CN102976962B - L-ornithine-aspirin double salt and preparation method and application thereof - Google Patents
L-ornithine-aspirin double salt and preparation method and application thereof Download PDFInfo
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- CN102976962B CN102976962B CN201210472148.6A CN201210472148A CN102976962B CN 102976962 B CN102976962 B CN 102976962B CN 201210472148 A CN201210472148 A CN 201210472148A CN 102976962 B CN102976962 B CN 102976962B
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- aspirin
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- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims abstract description 48
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- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims abstract description 16
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Abstract
The invention belongs to the field of medicines, and discloses L-ornithine-aspirin double salt and a preparation method and application thereof. The L-ornithine-aspirin composite is prepared by the following steps: preparing a water solution of free L-ornithine, adding aspirin for reaction to obtain a solution of L-ornithine aspirin salt, and separating out the solution in a crystalline form; or mixing the ethanol solution of aspirin and the ethanol solution of free L-ornithine to obtain the precipitate of L-ornithine aspirin salt, dissolving the precipitate, and recrystallizing to obtain the product. The molar ratio of L-ornithine to aspirin in the resulting crystals was 1: 1. The preparation method has the advantages of simple and easy operation, low cost, high yield, and improved quality of L-ornithine-aspirin. Animal experiment research proves that the L-ornithine aspirin has the functions of reducing fat and protecting liver, and can be used for preparing a medicament for reducing fat and protecting liver.
Description
Technical field
The invention belongs to field of medicaments, relate to L-ornithine-aspirin double salt double salt and its preparation method and application.
Background technology
Hyperlipidaemia is because Human Lipid Metabolism is disorderly, the paranormal a kind of illness of blood plasma inner lipid concentration, because lipid is many with protein binding in blood plasma, therefore also known as hyperlipoproteinemia.Main manifestations is that serum total cholesterol (TC), triglyceride level (TG) and low density lipoprotein cholesterol (LDL-C) level are too high or high density lipoprotein cholesterol (LDL-C) level is too low.Cholesterol in blood plasma, triglyceride level are the main components in atherosclerotic plaque, hyperlipidaemia is not only participated in directly and is promoted arteriosclerotic formation, and the formation of microthrombus is promoted by changing hemorheological property, cause microcirculation disturbance, result in generation and the development of cardiovascular and cerebrovascular disease, is one of important risk factor of cardiovascular disorder.Therefore, adjusting blood lipid and to improve the control of hemorheological property to cardiovascular diseases significant.Along with the raising of people's living standard, the sickness rate of hyperlipidaemia rises year by year, has become the focus of current research.In recent years, the development of medicine and pharmacology and research, the announcement of larger scale clinical experiment Intensive Lipid-lowing efficacy and saferry result, statins becomes and reduces the effective medicine of blood fat, using the basic medication as the control of clinical cardiovascular disease.But any one medicine all can exist potential toxicity and untoward reaction, and can strengthen along with the increase of dosage, and fat-reducing medicament can not reduce the lipidosis of liver through liver, sometimes can increase the weight of hepatic injury on the contrary.Therefore, the medicine actively finding a kind of effective fat-reducing liver-protecting is significant.
L-Orn Main Function in vivo participates in ornithine cycle, ornithine cycle in energy acute activation liver cell, the harmful carbonic acid gas produced under morbid state by body and ammonia are excreted by ornithine cycle, enzymes metabolism in liver is progressively recovered, thus the vigor of liver is restored, play the effect protecting the liver, protect liver.Research data is had to prove, L-Orn can promote that hypothalamus secretes tethelin, and tethelin can promote the metabolism of sugar with fat and the synthesis of protein, therefore, L-Orn can promote lipid metabolism and activate ornithine cycle, for body provides more multi-energy reduce blood ammonia.And acetylsalicylic acid can make the Serine acetoxylation in PG synthetic enzyme (cyclo-oxygenase) active centre and inactivation, reduce the platelet aggregation rate of ADP, collagen and human thrombin induction, reduce TAX in thrombocyte
2the generation of (thromboxane) and platelet aggregation-against and antithrombus formation, clinical in preventing and treating thrombosis and thrombotic disease.Have no the report of L-ornithine-aspirin double salt preparation method at present both at home and abroad, also there is no L-ornithine-aspirin double salt for the preparation of the report of fat-reducing liver-protecting medicine.
