Heavy metal removal composition with high stability, its uses, dosage forms, and manufacturing methods

Abstract

The highly stable heavy metal removal composition, its use, dosage form and manufacturing method belong to the field of pharmaceutical technology. The composition comprises (A) 70 to 95% by weight of a compound of formula (1) or a pharmaceutically acceptable salt thereof, (B) 1 to 25% by weight of a compound of formula (2) or a pharmaceutically acceptable salt thereof, and 0.001 to 5% by weight of a basic compound which is at least one of an alkali metal hydroxide, carbonate, bicarbonate, hydrogen phosphate, carboxylate or aqueous ammonia. The stability of the composition obtained by the present invention is greatly improved. While maintaining an excellent heavy metal removal effect, the dosage can be reduced to about 1 / 4 of the original amount without changing the effect of the drug. At the same time, the safety of pharmaceutical use is improved, and the stability of the pharmaceutical is improved, so that the costs of production, transportation and storage are effectively reduced, the expiration date is extended, and the cost of the pharmaceutical is effectively reduced.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceuticals, and in particular, to a heavy metal removal composition with high stability, the manufacture of pharmaceuticals for removing heavy metals and free radicals, the manufacture of anti-tumor drugs, and the use of the composition in the manufacture of pharmaceuticals for the prevention and treatment of related diseases caused by heavy metals, pharmaceuticals obtained with the composition as the main component and corresponding dosage forms, and a method for manufacturing the composition.

Background Art

[0002] Dithiocarbamates (DTC) are new complexing agents studied in the 1980s, and their structural formula is as follows. JPEG2025516821000073.jpg1519

[0003] As a kind of widely existing organic molecule, dithiocarbamates have various functional groups and heteroatoms, so they have strong metal-binding ability, can effectively chelate heavy metals, and remove free radical NO in the body. Various DTC derivatives exhibit many biological and pharmaceutical properties. For example, they not only have excellent anti-inflammatory, antibacterial, antioxidant effects, etc., but recently have also been reported as effective anti-cancer agents and apoptosis inhibitors.

[0004] GDTC (the one in which R in DTC 2 is substituted with glucosyl) has always been the focus of research in this field as a kind of drug that can remove heavy metals from renal cells. In 1989, Gale et al. obtained sodium 4-methoxybenzyl-D-glucosamine-N-dithiocarboxylate (4-Me) which showed excellent cadmium removal effect on chronic cadmium poisoning rats by substituting R 1 with methoxybenzyl. In 1995, Professor Zhao Jinyuan et al. substituted R 1Six different amino acids were substituted to obtain six new complexes. Furthermore, in the rat cadmium removal experiment, all of these six new complexes showed a cadmium removal effect superior to that of 4-Me. However, due to their toxicity, side effects, and strong irritation after injection, in severe cases, it may lead to death, so they could not be applied clinically for the time being. In 2005, Tang Xiaojiang et al. 1 was substituted with methionine, and 2 was substituted with glucosyl to obtain a new complex N-(2,3,4,5,6-pentahydroxyhexyl)-(N-disubstituted carboxylate sodium)-L-methionine sodium (GMDTC) that showed a significant effect on cadmium removal in the kidney and had low toxicity and side effects. And in 2016, it was proposed that GMDTC achieved the purpose of removing heavy metals in renal cells by freely entering and leaving renal tubular epithelial cells using a pair of glucose transporters of SGLT2-GLUT, laying the foundation for the application of such drugs [Xiaojiang Tang et al. Mobilization and removing of cadmium from kidney by GMDTC utilizing renal glucose reabsorption pathway, Toxicology and Applied Pharmacology 305 (2016) 143-152].

[0005] However, the stability problem of GDTC-based pharmaceuticals remains unsolved. It is difficult to manufacture pharmaceuticals, there are also problems with formulation stability, and they hydrolyze in solvents. Therefore, in animal experiments, it is often necessary to use high doses to achieve a good effect on heavy metal removal. On the other hand, due to poor stability, the manufacturing, transportation, and storage costs of such pharmaceuticals are high, it is difficult to prepare formulations, and the shelf life is short, so the practical application is limited.

[0006] Chinese Invention Application Publication No. CN108546242A discloses the use of aminodithiocarbamate compounds and their heavy metal removing agents, and although the stability was improved by changing the molecular structure, the data on its stability was only up to 14 hours at most, and it is still difficult to meet the transportation and storage needs during clinical application.

[0007] Chinese Invention Application Publication No. CN108276319A discloses the use of new thio compounds and their heavy metal removing agents. Similarly, the stability was improved by changing the molecular structure, but the data on its stability was only up to 24 hours at most, and it is still difficult to meet the transportation and storage needs during clinical application.

[0008] Therefore, in order to realize large-scale clinical application at an early stage and relieve the pain of patients, it is urgent to solve the stability problem of GDTC-based pharmaceuticals so as to meet the transportation and storage needs during clinical application.

Summary of the Invention

Problems to be Solved by the Invention

[0009] In the long-term and continuous research on GDTC-based pharmaceuticals, the inventors stepped out of the conventional idea of improving stability by changing the molecular structure. While maintaining the heavy metal removing performance of GDTC-based pharmaceuticals, they significantly improved the stability, enabling long-term storage under normal conditions. And due to the improved stability, the same therapeutic effect can be expected even if the drug dosage is significantly reduced, enhancing the drug use safety and reducing the treatment cost. The inventors developed the composition in another way.

[0010] The object of the present invention is to provide a highly stable heavy metal removal composition that solves the problem of the stability of GDTC-based pharmaceuticals and enables the preparation of GDTC-based pharmaceuticals into various formulations for wide use. The present invention further provides the use of the composition in the manufacture of pharmaceuticals for removing heavy metals and free radicals, the manufacture of anti-tumor drugs, and the manufacture of pharmaceuticals for the prevention and treatment of related diseases caused by heavy metals, pharmaceuticals and corresponding dosage forms obtained with the composition as the main component, and a method for manufacturing the composition. To achieve the above object, the present invention specifically adopts the following technical solutions.

[0011] The present invention relates to a highly stable heavy metal removal composition, comprising (A) 70 to 95% by weight of a compound of formula (1) or a pharmaceutically acceptable salt thereof, and (B) 1 to 25% by weight of a compound of formula (2) or a pharmaceutically acceptable salt thereof, and (C) 0.001 to 5% by weight of a basic compound which is at least one of an alkali metal hydroxide, carbonate, bicarbonate, hydrogen phosphate, carboxylate or aqueous ammonia, and wherein the compounds of formula (1) and formula (2) are each one selected from Table 1 to provide a composition. Table 1 Molecular structures of the compounds of formula (1) and formula (2) JPEG2025516821000074.jpg187152

[0012] Preferably, in the above composition, the compound of formula (1) is JPEG2025516821000075.jpg1742, and the compound of formula (2) is JPEG2025516821000076.jpg1442.

[0013] Preferably, in the above composition, the content of component (A) is 80 to 90% by weight, and the content of component (B) is 1 to 12% by weight.

[0014] Preferably, in the composition, the ratio of the mass percentage of component (A) in the composition to the mass percentage of component (B) in the composition is in the range of 90:1 to 9:1. More preferably, the ratio of the mass percentage of component (A) in the composition to the mass percentage of component (B) in the composition is in the range of 80:1 to 13:1.

[0015] Preferably, in the composition, the basic compound is at least one of sodium hydroxide, potassium hydroxide, sodium acetate, aqueous ammonia, sodium carbonate, sodium bicarbonate, ammonium bicarbonate, potassium carbonate, potassium bicarbonate, dipotassium hydrogen phosphate, and disodium hydrogen phosphate.

[0016] Preferably, the pH value when 1 mg of the composition is dissolved in 1 mL of water is 9.0 to 11.0.

[0017] The present invention provides the use of the composition in the manufacture of a pharmaceutical for removing heavy metals or free radicals in the body, or the use in the manufacture of a pharmaceutical for preventing or treating related diseases caused by heavy metal excess and poisoning, wherein the heavy metal is at least one of chromium, cobalt, arsenic, tin, cadmium, mercury, manganese, nickel, copper, thallium, technetium, uranium, bismuth, lead, iodine, palladium, and platinum.

[0018] The present invention provides an anti-tumor drug comprising 1 part by weight of a heavy metal-containing anti-tumor drug and 5 to 200 parts by weight of the above composition. Preferably, the heavy metal-containing anti-tumor drug is selected from the group consisting of platinum-based anti-tumor drugs, arsenic-based anti-tumor drugs, ruthenium-based anti-tumor drugs, and tin-based anti-tumor drugs. More preferably, the heavy metal-containing anti-tumor drug is selected from the group consisting of cisplatin, oxaliplatin, arsenic trioxide, and iodine-125.

[0019] The present invention provides the use of the composition in the manufacture of a pharmaceutical product for reducing the toxicity and side effects of a heavy metal-containing pharmaceutical product, wherein the heavy metal-containing pharmaceutical product contains at least one of cisplatin, carboplatin, oxaliplatin, nedaplatin, potassium bismuth citrate, colloidal bismuth pectin, technetium 99 dimethyl bisphosphonate, technetium 99mTc, arsenic trioxide, iodine 125, and palladium 103. Preferably, the heavy metal-containing pharmaceutical product contains at least one of cisplatin, potassium bismuth citrate, and technetium 99mTc.

[0020] The present invention provides an injectable powder containing, based on the total amount of the injectable powder, 60 to 90% by weight of the composition, 9 to 40% by weight of an excipient, and 0.001 to 10% by weight of a complexing agent. Preferably, the excipient is at least one selected from the group consisting of mannitol, aqueous ammonia, trehalose, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium acetate, ammonium acetate, and dipotassium hydrogen phosphate. More preferably, the excipient is at least one of mannitol and aqueous ammonia. Even more preferably, the excipient is aqueous ammonia, and in the injectable powder, ammonia is present as a complex or an ammonia adduct. Preferably, the complexing agent is at least one selected from the group consisting of ethylenediaminetetraacetate (EDTA), dimercaprol (BAL), and sodium dimercaptosuccinate (DMSA). More preferably, the complexing agent is EDTA.

[0021] The present invention provides an oral preparation comprising, based on the total amount of the oral preparation, 35 to 65% by weight of the composition, 20 to 40% by weight of a disintegrant, 0 to 5% by weight of a fluidizing agent, 0.1 to 5% by weight of a lubricant, 0 to 10% by weight of a film coating premix, and 0.001 to 10% of a complexing agent. Preferably, the disintegrant is at least one selected from the group consisting of crystalline cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl starch, starch, and polyvinylpyrrolidone; the fluidizing agent is at least one selected from the group consisting of talc and colloidal silica; the lubricant is at least one selected from the group consisting of talc and magnesium stearate; and the complexing agent is at least one selected from the group consisting of EDTA, BAL, and DMSA. More preferably, the disintegrant is crystalline cellulose, the fluidizing agent is colloidal silica, the lubricant is magnesium stearate, and the complexing agent is EDTA. Preferably, the oral preparation is an enteric-coated tablet or an enteric capsule. More preferably, the enteric-coated tablet is an enteric sustained-release tablet, and the enteric capsule is an enteric sustained-release capsule.

[0022] The present invention provides a transdermal preparation comprising, based on the total amount of the transdermal preparation, 20 to 65% by weight of the composition, 0.5 to 30% by weight of a transdermal enhancer, 0.5 to 25% by weight of a gelling agent, and 1 to 30% by weight of a solvent. Preferably, the transdermal enhancer is at least one selected from the group consisting of laurocapram, borneol, oleic acid, and peppermint oil; the gelling agent is at least one selected from the group consisting of carbomer, sodium hydroxypropyl cellulose, sodium ethyl cellulose, magnesium stearate, glycerin, and polyethylene glycol; and the solvent is at least one selected from the group consisting of water, methanol, ethanol, and DMSO.

[0023] The present invention provides a method for producing the composition, wherein the production process is carried out in an atmosphere of an inert gas and comprises the following steps: (1) Synthesis step of component (B): (1-1) Step of adding a basic compound, an amino acid, and glucose to a first solvent, dissolving them sufficiently, and reacting them. (1-2) Step of adding sodium borohydride to the reaction product of (1-1), reacting it, and purifying it by acidification. (1-3) Step of adding a basic compound and the reaction product of (1-2) to a first solvent, dissolving them sufficiently, reacting them, and obtaining component (B) as the reaction product. (2) Synthesis step of component (A): (2-1) Step of dissolving a basic compound and the reaction product of (1-2) in water to obtain a first solution. (2-2) CS 2 Step of dissolving it in a second solvent to obtain a second solution. (2-3) Step of mixing the first solution and the second solution, filtering after the reaction, extracting with a third solvent, and freeze-drying the aqueous layer to obtain a product. Here, the mixing ratio of the first solution and the second solution is controlled so that the product becomes only component (A). The first solvent is at least one of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, and water; the second solvent is at least one of acetone, acetonitrile, tetrahydrofuran, dioxane, and DMF; the third solvent is at least one of dichloromethane, ethyl acetate, propyl acetate, butyl acetate, and isopropyl acetate. (3) Mixing component (A), component (B), and a basic compound at a predetermined ratio to obtain a composition.

