CN102920670A - Preparation method of vitamin C freeze-dried powder - Google Patents
Preparation method of vitamin C freeze-dried powder Download PDFInfo
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- CN102920670A CN102920670A CN2012104456368A CN201210445636A CN102920670A CN 102920670 A CN102920670 A CN 102920670A CN 2012104456368 A CN2012104456368 A CN 2012104456368A CN 201210445636 A CN201210445636 A CN 201210445636A CN 102920670 A CN102920670 A CN 102920670A
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Abstract
The invention relates to a preparation method of vitamin C freeze-dried powder, the vitamin C freeze-dried powder is dried in a freezing state, after moisture is sublimated, needed vitamin C composition retains in an ice shelf in the freezing process to form a loose porous structure similar to a spongy shape, so that the prepared freeze-dried powder has no defects in appearance, is smooth in surface, and even and identical in color, and the volume of the prepared freeze-dried powder basically equals to that of in the freezing process, the prepared freeze-dried powder can be dissolved rapidly after adding of water and recover physical and chemical properties and biological activity of original aqueous solution, and is good in solubility, clarity and stability, not easy to pollute, long in quality guarantee period, and convenient to store and transport.
Description
Technical field
The invention belongs to the biological medicine technology field, relate to vitamin freeze-dried powder, be specifically related to a kind of preparation method of vitamin C lyophilized powder.
Background technology
Vitamin C has another name called L-AA, be one of necessary water soluble vitamins of human body, it participates in that amino acid metabolism, neurotransmitter are synthetic, matter is synthetic between collagen protein and histiocyte, can reduce the permeability of blood capillary, accelerates solidifying of blood, stimulate coagulation function, promote that ferrum absorbs at enteral, impel rate and blood-lipid decreased, increase the resistance to infecting, participate in function of detoxification, and the effect that antfhistamine effect is arranged and stop carcinogen to generate.Clinical vitamin C commonly used mostly is the form of injection at present, be widely used in the auxiliary treatment of preventing and treating vitamin C deficiency, chronic iron poisoning, idiopathic methemoglobinemia, various acute and chronic infectious disease and purpura etc., and the rescue of cardiogenic shock etc., determined curative effect, and without obvious adverse reaction.But injection is subject to the impact of illumination and temperature easily, and easy oxidation discoloration during high temperature carries out heat treated before easy crystallization need be used during low temperature, and curative effect is unstable, inconvenient operation.Lyophilized powder be solid-state via under gnotobasis, medicinal liquid being frozen into, then evacuation with moisture by solid state directly distillation be the dried product that steam and the process got rid of from goods obtain, than injection, it has following remarkable advantage: 1. drying is to carry out under vacuum condition, has good protective effect for the material of some easy oxidations; 2. can make albumen, microbiology class composition enter resting state fast and degeneration does not occur or lose activity, biological tissue and cellularity are not had damage substantially, can effectively protect the stability of thermal sensitivity composition; 3. loose, the color of freeze-dried products form after drying does not change substantially, adds physicochemical property and the biological activity that can dissolve fast and recover original aqueous solution behind the water; 4. goods are extremely low through water content after the lyophilizing, and not only stability improves, and contaminated chance reduces greatly; 5. store and convenient transportation, the shelf-life prolongs.
Existing vitamin C lyophilized powder is because preparation technology's restriction on the market, and ubiquity the shortcomings such as poor stability, zest are strong, poor solubility, the clarity disqualification rate is high, curative effect is unstable.
CN 1830438A discloses a kind of preparation method of vitamin medicaments injection vitamin C freeze dried powder injection; this method technical process mainly is that vitamin C and antioxidant sodium sulfite, metal chelating agent disodium edetate are prepared jointly; through supersound process; use saturated water for injection and the lucifuge nitrogen filled protection of carbon dioxide, and strictly control pH value and temperature.
Summary of the invention
The object of the invention is for the deficiencies in the prior art, and a kind of preparation method of vitamin C lyophilized powder is provided.
For achieving the above object, the present invention adopts following technical scheme:
A kind of preparation method of vitamin C lyophilized powder comprises the steps:
(1) gets water for injection (WFI), pass into CO
2To saturated, get the CO of vitamin C bulk pharmaceutical 5-10 times quality
2Saturated water for injection is for subsequent use.
Described 5-10 doubly, for example can be 5-7.5 doubly, 6.1-8.1 doubly, 9-10 doubly, 5 times, 5.4 times, 5.5 times, 5.9 times, 6 times, 6.2 times, 6.5 times, 6.7 times, 7 times, 7.3 times, 7.6 times, 8 times, 8.5 times, 8.8 times, 9 times, 9.1 times, 9.5 times, 10 times; Be preferably 7-9 doubly; Most preferably be 8 times.
(2) vitamin C bulk pharmaceutical is dissolved in the CO that the step (1) of 60wt%-90wt% obtains
2Stirring and dissolving in the saturated water for injection, gradation slowly add the NaHCO of vitamin C bulk pharmaceutical 0.3-0.5 times quality
3(sodium bicarbonate) adds the EDTA(ethylenediaminetetraacetic acid of vitamin C bulk pharmaceutical 0.0003-0.0005 times quality again) and the NaHSO of vitamin C bulk pharmaceutical 0.01-0.02 times quality
3(sodium sulfite) stirs, and regulates pH value to 6.0-6.2, adds remaining CO
2Saturated water for injection, recording pH value is 5.85-5.95, then is that content is qualified, enters next step.
Described 60wt%-90wt% for example can be 60wt%-73wt%, 69.4wt%-82.7wt%, 85wt%-90wt%, 60wt%, 62.5wt%, 65wt%, 68.1wt%, 70wt%, 74.6wt%, 75wt%, 77.9wt%, 80wt%, 81.2wt%, 84wt%, 86.3wt%, 90wt%; Be preferably 75wt%-85wt%; Most preferably be 80wt%.
Preferably, described gradation is 2-5 time, for example can be 2 times, 3 times, 4 times, 5 times; More preferably 2-4 time; Most preferably be 3 times.
Described 0.3-0.5 doubly, for example can be 0.3-0.37 doubly, 0.35-0.44 doubly, 0.42-0.5 doubly, 0.3 times, 0.33 times, 0.36 times, 0.38 times, 0.4 times, 0.41 times, 0.45 times, 0.47 times, 0.49 times, 0.5 times; Be preferably 0.35-0.45 doubly; Most preferably be 0.4 times.
