CN102657609A - Sulfadoxine composite nanoemulsion antibacterial medicine and preparation method thereof - Google Patents

Abstract

The invention discloses a sulfadoxine composite nanoemulsion antibacterial medicine. The sulfadoxine composite nanoemulsion antibacterial medicine comprises the following components in percentage by mass: 0.01 to 1.4 percent of sulfadoxine, 3 to 5.8 percent of oil, 28 to 35 percent of surfactant, 0 to 8.4 percent of cosurfactant and the balance of distilled water, wherein the mass percentage sum of the components is 100 percent. The sulfadoxine composite nanoemulsion antibacterial medicine is a clear and transparent liquid, has the characteristics of low viscosity, high stability, high dispersibility, quickness in absorption and the like, can improve the bioavailability of the medicine, prolongs the half-life period of the medicine in vivo, enhancea the curative effect, reduces the toxicity, has sustained release and targeted effects, and has the advantages of low energy consumption during manufacturing, low toxicity, high safety and the like.

Description

A kind of sulfadoxine composite nano-emulsion antibacterials and preparation method thereof

Technical field

The invention belongs to the Nano medication field, relate to a kind of novel form of antibacterials, particularly a kind of sulfadoxine composite nano-emulsion antibacterials and preparation method thereof.

Background technology

Sulfadoxine belongs to long-acting sulfonamides, has broad-spectrum antibacterial action, can stop the required folic acid of antibacterial with competition acts on the intravital dihydrofolate synthetase of antibacterial to the aminoacid benzoic acid, suppresses the growth and breeding of antibacterial.Be usually used in bacterial infections such as Hemolytic streptococcus, streptococcus pneumoniae and Shigella; And it is, effective to the drug-fast plasmodium of chloroquine with the pyrimethamine associating.

Cinnamic aldehyde (Cinnamaldehyde) is commonly referred to cinnamic aldehyde, and is colourless to the pale yellow oily liquid body, has intensive Cortex Cinnamomi abnormal smells from the patient.Natural being present in Sri Lanka's Oleum Cinnamomi, Oleum Cinnamomi, oil of Herba Pogostemonis, hyacinth oil and the Flos Rosae Rugosae wet goods quintessence oil.Have the sterilizing antisepsis, particularly fungus is had significant curative effect.Existing correlational study shows 22 kinds of condition pathogenic funguses carried out cinnamic aldehyde antifungal experiment, and cinnamic aldehyde is the antifungal active substance, mainly is through destroying fungal cell wall, medicine is infiltrated in the fungal cell, destroys organelle and plays bactericidal action.Certain research has been carried out in pharmacological action to its quintessence oil at home and abroad.

Carvacrol is claimed 2-hydroxyl cymene again; 2-methyl-5-isopropyl-phenol; 2-is to umbrella flower phenol; 2-methyl-5-isopropyl-phenol; Different thymol; 2-hydroxyl paracymene; The p-isopropyl o-cresol colourless oil liquid.The abnormal smells from the patient that thymol is arranged is used for spice, food additive, feed additive, antioxidant, sanitary disinfecting agent, anthelmintic, antiseptic, deodorization agent.

Sulfadoxine is because water insoluble, and revealing existing dosage form is the sulfadoxine dispersible tablet.These peroral dosage form diameter of aspirin particle are excessive, and oral post-absorption is not ideal, absorb not exclusively, are prone to form build-up effect in vivo, and therapeutic effect is undesirable.Thereby therefore how to seek the bioavailability that a kind of suitable dosage form improves sulfadoxine, targeting property, slow-releasing, the palatability of animal prolongs its half-life in vivo, and heightening the effect of a treatment becomes current urgent problem.

Summary of the invention

Shortcomings and deficiencies to above-mentioned prior art; The object of the present invention is to provide the how hot composite nano-emulsion antibacterials of a kind of bioavailability marfanil; This compound medicine has adopted the oil phase that has antibacterial effect equally again on the basis of sulfadoxine antimicrobial drug; Antimicrobial spectrum is enlarged, and antibacterial effect increases.

The technical scheme that realizes foregoing invention is a kind of sulfadoxine composite nano-emulsion antibacterials; The particle diameter of this nano-emulsion antibacterial drug is between 1 ~ 100nm, and its constituent and mass percent are: sulfadoxine 0.01% ~ 1.4%, oil phase 3% ~ 6.4%, surfactant 28% ~ 37.5% ,Cosurfactant 0% ~ 8.4%, surplus are distilled water, and mentioned component mass percent sum is 100%.

