CN101199477A - Ratification of highly purified tranexamic acid injection and quality standard thereof - Google Patents
Ratification of highly purified tranexamic acid injection and quality standard thereof Download PDFInfo
- Publication number
- CN101199477A CN101199477A CNA2007103020581A CN200710302058A CN101199477A CN 101199477 A CN101199477 A CN 101199477A CN A2007103020581 A CNA2007103020581 A CN A2007103020581A CN 200710302058 A CN200710302058 A CN 200710302058A CN 101199477 A CN101199477 A CN 101199477A
- Authority
- CN
- China
- Prior art keywords
- acid
- aminomethyl
- quality standard
- impurity
- peak area
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention in the end effectively reduces the impurities in tranexamic acid injection preparation through controlling the conductivity of the injection water to control the quality of the tranexamic acid injection preparation, and limits and controls the sort and the quantity of the impurities according to quality standard, thus obviously improving the stability of the preparation and the quality of the tranexamic acid injection preparation.
Description
Technical field the present invention is by the quality of control injection electrical conductivity of water with final effectively control tranexamic acid ejection preparation, and in quality standard, dopant species and amount thereof have been carried out effective control, obviously improved stability of formulation, promote the quality of tranexamic acid ejection preparation, belonged to chemical pharmacy field.
Background technology
Metal ion is the catalyst of medicine automatic oxidation reaction often, wherein with Cu
2+, Fe
3+, Pb
2+, Mn
2+, Pt
2+, Au
2+For the most common.Such as medicine to ion-sensitive, phenothiazine drug (example hydrochloric acid promethazine), have the adrenomimetic drug medicine of catecholamine structure and ascorbic acid, procaine hydrochloride, sodium salicylate, dopamine hydrochloride etc., having in the presence of the trace metal ion, can quicken variable color or decomposition, thereby cause the increase of injection impurity.As seen amount of ions is more lacked and is more helped the stable of pharmaceutical preparation.So, in actual injection liquid is produced, metal ion is to the catalytic action of medicine in the solvent, slow down oxidation, usually in injection with small volume, lyophilized formulations, often be allowed to add certain density disodium edetate or calcium disodium edetate, but then because the administration volume is bigger, other medical additives then are not allowed to for high-capacity injection.Consideration disodium edetate etc. is the material of external introducing after all, human body is belonged to foreign body, cause ectogenic infection probably or cause untoward reaction, therefore, our method of controlling the injection product quality best is exactly to reduce the number of metal ion in the ion-sensitive type pharmaceutical preparation as much as possible.
Tranexamic acid also belongs to this class ion-sensitive type medicine, its ejection preparation is aborning often because the existence of metal ion, cause tranexamic acid cis-aminomethyl naphthenic acid and other impurity are increased, about causing the impurity of preparation in 3 years, to increase to 2.5%, thereby influence the quality of final products, bring security concern definitely to clinical practice.
So, for with tranexamic acid as for the injection type of active component, how to reduce the metal ion in the preparation as much as possible, the used injection electrical conductivity of water of preparation tranexamic acid injection is controlled at the stability which kind of limit could effectively improve the tranexamic acid ejection preparation, reduce the total amount of impurity, guarantee that safety of clinical administration is effective?
Summary of the invention
As everyone knows, the essence of reduction electrical conductivity is the ion concentration that reduces in the water.Consider in the injection type that the water source is a key influence factor of introducing metal ion.Therefore, emphasis of the present invention is considered the influence of injection electrical conductivity of water to the tranexamic acid injection type.
Ionic product by water is 10
-14The limit conductance that can extrapolate theoretic high purity water is 0.0547 μ S.cm
-1, at present, China's pharmaceutical industry is not done a clear and definite requirement to the injection electrical conductivity of water.The present invention can adopt modes such as weak ionized method, ion-exchange process, distillation to control the injection electrical conductivity of water, and can adopt wherein a kind of method or several different methods to combine to realize the control to electrical conductivity repeatedly according to the different quality situation.Now illustrate a kind of method that reduces electrical conductivity, but be not limited to described water pretreatment method.
Be exemplified below: the present invention can be by following water pretreatment method, adopt two steps ro purified water system, flow process is a raw water box, and--------intermediate water tank--two-pass reverse osmosis--pure water case, obtaining one-level, to go out water conductivity be 3.5 μ S.cm to first-stage reverse osmosis in the carbon filter in husky filter
-1About, the secondary effluent electrical conductivity is 1.3 μ S.cm
-1About, secondary water is distilled, make final its electrical conductivity of gained water for injection be controlled at 0.6 μ S.cm
-1(20 ℃).
