CN103536564A - Cefonicid sodium composition powder for injection - Google Patents

Abstract

The invention provides a cefonicid sodium composition powder for injection, and belongs to the field of medicine and medicine preparation technology. The cefonicid sodium composition powder comprises following raw material ingredients, by weight, 7.26 to 9.17 parts of cefonicid sodium, 5.16 to 6.50 parts of chitosan nanoparticle, and 82.38 to 88.10 parts of injection water. dvantages of the cefonicid sodium composition powder are that: 1) antibacterial effect of the cefonicid sodium composition on Gram-negative escherichia coli and Gram-positive micrococcus tetragenus is increased significantly; 2) the chitosan nanoparticle is capable of passing through tissue spaces, staying in tissues and cells for a long period of time, and releasing medicines; and after intravenous injection, the chitosan nanoparticle is mainly gathered in organs with abundant mononuclear macrophages, especially in liver and bone marrow; 3) improvement of activity is capable of shortening medication cycle of patients, and reducing occurrence likelihood of adverse reaction caused by accumulation of cefonicid 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

Cefonicid for inj composition powder injection

Technical field:

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

Background technology:

Cefonicid sodium is semisynthetic third generation cephalosporin, most of gram positive bacterias and negative bacterium are had to powerful antibacterial activity, and antimicrobial spectrum comprises bacillus pyocyaneus, escherichia coli, pneumobacillus, hemophilus influenza, aerogenesis enterobacterial, Proteus, Diplococcus Ji Jin Portugal bacterium etc.

Cefonicid for inj effect is fast, clinical conventional.But safety range is little, effective plasma level scope is narrow, and therapeutic index is narrow, affects its pharmacokinetics many factors, eliminates speed individual variation larger in body, and clinical medicine dose is difficult to grasp.

The drug resistance that the abuse of medicine causes, has brought new problem to the control of bacterial infection disease.The appearance of superbacteria has been beaten alarm bell to us.How to reduce bacterial drug resistance, become the topic that people are more and more concerned about.Be conceived to the practical situation of current clinical application, drug combination is the effective ways that solve bacterial drug resistance.

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 as delivery system, can increase the dissolubility of medicine, improve the absorption of medicine and the bioavailability of raising medicine, change pharmacokinetic property, effectively reduce the toxic and side effects of dosage and reduction medicine, this nanoparticle is comparatively stable by the beta-lactamase of plasmid and Chromosome-encoded to most antibacterials, 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 containing the cefonicid sodium antibacterials of single component, to gram negative bacteria escherichia coli and gram positive bacteria tetracoccus is insensitive, curative effect is not good enough defect, problem that bioavailability is not high provide a kind of antimicrobial spectrum more extensively, cefonicid sodium antibacterial combination and the pharmaceutical preparation thereof of the stronger bioavailability of antibacterial action.

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

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

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

7.26～9.17 parts of cefonicid sodiums

5.16～6.50 parts of chitosan nanos

82.38～88.10 parts of waters for injection

The preparation method that the invention provides a kind of cefonicid for inj 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 cefonicid for inj 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 cefonicid 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 cefonicid 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 cefonicid sodium mixes in 1:0.7 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) said composition is entered antibacterial activity for gram negative bacteria escherichia coli and gram positive bacteria tetracoccus effect and is obviously improved.

2) and this nanoparticle energy penetrate tissue gap, can be in tissue and cell resident and discharge medicine for a long time, after intravenous injection, mainly concentrate in mononuclear phagocyte abundant organ, especially liver, bone marrow.

3) active enhancing is shortened patient's medication cycle, has reduced cefonicid 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-, cefonicid for inj composite freeze-dried powder, in 1000.

Prescription:

Cefonicid sodium 80g

Chitosan nano 56g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 56g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The cefonicid 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 cefonicid 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-, cefonicid for inj composite freeze-dried powder, in 1000.

1. write out a prescription:

Cefonicid sodium 80g

Chitosan nano 68g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 68g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The cefonicid 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 cefonicid 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-, cefonicid for inj composite freeze-dried powder, in 1000.

Prescription:

Cefonicid sodium 80g

Chitosan nano 47g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 47g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The cefonicid 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 cefonicid 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

1.1 method

1.1.1 dilute the aseptic solution that accurately takes cefonicid sodium (A department), cefonicid sodium (B department), embodiment mono-composition sample water dissolution and be diluted to 2048 μ g/mL of medicine, in one 20 ℃ of preservations.

1.1.2 the preparation of bacteria suspension, from escherichia coli, 3 bacterium colonies of tetracoccus agar culture medium flat board difference picking of incubated overnight, is inoculated in two kinds of identical MH meat soups and increases bacterium 6h.With colony counting method, carry out after count of bacteria, with MH meat soup dilution 1.5 * 105CFU/mL.

1.1.3 the mensuration of minimal inhibitory concentration (MIC) is with reference to each antibiotic minimal inhibitory concentration (MIC) of micro-broth dilution method.Cefonicid sodium (A department), cefonicid sodium (B department), 3 kinds of antibacterials of embodiment mono-composition sample are become to 23 concentration with sterilizing MH meat soup doubling dilution, be respectively 2048,1024 ... 0.0005 μ g/mL. gets respectively 100 μ L and adds successively 96 orifice plates, again 1.5 * 105CFU/mL bacterium liquid, 100 μ L are added in hand-hole, 37 ℃ of cultivations, observed result, the least concentration of asepsis growth of take is this medicine minimal inhibitory concentration MIC.

2 results and analysis

The MIC result (ug/mL) of five kinds of medicines of table 1 to escherichia coli ATCC25922

Can find out that no matter cefonicid sodium composition sample is to minimum compared with the cefonicid sodium of A, B two department's one-components to escherichia coli or tetracoccus minimal inhibitory concentration, this has illustrated that cefonicid composition of sodium has very strong antibacterial ability, 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 cefonicid for inj composite freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:

7.26～9.17 parts of cefonicid sodiums

5.16～6.50 parts of chitosan nanos

82.38～88.10 parts of waters for injection.

2. a preparation method for cefonicid for inj 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 cefonicid for inj 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 cefonicid 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 cefonicid 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.