Application of penicillamine trisulfide in preparation of products for heavy metal detoxification and metal metabolic diseases

Abstract

The invention provides an application of penicillamine trisulfide in preparation of a product for heavy metal detoxification and metal metabolic diseases, and relates to the field of medicines. The invention provides application of penicillamine trisulfide in preparation of products for heavy metal detoxification and metal metabolic diseases. The structural formula of the penicillamine trisulfide is shown in the specification. The new application of the penicillamine trisulfide is found, and the penicillamine trisulfide has a stronger detoxification effect on heavy metals than penicillamine through the complexing effect of the penicillamine trisulfide, and has a better curative effect on hepatolenticular degeneration. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the field of medical technology, and in particular to an application of penicillamine trisulfide in the preparation of products for heavy metal detoxification and metal metabolic diseases. Background Art

[0002] With the rapid development of modern industry, heavy metals are widely used in industry and agriculture. While people are enjoying a convenient life, the food and environmental pollution caused by human activities are also increasing. One of the most serious hazards is heavy metal pollution, which seriously endangers human health.

[0003] Most heavy metals (such as lead, mercury, copper, chromium, zinc, silver, etc.) and metalloids (such as arsenic, antimony, phosphorus, etc.) can combine with the sulfhydryl groups of various enzyme proteins in the body, thereby inhibiting the activity of these enzymes and hindering the normal metabolic function of cells. In addition to a series of inflammations caused by irritation of the digestive tract, livestock poisoning also causes liver and kidney damage and obvious neurological symptoms due to the absorption of poisons. Antidotes for metal and metalloid poisoning are mostly chelating agents containing sulfhydryl groups, which can combine with metal or metalloid ions to form cyclic complexes to form low-toxic or non-toxic soluble compounds that are excreted in urine.

[0004] Penicillamine is a derivative of penicillin, and its structural formula is shown below. Its chemical name is D-3-mercaptovaline. It is a commonly used heavy metal detoxifier. Due to the chemical properties of the amino and thiol functional groups in its structure: chelation of heavy metals, condensation ability with aldehydes, and exchange reaction with disulfides, D-penicillamine is used as a specific drug in the clinic to treat heavy metal poisoning, Wilson's disease, rheumatoid arthritis, chronic active hepatitis and other diseases.

[0005]

[0006] Wilson disease, also known as hepatolenticular degeneration (MIM277900), is an autosomal recessive copper metabolism disorder characterized by liver cirrhosis and basal ganglia damage caused by copper metabolism disorder. Its clinical features include varying degrees of liver cell damage, brain degeneration, and copper salt deposition rings at the edge of the cornea. This disease is also one of the few treatable neurogenetic diseases. The key is early detection, early diagnosis, and early treatment.

[0007] Penicillamine disulfide has been mentioned as a specific impurity for penicillamine-related substance detection. For example, Chinese patent CN108164444A provides a method for refining D-penicillamine, wherein the D-penicillamine to be refined is subjected to in-situ refining treatment under the coexistence of a reduction system containing a metal catalyst in an acidic system to obtain a corresponding reaction liquid; the metal in the metal catalyst is selected from metals and / or aluminum among transition elements; the insoluble matter is filtered out, and the pH value is adjusted to precipitate D-penicillamine to obtain refined D-penicillamine. The content of disulfide penicillamine impurities and sulfonic acid derivative impurities in D-penicillamine can be effectively reduced and removed, so that the content of both can be effectively controlled within 0.1%. However, penicillamine trisulfide is not mentioned.

[0008] The researchers of the present invention found that the content of penicillamine trisulfide in penicillamine is low, and the ultraviolet absorption is weak. It is not easy to detect with an ultraviolet detector, and an evaporative light detector is required for detection. Therefore, penicillamine trisulfide has not attracted attention or been mentioned. However, from the structural point of view, penicillamine trisulfide has a stronger complexing effect than penicillamine, and it is speculated that its activity is better than penicillamine. At present, there are no patent reports on the indications of penicillamine trisulfide and other related ones. Summary of the invention

[0009] In view of the above problems, the present invention provides an application of penicillamine trisulfide in the preparation of products for heavy metal detoxification and metal metabolic diseases.

[0010] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0011] In one aspect, the present invention provides a use of penicillamine trisulfide in the preparation of products for heavy metal detoxification and metal metabolic diseases.

[0012] Preferably, the structural formula of the penicillamine trisulfide is as follows:

[0013]

[0014] Preferably, the heavy metal comprises at least one of copper, zinc, iron, cobalt, nickel, manganese, thallium, magnesium, cadmium, mercury, tungsten, molybdenum, gold, silver, arsenic and lead.

[0015] Preferably, the product comprises at least one of food, medicine and nutrition. Further preferably, the product is medicine.

