Concentrated lactulose solution and preparation method thereof

Abstract

The invention belongs to the technical field of biological agents, and discloses a concentrated lactulose solution and a preparation method thereof.The preparation method comprises the steps that purified water and lactose are mixed and stirred to be uniform, then sodium metaaluminate is added, a heat preservation reaction is conducted till the lactose content is smaller than 9%, and then cooling is conducted; adjusting the pH value to 4-7 to obtain a lactulose-aluminum hydroxide flocculation mixed system; adding purified water into the mixed system, uniformly stirring, then adding polyaluminum chloride, uniformly stirring, and standing; carrying out residue-liquid separation on the obtained system, and collecting filtrate; desalting the filtrate until the conductivity is less than or equal to 50 [mu] s / cm, and concentrating to obtain a concentrated lactulose solution meeting the medicinal-grade standard. The problems of aluminum hydroxide precipitation, difficult filtration and low removal efficiency in the prior art are solved by using the polyaluminum chloride, the aluminum ion removal efficiency is higher, the purification operation step is greatly simplified, nanofiltration and resin operation are replaced by one-step electrodialysis desalination, the use of a large amount of purified water and the generation of aluminum salt wastewater are reduced, and the method is suitable for industrial production. The process steps are simplified, the cost is reduced, and the quality is controllable.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological agents, and particularly relates to a concentrated lactulose solution and a preparation method thereof. BACKGROUND

[0002] Lactulose, as an important functional sugar, has a wide range of applications in the medical and food fields. Its chemical name is 4-O-β-D-galactopyranosyl-D-fructose, which is a disaccharide composed of galactose and fructose and does not naturally exist in nature and needs to be prepared by artificial synthesis. Lactulose has unique physiological functions. In the field of medical treatment, it is mainly used for the treatment of constipation and hepatic encephalopathy. As an osmotic laxative, lactulose is hardly absorbed into the blood after oral administration, but is decomposed into organic acids by the intestinal flora after reaching the colon, thereby reducing the pH value in the intestinal tract, increasing the osmotic pressure in the colon, attracting water into the colon cavity, increasing the volume of the colon contents, stimulating colon peristalsis, and promoting defecation. At the same time, it can also regulate the physiological rhythm of the colon, promote the growth of beneficial bacteria such as bifidobacterium as a prebiotic, inhibit the growth of pathogenic bacteria such as salmonella, and help restore intestinal flora homeostasis. For the treatment of hepatic encephalopathy, lactulose reduces the pH value in the intestinal cavity, reduces the ammonia production in the intestinal tract, and converts the produced NH3 into NH4 + which is not easily absorbed, thereby indirectly reducing the blood ammonia level and being beneficial to the recovery of hepatic encephalopathy. In the food field, lactulose can be used as a low-calorie sweetener and a functional food additive. Its sweetness is about 40% to 60% of that of sucrose, has good moisture retention and stability, can improve the taste and texture of food, and also can endow food with certain health functions, such as regulating intestinal flora and promoting mineral absorption.

[0003] With the improvement of people's health consciousness, the demand for lactulose is increasing. Whether it is used for the treatment of related diseases in the medical field or added as a functional ingredient in the food industry, high-quality and high-purity lactulose products have broad market prospects. This also prompts researchers and enterprises to continuously explore more efficient and more economical lactulose preparation technologies.

[0004] In the production enterprises, the production capacity of concentrated lactulose solution in the world is mainly concentrated in European and American manufacturers. The enterprises producing lactulose raw materials mainly include Fresenius Kabi, the Solvay Group, and Morinaga Milk Industry Co., Ltd. In March 2024, Dalian Meiluo Traditional Chinese Medicine Factory Co., Ltd. completed the first registration and approval of concentrated lactulose solution raw materials, and Chinese manufacturers such as Haier Medicine and Laizhou Jiangbo Pharmaceutical Co., Ltd. basically use their own products, and their market share is small. With the growth of market demand and the continuous progress of technology, the concentrated lactulose solution industry is expected to usher in new development opportunities and changes.

