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CN103239434A - Ornithine aspartate composition - Google Patents

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Publication number
CN103239434A
CN103239434A CN2012105716998A CN201210571699A CN103239434A CN 103239434 A CN103239434 A CN 103239434A CN 2012105716998 A CN2012105716998 A CN 2012105716998A CN 201210571699 A CN201210571699 A CN 201210571699A CN 103239434 A CN103239434 A CN 103239434A
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Prior art keywords
aspartic acid
ornithine
pharmaceutical composition
acid ornithine
formula
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关屹
闫冬
李爽
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LIAONING MILLION BIOMEDICAL TECHNOLOGY Co Ltd
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LIAONING MILLION BIOMEDICAL TECHNOLOGY Co Ltd
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Abstract

The invention provides a pharmaceutical composition of ornithine aspartate, which contains the components of ornithine aspartate and a compound represented by the formula I, wherein the content of ornithine aspartate is not less than 97%; and the content of the compound represented by the formula I is not higher than 0.5%. Pharmacological experiments prove that the LD50 value of the compound represented by the formula I is far less than that of the ornithine aspartate, so that the serious adverse reaction of gastrointestinal systems of tested animals can be generated; and the fact that the LD50 value of the compound represented by the formula I is far less than that of the ornithine aspartate is the main reason for adverse reaction of ornithine aspartate medicines. According to the ornithine aspartate composition, the content of the compound represented by the formula I is effectively controlled within 0.0001-0.1%; simultaneously, the invention also provides a preparation method of the compound; and the ornithine aspartate composition disclosed by the invention can be used as a standard reference substance for detecting the quality of the ornithine aspartate and preparations of the ornithine aspartate.

