JPWO2018003965A1 - Process for producing powdered fumaric acid preparation - Google Patents

Abstract

An object of the present invention is to provide a powder fumaric acid preparation excellent in powder flowability and dissolution rate, and it is 0.5% by mass or more in terms of anhydride with respect to fumaric acid, hydrophilic nonionic surfactant and fumaric acid. Fumaric acid is coated with a hydrophilic nonionic surfactant and a nonreducing disaccharide or a disaccharide or less sugar alcohol, containing less than 10.0% by mass of a non-reducing disaccharide or less than or equal disaccharide sugar alcohol The problem is solved by providing a powdery fumaric acid preparation characterized by the following:

Description

  The present invention relates to a method for producing a powdered fumaric acid formulation containing fumaric acid as an active ingredient, and a powdered fumaric acid formulation obtained by the production method.

  Fumaric acid is an organic acid that has an acidity that is as strong as acetic acid and oxalic acid, and the acidity is said to be about 1.5 times that of citric acid and malic acid widely used in fruit juice beverages and the like ing. In addition, fumaric acid is non-volatile while acetic acid and boric acid are volatile, and fumaric acid is harmless while boric acid is physiologically harmful. Furthermore, fumaric acid is relatively widely used as a food additive such as an acidulant and a food preservative since it is relatively inexpensive and has a strong sterilizing ability. However, fumaric acid has a very low solubility in water (a solubility in water at 25 ° C. of 0.63 g / 100 ml) and a slow dissolution rate, making it difficult to disperse and dissolve in water in a short time. For this reason, the preparation operation of fumaric acid preparations in the form of solution such as acidulants, preservatives and disinfectants containing fumaric acid as an active ingredient is inefficient and usually requires much labor.

  As a technique for improving the dissolution rate of fumaric acid in water, for example, Patent Document 1 proposes that polyglycerin fatty acid esters be mixed and supported in a hydrophobic powder containing fumaric acid, in order to improve this drawback. ing. Further, Patent Document 2 discloses a disinfectant cleaner in which the dissolution rate is improved by coating fumaric acid particles with a hydrophilic nonionic surfactant. Further, Patent Document 3 discloses a fumaric acid preparation containing 2.5 to 10% by weight of a low dextrose equivalent of a maltodextrin wetting agent containing 75% by weight of a polysaccharide having three or more saccharides, with respect to fumaric acid. Patent Document 4 discloses that it exhibits a high dissolution rate in cold water, and Patent Document 4 is characterized by incorporating glucose or sucrose as an aid in a close-packed mixture of finely powdered fumaric acid and a surfactant. Methods of making fumaric acid-containing compositions with improved dissolution rates are disclosed, respectively. However, according to the findings obtained by the present inventors uniquely, among the methods disclosed in Patent Documents 1 to 4, in the methods described in Patent Documents 1 and 2, the surface of fumaric acid particles is not There is a problem that the fumaric acid preparation to be obtained is easily coagulated and clumped under the influence of these surfactants because it is coated with sucrose fatty acid ester or the like. On the other hand, in the method described in Patent Document 3, the dispersion solubility of the fumaric acid preparation is not sufficient. Furthermore, in the method described in Patent Document 4, a mixture of powdered fumaric acid and a surfactant with glucose or sucrose as an auxiliary agent is used. And other sugars must be mixed with fumaric acid by at least 10% by mass, and a relatively large amount of carbohydrate is used to fumaric acid, so the content of fumaric acid in the preparation decreases and the sterilization effect etc. There is a problem that the inherent effect of fumaric acid is reduced.

Japanese Patent Publication No. 62-19146 JP 2003-147392 Japanese Patent Publication No. 57-54110 Japanese Patent Publication No. 42-22184

  The present invention has been made to solve the above-mentioned disadvantages of the prior art, exhibits excellent solubility in solvents such as water, is less likely to clump or clump in the manufacturing process, and is easy to prepare. It is an object of the present invention to provide a method for producing a powdery fumaric acid preparation which maintains the original action and effect of fumaric acid such as a sterilization effect at a sufficient level, and a powdery fumaric acid preparation obtainable by the method. Do.

  The inventors of the present invention, in the process of examining solutions to the above problems, use the method disclosed in Patent Document 1 or 2 in which the surface of fumaric acid particles is coated with a hydrophilic nonionic surfactant such as glycerin fatty acid ester. Although the dissolution rate of fumaric acid powder is improved by preparing a fumaric acid powder preparation, the powder fumaric acid preparation is coagulated in the production process to reduce the passability of the sieve and the workability in the manufacture of the powder formulation is reduced. It has been found that the yield of powdered fumaric acid preparation is significantly reduced. Furthermore, according to the disclosure of Patent Document 4, when the surface of fumaric acid particles is coated with a hydrophilic nonionic surfactant and a saccharide, the present inventors are excellent in powder fluidity and dispersion solubility in water. Although a powdered fumaric acid preparation can be obtained, it has been found that there is a newly unknown new problem that the entire composition solidifies and solidifies in the manufacturing process, and places a heavy burden on the subsequent powdering process. . Further investigation based on these findings shows that the amount of carbohydrate added in the production of the powder fumaric acid preparation is adjusted to a range of 0.5% by mass or more and less than 10% by mass in terms of anhydride relative to fumaric acid Then, it was found that a powdered fumaric acid preparation can be easily manufactured without the granular composition being firmly consolidated in the manufacturing process (drying step) of the preparation, and the manufacturing method of the present invention was established.

That is, the present invention is a method for producing a powdered fumaric acid preparation containing fumaric acid as an active ingredient,
(1) Fumaric acid powder, hydrophilic nonionic surfactant, and fumaric acid powder, in terms of anhydride, 0.5 mass% or more and less than 10.0 mass% of non-reducing disaccharide or disaccharide or less Mixing the sugar alcohols in the presence of a solvent to obtain a fumaric acid-containing wet mixture;
(2) The obtained fumaric acid-containing wet mixture is dried, and the fumaric acid-containing particulate composition in which the fumaric acid particles are coated with a hydrophilic nonionic surfactant and a nonreducing disaccharide or a sugar alcohol smaller than the disaccharide And (3) pulverizing and classifying the obtained fumaric acid-containing particulate composition, if necessary, to obtain a powdered fumaric acid preparation;
The present invention solves the above-mentioned problems by providing a method for producing a powdered fumaric acid preparation comprising

  Furthermore, the present invention solves the above-mentioned problems by providing a powdered fumaric acid preparation produced by the above-mentioned production method, and the powdered fumaric acid preparation produced by the above production method is a solvent such as water It is excellent in solubility in water, especially in dissolution rate, and contains fumaric acid as the active ingredient at a level at which the function and effect of fumaric acid is sufficiently satisfied. Since it is hard to form, it has the feature of stably maintaining the flowability as a powder even during storage and distribution processes.

  According to the production method of the present invention, it is industrially applicable to a powder fumaric acid preparation having stable powder flowability and an excellent dissolution rate while maintaining the original bactericidal effect of fumaric acid as an active ingredient at a satisfactory level. Can be provided easily and in large quantities, inexpensively and stably. Further, the powder fumaric acid preparation obtained by the production method of the present invention is a high quality powder fumaric acid preparation excellent in powder flowability and dissolution rate.

The present invention relates to a method for producing a powdered fumaric acid preparation containing fumaric acid as an active ingredient, which comprises the following steps (1) to (3):
(1) Fumaric acid powder, hydrophilic nonionic surfactant, and fumaric acid powder, in terms of anhydride, 0.5 mass% or more and less than 10.0 mass% of non-reducing disaccharide or disaccharide or less Mixing the sugar alcohols in the presence of a solvent to obtain a fumaric acid-containing wet mixture;
(2) The obtained fumaric acid-containing wet mixture is dried, and the fumaric acid-containing particulate composition in which the fumaric acid particles are coated with a hydrophilic nonionic surfactant and a nonreducing disaccharide or a sugar alcohol smaller than the disaccharide And (3) pulverizing and classifying the obtained fumaric acid-containing particulate composition as necessary to obtain a powder fumaric acid preparation.

<Production Method of Powdered Fumaric Acid Preparation of the Present Invention>
The outline of the method for producing the powder fumaric acid preparation of the present invention is as follows. The fumaric acid powder is prepared by adding a hydrophilic nonionic surfactant and a non-reducing disaccharide or a sugar alcohol having a disaccharide or less. The fumaric acid particles are coated with a hydrophilic nonionic surfactant and a non-reducing disaccharide or a sugar alcohol having no more than a disaccharide by uniformly mixing, and then the solvent is removed by drying to obtain the granular form obtained. According to need, the composition is pulverized and classified to produce a powdered fumaric acid preparation.