[0005] Currently, chemical isomerization is the only way to produce lactulose commercially. The existing technology involves complex catalyst reaction conditions, such as H3BO3 / NaOH, NaAlO2 system, etc. The use of large amounts of soluble catalysts, the occurrence of sugar hydrolysis and browning in strong alkaline environment, and the residual of high-concentration salt substances in sugar syrup make the downstream lactulose separation and purification process difficult, increasing the cost of industrial production of lactulose. The NaAlO2 system greatly reduces the generation of aluminum wastewater and the difficulty of subsequent purification by filtering aluminum hydroxide precipitation. However, the viscosity of aluminum hydroxide material is relatively large and it is not easy to settle, which makes it difficult to remove by centrifugation in industrial production, increasing labor costs and limiting the further development of chemical NaAlO2 system for preparing lactulose.

[0006] In 2018, Jiangnan University applied for an international patent (Patent No.: PCT / CN2017096543) using sodium metaaluminate to catalyze lactose to produce lactulose, and then using multi-stage filtration to remove most of the aluminum hydroxide. The process is followed by resin and nanofiltration to remove salt. In this process, the viscosity of aluminum hydroxide material is relatively large, making the filtration process difficult. The water consumption for nanofiltration and the amount of wastewater generated by resin use are relatively large, increasing the production cost of lactulose and making it unsuitable for commercial production.

[0007] In 1990, Carobbi et al. applied for a US patent (Patent No.: 4957564, Process for preparing lactulose from lactose by epimerization with sodium aluminate). In this patent, Carobbi et al. first used sodium metaaluminate to catalyze lactose to produce lactulose, and then removed the sodium metaaluminate by centrifugation after converting it to aluminum hydroxide. The solid-liquid separation efficiency is very low, and a large amount of lactose is wrapped by aluminum hydroxide. This method has a large residual aluminum ion, which causes a large loss of electrodialysis membrane, increasing the production cost.

[0008] In addition to the above, there is also a biological method for producing lactulose. The biological method mainly uses the hydrolysis activity of β-galactosidase to hydrolyze lactose into galactose and glucose, and then transfers the galactose to a fructose acceptor to generate lactulose through its transglycosylation activity. The advantages of the biological method are that the reaction conditions are mild, generally at near room temperature, normal pressure and neutral pH, the equipment requirements are low, reducing equipment investment and maintenance costs. At the same time, the reaction process produces fewer by-products, which is environmentally friendly. However, the biological method also has some disadvantages, such as a slightly low yield of the first reaction and a slightly high cost of the catalyst. Moreover, the activity and stability of the enzyme are easily affected by factors such as temperature, pH, and substrate concentration, which requires strict control of the reaction conditions, increasing the complexity and difficulty of the production process. In addition, the source and preparation process of the enzyme also limit the large-scale application of the biological method.

[0009] In order to overcome the deficiencies of the prior art, some research attempts to combine chemical and biological methods, taking advantage of each other. There are also researches dedicated to finding more efficient catalysts or enzymes, optimizing reaction conditions to improve the conversion rate and purity of lactulose, reduce production costs, while in the separation and purification technology of lactulose, new methods and processes also constantly emerge, such as membrane separation technology, chromatographic separation technology, etc. The application of these technologies helps to improve the quality and production efficiency of lactulose products.

[0010] The information disclosed in this section is only intended to increase the understanding of the overall background of the present application and should not be considered as admitting or in any form implying that this information constitutes prior art known to those skilled in the art. SUMMARY

[0011] The present application is to solve the above problems, and aims to provide a lactulose concentrated solution and a preparation method thereof.

[0012] In a first aspect, the present application provides a preparation method of a lactulose concentrated solution, comprising the following steps:

[0013] Step S1, mix and stir purified water and lactose uniformly, then add sodium metaaluminate, after the addition is completed, keep the reaction at a temperature until the lactose content is less than 9%, and then cool down;

[0014] Step S2, adjust the pH value to 4-7 with acid, and precipitate aluminum hydroxide to obtain a lactulose-aluminum hydroxide flocculation mixed system;

[0015] Step S3, add purified water to the lactulose-aluminum hydroxide flocculation mixed system and stir uniformly, then add polyaluminum chloride and stir uniformly, and then stand still;

[0016] Step S4, perform residue-liquid separation on the system obtained in step S3, and collect the filtrate;

[0017] Step S5, desalt the filtrate by electrodialysis until the conductivity is ≤50 μs / cm, and then concentrate to obtain a lactulose concentrated solution meeting the pharmaceutical grade standard.

[0018] Preferably, in step S1, the weight ratio of lactose to purified water is 1:(1-3), and the weight ratio of lactose to sodium metaaluminate is 1:(0.1-0.3); more preferably, the weight ratio of lactose to purified water is 1:2, and the weight ratio of lactose to sodium metaaluminate is 1:0.25.

