CN107789365A - The medical composition and its use of various trace elements V - Google Patents

The medical composition and its use of various trace elements V Download PDF

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CN107789365A
CN107789365A CN201610752293.8A CN201610752293A CN107789365A CN 107789365 A CN107789365 A CN 107789365A CN 201610752293 A CN201610752293 A CN 201610752293A CN 107789365 A CN107789365 A CN 107789365A
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hydrate
acid
manganese
zinc
copper
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刘力
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/32—Manganese; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Abstract

The present invention provides to prepare prevention or treat people to be lacked with mammal various trace elements, such as the various trace elements new pharmaceutical compositions of zinc, manganese, copper, chromium, selenium deficiency and its syndrome, to reduce the adverse reaction in treating so that it is in clinical process with more preferable security, compliance and with new adaptation population etc..

Description

The medical composition and its use of various trace elements V
Technical field
The present invention relates to pharmaceutical technology field, be specifically to provide prevention or treatment zinc, manganese, chromium, copper, selenium deficiency and its One kind of multiple the micro-element injection pharmaceutical compositions and its preparation and use of syndrome etc..
Background technology
Zinc is indispensable trace element in organism, participates in the synthesis of many enzymes in vivo, and there is important physiology to adjust Save function.In tissue respiration, synthesis, erythrocyte membrane and hematopoiesis of the zinc to protein play an important role.Zinc energy and sulphur Alcohol combines, and blocks mercaptan and Tie Jietai, suppresses the catalytic oxidation of iron and forms free radical, zinc can also suppress the peroxide of fat Change acts on, and the attack that stabilizing cell membrane is allowed to free radical has more resistance, therefore, zinc not only cell growth but also to cell Protection it is significant.
Chromium (III) has a variety of biochemical functions as a kind of essential trace element of life, take part in glucide The processes such as metabolism, lipid material metabolism, chromium is lacked in human body will cause the generation of many diseases, chromium can be used as glucose-tolerant because The constituent of son, assist insulin play physiological function.
Copper participates in hematopoiesis and the metabolism of iron, influences the metabolism of connective tissue (such as skin, cartilage), influences collagen and bone group The formation knitted, and be the constituent of some copper enzymes.Animal is in the case of copper is lacked, the esoteric various pathologic, physiologics of machine Change is in close relations with lipid peroxidation.
Trace element manganese is the constituent of a variety of enzymes, participates in energy and fat metabolism, promote bone normal growth and Development, the enzyme system of activation chondroitin sulfate synthesis is participated in, promotes the synthesis of sclerotin；Must can not in normal brain function is maintained Lack, have certain relation with intellectual development, thinking, emotion, behavior.Manganese plays the role of to prevent anaemia, and manganese deficiency also can be to health Have undesirable effect, mainly there is the following aspects：1st, the synthesis of bone is suppressed, the time, which has been grown, will result in cartilage development not It is good, ossify slow, long bone is short, deformity of joint, and the empty increase of bone, sclerotin hardness has declined, and toughness reduces, osteoporosis, easily In fracture.Famine can also influence phosphatase activity in bone, cause stagnation of growing.2nd, slow down the metabolism of cell, add The aging of fast people.3rd, cause neurasthenia syndrome, influence intelligence development.4th, the reduction of insulin synthesis and secretion, shadow are caused Ring glycometabolism.
Substantial amounts of survey data illustrates there there is directly the height of Se content with the incidence of disease of cancer in regional a food and soil Connect relation.Scientific research finds that selenium has many pharmacological actions, for example strengthen immunity：Organic Selenium can remove interior free yl, Vivotoxin, generation that is anti-oxidant, can effectively suppressing lipid peroxide are excluded, prevents blood clot, removes cholesterol, strengthens people Body immunity function.Prevent diabetes：Selenium is the active component for forming glutathione peroxidase, and it can prevent beta Cell of islet Oxidative demage, make its function normal, promote sugared part metabolism, reduce blood glucose and glucose in urine, improve the symptom of diabetic.Prevent white Cataract or glaucoma：Selenium can protect retina, the finish of reinforcing glass body, improve eyesight, prevent cataract.Prevent heart and brain blood Pipe disease：Selenium is the important element for maintaining heart normal function, plays the role of to protect and repairs to heart human body.Human body blood selenium water Flat reduction, the hypofunction for removing free radical in vivo can be caused, cause hazardous material deposition to increase, blood pressure rise, vascular wall Thickening, blood vessel elasticity reduces, VPV is slack-off, send oxygen function reduction, so as to induce the rise of the incidence of disease of cardiovascular and cerebrovascular disease, But supply Se scientific has preferable effect to prevention cardiovascular and cerebrovascular disease, hypertension, artery sclerosis etc..
Generally speaking, trace element keeps machine to meeting human nutrition needs and maintaining human body biochemical reaction to be normally carried out Body eubolism and physiological function play an important roll.When trace element is insufficient, the activity reduction or complete of enzyme can be made Lose, obstacle will occur for the synthesis and metabolism of hormone, protein, vitamin etc., cause organism metabolism to be lacked of proper care, severe patient can Threat to life.Caused by 30% disease is directly microelement deficiencies or imbalance.As zinc-deficiency can cause mouth, eye, anus or outer Private parts redness, papule, eczema.And for example iron is one of main component for forming hemoglobin, and iron deficiency can cause hypoferric anemia.Text Offer report：Iron content, copper, zinc total amount are reduced in body, can weaken immunologic mechanism (resist the disease strength), reduce resistance against diseases, Bacterium infection is encouraged, and the metainfective death rate is also higher.Trace element it is disease-resistant, give protection against cancer, promote longevity etc. all also Play very important effect.Therefore, for a long time, the clinically more extensive clinical practice of trace element.
Nevertheless, excessive microelement is also not all right in biology, excessive microelement easily causes different diseases, including interior Parasecretion, the nervous system disease, angiocardiopathy, even cause tumour, the patient of the different state of an illness needs different ratio Trace element, the species of some needs is more, and the species of some needs is few, and the amount of some needs is more, and the amount of some needs is few, and more one There is this qualitative difference or say this qualitative difference in therapeutic administratp be present in kind or few one kind, cross in multi input body and cause toxicity anti- Should, this make it that Rare Elements Preparations prescription is had to variation.Because trace element participates in composition etc. of enzyme, organism it is various Property, body to external micro- very sensitive, also bring a variety of on prescription and preparation etc. by the sensitivity of variation and body Problem (Duan Yumei, it is necessary to effect and toxicity of the minor metallic element in human body, biology circular, 2004,39 (6):25- 26)。
However, multi-microelement injecta (- 5CONCENTRATE) it is used for the supplement of trace element With the treatment of some diseases, but many deficiencies be present, above-mentioned multi-microelement injecta is maintained under very low acidity and adopted It is main ingredient etc. with a large amount of zinc sulfate, the medicine has the too strong grade serious adverse reaction of blood vessel irritation, toxicity in Clinical practice Excessive and situation that patient's compliance is poor and other potential safety factors.Prior art various trace elements are injected Liquid (- 5CONCENTRATE) in component zinc sulfate have compared with severe corrosive, skin and mucous membrane irritation, Allergic dermatitis occurs during long-term steam contact.Although Human Physiology pH commonly reaches 7.4 or so, in the prior art in preparation The regulation of pH value sulfuric acid maintain very low level, general pH value be 2.0~3.0 between to prevent quality occurs in injection from asking Topic, strong acidity different intravenously administrables medicine prepare and clinical vein transfusion in bring a certain degree of safety risks and Some adverse reactions, including blood vessel irritation or phlebitis, local necrosis, patient tolerability difference or clinical accident etc., particularly Once particulate occurs in parenteral solution in process for preparation or in infusion process, easily occur during patient fluid infusion unexpected fatal Danger, these particulates may be that naked eyes be turned a blind eye in the case of background deficiency, but these are by long-standing neglect.
Prior art multi-microelement injecta (- 5CONCENTRATE) yet exist at certain It is not suitable for the situation of the patient of acid poisoning and renal insufficiency etc. in the case of a little, unknown in advance or in the case of being difficult to know Clinical application may bring adverse consequences；【Bibliography：Document 1, Yin Peida, the pathogenesis of distal renal tubular acidosis, Foreign medical science (clinical practice fascicle), phase nineteen eighty-two 12；Document 2, Zhou Lei, etc. 12 RTA patient cause in misdiagnosis point Analysis and nursing, Chinese Quotation Analysis, 17 phases in 2005；】.
Therefore, it is necessary to be reformed and innovated to the multi-microelement injecta of the above-mentioned drug standards, medicine is reduced not Good reaction, potential potential safety hazard is reduced, improve the security and compliance and clinical treatment effect etc. of clinical application.
The content of the invention
The present invention relates to pharmaceutical technology field, be specifically to provide prevention or treatment zinc, manganese, copper, selenium, chromium, shortage and One kind of multiple the micro-element injection pharmaceutical compositions and its preparation and use of its syndrome etc..
The pharmaceutical composition of the various trace elements of the injection of the present invention, a unit dose or unit formulation or list The ratio between the weight number of main ingredient component or parts by weight are in the said composition of position volume：Containing zinc (Zn) 4.5~5.5mg, copper (Cu) 0.9~1.1mg, manganese (Mn) 0.45~0.55mg, μ g of chromium (Cr) 9.0~11, the μ g of selenium 54~66；Or in said one unit dose Amount or the said composition of unit formulation or unit volume in containing above-mentioned each main ingredient component weight number or parts by weight 0.05 ~50 times；Said composition can be with pharmaceutically acceptable auxiliary material or excipient composition injection；Said one dosage unit or list Position volume can be 1ml or 2ml or 2.5ml or 3ml or 5ml or 10ml or 15ml or 20ml or 40ml or 50ml or 100ml etc.；
Above-mentioned micro- existence form can be that its atom is corresponding to being combined into again with acid, alkali after the combination of other atoms Pharmaceutical salts its ion or with acid, alkali be combined into corresponding pharmaceutical salts；Wherein, zinc or zinc salt are selected from zinc gluconate, lactose Sour zinc, zinc citrate, zinc lactate or Pfansteihl zinc, zinc acetate, D- or L- or DL- L-aminobutanedioic acids zinc, glycine zine, zinc glutamate Or their isomers or their hydrate or zinc ion pharmaceutically acceptable salt or one kind in their isomers or It is a variety of；
Copper or mantoquita are selected from copper chloride, copper sulphate, copper gluconate, lactobionic acid copper, copper citrate, copper lactate or Pfansteihl Copper, copper acetate, D- or L- or DL- L-aminobutanedioic acids copper, cupric glycinate, cupric glutamate or their isomers or their hydrate Or the one or more in bivalent cupric ion pharmaceutically acceptable salt or their chiral isomer；
Manganese or manganese salt are selected from manganese chloride, manganese sulfate, manganese gluconate, lactobionic acid manganese, manganese citrate, manganese lactate or Pfansteihl Manganese, manganese acetate, D- or L- or DL- L-aminobutanedioic acids manganese, Mn-Gly, glutamic acid manganese or their isomers or their hydrate Or the one or more in divalent manganesetion pharmaceutically acceptable salt or their chiral isomer；
Selenium is selected from selenous acid or sodium selenite or the one or more of its hydrate or the acceptable pharmaceutical salts of selenous acid；
Chromium or chromic salts are selected from chromium chloride, chromium sulfate, chromium gluconate [(C6H11O7)3Cr], chromium citrate, D- or L- or DL- L-aminobutanedioic acids chromium, Chromic lactate, chromic acetate, glycine chromium, glutamic acid chromium or their isomers or their hydrates or trivalent One or more in chromium ion pharmaceutically acceptable salt.
Furtherly, the pharmaceutical composition of the various trace elements of injection of the invention, a unit dose or list The ratio between the weight number of main ingredient component or parts by weight are in the said composition of position preparation or unit volume：Containing zinc (Zn) 4.5~ 5.5mg, copper (Cu) 0.9~1.1mg, manganese (Mn) 0.45~0.55mg, μ g of chromium (Cr) 9.0~11, the μ g of selenium 54~66；Or upper State the weight number or again containing above-mentioned each main ingredient component in a unit dose or the said composition of unit formulation or unit volume Measure number 0.05~50 times；Said composition can be with pharmaceutically acceptable auxiliary material or excipient composition injection；Said one Dosage unit or unit volume can be 1ml or 2ml or 3ml or 5ml or 10ml or 20ml or 40ml or 50ml or 100ml etc.；
Wherein, zinc or zinc salt are selected from zinc gluconate, lactobionic acid zinc, zinc citrate, zinc lactate or Pfansteihl zinc, acetic acid Zinc, D- or L- or DL- L-aminobutanedioic acids zinc, glycine zine, zinc glutamate or their isomers or their hydrate or zinc from One or more in sub- pharmaceutically acceptable salt or their chiral isomer；
Copper or mantoquita are selected from copper chloride, copper sulphate, copper gluconate, lactobionic acid copper, copper citrate, copper lactate or Pfansteihl Copper, copper acetate, D- or L- or DL- L-aminobutanedioic acids copper, cupric glycinate, cupric glutamate or their isomers or their hydrate Or the one or more in bivalent cupric ion pharmaceutically acceptable salt or their chiral isomer；
Manganese or manganese salt are selected from manganese chloride, manganese sulfate, manganese gluconate, lactobionic acid manganese, manganese citrate, manganese lactate or Pfansteihl Manganese, manganese acetate, D- or L- or DL- L-aminobutanedioic acids manganese, Mn-Gly, glutamic acid manganese or their isomers or their hydrate Or the one or more in divalent manganesetion pharmaceutically acceptable salt or their chiral isomer；
Selenium is selected from the one or more of selenous acid, sodium selenite or its hydrate or the acceptable pharmaceutical salts of selenous acid；
Chromium is selected from chromium chloride, chromium sulfate, chromium gluconate [(C6H11O7)3Cr], chromium citrate, L- or D- or DL- door winters Propylhomoserin chromium or their hydrate, Chromic lactate, chromic acetate, glycine chromium, glutamic acid chromium or their isomers or their hydrations One or more in thing or trivalent chromic ion pharmaceutically acceptable salt or their chiral isomer；
Pharmaceutically acceptable auxiliary material or excipient are in addition to water for injection, it may include pharmaceutically acceptable amide-type chemical combination Thing (for example niacinamide, Pyrazinamide, acetamide, urea, thiocarbamide etc.), pharmaceutically acceptable aminated compounds (for example second two Amine, diethylamine, diethanol amine, triethanolamine, meglumine, Portugal's ethamine, aminoguanidine, hydroxyethyltheophylline), amino acid or its is medicinal Salt, for example：D- or L- or DL-Lys or Lysine Acetate or arginine or acetic arginine or taurine or glycine OR gate Winter propylhomoserin or Monosodium L-aspartate or D- or L- or DL-histidine or cysteine or methionine or its salt, it is pharmaceutically acceptable Organic acid or its salt, for example L-AA, citric acid or sodium citrate or lactic acid, sodium lactate, lactobionic acid, sodium lactonic, Gluconic acid, sodium gluconate, pharmaceutically acceptable alcohol compound, for example sorbierite or mannitol or lactitol or xylose Alcohol, D-mannital, D- D-sorbites or antierythrite include its hydrate or their pharmaceutically acceptable salt etc. or it Chiral isomer in one or more, sorbierite include anhydrous sorbierite or the water thing of sorbierite half or 1 water sorbierite or One or more in sorbitol instant etc., it is above-mentioned to include its chiral isomer or its solvated compounds or its hydrate；Remove One or more injections in a unit dose in pharmaceutically acceptable auxiliary material or excipient outside water for injection In content be selected from 0.0010~0.40g；Or it can be expressed as：Pharmaceutically acceptable auxiliary material or tax in addition to water for injection One or more content in the injection of a unit dose in shape agent can be or selected from 0.0010~0.40g/ml.
