JP2008024700A - Berberine-containing aqueous composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an aqueous composition having improved stability of berberine to heat or light though containing the berberine and alginic acid. <P>SOLUTION: The aqueous composition is prepared as follows. (A) The berberine and/or a salt thereof and (B) the alginic acid and/or a salt thereof are formulated with (C) at least one kind selected from the group consisting of chlorpheniramine, tetrahydrozoline and a salt thereof. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a berberine-containing aqueous composition with improved stability. More particularly, it relates to an aqueous composition comprising berberine and alginic acid, wherein the berberine has improved heat or light stability. Furthermore, the present invention relates to a method for stabilizing an aqueous composition containing berberine and alginic acid.

  Berberine or a salt thereof is known to have an excellent anti-inflammatory action, and is widely used not only as an internal ingredient such as a gastrointestinal drug, but also as an external drug ingredient such as an ophthalmic drug or a hemorrhoid drug. ing. However, berberine has a property that it easily precipitates in the presence of chloride ions, and has a drawback that various pharmaceutical formulations cannot be employed (see, for example, Patent Document 1). Conventionally, there has been no report on a technique for suppressing precipitation due to berberine and chloride ions.

In addition, alginic acid has an action of gelation (high viscosity) by being partially cross-linked by a divalent or higher cation such as Ca ²⁺ ion. When an aqueous composition containing alginic acid is applied to the skin or mucous membrane. Then, Ca ²⁺ ions present on the skin and mucous membrane come into contact with alginic acid, and the aqueous composition gels on the skin and mucous membrane. It has been found that when an aqueous composition gels on the skin or mucous membrane, the retention of other active ingredients is increased. For these reasons, alginic acid is used for effectively expressing the pharmacological action of other active ingredients on mucous membranes and skin (for example, see Patent Document 2).

On the other hand, chlorpheniramine or a salt thereof is a tertiary amine-pyridine type H1 receptor blocker (antihistamine), and is known as an antiallergic agent applicable to mucous membranes and skin. Moreover, it is known that tetrahydrozoline or a salt thereof is a component having a vasoconstrictive action as an α-adrenergic agonist and having an effect of removing hyperemia in the ocular mucosa. However, it is not known what effect these components have on the destabilization of berberine or its salts.
JP-A-62-25991 JP 2002-332248 A

  In order to more effectively enjoy the pharmacological action of berberine or a salt thereof, an aqueous composition that can apply alginic acid or a salt thereof together with berberine or a salt thereof to mucous membranes or skin is considered to be effective. However, as a result of studies by the present inventors, when an aqueous composition is formulated by blending alginic acid or a salt thereof together with berberine or a salt thereof, the stability to heat or light of berberine or a salt thereof deteriorates, and heat or light is lost. It was confirmed that the exposure induces the degradation of berberine or its salt. Furthermore, in an aqueous composition containing berberine or a salt thereof and a chloride ion, a precipitate is likely to be generated. In particular, if the aqueous composition contains chlorpheniramine, tetrahydrozoline or a salt thereof, the precipitate It was confirmed that the generation of was remarkable. Therefore, in order to put an aqueous composition containing alginic acid or a salt thereof together with berberine or a salt thereof, it is necessary to develop a formulation that improves the stability of berberine or a salt thereof.

  Accordingly, an object of the present invention is to provide an aqueous composition containing alginic acid and / or a salt thereof together with berberine and / or a salt thereof, and having improved stability to heat or light of berberine and / or a salt thereof. Is to provide. Another object of the present invention is to provide an aqueous composition in which the formation of precipitates is suppressed even in the presence of berberine and / or a salt thereof and chloride ions. Furthermore, this invention aims at providing the method of stabilizing the aqueous composition containing berberine and / or its salt, and alginic acid and / or its salt. It is another object of the present invention to provide a method for suppressing precipitation of berberine and / or a salt thereof by chloride ions.

