JP2020100614A - Aqueous liquid formulation - Google Patents

Abstract

To provide a formulation technique pertaining to an aqueous liquid formulation that contains a water-soluble polymer, and brimonidine and/or a salt thereof.SOLUTION: An aqueous liquid formulation containing a water-soluble polymer, brimonidine and/or a salt thereof, and polyhexanide and/or a salt thereof can suppress decreases in viscosity over time, can also suppress decreases in the content of brimonidine and/or salt thereof over time, and can provide excellent formulation stability.SELECTED DRAWING: None

Description

The present invention relates to an aqueous liquid preparation containing a water-soluble polymer and brimonidine and/or a salt thereof, but capable of suppressing a decrease in viscosity with time and a decrease in the content of brimonidine and/or a salt with 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 the intraocular pressure. Show. Therefore, brimonidine and its salts are used for the treatment of glaucoma.

In order to enhance the bioavailability of the pharmacological component contained in the aqueous liquid preparation, the retention of the component on the ocular mucosa has been improved. For example, it is known that by mixing a water-soluble polymer as a thickening agent or a thickening agent in an aqueous liquid preparation, the retention of the pharmacological component contained in the aqueous liquid preparation can be improved. Therefore, various techniques for formulation of an aqueous liquid agent containing a water-soluble polymer have been conventionally studied (see, for example, Patent Documents 1 and 2).

JP, 2006-104114, A International Publication No. 2008/0507776

An object of the present invention is to provide a formulation technology regarding 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 liquid preparation containing brimonidine and/or a salt thereof.

The present inventor has found that an aqueous liquid agent containing a water-soluble polymer, brimonidine and/or a salt thereof, and polyhexanide and/or a salt thereof can suppress a decrease in viscosity with time, and also have a brimonidine and/or salt thereof with time. It has been found that it is possible to suppress the decrease in the content of sucrose and to provide excellent formulation stability. 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 agent is provided.
Item 1-1. An aqueous liquid preparation comprising a water-soluble polymer, brimonidine and/or a salt thereof, and polyhexanide and/or a salt thereof.
Item 1-2. Item 1. The aqueous liquid preparation according to Item 1-1, wherein the water-soluble polymer contains at least one selected from a cellulose-based polymer compound, a polyvinyl-based polymer compound, and a polysaccharide.
Item 1-3. Item 3. The aqueous liquid preparation according to Item 1-2, wherein the cellulose-based polymer compound contains carboxymethyl cellulose and/or a salt thereof.
Item 1-4. Item 3. The aqueous liquid preparation according to Item 1-3, wherein a 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 2. The aqueous liquid preparation according to Item 1-3, wherein a 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. Item 3. The aqueous liquid preparation according to any one of Items 1-3 to 1-5, wherein the degree of etherification of carboxymethyl cellulose and/or its salt is 0.70 to 0.85.
Item 1-7. Item 7. The aqueous liquid preparation according to any one of Items 1-3 to 1-6, wherein the degree of etherification of carboxymethyl cellulose and/or its salt is 0.79 to 0.85.
Item 1-8. Item 1. The aqueous liquid preparation 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. Item 11. The aqueous liquid preparation according to any one of items 1-1 to 1-8, wherein the brimonidine and/or the salt thereof is brimonidine tartrate.
Item 1-10. Item 1. The aqueous liquid preparation according to any one of Items 1-1 to 1-9, wherein the concentration of brimonidine and/or its salt is 0.05 to 0.5 w/v%.
Item 1-11. Item 1. The aqueous liquid preparation according to any one of items 1-1 to 1-10, wherein the amount of brimonidine and/or its salt is 2.5 to 500 parts by mass based on 100 parts by mass of the water-soluble polymer.
Item 1-12. Item 12. The aqueous liquid preparation according to any one of Items 1-1 to 1-11, wherein the polyhexanide and/or its salt is polyhexanide hydrochloride.
Item 1-13. Item 13. The aqueous liquid preparation according to any one of Items 1-1 to 1-12, wherein the concentration of polyhexanide and/or its salt is 0.01 to 30 ppm.
Item 1-14. The aqueous liquid preparation according to any one of Items 1-1 to 1-13, wherein the amount of polyhexanide and/or its salt 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 is Item 15. The aqueous liquid preparation 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 carboxymethylcellulose and/or a salt thereof, brimonidine and/or a salt thereof is brimonidine tartrate, polyhexanide and/or a salt thereof is polyhexanide hydrochloride, and carboxymethylcellulose and/or a salt thereof. The concentration of salt is 0.5 w/v%, the concentration of brimonidine tartrate is 0.1 w/v%, and the concentration of polyhexanide hydrochloride is 0.1 to 10 ppm. The aqueous liquid preparation according to any of the above.
Item 1-17. Item 3. The aqueous liquid preparation according to Item 1-2, wherein the cellulose-based polymer compound contains hydroxyethyl cellulose.
Item 1-18. Item 3. The aqueous liquid preparation according to Item 1-2, wherein the cellulose-based polymer compound contains methyl cellulose.
Item 1-19. Item 3. The aqueous liquid preparation according to Item 1-2, wherein the polyvinyl polymer compound contains polyvinylpyrrolidone.
Item 1-20. Item 3. The aqueous liquid preparation according to Item 1-2, wherein the polysaccharide contains hyaluronic acid and/or a salt thereof.
Item 1-21. Item 3. The aqueous liquid preparation according to Item 1-2, wherein the polysaccharide contains xanthan gum and/or a salt thereof.
Item 1-22. When the aqueous solution is stored for 2 weeks at 60°C under shading conditions immediately after preparation, the viscosity retention rate obtained from the viscosity of the aqueous solution before and after storage at 25°C is 90% or more. The aqueous liquid preparation according to any one of 1-21.
Item 1-23. Item 1-1-wherein the brimonidine content maintenance rate, which is determined from the brimonidine content in the aqueous liquid agent before and after storage, is 97% or more when the aqueous liquid agent is stored for 2 weeks at 60°C under shading conditions immediately after preparation. The aqueous liquid preparation according to any one of 1-22.
Item 1-24. Item 24. The aqueous liquid preparation according to any one of items 1-1 to 1-23, which is a pharmaceutical composition.
Item 1-25. Item 1. The aqueous liquid preparation according to Items 1-1 to 1-24, which is an ophthalmic composition.
Item 1-26. Item 1. The aqueous liquid preparation according to Item 1-25, which is an eye drop.
Item 1-27. Item 1. The aqueous liquid preparation according to Item 1-26, which is used for treatment of glaucoma.

