CN103565759A - Ceftibuten composition freeze-dried powder for injection - Google Patents

Abstract

The invention provides ceftibuten composition freeze-dried powder for injection, which relates to the field of medicine and medicine manufacturing technology. The ceftibuten composition freeze-dried powder for injection comprises the following raw material components in parts by weight: 1 part of ceftibuten, 0.1-1.0 part of chitosan nanoparticles and 5-10 parts of injection water. The ceftibuten composition freeze-dried powder for injection provided by the invention has the advantages that 1) the composition can significantly enhance the antibacterial effect of the ceftibuten, clinically reduce the ceftibuten dosage and reduce the adverse reactions of the ceftibuten, and as shown in experiments in vitro, 0.2 g of ceftibuten composition freeze-dried powder containing the chitosan nanoparticles has the same curative effect as 0.4 g of ceftibuten containing no chitosan nanoparticles; and 2) the chitosan nanoparticles can replace mannitol to serve as a freeze drying skeleton agent of the freeze-dried powder for injection so as to eliminate the activity of the mannitol on human body.

Description

Injection ceftibuten composite freeze-dried powder

Technical field:

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

Background technology:

Ceftibuten (ceftibuten) belongs to beta-lactam class antibiotic, be the 3rd generation cephalosporin.2 carboxyls of this product are free, at small intestinal, directly absorb.The NH2 link aminothiazole ring encircling on 7 has stronger antimicrbial power, has again carboxyl crotonamide can protect beta-lactam key, makes it have stronger enzyme stability, and chemical structural formula is as follows.

The features such as ceftibuten has bactericidal activity by anti-bacteria cell wall synthetic, and this medical instrument has that has a broad antifungal spectrum, antibacterial activity are strong, stable to plasmid-mediated B lactamase, long half time, untoward reaction are few.This medicine can be used for respiratory tract, skin soft tissue, Genitourinary System Infection clinically, and clinical effectiveness is good.Ceftibuten is developed by Japanese Shionogi company the earliest, in 1993 in Japanese Initial Public Offering.U.S. Schering Plough company limited obtains the mandate of Yan Yeyi company, and the dosage form that nineteen ninety-five obtains the listing of U.S. FDA approval ，Qi China is suspensoid and capsule, and the main untoward reaction of ceftibuten is gastrointestinal reaction, anaphylactic reaction etc.

Application number is 200710308427.8, name is called " Ceftibuten sustained-release capsule " and application number is 200710308426.3, name is called a kind of novel form that " preparation of ceftibuten dry suspension agent and application " discloses respectively ceftibuten, be used for the treatment of upper respiratory tract infection, tonsillitis, scarlet fever, nasal sinusitis, otitis media; Lower respiratory infection is as acute bronchitis, acute episode of chronic bronchitis, pneumonia; Urinary tract infection; Enteritis and gastroenteritis.

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, and chemical constitution is as above formula.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, and relative molecular mass is comparatively desirable in 8～100,000 chitosan anti-bacteria effect.Chitosan nano is the microgranule that a kind of particle diameter is less than 100nm, as a kind of pharmaceutical carrier, there is slow release and targeting and there is broad spectrum antibacterial, the growth of various bacteria is had to certain inhibitory action, but also there is no clinically the pharmaceutical dosage form of chitosan-containing nanoparticle at present.

summary of the invention:

The invention provides a kind of injection ceftibuten composite freeze-dried powder, said composition principal agent is: ceftibuten, chitosan nano, and described injection ceftibuten composite freeze-dried powder antibacterial action strengthens, and solubility is good.

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

The invention provides ceftibuten compositions, the prescription of said composition consists of ceftibuten, chitosan nano, water for injection (need in prescription remove solvent), it is characterized in that: chitosan nano can be used as synergist, the skeleton agent (chitosan nano itself has certain antibacterial activity, plays synergetic antibacterial effect after combining with ceftibuten) of ceftibuten.

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

1 part of ceftibuten

0.1～1.0 part of chitosan nano

5～10 parts of waters for injection.

Preferred weight part of described material composition is:

1 part of ceftibuten

0.4～0.6 part of chitosan nano

5～10 parts of waters for injection.

In addition, the present invention also provides a kind of preparation method of injection ceftibuten composite freeze-dried powder, it is characterized in that, comprises the steps:

(1) preparation of chitosan nano:

1, relative molecular mass after pulverizing, the chitosan powder between 8～100,000 is sieved through 100 eye mesh screens;

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 ceftibuten 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 ceftibuten the extremely clarification of stirring and dissolving of recipe quantity;

(3) with phosphoric acid, adjust pH to 3～4, add 0.1% active carbon to stir 30 minutes, filtering active carbon, medicinal liquid, again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detects intermediate content, and by ceftibuten, every bottle of 0.2g 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:

Inventor finds through test of many times, a kind of ceftibuten and chitosan nano have synergetic antibacterial effect, the compositions of mixing in specific proportions, and make injection freeze-dried powder and have the following advantages for tool as antibacterials: 1) this compositions can significantly strengthen the antibacterial effect of ceftibuten, can reduce ceftibuten consumption clinically, reduce ceftibuten untoward reaction, by experiment in vitro prove the 0.2g ceftibuten composition freeze-dried powder of chitosan-containing nanoparticle and not the 0.4g ceftibuten antibacterial efficacy of chitosan-containing nanoparticle be equal to.2) 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 ceftibuten composite freeze-dried powder (specification: 200mg, in ceftibuten), in 1000.

1, prescription:

Ceftibuten 200g

Chitosan nano 100g

Water for injection 2000ml

2, preparation technology:

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

2) add ceftibuten the extremely clarification of stirring and dissolving of recipe quantity.

