CN1820753A - Freeze-dried powder injection containing leucovorin sodium and its preparing method - Google Patents
Freeze-dried powder injection containing leucovorin sodium and its preparing method Download PDFInfo
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- CN1820753A CN1820753A CN 200510008527 CN200510008527A CN1820753A CN 1820753 A CN1820753 A CN 1820753A CN 200510008527 CN200510008527 CN 200510008527 CN 200510008527 A CN200510008527 A CN 200510008527A CN 1820753 A CN1820753 A CN 1820753A
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Abstract
The freeze dried powder for injection contains leucovorin sodium in 5-100wt% and freeze drying supplementary material in 0-95wt%, and the supplementary material includes excipient, buffering agent and/or isosmotic regulator. The preparation process and application in resisting tumor of the freeze dried powder for injection containing leucovorin sodium is also provided.
Description
Technical field
The present invention relates to a kind of freeze-dried drug, specifically, is a kind of freeze-dried powder that contains leucovorin sodium, and this medicine can be used for strengthening and the curative effect of auxiliary antitumor drug.
Background technology
Folinic acid is the equivalent raceme of the 5-formyl derivant of tetrahydrofolic acid (THF).Bioactive substance in this raceme is a levo form, is called citrovorum factor or l-leucovorin.Folinic acid does not need to participate in directly and use folic acid as shifting in the biological respinse of " carbon-based group " carrier in the body through the reduction of dihydrofolate reductase.L-folinic acid (L-5 formyl tetrahydrofolic acid) tachymetabolism (being followed successively by 5,10-methyl tetrahydrofolate and 5,10-methylene tetrahydrofolate) is the L-5-methyl tetrahydrofolate.The L-5-methyl tetrahydrofolate can be metabolised to 5 successively by other approach, the 10-methylene tetrahydrofolate, and 5, the 10-methylene tetrahydrofolate irreversibly is converted into the 5-methyl tetrahydrofolate by the catalytic reduction of FADH2 and NADPH coenzyme.The administration of folinic acid can be offset the treatment toxicity of the antifol (for example methotrexate) that suppresses dihydrofolate reductase; On the other hand, can also increase 5-fluorouracil class (as 5-fluorouracil) in oncotherapy curative effect and reduce its toxic action, but administration does not simultaneously show and can change the pharmacokinetics of 5-fluorouracil in blood plasma.5-fluorouracil in vivo metabolism be behind the deoxidation 5-fluorouracil nucleotide in conjunction with and suppress thymidylate synthetase (this enzyme is very important in DNA repairs and duplicates).Folinic acid is easy to change into another kind of reduced form folic acid in vivo, and promptly 5,10-methylene tetrahydrofolate, this conversion product can be stable in conjunction with deoxidation 5-fluorouracil nucleotide and thymidylate synthetase, and then strengthen the inhibitory action to this enzyme.
Folinic acid generally all is to make preparation with calcium salt forms, the injection calcium leucovorin preparation generally is divided into two kinds of lyophilizing and liquid drugs injections, but in the process of clinical practice, it is found that, though calcium folinate is soluble in water, but its aqueous stability is bad, be easy to generate precipitation, cause the inconvenience of using, the more important thing is, because folinic acid mainly is used in heavy dose of chemotherapy, promptly and 5-fu (5-fluorouracil) unite use because calcium ion has side effect to human heart, heavy dose is used calcium folinate, calcium ion wherein has side effects to people's cognition, and therefore general clinically dosage mostly is 200mg/m most
2This dosage is insufficient to treatment or auxiliary treatment (chemotherapy) under a lot of situations, at least not optimal dose, again because calcium salt can be produced precipitation with a lot of medicines (for example 5-fu), so the calcium folinate of being used in treatment (chemotherapy) must be individually dosed, the inconvenience that this causes the patient to use undoubtedly also becomes the hidden danger on the drug safety.
At present, injection leucovorin sodium hydro-acupuncture preparation has also appearred in the commercially available prod, this leucovorin sodium liquid drugs injection is when its clinical efficacy has obtained approval, it is found that this liquid drugs injection dosage form exists the unsettled defective of placement back product, be embodied at 40 ℃, test under 60 ℃ hyperthermy and/or the illumination conditions of 4500Lx, content of effective descends obviously in this hydro-acupuncture preparation, related substance (impurity) obviously increases, although in the process of this liquid drugs injection dosage form of preparation, added the PH buffer agent inevitably, pH value also obviously changes in the put procedure, color and luster deepens etc., and this has brought a serial difficult problem for the storage of medicine and application.
