JP6902897B2 - Method for Producing Glutathione-Containing Composition - Google Patents

Description

The present invention relates to a granular composition containing glutathione.

Glutathione is a peptide consisting of three amino acids, L-cysteine, L-glutamic acid, and glycine. It exists not only in the human body but also in many living organisms such as other animals, plants, and microorganisms, and has an active oxygen scavenging action and a detoxifying action. , Amino acid metabolism, etc., is an important compound for living organisms.

Glutathione is reduced glutathione (N- (N-γ-L-glutamyl-L-cystenyl) glycine, which is a form of SH in which the thiol group of the L-cysteine residue is reduced in vivo, hereinafter referred to as "GSH". (Sometimes) and oxidized glutathione (hereinafter sometimes referred to as "GSSG"), which is a form in which the thiol group of the L-cysteine residue of two GSH molecules is oxidized to form a disulfide bond between two glutathione molecules. It exists in any form of.

GSSG is useful in the fields of fertilizers, pharmaceuticals, cosmetics, etc., and processing techniques for processing compositions in a form suitable for each application are known. Patent Document 1 describes that granules containing glutathione as an active ingredient are subjected to stirring granulation and rolling granulation by adding purified water or the like to the mixture. Further, Patent Document 2 describes that the glutathione powder is preferably a crystalline powder rather than a non-crystalline amorphous in terms of hygroscopicity, safety and the like, and has fluidity, filling property, tableting property and the like. A method for producing glutathione crystals having excellent solubility is disclosed.

International release WO2001 / 072285 International release WO2008 / 047792

When a material containing glutathione (solid component) is granulated while adding a liquid binder such as water, the binding force (stickiness) of the material is significantly increased, and the material adheres to the device during granulation, or the granulated product. As the particle size of the product becomes large, it may not be possible to obtain a granulated product having a desired particle size. If the material adheres to the device, it is necessary to perform cleaning frequently, and if the proportion of granulated products with a large particle size that deviates from the desired particle size increases, the load of recycling work such as crushing increases, and manufacturing Efficiency is reduced.

Patent Document 1 describes granules containing glutathione as an active ingredient, but does not describe the production efficiency in granulation, and of course, no means for improving the production efficiency has been proposed. Patent Document 2 describes a method for producing glutathione crystals and tablets containing the same, but does not propose a method for granulating a granular composition containing glutathione by adding a liquid binder.

Therefore, an object of the present invention is to provide a method having excellent production efficiency in which a significant increase in the binding force of a material is suppressed in the production of a granular composition containing glutathione.

The present inventors have found that when glutathione-containing granular composition is produced, the inclusion of glutathione in crystalline form as glutathione suppresses a significant increase in the binding force of the material, and completes the present invention. I arrived. The following inventions are disclosed in the present specification.
(1) A method for producing a granular composition containing glutathione, wherein a liquid binder is added to a solid component containing glutathione in a crystalline form for granulation.
(2) The production method according to (1), wherein the crystallinity of glutathione contained in the solid component is 20% or more.
(3) The production method according to (2), wherein the solid component further contains a binder.
(4) The production method according to any one of (1) to (3), wherein the liquid binder is water or an aqueous solution using water as a solvent.
(5) The production method according to any one of (1) to (4), wherein the granulation method is any of stirring granulation, rolling granulation, and extrusion granulation.
(6) The production method according to any one of (1) to (5), wherein the average particle size of the granular composition is 50 to 5000 μm.

According to the present invention, it is possible to improve the production efficiency when producing a granular composition containing glutathione.

1. 1. Granular Composition The present invention relates to a glutathione-containing granular composition (hereinafter, may be referred to as “composition of the present invention”).

The use of the composition of the present invention is not particularly limited as long as it is used according to the use of glutathione. For example, the compositions of the present invention can be used for applications to plants. Hereinafter, the composition of the present invention will be specifically described.

The composition of the present invention is granulated by adding a liquid binder to a solid component containing glutathione. The solid component referred to here means, for example, a powdery substance, and the particle size thereof is, for example, 1 mm or less, preferably 0.5 mm or less, and may be fine particles of about 10 μm. The blending amount of glutathione in the granular composition of the present invention is not particularly limited and can be adjusted according to the use of the composition, etc., but glutathione is, for example, 0.01% by mass or more based on the total amount of the composition. It can be preferably 0.1% by mass or more, for example, 40% by mass or less, preferably 20% by mass or less. This range is particularly preferable when the granular composition is used for promoting the growth of plants.