In addition, as one 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, comprising:
A method for stabilizing viscosity, comprising a step of allowing a water-soluble polymer, brimonidine and/or a salt thereof, and polyhexanide and/or a salt thereof to coexist in an aqueous liquid preparation.

In addition, the following viscosity stabilizers are provided as one embodiment of the present invention.
Item 3-1. A viscosity stabilizer used for stabilizing the viscosity of an aqueous solution containing a water-soluble polymer and brimonidine and/or a salt thereof, comprising:
A viscosity stabilizer containing polyhexanide and/or a salt thereof.

Further, as one embodiment of the present invention, the following method for stabilizing the content of brimonidine and/or its salt is provided.
Item 4-1. A method for stabilizing the content of brimonidine and/or its salt in an aqueous solution containing brimonidine and/or its salt,
A method for stabilizing the content of brimonidine and/or its salt, which comprises the step of coexisting brimonidine and/or its salt and polyhexanide and/or its salt in an aqueous liquid preparation.
Item 4-2. Item 4. The method for stabilizing the content of brimonidine and/or its salt according to Item 4-1, wherein a water-soluble polymer is further allowed to coexist in the aqueous liquid preparation.

In addition, as one embodiment of the present invention, the following content stabilizer for brimonidine and/or its salt is provided.
Item 5-1. A content stabilizer used for stabilizing brimonidine and/or its salt in an aqueous solution containing brimonidine and/or its salt,
A content stabilizer for brimonidine and/or its salt, which contains polyhexanide and/or its salt.
Item 5-2. Item 5. The brimonidine and/or its salt content stabilizer according to Item 5-1, wherein the aqueous liquid preparation further contains a water-soluble polymer.

In addition, as one embodiment of the present invention, the following aqueous liquid agents are provided.
Item 6-1. An aqueous liquid preparation containing brimonidine and/or a salt thereof and polyhexanide and/or a salt thereof.
Item 6-2. Item 6. The aqueous liquid preparation according to Item 6-1, further containing a water-soluble polymer.

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

In addition, the aqueous liquid preparation of the present invention can suppress the decrease in the content of brimonidine and/or its salt over time, so that the content of brimonidine and/or its salt can be stabilized, and a desired amount based on brimonidine and/or its salt can be obtained. The pharmacological effect can be maintained for a long period of time.

1. Definitions It is to be understood that the terms used in this specification have meanings 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. In case of conflict, the present specification, including definitions, will control.

In the present specification, the “aqueous liquid formulation” is a formulation which contains water as a base and assumes a liquid form.

In the present specification, the "water-soluble polymer" refers to a water-soluble polymer.

In the present specification, the “cellulosic polymer compound” is a kind of water-soluble polymer and refers to a cellulose derivative in which a hydroxyl group of cellulose is partially converted into another substituent.

In the present specification, “carboxymethyl cellulose” (hereinafter, also referred to as “CMC”) is one kind of a cellulose-based polymer compound, and is a part of the hydroxyl group of glucose contained as a constituent unit of cellulose. This refers to a cellulose derivative in which a carboxymethyl group has an ether bond.

In the present specification, the “viscosity of CMC 2% aqueous solution” is the viscosity of the CMC 2% aqueous solution measured at 25° C. using a BM type viscometer. 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, the rotor No. 1 is rotated at a rotation speed of 30 rpm. 2 is used. The viscosity of a 2% CMC 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.

In the present specification, the “weight average molecular weight of CMC and/or a salt thereof” is a value obtained by a gel filtration chromatography (GPC) method using polystyrene as a standard substance. Specifically, it can be measured by gel filtration chromatography (GPC)-differential refractive index detector (RI) system. The weight average molecular weight is a value calculated as a PEG-converted numerical value.
(Operating conditions)
Eluent: 0.1M NaNO ₃
Flow rate: 1 ml/min
Sample: 0.02-0.3% by weight
Solvent: 0.1M NaNO ₃
Injection volume: 200 μl
(apparatus)
Liquid delivery pump: Shodex DS-4 (Showa Denko)
Degasser: ERC3115 (made by ERC)
Column: Shodex SB-806MHQ (manufactured by Showa Denko)
Differential Refractive Index Detector: Shodex RI-71 (Showa Denko)

In the present specification, the "degree of etherification of CMC and/or its salt" is an index showing the degree to which the OH group in anhydrous glucose in CMC and/or its salt has been replaced by a carboxymethyl group, It is a value obtained according to the method.
<Method for measuring degree of etherification of CMC and/or salt thereof>
A sample (anhydrous) of 0.5 to 0.7 g is precisely weighed, wrapped in filter paper and incinerated in a porcelain 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 boiled for 30 minutes. This is cooled, a phenolphthalein indicator is added, the excess acid is back-titrated with 0.1 mol/L potassium hydroxide, and the etherification degree is calculated according to the following formula.

The “alkalinity” or “acidity” used for calculating the degree of etherification is the alkali content (OH ⁻ , CO ₃ ²⁻ , HCO ₃ ) contained in an aqueous solution prepared by dissolving 2 g of a sample (anhydride) in 200 ml of water. ^It represents the total amount of anions such as ^- ) or acids (cations such as H ⁺ ) and is a value determined by the following method.
<Method of measuring alkalinity or acidity>
Precisely weigh 1 g of the sample (anhydrous) in a 300 ml Erlenmeyer flask and add 200 ml of water to dissolve it. To this, 5 ml of 0.05 mol/l sulfuric acid is added with a pipette, boiled for 10 minutes, cooled, a phenolphthalein indicator is added, and titrated with 0.1 mol/l potassium hydroxide (S ml). At the same time, a blank test is carried out (B ml), and calculated by the following formula.

In the present specification, the “polyvinyl-based polymer compound” is one type of water-soluble polymer and refers to a polymer compound obtained by homopolymerizing or copolymerizing a monomer having a vinyl group.

