JP2012036110A - Liquid agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a liquid agent under an acidic region in which rutin is clearly dissolved for a long period of time by dissolving the rutin without structural conversion.SOLUTION: The liquid agent contains components between (A) to (C): (A) rutin; (B) nonionic surfactant; and (C) povidone.

Description

  The present invention relates to a liquid preparation containing rutin, and more particularly to a liquid preparation in which rutin is clearly dissolved over a long period of time.

  Rutin is a citrus flavonoid discovered from the citrus family Ruta graveolens, and β-rutinose (6-O-α-L-rhamnosyl-D-β-glucose) is bound to the oxygen at the 3rd position of quercetin. Glycoside. Rutin is also found in not only citrus fruits, but also in legume enju and cape buckwheat.

  Rutin has been reported to have an antioxidant effect on cholesterol and an action to repair damaged capillaries, and is said to be effective in preventing arteriosclerosis. However, rutin is hardly soluble in the acidic region (pH 2 to 5), which is preferable for general liquids and the like. Therefore, in the preparation of liquids, the solubility is improved, and further, with time after compounding. There has been a demand for ensuring stability.

  As a method for solubilizing rutin, a method of dissolving already reported flavonoids in a strong alkaline solution and adding it to a thickening polysaccharide solution (Patent Document 1), a flavonoid and soybean saponin in an aqueous medium, and A method of solubilizing flavonoids by coexisting malonyl isoflavone glycoside (Patent Document 2) or a method of solubilizing by forming a complex of rutin and povidone in advance using an organic solvent such as acetone (patent) Use of document 3) is assumed.

  However, these methods can be applied only to neutral to alkaline liquidity by increasing the solubility by structural transformation, and solubilize under acidic conditions while maintaining the original rutin structure. It was not suitable as a method. In addition, in the case of using a solvent such as acetone, there is a problem that there is a concern that the solvent remains when the provided liquid is drunk.

JP-A-10-101705 Republished No. 2005-003112 Republished 2001-051081

  Therefore, development of a technique for dissolving rutin without causing structural transformation in an acidic region is required, and the present invention provides a liquid preparation that clearly dissolves rutin over a long period of time using such a technique. That is what we want to do.

  As a result of intensive studies on improving the solubility of rutin, the present inventors have found that the intended purpose can be achieved by blending a nonionic surfactant and povidone into the rutin compound solution, and the present invention. Was completed.

That is, the present invention includes the following components (A) to (C),
(A) Rutin (B) Nonionic surfactant (C) A liquid preparation containing povidone.

  In the present invention, the nonionic surfactant of component (B) is one or more selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and polyethylene glycol fatty acid ester. It is said liquid agent.

  Furthermore, this invention is the said liquid agent whose pH is 2-5.

  Furthermore, this invention is the said liquid agent which is a liquid agent for internal use.

  The liquid formulation containing rutin according to the present invention is stable in a clear state without precipitation or turbidity in appearance even when stored under severe conditions such as a wide range of temperature changes over a long period of time. it can. Furthermore, a clear state can be stably maintained even in an acidic region that is considered to be a liquid property of a general internal solution.

  The liquid agent of the present invention contains, as its components, rutin (component (A)), povidone (component (B)) and nonionic surfactant (component (B)).

  The component (A) rutin in the present invention is a kind of flavonoid, and is contained in a large amount of leguminous buds or flowers, and the appearance is a light yellow to light yellowish green crystalline powder with no odor. Or is said to have a slightly unique odor. Moreover, it is listed in the raw material specification for quasi-drugs 2006, and is widely used for pharmaceuticals, cosmetics, food additives and the like.

  The amount of rutin used in the present invention is an amount that is required to be blended as a liquid agent, and any amount can be used as long as the rutin can be clearly solubilized over a long period of time. In the case of an internal use drink, it is usually 0.0001 to 1.0 w / v%, preferably 0.0005 to 0.5 w / v%, more preferably 0.001 to 0.1 w / v%.

