CN103304597A - Creatine phosphate sodium compound and preparation method thereof, and pharmaceutical composition of compound and preparation method of composition - Google Patents
Creatine phosphate sodium compound and preparation method thereof, and pharmaceutical composition of compound and preparation method of composition Download PDFInfo
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- CN103304597A CN103304597A CN2013102686355A CN201310268635A CN103304597A CN 103304597 A CN103304597 A CN 103304597A CN 2013102686355 A CN2013102686355 A CN 2013102686355A CN 201310268635 A CN201310268635 A CN 201310268635A CN 103304597 A CN103304597 A CN 103304597A
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Abstract
The invention relates to a pharmaceutical compound, and particularly relates to a creatine phosphate sodium compound, a preparation method thereof, and a pharmaceutical composition of the compound and a preparation method of the composition. The structural formula of the creatine phosphate sodium compound is shown in a formula (I); and an X-ray powder diffraction pattern measured by a Cu-K-alpha ray is shown in a figure 1. A preparation prepared from the creatine phosphate sodium compound prepared by the method is good in stable performance, superior to the prior art, and suitable for clinical application.
Description
Technical field
The present invention relates to a kind of medical compounds, specifically, relate to a kind of creatine phosphate sodium compound, its preparation method and pharmaceutical composition thereof and preparation method thereof.
Background technology
At present, cardiovascular disorder is as a kind of persistent ailment, and still human health in serious threat.The oxidative metabolism Power supply deficiency that causes that slows down is the important factor of myocardial cell injury formation and development.Therefore, develop and develop a kind of effective myocardial preservation medicine and have undoubtedly deep social effect, Disodium phosphocreatine is as a kind of myocardial preservation medicine, efficient but also low toxicity not only, and its medical value occupies first of the similar drugs.In myocardial damage, the quantity of high-energy phosphate compound in the cell, and have close relation between the survival of cell and the contractile function restorability.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.Therefore keeping the level of high-energy phosphate compound to become the fundamental principle of various restriction myocardial damage methods, also is the basis of heart metabolic defence simultaneously.
Disodium phosphocreatine, chemical name are the Creatine PHospHate Sodium tetrahydrate, and molecular formula is C
4H
8N
3Na
2O
5P4H
2O, molecular weight: 327.14, structural formula is as follows:
Disclosed a lot of patents and document about Disodium phosphocreatine:
Patent ZL201010127288.0 discloses a kind of highly purified creatine phosphate sodium compound.Comprise the steps: that (1) is soluble in water with the Disodium phosphocreatine crude product, then slowly add acid, stirring reaction to pH value of solution is 2-4, produces the phosphocreatine precipitation, obtains phosphocreatine by suction filtration; (2) phosphocreatine that the upper step was obtained is dissolved in the solvent of 2-10 times of weight, adds the solution gac, stirs, and filters decarburization, collects filtrate; (3) filtrate that the upper step was obtained is utilized the preparative chromatography post to carry out separation and purification and is obtained the Disodium phosphocreatine highly finished product, and wherein the moving phase used of chromatographic column accounts for the methylene dichloride of moving phase 30-50% or acetone and volume as volume and accounts for the pH of moving phase 50-70% and be the aqueous sodium hydroxide solution of 7-10; Fixed phase stuffing is selected from silica gel or aluminum oxide.Collect filtrate, drying under reduced pressure, the Disodium phosphocreatine that obtains making with extra care.This invention adopts chromatographic column to separate and purifying, and equipment and later maintenance cost are high, is unfavorable for that large-scale industrialization becomes to produce.
Patent application 201110453070.9 discloses a kind of novel method for preparing high-purity creatine phosphate sodium, and its preparation process comprises: (1) creatinine phosphoryl chloride and carboxylate salt generate fat-soluble creatinine phosphoric acid carboxylic acid mixed anhydride in organic solvent; (2) creatinine phosphoric acid carboxylic acid mixed anhydride and aqueous sodium hydroxide solution reaction, crystallization gets the creatinine sodium phosphate; (3) creatinine sodium phosphate hydrolysis in aqueous sodium hydroxide solution, the organic carboxyl acid neutralization, crystallization gets Disodium phosphocreatine.The method complex steps needs to introduce a large amount of sodium hydroxide and Glacial acetic acid, and cost is high, and yield is on the low side.
