Background and overview[1][2]
Creatine phosphate is a natural active substance in the human body, designed to replenish energy for ATP, while A zinc sulfide TP is the most important energy source in any cell metabolism process. Exogenous creatine phosphate is a drug with myocardial protection. It can be used as an important auxiliary drug to reduce ischemic myocardial damage, ventricular arrhythmias and improve failure during cardiac surgery. Especially after the widespread application of treatment methods such as thrombolytic therapy for myocardial infarction, percutaneous transluminal coronary angioplasty (intracoronary stent), and coronary artery bypass grafting, it has driven the rapid growth of the creatine phosphate market. Cardiovascular disease is a disease that develops slowly, is sudden, and is extremely dangerous. Clinical treatment and medication are often subject to many limitations and unpredictable factors. The current medical community believes that early control of the development of cardiovascular and cerebrovascular diseases is the only effective prevention and treatment method at present. However, when people’s medical knowledge level and health awareness have not been generally improved, there is still a large gap. Therefore, for a considerable period of time, cardiovascular treatment drugs and auxiliary treatment drugs not only have a broad market, but also are a major category with great potential. Up to now, the raw materials for creatine phosphate sodium include biological extraction method, chemical synthesis method, and free enzyme synthesis method. However, there are no domestic reports on the synthesis of creatine phosphate sodium products using immobilized creatine kinase. Biological extraction methods have shortcomings such as low yield and difficult quality control. The disadvantages of the chemical synthesis method are that the reaction process is intense and the reaction conditions are not easy to control; toxic large sulfates and barium salts will be introduced into the preparation, reducing product safety; a large amount of three wastes are produced during the synthesis process, causing great pollution to the environment. The treatment of three wastes has also caused great technical and economic burdens on enterprises. The advantage of the free enzyme synthesis method is that the reaction kit is mild and easy to control; it completely simulates the synthesis process of creatine phosphate in the human body, avoiding the residues of various harmful intermediates caused by the chemical synthesis process, so the product is safer ; At the same time, this method is highly operable, pollution-free, meets people’s needs for efficient and environmentally friendly modern drug synthesis, and deserves to be widely promoted and applied.
Pharmacological effects[3]
Creatine phosphate plays an important role in energy metabolism for muscle contraction. It is the chemical energy reserve of cardiac and skeletal muscles and is used for the resynthesis of ATP, whose hydrolysis provides energy for the actomyosin contractile process. Insufficient energy supply caused by slowed oxidative metabolism is an important factor in the formation and development of cardiomyocyte damage. Insufficient levels of creatine phosphate have important clinical implications in the impairment of myocardial contractility and functional recovery. In fact, in myocardial injury, there is a close relationship between the amount of high-energy phosphate compounds in cells and the cell’s ability to survive and contractile function. Therefore, maintaining the level of high-energy phosphate compounds has become the basic principle of various methods to limit myocardial damage, and it is also the basis of cardiometabolic protection. Animal experiments and cardiac arrest trials in humans demonstrate the effects of creatine phosphate and its potential to protect the heart. Pharmacological tests show that: Preliminary intramuscular injection of creatine phosphate sodium is effective against isoproterenol (rats and pigeons), thyroxine (rats), ipecacine (guinea pigs), P-nitrophenol (rats), It has a dose-dependent protective effect on various myocardial diseases caused by labor (rats) and other causes. Sodium creatine phosphate exerts a positive inotropic effect on the isolated hearts of frogs, rats and guinea pigs, as well as the atrial appendages of guinea pigs. Sodium creatine phosphate can antagonize the negative inotropic effects of hypoxia on isolated guinea pig atria. In tests on a variety of in vivo and ex vivo experimental models, the addition of creatine phosphate sodium to cardioplegia solution enhanced myocardial protection. Creatine phosphate provides protection against experimental myocardial infarction and arrhythmias caused by coronary artery occlusion. The cardioprotective function of sodium creatine phosphate is related to the following effects: stabilizing the myofiber membrane; maintaining intracellular adenine nucleotide levels by inhibiting nucleolytic enzymes and inhibiting phospholipid degradation in ischemic myocardium; inhibiting ADP-induced Platelet aggregation improves microcirculation in ischemic areas.
