Stabilized 5-aminolevulinic acid composition

Abstract

To provide a composition of a 5-ALA compound that ensures high stability of the 5-ALA compound even in coexistence with water.SOLUTION: The present invention provides a stabilized composition which contains: 5-aminolevulinic acid (5-ALA) compound that is selected from 5-ALA, a derivative thereof, and a salt of 5-ALA or a derivative thereof; an aqueous medium; and a dextrin.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a stabilized 5-aminolevulinic acid composition. [Background technology]

[0002] 5-aminolevulinic acid (also called "5-ALA") is a type of natural amino acid, and is known to be a raw material for protoporphyrin IX and heme, and is expected to have a wide range of uses. However, 5-aminolevulinic acid is also known to have low stability, and methods for stabilizing 5-aminolevulinic acid according to various conditions of use are being investigated.

[0003] For example, Reference 1 discloses a solid fertilizer that contains 5-aminolevulinic acid, its derivatives or salts thereof, and fats and oils substantially uniformly in the solid fertilizer. The document also describes that the storage stability of 5-aminolevulinic acid, its derivatives or salts thereof in the composition can be sufficiently ensured. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] JP 2014-189469 A Summary of the Invention [Problem to be solved by the invention]

[0005] It was known that 5-aminolevulinic acid, being a type of amino acid, undergoes the Maillard reaction and is denatured when heated together with reducing sugars. However, the present inventors have found that 5-aminolevulinic acid becomes particularly unstable when coexisting with water even in the absence of reducing sugars, and the amount of 5-aminolevulinic acid may decrease over time.

[0006] Therefore, the present invention aims to provide a composition of a 5-ALA compound selected from 5-ALA, its derivatives, and salts thereof, which exhibits high stability of the 5-ALA compound even when coexisting with water. It also aims to provide an agent capable of preventing destabilization of the 5-ALA compound, a method for producing a composition in which the 5-ALA compound is stabilized, and a method for stabilizing the 5-ALA compound. [Means for solving the problem]

[0007] The present invention provides a stabilized composition comprising a 5-ALA compound selected from 5-aminolevulinic acid (5-ALA), its derivatives, and salts thereof, an aqueous medium, and dextrins, the term "dextrins" being defined below.

[0008] Since the stabilized composition of the present invention contains dextrins, it exhibits high stability of the 5-ALA compound even in the presence of the 5-ALA compound and an aqueous medium.

[0009] The composition is preferably acidic, in which case the stability of the 5-ALA compound is further improved.

[0010] The content of the aqueous medium relative to the 5-ALA compound may be a mass ratio of 45 to 90. Thus, even when the content of the aqueous medium relative to the content of the 5-ALA compound is high, the composition has excellent stability of the 5-ALA compound.

[0011] The composition may further include an excipient. When the composition includes an excipient, the composition can be easily handled as a solid, and is suitable for pellet production. The present invention also provides a heat-treated composition including an excipient.

[0012] The present invention also provides an agent for preventing the reaction between 5-ALA compounds, which comprises a dextrin.

[0013] The reaction inhibitor suppresses the reaction between 5-ALA compounds even when the 5-ALA compounds coexist with water. The present invention can be said to provide a method for producing a stabilized composition or a method for preventing the reaction between 5-ALA compounds, which comprises adding dextrins to a 5-ALA compound and an aqueous medium. Effect of the Invention

[0014] According to the present invention, there is provided a composition of a 5-ALA compound, which exhibits high stability of the 5-ALA compound even when coexisting with water. In addition, there are provided an agent capable of preventing destabilization of the 5-ALA compound, a method for producing a composition in which the 5-ALA compound is stabilized, and a method for stabilizing the 5-ALA compound. [Brief description of the drawings]

[0015] [Figure 1] 1 is a graph showing the residual 5-ALA rate of the compositions of Comparative Example 1 and Examples 1 to 3 after storage for 4 months. [Diagram 2] 1 is a graph showing the 5-ALA residual rate in heat-treated products of (a) the compositions of Comparative Example 2 and Examples 4 to 6, and (b) the compositions of Comparative Example 2 and Examples 7 to 9. [Diagram 3] 1 is a graph showing the change in the residual rate of 5-ALA due to heat treatment in the compositions of Comparative Example 3 and Example 10. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Hereinafter, several embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