Patent application 201210532765.0, disclose a kind of crystallization preparation method of Disodium phosphocreatine under 20～30 ℃, the Disodium phosphocreatine crude product is water-soluble, and making concentration is 0.5～1.1g/ml phosphocreatine sodium water solution, add activated carbon, continuously stirring was decoloured in 30～60 minutes; Filter rear filtrate and be moved in the crystallizer, hierarchy of control temperature to 5～45 ℃ add alcohols or organic solvent of ketone and carry out dilution crystallization; Carry out filtering separation, solvent wash, drying after the crystallization, obtain the Disodium phosphocreatine product.The main granularity of this phosphocreatine sodium crystal is 67.1～70.2 μ m.Product purity reaches more than 99.5%, and the one way molar yield of crystallisation process is more than 98.0%, and present method technique is simple, and cost is low, is fit to suitability for industrialized production.The purity of this product still remains to be improved.
Patent ZL201210014132.0 discloses this power injection for injecting creatine phosphate sodium composition of a kind of power injection for injecting creatine phosphate sodium composition and has been comprised of Disodium phosphocreatine and Xylotox; The mass ratio of described Disodium phosphocreatine and Xylotox is 500:7.92～9.9.The pain when main purpose of this invention is injected for alleviating.
For defective of the prior art and deficiency, special proposition the present invention.
Summary of the invention
Primary goal of the invention of the present invention is to have proposed a kind of creatine phosphate sodium compound.
The second goal of the invention of the present invention has been to propose the preparation method of this creatine phosphate sodium compound.
The 3rd goal of the invention of the present invention has been to propose to contain the pharmaceutical composition of this creatine phosphate sodium compound.
In order to realize purpose of the present invention, the technical scheme of employing is:
The present invention relates to a kind of creatine phosphate sodium compound, the structural formula of described creatine phosphate sodium compound as shown in the formula (I):
The X-ray powder diffraction pattern that described creatine phosphate sodium compound use Cu-K alpha-ray measures as shown in Figure 1.
The invention still further relates to a kind of preparation method of creatine phosphate sodium compound, may further comprise the steps:
(1) preparation Disodium phosphocreatine crude product saturated solution is stirred to fully dissolving;
(2) be that 20～25KHz, output rating are under the sound field of 20～80W in frequency, add while stirring 0～5 ℃ ether and the mixing solutions of ethyl acetate, after adding, mixing solutions stops to stir, under the effect of sound field, continue cooling, when being cooled to 1～5 ℃, stop sound field, under 0 ℃ of condition, left standstill growing the grain 12～24 hours, behind the crystallize out, washing, drying obtain creatine phosphate sodium compound.
Wherein: add the mixing solutions of ether and ethyl acetate volume be 2～6 times of Disodium phosphocreatine crude product saturated solution, preferred 3～6 times; Stirring velocity when adding mixed solvent is 150～180 rev/mins; Add the mixing solutions of ether and ethyl acetate adding speed be: be v
1=M/200～M/50, preferred v
1=M/150～M/60, wherein M is the volume of organic mixed solvent, and unit is milliliter, and the unit of speed v is ml/min; The volume ratio of ether and ethyl acetate is 5:1～3 in the described mixing solutions, preferred 5:1～2; After described mixed solvent added, the speed of cooling was v
2=M/20～M/2, preferred v
2=M/15～M/5; Wherein M is the volume of organic mixed solvent, and unit is for rising speed v
2Unit be ℃/hour; The formulation of described creatine phosphate sodium compound is the aseptic powder injection that direct packaging obtains.
The invention still further relates to a kind of pharmaceutical composition that contains described creatine phosphate sodium compound, contain creatine phosphate sodium compound 10 weight parts and pharmaceutical excipient 0.001～10 weight part in the described pharmaceutical composition, preferred 0.01～5 weight part; Described pharmaceutical excipient is selected from sodium-chlor or N.F,USP MANNITOL.