Clinical Application[4]
This product is a chemical energy reserve for cardiac and skeletal muscles and is used for the resynthesis of ATP, providing energy for the actomyosin contraction process and playing an important role in the energy metabolism of muscle contraction. Insufficient energy supply is an important factor in the formation and development of cardiomyocyte damage. It is suitable for protecting myocardial metabolic abnormalities under myocardial ischemia.
Pharmacokinetics[3]
After intramuscular injection of creatine phosphate into rabbits, the blood concentration reaches the peak 20 to 40 minutes later. At this time, about 25 to 28% of the administered dose is in the blood. The value then slowly decreased, and after 250 minutes 9% of exogenous creatine phosphate was still in the blood. An increase in blood ATP levels can be observed between 40 and 250 minutes after intramuscular injection of creatine phosphate, reaching the highest concentration after 100 minutes, at which time the ATP level increases by 25%. After intravenous administration to rabbits, creatine phosphate appears in the blood in its active form and gradually decreases within 30 minutes. Blood ATP levels increase (increase greater than 24% at peak) and return to normal after 300 minutes. The average elimination half-life of intravenously administered creatine phosphate in humans is 0.09 to 0.2 hours. After 40 minutes of relieving infusion of 5 g of creatine phosphate, the plasma concentration dropped to 5 nmol/ml. After 2 hours, it is still 1~2 nmol/ml. A 750 mg dose gives an approximate peak concentration of 11 to 12 nmol/ml. Analysis of tissues showed that exogenous creatine phosphate was mainly produced by��Cardiocardium and skeletal muscle, followed by brain and kidney tissue, lung and liver tissue at least. The metabolism and excretion process in the body is that creatine phosphate is catalytically dephosphorylated to form creatine, and then creatine is cyclized into creatinine, and finally excreted in the urine.
Usage[4]
For adults, 1g should be infused intravenously over 30-45 minutes 1 to 2 times a day. It can be added to cardioplegia to protect myocardium during cardiac surgery, with a concentration of 10 mmol/L.
Adverse reactions, contraindications and drug effects[4]
It is forbidden for those who are allergic to the components of this product; it is forbidden for those with chronic renal insufficiency to use large doses (5 ~ 10 g/d). Rapid intravenous injection of more than 1g can cause a decrease in blood pressure. Large-dose administration leads to large amounts of phosphate intake, which can affect calcium metabolism and the secretion of hormones that regulate homeostasis, and affect renal function and purine metabolism.
Preparation specifications[4]
Injection: 500 mg/tube, 1.0g/tube.