[0017] The stabilized composition according to one embodiment contains a 5-ALA compound, an aqueous medium, and dextrins. The stabilized composition refers to a composition in which the qualitative or quantitative changes of the components, including the 5-ALA compound, due to external factors such as heat, humidity, and pressure are reduced to a practically sufficient level. The qualitative changes referred to here include denaturation, alteration, decomposition, deterioration, and other chemical or physical changes of the components. For example, the qualitative changes include chemical reactions with other chemical substances or reactions between the same components (dimerization, etc.).

[0018] The 5-ALA compound is a compound selected from 5-aminolevulinic acid (5-ALA), its derivatives, and salts thereof. The 5-ALA compound may, for example, be a compound represented by the following formula (I): [ka] In formula (I), R 1 represents a hydrogen atom or an acyl group, R 2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group, or an aralkyl group.

[0019] In one embodiment, R 1 and R 2 may both be hydrogen atoms. In this case, the compound represented by formula (I) is 5-ALA, which is a type of amino acid.

[0020] In another embodiment, R 1 is a hydrogen atom, and R 2 may be a linear or branched alkyl group, a cycloalkyl group, an aryl group, or an aralkyl group; R 1 is an acyl group, and R 2 may be a hydrogen atom. Among the compounds represented by formula (I), compounds other than 5-ALA are included in the 5-ALA derivatives.

[0021] R 1Examples of the acyl group in the formula (I) include linear or branched alkanoyl groups having 1 to 8 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl, and benzylcarbonyl groups, and aroyl groups having 7 to 14 carbon atoms, such as benzoyl, 1-naphthoyl, and 2-naphthoyl groups.

[0022] R 2 Examples of the alkyl group in the formula (I) include linear or branched alkyl groups having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl groups.

[0023] R 2 Examples of the cycloalkyl group in the formula (I) include cycloalkyl groups having 3 to 8 carbon atoms, which may have a saturated or partially unsaturated bond, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, and 1-cyclohexenyl groups.

[0024] R 2 Examples of the aryl group in the formula (I) include aryl groups having 6 to 14 carbon atoms, such as phenyl, naphthyl, anthryl, and phenanthryl groups.

[0025] R 2 In the aralkyl group, the aryl portion can be exemplified as the above-mentioned aryl group, and the alkyl portion can be exemplified as the above-mentioned alkyl group. Specific examples include aralkyl groups having 7 to 15 carbon atoms, such as benzyl, phenethyl, phenylpropyl, phenylbutyl, benzhydryl, trityl, naphthylmethyl, and naphthylethyl groups.

[0026] The 5-ALA derivatives include R 1 is preferably a formyl, acetyl, propionyl, or butyryl group. 2is preferably a methyl, ethyl, propyl, butyl, pentyl group, etc. As the 5-ALA derivative, 1 and R 2 Preferred examples of the combinations include compounds in which the combinations of formyl and methyl, acetyl and methyl, propionyl and methyl, butyryl and methyl, formyl and ethyl, acetyl and ethyl, propionyl and ethyl, and butyryl and ethyl.

[0027] The 5-ALA derivative may be a prodrug of 5-ALA. The prodrug of 5-ALA is a compound that generates 5-ALA by being metabolized in the living body. Examples of the prodrug of 5-aminolevulinic acid include esters of 5-aminolevulinic acid such as methyl 5-aminolevulinic acid ester, ethyl 5-aminolevulinic acid ester, propyl 5-aminolevulinic acid ester, butyl 5-aminolevulinic acid ester, and pentyl 5-aminolevulinic acid ester.

[0028] Salts of 5-aminolevulinic acid (5-ALA) or its derivatives include, for example, inorganic acid salts such as hydrochloride, phosphate, and nitrate, alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt.