The invention still further relates to the preparation method of pharmaceutical composition, when the formulation of described pharmaceutical composition is aseptic powder injection:
(1) preparation creatine phosphate sodium compound;
(2) creatine phosphate sodium compound is mixed with pharmaceutical excipient, aseptic subpackaged;
When described pharmaceutical composition is freeze-dried powder:
(1) preparation creatine phosphate sodium compound;
(2) with the creatine phosphate sodium compound of recipe quantity water for injection stirring and dissolving, then add the pharmaceutical excipient of recipe quantity; Regulating the pH value is 7.5～8.5; The adding mass percent is 0.01% medicinal carbon, adsorbs filtering decarbonization 20～30 minutes; The essence filter is added sterilized water for injection to full dose, the essence filter;
Lyophilize: the filtrate lyophilize with step (2) obtains in aseptic condition lower cover, aluminium envelope, and get final product.
The below makes further explanation technical scheme of the present invention.
The present invention is by the unremitting research to the creatine phosphate sodium compound crystal formation, obtained a kind of brand-new creatine phosphate sodium compound crystalline compounds, this crystal uses X-ray powder diffraction pattern that the Cu-K alpha-ray measures as shown in Figure 1, and its proterties is white crystalline powder.And detect through high performance liquid chromatography, its purity is 99.95～99.98%, and the dissolvent residual denier.Fusing point is: 112～118 ℃.Adopt dsc to detect the crystal water that it has 4 molecules.
The present invention is by adding the mode of sound field, by adding organic solvent, and the adjusting by temperature, prepared a kind of brand-new crystal formation of Disodium phosphocreatine, and the conversion of crystal formation can not occur after with water dissolution this crystal formation.The Disodium phosphocreatine of the present invention's preparation has the advantage that purity is high, stability is good, is more applicable for clinical application; And this compound has good flowability, makes things convenient for the preparation of preparation in the pharmacy procedure.
Adopt the preparation of the creatine phosphate sodium compound preparation of the present invention's preparation, through the water absorbability experiment confirm, this crystal formation is difficult for moisture absorption, and confirms that through stability test the stability of this crystal formation is good, is better than prior art, is fit to very much clinical application.
The preparation method of creatine phosphate sodium compound of the present invention is simple, and yield is high, and organic solvent is reusable, is conducive to reduce enterprise cost, is fit to large-scale industrial production.
Description of drawings:
Fig. 1 is the X-ray powder diffraction pattern that the creatine phosphate sodium compound for preparing of embodiment 1 uses the Cu-K alpha-ray to measure.
The specific embodiment of the present invention only limits to further explain and explanation the present invention, not to Composition of contents restriction of the present invention.
Embodiment
Embodiment 1: the preparation of creatine phosphate sodium compound
(1) preparation Disodium phosphocreatine crude product saturated solution 5L is stirred to fully dissolving;
(2) be that 20KHz, output rating are under the sound field of 80W in frequency, add while stirring 5 ℃ ether and the mixing solutions 20L of ethyl acetate, stirring velocity is 180 rev/mins; Stop after mixing solutions adds stirring, continue cooling under the effect of sound field, when being cooled to 1 ℃, stop sound field, left standstill growing the grain 12 hours under 0 ℃ of condition, behind the crystallize out, washing, drying obtain creatine phosphate sodium compound; The adding speed of the mixing solutions of ether and ethyl acetate is 100 ml/min; The volume ratio of ether and ethyl acetate is 5:2; After mixed solvent added, cooling rate was 2 ℃/hour.
The X-ray powder diffraction pattern that this compound crystal use Cu-K alpha-ray measures as shown in Figure 1; Detect through high performance liquid chromatography, purity is 99.98%, yield 98.6%; Measuring its fusing point is 112～118 ℃.
Embodiment 2: the preparation of creatine phosphate sodium compound
(1) preparation Disodium phosphocreatine crude product saturated solution 5L is stirred to fully dissolving;
(2) be that 25KHz, output rating are under the sound field of 60W in frequency, add while stirring 0 ℃ ether and the mixing solutions 30L of ethyl acetate, stirring velocity is 160 rev/mins, stops after mixing solutions adds stirring, and continues cooling under the effect of sound field, when being cooled to 1 ℃, stop sound field, under 0 ℃ of condition, left standstill growing the grain 24 hours, behind the crystallize out, washing, drying obtain creatine phosphate sodium compound; Adding speed 150 ml/min of the mixing solutions of ether and ethyl acetate; The volume ratio of ether and ethyl acetate is 5:1; After mixed solvent added, the speed of cooling was 3 ℃/hour.