  As a result of diligent studies to solve the above problems, the present inventors have added (C) chlorphenic acid to an aqueous composition containing (A) berberine and / or a salt thereof and (B) alginic acid and / or a salt thereof. By adding one or more selected from the group consisting of lamin, tetrahydrozoline, and salts thereof, (A) the stability of berberine and / or its salt to light or heat is significantly improved. I found. Furthermore, it discovered that the aqueous composition of this invention also suppressed precipitation which arises in the coexistence of berberine and a chloride ion. The present invention has been completed by making further improvements based on these findings.

That is, the present invention is the following aqueous composition:
Item 1 An aqueous composition comprising the following components (A) to (C):
(A) Berberine and / or a salt thereof,
(B) Alginic acid and / or salt thereof,
(C) At least one selected from the group consisting of chlorpheniramine, tetrahydrozoline, and salts thereof.
Item 2. The aqueous composition according to claim 1, which is an ophthalmic composition.

Furthermore, the present invention is a method for stabilizing an aqueous composition listed below:
Item 3. A method for stabilizing an aqueous composition comprising (A) berberine and / or a salt thereof, and (B) alginic acid and / or a salt thereof, wherein (C) chlorpheniramine maleate, tetrahydrozoline, A stabilization method comprising blending at least one selected from the group consisting of a salt of tetrahydrozoline and sodium chloride.

Furthermore, the present invention is a method for suppressing precipitation of berberine and / or a salt thereof listed below:
Item 4. (A) A method for suppressing the formation of precipitates in an aqueous composition containing berberine and / or a salt thereof and a component that generates chloride ions, wherein (B) alginic acid and / or its A method of inhibiting, comprising blending a salt, and (C) chlorpheniramine, tetrahydrozoline, and a salt thereof.

  According to the present invention, while containing alginic acid and / or a salt thereof together with berberine and / or a salt thereof in an aqueous composition, the stability of berberine and / or a salt thereof against heat or light is improved. Can be stably maintained. Furthermore, according to the present invention, even when chloride ions that cause precipitation of berberine and / or its salts are contained in the aqueous composition, the formation of precipitates can be suppressed, so that it is possible to cope with diversification of formulations. is there.

  In addition, when chlorpheniramine, tetrahydrozoline and / or a salt thereof is used as the component (C), the aqueous composition of the present invention has the anti-inflammatory action based on the component (A) and the component (C). There is also an advantage that the antihistamine action and / or the decongestion action based on the above can be expressed at the same time. Furthermore, the aqueous composition of the present invention contains (B) alginic acid and / or a salt thereof, and this component contributes to gelation by being applied to mucous membranes and skin. These components and the component (C) can be retained for a long period of time, and these pharmacological actions can be expressed more effectively.

  Hereinafter, the present invention will be described in detail. In the present specification, w / v% indicates mass to volume percentage, and means the weight g of each component (solute) dissolved in 100 mL of the solution. Further, the term “contact lens” is used in the meaning of including all types of contact lenses such as hard, oxygen-permeable hard, and soft unless otherwise specified. In the present specification, the aqueous composition means a composition containing at least 5 parts by weight, preferably 20 parts by weight or more, more preferably 50 parts by weight or more, per 100 parts by weight of the composition. .

(I) Aqueous Composition The aqueous composition of the present invention contains berberine and / or a salt thereof (hereinafter sometimes simply referred to as component (A)). Berberine is a known compound having benzylisoquinoline as a skeleton.

  The salt of berberine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such a salt include hydrochloride, chloride, sulfate, tannate and the like. These berberine salts may be used alone or in any combination of two or more.

  Berberine and / or a salt thereof is a known compound, and may be synthesized by a known method or obtained as a commercial product.

  In the aqueous composition of the present invention, one of these berberines and salts thereof may be selected and used alone, or two or more may be used in any combination. The component (A) is preferably berberine sulfate and berberine chloride.

