Rare earth chelate as well as preparation method and application thereof
By preparing rare earth chelates as feed additives, the problem of poor treatment effect of praziquantel on trypanosomiasis in large yellow croaker was solved, achieving efficient killing and inhibition of parasites in large yellow croaker and improving the survival rate of large yellow croaker.
Patent Information
- Application Number
- CN202511016401.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-23
- Publication Date
- 2025-11-14
AI Technical Summary
In the existing technology, praziquantel is not very effective in treating trypanosomiasis in large yellow croaker and is difficult to effectively prevent and treat parasitic infections in large yellow croaker.
A rare earth chelate was prepared by coordination of rare earth elements and praziquantel and its derivatives, and used as a feed additive for the aquaculture of large yellow croaker. The molar ratio of rare earth elements to praziquantel was 1:1-3. The rare earth chelate was prepared by stirring and rotary evaporation and can be directly added to the feed.
Rare earth chelates significantly improved the killing and inhibition effects on trypanosomes in large yellow croaker, increased the survival rate of large yellow croaker, and the preparation method is simple and efficient.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of rare earth materials technology, and relates to a rare earth chelate, its preparation method and its application. Background Technology
[0002] Rare earth chelates are formed by the complexation of rare earth ions and organic ligands. They have a wide range of applications and are also effective as feed additives. For example, they can promote the efficient growth of animals, enhance immunity, and improve the production performance of poultry.
[0003] Parasites are an unavoidable problem in fish farming. Their impact on fish is significant, causing slow growth, infertility, weakened immunity, and even mass mortality. Trypanosoma spp. is one such parasite. In large yellow croaker farming, Trypanosoma easily infests the blood, damaging red blood cells, leading to anemia, weakened immunity, and affecting the fish's growth and survival rate. Currently, Trypanosoma disease in large yellow croaker is generally treated with topical antiparasitic drugs and / or oral anthelmintics, but the effects are often unsatisfactory.
[0004] Praziquantel is a broad-spectrum antiparasitic drug that kills a variety of parasites, including Schistosoma japonicum, Schistosoma haematobium, and Schistosoma mansoni. In addition, praziquantel is also effective against Paragonimus westermani, Clonorchis sinensis, Echinococcosis, Cysticercus, Spirocera mansoni, Fasciolopsis buski, and Tapeworms. However, praziquantel is not very effective against trypanosomiasis in large yellow croaker and requires further improvement. Summary of the Invention
[0005] To address the aforementioned technical problems, this invention provides a rare earth chelate, its preparation method, and its application.
[0006] The technical solution of the present invention is as follows:
[0007] A rare earth chelate, formed by coordination of rare earth elements and organic ligands;
[0008] The rare earth elements are selected from one or more combinations of lanthanum, cerium, praseodymium, neodymium, samarium, dysprosium, holmium, erbium, thulium, and yttrium;
[0009] The organic ligand is praziquantel and its derivatives.
[0010] Preferably, the molar ratio of the rare earth element to the organic ligand is 1:1-3.
[0011] Preferably, the rare earth element is selected from lanthanum and / or cerium.
[0012] A method for preparing a rare earth chelate, wherein the rare earth chelate is formed by coordination of a rare earth element and an organic ligand, wherein the organic ligand is praziquantel or its derivatives;
[0013] A rare earth inorganic salt solution was added to a solution of praziquantel and its derivatives, stirred, and the solvent was removed to obtain the rare earth chelate.
[0014] Preferably, the concentration of the solution of praziquantel and its derivatives is 1-20 mmol / L;
[0015] The solvent for the solution of praziquantel and its derivatives is an organic solvent, which is selected from polar organic solvents with a boiling point not exceeding 150°C under normal pressure.
[0016] Preferably, the molar ratio of praziquantel and its derivatives in the solution to the rare earth elements in the rare earth inorganic salt solution is 1-3:1.
[0017] Preferably, the concentration of the rare earth inorganic salt solution is 1-20 mmol / L, and the solvent of the rare earth inorganic salt solution is water.
[0018] Preferably, the rare earth inorganic salt in the rare earth inorganic salt solution is selected from one or a combination of two or more of chlorides, nitrates, sulfates and phosphates.