The X-ray powder diffraction pattern that this compound crystal use Cu-K alpha-ray measures as shown in Figure 1; Detect through high performance liquid chromatography, purity is 99.98%, yield 98.2%; Measuring its fusing point is 112～118 ℃.
Embodiment 3: the preparation of creatine phosphate sodium compound
(1) preparation Disodium phosphocreatine crude product saturated solution 5L is stirred to fully dissolving;
(2) be that 25KHz, output rating are under the sound field of 80W in frequency, add while stirring 3 ℃ ether and the mixing solutions 15L of ethyl acetate, stirring velocity is 150 rev/mins, stops after mixing solutions adds stirring, and continues cooling under the effect of sound field, when being cooled to 1 ℃, stop sound field, under 0 ℃ of condition, left standstill growing the grain 24 hours, behind the crystallize out, washing, drying obtain creatine phosphate sodium compound; The adding speed of the mixing solutions of ether and ethyl acetate is 100 ml/min; The volume ratio of ether and ethyl acetate is 5:3; After mixed solvent added, the speed of cooling was 2 ℃/hour.
The X-ray powder diffraction pattern that this compound crystal use Cu-K alpha-ray measures as shown in Figure 1; Detect through high performance liquid chromatography, purity is 99.98%, yield 98.3%; Measuring its fusing point is 112～118 ℃.
Embodiment 4: the preparation of aseptic powder injection
Get the creatine phosphate sodium compound that embodiment 1 prepares, direct aseptic subpackaged one-tenth 1g/ props up, and obtains aseptic powder injection.
Embodiment 5: the preparation of aseptic powder injection
Get the creatine phosphate sodium compound that embodiment 2 prepares, mix take weight ratio as 10:1 with sodium-chlor, direct aseptic subpackaged one-tenth 1.1g/ props up, and obtains aseptic powder injection.
Embodiment 6: the preparation of freeze-dried powder
(1) gets the creatine phosphate sodium compound 1000g water for injection stirring and dissolving that embodiment 3 prepares, add N.F,USP MANNITOL 500g, complement to 10L with water for injection;
(2) regulating the pH value is 7.5～8.5; The adding mass percent is 0.01% medicinal carbon, adsorbs filtering decarbonization 20～30 minutes; The essence filter is added sterilized water for injection to full dose, the essence filter;
(3) lyophilize: the filtrate lyophilize with step (2) obtains, under aseptic condition, be distributed into 1000, gland, aluminium envelope, and get final product.
Lyophilize is divided into pre-freeze, distillation and drying;
Pre-freeze: shelf temperature is down to-15 ℃ with the speed of 2.0 ℃/min, stops cooling, be incubated 2 hours, the speed with 1.5 ℃/min is cooled to-55 ℃ again;
Distillation: be evacuated to 15Pa, rise to-10 ℃ with the speed of 3 ℃/min, be incubated 2 hours; Speed with 1 ℃/min rises to 15 ℃ of maintenances 2 hours again;
Dry: the speed with 0.5 ℃/min rises to 40 ℃, dry 2 hours.
Test example 1: the Disodium phosphocreatine water absorbability detects
1. instrument and reagent
1.1 instrument
PL203 electronic balance (Mei Teletuo benefit instrument (Shanghai) Co., Ltd.);
LRH-250-S fixed temperature and humidity incubator (Guangdong Medical Apparatus and Instruments Factory);
HH-400SD testing chamber for medicine stability (Chongqing City immortality laboratory apparatus factory);
1.2 reagent
The creatine phosphate sodium compound that S1: embodiment 1 prepares (batch 1201): record moisture 0.69%;
D1: commercially available Disodium phosphocreatine (Haikou Qili Pharmaceutical Co., Ltd., the accurate word H20050193 of traditional Chinese medicines): record moisture 1.39%;
D2: patent application 201110453070.9 embodiment 1 method prepares Disodium phosphocreatine, records moisture 1.38%;
D3: patent application 201210532765.0 embodiment 1 method prepares Disodium phosphocreatine, records moisture 1.35%;
2
1Method
2.1
1The mensuration of moisture equilibrium time
Get the glass moisture eliminator (for guaranteeing that salts solution is saturated, the moisture eliminator bottom should have excessive salt to exist) that the bottom fills the salt supersaturated solution, the built-in weighing bottle of moisture eliminator is placed 48h to constant humidity in thermostat container.Sample thief is 2g approximately, puts in the weighing bottle, and is accurately weighed, bottle cap is opened, put into moisture eliminator top, put in 25 ℃ of fixed temperature and humidity incubators or 20 ℃ of stability test casees by the differing temps requirement and preserve, 3 parts of parallel runnings are weighed respectively at different time, calculate the rate of moisture absorption of different time.