Summary of the invention
The object of the invention is for above-mentioned technical problem, a kind of L-ornithine-aspirin double salt double salt is provided.
Another object of the present invention is to provide the preparation method of above-mentioned L-ornithine-aspirin double salt double salt.
A further object of the invention is to provide above-mentioned L-ornithine-aspirin double salt double salt and is preparing the application in fat-reducing liver-protecting medicine.
Object of the present invention is achieved through the following technical solutions:
A kind of L-ornithine-aspirin double salt double salt, this double salt is prepared by following method:
Method one: the aqueous solution of the free L-Orn of preparation, then add acetylsalicylic acid wherein and react, obtain the solution of L-ornithine-aspirin double salt salt, then it is separated out with the form of crystallization; Or
Method two: the ethanolic soln of the ethanolic soln of acetylsalicylic acid with free L-Orn is mixed, obtains the precipitation of L-ornithine-aspirin double salt salt, then resolution of precipitate is obtained the aqueous solution of L-ornithine-aspirin double salt salt, then carry out recrystallization, to obtain final product.
Described L-ornithine-aspirin double salt double salt, in its crystal, the mol ratio of L-Orn and acetylsalicylic acid is 1:1.
Described L-ornithine-aspirin double salt double salt, in this double salt, salicylic acid content is at below 0.2Wt%.
The preparation method of described L-ornithine-aspirin double salt double salt, the method comprises the following steps:
Method one: the aqueous solution of the free L-Orn of preparation, then add acetylsalicylic acid wherein, make both fully reactions, obtain the solution of L-ornithine-aspirin double salt salt, then it is separated out with the form of crystallization; Or
Method two: the ethanolic soln of the ethanolic soln of acetylsalicylic acid with free L-Orn is mixed, obtains the precipitation of L-ornithine-aspirin double salt salt, then resolution of precipitate is obtained the aqueous solution of L-ornithine-aspirin double salt salt, then carry out recrystallization, to obtain final product.
Described preparation method, wherein free L-Orn is obtained by following method: extraction from fermented liquid, chemosynthesis, enzyme reaction or obtained by desalination by L-Orn salt.
Described preparation method, wherein in reactant, the mol ratio of L-Orn and acetylsalicylic acid is 0.5 ~ 2:1, and temperature of reaction is 10 DEG C-25 DEG C.
In the method one of above-mentioned preparation method, the feeding mode of acetylsalicylic acid is: the aqueous solution of the crystal of acetylsalicylic acid or powder or the free L-Orn of solution input.
Described preparation method, wherein crystallization method is: in the solution of L-ornithine-aspirin double salt salt, add dissolved agent, or reduces the temperature of solution, or the solvent of evaporating solns, or add crystal seed and make it crystallization in solution, or the combination of these methods.
Described preparation method, wherein in crystallization method, L-ornithine-aspirin double salt salts solution is its aqueous solution, and its mass concentration is 30% ~ 60%.
Described preparation method, in crystallisation process, temperature controls at-10 DEG C ~ 25 DEG C, preferably 0 ~ 20 DEG C.
Described preparation method, wherein dissolved agent is hydrophilic organic solvent, one or more in particular methanol, ethanol, propyl alcohol, Virahol, butanols, ethylene glycol, acetone, acetonitrile; The add-on of dissolved agent is 1 ~ 8 times of L-ornithine-aspirin double salt salts solution volume, preferably 2 ~ 5 times.
Described preparation method, the speed that adds of wherein dissolved agent is 0.1mL.min
-1~ 1.5mL.min
-1, preferred 0.2mL.min
-1~ 0.8mL.min
-1, more preferably 0.4mL.min
-1~ 0.6mL.min
-1.