Further, the pharmaceutical composition of various trace elements of the invention, a unit dose or unit formulation or unit The ratio between the weight number of main ingredient component or parts by weight are about in the said composition of volume：Containing zinc (Zn) 4.5~5.5mg, copper (Cu) 0.9~1.1mg, manganese (Mn) 0.45~0.55mg, μ g of chromium (Cr) 9.0~11, the μ g of selenium 54~66；Or in said one unit dose Amount or the said composition of unit formulation or unit volume in containing above-mentioned each main ingredient component weight number or parts by weight 0.05 ~50 times；Said composition can form injection with pharmaceutically acceptable auxiliary material；Said one dosage unit or unit volume can To be 1ml or 2ml or 3ml or 5ml or 10ml or 20ml or 40ml or 50ml or 100ml etc.；
The present invention various trace elements pharmaceutical composition more preferably, a unit dose or unit formulation or unit bodies The ratio between the weight number of main ingredient component or parts by weight are about in long-pending said composition：Containing zinc (Zn) 5mg, copper (Cu) 1mg, manganese (Mn) 0.50mg, μ g of chromium (Cr) 10, the μ g of selenium 98；
The present invention various trace elements pharmaceutical composition more preferably, a unit dose or unit formulation or unit bodies The ratio between the weight number of main ingredient component or parts by weight are about in long-pending said composition：Containing zinc (Zn) 10mg, copper (Cu) 2mg, manganese (Mn) 1.0mg, μ g of chromium (Cr) 20, the μ g of selenium 196；
The present invention various trace elements pharmaceutical composition more preferably, a unit dose or unit formulation or unit bodies The ratio between the weight number of main ingredient component or parts by weight are about in long-pending said composition：Containing zinc (Zn) 15mg, copper (Cu) 3mg, manganese (Mn) 1.50mg, μ g of chromium (Cr) 30, the μ g of selenium 294；
The present invention various trace elements pharmaceutical composition more preferably, a unit dose or unit formulation or unit bodies The ratio between the weight number of main ingredient component or parts by weight are about in long-pending said composition：Containing zinc (Zn) 25mg, copper (Cu) 5mg, manganese (Mn) 2.50mg, μ g of chromium (Cr) 50, the μ g of selenium 490；
The present invention various trace elements pharmaceutical composition more preferably, a unit dose or unit formulation or unit bodies The ratio between the weight number of main ingredient component or parts by weight are about in long-pending said composition：Containing the 0mg of zinc (Zn) 5, copper (Cu) 10mg, manganese (Mn) 5.0mg, μ g of chromium (Cr) 100, the μ g of selenium 980；
The present invention various trace elements pharmaceutical composition more preferably, a unit dose or unit formulation or unit bodies The ratio between the weight number of main ingredient component or parts by weight are about in long-pending said composition：Containing zinc (Zn) 75mg, copper (Cu) 15mg, manganese (Mn) 7.5mg, μ g of chromium (Cr) 150, the μ g of selenium 1470；
The present invention various trace elements pharmaceutical composition more preferably, a unit dose or unit formulation or unit bodies The ratio between the weight number of main ingredient component or parts by weight are about in long-pending said composition：Containing zinc (Zn) 100mg, copper (Cu) 20mg, manganese (Mn) 10.0mg, μ g of chromium (Cr) 200, the μ g of selenium 1960；
Wherein, zinc or zinc salt be selected from zinc gluconate or zinc gluconate hydrate, zinc gluconate (II) dihydrate, The hydrate of zinc gluconate 3, lactobionic acid zinc or lactobionic acid zinc hydrate, zinc citrate or the zinc of citric acid three or its zinc citrate water Compound zinc citrate dihydrate, zinc lactate, the hydrate of Pfansteihl zinc 3, Pfansteihl zinc, the hydrate of Pfansteihl zinc 3, zinc acetate, The hydrate of zinc acetate 2, D- or L- or DL- L-aminobutanedioic acids zinc, glycine zine, zinc glutamate etc. or their isomers or its water One or more in compound；
Copper or mantoquita are selected from copper chloride, the hydrate of copper chloride 2, copper sulphate, copper sulfate monohydrate, three brochanites, five water sulphur Sour copper, copper gluconate, the hydrate of copper gluconate 1, the hydrate (C of copper gluconate 212H22O14Cu ﹒ 2H2O), lactobionic acid copper Or lactobionic acid copper hydrate, copper citrate or the bronze medal of citric acid three or its hydrate of copper citrate 2.5, copper lactate or Pfansteihl copper, Cupric glycinate, cupric glutamate or their isomers or its hydrate, D- or L- or DL- L-aminobutanedioic acid copper etc. or their hydration Thing, copper acetate or its hydrate of copper acetate 1 [(Ac)2Cu·H2O] in one or more；
Manganese or manganese salt are selected from manganese chloride or its hydrate [or the hydrate of manganese chloride 1 or the hydrate (MnCl of manganese chloride 22· 2H2) or the hydrate (MnCl of manganese chloride 4 O2·4H2O) or the hydrate of manganese chloride 5 or the hydrate of manganese chloride 6], manganese sulfate or, sulfuric acid The hydrate of manganese 1, manganese gluconate or manganese gluconate hydrate, lactobionic acid manganese or lactobionic acid manganese hydrate, manganese citrate or lemon Lemon three manganese of acid or manganese citrate hydrate, manganese lactate or Pfansteihl manganese or its hydrate, manganese acetate or the hydrate of manganese acetate 4, D- Or L- or DL- L-aminobutanedioic acids manganese, Mn-Gly, glutamic acid manganese etc. or their isomers or one kind or several in its hydrate Kind；
Selenium is selected from selenous acid, sodium selenite, the hydrate (Na of sodium selenite 52SeO3·5H2O), sodium hydrogen selenite or sub- selenium One or more in acid etc. or their acceptable pharmaceutical salts；
Chromium or chromic salts are selected from chromium chloride, the hydrate of chromium chloride 6, chromium sulfate, the hydrate of chromium sulfate 6, chromium gluconate or Portugal Grape saccharic acid chromium hydrate, chromium citrate or chromium citrate hydrate, Chromic lactate or Pfansteihl chromium or its hydrate, L- or D- or DL- L-aminobutanedioic acids chromium or their hydrate (such as hydrate of L-ASPARTIC ACID chromium 3), chromic acetate, glycine chromium, glutamic acid chromium Or the one or more of their isomers or its hydrate；
Pharmaceutically acceptable auxiliary material or excipient can include in addition to water：Pharmaceutically acceptable amides compound (example Such as niacinamide, Pyrazinamide, acetamide, urea, thiocarbamide), pharmaceutically acceptable aminated compounds (for example ethylenediamine, diethyl Amine, diethanol amine, triethanolamine, meglumine, Portugal's ethamine, aminoguanidine, hydroxyethyltheophylline), chiral or racemization or D- or L- or The amino acid of racemization or its pharmaceutical salts salt, such as D- or L- or DL-Lys, Lysine Acetate, cysteine, methionine, smart ammonia Acid or acetic arginine or L-aminobutanedioic acid or Monosodium L-aspartate, glutamic acid, glycine, taurine, alanine, valine, bright ammonia Acid, isoleucine, serine, threonine, cysteine, cystine, methionine, asparagine, glutamine, 5- hydroxyls rely ammonia Acid, histidine, phenylalanine, tyrosine, tryptophan, 3- hydroxy-prolines, 4- hydroxy-prolines, proline, homocysteine, Homocystine, homoserine, ornithine, citrulling, creatine, 3- alanine, theanine, 2-amino-butyric acid, 4-Aminobutanoicacid, 2- Amino-2-methyl propionic acid, 2- methyl -3- alanines, 2,6- diaminopimelic acids, 2- amino-3-phenyl butyrics, the sweet ammonia of phenyl Acid, canavanine, canaline, 4- hydroxyarginines, 4- hydroxyls ornithine, homoarginine, 4- hydroxyhomoarginines, β-rely Propylhomoserin, 2,4-diamino-butanoic, 2,3- diaminopropionic acids, 2- methyl serines etc., or trehalose, or it is pharmaceutically acceptable organic Acid or its salt, or unit or polybasic carboxylic acid or its pharmaceutical salts, for example malic acid, butanedioic acid, ascorbic acid, L-AA, different Ascorbic acid, sodium isoascorbate, nicotinic acid, niacinamide, pantothenic acid, sodium pantothenate, citric acid or sodium citrate or lactic acid, lactic acid Sodium, lactobionic acid, sodium lactonic, gluconic acid, sodium gluconate, pharmaceutically acceptable alcohol compound, for example maltitol, mountain Pears alcohol, mannitol, lactitol, xylitol, antierythrite etc. or its hydrate or their pharmaceutically acceptable salt or they One or more in chiral isomer etc., sorbierite include D- D-sorbites, anhydrous sorbierite or the water thing of sorbierite half or 1 water One or more in sorbierite or sorbitol instant etc., it is above-mentioned to include its chiral isomer；Medicine in addition to water for injection One or more content in the injection of a unit dose in acceptable auxiliary material or excipient can be or Selected from 0.0010~0.40g/ml；
Or contain above-mentioned each main ingredient in the said composition of said one unit dose or unit formulation or unit volume The weight number of component or 0.25~50 times of parts by weight；Said composition can form with pharmaceutically acceptable auxiliary material or excipient Injection；Said one dosage unit or unit volume can be 1ml or 2ml or 3ml or 5ml or 10ml or 15ml or 20ml or 40ml or 50ml or 100ml etc..
Alternatively, furtherly, for the pharmaceutical composition of various trace elements of the invention, a unit dose Or the ratio between the weight number of main ingredient component or parts by weight are in the said composition of unit formulation or unit volume：
Zinc gluconate or zinc gluconate hydrate, the zinc gluconate dihydrate or hydrate of zinc gluconate 3 (31.37594-38.34837mg with zinc gluconate anhydride weight calculation amount) or zinc acetate or the hydrate 15.0896- of zinc acetate 2 18.4429mg (with zinc acetate weight calculation amount) or L- or D- or DL- L-aminobutanedioic acids zinc or L- or D- or DL- L-aminobutanedioic acid zinc hydrates 22.6932-27.7363mg (with L-aminobutanedioic acid zinc anhydride weight calculation amount), copper gluconate or the hydrate of copper gluconate 1 or Portugal The hydrate 6.4240-7.8516mg of grape saccharic acid copper 2 (with copper gluconate anhydride weight calculation amount) or copper sulphate or cupric sulfate pentahydrate 3.537-4.323mg (with cupric sulfate pentahydrate weight calculation amount) or D- or L- or DL- L-aminobutanedioic acids copper or D- or L- or DL- L-aminobutanedioic acids Copper hydrate 4.6493-5.6825mg (with L-aminobutanedioic acid copper anhydride weight calculation amount) or the hydrate 2.8282- of copper acetate 1 3.4568mg, manganese chloride or the hydrate of manganese chloride 2 or the hydrate 1.03-1.26mg of manganese chloride 4 (with manganese chloride weight calculation amount) or Portugal Grape saccharic acid manganese or the hydrate 3.6512-4.4627mg of manganese gluconate 2 (with manganese gluconate anhydride weight calculation amount) or manganese sulfate 1 Hydrate 1.386-1.694mg or D- or L- or DL- L-aminobutanedioic acids manganese or D- or L- or DL- L-aminobutanedioic acid manganese hydrates 2.617- 3.1987mg (with L-aminobutanedioic acid anhydrous manganese thing weight calculation amount), the hydrate 46.17-56.43 μ g of chromium chloride 6 or chromium gluconate or Portugal Grape saccharic acid chromium hydrate (with chromium gluconate anhydride weight calculation amount) 110.4562-135.0021 μ g or D- or L- or DL- the door winters The hydrate 43.6-53.3 μ g of propylhomoserin chromium 3 or chromium citrate 107.3-131.2 μ g (weight is in terms of chromium citrate C18H15O21Cr), Selenium is selected from selenous acid 88.2--107.8 μ g or sodium selenite (with the hydrated basis weight of sodium selenite 5) or the hydrate of sodium selenite 5 130.6-159.64 μ g or sodium hydrogen selenite 74.96-91.63 μ g,
Or contain above-mentioned each main ingredient in the said composition of said one unit dose or unit formulation or unit volume The weight number of component or 0.25~50 times of parts by weight；Said composition can form with pharmaceutically acceptable auxiliary material or excipient Injection；One or more in pharmaceutically acceptable auxiliary material or excipient in addition to water for injection are in a unit dose Injection in content can be or selected from 0.0010~0.40g/ml be more preferably 0.010~0.30g/ml, more preferably 0.020~0.20g/ml.
This of the pharmaceutical composition of the various trace elements of the present invention, a unit dose or unit formulation or unit volume The ratio between the weight number of main ingredient component or parts by weight can be in composition：The hydrate 38.99729mg of zinc gluconate 3 or 39.0mg or zinc gluconate (with zinc gluconate weight calculation amount) 34.86215mg or 34.86mg or 34.7mg or L- or DL- doors Winter propylhomoserin zinc 25.21477mg or D- or L- or DL- L-aminobutanedioic acid zinc hydrate 25.21477mg or 25.21mg or 25.2mg or 25mg (with L-aminobutanedioic acid zinc weight calculation amount), the μ g of chromium gluconate 122.7 or the μ g of 6 hydrate of chromium chloride 51.3 or 51 μ g or L- door winters The μ g of 3 hydrate of propylhomoserin chromium 48.45 or 48.5 μ g, the hydrate 7.71078mg of copper gluconate 2 or the hydrate of copper gluconate 1 7.42715mg or 7.4272mg or 7.427mg or 7.43mg or 7.4mg or copper gluconate 7.1377909mg or 7.1377909mg or 7.137791mg or 7.13779mg or 7.1378mg or 7.138mg or 7.14mg or 7.1mg or five water sulphur Sour copper 3.93mg or 3.9mg or D- or L- or DL- L-aminobutanedioic acids copper or L-aminobutanedioic acid copper or D- or L- or DL- L-aminobutanedioic acid copper waters Compound 5.16592mg or 5.1659mg or 5.166mg or 5.17mg (with L-aminobutanedioic acid copper weight calculation amount), the hydrate of manganese chloride 2 or Manganese chloride 4 hydrate 1.14664mg or 1.15mg (with manganese chloride weight calculation amount) or the hydrate 4.38528mg of manganese gluconate 2 or 4.3853mg or 4.385mg or 4.39mg or 4.4mg or hydrate 1.54mg or L- or DL- the L-aminobutanedioic acid manganese of manganese sulfate 1 or D- Or L- or DL- L-aminobutanedioic acid manganese hydrate 2.90788mg or 2.91mg or 2.9mg (with L-aminobutanedioic acid manganese weight calculation amount), selenous acid Sodium (sodium selenite is with the hydrated basis weight of sodium selenite 5) or the μ g of 5 hydrate of sodium selenite 145.12 or 145.1 μ g or 145 μ g Or the μ g of sodium hydrogen selenite 83.29 or 83.3 μ g；In said one unit dose or unit formulation or the said composition of unit volume In the weight number containing above-mentioned each main ingredient component or 0.25~50 times of parts by weight；Said composition can with it is pharmaceutically acceptable Auxiliary material or excipient composition injection；Said one dosage unit or unit volume can be 1ml or 2ml or 3ml or 5ml or 10ml or 20ml or 40ml or 50ml or 100ml etc.；In pharmaceutically acceptable auxiliary material or excipient in addition to water for injection One or more content in the injection of a unit dose be selected from 0.0010~0.040g, more preferably for 0.0030~ 0.030g, more preferably 0.0040~0.025g；Or it can be expressed as：Pharmaceutically acceptable auxiliary material in addition to water for injection Or one or more content in the injection of a unit dose in excipient can be or selected from 0.0010~ 0.40g/ml, it is more preferably 0.010~0.30g/ml, more preferably 0.020~0.20g/ml；Or in said one unit dose Amount or the said composition of unit formulation or unit volume in containing above-mentioned each main ingredient component weight number or parts by weight 0.25 ~50 times.
This of the pharmaceutical composition of the various trace elements of the present invention, a unit dose or unit formulation or unit volume In composition the ratio between the weight number of main ingredient component or parts by weight can be or more preferably from：The hydrate of zinc acetate 2 16.76624mg or 16.7662mg or 16.766mg or 16.77mg or 16.8mg, the μ g of chromium gluconate 122.73 or 122.7 μ g Or 123 the μ g or μ g of 6 hydrate of chromium chloride 51.3 or 51 μ g or D- or μ g of 3 hydrate of L- or DL- L-aminobutanedioic acids chromium 48.45, grape The hydrate of saccharic acid copper 2 or the hydrate of copper gluconate 1 or copper gluconate (with copper gluconate weight calculation amount) 7.1377909mg or 7.1377909mg or 7.137791mg or 7.13779mg or 7.1378mg or 7.138mg or 7.14mg or cupric sulfate pentahydrate 3.93mg, the hydrate 1.54mg of manganese sulfate 1 or manganese gluconate 2 hydrate 4.385mg or 4.39mg, the μ g or sub- selenium of selenous acid 98 Sour the μ g of 5 hydrate of sodium or sodium selenite 145.12 or 145.1 μ g or the 145 μ g or μ g of sodium hydrogen selenite 83.29 or 83.3 μ g；Or Contain the weight number of above-mentioned each main ingredient component in the said composition of said one unit dose or unit formulation or unit volume Or 0.25~50 times of parts by weight；Said composition can be with pharmaceutically acceptable auxiliary material or excipient composition injection；It is above-mentioned One dosage unit or unit volume can be 1ml or 2ml or 2.5ml or 3ml or 5ml or 10ml or 20ml or 40ml or 50ml Or 100ml etc..
