CN101012240A - Creatine phosphate arginine salt and preparing method thereof - Google Patents
Creatine phosphate arginine salt and preparing method thereof Download PDFInfo
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- CN101012240A CN101012240A CN 200710026641 CN200710026641A CN101012240A CN 101012240 A CN101012240 A CN 101012240A CN 200710026641 CN200710026641 CN 200710026641 CN 200710026641 A CN200710026641 A CN 200710026641A CN 101012240 A CN101012240 A CN 101012240A
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- creatine phosphate
- arginine salt
- phosphate arginine
- phosphocreatine
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Abstract
The invention discloses a creatine phosphate arginine salt with structural formula (I), whose chemical name is N-{subhydrogen (phosphoramino) methyl}-N-methyl glycine diarginine salt at random hydrate pattern to protect myocardial under ischemic condition.
Description
Technical field
The present invention relates to the salt of phosphocreatine, the myocardial metabolism that adds when being used for heart operation under cardioplegic solution protection cardiac muscle and the treatment ischemia condition is unusual, and the preparation method and the medicinal use of this phosphocreatine salt.
Background technology
Phosphocreatine plays a significant role in the energy metabolism of Muscle contraction, and it is the chemical energy deposit of cardiac muscle and skeletal muscle, and is used for the resynthesis of ATP, and the actomyosin contraction process that is hydrolyzed to of ATP provides energy.
The oxidative metabolism energy undersupply that causes that slows down is the important factor of myocardial cell injury formation and development.Phosphocreatine level deficiency has the important clinical meaning in the damage of myocardial contraction and functional rehabilitation ability.In fact, in myocardial damage, the quantity of high phosphate cpd in the cell, and have close relation between the survival of cell and the contractile function restorability.So keep the level of high-energy phosphate compound to become the fundamental principle of various restriction myocardial damage methods, also be the basis of heart metabolic defence simultaneously.
What be used for a large amount of uses of myocardial preservation at present clinically is Disodium phosphocreatine.The asystole test of animal experiment and human body has shown the effect of Disodium phosphocreatine and the possibility of protection cardiac muscle thereof.
Pharmacology test shows:
1) intramuscularly Disodium phosphocreatine in advance; to Racemic isoproterenol (rat and pigeon), thyroxine (rat), ipecac phosphorus (cavy); p-nitrophenols (rat), the various cardiomyopathyes that work reasons such as (rats) causes have the provide protection of dose-dependently.
2) Disodium phosphocreatine is to the auricle performance positive inotropic action of stripped frog, rat and cavy.
3) but Disodium phosphocreatine antagonism oxygen to the negative inotropic action in guinea-pig heart room.
4) in to body and in the test of the multiple trial model that exsomatizes, all can strengthen protection to cardiac muscle with adding Disodium phosphocreatine in the heart cardioplegic solution.
5) Disodium phosphocreatine provides protection to experimental myocardial infarction and the heart disorder that coronary occlusion causes.
6) the myocardial preservation function of Disodium phosphocreatine is relevant with following effect: stablize sarcolemma: keep adenine nucleotide level in the cell by suppressing the Nucleotide lytic enzyme, suppress the phosphatide degraded at ischemic myocardium position; By suppressing the microcirculation that ADP-inductive platelet aggregation improves ishemic part.