  The fumaric acid powder used as a raw material in the manufacturing method of this invention can use a commercially available thing. Commercially available fumaric acid powder is usually a white crystalline powder, odorless and has a strong acidity. As commercially available fumaric acid powder, for example, trade name "fumaric acid" sold by Nippon Shokuhin Co., Ltd., trade name "fumaric acid" sold by Sakai Kogyo Co., Ltd., etc. can be used. The particle size of fumaric acid used as the active ingredient of the preparation is not particularly limited, but the smaller the particle size, the better the dispersibility in water and the dissolution rate. Therefore, when the particle size of commercially available fumaric acid as a raw material is relatively large, it is preferable to previously grind and adjust the particle size of fumaric acid to be usually 150 μm or less, desirably 75 μm or less. When the particle size of fumaric acid exceeds 150 μm, the dissolution rate in water tends to decrease.

  The surfactant added to the fumaric acid powder in the production method of the present invention is preferably a nonionic surfactant, and the surface of the fumaric acid particles is coated to improve the dispersibility of fumaric acid in water and the dissolution rate. Therefore, hydrophilic nonionic surfactants are preferable to lipophilic nonionic surfactants. Examples of hydrophilic nonionic surfactants include sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, etc. Among them, polyglycerin fatty acid ester is highly effective in improving the dissolution rate of fumaric acid. It is suitable. In addition, as a hydrophilic nonionic surfactant, Hydrophile-Lipophile Balance (hereinafter referred to as “HLB”) is abbreviated as “HLB.” HLB takes a value from 0 to 20, and is closer to 0 and more lipophilic. The higher the hydrophilicity is, the closer to 20 the hydrophilicity is higher.) It is preferable to use those having a range of 14 to 18, and when using a hydrophilic nonionic surfactant having an HLB in a range of 14 to 18, The advantage is obtained that the improvement in the rate of dissolution of fumaric acid in water is the highest. Moreover, since the above-mentioned hydrophilic nonionic surfactants are all safe substances designated as food additives, the powder fumaric acid preparation of the present invention obtained by adding it is also suitable for food use, for example. It also has the advantage of not hindering its use as a disinfectant cleaner.

  In the production method of the present invention, the addition amount of the hydrophilic nonionic surfactant used to coat the fumaric acid particles is not particularly limited as far as it improves the dispersibility and dissolution rate of fumaric acid in water, and it is relative to fumaric acid powder. It is preferable that the amount is usually about 0.1 to 3.0% by mass, preferably about 0.3 to 1.0% by mass, and more preferably about 0.5% by mass in terms of anhydride. The larger the amount of the hydrophilic nonionic surfactant added, the better the effect of improving the dissolution rate of the powder fumaric acid preparation, and a sufficient effect can generally be obtained if it is 0.1% by mass or more. On the other hand, when the addition amount is too large, the fumaric acid particles are easily aggregated, so that the addition amount of the hydrophilic nonionic surfactant is preferably 3.0% by mass or less.

  In the production method of the present invention, examples of carbohydrates used for coating fumaric acid particles include non-reducing disaccharides or sugar alcohols having less than disaccharides. Among the non-reducing disaccharides or sugar alcohols below disaccharides, trehalose, sorbitol and maltitol are preferred from the viewpoint of the effect of improving the cohesiveness and siftability of the powdered fumaric acid preparation. By using trehalose, sorbitol or maltitol, the dissolution rate of fumaric acid in a powdered fumaric acid preparation to water can be improved, and also, the cohesiveness and siftability of the powdered fumaric acid preparation can be improved. Here, each of trehalose, sorbitol and maltitol has no reducing aldehyde group and has low reactivity, so that it also has an advantage that the obtained powder fumaric acid preparation is difficult to be colored.

  In the production method of the present invention, the addition amount of the non-reducing disaccharide or the sugar alcohol below the disaccharide used for coating the fumaric acid particles is usually 0.5% by mass or more in terms of anhydride with respect to fumaric acid The content is preferably less than 10.0% by mass, and more preferably 1.0 to 5.0% by mass. When the addition amount of the non-reducing disaccharide or the sugar alcohol smaller than the disaccharide is 10.0% by mass or more, the fumaric acid particles coated with the hydrophilic nonionic surfactant and the above-mentioned carbohydrate in the manufacturing process are blocked. It tends to solidify and solidify, makes pulverization difficult, and reduces the working efficiency in production. In addition, when the addition amount of the non-reducing disaccharide or the sugar alcohol smaller than the disaccharide is less than 0.5% by mass, it is difficult to obtain the effect of improving the aggregability and the sieve passing property of the powder fumaric acid preparation.

  In the production method of the present invention, the solvent used to obtain the fumaric acid-containing wet mixture is not particularly limited as long as it dissolves a hydrophilic nonionic surfactant and a nonreducing disaccharide or a sugar alcohol having a disaccharide or less. Although it is not, it is preferable to use water or ethyl alcohol, more preferably water, in consideration of using the obtained powder fumaric acid preparation as a germicidal detergent for food and the like.

  In the production method of the present invention, the amount of the solvent used is not particularly limited as long as it is an amount capable of dissolving the added hydrophilic nonionic surfactant and the non-reducing disaccharide or the sugar alcohol below the disaccharide, Usually, it is preferable that it is 50 mass% or more with respect to an acid, and 80 mass% or more is more preferable. If the amount of the solvent used is less than 50% by mass, the flowability of the fumaric acid-containing wet mixture significantly decreases upon mixing, and a large load is imposed on the mixing operation, making uniform mixing difficult, resulting in poor workability. Is not desirable. On the other hand, when the amount of the solvent used is too large, the fumaric acid-containing wet mixture is dried and the process of removing the solvent requires a lot of time and energy. The amount is preferably 300% by mass or less, and more preferably 200% by mass or less.

  In the production method of the present invention, the fumaric acid powder particles are obtained by mixing the fumaric acid powder with a hydrophilic nonionic surfactant solution and a non-reducing disaccharide or a sugar alcohol solution having less than a disaccharide, and then removing the solvent. It is coated with a hydrophilic nonionic surfactant and a non-reducing disaccharide or a sugar alcohol below disaccharide. At this time, if the particle size of the fumaric acid powder to be used is too large, before adding and mixing the hydrophilic nonionic surfactant and the non-reducing disaccharide or the sugar alcohol below the disaccharide, by a mixer etc. in advance. It is preferable to grind | pulverize to 150 micrometers or less, more preferably about 75 micrometers or less.

  The step of mixing the fumaric acid powder with the hydrophilic nonionic surfactant and the non-reducing disaccharide or the sugar alcohol below the disaccharide in the presence of a solvent is carried out by simultaneously mixing the three in the presence of the solvent. The fumaric acid powder may be first mixed with a non-reducing disaccharide or a sugar alcohol having a disaccharide or less below the disaccharide in the presence of a suitable amount of solvent, and then further mixing with a hydrophilic nonionic surfactant. More preferably, As a result, the surface of the fumaric acid particles is first coated with a non-reducing disaccharide or a sugar alcohol smaller than a disaccharide and further coated with a hydrophilic nonionic surfactant, so that the fumaric acid-containing particulate composition is used in water. The improvement effect of the dissolution rate is improved.

  In the production method of the present invention, the step of mixing the fumaric acid powder, the hydrophilic nonionic surfactant and the non-reducing disaccharide or the sugar alcohol below the disaccharide in the presence of a solvent is carried out using any means. However, the mixing can be carried out using any suitable mixing means widely used in the art such as, for example, blenders, homogenizers, whisks, paste mixers, kneaders, extruders, mixing stirrers and the like. The conditions at the time of mixing are not particularly limited as long as the fumaric acid powder particles are coated with a hydrophilic nonionic surfactant and a non-reducing disaccharide or a sugar alcohol below the disaccharide, and if necessary, heating conditions It can also be mixed below.

  In the production method of the present invention, fumaric acid is removed by drying and removing the solvent from the wet mixture obtained after mixing fumaric acid powder, hydrophilic nonionic surfactant and non-reducing disaccharide or sugar alcohol below disaccharide. The step of preparing the acid-containing particulate composition may be carried out by any means, and is not particularly limited. Examples thereof include spray drying, drum drying, reduced pressure drying, heat drying, and freeze drying. It can carry out using the suitable means generally used by. Drying conditions vary depending on the type of solvent and the like, but when the solvent is, for example, water, it is desirable to heat at about 70 to 100 ° C. under reduced pressure and remove by reduced pressure drying to increase cost and increase efficiency.

