Monomer zinc lysine and preparation and application of reconverted zinc lysine complex

Abstract

The invention relates to the technical field of medicine preparation, and discloses preparation and application of monomer zinc lysine and a reconverted zinc lysine complex, and a preparation method of the monomer zinc lysine, which comprises the following steps: by taking L-lysine hydrochloride as a raw material, adding zinc chloride and sodium hydroxide to react, adjusting the pH value to be neutral, concentrating, adding ethanol to obtain a supersaturated solution, heating to 60 DEG C, standing, and filtering to obtain the monomer zinc lysine. The weight ratio of the L-lysine hydrochloride to the sodium hydroxide to the zinc chloride is 2: 2: 1, the pH value is adjusted to 6.5-7.5, the addition amount of the ethanol is 1.5-2 times of the total volume of the materials, and the concentration of the ethanol is 72-74 degrees. According to the method, the process is mature, complicated production equipment is not required, and the only used organic reagent is ethanol, so that the problem that acetic acid, citric acid and sodium phosphate buffers are frequently used in the existing preparation process of the monomer zinc lysine and then converting the monomer zinc lysine into the zinc lysine complex, so that impurities such as phosphoric acid and the like are generated is solved.

Description

Technical Field

[0001] The invention relates to the technical field of drug preparation, in particular to the preparation and use of monomer zinc lysine and its conversion into zinc lysine complex. Background Art

[0002] In 1958, Professor Kong Xiangrui of the Second Military Medical University of Shanghai led several of his students to take zinc sulfate orally to explore the reasonable dose of zinc sulfate that the human body could tolerate, which pioneered the use of zinc preparations to treat diseases in my country. In 1987, Guangdong Pharmaceutical Factory successfully developed zinc gluconate, which became the first new drug in Guangdong Province since the implementation of the National Drug Administration Law. Since then, it has been used in clinical treatment of zinc deficiency and gradually replaced zinc sulfate. Existing zinc supplements still use zinc sulfate and zinc gluconate, and their zinc carriers (i.e., sulfate and gluconate) are useless to the human body. Moreover, existing zinc supplements enter the human body in the form of ionic zinc, which has a stimulating effect on the gastrointestinal tract. Patients feel gastrointestinal discomfort when taking them, and severe side effects such as nausea and vomiting, so that they have to reduce the dose or stop taking the drug early, affecting the absorption rate of zinc.

[0003] International research has proven that zinc has important physiological functions and a wide range of pharmacological effects. Zinc can accelerate growth and development, increase appetite, promote wound healing, help brain development and improve intelligence, and improve immune function. Lysine produces therapeutic effects similar to elemental zinc in the human body through different mechanisms. The development of zinc lysine is to combine these two substances that are useful to the human body into one, creating a new type of zinc supplement that has both biochemical functions, and produces synergistic and additive therapeutic and health-care effects on the human body.

[0004] In the existing preparation process of monomer zinc lysine and its conversion into zinc lysine complex, buffers such as acetic acid, citric acid, sodium phosphate, etc. are often used, which will cause the problem of generating impurities such as phosphoric acid. Summary of the invention

[0005] In view of the shortcomings of the prior art, the present invention provides the preparation and use of monomer zinc lysine and its conversion into zinc lysine complex, which solves the problem that buffers such as acetic acid, citric acid, sodium phosphate, etc. are often used in the preparation process of the existing monomer zinc lysine and its conversion into zinc lysine complex, thereby causing the generation of impurities such as phosphoric acid.

[0006] To achieve the above purpose, the present invention is implemented by the following technical scheme: a preparation method of monomer zinc lysine, using L-lysine hydrochloride as a raw material, adding zinc chloride and sodium hydroxide to react, and adjusting the pH value to neutral, adding ethanol after concentration to obtain a supersaturated solution, heating to 60°C, standing, washing and filtering, and obtaining zinc lysine crystalline powder.

[0007] Preferably, the molar weight ratio of L-lysine hydrochloride to sodium hydroxide and zinc chloride is 2:2:1.