  The blending ratio of the component (A) in the aqueous composition of the present invention is not particularly limited, and can be appropriately set according to the use or form of the composition. As an example of the blending ratio of the component (A) in the aqueous composition, the ratio in which the total amount of the component is 0.0001 to 0.05 w / v%, preferably 0.0005 to 0.025 w / v% with respect to the total amount of the composition Is exemplified. More specifically, when the aqueous composition is an eye drop, it is more preferably 0.005 to 0.025 w / v%, particularly preferably 0.01 to 0.025 w / v%. Further, when the aqueous composition is an eye wash, it is more preferably 0.0005 to 0.0025 w / v%, particularly preferably 0.001 to 0.0025 w / v%.

  The aqueous composition of the present invention further contains alginic acid and / or a salt thereof (hereinafter sometimes simply referred to as component (B)). By containing alginic acid and / or a salt thereof, it becomes possible to improve the retention on the mucous membrane or skin of the component (A). In addition, alginic acid and / or a salt thereof can suppress the formation of precipitates induced in the presence of the above component (A), the component (C) described later, and chloride ions.

  Alginic acid is a polysaccharide composed of D-mannuronic acid (hereinafter sometimes simply referred to as “M”) and L-guluronic acid (hereinafter sometimes simply denoted as “G”). A block in which a homopolymer fraction of mannuronic acid (MM fraction), a homopolymer fraction of guluronic acid (GG fraction), and a fraction in which mannuronic acid and guluronic acid are randomly arranged (MG fraction) are bound arbitrarily. It is a copolymer.

  In the alginic acid used in the present invention, the constituent ratio (M / G ratio; molar ratio) of mannuronic acid to guluronic acid is not particularly limited. For example, the M / G ratio is in the range of 0.4 to 4.0. What is included in is widely used. The smaller the M / G ratio, the more easily the aqueous composition is gelled. From the viewpoint of improving the retention at the application site of berberine and / or its salt, the M / G ratio is preferably 2.5 or less, preferably Is 2.0 or less, more preferably 0.4 to 2.0, more preferably 0.5 to 1.6, and particularly preferably 1.0 to 1.6. In the present invention, the M / G ratio is a value calculated by fractionating alginic acid decomposed in block units and quantifying each, and specifically, A. Haug et al., Carbohyd. Res. 32 (1974), p.217-225.

  In the alginic acid used in the present invention, the ratio of the MM fraction, the GG fraction and the MG fraction is not particularly limited, and can be appropriately selected according to the use and shape of the aqueous composition.

  Moreover, the alginic acid used in the present invention can be suitably used from a low molecular weight to a high molecular weight.

  The salt of alginic acid is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of the alginic acid salt include sodium salt, potassium salt, triethanolamine salt, ammonium salt and the like. These alginic acid salts may be used alone or in any combination of two or more.

  In the aqueous composition of the present invention, as the component (B), from the above alginic acid and salts thereof, one kind may be selected and used alone, or two or more kinds may be arbitrarily combined. May be used. In particular, alginic acid, sodium alginate, and potassium alginate are water-soluble and are preferably used in the present invention.

  The blending ratio of the component (B) in the aqueous composition of the present invention is not particularly limited, and can be appropriately set according to the use and form of the composition. As an example of the blending ratio of the component (B) in the aqueous composition, the ratio in which the total amount of the component (B) is 0.001 to 5 w / v%, preferably 0.005 to 0.3 w / v% with respect to the total amount of the composition Is exemplified. More specifically, when the aqueous composition is an eye drop, it is more preferably 0.02 to 0.1 w / v%, particularly preferably 0.05 to 0.1 w / v%. Further, when the aqueous composition is an eye wash, it is more preferably 0.01 to 0.1 w / v%, particularly preferably 0.02 to 0.1 w / v%.

  Furthermore, the aqueous composition of the present invention contains at least one selected from the group consisting of chlorpheniramine, tetrahydrozoline, and salts thereof (hereinafter sometimes simply referred to as component (C)). In the aqueous composition containing the component (B), the stability of berberine and / or salt thereof to light or heat is impaired, and berberine and / or salt thereof is decomposed by exposure to light or heat. Although it shows a tendency, it becomes possible to suppress the destabilization of berberine and / or its salt itself induced by the component (B) by further coexisting the component (C). Among the components (C), chlorpheniramine and a salt thereof are useful for improving the light stability of berberine and / or a salt thereof in the presence of the component (B). Tetrahydrozoline and its salt are useful for improving the heat stability of berberine and / or its salt in the presence of component (B).