  The production method of the present invention includes the step of grinding the fumaric acid-containing particulate composition obtained by drying, as required. That is, if the particle size of the obtained fumaric acid-containing particulate composition satisfies the particle size condition required as a powder fumaric acid preparation, the fumaric acid-containing particulate composition obtained by drying is used as it is as a powder fumaric acid preparation However, when the particle size of the obtained fumaric acid-containing particulate composition is larger than the particle size required for the powder fumaric acid preparation, it may be appropriately pulverized. The grinding means is not particularly limited, but can be carried out using any suitable grinding means commonly used in the art, such as, for example, a mortar, a mill, a pulverizer, and an atomizer. Incidentally, when the addition amount of non-reducing disaccharide or sugar alcohol below disaccharide to fumaric acid powder is 10 mass% or more in conversion to anhydride, the whole fumaric acid-containing particulate composition solidifies firmly (block And caking, which makes the pulverization difficult, but in the production method of the present invention, such a problem relating to the pulverization does not occur because the amount of the sugar added is small.

  Furthermore, the production method of the present invention includes the step of classifying the fumaric acid-containing particulate composition obtained by drying or the ground product thereof as necessary, and adjusting it to the particle size distribution required for a powdered fumaric acid preparation. There is. The classification means is not particularly limited, and can be performed using any appropriate classification means generally used in the field such as wire mesh, test sieve, vibrating sieve, ultrasonic vibrating sieve and the like. Since the dispersibility of fumaric acid in water and the dissolution rate also relate to the particle size of the preparation, it is suitable to adjust the particle size to usually 500 μm or less, desirably 300 μm or less by classification.

<Powder fumaric acid preparation of the present invention>
The present invention is a powdered fumaric acid preparation produced by the above-mentioned production method of the present invention, that is, particles of fumaric acid are coated with a hydrophilic nonionic surfactant and a nonreducing disaccharide or a sugar alcohol less than a disaccharide The present invention also relates to a powdered fumaric acid preparation, and the powdered fumaric acid preparation is 0.5% by mass or more and less than 10.0% in terms of anhydride relative to fumaric acid according to the addition ratio of various compounds in the manufacturing method % Containing non-reducing disaccharides or sugar alcohols below disaccharides.

  As described above, the powder fumaric acid preparation of the present invention is in the form of a crystalline powder of fumaric acid coated with a hydrophilic nonionic surfactant and a specific amount of a non-reducing disaccharide or a sugar alcohol having less than a disaccharide Preparation characterized by

  In the powder fumaric acid preparation of the present invention, other components such as a chelating agent, a thickener, an emulsion, a fragrance, a coloring agent and the like can be appropriately blended, if necessary. In addition, other edible sterilizing agents can be added to the powder fumaric acid preparation of the present invention. Other edible disinfectants include, for example, sodium hypochlorite, sodium chlorite, high-grade salacia, hydrogen peroxide and the like.

  In the powder fumaric acid preparation of the present invention, an organic acid other than fumaric acid, a derivative thereof or a salt thereof can also be used appropriately in combination. Examples of the organic acid other than fumaric acid include citric acid, malic acid, tartaric acid, succinic acid, lactic acid, acetic acid, propionic acid, sorbic acid, benzoic acid, ascorbic acid and the like. Specific examples thereof include glycosyl derivatives, acylated derivatives, and phosphorylated derivatives, and examples of the salts thereof include sodium salts, potassium salts, magnesium salts, calcium salts, ammonium salts and the like. Above all, in view of the improvement of the antibacterial activity and / or the expansion of the antibacterial object, the combination of fumaric acid with citric acid, malic acid, tartaric acid, ascorbic acid is preferable, and particularly the combination with ascorbic acid or its derivative or its salt is preferable. . The amount of the organic acid other than fumaric acid, the derivative thereof or a salt thereof is preferably more than equivalent amount to fumaric acid, and more preferably twice or more. If the amount of the organic acid other than fumaric acid used or the derivative or salt thereof is less than the equivalent amount, the effect of improving the antibacterial activity and / or the expansion of the antibacterial object is reduced, which is not desirable. On the other hand, when the amount of organic acids other than fumaric acid to be combined, their derivatives or salts thereof is too large, it is difficult to obtain the effect of improving the cohesiveness and sieve passing property of the powdered fumaric acid preparation. The amount is preferably 20 times or less, more preferably 12 times or less.

An organic acid other than fumaric acid, a derivative thereof or a salt thereof is used in the method for producing a powdered fumaric acid preparation containing fumaric acid as an active ingredient described above;
(1) 0.5% by mass or more but less than 10.0% by mass of non-reducing disaccharide or disaccharide or less in terms of anhydride relative to fumaric acid powder, hydrophilic nonionic surfactant and fumaric acid Mixing sugar alcohols in the presence of a solvent to obtain a fumaric acid-containing wet mixture;
(2) The obtained fumaric acid-containing wet mixture is dried, and the fumaric acid-containing particulate composition in which the fumaric acid particles are coated with a hydrophilic nonionic surfactant and a nonreducing disaccharide or a sugar alcohol smaller than the disaccharide And (3) pulverizing and classifying the obtained fumaric acid-containing particulate composition, if necessary, to obtain a powdered fumaric acid preparation;
For example, in the step (1), other components may be added and mixed, and in the step (2), a wet mixture before or during the drying, Alternatively, it can be mixed into the granular composition after drying, and in the step (3), it can be mixed before, during or after grinding or classification. Furthermore, the powdered fumaric acid preparation produced through the steps (1) to (3) may be mixed with an organic acid other than fumaric acid, a derivative thereof or a salt thereof. The total amount of the organic acid other than fumaric acid, a derivative thereof or a salt thereof may be mixed at one time as described above, or may be divided into two or more and mixed at a plurality of timings. .

  The use of the powder fumaric acid preparation of the present invention is not particularly limited, but it may be used as it is or as it is or may be dispersed, dissolved or diluted as appropriate, and further containing alcohols such as ethanol, antimicrobial agents, etc. It can be used as an acidulant, preservative, disinfectant cleaner, or as a detergent for tanks and lines in food and food factories, etc. It can also be used as a general disinfectant cleaner .

When the powder fumaric acid preparation of the present invention is used as a germicidal detergent for food, it is usually dispersed and dissolved uniformly in water or warm water, and the concentration of fumaric acid is preferably 0.05 to 1% by mass, More preferably, it is used as a processing solution of about 0.1 to 0.5% by mass. If the concentration of the treatment solution is less than 0.05% by mass, it is difficult to obtain the intended sterilization effect. In addition, if the concentration of the treatment solution is too high, the food product etc. may have a strong acidity, which may impair the flavor. The processing solution of this food sanitizer cleaner can be used as a processing solution for disinfecting foodstuffs such as vegetables, fruits, fish and shellfish and meats.

For example, when the powder fumaric acid preparation of the present invention is used to treat foodstuffs of vegetables, fruits, fish and shellfish, meats, 0.05 to 1 mass of the powder fumaric acid preparation of the present invention as fumaric acid concentration The food material is immersed in the treatment liquid dispersed and dissolved to about 1% to eliminate bacteria. The immersion time is appropriately set according to the purpose. For example, in the case of vegetables such as cabbage, for about 30 seconds to 10 minutes, in the case of fish and shellfish such as squid, octopus and shrimp, for about 10 seconds to 10 minutes, and in the case of meats such as chicken, pork and beef Soak for about 60 minutes and disinfect. As a specific operation, in the case of vegetables, after washing with water, soaking the cut vegetables in the treatment solution for a short time, the vegetables are rinsed with water and used for cooking. Thus, the food disinfectant cleaner obtained by dissolving the powder fumaric acid preparation of the present invention when used for disinfecting foodstuffs including vegetables is a fumaric acid recognized as a food additive. Since it is highly safe and at the same time it exerts extremely strong eradicating ability against food poisoning bacteria such as E. coli, Pseudomonas aeruginosa and Salmonella bacteria, vegetables, fruits, fish and shellfish, meats, etc. It can be used effectively for the purpose of preventing the occurrence of food poisoning due to food.

  Hereinafter, based on various experiments, the method for producing the powder fumaric acid preparation according to the present invention and the powder fumaric acid preparation obtained by the production method will be described in more detail.

  The inventors of the present invention have disclosed in Patent Documents 1 and 2 that the solubility is improved by covering the surface of fumaric acid particles with a nonionic surfactant (hydrophilic nonionic surfactant) exhibiting hydrophilicity. The following preliminary experiments were conducted to confirm the disclosed prior art.