Described NaHCO
3(sodium bicarbonate) is in the present invention as pH adjusting agent.
Described 0.0003-0.0005 for example can be 0.0003 times, 0.00033 times, 0.00035 times, 0.00038 times, 0.0004 times, 0.00041 times, 0.00045 times, 0.00047 times, 0.0005 times doubly; Be preferably 0.00035-0.00045 doubly; Most preferably be 0.0004 times.
Described EDTA(ethylenediaminetetraacetic acid) in the present invention as chelating agent.
Described 0.01-0.02 for example can be 0.01,0.011 times, 0.012 times, 0.013 times, 0.014 times, 0.015 times, 0.016 times, 0.017 times, 0.018 times, 0.019 times, 0.02 times doubly; Be preferably 0.015-0.018 doubly; Most preferably be 0.016 times.
Described NaHSO
3(sodium sulfite) is in the present invention as antioxidant.
(3) filter with the micropore sterilizing filter of 0.22 μ m, 100 ℃ of flowing steam sterilization 10-30min then are filled under the aseptic condition in the sterilization container, press half plug with container closure, prepare to be transferred in the freeze dryer.
Described 10-30min for example can be 10-16.9min, 13.5-18.5min, 17-20min, 10min, 11min, 12.5min, 15min, 18.7min, 20min, 20.6min, 22min, 24.5min, 25min, 26.1min, 28min, 30min; Be preferably 10-20min; Most preferably be 15min.
Described pressure half plug both can prevent the loss of material and entering of foreign body in the container, the relative circulation that can also keep air.
(4) measure eutectic point: from the filtrate of step (2), take out a part as sample, a pair of platinum electrode is immersed wherein, sample is cooled to the low temperature below-40 ℃, then slowly heat up, measure its resistance with resistance bridge in the process that heats up, the temperature when resistance occurs to reduce suddenly is the eutectic point m that records.
Preferably, described slow intensification refers to heat up with the speed of 0.2-2 ℃/min, for example can be 0.2-0.5 ℃/min, 0.4-1.6 ℃/min, 1.1-2 ℃/min, 0.2 ℃/min, 0.35 ℃/min, 0.5 ℃/min, 0.62 ℃/min, 0.8 ℃/min, 0.97 ℃/min, 1 ℃/min, 1.25 ℃/min, 1.4 ℃/min, 1.5 ℃/min, 1.7 ℃/min, 1.83 ℃/min, 1.9 ℃/min, 2 ℃/min; 0.5-1.5 ℃/min more preferably; Most preferably be 1 ℃/min.
Preferably, described resistance bridge AC-powered, the electrolysis that can avoid unidirectional current to cause.
The whole process of this step instrument record.
(5) regulate temperature in the drying box of freeze dryer to 2-8 ℃, with step (2) fill the sterilization container of filtrate be transferred in the drying baker, insulation, be cooled to again (m-20) ℃～(m-10) ℃ between, insulation.
Described 2-8 ℃, for example can 2-4 ℃, 3.7-6.1 ℃, 5.5-8 ℃, 2 ℃, 2.2 ℃, 2.5 ℃, 3 ℃, 3.4 ℃, 3.5 ℃, 4 ℃, 4.1 ℃, 4.5 ℃, 5 ℃, 5.3 ℃, 5.9 ℃, 6 ℃, 6.5 ℃, 7 ℃, 7.2 ℃, 7.5 ℃, 7.7 ℃, 8 ℃; Be preferably 4-6 ℃; Most preferably be 5 ℃.
Described (m-20) ℃～(m-10) ℃, for example can (m-20) ℃～(m-17) ℃, (m-19) ℃～(m-14) ℃, (m-16) ℃～(m-10) ℃, (m-20) ℃, (m-19.5) ℃, (m-18) ℃, (m-17.6) ℃, (m-16.4) ℃, (m-15) ℃, (m-14.1) ℃, (m-13) ℃, (m-12) ℃, (m-11) ℃, (m-10.3) ℃, (m-10) ℃; Be preferably (m-18) ℃～(m-12) ℃; Most preferably be (m-15) ℃.
Preferably, the time of described insulation is 0.5-3h, for example can be 0.5-0.9h, 0.75-2.1h, 1.64-3h, 0.5h, 0.6h, 0.8h, 1h, 1.1h, 1.35h, 1.5h, 1.7h, 1.96h, 2h, 2.07h, 2.2h, 2.4h, 2.5h, 2.68h, 2.8h, 2.95h, 3h; 0.8-1.5h more preferably; Optimum bit selecting 1h.
This step is the pre-freeze stage, keeps a period of time can take into account lyophilizing efficient and product quality under 2-8 ℃ temperature first; It is following and keep a period of time to be cooled to eutectic point again, has reached the still generation of non crystallized surfusion of eutectic point solute though can overcome temperature.Thereby guaranteed that filtrate can obtain the structure of uniformity after freezing.
(6) in the control drying baker vacuum degree control of the temperature of shelf in 10 ℃, the temperature of freeze-dried products maintain m-5 ℃, drying baker between 0.1-0.3mbar, keep a period of time until freeze-dried products without the visible ice crystal of naked eyes.
Described vacuum degree control for example can be 0.1-0.17mbar, 0.12-0.24mbar, 0.19-0.3mbar, 0.1mbar, 0.13mbar, 0.15mbar, 0.16mbar, 0.18mbar, 0.2mbar, 0.21mbar, 0.22mbar, 0.25mbar, 0.27mbar, 0.29mbar, 0.3mbar between 0.1-0.3mbar; Be preferably 0.12-0.22mbar; Most preferably be 0.15mbar.
Preferably, described maintenance a period of time for example can be 10-13.5h, 12-17.8h, 16-20h, 10h, 10.4h, 11h, 11.8h, 12.5h, 13h, 14h, 14.6h, 15h, 16.2h, 17h, 18h, 18.1h, 19h, 19.9h, 20h for keeping 10-20h; Be preferably 12-18h; Most preferably be 15h.
This step can be described as sublimation stage, the moisture more than 90% can be removed.
(7) vacuum of control in the drying baker is between 0.15-0.3mbar, and the freeze-dried products of step (5) is warming up to rapidly 25-35 ℃, recovers fine vacuum behind the temperature stabilization, finishes lyophilizing behind the insulation 3-10h.
