CN101270101A - Method for preparing potassium sodium dehydroandroan drographolide succinate for injection and its freeze-dried injection - Google Patents
Method for preparing potassium sodium dehydroandroan drographolide succinate for injection and its freeze-dried injection Download PDFInfo
- Publication number
- CN101270101A CN101270101A CNA2008101060517A CN200810106051A CN101270101A CN 101270101 A CN101270101 A CN 101270101A CN A2008101060517 A CNA2008101060517 A CN A2008101060517A CN 200810106051 A CN200810106051 A CN 200810106051A CN 101270101 A CN101270101 A CN 101270101A
- Authority
- CN
- China
- Prior art keywords
- injection
- faint yellow
- potassium sodium
- dehydroandroan drographolide
- drographolide succinate
- 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
Images
Landscapes
- Medicinal Preparation (AREA)
Abstract
The present invention discloses a preparation method of Yanhuning and freeze-dried powder injection. In the preparation method of the Yanhuning, Chuanhuning is dissolved in injection water with the weight of 4 to 5 times of the Chuanhuning; then 0.1 to 0.2mol/L of the sodium hydroxide solution is used for adjusting the pH value of the mixture to be 7.1 to 7.5; activated carbon is added for separating impurities; microporous membranes with 0.45 Mu m and 0.22 Mu m are orderly used for filtration; the filtrate is collected, cooled and then dried; thus the Yanhuning can be prepared. In the preparation method of the freeze-dried injection, the Yanhuning and sodium chloride are dissolved in the injection water at the temperature of 45 to 60 DEG C; after the mixture is mixed well, the activated carbon that is used by a needle and weighs 0.1 percent of the weight of the solution is used, so that the pH of the solution can be controlled between 6.4 and 6.8; the injection water is added until the weight of the solution reaches to the required amount; the solution is filtered and decarbonized; then the solution is orderly filtered by the microporous membrane of 0.22 Mu m, the microporous membrane that can block the substance of molecular weight of 10000 Dalton and the microporous membrane of 0.22 Mu m; the filtrate is collected, cooled and dried; thus the freeze-dried injection of Yanhuning can be prepared.
Description
Technical field
The present invention relates to the preparation method of potassium sodium dehydroandroan drographolide succinate and lyophilized injectable powder thereof.
Background technology
Potassium sodium dehydroandroan drographolide succinate, its chemical name is: 14-deshydroxy-11,12-two dehydrogenation rographolides-3,19-disuccinic acid half ester k-na salt, molecular formula is: C
28H
34KNaO
10H
2O, structural formula is suc as formula shown in (I); It is the deoxydidehydrorographolide succinic acid half-ester k-na salt of being made through structure of modification by the diterpene compound rographolide that extracts from Chinese medicine Herba Andrographis, has the effect of antibiotic, detoxifcation, anti-inflammatory.
Formula (I)
Potassium sodium dehydroandroan drographolide succinate can suppress early stage capillary permeability and increase and inflammatory exudation and oedema, can excited specifically hypophysis-adrenal cortex function, and promote ACTH to discharge, increase the biosynthesizing of ACTH in the prepituitary gland; External effect with multiple viruses such as deactivation adenovirus, influenza virus, Respiroviruses.The clinical virus pneumonia that is used for, viral upper respiratory tract infection and bacillary dysentery etc.In practice, potassium sodium dehydroandroan drographolide succinate not only has direct killing action to some virus and bacterium, and can improve defence and the resistivity of human body to disease, treats the damage (virus that especially easily morphs) that various bacteriums and virus cause human body comprehensively.Clinical application have side effect little, have no drug resistance, curative effect is reliable, the characteristics of constant product quality, is one of comparatively commonly used and ideal medicine in the traditional Chinese medical science emergency treatment, broken and thought that Chinese medicine can only be used for treating traditional saying of chronic disease.
Though potassium sodium dehydroandroan drographolide succinate injection has the good clinical curative effect, but owing to reasons such as material purity, technologies, can contain a large amount of impurity (related substance) in the injection, the great like this security that influences preparation, can bring many anaphylaxis to the patient simultaneously, influenced curative effect, severe patient can bring anaphylactic shock, threatens patient's life.Existing clear and definite research data shows: the curative effect of Chinese medicine preparation and security and its " related substance " have certain linear, and just than higher, so handle " related substance " is controlled at and seems under the certain limit and be even more important to the purity requirement of Chinese medical extract.
The existing preparation method of potassium sodium dehydroandroan drographolide succinate and freeze-dried powder thereof is simpler, and uncontrollable factor is too many.Concrete grammar is: sodium hydroxide and potassium dehydroandrographolide succinate are dropped in the container, add an amount of water, stir and make dissolving, after the dissolving, the solution clarification filtration concentrates fully, and drying under reduced pressure promptly gets potassium sodium dehydroandroan drographolide succinate; Again that potassium sodium dehydroandroan drographolide succinate is water-soluble, stir and make dissolving, after dissolving fully, the solution clarification filtration, can, freeze-drying promptly get the potassium sodium dehydroandroan drographolide succinate preparation.Above-mentioned preparation method, because partial alkalescence is too big, making potassium sodium dehydroandroan drographolide succinate that ester may take place decomposes and cycloreversion reaction, adding drying under reduced pressure may make moisture content higher, so that the potassium sodium dehydroandroan drographolide succinate raw material of gained is at outward appearance, solution colour, especially the related substance item does not meet quality standard, can increase the risk that untoward reactions such as allergy take place in patient's use greatly, the yield of potassium sodium dehydroandroan drographolide succinate raw material is also lower simultaneously.
Summary of the invention
The preparation method who the purpose of this invention is to provide potassium sodium dehydroandroan drographolide succinate and lyophilized injectable powder thereof.
The preparation method of potassium sodium dehydroandroan drographolide succinate provided by the present invention is that potassium dehydroandrographolide succinate is dissolved in the water for injection of described potassium dehydroandrographolide succinate 4-5 times quality, regulates the pH value to 7.1-7.5 with the sodium hydroxide solution of 0.1-0.2mol/L then; Add remove impurity with active carbon matter then, then use the filtering with microporous membrane of 0.45 μ m, 0.22 μ m successively, collect filtrate, filtrate is carried out lyophilize handle, promptly obtain potassium sodium dehydroandroan drographolide succinate.