<Preliminary Experiment 1: Effect of Addition of Hydrophilic Nonionic Surfactant on Solubility of Powdered Fumaric Acid Preparation>
(1) Overview Various hydrophilic nonionic surfactants having different HLBs were added to fumaric acid, and the influence of each on the solubility of the powder fumaric acid preparation was examined.
(2) Experimental method (A) Preparation of test sample: 3.0 g of fumaric acid powder (trade name "fumaric acid (fine powder)", purity 99.0% by mass or more, sold by Sakai Chemical Industry Co., Ltd.) 3.0 g of various hydrophilic nonionics Surfactant, specifically, polyglycerin fatty acid ester (trade name "POEM J-0021", HLB 15.5, sold by Riken Vitamin Co., Ltd.), sucrose fatty acid ester (trade name "ryoto sugar ester", HLB 16 .0, Mitsubishi Chemical Foods Co., Ltd. sold), polyglycerin fatty acid ester (trade name “Lyoto polyglyester L-7D”, HLB 17, Mitsubishi Chemical Foods Co., Ltd. sold), sucrose fatty acid ester (trade name “DK Ester SS”) , HLB 16.0, Dai-ichi Kogyo Seiyaku Co., Ltd. sold), or polyoxyalkyl branched decyl ester (trade name "Nuygen X L-1000 ′ ′, HLB 19.3, sold by Daiichi Kogyo Seiyaku Co., Ltd.) 5 mL of any of aqueous solutions with a concentration of 3 mg / mL added and mixed, then the wet mixture is spread on a tray, and a hot air circulating drier And dried at 70 ° C. for 15 hours. Subsequently, each fumaric acid-containing granular composition obtained is crushed in a mortar, and then a sieve with an opening of 500 μm (trade name “THE IIDA TESTING SIEVE” manufactured by Iida Mfg. Co., Ltd .; The test samples 2 to 6 of powder fumaric acid preparations coated with various hydrophilic nonionic surfactants having different HLB values were obtained. The fumaric acid powder used as a raw material was not added with a hydrophilic nonionic surfactant, and subjected to only a treatment of passing through a sieve with an aperture of 500 μm to obtain a test sample 1. The obtained test samples 2 to 6 each contain 0.5 mass% of various hydrophilic nonionic surfactants with respect to fumaric acid.

(I) Solubility test For each of the powder fumaric acid preparations obtained above, each test sample is weighed in a 20 mL beaker so as to be 30 mg of fumaric acid, and 10 mL of pure water is added and stirred for 2 minutes , 0.22 μm pore filter. Next, each filtrate is diluted 10 times with pure water, and then the absorbance at a wavelength of 280 nm of the diluted solution is measured, and a 10-fold dilution of an aqueous solution in which 30 mg of fumaric acid is completely dissolved in 10 mL of pure water is additionally measured. The absorbance at a wavelength of 280 nm was 100%, and the relative fumaric acid dissolution rate (%) of each test sample was relatively evaluated. That is, the percentage (Y / X) occupied by the value (Y) at a wavelength 280 nm of a 10-fold dilution of each test sample relative to the value (X) of the absorbance at a wavelength 280 nm of a 0.15 mg / mL standard fumaric acid aqueous solution The relative fumaric acid dissolution rate was determined as × 100}. The results are shown in Table 1. In addition, it has been confirmed that the influence of the addition of various hydrophilic nonionic surfactants on the absorbance at a wavelength of 280 nm is negligible under the tested conditions.

  As shown in Table 1, in the test sample 1 in which the fumaric acid powder was treated only by passing through a 500 μm sieve, the relative fumaric acid dissolution rate was as low as 82.0% with respect to the control in which the fumaric acid powder was completely dissolved. It was confirmed that the solution was not sufficiently dissolved (slow dissolution rate) by stirring for 2 minutes. On the other hand, powder fumaric acid preparations (test samples 2 to 6) to which various hydrophilic nonionic surfactants were added and coated and treated showed a relative fumaric acid dissolution rate of 97.0% or more in each case. The addition of the nonionic surfactant was confirmed to have the effect of improving the dissolution rate of fumaric acid. Also, the HLB value of the hydrophilic nonionic surfactant did not significantly affect the dissolution rate within the tested range, but among hydrophilic nonionic surfactants, HBL is 15.5 and 15.5 respectively. The test samples 2 and 4 to which the polyglycerin fatty acid ester of 17.0 was added showed a relative fumaric acid dissolution rate of 100%, so the HBL is preferably in the range of about 14.0 to 18.0, In addition, among the same hydrophilic nonionic surfactants, polyglycerin fatty acid esters are considered to be more effective in improving the dissolution rate than sucrose fatty acid esters and polyoxyalkyl branched decyl esters.

  Although it has been confirmed that the dissolution rate of the powder fumaric acid preparation (test samples 2 to 6) in water is improved by adding a hydrophilic nonionic surfactant, these preparations (test samples 2 to 6) In the preparation process of the test sample of (a) above, it was difficult to obtain a sufficient amount of the test sample to pass through a 500 μm sieve. Therefore, in order to objectively evaluate the sieve passability of the test samples 2 to 6, the following sieve passability test was performed.

(C) Sieve Passability Test A portion of the test samples 1 to 6 obtained in the above (a) is stored at room temperature for 3 days, 3 g of each is weighed on a 500 μm sieve, and the sieve is vortexed (SCIENTIFIC Using INDUSTRIES, Inc., “MODEL G 560”, shaking was performed for 30 seconds with a scale of 5 and the weight of each test sample passed through the sieve was measured to evaluate the sieve passability. That is, the percentage {(B / A) × 100} occupied by the weight (B) of each test sample having passed through the sieve relative to the weight (A) of the original sample is calculated as the sieve passing rate (%), What evaluated the sieve passing rate of each calculated test sample by the following three steps is shown in Table 2:
+++: sieve passing rate of 50% or more after shaking for 30 seconds;
++: less than 25 to 50% sieve passing rate after shaking for 30 seconds;
+: Less than 25% sieve passing rate after shaking for 30 seconds.

  As shown in Table 2, test sample 1 in which only a treatment of passing through a sieve of 500 μm was applied to fumaric acid powder and test samples 2 to 6 which are powder fumaric acid preparations to which various hydrophilic nonionic surfactants were added In all cases, the sieve passability was remarkably low when the sieve passage rate after shaking tow for 30 seconds was less than 25% (+).

<Preliminary Experiment 2: Effect of added amount of polyglycerin fatty acid ester on dissolution rate improvement of powdered fumaric acid preparation>
Subsequently, using polyglycerin fatty acid ester (HLB 17) confirmed by preliminary experiment 1 to be excellent in dissolution rate improvement effect, the influence of the addition amount of hydrophilic nonionic surfactant on the dissolution rate improvement of fumaric acid The following preliminary experiments were performed on.

(1) Overview The addition amount of polyglycerin fatty acid ester (HLB 17) to fumaric acid powder was changed and tested to investigate the influence of the addition amount of polyglycerin fatty acid ester on the dissolution rate improvement of the powder fumaric acid preparation.
(2) Experimental method (A) Preparation of test sample: 3.0 g of fumaric acid powder (trade name "fumaric acid (fine powder)", purity 99.0% by mass or more, sold by Sakai Chemical Industry Co., Ltd.), polyglycerin fatty acid ester An aqueous solution with a concentration of 0.006, 0.3, 0.6, 3, 6, 18, 30, or 42 mg / mL (trade name “Lyoto polyglycester L-7D”, HLB17, sold by Mitsubishi Chemical Foods Co., Ltd.) After 5 mL of any of the above were mixed to prepare a wet mixture, the wet mixture was spread on a tray and dried by heating at 70.degree. C. for 15 hours in a hot air circulating dryer. Thereafter, the dried product was ground in a mortar and then passed through a sieve with an opening of 500 μm to obtain various powdered fumaric acid preparations (test samples 7 to 14) coated with polyglycerin fatty acid ester. The obtained test samples 7 to 14 were prepared by using the polyglycerin fatty acid ester with respect to fumaric acid at 0.001, 0.05, 0.1, 0.5, 1.0, 3.0, 5 respectively. .0 and 7.0 mass% are contained.

(A) Solubility test The various powder fumaric acid preparations described above are subjected to the same solubility test as described in (a) of preliminary experiment 1: (2), and the relative fumaric acid dissolution rates of the test samples 7 to 14 It asked for (%). The results are shown in Table 2.