Described vacuum for example can be 0.15-0.18mbar, 0.21-0.25mbar, 0.17-0.3mbar, 0.15mbar, 0.16mbar, 0.17mbar, 0.18mbar, 0.19mbar, 0.2mbar, 0.21mbar, 0.22mbar, 0.23mbar, 0.24mbar, 0.25mbar, 0.26mbar, 0.27mbar, 0.28mbar, 0.29mbar, 0.3mbar between 0.15-0.3mbar; Be preferably 0.18-0.28mbar; Most preferably be 0.25mbar.
Vacuum degree control in the drying baker between 0.15-0.3mbar, can be improved the heat-transfer effect of drying baker, make the temperature of freeze-dried products in the drying baker reach quickly temperature required, shorten the time of this one-phase of adsorption stripping and dry.Preferably, adopt the correction leak hole method that the pressure in the drying baker is controlled.
Described rapid intensification refers to heat up with the speed of 10-30 ℃/min, for example can be 10-16.5 ℃/min, 18.4-21.6 ℃/min, 25.1-30 ℃/min, 10 ℃/min, 10.5 ℃/min, 11 ℃/min, 12 ℃/min, 13.8 ℃/min, 14 ℃/min, 15 ℃/min, 16 ℃/min, 17.4 ℃/min, 18 ℃/min, 19.7 ℃/min, 20 ℃/min, 21 ℃/min, 22 ℃/min, 23 ℃/min, 24.4 ℃/min, 25 ℃/min, 26.7 ℃/min, 28 ℃/min, 29 ℃/min, 30 ℃/min; 15-25 ℃/min more preferably; Most preferably be 20 ℃/min.
Described 25-35 ℃ for example can be 25-29 ℃, 27.8-32 ℃, 30-35 ℃, 25 ℃, 25.5 ℃, 26 ℃, 26.1 ℃, 26.7 ℃, 27 ℃, 28 ℃, 28.4 ℃, 29 ℃, 29.6 ℃, 30 ℃, 30.7 ℃, 31 ℃, 32.3 ℃, 33 ℃, 33.1 ℃, 33.5 ℃, 34 ℃, 34.8 ℃, 35 ℃; Be preferably 28-32 ℃; Most preferably be 30 ℃.This temperature range is the maximum permissible temperature that the mannitol freeze-dried products can reach.
Described fine vacuum refers to that low vacuum is in 1.333 * 10
-1-1.333 * 10
-6Pa.
Described insulation 3-10h for example can be 3-6h, 4.2-7.8h, 8.5-10h, 3h, 3.5h, 4h, 4.2h, 4.9h, 5h, 5.4h, 5.5h, 5.7h, 6h, 6.1h, 6.5h, 6.8h, 7h, 7.3h, 7.5h, 8h, 8.1h, 8.6h, 9h, 9.2h, 9.5h, 9.7h, 10h; Be preferably 4-7h; Most preferably be 5h.
Preferably, determine as follows the opportunity of described end lyophilizing: close the drying baker of freeze dryer and the valve 30-60s between the condenser, the pressure changing in the case that sees drying.If the pressure in the drying baker, then illustrates drying less than significantly raising and substantially finishes, can finish lyophilizing.If the pressure in the drying baker is increased significantly, then explanation also has moisture content to overflow, and time expand proceed drying, until close after the valve between drying baker and the condenser pressure in the drying baker without obviously rising.
The goods that (8) will finish lyophilizing are preserved at the vacuum condition lower seal.
In sum, the technical scheme after the optimization of the present invention is:
A kind of preparation method of vitamin C lyophilized powder comprises the steps:
(1) gets water for injection (WFI), pass into CO
2To saturated, get the CO of vitamin C bulk pharmaceutical 5-10 times quality
2Saturated water for injection is for subsequent use;
(2) vitamin C bulk pharmaceutical is dissolved in the CO that the step (1) of 60wt%-90wt% obtains
2Stirring and dissolving in the saturated water for injection, gradation slowly add the NaHCO of vitamin C bulk pharmaceutical 0.3-0.5 times quality
3(sodium bicarbonate) adds the EDTA(ethylenediaminetetraacetic acid of vitamin C bulk pharmaceutical 0.0003-0.0005 times quality again) and the NaHSO of vitamin C bulk pharmaceutical 0.01-0.02 times quality
3(sodium sulfite) stirs, and regulates pH value to 6.0-6.2, adds remaining CO
2Saturated water for injection, recording pH value is 5.85-5.95, then is that content is qualified, enters next step;
(3) filter with the micropore sterilizing filter of 0.22 μ m, 100 ℃ of flowing steam sterilization 10-30min then are filled under the aseptic condition in the sterilization container, press half plug with container closure, prepare to be transferred in the freeze dryer;
(4) measure eutectic point: from the filtrate of step (2), take out a part as sample, a pair of platinum electrode is immersed wherein, sample is cooled to the low temperature below-40 ℃, then the speed with 0.2-2 ℃/min slowly heats up, measure its resistance with resistance bridge in the process that heats up, the temperature when resistance occurs to reduce suddenly is the eutectic point m that records;
(5) regulate temperature in the drying box of freeze dryer to 2-8 ℃, with step (2) fill the sterilization container of filtrate be transferred in the drying baker, keeps 2-8 ℃ temperature 0.5-3h, be cooled to again (m-20) ℃～(m-10) ℃ between, maintenance 0.5-3h;
(6) in the control drying baker vacuum degree control of the temperature of shelf in 10 ℃, the temperature of freeze-dried products maintain m-5 ℃, drying baker between 0.1-0.3mbar, keep 10-20h until freeze-dried products without the visible ice crystal of naked eyes;
(7) vacuum of control in the drying baker is between 0.15-0.3mbar, and the freeze-dried products of step (5) is warming up to rapidly 25-35 ℃ with the speed of 10-30 ℃/min, recovers fine vacuum 1.333 * 10 behind the temperature stabilization
-1-1.333 * 10
-6Pa finishes lyophilizing behind the insulation 3-10h;
The goods that (8) will finish lyophilizing are preserved at the vacuum condition lower seal.