Description

The aspartic acid ornithine compositions
Technical field
The present invention relates to the synthetic field of pharmaceutical chemistry, be specially a kind of aspartic acid ornithine pharmaceutical composition.
Background technology
Aspartic acid ornithine, chemical name: (S)-2, the 5-diaminovaleric acid-(S)-2-aminosuccinic acid salt, it is a kind of chemical compound that can be decomposed into Aspartic Acid and two kinds of components of ornithine in vivo, can be used for treatment clinically because of acute and chronic hepatopathy, as various hepatitis, liver cirrhosis, fatty liver, the blood ammonia that syndrome etc. causes after the hepatitis raises and hepatic encephalopathy.
Aspartic Acid participates in the synthetic of the interior nucleic acid of hepatocyte, is beneficial to repair the hepatocyte that is damaged.Because Aspartic Acid to the indirect facilitation of tricarboxylic cycle metabolic process in the hepatocyte, has promoted the energy in the hepatocyte to generate, and makes that damaged hepatocellular every function is recovered.In addition, ornithine almost relates to the overall process of the detoxifcation of the activation of ornithine cycle and ammonia.In this process, form arginine, divide carbamide then and form ornithine.Because aspartic acid ornithine can be participated in hepatocellular metabolism directly, and can activate two key enzymes in the liver detoxification function, thereby can assist to remove harmful free radical, strengthen the functions of expelling toxin of liver, reduce too high blood ammonia rapidly, promote reparation and the regeneration of hepatocyte self, thereby improve liver function effectively, recover the energy balance of body.
Common formulations has injection, injectable powder, granule at present.Aspartic acid ornithine injection as the production of German Mak's Company, the trade name Hepa Merz, the aspartic acid ornithine granule that Wuhan Qirui Pharmaceuticals Co., Ltd. produces, commodity are by name auspicious sweet, auspicious sweet main component be Aspartic Acid and ornithine form stablize two peptide polymers, can be decomposed into ornithine and Aspartic Acid again after oral.The aspartic acid ornithine untoward reaction generally has the property crossed gastrointestinal reactions such as nausea,vomiting,diarrhea, reduces drug dose or the transfusion speed that slows down, and these untoward reaction just can disappear.
The aqueous solution of aspartic acid ornithine is unstable under high temperature and alkali condition, easily generates other materials.
Summary of the invention
Scientific research personnel of the present invention is in research aspartic acid ornithine preparation stability process, be surprised to find that a kind of impurity compound, shown in formula I, the further separation and purification of the present invention and characterized the structure of matter and the activity thereof of this impurity often appears in the synthetic and storage process together at aspartic acid ornithine.
Figure 904339DEST_PATH_IMAGE001
Formula I
Chemical compound shown in the formula I is the ornithine lactams, and the synthetic of ornithine lactams generally has dual mode: (1) is raw material with the ornithine methyl ester, gets the ornithine lactams through cyclization; (2) with the dlornithine hydrochloride be raw material, dehydration condensation gets the ornithine lactams under alkalization, alumina catalyzation.
The present invention carries out the pharmacological toxicology test to chemical compound shown in the formula I, and the anxious poison test of mouse tail vein injection confirms that chemical compound has lower LD shown in the formula I 50Value, doses can cause dead mouse, and this material has certain toxicity, can cause gastrointestinal side effect, is the key substance that causes the aspartic acid ornithine drug side effect.
The invention provides a kind of pharmaceutical composition of safe aspartic acid ornithine, comprise chemical compound shown in aspartic acid ornithine, the formula I, described compositions comprises aspartic acid ornithine and content is not higher than chemical compound shown in 0.5% formula I, safety is good, and stability is high.
Further, the content that contains aspartic acid ornithine in the described pharmaceutical composition is not less than 97%, preferably is not less than 99%, more preferably is not less than 99.8%.
Further, compounds content shown in the formula I is not higher than 0.5%, preferably is not higher than 0.2%, preferably is not higher than 0.1%.
The invention provides a kind of aspartic acid ornithine preparation of compositions method.
Another object of the present invention provides the preparation method of impurity compound shown in a kind of formula I, can be used as reference substance, is used for quality-monitoring and the check of control aspartic acid ornithine and preparation thereof.
Further, the invention provides a kind of safe pharmaceutical composition, formed by described aspartic acid ornithine pharmaceutical composition and pharmaceutically acceptable carrier.