  All of the compounds included in component (C) are known compounds. Of the above component (C), the salt of chlorpheniramine and tetrahydrozoline is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of chlorpheniramine salts include chlorpheniramine maleate. Specific examples of the salt of tetrahydrozoline include tetrahydrozoline hydrochloride and tetrahydrozoline nitrate, preferably tetrahydrozoline hydrochloride.

  As the component (C), any one of chlorpheniramine, tetrahydrozoline, and salts thereof may be used alone. However, berberine and / or its salt are stable against light and heat. In order to improve both, it is desirable to use chlorpheniramine and / or a salt thereof in combination with tetrahydrozoline and / or a salt thereof. Preferred components (C) include chlorpheniramine maleate and tetrahydrozoline hydrochloride.

The blending ratio of the component (C) in the aqueous composition of the present invention is not particularly limited, and can be appropriately set according to the type of the component (C), the use and form of the composition, and the like. Specifically, the following ranges are illustrated as a mixture ratio of (C) component.
In the case of chlorpheniramine and / or a salt thereof: The total amount of chlorpheniramine and / or a salt thereof is 0.00005 to 0.05 w / v%, preferably 0.0003 to 0.03 w / v% based on the total amount of the aqueous composition; Is more preferably 0.003 to 0.03 w / v%, particularly preferably 0.006 to 0.03 w / v%; more preferably 0.0003 to 0.003 w / v%, especially if the aqueous composition is an eyewash. Preferably it is 0.0006-0.003w / v%.
In the case of tetrahydrozoline and / or salt thereof: The total amount of tetrahydrozoline and / or salt thereof is 0.0001 to 0.1 w / v%, preferably 0.0005 to 0.05 w / v%, based on the total amount of the aqueous composition; Is more preferably 0.005 to 0.05 w / v%, particularly preferably 0.01 to 0.05 w / v%; more preferably 0.0001 to 0.005 w / v%, particularly preferably if the aqueous composition is an eye wash. 0.001 to 0.005 w / v%.

  When component (C) satisfies the above ratio, berberine and / or a salt thereof can be provided with light or heat stability in the presence of component (B) in the aqueous composition of the present invention. become.

In particular, in the aqueous composition of the present invention, the above-mentioned components (A) to (C) satisfy the following ratios, respectively, so that the stability of berberine and / or a salt thereof to light or heat can be more effectively obtained. Can do.
In the case of chlorpheniramine and / or a salt thereof: (A) 100 parts by weight of component (B) 1 to 30000 parts by weight of component and (C) 1 to 1000 parts by weight; preferably (B) The component is 4 to 20000 parts by weight, and the component (C) is 1 to 500 parts by weight; more preferably the component (B) is 20 to 10,000 parts by weight, and the component (C) is 12 to 300 parts by weight; Component B) is 20 to 2000 parts by weight, and component (C) is 24 to 300 parts by weight.
In the case of tetrahydrozoline and / or a salt thereof: (A) 100 parts by weight of component, (B) component is 1 to 30000 parts by weight, and (C) component is 1 to 2000 parts by weight; preferably (B) component is 4 to 20000 parts by weight, and component (C) is 10 to 1000 parts by weight; more preferably, component (B) is 20 to 10,000 parts by weight, and component (C) is 20 to 500 parts by weight; more preferably (B) The component is 20 to 2000 parts by weight, and the component (C) is 40 to 500 parts by weight.

  The aqueous composition of the present invention may further contain a buffering agent in addition to the components (A) to (C). The buffer that can be incorporated into the aqueous composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, ε-aminocaproic acid, aspartic acid, aspartate and the like. These buffering agents may be used alone or in any combination of two or more. From the viewpoint of more efficiently achieving the effects of the present invention, among the above-described buffering agents, a borate buffer and a phosphate buffer are preferred in order to further improve the effects of the present invention. Agents are particularly suitable. Specific examples of the boric acid buffer include boric acid and salts thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.). In particular, boric acid and borax are suitable.