[0008] Preferably, the pH value is adjusted to 6.5-7.5.

[0009] Preferably, the amount of ethanol added is 1.5 to 2 times the total volume of the material, and the ethanol concentration should be between 72° and 74°.

[0010] The invention discloses a preparation method for converting monomer zinc lysine into zinc lysine complex. When zinc lysine is used as a preparation, corresponding L-lysine hydrochloride or L-lysine needs to be added to form a complex. The weight ratio of zinc lysine to L-lysine hydrochloride is 1:0.78.

[0011] The invention relates to the preparation and use of monomer zinc lysine and its conversion into zinc lysine complex. The zinc lysine complex is used for preparing clinical medicine or zinc enhancer.

[0012] The present invention provides the preparation and use of monomer zinc lysine and its conversion into zinc lysine complex. It has the following beneficial effects: 1. In the present invention, the process is mature and does not require complex production equipment. The only organic reagent used is ethanol, which can be obtained by fumigation with industrial ethanol. The mother liquor produced at the end can be used to recover ethanol and lysine, and no three wastes are generated. The product of the present invention is a crystalline monomer, and the purity is above 99% after content determination, thereby improving the existing monomer lysine zinc and the conversion to lysine zinc complex preparation process. Buffers such as acetic acid, citric acid, sodium phosphate, etc. are often used, which will cause the problem of generating impurities such as phosphoric acid.

[0013] 2. In the present invention, zinc deficiency is very common in both developing and industrialized countries. Currently, loss of appetite is considered a manifestation of zinc deficiency in infants and children. The lysine zinc of the present invention is a new type of zinc supplement. When it is made into a preparation, four lysines surround the zinc in the middle, and there is no irritation to the gastrointestinal tract. According to the pharmacological experiment of "Study on the Bioavailability of Lysine Zinc in Rabbits" conducted by Guangxi Institute of Traditional Chinese Medicine, the bioavailability of lysine zinc in rabbits is more than double that of the standard control of zinc sulfate, and is also about 50% higher than that of zinc gluconate, indicating that this product is easily absorbed in the human body in the form of chromium-combined zinc. The lysine in lysine zinc is an essential amino acid that the human body cannot synthesize itself, and the lysine content in the daily diet is not enough for normal people's daily needs. Therefore, lysine zinc not only supplements zinc to the human body, but also supplements lysine, killing two birds with one stone.

[0014] 3. In the present invention, as the efficacy of zinc lysine is recognized and widely used in clinical practice, it will have a positive and far-reaching significance for promoting the physical growth and intellectual development of children in my country. Zinc lysine will become an innovative product with independent intellectual property rights in my country, at least in the field of zinc supplements. In addition, four L-lysine hydrochlorides are needed to make one zinc lysine and finally make a complex preparation, which will promote the production of lysine in my country by several times, and its economic benefits are very considerable. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The chemical reaction formula for preparing the monomer zinc lysine of the present invention; Figure 2 is the chemical reaction formula of the tetracoordinated lysine zinc complex of the present invention; DETAILED DESCRIPTION

[0016] The technical solution of the present invention will be described clearly and completely below in conjunction with the accompanying drawings of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0017] Embodiment 1: Please see attached Figure 1 , L-lysine hydrochloride is used as the raw material, zinc chloride and sodium hydroxide are added to react, and the pH value is adjusted to neutral. After concentration, ethanol is added to obtain a supersaturated solution, which is heated to 60°C, allowed to stand, washed and filtered to obtain lysine zinc crystalline powder. The molar weight ratio of L-lysine hydrochloride to sodium hydroxide and zinc chloride is 2:2:1. The pH value is adjusted to 6.5~7.5. The amount of ethanol added is 1.5~2 times the total volume of the material, and the ethanol concentration should be between 72°~74°.