'Yanhuning ' frozen-dried powder injection provided by the present invention is to be made through lyophilize by following raw material; Described raw material comprises potassium sodium dehydroandroan drographolide succinate, sodium-chlor and the water for injection of following mass parts:
Potassium sodium dehydroandroan drographolide succinate 4-20 mass parts
Sodium-chlor 1-5 mass parts
Water for injection 200-300 mass parts.
Wherein, described raw material preferably includes:
Potassium sodium dehydroandroan drographolide succinate 4 mass parts
Sodium-chlor 1 mass parts
Water for injection 60-200 mass parts.
Described raw material also can comprise the pH regulator agent, specifically can be sodium hydroxide solution or the hydrochloric acid soln of 0.1～0.2mol/L.
Potassium sodium dehydroandroan drographolide succinate is 4: 1 with the massfraction ratio of sodium-chlor in the described raw material.
The method for preparing described 'Yanhuning ' frozen-dried powder injection, be that sodium-chlor with the potassium sodium dehydroandroan drographolide succinate of described amount and described amount is dissolved in 45-60 ℃ the water for injection, 0.1% of the described solution quality of adding needle-use activated carbon behind the mixing, the pH value of solution is transferred to 6.4～6.8 with described pH regulator agent, replenish water for injection to described amount; Filtering decarbonization is the filtering with microporous membrane of 10000 daltonian ultra-filtration membrane ultrafiltration, 0.22 μ m with filtering with microporous membrane, the molecular weight cut-off of 0.22 μ m more successively, collects filtrate, and lyophilize obtains 'Yanhuning ' frozen-dried powder injection.
The ratio of quality and the number of copies of potassium sodium dehydroandroan drographolide succinate and water for injection is 1 in the raw material of lyophilized injectable powder: in the time of (25-50), described lyophilize adopts following method to carry out:
Fs pre-freeze: adopt the mode of freezing slowly, product temperature is cooled to-45 ℃ by 20 ℃ of linearities, and kept 1.5 hours, need not vacuumize at-45 ℃ with 4 hours;
The subordinate phase sublimation drying: with 1.25 hours with temperature by-45 ℃ of linear temperature increases to-12 ℃, and kept 8 hours at-12 ℃; Vacuum tightness is 14-22Pa;
Phase III parsing-desiccation: temperature by-12 ℃ of linear temperature increases to 33 ℃, was carried out 7 hours, and kept 1～2 hour at 33 ℃; Vacuum tightness 1.0-5.0Pa.
The ratio of quality and the number of copies of potassium sodium dehydroandroan drographolide succinate and water for injection is 1 in the raw material of lyophilized injectable powder: in the time of (15-18.75), described lyophilize adopts following method to carry out:
Fs pre-freeze: adopt repeatedly the mode (be about to product and be cooled to-45 ℃ from 20 ℃ linearly, and then be warming up to-10 ℃, be cooled to-45 ℃ at last again) of pre-freeze, pre-freeze 8 hours is cooled to-45 ℃ with product temperature by 20 ℃;
The subordinate phase sublimation drying: with 1.5 hours with temperature by-45 ℃ of linear temperature increases to-12 ℃, and kept 12-15 hour at-12 ℃; Use 1 hour then with temperature by-12 ℃ of linear temperature increases to-5 ℃, and kept 6-8 hour at-5 ℃; Vacuum tightness 14-22Pa;
Phase III parsing-desiccation: temperature by-5 ℃ of linear temperature increases to 33 ℃, was carried out 4 hours, and kept 6-8 hour at 33 ℃; Vacuum tightness 1.0-5.0Pa.
Used potassium sodium dehydroandroan drographolide succinate in the above-mentioned lyophilized injectable powder is according to the method preparation for preparing potassium sodium dehydroandroan drographolide succinate that is provided among the present invention.
The present invention potassium dehydroandrographolide succinate and sodium hydroxide prepared in reaction potassium sodium dehydroandroan drographolide succinate, its reaction equation is as follows:
In the preparation method of potassium sodium dehydroandroan drographolide succinate, use the mode that adds after rarer sodium hydroxide solution and the employing, reduced the hydrolysis of potassium dehydroandrographolide succinate and potassium sodium dehydroandroan drographolide succinate, also reduced impurity simultaneously; PH value of solution value after the control dissolving makes the potassium dehydroandrographolide succinate salify complete 7.1～7.5, increases its solvability, has also reduced the potassium dehydroandrographolide succinate content in the potassium sodium dehydroandroan drographolide succinate simultaneously; The gac that uses can have been sloughed pigment impurity, also can adsorb impurity wherein; Film coarse filtration by 0.45 μ m is sloughed the impurity of gac and absorption thereof, and the smart elimination of the film by 0.22 μ m is except bacterium and the thinner insoluble impurities of particle; Reduce moisture by lyophilize, reduced the hydrolysis of potassium sodium dehydroandroan drographolide succinate, increased its stability, be beneficial to storage.
In the preparation process of 'Yanhuning ' frozen-dried powder injection, use cillin bottle, adopt the ultrasonic wave wash bottle, four water four dash, and 6 minutes sterilizing-dryings more than 350 ℃ guarantee the no foreign matter of cleaning; Adopt automatic washing machine to clean plug, guaranteed no dirt settling, no adhesion; Select for use sodium-chlor as the vehicle that plays skeleton function, make goods keep block, and loose, Yi Rong; Employed water for injection adopts now-making-now-using, recycles more than 85 ℃.Above-mentioned processing to raw material, auxiliary material, interior packaging material etc. carry out has reduced the introducing of impurity and has prevented contingent reaction simultaneously.