  When blending a buffering agent in the aqueous composition of the present invention, the blending ratio of the buffering agent varies depending on the type of buffering agent used and the expected effect, and cannot be defined uniformly, for example, In the aqueous composition, the total amount of the buffer is 0.01 to 3 w / v%, preferably 0.1 to 2 w / v%, more preferably 0.3 to 2 w / v based on the total amount of the composition. %, Particularly preferably 0.5 to 2 w / v%.

  In addition, the aqueous composition of the present invention can be adjusted to a pH within a range that is acceptable to a living body as long as the chemical stability of the components (A) to (C) is not significantly impaired. The appropriate pH varies depending on the application site, dosage form, and the like of the aqueous composition, but is usually 6 to 9, preferably 6.5 to 8.5, more preferably 6.8 to 8.2, and particularly preferably 7. ~ 8. If it is in this pH range, the effect of this invention can be made more remarkable. The pH can be adjusted by a method known in the art using the buffer, a pH adjuster, an isotonic agent, a salt or the like described later.

  If necessary, the aqueous composition of the present invention can be adjusted to an osmotic pressure ratio within a range acceptable for a living body. The appropriate osmotic pressure ratio varies depending on the application site, dosage form, etc., but is usually 0.3 to 4.2, preferably 0.3 to 2.1, more preferably 0.5 to 1.8, and more preferably 0.2. It is 6 to 1.5, particularly preferably 0.8 to 1.5. If it is in the range of this osmotic pressure ratio, the effect of this invention can be made more remarkable. The adjustment of the osmotic pressure can be performed by a known method in the technical field using an inorganic salt and a polyhydric alcohol, a sugar alcohol, a saccharide or the like.

  In the aqueous composition of the present invention, the osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of the 0.9 w / v% aqueous sodium chloride solution based on the 14th revised Japanese pharmacopoeia, and the osmotic pressure is the osmotic pressure described in the Japanese pharmacopoeia. Measure according to the pressure measurement method (freezing point depression method). The standard solution for measuring the osmotic pressure ratio was sodium chloride (Japanese Pharmacopoeia standard reagent) dried at 500 to 650 ° C. for 40 to 50 minutes, then allowed to cool in a desiccator (silica gel), and 0.900 g was accurately weighed. Dissolve in purified water to make exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (aqueous solution containing 0.9 w / v% sodium chloride).

  The aqueous composition of the present invention may contain a component that generates chloride ions in the aqueous composition for the purpose of adjusting pH, adjusting osmotic pressure, and the like. Chloride ions have the effect of promoting the formation of precipitates in the presence of the component (A), but the aqueous composition of the present invention includes the components (A) to (C) as a unit. The formation of precipitates can be suppressed even in the presence of chloride ions. In view of the effects of the present invention, an aqueous composition containing a component that generates chloride ions is mentioned as a preferred embodiment of the present invention. Examples of the component that generates chloride ions in the aqueous composition include hydrochloric acid, alkali metal chloride, and alkaline earth metal chloride, preferably sodium chloride and potassium chloride.

  When blending a component that generates chloride ions in the aqueous composition of the present invention, the blending ratio of the component differs depending on the type of the component, the blending purpose, etc., and cannot be defined uniformly. For example, the component is usually 0.05 to 2.0 w / v%, preferably 0.1 to 1.0 w / v%, more preferably 0.2 to 0.7 w / v%, particularly preferably 0.2 to 0.2% with respect to the total amount of the composition. A ratio of 0.5 w / v% is exemplified. The ratio of the component that generates chloride ions to the component (A) is, for example, 100 parts by weight of the component (A), and the total amount of the component is usually 100 to 10,000 parts by weight, preferably 400 to 5000 parts. Part by weight, more preferably 800 to 2800 parts by weight, particularly preferably 800 to 2000 parts by weight. According to the aqueous composition of the present invention, even if it contains a component that generates chloride ions at such a mixing ratio or mixing ratio, the formation of precipitates is suppressed and the aqueous composition can be held stably. Can do.