[0019] Preferably, the stirring time is 1-12 hours, and the solvent removal method is rotary evaporation.
[0020] The application of a rare earth chelate as described in any of the above embodiments or a rare earth chelate prepared by the preparation method described in any of the above embodiments as a feed additive or component of a feed additive for poultry, livestock and fish.
[0021] The beneficial effects of this invention are:
[0022] (1) The rare earth chelate of the present invention combines the characteristics of praziquantel and rare earth chelate, and has a good killing effect on parasites. Moreover, the preparation method is simple and efficient.
[0023] (2) The rare earth chelate of the present invention can be directly added to feed as an insecticide, which is convenient to use and effective. Detailed Implementation
[0024] The technical solution of the present invention will be further explained and described below through specific embodiments. In one aspect, the present invention proposes a rare earth chelate, which is formed by the coordination of rare earth elements and organic ligands;
[0025] Rare earth elements are selected from one or more combinations of lanthanum, cerium, praseodymium, neodymium, samarium, dysprosium, holmium, erbium, thulium, and yttrium;
[0026] The organic ligands are praziquantel and its derivatives.
[0027] The organic ligand of the rare earth chelate of the present invention is praziquantel and its derivatives. The structure of praziquantel is shown in formula (1) below. There are no particular limitations on praziquantel derivatives. For example, they can be shown in formulas (2)-(4) below.
[0028] (4)
[0030] Praziquantel and its derivatives have multiple hydroxyl groups in their structure, which can form good chelation / coordination with rare earth elements, resulting in rare earth chelates with good stability.
[0031] Praziquantel and its derivatives exhibit good antiparasitic properties, but their efficacy in treating trypanosomiasis in large yellow croaker is poor. The rare-earth chelate of this invention synergistically combines the properties of praziquantel and rare earth elements, demonstrating a better therapeutic effect on trypanosomiasis in large yellow croaker.
[0032] In some embodiments, the molar ratio of rare earth elements to organic ligands is 1:1-3. For example, the molar ratio can be any value or any value between 1:1, 1:1.2, 1:1.3, 1:1.5, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.3, 1:2.5, 1:2.6, 1:2.8, 1:3, etc., without any particular limitation.
[0033] For rare earth elements, these can be rare earth ions, such as lanthanum (+3 valence), cerium (+3 valence), praseodymium (+3 valence), neodymium (+3 valence), samarium (+3 valence), dysprosium (+3 valence), holmium (+3 valence), erbium (+3 valence), thulium (+3 valence), and yttrium (+3 valence). Considering the convenience and cost of obtaining raw materials, in some embodiments, the rare earth elements are selected from lanthanum and / or cerium, such as La (+3 valence) and Ce (+4 valence).
[0034] On the other hand, the present invention proposes a method for preparing rare earth chelates, wherein the rare earth chelates are formed by coordination of rare earth elements and organic ligands, and the organic ligands are praziquantel and its derivatives.
[0035] A rare earth inorganic salt solution was added to a solution of praziquantel and its derivatives, stirred, and the solvent was removed to obtain rare earth chelates.
[0036] The method for preparing the rare earth chelates of the present invention is simple. It only requires mixing praziquantel and its derivatives with a rare earth inorganic salt solution and stirring to react. Moreover, the yield is high, basically reaching 100%.
[0037] In some embodiments, the concentration of the solution of praziquantel and its derivatives is 1-20 mmol / L;
[0038] The solvent for solutions of praziquantel and its derivatives is an organic solvent, which is selected from polar organic solvents with a boiling point not exceeding 150°C under normal pressure.
[0039] For example, the concentration of solutions containing praziquantel and its derivatives can be any value or any value between 1 mmol / L, 2 mmol / L, 3 mmol / L, 4 mmol / L, 5 mmol / L, 6 mmol / L, 7 mmol / L, 8 mmol / L, 9 mmol / L, 10 mmol / L, 11 mmol / L, 12 mmol / L, 13 mmol / L, 14 mmol / L, 15 mmol / L, 16 mmol / L, 17 mmol / L, 18 mmol / L, 19 mmol / L, and 20 mmol / L, without particular limitation. The organic solvent can be methanol, anhydrous ethanol, isopropanol, ethyl acetate, butyl acetate, etc.