In the present specification, the “polysaccharide” is a kind of water-soluble polymer, and refers to a natural polymer in which a monosaccharide is polymerized by a glycosidic bond.

In the present specification, “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. Refers to. In the present specification, the concentration of brimonidine and/or its salt 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, the “polyhexanide” is a compound represented by the following general formula (1), which is a guanidine derivative also called polyhexamethylene biguanidine (PHMB). In this specification, the concentration of polyhexanide and/or its salt is the concentration converted to polyhexanide hydrochloride unless otherwise specified.

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

In the present specification, the "viscosity" of the aqueous liquid preparation is defined as "2.53 Viscosity measuring method" in "2. Method 2 rotational viscometer method" in "2. 1.3. Cone-plate type rotational viscometer (cone plate type viscometer)" (25°C, rotation speed 50 rpm, cone-plate type rotational viscometer, cone rotor used: 0.8° x 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 and stored for 2 weeks at 60° C. immediately after preparation under light-shielding conditions to the viscosity of the aqueous liquid agent immediately after preparation, and is calculated by the following formula. Refers to the value obtained according to.

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

In the present specification, expressions such as “suppressing decrease in viscosity with time” and the like indicate that the viscosity of an aqueous liquid agent after storage for a certain period of time can be suppressed from decreasing as compared with the aqueous liquid agent before storage. That is, it means that the viscosity maintenance ratio of the aqueous liquid preparation containing polyhexanide and/or its salt is higher than that of the aqueous liquid preparation containing no polyhexanide and/or its salt. Specifically, it can be said that when the viscosity retention rate is 90% or more, "the decrease in viscosity with time" can be suppressed.

In the present specification, expressions such as “stabilization of viscosity” indicate that the viscosity of the aqueous liquid agent is prevented from decreasing with time due to storage for a certain period, and the viscosity is maintained. Specifically, it can be said that “stabilization of viscosity” has been achieved when the viscosity retention rate is 90% or more.

In the present specification, the “brimonidine content retention rate” is a ratio of the brimonidine content in the aqueous liquid preparation immediately after preparation to the brimonidine content in the aqueous liquid preparation immediately after preparation and stored at 60° C. for 2 weeks under shaded conditions. Yes, and refers to the value calculated according to the following calculation formula.

In the present specification, a notation such as "a decrease in the content of brimonidine and/or a salt thereof over time" refers to a decrease in the brimonidine content in an aqueous solution by storage for a certain period of time, and, for example, the brimonidine content retention rate is When it is less than 97%, it can be said that "a decrease in the content of brimonidine and/or its salt over time" is recognized.

In the present specification, expressions such as “suppress the decrease in the content of brimonidine and/or its salt over time” mean that the aqueous liquid preparation after storage for a certain period has a lower brimonidine content than the aqueous liquid preparation before storage. It means that you can suppress. That is, it means that the brimonidine content maintenance ratio of the aqueous liquid preparation containing polyhexanide and/or its salt is higher than the brimonidine content maintenance ratio of the aqueous liquid preparation not 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 can be suppressed”.

In the present specification, a notation such as "stabilization of the content of brimonidine and/or a salt thereof" and the like means that in an aqueous solution, a decrease in the content of brimonidine and/or a salt thereof over time is suppressed, and the content of brimonidine and/or a salt thereof is suppressed. It means that is maintained stable. Specifically, when the brimonidine content maintenance rate is 97% or more, it can be said that “brimonidine and/or its salt content stabilization” has been achieved.

In the present specification, “formulation stability” refers to the degree to which the viscosity of an aqueous liquid and the content of brimonidine and/or its salt in the aqueous liquid are maintained by storage for a certain period of time, “stabilization of viscosity” and When "content stabilization of brimonidine and/or its salt" is completed, it can be said to have excellent "formulation stability".

In the present specification, the “viscosity stabilizing method” means a method that is carried out in order to suppress a decrease in viscosity of an aqueous liquid agent containing a water-soluble polymer and brimonidine and/or a salt thereof and maintain the viscosity stable. ..

In the present specification, the “viscosity stabilizer” is added in order to suppress a decrease in viscosity over time of an aqueous solution containing a water-soluble polymer and brimonidine and/or a salt thereof, and to maintain the viscosity stable. Means an agent. Examples of the “viscosity stabilizer” include polyhexanide and/or its salt itself or a composition containing polyhexanide and/or its salt.

In the present specification, “a method for stabilizing the content of brimonidine and/or a salt thereof” refers to a decrease in the content of brimonidine and/or a salt thereof over time in an aqueous solution containing a water-soluble polymer and brimonidine and/or a salt thereof. It means a method carried out for suppressing and keeping the content of brimonidine and/or its salt stable.

In the present specification, the term “brimonidine and/or salt content stabilizer” refers to a decrease in the content of brimonidine and/or salt thereof over time in an aqueous solution containing a water-soluble polymer and brimonidine and/or salt thereof. It means an agent added to suppress and maintain the content of brimonidine and/or its salt stably. Examples of the “brimonidine and/or its salt content stabilizer” include polyhexanide and/or its salt itself or a composition containing polyhexanide and/or its salt.

In the present specification, "osmotic pressure of aqueous liquid agent" is measured according to the method defined in "30. Osmotic pressure measuring method (osmolarity measuring method)" of "General test method" of the 17th revised Japanese Pharmacopoeia Is the value to be set.

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

In the present specification, the term “glaucoma” as used herein has a characteristic change in the optic nerve and visual field, and is usually a functional ocular that can improve or suppress optic neuropathy by sufficiently lowering the intraocular pressure. It refers to a disease characterized by structural abnormalities. In addition, "treatment" means alleviation, alleviation or slowing of the progression of a disease or symptom.

2. Description of the Preferred Embodiments A description of the preferred embodiments is provided below, but it should be understood that this embodiment is illustrative of the invention and the scope of the invention is not limited to such preferred embodiments. .. It should be understood that those skilled in the art can easily make modifications, changes and the like within the scope of the present invention with reference to the following preferred embodiments. Those skilled in the art can appropriately combine any of these embodiments.

