CN101863755B - Chromium malate complex and preparation method and application thereof - Google Patents
Chromium malate complex and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a chromium malate complex and a preparation method and application thereof, belonging to the technical field of pharmaceutical chemicals industrial production technology. The molecular formula of the chromium malate complex is Cr2 (C4H4O5) 3.5 H2O. The method of the invention comprises the following steps: obtaining malate by the reaction of malic acid and alkali liquor; and obtaining the chromium malate complex by the reaction of the malate and chromium trichloride; or mixing the malic acid and the chromium trichloride solution and then adding the alkali liquor for reaction to obtain the chromium malate complex, wherein the concentration of the malic acid and the chromium trichloride is 0.1-5mol/L, the mol ratio of the chromium ion to the malic acid is 1:1-1:3, and the reaction temperature is normal temperature-100 DEG C. The reaction solution is under the condition of pH 3-7, the reaction medium can be water, 20%-80% methanol or ethanol solution, and the used alkali is ammonia or sodium hydroxide solution or potassium hydroxide solution. The chromium malate complex can be used for preparing antidiabetic drugs for treating diabetes and hypoglycemic healthproducts. The chromium malate complex of the invention has obvious blood sugar lowering activity, has obvious promoting action on the synthesis of hepatic glycogen, and has stable structure and simple preparation method.
Description
Technical field
The present invention relates to chromium malate and its production and use, refer in particular to the chromium malate complex with hypoglycemic activity, belong to medication chemistry industrial manufacture process technical field.
Background technology
Along with the development of human society, diabetes have become the third-largest disease after cardiovascular disorder, tumour.According to the World Health Organization (WHO) and International Diabetes Federation (IDF) 1997 annual reports, nineteen ninety-five the whole world diabetic subject 1.25 hundred million people are approximately arranged, predict 2025 and will increase sharply to 2.99 hundred million people.In China, along with growth in the living standard and aging population, diabetes prevalence also is year by year ascendant trend.According to estimates, China diabetic subject in 1999 is up to more than 4,000 ten thousand people, the crowd who still has fifty-five million not made a definite diagnosis, and constantly rise with annual 0.1% speed.Diabetes also can cause various serious complication, such as fatal diseases of disabling such as ephrosis, retinopathy and vascular change at lower extremities.Therefore the research and development of hypoglycemic drug and functional foodstuff have become one of study hotspot.
Present hypoglycemic medicine mainly contains yellow ureas, biguanides, alpha-glucosidase inhibitor, euglycemic agent, free fatty acids oxidation retarder etc., some toxic side effect of these ofhypoglycemic medicines is obvious, some easily produces uncomfortable disease, be easy to cause hypoglycemia, appetite stimulator, urine ketosis, oxypathy etc. such as the yellow carbamide type medicine of long-term taking, biguanides easily causes lactic acidosis, and long-term taking increases liver kidney burden etc.
Cr
3+Being one of trace element of needed by human, is normal glucose and metabolism of fat essential trace element, and structure, function and the target tissue cell state of Regular Insulin all had a significant effect, and body lacks Cr
3+Can cause sugar, disorders of lipid metabolism, impel atherosclerosis, low-density lipoprotein increases, and causes diabetes, the symptoms such as hyperlipidemia.Because the combination degree of multi-form chromium in tissue is different, cause specific absorption different.Inorganic chromium not only toxicity is large, and the absorption level is low, is about 0.14～3.0%; Organic chromium absorbs rapidly and safety, and specific absorption can reach 10～25%.Pyridine acid chromium salt (picolinate chromium) is widely used as blood sugar reducing health product additive at European ﹠ American Market.But the pyridine acid group is as part, and itself does not have biological activity, has bibliographical information to replenish for a long time pyridine acid chromium salt and can cause the pyridine acid group to be accumulated in vivo, produces toxic side effect.
