CN104497038A - Creatine phosphate sodium compound and crystal form thereof - Google Patents
Creatine phosphate sodium compound and crystal form thereof Download PDFInfo
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- CN104497038A CN104497038A CN201410835077.0A CN201410835077A CN104497038A CN 104497038 A CN104497038 A CN 104497038A CN 201410835077 A CN201410835077 A CN 201410835077A CN 104497038 A CN104497038 A CN 104497038A
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Abstract
The invention belongs to the technical field of medicines, and discloses a creatine phosphate sodium compound and a crystal form thereof. The compound is a crystalline-form crystal (img file = 'DSA0000112344300000011. TIF' wi = '790' he = '277' /). Researches show that in the compound crystal, the content of creatine and creatinine in the impurity profile is less than 0.10%, the content of other single impurities is less than 0.30%, and the total content of impurities is less than 1.0%, and for a high-temperature test on raw materials, the content of creatine and creatinine in the impurity profile is less than 0.30%, the content of other single impurities is less than 0.50%, and the total content of impurities is less than 1.50%.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of creatine phosphate sodium compound and crystal formation thereof.
Background technology
Phosphocreatine (Creatine Phosphate, CP) is active substance own in human body, and being the energy source of supply that body weight for humans is wanted, is energy source ATP supplementing energy topmost in cellular process.CP is extensively present in body in each tissue, and the content in muscle tissue is the highest, reaches 90% of total amount in body, and pharmacokinetics evidence of cardiac, skeletal muscle, brain and kidney can absorb exogenous CP.Research finds, phosphocreatine has important pharmacological action, and especially its sodium salt compound Disodium phosphocreatine has been widely used in clinical.As a kind of high-efficiency myocardial protective agent, Disodium phosphocreatine to myocardial cell in metabolism with functionally there is provide protection, there is high efficiency energy arousal function simultaneously, its mechanism of action is: the gathering of haemolysis lipase can be suppressed during (1) heart ischemia to protect its cellularstructure, suppress sarcolemma 5'-NT with stable muscles tunica fibrosa, the electro physiology state of Absorbable organic halogens ischemic myocardial cells simultaneously, protection cardiac muscle is from Peroxidative damage; (2) enter cell and participate in the maintenance of energy-rich phosphate creatine level, adenosine diphosphate (ADP) ADP phosphorylation can be generated ATP, increase the available short-term energy of body.Clinically, mainly add protection cardiac muscle in cardioplegic solution when heart operation, and suppress the myocardial metabolism under ischemia condition abnormal.At present, cardiovascular disorder is as a kind of persistent ailment, and still human health in serious threat.Disodium phosphocreatine is as a kind of myocardial preservation medicine, and not only efficient but also low toxicity, its medical value occupies first of similar drugs.
Phosphocreatine sodium salt is as a kind of myocardial preservation medicine; all kinds of cardiopathic prevention and the assisting therapy such as myocardial ischemia, ventricular hypertrophy, myocardial infarction and heart failure are widely used in; due to its good effect, without any side effects, so its medical value occupies first of similar drugs.Take Disodium phosphocreatine as the preparation of raw material, clinically based on injection, therefore, research improves the quality of phosphocreatine sodium raw materials, is one of research emphasis work of a lot of medical personal.
Summary of the invention
For these reasons, applicant studies discovery, a new crystal formation for new creatine phosphate sodium compound, this crystal formation finds through research, and in its impurity spectrum, creatine, creatinine content are less than 0.10%, other single impurity are less than 0.30%, total impurities is less than 1.0%, and to raw material high temperature test, in its impurity spectrum, creatine, creatinine content are less than 0.30%, other single impurity are less than 0.50%, and total impurities content is less than 1.50%.
The present invention is realized by following proposal.
A kind of formula I, this compound is the crystal of crystallized form
For the new crystal of N-[imino-(phosphine is amino) methyl]-sarcosine disodium salt tetrahydrate.