  The aqueous composition of the present invention may contain an appropriate amount of various pharmacologically active ingredients and physiologically active ingredients in addition to the above-mentioned ingredients as long as the effects of the present invention are not hindered. Such an ingredient is not particularly limited, and examples thereof include active ingredients in various pharmaceuticals described in the over-the-counter drug manufacturing (import) approval standard 2000 edition (supervised by the Pharmaceutical Affairs Research Committee). Specific examples of components used in ophthalmic drugs include the following components.

  Epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, naphazoline nitrate, planoprofen, neostigmine methyl sulfate, zinc sulfate, zinc lactate, allantoin, ε-aminocaproic acid, lysozyme chloride, sodium azulene sulfonate, Dipotassium glycyrrhizinate, diphenhydramine hydrochloride, retinol acetate, retinol palmitate, pyridoxine hydrochloride, sodium flavin adenine dinucleotide, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, tocopherol acetate, aminoethylsulfonic acid (taurine), aspartic acid Potassium, magnesium aspartate, magnesium / potassium aspartate mixture, sulfur Methoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisomidine sodium, glucose, sodium hyaluronate, sodium chondroitin sulfate, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol (completely or partially saponified product), Polyvinylpyrrolidone and the like.

  In addition, in the aqueous composition of the present invention, various additives are appropriately selected according to conventional methods and used in combination with one or more, as long as the effects of the invention are not impaired. May be contained in an appropriate amount. Examples of such additives include various additives described in Pharmaceutical Additives Encyclopedia 2005 (edited by Japan Pharmaceutical Additives Association). Typical additives include the following additives.

  Macrogol, poloxamer, poloxamine, polysorbate 80, polyoxyethylene (60) hydrogenated castor oil, alkyldiaminoethylglycine, benzalkonium chloride, parabens, sorbic acid, potassium sorbate, polyhexamethylene biguanide or its hydrochloride, chloride Potassium, calcium chloride, magnesium sulfate, glycerin, propylene glycol, camphor, geraniol, borneol, menthol, fennel oil, cool mint oil, spearmint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil, sodium edetate, benzethonium chloride, Citric acid, trometamol, etc.

  The dosage form of the aqueous composition of the present invention is arbitrary, and various forms can be taken depending on its use. For example, it may be liquid or semi-solid such as ointment. Preferably it is liquid.

  Moreover, since the aqueous composition of the present invention can express the useful pharmacological action of the above components (A) to (C), it can be used as a preparation for pharmaceuticals and quasi drugs. Specific examples of the formulation of the aqueous composition of the present invention include eye drops [however, eye drops include eye drops that can be applied while wearing contact lenses], eye wash [however, eye drops are contacted. Ophthalmic compositions such as eyewashes that can be washed while wearing lenses], ophthalmic ointments, etc .; contact lens compositions [contact lens mounting solutions, contact lens care compositions (contact lens disinfectants, storage for contact lenses) Agents, contact lens cleaning agents, contact lens cleaning preservatives, etc.]]; nasal compositions such as nasal drops and nasal washings; oral compositions such as oropharyngeal drugs and gargles (mouth rinses); Examples include ear drops. In view of the pharmacological action of the above components (A) to (C), ophthalmic compositions are preferable, ophthalmic solutions and eyewashes are more preferable, and ophthalmic solutions are particularly preferable.

  The contact lens composition can be applied to all contact lenses including hard contact lenses and soft contact lenses.

  The aqueous composition of this invention can be manufactured by the well-known method according to the target dosage form and use.