[0019] Preferably, in step S1, the reaction temperature is 30-80°C, more preferably 60-70°C; the reaction time is 2-7h, more preferably 3-4h; and the temperature is cooled to 0-20°C, more preferably 0-10°C.

[0020] Preferably, in step S2, the pH value is adjusted to 6-7 by using inorganic acid. Further preferably, the inorganic acid is hydrochloric acid or sulfuric acid, and also includes any concentration of inorganic acid aqueous solution. More preferably, the concentration of hydrochloric acid is 1-12 mol / L, and more preferably 6 mol / L.

[0021] Preferably, in step S3, the amount of purified water added is 5-10 times the weight of lactose, and the amount of polyaluminum chloride added is 0.2-0.4 times the weight of sodium metaaluminate. More preferably, the amount of purified water added is 8 times the weight of lactose, and the amount of polyaluminum chloride added is 0.4 times the weight of sodium metaaluminate.

[0022] Preferably, in step S4, the method of residue-liquid separation is any one or several of sedimentation, filtration, centrifugation or membrane separation.

[0023] In a second aspect, the present application provides a concentrated lactulose solution prepared by the above method. The concentrated lactulose solution is a light yellow, clear and transparent liquid.

[0024] Effects of the present application

[0025] The method for preparing the concentrated lactulose solution provided by the present application produces a concentrated lactulose solution that meets the standard requirements. The method uses polyaluminum chloride, which produces high-molecular polymers with long molecular chains and many active sites upon hydrolysis, thereby accelerating precipitation. The various cations produced by the hydrolysis of polyaluminum chloride, such as [Al(H2O)6] 3+ , etc., make it easier for aluminum hydroxide colloids to come close to each other and aggregate together. For example, the aluminum ions in the solution after direct filtration without adding polyaluminum chloride were detected to be 500-600 ppm (comparative example 1), while the aluminum ions in the solution after filtration after the formation of a precipitate by adding polyaluminum chloride were detected to be 80-200 ppm (step S3 in the example). The use of polyaluminum chloride in the present application solves the problems of difficult precipitation and low removal efficiency of aluminum hydroxide in the existing process, and the efficiency of removing aluminum ions is higher. The present application greatly simplifies the purification operation steps, replacing nanofiltration and resin operation with one step of electrodialysis desalination, saving a large amount of purified water and reducing the generation of aluminum salt wastewater, thereby simplifying the process steps, reducing costs and controlling quality.

[0026] Compared with the prior art, the present application has at least the following beneficial effects:

[0027] (1) The addition of polyaluminum chloride to the system produces flocculation with aluminum hydroxide, making it easier for aluminum hydroxide to settle and the particles to become larger and easier to separate residue-liquid.

[0028] (2) From the filtration time in the examples, the present application converts the aluminum hydroxide colloid with high viscosity into aluminum hydroxide precipitate easy to filter, greatly increases the filtration efficiency of the aluminum hydroxide precipitate, and saves a lot of production time cost; for example, in Example 1, the filtration time is 13 min, while in Comparative Example 1, the filtration time needs 72 min.

[0029] (3) From Examples 1 and 2, the aluminum ion removal efficiency of the present application is 97% to 99%, which is higher than the traditional aluminum ion removal efficiency (about 95%, Comparative Example 1), reducing the generation of aluminum wastewater; for example, in Example 1, due to the addition of 1% polyaluminum chloride, the aluminum ion content before filtration is 7680.36 ppm, and the aluminum ion content after filtration is 83.06 ppm, with an aluminum ion removal rate of 98.9%; while in Comparative Example 1, due to the absence of polyaluminum chloride, the aluminum ion content before filtration is 7693.98 ppm, and the aluminum ion content after filtration is 522.06 ppm, with an aluminum ion removal rate of only 93.2%.

[0030] (4) Because the filtrate after filtration contains very low aluminum ions, only one step of electrodialysis is needed in the subsequent desalination process to obtain a lactulose concentrated solution meeting the quality standards, greatly reducing the process cost.

[0031] (5) The total yield of the present application is 53.5% to 67.1%. DETAILED DESCRIPTION

[0032] In order to make the technical means, creative features, purposes and effects achieved by the present application easy to understand, the following embodiments will be specifically described.