The wherein 2 θ angles of relative intensity more than 50% in crystal X-powder diffraction spectrum, described relative intensity represents with intense line percentage ratio most in collection of illustrative plates:
The wherein 2 θ angles of relative intensity more than 30% in crystal X-powder diffraction spectrum, described relative intensity represents with intense line percentage ratio most in collection of illustrative plates:
Wherein the testing conditions of crystal is: wherein crystal testing conditions: X-ray tube: Cu-K α target; X-ray wavelength:
pipe pressure: 40KV; Tube current: 40mA; Scanning angle: 3 degree of-39.99 degree.
Wherein crystal KBr compressing tablet-transmission method measures infrared spectra and has following absorption: 3425cm
-1, 1683cm
-1, 1622cm
-1, 1466cm
-1, 1394cm
-1, 1175cm
-1, 1102cm
-1, 987cm
-1.
Wherein at least comprise the crystalline compounds of 95% weight.
Wherein at least comprise the crystalline compounds of 99% weight.
Wherein at least comprise the crystalline compounds of 99.5% weight.
Described a kind of formula I is in preparation treatment cardiac nutrition and the application improved in myocardial metabolism medicine.
Described compound is the pharmaceutical preparation that raw material is prepared into.
Its pharmaceutical formulations comprises injection formulations.
Described a kind of formula I, its preparation method comprises: get Disodium phosphocreatine crude product, adds water for injection and dissolves completely, be heated to 60 DEG C-80 DEG C, add 1,3 butylene glycol, insulation 1-3 hour, is cooled to 25-35 DEG C, adds, adjust pH leaves standstill to 8.0-9.0,0-5 DEG C, filters, filter cake is with 1,3-butyleneglycol washs, and 40 DEG C of vacuum-dryings, to obtain final product.
Disodium phosphocreatine crude product of the present invention is obtained by our company laboratory, and its purity is 95.37%.
One, impurity spectrum research trial
Control group: commercially available phosphocreatine sodium raw materials (Jilin Yinglian Biopharmaceutical Co., Ltd.)
Test 1 group: the embodiment of the present invention 1.
Test 2 groups: the embodiment of the present invention 2.
Test 3 groups: the embodiment of the present invention 3.
[assay] measures according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).Chromatographic condition and system suitability octadecylsilane chemically bonded silica are weighting agent (Thermo, HyPERSIL GOLD, C18,250mm × 4.6mm, 5 μm; Or the suitable chromatographic column of usefulness); With the solution (with phosphoric acid adjust pH to 6.6) containing 0.2% potassium primary phosphate and 0.1% TBAH, for moving phase, determined wavelength is 210nm.Get Disodium phosphocreatine reference substance, creatine reference substance and creatinine reference substance in right amount each, put in same measuring bottle, add moving phase dissolve and quantitatively dilute the solution made respectively containing 1mg, 7.5 μ g and 7.5 μ g in every 1ml, as system suitability solution, get 20 μ l injection liquid chromatographies, peak sequence is followed successively by creatine, creatinine, Disodium phosphocreatine, and number of theoretical plate is pressed Disodium phosphocreatine peak and must not calculate lower than 2000, and the resolution at creatine peak and creatinine peak should be greater than 3.0.
It is appropriate, accurately weighed that assay method gets this product, and add moving phase and dissolve and quantitatively dilute the solution made about containing 0.1mg in every 1ml, precision measures 20 μ l injection liquid chromatographies, record color atlas; Separately get Disodium phosphocreatine reference substance appropriate, accurately weighed, be measured in the same method.By external standard method with calculated by peak area, to obtain final product.