Therefore, people wish to develop a kind of can be separately or administering drug combinations, dosage are wide in range, the least possible folinate preparation of adjuvant with the compatibility of other drug beyond good, the stable and active component.
Summary of the invention
In order to overcome above-mentioned defective, the present invention has developed the leucovorin sodium freeze-dried powder, through checking, the freeze-dried powder dissolubility of leucovorin sodium is good, be not easy to produce precipitation, especially the stability and the compatibility are good, are very wide as a kind of its prospect of novel lyophilized injectable powder.
Leucovorin sodium chemistry N-[4-[(2-amino by name-5-formoxyl-1,4,5,6,7,8-six hydrogen-4-oxo-6-pteridyl) methyl] amino] benzoyl-L-sodium glutamate, its molecular formula is C
20H
21Na
2N
7O
7, molecular weight is 517.51.
The object of the present invention is to provide a kind of freeze-dried powder that contains leucovorin sodium, this medicine stability is good, clinical application that can be heavy dose of, and the good compatibility is arranged with other drug.
The present invention also aims to provide a kind of preparation method that contains the freeze-dried powder of leucovorin sodium, be prepared, can obtain all good leucovorin sodium freeze-dried powder of every index by freeze-drying curve through screening.
For achieving the above object, the invention provides a kind of freeze-dried powder that contains leucovorin sodium, wherein contain the leucovorin sodium of percentage by weight (dry weight) 5～100% and 0～95% lyophilizing adjuvant.
Above-mentioned leucovorin sodium freeze-dried powder provided by the invention is the clinical injection medication, experiment showed, that its clarity and heavy dissolubility can be all good, can preserve at normal temperatures, the dissolving back is difficult for producing recrystallization, compares with containing the leucovorin sodium liquid drugs injection, and stability has obtained improving greatly.
Freeze-dried powder adjuvant of the present invention preferred shared dry weight ratio in this freeze-dried powder is 0～50%.
Described in a preferred embodiment of the invention leucovorin sodium freeze-dried powder, its principal agent is: leucovorin sodium; Adjuvant can comprise excipient and/or buffer agent and/or isoosmotic adjusting agent, more preferably excipient, isoosmotic adjusting agent and/or buffer agent.This adjuvant can be the conventional lyophilizing adjuvant that adopts in this area, for example, preferably, excipient is selected from mannitol, lactose, glycine, sorbitol, low molecular dextran and the sodium chloride at least a, buffer agent is selected from sodium dihydrogen phosphate, sodium hydrogen phosphate and the sodium citrate at least a, and isoosmotic adjusting agent is selected from sodium chloride, sodium bicarbonate and the dibastic sodium phosphate at least a; Wherein said leucovorin sodium freeze-dried powder preferably contains the lyophilizing pharmaceutic adjuvant of the leucovorin sodium and 2～25% (dry weight) of 75～98% (dry weights).
Finding through a large amount of screening experiment (seeing Table 1), in the present invention, is the freeze-dried powder of leucovorin sodium at principal agent, and above-mentioned adjuvant is sodium chloride and/or sodium citrate more preferably, most preferably is sodium chloride.
