CN102429942B - Freeze-drying method of pseudo-ginseng total saponin freeze-dried injection powder with filling amount more than 500 mg - Google Patents
Freeze-drying method of pseudo-ginseng total saponin freeze-dried injection powder with filling amount more than 500 mg Download PDFInfo
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Abstract
The invention relates to a freeze-drying method of pseudo-ginseng total saponin freeze-dried injection powder with a filling amount more than 500 mg. In the method, freeze-dried is carried out mainly through specific refrigerating parameters. The freeze-drying method provided by the invention has good drying effect and significantly shortened freeze-drying time, which is 20-50% of common freeze-drying time.
Description
Technical field
The present invention relates to field of medicine preparations, be specifically related to the freeze-drying method of the notoginsen triterpenes freeze-dried powder pin of the above loading amount of a kind of 500mg.
Background technology
Cryodesiccated the studying in great detail there are no open source literature of notoginsen triterpenes freeze-dried powder pin for 500mg and the above loading amount of 500mg reported, freeze drying process routinely, the Radix Notoginseng total arasaponins freeze-drying time of 500mg loading amount is more than 50 hours, and the shortest also needed about 40 hours.Below some Chinese medicines relevant with Freeze Drying Technique, preparation technology's document of Western medicine lyophilized injectable powder.
Chinese patent application 96101652.3 relates to a kind of medicine of the special form that is used for the treatment of cardiovascular and cerebrovascular disease, and lyophilizing finished product loading amount is 100mg, and application content does not provide concrete freezing method and condition.
Chinese patent application 200610010988.5 is write exactly in holding therein, by the Radix Notoginseng total arasaponins extracting solution subpackage after filtering, send into frozen vacuum dryer, be quickly cooled to-36～-39 ℃, 2-5 hour, is progressively slowly warming up to 39-48 ℃ (approximately needing 23 hours), takes out goods, roll lid, packing, check, obtain freeze-dried powder finished product.This lyophilizing finished product loading amount is between 100-800mg, and this patent has been used mannitol as adjuvant at freeze-drying process.
Chinese patent application 200910000859.1 relates to a kind of notoginsen triterpenes freeze-dried powder and preparation method thereof, in this patent, Radix Notoginseng total arasaponins is dissolved in 75 ℃ of waters for injection, stirring makes its dissolving, add again sodium chloride, after dissolving, add mannitol, be stirred to completely and dissolve, add medicinal charcoal to boil 15 minutes, filter, filtrate injects water to 2000ml, regulate pH value to 6.5-7.0, after sampling detection is qualified, fine straining, with 0.22 μ m filter circulating filtration, detect qualified after, fill, half tamponade, send into frozen vacuum dryer, first be chilled to fast-37～39 ℃, insulation 0.5-2 hour, then progressively heat up, sublimation drying, reach 22-28 ℃ to finished product temperature, tamponade, take out goods, roll lid.This lyophilizing finished product loading amount is 200,400mg, and this patent has been used mannitol as adjuvant at freeze-drying process equally.
In Chinese patent application 200710065619.0, disclosing Freeze Drying Technique comprises the steps: Radix Notoginseng total arasaponins mixed liquor to send into frozen vacuum dryer, be chilled to fast-40 ℃, keep 2-4 hour, be evacuated to below about 1Pa, progressively slowly be warming up to 30-40 ℃, insulation 2-4 hour.This lyophilizing finished product loading amount is 400-600mg, and this patent has been used mannitol as adjuvant at freeze-drying process equally.
It is as follows that Chinese patent application 200710178553.6 discloses Freeze Drying Technique: get Radix Notoginseng total arasaponins powder and lactose at 10: 1 with weight proportion, be dissolved in water for injection, add 0.5% activated carbon decolorizing, respectively with silk, the microporous filter membrane of 0.45 μ m and 0.2 μ m filters, filtrate injects water to by Radix Notoginseng total arasaponins 0.20g/ml, regulate pH value to 5.5, 0.2 μ m filtering with microporous membrane, subpackage, carry out lyophilization, first be quickly cooled to-38 ℃, be incubated 1 hour, then progressively heat up, sublimation drying, reach 25 ℃ to finished product temperature, lyophilizing finishes, omnidistance 15 hours.The loading amount of the not clear and definite lyophilizing finished product of this patent.