[0029] The content of the 5-ALA compound is not particularly limited, and may be 0.5% by mass or more, 1% by mass or more, 2% by mass or more, 3% by mass or more, 5% by mass or more, or 10% by mass or more, based on the total amount of the composition, and may be 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 10% by mass or less, or 5% by mass or less.

[0030] The aqueous medium is not necessarily limited, and may be a medium selected from the group consisting of water, ethanol, and a mixture of these two. The content of water relative to the total mass of the aqueous medium is preferably 30 to 100 mass%, 50 to 100 mass%, 70 to 100 mass%, 80 to 100 mass%, 90 to 100 mass%, or 95 to 100 mass%, and may be 100 mass%. The water is preferably distilled water, ion-exchanged water, pure water, or ultrapure water.

[0031] The content of the aqueous medium is preferably an amount that dissolves the 5-ALA compound contained in the composition, and may be an amount that dissolves the entire amount of the 5-ALA compound contained in the composition.

[0032] The content of the aqueous medium may be, based on the total amount of the composition, 1 mass% or more, 5 mass% or more, 10 mass% or more, 20 mass% or more, 30 mass% or more, 45 mass% or more, or 60 mass% or more, and may be 99 mass% or less, 95 mass% or less, 90 mass% or less, 80 mass% or less, 70 mass% or less, or 60 mass% or less.

[0033] The content of the aqueous medium relative to the 5-ALA compound may be, in terms of mass ratio (mass of aqueous medium / mass of 5-ALA compound), 1 or more, 5 or more, 10 or more, 20 or more, 30 or more, 40 or more, or 45 or more, and may be 100 or less, 90 or less, 80 or less, 50 or less, or 30 or less.

[0034] In the present invention, dextrins refer to decomposition products of polymers (such as starch) in which α-glucose is polymerized through glycosidic bonds, and include, for example, dextrin, maltodextrin, maltooligosaccharide, starch powder, and cyclodextrin. Dextrins may be a mixture of dextrins with different degrees of decomposition. However, dextrins consisting only of monosaccharides are excluded.

[0035] Dextrins can also be expressed as at least one selected from dextrin and its analogues. Dextrose equivalent (DE) is used as an index for classifying decomposition products of polymers (starch, etc.) in which α-glucose is polymerized by glycosidic bonds. DE can be calculated by multiplying the weight of direct reducing sugar (expressed as glucose) by 100 / weight of solids (dextrins), and the direct reducing sugar at the reducing end is quantified as glucose. Using this DE value, dextrin can be expressed as having a DE value of 4 to 10, and dextrin analogues include maltodextrin with a DE value of 11 to 21, maltooligosaccharide with a DE value of more than 21 and less than 23, and powdered sugar with a DE value of 23 to 40.

[0036] Since the stabilizing composition contains dextrins, the 5-ALA compound is highly stable and the reaction between the 5-ALA compounds is suppressed, even though the 5-ALA compound and the aqueous medium coexist in the stabilizing composition. That is, another embodiment of the present invention is an agent for preventing the reaction between 5-ALA compounds, which comprises dextrins.

[0037] The content of dextrins may be 5% by mass, 8% by mass or more, or 10% by mass or more, and may be 50% by mass or less, 40% by mass or less, or 30% by mass or less, based on the total amount of the composition.

[0038] The content of dextrins relative to the 5-ALA compound may be a mass ratio (mass of dextrins / mass of 5-ALA compound) of 0.5 or more, 1 or more, 2 or more, or 5 or more, and may be 50 or less, 30 or less, or 20 or less.

[0039] The stabilized composition may further contain an excipient. When the stabilized composition contains an excipient, for example, the fluidity of the stabilized composition decreases, and it can be handled as a solid. The stabilized composition may be a solid that does not have fluidity. When the stabilized composition is a solid, the dispersibility is improved, and it can be suitably used, for example, for the production of pellets that are raw materials for feed, etc.

[0040] Examples of excipients include porous carriers such as silica gel, rice bran, defatted rice bran, calcium carbonate, crystalline cellulose, calcium stearate, silicon dioxide, corn, wheat bran, and soybean meal.