Pharmaceutical preparation of the present invention is selected from: oral formulations, external preparation and or injection in one or more.Be preferably oral agents and injection.Oral agents comprises tablet, dispersible tablet, effervescent tablet, double-layer tablet, multilayer tablet, slow releasing tablet, soft capsule, hard capsule, granule, powder, pill, dry suspension, suspending agent, syrup etc.Be preferably tablet and capsule.Described injection is selected from injection, injectable sterile powder and concentrated solution for injection, can be used for intramuscular injection, intravenous injection, intravenous drip etc.The specification of injection of the present invention has been selected from 1mL, 2mL, 5mL, 10mL, 15mL, 20mL, 50mL, 100mL, 200mL, 250mL or 500mL.
Pharmaceutical preparation of the present invention can be unit formulation, in aspartic acid ornithine, contains aspartic acid ornithine as active constituents of medicine 0.01-500mg, preferred 5-250mg, more preferably 20-100mg.
Pharmaceutically acceptable carrier of the present invention is that this area is for the preparation of conventional excipients or the adjuvant of described preparation.Including but not limited to filler, lubricant, binding agent, disintegrating agent, antioxidant, emulsifying agent, antiseptic etc.Filler, as: starch, lactose, amylum pregelatinisatum, microcrystalline Cellulose etc.Lubricant, magnesium stearate, micropowder silica gel, Pulvis Talci etc.Binding agent comprises starch slurry, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hypromellose, polyvinylpyrrolidone etc.Disintegrating agent comprises that dried starch, carboxymethyl starch are received, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, gas-producing disintegrant etc.Antioxidant comprises: BHA, fourth hydroxy-methylbenzene, thiodipropionic acid, sulphite, bisulfites, dithiocar-bamate, sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate etc.Emulsifying agent comprises: sodium stearate, potassium stearate, enuatrol, calcium stearate, sodium lauryl sulphate, hexadecyl hydrosulfate Oleum Ricini, fatty acid monoglyceride, triglycerin fat acid esters, polyglycereol stearate, sucrose monolaurate, fatty acid Pyrusussuriensis are smooth, Polysorbate, Myrij, Brij, poloxamer, arabic gum, tragakanta, gelatin, apricot glue, as magnesium hydroxide, aluminium hydroxide, silicon dioxide, Bentonite etc.Antiseptic comprises: parabens, benzoate, sorbic acid, benzalkonium bromide, chlorhexidine acetate.
Further, the aspartic acid ornithine pharmaceutical composition of the present invention preparation can be used for treatment because of acute and chronic hepatopathy, as various hepatitis, and liver cirrhosis, fatty liver, the blood ammonia that syndrome etc. causes after the hepatitis raises and hepatic encephalopathy.
The specific embodiment
The preparation of embodiment 1 aspartic acid ornithine
(1) free ornithine preparation:
Get the 732# cation exchange resin 700g dress post after the activation, take by weighing the 35g ornithine hcl 99 and join wiring solution-forming in the 350ml purified water, with this solution resin column flow velocity 0.15ml/s that slowly flows through, be washed till effluent with purified water and show neutral and do not have Cl -(with pH detection paper effluent pH value, AgNO3 solution detects effluent and whether contains Cl -) with 4% ammonia spirit eluting, the control flow velocity is at 0.15ml/s, treat that effluent begins to collect effluent when showing alkalescence, detect the eluting terminal point with 1,2,3-indantrione monohydrate, stop to collect, effluent is revolved steam T=50 ℃, rotating speed 80 rpm, vacuum-0.09 ~-the i.e. free ornithine of faint yellow oily thing that 0.1Mpa obtains, product is weighed the back preparation into about 200mg/ml solution, and Liquid Detection concentration is delivered in sampling.
(2) preparation of aspartic acid ornithine salt:
Free ornithine after the Liquid Detection is mixed with the solution of 200mg/ml, the Aspartic Acid that adds 1.07 times of molar equivalents, stir and heat up, in the time of T=29 ℃, solid all dissolves, pH value of solution=8 ~ 9, T=50 ℃, behind the dropping absolute methanol 180ml (v=2.4ml/min), white particle occurs, continue to drip 150ml absolute methanol (v=1.5ml/min), sucking filtration while hot, filter cake 600ml mixed solvent (methanol: water=5:1) making beating and washing, drain, filter cake is with the making beating of 600ml absolute methanol and wash sucking filtration, filter cake is 55 ℃ of temperature, vacuum-0.09 ~-be dried to constant weight under the 0.1Mpa environment.
Content detection:
Chromatographic column: the amino bonded silicagel column, model: 250mm * 4.6mm, 5 μ m, Sepax,
Mobile phase: 0.05mol/L potassium dihydrogen phosphate: acetonitrile (42:58), mix the back and regulate pH value to 5.2 with phosphoric acid,
Detect wavelength: 200nm,
Column temperature: 30 ℃,
Flow velocity: 1.0ml/min,
Sampling volume: 20 μ l,
Need testing solution: precision is measured this product 1ml, puts in the 100ml measuring bottle, is diluted to scale with mobile phase, shakes up, namely.
Concrete operations: get system suitability solution 20 μ l, inject chromatograph of liquid, the record chromatogram.Each peak-to-peak separating degree all should be greater than 1.5, and theoretical cam curve is calculated by Aspartic Acid should be not less than 3000.