Calculation formula: rate of moisture absorption=(medicinal powder weight after the moisture absorption-moisture absorption prodrug grain weight amount)/moisture absorption prodrug grain weight amount * 100%.
Table 1: the rate of moisture absorption that records at different time
According to above-mentioned experiment as can be known, the water absorbability of the creatine phosphate sodium compound of the present invention's preparation is variant than prior art, is lower than prior art, points out the stability of this compound to be higher than prior art.
Test example 2: aseptic powder injection accelerates experiment
Since Disodium phosphocreatine to heat, light is all unstable, and have certain draw moist, so carry out following accelerated stability test:
Get three batches 101,102,103 of Disodium phosphocreatine sterile powder injection of embodiment 4 preparation, simulation listing packing, put in the sealing clean container, under 30 ± 2 ℃, 75 ± 5%RH condition, placed 6 months, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stable high spot reviews project is tested.Test-results is as shown in table 2.
Table 2:
The result shows: the aseptic powder injection of the Disodium phosphocreatine that the present invention prepares, through the accelerated test result as can be known, its stability is good.Aseptic powder injection to the creatine phosphate sodium compound of other embodiment of the present invention preparation accelerates experiment, has obtained identical experimental result.
Experimental example 3: aseptic powder injection test of long duration
Get three batches 201,202,203 of Disodium phosphocreatine aseptic powder injection of embodiment 4 gained, simulation listing packing, put in the sealing clean container, under 20 ℃ ± 2 ℃ conditions of temperature, placed 24 months, at duration of test respectively at the 3rd, 6,9,12,18,24 sampling at the end of month once, each Interventions Requested is tested.Test-results is as shown in table 3:
Table 3:
The result shows: the Disodium phosphocreatine aseptic powder injection that the present invention prepares, and through long-term test results as can be known, its stability is good, and all retention is stable.Disodium phosphocreatine aseptic powder injection to other embodiment preparation of the present invention carries out long-term experiment, has obtained identical experimental result.
Embodiment 4: lyophilized powder accelerates experiment
Get three batches 201,202,203 of sodium phosphocreatine freeze-dried injection of embodiment 7 gained, simulation listing packing, put in the sealing clean container, under 30 ± 2 ℃, 75 ± 5%RH condition, placed 6 months, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stable high spot reviews project is tested.Test-results is as shown in table 4.
Table 4:
The result shows: the freeze-dried powder of the Disodium phosphocreatine that the present invention prepares, through the accelerated test result as can be known, its stability is good.Creatine phosphate sodium freeze-dried powder pin to other embodiment preparation of the present invention accelerates experiment, has obtained identical experimental result.
Experimental example 5: lyophilized powder test of long duration
Get three batches 301,302,303 of sodium phosphocreatine freeze-dried injection of embodiment 7 gained, simulation listing packing, put in the sealing clean container, under 20 ℃ ± 2 ℃ conditions of temperature, placed 24 months, at duration of test respectively at the 3rd, 6,9,12,18,24 sampling at the end of month once, each Interventions Requested is tested.Assay adopts weighting method to detect, and test-results is as shown in table 5:
Table 5:
The result shows: the creatine phosphate sodium freeze-dried powder pin that the present invention prepares, through long-term test results as can be known, its stability is good.Creatine phosphate sodium freeze-dried powder pin to other embodiment preparation of the present invention carries out long-term experiment, has obtained identical experimental result.