By to finding by the comparative study of the tranexamic acid infusion solution of different quality preparation, the water intermediate ion is many more, be that electrical conductivity of water is big more, impurity increases just many more in its preparation, and be prolongation along with the time, what increase is obvious more, the results are shown in Table 1: different electrical conductivity waters for injection are prepared impurity investigation result in the stability test of tranexamic acid sodium chloride infusion solution.
Found in the infusion preparation just, though adopt same batch of raw material, but because used injection electrical conductivity of water is controlled, the result makes total impurities in the preparation reduce to about 1.0% by original about 2.5%, effectively controlled product quality, the inventor continues again tranexamic acid injection and lyophilized injectable powder (comprising self-control and commercially available sample) have been carried out corresponding preparation and quality research.
The present invention finds by careful comparative study just, and used injection electrical conductivity of water has closely and gets in touch when the product quality of tranexamic acid injection and its dosing, needs only and is no more than 1.0 μ S.cm when the water for injection electrical conductivity is controlled at 20 ℃
-1, the tranexamic acid small-volume injection that can control of this method or the total impurities of lyophilized injectable powder just can be effectively controlled so.The results are shown in Table 2.
The present invention fully takes into account bulk capacity injection owing to need in the preparation process through high temperature sterilize, so the easier impurity that causes increases, therefore, when the preparation bulk capacity injection, when more strictly being controlled at 20 ℃, the water for injection electrical conductivity is no more than 0.6 μ S.cm
-1
More particularly, a kind of minimizing provided by the invention is characterized in that with the method for tranexamic acid as impurity in the injection of active component: used injection electrical conductivity of water is controlled at and is no more than 1.0 μ S.cm when preparation small-volume injection or freeze-dried powder
-1(20 ℃); Used injection electrical conductivity of water is controlled at and is no more than 0.6 μ S.cm during the bulk capacity injection dosing
-1(20 ℃).
It is a kind of with the analytical method of tranexamic acid as impurity item in its quality standard of ejection preparation of active component that the present invention provides simultaneously, and impurity all detects as follows in the foregoing description and the comparative example preparation, and is specific as follows:
Chromatographic condition and system suitability research: make filler with octadecyl silane, (the 11.0g AMSP is dissolved in the 500ml water with methanol-phosphate buffer, add 5ml triethylamine and 1.4g sodium lauryl sulphate, add water to 700ml after regulating pH to 2.5 with phosphoric acid) 30: 70 (v/v) be mobile phase, the detection wavelength is 220nm, and column temperature is 30 ℃.The separating degree of tranexamic acid and 4-aminomethyl-1-cyclohexenecarboxylic acid should be not less than 2.0.
The preparation of reference substance solution precision respectively takes by weighing the tranexamic acid reference substance, two trans-4-carboxyl cyclohexane extraction methyl amine, cis-to aminomethyl naphthenic acid, paraaminomethyl benzoic acid and 4-aminomethyl-1-cyclohexenecarboxylic acid, put in the same 100ml measuring bottle, add water make every 1ml contain tranexamic acid 5.0mg, two trans-4-carboxyl cyclohexane extraction methyl amine 5 μ g, cis-to aminomethyl naphthenic acid 4 μ g, paraaminomethyl benzoic acid 5 μ g and 4-aminomethyl-1-cyclohexenecarboxylic acid 5 μ g, as the impurity reference substance solution;
The preparation precision of need testing solution is measured with tranexamic acid as the small-volume injection of active component or freeze-dried powder, bulk capacity injection preparation, and it is need testing solution that water is made the solution that contains tranexamic acid 5.0mg among every 1ml.
The preparation precision of contrast solution is measured need testing solution, and thin up is made the solution that contains 5ug among every 1ml, solution in contrast.
The algoscopy precision is measured reference substance solution, each 20 μ l of contrast solution and need testing solution, the record chromatogram is to 3 times of main constituent peak (tranexamic acid) retention time, paraaminomethyl benzoic acid, 4-aminomethyl-1-cyclohexenecarboxylic acid and cis-the aminomethyl naphthenic acid is calculated according to one point external standard method, wherein, the correction factor of paraaminomethyl benzoic acid peak area is 0.006, the correction factor of 4-aminomethyl-1-cyclohexenecarboxylic acid peak area is 0.005, and cis-to the correction factor of aminomethyl naphthenic acid peak area is 1.2; Two trans-cubage of 4-carboxyl cyclohexane extraction methyl amine and other unknown impurities adopts area normalization method.