Further it is stated another way, for the medicine composition injection of the various trace elements of the present invention, a list In position dosage or the said composition of unit formulation or unit volume the weight number of main ingredient component or the ratio between parts by weight can be or More preferably certainly：Zinc gluconate or zinc gluconate hydrate, the zinc gluconate dihydrate or hydrate of zinc gluconate 3 34.86mg or 34.9mg (with zinc gluconate anhydride weight calculation amount) or L- or DL- L-aminobutanedioic acids zinc or D- or L- or DL- door winters Propylhomoserin zinc hydrate 25.2mg (with L-aminobutanedioic acid zinc weight calculation amount)；The μ g of 6 hydrate of chromium chloride 51.3 or chromium gluconate or grape The μ g of saccharic acid chromium hydrate 122.7 (with chromium gluconate weight calculation amount)；Copper gluconate or the hydrate of copper gluconate 1 or glucose Sour copper 2 hydrate 7.138mg or 7.14mg (with copper gluconate weight calculation amount)；Manganese gluconate or the hydrate of manganese gluconate 2 4.06mg (with manganese gluconate weight calculation amount) or the hydrate 1.54mg of manganese sulfate 1 or the hydrate of manganese chloride 4 (are counted weight with manganese chloride Amount) 1.15mg；Sodium selenite or the μ g of the hydrate of sodium selenite 5 or sodium hydrogen selenite 145.12 or 145.1 μ g or 145 μ g (sub- selenium Sour sodium, sodium hydrogen selenite are with the hydrated basis weight of sodium selenite 5)；Or in said one unit dose or unit formulation or Weight number containing above-mentioned each main ingredient component or 0.25~50 times of parts by weight in the said composition of unit volume；Said composition Injection can be prepared into pharmaceutically acceptable auxiliary material or excipient；Pharmaceutically acceptable auxiliary material in addition to water for injection Or one or more content in the injection of a unit dose in excipient can be or selected from 0.0010~ 0.40g/ml, it is more preferably 0.010~0.30g/ml, more preferably 0.020~0.20g/ml；Said one dosage unit or list Position volume can be 1ml or 2ml or 2.5ml or 3ml or 5ml or 10ml or 20ml or 40ml or 50ml or 100ml etc..
Pharmaceutically acceptable auxiliary material or excipient in addition to water can be more preferably：D- or L- or DL- lysine, acetic acid relies Propylhomoserin, cysteine, methionine, arginine, acetic arginine, L-aminobutanedioic acid, Monosodium L-aspartate, glutamic acid, glycine, ox sulphur Acid, valine, threonine, cysteine, cystine, glutamine, 5- oxylysines, histidine, 3- hydroxy-prolines, 4- hydroxyls Base proline, proline, ornithine, citrulling, creatine, 3- alanine, theanine, 2-amino-butyric acid, 4-Aminobutanoicacid, 2- ammonia Base -2 Methylpropionic acid, 2- methyl -3- alanines, 2,6- diaminopimelic acids, 2- amino-3-phenyl butyrics, 4- hydroxyl essence ammonia Acid, 4- hydroxyls ornithine, 4- hydroxyhomoarginines, 2,4-diamino-butanoic, malic acid, butanedioic acid, ascorbic acid, L- Vitamin Cs Acid, arabo-ascorbic acid, sodium isoascorbate, nicotinic acid, niacinamide, pantothenic acid, sodium pantothenate, citric acid, sodium citrate, lactic acid, lactic acid Sodium, lactobionic acid, sodium lactonic, gluconic acid, sodium gluconate, trehalose, urea, thiocarbamide, maltitol, sorbierite, sweet dew Alcohol, lactitol, xylitol, antierythrite etc. or its hydrate or their pharmaceutically acceptable salt or their chiral isomer One or more in, one or more in above-mentioned pharmaceutically acceptable auxiliary material or excipient are in unit dose Content in injection can be or be more preferably 0.010~0.30g/ml, more preferably selected from 0.0010~0.40g/ml 0.020~0.20g/ml.
It is pointed out that than one unit of weight of main ingredient component weighed is needed in the composition in prepared by preparation The weight of the component of dosage is generally big, and its weight data there is a situation where to replace according to scaling and/or slightly province or equivalent, In the present invention, can be on scale or accurate according to the quantitative relation between the molecular weight of each component in itself or quality Extended on to the digit of different decimal points, or according to the regular further analogy that rounds up, for example the water of zinc gluconate 3 Between the 38997.29mg and 38997.3mg and 38997mg of compound, the 38.99g and 39.0g of the hydrate of zinc gluconate 3 it Between；Between the hydrate 7427.146mg of copper gluconate 1 and 7427.15mg, 7427.14mg, 7427.1mg, 7427mg；Grape Between the 4385.2778mg and 4385.278mg and 4385.28mg and 4385.3mg and 4385mg of the hydrate of saccharic acid manganese 2, chlorination Weight between the hydrate 51.3mg of chromium 6 and 51mg be equal effect or can mutual equivalent substitution, because effective digital is different Omit or accepted or rejected；Other or other components can by that analogy, main ingredient or auxiliary material in other compositions of the invention Effective digital accept or reject mode or principle it is also identical with this.
Change a component to say, the pharmaceutical composition of various trace elements, a unit dose or unit formulation or unit volume Said composition in main ingredient component weight number or the ratio between parts by weight be or more preferably from：Zinc gluconate or zinc gluconate Hydrate, the hydrate of zinc gluconate 2 or the hydrate of zinc gluconate 3 (with zinc gluconate anhydride weight calculation amount) 34.8622mg or 34.862mg or 34.86mg or 34.9mg or 35mg；The μ g of 6 hydrate of chromium chloride 51.3 or 51 μ g；Gluconic acid Copper or the hydrate 7.1377909mg or 7.13779mg or 7.1378mg of the hydrate of copper gluconate 1 or copper gluconate 2 or 7.138mg or 7.14mg or 7.1mg or 7.15mg (with copper gluconate weight calculation amount)；Manganese gluconate or the water of manganese gluconate 2 Compound 4.3852778mg or 4.385278mg or 4.38528mg or 4.3853mg or 4.385mg or 4.39mg or 4.4mg are (with Portugal The hydrated basis weight of grape saccharic acid manganese 2)；The μ g of selenous acid 98 or sodium selenite or the hydrate of sodium selenite 5 or sodium hydrogen selenite 145.12 μ g or 145.1 μ g or 145 μ g (sodium selenite, sodium hydrogen selenite are with the hydrated basis weight of sodium selenite 5)；Above-mentioned Contain the weight number or weight of above-mentioned each main ingredient component in one unit dose or the said composition of unit formulation or unit volume 0.20~50 times of number；Said composition can collectively constitute injection with other pharmaceutically acceptable auxiliary materials or excipient；Remove One or more injections in a unit dose in pharmaceutically acceptable auxiliary material or excipient outside water for injection In content be selected from 0.0010~0.040g, be more preferably 0.0030~0.030g, more preferably 0.0040~0.025g；Or can To be expressed as：One or more in pharmaceutically acceptable auxiliary material or excipient in addition to water for injection are in a unit dose Amount can be 0.0010~0.40g/ml by the content in the injection of solvent of water, be more preferably 0.010~0.30g/ml, More preferably 0.020~0.20g/ml；Pharmaceutically acceptable auxiliary material or excipient in addition to water can be more preferably：D- or L- or DL-Lys, Lysine Acetate, cysteine, methionine, arginine, acetic arginine, L-aminobutanedioic acid, Monosodium L-aspartate, paddy Propylhomoserin, glycine, taurine, valine, threonine, cysteine, cystine, glutamine, 5- oxylysines, histidine, 3- hydroxy-prolines, 4- hydroxy-prolines, proline, ornithine, citrulling, creatine, 3- alanine, theanine, 2- amino fourths Acid, 4-Aminobutanoicacid, 2- amino-2-methyls propionic acid, 2- methyl -3- alanines, 2,6- diaminopimelic acids, 2- amino -3- Phenylbutyric acid, 4- hydroxyarginines, 4- hydroxyls ornithine, 4- hydroxyhomoarginines, 2,4-diamino-butanoic, malic acid, amber Acid, ascorbic acid, L-AA, arabo-ascorbic acid, sodium isoascorbate, nicotinic acid, niacinamide, pantothenic acid, sodium pantothenate, lemon Acid, sodium citrate, lactic acid, sodium lactate, lactobionic acid, sodium lactonic, gluconic acid, sodium gluconate, trehalose, urea, thiocarbamide, Maltitol, sorbierite, mannitol, lactitol, xylitol, antierythrite etc. or its hydrate or theirs is pharmaceutically acceptable One or more in salt or their chiral isomer etc.；Said one dosage unit or unit volume can be 1ml or 2ml Or 2.5ml or 3ml or 5ml or 10ml or 20ml or 40ml or 50ml or 100ml etc..
In addition, the pharmaceutical composition of various trace elements of the present invention can also be expressed as, 100 or 1,000 unit doses or In the said composition of unit formulation or unit volume the ratio between the weight number of main ingredient component or parts by weight can be or more preferably from：
Zinc gluconate hydrate 34862.2mg (in terms of zinc gluconate anhydride), the hydrate 51.3mg of chromium chloride 6, The cupric sulfate pentahydrate 3930mg or hydrate 7137.79mg of the hydrate of copper gluconate or copper gluconate 1 or copper gluconate 2 or 7137.8mg or 7138mg (with copper gluconate weight calculation amount), the hydrate 1540mg of manganese sulfate 1 or manganese gluconate or glucose Sour the hydrate 4385.28mg or 4385.3mg of manganese 2 or 4385mg (with the hydrated basis weight of manganese gluconate 2), sodium selenite or Water thing (the Na of sodium selenite five2SeO3·5H2O) 145.12mg (in terms of the water thing of sodium selenite five)；
Above-mentioned said composition can be with pharmaceutically acceptable auxiliary material or excipient composition injection；In addition to water for injection One or more contents in the injection of a unit dose in pharmaceutically acceptable auxiliary material or excipient are selected from 0.0010~0.040g, it is more preferably 0.0030~0.030g, more preferably 0.0040~0.025g；Or it can be expressed as：Remove One or more in pharmaceutically acceptable auxiliary material or excipient outside water for injection are with water in unit dose It can be for the content in the injection of solution or be more preferably 0.010~0.30g/ml, more selected from 0.0010~0.40g/ml Preferably 0.020~0.20g/ml；
The pharmaceutical composition of the various trace elements of the injection of the present invention, wherein, zinc or zinc salt are more preferably from grape Saccharic acid zinc or zinc gluconate hydrate, the hydrate of zinc gluconate 2, the hydrate of zinc gluconate 3, lactobionic acid zinc or lactobionic acid Zinc hydrate, zinc citrate or the zinc of citric acid three or its zinc citrate hydrate zinc citrate dihydrate, zinc lactate, Pfansteihl The hydrate of zinc 3, the hydrate of zinc acetate 2, D- or L- or DL- L-aminobutanedioic acids zinc, glycine zine, D- or L- or DL- zinc glutamates etc. Or the one or more in its hydrate；
Copper or mantoquita are more preferably from cupric sulfate pentahydrate, copper gluconate, the hydrate of copper gluconate 1, the water of copper gluconate 2 Compound (C12H22O14Cu·2H2O), lactobionic acid copper or lactobionic acid copper hydrate, copper lactate or Pfansteihl copper or its hydrate, D- Or L- or DL- L-aminobutanedioic acids copper, copper acetate or its hydrate of copper acetate 1 [(Ac)2Cu ﹒ H2O], cupric glycinate, D- or L- or DL- One or more in cupric glutamate etc. or their hydrate；
Manganese or manganese salt more preferably from the manganese sulfate or hydrate of manganese sulfate 1, manganese gluconate or manganese gluconate hydrate, Lactobionic acid manganese or lactobionic acid manganese hydrate, the manganese citrate or manganese of citric acid three or manganese citrate hydrate, manganese lactate or Pfansteihl Manganese or its hydrate, manganese acetate or the hydrate of manganese acetate 4, D- or L- or DL- L-aminobutanedioic acid manganese etc. or its hydrate or they One or both of chiral isomer etc.；
Manganese or manganese salt are more preferably from manganese gluconate or manganese gluconate hydrate, lactobionic acid manganese or lactobionic acid manganese hydration Thing, manganese citrate or the manganese of citric acid three or manganese citrate hydrate, manganese lactate or Pfansteihl manganese or its hydrate, manganese acetate or vinegar The sour hydrate of manganese 4, D- or L- or DL- L-aminobutanedioic acids manganese, Mn-Gly, D- or L- or DL- glutamic acid manganese etc. or its hydrate or One or both of their chiral isomer etc.；
Selenium preferably is selected from selenous acid, sodium selenite, the hydrate (Na of sodium selenite 52SeO3·5H2O), sodium hydrogen selenite etc. or One or more in its hydrate；
Chromium or chromic salts are more preferably from chromium chloride, the hydrate of chromium chloride 6, chromium gluconate or chromium gluconate hydrate, lemon Lemon acid chromium or chromium citrate hydrate, Chromic lactate or Pfansteihl chromium or its hydrate, L- or D- or DL- L-aminobutanedioic acids chromium or they Hydrate (such as hydrate of L-ASPARTIC ACID chromium 3), glycine chromium, D- or L- or DL- glutamic acid chromium its hydrate or it Chiral isomer etc. in one or more；
Pharmaceutically acceptable auxiliary material or excipient in addition to water preferably from：D- or L- or DL-Lys, acetic acid rely ammonia Acid, cysteine, methionine, arginine, acetic arginine, L-aminobutanedioic acid, Monosodium L-aspartate, glutamic acid, glycine, ox sulphur Acid, valine, threonine, cysteine, cystine, glutamine, 5- oxylysines, histidine, 3- hydroxy-prolines, 4- hydroxyls Base proline, proline, ornithine, citrulling, creatine, 3- alanine, theanine, 2,6- diaminopimelic acids, 2- amino -3- Phenylbutyric acid, 4- hydroxyarginines, 4- hydroxyls ornithine, 4- hydroxyhomoarginines, 2,4-diamino-butanoic, malic acid, amber Acid, ascorbic acid, L-AA, arabo-ascorbic acid, sodium isoascorbate, nicotinic acid, niacinamide, pantothenic acid, sodium pantothenate, lemon Acid, sodium citrate, lactic acid, sodium lactate, lactobionic acid, sodium lactonic, gluconic acid, sodium gluconate, trehalose, urea, thiocarbamide, Maltitol, sorbierite, mannitol, lactitol, xylitol, antierythrite etc. or its hydrate or theirs is pharmaceutically acceptable One or more in salt or their chiral isomer etc..
The multi-microelement injecta and its preparation technology of the present invention：Method one, step 1, by pharmaceutically acceptable salt Or other auxiliary materials or excipient are dissolved with appropriate water for injection, with appropriate water for injection dissolving or with pharmaceutically acceptable PH adjusting agent is acidified；Step 2, by the acceptable pharmaceutical salts of zinc ion, manganese ion pharmaceutically acceptable salt, copper ion medicine Acceptable salt, chromium ion pharmaceutically acceptable salt are one by one with appropriate water for injection dissolving or with appropriate acidifying on Water for injection dissolves；Step 3, selenous acid or its pharmaceutical salts are dissolved with appropriate water for injection；Step 4, by each step solution It is sufficiently mixed uniformly, then adjusts pH value between 3.8~6.0 with pharmaceutically acceptable pH adjusting agent, more preferably pH value exists Between 4.0~5.5, or milipore filter removes thermal source, or adds activated carbon, stirring, places 5-40 minutes, filters decarburization, then moisturizing Constant volume, refined filtration, examine, it is filling, seal, sterilize, pack, examine.Wherein, the injection water system medication of acidifying is upper acceptable PH adjusting agent is acidified, and its pH is generally between 3.1-6.0.