3) with phosphoric acid, adjust PH to 3.5, add 0.1% active carbon to stir 30 minutes, filtering active carbon, medicinal liquid, again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detects intermediate content, and by ceftibuten, every bottle of 0.2g 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-, injection ceftibuten composite freeze-dried powder (specification: 200mg, in ceftibuten), in 1000.

1, prescription:

Ceftibuten 200g

Chitosan nano 120g

Water for injection 2000ml

2, preparation technology:

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

2) add ceftibuten the extremely clarification of stirring and dissolving of recipe quantity.

3) with phosphoric acid, adjust PH to 3.5, add 0.1% active carbon to stir 30 minutes, filtering active carbon, medicinal liquid, again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detects intermediate content, and by ceftibuten, every bottle of 0.2g 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-, injection ceftibuten composite freeze-dried powder (specification: 200mg, in ceftibuten), in 1000.

1. write out a prescription:

Ceftibuten 200g

Chitosan nano 80g

Water for injection 2000ml

2. preparation technology:

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

2) add ceftibuten the extremely clarification of stirring and dissolving of recipe quantity.

3) with phosphoric acid, adjust PH to 3.5, add 0.1% active carbon to stir 30 minutes, filtering active carbon, medicinal liquid, again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detects intermediate content, and by ceftibuten, every bottle of 0.2g 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.

Embodiment tetra-: extracorporeal bacteria inhibitor test

Comparison between the effect of the ceftibuten composite freeze-dried powder vitro inhibition bacterial growth that bacteriostatic test is prepared for the embodiment of the present invention and antimicrobial spectrum and ceftibuten, chitosan nano, blank assay.

1 test method-Kirby-Bauer(KB) disk diffusion method

The scraps of paper that contain quantitative antibacterials are attached to and are inoculated on the agar plate that detects bacterium.The scraps of paper in you the moisture in contained drug absorption agar after dissolving, just constantly to scraps of paper peripheral region, diffuse to form the gradient concentration successively decreasing.The growth that detects bacterium around the scraps of paper within the scope of Mlc is suppressed, thereby forms transparent inhibition zone.The size reflection of inhibition zone detects bacterium to measuring the sensitivity of medicine, and is negative correlation with the minimum inhibitory concentration (MIC) of this medicine, and inhibition zone is larger, and MIC is less, and its antibacterial action is stronger.

2 test procedures

Antibiotic discs preparation: select diameter 6.35mm, the special-purpose drug sensitive test paper of water absorption 20 μ l.Prepare respectively 5mg/ml ceftibuten, 5mg/ml chitosan nano, 2.5mg/ml(ceftibuten concentration) embodiment mono-, 2.5mg/ml(ceftibuten concentration) embodiment bis-, 2.5mg/ml(ceftibuten concentration) five groups of solution of embodiment tri-, respectively get 2ml and (separately add one group of blank) in test tube, and labelling.By the method for soaking, put respectively 2 scraps of paper and put into each test tube.After scraps of paper lyophilization, seal, put-20 ℃ and save backup.

Culture medium: adopt Mueller-Hinton agar (MHA), pH7.2.The flat board of 90mm internal diameter pours into 25ml, and to make agar thickness be 4mm, and MH agar plate, with preserving in 4 ℃ of refrigerators after plastic bag sealing, is put before use 35 ℃ and hatched 30min, makes its dry tack free.

Microbionation: the bacterium amount of antibacterial is 5 * 107CFU/ml, dips the Escherichia coli bacterium liquid of having hatched with aseptic continuous swab, at inside pipe wall, will after crowded the going of unnecessary bacterium liquid rotation, evenly be coated with inoculation 3 times, 60 ° of each Rotating Plates at agar surface.The dull and stereotyped Inner edge of tailing edge is smeared one week; Flat board is at room temperature close to agar surface with tweezers by the pastille scraps of paper after dry 3～5min, and each scraps of paper center is greater than 24mm apart, and scraps of paper anomaly plate Inner edge is greater than 15mm.Put 35 ℃ and read result after hatching 16～18h.

3 results are judged

With the vernier caliper measurement that degree of accuracy is 1/10mm, get antibacterial circle diameter, according to antibacterial circle diameter paper disk method, sensitivity standard is divided into three grades: responsive (antibacterial circle diameter > 18mm), medium sensitivity (15≤antibacterial circle diameter≤17mm), drug resistance (antibacterial circle diameter < 14), this result of the test is as follows:

By In Vitro Bacteriostasis, test and show that the 0.2g ceftibuten composition freeze-dried powder of chitosan-containing nanoparticle and the 0.4g ceftibuten antibacterial efficacy of chitosan-containing nanoparticle are not equal to, there is no significant difference, illustrate that ceftibuten and chitosan have synergism on antibacterial action, ceftibuten composite freeze-dried powder 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 ceftibuten composite freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:

1 part of ceftibuten

0.1～1.0 part of chitosan nano

5～10 parts of waters for injection.

2. a preparation method for injection ceftibuten composite freeze-dried powder described in claim 1, is characterized in that, comprises the steps:

(1) preparation of chitosan nano:

(1) relative molecular mass after pulverizing, the chitosan powder between 8～100,000 is sieved through 100 eye mesh screens;

(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 ceftibuten 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 ceftibuten the extremely clarification of stirring and dissolving of recipe quantity;

(3) with phosphoric acid, adjust pH to 3～4, add 0.1% active carbon to stir 30 minutes, filtering active carbon, medicinal liquid, again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detects intermediate content, and by ceftibuten, every bottle of 0.2g 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.