Described preparation method, wherein crystal seed adds period and is: when the volume of the hydrophilic organic solvent that stream adds is 0.1 ~ 2.5 times of L-ornithine-aspirin double salt salts solution volume, when being preferably 0.5 ~ 1.5 times; Seed charge is: 0.1 ~ 5wt% of the amount of the L-ornithine-aspirin double salt salt contained in relative response liquid, is preferably 0.5 ~ 2.5wt%.
The application in fat-reducing liver-protecting medicine prepared by described L-ornithine-aspirin double salt double salt.
Further, detailed technology scheme of the present invention is:
L-ornithine-aspirin double salt is the double salt of L-Orn and acetylsalicylic acid, and chemical structural formula is as follows, and outward appearance is white crystalline powder.
1, the preparation method of L-ornithine-aspirin double salt composite salt.
The first step: the free L-Orn of preparation.
The method obtaining free L-Orn is a lot.Can be that L-Orn salt (comprise hydrochloride, vitriol, phosphoric acid salt, Citrate trianion etc., and the salt of other various possible form) is obtained by desalination.Also can be obtain from fermented liquid or other reaction solution (as chemosynthesis and enzyme reaction solution), obtain remove the art breading such as thalline, decolouring, ion-exchange as fermentation liquor disclosed in by patent documentation CN101955901B after.What and for example adopt patent documentation CN1661026 report take L-arginine as the preparing L-omithine through immobilized ectocellular enzyme of raw material.
In certain embodiments, can by the aqueous solution of L-ornithine hydrochloride by JK006 storng-acid cation exchange resin, L-Orn is adsorbed, then removes the chlorion in resin voids with a certain amount of washing, finally use ammoniacal liquor wash-out, obtain the aqueous solution containing free L-Orn; Or with the aqueous solution of 330 weakly alkaline epoxy type anion exchange resin process L-ornithine hydrochloride, chlorion is adsorbed, and crosses the ion exchange resin filtered wherein, concentrated except ammonia, obtains the aqueous solution of free L-Orn.
Second step: the reaction of free L-Orn and acetylsalicylic acid.
The stability of acetylsalicylic acid in water is bad, and facile hydrolysis generates Whitfield's ointment, and soda acid all has certain katalysis to hydrolysis reaction.Therefore the selection of the reaction system of the two is very important, otherwise salicylic acid content in product can be caused to exceed standard.Reaction equation:
Following two kinds of methods can be adopted to realize this reaction, such as:
(1) first the aqueous solution of free L-Orn being concentrated to mass concentration is 36%, drop into 24g acetylsalicylic acid (existence form of acetylsalicylic acid can be crystal, powder, solution etc.) here wherein again, make both fully reactions, obtain the solution of L-ornithine-aspirin double salt salt;
(2) ethanolic soln of the ethanolic soln of acetylsalicylic acid with free L-Orn is mixed, obtain the precipitation of L-ornithine-aspirin double salt salt.Then resolution of precipitate is obtained the solution of L-ornithine-aspirin double salt salt, recrystallization.
In two kinds of methods, during reaction, substrate (L-Orn and acetylsalicylic acid) mol ratio is 0.5 ~ 2:1, and temperature of reaction controls at 10 DEG C ~ 25 DEG C.
3rd step: by L-ornithine-aspirin double salt salt crystallization from solution.
The method that crystallization adopts can be in the solution of above-mentioned L-ornithine-aspirin double salt salt, add dissolved agent, or reduce the temperature of above-mentioned solution, or evaporate the solvent of above-mentioned solution, or add crystal seed in above-mentioned solution, make it crystallization.Or also can implement these methods by combination and make crystallization.In some embodiments, preferably in the above-mentioned L-ornithine-aspirin double salt aqueous solution, add hydrophilic organic solvent as dissolved agent, crystal is separated out.
In some embodiments, add in the solution to L-ornithine-aspirin double salt salt dissolved agent make crystal separate out in, preferably this concentration of polymer solution is adjusted to 30% ~ 60%.
Dissolved agent can be hydrophilic organic solvent, includes but not limited to, methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, ethylene glycol, acetone, acetonitrile etc., or the combination of these materials.