Disodium phosphocreatine finds to exist some unavoidable problem, for example: have blood vessel irritation gradually in using all the year round; Sodium ion does not have physiologically active, and because large usage quantity (instiling each 1g, every day 1 ~ 2 time) at 30-45 minute internal jugular vein, the patient of the strict control of needs sodium ion absorptions such as, hypertension complete for cardiorenal function causes the generation of hypernatremia easily, causes adverse drug reaction; The above Disodium phosphocreatine of intravenous injection 1g may cause problems such as blood pressure drops fast.The present domestic harm that hypernatremia is brought that begins clinically more and more to pay attention to, the case fatality rate that the domestic hypernatremia of bibliographical information is arranged is 53%, the case fatality rate of danger disease severe can be higher, the hypernatremia incidence of cranial injury reaches 13%, the case fatality rate of acute hypernatremia is higher than chronic, the hypernatremia pilosity is born in cranial injury, severe infection, the fire victim, renal insufficiency, cardiac insufficiency, in heart failure, the organ transfer operation patient, cephalo, also mention large bolus injection this product in the sodium salt specification sheets of XiLin class and can cause hypernatremia, and Disodium phosphocreatine contain the sodium salt that the sodium amount is far longer than XiLin class, it contains the sodium amount is 17%, and it is 170mg that the Disodium phosphocreatine of 1g contains sodium, and it is 135mmol/l that human body normally contains the sodium amount, surpassing 145mmol/l is hypernatronemia, surpass 160mmol/l, case fatality rate increases greatly, so this is undoubtedly potential Hazard Factor, do not add up how many heart failures though there is document, the incidence of the hypernatremia before the patients with coronary heart disease death, but this factor is enough to cause our attention, and at this first aid medication of Disodium phosphocreatine, it is necessary fully avoiding some human factors.
In order to address the above problem, the medicine worker has carried out a large amount of fruitful work, for example: in the patent application 200510085607.5 (magnesium salts of phosphocreatine and preparation method thereof and the application in pharmacy), proposed phosphocreatine is made magnesium salts, because magnesium salts remains a kind of metal-salt, it is the metal ion that pharmacologically active is arranged, its effect to heart and body is many-sided, its therapeutic dose and safe dose are still a problem, whether can become an experimental study that preparation also need be a large amount of safely and effectively, still have the worry of clinical drug safety.The concentration of magnesium ion in intracellular fluid is only second to potassium ion, is the high ion of concentration in the enchylema second; In the soft tissue, magnesium ion is at heart, voluntary muscle, liver, concentration in kidney and the brain is high especially, this shows, magnesium ion has important effect in animal life, it not only keeps the integrity of bone and tooth, and transmit in the neuromuscular pulse, the activity of enzyme and energy i (in vivo), play an important role in albumen and the metabolism of fat, therefore magnesium ion is to participate in one of the metabolic important substance of cylinder electrolyte basis, its equilibrated destroys will be dangerous equally with hypernatremia, therefore in line with the salify base safe in utilization of should trying one's best, the principle of acid group is sought safer clinically, more effective, the base that patient compliance is good is a very important content.
Arginine was to be used as the treatment hepatogenic encephalopathy originally, but sometimes owing to his security, people are its base as non-activity, and its therapeutic dose is 15-20g, illustrates that also safety range is very big.The present invention makes arginic acid salt with phosphocreatine; this is not that those of ordinary skill just can be realized without creatively working; well solved the problem that Disodium phosphocreatine exists; with arginine as safety, when active little base is used; try hard to avoid too much sodium ion take in, when reducing its blood vessel irritation; behind unexpected discovery phosphocreatine and the arginine salify; the problems referred to above have not only been solved; and having synergy aspect the protection of ischemic myocardium, its intervention effect to the reperfusion injury of ischemic myocardium obviously is better than its sodium salt.
Summary of the invention
The purpose of this invention is to provide a kind of better efficacy and can avoid the salt of the phosphocreatine of Disodium phosphocreatine untoward reaction, with and preparation method thereof with pharmacy in purposes.
We provide a kind of myocardium creatine phosphate arginine salt of protection in the cardioplegic solution that adds when being used for the treatment of the unusual and heart operation of myocardial metabolism under the ischemia condition; optional form with hydrate exists; its chemical name is: inferior hydrogen base (phosphine amino) methyl of N-{ }-sarcosine two arginic acid salts, structural formula is:
More preferably be to contain four crystal water.
Can also contain two crystal water.
We also provide the preparation method of creatine phosphate arginine salt, comprise the following steps:
1) Disodium phosphocreatine is made the aqueous solution that mass percent is 4%-40%, used the cationic exchange resin adsorption metal ion, make it to become the phosphocreatine aqueous solution;
2) below 40 ℃, add arginine by phosphocreatine and 1: 1 mol ratio of arginine and react, promptly obtain the creatine phosphate arginine aqueous solution;
3) obtain the creatine phosphate arginine salt crystal with crystalline mode in lyophilize or the organic solvent.
The present invention also provides a kind of pharmaceutical composition of creatine phosphate arginine salt, is activeconstituents with the creatine phosphate arginine salt, also comprises pharmaceutically acceptable pharmaceutical carrier.
Add suitable auxiliary material and can make injection, transfusion, sterile powder for injection or injection lyophilized powder.
Creatine phosphate arginine salt adds the medicine of cardioplegic solution protection cardiac muscle in the time of can being used for preparing the unusual or heart operation of myocardial metabolism under the treatment ischemia condition.
Be particularly useful for preparing and be applicable to and need among the unusual patient of myocardial metabolism under the ischemia condition to control that sodium ion is taken in, cardiorenal function is complete or hyperpietic's medicine.
Phosphocreatine and arginine salify can solve the solvability of phosphocreatine; this is that those of ordinary skill is predictable; we have found that unexpectedly it can solve there is the hypernatremia risk in Disodium phosphocreatine to the part patient problem very cleverly after with phosphocreatine and arginine salify; surprisingly, pharmacological evaluation proof phosphocreatine and arginine have synergy on the myocardial preservation function.Analyze its reason, might be because: creatine phosphate arginine salt provided by the invention, not only provide the energy to cardiac muscle by the phosphocreatine negatively charged ion, and because arginine is the prodrug of NO, after the effect of NO enzyme, produce NO in vivo, NO is a nerve conduction medium, and vasodilatory effect is arranged, can anticoagulant.Utilize their synergy, reach the purpose of the rational infringement of control cardiac muscular tissue or heart cell dysfunction and cytopathy thereof, help cardiac muscular tissue and recover, myocardial cell's damage behind the minimizing myocardial ischemia.
Specific embodiment:
Embodiment 1: creatine phosphate arginine salt synthetic
Get Disodium phosphocreatine 25.5g, fully be dissolved in the 500ml water, the phosphocreatine aqueous solution slowly by 732 type cationic exchange resin adsorption metal ions, is collected the phosphocreatine aqueous solution.At room temperature, constantly stir adding arginine 17.4g down, fully reaction is filtered, and promptly obtains the creatine phosphate arginine aqueous solution.The lyophilize of the creatine phosphate arginine aqueous solution is got the creatine phosphate arginine salt crystal.This compound with chemical method and aas determination metal ion content, is measured moisture with the karl Fischer method with the content of specificity associating enzymatic assays phosphocreatine.The result is: phosphocreatine 34.2%, and arginine 54.5%, water 11.3%, approaching with theory contains 4 crystal water.Ultimate analysis: theoretical value C30.3% H6.3% O32.9%N24.3% P6.2%; Measured value C30.2% H6.2% O33.1% N24.2% P6.3%.
Embodiment 2: creatine phosphate arginine salt synthetic
Get Disodium phosphocreatine 25.5g, fully be dissolved in the 500ml water, the phosphocreatine aqueous solution slowly by 732 type cationic exchange resin adsorption metal ions, is collected the phosphocreatine aqueous solution.At room temperature, constantly stir adding arginine 17.4g down, fully reaction is filtered, and promptly obtains the creatine phosphate arginine aqueous solution.The lyophilize of the creatine phosphate arginine aqueous solution is got the creatine phosphate arginine salt crystal.This compound with chemical method and aas determination metal ion content, is measured moisture with the karl Fischer method with the content of specificity associating enzymatic assays phosphocreatine.The result is: phosphocreatine 34.3%, and arginine 54.3%, water 11.4%, approaching with theory contains 4 crystal water.Ultimate analysis: theoretical value C30.3% H6.3% O32.9%N24.3% P6.2%; Measured value C30.1% H6.1% O33.0% N24.5% P6.3%.
Embodiment 3: the preparation of injection creatine phosphate arginine lyophilized powder
Take by weighing creatine phosphate arginine salt 30g, fully be dissolved in the 200ml water for injection, add 2.4g N.F,USP MANNITOL again and fully dissolve, gac is crossed 0.22 micron millipore filtration after taking off charcoal, is sub-packed in the 7ml volumetric flask, and the 3ml/ bottle is jumped a queue, freeze-drying, and gland, the jewelling lid, promptly.