[0040] In some embodiments, the molar ratio of praziquantel and its derivatives in the solution to rare earth elements in the rare earth inorganic salt solution is 1-3:1. For example, the molar ratio can be any value or any value between 1:1, 1:1.2, 1:1.3, 1:1.5, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.3, 1:2.5, 1:2.6, 1:2.8, 1:3, etc., without any particular limitation.
[0041] In some embodiments, the concentration of the rare earth inorganic salt solution is 1-20 mmol / L, and the solvent for the rare earth inorganic salt solution is water. For example, the concentration of the rare earth inorganic salt solution can be any value or any value between 1 mmol / L, 2 mmol / L, 3 mmol / L, 4 mmol / L, 5 mmol / L, 6 mmol / L, 7 mmol / L, 8 mmol / L, 9 mmol / L, 10 mmol / L, 11 mmol / L, 12 mmol / L, 13 mmol / L, 14 mmol / L, 15 mmol / L, 16 mmol / L, 17 mmol / L, 18 mmol / L, 19 mmol / L, and 20 mmol / L, without any particular limitation.
[0042] In some embodiments, the rare earth inorganic salts in the rare earth inorganic salt solution are selected from one or a combination of two or more of chlorides, nitrates, sulfates, and phosphates. These rare earth inorganic salts are readily available from the market and have good water solubility. For example, the rare earth inorganic salts may be lanthanum chloride, lanthanum nitrate, cerium chloride, cerium nitrate, etc.
[0043] In some embodiments, the stirring time is 1-12 hours, and the solvent is removed by rotary evaporation. Sufficient stirring time is beneficial for the more complete formation of rare earth chelates between the rare earth inorganic salt and the organic ligand. For example, the stirring time can be any value or any value between 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, and 12 hours, without particular limitation. Further, the stirring time can be 3-6 hours. Since the solvent used has a low boiling point, it can be removed by rotary evaporation.
[0044] Furthermore, this invention proposes the application of the rare earth chelate described in any of the above embodiments, or the rare earth chelate prepared by the preparation method described in any of the above embodiments, as a feed additive or component of feed additives for poultry, livestock, and fish, and at least achieving the effect of repelling or killing insects. The rare earth chelate of this invention, as a feed additive, can be directly added to feed, and an addition amount of 5-100 ppm in the feed can achieve a good effect of repelling or killing insects.
[0045] The technical solutions of the present invention will be further described and explained below with reference to various embodiments.
[0046] Example 1
[0047] A ligand solution with a concentration of 10 mmol / L was prepared by adding praziquantel to 100 ml of anhydrous ethanol. A cerium chloride aqueous solution with a concentration of 10 mmol / L was then added. The molar ratio of praziquantel to cerium chloride was 1:1. The mixture was stirred at room temperature for 3 h. The solvent was removed by rotary evaporation to obtain a brown solid.
[0048] Example 2
[0049] The difference between this embodiment and Embodiment 1 is that in Embodiment 1, the molar ratio of praziquantel and cerium chloride was adjusted from 1:1 to 2:1. The remaining steps remain unchanged.
[0050] Example 3
[0051] The difference between this embodiment and Example 1 is that in Example 1, the molar ratio of praziquantel and cerium chloride was adjusted from 1:1 to 3:1. The remaining steps remain unchanged.
[0052] Example 4
[0053] A ligand solution with a concentration of 1 mmol / L was prepared by adding praziquantel to 100 ml of anhydrous ethanol. A cerium chloride aqueous solution with a concentration of 1 mmol / L was then added. The molar ratio of praziquantel to cerium chloride was 1:1. The mixture was stirred at room temperature for 8 h. The solvent was removed by rotary evaporation to obtain a brown solid.
[0054] Example 5
[0055] A ligand solution with a concentration of 20 mmol / L was prepared by adding praziquantel to 100 ml of anhydrous ethanol. A cerium chloride aqueous solution with a concentration of 20 mmol / L was then added. The molar ratio of praziquantel to cerium chloride was 1:1. The mixture was stirred at room temperature for 2 h. The solvent was removed by rotary evaporation to obtain a brown solid.