[0041] When the stabilized composition contains an excipient, the 5-ALA compound, the aqueous medium, and / or the dextrins may be supported by the excipient, for example, absorbed, attached, adsorbed or bound to the excipient. That is, the present invention also provides a support or a carrier in which the stabilized composition is supported by an excipient.

[0042] The blending ratio of the excipient to the stabilized composition (mass of excipient / mass of stabilized composition) may be 0.5 or more, 1 or more, 5 or more, 10 or more, 20 or more, or 30 or more, and may be 100 or less, 90 or less, 80 or less, 70 or less, 60 or less, or 50 or less.

[0043] The stabilized composition may contain other components, such as pH adjusters (citric acid, phosphoric acid, hydrochloric acid, etc.), stabilizers (EDTA, etc.), antibacterial agents (formic acid, propionic acid, etc.), hardened oils (hardened rapeseed oil, etc.), and metal-containing compounds.

[0044] Examples of the metal in the metal-containing compound include iron, magnesium, zinc, and cobalt, with iron, magnesium, and zinc being preferred, and iron being a particularly suitable example.

[0045] The iron-containing compound may be an organic salt or an inorganic salt, such as ferric chloride, ferric oxide, ferrous sulfate, or ferrous pyrophosphate. Examples of organic salts include carboxylates (hydroxycarboxylates, etc.), citrates (ferrous citrate, sodium ferrous citrate, sodium ferrous citrate (SFC), ammonium ferrous citrate, etc.), organic acid salts (ferrous pyrophosphate, heme iron, dextran iron, ferrous lactate, ferrous gluconate, sodium ferrous diethylenetriaminepentaacetate, ammonium ferrous diethylenetriaminepentaacetate, sodium ferrous ethylenediaminetetraacetate, ammonium ferrous ethylenediaminepentaacetate, sodium ferrous dicarboxymethylglutamate, ammonium ferrous dicarboxymethylglutamate, ferrous fumarate, ferrous acetate, ferrous oxalate, ferrous succinate, sodium ferrous succinate citrate, etc.), triethylenetetraamine iron, ferrous lactoferrin, ferrous transferrin, sodium ferrous chlorophyllin, ferrous ferritin, ferrous saccharide oxide, and ferrous glycine sulfate.

[0046] Examples of magnesium-containing compounds include magnesium citrate, magnesium benzoate, magnesium acetate, magnesium oxide, magnesium chloride, magnesium hydroxide, magnesium carbonate, magnesium sulfate, magnesium silicate, magnesium nitrate, magnesium diammonium diethylenetriaminepentaacetate, magnesium disodium ethylenediaminetetraacetate, and magnesium protoporphyrin.

[0047] Examples of zinc-containing compounds include zinc chloride, zinc oxide, zinc nitrate, zinc carbonate, zinc sulfate, diammonium zinc diethylenetriaminepentaacetate, disodium zinc ethylenediaminetetraacetate, zinc protoporphyrin, and zinc-containing yeast.

[0048] The above metal-containing compounds may be used alone or in combination of two or more.

[0049] The content or total content of each of the other components may be, for example, 20 mass % or less, 10 mass % or less, 5 mass % or less, or 1 mass % or less based on the total amount of the composition.

[0050] The stabilized composition may be acidic, neutral or basic. Since the 5-ALA compound is more stable under acidic conditions, the stabilized composition is preferably acidic. However, the stabilized composition according to one embodiment of the present invention exhibits high stability of the 5-ALA compound even when it is neutral or basic.

[0051] The above-mentioned stabilized composition can be produced, for example, by adding dextrins to the 5-ALA compound, an aqueous medium, and the above-mentioned excipients and / or other ingredients used as necessary.

[0052] The method for producing a stabilized composition according to one embodiment is a method for producing a stabilized composition that contains the dextrins in addition to the 5-ALA compound, an aqueous medium, and the excipients and / or other components used as necessary. The method also serves to prevent the reaction between 5-ALA compounds.