According to as above method impurity in the tranexamic acid injection is detected, the result shows: during the dosing of tranexamic acid injection, must control used injection electrical conductivity of water, its water for injection electrical conductivity is no more than 1.0 μ S.cm when preparation small-volume injection or freeze-dried powder
-1(20 ℃), and bulk capacity injection is no more than 0.6 μ S.cm
-1(20 ℃) only in this way, could effectively reduce impurity content in the injection, thereby improve with the quality of tranexamic acid as the injection of active component.Therefore, by achievement in research of the present invention, the inventor revises about the determination of foreign matter item the quality standard of tranexamic acid injection type, to limit of impurities concrete regulation be: the impurity that is provided with in the quality standard comprises impurity A: two trans-4-carboxyl cyclohexane extraction methyl amine, its peak area must not surpass 0.1% of need testing solution peak area; Impurity B: cis-to the aminomethyl naphthenic acid, its peak area is less than 0.08% of the need testing solution peak area; Impurity C:4-aminomethyl-1-cyclohexenecarboxylic acid, its peak area must not surpass 0.1% of need testing solution peak area; Impurity D: paraaminomethyl benzoic acid, its peak area must not surpass 0.1% of need testing solution peak area; Contain other single impurity and must not surpass 0.2% of need testing solution peak area, and single impurity content addition must not surpass 1.0%; The limit handling of total impurities amount is being no more than 1.2% in the preparation.Simultaneously, the limit of all kinds of Control of Impurities in the tranexamic acid crude drug must not be decided to be above 80% of various types of Control of Impurities limit in the preparation.
Exactly because the index to process water in the ejection preparation is carried out strict quality, thereby promoted the quality standard of preparation, finally effectively avoided opalescence appearance in the preparation, the generation of the potential untoward reaction that causes because of impurity during importantly effective reduction is clinical.
The present invention has stated that a kind of minimizing is with the method for tranexamic acid as impurity in the injection of active component, its limit of impurities of controlling can effectively, stably be controlled product quality, but for the method for detecting impurities of tranexamic acid injection, be not limited to above-mentioned a kind of method.
By control to raw material and preparation quality standard, the inventor is again to two known impurities that relate in the standard: 4-aminomethyl-1-cyclohexenecarboxylic acid and cis-toxicity of aminomethyl naphthenic acid has been carried out further investigation, with obtain to a greater degree clinical drug use in about the information of safety aspect.
(1) 4-aminomethyl-1-cyclohexenecarboxylic acid
Give healthy secondary mice (body weight 20g ± 2.5g) once irritate stomach to give 4-aminomethyl-1-cyclohexenecarboxylic acid, give 10mg/kg, 20mg/kg, 40mg/kg respectively, can observe general behavior and the sign of mice after the medication, result of the test shows: all dosage group mices tangible digestive tract reaction occurs at the filling stomach after 0.5 hour, vomiting, sialorrhea, the mice instability of gait of walking.
24 (body weight 100g ± 9.8g), be divided into 4 groups at random by body weight, male and female half and half of healthy secondary rat.Each dosage group is 6, divides three dosage to irritate stomach and gives 4-aminomethyl-1-cyclohexenecarboxylic acid.High dose group 20mg/kg, middle dosage group 10mg/kg, low dose group 5mg/kg.Blank group: gavage the equal-volume normal saline, tested 20 days by a definite date.Observe general behavior and sign: high dose group tangible digestive tract reaction occurred in 10 minutes after irritating stomach, vomiting, sialorrhea, food ration reduce even refusing to eat, and negative growth appears in body weight, the rat instability of gait of walking; Middle dosage group poisoning symptom is similar to high dose group, but degree obviously alleviates; Low dose group and matched group are not found obviously unusual.The result of histopathologic examination shows: high dose group: the liver relative weight has slight increase than matched group.Mild edema appears in dead rat hepatocytes, a small amount of vacuolar degeneration; High dose group rat stomach intestinal mucosa and mucous epithelium come off, and dead rat partly has gastrointestinal mucosa to change and exudative hemorrhage; Middle dosage group and each histoorgan of low dose group rat show no obvious abnormalities; The postmortem result shows 1 rats death of high dose group, and reason mostly is due to the liver degeneration.