The adjuvants such as aminoacid, glucose, lactose, mannitol, polyvinylpyrrolidone, low molecular dextran, sodium chloride, calcium gluconate or calcium phosphate in above-mentioned document, in the composition of disclosed notoginsen triterpenes freeze-dried powder pin, are added, its freezing dry process all, more than 20 hours, even reaches 60 hours.Although although patent application 200710178553.6 time used shorter (between 14-19 hour), because it has added the caffolding agent of lactose as freeze-drying process, makes final finished also contain lactose except Radix Notoginseng total arasaponins.
The safety issue of injection exposes a lot of problems in recent years, uses the adjuvant outside medicine in injection, can cause sufferer in therapeutic process, to have to accept how unnecessary material simultaneously and enter blood, has buried hidden danger for producing untoward reaction; And in preparation method, produce power consumption greatly, the turnaround time is long.
For the problem existing in existing freeze-drying method, inventor, through a large amount of research, has finally proposed the present invention.
Summary of the invention
The object of this invention is to provide the freeze-drying method of the notoginsen triterpenes freeze-dried powder pin of the above loading amount of a kind of 500mg.
The freeze-drying method of the notoginsen triterpenes freeze-dried powder pin of the above loading amount of 500mg provided by the invention, comprises the following steps:
Getting concentration is the Radix Notoginseng total arasaponins aqueous solution of 10.0-25.0% (g/ml), and subpackage is put into freeze drying equipment:
1) pre-freeze and thermal balance: start compressor, be located in 0.25-1h temperature in freeze drying equipment is down to-10 ℃, and maintain 0.5-1.5h;
2) freeze and system balancing: after heat release finishes, be located in 0.25h-1h temperature in freeze drying equipment is down to below-30 ℃, temperature is down to temperature in freeze drying equipment below-45 ℃ after arriving-30 ℃ in 0.5-1.0h; Control pressure in freeze drying equipment to 10Pa and maintain 1.0-2.0h;
3) distillation early stage: establish in freeze drying equipment temperature and maintain below 10Pa for-4 ℃ and vacuum, insulation 4-6h;
4) the distillation later stage: adjustment vacuum is 50 ± 30Pa, and maintain the interior temperature of freeze drying equipment at-4 ℃, continue insulation 6-9h;
5) resolve: after distillation finishes, establishing temperature in freeze drying equipment is 35 ℃-50 ℃, maintains 4-6h, and to adjust vacuum be 35 ± 20Pa;
6) when 35 ℃ and at least two product temperatures probes of temperature arrival in freeze drying equipment exceed after 25 ℃, the pressure of controlling in freeze drying equipment recovers 10Pa below and keeps, after 1h, obtaining freeze-dried powder.
Preferably, the freeze-drying method of the notoginsen triterpenes freeze-dried powder pin of the above loading amount of 500mg provided by the invention comprises the following steps:
Radix Notoginseng total arasaponins is prepared into the Radix Notoginseng total arasaponins aqueous solution that concentration is 10-25.0% (g/ml) with water for injection, subpackage, put into freeze drying equipment:
1) pre-freeze and thermal balance: start compressor, be located in 0.75h temperature in freeze drying equipment is dropped to-10 ℃, and maintain 0.5h;
2) freeze and system balancing: after heat release finishes, be located in 0.75h temperature in freeze drying equipment is down to below-30 ℃, temperature is down to temperature in freeze drying equipment below-45 ℃ after arriving-30 ℃ in 0.75h; Then control pressure in freeze drying equipment to 10Pa and maintain 1.5h;
3) distillation early stage: establish temperature in freeze drying equipment and be-4 ℃, and vacuum maintains below 10Pa, be incubated 5h;
4) the distillation later stage: adjustment vacuum is 50 ± 30Pa, and maintain the interior temperature of freeze drying equipment at-4 ℃, continue insulation 7.5h;
5) resolve: after distillation finishes, establishing temperature in freeze drying equipment is 35 ℃-50 ℃, maintains 5h, and to adjust vacuum be 25 ± 10Pa;
6) when 35 ℃ and at least two product temperatures probes of temperature arrival in freeze drying equipment exceed after 25 ℃, the pressure of controlling in freeze drying equipment recovers 10Pa below and keeps after 1h, packs.