It is or method two, step 1, pharmaceutically acceptable salt or other auxiliary materials or excipient is water-soluble with appropriate injection Solution, is acidified with pharmaceutically acceptable pH adjusting agent；Step 2, by manganese ion pharmaceutically acceptable salt, copper ion pharmacy Upper acceptable salt dissolves with appropriate water for injection dissolving or with the water for injection of appropriate acidifying respectively；Step 3, by zinc from The acceptable pharmaceutical salts of the son water for injection of appropriate acidifying dissolves；Step 4, chromium ion pharmaceutically acceptable salt is used and fitted The water for injection dissolving of amount is dissolved with the water for injection of appropriate acidifying；Step 5, selenous acid or its pharmaceutical salts are used respectively and fitted The water for injection dissolving of amount；Step 6, the solution of step 2 is sufficiently mixed uniformly with the solution of step 1 respectively；Step 7, it will walk Rapid 3 solution mixes with the solution of step 6；Step 8, the solution of step 4 and the solution of step 5 fully mixed, then with step Rapid 7 solution mixes, then with the pH value of pharmaceutically acceptable pH adjusting agent regulation solution between 3.8~6.0, preferably pH Value is between 4.0~5.5；Step 9, in solution add proper amount of active carbon, stir, place 5-40 minutes, filter decarburization, or micropore filter Membrane filtration, or use retention relative molecular mass or above-mentioned filter method is used in mixed way for 0.3 ten thousand to 300,000 membrane filtration, It is preferred that remaining thermal source, moisturizing constant volume are removed using the milipore filter of retention relative molecular mass 4000~60000；0.20-0.45μm Miillpore filter or ultrafiltration etc. carry out refined filtration, examine, filling, seal, and sterilize, and pack, and examine.Wherein, the injection water system of acidifying It is acidified with pharmaceutically acceptable pH adjusting agent, its pH is generally between 3.1-6.0.
Step in above-mentioned each method can intersect in different ways, in the case where not violating pharmaceutical principle or interaction is replaced Change use.
Pharmaceutical composition in the present invention can be with pharmaceutically acceptable auxiliary material or excipient composition injection；Except injection One or more containing in the injection of a unit dose in pharmaceutically acceptable auxiliary material or excipient outside water Amount is selected from 0.0010~0.40g/ml, is more preferably 0.010~0.30g/ml, more preferably 0.020~0.20g/ml；Or can be with It is expressed as：One or more in pharmaceutically acceptable auxiliary material or excipient in addition to water for injection are in a unit dose Can be using water as the content in the injection of solution or selected from 0.0010~0.40g/ml, more preferably for 0.010~ 0.30g/ml, more preferably 0.020~0.20g/ml.
For the drug combination injection in invention, every 1000ml of its pH adjusting agent pharmaceutically received in the present invention Parenteral solution can contain 0.0001-200.00 grams or more, and used pH adjusting agent is calculated with its active ingredient or molecular formula Its weight is calculated corresponding volume according to data such as concentration or density or calculated with molar concentration (M) or equivalent concentration (N). Used pH adjusting agent is added in the solution of composition during preparation of preparation in form of an aqueous solutions.When using alkali Property solution to adjust pH value when (such as one or more of sodium hydroxide, trisodium citrate, sodium gluconate), regulation process In, or it can be adjusted jointly with the mixed solution of soda acid, then adjusted with another kind, also can be after a kind of excess with pharmaceutically acceptable Acid solution adjusts back (for example, acetic acid, lactic acid, citric acid, gluconic acid solution), to control a suitable pH value, otherwise also So.
Pharmaceutically acceptable pH adjusting agent can be pharmaceutically acceptable inorganic acid or organic acid, inorganic base or organic The lewis acid or alkali of alkali or broad sense, one or several kinds can be contained, can be acetic acid and acetate, such as acetic acid Sodium etc., lactic acid and lactic acid pharmaceutical salts, citric acid pharmaceutical salts, sodium hydroxide, trihydroxy aminomethane, diethanol amine, monoethanolamine, two Isopropanolamine, 2- amino -2- (methylol) 1,3-PDs amine, N- methyl glucoses amine and their salt, multi-hydroxy carboxy acid and Pharmaceutical salts, such as glucuronic acid, gluconic acid, lactobionic acid, malic acid, threonic acid, glucoheptonic acid, amino acid or their pharmacy One or several kinds in upper acceptable salt etc..
The pharmaceutically acceptable antioxidant and stabilizer contained in the pharmaceutical compositions of the present invention can be sulfurous acid And its salt, bisulfites, pyrosulfite, dithionite, TGA and its pharmaceutical salts, thiolactic acid and its medicinal Salt, thio-2 acid and salt, amino acid and its pharmaceutical salts；Tartaric acid, sorbic acid or its pharmaceutical salts, nitrate, acetic acid are medicinal Salt, citrate, EDTA and edta salt, such as EDETATE SODIUM, the sodium of EDTA tetra-, Ca-EDTA sodium salt (including sodium ethylene diamine tetracetate Calcium or the hydrate of sodium ethylene diamine tetracetate calcium 2, the hydrate of sodium ethylene diamine tetracetate calcium 4), N- bis- (2- ethoxys) glycine, One kind in maltitol, xylitol, sorbierite, mannitol, taurine, amino acid or its pharmaceutically acceptable salt etc. or It is several；The salt of above-mentioned substance selects its pharmaceutically acceptable salt.
Pharmaceutically preservative or bacteriostatic agent can be contained in the injection of the pharmaceutical compositions of the present invention, as sorbic acid or its One or more in pharmaceutical salts, methyl hydroxybenzoate, phenmethylol, benzyl carbinol, anesin, Benzethonium etc..
In the injection of pharmaceutical composition of the present invention, pharmaceutically acceptable isotonic regulator can be used, pharmaceutically Acceptable isotonic regulator can be glucose, fructose, maltitol, lactitol, xylitol, sorbierite, mannitol, red moss One or more in sugar alcohol, inverted sugar, dextran, sodium lactate or sodium lactonic, gluconic acid or sodium gluconate etc..
Injection removes thermal source and degerming mode in preparing can add the activated carbon with liquid measure 0.005~1% to remove thermal source, Miillpore filter is degerming and pressure sterilizing, can also use heat sterilization, remove thermal source.In hyperfiltration process, flat board can be selected in ultrafilter Formula, rolling, tubular type, hollow fiber form or circle boxlike etc., more preferably rolling and hollow fiber form ultrafilter, using retention phase to dividing After the filter membrane that protonatomic mass is 50,000 to 300,000 removes most of heat generation material and bacterium, then using retention relative molecular mass 3000~60000 milipore filter removes remaining thermal source, the preferably milipore filter of relative molecular mass 6000~30000.
The advantages of following two experiment is embodied after specific aim of the present invention is improved
First, pharmaceutical composition of the invention is to mouse writhing reaction experiment
1st, test objective
The power of multi-microelement injecta pharmaceutical composition writhing response after intraperitoneal administration of the present invention is observed, with Investigate the degree of the adverse reaction of the pharmaceutical composition of different groups.
2nd, animal subject：Adult healthy white mouse, male and female half and half, body weight 18-22g.
3rd, test method：Mouse writhing method
Mouse 60, male and female half and half, fasting (can't help water) 12h, it is randomly divided into 6 groups, respectively vehicle control group, Duo Zhongwei Secondary element primary standard medicine composition injection control group (table 1, multi-microelement injecta,- 5CONCENTRATE) (prepared by the program with reference to the method for embodiment 1), 1 group of embodiment, 4 groups of embodiment, 5 groups of embodiment and embodiment 12 groups.Administering mode is intraperitoneal injection, and dosage is 0.2ml respectively, gives vehicle control group 0.2ml grapes respectively Sugared 5% parenteral solution, is injected intraperitoneally multi-microelement injecta control group solution (the original prescription control group solution ph in table 1 For 3.0) 0.2ml, after embodiment solution 0.2ml is injected intraperitoneally in remaining each group, mouse generation writhing is anti-in 15min after observation administration The number that should occur.
4th, result finds that vehicle control group does not produce writhing response, and the various trace elements in table 1 below are injected intraperitoneally Parenteral solution primary standard control group produce writhing response number respectively may be about 1.7 times of embodiment 1,2.3 times of 4 groups of embodiment, 2.5 times, 2.1 times or more of 12 groups of embodiment of 5 groups of embodiment, the results showed that, pharmaceutical composition of the invention it is bad anti- Degree is answered to be significantly less than control group.
The various trace elements medicine composition injection control group of table 1
2nd, medicine composition injection and control group solution ph stability experiment of the invention
Laboratory sample：Control group solution：Table 1, multi-microelement injecta,- 5CONCENTRATE, prepared according to the method mentioned in component in table 1 and mouse writhing reaction experiment, then, take 10ml respectively Sample is placed in two clean cillin bottles, is respectively 3.5,3.7 with the pH value of the 1M above-mentioned solution of sodium hydroxide solution regulation, Then seal, concussion mixing, lucifuge stands storage 12h, as a result finds that two samples are present and is visually evident that precipitation；
Experimental group solution：The sample 20ml that respectively prepared by Example 2, the method for embodiment 16 is respectively placed in two clean west In woods bottle, then seal, shake mixing, lucifuge stands storage 12h, and discovery has no precipitation generation, still keeps solution state.
Furtherly, the invention provides improved or more have the multi-microelement injecta pharmaceutical composition of advantage, The present invention also embodies further advantage simultaneously to be included：1st, eliminate that corrosivity is strong or the big zinc sulfate of dosage of strong toxicity so that this hair The adverse reaction of bright composition reduces, and it is anti-to reduce toxicity compared with the composition of the big zinc sulfate of prior art middle dosage etc. The incidence answered, the excitant and local necrosis for reducing or reducing intravenously administrable occur, improve the security of medication, be advantageous to change Compliance of the kind patient to medicine；2nd, after former composition prescription is removed in optimization, relative to original prescription, composition injection is contributed to The overall lifting of acidity so that with the medicine of other present or following listing in clinical medicine disposal process mixed preparings During parenteral solution, the pH value difference between different pharmaceutical preparation is reduced, reduces injection with the fatal foreign matter of liquid process or precipitation production It is raw, be advantageous to security and validity and the tolerance of patient when the stability after solution is prepared and Clinical practice；3rd, it is right New selection is provided in the patient for having occurred or easily having occurred acid poisoning, or reduces potential adverse reaction；4th, removing has haemolysis etc. The phenmethylol of side effect effect, improves clinical clinical safety etc..
Multi-microelement injecta pharmaceutical composition of the invention, prevent suitable for preparation for offer or treat zinc, Application in the multi-microelement injecta medicine of chromium, manganese, copper, selenium deficiency and its syndrome etc. so that product makes in clinic Use the tolerance having had more or new adaptation population or more preferable specific aim and more preferable clinical safety etc.；It is more suitable for The patient or children of acid poisoning etc..
Embodiment
Except in embodiment and when indicated otherwise, all numerical value used should be by specification and claims It is interpreted as being modified with term " about " in all examples, therefore, unless the contrary indication, this specification and appended The numerical parameter gone out given in claims is approximation, and it can be required for according to sought by by present disclosure Property and change, at least, and not be intended to limit doctrine of equivalents right application, each numerical parameter should The number and routine for considering effective digital round up method to explain.
Although the number range and parameter that set the wide scope of disclosure are approximations.But institute in a particular embodiment The numerical value provided is reported as precisely as possible, and any number is substantially comprising some by finding in their own test The error that standard deviation is necessarily led to.
It is pointed out that unless in text clearly in addition explanation, used in this specification and the appended claims Singulative "one", " one kind " and "the" include the plural form of referring to thing, so, such as.If refer to containing " one Mixture including two or more compounds during the composition of kind compound ", it is further noted that unless herein clearly Ground illustrates that term "or" generally includes "and/or" in addition.
Pharmaceutical composition
" pharmaceutical composition " used herein refers to the composition of medicine, and described pharmaceutical composition can contain at least one Pharmaceutically acceptable carrier.
" pharmaceutically acceptable excipient " used herein refers to the medicine that the compound for being applied to occasionally provide herein is administered With carrier or solvent, it includes, and well known to a person skilled in the art any examples of such carriers suitable for specific administration mode.
In the preparation technology of various embodiments of the present invention, the situation of the title of each component has been limited in the prescription of embodiment Under, for simplicity for each component in prescription, the simplification appellation or the property omitted address of following manner can be carried out, for example, can be with The hydrate of zinc gluconate 3 in prescription is referred to as zinc gluconate hydrate or zinc gluconate；Or the water of copper gluconate 1 Compound is referred to as gluconic acid copper hydrate or copper gluconate；Or the hydrate of chromium chloride 6 is referred to as chromium chloride hydrate or chlorine Change chromium；Or the hydrate of manganese sulfate 1 is referred to as manganese sulfate hydrate or manganese sulfate；Or sodium selenite pentahydrate is referred to as selenous acid Sodium；L-ASPARTIC ACID manganese hydrate is referred to as L-aminobutanedioic acid manganese hydrate or L-ASPARTIC ACID manganese or L-aminobutanedioic acid manganese etc., other The rest may be inferred for component.
In order to further appreciate that the present invention, the preferred embodiment of the invention is described with reference to embodiment, still It should be appreciated that these descriptions are simply further explanation the features and advantages of the present invention, rather than to the claims in the present invention Limitation.
Illustrate the effect of the present invention with specific embodiment below, but protection scope of the present invention is not limited by following examples System.
Specific embodiment
The preparation of the various trace elements drug combination injection of embodiment 1
Prescription：Zinc gluconate hydrate 34862mg (in terms of zinc gluconate anhydride)
2M gluconic acid solutions and 2M sodium citrate solutions are appropriate
Appropriate water for injection
Add to the full amount of water for injection 1000ml
Preparation technology：Weigh or prepare supplementary material by recipe quantity, step 1, by the sodium gluconate of recipe quantity, sorbierite, The water for injection stirring and dissolving of taurine, sodium pantothenate proper amount of fresh, pH value is acidified to 3.8 with gluconic acid solution；Step Rapid 2, the hydrate of chromium chloride 6, cupric sulfate pentahydrate, the hydrate of manganese sulfate 1 are acidified fresh injection with gluconic acid solution respectively Blunge dissolving, make solution keep clarifying and being mixed evenly；Step 3, the appropriate note of zinc gluconate hydrate acidifying Penetrate and dissolved with water, solution is kept clarification；Step 4, by the hydrate of sodium selenite 5 with appropriate water for injection stirring and dissolving；Step Rapid 5, the solution of step 3 and the solution of step 1 are mixed；Step 6, the solution of the solution of step 2 and step 4 is well mixed, The solution with step 5 mixes again；Step 7, with 2M gluconic acid solutions and 2M sodium citrate solutions pH value is adjusted to 3.8, add Water for injection is to full dose, and stir simultaneously 0.22 μm of miillpore filter 20min of circulating filtration；Then, using retention average molecular matter 8000-20000 ultrafiltration membrance filter is measured, filtrate is pressed 5ml/ branch embeddings, 121 DEG C of 15min sterilizings, produced.
Take appropriate above-mentioned sample lucifuge to be placed in 30 DEG C, placed 6 months in the environment of relative humidity 75% ± 5%, solution Keep clear and bright, the pH value for determining solution is 3.8.
The preparation of the various trace elements drug combination injection of embodiment 2
Prescription：The hydrate 38997mg of zinc gluconate 3, the hydrate 51.3mg of chromium chloride 6, cupric sulfate pentahydrate 3930mg, sulphur The sour hydrate 1540mg of manganese 1, the hydrate 145mg of sodium selenite 5, taurine 20g, sorbierite 50g, sodium gluconate 10g, L- are general Sour sodium 3g, 2M gluconic acid solution and 2M sodium lactate solutions are appropriate, appropriate water for injection, and add to the full amount of water for injection 1000ml
Preparation technology：Weigh or prepare supplementary material by recipe quantity, step 1, by the taurine of recipe quantity, sodium gluconate, The water for injection stirring and dissolving of sorbierite, L- sodium pantothenate proper amount of fresh, gluconic acid solution is acidified pH value to 3.8；Step 2nd, the appropriate injection for being acidified the hydrate of chromium chloride 6, cupric sulfate pentahydrate, the hydrate of manganese sulfate 1 with gluconic acid solution respectively Blunge dissolving, solution is kept clarification；Step 3, the hydrate of zinc gluconate 3 are water-soluble with the injection of acidifying fresh amount Solution；Step 4, by the hydrate of sodium selenite 5 respectively use proper amount of fresh water for injection stirring and dissolving；Step 5, by the molten of step 3 Liquid and the solution of step 1 mix；Step 6, the solution of step 2 is sufficiently mixed uniformly with the solution of step 4 successively, then with step 5 solution mixes, and then adjusts pH value to 3.8 with 2M gluconic acid solutions and 2M sodium gluconate solutions, adds water for injection To full dose, stir simultaneously 0.22 μm of miillpore filter 15min of circulating filtration；Then, using retention relative molecular mass 6000- 20000 ultrafiltration membrance filter, filtrate are pressed 10ml/ branch embeddings, 121 DEG C of 15min sterilizings, produced.