[0024] The present invention provides another production method of the above composition, wherein the production process is carried out in an atmosphere of an inert gas and includes the following steps: (1) Synthesis step of component (B): (1-1) Step of adding a basic compound, an amino acid, and glucose to a first solvent, dissolving them sufficiently, and reacting them. (1-2) Step of adding sodium borohydride to the reaction product of (1-1), reacting it, and purifying it by acidification. (1-3) Step of adding a basic compound and the reaction product of (1-2) to a first solvent, dissolving them sufficiently, reacting them, and obtaining component (B) as the reaction product. (2) Synthesis process of the composition: (2-1) Step of dissolving the basic compound and Component B in water to obtain a first solution, (2-2) CS 2 Dissolve it in a second solvent to obtain a second solution, (2-3) Step of mixing the first solution and the second solution, filtering after reaction, extracting with a third solvent, and lyophilizing the aqueous layer to obtain a product, Here, the addition amount of the basic compound in (2-1) and the mixing ratio of the first solution and the second solution in (2-3) are controlled so that the product of (2-3) becomes the composition. Preferably, in step (2), the molar ratio of the basic compound to Component (B) is 1.05:1 to 1.5:1, and CS 2 The molar ratio of to Component (B) is 1.3:1 to 5:1. More preferably, the molar ratio of the basic compound to Component (B) is 1.05:1 to 1.3:1, and CS 2 The molar ratio of to Component (B) is 1.8:1 to 3:1.

[0025] The first solvent is at least one of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, and water, the second solvent is at least one of acetone, acetonitrile, tetrahydrofuran, dioxane, and DMF, and the third solvent is at least one of dichloromethane, ethyl acetate, propyl acetate, butyl acetate, and isopropyl acetate.

[0026] The composition obtained by the present invention has the following beneficial technical effects. Compared with conventional GDTC-based pharmaceuticals, while maintaining an excellent heavy metal removal effect, the stability is greatly improved. Due to the improvement of stability, the usage amount can be reduced to about 1 / 4 without changing the drug efficacy, the use safety of the drug is improved, and since the stability of the drug is improved, the production, transportation, and storage costs can be effectively reduced, the expiration date can be extended, and the cost of the drug can be effectively reduced.

Brief Description of the Drawings

[0027]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Mode for Carrying Out the Invention

[0028] Hereinafter, with reference to the accompanying drawings, the technical solution of the present invention will be clearly and completely described through examples. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments that can be obtained by those skilled in the art without creative efforts are included within the protection scope of the present invention.

[0029] Synthesis of the composition The synthesis route of the composition is shown in FIG. 1. Scheme 1 (1) Synthesis of component (B) (1-1) Add a basic compound, an amino acid, and glucose to the first solvent, dissolve them sufficiently, and react. (1-2) Dropwise add water, and add sodium borohydride in multiple portions while maintaining the temperature at 0 to 15°C. Here, if the temperature is too high, the reaction will become violent and uncontrollable. Then, raise the temperature to 20 to 40°C for reaction, and subsequently, lower the temperature to 0 to 15°C and add the first solvent. Here, if the temperature is too high, the reaction will become uncontrollable and a large amount of reaction solution will overflow. Then, perform acidification purification, that is, add water for dilution, and further dropwise add concentrated hydrochloric acid to adjust the pH to 1 to 5. Here, if the pH is too high or too low, the product will not precipitate. (1-3) Add a basic compound and the reaction product of (1-2) to the first solvent to obtain component (B). (2) Synthesis of component (A) (2-1) Dissolve the basic compound and the reaction product of (1-2) in water to obtain a first solution. (2-2) CS 2 Dissolve it in a second solvent to obtain a second solution. (2-3) Dropwise add the first solution to the second solution, and stir after the addition is complete. Extract at 0 to 15 °C and perform lyophilization to obtain component (A). Mix component (A), component (B), and the basic compound in a predetermined ratio to obtain a composition. Component (A), component (B), and the basic compound can all control their specific components as needed, and the types of cations in the composition may be the same or different.

[0030] Scheme 2 (1) Synthesis of component (B) (1-1) Add a basic compound, an amino acid, and glucose to the first solvent, dissolve them sufficiently, and react. (1-2) Dropwise add water, and add sodium borohydride in multiple portions while maintaining the temperature at 0 to 15 °C. Here, if the temperature is too high, the reaction will become violent and uncontrollable. Then, raise the temperature to 20 to 40 °C to react, and subsequently lower the temperature to 0 to 15 °C and add the first solvent. Here, if the temperature is too high, the reaction will become uncontrollable and a large amount of reaction solution will overflow. Subsequently, perform acid purification, that is, add water for dilution, and then dropwise add 200 mL of concentrated hydrochloric acid to adjust the pH to 1 to 5. Here, if the pH is too high or too low, the product will not precipitate. (1-3) Add a basic compound and the reaction product of (1-2) to the first solvent to obtain component (B). (2) Synthesis of the composition (2-1) Dissolve the basic compound and component (B) in water such that the amount of substance (mol) of the basic compound is 1.05 to 1.2 times the amount of substance (mol) of component (B) to obtain a first solution. (2-2) CS 2 Dissolve it in a second solvent to obtain a second solution. (2-3) Drop the first solution into the second solution, extract at 0-15°C, and freeze-dry to obtain a composition. By controlling the amount of the basic compound added and the reaction time in the reaction process, the ratio of each component of the composition can be controlled, and the types of cations in the composition are the same.

[0031] Examples Hereinafter, examples of the present invention will be described. The examples described below are illustrative and are used only for explaining the present invention and should not be construed as limiting the present invention. When specific techniques and conditions are not specified in the examples, the techniques and conditions described in the literature of the relevant field or the product specifications shall be followed. Reagents and instruments for which the manufacturer is not indicated are all commercially available products commonly used in this field. In addition, the content of each component in the examples of the present application is based on the mass excluding crystal water unless otherwise specified.

[0032] A comparison table of the main raw materials used in the production process of the composition and the compounds shown in formulas (1) and (2) is shown in Table 2. Table 2 Comparison table of main raw materials and compounds shown in formulas (1) and (2) JPEG2025516821000077.jpg227167

[0033] Example 1 This example relates to the production of Composition 3 in Table 1, and the production process was carried out in an atmosphere of an inert gas, and the specific steps were as follows. (1) Synthesis of Compound 3B (1-1) At 10°C, add 48 g of sodium hydroxide, 149 g of methionine, and 200 g of glucose to 500 mL of methanol, stir until clear, heat up to 30°C, and react for 10 hours. (1-2) 1000 mL of water was added dropwise, and while maintaining the temperature at 5 °C, 1100 g of sodium borohydride was added in 5 portions, followed by reacting for 12 hours. Then, after raising the temperature to 35 °C and reacting for 24 hours, 200 mL of methanol as the solvent was added dropwise while maintaining the temperature at 10 °C, and stirred for 2 hours. Then, the temperature was lowered to 4 °C, 500 mL of water was added for dilution, 200 mL of concentrated hydrochloric acid was added dropwise, and crystallization, trituration, recrystallization, and recovery were carried out to obtain (2,3,4,5,6-pentahydroxyhexyl)methionine with a purity exceeding 99.6%. (1-3) Sodium hydroxide was dissolved in methanol, an equimolar amount of (2,3,4,5,6-pentahydroxyhexyl)methionine was added, stirred until clear, filtered, spin-dried, and recrystallized to obtain 3B with a purity exceeding 99.9%. The 1 H NMR spectrum and 13 C NMR spectrum of compound 3B measured with a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms(ES+,[M+H] + ) 336 1 H NMR(500 MHz,D 2 O) δ(ppm) 4.02(m,1H),3.81~3.61(m,4H),3.46(t,1H),3.01~3.12(m,2H),2.26(m,2H),2.06~2.03(m,2H).2.02(s,3H), 13 C NMR(125 MHz,D 2 O) δ(ppm)168.83,72.20,71.07,70.22,70.71,64.76,60.15,49.43,30.05,29.10,14.94.

[0034] (2) Synthesis of compound 3A (2-1) 314 g of (2,3,4,5,6-pentahydroxyhexyl)methionine and 216 g of sodium carbonate were dissolved in 1500 mL of purified water to obtain a first solution, and the temperature was maintained at 20 °C. (2-2) 100 mL of CS 2was dissolved in 300 mL of methanol to obtain a second solution. (2-3) The first solution was added dropwise to the second solution, and after the completion of the addition, the mixture was stirred for 8 hours. 20 mL of CS2 / methanol solution was added to the reaction system. The reaction system was cooled to 5°C and the temperature was maintained for 1 hour, after which it was filtered, extracted five times with dichloromethane, and freeze-dried to obtain 3A with a purity of over 99%. Compound 3A measured by nuclear magnetic resonance (Bruker AV500MHz) 1 H NMR spectrum and 13 The C NMR spectrum was as follows: Ms(ES+, [M+Na] + )456 1 H NMR (500 MHz, D 2 O) δ(ppm) 4.40(t,1H),3.96(m,1H),3.79(m,1H),3.56~3.59(m,2H),3.47(m,3H),2.42~2.29(m,2H),2.10(m,1H),2.06(s,3H),1.87(m,1H), 13 C NMR (125 MHz, D 2 O) δ(ppm)208.23,175.53,73.12,72.95,71.31,70.36,66.76,63.44,52.88,31.70,30.20,15.19.

[0035] (3) Preparation of Composition 3 800 g of 3A, 150 g of 3B, and 50 g of ammonium bicarbonate were dissolved in 10 L of water and freeze-dried to obtain composition 3.

[0036] Example 2 This example relates to the preparation of composition 5 in Table 1, and the preparation process was carried out under an inert gas atmosphere, and the specific steps were as follows. (1) Synthesis of compound 5B (1-1) 98 g of sodium hydroxide, 147 g of glutamic acid, and 200 g of glucose were added to 1,000 mL of methanol at 20° C., stirred until the mixture became clear, and then heated to 30° C. and reacted for 10 hours. (1-2) 1000 mL of water was added dropwise, and while maintaining the temperature at 8 °C, 80 g of sodium borohydride was added in 5 portions, and the reaction was carried out for 12 hours. After raising the temperature to 40 °C and reacting for 10 hours, the temperature was lowered to 4 °C, 500 mL of water was added for dilution, 400 mL of concentrated hydrochloric acid was added dropwise, and crystallization, pulverization, recrystallization, and recovery were performed to obtain an intermediate (2,3,4,5,6-pentahydroxyhexyl)glutamic acid with a purity exceeding 99.4%. (1-3) Sodium hydroxide was dissolved in methanol, an equimolar amount of (2,3,4,5,6-pentahydroxyhexyl)glutamic acid was added, and the mixture was stirred until clear, filtered, spin-dried, and recrystallized to obtain 5B with a purity exceeding 99.9%. The 1 H NMR spectrum and 13 C NMR spectrum of compound 5B measured by a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms(ES+,[M+H] + ) 356 1 H NMR(500 MHz,D 2 O) δ(ppm) 3.91~3.78(m,3H), 3.72~3.48(m,4H), 3.08~2.83(m,2H), 2.60~2.40(m,2H), 2.12~1.81(m,2H). 13 C NMR(125 MHz,D 2 O) δ(ppm) 176.98, 176.76, 72.20, 72.07, 71.22, 70.71, 64.76, 59.81, 49.44, 31.29, 24.16.

[0037] (2) Preparation of Composition 5 (2-1) 800 g of 5B and 300 g of sodium carbonate were dissolved in 2500 mL of purified water to obtain a first solution, and the temperature was maintained at 30 °C. (2-2) 95 mL of CS 2 was dissolved in 300 mL of dioxane to obtain a second solution. (2-3) The first solution was added dropwise to the second solution, and after the addition was complete, the mixture was stirred for 8 hours. Further, 1000 mL of dioxane was added, followed by filtration. The mixture was extracted 5 times with butyl acetate, the aqueous layer was taken, and freeze-dried to obtain Composition 5.

[0038] Example 3 This example relates to the production of Composition 7 in Table 1, and the production process was carried out under an atmosphere of inert gas. The specific steps were as follows. (1) Synthesis of Compound 7B (1-1) At 20 °C, 46 g of sodium hydroxide, 195 g of 4-methoxyphenylalanine, and 220 g of glucose were added to 600 mL of water, stirred until clear, heated to 35 °C, and reacted for 20 hours. (1-2) 800 mL of water was added dropwise, and while maintaining the temperature at 6 °C, 120 g of sodium borohydride was added in 5 portions, reacted for 12 hours, heated to 42 °C and reacted for 10 hours. Then, 300 mL of acetonitrile as a solvent was added dropwise, stirred for 2 hours, 250 mL of concentrated hydrochloric acid was added dropwise, cooled to room temperature, crystallized, pulverized, recrystallized, and recovered to obtain an intermediate with a purity exceeding 99.8%. (1-3) Sodium carbonate was dissolved in methanol, an equimolar amount of the intermediate was added, stirred until the reaction was complete, filtered, spin-dried, recrystallized, and 7B with a purity exceeding 99.9% was obtained. The 1 H NMR spectrum and 13 C NMR spectrum of Compound 7B measured by a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms(ES+,[M+H] + ) 382 1 H NMR(500 MHz,CD 3 OD) δ(ppm)7.12(m,2H),6.80(m,2H),3.93(dt,1H),3.86(dd,J=8.5,7.5 Hz,1H),3.78(s,3H),3.78~3.75(m,1H),3.72~3.61(m,4H),2.97~2.83(m,4H). 13 C NMR(125 MHz,CD 3OD) δ(ppm) 171.24, 158.51, 131.11, 130.27, 113.64, 73.20, 73.07, 72.22, 71.71, 64.76, 62.47, 55.33, 49.39, 36.42.

