CN100563632C - A kind of injection fleroxacin and preparation method thereof - Google Patents
A kind of injection fleroxacin and preparation method thereof Download PDFInfo
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- CN100563632C CN100563632C CNB2008101267476A CN200810126747A CN100563632C CN 100563632 C CN100563632 C CN 100563632C CN B2008101267476 A CNB2008101267476 A CN B2008101267476A CN 200810126747 A CN200810126747 A CN 200810126747A CN 100563632 C CN100563632 C CN 100563632C
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Abstract
The invention provides a kind of injection fleroxacin, form by fleroxacin, mannitol and lactic acid; The preparation method of Fleroxacin freeze-dry powder pin also is provided, fleroxacin and mannitol are joined in the water for injection, drip the lactic acid of recipe quantity again, constantly stirring is dissolved fleroxacin fully; Active carbon is joined in the above-mentioned mixed solution, filter; Filtrate is placed the freeze dryer charging tray, slowly cool at-30～-35 ℃, and keep-30～-35 ℃ preliminary freezing 2.5～3 hours, and then it is quickly cooled to about-45～-55 ℃, evacuation was warming up to-5～5 ℃ in 12～15 hours, the time of keeping-5～5 ℃ is 4～6 hours, be warming up to 25～30 ℃ again in 3～5 hours, the time of keeping 25～30 ℃ is 5～7 hours, promptly obtains Fleroxacin freeze-dry powder pin.Obtained freeze-drying powder pin, the prescription composition is simple, and stability, solubility is good, and moisture is low.
Description
Technical field
The present invention relates to a kind of injection Fleroxacin freeze-dry powder pin and preparation method thereof, belong to field of pharmaceutical preparations.
Background technology
Fleroxacin (Fleroxacin) is a third generation carbostyril family antibacterial drugs, has characteristics such as has a broad antifungal spectrum, antibacterial action are strong, wide, the long half time of distributing.To gram-negative bacteria, comprise that escherichia coli, pneumobacillus, Proteus, Salmonella typhi, bacillus paratyphosus, Shigella, enterobacter cloacae, clostridium perfringen, citric acid bacterium genus, serratia marcesens, Pseudomonas aeruginosa, Neisseria meningitidis, hemophilus influenza, mora mucositis bacterium, legionella pneumophilia, Diplococcus gonorrhoeae etc. all have stronger antibacterial action.Gram positive coccus such as staphylococcus, Streptococcus hemolyticus also had medium antibacterial action.
The chemical name of fleroxacin is 6,8-two fluoro-1-(2-fluoro ethyl)-1, and 4-dihydro-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid, molecular formula is C
17H
18F
3N
3O
3, its structure be for:
The fleroxacin injection discloses the infusion solution that has only volume bigger in patent DE3333719, DE3537761, owing to volume is big, corresponding all kinds of solvents, adjuvant and packing are along with increase, and promptly cost improves, and produces, transports, stores also inconvenient.
Chinese invention patent ZL96116516.2 discloses a kind of concentrated aqueous solution of rotatory enzyme inhibitor of injection for intravenous of high concentration, described rotatory enzyme inhibitor is 6,8-two fluoro-1-(2-fluoro ethyl)-1,4-dihydro-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid, i.e. fleroxacin.This fleroxacin concentrated solution mainly is made up of acid and an amount of medicinal formula adjuvant that fleroxacin, water, physiology allow, wherein, acid is lactic acid or acetic acid, the medicinal formula adjuvant comprises antioxidant, anti-photodissociation agent, chelating agent, pH regulator agent, cosolvent etc., the supplementary product kind that contains in this fleroxacin concentrated solution is more, cause interference for the performance of principal agent, give preparation technology also more complicated simultaneously.
Disclose a kind of Fleroxacin injection at number of patent application 200610016686.9, this injection is made up of fleroxacin and Aspartic Acid, and its both weight ratio is 1: 0.44, adds an amount of injection additives commonly used in case of necessity.
Fleroxacin injection in the prior art, its injection is placed through permanent, and solution no longer is clear and bright, has muddy phenomenon to produce, and uses for like this injection and makes troubles, and transportation simultaneously also makes things convenient for.Fleroxacin is prepared into the freeze-dried powder dosage form, and its stability improves the bioavailability advantages of higher.