The consumption of dissolved agent can be 1 ~ 8 times of the volume of the solution of L-ornithine-aspirin double salt salt, is preferably 2 ~ 5 times.The feed postition of dissolved agent can be at 0 ~ 25 DEG C, to be adjusted to above-mentioned concentration L-ornithine-aspirin double salt salt solution in slowly stream add.The flow acceleration of dissolved agent is: for the solution of 20mL, and dissolved agent stream rate of acceleration can control at 0.1mL.min
-1~ 1.5mL.min
-1, preferred 0.2mL.min
-1~ 0.8mL.min
-1, more preferably 0.4mL.min
-1~ 0.6mL.min
-1.
Crystal seed feed postition: when dissolved agent volume is 0.1 ~ 2.5 times of L-ornithine-aspirin double salt salts solution volume, when being preferably 0.5 ~ 1.5 times, adds a certain amount of crystal seed.
Seed load: 0.1 ~ 5.0wt% of the amount of the L-ornithine-aspirin double salt salt relatively contained in this reaction solution, is preferably 0.5 ~ 2.5wt%.
L-ornithine-aspirin double salt is hydrolyzed into L-Orn and acetylsalicylic acid after entering human body, has the effect of reducing blood-fat, can be used for preparing blood lipid-lowering medicine.
Beneficial effect of the present invention:
Preparation method of the present invention has the advantages such as simple possible, production cost are low, constant product quality, and L-ornithine-aspirin double salt can be used for preparing blood lipid-lowering medicine, for hypolipidemic research and development provide new selection.
Embodiment
Below by embodiment, the invention will be further elaborated.
Embodiment 1: preparation L-ornithine-aspirin double salt salt.
The first step: the free L-Orn of preparation;
Example 1:
The L-ornithine hydrochloride of 30g is dissolved in 1000mL water, regulates pH to 2.0, flow through the pillar having loaded JK006 storng-acid cation exchange resin.Rinse pillar with 300mL water, wash away the impurity such as chlorion wherein, then use the ammoniacal liquor wash-out L-Orn of 2mol/L of 400mL, concentrated except ammonia, obtain the L-Orn aqueous solution dissociated.
Example 2:
The L-Orn vitriol of 30g is dissolved in 1000mL water, regulates pH to 2.0, flow through the pillar having loaded JK006 storng-acid cation exchange resin.Rinse pillar with 300mL water, wash away the impurity such as sulfate radical wherein, then use the ammoniacal liquor wash-out L-Orn of 2mol/L of 400mL, concentrated except ammonia, obtain the L-Orn aqueous solution dissociated.
Example 3:
Adopt the chlorion in the anionite-exchange resin Static Adsorption L-ornithine hydrochloride aqueous solution, concrete operations are as follows: the L-ornithine hydrochloride of 30g be dissolved in 1000mL water, add 330 weakly alkaline epoxy type anion exchange resins, stirred at ambient temperature 1.5h, wherein chloride ion content is detected with Silver Nitrate, cross and filter resin, obtain the L-Orn aqueous solution dissociated.
Example 4:
According to method disclosed in patent documentation CN101955901B, obtain the fermented liquid containing L-Orn, after fermentation liquor removes thalline, pigment process, obtain the aqueous solution containing free L-Orn.
Second step: free L-Orn and acetylsalicylic acid react, and obtain L-ornithine-aspirin double salt salts solution, and adjust its concentration.
Example 1:
It is under 36%, 20 DEG C of water-baths that the free L-Orn aqueous solution the first step obtained is concentrated to mass concentration, and stir, and add 24g acetylsalicylic acid wherein, the mass concentration of the L-ornithine-aspirin double salt salt obtained is about 55%.
Example 2:
The free L-Orn aqueous solution the first step obtained concentrates, then uses 25mL dissolve with ethanol.Temperature controlled water baths is 20 DEG C, and stir, it is in the ethanolic soln of the acetylsalicylic acid of 200gL that the ethanolic soln stream of free L-Orn is added to 120mL concentration, filters, dry, obtains the white solid of L-ornithine-aspirin double salt salt.Above-mentioned white solid (41.6g) is dissolved in appropriate water, makes its mass concentration be 55%.