The mechanism that forms according to nano-emulsion, when HLB VALUE OF SURFACTANTS ( HLB) value and oily required HLBWhen value is equal or close, form the highly stable nano-emulsion of character easily.The present invention selects for use toxicity less relatively according to the method, does not allow to be subject to the influence of electrolyte, inorganic salts and soda acid and good with the compatibility of other surfactants RH-40( Cremephor RH40 HLB=14～16), EL-40( Cremophor ELHLB=13.5) tween 80 ( Tween-80 HLB=11) in any or two kinds of mixture as surfactant.

Cosurfactant is used for the reconciliation statement surface-active agent HLBValue makes surfactant and oil form nano-emulsion more easily.The present invention selects for use dehydrated alcohol to regulate as cosurfactant HLBValue, cosurfactant is not neccessary composition in the present invention, therefore when cosurfactant content is zero, can form the stabilized nano medicine yet.

Described oil is cinnamic aldehyde or carvacrol.

Oil phase cinnamic aldehyde that nano-emulsion antibacterial drug of the present invention is used or carvacrol also have antimicrobial effect except the function that molten medicine is arranged, and itself and sulfadoxine compound recipe not only can be increased the dissolubility of sulfadoxine, and fungistatic effect are remarkable.

A further object of the invention provides the method for preparing of sulfadoxine composite nano-emulsion antibacterials, it is characterized in that, may further comprise the steps:

1) take by weighing surfactant, cosurfactant, oil phase, sulfadoxine, distilled water by prescription, subsequent use;

2) sulfadoxine is added oil phase and be stirred to dissolving fully, subsequent use;

The oil that 3) will contain sulfadoxine adds in the mixed liquor of surfactant or surfactant and cosurfactant and stirs;

4) slowly add distilled water under the room temperature, and adding distil water limit, limit stirs, until form transparent clarifying liquid, colourless or yellow, viscosity is little and the liquid of good fluidity, promptly get.

Sulfadoxine composite nano-emulsion antibacterials study on the stability of the present invention

1. the high speed centrifugation test is to the influence of nano-emulsion stability

The sulfadoxine composite nano-emulsion antibacterials of getting preparation are put in the centrifuge tube in right amount; Sealing orifice is put in the high speed centrifuge, carries out centrifugal with the rotating speed of 12000r/min; Still keep clear through the centrifugal nanoemulsions of 20min, do not see that sulfadoxine is separated out and the profit lamination.

2. reserved sample observing test

Get part sulfadoxine composite nano-emulsion antibacterials and be sub-packed in several vials, place reserved sample observing 60d under refrigerator-4 ℃, 25 ℃, 40 ℃ conditions of room temperature after the sealing respectively, whenever observe at a distance from the 5d sampling.The result shows that this nano-emulsion keeps the outward appearance of clear under three kinds of conditions, and breakdown of emulsion, layering and crystallization are not separated out.Transmission electron microscope is observed down, and the drop of sulfadoxine composite nano-emulsion is spherical in shape, and its size is 1 ~ 100nm, and is evenly distributed, favorable dispersibility.

Through evidence, sulfadoxine composite nano-emulsion antibacterials are the liquid of clear, under the condition of low temperature-4 ℃, 25 ℃ of room temperatures, 40 ℃ of high temperature, have not both had crystallization and have separated out, and also do not have the breakdown of emulsion turbid phenomenon, and visible is a kind of stable pharmaceutical dosage form.

Sulfadoxine composite nano-emulsion antibacterials purposes of the present invention: be mainly used in responsive microbial light disease and infect, and be applicable to that treatment Hemolytic streptococcus, meningococcus, streptococcus pneumoniae etc. catch lasting medicine.As feed additive, be used to prevent and treat the infection of staphylococcus and Hemolytic streptococcus etc., promptly mainly treat fowl cholera, avian typhoid etc.

The method for using of these article is oral, is used for domestic animal and poultry.

Sulfadoxine composite nano-emulsion antibacterials of the present invention compared with prior art have the following advantages:

1) has characteristics such as viscosity is low, good stability, dispersibility is strong, absorption is rapid, slow-releasing is good, targeting drug release, and can improve bioavailability of medicament, prolong drug half-life, reduction toxic and side effects in vivo.