Summary of the invention
An object of the present invention is to provide a kind of injection Fleroxacin freeze-dry powder pin, the prescription of this freeze-dried powder is simple, good stability.
Another object of the present invention provides a kind of preparation method of injection Fleroxacin freeze-dry powder pin, and this preparation method technology is simple, and gained Fleroxacin freeze-dry powder needle set has advantages such as profile is full, solubility is good.
The invention provides a kind of injection Fleroxacin freeze-dry powder pin is made up of fleroxacin, mannitol and lactic acid.
The mass ratio of described fleroxacin and lactic acid is 1: 0.34～0.6, and it is preferred 1: 0.45～0.55 years old.
The mass ratio of described fleroxacin and lactic acid is more preferably 1: 0.47～0.50.
The mass ratio of described fleroxacin and mannitol is 1: 0.35～0.65, and it is preferred 1: 0.45～0.6 years old.
The poorly water-soluble of fleroxacin will be made into every performance injection powder pin up to specification, must add materials such as cosolvent or solubilizing agent.
The present invention selects the cosolvent of lactic acid as fleroxacin for use, and mannitol is as excipient.In the prior art, do not produce precipitation, add excessive lactic acid, but excessive lactic acid can cause the pH of injection to reduce again, can stimulate human body during injection in order to guarantee Fleroxacin injection; In the disclosed Fleroxacin injection of patent ZL96116516.5, except adding lactic acid, have in addition to have added the concentrated hydrochloric acid solubilising, perhaps needing to add other materials could be with the fleroxacin solubilising.In drug prescription, adjuvant still less have still less incompatibility and the clinical drug safety of Geng Gao, prior art is when adding lactic acid, other the alkaline Ph regulator or the cosolvent of other types have been added again, at this moment the performance to the active component fleroxacin has a negative impact, and the present invention only uses the cosolvent of a kind of material of lactic acid as fleroxacin.
Show by great deal of experiment data, lactic acid is the best adjuvant of fleroxacin solubilization-aid effect, the inventor only selects the cosolvent of lactic acid as fleroxacin for use, add an amount of mannitol simultaneously as excipient, in order to improve the dissolubility of fleroxacin, the lactic acid that adds excessive, in excessive lactic acid, add in an amount of mannitol, because the effect of mannitol and lactic acid, the PH of its feasible freeze-drying prods that finally obtains is controlled between 3.5～4.5, even add the phenomenon appearance that excessive lactic acid can not cause that solution PH reduces yet, the solubility property of fleroxacin is fine simultaneously, it is prepared into the dosage form of freeze-dried powder, mannitol plays bulk skeleton function, makes Fleroxacin freeze-dry powder pin keep original volume substantially, and color and luster is even, be easy to dissolve the clear and bright solution of formation, experimental example 1 is the screening experiment of the present invention to the mannitol consumption.
In order to realize that another object of the present invention provides a kind of injection Fleroxacin freeze-dry powder pin preparation method, adopts following technical scheme:
(1) fleroxacin and the mannitol with recipe quantity joins in the water for injection, is added dropwise to the lactic acid of recipe quantity while stirring, constantly stirs fleroxacin is dissolved fully;
(2) active carbon is joined in the above-mentioned mixed solution, at room temperature constantly stir 30min after, filter;
(3) filtrate that step (2) is obtained will be through lyophilization promptly.
Earlier mannitol and fleroxacin are mixed in solution in the above-mentioned steps (1), drip lactic acid again, lactic acid that splashes into and mannitol generation reversible reaction generate a small amount of ester, along with constantly splashing into of lactic acid, gradually with solution in mannitol be reacted into ester, because slightly there are a kind of dynamic chemical molecular balance in this ester that generates and mannitol, lactic acid in the acid medium described, lactic acid that exists in the solution and newly-generated ester all have good hydrotropy effect to fleroxacin, mannitol is excipient, plays good fluffy effect.
The consumption of active carbon is 0.035～0.05% (g/ml) of liquor capacity in the above-mentioned steps (2), preferred 0.04～0.045% (g/ml).