3. Aqueous liquid agent (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 develop the desired drug effect. Therefore, in designing and quality assurance of aqueous liquid formulations (particularly eye drops) containing these water-soluble polymers. It has become important to suppress the decrease in viscosity over time. In the case of the eye drop, the viscosity of the eye drop is kept constant to maintain the drug retention and adjust the amount of the drug transferred to the treatment site. Therefore, when the viscosity of the eye drop decreases, the amount of the drug transferred to the treatment site changes, which causes a situation in which effective treatment cannot be performed. Since long-term administration of a drug is necessary for the treatment of glaucoma, it is particularly important to suppress the decrease in viscosity of the eye drops used for the treatment of glaucoma with time.

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

In addition, the present inventors have found that, in an aqueous liquid preparation containing a water-soluble polymer and brimonidine and/or a salt thereof, not only a decrease in viscosity with time but also a decrease in the content of brimonidine and/or a salt with time occurs. I got to know. Such a decrease in the content of brimonidine and/or its salt results in diminished medicinal effect of brimonidine and/or its salt. Therefore, it is also extremely important to develop a formulation technique that suppresses the decrease in the content of brimonidine and/or its salt in an aqueous liquid formulation and stably maintains the content of brimonidine and/or its salt. However, it is not known what effect polyhexanide and/or its salt exerts on the decrease in the content of brimonidine and/or its salt in an aqueous solution containing the water-soluble polymer and brimonidine and/or its salt over time. Has not been done.

Under such circumstances, the present inventors have found that an aqueous liquid preparation containing a water-soluble polymer, brimonidine and/or a salt thereof, and polyhexanide and/or a salt thereof can suppress the decrease in viscosity with time and It has been found that it is possible to suppress a decrease in the content of brimonidine and/or its salt, and to provide excellent formulation stability.

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. In one aspect of the aqueous liquid preparation of the present invention, the problem that the viscosity of the aqueous liquid preparation containing a water-soluble polymer and brimonidine and/or a salt thereof decreases with time is solved. 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 an aqueous liquid preparation containing a water-soluble polymer and brimonidine and/or its salt is solved. It Hereinafter, the aqueous liquid preparation will be described.

[Water-soluble polymer]
The aqueous liquid preparation 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 liquid agent and is not particularly limited as long as it is pharmaceutically acceptable. Alternatively, a water-soluble polymer used as a thickener may be used. Specific examples of such water-soluble polymers include cellulose-based polymer compounds, polyvinyl-based polymer compounds, and polysaccharides.

Among the water-soluble polymers, examples of the cellulose-based polymer compound include carboxymethyl cellulose (hereinafter sometimes referred to as “CMC”), hydroxyethyl cellulose (hereinafter sometimes referred to as “HEC”), and methyl cellulose. (Hereinafter, it may be described as “MC”), hydroxypropylcellulose, hydroxypropylmethylcellulose, and salts thereof. These cellulose-based polymer compounds may be used alone or in combination of two or more. Among these cellulose-based polymer compounds, preferable from the viewpoint of more effectively suppressing the decrease in viscosity with time, or more effectively suppressing the decrease in content of brimonidine and/or its salt with time. Include CMC and/or a salt thereof, HEC, MC, or hydroxypropylmethylcellulose, more preferably CMC and/or a salt thereof. The salt type cellulose polymer compound may be an alkali metal salt in the case of CMC, for example. Examples of the alkali metal salt include CMC sodium or CMC potassium. From the viewpoint of more effectively suppressing the decrease in viscosity with time, or more effectively suppressing the decrease in content of brimonidine and/or its salt with time, the alkali metal salt of CMC is preferably CMC sodium. Is good.

The weight average molecular weight of 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. When the molecular weight of CMC and/or its salt increases, the viscosity of an aqueous solution of the CMC and/or its salt dissolved in purified water improves. 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. .. As a preferred embodiment of the CMC and/or its salt used in the present invention, from the viewpoint of more effectively suppressing the decrease in viscosity over time, a weight average molecular weight of 35,000 to 42,000 can be mentioned. .. The weight average molecular weight of another preferred embodiment of CMC and/or its salt used in the present invention is 75,000 to 85,000.

Further, the viscosity characteristics of CMC and/or its salt used in the present invention are not particularly limited, but for example, the viscosity of a 2% CMC aqueous solution is about 25 to 400 mPa·s. An example of the CMC and/or its salt used in the present invention is CMC and/or its salt in which the viscosity of a 2% CMC aqueous solution is about 25 to 35 mPa·s. Another embodiment of the CMC and/or its salt used in the present invention is CMC and/or its salt in which the viscosity of a 2% CMC aqueous solution is about 300 to 400 mPa·s. From the viewpoint of more effectively suppressing the decrease in viscosity over time, CMC and/or a salt thereof preferably having a CMC 2% aqueous solution viscosity of about 25 to 35 mPa·s can be mentioned.

The degree of etherification of CMC and/or its salt used in the present invention is not particularly limited, but may be, for example, 0.6 to 1.5. The etherification degree of CMC and/or its salt is preferably 0.70 to 0.85, and more preferably 0.79 to 0.85, from the viewpoint of further stabilizing the viscosity of the aqueous liquid agent. ..

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

As the CMC and/or its salt used in the present invention, commercially available products can be used. Examples of commercially available products of sodium CMC include, for example, Serogen (registered trademark) series PR-S (25° C., viscosity of 2% aqueous solution is 25 mPa·s to 35 mPa·s, sold by Daiichi Kogyo Seiyaku Co., Ltd., etherification). Degree 0.79 to 0.85), P-715A (25°C, viscosity of 2% aqueous solution is 80 mPa·s to 140 mPa·s, etherification degree 0.60 to 0.70), F-SC (25°C, Viscosity of 2% aqueous solution is 300 mPa·s to 400 mPa·s, degree of etherification is 0.70 to 0.85, AG-GUM (25°C, viscosity of 2% aqueous solution is 900 mPa·s to 1500 mPa·s, degree of etherification) 0.70 to 0.85) and the like, such as CMC Daicel series sold by Daicel Chemical Industries, Ltd., Sunrose F series sold by Nippon Paper Chemicals Co., Ltd., and the like.