2) it is low to have a surface tension, and the characteristics that wettability is good can make medicine well be attached on the antibacterial, and the emulsion droplet particle diameter is little, penetrates into its metabolism of antibacterial internal interference more easily and brings into play the bacteriostasis and sterilization effect than other existing dosage forms.

3) sulfadoxine and cinnamic aldehyde or carvacrol are brought into play bacteriostasis simultaneously, and the two is worked in coordination with can improve fungistatic effect greatly.

The specific embodiment

Below the result of use test of the method for preparing, formula for a product and the product that provide through the inventor come further to set forth the beneficial effect of medicine of the present invention.

Demonstration test:

1.1 verify the experiment of its curative effect:

With monensin, the sulfadoxine sheet, cinnamic aldehyde nano-emulsion and sulfadoxine composite nano-emulsion compare.

Inhibition zone is measured: each supplies the examination bacteria suspension to adopt the filter paper method to draw 0.1 mL successively, adds respectively on the LB plating medium, is coated with the rod coating evenly with aseptic glass triangle.With card punch filter paper is broken into the disk of diameter 5 mm, put into the flat board that has been coated with bacterium behind the autoclaving, every drips 10% sulfadoxine tablet suspension respectively, 10% cinnamic aldehyde folk prescription essence oil nanometer breast, 10% monensin, 10% sulfadoxine composite nano-emulsion; Each experiment repeats for 3 times, and each dull and stereotyped subsides is put 2.Plate places under the incubator thermophilic and cultivates, observed result.Be regarded as having fungistatic effect and measure the inhibition zone size the inhibition zone extract to occur.

Bacteriostasis rate is measured: the bacterium liquid that 10 μ L are configured is evenly coated in LB plating medium surface, adds the sulfadoxine tablet powder of 10mg, 5mg, 2.5mg, 1.25mg and 1.2% sulfadoxine composite nano-emulsion respectively and coats the media surface that is coated with bacterium.With identical bacterium liquid, not dosing is contrast.Each experiment repeats for 3 times.Place under the preference temperature and to cultivate observed result behind the certain hour, calculate the clump count in every ware.Bacteriostasis rate=((contrast clump count one is handled clump count)/contrast clump count) * 100%.

Table 1 compound nanometer emulsion and folk prescription quintessence oil inhibitory effect contrast (antibacterial circle diameter mm)

Sample	Escherichia coli	Staphylococcus aureus
			Monensin	28.82 ± 0.21	38.70 ± 0.68
10% cinnamic aldehyde nano-emulsion	14.30 ± 0.05	12.21 ± 1.50
			10% sulfadoxine sheet suspension	32.20 ± 0.31	40.38 ± 2.01
10% sulfadoxine composite nano-emulsion	46.28 ± 0.09	60.23 ± 0.13

Annotate: it is remarkable that same column data alphabet different table is shown in p≤0.05 level difference.

Can know by table 1, prepared control samples monensin, 10% cinnamic aldehyde nano-emulsion, 10% sulfadoxine sheet suspension and 10% sulfadoxine nano-emulsion all have inhibitory action to escherichia coli and staphylococcus aureus; Inhibitory effect is compared, and 10% sulfadoxine composite nano-emulsion is all strong than folk prescription cinnamic aldehyde nano-emulsion and 10% sulfadoxine sheet suspension to the inhibition ability of two kinds of bacterium, and the inhibition ability of staphylococcus aureus obviously is better than colibacillary inhibition ability.Can infer that these four kinds of materials can not only suppress gram negative bacteria, also can suppress gram positive bacteria.Above folk prescription nano-emulsion is provided by this laboratory.

Table 1 bacteriostasis rate is measured the result

Experimental result shows that fungistatic effect was more much higher than sulfadoxine tablet after sulfadoxine was processed nano-emulsion.

Below come further to set forth medicine according to the invention through specific embodiment composition and method for preparing.

1.2 verify its superiority:

(1) with transmission electron microscope medicine of the present invention is carried out microscopic observation, can see that the nanometer emulsion droplet for spherical, is evenly distributed good dispersion, and big or small homogeneous.

(2) measure nano-emulsion of the present invention with Particle Size Analyzer, the particle diameter of finding the sulfadoxine composite nano-emulsion accounts for 19% less than 20nm's, and particle diameter accounts for 11% greater than 30nm's, is distributed in to account for 70%, the about 22.6nm of mean diameter between 20nm～30nm.