[0039] (2) Synthesis of Compound 7A (2-1) 314 g of Intermediate and 350 g of sodium carbonate were dissolved in 1500 mL of purified water to obtain a first solution, and the temperature was maintained at 30 °C. (2-2) 100 mL of CS 2 was dissolved in 300 mL of methanol to obtain a second solution. (2-3) The first solution was added dropwise to the second solution. After the addition was complete, the mixture was stirred for 8 hours. After the temperature of the reaction system was lowered to 5 °C and maintained for 1 hour, it was filtered, extracted 5 times with ethyl acetate, the aqueous layer was taken, and freeze-dried to obtain 7A with a purity exceeding 99%. 1H NMR spectrum and 1 13C NMR spectrum of Compound 7A measured by a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. 13 Ms(ES+, [M+H] + ) 480 1 1H NMR (500 MHz, D 2 2O) δ(ppm) 7.08 (m, 2H), 6.85 (m, 2H), 4.48 (t, 1H), 4.14~3.91 (m, 3H), 3.83~3.72 (m, 4H), 3.70~3.59 (m, 3H), 3.16~3.03 (m, 2H). 13 13C NMR (125 MHz, D 2 2O) δ(ppm) 204.05, 171.96, 153.51, 134.04, 127.90, 113.64, 73.12, 72.95, 72.31, 70.48, 65.76, 64.61, 55.33, 53.06, 33.03.

[0040] (3) Preparation of Composition 7 900 g of 7A, 85 g of 7B, and 15 g of sodium bicarbonate were dissolved in 10 L of water and then freeze-dried to obtain Composition 7.

[0041] Example 4 This example relates to the production of Composition 10 in Table 1. The production process was carried out in an inert gas atmosphere, and the specific steps were as follows. (1) Synthesis of Compound 10B (1-1) At 20 °C, 60 g of potassium hydroxide, 105 g of serine, and 200 g of glucose were added to 600 mL of tetrahydrofuran, stirred until clear, heated to 35 °C, and reacted for 10 hours. (1-2) 800 mL of water was added dropwise, and while maintaining the temperature at 6 °C, 180 g of sodium borohydride was added in 5 portions, reacted for 12 hours, heated to 42 °C and reacted for 18 hours. Then, while maintaining the temperature at 10 °C, 280 mL of tetrahydrofuran as the solvent was added dropwise, stirred for 2 hours, 250 mL of concentrated hydrochloric acid was added dropwise, and crystallization, pulverization, recrystallization, and recovery were carried out to obtain an intermediate with a purity exceeding 99.8%. (1-3) Sodium hydroxide was added to acetonitrile, an equimolar amount of the intermediate was added, stirred until the reaction was complete, filtered, spin-dried, and recrystallized to obtain 10B with a purity exceeding 99.9%. The 1 H NMR spectrum and 13 C NMR spectrum of Compound 10B measured by a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms(ES+,[M+H] + )292 1 H NMR(500 MHz,D 2 O) δ(ppm)3.86~3.72(m,4H),3.71~3.54(m,5H),2.97~2.85(m,2H). 13 C NMR(125 MHz,D 2 O) δ(ppm)170.57,73.20,73.07,72.22,71.77,64.76,61.95,61.95,49.47.

[0042] (2) Synthesis of Compound 10A (2-1) 314 g of intermediate, 350 g of potassium carbonate were dissolved in 1500 mL of purified water to obtain a first solution, and the temperature was maintained at 30 °C. (2-2) 100 mL of CS 2 was dissolved in 300 mL of dioxane to obtain a second solution. (2-3) The first solution was added dropwise to the second solution. After the addition was complete, the mixture was stirred for 8 hours. After cooling the reaction system to 5 °C and maintaining the temperature for 1 hour, it was filtered, extracted 8 times with ethyl acetate, the aqueous layer was taken, and freeze-dried to obtain 10A with a purity exceeding 99%. The 1 1H NMR spectrum and 13 13C NMR spectrum of compound 10A measured with a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms(ES+,[M+K] + ) 460 1 1H NMR(500 MHz,D 2 2O) δ(ppm) 4.61(t,1H), 4.15~4.06(m,2H), 4.03~3.93(m,3H), 3.89~3.75(m,2H), 3.68~3.50(m,3H). 13 13C NMR(125 MHz,D 2 2O) δ(ppm) 204.34, 176.56, 73.12, 73.01, 72.31, 70.45, 64.76, 64.20, 61.16, 52.54.

[0043] (3) Preparation of Composition 10 900 g of 10A, 90 g of 10B, and 10 g of potassium bicarbonate were dissolved in 10 L of water and then freeze-dried to obtain Composition 10.

[0044] Example 5 This example relates to the preparation of Composition 11 in Table 1, and the manufacturing process was carried out in an atmosphere of inert gas. The specific steps were as follows. (1) Synthesis of Compound 11B (1-1) 48 g of sodium hydroxide, 161 g of S-allyl-cysteine, and 210 g of glucose were added to 200 mL of tetrahydrofuran at 30 °C, stirred until clear, and reacted at 30 °C for 10 hours. (1-2) 1000 mL of water was added dropwise, and while maintaining the temperature at 10 °C, 100 g of sodium borohydride was added in 5 portions, reacted for 12 hours, heated to 30 °C and reacted for 10 hours. Then, while maintaining the temperature at 10 °C, 200 mL of tetrahydrofuran was added dropwise, stirred for 2 hours, cooled to 10 °C, diluted by adding 500 mL of water, 240 mL of concentrated hydrochloric acid was added dropwise, and crystallization, pulverization, recrystallization, and recovery were performed to obtain an intermediate with a purity exceeding 99.2%. (1-3) An appropriate amount of the intermediate was added to aqueous ammonia, stirred until clear, filtered, spin-dried, and recrystallized to obtain 11B with a purity exceeding 99.9%. The 1 1H NMR spectrum and 13 13C NMR spectrum of compound 11B measured with a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms(ES+,[M+H] + ) 343 1 1H NMR(500 MHz,D 2 2O) δ(ppm)5.80(m,1H),5.11(m,2H),3.85~3.52(m,7H),3.24~3.14(m,2H),3.03~2.85(m,4H). 13 13C NMR(125 MHz,D 2 2O) δ(ppm)168.82,133.38,117.29,73.20,73.07,72.22,71.57,64.76,59.06,49.65,35.65,33.52.

[0045] (2) Synthesis of compound 11A (2-1) 325 g of the intermediate and 60 ml of aqueous ammonia were dissolved in 1600 ml of purified water to obtain a first solution, and the temperature was maintained at 30 °C. (2-2) 200 ml of CS 2 was dissolved in 300 mL of methanol to obtain a second solution. (2-3) The first solution was added dropwise to the second solution. After the addition was complete, the mixture was stirred for 8 hours. After cooling the reaction system to 5 °C and maintaining the temperature for 1 hour, it was filtered, extracted 5 times with isopropyl acetate, the aqueous layer was taken, and freeze-dried to obtain 11A with a purity exceeding 99%. The 1H NMR spectrum and 1 13C NMR spectrum of compound 11A measured with a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. 13 + Ms(ES+, [M+H] + ) 437 1 1H NMR (500 MHz, D 2 2O) δ (ppm) 5.80 (m, 1H), 5.11 (m, 2H), 4.68 (t, 1H), 4.16 - 3.98 (m, 3H), 3.89 - 3.75 (m, 2H), 3.67 - 3.51 (m, 3H), 3.27 - 3.07 (m, 4H). 13 13C NMR (125 MHz, D 2 2O) δ (ppm) 210.45, 170.18, 133.45, 117.25, 73.12, 73.01, 72.31, 70.31, 64.76, 61.31, 52.70, 35.82, 33.58.

[0046] (3) Preparation of Composition 11 910 g of 11A, 11 80 g of B, and 10 g of sodium carbonate were dissolved in 10 L of water and then freeze-dried to obtain Composition 11.

[0047] Example 6 This example relates to the preparation of Compositions 1, 2, 4, 6, 8, and 9 in Table 1. The procedures (1) and (2) in the preparation process were the same as those in Example 1, except that methionine in Example 1 was changed to the corresponding raw materials for Compositions 1, 2, 4, 6, 8, and 9 in Table 2 with the same amount of substance.

[0048] Each procedure (3) was as follows. Composition 1: 860 g of 1A, 132 g of 1B, and 8 g of potassium carbonate were dissolved in 10 L of water and then lyophilized to obtain Composition 1. The 1 1H NMR spectrum and 13 13C NMR spectrum of Compound 1A measured with a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms(ES+,[M+Na] + ) 414 1 1H NMR (500 MHz,D 2 2O) δ(ppm) 5.00 (d, 1H), 4.90 (d, 1H), 4.36 (m, 1H), 4.17 (m, 1H), 4.01 (m, 1H), 3.95 (m, 1H), 3.90 (m, 1H), 3.72~3.68 (m, 1H), 3.60~3.55 (m, 1H), 3.50~3.42 (m, 1H), 3.53 (q, 1H). 13 13C NMR (125 MHz,D 2 2O) δ(ppm) 213.73, 170.59, 81.10, 71.12, 71.01, 69.31, 69.53, 62.76, 61.14, 51.09. The 1 1H NMR spectrum and 13 13C NMR spectrum of Compound 1B measured with a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms(ES+,[M+H] + ) 294 1 1H NMR (500 MHz,D 2 2O) δ(ppm) 4.55 (d, 2H), 3.82 (t, 1H), 3.88 (m, 3H), 3.53 (m, 1H), 3.38 (m, 2H), 2.63 (t, 2H). 13 13C NMR (125 MHz,D 2 2O) 175.12, 82.47, 75.20, 74.07, 71.22, 70.76, 65.76, 64.97, 47.39

[0049] Composition 2: 900 g of 2A, 90 g of 2B, and 10 g of aqueous ammonia were dissolved in 10 L of water and then lyophilized to obtain Composition 2. The 1 1H NMR spectrum and 13 13C NMR spectrum of Compound 2A measured with a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms (ES+, [M+Na] + ) 424 1 1H NMR (500 MHz, D 2 2O) δ (ppm) 4.91 (d, 1H), 4.26 (m, 1H), 4.18 (m, 1H), 4.04 - 3.93 (m, 2H), 3.80 - 3.73 (m, 1H), 3.71 - 3.58 (m, 3H), 2.76 - 2.63 (m, 1H), 0.96 (m, 6H). 13 13C NMR (125 MHz, D 2 2O) δ (ppm) 205.08, 173.50, 73.12, 72.95, 72.31, 70.47, 67.97, 64.76, 53.25, 29.26, 18.31. The 1 1H NMR spectrum and 13 13C NMR spectrum of Compound 2B measured with a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms (ES+, [M+Na] + ) 326 1H NMR (500 MHz, D 2 2O) δ (ppm) 3.85 - 3.76 (m, 2H), 3.80 - 3.73 (m, 1H), 3.68 - 3.62 (m, 1H), 3.62 - 3.54 (m, 2H), 3.51 (d, J 1H), 2.95 - 2.87 (m, 1H), 2.83 - 2.74 (m, 1H), 1.96 (m, 1H), 0.93 (d, 3H), 0.88 (d, 3H). 13 13C NMR (125 MHz, D 2 2O) δ (ppm) 174.20, 73.20, 73.07, 72.22, 71.70, 65.76, 64.76, 49.62, 29.61, 18.79.

[0050] Composition 4: 920 g of 4A, 60 g of 4B, and 20 g of dipotassium hydrogen phosphate were dissolved in 10 L of water and then lyophilized to obtain Composition 4. The 1 H NMR spectrum and 13 C NMR spectrum of Compound 4A measured with a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms (ES+, [M+Na] + ) 472 1 H NMR (500 MHz, D 2 O) δ (ppm) 4.32 (t, 1H), 4.22~3.94 (m, 5H), 3.88~3.75 (m, 2H), 3.68~3.51 (m, 3H), 2.88~2.74 (m, 2H), 2.07 (m, 2H). 13 C NMR (125 MHz, D 2 O) δ (ppm) 206.05, 173.65, 138.61, 127.33, 126.57, 125.74, 73.12, 72.95, 72.31, 70.48, 64.76, 63.59, 53.03, 32.10. The 1 H NMR spectrum and 13 C NMR spectrum of Compound 4B measured with a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms (ES+, [M+H] + ) 352 1 H NMR (500 MHz, D 2 O) δ (ppm) 4.20 (d, 2H), 3.85~3.74 (m, 3H), 3.68~3.49 (m, 4H), 2.99~2.67 (m, 4H), 1.89 (m, 2H). 13 C NMR (125 MHz, D 2 O) δ (ppm) 171.15, 138.89, 126.86, 125.77, 73.20, 73.07, 72.22, 71.71, 64.76, 61.85, 49.39, 32.89.