In said method:
Described Radix Notoginseng total arasaponins can be by commercially available purchase, or prepares by conventional method, or preparation by the following method: Radix Notoginseng ethanol extraction, after extracting solution is concentrated, cross post, water, ethanol elution, collect ethanol elution, decolouring, collects the effluent after decolouring, refining, reclaim ethanol extremely without alcohol taste, it is 1.06-1.10 that filtrate is concentrated into relative density, dry, to obtain final product.
Described heat release refers to that solution is crossed and is as cold as after freezing point, and after producing nucleus in it, Free water just can start the form crystallization with ice, emits crystallization heat simultaneously and makes its temperature rise to freezing point, and the process of emitting crystallization heat is exactly exothermic process.
Described step 4) and 5) control method: adjust when vacuum, by opening air inlet from air vent opposite tank wall, make in case steam obtain external force and promote, accelerating steam discharges, thereby raising rate of drying, in this operating process, not exclusively destroys vacuum.
Described distillation refers to that moisture content in Radix Notoginseng total arasaponins concentrated solution is from the solid-state process that directly changes gaseous state without liquid state in the present invention.
Step 6) method of testing of described pressure is that pressure rises method of testing, is specially: in closing, every valve 120 seconds, control the pressure in freeze drying equipment; in 120 seconds, rise and be no more than 0.8Pa; confirm substantially anhydrous point of evaporation of product, pressure rises after test passes, shuts down.
The present invention also provides a kind of 500mg notoginsen triterpenes freeze-dried powder pin of above loading amount, is prepared from by following methods:
1) get Radix Notoginseng powder and be broken into coarse powder, 2-20 times of 50-95% ethanol heating extraction of use Radix Notoginseng volume 2-5 time, each 1-5 hour, merge extractive liquid,, filters, and filtrate recycling ethanol concentrating under reduced pressure are made every 1ml containing the about 0.1-1g of crude drug;
2) add 0.5-1.5% sodium chloride by concentrated solution volume, stir evenly, leave standstill 12-36 hour, filter;
3) filtrate, after ungrease treatment, is crossed macroporous adsorptive resins take flow velocity as 0.5-15BV/h, washes with water, and water lotion discards, and continues with 40-80% different concentration ethanol liquid eluting, collects eluent;
4) effluent pressurization is by neutral alumina column (the intrinsic pressure 1-100kg/cm of post of the 10-150% of medical material amount
2, flow velocity is 0.5-15BV/h), collect effluent;
5) effluent is refining, reclaim ethanol extremely without alcohol taste, it is 1.06-1.10 (50 ℃) that filtrate is concentrated into relative density, dry, adding water and making the concentration of Radix Notoginseng total arasaponins aqueous solution in solution is 5.0-25.0% (g/ml), then according to loading amount subpackage, put into freeze drying equipment:
Pre-freeze and thermal balance: start compressor, be located in 0.25-1h temperature in freeze drying equipment is down to-10 ℃, and maintain 0.5-1.5h;
Freeze and system balancing: after heat release finishes, be located in 0.25-1h temperature in freeze drying equipment is down to below-30 ℃, temperature is down to temperature in freeze drying equipment below-45 ℃ after arriving-30 ℃ in 0.5-1.0h; Then control pressure in freeze drying equipment to 10Pa and maintain 1.0-2.0h;
Distillation early stage: establish temperature in freeze drying equipment and be-4 ℃, and vacuum maintains below 10Pa, be incubated 4-6h;
The distillation later stage: adjustment vacuum is 50 ± 30Pa, and maintain the interior temperature of freeze drying equipment at-4 ℃, continue insulation 6-9h;
Resolve: after distillation finishes, establishing temperature in freeze drying equipment is 35 ℃-50 ℃, maintains 4-6h, and to adjust vacuum be 35 ± 10Pa;
When 35 ℃ and at least two product temperatures probes of temperature arrival in freeze drying equipment exceed after 25 ℃, the pressure of controlling in freeze drying equipment recovers 10Pa below and keeps, after 1h, obtaining final product.
