CN103550171A - Cefminox sodium composition freeze-dried powder injection for injection - Google Patents

Abstract

The invention provides a cefminox sodium composition freeze-dried powder injection for injection and relates to the field of medicines and medicine manufacturing technique. The cefminox sodium composition freeze-dried powder injection contains the following raw materials: by weight, 7.26-9.17 parts of cefminox sodium, 7.02-8.97 parts of chitosan nanoparticles and 81.38-87.10 parts of water for injection. The invention has advantages as follows: 1) the composition has a good antibacterial effect on klebsiella pneumonia, has sensitivity rate of 91.9%, and has obvious advantages in resisting ESBLs-producing klebsiella pneumonia; 2) the concentration of active ingredients of the composition is increased in a central compartment and cycling time is prolonged such that the medicine can play a better role in systemic treatment and curative effect of the medicine in a focus target site can be enhanced; 3) stability of the freeze-dried powder injection against beta-lactamase generated by gram-negative bacteria is enhanced, and distribution in vivo is good; 4) activity is enhanced such that medicine treatment cycle is shortened and possibility of adverse reaction caused by accumulation of cefminox sodium is reduced; and 5) the chitosan nanoparticles can replace mannitol to be used as a freeze-drying skeleton agent of the freeze-dried powder injection so as to eliminate the active effect of mannitol on human body.

Description

Cefminox sodium for injection composite freeze-dried powder

Technical field:

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

Background technology:

Cefminox sodium is cephamycin-type antibiotic, and it is stable to beta-lactamase.These product and beta-Lactam antibiotic application point penicillin-binding protein have very strong affinity, can suppress the biosynthesis of cell wall, and can be incorporated into peptide polysaccharide, and peptide for inhibiting polysaccharide is combined with lipoprotein and is promoted bacteriolyze.In addition, these product can also be combined with the meso diaminopimelic acid of the distinctive outer membrane lipoprotein of gram-negative bacteria, show at short notice the double sterilization effect that it is very strong.Klebsiella Pneumoniae is to cause one of all kinds of infection the main pathogenic fungi in hospital, in recent years due to being widely used of various antibacterials, and the especially appearance of multiple antibiotic resistant strain, causing kpn to infect mortality rate obviously increases.Kpn is the common bacteria that produces ESBLs, can cause to third generation cephalosporin monocycle amide-type and the 4th generation the beta-lactam antibiotic drug resistance such as cephalosporin.

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, just the acetylamino on sugar ring C2 has replaced hydroxyl, this acetylamino gives chitosan special characteristic, makes it can be for pharmaceutical preparation aspect, and a lot of physiologically actives of chitosan make it at field of medicaments, have a wide range of applications.Its chemical structural formula is as follows:

Chitosan nano is the microgranule that a kind of particle diameter is less than 100nm as novel anti-biotic material, not only can suppress the biomembranous formation of Klebsiella Pneumoniae and this nanoparticle owing to having improved the high-specific surface area of antibacterial and the special effects of high reaction activity, greatly strengthened whole antibacterial effect, can make microorganism comprise that the Growth and reproduction of antibacterial, fungus, yeast, algae and virus etc. keeps lower level.

Summary of the invention:

Object of the present invention is exactly for the Cefminox sodium antibacterials containing single component, and a kind of antimicrobial spectrum is wider, antibacterial action is stronger Cefminox 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 cefminox composition of sodium, the prescription of said composition consists of Cefminox 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 Cefminox sodium) of Cefminox sodium.

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

7.26～9.17 parts of Cefminox sodiums

7.02～8.97 parts of chitosan nanos

81.38～87.10 parts of waters for injection

The preparation method that the invention provides a kind of cefminox sodium 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 (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;

(2) preparation of cefminox sodium 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 Cefminox 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 Cefminox sodium, every bottle of 80mg 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 Cefminox sodium mixes in 1:0.9 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, and said composition tool has the following advantages: 1) Klebsiella Pneumoniae is had to good antibacterial action, responsive rate is 91.9%, with the obvious advantage in producing ESBLs Klebsiella Pneumoniae; 2) concentration of compositions effective ingredient in central compartment increases and circulation time prolongation, and this makes medicine can better bring into play whole body therapeutic effect, strengthens medicine in the curative effect of focus target site; 3) beta-lactam enzyme stability gram-negative bacteria being produced increases, and in body, distributes; 4) active enhancing is shortened patient's medication cycle, has reduced Cefminox sodium and has accumulated the probability that causes that untoward reaction occurs; 5) 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-, cefminox sodium for injection composite freeze-dried powder, in 1000.

1.prescription:

Cefminox sodium 80g

Chitosan nano 72g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 72g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The Cefminox sodium the extremely clarification of stirring and dissolving that add 80g.

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 Cefminox sodium, every bottle of 80mg 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-, cefminox sodium for injection composite freeze-dried powder, in 1000.

1. write out a prescription:

Cefminox sodium 80g

Chitosan nano 81g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 81g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The Cefminox sodium the extremely clarification of stirring and dissolving that add 80g.

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 Cefminox sodium, every bottle of 80mg 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-, cefminox sodium for injection composite freeze-dried powder, in 1000.

1.prescription:

Cefminox sodium 80g

Chitosan nano 64g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 64g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The Cefminox sodium the extremely clarification of stirring and dissolving that add 80g.

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 Cefminox sodium, every bottle of 80mg 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, experimental technique

Getting 100 μ L Klebsiella Pneumoniae bacterium liquid (1.0 * 106 cells) is inoculated in 96 porocyte culture plates, after 37 ℃ of cultivation 2h (sticking the stage), discard culture medium, PBS washes 3 times, add 100 μ Lrpmi1640 culture medium, as 0 point of cultivating, continue to cultivate, every 24 change 1 subculture.

Getting 100 μ L bacterium liquid is inoculated in 96 porocyte culture plates, 0 point of cultivating at biomembrane, Cefminox sodium (A department), Cefminox sodium (B department), mono-group of sample solution of embodiment (final concentration is 0.02-0.04mg/ml) of adding doubling dilution, blank group only adds culture medium, 37 ℃ are continued to cultivate after 48h, discard culture medium, PBS washes 3 times, every hole adds XTT100 μ L, the final concentration that makes XTT is that a 1 μ mol/L.37 ℃ lucifuge is hatched after 2h, microplate reader reads the OD value at 490nm wavelength place. and establish 3 multiple holes for every group, experiment repeats 3 times.

2, result and discussion

The bacteriostasis rate % of the different extension rates of table 1()

As shown in Table 1, the sample composition of embodiment mono-is obviously better than two groups of Cefminox sodium group (A) and Cefminox sodium groups (B) to the inhibition of Klebsiella Pneumoniae growth and biomembrane shape thereof, has greatly strengthened antibacterial effect.The compositions that this invention provides has synergism to suppressing the biomembranous formation of Klebsiella Pneumoniae, and clinic is promoted.

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 cefminox sodium for injection composite freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:

7.26～9.17 parts of Cefminox sodiums

7.02～8.97 parts of chitosan nanos

81.38～87.10 parts of waters for injection.

2. a preparation method for cefminox sodium 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 cefminox sodium 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 Cefminox 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 Cefminox sodium, every bottle of 80mg 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.