CN103536558A - Cefoperazone sodium composition freeze-dried powder for injection - Google Patents

Abstract

The invention provides a cefoperazone sodium composition freeze-dried powder for injection, and belongs to the field of medicine and medicine preparation technology. The cefoperazone sodium composition freeze-dried powder comprises following raw material ingredients, by weight, 7.26 to 9.17 parts of cefoperazone sodium, 4.36 to 5.50 parts of chitosan nanoparticle, and 84.38 to 89.10 parts of injection water. Advantages of the cefoperazone sodium composition freeze-dried powder are that: 1) antibacterial activity of the cefoperazone sodium composition is increased significantly; 2) antibacterial spectrum is widened, and drug tolerance is reduced greatly; 3) improvement of activity is capable of shortening medication cycle of patients, and reducing occurrence likelihood of adverse reaction caused by accumulation of cefoperazone sodium; and 4) the chitosan nanoparticle can be 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.

Description

Cefoperazone sodium in 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 cefoperazone sodium in injection composite freeze-dried powder.

Background technology:

Cefoperazone sodium is the semi-synthetic cephalosporin of third generation wide spectrum, can resist the Degradation of multiple beta-lactamase, has a broad antifungal spectrum, antibacterial action is strong, gram positive bacteria and negative bacterium are all had to effect, but due to irrational application clinically, cause antibacterial to produce drug resistance, Resistant strain increases gradually, has become a great problem of clinical application.Its drug resistance is mainly because cefoperazone is received to bacteriogenic ultraphotic spectrum lactamase unstable.

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, medicine is wrapped up and being made after nanoparticle, covered physical and chemical properties of drugs, its physicochemical property depends on nanoparticle surface nature, so the medicine of different in kind can be transported to lesions position in vivo simultaneously and realizes drug combination.This nanoparticle can the hydrolysis of competitive inhibition beta-lactamase to beta-lactam nucleus in beta-lactam antibiotic, has weak antibiotic, bacteriostasis when having slow release, targeting and using separately as a kind of pharmaceutical carrier.

Summary of the invention:

Object of the present invention is exactly for the cefoperazone sodium antibacterials containing single component, the defect insensitive to beta-lactamase bacterium, curative effect is not good enough, provides a kind of antimicrobial spectrum is wider, antibacterial action is stronger cefoperazone sodium antibacterial combination and pharmaceutical preparation thereof.

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

The invention provides cefoperazone composition of sodium, the prescription of said composition consists of cefoperazone 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 cefoperazone sodium) of cefoperazone sodium.

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

7.26～9.17 parts of cefoperazone sodiums

4.36～5.50 parts of chitosan nanos

84.38～89.10 parts of waters for injection

The preparation method that the invention provides a kind of cefoperazone sodium in 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 cefoperazone sodium in 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 cefoperazone 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 cefoperazone 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 cefoperazone sodium mixes in 1:0.6 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 of said composition obviously improves, 2) antimicrobial spectrum becomes wide and drug resistance and obviously declines, 3) active enhancing is shortened patient's medication cycle, has reduced cefoperazone sodium and has accumulated the probability that causes that untoward reaction occurs; 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-, cefoperazone sodium in injection composite freeze-dried powder, in 1000.

Prescription:

Cefoperazone sodium 40g

Chitosan nano 24g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 24g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The cefoperazone 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 cefoperazone 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-, cefoperazone sodium in injection composite freeze-dried powder, in 1000.

1. write out a prescription:

Cefoperazone sodium 40g

Chitosan nano 30g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 30g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The cefoperazone 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 cefoperazone 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-, cefoperazone sodium in injection composite freeze-dried powder, in 1000.

Prescription:

Cefoperazone sodium 40g

Chitosan nano 18g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 18g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The cefoperazone 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 cefoperazone 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 data and method

1.1 physical data are chosen the positive staphy lococcus infections basis of 48 strains of in March, 2011～2012 year December, from 48 routine infected patients, male's 25 examples wherein, women's 23 examples, mean age is (33～2.6) year, wherein there are 25 strains to occur drug resistance, utilize cefoxitin disk to carry out the judgement of drug resistance.

1.2 methods utilize the method for agar plate dilution of respective standard and the method for D mono-check to carry out antibacterial isolation identification, D mono-check and drug sensitive test.First be that microbiological analysis instrument carries out separation to antibacterial, and utilizing cefoxitin disk whether to have drug resistance to patient antibacterial identifies, moreover be the method for D mono-check, mainly will have on the positive staphylococcic agar of being attached to of antibiotic medicine, by diffusion, can control the concentration of the scraps of paper, by measuring the size of inhibition zone, reflect that positive staphylococcus is to antibiotic sensitivity, inhibition zone is larger, and antibacterial concentration is generally less.Be finally drug sensitive test, configure bacterium suspension, the single and antibiotic composition Cmin of application agar plate dilution test, by the design of checkerboard type, thereby calculates Combination index.

The optimum single cefoperazone sodium (A of 1-3 clinical observation contrast, B company produces), cefoperazone sodium antibiotic combinations substrate concentration, bacteriostasis rate, Combination index, in general, the situation that combines antibacterial index <l represents, the antibiotic of applied in any combination shows as collaborative effect, but the situation that combines antibacterial index >1 <2 represents, the antibiotic of applied in any combination shows as does not have interaction relationship, the situation that combines antibacterial index >2 represents, the antibiotic of applied in any combination shows as antagonism.

2 results

Table 1 Mlc information slip

The antibacterial index of table 2 combination

In conjunction with Mlc, show that with the antibacterial exponential experiment result of combination cefoperazone composition of sodium is relative high to the staphylococcic In Vitro Bacteriostasis rate of the positive, effect is obvious, for strengthening, positive staphylococcus drug resistance impact is little, a kind of safe, efficient Therapeutic Method of can yet be regarded as, clinic is applied.

Through homogeneity test of variance, show that variance is neat, embodiment mono-sample and A factory sample, B factory sample have significant difference (P<0.05), and the bacteriostasis of A factory sample and B factory example pharmaceuticals is without significant difference (P>0.05) simultaneously.

By experiment in vitro, prove that the cefoperazone sodium antimicrobial spectrum of chitosan nano becomes extensively and antibacterial activity significantly strengthens, said composition has good synergism in the forming process that suppresses bacterium colony, 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. a cefoperazone sodium in injection composite freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:

7.26～9.17 parts of cefoperazone sodiums

4.36～5.50 parts of chitosan nanos

84.38～89.10 parts of waters for injection.

2. a preparation method for cefoperazone sodium in 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 cefoperazone sodium in 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 cefoperazone 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 cefoperazone 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.