In said method:
Described Radix Notoginseng is Radix Notoginseng main root and/or Radix Notoginseng reed head.
Described step 3) in the type of macroporous adsorbent resin used be D101, D201, AB-8 or NKA-9 etc.
BV is the multiple of column volume.
The freeze-drying method of notoginsen triterpenes freeze-dried powder pin provided by the invention has the following advantages:
1, the time of freeze-drying process is very short: in Radix Notoginseng total arasaponins freezing dry process, increase convection current steam, shortened the drying time of Radix Notoginseng total arasaponins.
The experiment proved that, when low vacuum in case is during in 10Pa, unfavorable to conducting heat, product is difficult for obtaining heat, and rate of sublimation reduces on the contrary.But when vacuum is during higher than 100Pa, in product, the rate of sublimation of ice slows down, minimizing falls in product caloric receptivity.Therefore, the present invention is in the distillation later stage and resolve injecting gas, and vacuum degree control, between 10-80Pa, had not only been beneficial to the transmission of heat but also had been beneficial to the carrying out of distillation, has shortened exponentially freeze-drying time.
2, solubility is good: notoginsen triterpenes freeze-dried powder pin provided by the invention, and the redissolution time is short, in 1 minute, can all dissolve;
3, water content is low: in prior art, the water content of notoginsen triterpenes freeze-dried powder pin is between 3.0-5.5%, and freeze-dried powder water content provided by the invention is below 2%, even can reach 1% water content;
4, outward appearance forming: the invention provides notoginsen triterpenes freeze-dried powder pin mode of appearance hole loosely, there is spongy bulk structure, without duricrust, atrophy, subside, the phenomenon such as ash is loose.
5, compared with existing Freeze Drying Technique, the former freeze-drying time of the above loading amount of 500mg needs more than 50 hours, the freezing dry process of Radix Notoginseng total arasaponins of the present invention does not need to add adjuvant or caffolding agent, only need within 15-30 hour, can reach identical drying effect, make can only produce for former every 2-3 days and within a collection of 1-1.5 of rising to days, can produce a collection ofly, efficiency improves more than 50%.In addition, because shorten drying time, more than 50% expenditure also can be saved in energy consumption aspect, has significant economic benefit and social benefit.
6, in existing Chinese patent application 200710178553.6, disclose the embodiment that minimum use lyophilizing in 14 hours completes, but had the adjuvants such as lactose in this freeze-dried powder, need to assist to shorten freeze-drying time by foreign object.
The specific embodiment
Following examples are used for illustrating the present invention, but are not used for limiting the scope of the invention.
Radix Notoginseng total arasaponins provided by the invention can, by buying on market, also can be prepared, and the invention provides its preparation method, but should not limit Radix Notoginseng total arasaponins, the preparation method of Radix Notoginseng total arasaponins concentrated solution:
Radix Notoginseng powder is broken into coarse powder, with ethanol extraction 5 times, add 50% ethanol of 2 times of amounts of three seven weight, each 1 hour extraction time at every turn, merge extractive liquid,, filter, filtrate recycling ethanol concentrating under reduced pressure, make the concentrated solution of every 1ml containing the about 0.1g of crude drug, then add 0.5% sodium chloride of concentrated solution volume, stir evenly, leave standstill 12 hours, filter;
Filtrate, after ungrease treatment, is crossed D101 macroporous adsorptive resins take flow velocity as 0.5BV/h, wash with water, and water lotion discards; Then use successively 40%, 50%, 60%, 70%, 80% ethanol gradient elution, collect eluent.
