CN103536560A - Ceftezole sodium composition powder for injection - Google Patents

Abstract

The invention provides a ceftezole sodium composition powder for injection, and belongs to the field of medicine and medicine preparation technology. The ceftezole sodium composition powder comprises following raw material ingredients, by weight, 7.26 to 9.17 parts of ceftezole sodium, 5.78 to 7.67 parts of chitosan nanoparticle, and 81.38 to 87.10 parts of injection water. Advantages of the ceftezole sodium composition powder are that: 1) in vitro antibacterial activity spectrum is wider, and poor antibacterial activity of ceftezole sodium on pneumococcus, pseudomonas aeruginosa and acinetobacter is improved greatly; 2) the nanoparticle medicine carrier is capable of changing membrane transport mechanisms, and increasing medicine permeability against biological membranes, and is beneficial for exhibition of pharmacological functions in cells; 3) ceftezole sodium coated by the nanoparticle carrier is rapidly gathered at primary organs, such as liver and spleen, of the reticuloendothelial system along veins, so that toxicity caused by nonspecific gathering of medicine is reduced; and 4) the chitosan nanoparticle can be used as a freeze-dried skeleton agent of the freeze-dried powder injection instead of mannitol so as to avoid active effects of mannitol on human bodies.

Description

Ceftezole sodium used for injection composition powder injection

Technical field:

The present invention relates to medicine and medicine manufacture technology field, relate in particular to a kind of Ceftezole sodium used for injection composite freeze-dried powder.

Background technology:

Chemical name is: (6R, 7R)-3-[(1,3,4-thiadiazoles-2-yl) sulphomethyl]-8-oxo-7-[2-(1H-tetrazolium-1-yl) acetylamino]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2 sodium formate.

Character: this product for white to light yellow crystalline powder, odorless, have and draw moistly, structural formula is as follows:

Cefobutazine sodium is semisynthetic cephalosporins derivatives, and its mechanism of action is the synthetic antibacterial activity of bringing into play by anti-bacteria cell wall.This product is widely distributed in vivo, wherein the highest with kidney, is followed successively by serum, liver, lung, the heart, spleen.Indication is respiratory system infection, urinary system infection, septicemia, peritonitis.

Cefobutazine sodium has antibacterial activity to following antibacterial: 1, aerobic gram positive bacteria: staphylococcus aureus, streptococcus pneumoniae, micrococcus scarlatinae.2, aerobic gram-negative bacteria: escherichia coli, klebsiella pneumoniae, Bacillus proteus.Antimicrobial spectrum is narrower, and streptococcus pneumoniae, Pseudomonas aeruginosa, acinetobacter calcoaceticus and stenotrophomonas maltophilia are to its drug resistance.Many and other antibiotic coupling clinically, but occurred as untoward reaction such as anaphylaxis, granulocytopenia, eosinophilia, thrombocytopenia.

Patient compliance is major issue in the treatment of infected by microbes.Preparation various active thing is that single dosage form can improve patient compliance and causes remarkable clinical benefit.Yet effective in order to become medicine, this single dosage form must meet multiple ductile and require as stability.

Chitosan is a kind of aminopolysaccharide polymer, is that the chitin by natural non-activity obtains after deacetylation.Structure and the cellulose of chitosan are quite similar, and just the acetylamino on sugar ring C2 has replaced hydroxyl, and this acetylamino gives chitosan special characteristic, make it can be for pharmaceutical preparation aspect.Chitosan is easy to dissolve in weak acid solvent, it is worthy of note especially in solution after dissolving and contains amino, and these amino are by carrying out anti-bacteria in conjunction with negatron.Chitosan is alkalescence, has very strong hydrophilic, can be with hydrochloric acid and acetic acid etc. the inorganic or synthetic salt of organic acid.A lot of physiologically actives of chitosan make it at field of medicaments, have a wide range of applications.