Preparation[2]
A preparation method of sodium creatine phosphate, the preparation method includes the following steps:
1) Preparation of creatinine chloride: Use creatinine and phosphorus oxychloride as raw materials. The mass ratio of creatinine and phosphorus oxychloride is 1:25~40. According to the silicone oil manufacturer, according to the ratio between the raw materials Weigh the raw material creatinine and phosphorus oxychloride proportionally. First, add the raw material creatinine into the reaction vessel, then add phosphorus oxychloride, stir and heat, heat to 105~108°C for reflux reaction, reflux reaction until creatinine is completely dissolved, and creatinine is completely dissolved. Then continue the reflux reaction for 30 to 35 minutes. After the reflux reaction is completed, the temperature is cooled to 25 to 35°C to obtain a reaction liquid; the reaction liquid is subjected to conventional distillation separation using a vacuum distillation device, and excess phosphorus oxychloride is distilled out. After distillation, the reaction liquid is obtained The distillation substrate is the intermediate product creatinine chloride;
2) Preparation of crude sodium creatine phosphate: Add ice water to the distillation substrate obtained in step (1). The ratio of the addition amount between the distillation substrate and ice water is 1g: 0.8~1.2ml. After adding ice water, the temperature of the reaction solution drops to -5~0°C. Under constant stirring, a sodium hydroxide solution with a concentration of 10 mol/l is added dropwise to perform the hydrolysis reaction. The amount added between the distillation substrate and the sodium hydroxide solution is The ratio is 1g: 1.2~1.8ml. During the dropwise addition of the sodium hydroxide solution, control the temperature of the reaction solution to 4~0°C. After the sodium hydroxide solution is added, continue stirring until it is completely dissolved, and then stir at 0~4°C. Continue to stir the reaction for 1 to 1.5 hours; after the reaction is completed, heat the reaction solution to 45 to 50°C, stir at this temperature for 2 to 5 hours, and then cool to room temperature; after cooling to room temperature, slowly add 732 cationic resin under constant stirring to The pH value of the reaction solution is 8 to 9. Purify and remove impurities, and then filter to remove the 732 cationic resin to obtain a filtrate; add activated carbon for needles to the obtained filtrate and stir for 40 to 50 minutes to decolorize and remove impurities. The amount of activated carbon for needles accounts for 1 to 3% of the total volume of the filtrate, and then add ethanol accounting for 35 to 38% of the filtrate volume under stirring conditions. After adding ethanol, filter and remove the needle activated carbon to obtain the decolorized filtrate; under stirring conditions, in the decolorized filtrate Add ethanol accounting for 43 to 46% of its volume. After adding ethanol, cool down to -3 to -5°C and continue stirring. Use an ultrasonic probe to accelerate nucleation and crystallization. Stop stirring when the crystals precipitate and let stand at -10°C. Leave it for 13 to 16 hours, let it stand and then filter it with suction to obtain the wet crude creatine phosphate sodium product;
3) Refining of crude creatine phosphate sodium:
First refining: Stir and dissolve the wet sodium creatine phosphate product obtained in step (2) into purified water at room temperature. The ratio between the wet sodium creatine phosphate product and purified water is 1g:4 ~6ml, after complete dissolution, add activated carbon for needles and stir for 40-50 minutes. The mass ratio between wet sodium creatine phosphate and activated carbon for needles is 1:0.13~0.16, then filter to remove the activated carbon for needles, and slowly add it to the resulting filtrate The ratio of ethanol, sodium creatine phosphate wet product and ethanol is 1g:8~10ml. After ethanol is added, the temperature is cooled to -3~-5℃, and an ultrasonic probe is used under stirring conditions to accelerate nucleation. Crystals precipitate, stop stirring, and let stand for 15 to 17 hours at -10°C. After standing, filter to obtain the initially refined wet product of sodium creatine phosphate;
Second refining: Stir and dissolve the initially refined sodium creatine phosphate wet product into water for injection at room temperature. The ratio between the initially refined sodium creatine phosphate wet product and water for injection is 1g:4 ~6ml, after completely dissolved, add activated carbon for needles and stir for 40-50 minutes. The mass ratio between the initially refined sodium creatine phosphate wet product and activated carbon for needles is 1:0.15~0.18, then filter and remove the activated carbon for needles, and the result Slowly add ethanol to the filtrate. The ratio between the initially refined creatine phosphate wet product and ethanol is 1g: 6~8ml. After ethanol is added, cool down to -3~-5°C. Stop stirring when the crystals precipitate. , let it stand for 15 to 17 hours under the condition of -10°C, and then suction filtration to obtain the refined sodium creatine phosphate wet product. The wet product is vacuum-dried, and the product sodium creatine phosphate is obtained after drying.
Main reference materials
[1] CN201510679067.7 Preparation method of creatine phosphate sodium
[2] CN201210582243.1 Preparation method of creatine phosphate sodium
[3] Instructions for Creatine Phosphate Sodium Injection
[4] Handbook of Commonly Used New Drugs