(post is intrinsic pressure is 100kg/cm to Radix Notoginseng total arasaponins eluent pressurization 150% the neutral alumina column by medical material amount weight
2, flow velocity is 15BV/h), collect effluent.Effluent is refining, reclaims ethanol extremely without alcohol taste, and it is 1.03-1.10 (50 ℃) that filtrate is concentrated into relative density, dry, pulverize, and obtains Radix Notoginseng total arasaponins.
The notoginsen triterpenes freeze-dried powder pin of embodiment 1:500mg loading amount
Method: Radix Notoginseng total arasaponins is dissolved with water for injection, and the concentration that makes Radix Notoginseng total arasaponins in solution is 10.0% (g/ml), then according to 500mg loading amount subpackage, every bottle of fill 5ml, puts in freeze dryer:
1) pre-freeze and thermal balance: start compressor, be located in 0.75h lyophilizing built-in temperature is down to-10 ℃, and maintain 0.5h;
2) freeze and system balancing: after heat release finishes, be located in 0.75h lyophilizing built-in temperature is down to below-30 ℃, temperature is down to lyophilizing built-in temperature below-45 ℃ after arriving-30 ℃ in 0.75h; Control freeze dryer internal pressure to 10Pa and maintain 1.5h;
3) distillation early stage: establish lyophilizing built-in temperature and be-4 ℃, and vacuum maintains below 10Pa, be incubated 5h;
4) in the distillation later stage: adjustment vacuum is 50 ± 30Pa, and maintains lyophilizing built-in temperature at-4 ℃, continue insulation 7.5h;
5) resolve: after distillation finishes, establishing lyophilizing built-in temperature is 35 ℃, maintains 5h, and to adjust vacuum be 25 ± 10Pa.
6) when lyophilizing built-in temperature arrives 35 ℃, and at least two product temperatures probe exceedes after 25 ℃, controls that in freeze dryer, to recover 10Pa following and keep after 1h, carries out pressure and rises test, shuts down, and packing, obtains panax notoginseng saponins freeze-dried powder injection.
22.75 hours consuming time of freezing dry process.
The notoginsen triterpenes freeze-dried powder pin of embodiment 2:600mg loading amount
Method: Radix Notoginseng total arasaponins is dissolved with water for injection, and the concentration that makes Radix Notoginseng total arasaponins in solution is 12.0% (g/ml), and according to 600mg loading amount subpackage, every bottle of fill 5ml, puts in freeze dryer.
1) pre-freeze and thermal balance: start compressor, be located in 0.25h lyophilizing built-in temperature is dropped to-10 ℃, and maintain 1h;
2) freeze and system balancing: after heat release finishes, be located in 0.25h lyophilizing built-in temperature is down to below-30 ℃, temperature will be cooled in freeze dryer below-45 ℃ after arriving-30 ℃ in 0.5h; Control in freeze dryer to 10Pa and maintain 1h;
3) distillation early stage: establish lyophilizing built-in temperature and be-4 ℃, and vacuum maintains below 10Pa, be incubated 4h;
4) in the distillation later stage: adjustment vacuum is 50 ± 30Pa, and maintains lyophilizing built-in temperature at-4 ℃, continue insulation 6h;
5) resolve: after distillation finishes, establishing lyophilizing built-in temperature is 50 ℃, maintains 4h, and to adjust vacuum be 35 ± 20Pa;
6) when lyophilizing built-in temperature arrives 35 ℃, and at least two product temperatures probe exceedes after 25 ℃, and controlling freeze dryer internal pressure, to recover 10Pa following and keep after 1h, carries out pressure and rise test, shuts down, and packing, obtains panax notoginseng saponins freeze-dried powder injection.
18 hours consuming time of freezing dry process.
The notoginsen triterpenes freeze-dried powder pin of embodiment 3:700mg loading amount
Method: Radix Notoginseng total arasaponins is dissolved with water for injection, and the concentration that makes Radix Notoginseng total arasaponins in solution is 14.0% (g/ml), and according to 700mg loading amount subpackage, every bottle of fill 5ml, puts in freeze dryer.