Chitosan nano is the microgranule that a kind of particle diameter is less than 100nm as novel anti-biotic material, this nanoparticle is due to the high-specific surface area of antibacterial and the special effects of high reaction activity, greatly improved whole antibacterial effect, can make microorganism comprise that the Growth and reproduction of antibacterial, fungus, yeast, algae and virus etc. keeps lower level.The various goods made from chitosan nano, can effectively avoid the propagation of antibacterial, and can, when thering is slow release, targeting and using separately as a kind of pharmaceutical carrier, there is weak antibiotic, bacteriostasis.

Summary of the invention:

Object of the present invention is exactly for the cefobutazine sodium antibacterials containing single component, and a kind of antimicrobial spectrum is wider, antibacterial action is stronger cefobutazine sodium antibacterial combination and pharmaceutical preparation thereof are provided.

Technical problem to be solved by this invention realizes by the following technical solutions.

The invention provides ceftezole composition of sodium, the prescription of said composition consists of cefobutazine sodium, chitosan nano, water for injection, 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 cefobutazine sodium) of cefobutazine sodium.

A composite freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:

7.26～9.17 parts of cefobutazine sodiums

5.78～7.67 parts of chitosan nanos

81.38～87.10 parts of waters for injection

The preparation method that the invention provides a kind of Ceftezole sodium used for injection composite freeze-dried powder, 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) the chitosan powder that takes 100g at room temperature adds 0.1mol/l acetic acid solution 40L, and 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, 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 of cooling final vacuum, moisture is lower than 2%, particle diameter≤100nm, zeta current potential is about 15mv;

(2) preparation of Ceftezole sodium used for injection 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 cefobutazine sodium 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 5.1, add 0.1% active carbon to stir 30 minutes, 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 cefobutazine sodium, every bottle of 40mg calculates loading amount;

4) according to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, be incubated 2 as a child, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, be incubated 3 hours, lyophilization finishes, outlet.

Beneficial effect of the present invention is:

The invention provides the compositions that a kind of cefobutazine sodium mixes in 1:0.8 ratio with chitosan nano, and make injection freeze-dried powder as antibacterials for clinical.The inventor is by consulting a large amount of documents and materials and test of many times screening demonstration, said composition tool has the following advantages: 1) antibacterial activity in vitro spectrum is wider, has improved the anti-streptococcus pneumoniae of single cefobutazine sodium, Pseudomonas aeruginosa, the poor feature of acinetobacter calcoaceticus isoreactivity; 2) drug-carrying nanometer particle can change film operative mechanism, increases medicine to biomembranous permeability, is conducive to medicine drug effect performance in cell; 3) cefobutazine sodium of nano-carrier parcel is gathered in rapidly the major organs of the reticuloendothelial systems such as liver and spleen along vein, has reduced the toxicity that the nonspecific gathering due to medicine causes; 4) the alternative mannitol of chitosan nano, as the lyophilizing skeleton agent of freeze-dried powder, has been eliminated the active function of mannitol to human body.

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-, Ceftezole sodium used for injection composite freeze-dried powder, in 1000.

Prescription:

Cefobutazine sodium 40g

Chitosan nano 32g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 32g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The cefobutazine sodium the extremely clarification of stirring and dissolving that add 40g.

With the buffer salt of sodium dihydrogen phosphate and sodium hydrogen phosphate, adjust pH to 5.1, add 0.1% active carbon to stir 30 minutes, 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 cefobutazine sodium, every bottle of 40mg calculates loading amount.

According to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, be incubated 2 as a child, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, be incubated 3 hours, lyophilization finishes, outlet.

The preparation of embodiment bis-, Ceftezole sodium used for injection composite freeze-dried powder, in 1000.

1. write out a prescription:

Cefobutazine sodium 40g

Chitosan nano 25g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 25g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The cefobutazine sodium the extremely clarification of stirring and dissolving that add 40g.

With the buffer salt of sodium dihydrogen phosphate and sodium hydrogen phosphate, adjust pH to 5.1, add 0.1% active carbon to stir 30 minutes, 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 cefobutazine sodium, every bottle of 40mg calculates loading amount.

According to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, be incubated 2 as a child, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, be incubated 3 hours, lyophilization finishes, outlet.