[0016] Preferably, the metal metabolism disease comprises at least one of copper metabolism disorder, iron metabolism disorder, magnesium metabolism disorder and manganese metabolism disorder.

[0017] Further preferably, the metal metabolism disease is a copper metabolism disorder.

[0018] Preferably, the copper metabolism disorder is Wilson's disease.

[0019] Preferably, the drug comprises:

[0020] (1) Penicillamine trisulfide; and / or;

[0021] (2) a pharmaceutically acceptable carrier; and / or;

[0022] (3) Optional one or more other active substances for treating heavy metal poisoning or metal metabolic diseases.

[0023] Preferably, the pharmaceutically acceptable carrier comprises at least one of an excipient, a buffer, an emulsifier, a stabilizer, a diluent, a binder, a preservative, a lubricant, a pH adjuster, a cryoprotectant, a flavoring agent and a filler.

[0024] Preferably, the excipient is selected from at least one of microcrystalline cellulose, lactose, pregelatinized starch, cyclodextrin, carboxymethyl cellulose, mannitol, magnesium stearate, starch, calcium phosphate, ethyl cellulose, methyl cellulose, alginic acid, gelatin, gum arabic, glyceryl monostearate, sodium starch glycolate, guar gum, glycerol, and propylene glycol.

[0025] Preferably, the buffer is selected from at least one of sodium dihydrogen phosphate, sodium bicarbonate, ammonium bicarbonate, sodium acetate, citrate, histidine, and succinate.

[0026] Preferably, the emulsifier is selected from at least one of magnesium stearate, zinc stearate, calcium stearate, glyceryl stearate, sorbitan isostearate, sorbitan oleate, glyceryl oleate, and polyglyceryl-3 polyricinoleate.

[0027] Preferably, the stabilizer is selected from at least one of acacia gum, agar, alginic acid, cellulose ether and carboxymethyl chitosan.

[0028] Preferably, the diluent is selected from at least one of erythritol, mannitol, sorbitol, xylitol, lactose, sucrose, corn starch, potato starch, calcium phosphate, calcium citrate, and crystalline cellulose.

[0029] Preferably, the binder is selected from at least one of ethanol, starch slurry, pregelatinized starch, dextrin, syrup, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethylcellulose, ethyl cellulose, polyvinyl alcohol, polyethylene glycol, sodium alginate, polyvinyl pyrrolidone, gum arabic, gelatin, and alginic acid.

[0030] Preferably, the preservative is selected from at least one of methylparaben, propylparaben, methylparaben, ethylparaben, propylparaben, chlorobutanol, thimerosal, mercuric cyanide, phenoxyethanol, chlorhexidine, benzoic acid, sodium benzoate, chlorocresol, benzalkonium bromide, benzalkonium chloride, and ethylparaben.

[0031] Preferably, the lubricant is selected from at least one of magnesium stearate, zinc stearate, glyceryl monostearate, polyethylene glycol, stearic acid, talc, sodium chloride, sodium oleate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, and poloxamer.

[0032] Preferably, the pH adjuster is at least one selected from citric acid, fumaric acid, succinic acid, tartaric acid, malic acid and ascorbic acid.

[0033] Preferably, the cryoprotectant is selected from at least one of sucrose, glucose, mannitol, fructose, trehalose, dextrose, lactose, glycerol, methanol, ethanol, ethylene glycol, propylene glycol, dimethyl sulfoxide (DMSO), acetamide or formamide.

[0034] Preferably, the flavoring agent is selected from at least one of sweet orange flavor, vanilla flavor, strawberry flavor, milk flavor, banana flavor, and cherry flavor.

[0035] Preferably, the filler is selected from at least one of mannitol, xylitol, sorbitol, maltose, microcrystalline cellulose, glucose, lactose, sucrose, dextrin, starch, sodium alginate and sodium bicarbonate.

[0036] Preferably, the dosage form of the drug is drops, mixtures, tinctures, injections, tablets, powders, oral liquids, capsules, granules, ointments, suspensions, powders, emulsions, pellets, pills, buccal tablets, freeze-dried powder injections, gels, suppositories or aerosols.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] The researchers of the present invention have discovered a new use of penicillamine trisulfide. Through its complexation, penicillamine trisulfide has a stronger detoxification effect on heavy metals than penicillamine, and has a better therapeutic effect on Wilson's disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is the mass spectrum of penicillamine trisulfide.

[0040] Figure 2 This is the H NMR spectrum of penicillamine trisulfide.