[related substance] faces and uses brand-new.Get this product appropriate, accurately weighed, add moving phase and dissolve and quantitatively dilute the solution made about containing 1mg in every 1ml, as need testing solution; Precision measures 1ml, puts in 100ml measuring bottle, is diluted to scale by moving phase, shake up, in contrast solution.Precision measures contrast solution 5ml, puts in 200ml measuring bottle, is diluted to scale by moving phase, shake up, as sensitivity solution.Separately get creatine and creatinine reference substance is in right amount each, accurately weighed respectively, put in same measuring bottle, add moving phase and to dissolve and quantitatively dilution is made in every 1ml each about containing the solution of 7.5 μ g, as impurity reference substance solution.According to the chromatographic condition under assay item, get sensitivity solution 20 μ l injection liquid chromatography, regulate detection sensitivity, the signal to noise ratio at phosphocreatine peak is made to be greater than 10, precision measures each 20 μ l of need testing solution, impurity reference substance solution and contrast solution again, injection liquid chromatography respectively, record color atlas is to 2 times of need testing solution main peak retention time.If any the chromatographic peak identical with reference substance solution two main peak retention time in need testing solution color atlas, by external standard method respectively with calculated by peak area, all must not 0.30% be crossed containing creatine, creatinine; The peak area of other single unknown impurities must not be greater than 0.5 times (0.5%) of contrast solution main peak area; Total impurities must not cross 1.5%.In need testing solution color atlas, ignore in any peak being less than sensitivity solution main peak area.
Test-results: in table 1.
The impurity spectrum of table 1 different phosphate creatine acid sodium raw materials compares
Conclusion (of pressure testing): above-mentioned test shows, the content of the impurity creatine of the compounds of this invention new crystal, creatinine, single maximum contaminant and total impurities is all remarkable in commercially available Disodium phosphocreatine.
Two, thimble test
Get the raw material of four groups in test one, sample thief, be placed in small beaker, sealing membrane seals.Be placed on electric drying oven with forced convection (DHG-9023A, the permanent Science and Technology Ltd. in Shanghai one), place 10 days under 40 DEG C ± 1 DEG C condition, detect in the 5th day and sampling in the 10th day, result is compared with 0 month data.
Test-results is in table 2, table 3.
Table 2 different material high temperature test results contrast (5 days)
Table 3 different material high temperature test results contrast (5 days)
Conclusion (of pressure testing): in high temperature test, the single maximum contaminant of commercially available Disodium phosphocreatine increases at most, illustrate in commercially available Disodium phosphocreatine and create degradation impurity, and the single maximum contaminant of new crystal of the present invention changes hardly, applicant's research shows, the reason that in commercially available Disodium phosphocreatine, the content of impurity creatine and creatinine increases through high temperature test, may to increase and to degrade to cause with other impurity, thus further illustrate, new crystal of the present invention has more outstanding quality product.
Three, pharmacology comparison test
Trial drug:
Test 1 group: commercially available Disodium phosphocreatine;
Test 2 groups: the embodiment of the present invention 1 Disodium phosphocreatine.