The preparation of embodiment tri-, Ceftezole sodium used for injection composite freeze-dried powder, in 1000.

Prescription:

Cefobutazine sodium 40g

Chitosan nano 39g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 39g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The cefobutazine sodium the extremely clarification of stirring and dissolving that add 40g.

With the buffer salt of sodium dihydrogen phosphate and sodium hydrogen phosphate, adjust pH to 5.1, add 0.1% active carbon to stir 30 minutes, 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 cefobutazine sodium, every bottle of 40mg calculates loading amount.

According to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, be incubated 2 as a child, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, be incubated 3 hours, lyophilization finishes, outlet.

Experimental data

1 materials and methods

1.1 material

1.1.1 medicine and reagent Ceftezole sodium used for injection (by A department, being produced), Ceftezole sodium used for injection (by the production of B department), embodiment mono-composition sample.

1.1.2 strain streptococcus pneumoniae.

1.1.3 culture medium plain agar and broth bouillon, according to a conventional method preparation.

1.2.3 extracorporeal bacteria inhibitor test

1.2.3.1 bacterium solution preparation is inoculated in the streptococcus pneumoniae strain of preservation in nutrient broth medium, in 37 ℃ of calorstats, cultivate after 20h, bacterium liquid is pressed 10 times of serial dilutions with normal saline, be inoculated in respectively agar plate, put 37 ℃ and cultivate 20h, calculate bacterium colony number, select suitable concn to make bacterial concentration at 105cfu/mL-106cfu/mL the dilution of bacterium liquid, standby.

1.2.3.2 minimum inhibitory concentration (MIC) is measured and is adopted 10 times of dilution methods of test tube.If A, B, tri-groups of test tubes of C, every group 11, compiling is in order No. 1-No. 11, each test tube all adds 4.5mL dilution bacterium liquid (bacterium liquid 105cfu/mL-106cfu/mL), the Ceftezole sodium used for injection (being produced by A department) that adds 0.5mL to prepare in No. 1 test tube of A group, the Ceftezole sodium used for injection (being produced by B department) that adds 0.5mL to prepare in No. 1 test tube of B group, embodiment mono-composition sample that adds 0.5mL to prepare in No. 1 test tube of C group, all by 10 times of dilution methods, be diluted to the 8th pipe, all establish medicine control tube for every group, bacterium liquid control tube and blank pipe, put in 37 ℃ of calorstats and cultivate, with ocular estimate and matched group comparison, as the medicinal liquid test tube that adds antibacterial is still clarification, indicate without bacterial growth, this pipe drug level has bacteriostasis, as be muddy, showing that antibacterial grows, this concentration medicine is without bacteriostasis.Using the complete lowest drug concentration without bacterial growth as antibacterial the sensitivity to this medicine, be this medicine MIC.

2, result and discussion

2.1 Ceftezole sodium used for injection (being produced by A department), Ceftezole sodium used for injection (being produced by B department), embodiment mono-composition sample all have inhibitory action in various degree to streptococcus pneumoniae, its MIC average is respectively: 2.4,2.1,0.5(g/L), and embodiment mono-composition sample antibacterial effect provided by the invention is obviously better than other two groups, present good antibacterial and bactericidal effect, have significant difference, 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. a Ceftezole sodium used for injection composite freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:

7.26～9.17 parts of cefobutazine sodiums

5.78～7.67 parts of chitosan nanos

81.38～87.10 parts of waters for injection.

2. a preparation method for Ceftezole sodium used for injection 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) the chitosan powder that takes 100g at room temperature adds 0.1mol/l acetic acid solution 40L, and 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, 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 of cooling final vacuum, moisture is lower than 2%, particle diameter≤100nm, zeta current potential is about 15mv;

(2) preparation of Ceftezole sodium used for injection 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 cefobutazine sodium 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 5.1, add 0.1% active carbon to stir 30 minutes, 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 cefobutazine sodium, every bottle of 40mg calculates loading amount;

4) according to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, be incubated 2 as a child, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, be incubated 3 hours, lyophilization finishes, outlet.