Test example 6: aseptic powder injection stability simultaneous test:
The creatine phosphate sodium compound that S1: embodiment 1 prepares (batch 1201): record moisture 0.69%;
D1: commercially available Disodium phosphocreatine (Haikou Qili Pharmaceutical Co., Ltd., the accurate word H20050193 of traditional Chinese medicines): record moisture 1.39%;
D2: patent application 201110453070.9 embodiment 1 method prepares Disodium phosphocreatine, records moisture 1.38%;
D3: patent application 201210532765.0 embodiment 1 method prepares Disodium phosphocreatine, records moisture 1.35%;
With above-mentioned Comparative Examples, simulation listing packing is put in the sealing clean container, places 6 months under 30 ± 2 ℃, 75 ± 5%RH condition, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stable high spot reviews project is tested.Test-results is as shown in table 6.
Table 6:
The result shows: the aseptic powder injection of the Disodium phosphocreatine that the present invention prepares, through comparative test result as can be known, its good stability illustrates that in existing technology the present invention prepares aseptic powder injection and more is suitable for clinical application.
Test example 7: freeze-dried powder stability simultaneous test:
The creatine phosphate sodium compound that S1: embodiment 1 prepares (batch 1201): record moisture 0.69%;
D1: commercially available Disodium phosphocreatine (Haikou Qili Pharmaceutical Co., Ltd., the accurate word H20050193 of traditional Chinese medicines): record moisture 1.39%;
D2: patent application 201110453070.9 embodiment 1 method prepares Disodium phosphocreatine, records moisture 1.38%;
D3: patent application 201210532765.0 embodiment 1 method prepares Disodium phosphocreatine, records moisture 1.35%;
With above-mentioned Comparative Examples, prescription and method according to embodiment 7 prepare freeze-dried powder, simulation listing packing, put in the sealing clean container, under 30 ± 2 ℃, 75 ± 5%RH condition, placed 6 months, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stable high spot reviews project is tested.Test-results is as shown in table 7.
Table 7:
The result shows: the freeze-dried powder of the Disodium phosphocreatine that the present invention prepares, through comparative test result as can be known, its good stability illustrates that in existing technology the present invention prepares freeze-dried powder and more is suitable for clinical application.
Experimental example 8: the screening experiment of activated carbon concentration
Other processing parameter selects respectively the injection gac of different concns to adsorb all with embodiment 6, take the productive rate of Disodium phosphocreatine, purity as investigating index, the consumption of screening gac.The results are shown in Table 8:
Table 8: activated carbon dosage shaker test
| Concentration of activated carbon (w/v) % | Productive rate (%) | Purity (%) |
| 0.1 | 90.2 | 99.72 |
| 0.05 | 91.7 | 99.81 |
| 0.03 | 93.8 | 99.89 |
| 0.02 | 95.1 | 99.94 |
| 0.01 | 98.7 | 99.99 |
By drawing in the table, 0.01% gac can make the purity of Disodium phosphocreatine and yield reach best, is 0.01%(g/ml so select concentration) gac adsorb.
Experimental example 9: investigate the ratio of solvent in the reaction to the impact of creatine phosphate sodium compound
Adopt the preparation condition of embodiment 1, comparison of design example 1a～8a only changes listed condition in the table, and all the other steps and condition are with embodiment 1; Specifically shown in table 9,10.
Table 9:
| ? | Embodiment 1 | Comparative Examples 1a | Comparative Examples 2a | Comparative Examples 3a | Comparative Examples 4a |
| Ether and ethyl acetate volume ratio | 5：2 | 5：4 | 1：1 | 5：6 | 1：2 |
| Purity (HPLC) | 99.98% | 99.63% | 99.45% | 99.23% | 99.15% |
| Yield | 98.6% | 93.0% | 90.6% | 91.7% | 87.4% |
Table 10:
By above-mentioned experiment as can be known, the condition of employing of the present invention makes purity and two index optimizations of yield.
Claims (9)
1. a creatine phosphate sodium compound is characterized in that, the structural formula of described creatine phosphate sodium compound as shown in the formula (I):
The X-ray powder diffraction pattern that described creatine phosphate sodium compound use Cu-K alpha-ray measures as shown in Figure 1.
