CN103550247A - Cefpiramide sodium composition freeze-dried injection for injection - Google Patents

Abstract

The invention provides a cefpiramide sodium composition freeze-dried injection for injection, and relates to the technical field of medicines and medicine preparation. The cefpiramide sodium composition freeze-dried injection for injection comprises the following raw material components in parts by weight: 7.26-9.17 parts of cefpiramide sodium, 5.78-7.67 parts of chitosan nanoparticles and 81.38-87.10 parts of water for injection. The cefpiramide sodium composition freeze-dried injection for injection has the advantages that 1) the in vitro antimicrobial activity spectrum is wider and covers Gram-positive bacteria and Gram-negative bacteria (comprising Pseudomonas aeruginosa), the characteristics that the G+ bacterial and Pseudomonas aeruginosa resistance of the third and fourth generation cephalosporin and the activity of anaerobic bacteria are poor, and research and development direction of cephalosporin is met; 2) the injection is good in stability, thus greatly reducing the risk that the product quality is greatly reduced in production and circulation links (particularly commercial circulation; 3) the activity is enhanced, so that the medication period of the patient is shortened, and the probability of adverse reaction caused by accumulation of cefpiramide sodium is reduced; 4) the chitosan nanoparticles can replace mannitol as a freeze-dried skeleton agent of the freeze-dried injection, so that the activity of mannitol on human body is eliminated.

Description

Cefpiramide 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 cefpiramide sodium for injection composite freeze-dried powder.

Background technology:

Cefpiramide sodium is semisynthetic Third generation Cephalosporins antibiotic.The feature of this product is for having antimicrobial spectrum and sterilizing power widely, to beta lactamase quite stable.Clinically be mainly used in sensitive organism and infect pharyngolaryngitis, tonsillitis, acute/chronic bronchitis, pneumonia, pulmonary suppuration disease, meningitis and the gynecological infection etc. cause.The 1A of mechanism of action and penicillin-binding protein (PBP), 1B and 3 has very strong affinity, anti-bacteria cell wall synthetic, thereby performance bactericidal action.

In clinical practice, find that single cefpiramide sodium is to bacillus pyocyaneus and anaerobe poor activity, very general with other anti-infectives use in conjunction, but there is incompatibility phenomenon according to clinical data report cefpiramide sodium and other medicines, in injection, occur white opacity and floccule, frequent medication can cause nausea,vomiting,diarrhea, epilepsy etc.Along with people are more urgent to healthy demand, exploitation determined curative effect, safe preparation just can obtain the generally approval of doctor and patient.

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 comprised of macromolecular material, and particle diameter is in 1-100nm scope.Medicine can wrap up, be dissolved in wherein or adsorb, be attached to surface.This nanoparticle, due to the high-specific surface area of antibacterial and the special effects of high reaction activity, has improved whole antibacterial effect greatly, 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 have weak antibiotic, bacteriostasis can have slow release, targeting and use separately as a kind of pharmaceutical carrier time.

Summary of the invention:

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

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

7.26～9.17 parts of cefpiramide 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 cefpiramide 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 cefpiramide 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 cefpiramide 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 cefpiramide sodium, every bottle of 1.0g 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 cefpiramide 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, Grain-positive and gram-negative bacteria (comprising bacillus pyocyaneus) have been covered, improved the feature of the anti-G+ bacterium of the 3rd, the 4th generation cephalosporin, bacillus pyocyaneus and anaerobe poor activity, the R&D direction of having agreed with cephalosporin; 2) good stability, this greatly reduces in the danger of producing and intermediate links (particularly commercial distribution) product quality significantly reduces; 3) active enhancing is shortened patient's medication cycle, has reduced cefpiramide 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-, cefpiramide sodium for injection composite freeze-dried powder, in 1000.

Prescription:

Cefpiramide sodium 1000g

Chitosan nano 800g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 800g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The cefpiramide sodium the extremely clarification of stirring and dissolving that add 1000g.

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 cefpiramide sodium, every bottle of 1.0g 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-, cefpiramide sodium for injection composite freeze-dried powder, in 1000.

1. write out a prescription:

Cefpiramide sodium 1000g

Chitosan nano 865g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 865g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The cefpiramide sodium the extremely clarification of stirring and dissolving that add 1000g.

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 cefpiramide sodium, every bottle of 1.0g 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-, cefpiramide sodium for injection composite freeze-dried powder, in 1000.

1. write out a prescription:

Cefpiramide sodium 1000g

Chitosan nano 757g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 757g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The cefpiramide sodium the extremely clarification of stirring and dissolving that add 1000g.

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 cefpiramide sodium, every bottle of 1.0g 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 cefpiramide sodiums for drug injection (being produced by A department), cefpiramide sodium for injection (being produced by B department), embodiment mono-composition sample.

1.2 strain bacillus pyocyaneus and anaerobe

1.3 statistical method

Test data represents with mean ± standard deviation (x ± s).All measurement datas adopt t check, and enumeration data adopts rank test.

1.4 in-vitro antibacterial experiments

1.4.1 the preparation of Plating (1) Carnis Bovis seu Bubali cream soup agar culture medium: get Carnis Bovis seu Bubali cream 3g, peptone 10g, sodium chloride 5g, agar 20g; put in beaker; add after a small amount of distilled water heat fused; adding distil water is diluted to 1000ml again; with 0.1mol/L NaoH solution adjust pH to 7.5, filter, be sub-packed in conical flask; sterilizing 30min, standby; (2) preparation of pastille culture medium: get respectively reagent test liquid (1g/ml) 10ml first group of culture dish of labelling extremely, add 40ml and melted and be incubated the Carnis Bovis seu Bubali cream soup agar culture medium in 56 ℃, mix, make pastille agar culture medium; Draw again above-mentioned Carnis Bovis seu Bubali cream soup agar 25ml in second group of culture dish, add 25ml Carnis Bovis seu Bubali cream soup agar culture medium, mix, as these times of dilution, making final concentration is the pastille agar culture medium of 200,100,50,25,12.5,6.25,3.12,1.56 (1/5,1/10,1/20,1/40,1/80,1/160,1/320,1/640).After cooled and solidified, in the refrigerator of 4 ℃, save backup.With standby bacterial strain contrast and the negative control culture medium that does not contain medicine of legal system; (3) inoculation of bacterial strain and cultivation: the test of punch method and Plating gets that each strain is inoculated in respectively pastille agar plate, the bacterial strain containing medicine contrast and negative control flat board routinely, putting 37 ℃ of incubators cultivates after 24h, observe the growing state of different strain on the medicine flat board of variable concentrations, the least concentration that antibacterial does not grow is medicine to the minimum inhibitory concentration of this bacterium (MIC).

2, result and discussion

2.1 Plating cefpiramide sodium for injection (being produced by A department), cefpiramide sodium for injection (being produced by B department), embodiment mono-composition sample all have inhibitory action in various degree to bacillus pyocyaneus and anaerobe, its MIC is respectively: 3.5,3.1,0.9(g/L), and embodiment mono-composition sample antibacterial effect provided by the invention is obviously better than other two groups, 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 cefpiramide 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 cefpiramide sodiums

5.78～7.67 parts of chitosan nanos

81.38～87.10 parts of waters for injection.

2. a preparation method for cefpiramide 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 cefpiramide 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 cefpiramide 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 cefpiramide sodium, every bottle of 1.0g 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.