The consumption of active carbon is to the influence of product, if activated carbon dosage is too many, can cause the active component in the adsorbent solution, the productive rate of its product is reduced, if activated carbon dosage is very little, can not be fully with solution decolouring, the source of reducing phlegm and internal heat, the removal of impurity, and then influence the performance such as quality, purity of product.So the selection to the consumption of active carbon should be taken all factors into consideration.Experimental example 2 is screening experiment of activated carbon dosage of the present invention, and through the charcoal treatment after-filtration, the total impurities of gained filtrate is below 0.5%, and maximum contaminant is below 0.18%, and bacterial endotoxin is up to specification.
The described cryodesiccated technology of above-mentioned steps (3) is: the filtrate that step (2) is obtained places the freeze dryer charging tray, slowly cool at-30～-35 ℃, and kept-30～-35 ℃ of preliminary freezing 2.5-3 hours, and then it is quickly cooled to about-45～-55 ℃, evacuation, in 12～15 hours, be warming up to-5～5 ℃, the time of keeping-5～5 ℃ is 4～6 hours, in 3～5 hours, be warming up to 25～30 ℃ again, the time of keeping 25～30 ℃ is 5～7 hours, promptly obtains injection Fleroxacin freeze-dry powder pin.
The character of the technology of frozen preparation, the quality of product and drug solution has substantial connection, freezing dry process is the process of a dynamic change, different drug solutions need improve accordingly to three processes of refrigerating process, dry run, vacuum control of refrigerating process, just can draw standard compliant product.To this, the inventor has paid all effort, has obtained above freeze drying process.
In the above-mentioned steps (3), freezing dry process divides three phases, pre-freeze, distillation, dry run.
1, pre-freeze
In the freezing dry process of injection Fleroxacin freeze-dry powder pin of the present invention, the pre-freeze process of fleroxacin solution is finished in two steps.Take all factors into consideration the mode of appearance of frozen product dry run, product and the content of moisture, earlier with its quick freezing to eutectic point, and, it is tentatively freezed keeping a period of time in temperature.When fleroxacin solution slowly was cooled to-30～-35 ℃, because the control of thermograde and cooling rate, the removal of follow-up moisture was convenient in being of moderate size of the ice crystal of formation.
After tentatively freezing fleroxacin, further with its cooling, it is freezed fully again, if medicinal liquid does not freeze fully, when vacuum sublimation was dry, liquid boiling caused spray bottle phenomenon.Experimental example 3 is screening experiment of refrigerating process in the freeze drying process of the present invention.
In the freezing dry process of injection Fleroxacin freeze-dry powder pin of the present invention, because when drying, the temperature and time control of water sublimed, moisture more than 90% is removed, afterwards, it is dry to heat up, and the moisture of injection Fleroxacin freeze-dry powder pin can be lower than 0.8%, and the stability of active medicine improves.
2, distillation
After medicine freezes, start the vacuum machine and be evacuated to 10Pa, close fridge, heat up to make to medicine and freeze the product temperature and in 12-15 hour, rise to-5～5 ℃; Be incubated 4～6 hours then.
The choice relation of sublimation temperature is to the speed of distillation, why select-5～5 ℃, rather than higher temperature, and be that temperature is raised to-5～5 ℃ in 12～15 hours, be because when distillation, the upper materials drying that will take the lead in, if it is too fast that its temperature rises, might reach the temperature of caving in (or being referred to as the disintegrate temperature), porous skeleton rigidity reduces, and coming off appears in the granule in the drying layer, can seal the micro channel of drying nest, the carrying out that stops distillation, rate of sublimation is slowed down, even make underclad portion atrophy slightly, influence the content of goods residual moisture, cause solubility, stability and clarity is variation simultaneously, and experimental example 4 is screening experiment of sublimation temperature and rate of sublimation.
In addition, temperature retention time is unsuitable long, and this is that the ice crystal of gained is bigger because fleroxacin medicinal liquid of the present invention is that slowly the substep cooling is freezed, substantially the moisture removal of phase will distil when reaching sublimation temperature, be incubated a period of time again, the moisture that will distil is as far as possible removed, if but in the longer time of this temperature maintenance, moisture can not removed again, cause like this losing time, energy, simultaneously, influence the solubility and the outward appearance of freeze-drying prods.
