CN102525961B - Powder injection of meropenem composition for injection - Google Patents
Powder injection of meropenem composition for injection Download PDFInfo
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- CN102525961B CN102525961B CN 201210014120 CN201210014120A CN102525961B CN 102525961 B CN102525961 B CN 102525961B CN 201210014120 CN201210014120 CN 201210014120 CN 201210014120 A CN201210014120 A CN 201210014120A CN 102525961 B CN102525961 B CN 102525961B
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Abstract
The invention relates to the technical field of medicine and pharmacy and in particular relates to a powder injection of meropenem composition for injection. The powder injection of meropenem composition for injection contains meropenem, sodium carbonate and sodium alginate. The weight ratio of meropenem to sodium carbonate to sodium alginate is 50:100:(4.9-9.9). The trials show that the powder injection of meropenem composition for injection is better in stability under low-temperature, room temperature (25 DEG C), high-temperature and illumination conditions and has no significant difference (P greater than 0.05). The acceleration test and long-term test show that all the investigated indices are within the specialized range, which indicates that the powder injection of meropenem composition for injection is stable. The pharmacodynamic test of the powder injection of meropenem composition for injection is carried out, and the test results show that the powder injection of meropenem composition for injection has no significant difference (P greater than 0.05) as compared with the positive control group.
Description
Technical field
The present invention relates to medical injection field, particularly powder injection of meropenem composition for injection.
Background technology
Meropenem, wide spectrum carbapenem antibiotic for synthetic, meropenem penetrates the cell wall of most of Gram-positives and negative bacteria easily, reaches its action target spot penicillin-binding protein (PBPS), by the synthetic generation antibacterial action of anti-bacteria cell wall.Except metallo-β-lactamase, meropenem has stronger stability to the hydrolysis of most of beta-lactamases (comprising the penicillinase and the cephalosporinase that are produced by gram positive bacteria and gram negative bacteria).In vitro tests shows that to the isolated strains of some bacillus pyocyaneus, meropenem and aminoglycoside antibiotics share and can produce synergism.
Meropenem for injection can be used for the treatment of the inflammation such as pneumonia (comprising nosocomial pneumonia), urinary tract infection, gynecological infection (such as endometritis and pelvic inflammatory disease), skin soft-tissue infection, meningitis, septicemia.But, because meropenem is relatively poor at Stability in solution, therefore, provide a kind of meropenem powder ampoule agent for injection of good stability to have realistic meaning.
Summary of the invention
In view of this, the invention provides a kind of powder injection of meropenem composition for injection and preparation method thereof.This powder injection of meropenem composition for injection is better at the condition stability inferior of low temperature, room temperature (25 ℃), high humidity, illumination, without significant difference (P＞0.05); In accelerated test and the long term test, every investigation index all in prescribed limit, shows that powder injection of meropenem composition for injection provided by the invention is more stable.
In order to realize the foregoing invention purpose, the invention provides following technical scheme:
The invention provides a kind of powder injection of meropenem composition for injection, formed by meropenem, sodium carbonate, sodium alginate; The mass ratio of described meropenem, sodium carbonate, sodium alginate is 50: 100: 4.9～9.9.
As preferably, in the meropenem powder ampoule agent for injection provided by the invention, described powder ampoule agent for injection can be with the dissolving of injection liquid in when injection, and described injection liquid comprises that 0.9% sodium chloride injection, 5% or 10% glucose injection, 5% glucose add 0.02% sodium bicarbonate injection, 5% glucose and add that normal saline solution, 5% glucose add 0.225% sodium chloride injection, 5% glucose adds 0.15% potassium chloride injection, 2.5% or 10% formula mannitol injection liquid.
The present invention also provides a kind of preparation method of powder injection of meropenem composition for injection, and raw material is comprised of meropenem, sodium carbonate, sodium alginate, and the mass ratio of described meropenem, sodium carbonate, sodium alginate is 50: 100: 4.9～9.9; Take by weighing described raw material, cross 80～100 mesh sieves, obtain mixed liquor after the dissolving of adding water for injection, lyophilization makes described powder injection of meropenem composition for injection.