Get contrast solution 20 μ l, inject the liquid phase chromatograph of liquid, regulate detection sensitivity, make the main constituent peak height be about 5% ~ 10% of full scale.Precision is measured each 20 μ l of need testing solution, contrast solution and reference substance solution again, injects chromatograph of liquid respectively, and the record chromatogram is to 3.5 times of the Aspartic Acid retention time.
The result: the aspartic acid ornithine compounds content is 99.12%, ornithine lactams content 0.08%.
Synthesizing of embodiment 2 ornithine lactams
Take by weighing NaOH 23.8g, join wiring solution-forming in the 100ml distilled water; Take by weighing L-dlornithine hydrochloride 100g and join in the NaOH solution, T=25 ℃ was stirred 15 minutes; Take by weighing neutral Al 2O 3300g adds the 2L reaction bulb, measures 1L toluene and adds in the reaction bulb, and mechanical agitation joins reaction bulb with the free ornithine solution that makes, and is warming up to backflow, and with thin layer chromatography detection reaction terminal point, leaves standstill after reacting completely, and is cooled to room temperature; With behind the liquid coolant sucking filtration in T=40 ℃, vacuum is revolved and is steamed to grease under the-0.08MPa.
1H-NMR（CDCl 3，400?MHz）δ?7.0（1H，bs，N- H），3.2（2H，m，C H 2N），3.2（1H，dd， J=3.8，3.9Hz，C H-NH 2），1.5-2.1（4H，m， CH 2 CH 2 ），1.75（2H，bs，N H 2 ）；
MS?m/z（int）115（M+1,100），99（10），70（96），58（30），42（42）。
Total Elements C 52.51, H 8.66, and N 24.25%;
Theoretical value C 5H 10N 2O:C 52.63, and H 8.77, and N 24.56%.
Embodiment 3 aspartic acid ornithine related substances toxicity research
Kunming mouse, 60, male and female half and half, body weight 18-22g.The animal subject pretreatment: 7 days in advance with animal subject place the indoor observation of breeding observing (room temperature 21-23 ℃, relative temperature: 30-70%), natural lighting, mechanism material piece is fed.
Experimental animal is divided into 3 groups, is respectively the solvent control group, aspartic acid ornithine group, ornithine lactams group (being called for short the impurity group).Solvent adopts normal saline, embodiment 1 self-control aspartic acid ornithine, and embodiment 2 methods prepare impurity compound.All medicine adopts tail vein injection, at first uses the acute toxicity dosage that the purgation assessment is tried thing, carries out master trip then, observes death time of animal and dead quantity thereof, calculates LD 50Value.
Table 1 aspartic acid ornithine related substances The acute toxicity tests
Chemical compound LD 50? （mg/kg)
Aspartic acid ornithine 2625
The impurity group 52
As can be seen from the test results, the LD of aspartic acid ornithine 50Value is far longer than impurity, is 50 times of impurity group, and therefore, we think that the main matter that causes the aspartic acid ornithine adverse effect should be impurity compound ornithine lactams.
Embodiment 4 Gastrointestinal side effect
During aspartic acid ornithine treatment disease, easily cause gastrointestinal side effect, for research causes the reason of untoward reaction, carry out this test.
Choose 60 of healthy mices, body weight 18 ~ 22g, fasting is 12 hours before the experiment, male and female half and half are equally divided into 3 groups, are respectively matched group, the medicine group, the impurity group, normal saline is adopted in contrast, experimental group is the aspartic acid ornithine of embodiment 1 preparation, and the impurity group is the ornithine lactams of embodiment 2 preparations, 20 every group, intraperitoneal injection, successive administration 5 days, twice of every day, since the administration time calculating first time, mice activity and response situation after observation and the record administration.
The dosage design: 5g aspartic acid ornithine medicine joins in 0.9% sodium chloride solution of 250ml, is prepared into for injectable drug.According to human clinical's dosage, amount to animal-use drug dosage, medicine group animal subject injection 0.75ml/ is only; The impurity group is considered LD 50Be worth lessly, toxicity is bigger, reduces by 10 multiple doses, and 0.5 g ornithine lactams joins in 0.9% sodium chloride solution of 250ml, is prepared into for injectable drug, only injects with 0.75ml/.
Observation index: vomiting number of times and feed state.Result of the test sees Table 2.
Table 2 aspartic acid ornithine related substance gastrointestinal reaction result of the test
Medicine Accumulative total vomit number of times 1-3d/time Whether influence is taken food Accumulative total vomit number of times 1-5d/time Whether influence is taken food
Aspartic acid ornithine 0 Not 0 Not
Impurity group * P 13 Be 34 Be
*P<0.01
As can be known from the results, aspartic acid ornithine does not have obvious influence to the gastrointestinal tract of animal subject, and impurity group ornithine lactams has caused serious gastrointestinal side effect, and the vomiting phenomenon is more, number of times prolongs in time and increases, and has influenced the feed of animal subject.
Thus, we think that impurity ornithine lactams can cause serious gastrointestinal side effect, are the main and important substance of aspartic acid ornithine untoward reaction.