1) pre-freeze and thermal balance: start compressor, be located in 0.5h lyophilizing built-in temperature is dropped to-10 ℃, and maintain 0.75h;
2) freeze and system balancing: after heat release finishes, be located in 0.3h lyophilizing built-in temperature is down to below-30 ℃, temperature will be cooled in freeze dryer below-45 ℃ after arriving-30 ℃ in 1h; Control pressure in freeze dryer to 10Pa and maintain 1.3h;
3) distillation early stage: establish lyophilizing built-in temperature and be-4 ℃, and vacuum maintains below 10Pa, be incubated 5.5h;
4) in the distillation later stage: adjustment vacuum is 50 ± 30Pa, and maintains lyophilizing built-in temperature at-4 ℃, continue insulation 6.5h;
5) resolve: after distillation finishes, establishing lyophilizing built-in temperature is 45 ℃, maintains 6h, and to adjust vacuum be 30 ± 10Pa.
6) when lyophilizing built-in temperature arrives 35 ℃, and at least two product temperatures probe exceedes after 25 ℃, and controlling freeze dryer internal pressure, to recover 10Pa following and keep after 1h, carries out pressure and rise test, shuts down, and packing, obtains panax notoginseng saponins freeze-dried powder injection.
22.85 hours consuming time of freezing dry process.
The notoginsen triterpenes freeze-dried powder pin of embodiment 4:800mg loading amount
Radix Notoginseng total arasaponins is dissolved with water for injection, and making Radix Notoginseng total arasaponins concentration in solution is 20.0% (g/ml), and according to 800mg loading amount subpackage, every bottle of fill 4ml, puts in freeze dryer.
1) pre-freeze and thermal balance: start compressor, be located in 0.6h lyophilizing built-in temperature is dropped to-10 ℃, and maintain 1.3h;
2) freeze and system balancing: after heat release finishes, be located in 0.5h lyophilizing built-in temperature is down to below-30 ℃, temperature will be cooled in freeze dryer below-45 ℃ after arriving-30 ℃ in 0.8h; Control freeze dryer internal pressure to 10Pa and maintain 1.8h;
3) distillation early stage establish lyophilizing built-in temperature and be-4 ℃, and vacuum maintains below 10Pa, be incubated 4.5h;
4) in the distillation later stage: adjustment vacuum is 50 ± 30Pa, and maintains lyophilizing built-in temperature at-4 ℃, continue insulation 8.5h;
5) resolve: after distillation finishes, establishing lyophilizing built-in temperature is 40 ℃, maintains 5.5h, and to adjust vacuum be 25 ± 10Pa.
6) when 35 ℃ and at least two product temperatures probes of lyophilizing built-in temperature arrival exceed after 25 ℃, control freeze dryer internal pressure and recover 10Pa below and keep after 1h, carry out the test of pressure liter, shut down, packing, obtains panax notoginseng saponins freeze-dried powder injection.
24.5 hours consuming time of freezing dry process.
The notoginsen triterpenes freeze-dried powder pin of embodiment 5:900mg loading amount
Method: Radix Notoginseng total arasaponins is dissolved with water for injection, and making Radix Notoginseng total arasaponins concentration in solution is 18.0% (g/ml), and according to 900mg loading amount subpackage, every bottle of fill 5ml, puts in freeze dryer.
1) pre-freeze and thermal balance: start compressor, be located in 0.4h lyophilizing built-in temperature is dropped to-10 ℃, and maintain 6h;
2) freeze and system balancing: after heat release finishes, be located in 0.6h lyophilizing built-in temperature is down to below-30 ℃, temperature will be cooled in freeze dryer below-45 ℃ after arriving-30 ℃ in 0.6h; Control freeze dryer internal pressure to 10Pa and maintain 1.1h;
3) distillation early stage: establish lyophilizing built-in temperature and be-4 ℃, and vacuum maintains below 10Pa, be incubated 4.1h;
4) in the distillation later stage: adjustment vacuum is 50 ± 30Pa, and maintains lyophilizing built-in temperature at-4 ℃, continue insulation 6.2h;
5) resolve: after distillation finishes, establishing lyophilizing built-in temperature is 38 ℃, maintains 4.3h, and to adjust vacuum be 40 ± 5Pa.