  The rutin used in the present invention is preferably one that does not form a complex with other components, for example, by dissolving in advance in an organic solvent. When dissolved in an organic solvent in advance to form a complex with other components, as mentioned above, in addition to concerns about residual solvent problems, the chemical state of rutin changes, which can be taken Sometimes, rutin's original pharmacological effect may not be exhibited, which is not preferable. In particular, this solution should be avoided as much as possible when used as a medicine.

  On the other hand, povidone used as component (B) in the present invention is a linear polymer of N-vinyl-2-pyrrolidone, which is white to slightly yellow crystals. As this povidone, for example, Plusdon K-25 (K value: 25), Plusdon K-29 / 32 (K value: 29 to 32), Plusdon K-90 (K value: 90), Plusdon K-90D (K value) : 90), Plasdon K-90M (K value: 90) (manufactured by IPS Japan), Kollidon 25 (K value: 25), Kollidon 30 (K value: 30), Kollidon 90F (K value: 90) (BA) SDF Japan). Among these, in particular, a K value of 25 to 32 is preferable in use because rapid solubility can be obtained. Here, the K value means the K value of the fixture. The molecular weight of povidone is usually 40,000 to 400,000, preferably 100,000 to 380,000, more preferably 200,000 to 360,000. When the molecular weight of povidone is less than the above range, the amount used is increased and the pH is lowered, which is not preferable, and when it exceeds the above range, the viscosity of the liquid becomes too high.

  In the liquid preparation of the present invention, povidone can be used alone or in combination of two or more of the above compounds, and the blending amount is usually 0.001 to 10.0 w / v%, preferably 0.01. It is -5.0 w / v%, More preferably, it is 0.1-2.0 w / v%. If it is below the above range, it is not preferable because dissolution of rutin may be remarkably reduced. On the other hand, if it exceeds the above range, bitterness at the time of taking may increase.

  Furthermore, examples of the nonionic surfactant used as component (C) in the present invention include polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyethylene glycol fatty acid ester and the like. It is done.

  Among these, polyoxyethylene sorbitan fatty acid ester includes polyoxyethylene sorbitan laurate (polysorbate 20), polyoxyethylene sorbitan palmitate (polysorbate 40), polyoxyethylene sorbitan stearate (polysorbate 60), polyoxyethylene sorbitan tri Stearate (polysorbate 65), polyoxyethylene sorbitan oleate (polysorbate 80) and the like are polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil. Examples thereof include oil 50 and polyoxyethylene hydrogenated castor oil 60.

  Polyoxyethylene polyoxypropylene glycol includes polyoxyethylene (160) polyoxypropylene (30) glycol (Pluronic F68), polyoxyethylene (42) polyoxypropylene (67) glycol (Pluronic P123), polyoxyethylene Ethylene (54) Polyoxypropylene (39) Glycol (Pluronic P85), Polyoxyethylene (196) Polyoxypropylene (67) Glycol (Pluronic F127), Polyoxyethylene (20) Polyoxypropylene (20) Glycol (Pluronic L) -44) are polyethylene glycol fatty acid esters such as polyethylene glycol monolaurate, ethylene glycol monostearate, polyethylene monostearate. Glycol, polyethylene glycol monooleate, ethylene glycol monostearate, ethylene glycol distearate, polyethylene glycol distearate, etc. diisostearate polyethylene glycol are exemplified, respectively.

  Among these, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and polyethylene glycol fatty acid ester are particularly preferable, and among them, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and polyoxyl 40 stearate are more preferable.

  In the liquid preparation of the present invention, the nonionic surfactant can be used alone or in combination of two or more of the above compounds, and its blending amount is usually 0.001 to 10.0 w / v%, preferably Is 0.01 to 5.0 w / v%, more preferably 0.1 to 2.0 w / v%. If it is less than the above range, the solubility of rutin may be remarkably lowered, which is not preferable, and if it exceeds the above range, bitterness at the time of taking may be increased.

  The liquid preparation of the present invention can be made into any dosage form and any desired preparation as long as it is liquid, but among them, it is preferably produced as an internal liquid preparation (generally referred to as an internal drink drink). Can do.

