CN103536559A - Biapenem composition freeze-dried powder for injection - Google Patents
Biapenem composition freeze-dried powder for injection Download PDFInfo
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- CN103536559A CN103536559A CN201310481826.XA CN201310481826A CN103536559A CN 103536559 A CN103536559 A CN 103536559A CN 201310481826 A CN201310481826 A CN 201310481826A CN 103536559 A CN103536559 A CN 103536559A
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- biapenem
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Abstract
The invention provides a biapenem composition freeze-dried powder for injection, and belongs to the field of medicine and medicine preparation technology. The biapenem composition freeze-dried powder comprises following raw material ingredients, by weight, 1 part of biapenem, 0.2 to 10 parts of chitosan nanoparticle, and 91.18 to 93.08 parts of injection water. Advantages of the biapenem composition freeze-dried powder are that: the chitosan nanoparticle is used as a freeze-dried skeleton agent of the freeze-dried powder injection instead of mannitol, so that active effects of mannitol on human bodies are avoided, problems of stability and solubility are solved at the same time, antibacterial effect of biapenem is improved significantly, dosage of biapenem in clinic is reduced, and adverse reaction of biapenem is reduced. The biapenem composition freeze-dried powder is successfully developed, and is capable of providing novel ideas for clinical application of biapenem.
Description
Technical field:
The present invention relates to medicine and medicine manufacture technology field, relate in particular to a kind of injection biapenem composite freeze-dried powder.
Background technology:
Biapenem (Biapenem) chemical name is (-) 6-[[(4R, 5S, 6S)-2-carboxyl-6-[(1R)-1-ethoxy]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-3-yl] sulfur]-6,7-dihydro-5H-pyridine [1,2-a] [1,2,4] triazole-4-inner salt.
Biapenem is developed by Japanese Lederle company and American Cyanamid Company, by Japanese Lederle company and Japanese Mingzhi Co., Ltd., in March, 2002, is combined in Japan and goes on the market.
Biapenem is novel 1 Beta-methyl carbapenem antibiotic, and has a broad antifungal spectrum, all has good bactericidal action to gram negative bacteria, gram positive bacteria, aerobe and anaerobe; The specific activity imipenum of anti-gram negative bacteria, particularly anti Bacillus pyocyaneu Flugge is strong; To the antibacterial activity of aerobism gram positive bacteria slightly lower than imipenum; Anti-anaerobic activity is identical with imipenum.
This product is stable to beta-lactamase, does not need to share enzyme inhibitor.Stability to dehydropeptidase of kidney (DHP-I) is strong compared with Yi meter Pei Nan, need not with DHP-I inhibitor drug combination; Pharmacokinetic property is good, and toxicity is low, without nephrotoxicity and central nervous system toxicity; Concurrency intra-abdominal infection, lower respiratory infection and concurrency urinary tract infection are had to good therapeutic effect, better tolerance, untoward reaction rate is low.Clinically be applicable to treat bacterial meningitis, chronic bronchitis secondary infection, pneumonia, pulmonary suppuration disease, pyelonephritis, complexity cystitis, peritonitis and adnexitis, expectation can become the new first-line drug for the treatment of severe infection.Biapenem infects and all has good curative effect plastic operation infection, gynecological infection and otorhinolaryngology, a plurality of countries listing in the whole world.
The dosage form of biapenem list marketing is at present sterile packaged preparation, is the injectable powder being obtained by sterile bulk drug direct packaging, and this dosage form is higher to raw material and environmental requirement, and cost is larger; And biapenem stability in aqueous solution is poor, be not suitable for making hydro-acupuncture preparation.
Chinese invention patent (CN102068413) discloses a kind of biapenem lipidosome freeze-dried preparation, is by the liposomal encapsulated lyophilized formulations obtaining that for biapenem, the neutral phospholipid that contains antioxidant, negative charge phospholipid and cholesterol form.This lipidosome freeze-dried preparation toxic and side effects reduces, and drug effect does not reduce, and has solved quality stability problem.But the particle diameter of liposome is wide and it is wide to distribute, and its drug loading size is wayward, and clinical practice dosage is wayward.