China Patent No. CN 1431228A discloses " chitosan chromium and its production and use " on July 23rd, 2003, though the application of chitosan chromium aspect hypoglycemic has preferably result, can eliminate toxic side effect or harm that pyridine chromium etc. may bring to human body, but the molecular weight of chitosan is larger, is difficult to directly be absorbed by the body.Zhao's book waits clearly that (2003,20 (3): 115-118.) reported a kind of preparation method of chromium citrate, the method at first is Cr for the research of chromium citrate synthetic method, Heilongjiang University's natural science journal
2(SO
4)
36H
2O and ammoniacal liquor reaction generate chromium hydroxide precipitation, generate chromium citrate with citric acid reactions again.But chromium malate complex and preparation method thereof has no report both at home and abroad so far with hypoglycemic activity, also has no corresponding patent open.
Summary of the invention
The objective of the invention is provides a kind of chromium malate and preparation method thereof for solving the deficiency of above-mentioned background technology existence.This chromium malate is easily absorbed by the body, and can effectively replenish the required trivalent chromium of body, can eliminate the potential hazard that pyridine acid chromium salt etc. may bring to human body.The hypoglycemic purposes of this chromium malate is provided simultaneously, and it has the effect of lowering blood glucose, total cholesterol and triglyceride level, can be used as healthcare products or the foodstuff additive for the treatment of diabetes medicament and prevent diabetes.
The invention provides a kind of preparation method of novel complexes chromium malate, the method comprises the steps:
Oxysuccinic acid and alkaline reaction are obtained malate; With malate and chromium trichloride reaction, obtain chromium malate complex.
The present invention also provides another kind of chromium malate preparation method of the present invention, and the method comprises the steps:
Oxysuccinic acid is mixed with chromium trichloride solution, add again alkaline reaction, obtain chromium malate complex.When synthetic chromium malate complex of the present invention,
Wherein said oxysuccinic acid and chromium trichloride concentration 0.1～5mol.L
-1, the mol ratio of chromium ion and oxysuccinic acid is 1: 1～1: 3, temperature of reaction is normal temperature～100 ℃.
Wherein reaction soln can be to carry out under pH3～7 conditions under neutrallty condition in acidity, and reaction medium can make water, 20～80% methyl alcohol or ethanolic soln, and used alkali is ammoniacal liquor or sodium hydroxide solution or potassium hydroxide solution.
After synthetic the finishing, adopt easy method to isolate chromium malate, for example, can add the solubleness that alcohols or ketone equal solvent reduce chromium malate, settlement separate or centrifugation is finally by using the little solvent wash of chromium malate solvability, drying.
This title complex is confirmed as a kind of novel oxysuccinic acid title complex through ultraviolet-visible spectrum, infrared spectra, atomic absorption spectrum, ultimate analysis, heat analysis etc., and its molecular formula is Cr
2(C
4H
4O
5)
35H
2O.
Chromium malate of the present invention can be used for preparing ofhypoglycemic medicine and the health-caring product capable of reducing blood sugar for the treatment of diabetes, can the liquid or solid form foodstuff additive of organic trace element chromium (III) as a supplement; Can on various pharmaceutical preparations such as tablet, capsule and other medicines, use with composition forms.
Chromium malate provided by the invention and composition thereof mainly adopt oral method.
Chromium malate of the present invention has the lowering blood glucose effect, can make any formulation, such as tablet, capsule, solution, suspension agent, ointment, lyophilisate, pill, film, liposome etc.; Can make the protective foods with function of blood sugar reduction; Use as foodstuff additive, add to the liquid or solid powder type in the food such as beverage, cheese, bread, flour.
Chromium malate of the present invention is made for hypoglycemic medicine composition or health food composition, comprises chromium malate and other component drug carrier or auxiliary material.
In the chromium malate composition of the present invention, functional component is chromium malate.According to pharmacy and preparation needs, the carrier in the composition or auxiliary material are acceptable any with medicine.
The pharmaceutical composition that is used for the treatment of diabetes of the present invention or be used for hypoglycemic Halth-care composition and can be the formulations such as tablet, injection, capsule, injection liquid or oral liquid.
The usage quantity of chromium malate of the present invention can be determined the needs of different preparations according to pharmacy.
The invention has the advantages that: chromium malate of the present invention has obvious hypoglycemic activity, can regulate preferably triglyceride level and total cholesterol, and the synthetic of liver starch had obvious promoter action, and Stability Analysis of Structures, and the preparation method is easy.