[0053] In order to incorporate the 5-ALA compound, a single 5-ALA compound selected from the above-mentioned 5-ALA, its derivatives, and salts thereof may be used, or a mixture containing the 5-ALA compound, such as an aqueous solution containing 5-aminolevulinic acid (e.g., a crude 5-aminolevulinic acid solution), may be used.

[0054] The types and amounts of the 5-ALA compound, aqueous medium, dextrins, and other components used in the above-mentioned production method and reaction prevention method may be the same as the types and amounts of these components in the above-mentioned stabilized composition.

[0055] Another embodiment of the present invention is a heat-treated product of a composition containing an excipient. The heat-treated product may be used, for example, for feed and may be formed into pellets. The heat-treated product may be, for example, a stabilized composition containing an excipient that has been heated at a temperature of 60°C or higher, 80°C or higher, 100°C or higher, 120°C or higher, or 140°C or higher for 60 minutes or more. For example, in the production of pellets for feed, the raw material is heat-treated for a short time (about 10 minutes) at a temperature of about 80°C, about 100°C, or about 120°C, and then dried (about 60 minutes) at about 80°C, about 100°C, or about 120°C. The heat treatment is performed by heating the stabilized composition containing an excipient. The heat treatment may be performed in a batch manner or a continuous manner. In the case of a continuous manner, for example, an extruder is used. In either the batch manner or the continuous manner, a premix containing all the constituent components may be prepared and the premix may be heated, or each constituent component may be gradually or stepwise added while being heated.

[0056] The present inventors have found that when a composition containing a 5-ALA compound and an aqueous medium is used as a raw material for pellets, the 5-ALA compound becomes unstable during the above-mentioned heat treatment, and the content of the 5-ALA compound in the resulting heat-treated product decreases. However, the stabilized composition according to the present embodiment contains dextrins, so the 5-ALA compound is stabilized during the heat treatment. Therefore, the heat-treated product according to the present embodiment is prevented from decreasing the content of the 5-ALA compound. EXAMPLES

[0057] The present invention will be described in more detail below with reference to examples, although the present invention is not limited to these examples.

[0058] In the examples and comparative examples, the following components were used. (5-ALA compound) A-1: 5-aminolevulinic acid A-2: 5-aminolevulinic acid crude solution (aqueous solution containing 2.0 to 4.0% by mass of 5-ALA) (Dextrins) B-1: Matsutani Chemical Industry Co., Ltd. "Pine Index #4" (DE=19) B-2: Matsutani Chemical Industry Co., Ltd. "Pine Index #6" (DE=40) B-3: Matsutani Chemical Industry Co., Ltd. "Pine Index #100" (DE=4) B-4: Matsutani Chemical Industry Co., Ltd. "Pine Index #1" (DE=8) (Excipients) C-1: Silica gel (Other Ingredients) D-1: Citric acid

[0059] 1. Stability of the composition The components in the amounts shown in Table 1 were mixed with ultrapure water to prepare the compositions of Comparative Example 1 and Examples 1 to 3. Each composition was stored in an environment of 40°C / 75%RH for 4 months. 200 μL of each composition before and after storage was taken, and 1800 μL of water was added and mixed well using a vortex mixer. The obtained liquid was centrifuged (12000 rpm, 4°C, 10 minutes) using a centrifuge (Tomy Seiko Co., Ltd., "MR-150"), and the 5-ALA contained in the supernatant was quantified by HPLC analysis using reverse phase chromatography using the absolute calibration curve method (JP Patent Publication 2014-189492). The measurement conditions were as follows.

