CN104324040A - Pharmaceutical composition of sulfadimethoxine for injection - Google Patents

Abstract

The invention discloses a pharmaceutical composition, having cooperative antibacterial action of sulfadimethoxine for injection. The composition comprises the following components in parts by weight: 2-5 parts of sulfadimethoxine, 1-2 parts of trimethoprim, 1-5 parts of PLGA, 1-2 parts of PEG, 1-3 parts of PVP, 0.5-2 parts of glycine, 0.5-1 part of Tween and 1-3 parts of glycerinum. The pharmaceutical composition is high in stability, good in solubility, simple in preparation process and definite in curative effect, has a good inhibition effect on staphylococcus aureus and Gram-negative bacteria and is capable of reducing the dosage of a simple preparation and shortening treatment cycle.

Description

A kind of pharmaceutical composition of injection sulfadimethoxine

Technical field

The present invention relates to the compound preparation of a kind of sulfa drugs and trimethoprim (TMP), especially a kind of pharmaceutical composition of injection sulfadimethoxine.

Background technology

Sulfa drugs (Sulfonamides, SAs) refers to the general name of a class medicine with P-aminobenzene-sulfonamide structure, is the chemotherapeutic agent of a class for prevention and therapy bacterial infection disease.SAs kind can reach thousands of kinds, wherein apply comparatively wide and there is certain curative effect just have tens kinds.Sulphonamides is antibacterial and antiphlogistic medicine conventional in modern medicine, and it is various in style, has become huge " family "., sulfanilamide the earliest is but a member in dyestuff.Sulfa drugs can suppress gram positive bacteria and some negative bacterium.Have its extremely sensitive antibacterial: streptococcus, streptococcus pneumoniae, Salmonella, corynebacterium pyogenes, escherichia coli.There is inhibitory action to staphylococcus, pneumobacillus, pasteurellosis bacillus, anthrax bacillus, Shiga bacillus, Arizona bacterium etc., also have effect to some protozoon of harm poultry.

Sulfonamides Main Function is the breeding of anti-bacteria, during because of some bacterial growth, need utilize para-amino benzoic acid.Amino benzoic Acid and dihydro pteridine under the effect of dihydrofolate synthetase, synthesizing dihydro folic acid; Dihydrofoilic acid, under the effect of dihydrofolate reductase, generates tetrahydrofolic acid again; Tetrahydrofolic acid forms activated form tetrahydrofolic acid more further, namely coenzyme F, and it can transmit a carbon-based group and participate in purine, pyrimidine nucleotide synthesis.Due to chemical constitution and the amino benzoic Acid very elephant of sulfonamides, dihydrofolate synthetase can be competed with aminobenzoic acid, hinder the formation of dihydrofoilic acid, finally affect the synthesis of antibacterial nucleoprotein, thus the growth and breeding of anti-bacteria.To the antibacterial of sulfonamides sensitivity, all can obtain drug resistance in vivo and in vitro, and after drug resistance is produced to a kind of sulfanilamide, also often cross resistance is produced to other sulfanilamide, but the antibacterial of resistance to sulfonamides be still responsive to other antibacterials.Therefore, the normal and trimethoprim (TMP) conjunctive use of sulfa drugs is to overcome its drug resistance.

Summary of the invention

The invention provides a kind of medicinal composition for injections comprising sulfamethoxazole and trimethoprim with synergetic antibacterial effect, to staphylococcus aureus, staphylococcus epidermidis, enterococcus faecalis has good inhibitory action, greatly reduces the consumption of single preparations of ephedrine; This injection has the features such as solubility is good, good stability, and drug loading is high, safety of clinical trials is good, overcomes the deficiencies in the prior art part.

Have a pharmaceutical composition for the injection sulfadimethoxine of synergetic antibacterial effect, in compositions, the parts by weight of each component are: sulfadimethoxine 2-5 part; Trimethoprim 1-2 part; PLGA1-5 part; PEG1-2 part; PVP1-3 part; Glycine 0.5-2 part, tween 0.5-1 part; Glycerol 1-3 part.Described PLGA molecular weight is between 5000-20000, and wherein the polymer thing ratio of lactic acid and hydroxyacetic acid is 40::90-35:65.

As preferably, the weight ratio of described sulfadimethoxine and trimethoprim is 0.5:1-1:2.

As preferably, PLGA is 4-6 part.

As preferably, described tween is selected from Tween 80 or polysorbas20.

As preferably, described PVP is selected from PVP k10, the one in PVP k17 or PVP k30.