(2) cis-to aminomethyl naphthenic acid irritation test
6 of new zealand rabbits are divided into three groups of A, B, C at random by body weight, 2 every group.Wherein A group is to use the cis extracted from raw material-to the aminomethyl naphthenic acid, warp and tranexamic acid are mixed and made into the tranexamic acid sodium chloride injection, wherein sodium chloride-containing 0.9%, and per 100 milliliters contain tranexamic acid 0.5g, and containing cis-to the aminomethyl naphthenic acid is 5% of tranexamic acid; B group is a cis-to aminomethyl naphthenic acid content (content: the tranexamic acid sodium chloride injection that provides of higher certain company 0.6%); C group is the cis that provides of the sincere pharmaceutcal corporation, Ltd in sky, Changchun-to aminomethyl naphthenic acid content (content: lower tranexamic acid sodium chloride injection 0.07%).Inject A, B, three groups of test liquid 2ml/Kg of C respectively at left auricular vein, auris dextra is injected with the volume normal saline, and 1 time/day, for three days on end, totally 3 times.In the 3rd the injection blood vessel of back 30 minutes perusal injection sites and the variation of surrounding tissue, to get after auricular vein and surrounding tissue fix 24 hours, routine is got injection place auricle, through dehydration, paraffin wax flaking, dyeing, microscopy.The result shows: A group has clearly irritative response to the intravenous rabbit blood vessel; The result of the test of B group and C group shows, cis in the tranexamic acid-have nonirritant to have a direct impact to blood vessel to the height of aminomethyl naphthenic acid content, when cis in the tranexamic acid sodium chloride injection-when content of aminomethyl naphthenic acid is surpassed 0.5%, the intravenous rabbit blood vessel is slight irritant reaction.When cis in the tranexamic acid sodium chloride injection-when content of aminomethyl naphthenic acid is lower than 0.5%, the intravenous rabbit blood vessel is not almost had zest, relatively there is not evident difference with matched group.
The above further proof of experiment, the present invention is to the reasonability of tranexamic acid injection quality index control limit, thereby provides strong test basis for the quality control and the data for clinical drug use of this medicine.
The specific embodiment is as follows:
Embodiment 1 tranexamic acid sodium chloride injection (100ml: 0.5g)
Tranexamic acid 5.0g
Sodium chloride 8.5g
Water for injection is (20 ℃ the time: electrical conductivity 0.4 μ S.cm
-1) add to 1000ml
Embodiment 2 tranexamic acid sodium chloride injection (100ml: 0.5g)
Prescription is formed identical with embodiment 1, and used injection electrical conductivity of water is 0.5 μ S.cm when only being the injection dosing
-1(20 ℃)
Embodiment 3 tranexamic acid injection (5ml: 0.5g)
Tranexamic acid 100g
Disodium edetate 0.01g
Water for injection is (20 ℃ the time: electrical conductivity 0.8 μ S.cm
-1) add to 1000ml
Embodiment 4 injection tranexamic acids (0.5g)
Tranexamic acid 250g
Mannitol 500g
Water for injection is (20 ℃ the time: electrical conductivity 0.8 μ S.cm
-1) add to 1000ml