Chitosan is a kind of aminopolysaccharide polymer, is that the chitin by natural non-activity obtains after deacetylation.Chitosan is alkalescence, has very strong hydrophilic, can be with hydrochloric acid and acetic acid etc. the inorganic or synthetic salt of organic acid.Chitosan has good biocompatibility, degradability and mucoadhesive, and its a lot of physiologically actives make it at field of medicaments, particularly have a wide range of applications aspect pharmaceutical preparation.Chitosan nano is the microgranule that a kind of particle diameter is not more than 100nm, as a kind of pharmaceutical carrier, has slow release and targeting, but also there is no clinically the pharmaceutical dosage form of chitosan-containing nanoparticle at present.
Summary of the invention:
The present invention, on the basis of great many of experiments, has researched and developed a kind of injection biapenem composite freeze-dried powder, has solved this area deficiency of the biapenem powder pin of existence at present, for having opened up new situation in biapenem freeze-dried powder field.
Technical problem to be solved by this invention realizes by the following technical solutions.
Biapenem composite freeze-dried powder provided by the invention, by biapenem, chitosan nano, water for injection, formed, it is characterized in that: chitosan nano can be used as skeleton agent, solubilizing agent, the synergist (chitosan nano itself has certain antibacterial activity, plays synergetic antibacterial effect after combining with biapenem) of biapenem.
A biapenem composite freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:
1 part of biapenem
0.2～10 part of chitosan nano
91.18～93.08 parts of waters for injection.
The preparation method that the invention provides a kind of injection biapenem composite freeze-dried powder, is characterized in that, comprises the steps:
One, the preparation of chitosan nano:
1, will after the pulverizing of chitosan powder, through 100 eye mesh screens, sieve;
2, the chitosan powder that takes 100g at room temperature (20 ℃) adds 0.1mol/L acetic acid solution 40L, and magnetic agitation, dissolves chitosan completely, obtains chitosan acetic acid solution (C=2.5g/L);
3, with 1%NaOH, regulate pH=5.0;
4, add 1% sodium tripolyphosphate 1667g to chitosan acetic acid solution under stirring, making chitosan/sodium tripolyphosphate mass ratio is 6:1, and the electrostatic interaction by zwitterion is cross-linked into nanoparticle;
5,, by 4 ℃ of high speed centrifugations of above-mentioned colloid solution (18000r/min) 30min, collect lower sediment, with after pure water washing 3 times, cooling final vacuum dry (30 ℃ following) obtains chitosan nano, moisture is lower than 2%, particle diameter≤100nm, and zeta current potential is about 15mV;
Two, the preparation of injection biapenem composite freeze-dried powder:
1, the chitosan nano of recipe quantity is slowly joined in the water for injection of recipe quantity, stir while adding to dissolving;
2, the biapenem the extremely clarification of stirring and dissolving that add recipe quantity;
3, with the buffer salt of sodium dihydrogen phosphate and sodium hydrogen phosphate, adjust pH to 5.0, add 0.1% active carbon to stir 30min, filtering active carbon, medicinal liquid is again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detect intermediate content, by biapenem, every bottle of 0.2g calculates loading amount;
4, according to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, after insulation 2h, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, insulation 3h, lyophilization finishes, outlet.
Beneficial effect of the present invention is:
A Peinan composite freeze-dried powder provided by the invention is used chitosan nano to substitute mannitol as the lyophilizing skeleton agent of freeze-dried powder, eliminated the active function of mannitol to human body, not only solved well the problem of stability and dissolubility simultaneously, and significantly strengthened the antibacterial effect of biapenem, can reduce biapenem consumption clinically, reduce biapenem untoward reaction, a kind of successful biapenem composite freeze-dried powder preparation, for new approaches have been started in the clinical practice of biapenem.