3rd step: the crystallization of L-ornithine-aspirin double salt salt
Crystallization can adopt multiple method, can adopt and add dissolved agent in the solution of L-ornithine-aspirin double salt salt, or reduces the temperature of solution, or the solvent of evaporating solns, or in solution, adds crystal seed make it crystallization, or the combination of these methods.In crystallisation process, temperature controls at-10 DEG C ~ 25 DEG C, and the add-on of dissolved agent controls 1 ~ 8 times at L-ornithine-aspirin double salt salts solution volume, dissolved agent add rate-controlling at 0.1mL.min
-1~ 1.5mL.min
-1, crystal seed adds period and is: when the volume of the hydrophilic organic solvent that stream adds is 0.1 ~ 2.5 times of L-ornithine-aspirin double salt salts solution volume, Seed charge is: 0.1 ~ 5wt% of the amount of the L-ornithine-aspirin double salt salt contained in relative response liquid.
Example 1:
25 DEG C and stir condition under, in the L-ornithine-aspirin double salt salts solution that second step example 1 obtains, add dehydrated alcohol with the speed stream of 1.5mL/min, add 4.5g crystal seed after about 30min, stirring and crystallizing 30min, continue stream and add dissolved agent, after about 100min, stop stream adding.Filtration, drying, obtain the crystal of the L-ornithine-aspirin double salt salt of white needles, yield is 80.5%, and product purity is 97.6%.
Example 2:
10 DEG C and stir condition under, in the L-ornithine-aspirin double salt salts solution that second step example 1 obtains, add dehydrated alcohol with the speed stream of 1.0mL/min, add 4.5g crystal seed after about 45min, stirring and crystallizing 30min, continue stream and add dissolved agent, after about 150min, stop stream adding.Filtration, drying, obtain the crystal of the L-ornithine-aspirin double salt salt of white needles, yield is 85.5%, and product purity is 96.9%.
Example 3:
25 DEG C and stir condition under, in the L-ornithine-aspirin double salt salts solution that second step example 1 obtains, add dehydrated alcohol with the speed stream of 1.5mL/min, add 9.0g crystal seed after about 30min, stirring and crystallizing 30min, continue stream and add dissolved agent, after about 100min, stop stream adding.Filtration, drying, the crystal yield obtaining the L-ornithine-aspirin double salt salt of white needles is 81.2%, and product purity is 97.8%.
The Adjust-blood lipid hepatoprotective effect research of embodiment 2, L-ornithine-aspirin double salt double salt
2.1 experiment materials: healthy Wistar big white mouse 60, body weight (269.2 ± 50.9) g male and female dual-purpose.
Feed: normal diet; High lipid food formula is: basal feed 72.7%, cholesterol 2%, yolk powder 5%, lard 10%, propylthiouracil 0.2%, sucrose 10%, Sodium cholic acid 0.1%.(mass percent)
2.2 animal grouping and administrations: the experimental rat bought adapts to raising 1 week in laboratory, press order of weighing and compile original number, look into table of random number and be divided into blank group, model control group, L-ornithine-aspirin double salt 2mg/kg low dose group at random, dosage group in 4mg/kg, 8mg/kg high dose group, positive drug (Simvastatin 1.5mg/kg) control group.Often organize 10.From experiment from blank group, model control group gavage distilled water, administration group gavage relative medicine, 1 time/d, volume is 10ml/kg, weekly claim 1 body weight, according to body weight adjustment dosage.Blank group is fed and is raised normal diet, all the other respectively group feed and raise high lipid food, duration of test is freely ingested, freely drink water, and continuous modeling also prevents administration 8 weeks.
2.3 observation indexs: fasting 12h after last administration, can't help water.3% vetanarcol anesthetized rat, abdominal aortic blood, centrifugation serum, survey serum total cholesterol (TC), triacylglycerol (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), superoxide-dismutase (SOD), mda (MDA),
Gpt (ALT), glutamic-oxal(o)acetic transaminase (AST) value.