As preferably, in the powder ampoule agent for injection provided by the invention, described powder ampoule agent for injection can be with the dissolving of injection liquid in when injection, and described injection liquid comprises that 0.9% sodium chloride injection, 5% or 10% glucose injection, 5% glucose add 0.02% sodium bicarbonate injection, 5% glucose and add that 0.9% sodium chloride injection injection, 5% glucose add 0.225% sodium chloride injection, 5% glucose adds 0.15% potassium chloride injection, 2.5% or 10% formula mannitol injection liquid.
As preferably, as preferably, described cryodesiccated condition is: the pre-freeze temperature is-55～-30 ℃, and the pre-freeze time is 1～8h; Sublimation temperature is-35～-10 ℃, and the distillation time is 5～20h; Baking temperature is 15～50 ℃, and be 3～15h drying time.
Before the described lyophilization, also comprise the step of fine straining, fill, sealing.
The invention provides a kind of powder injection of meropenem composition for injection, formed by meropenem, sodium carbonate, sodium alginate; The mass ratio of described meropenem, sodium carbonate, sodium alginate is 50: 100: 4.9～9.9.Test shows that powder injection of meropenem composition for injection provided by the invention is better at the condition stability inferior of low temperature, room temperature (25 ℃), high humidity, illumination, without significant difference (P＞0.05); Respectively at 0,1,2,4, the 6h sampling, detect stability, color is without significant change, and related substance, meropenem content are without significant change, every investigation index all in prescribed limit, shows that powder injection of meropenem composition for injection provided by the invention is more stable; In the accelerated test, under the condition of 30 ± 2 ℃ of temperature, relative humidity 65 ± 5%, placed 6 months, respectively at the 0th, 1,2,3,6 sampling at the end of month once, color is without significant change, related substance slightly has rising, meropenem content slightly has decline, and every investigation index all in prescribed limit, shows that powder injection of meropenem composition for injection provided by the invention is more stable under acceleration environment; In the long term test, under 20 ± 2 ℃ of temperature, relative humidity 60 ± 10% conditions, placed 36 months.At duration of test respectively at the 3rd, 6,9,12,18 month, 24 samplings at the end of month once, powder injection of meropenem composition for injection provided by the invention is after placing 18 months and 24 months under this condition, related substance slightly has rising, content slightly has decline, all other investigation indexs all in prescribed limit, show that powder injection of meropenem composition for injection provided by the invention is better at long preservation condition stability inferior.Simultaneously powder injection of meropenem composition for injection provided by the invention is carried out the test of pesticide effectiveness, the result shows that powder injection of meropenem composition for injection provided by the invention and positive controls are all without significant difference (P＞0.05).
The specific embodiment
The invention discloses a kind of powder injection of meropenem composition for injection, those skilled in the art can use for reference this paper content, suitably improve technological parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, the related personnel obviously can change or suitably change and combination methods and applications as herein described within not breaking away from content of the present invention, spirit and scope, realizes and use the technology of the present invention.
The invention provides a kind of powder injection of meropenem composition for injection, formed by meropenem, sodium carbonate, sodium alginate; The mass ratio of described meropenem, sodium carbonate, sodium alginate is 50: 100: 4.9～9.9.