The preparation of the various trace elements drug combination injection of embodiment 3
Prescription：The hydrate 38997.3mg of zinc gluconate 3, the hydrate 51.3mg of chromium chloride 6, cupric sulfate pentahydrate 3930mg, The hydrate 1540mg of manganese sulfate 1, the hydrate 145.1mg of sodium selenite 5, taurine 30g, sorbierite 20g, glycine 20g, grape Sodium saccharate 12g, 2M gluconic acid solution and 2M sodium hydroxide solutions are appropriate, 5M sodium hydroxide solutions are appropriate, appropriate water for injection, Add to the full amount of water for injection 1000ml
Preparation technology：Weigh or prepare supplementary material by recipe quantity, step 1, by the taurine of recipe quantity, sorbierite, sweet ammonia Acid, the water for injection stirring and dissolving of sodium gluconate proper amount of fresh, are adjusted jointly with gluconic acid solution and sodium hydroxide solution The pH value of solution is saved to 3.9；Step 2, the hydrate of chromium chloride 6, cupric sulfate pentahydrate, the hydrate of manganese sulfate 1 used into glucose respectively The water for injection stirring and dissolving of acid solution acidifying (three kinds of solution ph are acidified to 3.1,3.9,3.8 respectively)；Step 3, glucose The sour zinc hydrate water for injection of acidifying fresh amount dissolves；Step 4, by sodium selenite hydrate respectively with proper amount of fresh Water for injection stirring and dissolving；Step 5, the solution of the solution of step 3 and step 1 mixed；Step 6, by the solution of step 2 successively It is well mixed with the solution of step 4, then is mixed with the solution of step 5, it is then molten with 2M gluconic acid solutions and 2M sodium hydroxides Liquid adjusts pH value to 3.9, and benefit adds to the full amount of water for injection, and stir simultaneously 0.22 μm of miillpore filter 20min of circulating filtration；So Afterwards, using retention relative molecular mass 8000-20000 ultrafiltration membrance filter, filtrate is respectively by 1ml/ branch, 2ml/ branch and 10ml/ Branch embedding, the injection of three kinds of specifications is sterilized respectively at 121 DEG C of 15min, produced.Appropriate above-mentioned sample lucifuge is taken to be placed in 30 DEG C, placed 6 months in the environment of relative humidity 75% ± 5%, solution keeps clear and bright, and the pH value for determining solution is 3.9.
The preparation of the various trace elements drug combination injection of embodiment 4
Prescription：Zinc gluconate 34862.2mg, the hydrate 51.3mg of chromium chloride 6, the hydrate of copper gluconate 1 7427.2mg, the hydrate 4385.3mg of manganese gluconate 2, the hydrate 145.1mg of sodium selenite 5, sorbierite 40g, taurine 80g, sodium gluconate 10g, 3M gluconic acid solution and 2M sodium gluconate aqueous solutions are appropriate, appropriate water for injection, filling is penetrated With water to full dose 1000ml
Preparation technology：Weigh or prepare supplementary material by recipe quantity, step 1, use the sorbierite of recipe quantity, sodium gluconate The water for injection stirring and dissolving of proper amount of fresh, gluconic acid solution is acidified pH value to 4.3；Step 2, by the hydrate of chromium chloride 6, The hydrate of copper gluconate 2, the hydrate of manganese gluconate 2, zinc gluconate are acidified fresh note with gluconic acid solution respectively Penetrate dissolving of blunging；The water for injection stirring and dissolving of step 3, the hydrate proper amount of fresh of sodium selenite 5；Step 4, will be each molten Liquid is well mixed, and then adjusts pH value to 4.5 with 3M gluconic acid solutions and 2M sodium gluconate solutions, benefit injects water to Full dose, stir simultaneously 0.22 μm of miillpore filter 20min of circulating filtration；Then, using retention relative molecular mass 8000- 20000 ultrafiltration membrance filter, 5ml/ branch embeddings, 121 DEG C of 15min sterilizings, produce.Appropriate above-mentioned sample lucifuge is taken to be placed in 30 DEG C, placed 6 months in the environment of relative humidity 75% ± 5%, solution keeps clear and bright, and the pH value for determining solution is 4.5.
The preparation of the various trace elements drug combination injection of embodiment 5
Prescription：The hydrate 38997.3mg of zinc gluconate 3, the hydrate 51.3mg of chromium chloride 6, the hydrate of copper gluconate 1 7427.2mg, the hydrate 4385.3mg of manganese gluconate 2, the hydrate 145.1mg of sodium selenite 5, sorbierite 10g, taurine 60g, L-thiamine 40g, 2M gluconic acid solution and 2M sodium gluconate solutions are appropriate, appropriate water for injection, add water for injection To full dose 1000ml
Preparation technology：Weigh or prepare supplementary material by recipe quantity, step 1, by the sorbierite of recipe quantity, taurine, L- tea The water for injection stirring and dissolving of propylhomoserin proper amount of fresh, with the pH value of gluconic acid solution souring soln to 4.5；Step 2, grape The hydrate of saccharic acid zinc 3, the hydrate of chromium chloride 6, the hydrate of copper gluconate 1, the hydrate of manganese gluconate 2 use gluconic acid respectively Solution is acidified fresh water for injection stirring and dissolving；Step 3, the hydrate of sodium selenite 5 stirred with the water for injection of proper amount of fresh Mix dissolving；Step 4, each solution is sufficiently mixed uniformly, then adjusted with 2M gluconic acid solutions and 2M sodium gluconate solutions PH value is to 4.5, and benefit adds to the full amount of water for injection, and stir simultaneously 0.22 μm of miillpore filter 20min of circulating filtration；Then, use Retain relative molecular mass 10000-20000 ultrafiltration membrance filter, it is seen that after foreign matter and pH value inspection, 10ml/ branch embeddings, 121 DEG C 15min sterilizing, is produced.10 above-mentioned sample lucifuges are taken to be placed in 25 DEG C or so of room temperature, in the environment of relative humidity 75% ± 5% Place 6 months, solution keeps clear and bright, and the pH value for determining solution is 4.5.
The preparation of the various trace elements drug combination injection of embodiment 6
Prescription：The hydrate 38997.3mg of zinc gluconate 3, the hydrate 51.3mg of chromium chloride 6, the hydrate of copper gluconate 1 7427.2mg, the hydrate 4385.3mg of manganese gluconate 2, the hydrate 145.1mg of sodium selenite 5, sorbierite 10g, glycine 50g, L-thiamine 60g, sodium gluconate 5g, 2M gluconic acid solution and 2M sodium gluconate solutions are appropriate, water for injection is fitted Amount, add to the full amount of water for injection 1000ml
Preparation technology：Weigh or prepare supplementary material by recipe quantity, step 1, by the sorbierite of recipe quantity, glycine, L- tea The water for injection stirring and dissolving of propylhomoserin, sodium gluconate proper amount of fresh, with gluconic acid solution and gluconic acid solution solution The pH value of common regulation solution is to 4.5；Step 2, by the hydrate of zinc gluconate 3, the hydrate of chromium chloride 6, the water of copper gluconate 1 Compound, the hydrate of manganese gluconate 2 are acidified fresh water for injection stirring and dissolving with gluconic acid solution respectively；Step 3, by Asia The water for injection stirring and dissolving of the hydrate proper amount of fresh of sodium selenate 5；Step 4, by each step solution mix, then with 2M grapes Sugar acid solution and 2M sodium gluconate solutions adjust pH value to 4.5, and benefit adds to the full amount of water for injection, and stir simultaneously circulating filtration 0.22 μm of miillpore filter 20min；Then, with retention relative molecular mass 10000-30000 ultrafiltration membrance filter, through visible foreign matters After being checked with pH value, by 10ml/ branch embeddings, 121 DEG C of 15min sterilizings, produce.Appropriate above-mentioned sample lucifuge is taken to be placed in 30 DEG C, Placed 6 months in the environment of relative humidity 75% ± 5%, solution keeps clear and bright, and the pH value for determining solution is 4.5.
The preparation of the various trace elements drug combination injection of embodiment 7
Prescription：The hydrate 38997.3mg of zinc gluconate 3, the hydrate 51.3mg of chromium chloride 6, the hydrate of copper gluconate 1 7427.2mg, the hydrate 4385.3mg of manganese gluconate 2, the hydrate 145.1mg of sodium selenite 5, xylitol 10g, glycine 20g, sodium gluconate 20g, 2M gluconic acid solution and 2M sodium gluconate solutions are appropriate, appropriate water for injection, add injection Water is to full dose 4000ml
Preparation technology：Supplementary material, step 1, xylitol, glycine, grape by recipe quantity are weighed or prepared by recipe quantity The water for injection stirring and dissolving of sodium saccharate proper amount of fresh, the pH value of solution is adjusted to 4.5 with gluconic acid solution；Step 2, incite somebody to action Zinc gluconate hydrate, chromium chloride hydrate, gluconic acid copper hydrate, manganese gluconate hydrate use gluconic acid respectively Solution is acidified fresh water for injection stirring and dissolving；Step 3, the water for injection stirring by sodium selenite hydrate proper amount of fresh Dissolving；Step 4, each step solution mixed, then with 2M gluconic acid solutions and 2M sodium gluconate solutions adjust pH value to 4.7, benefit adds to the full amount of water for injection, and stir simultaneously 0.22 μm of miillpore filter 20min of circulating filtration；Then, then through 0.22 μm Filtering with microporous membrane, after visible foreign matters and pH value check, by 2ml/ branch embeddings, 121 DEG C of 15min sterilizings, produce.
The preparation of the various trace elements drug combination injection of embodiment 8
Prescription：The hydrate 38997.3mg of zinc gluconate 3, chromium gluconate hydrate (with chromium gluconate weight calculation amount) 122.7mg, the hydrate 7427.2mg of copper gluconate 1, the hydrate 4385.3mg of manganese gluconate 2, the hydrate of sodium selenite 5 145.1mg, sorbierite 20g, taurine 30g, L-ASPARTIC ACID 20g, 4M gluconic acid solution and 2M sodium gluconates are appropriate, note Penetrate and use appropriate amount of water, add to the full amount of water for injection 1000ml
Preparation technology：Weigh or prepare supplementary material by recipe quantity, step 1, by the sorbierite of recipe quantity, taurine, L- doors The water for injection stirring and dissolving of winter propylhomoserin proper amount of fresh, pH value is acidified to 4.8 with gluconic acid solution；Step 2, by Portugal Grape saccharic acid zinc, chromium gluconate hydrate, gluconic acid copper hydrate, manganese gluconate hydrate use gluconic acid solution respectively It is acidified fresh water for injection stirring and dissolving；It is step 3, the stirring of the water for injection of sodium selenite hydrate proper amount of fresh is molten Solution；Step 4, each step solution mixed, then with 4M gluconic acid solutions and 2M sodium gluconate solutions adjust pH value to 5.2, benefit adds to the full amount of water for injection, and stir simultaneously 0.22 μm of miillpore filter 20min of circulating filtration；Then, using retention phase To molecular mass 5000-10000 ultrafiltration membrance filter, 15ml/ branch embeddings, 121 DEG C of 15min sterilizings, produce.Take appropriate above-mentioned Sample lucifuge is placed in 25 DEG C or so of room temperature, is placed 6 months in the environment of relative humidity 75% ± 5%, and solution keeps clear and bright, measure The pH value of solution is 5.2.
The preparation of the various trace elements drug combination injection of embodiment 9
Prescription：The hydrate 38997.29mg of zinc gluconate 3, the hydrate 51.3mg of chromium chloride 6, L-ASPARTIC ACID copper water are closed Thing 5165.9mg (with L-aminobutanedioic acid copper weight calculation amount), the hydrate 4385.28mg of manganese gluconate 2, the hydrate of sodium selenite 5 145.12mg, sorbierite 20g, taurine 100g, glycine 10g, 3M gluconic acid solution and 2M sodium gluconate solutions be appropriate, Appropriate water for injection, add to the full amount of water for injection 1000ml
Preparation technology：Supplementary material, step 1, taurine, glycine and sorb by recipe quantity are weighed or prepared by recipe quantity The water for injection stirring and dissolving of alcohol proper amount of fresh, pH value is acidified to 4.6 with gluconic acid solution；Step 2, by glucose It is molten that sour zinc, chromium chloride, L-aminobutanedioic acid copper, L-aminobutanedioic acid manganese are acidified fresh water for injection stirring with gluconic acid solution respectively Solution；Step 3, the water for injection stirring and dissolving by the hydrate proper amount of fresh of sodium selenite 5；Step 4, each step solution mixed It is even, pH value then is adjusted to 4.6 with 3M gluconic acid solutions and 2M sodium gluconate solutions, and benefit adds to the full amount of water for injection, and stirs Mix uniform and 0.22 μm of miillpore filter 20min of circulating filtration；Then, using retention relative molecular mass 5000-10000 ultrafiltration Membrane filtration, 20ml/ branch embeddings, 121 DEG C of 15min sterilizings, produce.Appropriate above-mentioned sample lucifuge is taken to be placed in 25 DEG C or so of room temperature, Placed 6 months in the environment of relative humidity 75% ± 5%, solution keeps clear and bright, and the pH value for determining solution is 4.6.
The preparation of the various trace elements drug combination injection of embodiment 10
Prescription：Zinc gluconate 34862mg, the hydrate 51.3mg of chromium chloride 6, the hydrate 7427mg of copper gluconate 1, Portugal The hydrate 4385mg of grape saccharic acid manganese 2, the hydrate 145mg of sodium selenite 5, sorbierite 60g, glycine 20g, gluconic acid 5g, 2M Gluconic acid solution and 2M sodium gluconate solutions are appropriate, 1M sodium hydroxide solutions are appropriate, appropriate water for injection, add water for injection To full dose 1000ml
Preparation technology：Supplementary material, step 1, sorbierite, glycine, grape by recipe quantity are weighed or prepared by recipe quantity The water for injection stirring and dissolving of saccharic acid proper amount of fresh, the pH of solution is adjusted with gluconic acid solution and sodium hydroxide solution solution It is worth to 4.5；Step 2, zinc gluconate, chromium chloride, copper gluconate, manganese gluconate be acidified with gluconic acid solution respectively The water for injection stirring and dissolving of fresh amount；The water for injection stirring and dissolving of step 3, the hydrate proper amount of fresh of sodium selenite 5； Step 4, each step solution mixed, then adjust pH value to 4.6 with 3M gluconic acid solutions and 2M sodium gluconate solutions, mend Add to the full amount of water for injection, stir simultaneously 0.22 μm of miillpore filter 20min of circulating filtration；Then, using retention average molecular Quality 5000-10000 ultrafiltration membrance filter, 40ml/ branch embeddings, 121 DEG C of 15min sterilizings, produce.
The preparation of the various trace elements drug combination injection of embodiment 11
Prescription：Zinc gluconate hydrate (in terms of zinc gluconate anhydride) 34862.2mg, the hydrate of chromium chloride 6 51.3mg, the hydrate 7427.2mg of copper gluconate 1, the hydrate 1540mg of manganese sulfate 1, the hydrate 145mg of sodium selenite 5, mountain Pears alcohol 10g, taurine 180g, sodium gluconate 10g, 1M gluconic acid solution and 1M sodium gluconate solutions are appropriate, injection Appropriate amount of water, add to the full amount of water for injection 2000ml
Preparation technology：Supplementary material, step 1, sorbierite, taurine, grape by recipe quantity are weighed or prepared by recipe quantity The water for injection stirring and dissolving of sodium saccharate proper amount of fresh, above-mentioned solution ph is acidified to 4.6 with gluconic acid solution；Step 2, Zinc gluconate, chromium chloride, copper gluconate, manganese sulfate are acidified to the water for injection of fresh amount with gluconic acid solution respectively Stirring and dissolving；Step 3, the water for injection stirring and dissolving by the hydrate proper amount of fresh of sodium selenite 5；It is step 4, each step is molten Liquid mixes, and then adjusts pH value to 4.6 with 3M gluconic acid solutions and 2M sodium gluconate solutions, benefit injects water to complete Amount, stir simultaneously 0.22 μm of miillpore filter 20min of circulating filtration；Then, using retention relative molecular mass 6000-20000 Ultrafiltration membrance filter, by 10ml/ branch embeddings, 121 DEG C of 15min sterilizings, produce.
The preparation of the various trace elements drug combination injection of embodiment 12
Prescription：The hydrate 42897mg of zinc gluconate 3, the hydrate 46.2mg of chromium chloride 6, the hydrate of copper gluconate 1 8169.8mg, the hydrate 1694mg of manganese sulfate 1, selenous acid 88.2mg, sorbierite 2g, glycine 15g, taurine 30g, L- tea ammonia Sour 8g, Cys 0.5g, Cit 1g, 3M gluconic acid solution and 3M sodium gluconate solutions are appropriate, water for injection In right amount, add to the full amount of water for injection 1000ml
Preparation technology：Weigh or prepare supplementary material by recipe quantity, step 1, by the sorbierite of recipe quantity, glycine, ox sulphur Acid, theanine, cysteine, the water for injection stirring and dissolving of Cit proper amount of fresh, with gluconic acid solution by solution PH value is acidified to 4.4；Step 2, by chromium chloride, copper gluconate, manganese chloride respectively with gluconic acid solution be acidified fresh amount Water for injection stirring and dissolving；Step 3, the zinc gluconate water for injection of acidifying fresh amount dissolve；Step 4, by sub- selenium The water for injection stirring and dissolving of acid proper amount of fresh；Step 4, each step solution mixed, then with 3M gluconic acid solutions and 3M sodium gluconate solutions adjust pH value to 4.4, and benefit adds to the full amount of water for injection, and stir simultaneously 0.22 μm of micropore of circulating filtration Filter membrane 20min；Then, using retention relative molecular mass 6000-20000 ultrafiltration membrance filter, it is seen that after inspection of foreign substance is qualified, 5ml/ branch embeddings, 121 DEG C of 15min sterilizings, are produced.