Therefore, excessive temperature or cross distillation for a long time or insulation all has adverse effect to the present invention, through a large amount of experiment screenings, can be elevated temperature and be-5～5 ℃ referring to experimental example 3, and temperature retention time is 4-6 hour.
Pressure during the distillation is 10Pa, rather than lower, though this is because the low distillation that helps ice in the product of pressure, because pressure is unfavorable to conducting heat when too low, product is difficult for the acquisition heat, and rate of sublimation reduces on the contrary.But when pressure was too high, the rate of sublimation of ice slowed down in the product, and minimizing falls in the product caloric receptivity.So the temperature of product self rises, when being higher than temperature of eutectic point, product will melt, and cause the lyophilizing failure.Therefore, pressure is set at 10Pa, not only has been beneficial to the transmission of heat but also has been beneficial to the carrying out of distillation.
3, drying
Promptly remove the process of bound water at dry period, behind sublimation drying, also remaining a part of adsorbed water and bound water, these water are not frozen, can not remove in sublimation drying.The present invention was warming up to 25～30 ℃ with temperature in 3～5 hours behind sublimation drying, the time of keeping 25～30 ℃ is 5～7 hours, the moisture of obtained freeze-drying product is lower than 0.8%, as well known to those skilled in the art, the moisture of freeze-drying prods is low more, and its stability is good more.
Freeze drying process preferred version of the present invention is: filtrate is placed the freeze dryer charging tray, slowly cool to-30～-32 ℃, and keep-30～-32 ℃ preliminary freezing 2.5～3 hours, and then it is quickly cooled to-50～-55 ℃, evacuation was warming up to 0～2 ℃ in 13～14 hours, the time of keeping 0～2 ℃ is 4～5 hours, be warming up to 25～30 ℃ again in 3.5～4 hours, the time of keeping 25～30 ℃ is 6.5～7 hours, promptly obtains injection Fleroxacin freeze-dry powder pin.
Pass through change among the present invention to injection Fleroxacin freeze-dry powder pin adjuvant, be specially mannitol and lactic acid, the solubility of the freeze-drying prods of gained is good, and it is 3.5～4.5 that the PH of aqueous solution promotes, make it more can meet the acidity scope of injection, the pH value of fleroxacin is all on the low side in the prior art, can not well satisfy the injection service condition.In addition, prescription at Fleroxacin freeze-dry powder pin of the present invention, improvement to the freeze-dry process of fleroxacin, make that the quality of prepared Fleroxacin freeze-dry powder is loose, add and to dissolve rapidly behind the water and recover the primary characteristic of medicinal liquid, moisture can reach 0.5%, and the stability of fleroxacin improves.Simultaneously, make the products obtained therefrom dose controlled, good appearance; Packaging volume is little, and packaging material require low, have reduced packing cost and cost of transportation.
The specific embodiment
Embodiment 1
Prescription:
Fleroxacin 206.08g
Mannitol 100g
Lactic acid 85.42ml
Water for injection adds to 2000ml
Totally 1000 bottles
Preparation technology: fleroxacin and the 100g mannitol of 206.08g are joined in the 1600mL water for injection, stir, drip again in the above-mentioned mixed liquor of 85.42mL lactic acid, being stirred to fleroxacin dissolves fully, the active carbon that in the solution of gained, adds 0.6g again, stirring at room 30min, remove active carbon through 0.45 μ m micro-pore-film filtration, add water for injection again to 2000mL, fully stir 20min and make the solution mix homogeneously, the mixed liquor that obtains through 0.22 μ m filtering with microporous membrane degerming, places the freeze dryer charging tray with filtrate again, slowly cools to-30 ℃, and keep-30 ℃ preliminary freezing 3 hours, and then will be quickly cooled to-55 ℃, evacuation was warming up to 2 ℃ in 14 hours, holding temperature is 4 hours 2 ℃ time, be warming up to 25 ℃ again in 3.5 hours, holding temperature is 7 hours 25 ℃ time, promptly obtains Fleroxacin freeze-dry powder pin.