Explain that sulfadoxine composite nano-emulsion particle diameter is little, and be evenly distributed that this is to be superior to other dosage form parts, make medicine, can improve bioavailability than in the easy entering of other dosage forms bacterial body.

Because it is good that the sulfadoxine composite nano-emulsion has a transdermal characteristic; Targeting property and slow-releasing, advantage such as bioavailability is high, and drug effect is high and lasting; Can be used for clinical middle domestic animal because responsive microbial light disease is infected, like epidemic cerebrospinal meningitis, urinary system infection, colitis, bacillary dysentery.Also can be used for preventing and treating the infection of staphylococcus and Hemolytic streptococcus etc., and be applicable to that treatment Hemolytic streptococcus, meningococcus, streptococcus pneumoniae etc. catch lasting medicine.

Below be through the constituent of the sulfadoxine composite nano-emulsion that provides after inventor's test of many times and the mass percent of each composition, further set forth the preparation scheme of this nano-emulsion.

Embodiment 1

1) takes by weighing 0.01 g, carvacrol 5.8 g, EL-40 35 g ,Cosurfactant 1 g, distilled water 58.19g is subsequent use;

2) sulfadoxine is added oil phase and be stirred to dissolving fully, subsequent use;

The oil that 3) will contain sulfadoxine adds in the mixed liquor of surfactant or surfactant and cosurfactant and stirs;

4) slowly add distilled water under the room temperature, and adding distil water limit, limit stirs, until form transparent clarifying liquid, colourless or yellow, viscosity is little and the liquid of good fluidity, promptly get.

Embodiment 2

Form by sulfadoxine 0.8g, cinnamic aldehyde 3.9g, EL-40 35.1g, distilled water 60.2g.

Embodiment 3

Form by sulfadoxine 1.0g, cinnamic aldehyde 4.2g, EL-40 34.9g, distilled water 59.9g.

Embodiment 4

Form by sulfadoxine 1.2g, cinnamic aldehyde 4.5g, EL-40 33.6g, dehydrated alcohol 6.8g, distilled water 53.9g.

Embodiment 5

Form by sulfadoxine 0.7g, cinnamic aldehyde 3.0g, tween 80 28.0g, distilled water 68.3g.

Embodiment 6

Form by sulfadoxine 0.9g, cinnamic aldehyde 3.8, RH-40 34.2g, distilled water 61.1g.

Embodiment 7

Sulfadoxine 1.3g; Cinnamic aldehyde 4.5g; RH-40 34.7g; Dehydrated alcohol 8.4g; Distilled water 54.3g forms.

Embodiment 8

Form by sulfadoxine 1.4g, dehydrated alcohol 8.4g, cinnamic aldehyde 4.5g, RH-40 33.6g, distilled water 52.1g.

Embodiment 9

Form by sulfadoxine 0.6g, carvacrol 6.4g, RH-40 37.1g, distilled water 55.9g.

Claims (3)

1. sulfadoxine composite nano-emulsion antibacterials is characterized in that the particle diameter of this nano-emulsion is made up of following raw materials by weight percentage between 1 ~ 100nm:

Sulfadoxine 0.01% ~ 1.4%, oil 3% ~ 6.4%, surfactant 28% ~ 37.5% ,Cosurfactant 0% ~ 8.4%, surplus are distilled water, and mentioned component mass percent sum is 100%;

Any in described surfactant polyoxyethylene 40 castor oil hydrogenated, Emulsifier EL-40, the Tween 80;

It is described that to help the show activity agent be dehydrated alcohol;

Described oil is cinnamic aldehyde or carvacrol.

2. according to the said sulfa drugs sulfadoxine of claim 1 composite nano-emulsion, it is characterized in that the particle diameter of this nano-emulsion is between 1 ~ 100nm.

3. according to the said sulfa drugs sulfadoxine of claim 1 composite nano-emulsion, its preparation method specifically may further comprise the steps:

1) take by weighing surfactant, cosurfactant, oil phase, sulfadoxine, distilled water by prescription, subsequent use;

2) sulfadoxine is added oil phase and be stirred to dissolving fully, subsequent use;

The oil that 3) will contain sulfadoxine adds in the mixed liquor of surfactant or surfactant and cosurfactant and stirs;

4) slowly add distilled water under the room temperature, and adding distil water limit, limit stirs, until form transparent clarifying liquid, colourless or yellow, viscosity is little and the liquid of good fluidity, promptly get.