6) when lyophilizing built-in temperature arrives 35 ℃, and at least two product temperatures probe exceedes after 25 ℃, and controlling freeze dryer internal pressure, to recover 10Pa following and keep after 1h, carries out pressure and rise test, shuts down, and packing, obtains panax notoginseng saponins freeze-dried powder injection.
18.9 hours consuming time of freezing dry process.
The freeze-drying method of the notoginsen triterpenes freeze-dried powder pin of embodiment 6:1000mg loading amount
Method: Radix Notoginseng total arasaponins is dissolved with water for injection, and making Radix Notoginseng total arasaponins concentration in solution is 25.0% (g/ml), and according to 1000mg loading amount subpackage, every bottle of fill 4ml, puts in freeze dryer.
1) pre-freeze and thermal balance: start compressor, be located in 1h lyophilizing built-in temperature is dropped to-10 ℃, and maintain 1.5h;
2) freeze and system balancing: after heat release finishes, be located in 1h temperature in lyophilizer is down to below-30 ℃, temperature will be cooled in freeze dryer below-45 ℃ after arriving-30 ℃ in 0.9h; Control freeze dryer internal pressure to 10Pa and maintain 2h;
3) distillation early stage: establish lyophilizing built-in temperature and be-4 ℃, and vacuum maintains below 10Pa, be incubated 6h;
4) in the distillation later stage: adjustment vacuum is 50 ± 30Pa, and maintains lyophilizing built-in temperature at-4 ℃, continue insulation 9h;
5) resolve: after distillation finishes, establishing lyophilizing built-in temperature is 43 ℃, maintains 5.8h, and to adjust vacuum be 25 ± 10Pa.
6) when 35 ℃ and at least two product temperatures probes of lyophilizing built-in temperature arrival exceed after 25 ℃, control freeze dryer internal pressure and recover 10Pa below and keep after 1h, carry out the test of pressure liter, shut down, packing, obtains panax notoginseng saponins freeze-dried powder injection.
28.2 hours consuming time of freezing dry process.
The freeze-drying method of comparative example 1:500mg notoginsen triterpenes freeze-dried powder pin
With reference to the embodiment 4 of Chinese patent application 200710178553.6.
Getting its Radix Notoginseng total arasaponins powder and lactose is 20: 1 according to weight proportion, be dissolved in water for injection, the concentration that obtains Radix Notoginseng total arasaponins is 15% (g/ml), add 0.5% medicinal charcoal decolouring, respectively with silk, the microporous filter membrane of 0.45 μ m and 0.2 μ m filters, filtrate injects water to by Radix Notoginseng total arasaponins 0.25g/ml, regulate pH value to 5.0, the filtering with microporous membrane of 0.2 μ m, carry out lyophilization, first be quickly cooled to-37 ℃, be incubated 2 hours, then progressively heat up, sublimation drying, to finished product temperature be 25 ℃, lyophilizing finishes, omnidistance 32 hours, after lyophilization, be ground into fine powder, then cross 100 mesh sieves, final point is filled in injection bottle made.
32 hours consuming time of freezing dry process.
Experimental example 1: the effect comparison of lyophilized powder
Radix Notoginseng total arasaponins lyophilization effect and content to embodiment 1-6 and comparative example 1 compare, and the results are shown in following table:
Table: the drying regime comparison of notoginsen triterpenes freeze-dried powder
| Sublimation drying (hour) | Solubility (second) | Water content (%) | |
| Embodiment 1 | 22.75 | 52 | 0.3 |
| Embodiment 2 | 18 | 47 | 0.7 |
| Embodiment 3 | 22.85 | 49 | 0.5 |
| Embodiment 4 | 24.5 | 53 | 0.6 |
| Embodiment 5 | 18.9 | 46 | 0.8 |
| Embodiment 6 | 28.2 | 50 | 0.4 |
| Comparative example 1 | 32 | 63 | 2.2 |
Upper table result shows: embodiment of the present invention 1-6 Radix Notoginseng total arasaponins freeze-drying time is less than comparative example 1, and solubility is fast, and water content is lower than comparative example 1, and importantly the embodiment of the present invention does not need to add the caffolding agent of any drying aid at freeze-drying process.