[0018] Specifically, the preparation route and basis: the α-amino group and the carboxyl group of L-lysine hydrochloride form an inner salt structure, and the ω-amino group and the hydrochloric acid form an amine salt structure. Zinc chloride and sodium hydroxide are added to the lysine hydrochloride solution, and the zinc ions and sodium ions are equally close to the carboxyl ions, and the hydroxide ions simultaneously grab the hydrogen ions on the α-amino group to form water, thereby obtaining an aqueous solution in which zinc lysine and sodium lysine coexist. After concentrating the solution, ethanol is added, and the zinc lysine first reaches supersaturation in the ethanol mother liquor, and can be crystallized after cooling.

[0019] According to the above chemical reaction formula, a technical scheme (production process) for preparing zinc lysine is proposed.

[0020] Material preparation (measured by molar ratio): 2 (g mol) L-lysine hydrochloride (dissolved in 10 times the amount of water) 2 (gram molecules) sodium hydroxide (prepared into 1 gram equivalent concentration aqueous solution) 1 (gram molecule) zinc chloride (dissolved in an equal volume of water with sodium hydroxide solution).

[0021] 2. Operation process steps: (1) Preparation of concentrated solution: Mix lysine and zinc chloride, add sodium hydroxide during stirring to obtain a turbid liquid, add concentrated hydrochloric acid dropwise, stir until the turbidity disappears, check with pH paper, limit the pH to 6.5-7.5, obtain a clear liquid, heat in a water bath and concentrate to 1 / 3-1 / 2 of the total volume of the material.

[0022] (2) Supersaturated solution of zinc lysine: Add ethanol to the concentrate while stirring until turbidity appears but does not disappear. This is a supersaturated solution. Its volume should be slightly less than 2 times the total volume of the material, with 2 times as the upper limit and the lower limit not less than 1.5 times the total volume. The ethanol concentration measured with an alcohol meter should be between 72° and 74°.

[0023] (3) Crystallization: The supersaturated solution is heated to 60°C in a water bath until the turbidity disappears and the clear liquid is left to stand for not less than 12 hours to precipitate small needle-like crystals. The crystals are collected by filtration, washed with ethanol and filtered to obtain a crystalline powder.

[0024] The reaction mother liquor contains lysine zinc and sodium lysine, sodium chloride, etc. which have not been crystallized. After the ethanol is recovered from the mother liquor, it can be acidified and lysine can be recovered by ion exchange resin column chromatography, or it can be further concentrated as a feed additive.

[0025] The chemical reagents used must be analytically pure, and the lead (Pb) content of zinc chloride must be below 10PPM as determined by atomic absorption spectroscopy. Ethanol can be fumigated with industrial ethanol, and the ethanol recovered in the process can also be reused.

[0026] The operating water must be purified by ion exchange resin or distilled water.

[0027] Please see attached Figure 2 , a preparation method for converting monomer zinc lysine into a zinc lysine complex. When zinc lysine is used as a preparation, the corresponding L-lysine hydrochloride or L-lysine needs to be added to form a complex, and the weight ratio of zinc lysine to L-lysine hydrochloride is 1:0.78.

[0028] Specifically, 1. Reaction principle and basis: Elemental zinc is a transition metal with a four-coordination number. Zinc salts are generally easy to hydrolyze in aqueous solution, and lysine zinc is no exception. When using L-lysine hydrochloride and zinc chloride to prepare lysine zinc, only a molecule composed of two lysines and one zinc can be obtained. The two lysine carboxyl groups on it only form a very weak ionic bond with zinc, and the four-coordination number of zinc itself is not satisfied, so it is easy to hydrolyze in aqueous solution. However, the hydrolysis is not thorough. According to experiments, no matter how much the concentration of lysine zinc in aqueous solution is, the limit of hydrolysis is 50%, that is, when the hydrolysis is halfway, it stops automatically. This is because the lysine generated by hydrolysis reveals the lone pair of electrons on the α-amino nitrogen atom, which is a necessary condition for forming a coordination bond with zinc in the solution, so the four-coordination number of zinc is satisfied, and lysine forms a four-coordination complex centered on zinc with the unhydrolyzed lysine zinc.