The shape of the composition of the present invention is not particularly limited as long as it is granular, and examples thereof include granules, pellets, and briquettes. The term "granular" as used herein means that the primary particles of the material are bonded to each other by a granulation operation and have a particle size of several tens of micrometers or more.

Examples of the components contained in the composition of the present invention include components permitted in the use of the composition, such as a binder, an inorganic carrier, an organic carrier, and an excipient.

Examples of the binder of the present invention include carboxymethyl cellulose, methyl cellulose, ethyl cellulose, polyvinylpyrrolidone, purulan, acrylic polymer, polyvinyl alcohol, gelatin, agar, arabic gum, arabic gum powder, xanthan gum, trangam, guar gum, gellan gum, and locust bean. Gum, pregelatinized starch, macrogol, starch, soluble starch, dextrin, tragacanth rubber, β-glucan, pectin, casein, soybean protein, hydroxyethyl cellulose, acetyl cellulose, lignin sulfonic acid, carboxymethyl starch, hydroxyethyl starch, polyvinyl methyl ether, Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, cellac, rosin, tall oil, ester gum, polyvinyl acetate, polylactic acid, polyvinyl chloride, polyester, polyurea, polyamide, kumaron resin, biodegradable Polymers, paraffin wax, microcrystallin wax, petrolatum, montan wax, carnauba wax, cotton wax, beeswax, wool wax, polymer nonionic surfactants, polymer anionic surfactants, polymer cations System surfactants, high molecular weight amphoteric surfactants, alginic acid (these are high molecular compounds), sodium silicate, glycerin, animal and vegetable oils, fats and oils, liquid paraffins, heavy oils, glucose, sucrose, mannitol, sorbitol, non- High molecular weight non-ionic surfactants, non-polymeric anionic surfactants, non-polymeric cationic surfactants, non-polymeric amphoteric surfactants (the above are non-polymeric compounds) Etc., these salts are mentioned, and at least one selected from these groups can be used.

Particularly preferable binders are polymer compound binders, and among them, preferred ones are selected from carboxymethyl cellulose and salts thereof, polyvinyl alcohol, starch, arabic gum, hydroxyethyl cellulose, lignin sulfonic acid and salts thereof, and polyethylene glycol. There is at least one species that is used. Examples of the salt of carboxymethyl cellulose include alkali metal salts such as sodium, potassium and lithium, and alkaline earth metal salts such as magnesium and calcium. Carboxymethyl cellulose and its salts are also considered to contribute to the improvement of storage stability of glutathione in the composition. By using these binders, it may be possible to realize sustained release of glutathione when the composition of the present invention is used for application to plants.

Inorganic carriers that can be contained in the composition of the present invention include talc, mica, bentonite, montmorillonite and smectite, clay, kaolin, activated clay, zeolite, diatomaceous earth, perlite, gicrite, sericite, pumice, silica, white carbon, vermiculite, Calcium carbonate and the like can be mentioned.

Examples of the organic carrier that can be contained in the composition of the present invention include dried plant materials such as fir, sawdust, soybean flour, corn stalk, and plant fiber, and organic porous carriers such as pulp flocs and activated carbon.

Excipients that can be contained in the composition of the present invention include lactose, trehalose, cellulose and the like.

The composition of the present invention may contain additional components as appropriate depending on the intended use. For example, when the composition of the present invention is used for application to a plant, a fertilizer component can be included as another component. Examples of fertilizer components include elements useful as fertilizers such as potassium, nitrogen, phosphorus, calcium and magnesium.

Examples of the liquid binder of the present invention include liquids such as water and alcohol, as well as molasses and pulp waste liquid, which may be used alone or in combination. Further, the above-mentioned binder may be dissolved in a liquid such as water or alcohol to form a liquid binder.