Comparative example 1: tranexamic acid sodium chloride injection (100ml: 0.5g)
Prescription is formed identical with embodiment 1, and used injection electrical conductivity of water is 1.9 μ S.cm when only being the injection dosing
-1(20 ℃)
Comparative example 2: tranexamic acid sodium chloride injection (100ml: 0.5g)
Prescription is formed identical with embodiment 1, and used injection electrical conductivity of water is 1.2 μ S.cm when only being the injection dosing
-1(20 ℃)
Comparative example 3: tranexamic acid sodium chloride injection (100ml: 0.5g)
Prescription is formed identical with embodiment 1, and used injection electrical conductivity of water is 2.5 μ S.cm when only being the injection dosing
-1(20 ℃)
Comparative example 4 commercially available tranexamic acid injection (5ml: 0.5g)
Comparative example 5 commercially available injection tranexamic acids (0.5g)
The different electrical conductivity waters for injection of table 1 are prepared in the stability test of tranexamic acid sodium chloride infusion solution impurity and are investigated the result
| Long term test | Electrical conductivity | |||||
| Comparative example 1 | Comparative example 2 | Comparative example 3 | Embodiment 1 | Embodiment 2 | ||
| 1.9μS.cm -1 | 1.2μS.cm -1 | 2.5μS.cm -1 | 0.4μS.cm -1 | 0.5μS.cm -1 | ||
| 0m | A | 0.420％ | 0.311％ | 0.480％ | 0.028％ | 0.031％ |
| B | 0.051％ | 0.024％ | 0.090％ | 0.006％ | 0.008％ | |
| C | 0.092％ | 0.081％ | 0.101％ | 0.006％ | 0.006％ | |
| D | 0.093％ | 0.086％ | 0.106％ | 0.011％ | 0.014％ | |
| Other | 0.230％ | 0.180％ | 0.450％ | 0.010％ | 0.010％ | |
| Total amount | 0.886％ | 0.682％ | 1.227％ | 0.061％ | 0.069％ | |
| 6m | A | 0.53％ | 0.400％ | 0.56％ | 0.039％ | 0.039％ |
| B | 0.073％ | 0.045％ | 0.117％ | 0.011％ | 0.013％ | |
| C | 0.107％ | 0.087％ | 0.113％ | 0.010％ | 0.010％ | |
| D | 0.108％ | 0.099％ | 0.120％ | 0.017％ | 0.019％ | |
| Other | 0.33％ | 0.31％ | 0.710％ | 0.040％ | 0.060％ | |
| Total amount | 1.148％ | 0.941％ | 1.620％ | 0.117％ | 0.141％ | |
| 12m | A | 0.590％ | 0.510％ | 0.63％ | 0.045％ | 0.047％ |
| B | 0.094％ | 0.057％ | 0.131％ | 0.016％ | 0.021％ | |
| C | 0.111％ | 0.092％ | 0.117％ | 0.018％ | 0.022％ | |
| D | 0.114％ | 0.107％ | 0.125％ | 0.023％ | 0.027％ | |
| Other | 0.590％ | 0.470％ | 0.850％ | 0.070％ | 0.109％ | |
| Total amount | 1.499％ | 1.236％ | 1.853％ | 0.172％ | 0.226％ | |
| 24m | A | 0.700％ | 0.630％ | 0.790％ | 0.052％ | 0.054％ |
| B | 0.110％ | 0.076％ | 0.154％ | 0.028％ | 0.027％ | |
| C | 0.116％ | 0.107％ | 0.126％ | 0.024％ | 0.027％ | |
| D | 0.123％ | 0.114％ | 0.139％ | 0.029％ | 0.032％ | |
| Other | 1.170％ | 1.030％ | 1.360％ | 0.110％ | 0.170％ | |
| Total amount | 2.219％ | 1.957％ | 2.569％ | 0.243％ | 0.310％ | |
| 36m | A | 0.770％ | 0.760％ | 0.870％ | 0.061％ | 0.067％ |
| B | 0.140％ | 0.083％ | 0.179％ | 0.041％ | 0.035％ | |
| C | 0.129％ | 0.112％ | 0.135％ | 0.030％ | 0.033％ | |
| D | 0.142％ | 0.128％ | 0.148％ | 0.034％ | 0.038％ | |
| Other | 1.330％ | 1.130％ | 1.410％ | 0.220％ | 0.280％ | |
| Total amount | 2.511％ | 2.213％ | 2.742％ | 0.386％ | 0.453％ | |
Annotate: 1, the stability test of patent specification indication carries out with reference to Chinese Pharmacopoeia, and the m among the 0m in the form, the 3m etc. represents the moon.