Description of drawings
The infrared spectrogram of Fig. 1 chromium malate complex of the present invention;
Fig. 2 chromium malate complex of the present invention and the chromium trichloride ultraviolet-visible spectrogram in water; Wherein a is chromium trichloride, the b chromium malate complex;
The heat of Fig. 3 chromium malate complex of the present invention is analyzed the TG-DSC-DTG curve.
Embodiment
In order to be illustrated more clearly in content of the present invention, be described as follows with specific embodiment, specific embodiment does not limit context of the present invention.
Take by weighing 532mg (approximately 2mmol) six hydrated chromium trichlorides and 804mg (approximately 6mmol) oxysuccinic acid in the 100mL there-necked flask, 50% ethanolic soln that adds 20mL, stirring makes its dissolving, the sodium hydroxide solution that dropwise adds again 2mol/L is regulated pH3, at 100 ℃ of lower heated and stirred reaction 10h, along with the prolongation in reaction times, the reaction solution color gradually becomes purple by green.Centrifugal concentrating becomes its volume original 1/2～1/4, adds the dehydrated alcohol of 4 times of amounts in concentrated solution, in a large number precipitation occurs, leaves standstill, and is centrifugal, collecting precipitation.With absolute ethanol washing for several times, remove chromium trichloride and the oxysuccinic acid of not participating in reaction, collecting precipitation, vacuum-drying namely gets hepatic pulverulent solids.
Compositional analysis, Cr
2(C
4H
4O
5)
35H
2O theoretical value: C 24.42, H 3.75, and Cr 17.61%, trial value: C 23.97, and H 3.82, and Cr 17.45%.Infrared spectra (accompanying drawing 1): 3399cm
-1, 1725cm
-1, 1605cm
-1, 1386cm
-1, 623cm
-1, 572cm
-1, 492cm
-1, 424cm
-1Ultraviolet-visible absorption spectroscopy (H
2O, accompanying drawing 2): chromium trichloride (a) maximum absorption band λ
1Max=594nm, λ
2Max=422nm, chromium malate (b) maximum absorption band λ
1Max=565nm, λ
2Max=391nm, heat is analyzed (accompanying drawing 3): the chromium malate complex heat absorption loses crystal water, and corresponding to thermogravimetric curve, rate of weight loss is 15.3%, loses the 5mol crystal water in the molecular formula of rate of weight loss and supposition and conforms to.
Take by weighing 804mg (approximately 6mmol) oxysuccinic acid in the 100mL there-necked flask, add 50% methanol solution of 20mL, stir and make its dissolving, the potassium hydroxide solution that dropwise adds 2mol/L is regulated pH5, adds 0.2mol/L CrCl again
36H
2The 50% methanol solution 20mL of O, at 60 ℃ of lower heated and stirred reaction 10h, along with the prolongation in reaction times, the reaction solution color gradually becomes purple by green.Subsequent disposal is carried out with embodiment 1, and through signs such as ultimate analysis, spectroscopic analysis, heat analyses, the gained material is identical with embodiment 1.
Take by weighing 11320mg (approximately 50mmol) six hydrated chromium trichlorides and 6700mg (approximately 50mmol) oxysuccinic acid in the 100mL there-necked flask, the deionized water that adds 20mL, stirring makes its dissolving, dropwise weak ammonia is regulated pH7 again, at normal temperatures heated and stirred reaction 10h, along with the prolongation in reaction times, the reaction solution color gradually becomes purple by green.Subsequent disposal is carried out with embodiment 1, and through signs such as ultimate analysis, spectroscopic analysis, heat analyses, the gained material is identical with embodiment 1.
The hypoglycemic test of chromium malate complex:
1 material and equipment
1.1 animal
The ICR mouse, male and female half and half, body weight 20 ± 2g, the cleaning level is purchased from Yangzhou University comparative medicine center, conformity certification numbering: SCXK (Soviet Union) 2007-0001.Quarantine 3d raises and stabilizes to 21 ± 1 ℃ before the experiment, and humidity is 60 ± 5%.