The granulation method of the composition of the present invention is not particularly limited, and examples thereof include granulation methods such as stirring granulation, rolling granulation, fluidized bed granulation, and extrusion granulation. As an application of the composition of the present invention, for example, in the case of using it for foliar spraying on a plant, it is necessary to make a granulated product that is easily dissolved because it needs to be dissolved in water at the time of application. Granulation is preferably performed by granulation, and stirring granulation is particularly preferable from the viewpoint of production cost. The average particle size of the granular composition at that time is preferably 50 μm or more in order to avoid deterioration of handleability due to powdering, and is preferably 2000 μm or less in consideration of the time required for dissolution in water. Further, in the case where the composition of the present invention is sprayed on soil as a fertilizer, it is preferable to granulate by rolling granulation or extrusion granulation in order to obtain physical strength that does not powder during application, and from the viewpoint of manufacturing cost. Rolling granulation is particularly preferred. The average particle size of the granular composition at that time is preferably 2000 to 5000 μm so that it can be applied with a sprayer such as a broad caster. That is, the particle size of the composition of the present invention is not particularly limited, but the average particle size thereof is preferably 50 to 5000 μm, and is appropriately adjusted according to the intended use.

2. Glutathione Glutathione may be in various forms such as free forms, salts formed by reaction with acids and / or bases, hydrates, mixtures thereof and the like. In the present invention, the mass of glutathione is represented by the mass converted as a free form unless otherwise specified.

In the present invention, glutathione may be oxidized glutathione (GSSG), reduced glutathione (GSH), or a mixture of GSSG and GSH.

2-1. Oxidized glutathione (GSSG)
GSSG is a substance formed by binding two molecules of GSH (N- (N-γ-L-glutamyl-L-cystenyl) glycine) via a disulfide bond, and the free form is represented by the following formula. ..

In the present invention, GSSG is a GSSG in various forms such as a free form which is not bound to other substances and is not ionized, a salt formed by GSSG and an acid or a base, a hydrate thereof, and a mixture thereof. Can be included.

GSSG has a characteristic structure in which two oligopeptide chains having the same amino acid sequence and having 3 n are linked by a disulfide bond via the side chain of each cysteine residue.

In the present invention, the composition mainly containing GSSG as glutathione is a composition in which the content of GSSG is relatively higher than the content of GSH in the composition, and it is more preferable that GSH is not substantially contained. .. More preferably, the total mass of GSSG (mass converted as a free form) is 70% by mass or more in total with respect to the total mass of GSSG and GSH contained in the composition (mass converted as a free form). , More preferably 80% by mass or more, more preferably 90% by mass or more, still more preferably 95% by mass or more, still more preferably 98% by mass or more, and most preferably 100% by mass.

The salt of GSSG is not particularly limited as long as it is one or more salts acceptable depending on the purpose such as ammonium salt, calcium salt, magnesium salt, sodium salt, lithium salt and the like, but ammonium salt, calcium salt and magnesium are preferable. One or more salts selected from salts. The solid ammonium salt, calcium salt and magnesium salt of GSSG are particularly preferable because they have low deliquescent properties, are easy to handle, and are highly water-soluble. Such salts are in contact with an aqueous medium selected from water and / or water soluble media in the presence of a substance capable of producing at least one selected from ammonium ions, calcium cations, and magnesium cations. It can be obtained as a solid by heating to a temperature of 30 ° C. or higher. The heating temperature is not particularly limited as long as it is 30 ° C. or higher, but is preferably 33 ° C. or higher, more preferably 35 ° C. or higher, particularly preferably 40 ° C. or higher, and the upper limit is not particularly limited, but is, for example, 80 ° C. or lower, preferably 80 ° C. or higher. It is 70 ° C. or lower, particularly preferably 60 ° C. or lower, and is particularly preferably in the range of 53 to 60 ° C. for industrial scale production. The aqueous medium may be used alone or in combination of two or more, but it is recommended to use water and a water-soluble medium in combination. In this case, water functions as a rich solvent for oxidized glutathione, and a water-soluble medium functions as a poor solvent. The volume of the water-soluble medium is, for example, about 1 to 1000 parts by volume, preferably about 5 to 500 parts by volume, more preferably about 10 to 100 parts by volume, and particularly about 12 to 50 parts by volume with respect to 10 parts by volume of water. Is. As the water-soluble medium, alcohols (methanol, ethanol, propanol, butanol, ethylene glycol, etc.), ketones (acetone, methyl ethyl ketone, etc.) and the like can be used. Examples of the GSSG salt obtained by this method include 1 ammonium salt of GSSG, 0.5 calcium salt or 1 calcium salt of GSSG, 0.5 magnesium salt or 1 magnesium salt of GSSG, and the like.

