CN103536556A - Pefloxacin mesylate composition freeze-dried powder for injection - Google Patents

Abstract

The invention provides a pefloxacin mesylate composition freeze-dried powder for injection, and belongs to the field of medicine and medicine preparation technology. The pefloxacin mesylate composition freeze-dried powder comprises following raw material ingredients, by weight, 7.26 to 9.17 parts of pefloxacin mesylate, 5.45 to 6.84 parts of chitosan nanoparticle, and 83.99 to 89.29 parts of injection water. Advantages of the pefloxacin mesylate composition freeze-dried powder are that: 1) the pefloxacin mesylate composition is capable of increasing antibacterial activities of pefloxacin mesylate on klebsiella, enterobacter and serratia significantly; 2) the size of the chitosan nanoparticle is ultra small, so that the chitosan nanoparticle is capable of passing through capillary vessels with a smallest diameter, and overcoming biological barriers, and rapid removing of the chitosan nanoparticle by macrophage is avoided, so that lasting time of the pefloxacin mesylate composition in blood is prolonged greatly; and 3) 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

Pefloxacin Mesylate 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 Pefloxacin Mesylate for Injection composite freeze-dried powder.

Background technology:

Pefloxacin mesilate is Comprecin, has broad-spectrum antibacterial action.By acting on the A subunit of DNA of bacteria helicase, suppress the synthetic of DNA and copy and cause antibacterial dead.Listing dosage form is mainly ointment, capsule, tablet at present, and its structural formula is as follows:

Purulent meningitis and antibiotic of less types by the septicemia due to Klebsiella, Enterobacter, Serratia for a long time, similar medicine often repeatedly, Use out of range, Resistant strain constantly occurs, causes drug dose constantly to increase, and poor effect.Some antibacterials is large to human body side effect, even has teratogenesis, carcinogenic risk.Therefore people expect to develop high-efficiency low-toxicity, are difficult for producing drug resistance, particularly with novel therapeutic purulent meningitis, the septicemia medicine of other antimicrobial drug without cross resistance.

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 drug delivery system, have and increase holdup time in vivo of drug solubility, prolong drug, increase the targeting of medicine and reduce toxicity 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 present invention relates to pharmaceutical composition, described pharmaceutical composition can be used for treatment, prophylaxis of microbial to be infected, or reduces the danger that infected by microbes occurs patient.The invention still further relates to method and the purposes of pharmaceutical composition in preparing medicament for the preparation of such pharmaceutical composition, wherein said medicament is used to treatment, prophylaxis of microbial infects, or reduce the danger that infected by microbes occurs patient, said composition principal agent is: pefloxacin mesilate, chitosan nano.

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

The invention provides pefloxacin mesilate compositions, the prescription of said composition consists of pefloxacin mesilate, 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 pefloxacin mesilate) of pefloxacin mesilate.

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

7.26～9.17 parts of pefloxacin mesilate

5.45～6.84 parts of chitosan nanos

83.99～89.29 parts of waters for injection

The preparation method that the invention provides a kind of Pefloxacin Mesylate for Injection 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 Pefloxacin Mesylate 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 pefloxacin mesilate 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 pefloxacin mesilate, 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:

The invention provides the compositions that a kind of pefloxacin mesilate 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) this compositions can significantly strengthen the antibacterial activity of pefloxacin mesilate to Klebsiella, Enterobacter, Serratia.2) the extra small volume of chitosan nano can pass through the thinnest blood capillary, overcomes biological barrier, avoid macrophage to remove rapidly, so greatly extends said composition persistent period in blood.3) 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-, Pefloxacin Mesylate for Injection composite freeze-dried powder, in 1000.

Prescription:

Pefloxacin mesilate 200g

Chitosan nano 140g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 140g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The pefloxacin mesilate the extremely clarification of stirring and dissolving that add 200g.

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 pefloxacin mesilate, every bottle of 0.2g 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-, Pefloxacin Mesylate for Injection composite freeze-dried powder, in 1000.

1. write out a prescription:

Pefloxacin mesilate 200g

Chitosan nano 128g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 128g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The pefloxacin mesilate the extremely clarification of stirring and dissolving that add 200g.

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 pefloxacin mesilate, every bottle of 0.2g 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-, Pefloxacin Mesylate for Injection composite freeze-dried powder, in 1000.

Prescription:

Pefloxacin mesilate 200g

Chitosan nano 152g

Water for injection 2000ml

2. preparation technology:

The chitosan nano that takes 152g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

The pefloxacin mesilate the extremely clarification of stirring and dissolving that add 200g.

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 pefloxacin mesilate, every bottle of 0.2g 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

Materials and methods

One material

(1) bacterial strain 100 strain klebsiella separation, from the CCMS liquid specimen of No. 1 Hospital Affiliated to Chinese Medical Univ 1-December inpatient in 2010, are non-repetition bacterial strain.Identification of strains adopts VITEK mono-2 systems, by pre-stage test, completes identification of strains.Quality Control bacterial strain is klebsiella ATCC25922, ATCC35218.

(2) tested antibacterials Pefloxacin Mesylate for Injection (being produced by A department), Pefloxacin Mesylate for Injection (being produced by B department), the embodiment of the present invention one composition sample.

(3) culture medium and main chemical reagent drug sensitive test are Britain OXOID company product with MH agar, and 6-phosphoric acid-glucose is purchased from Shanghai Sheng Gong biological engineering limited company.

Two, method

(1) minimum inhibitory concentration (MIC) is measured and is adopted the agar dilution that CLSI recommends to measure the MICE of antibacterials to clinical separation strain, antibacterials concentration 128-0.01mg/L, concentration to 0.01mg/L, adds 6-phosphoric acid-glucose of 25mg/L by 128mg/L successively two-fold dilution in culture medium while carrying out MIC mensuration according to CLSI standard.The single bacterium colony of picking in blood agar plate, is placed in 2mL normal saline dilution and becomes 0.5 Maxwell turbidity.The bacterium liquid of getting after a certain amount of dilution sequentially adds in 30 pore fungi dishes, add again the normal saline of respective amount to make 10 times of bacterium liquid dilutions, with multiple spot, inoculate instrument (MIP-P type) and be inoculated into containing in the culture medium of antibacterials of having prepared, quantity of microorganism inoculated is 10CFU/ml point, sentence read result after 37 ℃ of cultivation 18-24h of placement incubator.

(2) result of the test interpretation is according to CLSI2009 standard interpretation result of the test.

(3) statistical method data acquisition WHONET5.3 software analysis, carries out statistical analysis with check.

Result

Klebsiella resists the responsive rate of each antibacterials and is respectively Pefloxacin Mesylate for Injection (being produced by A department) 35%, Pefloxacin Mesylate for Injection (being produced by B department) 29%, the embodiment of the present invention one composition sample 92%.Klebsiella is extremely sensitive to said composition medicine, illustrates that this compositions can significantly strengthen the antibacterial activity of pefloxacin mesilate to Klebsiella.

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 Pefloxacin Mesylate for Injection composite freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:

7.26～9.17 parts of pefloxacin mesilate

5.45～6.84 parts of chitosan nanos

83.99～89.29 parts of waters for injection.

2. a preparation method for Pefloxacin Mesylate 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) 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 Pefloxacin Mesylate 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 pefloxacin mesilate 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 pefloxacin mesilate, 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.