The preparation of the various trace elements drug combination injection of embodiment 13
Prescription：The hydrate 38997.3mg of zinc gluconate 3, the hydrate 56.4mg of chromium chloride 6, cupric sulfate pentahydrate 3537mg, Manganese gluconate 3651.3mg, the hydrate 159.6mg of sodium selenite 5, sorbierite 10g, taurine 30g, glycine 10g, 3- hydroxyl Base proline 10g, sodium gluconate 10g, 3M gluconic acid solution are appropriate, 3M lactic acid solutions and 3M sodium gluconate solutions are fitted Amount, appropriate water for injection, add to the full amount of water for injection 1000ml
Preparation technology：Weigh or prepare supplementary material by recipe quantity, step 1, by the sorbierite of recipe quantity, glycine, ox sulphur Acid, the water for injection stirring and dissolving of 3- hydroxy-proline proper amount of fresh, solution is acidified pH value extremely with 3M gluconic acid solutions 4.0；Step 2, chromium chloride, cupric sulfate pentahydrate, manganese gluconate be acidified fresh appropriate injection with gluconic acid solution respectively Blunge dissolving；Step 3, the hydrate of zinc gluconate 3 are acidified fresh appropriate water for injection with gluconic acid solution and dissolved； Step 4, the water for injection stirring and dissolving by sodium selenite proper amount of fresh；Step 5, by each step solution mix, then use 3M Lactic acid solution and sodium gluconate solution adjust pH value to 4.1, and benefit adds to the full amount of water for injection, and stir simultaneously circulating filtration 0.22 μm of miillpore filter 20min；Then, using retention relative molecular mass 6000-20000 ultrafiltration membrance filter, by 2ml/ branch Embedding, 121 DEG C of 15min sterilizings, is produced.
The preparation of the various trace elements drug combination injection of embodiment 14
Prescription：The hydrate 16766.2mg of zinc acetate 2, chromium gluconate 122.7mg (weight is in terms of anhydride), glucose Sour copper 7137.7mg, manganese gluconate 4057mg, the hydrate 145.1mg of sodium selenite 5, sorbierite 10g, glycine 80g, grape Sodium saccharate 12g, 3M gluconic acid solution and 1M sodium gluconate solutions are appropriate, appropriate water for injection, adds to the full amount of water for injection 1000ml
Preparation technology：Supplementary material, step 1, sorbierite, glycine, grape by recipe quantity are weighed or prepared by recipe quantity The water for injection stirring and dissolving of sodium saccharate proper amount of fresh, gluconic acid solution is acidified pH value to 4.5；Step 2, by glucose Sour chromium, copper gluconate, manganese gluconate are acidified fresh water for injection stirring and dissolving with gluconic acid solution respectively；Step 3, The hydrate of zinc acetate 2 is acidified into fresh appropriate water for injection with gluconic acid solution to dissolve；Step 4, sodium selenite 5 is hydrated The water for injection stirring and dissolving of thing proper amount of fresh；Step 5, each step solution mixed, then with 3M gluconic acid solutions and 1M sodium gluconate solutions adjust pH value to 4.9, and benefit adds to the full amount of water for injection, and stir simultaneously 0.22 μm of micropore of circulating filtration Filter membrane 20min；Then, using retention relative molecular mass 10000-30000 ultrafiltration membrance filter, 1ml/ branch embeddings, 121 DEG C 15min sterilizes, and produces.
The preparation of the various trace elements drug combination injection of embodiment 15
Prescription：The hydrate 35097.6mg of zinc gluconate 3, the hydrate 56.4mg of chromium chloride 6, the hydrate of copper gluconate 1 6684.4mg, the hydrate 4823.8mg of manganese gluconate 2, the hydrate 130.6mg of sodium selenite 5, sorbierite 20g, taurine 60g, citrulling 20g, 3M gluconic acid solution and 2M sodium gluconate solutions are appropriate, appropriate water for injection, are injected water to Full dose 1000ml
Preparation technology：Weigh or prepare supplementary material by recipe quantity, step 1, by the sorbierite of recipe quantity, taurine, melon ammonia The water for injection stirring and dissolving of acid proper amount of fresh, gluconic acid solution is acidified pH value to 4.0；Step 2, by zinc gluconate 3 hydrates, chromium chloride, copper gluconate, manganese gluconate are acidified the water for injection of fresh amount with gluconic acid solution respectively Stirring and dissolving；Step 3, the water for injection stirring and dissolving by sodium selenite proper amount of fresh；Step 4, by each step solution mix, Then pH value is adjusted to 4.5 with 3M gluconic acid solutions and 2M sodium gluconate solutions, benefit adds to the full amount of water for injection, and stirring is equal Even and 0.22 μm of miillpore filter 20min of circulating filtration；Then, using retention relative molecular mass 5000-10000 milipore filter mistake Filter, by 1ml/ branch, 15ml/ branch embeddings after inspection, 121 DEG C of 15min sterilizings, pack, examine, produce.
The preparation of the various trace elements drug combination injection of embodiment 16
Prescription：The hydrate 41097.29mg of zinc gluconate 3, the hydrate 50mg of chromium chloride 6, the hydrate of copper gluconate 1 7222mg, the hydrate 4500mg of manganese gluconate 2, the hydrate 140mg of sodium selenite 5, sorbierite 30g, taurine 100g, 3M Portugals Grape sugar acid solution and 2M sodium gluconate solutions are appropriate, appropriate water for injection, add to the full amount of water for injection 1000ml
Preparation technology：Weigh or prepare supplementary material by recipe quantity, step 1, by the sorbierite of recipe quantity, taurine with appropriate Fresh water for injection stirring and dissolving, gluconic acid solution is acidified pH value to 4.5；Step 2, by manganese gluconate, glucose The sour copper water for injection of appropriate acidifying dissolves；Step 3, the injection by the hydrate of zinc gluconate 3 with appropriate acidifying Water dissolves；Step 4, chromium chloride dissolved with the water for injection of appropriate acidifying respectively；Step 5, by the hydrate of sodium selenite 5 Dissolved with appropriate water for injection；Step 6, by each step solution mix, then with 3M gluconic acid solutions and 2M gluconic acids Sodium adjusts pH value to 5.0, moisturizing constant volume；Step 7, the membrane filtration for being 50,000 to 100,000 by solution retention relative molecular mass, Thermal source, 0.22 μm of filtering with microporous membrane are removed with the milipore filter of retention relative molecular mass 8000~30000 again, filtrate is pressed after examining 10ml/ branch embeddings, sealing, 121 DEG C of 15min sterilizings, pack, examine, produce.Appropriate above-mentioned sample lucifuge is taken to be placed in 30 DEG C, Placed 6 months in the environment of relative humidity 75% ± 5%, solution keeps clear and bright, and the pH value for determining solution is 5.0.
The preparation of the various trace elements drug combination injection of embodiment 17
Prescription：The hydrate 38997.3mg of zinc gluconate 3, chromium gluconate hydrate (with chromium gluconate weight calculation amount) 122.7mg, L-ASPARTIC ACID copper hydrate 5166mg (with L-aminobutanedioic acid copper weight calculation amount), L-aminobutanedioic acid manganese hydrate 2907.8mg (with L-aminobutanedioic acid manganese weight calculation amount), the hydrate 145.1mg of sodium selenite 5, sorbierite 20g, glycine 40g, L-arginine 5g, wood Sugar alcohol 5g, sodium gluconate 40g, 3M gluconic acid solution and appropriate sodium gluconate solution, appropriate water for injection, add injection Water is to full dose 2000ml
Preparation technology：Supplementary material, step 1, sorbierite, glycine, the L- essence by recipe quantity are weighed or prepared by recipe quantity Propylhomoserin, xylitol, the water for injection stirring and dissolving of sodium gluconate proper amount of fresh, gluconic acid solution is acidified pH value extremely 4.9；Step 2, L-aminobutanedioic acid manganese hydrate, L-aminobutanedioic acid copper dissolved with appropriate water for injection；Step 3, by gluconic acid The hydrate of zinc 3 is dissolved with appropriate water for injection；Step 4, the water for injection dissolving by chromium gluconate fresh amount；Step 5th, the hydrate of sodium selenite 5 is dissolved with appropriate water for injection；Step 6, by the solution of step 2 successively respectively with step 1 Solution is well mixed；Step 7, the solution of the solution of step 3 and step 6 mixed；Step 8, solution and step 7 by step 4 Solution fully mix, then mixed with the solution of step 5, then with gluconic acid solution and sodium gluconate adjust pH value to 5.3 moisturizing constant volume；Step 9, the ultrafiltration membrance filter by solution with retention relative molecular mass 20000~40000, then with 0.22 μ M filtering with microporous membrane, filtrate are pressed 1ml/ branch, 5ml/ branch, 10ml/ branch embeddings, sealing, gone out respectively at 121 DEG C of 15min after examining Bacterium, pack, examine, produce.10 above-mentioned sample lucifuges are respectively taken to be placed in 25 DEG C or so of room temperature, relative humidity 75% ± 5% respectively In the environment of place 6 months, solution keep it is clear and bright, the pH value for determining solution is each about 5.3.
The preparation of the various trace elements drug combination injection of embodiment 18
Prescription：L-ASPARTIC ACID zinc hydrate 25214.7mg (with L-aminobutanedioic acid zinc anhydride weight calculation amount), chromium gluconate (with chromium gluconate weight calculation amount) 122.7mg, the hydrate 7427.15mg of copper gluconate 1, the hydrate of manganese gluconate 2 4385.28mg, sodium hydrogen selenite 83.29mg, antierythrite 30g, glycine 30g, taurine 90g, methionine 2g, glucose Sour sodium 10g, 2M gluconic acid solution and 2M sodium gluconate solutions are appropriate, appropriate water for injection, add to the full amount of water for injection 1000ml
Preparation technology：Weigh or prepare supplementary material by recipe quantity, step 1, by the glycine of recipe quantity, taurine, red moss Sugar alcohol, methionine, the water for injection stirring and dissolving of sodium gluconate proper amount of fresh, gluconic acid solution is acidified pH value extremely 5.2；Step 2, by the hydrate of manganese gluconate 2, the water for injection (pH=of the appropriate acidifying of the hydrate of copper gluconate 2 4.8) dissolve；Step 3, the water for injection dissolving by the appropriate acidifying of L-ASPARTIC ACID zinc hydrate；Step 4, by glucose The water for injection dissolving of sour chromium fresh amount；Step 5, sodium hydrogen selenite dissolved with appropriate water for injection respectively；Step 6th, the solution of step 2 is sufficiently mixed uniformly with the solution of step 1 respectively successively；Step 7, by the solution of step 3 and step 6 Solution mixes；Step 8, the solution of the solution of the solution of step 4 and step 5, step 7 mixed, then use gluconic acid solution With sodium gluconate regulation pH value to 5.9, moisturizing constant volume；Step 9, by solution use with retention relative molecular mass 10000~ 30000 ultrafiltration membrance filter, then 10ml/ branch embeddings are pressed after examining through 0.22 μm of filtering with microporous membrane, filtrate, seal, 121 DEG C 15min sterilizes, and packs, and examines, produces.
The preparation of the various trace elements drug combination injection of embodiment 19
Prescription zinc gluconate 34862.2mg, the hydrate 51.3mg of chromium chloride 6, the hydrate of copper gluconate 1 7427.2mg, the hydrate 4385.28mg of manganese gluconate 2, the hydrate 145.12mg of sodium selenite 5, sorbierite 10g, glycine 30g, sodium gluconate 5g, 2M lactic acid solution and appropriate sodium gluconate solution, 1M sodium hydroxide solutions are appropriate, water for injection is fitted Amount, add to the full amount of water for injection 1000ml
Preparation technology：Supplementary material, step 1, glycine, sorbierite, grape by recipe quantity are weighed or prepared by recipe quantity The water for injection stirring and dissolving of sodium saccharate proper amount of fresh, lactic acid solution is acidified pH value to 4.4；Step 2, by manganese gluconate 2 hydrates, the hydrate of copper gluconate 1 water for injection of appropriate acidifying dissolve, and clarify holding；Step 3, by glucose The sour zinc water for injection of appropriate acidifying dissolves；Step 4, the injection by chromium gluconate with lactic acid solution fresh amount Water dissolves, and clarifies holding；Step 5, sodium hydrogen selenite dissolved with appropriate water for injection respectively；It is step 6, each step is molten Liquid mixes, and then adjusts pH value to 4.5 with 2M lactic acid solutions solution and 2M sodium gluconates, moisturizing constant volume；Step 7, by solution With the ultrafiltration membrance filter with retention relative molecular mass 10000~30000, then through 0.22 μm of filtering with microporous membrane, pressed after inspection 10ml/ branch embeddings, sealing, 121 DEG C of 15min sterilizings, pack, examine, produce.10 above-mentioned sample lucifuges are respectively taken to be placed in room respectively It is warm 25 DEG C or so, placed 6 months in the environment of relative humidity 75% ± 5%, solution keeps clear and bright, determines the pH value of solution about For 4.5.
Embodiment 20, pharmaceutical composition intravascular injection irritation test
1st, test objective：Observe animal the physiological saline of drip-feed 0.9%, the present invention medicine composition injection and After comparison medicine parenteral solution, caused vascular stimulation response situation.
2nd, test material：2.1. animal：The white Female rabbits of the big ear of adult healthy New Zealand, 2.5~3.0kg of body weight.
2.2. tested material：Medicine composition injection and various trace elements the medicine composition injection control of the present invention Group, compound method：Each embodiment of pharmaceutical composition (prepared by embodiment 6, embodiment 9, the method for embodiment 18) of the present invention is taken respectively Parenteral solution and the parenteral solution 4ml of various trace elements medicine composition injection control group be added to 150ml 0.9% physiology In salt solution, mix.
3rd, test method：Female rabbits 5, the 1st unused any medicine, make the observation of blank parallel control；Other 4 points Not in auris dextra edge drip-feed contrast solution (the various trace elements medicine composition injection pair that the component according to table 1 is prepared According to group [multi-microelement injecta (- 5 CONCENTRATE)] (with reference to the program system of the method for embodiment 1 Standby, then diluted with normal saline) and prepared respectively by embodiment 6, embodiment 9, the method for embodiment 18, then physiology Saline dilute solution；Administered volume is 20ml/kg, and drip velocity is 25~30 drops/min；Left auricular vein, which is given etc., to be held Amount physiological saline compares, and drip velocity is identical with by reagent.Once a day, continuous drip 5 days.During instillation, daily visually The irritative response of auricular vein is observed in timing.Rabbit is put to death within 7th day, in bilateral auricular vein proximal part away from injection site Draw materials at 1.0cm~1.5cm, fixed with formaldehyde, do conventional organization section, carry out pathological examination.
4th, result of the test
4.1. naked eyes result：
Drip-feed the present embodiment each group (is prepared) by embodiment 6, embodiment 9, the method for embodiment 18 respectively, the vein of administration Compared with physiological saline to the slight expansion of lateral vein, after drug withdrawal 24h, it is seen that the oozing of blood at acupuncture forms subcutaneous induration around vein, Administration side is with giving drip-feed physiological saline side no significant difference, and other macroscopic results are with physiological saline side without obvious poor It is different.
Repeatedly struggle is more violent for animal during instillation for various trace elements medicine composition injection control group, prompts Control group has certain excitant to body, can cause vascular pain, and has that the congestion of blood vessel is rubescent, and vascular endothelial cell is slight The inflammatory reaction situation such as swelling, peripheral tissue edema.
4.2. pathological examination：
Blank control group：See that venous blood tube chamber is complete under mirror, have no narrow, its tube wall has no inflammatory cell infiltration.
Physiological saline side：See that venous blood tube chamber is complete under (left auricular vein, instillation normal saline solution) mirror, its tube wall is shown in A little inflammatory cell infiltration.It is remaining to have no obvious lesion.
Test medicine group of the present invention：See venous blood tube chamber under (right auricular vein, the pharmaceutical composition for the present invention that instils) mirror Completely, its tube wall is shown in a little inflammatory cell infiltration.It is remaining to have no obvious lesion.