(II) Stabilization method As described above, in an aqueous composition containing (A) berberine and / or a salt thereof, and (B) alginic acid and / or a salt thereof, (C) chlorpheniramine, tetrahydrozoline, and these By coexisting at least one selected from the group consisting of the salts of (B), the destabilization of component (A) induced by the presence of component (B) can be improved. Therefore, from another viewpoint, the present invention provides an aqueous composition containing (A) berberine and / or a salt thereof, and (B) alginic acid and / or a salt thereof, (C) chlorpheniramine, tetrahydrozoline, and these There is provided a method for stabilizing an aqueous composition containing the components (A) and (B), which comprises blending at least one selected from the group consisting of salts of:

  In this method, when chlorpheniramine and / or a salt thereof is selected as the component (C), it is useful as a method for stabilizing the component (A) in the aqueous composition against exposure to light. Further, when tetrahydrozoline and / or a salt thereof is selected as the component (C), it is useful as a method for stabilizing the component (A) in the aqueous composition against heat exposure.

  In the stabilization method, the types and concentrations of the components (A) to (C) to be used, the types and concentrations of other ingredients, the use and form of the aqueous composition, etc. It is the same as the case of.

(III) Method for inhibiting precipitation As described above, (C) chlorpheniramine, tetrahydrozoline, and salts thereof in an aqueous composition containing (A) berberine and / or a salt thereof, and a component that generates chloride ions. By coexisting at least one selected from the group consisting of, it is possible to suppress the formation of precipitates promoted by the presence of chloride ions. Therefore, from another viewpoint, the present invention provides (A) berberine and / or a salt thereof, and an aqueous composition containing a component that generates chloride ions, (B) alginic acid and / or a salt thereof, and (C In an aqueous composition containing (A) a component and a component that generates chloride ions, characterized in that it contains at least one selected from the group consisting of chlorpheniramine, tetrahydrozoline, and salts thereof, A method for suppressing the formation of precipitates is provided.

  In the stabilization method, the types and concentrations of the components (A) to (C) to be used, the types and concentrations of components that generate chloride ions, the types and concentrations of other compounding components, the use and form of the aqueous composition, etc. Is the same as in the case of “(I) aqueous composition”.

  EXAMPLES Hereinafter, although this invention is demonstrated in detail based on an Example, a test example, etc., this invention is not limited by these. In the following examples and the like, alginic acid was derived from Lessonia nigrescens having a M / G ratio standard of 1.0 to 1.6.

Test Example 1 Light Stability Test Using Chlorpheniramine Maleate According to the formulation shown in Table 1, a berberine sulfate-containing aqueous composition was prepared (Example 1 and Comparative Example 1-2). The following photostability evaluation tests were conducted using these berberine sulfate-containing aqueous compositions.

  8 mL of each berberine sulfate-containing aqueous composition was filled into a transparent glass screw vial (capacity 10 mL), and these were used as test samples (n = 2). For this test sample, light stability test equipment ("Light-Tron LT-120 D3CJ type", manufactured by Nagano Kagaku Co., Ltd.) is used. Was continuously irradiated for 240 hours, and the test solution was exposed to light with an integrated irradiation amount of 1,200,000 lx · hr. Berberine sulfate concentration in the test sample before and after light exposure was measured by high performance liquid chromatography. From the measured berberine sulfate concentration of each test sample, the remaining rate (%) of berberine sulfate was calculated according to the following formula.

  The obtained results are shown in Table 1. From this result, in the aqueous composition of Comparative Example 2 in which berberine sulfate and alginic acid were used in combination, berberine sulfate was unstable to light, but Example 1 was formulated with chlorpheniramine maleate together with berberine sulfate and alginic acid. It was revealed that the photostability of berberine sulfate was significantly improved in the aqueous composition.

Test Example 2 Thermal Stability Test Using Tetrahydrozoline Hydrochloride A berberine sulfate-containing aqueous composition was prepared according to the formulation described in Table 2 (Example 2 and Comparative Example 3-4). The following thermal stability evaluation tests were conducted using these berberine sulfate-containing aqueous compositions.

  8 mL of each berberine sulfate-containing aqueous composition was filled into a transparent glass ampoule tube (capacity 10 mL), and these were used as test samples (n = 2). This test sample was stored in a thermostat at 70 ° C. for 21 days under light shielding. The concentration of berberine sulfate in the test sample before and after storage was measured by high performance liquid chromatography. From the measured berberine sulfate concentration of each test sample, the residual rate (%) of berberine sulfate was calculated by the same calculation method as in Test Example 1 above.