Technical scheme after the present invention further optimizes is:
A kind of preparation method of vitamin C lyophilized powder comprises the steps:
(1) gets water for injection (WFI), pass into CO
2To saturated, get the CO of vitamin C bulk pharmaceutical 7-9 times quality
2Saturated water for injection is for subsequent use;
(2) vitamin C bulk pharmaceutical is dissolved in the CO that the step (1) of 75wt%-85wt% obtains
2Stirring and dissolving in the saturated water for injection, gradation slowly add the NaHCO of vitamin C bulk pharmaceutical 0.35-0.45 times quality
3(sodium bicarbonate) adds the EDTA(ethylenediaminetetraacetic acid of vitamin C bulk pharmaceutical 0.00035-0.00045 times quality again) and the NaHSO of vitamin C bulk pharmaceutical 0.015-0.018 times quality
3(sodium sulfite) stirs, and regulates pH value to 6.0-6.2, adds remaining CO
2Saturated water for injection, recording pH value is 5.85-5.95, then is that content is qualified, enters next step;
(3) filter with the micropore sterilizing filter of 0.22 μ m, 100 ℃ of flowing steam sterilization 10-20min then are filled under the aseptic condition in the sterilization container, press half plug with container closure, prepare to be transferred in the freeze dryer;
(4) measure eutectic point: from the filtrate of step (2), take out a part as sample, a pair of platinum electrode is immersed wherein, sample is cooled to the low temperature below-40 ℃, then the speed with 0.5-1.5 ℃/min slowly heats up, measure its resistance with resistance bridge in the process that heats up, the temperature when resistance occurs to reduce suddenly is the eutectic point m that records;
(5) regulate temperature in the drying box of freeze dryer to 4-6 ℃, with step (2) fill the sterilization container of filtrate be transferred in the drying baker, keeps 4-6 ℃ temperature 0.8-1.5h, be cooled to again (m-18) ℃～(m-12) ℃ between, maintenance 0.8-1.5h;
(6) in the control drying baker vacuum degree control of the temperature of shelf in 10 ℃, the temperature of freeze-dried products maintain m-5 ℃, drying baker between 0.12-0.22mbar, keep 12-18h until freeze-dried products without the visible ice crystal of naked eyes;
(7) vacuum of control in the drying baker is between 0.18-0.28mbar, and the freeze-dried products of step (5) is warming up to rapidly 28-32 ℃ with the speed of 15-25 ℃/min, recovers fine vacuum 1.333 * 10 behind the temperature stabilization
-1-1.333 * 10
-6Pa finishes lyophilizing behind the insulation 4-7h;
The goods that (8) will finish lyophilizing are preserved at the vacuum condition lower seal.
The optimized technical scheme of the present invention is:
A kind of preparation method of vitamin C lyophilized powder comprises the steps:
(1) gets water for injection (WFI), pass into CO
2To saturated, get the CO of 8 times of quality of vitamin C bulk pharmaceutical
2Saturated water for injection is for subsequent use;
(2) vitamin C bulk pharmaceutical is dissolved in the CO that the step (1) of 80wt% obtains
2Stirring and dissolving in the saturated water for injection, gradation slowly add the NaHCO of 0.4 times of quality of vitamin C bulk pharmaceutical
3(sodium bicarbonate) adds the EDTA(ethylenediaminetetraacetic acid of 0.0004 times of quality of vitamin C bulk pharmaceutical again) and the NaHSO of 0.016 times of quality of vitamin C bulk pharmaceutical
3(sodium sulfite) stirs, and regulates pH value to 6.0-6.2, adds remaining CO
2Saturated water for injection, recording pH value is 5.85-5.95, then is that content is qualified, enters next step;
(3) filter with the micropore sterilizing filter of 0.22 μ m, 100 ℃ of flowing steam sterilization 15min then are filled under the aseptic condition in the sterilization container, press half plug with container closure, prepare to be transferred in the freeze dryer;
(4) measure eutectic point: from the filtrate of step (2), take out a part as sample, a pair of platinum electrode is immersed wherein, sample is cooled to the low temperature below-40 ℃, then the speed with 1 ℃/min slowly heats up, measure its resistance with resistance bridge in the process that heats up, the temperature when resistance occurs to reduce suddenly is the eutectic point m that records;
(5) regulate temperature to 5 ℃ in the drying box of freeze dryer, with step (2) fill the sterilization container of filtrate be transferred in the drying baker, keeps 5 ℃ temperature 1h, be cooled to again (m-15) ℃, maintenance 1h;
(6) in the control drying baker vacuum degree control of the temperature of shelf in 10 ℃, the temperature of freeze-dried products maintain m-5 ℃, drying baker between 0.15mbar, keep 15h until freeze-dried products without the visible ice crystal of naked eyes;
(7) vacuum of control in the drying baker is at 0.25mbar, and the freeze-dried products of step (5) is warming up to rapidly 30 ℃ with the speed of 20 ℃/min, recovers fine vacuum 1.333 * 10 behind the temperature stabilization
-1-1.333 * 10
-6Pa finishes lyophilizing behind the insulation 5h;
The goods that (8) will finish lyophilizing are preserved at the vacuum condition lower seal.
Compared with prior art, the preparation method of vitamin C lyophilized powder provided by the invention, under the state that freezes, carry out drying, after the water sublimed in the required left ice shelf when freezing of vitamin C composition, form the spongy loose porous framework of class, the lyophilized powder outward appearance N/D of therefore preparing, surfacing, the volume of volume when freezing equates substantially, color even is consistent, adds physicochemical property and the biological activity that can dissolve fast and recover original aqueous solution behind the water, and dissolubility is good, clarity is good, water content is extremely low after lyophilizing simultaneously, and good stability is not vulnerable to pollute, the shelf-life significant prolongation stores and convenient transportation.
Below in conjunction with embodiment the present invention is described in further detail.But following embodiment only is simple and easy example of the present invention, does not represent or limit the scope of the present invention, and interest field of the present invention is as the criterion with claims.
