [preparation of aqueous solution]
An aqueous solution was prepared according to the formulation shown in Table 3. Each aqueous solution was isotonic by adding an appropriate amount of sodium chloride, and the pH was adjusted with hydrochloric acid or sodium hydroxide.

[Accelerated deterioration test]
An accelerated deterioration test was conducted under the same conditions as in Test Example 1.

[Viscosity measurement]
Under the same conditions as in Test Example 1, the viscosity of the aqueous liquid before and after the accelerated deterioration test was measured, and the viscosity retention rate (%) was calculated.

[Test results]
The results obtained are shown in Table 3. An aqueous solution containing polyhexanide hydrochloride together with a water-soluble polymer (HA sodium, HEC, xanthan gum or PVP) and brimonidine tartrate (Examples 7 to 10) had a viscosity retention rate of 90% or more, and the viscosity retention rate was increased by polyhexanide hydrochloride. Was improved.

Test Example 4: Evaluation of change in brimonidine content in aqueous solution [Preparation of aqueous solution]
An aqueous solution was prepared according to the formulation shown in Table 4. Each aqueous solution was isotonic by adding an appropriate amount of sodium chloride, and the pH was adjusted with hydrochloric acid or sodium hydroxide.

[Accelerated deterioration test]
An accelerated deterioration test was conducted under the same conditions as in Test Example 2.

[Measurement of brimonidine content]
Under the same conditions as in Test Example 2, the brimonidine content in the aqueous solution before and after the accelerated deterioration test was measured, and the brimonidine content retention rate (%) was calculated.

[Test results]
The results obtained are shown in Table 4. In the aqueous liquid preparation containing brimonidine tartrate and polyhexanide hydrochloride (Examples 11 to 16), the brimonidine content retention rate was 97% or more, and the brimonidine content retention rate was improved depending on the concentration of polyhexanide hydrochloride.

Comprehensive Discussion From the results of Test Examples 1 to 4, the aqueous solution containing a water-soluble polymer (CMC sodium, HA sodium, HEC, MC, xanthan gum or PVP), brimonidine tartrate, and polyhexanide hydrochloride showed a decrease in viscosity over time. It was confirmed that it was possible to suppress the decrease in the content of brimonidine tartrate over time, and it was clarified that it had excellent formulation stability. It was also clarified that by adding polyhexanide hydrochloride together with brimonidine tartrate in the aqueous solution, the decrease in brimonidine tartrate content over time can be suppressed.

Production Example As a specific embodiment of the ophthalmic composition of the present invention, eye drops of the components shown in Tables 5 to 7 can be mentioned. In Tables 5 to 7, CMC sodium A is "Cerogen F-SC" (Daiichi Kogyo Seiyaku Co., Ltd.) (viscosity of 2% aqueous solution of CMC: 300 to 400 mPa · s, degree of etherification: 0.70 to 0.85). CMC sodium B is "Cerogen PR-S" (Daiichi Kogyo Seiyaku Co., Ltd.) (viscosity of CMC 2% aqueous solution: 25 to 35 mPa · s, degree of etherification: 0.79 to 0.85), polyhexanide hydrochloride is Ark Pharm Made by Inc. was used.

Claims (5)

An aqueous solution containing brimonidine and / or a salt thereof, and polyhexanide and / or a salt thereof (provided that a cellulosic polymer compound, a polyvinyl polymer compound, or a polysaccharide is contained, or a benzalkonium ion is contained . except). The aqueous solution according to claim 1, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.1 w / v%. The aqueous solution according to claim 1 or 2, wherein the concentration of polyhexanide and / or a salt thereof is 0.01 to 30 ppm. A method for stabilizing the content of brimonidine and / or a salt thereof in an aqueous solution containing brimonidine and / or a salt thereof.
Brimonidine and / or a salt thereof, and polyhexanide and / or its in an aqueous solution (except when it contains a cellulosic polymer compound, a polyvinyl polymer compound, or a polysaccharide , and when it contains a benzalkonium ion ). A method for stabilizing the content of brimonidin and / or a salt thereof, which comprises a step of coexisting a salt. Brimonidine and / or its in an aqueous solution containing brimonidine and / or a salt thereof (except when it contains a cellulosic polymer compound, a polyvinyl polymer compound, or a polysaccharide , and when it contains a benzalkonium ion ). A content stabilizer used to stabilize salts,
A content stabilizer for brimonidine and / or a salt thereof, which comprises polyhexanide and / or a salt thereof.