Test method: healthy SD rat, body weight 200 ~ 250g, male and female are not limit, and are divided into 4 groups at random: (1) sham operated rats (A group, n=10), do not carry out cecal ligation and perforation art, the physiological saline of 1h abdominal injection 1ml before sham-operation; (2) Sepsis group (B group, n=10), injects the physiological saline of 1ml in the preoperative 1h of cecal ligation and perforation; (3) commercially available Disodium phosphocreatine group (C group, n=10), in cecal ligation and perforation preoperative 1h abdominal injection Disodium phosphocreatine 100mg/kg (1ml).(4) embodiment of the present invention 1 group (D group, n=10), in cecal ligation and perforation preoperative 1h abdominal injection Disodium phosphocreatine 100mg/kg (1ml).Sham operated rats animal only opens abdomen, closes abdomen and recovery, not ligation, caecum of not boring a hole.Cecal ligation and perforation art (caecum ligationperforation, CLP) ALI animal model reference [Riedemann NC is prepared, Guo RF, WardPA.Novel strategies for the treatmentof sepsis [J] .Nat Med, 2003,9:517-524], art finishes subcutaneous injection 50ml/kg ringer's solution antishock immediately.After off-test, cut thoracic cavity open, expose heart, fast fetching Liang Kuai cardiac muscular tissue (respectively about 1cm
3) and 1mm
3), for detecting activity and the transmission electron microscope observing of glucose-6-phasephate dehydrogenase.Be clipped in heart original position with the aluminium of Liquid nitrogen storage freezing simultaneously, get and organize 100mg, be placed in liquid nitrogen cryopreservation, high performance liquid chromatography detects adenylic acid (AMP) level.The half-quantitative detection of glucose-6-phasephate dehydrogenase activity: get 1cm
3tissue block fixes 3h in 2.5% glutaraldehyde solution and cacodylic acid damping fluid, preparation section is to be checked on request, with daily output LUZEX-F analyser microscopy and semi-quantitative analysis, carry out the activity of half-quantitative detection glucose-6-phasephate dehydrogenase according to the total area size of dark brown lead sulfide precipitation distribution in cell.ATP, ADP and AMP assay: high performance liquid chromatograph is produced by Waters, US, ATP, ADP and AMP standard substance are provided by Sigma Co., USA.Pre-column is Nova.pakC18, and chromatographic column is Nova-pakC 18 (3.9mm × 150mm), special messenger's proper operation on request.ATP, ADP and AMP standard substance are mixed with 0.01mmol/L respectively, the reference liquid of 0.02mmol/L, 0.0625mmol/L and 0.125mmol/L, get 20 μ l sample introductions, draw typical curve.Standard concentration and peak area is made to be good linear relationship.Peak area sample ATP, ADP and AMP obtained, compared with peak area, calculates the content of sample ATP, ADP and AMP.
Test-results: see 4.
Table 4 is group rat heart muscle G-6-PD activity, ATP, ADP and AMP assay value (x ± s, n=10) respectively
Note: compare * * P < 0.01, * P < 0.05 with septicopyemia group.
Conclusion (of pressure testing): new crystal dosage of the present invention has identical effect with commercially available group: Sepsis energy metabolism of myocardial obstacle can be improved.
Four, sensitivity test research
Trial drug:
Test 1 group: commercially available Disodium phosphocreatine 100g, add the stirring of appropriate water for injection to make it to dissolve, add the needle-use activated carbon of amount of solution 0.1%, stirring at room temperature 15min, de-carbon filters, Sterile Filtration, obtain clear liquid, mend water for injection to 300ml, stir evenly, cross 0.22 μm of millipore filtration, according to dosage filling in 10ml cillin bottle, every bottle of 3ml, after lyophilize and get final product.
Test 2 groups: test 1 group of preparation and be placed on 60 DEG C of lower preparations obtained for 10 days of condition.
Test 3 groups: embodiment 1 Disodium phosphocreatine 100g, add the stirring of appropriate water for injection to make it to dissolve, add the needle-use activated carbon of amount of solution 0.1%, stirring at room temperature 15min, de-carbon filters, Sterile Filtration, obtain clear liquid, mend water for injection to 300ml, stir evenly, cross 0.22 μm of millipore filtration, according to dosage filling in 10ml cillin bottle, every bottle of 3ml, after lyophilize and get final product.
Test 4 groups: the preparation testing 3 groups is placed on 60 DEG C of lower preparations obtained for 10 days of condition.
Experimental animal: cavy, regular grade, weight 300-400g, male and female are regardless of.