In the preparation process of 'Yanhuning ' frozen-dried powder injection, the temperature of control Agitation Tank is at 45～60 ℃, be in order to make potassium sodium dehydroandroan drographolide succinate in the process of dissolving formation solution, be unlikely to degrade, also to be unlikely to form colloidal state in conjunction with more water because of temperature is too low because of temperature is too high; Add the needle-use activated carbon of described solution quality 0.1%,,, use it to come adsorpting pigment and impurity in order to reduce possible impurity though main ingredient is had absorption; The pH value of soup is controlled at 6.4～6.8, the one, venoclysis uses injection liquid general requirement pH value between 4-9, and the 2nd, by technical study, under the condition of pH value 6.4～6.8, potassium sodium dehydroandroan drographolide succinate solution is the most stable; To the filtration of soup, adopt level Four technology, the one, decarbonization filtering, remove the impurity of gac and absorption thereof, two is 0.22 μ m filtering with microporous membrane, removes bacterium and major diameter material, alleviate the ultra-filtration membrane load, three is ultra-filtration membrane ultrafiltration of 10000 Dalton molecular weights, removes macromolecular substance such as intracellular toxin, improves clarity, the 4th, after 0.22 μ m filtering with microporous membrane, remove bacterium, eliminate concentration gradient, improve clarity.Adopt such filtering technology of joining, reduced the introducing of impurity, prevent bacterium, improve the stability of potassium sodium dehydroandroan drographolide succinate under solution state simultaneously.
Cryodesiccated step in the preparation 'Yanhuning ' frozen-dried powder injection, different according to preparation specification and can amount, and formulated different freeze-dry process curves according to its eutectic temperature, controlled the moisture limit of freeze-dried products, reduce local possibility of dissolving, and improved stability.
The product that obtains after the freeze-drying adopts tamponade under the vacuum state, and packing back finished product is stored at shady and cool dry place, is in order to get rid of the oxidative degradation of main ingredient, and temperature, humidity, illumination improve stability to the influence of main ingredient.
Potassium sodium dehydroandroan drographolide succinate and freeze-dried preparation thereof---the injection potassium sodium dehydroandroan drographolide succinate of the present invention's preparation, owing to adopted above-mentioned various effective measure of control, " related substance " of injection potassium sodium dehydroandroan drographolide succinate is controlled at below 1%, improved curative effect and the security of injection potassium sodium dehydroandroan drographolide succinate when clinical application greatly, and the standard that " related substance " item is controlled at below 1% is highest standard at home at present, also improve simultaneously the content of potassium sodium dehydroandroan drographolide succinate, strengthened curative effect.
Description of drawings
Fig. 1 is preparation technology's schema of 'Yanhuning ' frozen-dried powder injection.
Fig. 2 is the freeze-drying curve of embodiment 1.
Fig. 3 is the freeze-drying curve of embodiment 2.
Fig. 4 is the freeze-drying curve of embodiment 4.
Embodiment
The preparation of embodiment 1, potassium sodium dehydroandroan drographolide succinate
5g sodium hydroxide is dissolved in the 625ml water for injection, obtains the sodium hydroxide solution that concentration is 0.2mol/L, standby.The potassium dehydroandrographolide succinate (Mt. Tiantai, Chengdu pharmaceutical Co. Ltd, the accurate word H51023411 of traditional Chinese medicines) of 70g is dissolved in the 375ml water for injection, under whipped state, adds above-mentioned sodium hydroxide solution, regulate pH value to 7.3.The gac that adds described solution quality 0.1% then stirs 20min under room temperature, cross 0.45 μ m millipore filtration coarse filtration, after the smart filter of 0.22 μ m millipore filtration, filtrate is carried out lyophilize, obtains flaxen powder, is potassium sodium dehydroandroan drographolide succinate.
Lyophilize is operated according to freeze-drying curve Fig. 2:
Fs pre-freeze: adopt the mode of freezing slowly, product temperature is cooled to-45 ℃ by 20 ℃ of linearities, and kept 2 hours, need not vacuumize at-45 ℃ with 3 hours;
The subordinate phase sublimation drying: with 2 hours with temperature by-45 ℃ of linear temperature increases to-12 ℃, and kept 6 hours at-12 ℃; Vacuum tightness is 14-22Pa;
Phase III parsing-desiccation: with 7 hours temperature is risen to 33 ℃ by-12 ℃ of linear temperature increases, and kept 2 hours at 33 ℃; Vacuum tightness 1.0-5.0Pa.
Adopt the content of spectrophotometry potassium sodium dehydroandroan drographolide succinate, concrete grammar is: get this product 28mg, the accurate title, decide, and puts in the 1000ml measuring bottle, add Diluted Alcohol and make dissolving in right amount, add acetic acid 0.1ml, be diluted to scale, shake up with Diluted Alcohol, the accurate 5ml that draws, put in the 50ml measuring bottle, add Diluted Alcohol and be diluted to scale, shake up; As need testing solution.It is that siccative is an amount of to the deoxydidehydrorographolide succinic acid half-ester reference substance of constant weight at 60 ℃ of drying under reduced pressure that other precision takes by weighing with the Vanadium Pentoxide in FLAKES, makes the solution that contains 25 μ g among every 1ml by the same method, in contrast product solution.Get above-mentioned two kinds of solution, measure optical density at the wavelength place of 251nm, calculate the content and 1.1128 of trying to achieve deoxydidehydrorographolide succinic acid half-ester in the trial-product and multiply each other, promptly get potassium sodium dehydroandroan drographolide succinate C in the trial-product according to spectrophotometry
28H
34KNaO
10Weight, the experiment establish three repetitions, be respectively 96.32%, 97.11%, 96.70% by dry product calculation result.The content that shows the potassium sodium dehydroandroan drographolide succinate that embodiment 1 is prepared is 96.71 ± 0.39%.
The eutectic point that adopts electrical resistance method to record potassium sodium dehydroandroan drographolide succinate is-10 ℃.
Concrete grammar is as follows:
1, resistance measurement method principle: material is in freezing process, and temperature drops to freezing point, and moisture begins to generate ice crystal in the material.Along with decrease of temperature, ice crystal is more and more, and the resistance of material is also increasing.When temperature drops to certain some time, the resistance value of material increases suddenly, and the temperature of this moment is exactly the eutectic point of material.