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

Among the water-soluble polymers, examples of polysaccharides include xanthan gum, chondroitin sulfate, hyaluronic acid (hereinafter sometimes referred to as “HA”), and alginic acid. These polysaccharides may be in salt form. Examples of the salt-form polysaccharides 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, preferably xanthan gum and from the viewpoint of more effectively suppressing the decrease in viscosity with time, or more effectively suppressing the decrease in content of brimonidine and/or its salt with 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, from the viewpoint of more effectively suppressing the decrease in viscosity with time, or more effectively suppressing the decrease in content of brimonidine and/or its salt with time, it is preferable. , Cellulose-based polymer compounds, and/or polyvinyl-based polymer compounds, more preferably cellulose-based 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 a cellulosic polymer, a polyvinyl polymer compound, and a polysaccharide, and substantially contains another component. Embodiments that do not include a sticky agent or a thickening agent are included. In addition, as one mode of the aqueous liquid preparation of the present invention, a mode in which the water-soluble polymer contains a cellulosic polymer and no other thickener or thickener is included. In addition, as one embodiment of the aqueous liquid preparation of the present invention, there is an embodiment that contains a polyvinyl polymer as the water-soluble polymer and does not contain other thickener or thickener.

The concentration of the water-soluble polymer in the aqueous liquid agent of the present invention may be appropriately set depending on the type of the water-soluble polymer used, the viscosity to be imparted, etc. %. From the viewpoint of more effectively suppressing a decrease in viscosity with time, more effectively suppressing a decrease in concentration of brimonidine and/or a salt thereof with time, or maintaining the usability, The concentration is preferably 0.1 w/v% to 1.0 w/v%, more preferably 0.2 w/v% to 0.7 w/v%, particularly preferably 0.3 to 0.6 w/v%. Can be mentioned.

[Brimonidine and/or its salt]
The aqueous liquid preparation 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, but includes an organic acid salt or an inorganic acid salt. Examples of the organic acid salt include tartaric acid salt and acetate. Examples of the inorganic acid salt include hydrochloride and the like. In addition, brimonidine or a salt thereof may be in the form of a solvate such as a hydrate. Among brimonidine or a salt thereof, brimonidine tartrate is marketed as a medicine and its safety is established, so that it is preferably used.

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

The concentration of brimonidine and/or its salt in the aqueous liquid preparation of the present invention is, for example, 0.05 to 0.5 w/v%. From the viewpoint of more effectively suppressing a decrease in viscosity with time, more effectively suppressing a decrease in concentration of brimonidine and/or a salt thereof with time, or completely dissolving brimonidine and/or a salt thereof. The concentration of brimonidine and/or its salt is preferably 0.1 to 0.2 w/v%, more preferably 0.1 w/v%.

In the aqueous liquid preparation of the present invention, the ratio of brimonidine and/or its salt to the water-soluble polymer is not particularly limited, but for example, brimonidine and/or its salt 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 salt thereof]
The aqueous liquid preparation of the present invention contains polyhexanide and/or a salt thereof. By containing polyhexanide and/or a salt thereof in an aqueous liquid preparation containing a water-soluble polymer and brimonidine and/or a salt thereof, it is possible to suppress a decrease in viscosity of the aqueous liquid preparation with time, and further, brimonidine in the aqueous liquid preparation. And/or it is possible to prevent the content of the salt thereof from decreasing with 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 each is 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 General formula (1), n shows the integer of 1-500. As n, an integer of 2 to 200 is preferable, an integer of 4 to 100 is more preferable, and an integer of 8 to 20 is particularly preferable.

The polyhexanide salt 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.

In the aqueous liquid preparation of the present invention, one kind may be selected from polyhexanide and salts thereof and used alone, or two or more kinds may be used in combination from these.

Among the polyhexanides and salts thereof, from the viewpoint of more effectively suppressing the decrease in viscosity of the aqueous solution over time, preferably a salt of polyhexanide, more preferably an inorganic acid salt of polyhexanide, and particularly preferably polyhexanide hydrochloride. To be

The concentration of polyhexanide and/or its salt in the aqueous liquid preparation of the present invention is, for example, 0.01 to 30 ppm. From the viewpoint of more effectively suppressing the decrease in viscosity with time, or more effectively suppressing the decrease in content of brimonidine and/or its salt with time, the concentration of polyhexanide and/or its salt is preferably Is 0.1 to 10 ppm, more preferably 0.5 to 10 ppm, and particularly preferably 1 to 10 ppm.

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

[Buffer]
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. For example, borate buffer, citrate buffer, phosphate buffer, Tris buffer, tartaric acid buffer. , Acetate buffers, amino acid buffers and the like.

Specific examples of the borate buffer include boric acid and/or its salt. 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 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 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, morpholine, piperazine and pyrrolidine. The boric acid/or its salt may also be in the form of a hydrate, such as borax. As the boric acid buffer, one kind may be selected from boric acid and salts thereof and used alone, or two or more kinds may be used in combination. Among boric acid and its salts, at least one of boric acid and borax is preferable, and at least one of orthoboric acid and borax is more preferable.

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 salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts. To be Also, the salt of citric acid may be in the form of a solvate such as a hydrate. As the citric acid buffer, one kind may be selected from citric acid and salts thereof and used alone, or two or more kinds may be used in combination. Among citric acid and its salts, citric acid salts are preferred, citric acid alkali metal salts are more preferred, and sodium citrate is particularly preferred.

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

Specific examples of the Tris buffer include trometamol and/or a salt thereof. The salt of trometamol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include organic acid salts such as acetate and inorganic acid salts such as hydrochloride and sulfonate. As the tris acid buffer, one kind may be selected from trometamol and a salt thereof and used alone, or two or more kinds may be used in combination. Among trometamol and salts thereof, trometamol is preferable.

Specific examples of the tartaric acid buffer include tartaric acid and/or its salt. The tartaric 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; 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 a hydrate. As the tartaric acid buffer, one kind may be selected from tartaric acid and salts thereof and used alone, or two or more kinds may be used in combination.

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

Specific examples of the amino acid buffer include acidic amino acids and/or their salts. Specific examples of the acidic amino 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 buffers may be used alone or in combination of two or more.

Among these buffers, borate buffers are preferable from the viewpoint of more effectively suppressing the decrease in viscosity over time.