  The results are shown in Table 2. It has been confirmed that the heat destabilization of berberine sulfate caused by the combined use of berberine sulfate and alginic acid can be improved by the incorporation of tetrahydrozoline hydrochloride.

Test Example 3 Light or Thermal Stability Test According to the formulations described in Tables 3 and 4, berberine sulfate or berberine chloride-containing aqueous composition (Example 3-19; all eye drops) was prepared.

  Using the aqueous compositions of Examples 3-7, 10-14, and 16, a light stability test was conducted in the same manner as in Test Example 1 above. In any composition, berberine sulfate or berberine chloride was used. Stabilization of was confirmed. That is, also from this result, it was confirmed that by using chlorpheniramine maleate, instability to light of berberine sulfate or berberine chloride caused in the presence of alginic acid can be suppressed.

  Moreover, when the thermal stability test was conducted in the same manner as in Test Example 2 using the aqueous composition of Examples 8-19, berberine sulfate or berberine chloride was stabilized in any composition. confirmed. Therefore, also from this result, it became clear that the destabilization to heat of berberine sulfate or berberine chloride caused in the presence of alginic acid can be suppressed by using tetrahydrozoline hydrochloride.

Test Example 4 Evaluation Test for Feeling of Use and Suppression of Precipitates According to the formulations described in Tables 5 and 6, by adding berberine sulfate to an aqueous solution in which compounding ingredients other than berberine sulfate are dissolved and mixed, berberine sulfate-containing aqueous composition (Examples 20-23, Comparative Example 5-10; all eye drops) were prepared.

  Three healthy persons instilled the berberine sulfate-containing aqueous composition immediately after preparation and evaluated the feeling of use. As a result, in Example 20-23, compared with Comparative Example 5-10, there is a pleasant astringent feeling (feeling to be crumpled) felt after instillation, a moist feeling is more effectively sensed, and a comprehensive effect is also achieved. The feeling was excellent.

Further, using 50 mL of the berberine sulfate-containing aqueous composition prepared above, stirring was continued for 1 hour under light-shielding conditions at 25 ° C. The state of each berberine sulfate-containing aqueous composition after 1 hour of stirring was visually observed, and the properties were evaluated according to the following criteria.
<Criteria>
○: Precipitation does not occur Δ: Precipitation clearly occurs ×: Precipitation occurs as the whole liquid becomes cloudy.

  The results of property evaluation are shown in Tables 5 and 6. From this result, in the presence of a component that generates chloride ions and berberine sulfate, a tendency that precipitates are easily generated was observed (Comparative Example 5-10). In particular, precipitates generated in the presence of chloride ions and berberine sulfate became more prominent in the presence of tetrahydrozoline hydrochloride or chlorpheniramine maleate (Comparative Examples 6-7 and 9-10). On the other hand, when berberine sulfate, alginic acid, and tetrahydrozoline hydrochloride or chlorpheniramine maleate were blended, it was confirmed that the formation of precipitates was suppressed, and an aqueous composition that could withstand practical use was obtained. Example 20-23).

Examples 24-56
In the formulations shown in Table 7-10 below, eye drops (Examples 24-41 and 50-53), eye drops usable during contact lens wearing (Examples 42-44 and 54), eyewashes (Examples) 45-47 and 55-56), and contact lens stock solutions (Examples 48-49) were prepared.

Claims (3)

An aqueous composition comprising the following components (A) to (C):
(A) Berberine and / or a salt thereof,
(B) Alginic acid and / or salt thereof,
(C) At least one selected from the group consisting of chlorpheniramine, tetrahydrozoline, and salts thereof.   The aqueous composition according to claim 1, which is an ophthalmic composition.   A method for stabilizing an aqueous composition comprising (A) berberine and / or a salt thereof, and (B) alginic acid and / or a salt thereof, wherein (C) chlorpheniramine, tetrahydrozoline, and A stabilization method comprising blending at least one selected from the group consisting of salts of: