CN104530121A - Phosphocreatine citrulline salt, and preparing method and application thereof - Google Patents
Phosphocreatine citrulline salt, and preparing method and application thereof Download PDFInfo
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- CN104530121A CN104530121A CN201510013493.7A CN201510013493A CN104530121A CN 104530121 A CN104530121 A CN 104530121A CN 201510013493 A CN201510013493 A CN 201510013493A CN 104530121 A CN104530121 A CN 104530121A
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- phosphocreatine
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Abstract
The invention discloses a phosphocreatine citrulline salt, and a preparing method and an application of the salt, and relates to the technical field of amide compounds containing phosphoric acid. According to the preparing method, phosphocreatine disodium salt is adsorbed by cation exchange resin to remove sodion and impurities and made into a phosphocreatine solution, then citrulline is added into the phosphocreatine solution till to be dissolved completely, after concentration is carried out, activated carbon decoloration is carried out under the low-temperature condition, obtained feed liquid is filtered in a sterilizing mode, and then solvent-out crystallization is carried out to obtain the phosphocreatine citrulline composite salt finally. The compound has the myocardial protection function and the cardiovascular protection function. The method is used for producing sterile phosphocreatine citrulline composite salt products and phosphocreatine citrulline tablets, oral liquid, capsules and particle drugs.
Description
Technical field
The present invention relates to the amides technical field of phosphoric acid.
Background technology
Phosphocreatine is distributed widely in health respectively to be organized, 90% in muscle tissue, is the chemical energy store of cardiac muscle and skeletal muscle, is one of important substance participating in cellular energy metabolism, be mainly used in the synthesis of ATP, the actomyosin contraction process that is hydrolyzed to of ATP provides energy.
Disodium creatine phosphate is a kind of common drug, be mainly used in treatment myocardial contraction obstacle, be widely used in clinical at present, but in using throughout the year, find that this medicine has hormesis to blood vessel, the sodium ion of phosphocreatine sodium salt is without physiologically active, and large usage quantity can be incomplete to cardiorenal function, the patients such as hypertension cause adverse drug reaction, the sodium amount that contains of phosphocreatine is up to 17%, and human normal is 135mmol/L containing sodium amount, be hypernatronemia more than 140mmol/L, can greatly increase more than 160mmol/L case fatality rate, therefore, phosphocreatine receives salt for protection treatment is cardiovascular and effect that is myocardial ischemia is very limited, use is clinically potential Hazard Factor.
For avoiding above-mentioned phenomenon, application number is magnesium salts of 200510085607.5(phosphocreatine and preparation method thereof and the application in pharmacy) Chinese patent provide a kind of phosphocreatine magnesium salts and preparation method thereof, but life-time service magnesium salts can cause magnesium ion in body to raise, cause magnesium poisoning, and affect Calcium-ion absorption.Application number is 200710026641.4(creatine phosphate arginine salt and preparation method thereof) Chinese patent provide a kind of creatine phosphate arginine salt and preparation method thereof, in patent, the preparation method of creatine phosphate arginine salt compares therewith, the advantage of technical solution of the present invention is simple to operate, cost is low, quality is high, good stability, is convenient to direct packaging.
Citrulline is a kind of alpha amino acid, and name is by the watermelon first extracting citrulline.Citrulline generates ornithine cycle from ornithine and amido first vinegar phosphoric acid salt, or generate arginic by product through nitricoxide synthase (NOS) catalysis.The effect of citrulline improves human immune system's function, increase energy, safeguard joint fortune merit function, the blood vessel of people is obtained lax, help human body relieving fatigue and pressure, help the normal glucose level of balance and keep cholesterol levels, the pulmonary function of maintaining healthy, improves the effects such as mental sharpness.Citrulline absorbs harmful free radical containing abundant antioxidant, and contributes to other cardiovascular disordeies such as treatment myocardial contraction obstacle and myocardial ischemia etc. after Disodium phosphocreatine salt binding generation composite salt, and does not have drug side effect.
Summary of the invention
The object of the present invention is to provide a kind of phosphocreatine citrulline salt, Preparation Method And The Use; be used for preparing the medicine for the treatment of myocardial contraction obstacle and myocardial ischemia; this medicine has myocardial preservation function and cardiovascular protection function; the patient being particularly useful for intentionally renal insufficiency or vascular hypertension is used for the treatment of myocardial contraction obstacle and myocardial ischemia; result for the treatment of is good; have no side effect, method for producing medicines is simple to operate.
To achieve these goals, present invention employs following technical scheme:
A kind of phosphocreatine citrulline salt, it is the phosphocreatine citrulline salt with following structural formula:
Preparation method's step of phosphocreatine citrulline salt is:
(1) at ambient temperature, disodium creatine phosphate is made the aqueous solution that mass percent is 5% ~ 50%, remove sodium ion by cationic exchange resin adsorption, then go up mixed bed and carry out second adsorption removal impurity, make it to become phosphocreatine solution;
(2) being 1:2 ~ 4 by the mol ratio of phosphocreatine and citrulline, adding citrulline to dissolving completely;
After solution is concentrated at (3) 10 DEG C ~ 55 DEG C temperature, add gac and decolour, then the feed liquid after decolouring is carried out Sterile Filtration and remove gac;
(4) feed liquid is imported in crystallizer carry out solvent crystal, finally obtain phosphocreatine citrulline composite salt.
As preferably, the citrulline adopted in step (2) is Cit.
As preferably, the solvent adopted in step (3) is one or more mixing in ethyl acetate, ethanol, Virahol, acetone.
As preferably, the Sterile phosphate creatine citrulline composite salt product that the present invention produces, its drug form is tablet, oral liquid, capsule, granule medicament.
The phosphocreatine citrulline salt pair cardiovascular disorder adopting such scheme to provide has the different mechanism of action, phosphocreatine negatively charged ion is to heart muscle with energy, citrulline itself absorbs harmful free radical containing abundant antioxidant, there is the effect of blood vessel of releiving, the synergy of phosphocreatine and citrulline is utilized to protect ischemic myocardium and cardiovascular, reach protection cardiac muscle and the cardiovascular object of protection, phosphocreatine citrulline salt solves the adverse drug reaction that phosphocreatine sodium salt causes, be applicable to preparation treatment myocardial contraction obstacle and myocardial ischemia drug, be particularly useful for preparing the intake being applicable to need in myocardial contraction obstacle and Patients with Myocardial Ischemia to control sodium ion, the medicine of the patients such as the complete and hypertension of cardiorenal function, this medicine is free from side effects.
Embodiment
Below in conjunction with embodiment, the present invention is further detailed explanation.
Prepare a method for phosphocreatine citrulline salt, comprise the following steps:
Example 1: get disodium creatine phosphate 30g at ambient temperature and be dissolved in the purified water of 60ml, dissolve completely and cross Zeo-karb, flow liquid 130ml must be crossed, second adsorption removal impurity is carried out by crossing mixed bed on flow liquid, flow liquid 195ml must be crossed, detect phosphocreatine content 10.7%, Cit 29.2g is added in solution, dissolve completely, 44 DEG C are concentrated into volume is 75ml, gac 3.5g is added in solution, decolouring filters removal gac through decarburization after half an hour, feed liquid is imported in crystallizer, control temperature 30 DEG C slowly adds 6 times of ethanol in crystallizer, be cooled to 10 DEG C afterwards, suction filtration obtains white solid, drying obtains 40.37g, mass yield 68.1%.
Example 2: get disodium creatine phosphate 30g and be dissolved in the purified water of 60ml, control temperature is no more than 35 DEG C, dissolve completely and cross Zeo-karb, flow liquid 146ml must be crossed, second adsorption removal impurity is carried out by crossing mixed bed on flow liquid, flow liquid 220ml must be crossed, detect phosphocreatine content 9.4%, Cit 29.0g is added in solution, dissolve completely, 45 DEG C are concentrated into volume is 74ml, gac 3.5g is added in solution, decolouring filters removal gac through decarburization after half an hour, feed liquid is imported in crystallizer, control temperature 3 DEG C slowly adds 6 times of Virahols in crystallizer, obtain white solid, drying obtains 40.7g, mass yield 68.7%.
Example 3: get disodium creatine phosphate 30g and be dissolved in purified water, phosphocreatine two sodium content is regulated to be 50%, control temperature is no more than 35 DEG C, dissolve completely and cross Zeo-karb, flow liquid 177ml must be crossed, second adsorption removal impurity is carried out by crossing mixed bed on flow liquid, flow liquid 250ml must be crossed, detect phosphocreatine content 9.4%, Cit 29.0g is added in solution, dissolve completely, 55 DEG C are concentrated into volume is 80ml, gac 3.5g is added in solution, decolouring filters removal gac through decarburization after half an hour, feed liquid is imported in crystallizer, control temperature 3 DEG C slowly adds 6 times of Virahols in crystallizer, obtain white solid, drying obtains 39.7g, mass yield 65.7%.
Example 4: get disodium creatine phosphate 40g and be dissolved in purified water under normal temperature condition, purified water is regulated to add to come that, material concentration is regulated to be 5%, Zeo-karb is crossed after concentration determination, flow liquid 200ml must be crossed, second adsorption removal impurity is carried out by crossing mixed bed on flow liquid, flow liquid 265ml must be crossed, detect phosphocreatine content 9.6%, Cit 39g is added in solution, dissolve completely, 44 DEG C are concentrated into volume is 75ml, gac 4g is added in solution, decolouring filters removal gac through decarburization after half an hour, feed liquid is imported in crystallizer, control temperature 30 DEG C slowly adds 6 times of ethanol in crystallizer, be cooled to 10 DEG C afterwards, suction filtration obtains white solid, drying obtains 53.2g, mass yield 67.9%.
Claims (7)
1. a phosphocreatine citrulline salt, is characterized in that it is the phosphocreatine citrulline salt with following structural formula:
。
2. the preparation method of phosphocreatine citrulline salt as claimed in claim 1, is characterized in that comprising the following steps:
(1) at ambient temperature, disodium creatine phosphate is made the aqueous solution that mass percent is 5% ~ 50%, remove sodium ion by cationic exchange resin adsorption, then go up mixed bed and carry out second adsorption removal impurity, make it to become phosphocreatine solution;
(2) being 1:2 ~ 4 by the mol ratio of phosphocreatine and citrulline, adding citrulline to dissolving completely;
After solution is concentrated at (3) 10 DEG C ~ 55 DEG C temperature, add gac and decolour, then the feed liquid after decolouring is carried out Sterile Filtration and remove gac;
(4) feed liquid is imported in crystallizer carry out solvent crystal, finally obtain phosphocreatine citrulline composite salt.
3. the preparation method of phosphocreatine citrulline salt according to claim 2, is characterized in that the citrulline adopted in step (2) is Cit.
4. the preparation method of phosphocreatine citrulline salt according to claim 2, is characterized in that the solvent adopted in step (4) is one or more mixing in ethyl acetate, ethanol, Virahol, acetone.
5. the application of phosphocreatine citrulline salt as claimed in claim 1 in preparation treatment myocardial contraction obstacle and myocardial ischemia drug.
6. phosphocreatine citrulline salt according to claim 5 preparation treatment myocardial contraction obstacle and myocardial ischemia drug in application, it is characterized in that for the preparation of in myocardial contraction obstacle and Patients with Myocardial Ischemia intentionally renal insufficiency or vascular hypertension patient treatment myocardial contraction obstacle and myocardial ischemia drug in application.
7. the treatment myocardial contraction obstacle according to claim 5 or 6 and the medicine of myocardial ischemia, is characterized in that drug form is tablet, oral liquid, capsule and particle.
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| CN201510013493.7A CN104530121A (en) | 2015-01-12 | 2015-01-12 | Phosphocreatine citrulline salt, and preparing method and application thereof |
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| CN201510013493.7A CN104530121A (en) | 2015-01-12 | 2015-01-12 | Phosphocreatine citrulline salt, and preparing method and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113951355A (en) * | 2021-10-15 | 2022-01-21 | 上海舒泽生物科技研究所 | Citrulline tablet candy for promoting synthesis of nitric oxide in human body and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0199117A2 (en) * | 1985-04-17 | 1986-10-29 | SCHIAPPARELLI FARMACEUTICI S.p.A. | New therapeutical use of phosphocreatine |
| CN1729988A (en) * | 2005-08-05 | 2006-02-08 | 杨喜鸿 | Composite medicine of creatine phosphate sodium and magnesium salt |
| CN101012240A (en) * | 2007-01-31 | 2007-08-08 | 广东中科药物研究有限公司 | Creatine phosphate arginine salt and preparing method thereof |
| CN102872061A (en) * | 2011-07-14 | 2013-01-16 | 王乐 | Composition of creatine phosphate and arginine |
-
2015
- 2015-01-12 CN CN201510013493.7A patent/CN104530121A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0199117A2 (en) * | 1985-04-17 | 1986-10-29 | SCHIAPPARELLI FARMACEUTICI S.p.A. | New therapeutical use of phosphocreatine |
| CN1729988A (en) * | 2005-08-05 | 2006-02-08 | 杨喜鸿 | Composite medicine of creatine phosphate sodium and magnesium salt |
| CN101012240A (en) * | 2007-01-31 | 2007-08-08 | 广东中科药物研究有限公司 | Creatine phosphate arginine salt and preparing method thereof |
| CN102872061A (en) * | 2011-07-14 | 2013-01-16 | 王乐 | Composition of creatine phosphate and arginine |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113951355A (en) * | 2021-10-15 | 2022-01-21 | 上海舒泽生物科技研究所 | Citrulline tablet candy for promoting synthesis of nitric oxide in human body and preparation method thereof |
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Application publication date: 20150422 |