1.2 medicine and reagent
Tetraoxypyrimidine, the rich U.S. biotechnology in Hefei limited liability company
Chromium malate complex: laboratory self-control (be 17.56% through its chrome content of atomic absorption detecting)
CrCl
36H
2O: Chemical Reagent Co., Ltd., Sinopharm Group, analytical pure.
Glyburide: Beijing Pharma Pacific Pty. Ltd.
Physiological saline: Hunan Cologne Pharmaceutical Co., Ltd, the accurate word H51021158 of traditional Chinese medicines
The anthrone of anthrone reagent: 0.2g is dissolved in (adapted on the same day) in the 100mL vitriol oil;
The Triglyceride Reagent box: bio-engineering research institute is built up in Nanjing;
Cholesterol Kit: bio-engineering research institute is built up in Nanjing.
1.3 key instrument equipment
Steady bold and unconstrained type blood glucose meter and supporting blood sugar test paper thereof: medicine equipment company limited of Johnson ﹠ Johnson (China);
Spectra Max 190 microplate reader: U.S. molecular device company;
1.4 statistical method
Data are processed with the Excel statistical software.The result uses
Expression is with the significance of each administration group and control group difference relatively of ANOVA check between group.* represent p＜0.05, represent this administration group and control group significant difference.
2 experimental techniques
2.1 the preparation of alloxan diabetes model
Except the blank group, all mouse shift to an earlier date fasting 12h, freely drink water, tetraoxypyrimidine is mixed with 0.8% injection liquid with physiological saline, every mouse is pressed the disposable injection in 200mg/kg dosage abdominal cavity, afterbody is got blood and is surveyed fasting plasma glucose behind the injection 5d, and fasting blood sugar is included diabetes model in the above person of 11.1mmol/L.
2.2 grouping
Get 10 not mouse of modeling, be the blank group; With hyperglycemia mouse random packet, 10 every group, totally 6 groups: dosage group, chromium malate complex high dose group, chromium trichloride group in hyperglycemia model control group, positive drug group, chromium malate complex low dose group, the chromium malate complex.
2.3 dosage design
As shown in table 1, be the dosage of each administration group, each administration group administration 14d.
Each administration group dosage of table 1
Annotate: dosage calculates with chromium malate complex and six hydrated chromium trichlorides, and wherein the chromium malate complex chrome content is that 17.45%, six hydrated chromium trichloride chrome content is 19.51%.
2.4 detection index
(1) growth of animal situation
Observe animal every day once, observe animal mental status, behavior and hair color and have or not unusually, weigh and record to understand the weight of animals growth pattern.
(2) fasting plasma glucose pH-value determination pH
Behind fasting 3h after the administration of 14d last, deduct Mouse Tail-tip, test paper is inserted blood glucose meter, droplets of whole blood records reading on blood sugar test paper.
(3) mensuration of blood fat (comprising total cholesterol TCH, triglyceride level TG)
Administration is got blood with mouse orbit after finishing, and collects approximately 1.5mL of whole blood, the centrifugal 10min of 3000rpm.Get supernatant liquor 100 μ L, measure the content of total cholesterol and triglyceride level in strict accordance with the test kit operation instructions.
(4) mensuration of liver starch level
Put to death mouse, get liver, blot through the blank rinsing filter paper of physiological saline, accurately take by weighing liver 100mg in vitro, add 8mL trichoroacetic acid(TCA) homogenate 1min, 3000r/min, centrifugal 15min.Get supernatant liquor in another in vitro, with the content of anthrone colorimetric method for determining liver starch.
3 experimental results
3.1 each medicine is to the impact effect of diabetic mice body weight.