[0051] Composition 6: 910 g of 6A, 75 g of 6B, and 15 g of sodium acetate were dissolved in 10 L of water and freeze-dried to obtain Composition 6. The 1 H NMR spectrum and 13 C NMR spectrum of Compound 6A measured with a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms(ES+,[M+Na] + ) 478 1 H NMR (500 MHz, D 2 O) δ(ppm) 4.18~4.06 (m, 3H), 3.63~3.44 (m, 3H), 3.29~3.01 (m, 3H), 2.10~1.83 (m, 3H), 1.59~1.15 (m, 10H) 13 C NMR (125 MHz, D 2 O) δ(ppm) 204.23, 171.80, 73.12, 72.95, 72.31, 70.36, 64.76, 62.10, 52.95, 34.38, 34.12, 32.76, 26.16, 25.99. The 1 H NMR spectrum and 13 C NMR spectrum of Compound 6B measured with a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms(ES+,[M+H] + ) 358 1 H NMR (500 MHz, D 2 O) δ(ppm) 4.20 (d, 2H), 3.84~3.72 (m, 3H), 3.68~3.62 (m, 4H), 2.98~2.68 (m, 3H), 1.89~1.56 (mm, 10H). 13 C NMR (125 MHz, D 2 O) δ(ppm) 172.04, 73.14, 72.22, 71.71, 64.76, 59.63, 49.51, 35.56, 33.61, 33.11, 26.16, 25.99.

[0052] Composition 8: 900 g of 8A, 85 g of 8B, and 15 g of sodium bicarbonate were dissolved in 10 L of water and freeze-dried to obtain Composition 8. The 1 1H NMR spectrum and 13 13C NMR spectrum of Compound 8A measured with a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms(ES+, [M+Na] + ) 478 1 1H NMR (500 MHz, D 2 2O) δ (ppm) 7.26 (m, 1H), 6.92 (m, 1H), 6.75 (m, 1H), 4.64 (t, 1H), 4.18 - 3.94 (m, 3H), 3.89 - 3.76 (m, 2H), 3.67 - 3.51 (m, 3H), 3.43 - 3.27 (m, 2H). 13 13C NMR (125 MHz, D 2 2O) δ (ppm) 211.05, 178.68, 152.88, 142.18, 133.53, 73.12, 72.95, 72.31, 70.48, 64.76, 64.29, 53.03, 28.99. The 1 1H NMR spectrum and 13 13C NMR spectrum of Compound 8B measured with a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms(ES+, [M+H] + ) 358 1 1H NMR (500 MHz, D 2 2O) δ (ppm) 7.26 (d, 1H), 6.93 (d, 1H), 6.72 (dd, 1H), 3.86 - 3.56 (m, 7H), 3.13 - 2.87 (m, 4H). 13 13C NMR (125 MHz, D 2 2O) δ (ppm) 176.22, 152.92, 142.59, 133.81, 73.20, 73.07, 72.22, 71.70, 64.76, 61.48, 49.39, 30.68.

[0053] Composition 9: 910 g of 9A, 85 g of 9B, and 5 g of sodium bicarbonate were dissolved in 10 L of water and then lyophilized to obtain Composition 9. The 1 1H NMR spectrum and 13 13C NMR spectrum of Compound 9A measured with a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms (ES+, [M+H] + ) 479 1 1H NMR (500 MHz, D 2 2O) δ (ppm) 8.57 (d, 1H), 7.42 (d, 1H), 4.64 (t, 1H), 4.19~3.94 (m, 3H), 3.90~3.75 (m, 2H), 3.69~3.41 (m, 4H), 3.29 (m, 1H). 13 13C NMR (125 MHz, D 2 2O) δ (ppm) 206.05, 170.68, 152.88, 142.18, 133.53, 73.12, 72.95, 72.31, 70.48, 64.76, 64.29, 53.03, 28.99. The 1 1H NMR spectrum and 13 13C NMR spectrum of Compound 9B measured with a nuclear magnetic resonance apparatus (Bruker AV500 MHz) were as follows. Ms (ES+, [M+H] + ) 359 1 1H NMR (500 MHz, D 2 2O) δ (ppm) 8.58 (d, 1H), 7.43 (d, 1H), 3.91~3.73 (m, 4H), 3.72~3.53 (m, 3H), 3.24~2.85 (m, 4H). 13 13C NMR (125 MHz, D 2 2O) δ (ppm) 171.22, 152.92, 142.59, 133.81, 73.20, 73.07, 72.22, 71.70, 64.76, 61.48, 49.39, 30.68.

[0054] Example 7 In this example, an injection powder was produced using Composition 3 manufactured in Example 1 as the main component. 1250 g of the composition, 5 g of ETDA, 400 g of mannitol, and 400 g of aqueous ammonia were dissolved in 15 L of ice water under a nitrogen atmosphere, stirred uniformly, and automatically dispensed into 20 mL vials in 7.5 mL aliquots. After pre-cooling to -40°C, they were freeze-dried to obtain an injection powder of Composition 3, 500 mg per vial.

[0055] Example 8 In this example, an injection powder was produced using Composition 5 manufactured in Example 2 as the main component. 1111 g of Composition 5, 10 g of ETDA, 300 g of trehalose, and 50 g of sodium bicarbonate were dissolved in 15 L of ice water under a nitrogen atmosphere, stirred uniformly, and automatically dispensed into 20 mL vials in 7.5 mL aliquots. After pre-cooling to -40°C, they were freeze-dried to obtain a preparation of Composition 5, 500 mg per vial.

[0056] Example 9 In this example, an injection powder was produced using Composition 7 manufactured in Example 3 as the main component. 1100 g of Composition 7, 1 g of BAL, 200 g of mannitol, and 85 g of ammonium acetate were dissolved in 15 L of ice water under a nitrogen atmosphere, stirred uniformly, and automatically dispensed into 20 mL vials in 7.5 mL aliquots. After pre-cooling to -40°C, they were freeze-dried to obtain a preparation of Composition 7, 500 mg per vial.

[0057] Example 10 In this example, enteric-coated granules (tablets) were produced using Composition 3 manufactured in Example 1 as the main component. 300 g of the composition, 1 g of EDTA, 287 g of crystalline cellulose (PH102), 6 g of colloidal silica, 6 g of magnesium stearate MF-2-V, 17 g of film coating premix (gastric-soluble), and 480 g of film coating premix (enteric-soluble) were each sieved through a 40-mesh sieve for pretreatment. Then, crystalline cellulose, the composition, EDTA, colloidal silica, and magnesium stearate were sieved together through a 40-mesh sieve, mixed, put into a dry granulator, and granules of 14 - 30 mesh were collected. A gastric-soluble coating solution was prepared at a concentration of 5% by a fluidized bed for the isolation layer coating, and an enteric-soluble coating solution was prepared at a concentration of 20% for the enteric coating to obtain enteric-coated granules. After tableting, further enteric coating was performed to obtain enteric-coated tablets.

[0058] Example 11 In this example, enteric-coated capsules were produced using Composition 3 manufactured in Example 1 as the main component. 300 g of the composition, 3 g of EDTA, 285 g of crystalline cellulose (PH102), 6 g of colloidal silica, and 6 g of magnesium stearate MF-2-V were each sieved through a 40-mesh sieve for pretreatment. Then, crystalline cellulose, the composition, EDTA, colloidal silica, and magnesium stearate were sieved together through a 40-mesh sieve, mixed, put into a dry granulator, and granules of 14 - 30 mesh were collected and filled into No. 2 enteric-coated capsules to obtain enteric-coated capsules of 300 mg per capsule.

[0059] Example 12 In this example, enteric-coated sustained-release granules (tablets) were produced using Composition 3 manufactured in Example 1 as the main component. 300 g of composition, 6 g of EDTA, 200 g of crystalline cellulose (PH102), 84 g of hydroxypropylmethylcellulose, 5 g of colloidal silica, 5 g of magnesium stearate MF-2-V, 17 g of film coating premix (gastric soluble), and 480 g of film coating premix (enteric soluble) were each sieved through a 40-mesh sieve for pretreatment. Then, crystalline cellulose, the composition, EDTA, colloidal silica, and magnesium stearate were sieved together through a 40-mesh sieve, mixed, put into a dry granulator, and granules of 14 - 30 mesh were collected. A gastric-soluble coating solution was prepared at a concentration of 5% by a fluidized bed for an isolation layer coating, and an enteric-soluble coating solution was prepared at a concentration of 20% for an enteric-soluble coating to obtain enteric-soluble sustained-release granules. After tableting, an additional enteric-soluble coating was performed to obtain enteric-soluble sustained-release tablets.

[0060] Example 13 This example used Composition 3 produced in Example 1 as the main component to manufacture enteric-soluble sustained-release capsules. 300 g of composition, 5 g of EDTA, 200 g of crystalline cellulose (PH102), 88 g of hydroxypropylmethylcellulose, 6 g of colloidal silica, and 6 g of magnesium stearate MF-2-V were each sieved through a 40-mesh sieve for pretreatment. Then, crystalline cellulose, the composition, EDTA, colloidal silica, and magnesium stearate were sieved together through a 40-mesh sieve, mixed, put into a dry granulator, and granules of 14 - 30 mesh were collected and filled into No. 2 enteric-soluble capsules to obtain enteric-soluble sustained-release capsules of 300 mg per capsule.

[0061] Example 14 This example used Composition 3 produced in Example 1 as the main component to manufacture a transdermal preparation. 200 g of composition, 10 g of EDTA, 80 g of sodium hydroxypropylcellulose, 100 g of laurocapram, 200 g of sesame oil, 80 g of magnesium stearate, 40 g of polyethylene glycol 400, and 290 g of water were mixed and stirred until it became gel-like, with an area of 10000 cm 2It was uniformly applied to the lining material and divided into a predetermined size as needed to obtain a transdermal preparation containing Composition 3 as the main component.

[0062] Example 15 In this example, Compound 3A, Composition 3 produced in Example 1, Composition 3-1 consisting of 80 wt% 3A and 20 wt% 3B, Composition 3-2 consisting of 80 wt% 3A and 20 wt% sodium carbonate, and a powder for injection (hereinafter simply referred to as Composition 3 preparation) containing Composition 3 produced in Example 7 as the main component were compared and examined for their solid and formulation stabilities.

[0063] Compound 3A of the present invention is D3 in Chinese Patent 2005100353771, that is, GMDTC mentioned in the background art section. For the purpose of showing the comparison with Chinese Patent 2005100353771, in this example and subsequent examples, it is all denoted as D3.

[0064] D3, Composition 3-1, Composition 3-2, Composition 3, and Composition 3 preparation were each left in an environment of -25°C, 5 ± 3°C, 25 ± 2°C / 60 ± 5% RH, and 40 ± 2°C / 75 ± 5% RH for 0 d, 5 d, 10 d, 30 d, and 180 d (d means day), and the change in the content of the main component (taking the content of the main component at 0 d as 100%) was measured and shown in Table 3. Table 3 Changes in the content of the main component over time under different conditions for different groups JPEG2025516821000078.jpg112164

[0065] The data in the table with a content exceeding 100% was due to integration errors (the same applies hereinafter). D3, Composition 3-1, Composition 3-2, Composition 3, and Composition 3 preparation were all adjusted to a solution with a main component concentration of 2 mg / ml, with the solvent being physiological saline and 5% glucose injection solution, the pH was measured, and then left at room temperature for 8 hours to detect the change in the content of the main component (taking the content at 0 h as 100%), and the results are shown in Table 4. Table 4 Changes in the content of the main component over time in the solutions of different groups JPEG2025516821000079.jpg56165

[0066] As can be seen from Table 3, Composition 3 and the formulation of Composition 3 were stable even after 180 days under the condition of 5 ± 3°C. However, for Composition 3-1 and Composition 3-2, the content of the main component decreased by about 9% after 180 days under this condition, and for D3, it decreased by 18.8% after 180 days. On the other hand, when the temperature rose to 25 ± 2°C, the stability of both Composition 3-1 and Composition 3-2 decreased, and the main component decreased by about 17% after 180 days. For Composition 3, the main component decreased by 5.8%, but the formulation of Composition 3 was relatively stable. From this, it can be seen that the stability of the formulation of Composition 3 and Composition 3 is significantly superior to that of Composition 3-1, Composition 3-2, and D3, and it can effectively reduce the costs of transportation and storage and can extend the expiration date.

[0067] As can be seen from Table 4, the formulation of Composition 3 and Composition 3 had good stability at the measurement stage with almost no change. D3 had relatively poor stability and was hydrolyzed by 30% - 50% after 8 hours. Composition 3-1 and Composition 3-2 were hydrolyzed by 10% - 20 % hydrolyzed. From this, it can be seen that the formulation of Composition 3 and Composition 3 are significantly superior in blending stability to Composition 3-1, Composition 3-2, and D3, and it can be applied clinically.

[0068] Example 16 In this example, the acute toxicity of Composition 3 produced in Example 1, the injectable powder of Composition 3 produced in Example 7, and the oral formulations of Composition 3 produced in Examples 10, 11, and 13 were examined. One hundred and forty SPF-grade SD rats, 70 males and 70 females, weighing 180 - 220 g, were divided into 7 groups of 10 males and 10 females each. In the first group, D3 was intravenously injected at 3 g / kg; in the second group, Composition 3 was intravenously injected at 3 g / kg; in the third group, the injection powder of Composition 3 was intravenously injected at 3 g / kg; in the fourth group, the enteric-coated granules of Composition 3 were orally administered at 5 g / kg; in the fifth group, the enteric-coated capsules of Composition 3 were orally administered at 5 g / kg; in the sixth group, the enteric-coated sustained-release capsules of Composition 3 were orally administered at 5 g / kg; and the seventh group was the blank group. After administration, the poisoning situation was observed daily, but no obvious toxic reaction was confirmed. As a result of measuring the body weights of the animals on days 0, 3, 7, and 14, the body weights of the animals were normal, no obvious toxicity was observed, and no abnormalities were found in each organ after autopsy. Therefore, when injecting D3, the MTD of rats exceeded 3 g / kg, and when orally administering, the MTD of rats exceeded 5 g / kg. The toxicity of each group was equivalent to that of D3, and it was found that the toxicity was extremely low.