Test method: get healthy guinea pig 36, be divided into 6 groups at random, often organizes 6: (1) negative control group, gives 0.9% sodium chloride injection; (2) positive controls, gives 0.5% bovine serum albumin; Test 1 group to test 4 groups, give injection Disodium phosphocreatine, administration mass concentration is set to 125mg/ml, priming dose 357.2mg/ml, and booster dose is 714.4mg/ml.The next day every only each abdominal injection trial-product 1.0ml, totally 3 times, carry out sensitization.Then each group is further divided into 2 groups, often organizes 3, after injecting first the 14th day and the 21st day respectively, is attacked by auricular vein injection trial-product 2ml.Observe the symptom of every animal every day, first, last sensitization and measure and record the weight of every animal before exciting.At once to 30 minute after intravenous injection, observes the reaction of every animal in detail by symptom, the appearance of symptom and extinction time, the longest observation 3h.Sequence number 0, normally; 1, restless; 2, perpendicular hair; 3, tremble; 4, scratch nose; 5, sneeze; 6, cough; 7, be short of breath; 8, urinate; 9, defecation; 10, shed tears; 11, expiratory dyspnea; 12, wheezing sound; 13, purpura; 14, instability of gait; 15, jump; 16, pant; 17, spasm; 18, rotate; 19, cheyne stokes respiration; 20, dead.By predisposing medical conditions judgement criteria: 0, anaphylaxis is negative, and one; 1-4, the weak positive of anaphylaxis ,+; 5-10, anaphylaxis is positive, ++; 11-19, anaphylaxis strong positive, +++; 20, the extremely strong positive of anaphylaxis, ++++.Judge anaphylaxis occurrence degree, calculate anaphylaxis incidence, carry out comprehensive descision according to anaphylaxis incidence and occurrence degree.
Test-results is in table 5.
Table 5 cavy anaphylaxis incidence and occurrence degree
Conclusion (of pressure testing): above-mentioned test shows, injection formulations prepared by crystal formation of the present invention has better security than commercial preparation.
Accompanying drawing explanation
1, Fig. 1 is that embodiment 1 obtains the compounds of this invention crystal X-powder diffraction spectrum.
Preparation embodiment
Embodiment 1
Get Disodium phosphocreatine crude product 100g, add water for injection 100ml and dissolve completely, be heated to 70 DEG C, add 3.5L 1,3 butylene glycol, be incubated 2 hours, be cooled to 30 DEG C, add, adjust pH to 8.5,3 DEG C leave standstill, and filter, filter cake is with 1,3-butyleneglycol washs, 40 DEG C of vacuum-dryings, obtain new crystal 92.6g of the present invention, and purity is 99.3%.
Embodiment 2
Get Disodium phosphocreatine crude product 100g, add water for injection 100ml and dissolve completely, be heated to 65 DEG C, add 1,3 butylene glycol 300ml, be incubated 1.5 hours, be cooled to 28 DEG C, add, adjust pH leaves standstill to 8.20-5 DEG C, filter, filter cake 1,3 butylene glycol washs, 40 DEG C of vacuum-dryings, obtain new crystal 92.2g of the present invention, purity is 99.0%.
Embodiment 3
Get Disodium phosphocreatine crude product 100g, add water for injection 100ml and dissolve completely, be heated to 75 DEG C, add 1,3 butylene glycol 400ml, be incubated 2.5 hours, be cooled to 33 DEG C, add, adjust pH to 8.8,4 DEG C leave standstill, and filter, filter cake is with 1,3-butyleneglycol washs, 40 DEG C of vacuum-dryings, obtain new crystal 92.1g of the present invention, and purity is 99.4%.
Embodiment 4
Get Disodium phosphocreatine crude product 1000g, add water for injection 1000ml and dissolve completely, be heated to 70 DEG C, add 1,3 butylene glycol 4000ml, be incubated 2.5 hours, be cooled to 33 DEG C, add, adjust pH to 8.5,4 DEG C leave standstill, and filter, filter cake is with 1,3-butyleneglycol washs, 40 DEG C of vacuum-dryings, obtain new crystal 925.1g of the present invention, and purity is 99.3%.