Meropenem is by its covalent bond, can with penicillin-binding protein (PBPs) combination that participates in Cell wall synthesis, thereby the anti-bacteria cell wall is synthetic, plays antibacterial action.Meropenem is all responsive to gram positive bacteria, gram-negative bacteria, especially gram-negative bacteria is had very strong antibacterial activity.Minimal inhibitory concentration (MIC) to about 90% Enterobacter is 0.08～0.15mg/L; Pseudomonas aeruginosa strains more than 90% is extremely sensitive to it, minimal inhibitory concentration (MIC)＜4mg/L; All haemophilus (comprising the bacterial strain of anti-the ampicillin) is extremely sensitive to it, and minimal inhibitory concentration (MIC) is 0.06～1mg/L; Gonococcus is also extremely sensitive to meropenem, and its activity is better than 15 times of imipenums; Staphylococcus epidermidis, staphylococcus saprophyticus and other coagulase negative staphylococcus are responsive to meropenem; Most of bacterial strains of enterococcus faecalis are to meropenem height or medium sensitivity; Meropenem can suppress most bacteroides fragilis; Anaerobe such as Peptostreptococcus, propionibacterium, actinomyces etc. are also responsive to meropenem.As preferably, in the powder ampoule agent for injection provided by the invention, described powder ampoule agent for injection can be with the dissolving of injection liquid in when injection, and described injection liquid comprises that 0.9% sodium chloride injection, 5% or 10% glucose injection, 5% glucose add 0.02% sodium bicarbonate injection, 5% glucose and add that normal saline solution, 5% glucose add 0.225% sodium chloride injection, 5% glucose adds 0.15% potassium chloride injection, 2.5% or 10% formula mannitol injection liquid.
The present invention also provides a kind of preparation method of powder injection of meropenem composition for injection, and raw material is comprised of meropenem, sodium carbonate, sodium alginate, and the mass ratio of described meropenem, sodium carbonate, sodium alginate is 50: 100: 4.9～9.9; Take by weighing described raw material, cross 80～100 mesh sieves, obtain mixed liquor after the dissolving of adding water for injection, lyophilization makes described powder injection of meropenem composition for injection.
As preferably, in the powder ampoule agent for injection provided by the invention, described powder ampoule agent for injection can be with the dissolving of injection liquid in when injection, and described injection liquid comprises that 0.9% sodium chloride injection, 5% or 10% glucose injection, 5% glucose add 0.02% sodium bicarbonate injection, 5% glucose and add that 0.9% sodium chloride injection, 5% glucose add 0.225% sodium chloride injection, 5% glucose adds 0.15% potassium chloride injection, 2.5% or 10% formula mannitol injection liquid.
As preferably, described cryodesiccated condition is: the pre-freeze temperature is-55～-30 ℃, and the pre-freeze time is 1～8h; Sublimation temperature is-35～-10 ℃, and the distillation time is 5～20h; Baking temperature is 15～50 ℃, and be 3～15h drying time.
Before the described lyophilization, also comprise the step of fine straining, fill, sealing.
The invention provides a kind of powder injection of meropenem composition for injection, formed by meropenem, sodium carbonate, sodium alginate; The mass ratio of described meropenem, sodium carbonate, sodium alginate is 50: 100: 4.9～9.9.
Test shows that powder injection of meropenem composition for injection provided by the invention is better at the condition stability inferior of low temperature, room temperature (25 ℃), high humidity, illumination, without significant difference (P＞0.05); Respectively at 0,1,2,4, the 6h sampling, detect stability, color is without significant change, and related substance, meropenem content are without significant change, every investigation index all in prescribed limit, shows that powder injection of meropenem composition for injection provided by the invention is more stable; In the accelerated test, under the condition of 30 ± 2 ℃ of temperature, relative humidity 65 ± 5%, placed 6 months, respectively at the 0th, 1,2,3,6 sampling at the end of month once, color is without significant change, related substance slightly has rising, meropenem content slightly has decline, and every investigation index all in prescribed limit, shows that powder injection of meropenem composition for injection provided by the invention is more stable under acceleration environment; In the long term test, under 20 ± 2 ℃ of temperature, relative humidity 60 ± 10% conditions, placed 36 months.At duration of test respectively at the 3rd, 6,9,12,18 month, 24 samplings at the end of month once, powder injection of meropenem composition for injection provided by the invention is after placing 18 months and 24 months under this condition, related substance slightly has rising, content slightly has decline, all other investigation indexs all in prescribed limit, show that powder injection of meropenem composition for injection provided by the invention is better at long preservation condition stability inferior.Simultaneously powder injection of meropenem composition for injection provided by the invention is carried out the test of pesticide effectiveness, the result shows that powder injection of meropenem composition for injection provided by the invention and positive controls are all without significant difference (P＞0.05).