2, other: represent other total impurities
The different electrical conductivity waters for injection of table 2 are prepared the impurity study on the stability result of tranexamic acid low capacity and lyophilized formulations
| Long term test | Electrical conductivity | ||||
| Comparative example 4 | Comparative example 5 | Embodiment 3 | Embodiment 4 | ||
| Unknown | Unknown | 0.8μS.cm -1 | 0.8μS.cm -1 | ||
| 0m | A | ------ | ------ | 0.027％ | 0.031％ |
| B | 0.011％ | 0.014％ | |||
| C | 0.010％ | 0.012％ | |||
| D | 0.010％ | 0.008％ | |||
| Other | 0.020％ | 0.030％ | |||
| Total amount | 0.078％ | 0.095％ | |||
| 6m | A | ------ | ------ | 0.033％ | 0.039％ |
| B | 0.027％ | 0.032％ | |||
| C | 0.016％ | 0.022％ | |||
| D | 0.014％ | 0.015％ | |||
| Other | 0.040％ | 0.070％ | |||
| Total amount | 0.130％ | 0.176％ | |||
| 12m | A | 0.493％ | 0.442％ | 0.045％ | 0.045％ |
| B | 0.061％ | 0.058％ | 0.032％ | 0.041％ | |
| C | 0.114％ | 0.095％ | 0.022％ | 0.031％ | |
| D | 0.102％ | 0.092％ | 0.023％ | 0.029％ | |
| Other | 0.630％ | 0.510％ | 0.110％ | 0.170％ | |
| Total amount | 1.401％ | 1.197％ | 0.232％ | 0.316％ | |
| 24m | A | 0.680％ | 0.580％ | 0.054％ | 0.057％ |
| B | 0.084％ | 0.080％ | 0.048％ | 0.054％ | |
| C | 0.126％ | 0.103％ | 0.031％ | 0.036％ | |
| D | 0.122％ | 0.109％ | 0.031％ | 0.038％ | |
| Other | 1.070％ | 0.840％ | 0.190％ | 0.250％ | |
| Total amount | 2.082％ | 1.712％ | 0.354％ | 0.427％ | |
| 36m | A | 0.790％ | 0.660％ | 0.063％ | 0.069％ |
| B | 0.097％ | 0.097％ | 0.052％ | 0.057％ | |
| C | 0.138％ | 0.125％ | 0.037％ | 0.042％ | |
| D | 0.146％ | 0.114％ | 0.046％ | 0.049％ | |
| Other | 1.332％ | 1.120％ | 0.370％ | 0.422％ | |
| Total amount | 2.504％ | 2.116％ | 0.568％ | 0.639％ | |
Claims (9)
1. a minimizing is characterized in that with the method for tranexamic acid as impurity in the ejection preparation of active component: small-volume injection or freeze-dried powder used injection electrical conductivity of water when dosing must not surpass 1.0 μ S.cm in the time of 20 ℃
-1Used injection electrical conductivity of water must not surpass 0.6 μ S.cm at 20 ℃ during the bulk capacity injection dosing
-1
2. one kind with the ejection preparation quality standard of tranexamic acid as active component, it is characterized in that the method for detecting impurities that is provided with in the quality standard is: chromatographic condition and system suitability: make filler with octadecyl silane, (the 11.0g AMSP is dissolved in the 500ml water with methanol-phosphate buffer, add 5ml triethylamine and 1.4g sodium lauryl sulphate, obtain with adding water to 700ml behind phosphoric acid adjusting pH to 2.0～3.0) (20～39): (61～80) are mobile phase, the detection wavelength is 220nm, column temperature is 25 ℃～30 ℃, and the separating degree of tranexamic acid and 4-aminomethyl-1-cyclohexenecarboxylic acid should be not less than 2.0;
The preparation of reference substance solution: precision takes by weighing the tranexamic acid reference substance respectively, two trans-4-carboxyl cyclohexane extraction methyl amine reference substance, cis-to aminomethyl naphthenic acid reference substance, paraaminomethyl benzoic acid reference substance and 4-aminomethyl-1-cyclohexenecarboxylic acid reference substance, put in the same 100ml measuring bottle, add water make every 1ml contain tranexamic acid 5.0mg, two trans-4-carboxyl cyclohexane extraction methyl amine 5 μ g, cis-to the solution of aminomethyl naphthenic acid 4 μ g, paraaminomethyl benzoic acid 5 μ g and 4-aminomethyl-1-cyclohexenecarboxylic acid 5 μ g, as the impurity reference substance solution;
The preparation of need testing solution: precision is measured with tranexamic acid as the small-volume injection of active component or freeze-dried powder, bulk capacity injection,
It is need testing solution that water is made the solution that contains tranexamic acid 5.0mg among every 1ml;
The preparation of contrast solution: precision is measured need testing solution, and thin up is made the solution that contains 5 μ g among every 1ml, solution in contrast;
Algoscopy: precision is measured reference substance solution, each 20 μ l of contrast solution and need testing solution, the record chromatogram is to 3 times of main constituent peak retention time, paraaminomethyl benzoic acid, 4-aminomethyl-1-cyclohexenecarboxylic acid and cis-the aminomethyl naphthenic acid is calculated according to one point external standard method, wherein the correction factor of paraaminomethyl benzoic acid peak area is 0.006, the correction factor of 4-aminomethyl-1-cyclohexenecarboxylic acid peak area is 0.005, and cis-to the correction factor of aminomethyl naphthenic acid peak area is 1.2.
3. quality standard according to claim 2 is characterized in that the impurity that is provided with in the quality standard comprises impurity A: two trans-4-carboxyl cyclohexane extraction methyl amine, its peak area must not surpass 0.1% of need testing solution peak area.