Embodiment 2
Prescription:
Fleroxacin 206.08g
Mannitol 82.5g
Lactic acid 80.31ml
Water for injection adds to 2000ml
Totally 1000 bottles
Preparation technology: fleroxacin and the 82.5g mannitol of 206.08g are joined in the 1600mL water for injection, stir, drip again in the above-mentioned mixed liquor of 80.31mL lactic acid, being stirred to fleroxacin dissolves fully, the active carbon that in the solution of gained, adds 0.68g again, stirring at room 30min, remove active carbon through 0.45 μ m micro-pore-film filtration, add water for injection again to 2000mL, fully stir 20min and make the solution mix homogeneously, the mixed liquor that obtains through 0.22 μ m filtering with microporous membrane degerming, places the freeze dryer charging tray with filtrate again, slowly cools at-32 ℃, and keep-32 ℃ preliminary freezing 2.5 hours, and then will be quickly cooled to-50 ℃, evacuation was warming up to 0 ℃ in 13 hours, holding temperature is 5 hours 0 ℃ time, be warming up to 30 ℃ again in 4 hours, holding temperature is 6.5 hours 30 ℃ time, promptly obtains Fleroxacin freeze-dry powder pin.
Embodiment 3
Prescription:
Fleroxacin 206.08g
Mannitol 123g
Lactic acid 68.35ml
Water for injection adds to 2000ml
Totally 1000 bottles
Preparation technology: fleroxacin and the 123g mannitol of 206.08g are joined in the 1600mL water for injection, stir, drip again in the above-mentioned mixed liquor of 68.35mL lactic acid, being stirred to fleroxacin dissolves fully, the active carbon that in the solution of gained, adds 0.53g again, stirring at room 30min, remove active carbon through 0.45 μ m micro-pore-film filtration, add water for injection again to 2000mL, fully stir 20min and make the solution mix homogeneously, the mixed liquor that obtains through 0.22 μ m filtering with microporous membrane degerming, places the freeze dryer charging tray with filtrate again, slowly cools at-35 ℃, and keep-35 ℃ preliminary freezing 2.5 hours, and then will be quickly cooled to-45 ℃, evacuation was warming up to-5 ℃ in 12 hours, holding temperature is 6 hours-5 ℃ time, be warming up to 30 ℃ again in 3 hours, holding temperature is 5 hours 30 ℃ time, promptly obtains Fleroxacin freeze-dry powder pin.
Embodiment 4
Prescription:
Fleroxacin 206.08g
Mannitol 92.8g
Lactic acid 93.9ml
Water for injection adds to 2000ml
Totally 1000 bottles
Preparation technology: fleroxacin and the 192.8g mannitol of 206.08g are joined in the 1600mL water for injection, stir, drip again in the above-mentioned mixed liquor of 93.9mL lactic acid, being stirred to fleroxacin dissolves fully, the active carbon that in the solution of gained, adds 0.75g again, stirring at room 30min, remove active carbon through 0.45 μ m micro-pore-film filtration, add water for injection again to 2000mL, fully stir 20min and make the solution mix homogeneously, the mixed liquor that obtains through 0.22 μ m filtering with microporous membrane degerming, places the freeze dryer charging tray with filtrate again, slowly cools at-30 ℃, and keep-30 ℃ preliminary freezing 3 hours, and then will be quickly cooled to-50 ℃, evacuation was warming up to 5 ℃ in 15 hours, holding temperature is 4 hours 5 ℃ time, be warming up to 25 ℃ again in 3.5 hours, holding temperature is 7 hours 25 ℃ time, promptly obtains Fleroxacin freeze-dry powder pin.
Experimental example 1
This experimental example is the screening experiment that adds the consumption of mannitol in to Fleroxacin freeze-dry powder pin, other parameters and technology reference example 1, and wherein fleroxacin is got 200g.
The screening test of table 1 mannitol consumption
| Mannitol consumption (g) | 50 | 70 | 90 | 110 | 130 | 150 |
| Dissolution velocity (s) | 54 | 40 | 35 | 32 | 26 | 23 |
| The freeze-dried powder profile | Subside | Full | Full | Full | Full | Full |
| PH value of solution | 3.02 | 3.65 | 4.07 | 4.34 | 4.47 | 4.48 |
Take all factors into consideration the factor of aspects such as pH of profile, the solution of consumption, the freeze-dried powder of adjuvant, experimental data draws from table, the mannitol consumption is at 70～130g, and promptly the amount ratio of fleroxacin and mannitol was at 1: 0.35～0.65 o'clock, and every index of Fleroxacin freeze-dry powder pin is all desirable.