Each medicine of table 2 is on the impact of diabetic mice body weight (g)
Compare with the blank group,
*P＜0.05
As can be seen from Table 2, the diabetic mice body weight of modeling success significantly is lower than the blank mouse of organizing behind the 14d.Wanting that diabetic mice weight ratio model group mouse after giving medicine increases is many, shows that chromium malate has certain effect to the increase of diabetic mice body weight
3.2 each medicine is on the impact of blood glucose in diabetic mice
Each medicine of table 3 is on the impact of blood glucose in diabetic mice (mmol/L)
Compare with the blank group,
*P＜0.05
As shown in table 3, the blood glucose value of blank group mouse remains on normal value behind the 14d, and the mouse blood sugar value of model group is organized mouse apparently higher than blank.Compare the decline that has in various degree before basic, normal, high three the dosage groups of chromium malate complex and the administration, its inhibiting rate all is higher than the chromium trichloride group, and visible chromium malate complex blood sugar decreasing effect is better than chromium trichloride.
3.3 each medicine is on the impact of diabetic mice blood fat
(1) each medicine is on the impact of diabetic mice triglyceride level
As shown in table 4, chromium malate complex has certain regulating effect to triglyceride level.
(2) each medicine is on the impact of diabetic mice total cholesterol
As shown in table 5, chromium malate complex has preferably regulating effect to the hypercholesterolemia symptom.
Each medicine of table 4 is on the impact of diabetic mice triglyceride level (mg/dl)
The group triglyceride level
Blank group 0.815 ± 0.27
Model group 1.17 ± 0.36
Positive drug group 1.13 ± 0.34
Chromium malate low dose group 1.13 ± 0.21
Dosage group 0.815 ± 0.37 in the chromium malate
*
Chromium malate high dose group 0.951 ± 0.46
Chromium trichloride group 1.07 ± 0.16
Compare with model group,
*P＜0.05
Each medicine of table 5 is on the impact of diabetic mice total cholesterol (mg/dl)
The group total cholesterol
Blank group 2.30 ± 0.34
Model group 2.69 ± 0.47
Positive drug group 2.09 ± 0.39
Chromium malate low dose group 2.34 ± 0.20
Dosage group 2.09 ± 0.66 in the chromium malate
Chromium malate high dose group 2.34 ± 0.27
Chromium trichloride group 2.35 ± 0.41
3.4 each medicine is on the impact of diabetic mice liver starch
As shown in table 6, chromium malate complex liver starch synthetic has obvious promoter action, and its impact on liver starch is better than Glyburide and chromium trichloride.
Each medicine of table 6 is on the impact of diabetic mice liver starch (μ g/100mg)
The group liver starch
Model group 315.95 ± 198.93
Positive drug group 379.82 ± 253.31
Chromium malate low dose group 387.38 ± 238.20
Dosage group 473.75 ± 190.42 in the chromium malate
Chromium malate high dose group 622.95 ± 210.20
*
Chromium trichloride group 348.09 ± 217.46
Compare with the blank group,
*P＜0.05
4 conclusion chromium malates have obvious hypoglycemic activity, can regulate preferably triglyceride level and total cholesterol, and liver starch synthetic had obvious promoter action.
The chromium malate complex acute toxicity test
1 material and instrument
1.1 animal
The ICR mouse, male and female half and half, body weight 20 ± 2g, the cleaning level is purchased from Yangzhou University comparative medicine center, conformity certification numbering: SCXK (Soviet Union) 2007-0001.Quarantine 3d raises and stabilizes to 21 ± 1 ℃ before the experiment, and humidity is 60 ± 5%.
1.2 medicine and reagent
Chromium malate complex, laboratory self-control (be 17.56% through its chrome content of atomic absorption detecting).
1.3 key instrument equipment
The B3200S supersonic cleaning machine must be believed ultrasonic Shanghai company limited
BS124S type analysis balance Beijing Sai Duolisi instrument system company limited
Electronic balance BS124S Beijing Sai Duolisi Instr Ltd.
2 experimental techniques
Quarantine 3d before the experiment, getting immediately respectively 10 healthy mices is blank group and administration group, presses dosage 15231mg/kg, 0.15mL/10g per os gavage gives tested material.Animal overnight fasting before the gavage is freely drunk water, and continues after the administration to give normal diet behind the fasting 4h.Observe a week, observe animal every day once, record mouse mental status, behavior and hair color have or not unusually, weigh and record to understand the weight of animals growth pattern.
