CN103536561A - Sulbactam sodium composition freeze-dried powder for injection - Google Patents

Abstract

The invention provides a sulbactam sodium composition freeze-dried powder for injection, and belongs to the field of medicine and medicine preparation technology. The sulbactam sodium composition freeze-dried powder comprises following raw material ingredients, by weight, 7.26 to 9.17 parts of sulbactam sodium, 6.02 to 7.97 parts of chitosan nanoparticle, and 81.34 to 87.55 parts of injection water. Advantages of the sulbactam sodium composition freeze-dried powder are that: 1) the sulbactam sodium composition freeze-dried powder possesses excellent synergistic antimicrobial effect with sulbactam sodium, antibiotic sensitive rate of various bacteria on the sulbactam sodium composition freeze-dried powder is high; 2) stability of sulbactam sodium against beta-lactamase is increased, and in vivo distribution is excellent; 3) improvement of activity is capable of shortening medication cycle of patients, and reducing occurrence likelihood of adverse reaction caused by accumulation of sulbactam 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 as to avoid active effects of mannitol on human bodies.

Description

Injection sulbactam sodium composition freeze-dried powder

Technical field:

The present invention relates to medicine and medicine manufacture technology field, relate in particular to a kind of injection sulbactam sodium composition freeze-dried powder.

Background technology:

Chemical name: (2S, 5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3,2,0] heptane-2-carboxylic acid sodium-4,4-dioxide.

Molecular formula: C8H10NNaO5S.Molecular weight: 255.22.

Structural formula:

Character: sulbactam sodium is white or off-white color crystalline powder, micro-have special smell, a mildly bitter flavor.Easily molten in water, slightly soluble in methanol, soluble,very slightly in ethanol, almost insoluble in acetone or ethyl acetate.

Sulbactam sodium is the irreversibility competitive type beta-lactamase inhibitor by synthetic, conventionally and penicillins and Cephalosporins share, make it avoid being destroyed by beta-lactamase, strengthen antibacterial activity, for infection such as respiratory system, urinary system, skin soft tissues.But this administering mode that share has occurred that cross allergy phenomenon, long-term prescription be shown in the untoward reaction such as the rising of liver enzyme, anemia, thrombocytopenia, leukopenia clinically.When especially, monocytosis patient applies these product, erythra incidence rate is higher.

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 as novel anti-biotic material, there is good bioadhesive, coagulability and immune activation active, to escherichia coli, staphylococcus aureus, streptococcus albus etc., there are remarkable inhibitory action and this nanoparticle to improve the high-specific surface area of antibacterial and the special effects of high reaction activity, greatly strengthened whole antibacterial effect, can make microorganism comprise that the Growth and reproduction of antibacterial, fungus, yeast, algae and virus etc. keeps lower level.

Summary of the invention:

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

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

7.26～9.17 parts of sulbactam sodium

6.02～7.97 parts of chitosan nanos

81.34～87.55 parts of waters for injection

The preparation method that the invention provides a kind of injection sulbactam sodium composition 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 injection sulbactam sodium composition 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 sulbactam 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 sulbactam sodium, every bottle of 60mg 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 sulbactam 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) sulbactam sodium is had to good synergetic antibacterial effect, all kinds of strains are high to its responsive rate; 2) sulbactam sodium increases beta-lactam enzyme stability, in body, distributes; 3) active enhancing is shortened patient's medication cycle, has reduced sulbactam 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-, injection sulbactam sodium composition freeze-dried powder, in 1000.

Prescription:

Sulbactam sodium 60g

Chitosan nano 42g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 42g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The sulbactam sodium the extremely clarification of stirring and dissolving that add 60g.

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 sulbactam sodium, every bottle of 60mg 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-, injection sulbactam sodium composition freeze-dried powder, in 1000.

1. write out a prescription:

Sulbactam sodium 60g

Chitosan nano 35g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 35g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The sulbactam sodium the extremely clarification of stirring and dissolving that add 60g.

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 sulbactam sodium, every bottle of 60mg 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-, injection sulbactam sodium composition freeze-dried powder, in 1000.