The screening experiment of table 1. adjuvant
| The prescription sequence number | A | B | C | D | E | F | G | H | |
| Leucovorin sodium | 109.3g | 109.3g | 109.3g | 109.3g | 109.3g | 109.3g | 109.3g | 109.3g | |
| Sodium chloride | 17.8g | 17.2g | |||||||
| Mannitol | 100g | ||||||||
| Lactose | 50g | ||||||||
| Glycine | 100g | ||||||||
| Sorbitol | 100g | ||||||||
| Low molecular dextran | 100g | ||||||||
| Sodium citrate | 2.3g | 2.3g | |||||||
| Sodium bicarbonate | 27.4g | 26.5g | |||||||
| The injection pH value | 8.0 | 8.0 | 8.0 | 8.02 | 8.0 | 8.0 | 8.0 | 8.0 | |
| Assessment item | PH value after the lyophilizing | 7.87 | 7.95 | 8.02 | 7.75 | 7.81 | 8.00 | 8.01 | 7.99 |
| The finished product face shaping | Easy chunky shape | Full bulk | Full bulk | Full bulk | Full bulk | Loose powder | Loose block | Loose block | |
| Color and luster | Little Huang | Little Huang | Little Huang | Little Huang | Little Huang | Little Huang | Little Huang | Little Huang | |
| Clarity | Clear and bright | Clear and bright | Clear and bright | Clear and bright | Clear and bright | Little Huang | Little Huang | Little Huang | |
| Heavy dissolubility | Hurry up | Hurry up | Hurry up | Hurry up | Hurry up | Hurry up | Hurry up | Hurry up | |
| 60 ℃ of hot tests (10 days) | Do not change | Do not change | Do not change | Slightly shrink | Slightly shrink | Contraction is arranged | Contraction is arranged | Contraction is arranged | |
| Highlight test (10 days) | Do not change | Do not change | Do not change | Do not change | Do not change | Do not change | Do not change | Do not change |
The applicant finds in the experiment, and leucovorin sodium is more stable under pH neutrality and weak basic condition, is 8.0 so the prescription pH value that the present invention determines at 7.0-9.0, is preferably pH.And in screening process, find, for principal agent of the present invention is leucovorin sodium, in this prescription, whether add buffer agent, and the amount of the buffer agent that is added does not have a significant impact the pH value of medicine, take all factors into consideration, the adjuvant that is added in the preferred embodiment of freeze-dried powder of the present invention does not comprise buffer agent (as sodium citrate), those skilled in the art on this basis can according to the needs on actual the using take the circumstances into consideration to determine whether to add buffer agent with and addition.
Hence one can see that, and preferred its weight (dry weight) proportioning of freeze-dried powder of the present invention is: 80～90% leucovorin sodium and 10～20% sodium chloride.The present invention is with the preferred excipient of sodium chloride as the calcium folinate dried frozen aquatic products, greatly degree has reduced the supplementary product kind that adds in the product, the product that obtains is heavy to be met physiology etc. after molten preferably and oozes requirement, facing the time spent is dissolved into the concentration that every ml contains leucovorin sodium 25mg with water for injection respectively, the approximate physiology of the osmotic pressure of this moment etc. oozes a little 7.4 atmospheric pressure, and comprehensive every index all reaches optimum efficiency.
Its most preferred proportioning (dry weight) of freeze-dried powder that contains leucovorin sodium of the present invention is 85% leucovorin sodium and 15% sodium chloride, this proportioning is compared with other prescriptions, have that profile is more attractive in appearance, product is more stable, the advantage that outward appearance remained unchanged substantially under 60 ℃ of high temperature were investigated, other prescriptions all slightly shrink, or profile is loose.
Through experimental verification, can preserve under the leucovorin sodium freeze-dried powder room temperature of the present invention, stability is compared than calcium folinate (lyophilizing and liquid drugs injection) and leucovorin sodium liquid drugs injection dosage form and has been obtained very big improvement, made things convenient for and stored and use, it will be further appreciated that, use its sodium salt (leucovorin sodium) not need to consider to resemble the problem that may occur the calcium salt (calcium folinate) clinically, even clinical administration dosage can be increased to 500mg/m
2, and can be made into transfusion with many medicament mixed of for example 5-fu and so on and give the patient simultaneously and use administration, the compatibility of itself and other drug is good, and this is those skilled in the art according to formerly disclosed technology institute is unforeseeable.
Leucovorin sodium freeze-dried powder of the present invention can be used as antitumor drug or antitumour auxiliary drug.
For realizing such scheme, the present invention also provides a kind of freeze-dried powder preparation method that contains leucovorin sodium, comprise with leucovorin sodium being that crude drug (can commercially availablely be buied or preparation voluntarily, compound method becomes sodium salt for folinic acid is dropped in the NaOH aqueous solution), make the leucovorin sodium aqueous solution of required ratio, add adjuvant dissolving (also can not add adjuvant) in this solution, it is neutral regulating pH value, lyophilization (abbreviation lyophilizing).
In freeze-drying process, parameter (freeze-drying curve) is set different, obtains properties of product difference to some extent, and through screening, the inventive method is preferably: the leucovorin sodium aqueous solution of (1) preparation desired concn ratio, and it is neutral transferring pH value; (2) freezing curve is set, with the lyophilization of above-mentioned leucovorin sodium aqueous solution; Wherein freeze-drying curve be with the plate temperature drop to solidification point-10～-60 ℃, preferred-35～-55 ℃ (as-50 ℃), retaining plate temperature 2-8hr; Open cold condenser, condenser temperature reach near solidification point minimum point (as-50 ℃ ,-55 ℃ or-60 ℃), open the vacuum system evacuation, vacuum 3～30Pa, subliming by heating to 0～60 ℃ (preferred about 30 ℃) and take off water of crystallization.