As preferably, described PEG is selected from PEG400 or PEG600.

The preparation method of the pharmaceutical composition of above-mentioned injection sulfadimethoxine, comprises the steps:

(1) each component is taken by formula proportion;

(2) sulfadimethoxine, PEG and trimethoprim are added successively in water for injection, stirring and dissolving obtains interior aqueous phase W1;

(3) PLGA, tween being dissolved in volume ratio is in the dichloromethane/acetone of 3: 1, obtains oil phase;

(4) PVP, glycerol and glycine are added in water for injection to be stirred to dissolve completely, obtain outer aqueous phase W2;

(5) under agitation slowly added in oil phase by W1, under ice bath, supersound process 20s obtains colostrum; Slowly added in W2 by colostrum and stir 10min and obtain emulsion, poured into by emulsion in the aqueous solution for injection of sodium chloride, ice bath stirs 4h volatile residue organic solvent, and collect microsphere by 0.45 μm of filtering with microporous membrane, water for injection washs 3 times, vacuum lyophilization.

Compared with the prior art, pharmaceutical composition of injection sulfadimethoxine provided by the invention and trimethoprim and preparation method thereof, has the following advantages:

1, good stability: the pharmaceutical composition of sulfadimethoxine provided by the invention and trimethoprim, wrapped up and be adsorbed in nanoparticulate carriers material, its active component is effectively protected, therefore the more excellent commercially available product of stability is more excellent.Acceleration June and long-time stability are investigated result and are also shown that solution colour, pH value, related substance, content all do not have significant change, and envelop rate is good, drastically increases medicine stability.

2, solubility is good, Save Range is wide: the employing of Freeze Drying Technique effectively avoids the degraded of polymeric material, medicine is revealed or drug degradation, make medicine preservation condition wider, solubility is good, and after redissolving, the various physicochemical property of medicine is substantially identical with before lyophilizing.

3, antibacterial activity is high: in the present invention, sulfadimethoxine and trimethoprim coordinate with specific ratio, can produce cooperative effect, when reducing dosage, farthest plays Antifungal activity.

Detailed description of the invention

Embodiment 1: a kind of pharmaceutical composition of injection sulfadimethoxine

Sulfadimethoxine, PEG and trimethoprim are added successively in 1000mL water for injection, stirring and dissolving obtains interior aqueous phase W1; It is in the 1000mL dichloromethane/acetone of 3: 1 that PLGA (molecular weight be 6000, LA:GA polymerization than for 50:50), tween are dissolved in volume ratio, obtains oil phase;

PVP, glycerol and glycine are added in water for injection to be stirred to and dissolves completely, obtain outer aqueous phase W2;

Under agitation slowly added in oil phase by W1, under ice bath, supersound process 20s obtains colostrum; Colostrum is slowly added in W2 and stirs 10min and obtain emulsion, poured into by emulsion in the aqueous solution for injection of 1000mL sodium chloride, ice bath stirs 4h volatile residue organic solvent, collects microsphere by 0.45 μm of filtering with microporous membrane, water for injection washs 3 times, vacuum lyophilization.

Embodiment 2: a kind of pharmaceutical composition of injection sulfadimethoxine

Sulfadimethoxine, PEG and trimethoprim are added successively in 1000mL water for injection, stirring and dissolving obtains interior aqueous phase W1; It is in the 1000mL dichloromethane/acetone of 3: 1 that PLGA (molecular weight be 5000, LA:GA polymerization than for 50:50), tween are dissolved in volume ratio, obtains oil phase;

PVP, glycerol and glycine are added in water for injection to be stirred to and dissolves completely, obtain outer aqueous phase W2;

Under agitation slowly added in oil phase by W1, under ice bath, supersound process 20s obtains colostrum; Colostrum is slowly added in W2 and stirs 10min and obtain emulsion, poured into by emulsion in the aqueous solution for injection of 1000mL sodium chloride, ice bath stirs 4h volatile residue organic solvent, collects microsphere by 0.45 μm of filtering with microporous membrane, water for injection washs 3 times, vacuum lyophilization.