[0069] Forty-two ordinary-grade beagle dogs, 10 males and 10 females each, weighing 8 - 10 kg, were divided into 7 groups. In the first group, D3 was intravenously injected at 2 g / kg; in the second group, Composition 3 was intravenously injected at 2 g / kg; in the third group, the injection powder of Composition 3 was intravenously injected at 2 g / kg; in the fourth group, the enteric-coated granules of Composition 3 were orally administered at 5 g / kg; in the fifth group, the enteric-coated capsules of Composition 3 were orally administered at 5 g / kg; in the sixth group, the enteric-coated sustained-release capsules of Composition 3 were orally administered at 5 g / kg; and the seventh group was the blank group. After administration, the poisoning situation was observed daily, but no obvious toxic reaction was confirmed. As a result of measuring the body weights of the animals on days 0, 3, 7, and 14, the body weights of the animals were normal, and no obvious toxicity was confirmed. Therefore, when injecting D3, the MTD of dogs exceeded 2 g / kg, and when orally administering, the MTD of dogs exceeded 5 g / kg. The toxicity of each group was equivalent to that of D3, and it was found that the toxicity was extremely low.

[0070] Example 17 This example examined the long-term toxicity of Composition 3 manufactured in Example 1 and the injection powder of Composition 3 manufactured in Example 7. One hundred and five SPF-grade SD rats weighing 180-220 g, 105 males and 105 females, were divided into 7 groups with 15 males and 15 females in each group. The first group was intravenously injected with the injection powder of Composition 3 at 200 mg / kg, the second group was intravenously injected with the injection powder of Composition 3 at 500 mg / kg, the third group was intravenously injected with the injection powder of Composition 3 at 1000 mg / kg, and continuous administration was carried out for 28 days. The fifth group was intravenously injected with Composition 3 at 200 mg / kg, the sixth group was intravenously injected with Composition 3 at 500 mg / kg, the seventh group was intravenously injected with Composition 3 at 1000 mg / kg, and continuous administration was carried out for 28 days. The fourth group was the blank group. The poisoning situation was observed every day, and after the completion of administration, blood biochemical examination was carried out. As a result, no obvious difference was observed between Composition 3 and the preparation of Composition 3. In the high-dose groups, HGB decreased slightly in all of them, and mild swelling and ulcers were observed at the injection site of the tail. The body weights of the animals were measured on days 0, 7, 14, 21, and 28, and the body weights of the animals were normal. Among each group, 10 males and 10 females in each group were euthanized 24 hours after administration on the 28th day, dissected, and each organ was roughly observed. As a result, there were no abnormalities, the organ coefficients were normal, and microscopic examination showed that there were no abnormalities in each organ. Five males and five females in each of the remaining groups recovered for 28 days, and blood biochemical examination was carried out. As a result, each function was normal. After dissection, each organ was roughly observed, and there were no abnormalities, the organ coefficients were normal, and microscopic examination showed that no abnormalities were observed in each organ. The NOAEL values of Composition 3 and the injection powder of Composition 3 in rats were both 500 mg / kg.

[0071] Example 18 In this example, the cadmium removal effects of D3, Compound 3B, Composition 3 prepared in Example 1, and the injection powder of Composition 3 prepared in Example 7 (simply referred to as the preparation of Composition 3) were examined. Two hundred and five male New Zealand rabbits weighing 1.8-2.2 kg were randomly divided into a blank control group of 25 rabbits and a chronic cadmium poisoning model group of 180 rabbits. CdCl at 1.5 μmol / kg body weight was injected into the auricular vein of the model rabbits. 2A mixed solution containing 30 μmol / kg body weight of mercaptoethanol (ME) was injected once a day for 5 consecutive days and observed for 35 days. After 35 days, qualified rabbits were selected according to their body weight. Among them, 18 rabbits were in the blank group and 162 rabbits were in the model group. Furthermore, the rabbits in the model group were randomly divided into 18 rabbits in the model control group, 18 rabbits in the high-dose D3 group, 18 rabbits in the low-dose D3 group, 18 rabbits in the high-dose compound 3B group, 18 rabbits in the low-dose compound 3B group, 18 rabbits in the high-dose composition 3 group, 18 rabbits in the low-dose composition 3 group, 18 rabbits in the high-dose injection powder of composition 3 group, and 18 rabbits in the low-dose injection powder of composition 3 group. The blank group and the model group were intravenously drip-injected with physiological saline in the same volume at 30 drops per minute for about 2 hours once a day, 5 days a week. The grouping and dosage are shown in Table 5. After administration on the last day of the first week, the second week, and the fourth week, the urine of the planned rabbits from 0 to 6 hours and 7 to 24 hours was collected respectively, and the cadmium content in the blood, urine, and kidneys was measured. The cadmium removal rates of cadmium in the blood cadmium and kidney cadmium were calculated, and the results are shown in Table 6. Table 5 Grouping and Dosage of New Zealand Rabbits in Example 18 JPEG2025516821000080.jpg61166 Table 6 Cadmium Removal Rates of Blood Cadmium and Kidney Cadmium in Rabbit Models with Different Dosage Forms of GMDTC Composition ( JPEG2025516821000081.jpg55±s) JPEG2025516821000082.jpg223169

[0072] In this table and the following tables, * indicates p < 0.05 compared with the model group at the same treatment time, and ** indicates p < 0.01 compared with the model group at the same treatment time. As can be seen from the measurement results of the cadmium content in the kidneys, compared with the model group with the same treatment time, in the case of administration in the first week, the D3 low-dose, D3 high-dose, composition 3 low-dose group, composition 3 high-dose group, composition 3 formulation low-dose group, and composition formulation 3 high-dose group all showed a significant decrease in the cadmium content in the kidneys compared with the model group, with a statistically significant difference. The cadmium removal rates in the kidneys of the high-dose groups of D3, the composition, and the composition formulation were 47.8%, 49.4%, and 51.4% respectively. In the case of administration in the second week, the cadmium removal rates in the kidneys were 77.0%, 77.6%, and 78.8% respectively. In the case of administration in the fourth week, the cadmium removal rates in the kidneys of each group were 91.7%, 94.0%, and 95.1%. Although the dosages of the composition and the composition formulation were 1 / 4 of the dosage of compound D3 in Chinese Patent CN200510035377.1, the cadmium removal rates were equivalent. On the other hand, there was no significant difference between compound 3B and the model group, indicating that compound 3B has no cadmium removal effect. When D3, the composition, and the composition formulation were administered at the same dosage of 108 mg / kg, the cadmium removal rates of the composition and the composition formulation after 4 weeks were significantly higher than that of compound D3. In addition, the urinary β 2 -microglobulin data of the D3 low-dose group, D3 high-dose group, compound 3B low-dose group, compound 3B high-dose group, composition 3 low-dose group, composition 3 high-dose group, composition 3 formulation low-dose group, and composition 3 formulation high-dose group after an additional 4-week administration were also measured and are shown in Table 7. Table 7 Urinary β 2 -microglobulin values ( JPEG2025516821000083.jpg55±s) JPEG2025516821000084.jpg80128 From the measurement results of β 2 -microglobulin, a kidney injury marker, in the high-dose groups of composition 3 and composition 3 formulation, both were able to effectively reduce the β 2 -microglobulin content, suggesting that the kidney injury was repaired. Therefore, Composition 3 and the formulation of Composition 3 can reduce the dosage of the drug without affecting the therapeutic effect, thereby reducing the drug exposure in the human body, reducing the risk of drug use, and being able to repair kidney damage. In addition, the reduction of the drug dosage can effectively reduce the drug use cost and also reduce the burden on patients.

[0073] Example 19 This example examined the cadmium removal effect of the oral formulation of Composition 3. According to the manufacturing methods of Examples 10, 11, and 13, a predetermined number of oral formulations were manufactured, and their cadmium removal effects were measured through animal experiments. Forty-eight male New Zealand rabbits were used and randomly divided into a blank control group of 6 rabbits and a chronic cadmium poisoning model group of 42 rabbits. For the rabbits in the model group, a mixed solution containing CdCl at 1.5 μmol / kg body weight and 30 μmol / kg body weight of mercaptoethanol (ME) was injected once a day for 5 consecutive days through the auricular vein, and they were observed for 35 days. After successful model establishment, the rabbits in the model group were randomly divided into a model control group 2 of [number of rabbits], high-dose and low-dose groups of 6 rabbits each for enteric-coated granules, enteric-coated capsules, and enteric-coated sustained-release capsules. The enteric-coated granules, enteric-coated capsules, and enteric-coated sustained-release capsules were administered continuously at low doses of 300 mg / day and high doses of 900 mg / day for 14 days. When the high-dose enteric-coated granules, enteric-coated capsules, and enteric-coated sustained-release capsules were administered for 2 weeks, the results were 45.0% respectively, 6 and 45.3% and 57.3% as shown in Table 8. Table 8 Cadmium removal rate in the kidneys after 14 consecutive days of oral administration of the oral formulation ( JPEG2025516821000085.jpg55±s) JPEG2025516821000086.jpg45169 As can be seen from Table 8, each oral formulation of Composition 3 has a certain cadmium removal effect, and the effect of the sustained-release capsule is superior to that of the enteric-coated granules and enteric-coated capsules. From this, it is clear that the longer the action time of the drug, the better the cadmium removal effect.

[0074] Example 20 This example examined the cadmium removal effect of the transdermal preparation of Composition 3 manufactured in Example 14. Twenty-four male New Zealand rabbits were used and randomly divided into a blank group of 6 rabbits and a model group of 18 rabbits. A mixed solution containing 1.5 μmol / kg body weight of CdCl 2 and 30 μmol / kg body weight of mercaptoethanol (ME) was injected once a day for 5 consecutive days, and the rabbits were observed for 49 days. After successful model establishment, the 18 rabbits in the model group were divided into a control group, a low-dose group, and a high-dose group, with 6 rabbits in each group. The hair on the abdomen of all rabbits was shaved. A transdermal preparation without Composition 3 (size 4 cm × 4 cm) was applied to the blank group and the control group, a transdermal preparation of Composition 3 (size 4 cm × 4 cm) was applied to the low-dose group, and a transdermal preparation of Composition 3 (size 8 cm × 8 cm) was applied to the high-dose group. Each was replaced once in the morning and evening every day and continuously administered for 28 days. Urine was collected on the 28th day, and urinary cadmium and β 2 -microglobulin were measured. Furthermore, the rabbits were euthanized on the 29th day, the kidneys were excised, and cadmium in the kidneys was measured. The results are shown in Table 9. Table 9 Therapeutic effect after continuous administration of the transdermal preparation of Composition 3 for 28 days ( JPEG2025516821000087.jpg55±s) JPEG2025516821000088.jpg34169As can be seen from Table 9, in the high-dose group and the low-dose group of the transdermal preparation of Composition 3, a significant increase in urinary cadmium and a significant decrease in renal cadmium were observed compared with the model group. From this, it was revealed that the transdermal preparation of Composition 3 has an obvious cadmium removal effect, and this effect shows a dose-dependent relationship. And in the high-dose group, a significant decrease in β 2 -microglobulin was observed compared with the model group, indicating that kidney damage had recovered.

[0075] Example 21 This example examined the therapeutic effect of the injection powder of Composition 3 (simply referred to as the Composition 3 preparation) manufactured in Example 7 on mercury poisoning. Thirty rabbits, half male and half female, weighing 1.5 - 2.0 kg, were subcutaneously injected with 1% mercury chloride at a dose of 0.8 mL per rabbit daily for three consecutive days. As a result, β 2 -microglobulin increased significantly, suggesting the formation of kidney injury symptoms, and the model establishment was successful. After successful model establishment, there were 6 rabbits in the blank group and 24 rabbits in the model group. The rabbits in the model group were randomly divided into 6 rabbits in the model control group, 6 rabbits in the low-dose group of 3 formulations of the composition, 6 rabbits in the medium-dose group of 3 formulations of the composition, and 6 rabbits in the high-dose group of 3 formulations of the composition. In the blank group and the model group, physiological saline was used for intravenous drip injection, and in the drug administration groups, physiological saline solutions of the corresponding drugs were administered. The dosage of each group was the same volume, the drip rate was 30 drops / minute, the drip time was about 2 hours, once a day, 5 days a week, and the administration was carried out for a total of 4 weeks. The group division and dosage are shown in Table 10. Blood and urine were collected on day 0, day 1, day 5, day 12, day 19, and day 26 respectively, the mercury concentration in blood and the mercury concentration in urine were measured, the mercury content in urine was calculated, and β 2 -microglobulin in urine was measured. The mercury concentration in blood is shown in Table 11, the mercury content in urine is shown in Table 12, and β 2 -microglobulin in urine is shown in Table 13. Table 10 Group division and dosage of New Zealand rabbits in Example 21 JPEG2025516821000089.jpg50164 Table 11 Measurement results of mercury concentration in blood of different groups (ng / ml)( JPEG2025516821000090.jpg55±s) JPEG2025516821000091.jpg55165 Table 12 Measurement results of total 24-hour urine mercury volume of different groups (ng)( JPEG2025516821000092.jpg55±s) JPEG2025516821000093.jpg54167 Table 13 β 2 -microglobulin values in urine of different groups after 4-week administration( JPEG2025516821000094.jpg55±s) JPEG2025516821000095.jpg43128As can be seen from the above experimental results, compared with the model group, the medium-dose group and the high-dose group had significantly lower blood mercury concentrations and significantly increased urinary mercury excretion. From this, it was revealed that the composition 3 preparation can increase mercury excretion. Also, β 2 -Since the microglobulin content was significantly decreased, it was clarified that the composition 3 preparation can treat kidney damage caused by mercury.