Below in conjunction with embodiment, further set forth the present invention:
Embodiment 1 powder injection of meropenem composition for injection provided by the invention
Accurately take by weighing meropenem 50mg, sodium carbonate 100mg, sodium alginate 6mg crosses 80 mesh sieves, and after the dissolving of adding water for injection, then fine straining, fill, sealing are-55 ℃ in the pre-freeze temperature, and the pre-freeze time is 1h; Sublimation temperature is-35 ℃, and the distillation time is 5h; Baking temperature is 15 ℃, and be to carry out lyophilization under the condition of 15h drying time,, make powder injection of meropenem composition for injection.
Embodiment 2 powder injection of meropenem composition for injections provided by the invention
Accurately take by weighing meropenem 50mg, sodium carbonate 100mg, sodium alginate 9.9mg crosses 100 mesh sieves, and after the dissolving of adding water for injection, then fine straining, fill, sealing are-45 ℃ in the pre-freeze temperature, and the pre-freeze time is 3h; Sublimation temperature is-25 ℃, and the distillation time is 15h; Baking temperature is 30 ℃, and be to carry out lyophilization under the condition of 7h drying time, makes powder injection of meropenem composition for injection.
Embodiment 3 powder injection of meropenem composition for injections provided by the invention
Accurately take by weighing meropenem 50mg, sodium carbonate 100mg, sodium alginate 8mg crosses 90 mesh sieves, and after the dissolving of adding water for injection, then fine straining, fill, sealing are-30 ℃ in the pre-freeze temperature, and the pre-freeze time is 8h; Sublimation temperature is-10 ℃, and the distillation time is 20h; Baking temperature is 50 ℃, and be to carry out lyophilization under the condition of 3h drying time, makes powder injection of meropenem composition for injection.
Embodiment 4 powder injection of meropenem composition for injections provided by the invention
Accurately take by weighing meropenem 50mg, sodium carbonate 100mg, sodium alginate 7mg crosses 80 mesh sieves, and after the dissolving of adding water for injection, then fine straining, fill, sealing are-45 ℃ in the pre-freeze temperature, and the pre-freeze time is 5h; Sublimation temperature is-25 ℃, and the distillation time is 12h; Baking temperature is 35 ℃, and be to carry out lyophilization under the condition of 7h drying time, makes powder injection of meropenem composition for injection.
Embodiment 5 powder injection of meropenem composition for injections provided by the invention
Accurately take by weighing meropenem 50mg, sodium carbonate 100mg, sodium alginate 5.9mg crosses 100 mesh sieves, and after the dissolving of adding water for injection, then fine straining, fill, sealing are-40 ℃ in the pre-freeze temperature, and the pre-freeze time is 3h; Sublimation temperature is-15 ℃, and the distillation time is 16h; Baking temperature is 40 ℃, and be to carry out lyophilization under the condition of 5h drying time, makes powder injection of meropenem composition for injection.
Embodiment 6 powder injection of meropenem composition for injections provided by the invention
Accurately take by weighing meropenem 50mg, sodium carbonate 100mg, sodium alginate 4.9mg crosses 80 mesh sieves, and after the dissolving of adding water for injection, then fine straining, fill, sealing are-35 ℃ in the pre-freeze temperature, and the pre-freeze time is 6h; Sublimation temperature is-28 ℃, and the distillation time is 8h; Baking temperature is 20 ℃, and be to carry out lyophilization under the condition of 12h drying time, makes powder injection of meropenem composition for injection.