The specific embodiment
For the present invention is described better, be convenient to understand technical scheme of the present invention, typical but non-limiting embodiment of the present invention is as follows:
Embodiment 1:
Be prepared as follows the vitamin C lyophilized powder:
(1) gets fresh water for injection, pass into capacity CO
2To saturated, get CO
2Saturated water for injection 1000ml is for subsequent use;
(2) the 125g vitamin C bulk pharmaceutical is dissolved in the CO that 800ml step (1) obtains
2Stirring and dissolving in the saturated water for injection, gradation slowly add 49g NaHCO
3, add again 0.05g EDTA and 2.0gNaHSO
3, stir, regulate pH value to 6.0-6.2, add remaining CO
2Saturated water for injection, recording pH value is 5.85-5.95, then is that content is qualified, enters next step;
(3) filter with the micropore sterilizing filter of 0.22 μ m, 100 ℃ of flowing steam sterilization 15min then are filled under the aseptic condition in the sterilization container, press half plug with container closure, prepare to be transferred in the freeze dryer;
(4) measure eutectic point: from the filtrate of step (2), take out a part as sample, a pair of platinum electrode is immersed wherein, sample is cooled to the low temperature below-40 ℃, then the speed with 1 ℃/min slowly heats up, in the process that heats up, measure its resistance with resistance bridge, temperature when resistance occurs to reduce suddenly is the eutectic point m that records, and records eutectic point m and is-15 ℃;
(5) regulate temperature to 5 ℃ in the drying box of freeze dryer, with step (2) fill the sterilization container of filtrate be transferred in the drying baker, keeps 5 ℃ temperature 1h, be cooled to again-30 ℃, maintenance 1h;
(6) in the control drying baker vacuum degree control of the temperature of shelf in 10 ℃, the temperature of freeze-dried products maintain-20 ℃, drying baker between 0.15mbar, keep 15h until freeze-dried products without the visible ice crystal of naked eyes;
(7) vacuum of control in the drying baker is at 0.25mbar, and the freeze-dried products of step (5) is warming up to rapidly 30 ℃ with the speed of 20 ℃/min, recovers fine vacuum 1.333 * 10 behind the temperature stabilization
-1-1.333 * 10
-6Pa finishes lyophilizing behind the insulation 5h;
The goods that (8) will finish lyophilizing are preserved at the vacuum condition lower seal.
Embodiment 2:
Be prepared as follows the vitamin C lyophilized powder:
(1) gets fresh water for injection, pass into capacity CO
2To saturated, get CO
2Saturated water for injection 1125ml is for subsequent use;
(2) the 125g vitamin C bulk pharmaceutical is dissolved in the CO that 844ml step (1) obtains
2Stirring and dissolving in the saturated water for injection, gradation slowly add 56.25g NaHCO
3, add again 0.05625g EDTA and 2.25g NaHSO
3, stir, regulate pH value to 6.0-6.2, add remaining CO
2Saturated water for injection, recording pH value is 5.85-5.95, then is that content is qualified, enters next step;
(3) filter with the micropore sterilizing filter of 0.22 μ m, 100 ℃ of flowing steam sterilization 20min then are filled under the aseptic condition in the sterilization container, press half plug with container closure, prepare to be transferred in the freeze dryer;
(4) measure eutectic point: from the filtrate of step (2), take out a part as sample, a pair of platinum electrode is immersed wherein, sample is cooled to the low temperature below-40 ℃, then the speed with 0.5 ℃/min slowly heats up, in the process that heats up, measure its resistance with resistance bridge, temperature when resistance occurs to reduce suddenly is the eutectic point m that records, and records eutectic point m and is-17 ℃;
(5) regulate temperature to 4 ℃ in the drying box of freeze dryer, with step (2) fill the sterilization container of filtrate be transferred in the drying baker, keeps 4 ℃ temperature 1.5h, be cooled to again between-35 ℃ maintenance 1.5h;
(6) in the control drying baker vacuum degree control of the temperature of shelf in 10 ℃, the temperature of freeze-dried products maintain-22 ℃, drying baker between 0.22mbar, keep 12h until freeze-dried products without the visible ice crystal of naked eyes;
(7) vacuum of control in the drying baker is between 0.28mbar, and the freeze-dried products of step (5) is warming up to rapidly 28 ℃ with the speed of 15 ℃/min, recovers fine vacuum 1.333 * 10 behind the temperature stabilization
-1-1.333 * 10
-6Pa finishes lyophilizing behind the insulation 4h;
The goods that (8) will finish lyophilizing are preserved at the vacuum condition lower seal.
Embodiment 3:
Be prepared as follows the vitamin C lyophilized powder:
(1) gets fresh water for injection, pass into capacity CO
2To saturated, get CO
2Saturated water for injection 875ml is for subsequent use;
(2) the 125g vitamin C bulk pharmaceutical is dissolved in the CO that 744ml step (1) obtains
2Stirring and dissolving in the saturated water for injection, gradation slowly add 43.75g NaHCO
3, add again 0.04375g EDTA and 1.875g NaHSO
3, stir, regulate pH value to 6.0-6.2, add remaining CO
2Saturated water for injection, recording pH value is 5.85-5.95, then is that content is qualified, enters next step;
(3) filter with the micropore sterilizing filter of 0.22 μ m, 100 ℃ of flowing steam sterilization 10min then are filled under the aseptic condition in the sterilization container, press half plug with container closure, prepare to be transferred in the freeze dryer;
(4) measure eutectic point: from the filtrate of step (2), take out a part as sample, a pair of platinum electrode is immersed wherein, sample is cooled to the low temperature below-40 ℃, then the speed with 1.5 ℃/min slowly heats up, in the process that heats up, measure its resistance with resistance bridge, temperature when resistance occurs to reduce suddenly is the eutectic point m that records, and records eutectic point m and is-19 ℃;
(5) regulate temperature to 6 ℃ in the drying box of freeze dryer, with step (2) fill the sterilization container of filtrate be transferred in the drying baker, keeps 6 ℃ temperature 0.8h, be cooled to again between-31 ℃ maintenance 0.8h;
(6) in the control drying baker vacuum degree control of the temperature of shelf in 10 ℃, the temperature of freeze-dried products maintain-24 ℃, drying baker between 0.12mbar, keep 18h until freeze-dried products without the visible ice crystal of naked eyes;
(7) vacuum of control in the drying baker is between 0.18mbar, and the freeze-dried products of step (5) is warming up to rapidly 32 ℃ with the speed of 25 ℃/min, recovers fine vacuum 1.333 * 10 behind the temperature stabilization
-1-1.333 * 10
-6Pa finishes lyophilizing behind the insulation 7h;
The goods that (8) will finish lyophilizing are preserved at the vacuum condition lower seal.