[0029] Zinc lysine will hydrolyze and produce zinc hydroxide precipitation when it meets water, which obviously affects its medical application. Based on the study of the hydrolysis properties of zinc lysine, we know that its hydrolysis is not thorough. According to the theory that zinc has a four-coordination number, zinc ions tend to form complexes in aqueous solution to meet the needs of its four-coordination number. In this way, when zinc lysine is used as a preparation, the corresponding L-lysine hydrochloride is added to inhibit the hydrolysis of zinc lysine and form a stable complex in the solution. This step breaks through the obstacles of zinc lysine in practical application, constitutes the uniqueness of zinc lysine in practical application, and also gives zinc lysine innovativeness in practical application.

[0030] 2. Preparation and dosage control of lysine zinc complex preparation When preparing the lysine zinc complex, L-lysine hydrochloride or L-lysine is used.

[0031] According to the above principle, zinc lysine is used to prepare clinical drugs or zinc fortifiers. First, zinc lysine is accurately weighed according to the zinc content allowed by the preparation, and then an amount of L-lysine hydrochloride equivalent to the lysine contained in the sample or an equivalent amount of L-lysine is weighed. Then the two samples are mixed and other auxiliary materials are added. Then, the samples can be pressed into tablets or prepared into oral solutions.

[0032] The following example illustrates the operation process: Clinical zinc supplements contain 10 mg of zinc per tablet. Based on a batch of 1,000 tablets, lysine zinc contains 14.07% zinc, so the lysine zinc should be weighed 10×1000÷14.07%=71073 (mg)=71.073 (g).

[0033] The content of L-lysine hydrochloride in lysine zinc is 78.61%, so 71.073 g of L-lysine hydrochloride × 78.61% = 55.86 g should be weighed.

[0034] Mix the two samples evenly, add flavoring agents and other auxiliary materials, and 1000 tablets can be made. The same operation can be used to prepare an oral solution containing 10 mg of zinc per vial.

[0035] Note: (1) Because α-amino acids and reducing sugars will react chemically if left together for a long time, when using zinc lysine and L-lysine hydrochloride preparations, flavoring agents cannot be monosaccharides, only disaccharides can be used. For example, sucrose can be used, but glucose cannot be used.

[0036] (2) Lysine will denature under high temperature. Therefore, when preparing zinc lysine preparations, if the process requires heating, the material must be cooled to 60°C before adding zinc lysine and L-lysine hydrochloride.

[0037] The invention relates to the preparation and use of monomer zinc lysine and its conversion into zinc lysine complex. The zinc lysine complex is used for preparing clinical medicine or zinc enhancer.

[0038] Specific dosage instructions: The zinc content in lysine zinc is 14.07%. According to the calculation that adults generally need 15 mg of zinc per day, taking 100 mg of lysine zinc can basically meet the needs. So, after taking lysine zinc preparations, will the lysine that enters the body at the same time exceed the daily needs? No, because male adults need 800 mg of lysine per day. Taking 100 mg of lysine zinc will also supplement 78.6 mg of lysine (L-lysine hydrochloride accounts for 78.61% of lysine zinc), which is less than one-tenth of the daily needs of male adults. In addition, double the amount of L-lysine hydrochloride added to prepare complex preparations, a total of 157 mg is supplemented, which is less than a quarter of the daily needs of male adults, and less than half of the 400 ml of lysine that female adults need per day. Therefore, if zinc is supplemented at a reasonable dose, the lysine taken at the same time will not exceed the normal needs. Children need to supplement 10 mg of zinc per day, and the lysine taken at the same time will not exceed the normal needs.

[0039] For patients with zinc deficiency, take lysine zinc preparations containing 10 mg of zinc per dose. The daily dosage and course of treatment should be based on the doctor's advice.