2, test material pre-treatment: the potassium sodium dehydroandroan drographolide succinate of embodiment 1 preparation is water-soluble, be mixed with and set concentration (solution of 72.0mg/ml～78.0mg/ml) is put into then and freezed case and freeze, and liquid thickness is advisable with 20mm～25mm and is laid in the pallet.
3, experimental result: from experimentation repeatedly, do not resemble theoretical analysis an especially significantly resistance value catastrophe point is arranged, may be all multifactor influences, the resistance value sudden change value of material occurs in the temperature range of temperature-fall period, in order to guarantee freezing fully of material, we get the eutectic point of the lower limit of this temperature range as this material.
Embodiment 2, specification are the preparation of the 'Yanhuning ' frozen-dried powder injection of 40mg
According to preparation technology's flow preparation 'Yanhuning ' frozen-dried powder injection of Fig. 1, concrete grammar is as follows: 1600ml water for injection is added in the dosing filling, open and stir, the temperature of control Agitation Tank is at 45-55 ℃.Accurately take by weighing potassium sodium dehydroandroan drographolide succinate 40g, add above-mentioned dosing and be stirred to dissolving in irritating.Accurately take by weighing sodium-chlor 10g, be dissolved in the 200ml water for injection, add in the above-mentioned Agitation Tank.With the solution stirring in the Agitation Tank evenly after, add 0.1% needle-use activated carbon of described solution quality, stirring and refluxing 15min is 6.4～6.8 with the pH value of the hydrochloric acid soln adjusting soup of 0.1～0.2mol/L, complements to 2000ml with water for injection then.Filter decarburization, then, clear and bright to filtrate successively with 0.22 μ m filtering with microporous membrane, be 10000 daltonian ultra-filtration membrane ultrafiltration, use 0.22 μ m filtering with microporous membrane again with the molecular retention amount.Sampling, the content that records potassium sodium dehydroandroan drographolide succinate in the above-mentioned filtrate is 19.4～20.6mg/ml.Filtrate is divided into 1000 parts, and sterile filling is in cillin bottle respectively, and the false add plug is put into freeze drier and carried out lyophilize, gets freeze-drying prods.
Lyophilize is operated according to freeze-drying curve Fig. 3:
Fs pre-freeze: adopt the mode of freezing slowly, product temperature is cooled to-45 ℃ by 20 ℃ of linearities, and kept 1.5 hours, need not vacuumize at-45 ℃ with 4 hours;
The subordinate phase sublimation drying: with 1.25 hours with temperature by-45 ℃ of linear temperature increases to-12 ℃, and kept 8 hours at-12 ℃; Vacuum tightness is 14-22Pa;
Phase III parsing-desiccation: temperature by-12 ℃ of linear temperature increases to 33 ℃, was carried out 7 hours, and kept 1～2 hour at 33 ℃; Vacuum tightness 1.0-5.0Pa.
The content of potassium sodium dehydroandroan drographolide succinate by dry product, does not change before and after freeze-drying.After the freeze-drying, potassium sodium dehydroandroan drographolide succinate redissolves all right, and insolubles is not seen in dissolving on time.Main project checks and accelerated test result, long-term test results are as follows:
Table 1 injection potassium sodium dehydroandroan drographolide succinate accelerated test result (40mg)
| Lot number | Time (moon) | Proterties | Potential of hydrogen (pH value) | Visible foreign matters | Aseptic | Related substance (%) | Labelled amount (%) |
| 0602011 | 0 1 2 3 6 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.78 6.72 6.70 6.77 6.75 | Up to specification up to specification | Up to specification up to specification | 0.57 0.62 0.65 0.70 0.80 | 99.83 99.75 99.63 99.60 99.48 |
| 0602021 | 0 1 2 3 6 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.74 6.79 6.77 6.72 6.70 | Up to specification up to specification | Up to specification up to specification | 0.61 0.65 0.68 0.73 0.78 | 99.89 99.86 99.78 99.72 99.66 |
| 0602031 | 0 1 2 3 6 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.72 6.76 6.76 6.73 6.75 | Up to specification up to specification | Up to specification up to specification | 0.60 0.67 0.70 0.76 0.80 | 100.08 100.01 99.94 99.87 99.79 |
Table 2 injection potassium sodium dehydroandroan drographolide succinate long-term test results (40mg)
| Lot number | Time (moon) | Proterties | Potential of hydrogen (pH value) | Visible foreign matters | Aseptic | Related substance (%) | Labelled amount (%) |
| 0602011 | 0 3 6 9 12 18 24 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.78 6.60 6.72 6.69 6.68 6.75 6.78 | Up to specification up to specification up to specification | Up to specification up to specification up to specification | 0.57 0.61 0.65 0.68 0.73 0.76 0.78 | 99.83 99.71 99.68 99.63 99.58 99.54 99.50 |
| 0602021 | 0 3 6 9 12 18 24 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.74 6.66 6.71 6.70 6.55 6.72 6.70 | Up to specification up to specification up to specification | Up to specification up to specification up to specification | 0.61 0.62 0.65 0.67 0.71 0.75 0.78 | 99.89 99.87 99.83 99.80 99.75 99.72 99.68 |
| 0602031 | 0 3 6 9 12 18 24 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.72 6.65 6.68 6.77 6.65 6.67 6.75 | Up to specification up to specification up to specification | Up to specification up to specification up to specification | 0.60 0.64 0.68 0.71 0.74 0.77 0.79 | 100.08 100.01 99.98 99.94 99.89 99.85 99.82 |
Embodiment 3, specification are the preparation of the 'Yanhuning ' frozen-dried powder injection of 80mg
1600ml water for injection is added in the dosing filling, open and stir, the temperature of control Agitation Tank is at 45-55 ℃.Accurately take by weighing potassium sodium dehydroandroan drographolide succinate 80g, add above-mentioned dosing and be stirred to dissolving in irritating.Accurately take by weighing sodium-chlor 20g, be dissolved in the 200ml water for injection, add in the above-mentioned Agitation Tank.With the solution stirring in the Agitation Tank evenly after, add 0.1% needle-use activated carbon of described solution quality, stirring and refluxing 15min is 6.4～6.8 with the pH value of the hydrochloric acid soln adjusting soup of 0.1～0.2mol/L, complements to 2000ml with water for injection then.Filter decarburization, then, clear and bright to filtrate successively with 0.22 μ m filtering with microporous membrane, be 10000 ultra-filtration membrane ultrafiltration, use 0.22 μ m filtering with microporous membrane again with the molecular retention amount.Sampling, the content that records potassium sodium dehydroandroan drographolide succinate in the above-mentioned filtrate is 38.8～41.2mg/ml.Filtrate is divided into 1000 parts, and sterile filling is in cillin bottle respectively, and the false add plug is put into freeze drier and carried out lyophilize, gets freeze-drying prods.