Wherein step (1) also comprises the adding adjuvant and/or regulates pH value and/or remove the process of thermal source and degerming.
The container of splendid attire freeze-dried powder involved in the present invention (lyophilizing bottle) is the commercially available prod of any specification and model, and the operation of series such as canned and gland also is well-known to those skilled in the art, repeats no more.
Draw through test, if freeze-drying process adopts the technology of pre-freeze, the freeze-drying prods outward appearance that obtains is more complete, and globality is better.So preparation method of the present invention preferably adopts the technology of pre-freeze, promptly freeze dryer plate temperature is made as a refrigerated temperature earlier, the arbitrary temperature between for example 0 ℃～-55 ℃, preferred-35 ℃, load sample then.
In a preferred embodiment of the invention, preparation method is: behind the direct wiring solution-forming of leucovorin sodium, add adjuvant sodium chloride (leucovorin sodium: dissolving sodium chloride=85%: 15%), regulate between the pH value 7.0～9.0 with 1M sodium hydroxide/hydrochloric acid, remove thermal source and filtration sterilization according to a conventional method, be preferably and add active carbon and stir after-filtration reuse microporous filter membrane or heat sterilization; Freeze-drying curve also comprises pre-freeze, freezes process (preferred 2～6 hours) with quick-freezing slowly, pre-freeze process freeze dryer plate temperature is-30 ℃～-40 ℃ (preferred-35 ℃), load sample, 5 ℃～15 ℃ (preferred 10 ℃) per hour fall in the process of freezing slowly, the quick-freezing process is per hour fallen 20-30 ℃, the plate temperature is set-50 ℃ approximately, and the time of each process can be done conventional the adjustment according to the difference of load sample amount; Insulation afterwards, the temperature for the treatment of the freeze dryer rear cabinet is reduced to evacuation below-55 ℃, vacuum is 5～15Pa, the plate temperature control was-10 ℃～-20 ℃ (preferred-15 ℃) sublimation dryings 15～30 hours, do not have moisture content to have (range estimation gets final product according to routine) until sample, be warming up to 0～60 ℃ (preferred 20～40 ℃) again and remove residual water of crystallization.
The assay of the injection leucovorin sodium freeze-dried powder of producing with above-mentioned preparation method sees Table 2.
Standard reference of the present invention is according to the injection leucovorin sodium standard of injection calcium folinate revision, itself and American Pharmacopeia and European Pharmacopoeia basically identical, high effective liquid chromatography for measuring related substance and content.
Chromatographic condition and system try out the property test:
With octadecylsilane chemically bonded silica is filler, get diluent methanol-water (25: 75) 900ml, add 10% TBAH solution 13ml, with 2mol/L sodium dihydrogen phosphate adjust pH 7.5 ± 0.1, adding diluent is mobile phase to 1000ml, and the detection wavelength is 254nm.Take by weighing leucovorin sodium and 10-formylpropionic acid reference substance is an amount of, be dissolved in water to make the solution that contains 500 μ g and 10 μ g among every 1ml respectively approximately, the sample introduction analysis, the separating degree of leucovorin sodium and 10-formylpropionic acid should be greater than 1.5; Repeat sample introduction, the relative standard deviation of leucovorin sodium peak area and retention time must not be greater than 2.0%.
The testing result of three batches of leucovorin sodium freeze-dried powders of table 2.
| Lot number | Character | Basicity | Related substance | Loss on drying | Content uniformity | Aseptic | Bacterial endotoxin | Clarity | Assay |
| 20020901 | Little yellow is loose block | 7.9 | Up to specification | 2.5％ | Up to specification | Up to specification | Up to specification | Up to specification | 99.9％ |
| 20020902 | Little yellow is loose block | 7.9 | Up to specification | 2.5％ | Up to specification | Up to specification | Up to specification | Up to specification | 100.4％ |
| 20020903 | Little yellow is loose block | 8.0 | Up to specification | 2.6％ | Up to specification | Up to specification | Up to specification | Up to specification | 100.2 |
This shows that product of the present invention meets touchstone fully.