Embodiment 7 powder injection of meropenem composition for injections provided by the invention
Accurately take by weighing meropenem 50mg, sodium carbonate 100mg, sodium alginate 8.5mg crosses 90 mesh sieves, and after the dissolving of adding water for injection, then fine straining, fill, sealing are-30 ℃ in the pre-freeze temperature, and the pre-freeze time is 8h; Sublimation temperature is-10 ℃, and the distillation time is 20h; Baking temperature is 50 ℃, and be to carry out lyophilization under the condition of 3h drying time, makes powder injection of meropenem composition for injection.
Embodiment 8 powder injection of meropenem composition for injections provided by the invention
Accurately take by weighing meropenem 50mg, sodium carbonate 100mg, sodium alginate 7.5mg crosses 90 mesh sieves, and after the dissolving of adding water for injection, then fine straining, fill, sealing are-55 ℃ in the pre-freeze temperature, and the pre-freeze time is 2h; Sublimation temperature is-35 ℃, and the distillation time is 8h; Baking temperature is 20 ℃, and be to carry out lyophilization under the condition of 11h drying time, makes powder injection of meropenem composition for injection.
Embodiment 9 powder injection of meropenem composition for injections provided by the invention
Accurately take by weighing meropenem 50mg, sodium carbonate 100mg, sodium alginate 6.5mg crosses 90 mesh sieves, and after the dissolving of adding water for injection, then fine straining, fill, sealing are-55 ℃ in the pre-freeze temperature, and the pre-freeze time is 1h; Sublimation temperature is-35 ℃, and the distillation time is 5h; Baking temperature is 15 ℃, and be to carry out lyophilization under the condition of 15h drying time, makes powder injection of meropenem composition for injection.
10 pairs of powder injection of meropenem composition for injections provided by the invention of embodiment detect
With reference to " Chinese pharmacopoeia version in 2010 adopts high performance liquid chromatography that the powder injection of meropenem composition for injection that embodiment 2 to 10 provides is carried out qualitative identification; Adopt the carbonate differential method that the powder injection of meropenem composition for injection that embodiment 2 to 10 provides is differentiated.
Basicity: according to " Chinese pharmacopoeia 2005 and version in 2010 are got the powder injection of meropenem composition for injection that embodiment 2 to 10 provides, and measure according to the method among two appendix VI of Chinese Pharmacopoeia version in 2010 H.
Clarity and colour of solution: but the quality condition of the color of the solution indirect reaction product, according to " we have worked out this inspection Chinese pharmacopoeia 2005 and version in 2010.
Related substance: adopt high performance liquid chromatography, with reference to the USP31 version and " " meropenem for injection " related substance detection method in two ones of the Chinese Pharmacopoeia 2005 versions contrasts.Experimental result shows that the test method in the USP31 version more is conducive to the detection of the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides.By system suitability and destructive testing, prove in each course of reaction intermediate all can with the main peak effective separation, each destroys product and main peak all can be realized baseline separation, shows that this chromatographic condition is applicable to the inspection of related substance.When the injection sample introduction concentration of the powder injection of meropenem composition for injection preparation that the related substance linear relationship evidence embodiment of the invention 2 to 10 provides is 12.5～37.6g/mL, peak area and sample size are good linear relationship, related substance checks that precision test RSD is 0.29%, shows that the powder injection of meropenem composition for injection precision that the embodiment of the invention 2 to 10 provides is good; Related substance inspection need testing solution is placed 5h under low temperature (4 ℃) condition, its main constituent peak area RSD is 0.49%, single mixing and total assorted variation not quite, show that the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides is basicly stable in the 5h under low temperature (4 ℃) condition, through test, the powder injection of meropenem composition for injection related substance inspection that the embodiment of the invention 2 to 10 provides is all up to specification.
Loss on drying: with reference to " Chinese pharmacopoeia 2005 and version in 2010, the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 is provided are carried out loss on drying and are detected: at 60 ℃ of drying under reduced pressure to constant weight, and weighing and recording quality.