Lyophilize is according to freeze-drying curve Fig. 3 operation among the embodiment 2.
The content of potassium sodium dehydroandroan drographolide succinate by dry product, does not change before and after freeze-drying.After the freeze-drying, potassium sodium dehydroandroan drographolide succinate redissolves all right, and insolubles is not seen in dissolving on time.Main project checks and accelerated test result, long-term test results are as follows:
Table 3 injection potassium sodium dehydroandroan drographolide succinate accelerated test result (80mg)
| Lot number | Time (moon) | Proterties | Potential of hydrogen (pH value) | Visible foreign matters | Aseptic | Related substance (%) | Labelled amount (%) |
| 0603011 | 0 1 2 3 6 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.88 6.82 6.80 6.87 6.85 | Up to specification up to specification | Up to specification up to specification | 0.60 0.63 0.67 0.71 0.75 | 99.83 99.78 99.75 99.70 99.59 |
| 0603021 | 0 1 2 3 6 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.84 6.89 6.87 6.82 6.80 | Up to specification up to specification | Up to specification up to specification | 0.61 0.65 0.67 0.70 0.75 | 99.89 99.82 99.77 99.70 99.60 |
| 0603031 | 0 1 2 3 6 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.82 6.86 6.86 6.83 6.85 | Up to specification up to specification | Up to specification up to specification | 0.60 0.64 0.70 0.72 0.77 | 100.05 100.00 99.93 99.87 99.81 |
Table 4 injection potassium sodium dehydroandroan drographolide succinate long-term test results (80mg)
| Lot number | Time (moon) | Proterties | Potential of hydrogen (pH value) | Visible foreign matters | Aseptic | Related substance (%) | Labelled amount (%) |
| 0603011 | 0 3 6 9 12 18 24 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.88 6.70 6.68 6.79 6.81 6.85 6.80 | Up to specification up to specification up to specification | Up to specification up to specification up to specification | 0.60 0.61 0.65 0.68 0.73 0.76 0.78 | 99.83 99.71 99.68 99.63 99.58 99.54 99.50 |
| 0603021 | 0 3 6 9 12 18 24 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.84 6.86 6.81 6.80 6.75 6.82 6.85 | Up to specification up to specification up to specification | Up to specification up to specification up to specification | 0.61 0.62 0.65 0.67 0.71 0.75 0.78 | 99.89 99.87 99.83 99.80 99.75 99.72 99.68 |
| 0603031 | 0 3 6 9 12 18 24 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.82 6.75 6.78 6.77 6.75 6.77 6.77 | Up to specification up to specification up to specification | Up to specification up to specification up to specification | 0.60 0.64 0.68 0.71 0.74 0.77 0.79 | 100.05 100.01 99.98 99.94 99.89 99.85 99.80 |
Embodiment 4, specification are the preparation of the 'Yanhuning ' frozen-dried powder injection of 160mg
2400ml water for injection is added in the dosing filling, open and stir, the temperature of control Agitation Tank is at 55-60 ℃.Accurately take by weighing potassium sodium dehydroandroan drographolide succinate 160g, add above-mentioned dosing and be stirred to dissolving in irritating.Accurately take by weighing sodium-chlor 40g, be dissolved in the 300ml water for injection, add in the above-mentioned Agitation Tank.With the solution stirring in the Agitation Tank evenly after, add 0.1% needle-use activated carbon of described solution quality, stirring and refluxing 15min is 6.4～6.8 with the pH value of the hydrochloric acid soln adjusting soup of 0.1～0.2mol/L, complements to 3000ml with water for injection then.Filter decarburization, then, clear and bright to filtrate successively with 0.22 μ m filtering with microporous membrane, be 10000 ultra-filtration membrane ultrafiltration, use 0.22 μ m filtering with microporous membrane again with the molecular retention amount.Sampling, the content that records potassium sodium dehydroandroan drographolide succinate in the above-mentioned filtrate is 51.8～54.9mg/ml.Filtrate is divided into 1000 parts, and sterile filling is in cillin bottle respectively, and the false add plug is put into freeze drier and carried out lyophilize, gets freeze-drying prods.
Lyophilize is operated according to freeze-drying curve Fig. 4:
Fs pre-freeze: adopt repeatedly the mode of pre-freeze (being about to product linearly from 20 ℃～-45 ℃～10 ℃～-45 ℃), pre-freeze 8 hours is cooled to-45 ℃ with product temperature by 20 ℃;
The subordinate phase sublimation drying: with 1.5 hours with temperature by-45 ℃ of linear temperature increases to-12 ℃, and kept 12-15 hour at-12 ℃; Use 1 hour then with temperature by-12 ℃ of linear temperature increases to-5 ℃, and kept 6-8 hour at-5 ℃; Vacuum tightness 14-22Pa;
Phase III parsing-desiccation: temperature by-5 ℃ of linear temperature increases to 33 ℃, was carried out 4 hours, and kept 6-8 hour at 33 ℃; Vacuum tightness 1.0-5.0Pa.