[0041] Figure 3 This is the carbon NMR spectrum of penicillamine trisulfide. DETAILED DESCRIPTION

[0042] In order to make the technical means, creative features, purpose and effect of the present invention easy to understand, the present invention is further explained below in conjunction with specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all. Based on the embodiments in the implementation mode, other embodiments obtained by those skilled in the art without making creative work all belong to the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all common commercial products, and their sources are not specifically limited. The technology and scientific terms used in the embodiments have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0043] The reagents used in the implementation process are as follows:

[0044] name source Penicillamine trisulfide Homemade (Beijing Honghuixin Pharmaceutical Technology Co., Ltd.) Penicillamine Jiangxi Dongfeng Pharmaceutical Co., Ltd. Copper sulfate Fuchen (Tianjin) Chemical Reagent Co., Ltd. water Watsons drinking water Experimental rat pellet feed Beijing Huafukang Biotechnology Co., Ltd.

[0045] The penicillamine trisulfide used in the present invention is prepared by the following method:

[0046] Take penicillamine, add a certain concentration of hydrogen peroxide aqueous solution to dissolve it, leave it at room temperature for several days, separate, purify and dry it to obtain penicillamine trisulfide.

[0047] Its mass spectrum, hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum are as follows Figure 1-3 shown.

[0048] Test Example 1

[0049] Animal copper loading test

[0050] Rats were used, all of which were 3 months old and weighed within the range of 250±20g. They were randomly divided into 3 groups, 10 in each group. The control group was Group A, the penicillamine treatment group was Group B, and the penicillamine trisulfide treatment group was Group C. All rats were raised according to the standard for 12 weeks and fed with copper sulfate-containing feed and water. Starting from the 4th week, Group B was treated with penicillamine and Group C was treated with penicillamine trisulfide, with a therapeutic dose of 20 mg / kg. The control group A was given an equal dose of water. Tail blood was taken from each group every 2-4 weeks to measure the copper and zinc content. The results are shown in the following table:

[0051] Table 1. Results of serum copper content in rats (mean value, μg / mL)

[0052]

[0053] As shown in Table 1 above, the serum copper content of group A increased significantly from the 4th week, and was positively correlated with time. The serum copper content in week 12 was about 1.5 times that in week 0. Under the intervention of drugs, the serum copper content of groups B and C decreased significantly after the 4th week, and the rate of decrease in group C was faster than that in group B.

[0054] Table 2. Results of serum zinc content in rats (mean value, μg / mL)

[0055]

[0056]

[0057] As shown in Table 2 above, there was no significant change in serum zinc content in group A. Under the intervention of drugs, the serum zinc content in groups B and C decreased significantly after the fourth week, and the rate of decrease in group C was faster than that in group B.

[0058] Test Example 2

[0059] After the 12th week of the experiment in Test Example 1, the rats were killed, and the liver and brain tissues were taken to test the copper content.

[0060] Table 3. Results of copper content test in rat liver and brain (average value, μg / g)

[0061] Group liver brain A 31.263 3.563 B 18.059 2.706 C 13.466 2.383

[0062] As shown in Table 3 above, the copper content in the liver and brain of group A was significantly higher than that of groups B and C. Under the intervention of drugs, the copper content of groups B and C decreased significantly, and the rate of decrease in group C was faster than that in group B.

[0063] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. Application of penicillamine trisulfide in the preparation of products for heavy metal detoxification and metal metabolic diseases.

2. The use according to claim 1, characterized in that: The heavy metal includes at least one of copper, zinc, iron, cobalt, nickel, manganese, thallium, magnesium, cadmium, mercury, tungsten, molybdenum, gold, silver, arsenic and lead.

3. The use according to claim 1, characterized in that: The product comprises at least one of food, medicine and nutrition.

4. The use according to claim 3, characterized in that: The product described is a drug.

5. The use according to claim 1, characterized in that: The metal metabolism disease comprises at least one of copper metabolism disorder, iron metabolism disorder, magnesium metabolism disorder and manganese metabolism disorder.

6. The use according to claim 5, characterized in that: The metal metabolism disease is a copper metabolism disorder disease.

7. The use according to claim 6, characterized in that: The copper metabolism disorder disease is Wilson's disease.

8. The use according to claim 4, characterized in that: The drugs include: (1) Penicillamine trisulfide; and / or; (2) a pharmaceutically acceptable carrier; and / or; (3) Optional one or more other active substances for treating heavy metal poisoning or metal metabolic diseases.

9. The use according to claim 8, characterized in that: The pharmaceutically acceptable carrier includes at least one of an excipient, a buffer, an emulsifier, a stabilizer, a diluent, a binder, a preservative, a lubricant, a pH adjuster, a cryoprotectant, a flavoring agent and a filler.

10. The use according to claim 4, characterized in that: The dosage form of the drug is drops, mixtures, tinctures, injections, tablets, powders, oral liquids, capsules, granules, ointments, suspensions, powders, emulsions, pellets, pills, buccal tablets, freeze-dried powder injections, gels, suppositories or aerosols.

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