  As shown in Table 3, the relative fumaric acid dissolution rate improves as the amount of polyglycerin fatty acid ester to be mixed increases, and when the amount becomes 1.0% by mass or more with respect to fumaric acid (test samples 11 to 14) It was confirmed that the dissolution rate was improved to such an extent that the solution was completely dissolved in water by stirring for 2 minutes.

  Moreover, also in this preliminary experiment, when the polyglycerin fatty acid ester is added, the phenomenon that the powder fumaric acid preparation is aggregated was confirmed. That is, as the amount of polyglycerin fatty acid ester increases, the degree of aggregation of the fumaric acid particles tends to increase, and the powder passability when using a sieve with an opening of 500 μm decreases, and the powder in the sieving process It has been observed that the recovery of fumaric acid preparation is significantly reduced. Although details are omitted, when the obtained test samples 7 to 14 were subjected to the same screen passability test as in the preliminary experiment 1, it was found that the sieve pass ratio after shaking to 30 seconds was less than 25% (+) in all cases. It was evaluated and the sieve passability was extremely low.

  From the results of the preliminary experiments 1 and 2 above, when fumaric acid particles are coated with a hydrophilic nonionic surfactant such as polyglycerin fatty acid ester, although the dissolution rate of fumaric acid is improved, powder fumaric acid particles are aggregated in the manufacturing process As a result, it was found that the passability of the sieve was reduced, and the workability in the manufacturing process and the recovery rate of the powdered fumaric acid preparation were significantly reduced. In addition, the cohesiveness of the powder fumaric acid particles is expressed even in the storage and distribution process of the powder fumaric acid preparation, and there is a concern that the flowability of the powder fumaric acid preparation as a powder may be lost. These findings are new findings that the present inventors have uniquely found.

<Experiment 1: The effect of the type of carbohydrate on the sifting ability of a powdered fumaric acid preparation containing polyglycerin fatty acid ester>
Based on the above new findings, the following experiments were conducted to achieve both improvement in dissolution rate and improvement in aggregation and consolidation.
(1) Overview Various carbohydrates were added to the powder fumaric acid formulation which mix | blended a fixed amount of polyglyceryl fatty acid ester, and the kind of saccharide | sugar compared about the sieve passage property of powder fumaric acid formulation.
(2) Experimental method (A) Preparation of test sample: Polyglycerin fatty acid ester in 20.0 g of fumaric acid powder (trade name "fumaric acid (fine powder)", purity 99.0 mass% or more, sold by Sakai Chemical Industry Co., Ltd.) 1 g of an aqueous solution with a concentration of 10% by mass (trade name “Ryoto polyglycester L-7D, HLB17, sold by Mitsubishi Chemical Foods Co., Ltd.), and various carbohydrates with a concentration of 10% by mass in terms of anhydride, specifically Glucose (reagent grade, sold by Wako Pure Chemical Industries, Ltd.), sucrose (reagent grade, sold by Wako Pure Chemical Industries, Ltd.), trehalose (trade name "Treha", sold by Hayashibara Co., Ltd.), sorbitol (reagent grade, Wako Pure Chemical Industries, Ltd. Industrial Co., Ltd. sales), maltitol (reagent grade, Wako Pure Chemical Industries, Ltd. sale), maltose (brand name “Sanmalto (green)”, Hayashibara co., Ltd. sale), lactose (reagent grade Add 10g of either an aqueous solution containing Wako Pure Chemical Industries, Ltd. (sales) or partially degraded starch (product name "PANIX # 1, sold by Matsutani Chemical Industry Co., Ltd.) at a concentration of 10% by mass in terms of anhydride Further, after adding 25.1 g of pure water, after mixing for 3 minutes using a blender, the resulting wet mixture is dried by heating at 70 ° C. for 20 hours in a hot air circulating dryer, and various types of drying I got a thing. Thereafter, the dried product was ground in a mortar and then passed through a sieve with an opening of 500 μm to obtain powdered fumaric acid preparations (test samples 15 to 22) coated with various carbohydrates together with polyglycerin fatty acid ester. In addition, the various powder fumaric-acid preparations (test samples 15 to 22) obtained contain 0.5 mass% in conversion of anhydride with respect to various saccharides with respect to fumaric acid.

(A) Sieve passability test The various powder fumaric acid preparations described above are subjected to the same sieve passability test as described in (1) of preliminary experiment 1: (2) to determine the siftability of each test sample. ,evaluated. The results are shown in Table 4.

  As shown in Table 4, a given amount of polyglycerin fatty acid ester and various sugars are added to and mixed with fumaric acid powder, and fumaric acid particles are coated with polyglycerin fatty acid ester and various sugars. Each of the powdered fumaric acid preparations (test samples 15 to 22) had improved sieving properties as compared with the powdered fumaric acid preparations obtained by coating only with the control surfactant (polyglycerin fatty acid ester) alone. Was confirmed. With regard to the sieve passability, a difference is also seen among carbohydrates, and non-reducing disaccharide trehalose (test sample 17), a disaccharide or less sugar alcohol sorbitol (test sample 18), and maltitol (test sample 19) ) Was evaluated as "++ +: sieve pass rate of 50% or more after shaking for 30 seconds", and showed particularly excellent sieve passability.

  Furthermore, in order to confirm the influence of the added amount of carbohydrates on the sieve passability of the powdered fumaric acid preparation, the following experiment was conducted using trehalose which showed particularly excellent sieve passability in Experiment 1.

<Experiment 2: Effect of added amount of carbohydrate on sifting ability of powdered fumaric acid preparation>
(1) Outline A test sample is prepared in the same manner as in Experiment 1 except that trehalose is selected as the carbohydrate to be blended and the addition amount of trehalose is varied, and the difference in the addition amount of carbohydrate is the powder fumaric acid preparation The effects on the sieve passability were compared.
(2) Experimental method (a) Preparation of test sample 20.0 g of fumaric acid powder (trade name "fumaric acid (fine powder)", sold by Suga Chemical Industry Co., Ltd.), polyglycerin fatty acid ester (trade name "Glyo polyglyester 1 g of a 10% strength by weight aqueous solution of L-7 D, HLB 17 (manufactured by Mitsubishi Chemical Foods Co., Ltd.), at a concentration of 0.1, 0.2, 0.6, 1.0, 2.0, 4 in terms of anhydride The total amount of water is 35.0 g (including the amount of water in the aqueous solution) by adding 10 g of either a 0, 10.0, 20.0, 40.0 or 60.0 mass% trehalose aqueous solution. Pure water is added to be 175% by mass with respect to fumaric acid, mixed for 3 minutes using a blender, and the resulting wet mixture is heated at 70 ° C. for 20 hours in a hot air circulating dryer. And dried to obtain various dried products . Thereafter, the dried product was ground in a mortar and then passed through a sieve with an opening of 500 μm to obtain a powdered fumaric acid preparation (test samples 23 to 32) in which the fumaric acid particles were coated with polyglycerin fatty acid ester and trehalose. In addition, the various powder fumaric acid preparations (test samples 23 to 32) obtained were 0.05, 0.1, 0.2, 0.3, 0 in terms of anhydride to trehalose, respectively. .4, 0.5, 1.0, 2.0, 5.0, 10.0, 20.0, and 30.0% by mass. Moreover, as a comparison for confirming the coating effect by carbohydrate, fumaric acid powder and polyglycerin fatty acid ester are mixed in the above-mentioned quantitative ratio in the presence of water, and fumaric acid particles are coated only with polyglycerin fatty acid ester The mixed powder was first prepared, and trehalose was simply mixed with it as a powder to prepare a powder (comparative sample) of a powder of fumaric acid and trehalose powder coated with fumaric acid only with polyglycerin fatty acid ester.

(A) Sift passability test In addition to the various fumaric acid preparations described above (test samples 23 to 32 and comparative samples), fumaric acid powder as a raw material as control 1, fumaric acid powder as a control 2 and polyglycerin fatty acid ester The mixture was subjected to the same sieve passability test as described in preliminary experiment 1: (2) (c) to evaluate fumaric acid sieve passability of each sample. The results are shown in Table 5.

  As shown in Table 5, in powder fumaric acid preparations (test samples 23 to 32) prepared by coating fumaric acid particles with polyglycerin fatty acid ester and trehalose, the addition amount of trehalose is 0.05 to fumaric acid. In the case of 0.3% by mass (test samples 23 to 25), no improvement effect on cohesion was observed, and the sieve passing rate was as low as less than 25% by mass (+) or less than 50% by mass (++). On the other hand, when the addition amount of trehalose is 0.5 to 5.0 mass (test samples 26 to 29), the sieve passing rate of the powder fumaric acid preparation is improved to 50 mass% or more (+++), and the aggregation property is improved. An effect was observed.