Stability study
According to the medicine stability test guideline that requirement and Chinese Pharmacopoeia version appendix in 2000 XIXC are examined in the medicine registration, injection leucovorin sodium and leucovorin sodium liquid drugs injection are carried out influence factor's test, result such as table 3,4:
Table 3. injection leucovorin sodium (freeze-dried powder, lot number 20020901)
| Inspection item | Appearance luster | PH value | Clarity | Related substance | Content | |
| 60 ℃ of hot tests | 0 day | Little yellow is loose block | 8.01 | Qualified | Up to specification | 100.4％ |
| 5 days | Little yellow is loose block | 7.95 | Qualified | Up to specification | 99.9％ | |
| 10 days | Little yellow is loose block | 7.85 | Qualified | Up to specification | 99.0％ | |
| 25 ℃ of relative humiditys cross 90% ± 5%, lucifuge | 0 day | Little yellow is loose block | 8.01 | Qualified | Up to specification | 100.4％ |
| 5 days | Little yellow is loose block | 7.97 | Qualified | Up to specification | 100.1％ | |
| 10 days | Little yellow is loose block | 7.97 | Qualified | Up to specification | 99.6％ | |
| Illumination 4500Lx ± 500Lx | 0 day | Little yellow is loose block | 8.01 | Qualified | Up to specification | 100.4％ |
| 5 days | Little yellow is loose block | 7.96 | Qualified | Up to specification | 100.2％ | |
| 10 days | Little yellow is loose block | 7.89 | Qualified | Up to specification | 99.8％ | |
Table 4. leucovorin sodium liquid drugs injection lot number 20020701
| Inspection item | Appearance luster | PH value | Clarity | Related substance | Content | |
| 60 ℃ of hot tests | 0 day | Pale yellow solution | 8.00 | Qualified | Up to specification | 100.2％ |
| 5 days | Yellow solution | 7.05 | Qualified | Against regulation | 90.6％ | |
| 10 days | Yellow solution | 6.75 | Qualified | Against regulation | 87.4％ | |
| 40 ℃ of hot tests | 0 day | Pale yellow solution | 8.00 | Qualified | Up to specification | 100.2％ |
| 5 days | Pale yellow solution | 7.88 | Qualified | Up to specification | 98.9％ | |
| 10 days | Yellow solution | 7.45 | Qualified | Against regulation | 93.6％ | |
| 25 ℃ of relative humiditys 90% ± 5%, lucifuge | 0 day | Pale yellow solution | 8.00 | Qualified | Up to specification | 100.2％ |
| 5 days | Pale yellow solution | 7.97 | Qualified | Up to specification | 100.1％ | |
| 10 days | Pale yellow solution | 7.87 | Qualified | Up to specification | 99.0％ | |
| Illumination 4500Lx ± 500Lx | 0 day | Pale yellow solution | 8.00 | Qualified | Up to specification | 100.2％ |
| 5 days | Pale yellow solution | 7.86 | Qualified | Up to specification | 99.2％ | |
| 10 days | Pale yellow solution | 7.69 | Qualified | Against regulation | 97.8％ | |
As from the foregoing, injection leucovorin sodium freeze-dried powder under 60 ℃ of conditions of high temperature 10 days, content descends not obvious, and related substance (impurity) increases not obvious, and pH value does not have significant change, and clarity is qualified; And the leucovorin sodium liquid drugs injection was placed 5 days under 60 ℃ of conditions of high temperature, and content obviously descends, and related substance obviously increases, and pH value obviously descends; As can be seen, injection leucovorin sodium freeze-dried powder is more stable than sodium folinate injection.
Medicine stability test guideline by Chinese Pharmacopoeia version appendix in 2000 XIXC is quickened and long term test, sees Table 5.
Table 5. injection leucovorin sodium (freeze-dried powder, lot number 20020901)
| Index | Appearance luster | PH value | Clarity | Related substance | Labelled amount % content | |
| Accelerated test | 0 month | Little yellow is loose block | 8.01 | Qualified | Up to specification | 100.2％ |
| 1 month | Little yellow is loose block | 7.95 | Qualified | Up to specification | 99.8％ | |
| 2 months | Little yellow is loose block | 7.88 | Qualified | Up to specification | 99.6％ | |
| 3 months | Little yellow is loose block | 7.82 | Qualified | Up to specification | 99.2％ | |
| 6 months | Little yellow is loose block | 7.77 | Qualified | Up to specification | 98.9％ | |
| Long term test | 3 months | Little yellow is loose block | 8.00 | Qualified | Up to specification | 100.1％ |
| 6 months | Little yellow is loose block | 7.98 | Qualified | Up to specification | 99.9％ | |
| 9 months | Little yellow is loose block | 8.00 | Qualified | Up to specification | 99.7％ | |
| 12 months | Little yellow is loose block | 7.95 | Qualified | Up to specification | 99.5％ | |
| 18 months | Little yellow is loose block | 7.90 | Qualified | Up to specification | 99.0％ | |
| 24 months | Little yellow is loose block | 7.87 | Qualified | Up to specification | 98.1％ | |
The three batch samples process of different lot numbers is quickened and long term test, and the result is similar to table 5.As from the foregoing, leucovorin sodium freeze-dried powder product stability of the present invention is good, and 2 years quality of long term test meet the requirements.