The concentration of the buffer agent in the aqueous liquid agent of the present invention may be appropriately set within a range capable of imparting a desired buffering ability to the aqueous liquid agent, and may be, for example, 0.01 to 3 w/v%. From the viewpoint of more efficiently suppressing the decrease in viscosity with time or the decrease in brimonidine content with 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 liquid preparation of the present invention contains an isotonicity agent, a polyhydric alcohol, a surfactant, a chelating agent, a preservative or a preservative, a cooling agent, a stabilizing agent, and a pH adjusting agent, if necessary. You may contain additives, such as an agent.

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 tonicity 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, for example, tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxy. Nonionic surfactants such as nols; amphoteric surfactants such as alkyldiaminoethylglycine, lauryldimethylaminoacetic acid betaine; alkyl sulfates, N-acyl taurine salts, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyls 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 chelating agent is not particularly limited as long as it is pharmaceutically acceptable, for example, edetic acid, citric acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1, Examples thereof include 1-diphosphonic acid, polyphosphoric acid, metaphosphoric acid, hexametaphosphoric acid, 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, 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 its salts, benzethonium chloride, benzyl alcohol, zinc chloride, parachlormethacylenol, chlorcresol, phenethyl alcohol, chloride Examples thereof include polydronium, thimerosal, dibutylhydroxytoluene and the like. These preservatives or preservatives 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 cooling 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, for example, polyvinylpyrrolidone, sulfite, 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.

The pH adjuster is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid; sodium hydroxide, potassium hydroxide. , Borax, triethanolamine, monoethanolamine, sodium hydrogen carbonate, alkali such as sodium carbonate. These pH adjusters may be used alone or in combination of two or more.

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

[Other pharmacological ingredients]
In one embodiment, the aqueous liquid preparation of the present invention may contain a pharmacological component other than brimonidine and/or its salt, if necessary. Such pharmacological components include, for example, prostaglandins such as tafluprost, latanoprost and isopropylunoprostone; parasympathomimetics such as pilocarpine hydrochloride; anticholinesterase drugs such as distigmine bromide; sympathetic nerves such as dipivefrin hydrochloride. Stimulants; β ₁ blockers such as betaxolol hydrochloride; β blockers such as timolol maleate; α ₁ /β blockers such as nipradilol, levobunolol hydrochloride; α ₁ blockers such as bunazosin hydrochloride .. These pharmacological components may be used alone or in combination of two or more. The concentrations of these pharmacological components may be appropriately set according to the type of the pharmacological component used, the drug effect to be imparted, and the like.

In another embodiment, the aqueous liquid preparation of the present invention includes a mode in which brimonidine and/or a salt thereof is directly contained as an active ingredient against glaucoma, and substantially no other active ingredient is included.

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

Further, the aqueous liquid preparation of the present invention can have a high viscosity retention rate by containing polyhexanide and/or its salt together with the water-soluble polymer and brimonidine and/or its salt. The viscosity retention rate of the aqueous liquid agent of the present invention is not particularly limited, but one aspect of the aqueous liquid agent of the present invention is, for example, a viscosity retention rate of 90% or more. From the viewpoint of suppressing a decrease in viscosity of the aqueous liquid agent with time, the viscosity retention rate is preferably 91% or more, more preferably 92% or more, particularly preferably 93% or more, further 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 alleviating eye irritation applicable to the ocular mucosa. It is more preferably 6.9 to 7.1, particularly preferably 7.0 to 7.1, and further preferably 7.0.

[Osmotic pressure/osmotic pressure ratio]
The osmotic pressure of the aqueous liquid preparation of the present invention is not particularly limited as long as it is applicable to the intended use. For example, when applied to the ocular mucosa, the osmotic pressure may be 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 is applicable to the intended use. For example, when applied to the ocular mucosa, the osmotic pressure ratio may be 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 liquid preparation of the present invention can have a high brimonidine content retention rate by including polyhexanide and/or its salt in a liquid preparation containing a water-soluble polymer and brimonidine and/or its salt. There is. As an 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 its salt over time, the brimonidine content retention rate is preferably 98% or more, more preferably 99% or more.

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

The aqueous liquid preparation of the present invention is prepared into a pharmaceutical composition for various uses such as ophthalmology, dentistry, otolaryngology, dermatology, and used as a topical preparation. As one aspect of the aqueous liquid preparation of the present invention, ophthalmic, dental, otolaryngological, or dermatological compositions can be mentioned, preferably ophthalmic compositions.

Specific examples of the ophthalmic composition include eye drops, eye washes, contact lens agents, and injections. Of these, eye drops are preferable.

[Usage/Dose/Usage]
Brimonidine and/or a salt thereof contained in the aqueous liquid agent of the present invention suppress the production of aqueous humor and can exert an effect of lowering intraocular pressure, and therefore, in one aspect of the aqueous liquid agent of the present invention, as an eye drop It is provided and can be suitably used for the therapeutic use of glaucoma.

When the aqueous solution of the present invention is used as an eye drop, it may be applied once a day or once or several times a day. In addition, in one embodiment 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, if the aqueous solution of the present invention is an eye drop, it is conventional. What is used as an eye drop container can be used. The material of the container for containing the aqueous liquid preparation of the present invention is not particularly limited, and may be made of glass or plastic. When a plastic container is used as the container for containing the aqueous liquid agent of the present invention, the constituent material of the plastic container is not particularly limited, and examples thereof include polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene, polyethylene and polyimide. Any one kind, or two or more kinds of blend polymers may be mentioned. From the viewpoint of more efficiently suppressing the decrease in the brimonidine content over time, the material of the container body (the member forming the container for containing the ophthalmic composition) is preferably polyethylene or polypropylene, and more preferably Examples include polyethylene.

[Production method]
The aqueous liquid preparation of the present invention may be produced according to a known preparation method depending on its formulation form, and can be produced, for example, by the method described in the 17th Revised Japanese Pharmacopoeia General Rules for Preparation.

Specifically, in one embodiment, the method for producing an aqueous liquid agent of the present invention comprises a pharmaceutically acceptable aqueous solution comprising a water-soluble polymer, brimonidine and/or a salt thereof, and polyhexanide and/or a salt thereof. The step of compounding with a medium is included. "Pharmaceutically acceptable aqueous medium" means an aqueous medium that is pharmaceutically acceptable and includes, for example, purified water. In addition, in the blending step, the order of blending each component is not particularly limited, and may be sequentially blended in any order, or may be blended simultaneously. Further, after the blending step, a sterilization step such as filter sterilization, filter sterilization, dry heat sterilization, electron beam sterilization, gamma ray sterilization, etc. may be carried out, if necessary.