  In addition, the amount of added trehalose relative to fumaric acid was 0. 0 as compared with that of the control raw material fumaric acid powder (control 1) or the one coated only with surfactant (polyglycerin fatty acid ester) (control 2). It was confirmed that when it is 3% by mass or more, the sieve passing property of the powdered fumaric acid preparation is improved. The effect increased as the added amount of trehalose increased. In addition, in the comparative sample obtained by only mixing the trehalose powder after coating fumaric acid particles only with polyglycerin fatty acid ester, the improvement effect of the sieve passing amount was not confirmed.

  In the case where the addition amount of trehalose is 10% by mass (test sample 30: indicated by “*” in Table 5), the sift passability is improved and although the cohesion improvement effect is recognized, the test The degree of solidification of the dried product obtained in the sample preparation process became strong, and pulverization by pulverization became partially difficult. Furthermore, when the addition amount of trehalose is 20% by mass and 30% by mass (test samples 31 and 32: indicated by “**” in Table 5), the dried product obtained in the test sample preparation step is It solidified so that it became a block-like lump, and grinding became very difficult. From the above results, the agent prepared by adding 10% by mass or more trehalose in terms of anhydride to fumaric acid becomes difficult to grind, and the workability in the process of producing the powder fumaric acid preparation is remarkably reduced It became clear to do.

  Conventionally, as shown in, for example, Patent Document 4, in order to improve the dissolution rate and stability of the powder fumaric acid preparation, it has been essential to add a large amount of carbohydrate of 10% by mass or more. As described above, according to the inventors of the present invention, according to experiments, in order to make the improvement of the dissolution rate and the improvement of the cohesion be compatible, the addition amount of the nonreducing disaccharide or the sugar alcohol below the disaccharide is Rather, the result was that a smaller amount of less than 10% by mass with respect to fumaric acid was better. This is a new finding that reverses conventional technical common sense.

  Acetic acid is known as an organic acid generally used as a food-use disinfectant cleaner, and acetic acid is generally known to act more effectively against gram-negative bacteria than gram-positive bacteria. ("The Japan Food Industry Association", vol. 41, No. 10, p. 687-701, 1994). Although the difference in the antibacterial action is not clear, it is due to the structural difference between a gram negative bacteria having two lipid membranes, a cell membrane and an outer membrane, and a gram positive bacteria having no outer membrane and a thick peptidoglycan layer. It is considered to be a thing. Therefore, the present inventors intended to improve the antibacterial activity and / or expand the antibacterial object, and when experiment was performed by combining fumaric acid and ascorbic acid as a model experiment, it was unexpectedly obtained against gram-positive bacteria. It was confirmed that there is a fungal effect. Therefore, the present inventors conducted the following experiment in order to confirm the influence of the difference in concentration of ascorbic acid when fumaric acid and ascorbic acid are combined on the eradication action against gram-positive bacteria.

<Experiment 3: The effect of fumaric acid and ascorbic acid combination on the eradication effect on gram positive bacteria>
(1) Overview Ascorbic acid solutions of different concentrations are added to a solution having a certain amount of fumaric acid, and the difference in ascorbic acid concentration when fumaric acid and ascorbic acid are combined affects the eradication effect against gram-positive bacteria We compared about.
(2) Experimental method (A) Preparation of test sample Fumaric acid powder (fumaric acid (fine powder), sold by Sakai Chemical Industry Co., Ltd.) dissolved in pure water to a concentration of 0.3% by mass Separately prepared 1.5 mL of ascorbic acid aqueous solution with separately prepared ascorbic acid concentration of 0.6 mass% was mixed with 1.5 mL of acid-containing aqueous solution to obtain a total solution of 3 mL of fumaric acid and ascorbic acid (test sample 33) . The obtained mixed solution (test sample 33) contains fumaric acid at a concentration of 0.15% by mass and contains ascorbic acid at a concentration of 0.3% by mass. Subsequently, a mixed solution of two kinds of fumaric acid and ascorbic acid (test samples 34 and 35) (3 mL each) in the same manner except that the concentration of the aqueous ascorbic acid solution to be mixed is changed to 1.8 or 3.6% by mass Got). The obtained mixed solution (test samples 34 and 35) contains fumaric acid at a concentration of 0.15% by mass and contains ascorbic acid at a concentration of 0.9 and 1.8% by mass, respectively. .

(A) Preparation of bacterial solution As Gram-positive bacteria, Staphylococcus aureus, Staphylococcus aureus NBRC 12732 strain, which is the causative agent of food poisoning, was used. Physiological saline was added to the freeze-dried ampoules of the test bacteria, and one platinum ear was inoculated to a slant of a nutrient agar medium and cultured at 37 ° C. for 24 hours. Then, the test fungus grown in the slant medium was inoculated into a platinum loop in an Erlenmeyer flask containing 100 mL of nutrient broth broth, and cultured at 37 ° C. for 15 hours with shaking to make a seed culture. The obtained seed culture solution was inoculated at 1.0% in an Erlenmeyer flask containing 100 mL of fresh nutrient broth liquid medium, and shake culture was performed at 37 ° C. for 4 hours. After completion of the culture, 50 mL of the bacterial solution is centrifuged at 5,000 rpm for 5 minutes, and after removing the supernatant, washing is performed three times using phosphate buffered saline (PBS), Absorbance at a wavelength of 660 nm was measured, and PBS was added so that the number of bacteria is 5 × 10 ⁶ CFU / mL, to prepare a bacterial solution.

(C) Bacterial elimination test 3 mL of the above bacterial solution is added to 3 mL of each of various test sample solutions (33 to 35), and the fumaric acid concentration is 0.075 mass%, and the ascorbic acid concentration is 0.15, 0. A solution containing 45 or 0.90% by mass is kept in a water bath at 30 ° C. for a predetermined time (1, 5, 10, 20 minutes), 1 mL is sampled at each time point, and 9 mL of PBS is used. Prepare solutions of 10-fold dilution series (10 ¹ times, 10 ² times, 10 ³ times, 10 ⁴ times), and dispense 1 ml of each dilution series solution into sterile petri dishes, and add 15 mL of nutrient agar medium The cells were cultured at 37 ° C. for 18 hours, the number of colonies was counted, and the number of bacteria per 1 mL was calculated. The results are shown in Table 6.

As shown in Table 6, in Control 1 (fumaric acid concentration 0.075%) and Control 2 (ascorbic acid concentration 0.90%), the number of bacteria at the start of treatment was 2.5 × 10 ⁶ CFU / mL. There is almost no change in the number of bacteria after 5 minutes of treatment time to 2.1 × 10 ⁶ CFU / mL and 2.3 × 10 ⁶ CFU / mL, respectively, and even after 20 minutes of treatment time, 1.9 or less, respectively. Although a slight decrease in the number of bacteria such as 10 ⁶ CFU / mL and 1.5 × 10 ⁶ CFU / mL was confirmed, it was also confirmed that none of them showed any eradication effect at this concentration. On the other hand, in a solution of fumaric acid concentration of 0.075% and ascorbic acid concentration of 0.15 to 0.90% (test samples 33 to 35) in which both were combined, the number of bacteria after 5 minutes of treatment time was 7. 7 × 10 ⁵ CFU / mL, 4.0 × 10 ⁴ CFU / mL, 2.0 × 10 ⁴ CFU / mL, and a marked decrease in the number of bacteria from 1/3 to 1/125 from the number of bacteria at the start of treatment Was confirmed, and the eradication effect was observed. The effect increased as the treatment time and content of ascorbic acid increased. In a solution with an ascorbic acid concentration of 0.45% and 0.90% (test samples 34 to 35), after 10 minutes of treatment time, the number of bacteria becomes less than 10 CFU / mL, and it is confirmed that the test bacteria are completely killed It was done.

  Furthermore, the inventor conducted the following experiment to confirm the eradication effect of the combination of fumaric acid and ascorbic acid on gram-negative bacteria.

<Experiment 4: Effect of fumaric acid and ascorbic acid combination on eradication effect against gram negative bacteria>
(1) Overview Ascorbic acid solutions of different concentrations are added to a solution containing a certain amount of fumaric acid, and the combination of fumaric acid and ascorbic acid and the effect of the difference in ascorbic acid concentration on the eradication effect against gram negative bacteria Compared.
(2) Experimental method (a) Preparation of test sample and cell suspension Fumaric acid prepared by adding an ascorbic acid solution having different concentrations to a solution containing a certain amount of fumaric acid so as to obtain the same concentration as in Experiment 3. Ascorbic acid mixed solution (test samples 33 to 35) is used, and as gram-negative bacteria, culture is performed under the same conditions as in Experiment 3 using E. coli strain Escherichia coli NBRC 3301 and after the culture is completed, After centrifuging 50 mL of the bacterial solution at 5,000 rpm for 5 minutes, removing the supernatant, and washing three times with phosphate buffered saline (PBS), the absorbance at a wavelength of 660 nm Was measured, and PBS was added so that the number of bacteria was 5 × 10 ⁶ CFU / mL, to prepare a bacterial solution.