Aseptic: with reference to " Chinese pharmacopoeia 2005 and version in 2010; get the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides; add 0.1% aseptic peptone and be diluted to the solution of 20mg/mL; adopt membrane-filter procedure (every membrane filtration amount is not more than the 3g test sample); with 0.1% aseptic peptone water solution flushing; flushing dose 500mL/ film; minute 5 flushings (each 100mL); antibacterial adopt contain penicillinase (greater than the THIOGLYCOLLIC ACID salt fluid culture medium culturing of 3,000,000 units/100mL); with staphylococcus aureus as the positive control bacterium, in accordance with the law inspection (two appendix XI of Chinese Pharmacopoeia version in 2010 H).
Bacterial endotoxin: with reference to " Chinese pharmacopoeia 2005 and version in 2010 are got the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides, and check (appendix XI E) in accordance with the law.
Uniformity of dosage units: with reference to " Chinese pharmacopoeia 2005 and version in 2010, appendix X E checks.
Visible foreign matters: with reference to " two appendix IX of Chinese pharmacopoeia version in 2010 C, the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 is provided carries out the visible foreign matters inspection.
Particulate matter: with reference to " two appendix IX of Chinese pharmacopoeia version in 2010 C, the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 is provided carries out particulate determination.
The Carbon Dioxide sodium content checks: with reference to national standard YBH25002006, adopt sulphuric acid volumetric solution (0.25mol/L) titration natrium carbonicum calcinatum, and calculate the content of natrium carbonicum calcinatum.Through test, meropenem does not disturb the mensuration of natrium carbonicum calcinatum, and the response rate and precision test are good.Investigate result, natrium carbonicum calcinatum steady quality according to stability test.Concrete testing result sees Table 1.
Table 1 powder injection of meropenem composition for injection testing result provided by the invention
Assay: with reference to " Chinese pharmacopoeia 2005 and version in 2010 adopt high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2010 D) to measure.Through test, it is 0.35% that the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 is provided carries out replica test RSD, middle precision test RSD is 0.23%, shows that the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 is provided carries out repeatability and middle precision is good.In the recovery test, the meropenem average recovery rate is 100.34%, RSD is 0.49%, it is good to show that the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 is provided carries out accuracy, the powder injection of meropenem composition for injection that in stability test the embodiment of the invention 2 to 10 is provided carries out at the lower 6h of placement of room temperature (25 ℃), main constituent peak area RSD is 0.45%, shows that the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides is stable in the 6h under room temperature (25 ℃) condition.
The stability test of embodiment 11 powder injection of meropenem composition for injections provided by the invention
Factors affecting stability test: get the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides, carry out following test:
Low-temperature test: get the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides, under 4 ℃ of conditions of low temperature, place, respectively at sampling in 0,5,10 day, detect by stable high spot reviews project.
Room temperature test: get the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides, place at ambient temperature, respectively at sampling in 0,5,10 day, detect by stable high spot reviews project.
Hot test: get the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides, under 40 ℃ of temperature and temperature 60 C condition, place respectively, respectively at sampling in 0,5,10 day, detect by stable high spot reviews project.
High humility test: get the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides, under the room temperature condition, in the constant humidity hermetic container respectively at relative humidity 75% (saturated aqueous sodium chloride) and relative humidity 92.5% (potassium nitrate saturated aqueous solution), respectively at sampling in 0,5,10 day, detect by stable high spot reviews project.
Strong illumination test: get the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides, nakedly under the 4500Lx illumination condition put and pack placement, respectively at sampling in 0,5,10 day, detect by stable high spot reviews project.Its result of the test sees Table 2, table 3.
Table 2 factors influencing
Table 3 influence factor tests the situation of change of each high spot reviews project
Annotate: variable quantity refers to the changing value with respect to 0 day, and " ↑ " expression raises; " ↓ " expression reduces; " 0 " expression is unchanged.