[0056] Comparative Example 1
[0057] The difference between this comparative example and Example 1 is that in Example 1, the cerium chloride aqueous solution was replaced with an ferric chloride solution of the same concentration. The remaining steps remained unchanged, and a reddish-brown solid was obtained.
[0058] Comparative Example 2
[0059] The difference between this comparative example and Example 1 is that in Example 1, the cerium chloride aqueous solution was replaced with an aqueous solution of ruthenium trichloride of equal concentration. The remaining steps remained unchanged, and a reddish-brown solid was obtained.
[0060] Comparative Example 3
[0061] This comparative example uses praziquantel, which is directly obtained from the market.
[0062] Example 6
[0063] A ligand solution with a concentration of 5 mmol / L was prepared by adding the praziquantel derivative shown in formula (2) to 100 ml of anhydrous ethanol. A lanthanum nitrate aqueous solution with a concentration of 10 mmol / L was then added. The molar ratio of praziquantel to lanthanum nitrate was 1.5:1. The mixture was stirred at room temperature for 6 h, and the solvent was removed by rotary evaporation to obtain a transparent white solid.
[0064] Example 7
[0065] A ligand solution with a concentration of 5 mmol / L was prepared by adding the praziquantel derivative shown in formula (2) to 100 ml of anhydrous ethanol. A lanthanum nitrate aqueous solution with a concentration of 15 mmol / L was then added. The molar ratio of praziquantel to lanthanum nitrate was 1:1. The mixture was stirred at room temperature for 6 h, and the solvent was removed by rotary evaporation to obtain a transparent white solid.
[0066] Performance testing
[0067] (1) Half-maximal inhibitory concentration (IC50) 50Test: Dissolve the test drug in PEG-400 to prepare a 2wt% solution. Take a small amount (5-50 μL) of the solution and dilute it to the required concentration (0.0001-100 μg / ml) with culture medium (prepared with Tyrode's solution and fetal bovine serum at a weight ratio of 9:1, pH 7.4, containing 100 IU / ml each of penicillin and streptomycin). Collect the trypanosoma from large yellow croaker (100±5 g weight) infected with Trypanosoma spp. for 2 weeks under aseptic conditions. Wash the croaker twice with Tyrode's solution, then transfer it to culture medium and incubate at 37℃ for later use. Select viable worms (strong adhesion, active swimming, and intact body shape) and transfer them to cartridge culture flasks containing 4 ml of culture medium with different concentrations of the test reagent (one pair of worms per flask). Incubate at 37℃ for different times, then observe the worm activity and surface changes at room temperature using a stereomicroscope (30×) and an inverted microscope (250×). The degree of worm activity is defined as follows:
[0068] Level 5 - The insect body twists or rolls rapidly;
[0069] Level 4 - Frequent wriggling or paroxysmal trembling of the insect body;
[0070] Level 3 - The worm swims naturally and exhibits intestinal peristalsis (normal activity);
[0071] Level 2 - Reduced worm activity and loss of intestinal peristalsis;
[0072] Level 1 - Only minor movements of the mouth or suction cup (visible at 250×);
[0073] Level 0 - Completely immobile; if no response is observed after 5 minutes, the individual is considered dead.
[0074] Levels 5 and 4 indicate excitability of the parasite; level 3 indicates normal parasite activity; levels 2 and 1 indicate inhibition; level 0, if the parasite remains motionless after 5 minutes of observation, is considered dead. The half-maximal inhibitory concentration (IC50) is determined using Probit analysis. 50 The results are shown in Table 1 below.
[0075] (2) Killing rate and inhibition efficiency test: Following the test method described above, 100 intact, swimming, and entwined Trypanosoma haematomarginatus were selected and placed in 4 ml of culture medium containing 20 ppm of the test agent in a cartridge culture bottle, 1 pair per bottle. After incubation at 37℃ for 72 h, the killing rate (grade 0) and inhibition efficiency (grade 0, grade 1, and grade 2) of Trypanosoma haematomarginatus were observed. The results are shown in Table 1 below.