The content of potassium sodium dehydroandroan drographolide succinate by dry product, does not change before and after freeze-drying.After the freeze-drying, potassium sodium dehydroandroan drographolide succinate redissolves all right, and insolubles is not seen in dissolving on time.Main project checks and accelerated test result, long-term test results are as follows:
Table 5 injection potassium sodium dehydroandroan drographolide succinate accelerated test result (0.16g)
| Lot number | Time (moon) | Proterties | Potential of hydrogen (pH value) | Visible foreign matters | Aseptic | Related substance (%) | Labelled amount (%) |
| 0602012 | 0 1 2 3 6 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.75 6.78 6.75 6.76 6.81 | Up to specification up to specification | Up to specification up to specification | 0.60 0.63 0.67 0.70 0.74 | 100.06 100.00 99.93 99.86 99.80 |
| 0602022 | 0 1 2 3 6 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.78 6.80 6.79 6.82 6.80 | Up to specification up to specification | Up to specification up to specification | 0.59 0.63 0.66 0.71 0.76 | 99.96 99.90 99.84 99.80 99.76 |
| 0602032 | 0 1 2 3 6 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.72 6.74 6.73 6.77 6.83 | Up to specification up to specification | Up to specification up to specification | 0.61 0.63 0.67 0.70 0.75 | 100.12 100.05 99.93 99.88 99.82 |
Table 6 injection potassium sodium dehydroandroan drographolide succinate long-term test results (0.16g)
| Lot number | Time (moon) | Proterties | Potential of hydrogen (pH value) | Visible foreign matters | Aseptic | Related substance (%) | Labelled amount (%) |
| 0602012 | 0 3 6 9 12 18 24 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.75 6.68 6.70 6.69 6.71 6.72 6.72 | Up to specification up to specification up to specification | Up to specification up to specification up to specification | 0.60 0.62 0.65 0.68 0.73 0.75 0.79 | 100.06 100.01 99.95 99.84 99.75 99.68 99.62 |
| 0602022 | 0 3 6 9 12 18 24 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.78 6.79 6.80 6.71 6.80 6.83 6.83 | Up to specification up to specification up to specification | Up to specification up to specification up to specification | 0.59 0.64 0.68 0.70 0.74 0.76 0.77 | 99.96 99.94 99.92 99.89 99.84 99.80 99.77 |
| 0602032 | 0 3 6 9 12 18 24 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.72 6.75 6.68 6.74 6.70 6.79 6.79 | Up to specification up to specification up to specification | Up to specification up to specification up to specification | 0.61 0.61 0.62 0.65 0.68 0.71 0.74 | 100.12 100.08 100.05 100.01 99.99 99.97 99.92 |
2400ml water for injection is added in the dosing filling, open and stir, the temperature of control Agitation Tank is at 55-60 ℃.Accurately take by weighing potassium sodium dehydroandroan drographolide succinate 200g, add above-mentioned dosing and be stirred to dissolving in irritating.Accurately take by weighing sodium-chlor 50g, be dissolved in the 300ml water for injection, add in the above-mentioned Agitation Tank.With the solution stirring in the Agitation Tank evenly after, add 0.1% needle-use activated carbon of described solution quality, stirring and refluxing 15min is 6.4～6.8 with the pH value of the hydrochloric acid soln adjusting soup of 0.1～0.2mol/L, complements to 3000ml with water for injection then.Filter decarburization, then, clear and bright to filtrate successively with 0.22 μ m filtering with microporous membrane, be 10000 ultra-filtration membrane ultrafiltration, use 0.22 μ m filtering with microporous membrane again with the molecular retention amount.Sampling, the content that records potassium sodium dehydroandroan drographolide succinate in the above-mentioned filtrate is 64.7～68.6mg/ml.Filtrate is divided into 1000 parts, and sterile filling is in cillin bottle respectively, and the false add plug is put into freeze drier and carried out lyophilize, gets freeze-drying prods.
Lyophilize is according to freeze-drying curve Fig. 4 operation among the embodiment 4.
The content of potassium sodium dehydroandroan drographolide succinate by dry product, does not change before and after freeze-drying.After the freeze-drying, potassium sodium dehydroandroan drographolide succinate redissolves all right, and insolubles is not seen in dissolving on time.Main project checks and accelerated test result, long-term test results are as follows:
Table 7 injection potassium sodium dehydroandroan drographolide succinate accelerated test result (0.2g)
| Lot number | Time (moon) | Proterties | Potential of hydrogen (pH value) | Visible foreign matters | Aseptic | Related substance (%) | Labelled amount (%) |
| 0603012 | 0 1 2 3 6 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.65 6.70 6.68 6.66 6.71 | Up to specification up to specification | Up to specification up to specification | 0.60 0.64 0.67 0.71 0.76 | 100.05 100.00 99.95 99.92 99.86 |
| 0603022 | 0 1 2 3 6 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.68 6.70 6.69 6.72 6.77 | Up to specification up to specification | Up to specification up to specification | 0.60 0.64 0.69 0.74 0.77 | 99.97 99.93 99.86 99.82 99.75 |
| 0603032 | 0 1 2 3 6 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.62 6.74 6.73 6.67 6.73 | Up to specification up to specification | Up to specification up to specification | 0.60 0.63 0.66 0.69 0.75 | 100.12 100.08 100.04 99.97 99.91 |
Table 8 injection potassium sodium dehydroandroan drographolide succinate long-term test results (0.2g)
| Lot number | Time (moon) | Proterties | Potential of hydrogen (pH value) | Visible foreign matters | Aseptic | Related substance (%) | Labelled amount (%) |
| 0603012 | 0 3 6 9 12 18 24 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.65 6.68 6.70 6.69 6.71 6.72 6.70 | Up to specification up to specification up to specification | Up to specification up to specification up to specification | 0.60 0.62 0.65 0.68 0.73 0.75 0.75 | 100.05 100.01 99.95 99.84 99.75 99.68 99.60 |
| 0603022 | 0 3 6 9 12 18 24 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.68 6.69 6.70 6.71 6.70 6.73 6.75 | Up to specification up to specification up to specification | Up to specification up to specification up to specification | 0.60 0.64 0.68 0.70 0.74 0.76 0.78 | 99.97 99.94 99.92 99.89 99.84 99.80 99.70 |
| 0603032 | 0 3 6 9 12 18 24 | The faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of the faint yellow block of faint yellow block | 6.62 6.65 6.68 6.64 6.70 6.69 6.72 | Up to specification up to specification up to specification | Up to specification up to specification up to specification | 0.60 0.61 0.62 0.65 0.68 0.71 0.73 | 100.12 100.04 100.00 99.94 99.89 99.77 99.70 |
Claims (10)
1, a kind of preparation method of potassium sodium dehydroandroan drographolide succinate is that potassium dehydroandrographolide succinate is dissolved in the water for injection of described potassium dehydroandrographolide succinate 4-5 times quality, regulates pH value to 7.1～7.5 with the sodium hydroxide solution of 0.1-0.2mol/L then; Add remove impurity with active carbon matter then, then use the filtering with microporous membrane of 0.45 μ m, 0.22 μ m successively, collect filtrate, filtrate is carried out lyophilize handle, promptly obtain potassium sodium dehydroandroan drographolide succinate.
