CN103585171A - Aztreonam composition freeze-dried powder for injection - Google Patents

Abstract

The invention provides an aztreonam composition freeze-dried powder for injection, relating to the technical field of drugs and drug preparation. The aztreonam composition freeze-dried powder comprises the following raw material components in parts by weight: 9.47-11.58 parts of aztreonam, 4.74-5.79 parts of chitosan nanoparticles and 75.79-92.63 parts of water for injection. The aztreonam composition freeze-dried powder has the advantages: (1) a composition composed of aztreonam and chitosan nanoparticles according to the proportion of 1:0.5 not only can be used for improving the solubility of aztreonam in water, but also can be used for shortening the dissolving time of aztreonam so as to be beneficial for clinical application; (2) the composition can be used for remarkably enhancing the antibacterial effect of aztreonam and can be used for clinically reducing the dosage and adverse reaction of aztreonam, and an in-vitro experiment proves that 0.2g of aztreonam containing the chitosan nanoparticles has the same antibacterial effect with 0.4g of aztreonam not containing the chitosan nanoparticles; (3) the chitosan nanoparticles can be used as a freeze-dried skeleton agent of the freeze-dried powder for injection to replace arginine, so that the activation effect of arginine to human bodies is eliminated.

Description

Aztreonam 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 aztreonam for injection composite freeze-dried powder.

Background technology:

Aztreonam is a kind of monocycle beta-lactam antibiotic of synthetic.Its antibacterial action mechanism is to pass through rapidly the outer membranous wall of Gram-negative aerobic cell, to penicillin-binding protein 3(PBP-3) there is high affinity, by acting on PBP-3, synthesizing of anti-bacteria cell wall, causes cytolysis and death.Aztreonam has the antibacterial activity of height to most of aerobic gram-negative bacterias, comprise escherichia coli, the pneumobacillus of Klebsiella and OKCY holder bacterium, aerobacteria, bacillus cloacae, serratia marcecens, citric acid bacterium genus, Shigella Deng Chang section antibacterial, and hemophilus influenza, gonococcus, meningococcus etc., it also has good antibacterial action to Pseudomonas aeruginosa.

Oral absorb hardly (less than 1%) of aztreonam, intramuscular injection absorbs rapidly, completely, is distributed widely in vivo in various tissues and body fluid, and can reaches effective treatment concentration, thereby suitablely make injection administration.Because aztreonam is poor at solution state stability inferior, can not tolerate heat sterilization, thereby can not be developed to solution form injection simultaneously, can only be developed to the injection of solid form, i.e. aztreonam for injection.

In existing production technology, aztreonam for injection adopts three kinds of methods to produce conventionally, and the first is dissolved in the water aztreonam and arginine according to a certain percentage, carries out aseptic without carrying out lyophilization after thermal source processing; It two is to adopt aztreonam to mix with arginine, direct aseptic subpackaged acquisition; It three is to adopt aztreonam and arginine salify in organic solvent, and the solid of recrystallization acquisition is directly aseptic subpackaged.It four is that the form with a kind of sterilized powder exists respectively by the independent packing respectively of aztreonam and arginine, during use, arginine solution is expelled in the bottle that aztreonam sterilized powder is housed, to be dissolved after, with solvent for injection dilution, use.

Yet, the equal Shortcomings of above method; First, aztreonam is aseptic subpackaged after mixing with arginine, and the two is difficult to mix homogeneously, the vibrations in minute process of assembling, and storage, in transportation, easily causes the two layering, mixes unevenly, and the stability between causing every bottle is inconsistent.Secondly, adopt after aztreonam and arginine salify, the method for recrystallization, shortcoming is to use lossy poisonous organic solvent, unfriendly to environment.The 3rd, while using together with arginine, use amount is larger, and side effect is also larger.

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, 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 a kind of pharmaceutical carrier, has slow release and targeting, but also there is no clinically the pharmaceutical dosage form of chitosan-containing nanoparticle at present.

Summary of the invention:

An object of the present invention is to provide a kind of aztreonam for injection lyophilized powder compositions, said composition principal agent is: aztreonam, chitosan nano.

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

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

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

9.47～11.58 parts of aztreonam

4.74～5.79 parts of chitosan nanos

75.79～92.63 parts of waters for injection

The invention provides a kind of preparation method of aztreonam for injection composite freeze-dried powder,, it is characterized in that, comprise the steps:

The preparation of chitosan nano:

1. after chitosan powder being pulverized, 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. under stirring, add 1% sodium tripolyphosphate 1667g to chitosan acetic acid solution, 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;

The preparation of aztreonam for injection composite freeze-dried powder agent:

1. the chitosan nano of recipe quantity is slowly joined in the water for injection of recipe quantity, stir while adding to dissolving;

2. the aztreonam the extremely clarification of stirring and dissolving that add 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 aztreonam, every bottle of 0.5g 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 aztreonam mixes in 1:0.5 ratio with chitosan nano, and make injection freeze-dried powder as antibacterials for clinical.Through inventor's many experiments checking said composition tool, have the following advantages: 1) in 1:0.5(aztreonam: chitosan nano) compositions of ratio composition can not only improve the dissolubility of aztreonam in water and can shorten its dissolution time, is conducive to clinical practice.2) this compositions can significantly strengthen the antibacterial effect of aztreonam, can reduce aztreonam consumption clinically, reduce aztreonam untoward reaction, by experiment in vitro prove the 0.2g aztreonam of chitosan-containing nanoparticle and not the 0.4g aztreonam antibacterial efficacy of chitosan-containing nanoparticle be equal to.3) the alternative arginine of chitosan nano, as the lyophilizing skeleton agent of freeze-dried powder, has been eliminated the active function of arginine 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-, aztreonam for injection composite freeze-dried powder, in 1000.