[0076] (3) Select healthy large yellow croakers weighing 100±5g, and feed them according to 1×10 4One hundred large yellow croakers were injected intraperitoneally with a suspension of trypanosomes and placed in aquariums of the same size. Each aquarium contained 100 large yellow croakers, which were fed a compound feed once a day at a fixed time and in a fixed quantity. After one month, the number of surviving large yellow croakers was observed, and the survival rate was calculated. The control group was fed feed without the tested drug.
[0077] The feed composition (by 100% weight) was: 30% fish meal, 15% soybean meal, 10% corn meal, 10% meat and bone meal, 1% malt meal, 2% fish oil, 2% soybean oil, and the remainder was wheat flour. 100 ppm of the test agent was added to the feed to prepare a compound feed.
[0078] (4) Plasma half-life test: The test drug was weighed and prepared into a 10 mg / ml suspension with 0.5% methylcellulose aqueous solution. After shaking and sonicating to ensure uniform mixing, the drug was administered to large yellow croaker weighing 100 ± 5 g by gavage at a dose of 10 ml / kg (i.e., 100 mg / kg) (N = 3). Blood samples were collected from the large yellow croaker before administration and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 16 h, and 24 h after administration. Plasma was obtained by centrifugation and the blood drug concentration was analyzed by HPLC-MS. The half-life results of the test drug are shown in Table 1 below.
[0079] Table 1
[0080]
[0081]
[0082] The results above show that the rare earth chelate of the present invention has a good killing and inhibitory effect on Trypanosoma haematobium, and adding it to feed can significantly improve the survival rate of large yellow croaker infected with Trypanosoma haematobium.
[0083] As described above, the basic principles, main features, and advantages of the present invention have been shown and described. Those skilled in the art should understand that the present invention is not limited to the above embodiments, which are merely preferred embodiments and should not be construed as limiting the scope of the invention. All equivalent changes and modifications made in accordance with the scope of the patent and the description should still fall within the scope of the present invention. The scope of protection of this invention is defined by the appended claims and their equivalents.
Claims
1. A rare earth chelate, characterized in that, It is composed of rare earth elements and organic ligands; The rare earth elements are selected from one or more combinations of lanthanum, cerium, praseodymium, neodymium, samarium, dysprosium, holmium, erbium, thulium, and yttrium; The organic ligand is praziquantel and its derivatives.
2. The rare earth chelate according to claim 1, characterized in that, The molar ratio of the rare earth element to the organic ligand is 1:1-3.
3. The rare earth chelate according to claim 1, characterized in that, The rare earth element is selected from lanthanum and / or cerium.
4. A method for preparing rare earth chelates, characterized in that, The rare earth chelate is formed by coordination of rare earth elements and organic ligands, wherein the organic ligands are praziquantel and its derivatives; A rare earth inorganic salt solution was added to a solution of praziquantel and its derivatives, stirred, and the solvent was removed to obtain the rare earth chelate.
5. The method for preparing rare earth chelates according to claim 4, characterized in that, The concentration of the solution of praziquantel and its derivatives is 1-20 mmol / L; The solvent for the solution of praziquantel and its derivatives is an organic solvent, which is selected from polar organic solvents with a boiling point not exceeding 150°C under normal pressure.
6. The method for preparing rare earth chelates according to claim 4, characterized in that, The molar ratio of praziquantel and its derivatives in the solution to rare earth elements in the rare earth inorganic salt solution is 1-3:
1.
7. The method for preparing rare earth chelates according to claim 4, characterized in that, The concentration of the rare earth inorganic salt solution is 1-20 mmol / L, and the solvent of the rare earth inorganic salt solution is water.
8. The method for preparing rare earth chelates according to claim 4, characterized in that, The rare earth inorganic salt in the solution is selected from one or a combination of two or more of chlorides, nitrates, sulfates and phosphates.
9. The method for preparing rare earth chelates according to claim 4, characterized in that, The stirring time is 1-12 hours, and the solvent removal method is rotary evaporation.
10. The application of a rare earth chelate according to any one of claims 1-3 or a rare earth chelate prepared by the preparation method according to any one of claims 4-9, characterized in that, As a feed additive or component of feed additives for poultry, livestock and fish.