Experimental example 2
This experimental example is the screening experiment of concentration of activated carbon.Other component technological parameter selects for use the injection active carbon of variable concentrations to adsorb respectively all with embodiment 1, serves as to investigate index with fleroxacin content, clarity, the consumption of screening active carbon.The inspection employing of clarity " two clarity inspection techniques of Chinese pharmacopoeia version in 2000 the results are shown in Table 2:
Table 2 activated carbon dosage screening test
| Concentration of activated carbon (%) | Fleroxacin content (%) | Clarity |
| 0.02 | 99.84 | Opalescence is arranged, muddiness |
| 0.03 | 99.67 | Opalescence is arranged, muddiness |
| 0.035 | 99.41 | Up to specification |
| 0.04 | 99.34 | Up to specification |
| 0.045 | 99.08 | Up to specification |
| 0.05 | 98.87 | Up to specification |
| 0.06 | 97.45 | Up to specification |
By drawing in the table, active carbon has certain absorption to fleroxacin, and the consumption of active carbon was at 0.035%～0.05% o'clock, and is not obvious to the influence of content, and the clarity of solution is also fine.
Experimental example 3
The screening experiment of this experimental example Fleroxacin freeze-dry powder pin temperature retention time of sublimation temperature, rate of sublimation, sublimation temperature in freezing dry process.
Table 3 is screening tests that fleroxacin freezes sublimation temperature in the product freezing dry process, and table 4 is screening tests that fleroxacin freezes the distillation time in the product freezing dry process, and table 5 is screening experiment that fleroxacin freezes the temperature retention time of product when sublimation temperature.Other parameter is with embodiment 1.
The screening experiment of table 3 sublimation temperature
| Parameter | First | Second batch | The 3rd batch | The 4th batch | The 5th batch |
| Sublimation temperature (℃) | -10 | -5 | 0 | 5 | 10 |
| Moisture (%) | 1.53 | 0.67 | 0.55 | 0.50 | 1.51 |
| Related substance (%) | 0.34 | 0.38 | 0.46 | 0.48 | 1.02 |
| Clarity | Qualified | Qualified | Qualified | Qualified | Muddy |
| Character | The white loose piece | The white loose shape | The white loose shape | Layering | Subside |
Table 4 is warming up to the screening of used time of sublimation temperature
| First | Second batch | The 3rd batch | The 4th batch | The 5th batch | The 6th batch | |
| Time (h) | 10 | 12 | 13 | 14 | 15 | 16 |
| Moisture (%) | 1.51 | 0.67 | 0.62 | 0.65 | 0.74 | 1.62 |
| Related substance (%) | 0.35 | 0.37 | 0.41 | 0.48 | 0.50 | 1.15 |
Table 5 is in the screening of sublimation temperature temperature retention time
| First | Second batch | The 3rd batch | The 4th batch | The 5th batch | |
| Time (h) | 3 | 4 | 5 | 6 | 7 |
| Moisture (%) | 1.25 | 0.68 | 0.61 | 0.57 | 0.62 |
| Related substance (%) | 0.36 | 0.39 | 0.44 | 0.46 | 0.74 |
According to table 3,4,5 interpretations, the aspects such as angle of energy consumption are considered from every index of final Fleroxacin freeze-dry product, operating process, determine at sublimation stage, in 12-15 hour, temperature is risen to-5～5 ℃, and under this temperature, kept 4～6 hours.
Experimental example 4
This experimental example is to five batches of Fleroxacin freeze-dry powder pin Performance Detection of the present invention, concrete detection method all according to " 2000 editions second one of Chinese pharmacopoeia the results are shown in following table:
The Performance Detection of table 6 Fleroxacin freeze-dry powder of the present invention pin
| Batch | Clarity | Related substance | Drug content | Moisture | Aseptic | Bacterial endotoxin |
| First | Clear and bright | 0.46％ | 99.6％ | 0.71％ | Up to specification | Up to specification |
| Second batch | Clear and bright | 0.51％ | 99.8％ | 0.66％ | Up to specification | Up to specification |
| The 3rd batch | Clear and bright | 0.38％ | 99.7％ | 0.70％ | Up to specification | Up to specification |
| The 4th batch | Clear and bright | 0.42％ | 100.2％ | 0.61％ | Up to specification | Up to specification |
| The 5th batch | Clear and bright | 0.50％ | 99.8％ | 0.54％ | Up to specification | Up to specification |
Kind can learn that every performance of gained Fleroxacin freeze-dry powder pin of the present invention is all qualified at table 6, and the content of related substance, moisture improve than prior art all.