2-2. Reduced glutathione (GSH)
GSH is also referred to as N- (N-γ-L-glutamyl-L-cystenyl) glycine). In the present invention, GSH is a free form that is not bound to other substances and is not ionized, a salt formed by GSH and an acid or a base, a hydrate thereof, a mixture thereof, and the like. Can be included.

In the present invention, the composition mainly containing GSH as glutathione is a composition in which the content of GSH is relatively higher than the content of GSSG in the composition, and it is more preferable that the composition does not substantially contain GSSG. .. More preferably, the total mass of GSH (mass converted as a free form) is 70% by mass or more in total with respect to the total mass of GSSG and GSH contained in the composition (mass converted as a free form). , More preferably 80% by mass or more, more preferably 90% by mass or more, still more preferably 95% by mass or more, still more preferably 98% by mass or more, and most preferably 100% by mass.

The GSH salt is not particularly limited as long as it is one or more salts that are acceptable depending on the purpose, such as ammonium salt, calcium salt, magnesium salt, sodium salt, and lithium salt.

2-3. Glutathione Form The glutathione of the present invention is preferably in crystalline form. If there is a large amount of amorphous glutathione relative to the entire glutathione, the binding force (stickiness) of the material will be significantly increased when granulating while adding a liquid binder such as water, and the material may adhere to the device during granulation. The particle size of the granulated product becomes large, and the yield of the granulated product is significantly reduced. Therefore, the crystallinity representing the proportion of crystalline substance in glutathione may be 20% or more, preferably 23% or more and 32% or more, and more preferably 34% or more, 35% or more and 36% or more. preferable. The crystallinity of glutathione here means the ratio of glutathione in the crystalline form in glutathione.

The crystallinity of glutathione can be determined by powder X-ray diffraction. For example, an X-ray diffraction pattern (SmartLab, manufactured by Rigaku) is used to acquire an X-ray diffraction pattern, and analysis software (PDXL, manufactured by Rigaku) is used to apply the multiple peak separation method in a scanning range of 2 to 60 °. Can be calculated.

Hereinafter, the present invention will be described with reference to specific examples. However, the following specific examples do not limit the scope of the present invention.

<Test 1>
The GSSG-containing granules having each composition shown in Table 1 were produced by stirring granulation, and the yield of the granulated products having a particle size of 53 μm to 2 mm was determined. The procedure is as follows.
Each component was weighed and mixed so that the total was 520 g. This was crushed with a crusher (LM-05 type, manufactured by Dalton). 500 g of the pulverized product was weighed, and 26.5 g of water was added as a liquid binder with a stirring granulator (SPGJ-2TG type, manufactured by Dalton) to perform stirring granulation. The granules obtained by this stirring granulation were dried in a fluidized bed dryer (GB22 type, manufactured by Yamato Scientific Co., Ltd.). The obtained dried product was classified by a vibrating sieve (manufactured by FRITSCH) using a sieve having an opening of 2 mm and 53 μm. The weight of the fraction that passed through a sieve having a mesh size of 2 mm and did not pass through a sieve having a mesh size of 53 μm was measured, and the yield with respect to the charged amount was determined. In addition, the suppression of large grain generation in the granulated product was evaluated.

The evaluation of the suppression of large grain generation was carried out from the following viewpoints. When the above granulation method is carried out, if a granulated product having a particle size of 5 mm or more is not produced, it is evaluated as "○", and if a granulated product having a particle size of 5 mm to 20 mm is produced, it is evaluated as "○". It was evaluated as "Δ", and when a granulated product having a particle size of 20 mm or more was produced, it was evaluated as "x". In addition, the suppression of material adhesion to the granulator during granulation was evaluated. The evaluation of adhesion suppression was performed from the following viewpoints. When the above granulation method was carried out, those with almost no adhesion to the device were evaluated as "○", and those with a wall thickness of less than about 1 mm were visually evaluated as "△". Those showing wall adhesion with a thickness of about 1 mm or more were evaluated as "x". Table 1 shows the yield and evaluation results of each granulated product.

The granulated product of Comparative Example 1 in which the proportion of amorphous glutathione as glutathione in the granulation material is 100% by mass (that is, the crystallinity of glutathione is 0%) has a high adhesion between the materials during granulation. It tended to be strong and large, and the yield of granulated products having a particle size of 53 μm to 2 mm was low. In addition, the adhesion to the inner wall of the granulator was also severe. On the other hand, the granulated products of Examples 1 to 6 containing glutathione in the crystalline form as glutathione in the granulation material have a particle size of 53 μm or more as compared with Comparative Example 1 in which glutathione in the crystalline form is not contained as glutathione in the granulation material. The yield of 2 mm was high, and in particular, in Examples 1 to 3, almost no adhesion to the granulator was observed.