[0033] Unless otherwise specified, the raw materials used in the present application are purchased through general commercial channels. The source information of some raw materials, materials and instruments involved in the following examples or comparative examples is as follows:

[0034] Lactose, CAS No.: 63-42-3; purchased from Shanghai Huamao Pharmaceutical Co., Ltd., grade: pharmaceutical grade;

[0035] Polyaluminum chloride, CAS No.: 1327-41-9; purchased from Nantong Zhonghe New Material Co., Ltd., grade: industrial grade;

[0036] Sodium metaaluminate, CAS No.: 11138-49-1, purchased from Shandong Lier New Material Co., Ltd., grade: industrial grade;

[0037] Purified water meets the standard of purified water in the 2020 Chinese Pharmacopoeia;

[0038] Inductively coupled plasma mass spectrometer (ICP-MS), purchased from Thermo Fisher Scientific, model ICAP-RQ.

[0039] The reaction of polyaluminum chloride and aluminum hydroxide is relatively complex, and the reaction equation can be different according to different reaction conditions and specific forms of polyaluminum chloride. The general formula of polyaluminum chloride is [Al2(OH) n Cl 6-n ] m (n = 1-5, m≤10) for example, the reaction equation with aluminum hydroxide can be represented as:

[0040] [Al2(OH) n Cl 6-n ] m +(6-n)mAl(OH)3=2mAl(OH)3+(6-n)mCl - .

[0041] In this reaction, the chloride ion in polyaluminum chloride reacts with aluminum hydroxide to form aluminum hydroxide precipitate and chloride ion.

[0042] <Example 1>

[0043] Step S1, 200.00g purified water, 100.00g lactose were added to the reaction bottle and stirred uniformly, then 25.00g sodium metaaluminate was added, and the temperature was raised to 60-70℃, and reacted for 3h, and then cooled to 0-10℃.

[0044] Step S2, neutralize the pH value to 7 with 6mol / L hydrochloric acid, and precipitate aluminum hydroxide to obtain lactulose-aluminum hydroxide flocculation mixed system.

[0045] Step S3, 800ml purified water was added to the lactulose-aluminum hydroxide flocculation mixed system and stirred to disperse the system for 1h, and the sample was detected by ICP-MS, and the aluminum ion content was 7680.36ppm; then 10.00g polyaluminum chloride was added, and stirred for half an hour, and then placed for 2h.

[0046] Step S4, the system obtained in step S3 was filtered using medium-speed filter paper, and the filtration time was 13 minutes, and the filtrate was collected; the aluminum ion content of the filtrate was detected by ICP-MS, and the aluminum ion content was 83.06ppm.

[0047] Step S5, the filtrate obtained in step S4 was desalted by electrodialysis to a conductivity of≤50μs / cm, and then the filtrate was filtered through a 0.22μm filter membrane, and the obtained filtrate was concentrated at 80℃ and a vacuum degree of-0.09Mpa to obtain 94.00g lactulose concentrated solution.

[0048] The lactulose concentrated solution was detected by liquid phase, and the content of lactulose was 67.21%, and the purity was 83.56%; by ICP-MS detection, the content of aluminum ions in the lactulose concentrated solution was 2.12 ppm, and the content of sodium ions was 88.78 ppm, which met the pharmaceutical grade standard. In this embodiment, the yield of the lactulose concentrated solution was 66.7%.

[0049] <Example 2>

[0050] Step S1, 300.00 g of purified water, 100.00 g of lactose were added to a reaction bottle and stirred uniformly, then 30.00 g of sodium metaaluminate was added, and the temperature was increased to 60-70°C, and the reaction was carried out for 3 h, and then the temperature was decreased to 0-15°C.

[0051] Step S2, the pH value was neutralized to 6 by 6 mol / L hydrochloric acid, and aluminum hydroxide was precipitated to obtain a lactulose-aluminum hydroxide flocculation mixed system.

[0052] Step S3, 1000 ml of purified water was added to the lactulose-aluminum hydroxide flocculation mixed system, and the system was dispersed by stirring for 1 h, and the sample was detected by ICP-MS, and the aluminum ion was 7700.24 ppm, and then 6.00 g of polyaluminum chloride was added, and stirred for half an hour, and then placed for 2 h.

[0053] Step S4, the system obtained in step S3 was filtered using medium-speed filter paper for 28 minutes, and the filtrate was collected, and the aluminum ion was detected by ICP-MS and was 102.02 ppm.

[0054] Step S5, the filtrate obtained in step S4 was directly subjected to electrodialysis until the conductivity was ≤50 μs / cm, and then the filtrate was filtered through a 0.22 μm filter membrane, and 85.30 g of lactulose concentrated solution was obtained by concentrating the filtrate.