Embodiment 4: the preparation of creatine phosphate arginine salt injection liquid
Prescription: creatine phosphate arginine salt 30g
Sodium-chlor: 8g
1000ml
Accurately taking by weighing creatine phosphate arginine salt by recipe quantity puts in the container, add an amount of water for injection, sodium-chlor 8g under agitation is fully after the dissolving, regulate pH to 8.5-8.8, add the injection water to 1000ml, add the 2g needle-use activated carbon, boil 15min, the suction filtration decarburization, solution is through 0.22 μ m filtering with microporous membrane, and in the solution embedding what 100ml infusion bottle (every bottle of phosphoric acid creatine 1g), preparation gets final product through 115 ℃ of pressurization sterilization 30min.
Embodiment 6: creatine phosphate arginine salt is to the provide protection of rat heart muscle infarct
Animal: rat, body weight (250 ± 30) g.
Sample: creatine phosphate arginine salt injection liquid (embodiment 4 preparations)
The Disodium phosphocreatine control group
Nitroglycerin injection
Method: rat heart muscle infarct model is set up in modelling and grouping.Raising more than or equal to 0.1mV with the J point is model success mark.Model success rat is divided into 7 groups at random: 1. model control group, wait capacity physiological saline; 2. creatine phosphate arginine salt injection liquid group (in phosphocreatine 100mg/kg); 3. phosphocreatine sodium injection (in phosphocreatine 100mg/kg); 4. pannonit group (NTG5mg/kg).Below respectively organize in model success back 5min and give respectively and relative medicine by femoral vein.
Myocardial infarct size is measured: sacrificed by exsanguination rat behind the ligation coronary artery 4h, take out heart at once, and cardiac muscle is carried out TTC dyeing, separate infarcted region in the myocardium sheet, weigh, calculate infarcted myocardium (weight in wet base) and account for the per-cent of chamber (weight in wet base) whole-heartedly.
The results are shown in Table shown in 1:
Table 1 creatine phosphate arginine salt influences coronary ligation rat heart muscle infarction size
| Group | Dosage (in phosphocreatine) mg/kg | Myocardial infarct size/% |
| Control group | 100 | 22.7±2.1 |
| The creatine phosphate arginine salt group | 100 | 11.7±1.6 |
| The Disodium phosphocreatine group | 100 | 16.8±1.0 |
| The pannonit group | 5 | 18.8±0.9 |
Conclusion: as shown in table 1, it is obvious than Disodium phosphocreatine group, pannonit fat group that the creatine phosphate arginine salt group reduces myocardial infarct size.The prompting creatine phosphate arginine salt can reduce myocardial infarct size, and is better than control group, has obvious synergistic effect behind phosphocreatine and the arginine salify.
Embodiment 7: the test of creatine phosphate arginine salt blood vessel irritation
Getting creatine phosphate arginine salt injection liquid (1g/100ml/ bottle) is the solution of 2mg/ml with the physiological saline dilution.Get 9 of large ear rabbits, body weight 2.0-2.4kg is divided into 3 groups, 3 every group.The administration group adopts the primary sterilization infusion set that soup is instiled with 5ml/kg (dosage is 10mg/kg) through the left side auricular vein, dripping speed is 2～3ml/min, and control group instils with 5ml/kg through the left side auricular vein, and dripping speed is 2～3ml/min, once a day, for three days on end.Observe the intravascular injection position and whole outer auricular concha has or not variation every day during the administration.Put to death animal in 48 hours after the last administration, draw medicine place blood vessel and surrounding tissue, carry out gross anatomy and histopathologic examination, observation has or not thrombosis, endothelial injury and other pathological changes.