Heavy molten rear stability test:
A. every bottle of injection leucovorin sodium (0.1g freeze-dried powder) adds injection water 4ml dissolving.
B. every bottle of injection calcium folinate (0.1g freeze-dried powder) adds injection water 10ml dissolving.
C. the lercovorin calcium inj (liquid drugs injection) of specification 10ml (0.1g).
To go up the airtight lucifuge of solution and be positioned in the room temperature environment, due to 0,12,24,36, every index is investigated in sampling in 48 hours, sees Table 6.
Heavy molten back of table 6. injection leucovorin sodium and injection calcium folinate and lercovorin calcium inj study on the stability result
| Sample | The investigation time (hour) | Solution colour | PH value | Clarity | Its related substances % | Content % (labelled amount) |
| Injection leucovorin sodium (lyophilizing) | 0 | Faint yellow | 8.0 | Qualified | Up to specification | 100.2 |
| 12 | Faint yellow | 8.0 | Qualified | Up to specification | 100.1 | |
| 24 | Faint yellow | 7.9 | Qualified | Up to specification | 99.8 | |
| 36 | Faint yellow | 7.9 | Qualified | Up to specification | 99.8 | |
| 48 | Faint yellow | 7.8 | Qualified | Up to specification | 99.6 | |
| Injection calcium folinate (lyophilizing) | 0 | Faint yellow | 7.5 | Qualified | Up to specification | 100.6 |
| 12 | Faint yellow | 7.5 | Qualified | Up to specification | 99.9 | |
| 24 | Yellow | 7.3 | Crystallization is separated out | Against regulation | 96.6 | |
| 36 | Yellow | 7.2 | Crystallization is separated out | Against regulation | 93.3 | |
| 48 | Yellow | 7.1 | Crystallization is separated out | Against regulation | 86.5 | |
| Lercovorin calcium inj (liquid drugs injection) | 0 | Faint yellow | 7.5 | Qualified | Up to specification | 100.3 |
| 12 | Faint yellow | 7.5 | Qualified | Up to specification | 100.1 | |
| 24 | Yellow | 7.4 | Crystallization is separated out | Against regulation | 96.8 | |
| 36 | Yellow | 7.3 | Crystallization is separated out | Against regulation | 94.8 | |
| 48 | Yellow | 7.0 | Crystallization is separated out | Against regulation | 88.2 |
Conclusion:
Heavy molten back of injection leucovorin sodium and injection calcium folinate and lercovorin calcium inj, room temperature was deposited 48 hours under airtight shading condition, and injection leucovorin sodium every index after 48 hours is all qualified as a result; The injection calcium folinate began to have crystallization to separate out after 24 hours, and clarity is defective; Lercovorin calcium inj had crystallization to separate out after 24 hours, and clarity is defective.This shows that the aqueous solution of calcium folinate is all unstable, be easy to generate precipitation, and leucovorin sodium dissolubility in water is good, is not easy to produce the phenomenon of recrystallization.
The specific embodiment
Describe the present invention in detail below in conjunction with embodiment, but do not limit practical range of the present invention.