[0060] For each of the compositions of Comparative Example 1 and Examples 1 to 3, the composition was prepared as described above, and the 5-ALA content was measured three times. The average value of the 5-ALA content was calculated, and the 5-ALA residual rate was calculated using the following formula. The results are shown in Figure 1. 5-ALA residual rate = (average value of 5-ALA content in samples after storage / average value of 5-ALA content in samples before storage) x 100

[0061] [Table 1]

[0062] 2. Stability of compositions containing excipients against heat treatment The compositions of Comparative Example 2 and Examples 4 to 9 were prepared by mixing the components other than silica gel (C-1) in the compounding ratios shown in Table 2, and then adding silica gel (C-1) in the compounding ratios shown in Table 2. 4 g of each composition was weighed out onto a magnetic dish and heat-treated at 100°C for 1 hour. 0.50 g of each composition before and after heating was taken, and 10 mL of ultrapure water was added and shaken to obtain a liquid. Approximately 1.2 mL of the liquid was transferred to an Eppendorf tube and centrifuged (12,000 rpm, 4°C, 10 minutes) using a centrifuge (Tomy Seiko Co., Ltd. "MR-150"). 1 mL of the supernatant was collected using a syringe and filtered through a 0.45 μm filter (Advantec Corporation's "DISMIC (registered trademark) 13HP045AN"), and the 5-ALA contained in the filtrate was quantified by HPLC analysis using reverse phase chromatography using the absolute calibration curve method (JP Patent Publication 2014-189492). The measurement conditions were as follows.

[0063] The residual rate of 5-ALA was calculated using the following formula. The results are shown in Figure 2. 5-ALA residual rate = (5-ALA content in heated sample / 5-ALA content in unheated sample) x 100

[0064] [Table 2]

[0065] 3. Stability of compositions containing excipients to heat treatments simulating pelleting processes The compositions of Comparative Example 3 and Example 7 were prepared by mixing the components other than silica gel (C-1) in the compounding ratios shown in Table 3, and then adding silica gel (C-1) in the compounding ratios shown in Table 2. 2 g of each composition was weighed out onto a magnetic dish, and heat-treated at 100°C for 10 minutes, and then at 80°C for 60 minutes. 0.50 g of each composition was collected before heating, after heating at 100°C for 10 minutes, after heating at 80°C for 30 minutes, and after heating at 80°C for 60 minutes, and 10 mL of ultrapure water was added and shaken to obtain a liquid. Approximately 1.2 mL of the liquid was transferred to an Eppendorf tube and centrifuged (12000 rpm, 4°C, 10 minutes) using a centrifuge (Tomy Seiko Co., Ltd. "MR-150"). 1 mL of the supernatant was collected using a syringe and filtered through a 0.45 μm filter (Advantec Corporation's "DISMIC (registered trademark) 13HP045AN"), and the 5-ALA contained in the filtrate was quantified by HPLC analysis using reverse phase chromatography using the absolute calibration curve method (JP Patent Publication 2014-189492). The measurement conditions were as follows.

[0066] For each of the compositions of Comparative Example 3 and Example 7, the composition was prepared as described above, and the procedure for quantifying 5-ALA was repeated five times, and the 5-ALA residual rate at each time point was calculated using the following formula. A graph showing the change in the residual rate is shown in Figure 3. 5-ALA residual rate = (average value of 5-ALA content in composition samples at each time point / average value of 5-ALA content in composition samples before heating) x 100

[0067] [Table 3]

Claims

1. A stabilized composition comprising a 5-aminolevulinic acid (5-ALA) compound selected from 5-ALA, its derivatives and salts thereof, an aqueous medium and dextrins.

2. The composition of claim 1 , which is acidic.

3. The composition according to claim 1 or 2, wherein the content of the aqueous medium relative to the 5-ALA compound is 45 to 90 in mass ratio.

4. The composition of any one of claims 1 to 3, further comprising an excipient.

5. A heat-treated product of the composition according to claim 4.

6. The agent for preventing reaction between 5-aminolevulinic acid (5-ALA) compounds selected from 5-ALA, its derivatives and salts thereof, is composed of dextrins.

7. A method for producing a stabilized composition, comprising adding a 5-ALA compound selected from 5-aminolevulinic acid (5-ALA), its derivatives and salts thereof, and a dextrin to an aqueous medium.

8. A method for preventing a reaction between 5-aminolevulinic acid (5-ALA) compounds, comprising adding a 5-ALA compound selected from 5-ALA, its derivatives, and salts thereof, and a dextrin to an aqueous medium.

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