The specific embodiment:
Following examples are used for illustrating the present invention, yet these embodiment do not limit the scope of the invention.
The preparation of embodiment mono-, injection biapenem composite freeze-dried powder, in 1000.
1, prescription:
Biapenem 200g
Chitosan nano 100g
Water for injection 2000ml
2, preparation technology:
The chitosan nano that takes 100g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.
The biapenem the extremely clarification of stirring and dissolving that add 200g.
With the buffer salt of sodium dihydrogen phosphate and sodium hydrogen phosphate, adjust pH to 5.0, add 0.1% active carbon to stir 30min, filtering active carbon, medicinal liquid is again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detect intermediate content, by biapenem, every bottle of 0.2g calculates loading amount.
According to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, after insulation 2h, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, insulation 3h, lyophilization finishes, outlet.
The preparation of embodiment bis-, injection biapenem composite freeze-dried powder, in 1000.
1, prescription:
Biapenem 200g
Chitosan nano 130g
Water for injection 2000ml
2, preparation technology:
The chitosan nano that takes 130g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.
The biapenem the extremely clarification of stirring and dissolving that add 200g.
With the buffer salt of sodium dihydrogen phosphate and sodium hydrogen phosphate, adjust pH to 5.0, add 0.1% active carbon to stir 30min, filtering active carbon, medicinal liquid is again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detect intermediate content, by biapenem, every bottle of 0.2g calculates loading amount.
According to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, after insulation 2h, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, insulation 3h, lyophilization finishes, outlet.
The preparation of embodiment tri-, injection biapenem composite freeze-dried powder, in 1000.
1, prescription:
Biapenem 200g
Chitosan nano 80g
Water for injection 2000ml
2, preparation technology:
The chitosan nano that takes 80g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.
The biapenem the extremely clarification of stirring and dissolving that add 200g.
With the buffer salt of sodium dihydrogen phosphate and sodium hydrogen phosphate, adjust pH to 5.0, add 0.1% active carbon to stir 30min, filtering active carbon, medicinal liquid is again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detect intermediate content, by biapenem, every bottle of 0.2g calculates loading amount.
According to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, after insulation 2h, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, insulation 3h, lyophilization finishes, outlet.
Biocidal property experiment
Experiment purpose: the bacteriostasis of observing injection biapenem composite freeze-dried powder;
Medicine: 40mg/ml biapenem solution, 40mg/ml chitosan nano solution, 20mg/ml biapenem composition solution;
Method and criterion: use paper disk method, observe the size of inhibition zone.Inhibition zone is larger, represents that medicine bacteriostasis is stronger, and antibacterial is higher to this susceptibility sensitivity.Bacteriostatic level standard is as follows: inhibition zone <10mm, represents insensitive or slight sensitive; Inhibition zone 10mm～15mm, represents medium sensitivity; Inhibition zone >15mm, represents extremely sensitive.
Step:
1, with the little cotton swab of sterilizing, dip the staphylococcus aureus liquid (concentration is 108cfu/ml) having prepared, take and just soak whole cotton swab as degree, from 4 different directions level crossing line, make bacterium liquid evenly coat whole agar plate surface lightly.
2, prepare respectively 40mg/ml biapenem solution, 40mg/ml chitosan nano solution, 20mg/ml biapenem composition solution, respectively gets 2ml and (separately add one group of blank) in test tube, and labelling.With aseptic pincet, get 8 of circular filter papers, every two are dipped in same medicinal liquid, soak into rear taking-up, drain too much medicinal liquid.2 filter paper containing a kind of medicinal liquid are placed on respectively to the zones of different of the agar plate surface of inoculated bacteria.For location interval is accurate, at the bottom of ware, of marker pen, making mark in advance.
3, culture dish is put into incubator and is hatched 24h in 37 ℃, observe the scraps of paper and have or not inhibition zone around, by outcome record in table 1.Measure the diameter of inhibition zone, relatively the antibacterial efficacy of each medicine.