2.4 result
A) L-ornithine-aspirin double salt is on the impact of Serum Lipids in Experimental HypercholesterolemicRats
From table 1, compared with normal group, in model group rats serum, the level of TC, TG, LDL-C obviously raises (P < 0.05), presents typical lipid metabolism disorders, shows the success of Experimental Hyperlipemia model copy.Compared with model group, treatment group obviously can reduce serum TC, TG, LDL-C content (P < 0.05), and can remarkable elevating HDL-C content (P < 0.01) and present dose-dependently.
Table 1 respectively group rat fat change (
n=10)
B) L-ornithine-aspirin double salt is on the impact of Liver Function
Serum alt and AST can react liver function.High lipid food group ALT and AST, apparently higher than basal feed group (P<0.05), illustrates that liver has certain infringement.And each administration group has obvious reduction, and compared with Normal group, difference is very significant (P<0.01); L-ornithine-aspirin double salt group can reduce ALT and AST of Rats with Fatty Liver, contrasts with model group, and difference has pole significant (P<0.01), and it the results are shown in Table 2.
Table 2 each group Liver Function changing conditions (
n=10)
C) L-ornithine-aspirin double salt is on the impact of rat model hepatic tissue SOD, MDA content
Compare with blank group, model group rats activity of SOD in serum significantly reduces (P<0.01), MDA content obviously raises (P<0.01).Compare with model group, each administration group liver injury model rat blood serum SOD activity all has rising in various degree, with L-ornithine-aspirin double salt high dose group significantly (P<0.05), MDA content obviously reduces (P<0.01), result shows, L-ornithine-aspirin double salt has good lipoid peroxidization resistant to hyperlipemia rat.It the results are shown in Table 3.
Table 3 respectively organize activity of SOD in serum, MDA comparision contents (
n=10)
During hyperlipidaemia, the Radical Metabolism balance in body in liver cell will be lacked of proper care, and also can decline to the defence capability of free radical, too much free radical with the lipoids generation peroxidation in cytolemma, can cause the destruction of cytolemma, cause necrocytosis; Simultaneously the degradation production (MDA) of lipid peroxide also can be combined with the material such as protein and phosphatide, and be deposited on histocyte, damaging cells film, causes cell functional disorders, finally causes cell cannot maintain eubolism and dead.Above-mentioned test-results shows, SOD in model group rats serum is active significantly lower than normal group, MDA content is then apparently higher than normal group, illustrate that rising and the lipid peroxidation of blood fat are proportionate, after hyperlipidemia rats gavages L-ornithine-aspirin double salt, its TC, TG, LDL-C content obviously reduces, and HDL-C content raises; In serum, MDA content obviously reduces, and SOD is active obviously to be raised; The serum alt cause high lipid food and increasing of AST have restraining effect.Illustrate that L-ornithine-aspirin double salt can regulate and improve Radical Metabolism balance, facilitate fatty acid metabolism, have certain tune fat liver protection effect, and its Lipid-regulating effect may have certain relation with its interior antioxidation action, but its concrete adjusting blood lipid mechanism needs to be studied further.
In addition, L-ornithine-aspirin double salt double salt very well water-soluble, the pH of its aqueous solution is neutral meta-acid, can be used for intramuscular injection and quiet note, avoid oral administration to GI stimulation, hepatotoxic incidence can be reduced to a certain extent, especially higher to liver function damage risk level hyperlipemic patients.
Claims (1)
- The application in Adjust-blood lipid hepatoprotective prepared by 1.L-ornithine acetylsalicylic acid double salt.
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| CA2416288A1 (en) * | 2000-07-18 | 2003-01-15 | Bayer Aktiengesellschaft | Stable salts of o-acetylsalicylic acid with basic amino acids |
| CN1660321A (en) * | 2004-12-31 | 2005-08-31 | 北京阜康仁生物制药科技有限公司 | Medicinal preparation of extractive from compound aspirin and rice fermentred with red yeast |
| WO2012087742A2 (en) * | 2010-12-21 | 2012-06-28 | Nestec S.A. | Methods and compositions suitable for managing blood glucose in animals |
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