Although, above use general explanation, the specific embodiment and test, the present invention is described in detail, on basis of the present invention, can make some modifications or improvement to it, and this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (7)
1. a freeze-drying method for the notoginsen triterpenes freeze-dried powder pin of the above loading amount of 500mg, is characterized in that, said method comprising the steps of:
In g/ml, getting concentration is the Radix Notoginseng total arasaponins aqueous solution of 10.0-25.0%, and subpackage is put into freeze drying equipment:
1) pre-freeze and thermal balance: be located in 0.25h-1h temperature in freeze drying equipment is down to-10 ℃, and maintain 0.5-1.5h;
2) freeze and system balancing: after heat release finishes, be located in 0.25h-1.0h temperature in freeze drying equipment is down to below-30 ℃, after temperature arrives-30 ℃, in 0.5-1.0h, temperature in lyophilizer is down to below-45 ℃, then controls pressure in freeze drying equipment to 10Pa and maintain 1.0-2.0h;
3) distillation early stage: establish temperature in freeze drying equipment and be-4 ℃, and vacuum maintains below 10Pa, be incubated 4-6h;
4) the distillation later stage: adjustment vacuum is 50 ± 30Pa, and maintain the interior temperature of freeze drying equipment at-4 ℃, continue insulation 6-9h;
5) resolve: after distillation finishes, establishing temperature in freeze drying equipment is 35 ℃-50 ℃, maintains 4-6h, and to adjust vacuum be 35 ± 20Pa;
6) when 35 ℃ and at least two product temperatures probes of temperature arrival in freeze drying equipment exceed after 25 ℃, the vacuum in freeze drying equipment is recovered to 10Pa below and kept after 1h, packing.
2. freeze-drying method according to claim 1, is characterized in that, described Radix Notoginseng total arasaponins is prepared by following methods: Radix Notoginseng ethanol extraction, after extracting solution is concentrated, cross post, water, ethanol elution, collect ethanol elution, decolouring, collects the effluent after decolouring, refining, reclaim ethanol extremely without alcohol taste, it is 1.06-1.10 that filtrate is concentrated into relative density, dry, to obtain final product.
3. freeze-drying method according to claim 1, it is characterized in that described step 2): after heat release finishes, be located in 0.75h temperature in freeze drying equipment is down to below-30 ℃, temperature is down to temperature in freeze drying equipment below-45 ℃ after arriving-30 ℃ in 0.75h; Then control pressure in freeze drying equipment to 10Pa, and maintain 1.5h.
4. freeze-drying method according to claim 1, is characterized in that, described step 3): establish in freeze drying equipment temperature and maintain below 10Pa for-4 ℃ and vacuum, insulation 5h.
5. freeze-drying method according to claim 1, is characterized in that, described step 4): adjustment vacuum is 50 ± 30Pa, and maintains the interior temperature of freeze drying equipment at-4 ℃, continues insulation 7.5h.
6. freeze-drying method according to claim 1, is characterized in that, the control method of described step 4) and step 5): in the situation that not destroying vacuum, open air inlet from air vent opposite tank wall, maintain certain pressure.
7. freeze-drying method according to claim 1, is characterized in that, the method for testing of pressure is that pressure rises method of testing described in step 6): in closing every valve 120 seconds; observe freeze drying equipment internal pressure; in 120 seconds, rise and be no more than 0.8Pa, confirm substantially anhydrous point of evaporation of product, shut down.
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| CN101450091A (en) * | 2008-12-30 | 2009-06-10 | 云南云科药业有限公司 | Purification method of Panax notoginseng saponins |
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| CN101450091A (en) * | 2008-12-30 | 2009-06-10 | 云南云科药业有限公司 | Purification method of Panax notoginseng saponins |
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