2. the preparation method of a creatine phosphate sodium compound as claimed in claim 1 is characterized in that, may further comprise the steps:
(1) preparation Disodium phosphocreatine crude product saturated solution is stirred to fully dissolving;
(2) be that 20～25KHz, output rating are under the sound field of 40～80W in frequency, add while stirring 0～5 ℃ ether and the mixing solutions of ethyl acetate, after adding, mixing solutions stops to stir, under the effect of sound field, continue cooling, when being cooled to 1～5 ℃, stop sound field, under 0 ℃ of condition, left standstill growing the grain 12～24 hours, behind the crystallize out, washing, drying obtain creatine phosphate sodium compound.
3. preparation method according to claim 2 is characterized in that, add the mixing solutions of ether and ethyl acetate volume be 2～6 times of Disodium phosphocreatine crude product saturated solution, preferred 3～6 times.
4. preparation method according to claim 2 is characterized in that, the adding speed v of the mixing solutions of ether and ethyl acetate
1=M/200～M/50, preferred v
1=M/150～M/60; Wherein M is the volume of organic mixed solvent, and unit is milliliter, speed v
1Unit be ml/min.
5. follow according to preparation method claimed in claim 2, it is characterized in that, the volume ratio of ether and ethyl acetate is 5:1～3 in the described mixing solutions, preferred 5:1～2; Stirring velocity when adding mixed solvent is 150～180 rev/mins.
6. follow according to preparation method claimed in claim 2, it is characterized in that, after described mixed solvent adds, the speed v of cooling
2=M/20～M/2, preferred v
2=M/15～M/5, wherein M is the volume of organic mixed solvent, unit is for rising speed v
2Unit be ℃/hour.
7. creatine phosphate sodium compound according to claim 1 is characterized in that, the formulation of described creatine phosphate sodium compound is the aseptic powder injection that direct packaging obtains.
8. a pharmaceutical composition that contains creatine phosphate sodium compound claimed in claim 1 is characterized in that, contains creatine phosphate sodium compound 10 weight parts and pharmaceutical excipient 0.001～10 weight part in the described pharmaceutical composition, preferred 0.01～5 weight part; Described pharmaceutical excipient is selected from sodium-chlor or N.F,USP MANNITOL.
9. the preparation method of a pharmaceutical composition as claimed in claim 8 is characterized in that,
When the formulation of described pharmaceutical composition is aseptic powder injection:
(1) preparation creatine phosphate sodium compound;
(2) creatine phosphate sodium compound is mixed with pharmaceutical excipient, aseptic subpackaged;
When described pharmaceutical composition is freeze-dried powder:
(1) preparation creatine phosphate sodium compound;
(2) with the creatine phosphate sodium compound of recipe quantity water for injection stirring and dissolving, then add the pharmaceutical excipient of recipe quantity; Regulating the pH value is 7.5～8.5; The adding mass percent is 0.01% medicinal carbon, adsorbs filtering decarbonization 20～30 minutes; The essence filter is added sterilized water for injection to full dose, the essence filter;
(3) lyophilize: the filtrate lyophilize with step (2) obtains in aseptic condition lower cover, aluminium envelope, and get final product.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104497038A (en) * | 2014-12-30 | 2015-04-08 | 上海华拓医药科技发展有限公司 | Creatine phosphate sodium compound and crystal form thereof |
| CN104530120A (en) * | 2014-12-30 | 2015-04-22 | 哈尔滨莱博通药业有限公司 | Creatine phosphate sodium compound and crystal form thereof |
| CN112979697A (en) * | 2019-12-17 | 2021-06-18 | 重庆圣华曦药业股份有限公司 | Creatine phosphate tetrahydrate sodium with good fluidity and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104497038A (en) * | 2014-12-30 | 2015-04-08 | 上海华拓医药科技发展有限公司 | Creatine phosphate sodium compound and crystal form thereof |
| CN104530120A (en) * | 2014-12-30 | 2015-04-22 | 哈尔滨莱博通药业有限公司 | Creatine phosphate sodium compound and crystal form thereof |
| CN104530120B (en) * | 2014-12-30 | 2017-06-16 | 哈尔滨莱博通药业有限公司 | A kind of creatine phosphate sodium compound and its crystal formation |
| CN112979697A (en) * | 2019-12-17 | 2021-06-18 | 重庆圣华曦药业股份有限公司 | Creatine phosphate tetrahydrate sodium with good fluidity and preparation method thereof |
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| CN103304597B (en) | 2015-02-25 |
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