[0055] By liquid phase detection, the content of lactulose in the lactulose concentrated solution was 66.12%, and the purity was 82.60%; by ICP-MS detection, the content of aluminum ions in the lactulose concentrated solution was 2.89 ppm, and the content of sodium ions was 146.99 ppm, which met the pharmaceutical grade standard. In this embodiment, the yield of the lactulose concentrated solution was 59.5%.

[0056] <Example 3>

[0057] Step S1, 100.00 g of purified water, 100.00 g of lactose were added to a reaction bottle and stirred uniformly, then 10.00 g of sodium metaaluminate was added, and the temperature was increased to 60-70°C, and the reaction was carried out for 3 h, and then the temperature was decreased to 0-15°C.

[0058] Step S2, the pH value was neutralized to 6 by 6 mol / L hydrochloric acid, and aluminum hydroxide was precipitated to obtain a lactulose-aluminum hydroxide flocculation mixed system.

[0059] Step S3, 500 ml purified water was added into the lactulose-aluminum hydroxide flocculation mixed system, and the system was dispersed by stirring for 1 h. Then, 4.00 g of polyaluminum chloride was added into the system, and stirred for 0.5 h, and then left to stand for 2 h.

[0060] Step S4, the system obtained in step S3 was filtered using medium-speed filter paper for 8 min, and the filtrate was collected. The aluminum ion content in the filtrate was detected by ICP-MS to be 200.05 ppm.

[0061] Step S5, the filtrate obtained in step S4 was directly subjected to electrodialysis to a conductivity of ≤50 μs / cm. Then, the filtrate was filtered through a 0.22 μm filter membrane, and concentrated to obtain 75.53 g of lactulose.

[0062] The concentrated lactulose solution was detected by liquid phase to have a lactulose content of 67.11%, and a purity of 81.36%. The aluminum ion content in the concentrated lactulose solution was 2.27 ppm, and the sodium ion content was 127.65 ppm, which met the pharmaceutical grade standard. In this embodiment, the yield of the concentrated lactulose solution was 53.5%.

[0063] <Example 4>

[0064] Preparation of lactulose in kilogram scale

[0065] Step S1, 300.00 L of purified water and 100.00 kg of lactose were added into a 500 L reactor, and stirred uniformly. Then, 25.00 kg of sodium metaaluminate was added, and the system was stirred and reacted at 70-80 °C for 3 h. The lactose content was detected by HPLC to be <9%. After the reaction was completed, the system was cooled to 0-10 °C.

[0066] Step S2, the pH value was neutralized to 6 by using 6 mol / L hydrochloric acid, and aluminum hydroxide was precipitated to obtain a lactulose-aluminum hydroxide flocculation mixed system.

[0067] Step S3, 800.00 L of deionized water was added into the above lactulose-aluminum hydroxide flocculation mixed system to disperse the aluminum hydroxide for 1 h. Then, 10.00 kg of polyaluminum chloride was added into the system, stirred for 1 h, and left to stand for 2 h.

[0068] Step S4, the system obtained in step S3 was centrifuged using 300 mesh filter cloth for 50 min. The filtrate was clear and transparent. The aluminum ion content in the filtrate was detected by ICP-MS to be 83.66 ppm.

[0069] Step S5, the filtrate obtained in step S4 was directly subjected to electrodialysis to a conductivity of ≤50 μs / cm. Then, the filtrate was filtered through a 0.22 μm filter membrane, and concentrated to obtain 96.23 kg of concentrated lactulose solution.

[0070] The lactulose concentrated solution is detected by liquid phase, and the lactulose content is 66.08%, and the purity is 92.87%; the aluminum ion content in the lactulose concentrated solution is 1.56 ppm, and the sodium ion content is 89.00 ppm, which meets the pharmaceutical grade standard. In this embodiment, the yield of the lactulose concentrated solution is 67.1%.

[0071] <Comparative Example 1>

[0072] This comparative example refers to Example 1 in the U.S. Patent (Patent No. 4957564) applied by Carobbi et al. in 1990.

[0073] Step S1, 200.00 g of purified water, 100.00 g of lactose, 25.00 g of sodium metaaluminate are added into a reaction bottle and stirred uniformly, and then the temperature is increased to 60-70℃, and the reaction is carried out for 3 h, and then the temperature is decreased to 0-10℃;

[0074] Step S2, the pH value is neutralized to 7 by using 6 mol / L hydrochloric acid, and aluminum hydroxide is precipitated to obtain a lactulose-aluminum hydroxide flocculation mixed system.