After 7d is observed in mouse contamination, put to death mouse, each composition is not 1 of blank group mouse and 2 of chromium malate groups.The random mouse liver that takes out rapidly fritter, heart and kidney are fixed (the tissue block size is 2.0cm * 2.0cm * 0.3cm, and the ratio of tissue block and formalin solution is 1: 10) with 10% formalin immediately.The dehydration of tissue block, embedding, section, HE dyeing are finished by the technician of Pathology Deparment of Zhenjiang City No.1 People's Hospital.
3 results
3.1 overview
1 all interior mouse do not occur unusual and dead after the mouse administration.Epidemiological Analysis by statistics, behind administration 3d and the 7d, oxysuccinic acid group and control group body weight change there was no significant difference (seeing Table 1); Mouse all increases weight, and puts to death after 1 week and dissects, and the visual inspection heart, liver, spleen, lung, kidney, stomach, intestines, thoracic cavity, abdominal cavity, each organ are all without unusual.Female, male its mouse oral LD
50Greater than 15000mg/kg.According to acute toxicity grading criteria regulation in " food safety toxicity assessment process and method ", chromium malate complex belongs to nontoxic level to the chmice acute Oral toxicity.
3.2 the impact on each tissue of mouse
The heart of blank group and chromium malate group test mice, liver, kidney is made section, after dyeing with the HE staining, examines under a microscope.Heart, liver, the kidney of finding chromium malate group mouse has no parenchyma sex change, necrosis, weave construction and has no variation.As seen chromium malate is to the heart of mouse, and liver, kidney also have no side effect.
Table 1 chromium malate complex maximum dosage-feeding is measured the body weight of mouse
4 conclusions
Studies on acute toxicity to chromium malate complex shows, within the observation period of 7d, abnormal conditions and death do not appear in mouse, the postmortem no abnormality seen.The tissue slice of heart, liver, kidney has no parenchymatous degeneration, necrosis, and weave construction has no variation.Female, male mice per os LD
50Greater than 15000mg/kg.And female, the male mice LD50 of passing through mouth of bibliographical information chromium trichloride are 2143.3mg/kg, and toxicity obviously reduced after visible chromium trichloride and oxysuccinic acid formed title complex.
Claims (1)
1. the preparation method of chromium malate complex is characterized in that the method comprises the steps: oxysuccinic acid and alkaline reaction are obtained malate; With malate and chromium trichloride reaction, obtain chromium malate complex, described oxysuccinic acid and chromium trichloride concentration 0.1～5mol.L
-1, the mol ratio of chromium ion and oxysuccinic acid is 1:1 ~ 1:3, temperature of reaction is normal temperature ~ 100 ℃.
2. the preparation method of chromium malate complex according to claim 1, it is characterized in that the method can also carry out in the steps below: oxysuccinic acid is mixed with chromium trichloride solution, add again alkaline reaction, obtain chromium malate complex, described oxysuccinic acid and chromium trichloride concentration 0.1～5mol.L
-1, the mol ratio of chromium ion and oxysuccinic acid is 1:1 ~ 1:3, temperature of reaction is normal temperature ~ 100 ℃.
3. the preparation method of chromium malate complex according to claim 1 and 2, it is characterized in that described reaction soln can be to carry out under pH3 ~ 7 conditions in acidity under neutrallty condition, reaction medium can make water, 20 ~ 80% methyl alcohol or ethanolic soln, and used alkali is ammoniacal liquor or sodium hydroxide solution or potassium hydroxide solution.
4. molecular formula is Cr
2(C
4H
4O
5)
35H
2The chromium malate complex of O is in the application of the ofhypoglycemic medicine of preparation treatment diabetes.
5. molecular formula is Cr
2(C
4H
4O
5)
35H
2The chromium malate complex of O is in the application of the health-caring product capable of reducing blood sugar of preparation treatment diabetes.
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| CN101495439A (en) * | 2006-07-10 | 2009-07-29 | 日本化学工业株式会社 | Aqueous solutions of organic acid chromium(III) salts and process for preparation thereof |
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| CN101117316A (en) * | 2007-07-07 | 2008-02-06 | 李恕勤 | Oral liquid for preventing and remitting diabetes |
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