Test-results shows: administration treated animal administration place blood vessel and surrounding tissue and blood vessel all do not have pathological changes such as hyperemia, hemorrhage, oedema, thrombus, necrosis, and control animals administration place blood vessel and surrounding tissue and blood vessel be the no abnormality seen pathological change also.Pathological examination results shows that control animals auricular vein blood vessel structure is normal, does not have hyperemia, and vascular endothelial cell is harmless to injure inflammatory lesion, and surrounding tissue is not seen abnormal changes such as inflammatory lesion, oedema, necrosis yet; Administration treated animal auricular vein blood vessel is compared all no abnormal discovery with control group.Show that the creatine phosphate arginine salt injection liquid does not have the obvious stimulation effect to large ear rabbit auricular vein blood vessel, and spell out Disodium phosphocreatine instillation position pain in the injection Disodium phosphocreatine specification sheets.
Claims (9)
1, a kind of creatine phosphate arginine salt that adds protection cardiac muscle in the cardioplegic solution when being used for the treatment of the unusual and heart operation of myocardial metabolism under the ischemia condition; optional form with hydrate exists; its chemical name is: inferior hydrogen base (phosphine amino) methyl of N-{ }-sarcosine two arginic acid salts, structural formula is:
2, creatine phosphate arginine salt as claimed in claim 1 is characterized in that being tetrahydrate.
3, creatine phosphate arginine salt as claimed in claim 1 is characterized in that being dihydrate.
4,, it is characterized in that comprising the following steps: according to the preparation method of the described creatine phosphate arginine salt of claim 1-3
1) Disodium phosphocreatine is made the aqueous solution that mass percent is 4%-40%, used the cationic exchange resin adsorption metal ion, make it to become the phosphocreatine aqueous solution;
2) below 40 ℃, add arginine by phosphocreatine and 1: 1 mol ratio of arginine and react, promptly obtain the creatine phosphate arginine aqueous solution;
3) obtain the creatine phosphate arginine salt crystal with crystalline mode in lyophilize or the organic solvent.
5, a kind of pharmaceutical composition of creatine phosphate arginine salt is characterized in that with the creatine phosphate arginine salt being activeconstituents, also comprises pharmaceutically acceptable pharmaceutical carrier.
6, creatine phosphate arginine salt pharmaceutical composition as claimed in claim 5 is characterized in that formulation is injection, transfusion, sterile powder for injection or injection lyophilized powder.
7, be used for the treatment of the application in the unusual medicine of myocardial metabolism under the ischemia condition as the described creatine phosphate arginine salt of claim 1-3 in preparation.
8, when preparing heart operation, add the application of protecting in the cardioplegic solution in the myocardium medicine as the described creatine phosphate arginine salt of claim 1-3.
9, creatine phosphate arginine salt as claimed in claim 7 is used for the treatment of the application in the unusual medicine of myocardial metabolism under the ischemia condition in preparation, it is characterized in that preparation be used for the unusual patient of myocardial metabolism under the ischemia condition need to control sodium ion is taken in, cardiorenal function is complete or hyperpietic's medicine in application.
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| CN 200710026641 CN101012240A (en) | 2007-01-31 | 2007-01-31 | Creatine phosphate arginine salt and preparing method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2377578A1 (en) * | 2010-04-08 | 2011-10-19 | John H. Owoc | Stable aqueous compositions comprising amide-protected bioactive creatine species and uses thereof |
| CN102872061A (en) * | 2011-07-14 | 2013-01-16 | 王乐 | Composition of creatine phosphate and arginine |
| CN104530121A (en) * | 2015-01-12 | 2015-04-22 | 精晶药业股份有限公司 | Phosphocreatine citrulline salt, and preparing method and application thereof |
-
2007
- 2007-01-31 CN CN 200710026641 patent/CN101012240A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2377578A1 (en) * | 2010-04-08 | 2011-10-19 | John H. Owoc | Stable aqueous compositions comprising amide-protected bioactive creatine species and uses thereof |
| US8445466B2 (en) | 2010-04-08 | 2013-05-21 | John H. Owoc | Stable aqueous compositions comprising amide-protected bioactive creatine species and uses thereof |
| CN102872061A (en) * | 2011-07-14 | 2013-01-16 | 王乐 | Composition of creatine phosphate and arginine |
| CN104530121A (en) * | 2015-01-12 | 2015-04-22 | 精晶药业股份有限公司 | Phosphocreatine citrulline salt, and preparing method and application thereof |
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Open date: 20070808 |