4. quality standard according to claim 2 is characterized in that the impurity that is provided with in the quality standard comprises impurity B: cis-to the aminomethyl naphthenic acid, its peak area is less than 0.08% of the need testing solution peak area.
5. quality standard according to claim 2 is characterized in that the impurity that is provided with in the quality standard comprises impurity C:4-aminomethyl-1-cyclohexenecarboxylic acid, and its peak area must not surpass 0.1% of need testing solution peak area.
6. quality standard according to claim 2 is characterized in that the impurity that is provided with in the quality standard comprises impurity D: paraaminomethyl benzoic acid, its peak area must not surpass 0.1% of need testing solution peak area.
7. quality standard according to claim 2 is characterized in that the peak area of other single impurity must not surpass 0.2% of need testing solution peak area, and the content addition of single impurity must not surpass 1.0%.
8. quality standard according to claim 2 is characterized in that tranexamic acid ejection preparation total impurities must not surpass 1.2%.
9. quality standard according to claim 2 is characterized in that the limit of various types of Control of Impurities in the tranexamic acid crude drug must not be above various types of Control of Impurities limit 80% in the preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710302058A CN100579511C (en) | 2007-12-21 | 2007-12-21 | Ratification of highly purified tranexamic acid injection and quality standard thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710302058A CN100579511C (en) | 2007-12-21 | 2007-12-21 | Ratification of highly purified tranexamic acid injection and quality standard thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101199477A true CN101199477A (en) | 2008-06-18 |
| CN100579511C CN100579511C (en) | 2010-01-13 |
Family
ID=39514961
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200710302058A Expired - Fee Related CN100579511C (en) | 2007-12-21 | 2007-12-21 | Ratification of highly purified tranexamic acid injection and quality standard thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100579511C (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102743345A (en) * | 2012-06-25 | 2012-10-24 | 瑞阳制药有限公司 | Small-size tranexamic acid freeze-dried powder injection, preparation method and production device thereof |
| CN106109401A (en) * | 2016-07-01 | 2016-11-16 | 北京佳诚医药有限公司 | A kind of high-purity tranexamic acid injection and preparation method thereof and in the application of cardiac operation Perioperation of Cardiopulmonary Bypass Surgery indication |
| CN108732288A (en) * | 2017-04-18 | 2018-11-02 | 伽蓝（集团）股份有限公司 | A kind of tranexamic acid or its detection method in relation to content of material |
| CN110215432A (en) * | 2019-04-08 | 2019-09-10 | 辽宁海神联盛制药有限公司 | A kind of aminomethylbenzoic acid sodium chloride injection and preparation method thereof |
| CN110237029A (en) * | 2019-06-20 | 2019-09-17 | 南京知和医药科技有限公司 | A kind of tranexamic acid injection and preparation process |
| CN112595795A (en) * | 2020-12-18 | 2021-04-02 | 山东北大高科华泰制药有限公司 | Aminomethylbenzoic acid lyophilized preparation |
| CN115856160A (en) * | 2023-02-28 | 2023-03-28 | 长沙晶易医药科技股份有限公司 | Method for determining content of related substances in compound tranexamic acid tablet |
-
2007
- 2007-12-21 CN CN200710302058A patent/CN100579511C/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102743345A (en) * | 2012-06-25 | 2012-10-24 | 瑞阳制药有限公司 | Small-size tranexamic acid freeze-dried powder injection, preparation method and production device thereof |
| CN102743345B (en) * | 2012-06-25 | 2015-12-16 | 瑞阳制药有限公司 | Small size tranexamic acid freeze-dried powder, its preparation method and process units thereof |
| CN106109401A (en) * | 2016-07-01 | 2016-11-16 | 北京佳诚医药有限公司 | A kind of high-purity tranexamic acid injection and preparation method thereof and in the application of cardiac operation Perioperation of Cardiopulmonary Bypass Surgery indication |
| CN108732288A (en) * | 2017-04-18 | 2018-11-02 | 伽蓝（集团）股份有限公司 | A kind of tranexamic acid or its detection method in relation to content of material |
| CN110215432A (en) * | 2019-04-08 | 2019-09-10 | 辽宁海神联盛制药有限公司 | A kind of aminomethylbenzoic acid sodium chloride injection and preparation method thereof |
| CN110237029A (en) * | 2019-06-20 | 2019-09-17 | 南京知和医药科技有限公司 | A kind of tranexamic acid injection and preparation process |