By table 2, table 3 as can be known, the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides is under cryogenic conditions, character, Clarity and colour of solution and pH value are without significant change, 10 days single contaminants of related substance have raise 0.09%, total impurities has raise 0.09%, occurs without other impurity; Meropenem and carbonate content are without significant change.
The powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides at ambient temperature, character, Clarity and colour of solution and pH value are without significant change, 10 days single contaminants of related substance have raise 0.63%, total impurities raises 0.73%; The meropenem content decrease 0.71%, carbonate content is without significant change.
The powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides is under hot conditions, this product heavy damage, related substance (40 ℃ of the high temperature that obviously raise, single contaminant raise 5.4% in 5 days, raise 9.20% in 10 days, 60 ℃ of high temperature, single contaminant raise 10.66% in 5 days, raise 12.11% in 10 days), meropenem content descends to some extent, and (40 ℃ of high temperature descended 5.73% in 10 days, 60 ℃ of high temperature descended 13.11% in 10 days), Clarity and colour of solution and pH value and carbonate content show that without significant change the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides reduces at the hot conditions stability inferior.
The powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides is under super-humid conditions, character, Clarity and colour of solution and pH value are without significant change, (high humidity 75% total impurities raise 0.08% to related substance in 10 days, high humidity 92.5% total impurities raises 0.07%), meropenem content descends (high humidity descended 0.12% in 75%10 days, high humidity descended 0.06% in 92.5%10 days) to some extent, and carbonate content is without significant change.
The powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides is nakedly respectively put and is packed under illumination condition, investigate character, with Clarity and colour of solution, pH value and carbonate content after the dissolving of injection liquid all without significant change; Put under the condition in that illumination is naked, related substance raises (single contaminant rose 2.75% in 10 days, and total impurities rose 3.16% in 10 days), and the meropenem content decrease descended 3.39% in 10 days; Under the illumination terms of packing, without significant change.
The powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 is provided respectively at 0,1,2,4, the 6h sampling, detect stability, color is without significant change, related substance, meropenem content are without significant change, every investigation index shows that the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides is more stable all in prescribed limit.
Accelerated test: the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides was placed 6 months under the condition of 30 ± 2 ℃ of temperature, relative humidity 65 ± 5%, respectively at the 0th, 1,2,3,6 sampling at the end of month once, measure by the high spot reviews project.By the accelerated test result as can be known, the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides was placed 6 months under this condition, color is without significant change, related substance slightly has rising, meropenem content slightly has decline, every investigation index shows that the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides is more stable under acceleration environment all in prescribed limit.
Long term test: get the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides, under 20 ± 2 ℃ of temperature, relative humidity 60 ± 10% conditions, placed 36 months.At duration of test respectively at the 3rd, 6,9,12,18 month, 24 samplings at the end of month once, detect by stable high spot reviews project.By long-term test results as can be known, the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides is after placing 18 months and 24 months under this condition, related substance slightly has rising, content slightly has decline, all other investigate indexs all in prescribed limit, show that the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 provides is more stable under the long preservation condition.
The embodiment 12 powder injection of meropenem composition for injection tests of pesticide effectiveness provided by the invention
The powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 is provided carries out acute toxicity test, chronic toxicity test, reproductive toxicity test, antigen test, mutagenicity test, renal toxicity test, central nervous system toxicity test.
Acute toxicity (LD
50, mg/kg) test: result of the test sees Table 7.
By body weight mice is divided into four groups at random, every group 5 hero 5 is female, and dosage is respectively 2650mg/kg, 2850mg/kg, 2950mg/kg, 3200mg/kg.Water is can't help in fasting in front 12 hours of the experiment mice administration.The administration of tail vein single injection administering mode is adopted in experiment, and the administration volume is 25mL/kg, and administration time is finished in 30s.Observe immediately and record poisoning symptom and the death condition of experiment mice after the administration.