Claims (8)

1. an aspartic acid ornithine pharmaceutical composition contains chemical compound shown in aspartic acid ornithine and the formula I, it is characterized in that: aspartic acid ornithine content is not less than 97%, the 0.0001-0.5% of compounds content shown in the formula I.
2. the described aspartic acid ornithine pharmaceutical composition of claim 1, it is characterized in that: aspartic acid ornithine content is not less than 99%.
3. the described aspartic acid ornithine pharmaceutical composition of claim 1 is characterized in that: the 0.0001-0.2% of compounds content shown in the formula I.
4. the described aspartic acid ornithine pharmaceutical composition of claim 1 is characterized in that: the 0.0001-0.1% of compounds content shown in the formula I.
5. contain the pharmaceutical composition that the described aspartic acid ornithine pharmaceutical composition of claim 1 and acceptable accessories form, it is characterized in that being selected from oral formulations, external preparation and the injection one or more.
6. the described pharmaceutical composition of claim 5, oral formulations wherein comprises tablet, dispersible tablet, effervescent tablet, double-layer tablet, multilayer tablet, slow releasing tablet, soft capsule, hard capsule, granule, powder, pill, dry suspension, suspending agent, syrup.
7. the described pharmaceutical composition of claim 5, injection wherein is selected from injection, injectable sterile powder and concentrated solution for injection.
8. the application of the described aspartic acid ornithine pharmaceutical composition of arbitrary claim aspect the acute and chronic liver disease drug for the treatment of among the claim 1-7.
CN2012105716998A 2012-12-26 2012-12-26 Ornithine aspartate composition Pending CN103239434A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103705490A (en) * 2013-10-31 2014-04-09 蚌埠丰原医药科技发展有限公司 Slow-release preparation of ornithine aspartate and preparation process thereof
CN103864634A (en) * 2014-03-27 2014-06-18 常州兰陵制药有限公司 Method for preparing ornithine aspartate
CN104292149A (en) * 2014-09-29 2015-01-21 蚌埠丰原医药科技发展有限公司 Method of preparing ornithine lactam
CN103864634B (en) * 2014-03-27 2016-11-30 常州兰陵制药有限公司 The preparation method of aspartic acid ornithine
WO2017016930A1 (en) * 2015-07-24 2017-02-02 Evonik Technochemie Gmbh Effervescent formulations of ornithine aspartate
CN107573404A (en) * 2017-09-22 2018-01-12 南京优科生物医药研究有限公司 The active salt of the dipeptide compound of ornithine and L-aminobutanedioic acid and its application

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101987094A (en) * 2009-08-07 2011-03-23 上海秀新臣邦医药科技有限公司 Ornithine aspartate injection and preparation method thereof
CN102274166A (en) * 2011-07-13 2011-12-14 辽宁科泰生物基因制药股份有限公司 Medicinal composition containing ornithine aspartate
CN102288687A (en) * 2010-06-21 2011-12-21 武汉启瑞药业有限公司 Method for analysing and detecting impurities in ornithine aspartate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101987094A (en) * 2009-08-07 2011-03-23 上海秀新臣邦医药科技有限公司 Ornithine aspartate injection and preparation method thereof
CN102288687A (en) * 2010-06-21 2011-12-21 武汉启瑞药业有限公司 Method for analysing and detecting impurities in ornithine aspartate
CN102274166A (en) * 2011-07-13 2011-12-14 辽宁科泰生物基因制药股份有限公司 Medicinal composition containing ornithine aspartate

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103705490A (en) * 2013-10-31 2014-04-09 蚌埠丰原医药科技发展有限公司 Slow-release preparation of ornithine aspartate and preparation process thereof
CN103705490B (en) * 2013-10-31 2016-08-17 蚌埠丰原医药科技发展有限公司 The slow releasing preparation of a kind of aspartic acid ornithine and preparation technology thereof
CN103864634A (en) * 2014-03-27 2014-06-18 常州兰陵制药有限公司 Method for preparing ornithine aspartate
CN103864634B (en) * 2014-03-27 2016-11-30 常州兰陵制药有限公司 The preparation method of aspartic acid ornithine
CN104292149A (en) * 2014-09-29 2015-01-21 蚌埠丰原医药科技发展有限公司 Method of preparing ornithine lactam
CN104292149B (en) * 2014-09-29 2016-08-17 蚌埠丰原医药科技发展有限公司 A kind of method preparing ornithine lactams
WO2017016930A1 (en) * 2015-07-24 2017-02-02 Evonik Technochemie Gmbh Effervescent formulations of ornithine aspartate
CN108024968A (en) * 2015-07-24 2018-05-11 赢创工业化学有限公司 The effervescent formulation of aspartic acid ornithine
RU2734417C2 (en) * 2015-07-24 2020-10-16 Эвоник Оперейшенс ГмбХ Fizzy compositions based on ornithine aspartate
AU2016299246B2 (en) * 2015-07-24 2021-10-21 Evonik Operations Gmbh Effervescent formulations of ornithine aspartate
CN108024968B (en) * 2015-07-24 2022-07-05 赢创运营有限公司 Effervescent preparation of ornithine aspartate
CN107573404A (en) * 2017-09-22 2018-01-12 南京优科生物医药研究有限公司 The active salt of the dipeptide compound of ornithine and L-aminobutanedioic acid and its application

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Application publication date: 20130814