<Test 2>
(Comparative Example 2)
Similar to Comparative Example 1 except that the amount of water added during stirring granulation was set to 15.5 g in order to confirm whether the generation of large grains and adhesion to the apparatus could be suppressed by reducing the amount of water added as a binder. The yield was determined in the same manner with the component composition (Comparative Example 2). As a result, the yield in Comparative Example 2 was 10.2%. In Comparative Example 2, although the amount of water added was significantly reduced as compared with Comparative Example 1, the material had a strong adhesiveness during granulation and tended to be large, as in Comparative Example 1, and the particle size was 53 μm. The yield of granules of ~ 2 mm was low. Further, in Comparative Example 2, the adhesion to the inner wall of the granulator was severe as in Comparative Example 1.

<Test 3>
(Example 7)
A GSSG-containing granule was produced by rolling granulation with the same composition as in Example 1, and the yield of the granulated product having a particle size of 2 mm to 4 mm was determined. The procedure is as follows.
Each component was weighed and mixed so that the total was 220 g. This was crushed with a crusher (LM-05 type, manufactured by Dalton). 200 g of the pulverized product was weighed, and 19.8 g of water was added as a liquid binder with a rolling granulator (PZ-01R type, manufactured by AS ONE) to obtain granules by rolling granulation. The granules were dried in a fluidized bed dryer (GB22 type, manufactured by Yamato Scientific Co., Ltd.). The obtained dried product was classified by a vibrating sieve (manufactured by FRITSCH) using a sieve having a mesh size of 4 mm and 2 mm. The weight of the fraction that passed through the sieve with a mesh opening of 4 mm and did not pass through the sieve with a mesh opening of 2 mm was measured, and the yield with respect to the charged amount was determined.
The yield in Example 7 was as good as 85.7%, and the adhesion to the granulator was slight.

<Test 4>
(Example 8)
The GSSG-containing granules having each composition shown in Table 2 were produced by extrusion granulation, and the yield of the granulated products having a particle size of 2 mm to 4 mm was determined. The procedure is as follows.
Each component was weighed and mixed so that the total amount was 500 g. To this, 95.3 g of water was added as a liquid binder and kneaded with a kneader (SPGJ-2TG type (using kneading blades), manufactured by Dalton). The kneaded product was subjected to an extrusion granulator (MG-55-1 type, die hole diameter 3 mm) and then molded with a granulator (QJ-230T-2 type) to obtain granules. The granules were dried in a fluidized bed dryer (GB22 type, manufactured by Yamato Scientific Co., Ltd.). The obtained dried product was classified by a vibrating sieve (manufactured by FRITSCH) using a sieve having a mesh size of 4 mm and 2 mm. The weight of the fraction that passed through the sieve with a mesh opening of 4 mm and did not pass through the sieve with a mesh opening of 2 mm was measured, and the yield with respect to the charged amount was determined.
The yield in Example 8 was as good as 94.8%, and the adhesion to the granulator was slight.

<Test 5>
(Example 9)
GSH-containing granules were produced by stirring granulation, and the yield of granulated products having a particle size of 53 μm to 2 mm was determined. In Example 9, the same composition as in Example 1 except that a reduced glutathione-free form (crystallinity 70%) was used instead of the oxidized glutathione 1 ammonium salt (crystallinity 45%). The yield was determined by the above procedure.
As a result, the yield in Example 9 was as good as 94.6%, and the adhesion to the granulator was slight.

Claims (5)

A method for producing a granular composition containing oxidized glutathione.
Look containing oxidized glutathione in crystalline form, granulated with the addition of liquid binder with respect to the solid component crystallinity of oxidized glutathione is 20% or more, the production method of the granular composition. The solid component further comprises a binding agent, the production method according to claim 1. The production method according to claim 1 or 2 , wherein the liquid binder is water or an aqueous solution using water as a solvent. Granulation method, agitation granulation, tumbling granulation, either extrusion granulating method according to any one of claims 1-3. The production method according to any one of claims 1 to 4 , wherein the average particle size of the granular composition is 50 to 5000 μm.