CN103536555A - Ceftriaxone sodium composition freeze-dried powder for injection - Google Patents

Abstract

The invention provides a ceftriaxone sodium composition freeze-dried powder for injection, and belongs to the field of medicine and medicine preparation technology. The ceftriaxone sodium composition freeze-dried powder comprises following raw material ingredients, by weight, 7.26 to 9.17 parts of ceftriaxone sodium, 5.78 to 7.67 parts of chitosan nanoparticle, and 81.38 to 87.10 parts of injection water. Advantages of the ceftriaxone sodium composition freeze-dried powder are that: 1) activity of the ceftriaxone sodium composition in treatment of gonorrhoea is increased significantly, so that combination medication of other antibiotics with ceftriaxone sodium with unknown action mechanisms is avoided in clinic; 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 ceftriaxone 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

Ceftriaxone for inj composite freeze-dried powder

Technical field:

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

Background technology:

This medicine of ceftriaxone 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 enterobacteria, Proteus, Diplococcus Ji Jin Portugal bacterium etc.This medicine is stable to beta lactamase.

Clinical meningitis, pneumonia, skin soft-tissue infection, peritonitis, urinary system infection, gonorrhea, liver and gall infection, the surgical wound that sensitive organism infects, septicemia and genital infection etc., the First Line medicine of conduct treatment gonorrhea of being mainly used in.Clinician is when selecting such antibacterials, in order to heighten the effect of a treatment, to reduce untoward reaction or delaying drug resistance, produce, normal employing drug combination mode, but also occurred that irrational drug combination causes antibacterial action to weaken situations such as even producing serious toxic and side effects, superinfection clinically.

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, 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 the microgranule that a kind of particle diameter is less than 100nm, 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 ceftriaxone sodium antibacterials containing single component, and a kind of antimicrobial spectrum is wider, antibacterial action is stronger ceftriaxone 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 ceftriaxone composition of sodium, the prescription of said composition consists of ceftriaxone 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 ceftriaxone sodium) of ceftriaxone sodium.

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

7.26～9.17 parts of ceftriaxone sodium

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 ceftriaxone 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 ceftriaxone 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 ceftriaxone 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 ceftriaxone 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 ceftriaxone 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) said composition is active when treatment gonorrhea obviously improves, and has avoided clinically the not clear drug combination of other antibiotic and ceftriaxone sodium mechanism of action; 2) antimicrobial spectrum becomes wide and drug resistance and obviously declines; 3) active enhancing is shortened patient's medication cycle, has reduced ceftriaxone 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-, ceftriaxone for inj composite freeze-dried powder, in 1000.

1.prescription:

Ceftriaxone 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 ceftriaxone 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 ceftriaxone 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-, ceftriaxone for inj composite freeze-dried powder, in 1000.

1. write out a prescription:

Ceftriaxone 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 ceftriaxone 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 ceftriaxone 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-, ceftriaxone for inj composite freeze-dried powder, in 1000.

1.prescription:

Ceftriaxone 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 ceftriaxone 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 ceftriaxone 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 material

1.1.1 antibiotic ceftriaxone sodium (A department product), lot number: 010104,1.0g/ bottle. ceftriaxone sodium (B department product), lot number: 010107,1.0g/ bottle. the sample that embodiment mono-is worth.

1.1.2 bacterial strain gonorrhea diplococcus (30380395), staphylococcus aureus (00080855), dust Xi Shi escherichia coli (99092273), bacillus pyocyaneus (00080840).Enzyme antibacterial is produced in totally 4 strains, by the attached three institute's Respiratory Medicine laboratorys of Zhongshan Medical Univ., provides.

1.1.3 animal Kunming mouse, body weight 18～22g, male and female half and half ，You Xian Medical Univ Experimental Animal Center provides, the animal quality certification number: No. 08-004, the real moving word of Shaanxi doctor.

1.2 method

1.2.1 in body antibacterial tests by the design of improvement karber's method and the clinical front guideline of 5 new drugs (Western medicine) the interior antibacterial test of 6 bodies that collects, experiment the previous day, quantitative inoculated bacteria was in nutrient broth, 37e temperature is incubated 6h, get bacterium liquid 0.1mL transferred species in 10mL nutrient broth, 37e cultivates hatches 18h, the dry yeast liquid that bacterium stock solution is 0.5% with mass fraction is made zoogenetic infection bacterium liquid (1MLD is 100% minimum lethal bacterium amount).Laboratory animal is divided at random by empty stomach body weight, sex: (1) ceftriaxone sodium group (A); (2) ceftriaxone sodium group (B); (3) embodiment mono-sample sets; (4) matched group (giving equal-volume water for injection); (each tested pharmaceutical injection is with after water dissolution for every group of 6 drug level, be diluted to desired concn, agent spacing is 1:0.75), each drug level is used 10 of animals, male and female half and half, and every mouse peritoneal injection bacterium amount of test group is that 1MLD bacterium liquid 0.5mL is with infecting mouse, infect at once with infect after 6h is subcutaneous respectively gives to be respectively subject to reagent 0.2mL/ Mus, Continuous Observation 7d, records each treated animal death condition, and dead mice is cutd open to inspection.

1.2.2 data processed result goes out ceftriaxone sodium group (A), ceftriaxone sodium group (B), 95% fiducial limit of embodiment mono-sample sets to the ED50 value of each bacterial strain and ED50 with Bliss method meter, application variance analysis LSD method of inspection compares between two to every group of mean, and P<0.05 represents to have significant difference.

2 results

In body, the anti-bacterial result shows: the anti-gonococcal ED50 value of embodiment mono-ceftriaxone sodium composition sample is starkly lower than ED50 value (0.0056mg*kg-1 and the 0.0068mg*kg-1vs0.01147mg*kg-1 of ceftriaxone sodium A department, P is <0.01 and <0.05 respectively) and the ED50 value (0.0056mg*kg-1 and 0.0068mg*kg-1vs0.0649mg*kg-1, P<0.01) of ceftriaxone sodium B department; Embodiment mono-ceftriaxone sodium composition sample is also starkly lower than other two groups in the ED50 value of anti-Staphylococcus aureus, dust Xi Shi escherichia coli, bacillus pyocyaneus simultaneously.Said composition not only active obviously raising when anti-gonorrhea diplococcus is described, and antimicrobial spectrum becomes extensively and drug resistance obviously declines.

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

7.26～9.17 parts of ceftriaxone sodium

5.78～7.67 parts of chitosan nanos

81.38～87.10 parts of waters for injection.

2. a preparation method for ceftriaxone 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 ceftriaxone 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 ceftriaxone 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 ceftriaxone 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.