4. Viscosity Stabilizing Method As an embodiment of the present invention, there is provided a method for stabilizing the viscosity of an aqueous solution containing a water-soluble polymer and brimonidine and/or a salt thereof, wherein the water-soluble polymer, brimonidine and/or Or a salt thereof, and a step of coexisting polyhexanide and/or a salt thereof, to provide a viscosity stabilizing method.

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

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

In the viscosity stabilizing method of the present invention, the type and concentration of the water-soluble polymer, the type and concentration of brimonidine and/or its salt, the type and concentration of polyhexanide and/or its salt, and other additives to be added to the aqueous liquid preparation. The types of pharmacological components, viscosity of aqueous liquid agents, pH, osmotic pressure, formulation form, applications, etc. are as described in the section of “3. Aqueous liquid agent (1)”.

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

ADVANTAGE OF THE INVENTION According to the viscosity stabilizer of this invention, the effect which can suppress the time-dependent viscosity fall with respect to a water-soluble polymer and an aqueous liquid agent containing brimonidine and/or its salt can be provided, and viscosity which can maintain viscosity stably It becomes possible to provide a liquid agent.

The viscosity stabilizer of the present invention may be provided in the form of a liquid or solid (eg powder or tablet).

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

6. Method for stabilizing the content of brimonidine and/or its salt As one 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 Among them, a method for stabilizing the content is provided, which comprises a step of coexisting a water-soluble polymer, brimonidine and/or a salt thereof, and polyhexanide and/or a salt thereof.

ADVANTAGE OF THE INVENTION According to the content stabilization method of this invention, the time-dependent fall of the content of brimonidine and/or its salt in the aqueous liquid agent containing brimonidine and/or its salt can be suppressed, and brimonidine and/or its salt are maintained stably. It is possible to provide a possible aqueous liquid preparation.

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

The content stabilizing method of the present invention is carried out, for example, by adding brimonidine and/or a salt thereof and polyhexanide and/or a salt thereof to an aqueous medium (such as purified water). The order is not particularly limited. Moreover, each component to be mixed may be in a solid state or a liquid state.

In the content stabilizing method of the present invention, the type and concentration of brimonidine and/or its salt, the type and concentration of polyhexanide and/or its salt, and the same as described in the section of “3. Aqueous liquid preparation (1)”. Further, in the content stabilizing 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 to be added to the aqueous liquid agent, the viscosity of the aqueous liquid agent, the pH, The osmotic pressure, formulation form, application, etc. are also as described in the section of "3. Aqueous liquid preparation (1)".

7. Brimonidine and/or salt thereof content stabilizer As one embodiment of the present invention, an agent added for stabilizing the content of brimonidine and/or salt thereof in an aqueous liquid preparation containing brimonidine and/or salt thereof is provided. provide. Examples of the content stabilizer include polyhexanide and/or its salt itself or a composition containing polyhexanide and/or its salt.

According to the content stabilizer of the present invention, to an aqueous liquid preparation containing brimonidine and/or a salt thereof, an effect of suppressing a decrease in the content of brimonidine and/or a salt thereof over time can be imparted, and brimonidine and/or 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 liquid formulation to be applied may contain a water-soluble polymer in addition to brimonidine and/or its salt.

The content stabilizer of the present invention may be provided in the form of liquid or solid (eg powder or tablet).

In the content stabilizer of the present invention, the type and concentration of polyhexanide and/or its salt to be used are as described in the section of “3. Aqueous liquid preparation (1)”. Further, in the content stabilizer of the present invention, the type and concentration of brimonidine and/or a salt thereof contained in the aqueous liquid to be applied, the type and concentration of the water-soluble polymer used as necessary, and blended The types of other additives and pharmacological components, the viscosity of aqueous solutions, pH, osmotic pressure, formulation form, applications, etc. are also as described in the section of “3. Aqueous solutions (1)”.

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

In the aqueous liquid preparation of this embodiment, the type and concentration of brimonidine and/or its salt and the type and concentration of polyhexanide and/or its salt are as described in the section of “3. Aqueous liquid preparation (1)”. Further, in the aqueous liquid preparation of such an embodiment, the type and concentration of the water-soluble polymer that is added as necessary, the type of other additives and pharmacological components that are added to the aqueous liquid preparation, the viscosity of the aqueous liquid preparation, the pH, and the penetration. The pressure, formulation form, application, etc. are also as described in the section of “3. Aqueous liquid preparation (1)”.

Hereinafter, the present invention will be described specifically 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 liquid preparation was prepared according to the formulation shown in Table 1. Each aqueous solution was made isotonic by adding an appropriate amount of sodium chloride, and the pH was adjusted using hydrochloric acid or sodium hydroxide.

[Accelerated deterioration test]
Immediately after preparation, the aqueous liquid preparation was filtered through a 0.22 μm filter, and 5 mL thereof was filled in a 5 mL volume colorless glass ampoule. Each glass ampoule was placed in a tabletop constant temperature and humidity chamber (NST-80, Nagano Science Co., Ltd.) and stored at 60° C. for 2 weeks under light-shielded conditions.

[Viscosity measurement]
The viscosity of the aqueous liquid agent is specified in the 17th revised Japanese Pharmacopoeia General test method, "2.53 Viscosity measurement method", "2. Method 2 rotational viscometer method", "2.1.3. Type rotational viscometer (cone plate type viscometer)", using a TVE-25 type viscometer (cone plate) (TVE-25L, Toki Sangyo Co., Ltd.) at 25°C and a rotation speed of 50 rpm. The cone rotor used was 0.8° x R24 (rotor code: 00). The viscosity measurement was performed before and after the accelerated deterioration 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 liquid preparation containing CMC sodium and brimonidine tartrate and containing no polyhexanide hydrochloride (Comparative Example 1) had a viscosity retention rate after storage at 60° C. for 2 weeks of 88%, which was below 90%. On the other hand, in the aqueous liquid preparations containing polyhexanide hydrochloride together with sodium CMC 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 case of aqueous liquid preparations (Examples 4 to 6) using CMC sodium B having a low CMC 2% aqueous solution viscosity of 25 to 35 mPa·s as CMC sodium, the CMC 2% aqueous solution has a high CMC of 300 to 400 mPa·s. The viscosity retention rate was higher than that when sodium A was used (Examples 1 to 3).