Embodiment 5
Get Disodium phosphocreatine crude product 2000g, add water for injection 2000ml and dissolve completely, be heated to 75 DEG C, add 1,3 butylene glycol 8000ml, be incubated 3 hours, be cooled to 25 DEG C, add, adjust pH to 8.5,0 DEG C leaves standstill, and filter, filter cake is with 1,3-butyleneglycol washs, 40 DEG C of vacuum-dryings, obtain new crystal 1848.1g of the present invention, and purity is 99.1%.
Disodium phosphocreatine crude product described above is obtained by our company laboratory, and its purity is 95.37%.
Ka Er-Fei Xiushi method measures moisture, containing crystal water 22.01%.
Described embodiment includes but not limited to above-mentioned.
Claims (9)
1. a formula I, is characterized in that: this compound is the crystal of crystallized form
2. a kind of formula I according to claim 1, the wherein 2 θ angles of relative intensity more than 50% in crystal X-powder diffraction spectrum, described relative intensity represents with intense line percentage ratio most in collection of illustrative plates:
3. a kind of formula I according to claim 1, the wherein 2 θ angles of relative intensity more than 30% in crystal X-powder diffraction spectrum, described relative intensity represents with intense line percentage ratio most in collection of illustrative plates:
4. a kind of formula I according to any one of claim 1-3, wherein the testing conditions of crystal is: wherein crystal testing conditions: X-ray tube: Cu-K α target; X-ray wavelength:
pipe pressure: 40KV; Tube current: 40mA; Scanning angle: 3 degree of-39.99 degree.
5. a kind of formula I according to any one of claim 1-3, wherein crystal KBr compressing tablet-transmission method measures infrared spectra and has following absorption: 3425cm
-1, 1683cm
-1, 1622cm
-1, 1466cm
-1, 1394cm
-1, 1175cm
-1, 1102cm
-1, 987cm
-1.
6. a kind of formula I according to any one of claim 1-3 is in preparation treatment cardiac nutrition and the application improved in myocardial metabolism medicine.
7. a kind of formula I according to any one of claim 1-3, is characterized in that compound is the pharmaceutical preparation that raw material is prepared into.
8. a kind of formula I according to claim 10, its pharmaceutical formulations comprises injection formulations.
9. a kind of formula I according to claim 3, its preparation method comprises: get Disodium phosphocreatine crude product, adds water for injection and dissolves completely, be heated to 60 DEG C-80 DEG C, add 1,3 butylene glycol, insulation 1-3 hour, is cooled to 25-35 DEG C, adds, adjust pH leaves standstill to 8.0-9.0,0-5 DEG C, filters, filter cake is with 1,3-butyleneglycol washs, and 40 DEG C of vacuum-dryings, to obtain final product.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304597A (en) * | 2013-06-28 | 2013-09-18 | 四川省惠达药业有限公司 | Creatine phosphate sodium compound and preparation method thereof, and pharmaceutical composition of compound and preparation method of composition |
| CN104109171A (en) * | 2013-04-19 | 2014-10-22 | 上海和臣医药工程有限公司 | Disodium N-[imino(phosphinoamino)methyl]-N-methylglycinate hydrate and preparation method thereof |
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- 2014-12-30 CN CN201410835077.0A patent/CN104497038A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104109171A (en) * | 2013-04-19 | 2014-10-22 | 上海和臣医药工程有限公司 | Disodium N-[imino(phosphinoamino)methyl]-N-methylglycinate hydrate and preparation method thereof |
| CN103304597A (en) * | 2013-06-28 | 2013-09-18 | 四川省惠达药业有限公司 | Creatine phosphate sodium compound and preparation method thereof, and pharmaceutical composition of compound and preparation method of composition |
Non-Patent Citations (1)
| Title |
|---|
| 谭佩幸等，: "《现代化学试剂手册，第三分册，生化试剂（二）》", 31 October 1991, 化学工业出版社 * |
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Application publication date: 20150408 |