Embodiment 4:
Be prepared as follows the vitamin C lyophilized powder:
(1) gets fresh water for injection, pass into capacity CO
2To saturated, get CO
2Saturated water for injection 1250ml is for subsequent use;
(2) the 125g vitamin C bulk pharmaceutical is dissolved in the CO that 750ml step (1) obtains
2Stirring and dissolving in the saturated water for injection, gradation slowly add 62.5g NaHCO
3, add again 0.0625g EDTA and 2.5g NaHSO
3, stir, regulate pH value to 6.0-6.2, add remaining CO
2Saturated water for injection, recording pH value is 5.85-5.95, then is that content is qualified, enters next step;
(3) filter with the micropore sterilizing filter of 0.22 μ m, 100 ℃ of flowing steam sterilization 10min then are filled under the aseptic condition in the sterilization container, press half plug with container closure, prepare to be transferred in the freeze dryer;
(4) measure eutectic point: from the filtrate of step (2), take out a part as sample, a pair of platinum electrode is immersed wherein, sample is cooled to the low temperature below-40 ℃, then the speed with 0.2-2 ℃/min slowly heats up, in the process that heats up, measure its resistance with resistance bridge, temperature when resistance occurs to reduce suddenly is the eutectic point m that records, and records eutectic point m and is-18 ℃;
(5) regulate temperature to 2 ℃ in the drying box of freeze dryer, with step (2) fill the sterilization container of filtrate be transferred in the drying baker, keeps 2 ℃ temperature 3h, be cooled to again between-28 ℃ maintenance 3h;
(6) in the control drying baker vacuum degree control of the temperature of shelf in 10 ℃, the temperature of freeze-dried products maintain-23 ℃, drying baker at 0.1mbar, keep 20h until freeze-dried products without the visible ice crystal of naked eyes;
(7) vacuum of control in the drying baker is between 0.15mbar, and the freeze-dried products of step (5) is warming up to rapidly 35 ℃ with the speed of 30 ℃/min, recovers fine vacuum 1.333 * 10 behind the temperature stabilization
-1-1.333 * 10
-6Pa finishes lyophilizing behind the insulation 3h;
The goods that (8) will finish lyophilizing are preserved at the vacuum condition lower seal.
Embodiment 5:
Be prepared as follows the vitamin C lyophilized powder:
(1) gets fresh water for injection, pass into capacity CO
2To saturated, get CO
2Saturated water for injection 625ml is for subsequent use;
(2) the 125g vitamin C bulk pharmaceutical is dissolved in the CO that 562.5ml step (1) obtains
2Stirring and dissolving in the saturated water for injection, gradation slowly add 37.5g NaHCO
3, add again 0.0375g EDTA and 1.25g NaHSO
3, stir, regulate pH value to 6.0-6.2, add remaining CO
2Saturated water for injection, recording pH value is 5.85-5.95, then is that content is qualified, enters next step;
(3) filter with the micropore sterilizing filter of 0.22 μ m, 100 ℃ of flowing steam sterilization 30min then are filled under the aseptic condition in the sterilization container, press half plug with container closure, prepare to be transferred in the freeze dryer;
(4) measure eutectic point: from the filtrate of step (2), take out a part as sample, a pair of platinum electrode is immersed wherein, sample is cooled to the low temperature below-40 ℃, then the speed with 0.2-2 ℃/min slowly heats up, in the process that heats up, measure its resistance with resistance bridge, temperature when resistance occurs to reduce suddenly is the eutectic point m that records, and records eutectic point m and is-16 ℃;
(5) regulate temperature to 8 ℃ in the drying box of freeze dryer, with step (2) fill the sterilization container of filtrate be transferred in the drying baker, keeps 8 ℃ temperature 0.5h, be cooled to again between-36 ℃ maintenance 0.5h;
(6) in the control drying baker vacuum degree control of the temperature of shelf in 10 ℃, the temperature of freeze-dried products maintain-21 ℃, drying baker between 0.3mbar, keep 10h until freeze-dried products without the visible ice crystal of naked eyes;
(7) vacuum of control in the drying baker is between 0.3mbar, and the freeze-dried products of step (5) is warming up to rapidly 25 ℃ with the speed of 10 ℃/min, recovers fine vacuum 1.333 * 10 behind the temperature stabilization
-1-1.333 * 10
-6Pa finishes lyophilizing behind the insulation 10h;
The goods that (8) will finish lyophilizing are preserved at the vacuum condition lower seal.
Should be noted that and understand, in the situation that does not break away from the desired the spirit and scope of the present invention of accompanying claim, can make to the present invention of foregoing detailed description various modifications and improvement.Therefore, the scope of claimed technical scheme is not subjected to the restriction of given any specific exemplary teachings.
Applicant's statement, above content is the further description of the present invention being done in conjunction with concrete preferred implementation, can not assert that implementation of the present invention is confined to these explanations.For the general technical staff of the technical field of the invention, without departing from the inventive concept of the premise, can also make some simple deduction or replace, all should be considered as belonging to protection scope of the present invention.
Claims (10)
1. the preparation method of a vitamin C lyophilized powder is characterized in that, comprises the steps:
(1) gets water for injection, pass into CO
2To saturated, get the CO of vitamin C bulk pharmaceutical 5-10 times quality
2Saturated water for injection is for subsequent use;
(2) vitamin C bulk pharmaceutical is dissolved in the CO that the step (1) of 60wt%-90wt% obtains
2Stirring and dissolving in the saturated water for injection, gradation slowly add the NaHCO of vitamin C bulk pharmaceutical 0.3-0.5 times quality
3, add again the EDTA of vitamin C bulk pharmaceutical 0.0003-0.0005 times quality and the NaHSO of vitamin C bulk pharmaceutical 0.01-0.02 times quality
3, stir, regulate pH value to 6.0-6.2, add remaining CO
2Saturated water for injection, recording pH value is 5.85-5.95, then is that content is qualified, enters next step;
(3) filter with the micropore sterilizing filter of 0.22 μ m, 100 ℃ of flowing steam sterilization 10-30min then are filled under the aseptic condition in the sterilization container, press half plug with container closure, prepare to be transferred in the freeze dryer;
(4) measure eutectic point: from the filtrate of step (2), take out a part as sample, a pair of platinum electrode is immersed wherein, sample is cooled to the low temperature below-40 ℃, then slowly heat up, measure its resistance with resistance bridge in the process that heats up, the temperature when resistance occurs to reduce suddenly is the eutectic point m that records;
(5) regulate temperature in the drying box of freeze dryer to 2-8 ℃, with step (2) fill the sterilization container of filtrate be transferred in the drying baker, insulation, be cooled to again (m-20) ℃～(m-10) ℃ between, insulation;
(6) in the control drying baker vacuum degree control of the temperature of shelf in 10 ℃, the temperature of freeze-dried products maintain m-5 ℃, drying baker between 0.1-0.3mbar, keep a period of time until freeze-dried products without the visible ice crystal of naked eyes;
(7) vacuum of control in the drying baker is between 0.15-0.3mbar, and the freeze-dried products of step (5) is warming up to rapidly 25-35 ℃, recovers fine vacuum behind the temperature stabilization, finishes lyophilizing behind the insulation 3-10h;
The goods that (8) will finish lyophilizing are preserved at the vacuum condition lower seal.