Embodiment 1: the prescription of leucovorin sodium freeze-dried powder is formed and preparation
Prescription: leucovorin sodium 0.1093g (production of the south of the Five Ridges, Guangdong Province pharmaceutical factory)
Sodium chloride 0.0178g
Preparation method (1000 bottles):
A. leucovorin sodium 109.3g (production of the south of the Five Ridges, Guangdong Province pharmaceutical factory) directly is made into the about 1500ml of aqueous solution, adds sodium chloride 17.8g, 1. stirring and dissolving gets solution;
B. 1. solution being regulated pH value with the sodium hydroxide of 1M or hydrochloric acid is 7～9, and preferred pH value is 8.0, obtains solution 2., then with water for injection be diluted to volume required (for example: 2000ml);
C. 2. solution removed thermal source and 3. aseptic filtration obtain solution, 2. solution stir after-filtration reuse 0.45 μ m and the degerming of twice filtering with microporous membrane method of 0.22 μ m by adding active carbon;
D. 3. solution pressed the recipe quantity fill, half tamponade, freeze dryer is set freeze-drying curve A or B, through lyophilizing, the vacuum tamponade, packing is made clinical operable qualified preparation;
A. freeze-drying curve: the sample that fill is good moves to freeze drying box, and the plate temperature drop is to solidification point-10～-60 ℃, and preferred-50 ℃, configure the plate temperature then, kept about 4 hours; The open cold condenser when condenser temperature reaches about-55 ℃, is opened the vacuum system evacuation, vacuum reaches about 10Pa, plate temperature control-15 ℃ left and right sides subliming by heating is not estimated moisture content until goods and is existed, and distillation is warming up to about 30 ℃ again and removes residual water of crystallization;
B. the freeze-drying curve that has pre-freeze technology: earlier freeze dryer plate temperature drop is arrived-35 ℃, then that fill is good sample moves in the freeze drying box, set about plate temperature-50 ℃, about 2 hours, the temperature of freeze dryer rear cabinet is reduced to below-55 ℃ between soak, the open cold condenser when condenser temperature reaches about-55 ℃, is opened the vacuum system evacuation; Vacuum is reached about 10Pa, and the plate temperature control is not estimated moisture content until goods and is existed in-15 ℃ of left and right sides subliming by heating (about 15 hours), and distillation is warming up to about 30 ℃ again and removes residual water of crystallization.
Product specification can be: in folinic acid, every bottle of (propping up) content is 3mg, 5mg, 15mg, 25mg, 30mg, 50mg, 100mg, 200mg, 300mg, 350mg, 500mg, or 900mg.
The product character: profile is full, and the little Huang of color and luster is all good through its dissolubility of measuring and heavy dissolubility.
Embodiment 2: the leucovorin sodium freeze-dried powder
Prescription: leucovorin sodium 0.1093g (production of the south of the Five Ridges, Guangdong Province pharmaceutical factory).
Preparation method (1000 bottles):
A. leucovorin sodium 109.3g directly is made into the about 1500ml of aqueous solution, gets solution 1.;
Other steps are with embodiment 1.
The product character: easy chunky shape, the little Huang of color and luster is all good through its dissolubility of measuring and heavy dissolubility.
Embodiment 3: the leucovorin sodium freeze-dried powder
Prescription: leucovorin sodium 0.1093g (production of the south of the Five Ridges, Guangdong Province pharmaceutical factory)
Mannitol 0.100g
Sodium bicarbonate 0.0274g
Preparation method (1000 bottles):
A. leucovorin sodium 109.3g (production of the south of the Five Ridges, Guangdong Province pharmaceutical factory) directly is made into the about 1500ml of aqueous solution, adds mannitol 100.0g and sodium bicarbonate 27.4g, 1. stirring and dissolving gets solution;
Other steps are with embodiment 1.
The product character: profile is full, and the little Huang of color and luster is all good through its dissolubility of measuring and heavy dissolubility.
Embodiment 4: the leucovorin sodium freeze-dried powder
Prescription: leucovorin sodium 0.1093g (production of the south of the Five Ridges, Guangdong Province pharmaceutical factory)
Lactose 0.050g
Sodium bicarbonate 0.0274g
Preparation method (1000 bottles):
A. leucovorin sodium 109.3g (production of the south of the Five Ridges, Guangdong Province pharmaceutical factory) directly is made into the about 1500ml of aqueous solution, adds lactose 50.0g and sodium bicarbonate 27.4g, 1. stirring and dissolving gets solution;
Other steps are with embodiment 1.
The product character: profile is full, and the little Huang of color and luster is all good through its dissolubility of measuring and heavy dissolubility.
Claims (10)
1. freeze-dried powder that contains leucovorin sodium wherein contains percentage by weight and is 5～100% leucovorin sodium and 0～95% lyophilizing adjuvant.
2. freeze-dried powder as claimed in claim 1, wherein this adjuvant comprises excipient and/or buffer agent and/or isoosmotic adjusting agent, adjuvant shared percentage by weight in medicine is 0～50%.