2, a kind of 'Yanhuning ' frozen-dried powder injection is to be made through freeze-drying by following raw material; Described raw material comprises potassium sodium dehydroandroan drographolide succinate, sodium-chlor and the water for injection of following mass parts:
Potassium sodium dehydroandroan drographolide succinate 4-20 mass parts
Sodium-chlor 1-5 mass parts
Water for injection 200-300 mass parts.
3, lyophilized injectable powder according to claim 2 is characterized in that: described raw material comprises potassium sodium dehydroandroan drographolide succinate, sodium-chlor and the water for injection of following mass parts:
Potassium sodium dehydroandroan drographolide succinate 4 mass parts
Sodium-chlor 1 mass parts
Water for injection 60-200 mass parts.
4, according to claim 2 or 3 described lyophilized injectable powders, it is characterized in that: described raw material also comprises the pH regulator agent; Potassium sodium dehydroandroan drographolide succinate is 4: 1 with the massfraction ratio of sodium-chlor in the described raw material.
5, lyophilized injectable powder according to claim 4 is characterized in that: sodium hydroxide solution or hydrochloric acid soln that described pH regulator agent is 0.1～0.2mol/L.
6, according to arbitrary described lyophilized injectable powder among the claim 2-5, it is characterized in that: described potassium sodium dehydroandroan drographolide succinate is by the described method preparation of claim 1.
7, the method for preparing arbitrary described lyophilized injectable powder among the claim 2-6, be that sodium-chlor with the potassium sodium dehydroandroan drographolide succinate of described amount and described amount is dissolved in 45-60 ℃ the water for injection, 0.1% of the described solution quality of adding needle-use activated carbon behind the mixing, with described pH regulator agent the pH of solution is controlled at 6.4～6.8, replenishes water for injection to described amount; Filtering decarbonization is the filtering with microporous membrane of 10000 daltonian ultra-filtration membrane ultrafiltration, 0.22 μ m with filtering with microporous membrane, the molecular weight cut-off of 0.22 μ m more successively, collects filtrate, and lyophilize obtains 'Yanhuning ' frozen-dried powder injection.
8, method according to claim 7 is characterized in that: the ratio of quality and the number of copies of potassium sodium dehydroandroan drographolide succinate and water for injection is 1 in the raw material of described lyophilized injectable powder: (25-50), described lyophilize adopts following method to carry out:
Fs pre-freeze: with 4 hours product temperature is cooled to-45 ℃ by 20 ℃ of linearities, and kept 1.5 hours, do not need to vacuumize at-45 ℃;
The subordinate phase sublimation drying: with 1.25 hours with temperature by-45 ℃ of linear temperature increases to-12 ℃, and kept 8 hours at-12 ℃; Vacuum tightness is 14-22Pa;
Phase III parsing-desiccation: temperature by-12 ℃ of linear temperature increases to 33 ℃, was carried out 7 hours, and kept 1～2 hour at 33 ℃; Vacuum tightness 1.0-5.0Pa.
9, method according to claim 8 is characterized in that: the ratio of quality and the number of copies of potassium sodium dehydroandroan drographolide succinate and water for injection is 1 in the raw material of described lyophilized injectable powder: (15-18.75), described lyophilize adopts following method to carry out:
Fs pre-freeze: adopt repeatedly the mode of pre-freeze, product is cooled to-45 ℃ from 20 ℃ of linearities, and then, be cooled to-45 ℃ from-10 ℃ of linearities more at last, pre-freeze 8 hours from extremely-10 ℃ of-45 ℃ of linear temperature increases;
The subordinate phase sublimation drying: with 1.5 hours with temperature by-45 ℃ of linear temperature increases to-12 ℃, and kept 12-15 hour at-12 ℃; Use 1 hour then with temperature by-12 ℃ of linear temperature increases to-5 ℃, and kept 6-8 hour at-5 ℃; Vacuum tightness 14-22Pa;
Phase III parsing-desiccation: temperature by-5 ℃ of linear temperature increases to 33 ℃, was carried out 4 hours, and kept 6-8 hour at 33 ℃; Vacuum tightness 1.0-5.0Pa.