[0040] Embodiment 2: Dissolve 36.5g of L-lysine hydrochloride (Guangxi Nanning Yongjiang Pharmaceutical Factory, pharmaceutical grade) in 365ml of water in a beaker, and dissolve 13.6g of zinc chloride in 200ml of water. If turbidity occurs, it is not necessary to filter it. Pour it into the beaker, add 200ml of 1N sodium hydroxide solution while stirring, and add concentrated hydrochloric acid drop by drop while stirring until the turbidity disappears and a clear solution is obtained. The pH test paper should be neutral (pH=7). The reaction mother liquor was transferred to an evaporating dish, heated and concentrated on a water bath. Suspended impurities gradually appeared on the liquid surface. After filtration, it was continued to concentrate to obtain about 300 ml of concentrated solution. It was cooled, and 900 ml of recovered 90% ethanol was added first, and then 200 ml of fumigated ethanol (95%) was added. The ethanol concentration was measured with an alcohol meter, which should be 73% (if it is not this concentration, it should be adjusted with anhydrous ethanol to reach 73°). The total volume of the solution was about 1500 ml. It was transferred to a glass conical flask and heated to 60°C on a water bath. The turbidity disappeared and a clear solution was obtained. It was placed at room temperature for 12 hours, and the crystals were filtered out. They were washed with ethanol and filtered twice, and dried to obtain 30 g of the product with a yield of 64%.

[0041] Embodiment 3: Dissolve 146 g of L-lysine hydrochloride in 1400 ml of water in an enamel bucket, add 800 ml of zinc chloride (54.4 g) aqueous solution, stir evenly, and add 800 ml of 1N sodium hydroxide solution (32 g), which becomes turbid. Add concentrated hydrochloric acid dropwise and stir until a clear solution is obtained. The pH value test paper is neutral. The total volume of the solution is 3000 ml. Place it in batches in an evaporating dish and heat it on a water bath to concentrate. As the temperature of the solution rises, a small amount of suspended impurities appear on the liquid surface. After filtering, continue to concentrate, combine the concentrated solution to obtain 1200 ml, cool it, pour it into an enamel bucket, add 3600 ml of recovered ethanol (90%), and then add 95% ethanol in portions for a total of 950 ml. The solution becomes turbid, and the alcohol meter measures 73°. The total volume is about 5700 ml. Heat it to 60°C on a water bath until the turbidity disappears. The clear solution is placed for 12 hours, and the crystals are filtered out. The product is washed with ethanol and filtered twice, and dried to obtain 110 g of the product with a yield of 59%.

[0042] The invention relates to the preparation and use of monomer zinc lysine and its conversion into zinc lysine complex. The zinc lysine complex is used for preparing clinical medicine or zinc enhancer.

[0043] Specifically, by preparing the monomer zinc lysine into a zinc lysine complex for clinical medication or zinc fortifier, the zinc element in the human body can be effectively supplemented, and its role in treating zinc deficiency or nutritional fortification can be played, and its complex form may improve bioavailability and stability.

[0044] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing monomeric zinc lysine, characterized in that: Take L-lysine hydrochloride as raw material, add zinc chloride and sodium hydroxide to react, adjust the pH value to neutral, add ethanol after concentration to obtain a supersaturated solution, heat to 60°C, let stand, wash and filter to obtain lysine zinc crystalline powder.

2. The method for preparing monomeric zinc lysine according to claim 1, characterized in that: The molar weight ratio of L-lysine hydrochloride to sodium hydroxide and zinc chloride is 2:2:

1.

3. The method for preparing monomeric zinc lysine according to claim 1, characterized in that : The pH value is adjusted to 6.5-7.

5.

4. The method for preparing monomeric zinc lysine according to claim 1, characterized in that: The amount of ethanol added is 1.5 to 2 times the total volume of the material, and the ethanol concentration should be between 72° and 74°.

5. A method for preparing a zinc lysine complex from a monomer zinc lysine, characterized in that: When zinc lysine is used as a preparation, the corresponding L-lysine hydrochloride or L-lysine needs to be added to form a complex, and the weight ratio of zinc lysine to L-lysine hydrochloride is 1:0.

78.

6. Preparation and use of monomeric zinc lysine and its conversion into zinc lysine complex, characterized in that: The lysine zinc complex is used for preparing clinical medicine or zinc enhancer.

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