  In the production of the liquid preparation of the present invention, in addition to the above-mentioned components, other drugs and other optional components can be appropriately blended within the range not impairing the effects of the present invention, as long as the effects of the present invention are not impaired. .

  There is no restriction | limiting in particular as said other medicine, According to the objective, it can select suitably. Specific examples include water-soluble vitamins such as vitamin B group and vitamin C, and fat-soluble vitamins such as vitamin A, vitamin D and vitamin E. These can be used individually by 1 type or in combination of 2 or more types, The effective amount suitable for each drug can be mix | blended in the range which does not inhibit the effect of this invention.

  Other optional ingredients include sweeteners, stabilizers, pH adjusters / buffers, preservatives, solubilizers, antioxidants, solvents, solubilizers, suspending agents, flavoring agents / fragrances, Examples thereof include additives such as colorants, water and the like.

  Among these, there is no restriction | limiting in particular in the sweetening agent as an additive, According to the objective, it can select suitably. Specifically, sugar alcohols such as erythritol, xylitol, sorbitol, maltitol, maltose, mannitol, aspartame, acesulfame potassium, saccharin, saccharin sodium, sucralose, stevia extract, thaumatin, glycine, glycyrrhizic acids such as dipotassium glycyrrhizinate, etc. Sweeteners can be exemplified, and these can be used alone or in combination of two or more.

  Moreover, there is no restriction | limiting in particular in the stabilizer as an additive, According to the objective, it can select suitably. Specifically, stabilizers such as carboxyvinyl polymer, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, polyvinyl alcohol, macrogol, and methyl cellulose can be exemplified, and these are used alone or in combination of two or more. can do.

  Furthermore, there is no restriction | limiting in particular also as a pH adjuster and a buffering agent, According to the objective, it can select suitably. Specifically, hydrochloric acid, dilute hydrochloric acid, citric acid, calcium citrate, sodium citrate, calcium gluconate, acetic acid, sodium acetate, tartaric acid, sodium hydroxide, potassium hydroxide, sodium bicarbonate, lactic acid, calcium lactate, boric acid, Examples of the pH adjusting agent such as malic acid and phosphoric acid can be used singly or in combination of two or more.

  Furthermore, the preservative is not particularly limited and can be appropriately selected according to the purpose. Specifically, benzoic acid, sodium benzoate, ethanol, sodium edetate, dry sodium sulfite, citric acid, sodium citrate , Salicylic acid, sodium salicylate, phenyl salicylate, dibutylhydroxytoluene, sorbitol, sorbic acid, potassium sorbate, dehydroacetic acid, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, paraoxy Examples include propyl benzoate, methyl paraoxybenzoate, propylene glycol, boric acid, l-menthol, eucalyptus oil, etc., and these can be used alone or in combination of two or more. .

  Among the additives, the solubilizer is not particularly limited and can be appropriately selected according to the purpose. Specifically, ethanol, glycerin, propylene glycol, glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester , Sodium lauryl sulfate and the like are exemplified, and these can be used singly or in combination of two or more.

  Of the additives, the antioxidant is not particularly limited and can be appropriately selected according to the purpose. Specifically, ascorbic acid, ascorbic acid stearate, sodium bisulfite, sodium sulfite, sodium edetate, Examples include erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, sodium pyrosulfite, butylhydroxyanisole, propyl gallate, etc., and these can be used alone or in combination of two or more.

  Of the additives, the solvent is not particularly limited and may be appropriately selected depending on the purpose. Specific examples include ethanol, glycerin, concentrated glycerin, propylene glycol, macrogol, and the like. Or two or more types can be used in combination.

  The liquid preparation of the present invention can be produced according to a conventional method, and the method is not particularly limited. In particular, components other than rutin, especially povidone and a nonionic surfactant are added to purified water in advance, and the mixture is heated and stirred. After dissolution, the rutin is preferably added and filtered or sterilized as necessary.

  Hereinafter, the present invention will be described in detail with reference to examples and comparative examples. However, the present invention is not limited to these examples.