Experimental example 5
This experimental example is got three batch samples respectively according to " 2005 editions second accelerated test methods of Chinese pharmacopoeia, respectively at the every index of 1,2,3,6 sampling and measuring at the end of month, result of the test sees Table 7.The result shows, this product is that 40 ± 2 ℃, relative humidity are to place 6 months under 75 ± 5% conditions in temperature, and related substance, moisture and other index have no significant change, and this product quality is basicly stable.
Table 7 injection Fleroxacin freeze-dry powder sample needle accelerated test
| Batch | Time (moon) | Character | Clarity | PH | Related substance | Indicate content |
| First | 0 1 2 3 6 | White powder white powder white powder white powder white powder | Clear and bright clear and bright | 3.87 3.85 3.85 3.78 3.64 | 0.36％ 0.38％ 0.43％ 0.45％ 0.44％ | 100.16％ 99.87％ 99.65％ 99.19％ 98.46％ |
| Second batch | 0 1 2 3 6 | White powder white powder white powder white powder white powder | Clear and bright clear and bright | 3.98 3.86 3.92 3.82 3.79 | 0.46％ 0.43％ 0.42％ 0.53％ 0.52％ | 100.20％ 100.07％ 99.83％ 99.67％ 98.75％ |
| The 3rd batch | 0 1 2 3 6 | White powder white powder white powder white powder white powder | Clear and bright clear and bright | 4.12 4.10 4.04 4.02 3.93 | 0.41％ 0.43％ 0.48％ 0.49％ 0.51％ | 99.87％ 99.60％ 99.74％ 98.84％ 98.29％ |
Get three batch samples respectively according to " 2005 editions second minister's phase test methods of Chinese pharmacopoeia, respectively at the every index of 3,6,9,12,24,36 sampling and measuring at the end of month, result of the test sees Table 8.
Table 8 injection Fleroxacin freeze-dry powder pin long term test
| Batch | Time (moon) | Character | Clarity | PH | Related substance | Indicate content |
| First | 0 3 6 | White powder white powder white powder | Clear and bright clear and bright | 4.25 4.18 4.12 | 0.31％ 0.35％ 0.36％ | 99.96％ 99.87％ 99.49％ |
| 9 12 24 36 | White powder white powder white powder white powder | Clear and bright | 4.10 4.00 3.94 3.72 | 0.35％ 0.38％ 0.47％ 0.43％ | 98.97％ 98.64％ 98.36％ 97.67％ | |
| Second batch | 0 3 6 9 12 24 36 | White powder white powder white powder white powder white powder white powder white powder | Clear and bright clear and bright clear and bright | 3.91 3.88 3.82 3.84 3.82 3.78 3.62 | 0.34％ 0.39％ 0.35％ 0.41％ 0.45％ 0.49％ 0.51％ | 100.16％ 99.93％ 99.69％ 98.86％ 98.58％ 98.13％ 97.27％ |
| The 3rd batch | 0 3 6 9 12 24 36 | White powder white powder white powder white powder white powder white powder white powder | Clear and bright clear and bright clear and bright | 4.46 4.43 4.38 4.39 4.35 4.32 4.01 | 0.48％ 0.49％ 0.47％ 0.53％ 0.57％ 0.58％ 0.62％ | 100.25％ 100.12％ 99.86％ 99.72％ 98.51％ 98.17％ 97.59％ |
Claims (7)
1, a kind of injection Fleroxacin freeze-dry powder pin, it is characterized in that, this freeze-dried powder is made up of fleroxacin, mannitol and lactic acid, and the mass ratio of described fleroxacin and lactic acid is 1: 0.34～0.6, and the mass ratio of described fleroxacin and mannitol is 1: 0.35～0.65;
Described Fleroxacin freeze-dry powder pin prepares by the following method:
(1) fleroxacin and the mannitol with recipe quantity joins in the water for injection, is added dropwise to the lactic acid of recipe quantity while stirring, constantly stirs fleroxacin is dissolved fully, adds sterilized water for injection to full dose;
(2) active carbon is joined in the above-mentioned mixed solution, at room temperature constantly stir 30min after, filter;
(3) filtrate that step (2) is obtained will be through lyophilization promptly;
Cryodesiccated technology described in the step (3) is: the filtrate that step (2) is obtained places the freeze dryer charging tray, slowly cool at-30～-35 ℃, and kept-30～-35 ℃ of preliminary freezing 2.5-3 hours, and then will be quickly cooled to about-45～-55 ℃, evacuation, in 12～15 hours, be warming up to-5～5 ℃, the time of keeping-5～5 ℃ is 4～6 hours, in 3～5 hours, be warming up to 25～30 ℃ again, the time of keeping 25～30 ℃ is 5～7 hours, promptly obtains injection Fleroxacin freeze-dry powder pin.