Result:
Table 1 biocidal property result of the test (n=8)
| Medicine | Average diameter of inhibition zone (mm) |
| Blank | 0 |
| Biapenem | 16.52 |
| Chitosan nano | 9.75 |
| Biapenem compositions | 17.60 |
By experiment in vitro, prove that the 0.2g biapenem of chitosan-containing nanoparticle is close with the 0.4g biapenem antibacterial efficacy of chitosan-containing nanoparticle not, visible, said composition has good synergism in the forming process that suppresses bacterium colony, the use of chitosan nano has reduced the consumption of biapenem, and clinic is applied.
More than show and described ultimate principle of the present invention, principal character and advantage of the present invention.The technical staff of the industry should understand; the present invention is not restricted to the described embodiments; what in above-described embodiment and description, describe is only preference of the present invention; be not used for limiting the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (2)
1. an injection biapenem composite freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:
1 part of biapenem
0.2～10 part of chitosan nano
91.18～93.08 parts of waters for injection.
2. a preparation method for injection biapenem composite freeze-dried powder described in claim 1, is characterized in that, comprises the steps:
(1) preparation of chitosan nano:
(1) will after the pulverizing of chitosan powder, through 100 eye mesh screens, sieve;
(2) take the chitosan powder 100g of above-mentioned mistake 100 eye mesh screens, add 0.1mol/L acetic acid solution 40L under room temperature, magnetic agitation, dissolves chitosan completely, obtains chitosan acetic acid solution;
(3) with 1%NaOH, regulate pH=5.0;
(4) add 1% sodium tripolyphosphate 1667g to chitosan acetic acid solution under stirring, obtain colloid solution, making chitosan/sodium tripolyphosphate mass ratio is 6:1, and the electrostatic interaction by zwitterion is cross-linked into nanoparticle;
(5) by 4 ℃ of high speed centrifugation 30min of above-mentioned colloid solution, collect lower sediment, with after pure water washing 3 times, the dry chitosan nano that obtains in cooling juxtaposition drying under reduced pressure case, moisture is lower than 2%, particle diameter≤100nm, zeta current potential is about 15mv;
(2) preparation of injection biapenem composite freeze-dried powder:
(1) chitosan nano of recipe quantity is slowly joined in the water for injection of recipe quantity, stir while adding to dissolving;
(2) add biapenem the extremely clarification of stirring and dissolving of recipe quantity;
(3) with the buffer salt of sodium dihydrogen phosphate and sodium hydrogen phosphate, adjust pH to 5.0, add 0.1% active carbon to stir 30min, filtering active carbon, medicinal liquid is again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detect intermediate content, by biapenem, every bottle of 0.2g calculates loading amount;
(4) according to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, after insulation 2h, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, insulation 3h, lyophilization finishes, outlet.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110812357A (en) * | 2019-11-06 | 2020-02-21 | 山东省农业科学院奶牛研究中心 | Application of biapenem in preparation of medicine for preventing and treating bovine enterovirus infection |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102319219A (en) * | 2011-09-30 | 2012-01-18 | 四川金瑞克动物药业有限公司 | Chitosan nanoparticle preparation of ceftiofur sodium, and preparation method thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102319219A (en) * | 2011-09-30 | 2012-01-18 | 四川金瑞克动物药业有限公司 | Chitosan nanoparticle preparation of ceftiofur sodium, and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 刘慧: "《壳聚糖微球/纳米粒的制备及其性能研究》", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110812357A (en) * | 2019-11-06 | 2020-02-21 | 山东省农业科学院奶牛研究中心 | Application of biapenem in preparation of medicine for preventing and treating bovine enterovirus infection |
| CN110812357B (en) * | 2019-11-06 | 2022-09-23 | 山东省农业科学院奶牛研究中心 | Application of biapenem in preparation of medicine for preventing and treating bovine enterovirus infection |
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Application publication date: 20140129 |