(B) Germination test The same treatment as in Experiment 3 was performed except that the retention time in a water bath at 30 ° C. was changed to 40 seconds (only control 2 was not measured) and 80 seconds, and the number of bacteria per mL was calculated. did. The results are shown in Table 7.

As shown in Table 7, in Control 2 (ascorbic acid concentration 0.90%), the number of bacteria after treatment for 80 seconds is 1 against the number of bacteria of 2.5 × 10 ⁶ CFU / mL at the start of treatment. Although a slight decrease in the number of bacteria was confirmed as 4 × 10 ⁶ CFU / mL, it was confirmed that the concentration hardly shows the eradication effect. On the other hand, in Control 1 (fumaric acid concentration: 0.075%), a reduction in the number of bacteria after 40 seconds of the treatment time was confirmed to 2.6 × 10 ⁵ CFU / mL, and the treatment time 80 After a second, a further reduction in the number of bacteria was confirmed at 9.8 × 10 ⁴ CFU / mL, and the eradication effect was confirmed. On the other hand, in a solution of fumaric acid concentration of 0.075% and ascorbic acid concentration of 0.15 to 0.90% (test samples 33 to 35) in which both were combined, the number of bacteria after 40 seconds of treatment time was 1. 2 × 10 ⁵ CFU / mL, 7.2 × 10 ⁴ CFU / mL, 9.6 × 10 ⁴ CFU / mL, and a marked decrease in the number of bacteria from 1/20 to 1/35 from the number of bacteria at the start of treatment Was confirmed, and the eradication effect was observed. At this concentration, as the treatment time increases, the eradication effect is further exerted, and the number of bacteria after 80 seconds of treatment time is 9.3 × 10 ³ CFU / mL and 6.2 × 10 ³ CFU / mL, respectively. Further reduction of the number of bacteria was confirmed, at 4.4 × 10 ³ CFU / mL.

  From the results of the above experiments 3 and 4, by combining fumaric acid and ascorbic acid, a stronger eradication effect can be obtained against gram-positive bacteria and gram-negative bacteria than when acting alone, and the effect is As the content increased, it became clear to increase. These findings are new findings that the present inventors have uniquely found.

  Then, while preparing the powder fumaric acid formulation containing ascorbic acid by the method described in Example 5 mentioned later, a powder fumaric acid formulation is separately prepared by the method described in Example 1, and both were experiment 3 and It was subjected to the same eradication effect comparison test as in 4. As a result, in Experiment 4 in which the bactericidal effect against gram-negative bacteria is observed, the powder fumaric acid preparations prepared by the methods of Examples 1 and 5 all have a bactericidal effect confirmed, and are effective as food sanitizers Was confirmed. Furthermore, in Experiment 3 where the eradication effect against gram-positive bacteria was observed, the powder fumaric acid preparation prepared by the method of Example 1 showed no eradication effect but was prepared by the method of Example 5 containing ascorbic acid. It was found that the powdered fumaric acid preparation exhibits an excellent sterilization effect and exhibits a broad antibacterial effect.

  EXAMPLES The present invention will next be described in more detail by way of examples, which should not be construed as limiting the invention thereto.

Powdered fumaric acid preparation
200 parts by mass of a commercially available fumaric acid powder (trade name "fumaric acid (fine powder)", sold by Sakai Chemical Industry Co., Ltd.) was ground in a mortar and sieved through a 500 μm mesh to adjust the particle diameter to 500 μm or less. On the other hand, polyglycerin fatty acid ester (trade name "Ryoto polyglycester L-7D, HLB 17, manufactured by Mitsubishi Chemical Foods Co., Ltd.) was added to water and dissolved to prepare 10 parts by mass of a 10% by mass aqueous solution. In addition, trehalose (trade name "TREHA", manufactured by Hayashibara Co., Ltd.) was dissolved in water to prepare 20 parts by mass of a 50% by mass aqueous solution of trehalose. 199 parts by mass of the pulverized fumaric acid powder is placed in a plastic container, the polyglycerin fatty acid ester aqueous solution and the trehalose aqueous solution are simultaneously added, and then 331 parts by mass of pure water is added and mixed using a blender A mixture was obtained. Next, the resulting wet mixture is spread on a tray and predried by heating at 70 ° C. for 2 hours in a hot air circulating drier, and the dried product is once loosened and then further reduced to 95 ° C. under reduced pressure. The water was removed by drying for 5 hours and dried. The resulting dried product is ground in a mortar, passed through a 500 μm mesh sieve, and powdered fumaric acid containing 94.8% by mass of fumaric acid, 0.48% by mass of polyglycerin fatty acid ester, and 4.8% by mass of trehalose An acid preparation was obtained.

  In this product, the amount of carbohydrates to fumaric acid is reduced to less than 10% by mass in terms of anhydride, and the agent does not solidify in the form of blocks during the production process (after drying), which causes problems in pulverization. Was a powder with the advantage of no In addition, since this product is coated with fumaric acid using trehalose together with polyglycerin fatty acid ester, a phenomenon that hinders aggregation of the obtained powder fumaric acid preparation and classification with a sieve is also reduced. . Furthermore, the product has an excellent property of being able to easily prepare a disinfectant for food and the like because its dissolution rate in water has also been improved.

Powdered fumaric acid preparation
A commercially available fumaric acid powder is first mixed with an aqueous solution of trehalose, and then the resulting mixture is mixed with an aqueous solution of polyglycerin fatty acid ester, and the procedure is the same as in Example 1 except that the amount of pure water added is changed to 181 parts by mass. A powder fumaric acid preparation containing 94.8% by mass of fumaric acid, 0.48% by mass of polyglycerin fatty acid ester, and 4.8% by mass of trehalose was obtained.

In this product, the amount of carbohydrates to fumaric acid is reduced to less than 10% by mass in terms of anhydride, and the agent does not solidify in the form of blocks during the production process (after drying), which causes problems in pulverization. Was a powder with the advantage of no In addition, since the product is coated with fumaric acid using trehalose together with polyglycerin fatty acid ester, a phenomenon which causes trouble when the obtained powder is aggregated and classified with a sieve has been reduced. Furthermore, the product has an excellent property of being able to easily prepare a disinfectant for food and the like because its dissolution rate in water has also been improved.
Incidentally, when the dissolution rate of this product in water was compared with that of the powder fumaric acid preparation obtained in Example 1, it was subjected to the same solubility test as described in (i) of preliminary experiment 1: (2). It showed the property of completely dissolving in a short time.

Powdered fumaric acid preparation
Instead of trehalose, sorbitol ("reagent", sold by Wako Pure Chemical Industries, Ltd.) is used as carbohydrate to coat fumaric acid particles, the amount of a 50% by mass aqueous solution of sorbitol is 15 parts by mass, and pure water to be added is 142 .5 Powdered fumaric acid preparation which contains 95.9% by mass of fumaric acid, 0.48% by mass of polyglycerin fatty acid ester and 3.6% by mass of sorbitol after the same treatment as in Example 1 except that the amount is changed to 5 parts by mass I got

  In this product, the amount of carbohydrates to fumaric acid is reduced to less than 10% by mass in terms of anhydride, and the agent does not solidify in the form of blocks during the production process (after drying), which causes problems in pulverization. Was a powder with the advantage of no In addition, since the product is coated with fumaric acid using sorbitol together with polyglycerin fatty acid ester, a phenomenon which causes trouble when the obtained powder is aggregated and classified with a sieve has been reduced. Furthermore, the product has an excellent property of being able to easily prepare a disinfectant for food and the like because its dissolution rate in water has also been improved.