Venous blood tube chamber swelling, tube wall inflammation are seen under control drug group (right auricular vein, instillation control drug group solution) mirror Property cellular infiltration is obvious.
5th, conclusion (of pressure testing)
Rabbit auricular vein instil the present invention pharmaceutical composition of the invention dilute solution after 5 days, injection site without Finding of naked eye irritative response, and the irritative response of finding of naked eye be present in the control group for planting microelement composition.Micro- disease Reason inspection result shows, has no blood vessel structure exception, endothelial injuries, thrombosis and other pathological changes, this result and solvent Control group is consistent；The damage on pathology then be present in control drug group.Prompting：The pharmaceutical composition of the present invention is to blood vessel without obvious thorn Swash property, and the control group of various trace elements composition then has obvious excitant to blood vessel.
Industrial applicibility etc. and its explanation etc.：
The present invention is described in detail above by embodiment and embodiment, it will nevertheless be understood that these are said Bright that any restrictions are not formed to the scope of the present invention, person skilled substantially can be in the spirit without departing from the present invention and guarantor In the case of protecting scope, technical solutions and their implementation methods of the present invention can be carried out with a variety of modifications, improvement and replacement and group Close, to realize the technology of the present invention, these are because falling within the scope of protection of the present invention.In particular, it will be understood that The change of many details is possible, and all similar replacements and change are apparent for a person skilled in the art , they are considered as being included in the spirit, scope and content of the present invention, and the present invention is not limited to above-described embodiment.

Claims (10)

1. the pharmaceutical composition of various trace elements V, it is characterised in that：One unit dose or unit formulation or unit volume Said composition in main ingredient component weight number or the ratio between parts by weight be：Containing zinc (Zn) 4.5~5.5mg, copper (Cu) 0.9~ 1.1mg, manganese (Mn) 0.45~0.55mg, μ g of chromium (Cr) 9.0~11, the μ g of selenium 54~66；Or in said one unit dose or In the said composition of unit formulation or unit volume containing above-mentioned each main ingredient component weight number or parts by weight 0.25~50 Times；
Wherein, zinc or zinc salt are selected from zinc gluconate, lactobionic acid zinc, zinc citrate, zinc lactate or Pfansteihl zinc, zinc acetate, door Winter propylhomoserin zinc, glycine zine, zinc glutamate or their hydrate or their isomers or zinc ion are pharmaceutically acceptable One or more in salt；
Copper or mantoquita be selected from copper sulphate, copper gluconate, lactobionic acid copper, copper citrate, copper lactate or Pfansteihl copper, copper acetate, D- or L- or DL- L-aminobutanedioic acids copper, cupric glycinate, cupric glutamate or their isomers or their hydrate or cupric from One or more in sub- pharmaceutically acceptable salt；
Manganese or manganese salt be selected from manganese sulfate, manganese gluconate, lactobionic acid manganese, manganese citrate, manganese lactate or Pfansteihl manganese, manganese acetate, L-ASPARTIC ACID manganese, DL- L-aminobutanedioic acids manganese, Mn-Gly, glutamic acid manganese or their isomers or their hydrate or two One or more in valency manganese ion pharmaceutically acceptable salt；
Chromium or chromic salts are selected from chromium chloride, chromium sulfate, chromium gluconate, chromium citrate, Chromic lactate, L-aminobutanedioic acid chromium, chromic acetate, sweet One kind in propylhomoserin chromium, glutamic acid chromium or their isomers or their hydrates or trivalent chromic ion pharmaceutically acceptable salt It is or a variety of；Selenium is selected from the one or more of selenous acid, sodium selenite or its hydrate or the acceptable pharmaceutical salts of selenous acid.
2. the pharmaceutical composition of various trace elements V, it is characterised in that：One unit dose or unit formulation or unit volume Said composition in main ingredient component weight number or the ratio between parts by weight be：Containing zinc (Zn) 4.5~5.5mg, copper (Cu) 0.9~ 1.1mg, manganese (Mn) 0.45~0.55mg, μ g of chromium (Cr) 9.0~11, the μ g of selenium 54~66；Or in said one unit dose or In the said composition of unit formulation or unit volume containing above-mentioned each main ingredient component weight number or parts by weight 0.25~50 Times；Said composition can form injection with pharmaceutically acceptable auxiliary material；
Wherein, zinc or zinc salt are selected from zinc gluconate, lactobionic acid zinc, zinc citrate, zinc lactate or Pfansteihl zinc, zinc acetate, door Winter propylhomoserin zinc, glycine zine, zinc glutamate or their isomers or their hydrate or zinc ion are pharmaceutically acceptable One or more in salt；
Copper or mantoquita be selected from copper sulphate, copper gluconate, lactobionic acid copper, copper citrate, copper lactate or Pfansteihl copper, copper acetate, D- or L- or DL- L-aminobutanedioic acids copper, cupric glycinate, cupric glutamate or their isomers or their hydrate or cupric from One or more in sub- pharmaceutically acceptable salt；
Manganese or manganese salt be selected from manganese sulfate, manganese gluconate, lactobionic acid manganese, manganese citrate, manganese lactate or Pfansteihl manganese, manganese acetate, L-ASPARTIC ACID manganese, DL- L-aminobutanedioic acids manganese, Mn-Gly, glutamic acid manganese or their isomers or their hydrate or two One or more in valency manganese ion pharmaceutically acceptable salt；
Chromium or chromic salts are selected from chromium chloride, chromium sulfate, chromium gluconate, chromium citrate, Chromic lactate, L-aminobutanedioic acid chromium, chromic acetate, sweet One kind in propylhomoserin chromium, glutamic acid chromium or their isomers or their hydrates or trivalent chromic ion pharmaceutically acceptable salt It is or a variety of；Selenium is selected from the one or more of selenous acid, sodium selenite or its hydrate or the acceptable pharmaceutical salts of selenous acid；
Pharmaceutically acceptable auxiliary material or excipient are in addition to water for injection, it may include pharmaceutically acceptable amides compound, Pharmaceutically acceptable aminated compounds, amino acid or its pharmaceutical salts, for example：D- or L- or DL-Lys or Lysine Acetate or Arginine or acetic arginine or taurine or glycine or L-aminobutanedioic acid or Monosodium L-aspartate or D- or L- or DL-histidine Or cysteine or methionine or its salt, pharmaceutically acceptable organic acid or its salt, pharmaceutically acceptable alcohol compound or One or more in their pharmaceutically acceptable salt etc. or their isomers or its solvated compounds or its hydrate.
3. the pharmaceutical composition of various trace elements V, it is characterised in that：One unit dose or unit formulation or unit volume Said composition in main ingredient component weight number or the ratio between parts by weight be：Containing zinc (Zn) 4.5~5.5mg, copper (Cu) 0.9~ 1.1mg, manganese (Mn) 0.45~0.55mg, μ g of chromium (Cr) 9.0~11, the μ g of selenium 54~66；Or in said one unit dose or In the said composition of unit formulation or unit volume containing above-mentioned each main ingredient component weight number or parts by weight 0.25~50 Times；Said composition can form injection with pharmaceutically acceptable auxiliary material；
Wherein, zinc or zinc salt are selected from zinc gluconate or zinc gluconate hydrate, zinc gluconate (II) dihydrate, grape The hydrate of saccharic acid zinc 3, lactobionic acid zinc or lactobionic acid zinc hydrate, zinc citrate or the zinc of citric acid three or its zinc citrate hydrate Zinc citrate dihydrate, zinc lactate, the hydrate of Pfansteihl zinc 3, Pfansteihl zinc, the hydrate of Pfansteihl zinc 3, zinc acetate, acetic acid One or more in the hydrate of zinc 2, D- or L- or DL- L-aminobutanedioic acids zinc, glycine zine, zinc glutamate or its hydrate；
Copper or mantoquita are selected from copper sulphate, copper sulfate monohydrate, three brochanites, cupric sulfate pentahydrate, copper gluconate, copper gluconate 1 hydrate, the hydrate of copper gluconate 2, lactobionic acid copper or lactobionic acid copper hydrate, copper citrate or the bronze medal of citric acid three or its lemon The hydrate of lemon acid copper 2.5, copper lactate or Pfansteihl copper or its hydrate, D- or L- or DL- L-aminobutanedioic acids copper or their hydration One or more in thing, copper acetate or its hydrate of copper acetate 1, cupric glycinate, cupric glutamate；
Manganese or manganese salt be selected from manganese sulfate or, the hydrate of manganese sulfate 1, manganese gluconate, manganese gluconate hydrate, lactobionic acid manganese, Or lactobionic acid manganese hydrate, manganese citrate or the manganese of citric acid three or manganese citrate hydrate, manganese lactate or Pfansteihl manganese or its water Compound, manganese acetate or the hydrate of manganese acetate 4, L-ASPARTIC ACID manganese, DL- L-aminobutanedioic acids manganese, Mn-Gly, glutamic acid manganese or its water One or more in compound；
Chromium or chromic salts are selected from chromium chloride, the hydrate of chromium chloride 6, chromium sulfate, the hydrate of chromium sulfate 6, chromium gluconate or glucose Sour chromium hydrate, chromium citrate or chromium citrate hydrate, Chromic lactate or Pfansteihl chromium or its hydrate, D- or L- or DL- doors Winter propylhomoserin chromium or D- or the hydrate of L- or DL-- L-aminobutanedioic acids chromium 3, chromic acetate, glycine chromium, glutamic acid chromium or its hydrate It is one or more；Selenium is selected from the one or more of selenous acid, sodium selenite or its hydrate or the acceptable pharmaceutical salts of selenous acid；
In above-mentioned composition and pharmaceutically acceptable auxiliary material or excipient composition injection, the pharmacy in addition to water for injection One or more contents in the injection of a unit dose in upper acceptable auxiliary material or excipient are selected from 0.0010 ~0.40g, it is more preferably 0.010~0.30g, more preferably 0.020~0.20g；
Pharmaceutically acceptable auxiliary material or excipient are in addition to water for injection, it may include pharmaceutically acceptable amides compound, Pharmaceutically acceptable aminated compounds, amino acid or its pharmaceutical salts, for example：D- or L- or DL-Lys or Lysine Acetate or Arginine or acetic arginine or taurine or glycine or L-aminobutanedioic acid or Monosodium L-aspartate or D- or L- or DL-histidine Or cysteine or methionine or its salt, pharmaceutically acceptable organic acid or its salt, pharmaceutically acceptable alcohol compound or Their pharmaceutically acceptable salt etc. or their chiral isomer or its solvated compounds or one kind in its hydrate or It is a variety of.
4. the pharmaceutical composition of various trace elements V, it is characterised in that：One unit dose or unit formulation or unit volume Said composition in main ingredient component weight number or the ratio between parts by weight be：Containing zinc (Zn) 5mg, copper (Cu) 1mg, manganese (Mn) 0.50mg, μ g of chromium (Cr) 10, the μ g of selenium 98；Or in said one unit dose or unit formulation or the said composition of unit volume In the weight number containing above-mentioned each main ingredient component or 0.25~50 times of parts by weight；Said composition can with it is pharmaceutically acceptable Auxiliary material forms injection；
The pharmaceutical composition of the various trace elements of the present invention more preferably, a unit dose or unit formulation or unit volume The ratio between the weight number of main ingredient component or parts by weight are about in said composition：Containing zinc (Zn) 10mg, copper (Cu) 2mg, manganese (Mn) 1.0mg, μ g of chromium (Cr) 20, the μ g of selenium 196；Said composition can form injection with pharmaceutically acceptable auxiliary material；
The pharmaceutical composition of the various trace elements of the present invention more preferably, a unit dose or unit formulation or unit volume The ratio between the weight number of main ingredient component or parts by weight are about in said composition：Containing zinc (Zn) 15mg, copper (Cu) 3mg, manganese (Mn) 1.50mg, μ g of chromium (Cr) 30, the μ g of selenium 294；Said composition can form injection with pharmaceutically acceptable auxiliary material；
The pharmaceutical composition of the various trace elements of the present invention more preferably, a unit dose or unit formulation or unit volume The ratio between the weight number of main ingredient component or parts by weight are about in said composition：Containing zinc (Zn) 25mg, copper (Cu) 5mg, manganese (Mn) 2.50mg, μ g of chromium (Cr) 50, the μ g of selenium 490；Said composition can form injection with pharmaceutically acceptable auxiliary material；
The pharmaceutical composition of the various trace elements of the present invention more preferably, a unit dose or unit formulation or unit volume The ratio between the weight number of main ingredient component or parts by weight are about in said composition：Containing the 0mg of zinc (Zn) 5, copper (Cu) 10mg, manganese (Mn) 5.0mg, μ g of chromium (Cr) 100, the μ g of selenium 980；Said composition can form injection with pharmaceutically acceptable auxiliary material；
The pharmaceutical composition of the various trace elements of the present invention more preferably, a unit dose or unit formulation or unit volume The ratio between the weight number of main ingredient component or parts by weight are about in said composition：Containing zinc (Zn) 75mg, copper (Cu) 15mg, manganese (Mn) 7.5mg, μ g of chromium (Cr) 150, the μ g of selenium 1470；Said composition can form injection with pharmaceutically acceptable auxiliary material；
Wherein, zinc or zinc salt are selected from zinc gluconate or zinc gluconate hydrate, zinc gluconate (II) dihydrate, grape The hydrate of saccharic acid zinc 3, lactobionic acid zinc or lactobionic acid zinc hydrate, zinc citrate or the zinc of citric acid three or its zinc citrate hydrate Zinc citrate dihydrate, zinc lactate, the hydrate of Pfansteihl zinc 3, Pfansteihl zinc, the hydrate of Pfansteihl zinc 3, zinc acetate, acetic acid One or more in the hydrate of zinc 2, D- or L- or DL- L-aminobutanedioic acids zinc, glycine zine, zinc glutamate or its hydrate；
Copper or mantoquita are selected from copper sulphate, copper sulfate monohydrate, three brochanites, cupric sulfate pentahydrate, copper gluconate, copper gluconate 1 hydrate, the hydrate of copper gluconate 2, lactobionic acid copper or lactobionic acid copper hydrate, copper citrate or the bronze medal of citric acid three or its lemon The hydrate of lemon acid copper 2.5, copper lactate or Pfansteihl copper or its hydrate, D- or L- or DL- L-aminobutanedioic acids copper or their hydration One or more in thing, copper acetate or its hydrate of copper acetate 1, cupric glycinate, cupric glutamate；
Manganese is selected from manganese sulfate or the hydrate of manganese sulfate 1, manganese gluconate, manganese gluconate hydrate, lactobionic acid manganese or lactose Sour manganese hydrate, manganese citrate or the manganese of citric acid three or manganese citrate hydrate, manganese lactate or Pfansteihl manganese or its hydrate, vinegar In the sour hydrate of manganese or manganese acetate 4, L-ASPARTIC ACID manganese, DL- L-aminobutanedioic acids manganese, Mn-Gly, glutamic acid manganese or its hydrate One or more；
Chromium or chromic salts are selected from chromium chloride, the hydrate of chromium chloride 6, chromium sulfate, the hydrate of chromium sulfate 6, chromium gluconate or glucose Sour chromium hydrate, chromium citrate or chromium citrate hydrate, Chromic lactate or Pfansteihl chromium or its hydrate, D- or L- or DL- doors Winter propylhomoserin chromium or D- or the hydrate of L- or DL-- L-aminobutanedioic acids chromium 3, chromic acetate, glycine chromium, glutamic acid chromium or its hydrate It is one or more；Selenium is selected from selenous acid, sodium selenite, the hydrate of sodium selenite 5, sodium hydrogen selenite or the acceptable medicine of selenous acid With the one or more in salt；
In above-mentioned composition and pharmaceutically acceptable auxiliary material or excipient composition injection, the pharmacy in addition to water for injection One or more contents in the injection of a unit dose in upper acceptable auxiliary material or excipient are selected from 0.0010 ~0.40g, it is more preferably 0.010~0.30g, more preferably 0.020~0.20g；
Pharmaceutically acceptable auxiliary material or excipient are in addition to water more preferably：D- or L- or DL- lysine, Lysine Acetate, half Cystine, methionine, arginine, acetic arginine, L-aminobutanedioic acid, Monosodium L-aspartate, glutamic acid, glycine, taurine, figured silk fabrics ammonia Acid, threonine, cysteine, cystine, glutamine, 5- oxylysines, histidine, 3- hydroxy-prolines, 4- hydroxyl dried meat ammonia Acid, proline, ornithine, citrulling, creatine, 3- alanine, theanine, 2-amino-butyric acid, 4-Aminobutanoicacid, 2- amino -2- Methylpropanoic acid, 2- methyl -3- alanines, 2,6- diaminopimelic acids, 2- amino-3-phenyl butyrics, 4- hydroxyarginines, 4- It is hydroxyl ornithine, 4- hydroxyhomoarginines, 2,4-diamino-butanoic, malic acid, butanedioic acid, ascorbic acid, L-AA, different Ascorbic acid, sodium isoascorbate, nicotinic acid, niacinamide, pantothenic acid, sodium pantothenate, citric acid, sodium citrate, lactic acid, sodium lactate, breast Saccharic acid, sodium lactonic, gluconic acid, sodium gluconate, trehalose, urea, thiocarbamide, maltitol, sorbierite, mannitol, breast In sugar alcohol, xylitol, antierythrite or its hydrate or their pharmaceutically acceptable salt or their chiral isomer etc. It is one or more.