2. the preparation method of vitamin C lyophilized powder according to claim 1 is characterized in that, CO described in the described step (1)
2The amount of saturated water for injection is 7-9 times of vitamin C bulk pharmaceutical quality; Be preferably 8 times.
3. the preparation method of vitamin C lyophilized powder according to claim 1 and 2 is characterized in that, vitamin C bulk pharmaceutical described in the described step (2) is dissolved in the CO of step (1) acquisition of 75wt%-85wt%
2In the saturated water for injection; Be preferably the CO of step (1) acquisition that is dissolved in 80wt%
2In the saturated water for injection;
Preferably, described gradation is 2-5 time; Most preferably be 3 times;
Preferably, described NaHCO
3Addition be the vitamin C bulk pharmaceutical quality 0.35-0.45 doubly; Most preferably be 0.4 times;
Preferably, the addition of described EDTA be the vitamin C bulk pharmaceutical quality 0.00035-0.00045 doubly; Most preferably be 0.0004 times;
Preferably, described NaHSO
3Addition be the vitamin C bulk pharmaceutical quality 0.015-0.018 doubly; Most preferably be 0.016 times.
4. one of according to claim 1-3 the preparation method of described vitamin C lyophilized powder is characterized in that sterilization time is 10-20min described in the described step (3); Be preferably 15min.
5. one of according to claim 1-4 the preparation method of described vitamin C lyophilized powder is characterized in that, slowly heating up described in the described step (4) refers to heat up with the speed of 0.2-2 ℃/min; The speed that is preferably with 0.5-1.5 ℃/min heats up; The speed that most preferably is with 1 ℃/min heats up;
Preferably, described resistance bridge AC-powered.
6. one of according to claim 1-5 the preparation method of described vitamin C lyophilized powder is characterized in that, the temperature in the drying baker described in the described step (5) is 4-6 ℃; Be preferably 5 ℃;
Preferably, the time of described insulation is 0.5-3h; Be preferably 0.8-1.5h; Most preferably be 1h.
7. one of according to claim 1-6 the preparation method of described vitamin C lyophilized powder is characterized in that vacuum degree control is between 0.12-0.22mbar described in the described step (6); Be preferably 0.15mbar;
Preferably, described maintenance a period of time is for keeping 10-20h; More preferably keep 12-18h; Most preferably be and keep 15h.
8. one of according to claim 1-7 the preparation method of described vitamin C lyophilized powder is characterized in that vacuum is between 0.18-0.28mbar described in the described step (7); Be preferably 0.25mbar;
Preferably, described rapid intensification refers to heat up with the speed of 10-30 ℃/min; More preferably the speed with 15-25 ℃/min heats up; The speed that most preferably is with 20 ℃/min heats up;
Preferably, described intensification is for rising to 28-32 ℃; Most preferably be and be warming up to 30 ℃;
Preferably, described fine vacuum refers to that low vacuum is in 1.333 * 10
-1-1.333 * 10
-6Pa;
Preferably, the time of described insulation is 4-7h; Most preferably be 5h;
Preferably, determine as follows the opportunity of described end lyophilizing: close the drying baker of freeze dryer and the valve 30-60s between the condenser, the pressure changing in the case that sees drying.If the pressure in the drying baker, then illustrates drying less than significantly raising and substantially finishes, can finish lyophilizing.If the pressure in the drying baker is increased significantly, then explanation also has moisture content to overflow, and time expand proceed drying, until close after the valve between drying baker and the condenser pressure in the drying baker without obviously rising.
9. one of according to claim 1-8 the preparation method of described vitamin C lyophilized powder is characterized in that, comprises the steps:
(1) gets water for injection, pass into CO
2To saturated, get the CO of vitamin C bulk pharmaceutical 5-10 times quality
2Saturated water for injection is for subsequent use;
(2) vitamin C bulk pharmaceutical is dissolved in the CO that the step (1) of 60wt%-90wt% obtains
2Stirring and dissolving in the saturated water for injection, gradation slowly add the NaHCO of vitamin C bulk pharmaceutical 0.3-0.5 times quality
3, add again the EDTA of vitamin C bulk pharmaceutical 0.0003-0.0005 times quality and the NaHSO of vitamin C bulk pharmaceutical 0.01-0.02 times quality
3, stir, regulate pH value to 6.0-6.2, add remaining CO
2Saturated water for injection, recording pH value is 5.85-5.95, then is that content is qualified, enters next step;
(3) filter with the micropore sterilizing filter of 0.22 μ m, 100 ℃ of flowing steam sterilization 10-30min then are filled under the aseptic condition in the sterilization container, press half plug with container closure, prepare to be transferred in the freeze dryer;
(4) measure eutectic point: from the filtrate of step (2), take out a part as sample, a pair of platinum electrode is immersed wherein, sample is cooled to the low temperature below-40 ℃, then the speed with 0.2-2 ℃/min slowly heats up, measure its resistance with resistance bridge in the process that heats up, the temperature when resistance occurs to reduce suddenly is the eutectic point m that records;
(5) regulate temperature in the drying box of freeze dryer to 2-8 ℃, with step (2) fill the sterilization container of filtrate be transferred in the drying baker, keeps 2-8 ℃ temperature 0.5-3h, be cooled to again (m-20) ℃～(m-10) ℃ between, maintenance 0.5-3h;
(6) in the control drying baker vacuum degree control of the temperature of shelf in 10 ℃, the temperature of freeze-dried products maintain m-5 ℃, drying baker between 0.1-0.3mbar, keep 10-20h until freeze-dried products without the visible ice crystal of naked eyes;
(7) vacuum of control in the drying baker is between 0.15-0.3mbar, and the freeze-dried products of step (5) is warming up to rapidly 25-35 ℃ with the speed of 10-30 ℃/min, recovers fine vacuum 1.333 * 10 behind the temperature stabilization
-1-1.333 * 10
-6Pa finishes lyophilizing behind the insulation 3-10h;
The goods that (8) will finish lyophilizing are preserved at the vacuum condition lower seal;
Preferably, described preparation method comprises the steps:
(1) gets water for injection, pass into CO
2To saturated, get the CO of vitamin C bulk pharmaceutical 7-9 times quality
2Saturated water for injection is for subsequent use;