Embodiment 3: a kind of pharmaceutical composition of injection sulfadimethoxine

Sulfadimethoxine, PEG and trimethoprim are added successively in 1000mL water for injection, stirring and dissolving obtains interior aqueous phase W1; It is in the 1000mL dichloromethane/acetone of 3:1 that PLGA (molecular weight be 5500, LA:GA polymerization than for 50:50), tween are dissolved in volume ratio, obtains oil phase;

PVP, glycerol and glycine are added in water for injection to be stirred to and dissolves completely, obtain outer aqueous phase W2;

Under agitation slowly added in oil phase by W1, under ice bath, supersound process 20s obtains colostrum; Colostrum is slowly added in W2 and stirs 10min and obtain emulsion, poured into by emulsion in the aqueous solution for injection of 1000mL sodium chloride, ice bath stirs 4h volatile residue organic solvent, collects microsphere by 0.45 μm of filtering with microporous membrane, water for injection washs 3 times, vacuum lyophilization.

Embodiment 4: droplet measurement

The injection of Example 1-3, is dissolved in water into the solution of every 1mL containing 1mg sulfadimethoxine, measures with laser diffraction particle size instrument.The injection of the sulfamethoxazole that acetonideexample 1-3 prepares and trimethoprim is spherical shape, and even particle size distribution, whole particle diameter is between 350-650nm.

Embodiment 5: envelop rate detects

Sulfadimethoxine and the injection of trimethoprim are dissolved in water into the solution of every 1mL containing sulfadimethoxine 1mg, with the centrifugation 15min of 6000r/min, get supernatant 1mL, with dissolve with methanol, measure the content of sulfadimethoxine.

Dose in envelop rate=microsphere/(dose in the dose+medium in microsphere) × 100%

The envelop rate of injection prepared by embodiment 1-3, between 88%-95%.

Embodiment 6: dissolution velocity is investigated

Each two bottles of injection in random selecting embodiment 1-3, numbering 1-6, sample number into spectrum 7 after physical mixed, the sulfadimethoxine freeze-dried powder numbering 8 of having gone on the market, by the dissolving method of clinical application, inject 10mL water for injection respectively, eddy mixer jolts, completely clear and bright for index to dissolve, calculate dissolution velocity.

Experimental result shows that the dissolution velocity of injection of the present invention is obviously better than the injection of direct packaging.

Embodiment 7: study on the stability

The injection that the sample prepared by embodiment 1-3 and raw material directly mix subpackage is placed in high temperature 40 DEG C, lower 6 months of relative humidity 75% ± 5% condition respectively, carries out acceleration and investigates.

Claims (7)

1. have a pharmaceutical composition for the injection sulfadimethoxine of synergetic antibacterial effect, in compositions, the parts by weight of each component are:

Sulfadimethoxine 1-5 part;

Trimethoprim 2-3 part;

PLGA 1-4 part;

PEG 1-2 part;

PVP 1-3 part;

Glycine 0.5-2 part;

Tween 0.5-1 part;

Glycerol 1-3 part;

Described PLGA molecular weight is between 5000-20000, and wherein the polymer thing ratio of lactic acid and hydroxyacetic acid is 40:80-35:65.

2. pharmaceutical composition as claimed in claim 1, is characterized in that the weight ratio of described sulfadimethoxine and trimethoprim is 0.5:1-1:2.

3. pharmaceutical composition as claimed in claim 1, is characterized in that PLGA is 4-6 part.

4. pharmaceutical composition as claimed in claim 1, is characterized in that described tween is selected from polysorbas20 or polysorbate40.

5. the pharmaceutical composition as described in claim arbitrary in claim 1-3, is characterized in that described PVP is selected from PVP k13, the one in PVP k23 or PVP k40.

6. pharmaceutical composition as claimed in claim 1, is characterized in that described PEG is selected from PEG-400 or PEG-600.

7. the preparation method of the pharmaceutical composition of injection sulfadimethoxine as described in claim arbitrary in claim 1-5, comprises the steps:

(1) each component is taken by formula proportion;

(2) sulfadimethoxine, PEG and trimethoprim are added successively in water for injection, stirring and dissolving obtains interior aqueous phase W1;

(3) PLGA, tween being dissolved in volume ratio is in the dichloromethane/acetone of 3: 1, obtains oil phase;

(4) PVP, glycerol and glycine are added in water for injection to be stirred to dissolve completely, obtain outer aqueous phase W2;

(5) under agitation slowly added in oil phase by W1, under ice bath, supersound process 20s obtains colostrum; Slowly added in W2 by colostrum and stir 10min and obtain emulsion, poured into by emulsion in the aqueous solution for injection of sodium chloride, ice bath stirs 4h volatile residue organic solvent, and collect microsphere by 0.45 μm of filtering with microporous membrane, water for injection washs 3 times, vacuum lyophilization.