Powdered fumaric acid preparation
Maltitol (trade name "Crystal maltitol", sold by Mitsubishi Shoji Foodtech Co., Ltd.) is used instead of trehalose as carbohydrate to coat fumaric acid particles, and the amount of 50% by mass aqueous solution of maltitol is 25 parts by mass. Further, using sucrose fatty acid ester (trade name “Ryoto sugar ester S-1670”, HLB16, manufactured by Mitsubishi Chemical Foods Co., Ltd.) as a hydrophilic nonionic surfactant, the amount of 10% by mass aqueous solution of sucrose fatty acid ester Powder fumaric acid preparation containing 93.2% by mass of fumaric acid, 0.94% by mass of sucrose fatty acid ester, and 5.85% by mass of maltitol except that 20 parts by mass of I got

  In this product, the amount of carbohydrates to fumaric acid is reduced to less than 10% by mass in terms of anhydride, and the agent does not solidify in the form of blocks during the production process (after drying), causing problems in pulverization. Was a powder with the advantage of no In addition, since the product is coated with fumaric acid using maltitol together with sucrose fatty acid ester, a phenomenon which causes trouble when the obtained powder is aggregated and classified with a sieve has been reduced. Furthermore, the product has an excellent property of being able to easily prepare a disinfectant for food and the like because its dissolution rate in water has also been improved.

Powdered fumaric acid preparation
6 parts by mass of ascorbic acid (reagent grade, sold by Wako Pure Chemical Industries, Ltd.) is added to 1 part by mass of fumaric acid in the powdered fumaric acid preparation obtained in Example 1, ground and mixed in a mortar, The mixture was passed through a sieve with an opening of 500 μm to obtain a powdered fumaric acid preparation containing an organic acid other than fumaric acid (ascorbic acid).

  Although this product contains a relatively large amount of ascorbic acid, it has been coated with fumaric acid particles using trehalose together with polyglycerin fatty acid ester, and therefore the powder obtained may be aggregated and classified with a sieve. Phenomenon has been reduced. Furthermore, the product has an excellent property of being able to easily prepare a disinfectant for food and the like because its dissolution rate in water has also been improved.

Powdered fumaric acid preparation
To 1 part by mass of fumaric acid in the powdered fumaric acid preparation obtained in Example 1, 3 parts by mass of ascorbic acid 2-glucoside (reagent grade, sold by Wako Pure Chemical Industries, Ltd.) is added and ground and mixed in a mortar Then, it was passed through a sieve of 500 μm mesh to obtain a powdered fumaric acid preparation containing a derivative of an organic acid other than fumaric acid (ascorbic acid 2-glucoside).

  Although the product contains a relatively large amount of ascorbic acid 2-glucoside, which is a derivative of ascorbic acid, the powder obtained is aggregated because the fumaric acid particles are coated with trehalose together with polyglycerin fatty acid ester. The phenomenon which is a hindrance when classifying with a sieve has been reduced. Furthermore, the product has an excellent property of being able to easily prepare a disinfectant for food and the like because its dissolution rate in water has also been improved.

<Sterilization cleaner for vegetables>
The powdered fumaric acid preparation obtained in Example 2 was dissolved in pure water so as to have a fumaric acid concentration of 0.3% by mass, and used as a disinfectant cleaner for vegetables. The general viable count of cut vegetables can be significantly reduced by immersing the cut vegetables in the present disinfectant cleaner for 30 seconds or more.

<Sterilizer for meat>
The powdered fumaric acid preparation obtained in Example 3 was dissolved in pure water so as to have a fumaric acid concentration of 0.5% by mass, and it was used as a microbe elimination cleaner for meat. The general viable count of chicken can be remarkably reduced by immersing the chicken which has been cut into the present disinfectant cleaner at 25 ° C. for 60 minutes.

Comparative Example 1

Powdered fumaric acid preparation
The same treatment as in Example 1 is carried out except that the addition amount of a 50% by mass aqueous solution of trehalose is 50 parts by mass, 88.4% by mass of fumaric acid, 0.44% by mass of polyglycerin fatty acid ester, 11.1% by mass trehalose % Powder fumaric acid preparation was obtained.

  This product contains a large amount of carbohydrate relative to fumaric acid in excess of 10% by mass in terms of anhydride, and since the agent solidified in a block during the manufacturing process (after drying), grinding becomes difficult The sex has dropped significantly.

Comparative example 2

Powdered fumaric acid preparation
The same treatment as in Example 1 was carried out except that 50% by mass aqueous solution of trehalose was not added, and a powdery fumaric acid preparation containing 99.5% by mass of fumaric acid and 0.5% by mass of polyglycerin fatty acid ester was obtained .

  In this product, the surface of the fumaric acid particles is only coated with the polyglycerin fatty acid ester which is a surfactant, and although the dissolution rate of fumaric acid itself is improved, the powder fumaric acid preparation is aggregated in the manufacturing process. As a result, the passability of the sieves was reduced, and the workability in the production of the powder fumaric acid preparation and the recovery rate of the preparation were significantly reduced.

  As described above, according to the present invention, a powder fumaric acid preparation excellent in powder flowability and dissolution rate can be easily manufactured. The powder fumaric acid preparation obtained by the production method of the present invention is superior to the conventional powder fumaric acid preparation in powder flowability, is hard to be consolidated, is easy to handle as a powder preparation, and is soluble in water Since (dissolution rate) is also good, it can be advantageously used in the food field as an acidulant, preservative, disinfectant and the like. The impact of the present invention on the art is thus enormous, and the industrial applicability of the present invention is extremely large.

Claims (14)

A method for producing a powdered fumaric acid preparation containing fumaric acid as an active ingredient, comprising the following steps (1) to (3):
(1) Fumaric acid powder, hydrophilic nonionic surfactant, and fumaric acid in an amount of 0.5% by mass or more and less than 10.0% by mass of non-reducing disaccharide or disaccharide or less in terms of anhydride Mixing sugar alcohols in the presence of a solvent to obtain a fumaric acid-containing wet mixture;
(2) The obtained fumaric acid-containing wet mixture is dried, and the fumaric acid particles are coated with a hydrophilic nonionic surfactant and a nonreducing disaccharide or a sugar alcohol having a disaccharide or less, and the fumaric acid-containing particulate composition is coated And (3) pulverizing and classifying the obtained fumaric acid-containing particulate composition, if necessary, to obtain a powdered fumaric acid preparation.   In the step (1), a fumaric acid is mixed with a nonreducing disaccharide or a sugar alcohol having a disaccharide or less than the disaccharide in the presence of a solvent, and then a hydrophilic nonionic surfactant is added and mixed. A method of producing the powdered fumaric acid preparation according to claim 1.   The method for producing a powdered fumaric acid preparation according to claim 1 or 2, wherein the non-reducing disaccharide is trehalose, and the sugar alcohol below the disaccharide is either sorbitol or maltitol.   The method according to claim 1, wherein the amount of the hydrophilic nonionic surfactant mixed in the step (1) is 0.1 to 3.0% by mass in terms of anhydride relative to fumaric acid. 4. A method for producing the powdered fumaric acid preparation according to any one of 3. to 3.   The method for producing a powdered fumaric acid preparation according to any one of claims 1 to 4, wherein the hydrophilic nonionic surfactant to be mixed in the step (1) is a polyglycerin fatty acid ester.   The method for producing a powdered fumaric acid preparation according to any one of claims 1 to 5, wherein the amount of the solvent used for mixing in the step (1) is 50% by mass or more with respect to fumaric acid.   In the process of any one of (1) to (3), an organic acid other than fumaric acid, a derivative thereof or a salt thereof is further mixed, or an organic acid other than fumaric acid in the obtained powder formulation, The method for producing a powdered fumaric acid preparation according to any one of claims 1 to 6, wherein the derivative or a salt thereof is mixed.   A fumaric acid, a hydrophilic nonionic surfactant, and a nonreducing disaccharide or a disaccharide or less disaccharide sugar alcohol which is 0.5% by mass or more and less than 10.0% by mass in terms of anhydride relative to the fumaric acid, A powdery fumaric acid preparation, wherein fumaric acid particles are coated with the hydrophilic nonionic surfactant and the non-reducing disaccharide or a sugar alcohol smaller than the disaccharide.   9. The powdered fumaric acid preparation according to claim 8, wherein the non-reducing disaccharide is trehalose, and the sugar alcohol smaller than the disaccharide is either sorbitol or maltitol.   The powdery fumaric acid preparation according to claim 8 or 9, wherein the content of the hydrophilic nonionic surfactant is 0.1 to 3.0% by mass with respect to fumaric acid.   The powdered fumaric acid preparation according to any one of claims 8 to 10, wherein the hydrophilic nonionic surfactant is a polyglycerin fatty acid ester.   The powdered fumaric acid preparation according to any one of claims 8 to 11, further comprising an organic acid other than fumaric acid.   The powdered fumaric acid preparation according to claim 12, wherein the amount of the organic acid other than fumaric acid is 2 to 12 times the amount of fumaric acid. The powdered fumaric acid preparation according to claim 12 or 13, wherein the organic acid other than fumaric acid is ascorbic acid.