Example 1
300 mL of purified water is heated to 80 ° C., 0.1 g of rutin, 1.25 g of povidone (K value: 30) and 2.5 g of polyoxyethylene hydrogenated castor oil 60 are added and dissolved by stirring, and 60 g of purified white sugar is further added. And dissolve with stirring. After allowing this liquid to cool, 0.5 g of citric acid and 0.25 g of sodium benzoate were added and dissolved by stirring, and then purified water was added to make the total volume 500 mL, thereby obtaining an internal solution containing rutin. The pH of this solution was 3.38.

Example 2
300 mL of purified water is heated to 80 ° C., 0.1 g of rutin, 1.25 g of povidone (K value: 30) and 2.5 g of polysorbate 80 are added and dissolved by stirring, and 60 g of purified white sugar is further added and dissolved by stirring. After allowing this liquid to cool, 0.5 g of citric acid and 0.25 g of sodium benzoate were added and dissolved by stirring, and then purified water was added to make the total volume 500 mL, thereby obtaining an internal solution containing rutin. The pH of this solution was 3.40.

Example 3
300 mL of purified water is heated to 80 ° C., 0.1 g of rutin, 1.25 g of povidone (K value: 30) and 2.5 g of monostearic polyethylene glycol 25 are added and dissolved by stirring, and 60 g of purified white sugar is further added and stirred. Dissolve. After allowing this liquid to cool, 0.5 g of citric acid and 0.25 g of sodium benzoate were added and dissolved by stirring, and then purified water was added to make the total volume 500 mL, thereby obtaining an internal solution containing rutin. The pH of this solution was 3.41.

Example 4
300 mL of purified water is heated to 80 ° C., 0.1 g of rutin, 1.25 g of povidone (K value: 25) and 2.5 g of polyoxyethylene hydrogenated castor oil 60 are added and dissolved by stirring, and 60 g of purified white sugar is further added. And dissolve with stirring. After allowing this liquid to cool, 0.5 g of citric acid and 0.25 g of sodium benzoate were added and dissolved by stirring, and then purified water was added to make the total volume 500 mL, thereby obtaining an internal solution containing rutin. The pH of this solution was 3.41.

Comparative Example 1
As Comparative Example 1, an internal liquid preparation containing rutin was produced in the same manner as in Example 1 except that povidone was not used. The pH of this solution was 3.38.

Comparative Example 2
Comparative Example 2 was prepared in the same manner as in Example 2 except that polyethylene-hardened castor oil 60 was not used, and an internal solution containing rutin was obtained. The pH of this solution was 3.38.

Comparative Example 3
Comparative Example 3 was prepared in the same manner as in Example 3 except that povidone and polyethylene hydrogenated castor oil 60 were not used, and an internal solution containing rutin was obtained. The pH of this solution was 3.37.

Test Example About the internal liquid preparations containing rutin obtained in Examples 1 to 4 and Comparative Examples 1 to 3, the appearance (precipitation and the like) immediately after preparation and after storage for 2 weeks at temperatures of 5 ° C. and 25 ° C. The formation of turbidity) was observed. The results are shown in Table 1.

  The rutin-containing internal preparation prepared in Examples 1 to 4 showed no precipitation or turbidity immediately after preparation or after storage at 5 ° C. and 25 ° C. for 2 weeks. On the other hand, the internal liquid preparations containing rutin produced in Comparative Examples 1 to 3 did not dissolve immediately after preparation, or generation of precipitation or turbidity was observed over time.

  From the above, it is understood that rutin can be dissolved in a clear manner over a long period of time by blending a nonionic surfactant and povidone in a liquid formulation blended with rutin.

A liquid preparation containing the rutin of the present invention, to which a nonionic surfactant and povidone are added, can dissolve rutin clearly over a long period of time. Therefore, this invention is useful in the field | areas, such as an internal use drink, for example.

Claims (4)

The following components (A) to (C),
(A) Rutin (B) Nonionic surfactant (C) A liquid agent containing povidone.   The nonionic surfactant of component (B) is one or more selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and polyethylene glycol fatty acid ester. Solution.   The liquid agent of Claim 1 or 2 whose pH is 2-5. The liquid agent according to any one of claims 1 to 3, which is an internal liquid agent.