[0076] Example 22 In this example, the therapeutic effect of the injection powder of composition 3 (simply referred to as the composition 3 preparation) produced in Example 7 on lead poisoning was examined. Thirty SD rats weighing 180 - 200 g were used. The control group was allowed to freely ingest deionized water containing 12.5 μL of acetic acid for 3 weeks, and the lead poisoning group was allowed to freely ingest an aqueous solution of lead acetate (containing 12.5 μL / L of acetic acid) at 2.5 g / L for 3 weeks to induce experimental lead poisoning in the rats. The lead content in the whole blood of the control group rats was (35.16 ± 0.78) μg / L. When the rats were poisoned for 3 weeks, the blood lead content was (2459.12 ± 38.27) μg / L (P < 0.01), indicating that the lead absorbed by the intestinal tract caused lead poisoning in the rats. After successful model preparation, 6 rats were selected for the blank group and 30 rats for the model group. All groups were administered drugs once a day, 5 days a week, for a total of 4 weeks. The blank group and the model group were given intravenous drip injections using physiological saline, and the drug administration group was given an aqueous solution of the corresponding drug in physiological saline. The dosage of each group was the same volume, with a drip rate of 30 drops / minute, a drip time of about 1 hour, once a day, 5 days a week. The grouping and dosage of the SD rats in Example 22 are shown in Table 14. Twenty-four hours after the final day of administration, the rats were euthanized, and blood, kidneys, brains, and livers were taken, and the lead contents of these organs were measured by ICP-MS. The measurement results are shown in Table 15. Also, the concentrations of calcium, magnesium, iron, copper, and zinc in the blood were measured, and the measurement results are shown in Table 16. Table 14 Grouping and Dosage of SD Rats in Example 22 JPEG2025516821000096.jpg61152Table 15 Lead content in blood and organs of different groups( JPEG2025516821000097.jpg55±s) JPEG2025516821000098.jpg64166JPEG2025516821000099.jpg44 showed p<0.05 compared with the EDTA group with the same treatment time, JPEG2025516821000100.jpg48 showed p<0.01 compared with the EDTA group with the same treatment time. Table 16 Concentrations of calcium, magnesium, iron, copper, and zinc in blood of different groups( JPEG2025516821000101.jpg55±s) JPEG2025516821000102.jpg70165JPEG2025516821000103.jpg44 showed p<0.05 compared with the blank group with the same treatment time, JPEG2025516821000104.jpg48 showed p<0.01 compared with the blank group with the same treatment time. As can be seen from the above experimental results, compared with the model group, the medium-dose group and high-dose group of EDTA and Formulation 3 of the composition had a significantly decreased blood lead concentration. Therefore, it was clearly shown that both EDTA and Formulation 3 of the composition could decrease the blood lead content. However, the high-dose group of Formulation 3 of the composition was significantly superior to EDTA. Compared with the model group and the EDTA group, the lead in the kidneys of the medium-dose group and high-dose group of Formulation 3 of the composition was significantly decreased, and it was clearly shown that Formulation 3 of the composition could increase the excretion of lead in the kidneys. Also, at this dose, there was no significant difference between the treatment group of Formulation 3 of the composition and the blank group and the model group. It was clearly shown that Formulation 3 of the composition had no effect on calcium, magnesium, iron, copper, and zinc in the blood at this experimental dose.

[0077] Example 23 In this example, the therapeutic effect of the injectable powder of Composition 3 (simply referred to as Formulation 3 of the composition) produced in Example 7 on arsenic poisoning was examined. Sixty Wistar rats weighing 180 - 200 g were used. In the blank group, deionized water was freely available for drinking for 3 months. In the arsenic poisoning group, an aqueous solution of 100 mg / L As 2 O 3 was freely available for drinking. Here, about 20 ml was consumed daily, corresponding to an oral dose of 10 mg / kg. As a result of continuous feeding for 3 months, drinking water-type arsenic poisoning was induced in the rats. After successful model establishment, 10 rats in the blank group and 50 rats in the model group were selected. All groups were administered drugs once a day, 5 days / week, for a total of 4 weeks. In the blank group and the model group, physiological saline was used for intravenous drip injection. In the drug administration group, an aqueous solution of the corresponding drug in physiological saline was administered. The dosage of each group was the same volume, the drip rate was 30 drops / min, the drip time was about 1 hour, once a day, 5 days / week, for a total of 4 weeks. The grouping and dosage of Wistar rats are shown in Table 17. Urine was collected on the 1st and 26th days, and the arsenic excretion was measured. After 24 hours on the 26th day of administration, the blood and kidneys of the rats were taken, and the concentrations of arsenic in the blood and kidneys were measured by ICP-MS. The results are shown in Table 18. Table 17 Grouping and Dosage of Wistar Rats in Example 23 JPEG2025516821000105.jpg59164 Table 18 Concentrations of Arsenic in Blood and Kidneys and Arsenic Content in Urine of Different Groups ( JPEG2025516821000106.jpg55±s) JPEG2025516821000107.jpg67164 As can be seen from the above experimental results, compared with the model group, both the medium-dose group and the high-dose group of Composition 3 formulation can significantly reduce the concentrations of arsenic in the blood and kidneys. Since the arsenic content in urine on the 1st day increased significantly, it was clarified that the Composition 3 formulation has an obvious promoting effect on arsenic excretion.

[0078] Example 24 In this example, the therapeutic effect of the injection powder of Composition 3 (simply referred to as Composition 3 formulation) produced in Example 7 on thallium poisoning was examined. Sixty Wistar rats weighing 180 - 200 g were used. In the blank group, deionized water was freely available for drinking for one month. In the thallium poisoning group, an aqueous solution of 40 mg / L Tl 2 SO 4 was freely available for drinking, with approximately 20 ml consumed daily, corresponding to an oral dose of 4 mg / kg. The rats were continuously fed for one month, inducing drinking water-type thallium poisoning in the rats. After successful model establishment, 10 rats in the blank group and 50 rats in the model group were selected, and the group division and dosage are shown in Table 19. All groups were administered drugs once a day, 5 days / week, for a total of 4 weeks. In the blank group and the model group, physiological saline was used for intravenous drip injection, and in the drug administration groups, physiological saline solutions of the corresponding drugs were administered. The dosage of each group had the same volume, with a drip rate of 30 drops / minute, a drip time of approximately 1 hour, once a day, 5 days / week, for a total of 4 weeks. Twenty-four hours after the final day of administration, the rats were euthanized, and blood, kidneys, brains, and livers were taken. The thallium content in these organs was measured by ICP-MS, and the measurement results are shown in Table 20. Table 19 Group division and dosage of Wistar rats in Example 24 JPEG2025516821000108.jpg59162 Table 20 Thallium content in blood and organs of different groups ( JPEG2025516821000109.jpg55±s) JPEG2025516821000110.jpg67164 As can be seen from the above experimental results, compared with the model group, both the medium-dose group and the high-dose group of Composition 3 formulation can significantly reduce the concentrations of thallium in blood, kidneys, and livers. On the other hand, EDTA did not reduce the concentrations of thallium in kidneys and livers. From this, it was clearly shown that the Composition 3 formulation has an obvious promoting effect on thallium excretion.

[0079] Example 25 This example examined the therapeutic effect of the injection powder of Composition 3 (simply referred to as the Composition 3 formulation) produced in Example 7 on copper poisoning. Thirty SD rats weighing 80 - 100 g were used and divided into three groups: A, B, and C. Group A was the blank group, allowed free access to food and water. Groups B and C were copper poisoning groups, with 1.60 g / kg of CuSO 4 added to the feed. They were allowed free access to food and water daily in an SPF environment and continuously raised for two months to establish a copper poisoning model in the rats. After successful model establishment, the whole group was administered drugs once a day, 5 days a week, for a total of 4 weeks. Here, groups A and B were administered by intraperitoneal injection using physiological saline, and group C was administered by intraperitoneal injection with a physiological saline solution of 433 mg / kg of the composition 3 preparation. The dosage of each group was the same volume, administered once a day for 5 days. Urine was collected 24 hours after each daily administration, and the concentration of copper in the urine was measured by ICP - MS, and the excretion amount was calculated, as shown in Figure 2. As can be seen from Figure 2, the composition 3 preparation can significantly increase the excretion of copper ions at a dosage of 433 mg / kg.

[0080] Example 26 This example examined the therapeutic effect of the injection powder of composition 3 (simply referred to as the composition 3 preparation) produced in Example 7 on chromium, cobalt, nickel, and manganese mixed poisoning. Forty New Zealand rabbits weighing 1.5 - 2.0 kg were used. Physiological saline was injected into the auricular vein of the blank group for 5 days, and a mixed solution of 5 mg / ml of CrCl 3 , 3 mg / ml of C℃l 2 , 1 mg / ml of NiCl 2 , and 2 mg / ml of MnCl 2 was injected into the auricular vein of the poisoning group at a dosage of 2 ml / kg and continuously administered for 5 days. After observing for 25 days, a chromium, cobalt, nickel, and manganese mixed poisoning model of New Zealand rabbits was established. After successful model preparation, 8 rabbits in the blank group and 24 rabbits in the model group were selected. All groups were administered drugs once a day for a total of 3 days. Here, physiological saline was used for intravenous drip injection in the blank group and the model group, and a physiological saline solution of the corresponding drug was administered to the drug administration group. The dosage of each group was set to the same volume, with a drip rate of 30 drops / minute, a drip time of approximately 2 hours, once a day, for a total of 3 days. The grouping and dosage of New Zealand rabbits are shown in Table 21. Urine was collected for 24 hours every day for a total of 3 days, and the total amounts of chromium, cobalt, nickel, and manganese excreted in the urine over 3 days were calculated and shown in Table 22. Table 21 Grouping and Dosage of New Zealand Rabbits in Example 26 JPEG2025516821000111.jpg44152 Table 22 Total Amounts of Chromium, Cobalt, Nickel, and Manganese Excreted in the Urine of New Zealand Rabbits during 3-Day Treatment ( JPEG2025516821000112.jpg55±s) JPEG2025516821000113.jpg62166 JPEG2025516821000114.jpg44 showed p<0.05 compared with the EDTA group with the same treatment time, JPEG2025516821000115.jpg48 showed p<0.01 compared with the EDTA group with the same treatment time. As can be seen from the above experimental results, compared with the model group and the EDTA group, the total amounts of chromium, cobalt, nickel, and manganese excreted in the urine in the Composition 3 formulation group were all significantly increased. It was found that the Composition 3 formulation had a promoting effect on the excretion of chromium, cobalt, nickel, and manganese and was superior to EDTA.

[0081] Example 27 This example examined the tin removal effect of the injection powder of Composition 3 (simply referred to as the Composition 3 formulation) produced in Example 7 and its protective effect against oxidative damage caused by tin-based compounds. Thirty-six ICR mice were randomly divided into three groups of 12 each. The control group was intraperitoneally injected with physiological saline, and the model group and the drug administration group were intraperitoneally injected with 0.5 mg / kg of trimethyltin chloride to induce poisoning. Three days after poisoning, the control group and the model group were intraperitoneally injected with physiological saline, and the drug administration group was intraperitoneally injected with a physiological saline solution of 252.2 mg / kg of the composition 3 formulation for 3 days. Urine was collected for three days, and the total amount of tin in the urine was measured. After three days, the mice were euthanized, the livers of the mice were removed and stored in liquid nitrogen, and the contents of reactive oxygen species (ROS) and malondialdehyde (MDA) were measured. The measurement results are shown in Table 23. Table 23 Urinary tin content, (ROS) and (MDA) content of mice in different groups JPEG2025516821000116.jpg55±s) As can be seen from the above experimental results, compared with the model group, the treatment group had a significantly increased excretion of tin in the urine, indicating that the composition 3 formulation could effectively promote the excretion of tin. In addition, ROS and MDA were significantly decreased, indicating that the oxidative stress response in the body was restored. Therefore, it was revealed that the composition 3 formulation had a promoting effect on the excretion of tin and further had a protective effect against oxidative damage caused by tin-based compounds.

[0082] Example 28 In this example, the free radical scavenging effect of the injection powder of composition 3 (simply referred to as composition 3 formulation) prepared in Example 7 was investigated. Forty Wistar rats, weighing 200 - 230 g and evenly divided between males and females, were used. They were placed in a clean - grade animal room, weighed, numbered, and randomly divided into groups A, B, C, and D. To establish an aging model, for groups B, C, and D, D - galactose was prepared into an injection solution with a concentration of 5% in physiological saline and subcutaneously injected into the abdomen of the rats at a dose of 500 mg / (kg·d). Group A was the blank group, and the same dose of physiological saline was injected into the abdomen of the rats. The injection was continuously carried out for 56 days. On the first day after successful model establishment, the composition 3 preparations at 108 mg / kg and 216 mg / kg were intraperitoneally administered to groups C and D respectively, and 10 mL / kg of physiological saline was administered to groups A and B. The rats were allowed to freely ingest food and water for 30 consecutive days. Eight hours after the final administration, 3% sodium pentobarbital was intraperitoneally injected for anesthesia, the abdomen was exposed, blood was collected from the inferior vena cava, and after centrifugation, the supernatant was used as the test serum, and the serum hydroxyl radical (OH - ·) removal rate, superoxide dismutase (SOD), glutathione peroxidase (GSH - PX), and malondialdehyde (MDA) were measured, and the results are shown in Table 24. Table 24 Contents of (OH - ·) removal rate, SOD, GSH - PX, and MDA in rats of different groups ( JPEG2025516821000118.jpg55 ± s) JPEG2025516821000119.jpg52164 As can be seen from the above experimental results, compared with the model group B, in the treatment groups, the activities of both SOD and GSH - PX were significantly improved, the content of MDA was obvious, indicating that the composition 3 preparation has an obvious removal effect on free radicals in the body.