10, according to arbitrary described method among the claim 7-9, it is characterized in that: described potassium sodium dehydroandroan drographolide succinate is by the described method preparation of claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101060517A CN101270101B (en) | 2008-05-08 | 2008-05-08 | Method for preparing potassium sodium dehydroandroan drographolide succinate for injection and its freeze-dried injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101060517A CN101270101B (en) | 2008-05-08 | 2008-05-08 | Method for preparing potassium sodium dehydroandroan drographolide succinate for injection and its freeze-dried injection |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910247073A Division CN101780051A (en) | 2008-05-08 | 2008-05-08 | Preparation methods of potassium sodium dehydroandroan drographolide succinate and freeze-dried powder injection thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101270101A true CN101270101A (en) | 2008-09-24 |
| CN101270101B CN101270101B (en) | 2011-01-26 |
Family
ID=40004353
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008101060517A Active CN101270101B (en) | 2008-05-08 | 2008-05-08 | Method for preparing potassium sodium dehydroandroan drographolide succinate for injection and its freeze-dried injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101270101B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102657623A (en) * | 2012-05-28 | 2012-09-12 | 王保明 | Andrographolide lyophilized powder injection and preparation method thereof |
| CN104744412A (en) * | 2015-04-07 | 2015-07-01 | 重庆药友制药有限责任公司 | Dehydroandrographolide succinate compound |
| CN104840458A (en) * | 2015-04-27 | 2015-08-19 | 海口通用康力制药有限公司 | Dehydroandrographolide succinate freeze-dried powder injection and preparation method thereof |
| CN106474078A (en) * | 2015-11-30 | 2017-03-08 | 湖南恒生制药股份有限公司 | The preparation method of Andrographolide in Andrographolide for Injection |
| CN107184556A (en) * | 2017-06-13 | 2017-09-22 | 成都万维优方科技有限公司 | A kind of andrographolide lyophilized formulations and preparation method thereof |
| CN107773540A (en) * | 2016-08-31 | 2018-03-09 | 海南斯达制药有限公司 | A kind of andrographolide freeze dried powder and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1223589C (en) * | 2004-02-06 | 2005-10-19 | 重庆药友制药有限责任公司 | Potassium sodium dehydroandroandrographolide succinates and their preparations |
| CN100465171C (en) * | 2005-09-06 | 2009-03-04 | 黄金秀 | Preparation method of potassium sodium dehydroandroan drographolide succinate, potassium sodium dehydroandroan drographolide succinate preparation and preparation method thereof |
-
2008
- 2008-05-08 CN CN2008101060517A patent/CN101270101B/en active Active
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102657623A (en) * | 2012-05-28 | 2012-09-12 | 王保明 | Andrographolide lyophilized powder injection and preparation method thereof |
| CN104744412A (en) * | 2015-04-07 | 2015-07-01 | 重庆药友制药有限责任公司 | Dehydroandrographolide succinate compound |
| CN104840458A (en) * | 2015-04-27 | 2015-08-19 | 海口通用康力制药有限公司 | Dehydroandrographolide succinate freeze-dried powder injection and preparation method thereof |
| CN106474078A (en) * | 2015-11-30 | 2017-03-08 | 湖南恒生制药股份有限公司 | The preparation method of Andrographolide in Andrographolide for Injection |
| CN107773540A (en) * | 2016-08-31 | 2018-03-09 | 海南斯达制药有限公司 | A kind of andrographolide freeze dried powder and preparation method thereof |
| CN107773540B (en) * | 2016-08-31 | 2020-07-14 | 海南斯达制药有限公司 | Potassium sodium dehydroandroan drographolide succinate freeze-dried powder and preparation method thereof |
| CN107184556A (en) * | 2017-06-13 | 2017-09-22 | 成都万维优方科技有限公司 | A kind of andrographolide lyophilized formulations and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101270101B (en) | 2011-01-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101780051A (en) | Preparation methods of potassium sodium dehydroandroan drographolide succinate and freeze-dried powder injection thereof | |
| CN101270101B (en) | Method for preparing potassium sodium dehydroandroan drographolide succinate for injection and its freeze-dried injection | |
| CN102512380B (en) | Freeze-dried powder injection with omeprazole sodium as active component and preparation method thereof | |
| CN103251565A (en) | Voriconazole freeze-dried powder injection for injection and preparation method thereof | |
| CN101530393B (en) | Clindamycin phosphate lipidosome freeze-dried preparation | |
| CN104352454B (en) | Sodium fusidafe as injection powder-injection pharmaceutical composition and preparation method | |
| CN102525963B (en) | Netilmicin sulfate lyophiled powder injection and preparation method thereof | |
| CN101530392B (en) | Omeprazole sodium freeze-dried lipidosome preparation | |
| CN113455504B (en) | Chitosan-loaded caffeic acid ester nano-medicament and preparation method and application thereof | |
| CN104414983A (en) | Sterile freeze-dried fosaprepitant-dimeglumine powder for injection and preparation process of sterile freeze-dried fosaprepitant-dimeglumine powder | |
| CN103565755A (en) | Clindamycin phosphate injection composition and preparation method thereof | |
| WO2021093299A1 (en) | Astragalus-paecilomyces cicadae fermented fungal substance, preparation method and application thereof | |
| CN104324007A (en) | Preparation technology and application of natural recombinant nanostructured lipid carrier | |
| CN103735514A (en) | Polyethylene glycol vitamin E succinate and calprotectin modified nanoparticle and preparation method thereof | |
| CN100502878C (en) | Fusidate sodium composition and preparation of its freeze-drying formulation | |
| CN103494780A (en) | Gamithromycin composition lyophilized powder for injection and preparation method | |
| CN1947749B (en) | Medicine composition containing Poria cocos and Touhualiao (polygonaceae) | |
| CN102743342B (en) | Sodium fusidate lyophilized composition for injection | |
| CN102670524B (en) | Pantoprazole sodium freeze-dried preparation for injection and preparation method thereof | |
| CN101455648A (en) | Puerarin freeze-drying preparation | |
| CN103735522B (en) | A kind of Yanhuning freeze dried powder for injection and preparation method thereof | |
| CN102626427A (en) | Ginkgo dipyridamole composition and preparation method of preparation thereof | |
| CN108379252B (en) | Gooseberry anthocyanidin is preparing the application in anti-hepatic fibrosis drug or health care product | |
| CN101554405A (en) | Selfheal, mulberry leaf and wild chrysanthemum dripping pills and preparation method thereof | |
| CN106074399B (en) | A kind of SC 69124 sodium freeze-dried preparation and preparation method thereof |
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 | ||
| CP02 | Change in the address of a patent holder |
Address after: 571425, Qionghai City, Hainan Province Road Patentee after: STAR PHARMACEUTICAL Ltd. Address before: Hainan province Haikou City Jinmao road 570125 No. 1 Haitian Pavilion 21 floor hillside garden Patentee before: STAR PHARMACEUTICAL Ltd. |
|
| CP02 | Change in the address of a patent holder |