(2) vitamin C bulk pharmaceutical is dissolved in the CO that the step (1) of 75wt%-85wt% obtains
2Stirring and dissolving in the saturated water for injection, gradation slowly add the NaHCO of vitamin C bulk pharmaceutical 0.35-0.45 times quality
3, add again the EDTA of vitamin C bulk pharmaceutical 0.00035-0.00045 times quality and the NaHSO of vitamin C bulk pharmaceutical 0.015-0.018 times quality
3, stir, regulate pH value to 6.0-6.2, add remaining CO
2Saturated water for injection, recording pH value is 5.85-5.95, then is that content is qualified, enters next step;
(3) filter with the micropore sterilizing filter of 0.22 μ m, 100 ℃ of flowing steam sterilization 10-20min then are filled under the aseptic condition in the sterilization container, press half plug with container closure, prepare to be transferred in the freeze dryer;
(4) measure eutectic point: from the filtrate of step (2), take out a part as sample, a pair of platinum electrode is immersed wherein, sample is cooled to the low temperature below-40 ℃, then the speed with 0.5-1.5 ℃/min slowly heats up, measure its resistance with resistance bridge in the process that heats up, the temperature when resistance occurs to reduce suddenly is the eutectic point m that records;
(5) regulate temperature in the drying box of freeze dryer to 4-6 ℃, with step (2) fill the sterilization container of filtrate be transferred in the drying baker, keeps 4-6 ℃ temperature 0.8-1.5h, be cooled to again (m-18) ℃～(m-12) ℃ between, maintenance 0.8-1.5h;
(6) in the control drying baker vacuum degree control of the temperature of shelf in 10 ℃, the temperature of freeze-dried products maintain m-5 ℃, drying baker between 0.12-0.22mbar, keep 12-18h until freeze-dried products without the visible ice crystal of naked eyes;
(7) vacuum of control in the drying baker is between 0.18-0.28mbar, and the freeze-dried products of step (5) is warming up to rapidly 28-32 ℃ with the speed of 15-25 ℃/min, recovers fine vacuum 1.333 * 10 behind the temperature stabilization
-1-1.333 * 10
-6Pa finishes lyophilizing behind the insulation 4-7h;
The goods that (8) will finish lyophilizing are preserved at the vacuum condition lower seal.
10. one of according to claim 1-9 the preparation method of described vitamin C lyophilized powder is characterized in that, comprises the steps:
(1) gets water for injection, pass into CO
2To saturated, get the CO of 8 times of quality of vitamin C bulk pharmaceutical
2Saturated water for injection is for subsequent use;
(2) vitamin C bulk pharmaceutical is dissolved in the CO that the step (1) of 80wt% obtains
2Stirring and dissolving in the saturated water for injection, gradation slowly add the NaHCO of 0.4 times of quality of vitamin C bulk pharmaceutical
3, add again the EDTA of 0.0004 times of quality of vitamin C bulk pharmaceutical and the NaHSO of 0.016 times of quality of vitamin C bulk pharmaceutical
3, stir, regulate pH value to 6.0-6.2, add remaining CO
2Saturated water for injection, recording pH value is 5.85-5.95, then is that content is qualified, enters next step;
(3) filter with the micropore sterilizing filter of 0.22 μ m, 100 ℃ of flowing steam sterilization 15min then are filled under the aseptic condition in the sterilization container, press half plug with container closure, prepare to be transferred in the freeze dryer;
(4) measure eutectic point: from the filtrate of step (2), take out a part as sample, a pair of platinum electrode is immersed wherein, sample is cooled to the low temperature below-40 ℃, then the speed with 1 ℃/min slowly heats up, measure its resistance with resistance bridge in the process that heats up, the temperature when resistance occurs to reduce suddenly is the eutectic point m that records;
(5) regulate temperature to 5 ℃ in the drying box of freeze dryer, with step (2) fill the sterilization container of filtrate be transferred in the drying baker, keeps 5 ℃ temperature 1h, be cooled to again (m-15) ℃, maintenance 1h;
(6) in the control drying baker vacuum degree control of the temperature of shelf in 10 ℃, the temperature of freeze-dried products maintain m-5 ℃, drying baker between 0.15mbar, keep 15h until freeze-dried products without the visible ice crystal of naked eyes;
(7) vacuum of control in the drying baker is at 0.25mbar, and the freeze-dried products of step (5) is warming up to rapidly 30 ℃ with the speed of 20 ℃/min, recovers fine vacuum 1.333 * 10 behind the temperature stabilization
-1-1.333 * 10
-6Pa finishes lyophilizing behind the insulation 5h;
The goods that (8) will finish lyophilizing are preserved at the vacuum condition lower seal.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012104456368A CN102920670A (en) | 2012-11-09 | 2012-11-09 | Preparation method of vitamin C freeze-dried powder |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012104456368A CN102920670A (en) | 2012-11-09 | 2012-11-09 | Preparation method of vitamin C freeze-dried powder |
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| CN102920670A true CN102920670A (en) | 2013-02-13 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109187781A (en) * | 2018-09-03 | 2019-01-11 | 美康生物科技股份有限公司 | Serotype freeze-dried powder 25-hydroxyvitamin D3 and D2 quality control substance matter and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999043342A1 (en) * | 1998-02-28 | 1999-09-02 | Lg Chemical Ltd. | Somatotropin compositions mixed with vitamins |
| CN1830438A (en) * | 2005-03-08 | 2006-09-13 | 阿尔贝拉医药控股(通化)有限公司 | Preparation method of vitamin C freeze dried powder injection |
| CN1843362A (en) * | 2006-04-30 | 2006-10-11 | 贵阳云岩西创药物科技开发有限公司 | Composite vitamin injection and its preparation method |
-
2012
- 2012-11-09 CN CN2012104456368A patent/CN102920670A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999043342A1 (en) * | 1998-02-28 | 1999-09-02 | Lg Chemical Ltd. | Somatotropin compositions mixed with vitamins |
| CN1830438A (en) * | 2005-03-08 | 2006-09-13 | 阿尔贝拉医药控股(通化)有限公司 | Preparation method of vitamin C freeze dried powder injection |
| CN1843362A (en) * | 2006-04-30 | 2006-10-11 | 贵阳云岩西创药物科技开发有限公司 | Composite vitamin injection and its preparation method |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109187781A (en) * | 2018-09-03 | 2019-01-11 | 美康生物科技股份有限公司 | Serotype freeze-dried powder 25-hydroxyvitamin D3 and D2 quality control substance matter and preparation method thereof |
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Application publication date: 20130213 |