[0083] Example 29 This example examined the removal effect of the injection powder of composition 3 (simply referred to as composition 3 preparation) prepared in Example 7 on bismuth. Forty Wistar rats weighing 180 - 200 g were used. The rats in the blank group were allowed to freely ingest deionized water for one month, and the rats in the bismuth poisoning group were allowed to freely ingest an aqueous solution of potassium bismuth citrate at a concentration of 100 mg / L. They were continuously fed at approximately 20 ml per day for three months to induce bismuth poisoning in the rats. After successful model establishment, 10 rats in the blank group and 30 rats in the model group were selected. The 30 rats in the model group were divided into a control group, a low-dose group, and a high-dose group, with 10 rats in each group. Each group was administered once a day for 5 consecutive days. The blank group and the control group were intraperitoneally injected with physiological saline. The low-dose group in the drug administration group was administered an aqueous solution of 3 preparations of the composition at a dose of 27 mg / kg in physiological saline, and the High high-dose group in the drug administration group was administered an aqueous solution of 3 preparations of the composition at a dose of 108 mg / kg in physiological saline. The administration volume of each group was the same, and they were administered by intraperitoneal injection once a day, 5 days a week. The urine was collected daily to measure the bismuth concentration, and the amount of bismuth excreted daily was calculated. The results are shown in Figure 3. As can be seen from Figure 3, compared with the control group, both the high-dose group and the low-dose group of the 3 preparations of the composition could significantly improve the excretion of urinary bismuth, and a dose-response relationship was shown.

[0084] Example 30 In this example, the reducing effect of the injection powder of Composition 3 (simply referred to as Composition 3 preparation) produced in Example 7 on cisplatin-induced ototoxicity was investigated. Sixty SPF-class NIH mice were used. After a 3-day quarantine, they were randomly divided into 6 groups, and the grouping and administration status are shown in Table 25. The administration volume of each group was the same, and they were administered by intraperitoneal injection once a day, 5 days a week, for a total of 2 weeks. The administration time is shown in Table 26. Before and after intraperitoneal injection into the mice, an auditory brainstem response (ABR) test was performed using the auditory evoked potential diagnostic system "Intelligent EP" to evaluate the auditory function. Table 25 Grouping and Administration Dosage Status of NIH Mice in Example 30 JPEG2025516821000120.jpg59166 Table 26 Administration Time Table of Mice in Different Groups in Example 30 JPEG2025516821000121.jpg 51164 Before administration and after 12 days of completed administration, mice were anesthetized by intraperitoneal injection of ketamine (90 mg / kg), and tests were conducted in a controlled acoustic chamber. At this time, the grounding electrode was placed on the posterior side, the positive electrode was directly inserted between the two ears at the top of the skull, the negative electrode was placed under the auricle, and a high-frequency probe was used to decrease the sound stimulus intensity from 80 dB SPL by 5 dB each at frequencies of 8, 16, and 32 KHz. The difference in reaction thresholds at the same stimulus frequencies before and after administration was recorded as the ABR threshold shift. The results are shown in Figure 4. As can be seen from Figure 4, there was no significant difference between the Composition 3 formulation group and the blank group, indicating that the Composition 3 formulation itself does not cause ototoxicity. There was a significant difference between the combined treatment group and the cisplatin group. As is clear from this, the combined treatment group could significantly reduce the ototoxicity caused by cisplatin and showed an obvious dose-dependence.

[0085] Example 31 This example examined the toxicity-reducing effect of Composition 3 produced in Example 1 against cisplatin. Forty SPF-grade New Zealand rabbits aged 4 - 8 weeks and weighing 1.8 - 2.2 kg were selected, fed a standard diet, allowed to drink water freely, and randomly divided into four groups: A, B, C, and D. Group A was the blank group and was injected with 0.9% sodium chloride injection into the ear vein. Group B was the cisplatin group and was injected with 4 mg / kg cisplatin injection into the ear vein twice a week, and physiological saline was injected on the remaining three days. Group C was the cisplatin-D3 group and was injected with 4 mg / kg cisplatin injection into the ear vein twice a week, and 433 mg / kg of D3 was drip-injected into the ear vein every day. Group D was the cisplatin-Composition 3 group and was injected with 4 mg / kg cisplatin injection into the ear vein twice a week, and 433 mg / kg of Composition 3 was drip-injected into the ear vein five times a week. All New Zealand rabbits were administered for 3 weeks, 5 days a week, and the behavioral activities of the rabbits were observed. The grouping and dosage are shown in Table 27, and the administration schedule is shown in Table 28. Table 27 Grouping and Dosage Status of Example 31 JPEG2025516821000122.jpg44164Table 28 Administration Schedule of Example 31 JPEG2025516821000123.jpg39163Experimental Results: In Group B, weight loss, hair loss, and loose stools were observed after 1 week. All rabbits had a weight loss of more than 20% during the 2-week period, became significantly thinner, and showed lethargy, hair loss, loose stools, bleeding from the nose and mouth, weak breathing, reached the humane endpoint, and were euthanized. In Group C, weight loss, hair loss, loose stools, bleeding from the nose and mouth were observed after 1 week. All rabbits had a weight loss of more than 20% between the 2nd and 3rd weeks, became significantly thinner, showed lethargy, weak breathing, reached the humane endpoint, and were euthanized. In Group D, when administered for 3 weeks, the body weight decreased by 5% - 15%, became slightly thinner, and after the administration was stopped, the body weight began to recover. The above experimental results showed that at the same dosage, the toxicity-reducing effect of Composition 3 on cisplatin was superior to that of D3.

[0086] Example 32 This example examined the reduction of the side effects of radioactive elements on the pancreatic cancer model of nude mice by the Composition 3 produced in Example 1. Four-week-old nude mice with a pancreatic cancer model weighing 16 - 20 g were selected, anesthetized, divided into 4 groups, and observed for 14 days. The tumor size was measured, and they were randomly divided into 5 groups, namely A, B, C, D, and E, according to the tumor size and body weight. Group A was allowed to eat and drink freely. Iodine-125 was transplanted into Groups B and C, and Palladium-103 was transplanted into Groups D and E. Groups B and D were continuously administered 108 mg / kg of Composition 3 daily for 14 days, and the tumor size was measured on the 0th, 7th, and 14th days, as shown in Table 29. Urine and blood were collected on the 14th day, and the radiation intensity was measured using a liquid scintillation counter. Liquid Scintillation Counter Results: Compared with Group C, Group B had a lower blood radiation intensity than Group C, p < 0.05. Regarding urine radioactivity, Group B had a higher radiation intensity than Group C. Compared with Group E, Group E had a lower blood radiation intensity than Group D, p < 0.05. Regarding urine radioactivity, Group E had a higher radiation intensity than Group D. Table 29 Size of Nude Mouse Tumor Volume cm 3 (x±s) As can be seen from the above results, the use of Composition 3 did not affect the antitumor effects of iodine-125 and palladium-103. And Composition 3 can form a complex with iodine-125 and palladium-103 and can be excreted from the body.

[0087] Example 33 This example examined the excretion effect of Composition 3 prepared in Example 1 on Tc. Sixteen New Zealand rabbits weighing 1.5 - 2.0 kg were used and divided into two groups, Group A and Group B. In Group A, sodium pertechnetate [99mTc] injection was administered by intravenous bolus, and after 3 hours, physiological saline was administered. In Group B, sodium pertechnetate [99mTc] injection was administered by intravenous bolus, and after 3 hours, 433 mg / kg of Composition 3 was administered. The dosage of each group was made the same volume, the drip rate was 15 drops / min, and the drip time each time was about 3 hours. The urine in the first 12 hours was collected, the Tc concentration in the urine was measured by ICP-MS, and the total excretion amount of Tc was calculated. Experimental results: The amount of technetium excreted by urine in Group A was 42.3% of the injection dosage, and the amount of technetium excreted by urine in Group B was 74.5% of the injection dosage. From this, it is shown that the use of Composition 3 can significantly increase the excretion of technetium, and compared with Group A, the amount of technetium excreted by urine increased by 76.1%.

[0088] Example 34 This example examined the therapeutic effect of an antitumor drug consisting of the injection powder of Composition 3 (simply referred to as Composition 3 preparation) prepared in Example 7 and cisplatin on a rabbit VX2 liver tumor model. SPF - level New Zealand rabbits aged 4 - 8 weeks and weighing 1.8 - 2.2 kg were selected, fed a standard diet, allowed to drink water freely, and raised under a 12 - hour light - dark cycle, with the temperature maintained at (23 ± 2) °C and the humidity at (55 ± 15)%. The animals were anesthetized, and under ultrasonic guidance, VX2 liver cancer cells were minimally invasively introduced into the liver. After observing the New Zealand rabbits for 14 days, the tumor size was observed by ultrasonic examination. Then, according to the tumor size and body weight, the rabbits were randomly divided into 4 groups of 10 each, and drug treatment was started on the 15th day. The control group was injected with 0.9% sodium chloride injection into the ear vein. The cisplatin treatment group was injected with 4 mg / kg of cisplatin into the ear vein once a week. Treatment group A (in the drug composition, cisplatin: formulation of composition 3 = 1:20) was injected with 4 mg / kg of cisplatin once a week. Two hours after injecting cisplatin into the ear vein, 60 mg / kg of the formulation of composition 3 was injected. Treatment group B (in the drug composition, cisplatin: formulation of composition = 1:100) was injected with 4 mg / kg of cisplatin once a week. Two hours after injecting cisplatin into the ear vein, 400 mg / kg of the formulation of composition 3 was injected. All New Zealand rabbits were treated for 4 weeks. V = π(a×b 2 ) / 6. Here, a and b are the longest and shortest diameters of the tumor measured using calipers. During the experimental period, the body weight of the New Zealand rabbits was monitored every 3 - 4 days. At the end of the treatment, the New Zealand rabbits were euthanized, blood was collected, and AST, ALT, and CREA were measured. The results are shown in Table 30. After anesthetizing the rabbits with 0.1 ml / kg of each of terazol 50 and xylazine, as the final treatment, blood was released from the carotid artery. Also, immediately after euthanasia, the tumors were removed, and the volumes were recorded as shown in Figure 5. Table 30 Measured values of AST, ALT, and CREA of rabbits in different groups (x ± s) As can be seen from the above experimental results, there is no obvious difference in the inhibitory effect on tumors between cisplatin and the anti-tumor drug composed of Composition 3 formulation and cisplatin. Both can effectively inhibit the proliferation of tumor cells and kill tumor cells. Compared with the single use of cisplatin, the combined drug group can significantly reduce the liver toxicity and kidney toxicity caused by cisplatin. For this anti-tumor drug, the reduction of liver toxicity and kidney toxicity caused by cisplatin in Treatment Group B is superior to that in Treatment Group A.

[0089] Example 35 In this example, the inhibitory effect on tumors of an anti-tumor drug composed of the injection powder of Composition 3 (simply referred to as Composition 3 formulation) manufactured in Example 7 and PENAO (the structural formula is as follows) was examined. JPEG2025516821000126.jpg2050PENAO Here, the anti-tumor drug in Group A is PENAO:Composition 3 formulation = 1:20, the anti-tumor drug in Group B is PENAO:Composition 3 formulation = 1:50, the anti-tumor drug in Group C is PENAO:Composition 3 formulation = 1:125, and the anti-tumor drug in Group D is PENAO:Composition 3 formulation = 1:312. U87 malignant glioma cells were taken, and the IC 50 of PENAO, Composition 3 formulation, and the anti-tumor drug combined with PENAO and Composition 3 was measured. Here, the initial drug concentrations used in different groups were the same. The results are shown in Figure 6. As can be seen from Figure 6, Composition 3 formulation has no obvious inhibitory effect on U87 malignant glioma cells, PENAO shows an obvious inhibitory effect on U87 malignant glioma cells, and the anti-tumor drug combined with PENAO and Composition 3 has an obviously enhanced inhibitory effect on glioma cells, which is superior to the single use of PENAO.