2, Fleroxacin freeze-dry powder pin according to claim 1 is characterized in that, the mass ratio of described fleroxacin and lactic acid is 1: 0.45～0.55, and the mass ratio of described fleroxacin and mannitol is 1: 0.45～0.6
3, the preparation method of the described injection Fleroxacin freeze-dry of a kind of claim 1 powder pin comprises the steps:
(1) fleroxacin and the mannitol with recipe quantity joins in the water for injection, is added dropwise to the lactic acid of recipe quantity while stirring, constantly stirs fleroxacin is dissolved fully, adds sterilized water for injection to full dose;
(2) active carbon is joined in the above-mentioned mixed solution, at room temperature constantly stir 30min after, filter;
(3) filtrate that step (2) is obtained will be through lyophilization promptly.
4, preparation method according to claim 3 is characterized in that, the consumption of described active carbon is 0.035～0.05% of a liquor capacity.
5, preparation method according to claim 4 is characterized in that, the consumption of described active carbon is 0.04～0.045% of a liquor capacity.
6, preparation method according to claim 3, it is characterized in that, cryodesiccated technology described in the step (3) is: the filtrate that step (2) is obtained places the freeze dryer charging tray, slowly cool at-30～-35 ℃, and kept-30～-35 ℃ of preliminary freezing 2.5-3 hours, and then will be quickly cooled to about-45～-55 ℃, evacuation, in 12～15 hours, be warming up to-5～5 ℃, the time of keeping-5～5 ℃ is 4～6 hours, be warming up to 25～30 ℃ again in 3～5 hours, the time of keeping 25～30 ℃ is 5～7 hours, promptly obtains injection Fleroxacin freeze-dry powder pin.
7, preparation method according to claim 6, it is characterized in that, freeze drying process is: filtrate is placed the freeze dryer charging tray, slowly cool to-30～-32 ℃, and keep-30～-32 ℃ preliminary freezing 2.5～3 hours, and then it is quickly cooled to-50～-55 ℃, evacuation, in 13～14 hours, be warming up to 0～2 ℃, the time of keeping 0～2 ℃ is 4～5 hours, be warming up to 25～30 ℃ again in 3.5～4 hours, the time of keeping 25～30 ℃ is 6.5～7 hours, promptly obtains injection Fleroxacin freeze-dry powder pin.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2008101267476A CN100563632C (en) | 2008-06-20 | 2008-06-20 | A kind of injection fleroxacin and preparation method thereof |
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| CNB2008101267476A CN100563632C (en) | 2008-06-20 | 2008-06-20 | A kind of injection fleroxacin and preparation method thereof |
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| CN100563632C true CN100563632C (en) | 2009-12-02 |
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Non-Patent Citations (4)
| Title |
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| 国家药品标准（新药转正标准）. 国家药典委员会，化学工业出版社. 2005 |
| 国家药品标准（新药转正标准）. 国家药典委员会，化学工业出版社. 2005 * |
| 紫外分光光度法测定注射用氟罗沙星半成品含量的考察. 关萍等.辽宁医药，第16卷第3期. 2001 |
| 紫外分光光度法测定注射用氟罗沙星半成品含量的考察. 关萍等.辽宁医药，第16卷第3期. 2001 * |
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