3. freeze-dried powder as claimed in claim 2 wherein contains percentage by weight and is 75%～98% leucovorin sodium and 2%～25% lyophilizing adjuvant.
4. freeze-dried powder as claimed in claim 2, wherein this adjuvant is excipient, isoosmotic adjusting agent and/or buffer agent.
5. freeze-dried powder as claimed in claim 3, wherein said excipient is selected from mannitol, lactose, glycine, sorbitol, low molecular dextran and the sodium chloride at least a, buffer agent is selected from sodium dihydrogen phosphate, sodium hydrogen phosphate and the sodium citrate at least a, and isoosmotic adjusting agent is selected from sodium chloride, sodium bicarbonate and the dibastic sodium phosphate at least a.
6. freeze-dried powder as claimed in claim 4, wherein this adjuvant is sodium chloride and/or sodium citrate.
7. freeze-dried powder as claimed in claim 2 is 80～90% leucovorin sodium and 10～20% sodium chloride comprising percentage by weight.
8. prepare each described method that contains the freeze-dried powder of leucovorin sodium of claim 1-7, comprising:
(1) the leucovorin sodium aqueous solution of preparation desired concn ratio, it is neutral transferring pH value;
(2) freezing curve is set, with the lyophilization of above-mentioned leucovorin sodium aqueous solution;
Wherein, described freeze-drying curve is: refrigerating process plate temperature drop is to solidification point-10～-60 ℃, retaining plate temperature 2-8 hour then; The open cold condenser, when condenser temperature reaches near the solidification point minimum point, evacuation, vacuum 3～30Pa, reheat distil and take off water of crystallization.
9. preparation method as claimed in claim 8, wherein, the refrigerating process of freeze-drying curve also comprises pre-freeze, freezes and quick-freezing slowly, pre-freeze process freeze dryer plate temperature is-30～-40 ℃, load sample then, the process of freezing is slowly per hour fallen 5～15 ℃, and the quick-freezing process is per hour fallen 20-30 ℃; The plate temperature is set at insulation after-50 ℃, treats that the temperature of freeze dryer rear cabinet is reduced to-evacuation below 55 ℃, and vacuum is 5～15Pa, and the plate temperature control is warming up to 0～60 ℃ again and removes residual water of crystallization-10 ℃～-20 ℃ sublimation dryings 15～30 hours.
10. preparation method as claimed in claim 8, wherein step (1) also comprises the adding adjuvant and/or regulates pH value and/or remove the process of thermal source and degerming.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510008527XA CN100544723C (en) | 2005-02-18 | 2005-02-18 | Contain freeze-dried powder of leucovorin sodium and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB200510008527XA CN100544723C (en) | 2005-02-18 | 2005-02-18 | Contain freeze-dried powder of leucovorin sodium and preparation method thereof |
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| CN1820753A true CN1820753A (en) | 2006-08-23 |
| CN100544723C CN100544723C (en) | 2009-09-30 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101229167B (en) * | 2008-02-21 | 2011-08-24 | 齐建新 | Method of preparing sodium levofolinate and applications thereof on preparing tumour-curing medicines |
| CN102258463A (en) * | 2011-07-18 | 2011-11-30 | 重庆煜澍丰医药有限公司 | Stable sodium folinate injection |
| CN113357880A (en) * | 2021-05-17 | 2021-09-07 | 云南易门丛山食用菌有限责任公司 | Processing technology of semi-freeze-dried tricholoma matsutake |
-
2005
- 2005-02-18 CN CNB200510008527XA patent/CN100544723C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101229167B (en) * | 2008-02-21 | 2011-08-24 | 齐建新 | Method of preparing sodium levofolinate and applications thereof on preparing tumour-curing medicines |
| CN102258463A (en) * | 2011-07-18 | 2011-11-30 | 重庆煜澍丰医药有限公司 | Stable sodium folinate injection |
| CN113357880A (en) * | 2021-05-17 | 2021-09-07 | 云南易门丛山食用菌有限责任公司 | Processing technology of semi-freeze-dried tricholoma matsutake |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100544723C (en) | 2009-09-30 |
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Assignee: Lingnan Pharmaceutical Ltd. Assignor: Xu Wenkai Contract record no.: 2010440001553 Denomination of invention: Freeze-dried powder injection containing leucovorin sodium and its preparing method Granted publication date: 20090930 License type: Exclusive License Open date: 20060823 Record date: 20101229 |
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