[0090] Example 36 In this example, the cadmium removal effects of Compositions 1 - 11 were examined. 150 male New Zealand rabbits weighing 1.8 - 2.2 kg per rabbit were randomly divided into a blank control group of 15 rabbits and a chronic cadmium poisoning model group of 135 rabbits. A mixed solution containing 1.5 μmol / kg body weight of CdCl 2 and 30 μmol / kg body weight of mercaptoethanol (ME) was injected once a day for 5 consecutive days into the auricular veins of the model rabbits, and the rabbits were observed for 35 days. After 35 days, qualified rabbits were selected according to their body weights. Among them, 10 rabbits were in the blank group and 110 rabbits were in the model group. The model group rabbits were randomly divided into a model control group of 10 rabbits and each of the formulation groups of compositions 1 - 11 with 10 rabbits in each group. The blank group and the model group were intravenously drip - injected with physiological saline at the same volume, at a rate of 30 drops per minute, for a drip time of about 2 hours, once a day, 5 days a week, for a total of 2 weeks. In the drug - administration groups, the dosage was 0.25 mmol / kg, at a rate of 30 drops per minute, for a drip time of about 2 hours, once a day, 5 days a week, for a total of 2 weeks. After 2 weeks, the cadmium content in the kidneys was measured, and the results are shown in Table 31. Table 31 Removal ability of compositions 1 - 11 on cadmium in the kidneys at the same administration concentration As can be seen from the measurement results of the cadmium content in the kidneys in JPEG2025516821000127.jpg104165, when administered for 2 weeks, compared with the model group with the same treatment time, compositions 1 - 11 all showed good removal effects on cadmium in the rabbit kidneys, and composition 3 had a cadmium removal efficiency superior to that of the other 10 groups of compounds. Incidentally, (1) For example, conventional heavy metal removal agents such as EDTA-based complexing agents, dimercaprol, and sodium dimercaptopropanesulfonate are all unable to remove heavy metals in the kidneys, and the use of these drugs increases the burden on the kidneys. Therefore, although the cadmium removal rates in the kidneys of Compositions 1, 6, and 7 are significantly lower than those of other groups, the compositions of these groups still have clinical value. (2) The results of the drug effects shown in this example were completed under specific administration conditions for specific experimental animals. Although the cadmium removal rates in the kidneys of Compositions 1, 6, and 7 are significantly lower than those of other groups, the cadmium removal rate in the kidneys can be improved by extending the administration time or increasing the dosage, and the ability of the drug to remove cadmium in the kidneys may vary among different ethnic groups. (3) Compounds 1, 6, and 7 have good liposolubility, which is advantageous for absorption from the intestinal tract when formulated into oral preparations and is superior in terms of bioavailability.

[0091] Example 37 Compositions 1 to 11 and Compounds 1A to 11A were each left standing at -25°C, 5 ± 3°C, 25 ± 2°C / 60 ± 5% RH, 40 ± 2°C / 75 ± 5% RH, and 60°C for 0 d, 5 d, and 10 d (d stands for day), and the change in the content of the main component (taking the content of the main component at 0 d as 100%) was measured, and the results are shown in Table 32. Table 32 Time-dependent changes in the content of the main component of Compositions 1 to 11 and Compounds 1A to 11A under different conditions JPEG2025516821000128.jpg255164JPEG2025516821000129.jpg255164JPEG2025516821000130.jpg46164

[0092] For each temperature condition in Table 32, in the case of -25°C, the corresponding cold chain storage and transportation costs are extremely high; in the case of 5°C, the corresponding cold chain storage and transportation costs are relatively high; in the case of 25°C, the corresponding normal temperature storage and transportation costs are relatively low; for 40°C and 60°C, they are accelerated decomposition conditions for saving experimental time, and generally, storage and transportation are not carried out at such temperatures. As can be seen from the experimental results in Table 32, at 25°C, the stability of Compositions 1 to 11 after 5 days and 10 days is better than that of Compounds 1 to 11A, which indicates that at normal temperature, the stability of each composition within 10 days is better than that of the individual compound. Under accelerated conditions (40°C and 60°C), the stability of Compositions 1 to 11 after 5 days and 10 days is clearly better than that of Compounds 1 to 11A, suggesting that at normal temperature, the stability of each composition within a long time exceeding 10 days is better than that of the individual compound.

[0093] As described above, the embodiments of the present invention have been shown and explained. However, the above embodiments are illustrative, and it is not possible to understand the limitations of the present invention. Those skilled in the art can modify, correct, substitute, and transform the above embodiments within the scope of the present invention without departing from the principles and spirits of the present invention. The protection scope of the present invention is defined by the claims and their equivalents.

Claims

1. A heavy metal removal composition with high stability, comprising: (A) 70 to 95% by weight of a compound of formula (1) or a pharmaceutically acceptable salt thereof; (B) 1 to 25% by weight of a compound of formula (2) or a pharmaceutically acceptable salt thereof; (C) 0.001 to 5% by weight of a basic compound which is at least one of an alkali metal hydroxide, carbonate, bicarbonate, hydrogen phosphate, carboxylate or aqueous ammonia; wherein the compound of formula (1) and the compound of formula (2) are each selected from the following table Characterized in that it is a composition.

2. The compound of formula (1) is and the compound of formula (2) is Characterized in that it is a composition according to Claim 1.

3. The composition according to Claim 1, characterized in that the content of component (A) is 80 to 90% by weight and the content of component (B) is 1 to 12% by weight.

4. The composition according to Claim 1, characterized in that the ratio of the mass percentage of component (A) in the composition to the mass percentage of component (B) in the composition is in the range of 90:1 to 9:

1.

5. The composition according to Claim 4, characterized in that the ratio of the mass percentage of component (A) in the composition to the mass percentage of component (B) in the composition is in the range of 80:1 to 13:

1.

6. The composition according to Claim 1, characterized in that the basic compound is at least one of sodium hydroxide, potassium hydroxide, sodium acetate, aqueous ammonia, sodium carbonate, sodium bicarbonate, ammonium bicarbonate, potassium carbonate, potassium bicarbonate, dipotassium hydrogen phosphate, disodium hydrogen phosphate.

7. The composition according to Claim 1, characterized in that the pH value when 1 mg of the composition is dissolved in 1 mL of water is 9.0 to 11.

0.

8. Use of the composition according to any one of Claims 1 to 7 in the manufacture of a pharmaceutical or functional food for removing heavy metals or free radicals in the body, or in the manufacture of a pharmaceutical for preventing or treating related diseases caused by heavy metal excess and poisoning, wherein the heavy metal is at least one of chromium, cobalt, arsenic, tin, cadmium, mercury, manganese, nickel, copper, thallium, technetium, uranium, bismuth, lead, iodine, palladium and platinum.

9. ​ An antitumor drug comprising 1 part by weight of a heavy metal-containing antitumor drug and 5 to 200 parts by weight of the composition according to any one of claims 1 to 7.

10. The antitumor drug according to claim 9, wherein the heavy metal-containing antitumor drug is selected from the group consisting of platinum-based antitumor drugs, arsenic-based antitumor drugs, ruthenium-based antitumor drugs, and tin-based antitumor drugs.

11. The antitumor drug according to claim 9, wherein the heavy metal-containing antitumor drug is selected from the group consisting of cisplatin, oxaliplatin, arsenic trioxide, and iodine 125.

12. Use in the manufacture of a pharmaceutical for reducing the toxicity and side effects of a heavy metal-containing pharmaceutical of the composition according to any one of claims 1 to 7, wherein the heavy metal-containing pharmaceutical comprises at least one of cisplatin, carboplatin, oxaliplatin, nedaplatin, potassium bismuth citrate, colloidal pectin bismuth, technetium 99 dimethyl bisphosphonate, technetium 99mTc, arsenic trioxide, iodine 125, and palladium 103.

13. The use according to claim 12, wherein the heavy metal-containing pharmaceutical comprises at least one of cisplatin, potassium bismuth citrate, and technetium 99mTc.

14. Based on the total amount of the injectable powder, 60 to 90% by weight of the composition according to any one of claims 1 to 7, 9 to 40% by weight of an excipient, 0.001 to 10% by weight of a complexing agent, An injectable powder comprising.

15. The injectable powder according to claim 14, wherein the excipient is at least one selected from the group consisting of mannitol, aqueous ammonia, trehalose, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium acetate, ammonium acetate, and dipotassium hydrogen phosphate.

16. The injectable powder according to claim 15, wherein the excipient is at least one of mannitol and aqueous ammonia.

17. The injectable powder according to claim 15, wherein the excipient is aqueous ammonia, and in the injectable powder, ammonia is present as a complex or an ammonia adduct.

18. The chelating agent is at least one selected from the group consisting of ethylenediaminetetraacetate, dimercaprol, and sodium dimercaptosuccinate, and the powder for injection according to any one of claims 14 to 17 is characterized in that.

19. The chelating agent is ethylenediaminetetraacetate, and the powder for injection according to claim 18 is characterized in that.

20. Based on the total amount of the oral preparation, 35 to 65% by weight of the composition according to any one of claims 1 to 7, 20 to 40% by weight of a disintegrant, 0 to 5% by weight of a fluidizing agent, 0.1 to 5% by weight of a lubricant, 0 to 10% by weight of a film coating premix, 0.001 to 10% by weight of a chelating agent, An oral preparation, characterized by comprising.

21. The disintegrant is at least one selected from the group consisting of crystalline cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl starch, starch, and polyvinylpyrrolidone, the fluidizing agent is at least one selected from the group consisting of talc and colloidal silica, the lubricant is at least one selected from the group consisting of talc and magnesium stearate, and the chelating agent is at least one selected from the group consisting of ethylenediaminetetraacetate, dimercaprol, and sodium dimercaptosuccinate, and the oral preparation according to claim 20 is characterized in that.

22. The disintegrant is crystalline cellulose, the fluidizing agent is colloidal silica, the lubricant is magnesium stearate, and the chelating agent is ethylenediaminetetraacetate, and the oral preparation according to claim 21 is characterized in that.

23. The oral preparation is an enteric-coated tablet or an enteric capsule, and the oral preparation according to claim 22 is characterized in that.

24. The enteric-coated tablet is an enteric-coated sustained-release tablet, and the enteric capsule is an enteric-coated sustained-release capsule, and the oral preparation according to claim 23 is characterized in that.

25. Based on the total amount of the transdermal preparation, 20 to 65% by weight of the composition according to any one of claims 1 to 7, 0.5 to 30% by weight of a transdermal enhancer, 0.5 to 25% by weight of a gelling agent, 1 to 30% by weight of a solvent, A transdermal preparation, characterized by comprising.

26. The transdermal enhancer is at least one selected from the group consisting of laurocapram, borneol, oleic acid, and peppermint oil, the gelling agent is at least one selected from the group consisting of carbomer, sodium hydroxypropylcellulose, sodium ethylcellulose, magnesium stearate, glycerin, and polyethylene glycol, and the solvent is at least one selected from the group consisting of water, methanol, ethanol, and DMSO. The transdermal preparation according to claim 25, characterized in that.

27. A method for producing the composition according to any one of claims 1 to 7, characterized in that the production process is carried out in an atmosphere of an inert gas and includes the following steps. (1) Synthesis step of component (B): (1-1) A step of adding a basic compound, an amino acid, and glucose to a first solvent, dissolving them sufficiently, and reacting them. (1-2) A step of adding sodium borohydride to the reaction product of (1-1), reacting it, and subjecting it to acidification purification. (1-3) A step of adding a basic compound and the reaction product of (1-2) to a first solvent, dissolving them sufficiently, reacting them, and obtaining component (B) as the reaction product. (2) Synthesis step of component (A): (2-1) A step of dissolving a basic compound and the reaction product of (1-2) in water to obtain a first solution. (2-2) CS ２ Dissolving it in a second solvent to obtain a second solution; (2-3) A step of mixing the first solution and the second solution, filtering after the reaction, extracting with a third solvent, and freeze-drying the aqueous layer to obtain a product. Here, the mixing ratio of the first solution and the second solution is controlled so that the product becomes only component (A). The first solvent is at least one of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, and water, the second solvent is at least one of acetone, acetonitrile, tetrahydrofuran, dioxane, and DMF, and the third solvent is at least one of dichloromethane, ethyl acetate, propyl acetate, butyl acetate, and isopropyl acetate. (3) A step of mixing component (A), component (B), and a basic compound in a predetermined ratio to obtain a composition.

28. A method for producing the composition according to any one of claims 1 to 7, characterized in that the production process is carried out in an atmosphere of an inert gas and includes the following steps. (1) Synthesis step of component (B): (1-1) A step of adding a basic compound, an amino acid, and glucose to a first solvent, dissolving them sufficiently, and reacting them. A step of adding sodium borohydride to the reaction product of (1-2) (1-1), reacting it, and subjecting it to acid purification; A step of adding a basic compound and the reaction product of (1-2) to a first solvent, sufficiently dissolving and reacting them to obtain component (B) as a reaction product; (2) Composition synthesis step: A step of dissolving a basic compound and component (B) in water to obtain a first solution; (2-2) CS ２ Dissolving ２ in a second solvent to obtain a second solution, A step of mixing the first solution and the second solution, filtering after the reaction, extracting with a third solvent, and freeze-drying the aqueous layer to obtain a product; Here, the addition amount of the basic compound in (2-1) and the mixing ratio of the first solution and the second solution in (2-3) are controlled so that the product in (2-3) becomes a composition; The first solvent is at least one of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, and water, the second solvent is at least one of acetone, acetonitrile, tetrahydrofuran, dioxane, and DMF, and the third solvent is at least one of dichloromethane, ethyl acetate, propyl acetate, butyl acetate, and isopropyl acetate.

29. In step (2), the molar ratio of the basic compound to component (B) is from 1.05:1 to 1.5:1, and the molar ratio of CS ２ to component (B) is from 1.3:1 to 5:1, characterized in that the production method according to claim 28.

30. The molar ratio of the basic compound to component (B) is 1.05:1 to 1.3:1, and the molar ratio of CS ２ to component (B) is 1.8:1 to 3:

1. The production method according to claim 29, characterized by this.

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