Prescription:

Aztreonam 250g

Chitosan nano 100g

Water for injection 2000ml

2. preparation technology:

(1) chitosan nano that takes 250g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

(2) add aztreonam the extremely clarification of stirring and dissolving of 500g.

(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 aztreonam, every bottle of 0.5g 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.

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

1. write out a prescription:

Aztreonam 250g

Chitosan nano 125g

Water for injection 2000ml

2. preparation technology:

(1) chitosan nano that takes 250g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

(2) add aztreonam the extremely clarification of stirring and dissolving of 500g.

(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 aztreonam, every bottle of 0.5g 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.

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

Prescription:

Aztreonam 250g

Chitosan nano 150g

Water for injection 2000ml

2. preparation technology:

(1) chitosan nano that takes 300g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

(2) add aztreonam the extremely clarification of stirring and dissolving of 500g.

(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 aztreonam, every bottle of 0.5g calculates loading amount.

(4), according to testing requirement fill, after half tamponade, send in freezer dryer outlet after lyophilizing, good forming ability.

Experimental data

One, accelerated test.

The prepared product of sample 1 embodiment 2

The aztreonam for injection (A of producer) that sample 2 is commercially available

The aztreonam for injection (B of producer) that sample 3 is commercially available

Respectively sample 1, sample 2, sample 3 are put respectively to 40 ℃, under the condition of RH=75%, place 6 months, in 0,1,2,3, sampling in June detects its related substance.

Table 2 sample accelerated test related substance result

From the above experimental results, this product has good stability.

Two: biocidal property experiment

1. experimental technique:

Paper disk method is a kind of (available plastic foam or Oxford cup substitute the scraps of paper) in diffusion method, is that Experiment on Microbiology medium sensitivity is higher, a kind of method of extensive employing.Application antibiotic virgin paper sheet is seeded in the diffusion in germy culture medium, and active drug can cause the scraps of paper and occur the not region of long bacterium of a circle around, claims inhibition zone.Inhibition zone is larger, represents that medicine bacteriostasis is stronger, and this bacterium is higher to this susceptibility sensitivity.Paper disk method can be with reference to following standard recording result: inhibition zone <10mm, represents insensitive; 10mm represents slight sensitive; 11mm～15mm, represents medium sensitivity; 16mm～20mm, represents extremely sensitive.

2. experimental procedure:

(1) with the little cotton swab of sterilizing, dip the staphylococcus aureus liquid (concentration is 96cfu/ml) having prepared, take and just soak whole cotton swab as degree, from 4 different directions level crossing line, make bacterium liquid evenly coat whole agar plate surface lightly.

(2) prepare respectively aztreonam, 250mg/ml chitosan nano, the 125mg/ml(aztreonam concentration of 250mg/ml) three groups of solution of compositions of embodiment mono-, respectively get 2ml and (separately add one group of blank) in test tube, and labelling.With aseptic pincet, get 8 of circular filter papers, every two are dipped in same medicinal liquid, soak into rear taking-up, drain too much medicinal liquid.2 filter paper containing a kind of medicinal liquid are placed on respectively to the zones of different of the agar plate surface of inoculated bacteria.For location interval is accurate, at the bottom of ware, of marker pen, making mark in advance.

(3) culture dish is put into incubator and is hatched 24h in 37 ℃, observe the scraps of paper and have or not inhibition zone around, by outcome record in table.Measure the diameter of inhibition zone, relatively the antibacterial efficacy of each medicine.

2. experimental result:

Table 1 biocidal property experimental result

By experiment in vitro, prove that the 0.2g aztreonam of chitosan-containing nanoparticle and the 0.4g aztreonam antibacterial efficacy of chitosan-containing nanoparticle are not equal to, 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. an aztreonam for injection composite freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:

9.47～11.58 parts of aztreonam

4.74～5.79 parts of chitosan nanos

75.79～92.63 parts of waters for injection.

2. a preparation method for aztreonam 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) take the chitosan powder 100g of above-mentioned mistake 100 eye mesh screens, add 0.1mol/L acetic acid solution 40L under room temperature, 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, obtain colloid solution, 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 in cooling juxtaposition drying under reduced pressure case, moisture is lower than 2%, particle diameter≤100nm, zeta current potential is about 15mv;

(2) preparation of aztreonam 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 aztreonam 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 aztreonam, every bottle of 0.5g 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.