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

[Accelerated deterioration test]
Immediately after preparation, the aqueous liquid preparation was filtered through a 0.22 μm filter, and 5 mL thereof was filled in a 5 mL volume colorless glass ampoule. Each glass ampoule was placed in a tabletop constant temperature and humidity chamber (NST-80, Nagano Science Co., Ltd.) and stored at 60° C. for 2 weeks under light-shielded conditions.

[Brimonidine content measurement]
The brimonidine content in the aqueous liquid preparation was measured by liquid chromatography (Shimadzu high performance liquid chromatograph: Prominence) under the following conditions.
(Measurement condition)
Detector: ultraviolet absorptiometer (measurement wavelength: 230 nm)
Column: Symmetry C18, 4.6 mm I.S. 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

Further, the brimonidine content retention rate was determined according to the following calculation formula.

[Test results]
The obtained results are shown in Table 2. The aqueous liquid preparations containing brimonidine tartrate and containing no polyhexanide hydrochloride (Comparative Examples 1 and 2) had a brimonidine content retention rate of less than 97% after being stored at 60° C. for 2 weeks. On the other hand, in the aqueous liquid preparations containing polyhexanide hydrochloride together with brimonidine tartrate (Examples 1 to 6), the brimonidine content retention rate was 97% or more, and the brimonidine content retention rate was improved depending on the concentration of polyhexanide hydrochloride. Was there.

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

[Accelerated deterioration test]
An accelerated deterioration test was performed 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 agent 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. The water-soluble polymer (HA sodium, HEC, xanthan gum or PVP) and the brimonidine tartrate together with the aqueous solution containing polyhexanide hydrochloride (Examples 7 to 10) had a viscosity maintenance rate of 90% or more, and the viscosity maintenance rate was increased by polyhexanide hydrochloride. Had been improved.

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

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

[Brimonidine content measurement]
Under the same conditions as in Test Example 2, the brimonidine content in the aqueous liquid agent 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 preparations containing polyhexanide hydrochloride together with brimonidine tartrate (Examples 11 to 16), the brimonidine content retention rate was 97% or higher, and the brimonidine content retention rate was improved depending on the concentration of polyhexanide hydrochloride.

Comprehensive consideration From the results of Test Examples 1 to 4, water-soluble polymers (CMC sodium, HA sodium, HEC, MC, xanthan gum or PVP), brimonidine tartrate, and aqueous solutions containing polyhexanide hydrochloride show a decrease in viscosity over time. It was confirmed that it could be suppressed, and further the decrease in the content of brimonidine tartrate with time could be suppressed, and it was revealed that it has excellent formulation stability. It was also clarified that by containing polyhexanide hydrochloride together with brimonidine tartrate in the aqueous liquid preparation, it is possible to suppress the decrease in the content of brimonidine tartrate over time.

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 “Serogen F-SC” (Daiichi Kogyo Seiyaku Co., Ltd.) (viscosity of CMC 2% aqueous solution: 300 to 400 mPa·s, degree of etherification: 0.70 to 0.85), CMC sodium B is “Serogen PR-S” (Daiichi Kogyo Seiyaku Co., Ltd.) (CMC 2% aqueous solution viscosity: 25 to 35 mPa·s, degree of etherification: 0.79 to 0.85), polyhexanide hydrochloride is Ark Pharm. , Inc. was used.

Claims (12)

An aqueous liquid preparation comprising a water-soluble polymer, brimonidine and/or a salt thereof, and polyhexanide and/or a salt thereof. The aqueous liquid preparation according to claim 1, wherein the water-soluble polymer contains at least one selected from a cellulose-based polymer compound, a polyvinyl-based polymer compound, and a polysaccharide. The aqueous liquid preparation according to claim 2, wherein the cellulose-based polymer compound contains carboxymethyl cellulose and/or a salt thereof. The aqueous liquid preparation according to claim 1, wherein the concentration of polyhexanide and/or its salt is 0.01 to 30 ppm. The aqueous liquid preparation according to claim 1, wherein the concentration of the water-soluble polymer is 0.1 to 2.0 w/v%. The aqueous liquid preparation according to claim 1, wherein the concentration of brimonidine and/or its salt is 0.05 to 0.5 w/v %. 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 is 0.01 to 30 ppm,
The aqueous liquid preparation according to any one of claims 1 to 6. The water-soluble polymer is carboxymethyl cellulose and/or a salt thereof,
Brimonidine and/or its salt is brimonidine tartrate,
The polyhexanide and/or its salt is polyhexanide hydrochloride, and the concentration of carboxymethyl cellulose and/or its salt is 0.5 w/v%,
The concentration of brimonidine tartrate is 0.1 w/v%,
The concentration of polyhexanide hydrochloride is 0.1 to 10 ppm,
The aqueous liquid preparation according to claim 1. A method for stabilizing the viscosity of an aqueous solution containing a water-soluble polymer and brimonidine and/or a salt thereof, comprising:
A method for stabilizing viscosity, comprising a step of allowing a water-soluble polymer, brimonidine and/or a salt thereof, and polyhexanide and/or a salt thereof to coexist in an aqueous liquid preparation. A viscosity stabilizer used for stabilizing the viscosity of an aqueous solution containing a water-soluble polymer and brimonidine and/or a salt thereof, comprising:
A viscosity stabilizer containing polyhexanide and/or a salt thereof. A method for stabilizing the content of brimonidine and/or its salt in an aqueous solution containing brimonidine and/or its salt,
A method for stabilizing the content of brimonidine and/or its salt, which comprises the step of coexisting brimonidine and/or its salt and polyhexanide and/or its salt in an aqueous liquid preparation. A content stabilizer used for stabilizing the content of brimonidine and/or its salt in an aqueous solution containing brimonidine and/or its salt,
A content stabilizer for brimonidine and/or its salt, which contains polyhexanide and/or its salt.