[0075] Step S3, 800 ml of purified water is added into the lactulose-aluminum hydroxide flocculation mixed system, and the system is dispersed by stirring for 1 h, and then the aluminum ion is detected by ICP-MS, and the aluminum ion is 7693.98 ppm, and then polyaluminum chloride is not added, and the system is stirred for half an hour, and then is placed for 2 h.

[0076] Step S4, the aluminum hydroxide colloid is directly used without precipitation, and is filtered by using a medium-speed filter paper, and the time is 72 minutes, and then the aluminum ion in the filtrate is detected by ICP-MS, and the aluminum ion is 522.06 ppm.

[0077] Step S5, the filtrate obtained in Step S4 is directly subjected to electrodialysis until the conductivity is less than or equal to 50 μs / cm, and then is filtered by using a 0.22 μm filter membrane, and then the filtrate is concentrated to obtain 82.00 g of a lactulose concentrated solution.

[0078] The lactulose concentrated solution is detected by liquid phase, and the lactulose content is 65.86%, and the purity is 82.60%; the aluminum ion content in the lactulose concentrated solution is 4.56 ppm, and the sodium ion content is 102.16 ppm, which meets the pharmaceutical grade standard. In this embodiment, the yield of the lactulose concentrated solution is 57.00%.

[0079] The above-mentioned embodiments are preferred cases of the present application, and are not used to limit the protection scope of the present application.

Claims

1. A method for preparing a concentrated solution of lactulose, characterized in that, The method comprises the following steps: S1, mixing purified water and lactose and stirring until uniform, then adding sodium metaaluminate, and after the addition is completed, keeping the reaction at a temperature until the lactose content is less than 9%, and then cooling; S2, adjusting the pH value to 4-7 with an acid, and precipitating aluminum hydroxide to obtain a lactulose-aluminum hydroxide flocculation mixed system; S3, adding purified water to the lactulose-aluminum hydroxide flocculation mixed system and stirring until uniform, then adding polyaluminum chloride and stirring until uniform, and then standing; S4, performing residue-liquid separation on the system obtained in step S3, and collecting the filtrate; S5, desalting the filtrate by electrodialysis until the conductivity is less than or equal to 50 μs / cm, and then concentrating to obtain a lactulose concentrated solution; In step S1, the weight ratio of the lactose to the purified water is 1:(1-3), and the weight ratio of the lactose to the sodium metaaluminate is 1:(0.1-0.3); In step S3, the amount of the purified water added is 1:(5-10) in terms of the weight ratio of the lactose to the purified water, and the amount of the polyaluminum chloride added is 1:(0.2-0.4) in terms of the weight ratio of the sodium metaaluminate to the polyaluminum chloride.

2. The method according to claim 1, wherein in step S2, the pH value is adjusted to 4-7 with an inorganic acid. wherein 3. The method according to claim 2, wherein in step S2, the inorganic acid is hydrochloric acid or sulfuric acid.

4. The method according to claim 3, wherein the concentration of the hydrochloric acid is 1-12 mol / L. wherein, 5. The method according to claim 1, wherein in step S1, the weight ratio of the lactose to the purified water is 1:2, the weight ratio of the lactose to the sodium metaaluminate is 1:0.25, the reaction temperature is 30-80°C, and the reaction time is 2-7 h, and the temperature is then lowered to 0-20°C.

6. The method according to claim 5, wherein in step S1, the reaction temperature is 60-70°C, the reaction time is 3-4 h, and the temperature is then lowered to 0-10°C. wherein 7. The method according to claim 1, wherein in step S3, the amount of the purified water added is 1:8 in terms of the weight ratio of the lactose to the purified water, and the amount of the polyaluminum chloride added is 1:0.4 in terms of the weight ratio of the sodium metaaluminate to the polyaluminum chloride.

8. The method according to claim 1, wherein in step S4, the residue-liquid separation method is any one or several of sedimentation, filtration, centrifugation, or membrane separation. wherein The lactulose concentrated solution is prepared by the method according to any one of claims 1-8, and the lactulose concentrated solution is a light yellow, clear and transparent liquid. ​ wherein ​ ​ wherein ​ ​ wherein, ​ 9. A concentrated solution of lactulose, characterized in that, ​