Prescription:

Sulbactam sodium 60g

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 sulbactam sodium the extremely clarification of stirring and dissolving that add 60g.

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 sulbactam sodium, every bottle of 60mg 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 experiment material

1.1.1 1. strain tests with medical mycology: Candida albicans (numbering ATCC11006), trichophyton, microsporon gypseum, Pilus Caprae seu Ovis sample sporidiole bacteria, Sabouraudites lanosus, Malassezia (numbering CMCC (F) I/17a), 2. medical science antibacterial is used in experiment: staphylococcus aureus (numbering 26003), anthrax bacillus (numbering 63601), Staphylococcus albus (numbering 26101), Bacillus proteus (numbering 49001), bacillus pyocyaneus (being numbered 10102), drug resistance escherichia coli.

1.1.2 culture medium superficial mycosis and Candida albicans are selected Sharpe maltose peptone agar base (the weak culture medium in husky fort), and Malassezia adopts LNA culture medium, and antibacterial adopts nutrient agar.

1.1.3 sulbactam sodium for drug injection (being produced by A department), injection sulbactam sodium (by the production of B department), embodiment mono-composition sample.

1.2 experimental technique

1.2.1 Antifungi is tested 1. drug dilution method (test tube method): prepare the culture medium of each medicine group, every group of 30 examples; PH value is 5, test tube packing autoclaving, and the inclined-plane that congeals into, standby.2. blank group and 20% ethanol matched group are set respectively, every group of 30 examples.3. carry out after stochastic sampling inoculating strain.4. Antifungi experimental result: Candida albicans is observed after cultivating 48h, Malassezia is observed after cultivating 72h, and other bacterium are observed after cultivating 14d.

1.2.2 anti-bacteria is tested 1. strain inoculation: inoculating loop is respectively got the streak inoculation of grain of rice size difference within containing the plate of nutrient agar by fresh antibacterial, every group of antibacterial culturing 30 examples.2. cup-plate method: each plate is placed respectively standard drug sensitive test paper and two sterilizing stainless steel tubules that diameter is 5mm, adds respectively original liquid and the 20% ethanol contrast liquid of 200pl in pipe, be placed in 37 ℃ of constant incubators.3. anti-bacteria experimental result: observed result after 24h, with vernier caliper measurement inhibition zone diameter record.

2 results

2.1 Antifungi experimental results

Embodiment mono-composition sample and sulbactam sodium (by A department, being produced), sulbactam sodium (being produced by B department) are relatively, inhibitory action to Pilus Caprae seu Ovis sample sporidiole bacteria, microsporon gypseum, Sabouraudites lanosus, trichophyton, Candida albicans, Malassezia is obvious, and difference has statistical significance (P<0.05); Sulbactam sodium (being produced by A department) group is compared with sulbactam sodium (being produced by B department) group, to above-mentioned 4 kinds of fungus inhibitory action difference not statistically significants (P>0.05);

2.2 anti-bacteria experimental results

Suppressing gram negative bacilli experimental result shows: embodiment mono-composition sample has inhibitory action to bacillus pyocyaneus, Bacillus proteus, drug resistance escherichia coli, difference has statistical significance (P<0.05), and 20% ethanol matched group is all invalid to experimental strain.

Suppressing gram positive bacteria experimental result shows: staphylococcus aureus, anthrax bacillus, Staphylococcus albus are had to inhibitory action to embodiment mono-composition sample but inhibitory action is better than other two groups, difference has statistical significance (P<0.05), and 20% ethanol matched group is all invalid to experimental strain.

Description of test chitosan nano has good synergetic antibacterial effect to sulbactam sodium, and all kinds of strains are high to its sensitivity, 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 injection sulbactam sodium composition freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:

7.26～9.17 parts of sulbactam sodium

6.02～7.97 parts of chitosan nanos

81.34～87.55 parts of waters for injection.

2. a preparation method for injection sulbactam sodium composition 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 injection sulbactam sodium composition 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 sulbactam 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 sulbactam sodium, every bottle of 60mg 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.