Viewing duration, each is organized experiment mice obvious toxic reaction is not all occured, and also none example is dead.
Chronic toxicity test: Wister class rat is implemented intravenous injection in 6 months test according to 1～1000mg/kg and to hunting dog according to 1～500mg/kg, have no virose histology and change.
Reproductive toxicity test: Wister class rat is implemented the intravenous injection test according to 120～1000mg/kg and to macaque according to 120～360mg/kg, do not find that its reproductive function to animal is influential, and have no embryo, tire son had and cause death and teratogenesis shape property.
Antigen test: Hartley class Cavia porcellus is implemented the intravenous injection test, whole body allergy and PCA reaction are positive, the delayed reaction identical with imipenum appears in skin test, PHA reaction test so that the serum of New Zealand white class sensitization rabbit carries out detects low-level anti-meropenem antibody.
Mutagenicity test: in the back mutation experiment of microorganism, the experiment of mutagenicity frequency uses the chromosomal aberration test of cultured cell to reach with in the micronucleus test of mice as object, without mutagenicity.
Renal toxicity test: Wister class rat is implemented in 2 all intravenous injection tests according to 500mg/kg and 1000mg/kg, identical with ceftazidime 1000mg/kg administration group with cefotaxime, occur slightly changing, but have no the variation that can be used as the nephrotoxicity index.
Central nervous system toxicity: use the research of mice ventricles of the brain dose regimen to cause convulsion effect and the results are shown in Table 4.
Table 4 powder injection of meropenem composition for injection provided by the invention is to the central nervous system toxicity testing result
Test as can be known powder injection of meropenem composition for injection better tolerance of the present invention, safe by above acute toxicity testing, long term toxicity test, reproductive toxicity testing, antigenicity experiment, mutagenicity experiment, nephrotoxicity experiment, central nervous system toxicity.
The embodiment 13 powder injection of meropenem composition for injection tests of pesticide effectiveness provided by the invention
Each 300 patient of heating disease that the powder injection of meropenem composition for injection that the embodiment of the invention 2 to 10 is provided reduces pneumonia, children's's pseudomonas aeruginosa pneumonia, gynecological infection, meningitis, skin soft-tissue infection, septicemia, companion's neutrophilic granulocyte execute and control, and the results are shown in Table 5.
Table 5 test of pesticide effectiveness
By the test of pesticide effectiveness as can be known, heating disease effective percentage, cure rate that powder injection of meropenem composition for injection reduces pneumonia, children's's pseudomonas aeruginosa pneumonia, gynecological infection, meningitis, skin soft-tissue infection, septicemia, companion's neutrophilic granulocyte are high, show the powder injection of meropenem composition for injection good drug efficacy that the present invention prepares.
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (4)
1. a powder injection of meropenem composition for injection is characterized in that, is comprised of meropenem, sodium carbonate, sodium alginate; The mass ratio of described meropenem, sodium carbonate, sodium alginate is 50:100:4.9～9.9.
2. the preparation method of a powder injection of meropenem composition for injection is characterized in that, raw material is comprised of meropenem, sodium carbonate, sodium alginate, and the mass ratio of described meropenem, sodium carbonate, sodium alginate is 50:100:4.9～9.9; Take by weighing described raw material, cross 80～100 mesh sieves, obtain mixed liquor after the dissolving of adding water for injection, fine straining, fill, sealing and lyophilization make described powder injection of meropenem composition for injection.
3. preparation method as claimed in claim 2 is characterized in that, described cryodesiccated condition is: the pre-freeze temperature is-55～-30 ℃, and the pre-freeze time is 1～8h; Sublimation temperature is-35～-10 ℃, and the distillation time is 5～20h; Baking temperature is 15～50 ℃, and be 3～15h drying time.
4. preparation method as claimed in claim 2 is characterized in that, before the described lyophilization, also comprises the step of fine straining, fill, sealing.
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