5. the pharmaceutical composition of various trace elements V according to claim 1-3, it is characterised in that：The present invention's is a variety of micro- The medicine composition injection of secondary element V, main ingredient group in a unit dose or the said composition of unit formulation or unit volume The ratio between the weight number divided or parts by weight are：
Zinc gluconate or zinc gluconate hydrate, the zinc gluconate dihydrate or hydrate 31.37- of zinc gluconate 3 38.35mg (with zinc gluconate anhydride weight calculation amount) or zinc acetate or the hydrate 15.08-18.45mg of zinc acetate 2 are (with acetic acid Zinc weight calculation amount) or L- or D- or DL- L-aminobutanedioic acids zinc or L- or D- or DL- L-aminobutanedioic acid zinc hydrates 22.69-27.74mg (with L-aminobutanedioic acid zinc anhydride weight calculation amount),
Copper gluconate or the hydrate 6.4240-7.8516mg of the hydrate of copper gluconate 1 or copper gluconate 2 are (with glucose Sour copper anhydride weight calculation amount) or copper sulphate or cupric sulfate pentahydrate 3.537-4.323mg (with cupric sulfate pentahydrate weight calculation amount) or D- or L- or DL- L-aminobutanedioic acids copper or D- or L- or DL- L-aminobutanedioic acid copper hydrates 4.64-5.69mg are (with L-aminobutanedioic acid copper anhydride Weight calculation amount) or the hydrate 2.82-3.46mg of copper acetate 1, manganese chloride or the hydrate of manganese chloride 2 or the hydrate 1.03- of manganese chloride 4 1.26mg (with manganese chloride weight calculation amount) or manganese gluconate or the hydrate 3.65-4.47mg of manganese gluconate 2 are (with manganese gluconate Anhydride weight calculation amount) or the hydrate 1.38-1.7mg or D- of manganese sulfate 1 or L- or DL- L-aminobutanedioic acids manganese or D- or L- or DL- doors Winter propylhomoserin manganese hydrate 2.6-3.2mg (with L-aminobutanedioic acid anhydrous manganese thing weight calculation amount),
The hydrate 46.17-56.43 μ g of chromium chloride 6 or chromium gluconate or chromium gluconate hydrate are (anhydrous with chromium gluconate Thing weight calculation amount) 110-135 μ g or D- or L- or DL- L-aminobutanedioic acids chromium 3 hydrate 43.6-53.3 μ g or chromium citrate 107- 131.2μg；
Selenium is selected from selenous acid 88.2--107.8 or sodium selenite or the hydrate 130.6-160 μ g of sodium selenite 5 or sodium hydrogen selenite The one or more of 74.96-91.63 μ g or its hydrate or the acceptable pharmaceutical salts of selenous acid；
Or contain above-mentioned each main ingredient component in the said composition of said one unit dose or unit formulation or unit volume Weight number or 0.25~50 times of parts by weight；Said composition can inject with pharmaceutically acceptable auxiliary material or excipient composition Agent；In the injection of aforementioned pharmaceutical compositions, in the pharmaceutically acceptable auxiliary material or excipient in addition to water for injection One or more content in the injection of a unit dose is selected from 0.0010~0.40g, more preferably for 0.010~ 0.30g, more preferably 0.020~0.20g；
Pharmaceutically acceptable auxiliary material or excipient are in addition to water more preferably：D- or L- or DL- lysine, Lysine Acetate, half Cystine, methionine, arginine, acetic arginine, L-aminobutanedioic acid, Monosodium L-aspartate, glutamic acid, glycine, taurine, figured silk fabrics ammonia Acid, threonine, cysteine, cystine, glutamine, 5- oxylysines, histidine, 3- hydroxy-prolines, 4- hydroxyl dried meat ammonia Acid, proline, ornithine, citrulling, creatine, 3- alanine, theanine, 2-amino-butyric acid, 4-Aminobutanoicacid, 2- amino -2- Methylpropanoic acid, 2- methyl -3- alanines, 2,6- diaminopimelic acids, 2- amino-3-phenyl butyrics, 4- hydroxyarginines, 4- It is hydroxyl ornithine, 4- hydroxyhomoarginines, 2,4-diamino-butanoic, malic acid, butanedioic acid, ascorbic acid, L-AA, different Ascorbic acid, sodium isoascorbate, nicotinic acid, niacinamide, pantothenic acid, sodium pantothenate, citric acid, sodium citrate, lactic acid, sodium lactate, breast Saccharic acid, sodium lactonic, gluconic acid, sodium gluconate, trehalose, urea, thiocarbamide, maltitol, sorbierite, mannitol, breast In sugar alcohol, xylitol, antierythrite or its hydrate or their pharmaceutically acceptable salt or their chiral isomer etc. It is one or more.
6. the pharmaceutical composition of various trace elements V according to claim 1-5, it is characterised in that：One unit dose or The ratio between the weight number of main ingredient component or parts by weight are in the said composition of unit formulation or unit volume：
Zinc gluconate or zinc gluconate hydrate, the zinc gluconate dihydrate or hydrate 34.86mg of zinc gluconate 3 Or 34.9mg (with zinc gluconate anhydride weight calculation amount) or D- or L- or DL- L-aminobutanedioic acids zinc 25.21mg or D- or L- or DL- L-aminobutanedioic acid zinc hydrate 25.21mg or 25.2mg (with L-aminobutanedioic acid zinc weight calculation amount)；The μ g of 6 hydrate of chromium chloride 51.3 or grape Saccharic acid chromium or the μ g of chromium gluconate hydrate 122.7 (with chromium gluconate weight calculation amount)；Copper gluconate or the water of copper gluconate 1 Compound or copper gluconate 2 hydrate 6.42mg or 6.4mg (with copper gluconate weight calculation amount) or cupric sulfate pentahydrate 3.93mg；Portugal Grape saccharic acid manganese or the hydrate 4.06mg of manganese gluconate 2 (with manganese gluconate weight calculation amount) or the hydrate 1.54mg of manganese sulfate 1；It is sub- The μ g of selenic acid 98 or sodium selenite or the μ g of 5 hydrate of sodium selenite 145.12 or 145.1 μ g or the 145 μ g or μ of sodium hydrogen selenite 83.29 G or 83.3 μ g；Or contain above-mentioned each main ingredient in the said composition of said one unit dose or unit formulation or unit volume The weight number of component or 0.25~50 times of parts by weight；Said composition can be prepared with pharmaceutically acceptable auxiliary material or excipient Into injection；In the injection of aforementioned pharmaceutical compositions, pharmaceutically acceptable auxiliary material or figuration in addition to water for injection One or more contents in the injection of a unit dose in agent are selected from 0.0010~0.40g, are more preferably 0.010 ~0.30g, more preferably 0.020~0.20g；
Pharmaceutically acceptable auxiliary material or excipient are in addition to water more preferably：D- or L- or DL- lysine, Lysine Acetate, half Cystine, methionine, arginine, acetic arginine, L-aminobutanedioic acid, Monosodium L-aspartate, glutamic acid, glycine, taurine, figured silk fabrics ammonia Acid, threonine, cysteine, cystine, glutamine, 5- oxylysines, histidine, 3- hydroxy-prolines, 4- hydroxyl dried meat ammonia Acid, proline, ornithine, citrulling, creatine, 3- alanine, theanine, 2-amino-butyric acid, 4-Aminobutanoicacid, 2- amino -2- Methylpropanoic acid, 2- methyl -3- alanines, 2,6- diaminopimelic acids, 2- amino-3-phenyl butyrics, 4- hydroxyarginines, 4- It is hydroxyl ornithine, 4- hydroxyhomoarginines, 2,4-diamino-butanoic, malic acid, butanedioic acid, ascorbic acid, L-AA, different Ascorbic acid, sodium isoascorbate, nicotinic acid, niacinamide, pantothenic acid, sodium pantothenate, citric acid, sodium citrate, lactic acid, sodium lactate, breast Saccharic acid, sodium lactonic, gluconic acid, sodium gluconate, trehalose, urea, thiocarbamide, maltitol, sorbierite, mannitol, breast One kind in sugar alcohol, xylitol, antierythrite or its hydrate or their pharmaceutically acceptable salt or their isomers etc. It is or a variety of.
7. the pharmaceutical composition of various trace elements V according to claim 1-6, it is characterised in that：The present invention's is a variety of micro- The medicine composition injection of secondary element V, main ingredient group in a unit dose or the said composition of unit formulation or unit volume The ratio between the weight number divided or parts by weight are：Zinc acetate 2 hydrate 16.77mg or 16.8mg, the μ g of chromium gluconate 122.7 or chlorine Change the μ g or 51 μ g of 6 hydrate of chromium 51.3 or μ g of 3 hydrate of L-ASPARTIC ACID chromium 48.45, the hydrate of copper gluconate 2 or glucose The sour hydrate of copper 1 or copper gluconate 7.14mg (with copper gluconate weight calculation amount) or cupric sulfate pentahydrate 3.93mg, the water of manganese sulfate 1 The compound 1.54mg or hydrate 4.39mg of manganese gluconate 2；The μ g of selenous acid 98 or sodium selenite or the hydrate of sodium selenite 5 The 145.12 μ g or 145.1 μ g or 145 μ g or μ g of sodium hydrogen selenite 83.29 or 83.3 μ g；Or in said one unit dose or In the said composition of unit formulation or unit volume containing above-mentioned each main ingredient component weight number or parts by weight 0.25~50 Times；Said composition can be with pharmaceutically acceptable auxiliary material or excipient composition injection；In the injection of aforementioned pharmaceutical compositions In, one or more notes in a unit dose in the pharmaceutically acceptable auxiliary material or excipient in addition to water for injection The content penetrated in agent is selected from 0.0010~0.40g, is more preferably 0.010~0.30g, more preferably 0.020~0.20g.
Pharmaceutically acceptable auxiliary material or excipient are in addition to water more preferably：D- or L- or DL- lysine, Lysine Acetate, half Cystine, methionine, arginine, acetic arginine, L-aminobutanedioic acid, Monosodium L-aspartate, glutamic acid, glycine, taurine, figured silk fabrics ammonia Acid, threonine, cysteine, cystine, glutamine, 5- oxylysines, histidine, 3- hydroxy-prolines, 4- hydroxyl dried meat ammonia Acid, proline, ornithine, citrulling, creatine, 3- alanine, theanine, 2-amino-butyric acid, 4-Aminobutanoicacid, 2- amino -2- Methylpropanoic acid, 2- methyl -3- alanines, 2,6- diaminopimelic acids, 2- amino-3-phenyl butyrics, 4- hydroxyarginines, 4- It is hydroxyl ornithine, 4- hydroxyhomoarginines, 2,4-diamino-butanoic, malic acid, butanedioic acid, ascorbic acid, L-AA, different Ascorbic acid, sodium isoascorbate, nicotinic acid, niacinamide, pantothenic acid, sodium pantothenate, citric acid, sodium citrate, lactic acid, sodium lactate, breast Saccharic acid, sodium lactonic, gluconic acid, sodium gluconate, trehalose, urea, thiocarbamide, maltitol, sorbierite, mannitol, breast One kind in sugar alcohol, xylitol, antierythrite or its hydrate or their pharmaceutically acceptable salt or their isomers etc. It is or a variety of.
8. the pharmaceutical composition of the various trace elements according to claim 1-7, it is characterised in that：Its preparation method selects From：Method one, step 1, pharmaceutically acceptable salt or other auxiliary materials or excipient dissolved with appropriate water for injection, with appropriate Water for injection dissolving or be acidified with pharmaceutically acceptable pH adjusting agent；It is step 2, zinc ion is acceptable medicinal Salt, manganese ion pharmaceutically acceptable salt, copper ion pharmaceutically acceptable salt, chromium ion pharmaceutically acceptable salt are used one by one Appropriate water for injection dissolving or the water for injection dissolving with appropriate acidifying；Step 3, by selenous acid or its pharmaceutical salts with appropriate Water for injection dissolving；Step 4, each step solution is well mixed, then adjusts pH with pharmaceutically acceptable pH adjusting agent For value between 3.8~6.0, more preferably pH value is between 4.0~5.5, or milipore filter removes thermal source, or adds activated carbon decolorizing, mistake Decarburization is filtered, then moisturizing constant volume, refined filtration, examined, it is filling, seal, sterilize, pack, examine.Wherein, the injection water system of acidifying It is acidified with pharmaceutically acceptable pH adjusting agent, its pH is generally between 3.1-6.0.
Or method two, step 1, dissolve pharmaceutically acceptable salt or other auxiliary materials or excipient with appropriate water for injection, use Pharmaceutically acceptable pH adjusting agent is acidified；Step 2, manganese ion pharmaceutically acceptable salt, copper ion pharmaceutically may be used The salt of receiving dissolves with appropriate water for injection dissolving or with the water for injection of appropriate acidifying respectively；Step 3, can by zinc ion The pharmaceutical salts of the receiving water for injection of appropriate acidifying dissolves；Step 4, by chromium ion pharmaceutically acceptable salt with appropriate Water for injection dissolves or dissolved with the water for injection of appropriate acidifying；Step 5, by selenous acid or its pharmaceutical salts respectively with appropriate Water for injection dissolves；Step 6, solution of the solution of step 2 respectively with step 1 is well mixed；Step 7, the solution by step 3 Mixed with the solution of step 6；Step 8, the solution of the solution of step 4 and step 5 mixed, then the solution with step 7 mixes, Then with pharmaceutically acceptable pH adjusting agent adjust solution pH value between 3.8~6.0, preferable ph 4.0~5.5 it Between；Step 9, in solution add proper amount of active carbon to decolourize, filter decarburization, or filtering with microporous membrane, or using retention average molecular matter The membrane filtration for 0.3 ten thousand to 300,000 is measured, or above-mentioned filter method is used in mixed way, it is preferred to use retention relative molecular mass 3000 ~60000 milipore filter removes remaining thermal source, moisturizing constant volume；0.20-0.45 μm of miillpore filter or ultrafiltration etc. carry out refined filtration, inspection Test, it is filling, seal, sterilize, pack, examine.Wherein, the upper acceptable pH adjusting agent of the injection water system medication of acidifying by its Acidifying, its pH is generally between 3.1-6.0；
Step in above-mentioned each method can intersect in different ways, in the case where not violating pharmaceutical principle or interaction replacement makes With.
9. the preparation method of the pharmaceutical composition of various trace elements V according to claim 8, it is characterised in that：The group Compound and pharmaceutically acceptable auxiliary material or excipient form injection pH value between 3.8-6.0, and pH value is preferably in 4.0-5.5 Between.
10. the pharmaceutical composition of various trace elements V according to claims 1 to 7, it is characterised in that：Its purposes exists In：Application in the medicine of prevention or treatment people with mammal zinc, manganese, copper, selenium, chromium deficiency and its syndrome is prepared.
CN201610752293.8A 2016-08-29 2016-08-29 The medical composition and its use of various trace elements V Pending CN107789365A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113045559A (en) * 2021-03-15 2021-06-29 贵州医科大学 Diaryl urea PI3K alpha/mTOR double-target inhibitor and pharmaceutical composition and application thereof

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Publication number Priority date Publication date Assignee Title
CN103340895A (en) * 2013-06-27 2013-10-09 江西博意特科技有限公司 Composition containing various microelements, preparation and preparation method thereof
CN104971074A (en) * 2014-04-10 2015-10-14 北京京卫信康医药科技发展有限公司 Multiple trace element composition and preparation method thereof

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Publication number Priority date Publication date Assignee Title
CN103340895A (en) * 2013-06-27 2013-10-09 江西博意特科技有限公司 Composition containing various microelements, preparation and preparation method thereof
CN104971074A (en) * 2014-04-10 2015-10-14 北京京卫信康医药科技发展有限公司 Multiple trace element composition and preparation method thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113045559A (en) * 2021-03-15 2021-06-29 贵州医科大学 Diaryl urea PI3K alpha/mTOR double-target inhibitor and pharmaceutical composition and application thereof

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Application publication date: 20180313