| CN112595795A (en) * | 2020-12-18 | 2021-04-02 | 山东北大高科华泰制药有限公司 | Aminomethylbenzoic acid lyophilized preparation |
| CN112595795B (en) * | 2020-12-18 | 2022-08-02 | 山东北大高科华泰制药有限公司 | Aminomethylbenzoic acid lyophilized preparation |
| CN115856160A (en) * | 2023-02-28 | 2023-03-28 | 长沙晶易医药科技股份有限公司 | Method for determining content of related substances in compound tranexamic acid tablet |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100579511C (en) | 2010-01-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100579511C (en) | Ratification of highly purified tranexamic acid injection and quality standard thereof | |
| Dvorchik et al. | Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects | |
| CN103463565A (en) | Zedoary oil injection and preparation method thereof | |
| Wu et al. | Development of a HPLC/MS/MS method for simultaneous determination of tinidazole, dyclonine and chlorhexidine in rat plasma and its application in the pharmacokinetic research of a film-forming solution | |
| CN107952064A (en) | Pharmaceutical preparation containing polyethylene glycol Luo Saina peptides and preparation method thereof | |
| CN108205021A (en) | A kind of detection method of Vonoprazan fumarate in relation to substance | |
| CN103006554B (en) | Ornidazole injection and preparation method thereof | |
| CN110269837B (en) | Naloxone hydrochloride injection and preparation method thereof | |
| CN104095809A (en) | Pharmaceutical composition of clindamycin phosphate injection and preparation method | |
| CN105640873A (en) | Sodium valproate injection, preparation method and applications thereof | |
| CN111265474B (en) | Parthenocinolate injection and preparation method thereof | |
| CN104323984A (en) | Retapamulin ointment pharmaceutical composition and preparation method thereof | |
| CN103483352A (en) | Medicinal bulk drug for resisting tumors | |
| Min et al. | Quantitative determination of carfilzomib in mouse plasma by liquid chromatography–tandem mass spectrometry and its application to a pharmacokinetic study | |
| US9481767B2 (en) | Poly(4-hydroxybutyrate)-B-monomethoxy(polyethylene glycol) copolymer nanoparticles, production method for same and pharmaceutical composition for brain disorder treatment containing same as active ingredient | |
| CN101703466A (en) | Borneol injection and preparation method thereof | |
| CN113219080A (en) | HPLC (high Performance liquid chromatography) detection method for high-molecular impurities in cefepime and preparation thereof | |
| CN107753481B (en) | A pharmaceutical composition containing buffer for treating cancer | |
| CN107744501A (en) | A kind of medicinal composition for injections of tetrandrine | |
| CN113476399B (en) | Sodium carbazochrome injection and preparation method thereof | |
| CN111568860B (en) | Ornidazole injection and preparation method thereof | |
| Stanley et al. | Comparison for pharmaceutical equivalence of FDA-approved products and compounded preparations of ketoprofen, amikacin, and boldenone. | |
| CN106214629A (en) | A kind of preparation method of breviscapine drug injection preparation stability compositions | |
| Lee et al. | Development of HPLC assay method of fusidate sodium tablets | |
| Melikyan et al. | Development and validation of HPLC method for the determination of metronidazole benzoate and related impurites in bulk and pharmaceutical formulations |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Beijing Sino Pharmaceutical Technology Co., Ltd. Assignor: Beijing Jiacheng Medicine Co., Ltd. Contract record no.: 2011990000511 Denomination of invention: Ratification of highly purified tranexamic acid injection and quality standard thereof Granted publication date: 20100113 License type: Exclusive License Open date: 20080618 Record date: 20110629 |
|
| DD01 | Delivery of document by public notice |
Addressee: Beijing Jiacheng Medicine Co., Ltd. Document name: Notification to Pay the Fees |
|
| DD01 | Delivery of document by public notice |
Addressee: Beijing Jiacheng Medicine Co., Ltd. Document name: Notification of Termination of Patent Right |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100113 Termination date: 20141221 |
|
| EXPY | Termination of patent right or utility model | ||
| DD01 | Delivery of document by public notice |
Addressee: Beijing Jiacheng Medicine Co., Ltd. Document name: Notification of Decision on Request for Restoration of Right |
|
| DD01 | Delivery of document by public notice |
Addressee: Beijing Jiacheng Medicine Co., Ltd. Document name: Notification of Decision on Request for Restoration of Right |