CN102895245A - Compound trimethoprim and doxycycline hydrochloride nanoemulsion preparation and preparation method thereof - Google Patents
Compound trimethoprim and doxycycline hydrochloride nanoemulsion preparation and preparation method thereof Download PDFInfo
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- CN102895245A CN102895245A CN2012104232564A CN201210423256A CN102895245A CN 102895245 A CN102895245 A CN 102895245A CN 2012104232564 A CN2012104232564 A CN 2012104232564A CN 201210423256 A CN201210423256 A CN 201210423256A CN 102895245 A CN102895245 A CN 102895245A
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Abstract
The invention discloses a compound trimethoprim and doxycycline hydrochloride nanoemulsion preparation. The nanoemulsion preparation is of an oil-in-water type, and the grain size of the nanoemulsion preparation is between 1nm and 100nm. The nanoemulsion preparation is prepared from the following raw materials in weight percentage: 0.01-1.75 percent of trimethoprim, 0.04-6.99 percent of doxycycline hydrochloride, 21.8-35.7 percent of surfactant, 7.94-11.9 percent of cosurfactant, 3.49-4.76 percent of oil and the balance of distilled water. The compound preparation is an oil-in-water type nanoemulsion; the compound preparation is flaxen and transparent in appearance; the grain size of the compound preparation is between 1nm and 100nm, so that the stability is high; and the trimethoprim and the doxycycline hydrochloride in the preparation show up an obvious synergistic effect, The compound nanoemulsion preparation has the advantages of safety, broad spectrum, high efficiency, targeting and slow release.
Description
Technical field
The invention belongs to field of veterinary, relate to a kind of composite antibacterial drugs of novel form, be specifically related to a kind of compound recipe trimethoprim and doxycycline hydrochloride nano-emulsion preparation and preparation method thereof.
Background technology
Antimicrobial drug has the advantages such as rapid-action, that production cost is low at the treatment animal infectious disease, and it is had a wide range of applications at veterinary clinic.But the gradually increase of the limitation of conventional dosage forms and drug resistance, so that its treatment cost rises and curative effect descends.For this reason, in the clinical practice normal adopt to unite use two or more antibacterials, to reach the expansion antimicrobial spectrum, heighten the effect of a treatment, reduce dosage, reduce or avoid toxic and side effects, reduce or delay the purpose that Resistant strain produces.
Trimethoprim (TMP) belongs to synthetic broad spectrum antimicrobicide, is lipotropy weak base, and multiple gram positive bacteria and gram negative bacteria are all had antibacterial action.Alone easy generation drug resistance, its drug resistance mechanism may be that antibacterial changes metabolic pathway, for example produce more dihydrofolate synthetase, or directly utilize exogenous folic acid.Doxycycline hydrochloride is semi-synthetic tetracycline antibiotics, be broad-spectrum antibacterial medicine, high concentration has bactericidal action, and is responsive to gram negative bacterias such as the gram positive bacteria such as streptococcus pneumoniae, streptococcus, part staphylococcus and escherichia coli, Salmonella, haemophiluss.This medicine clinical drug-resistant phenomenon is serious, and common fastbacteria is gram positive bacteria and the gram negative bacterias such as staphylococcus.After antibacterial produces drug resistance, curative effect is reduced, and can cause the propagation of Resistant strain, bring difficulty to treatment.Therefore, how by drug combination and the shortcoming that the exploitation novel form solves trimethoprim and exists more than the doxycycline hydrochloride, improve two medicine clinical application curative effects and become current urgent problem.
Summary of the invention
For problems of the prior art, the object of the invention is to provide the nano-emulsion novel form of a kind of compound recipe trimethoprim and doxycycline hydrochloride, the antibacterial activity that this nano-emulsion preparation can strengthen trimethoprim and doxycycline hydrochloride when using separately and enlarge antimicrobial spectrum, drug resistance, slow releasing pharmaceutical, prolong drug action time, reduce toxic and side effects and dosage, improve drug bioavailability and stability.
A kind of compound recipe trimethoprim and doxycycline hydrochloride nano-emulsion preparation, this nano-emulsion preparation is oil-in-water type, particle diameter is between 1～100 nm, raw material by following weight percentage ratio is made: trimethoprim 0.01～1.75%, doxycycline hydrochloride 0.04～6.99%, surfactant 21.8～35.7%, cosurfactant 7.94～11.9%, oil 3.49～4.76%, surplus is distilled water.
Concrete, described surfactant is preferably tween 80 or castor oil polyoxyethylene ether (EL-40); Described cosurfactant is preferably ethanol or 1,2-PD (PG); Described oil is preferably isopropyl myristate (IPM) or ethyl acetate.
Described surfactant and cosurfactant mass ratio are to be advisable between 2-3:1.
The preparation method of described compound recipe trimethoprim and doxycycline hydrochloride nano-emulsion preparation, it may further comprise the steps:
1) takes by weighing respectively in proportion each raw material; Trimethoprim is dissolved in the cosurfactant fully, then adds surfactant and oil, mixing gets system a, and is for subsequent use;
2) doxycycline hydrochloride is dissolved in distilled water, gets solution b, for subsequent use;
3) under the room temperature solution b is slowly joined among the system a, constantly stir simultaneously, until form the system of homogeneous transparent, namely get the nano-emulsion preparation of appearance transparent.
The theory of constitution of medicine of the present invention and scientific basis: because trimethoprim is insoluble in water, doxycycline hydrochloride is soluble in water, therefore with the aqueous solution of doxycycline hydrochloride crude drug as aqueous portion, with trimethoprim as the oil phase part.Adopt pseudo-ternary phase diagram to filter out optimum formula and prepare the trimethoprim nano-emulsion.Surfactant is tween 80 or EL-40, and cosurfactant is ethanol or PG, and oil is IPM or ethyl acetate.When surfactant and cosurfactant mass ratio were 2:1 or 3:1, the nano-emulsion district that the mass ratio of surfactant, cosurfactant sum and oil forms when being 9:1～7:3 was maximum, the most stable, and drug loading is the highest.Used tween 80 or EL-40 toxicity less in the prescription is not subject to the impact of electrolyte, inorganic salts and soda acid; Ethanol or PG are not only stable as the nano-emulsion that cosurfactant forms, and as the solvent of trimethoprim, have improved the content of trimethoprim in this compound nanometer emulsion; Isopropyl myristate (IPM) approaches with the HLB value of tween 80, easily forms stable nano-emulsion.
Utilize speed that oil-soluble dyes tonyred and water-soluble dye methylene blue spread in compound recipe trimethoprim and doxycycline hydrochloride nano-emulsion to judge the type of nano-emulsion, find that methylene blue solution has diffusion in nano-emulsion, tonyred solution is then not diffusion in nano-emulsion, shows that prepared compound nanometer emulsion is oil-in-water type (O/W).
Compound recipe trimethoprim of the present invention and doxycycline hydrochloride nano-emulsion appearance transparent, particle diameter is between 1～100 nm, its viscosity can add the distilled water adjustment of arbitrary proportion as required, makes things convenient for clinical administration, and the structure of two kinds of crude drug trimethoprims and doxycycline hydrochloride does not all change.Compound recipe trimethoprim of the present invention and doxycycline hydrochloride nano-emulsion can be used for treatment to be infected by the microbial all kinds of poultry of sensitivity.Preparation technology of the present invention is simple, and production cost is low, does not need special installation namely to be produced on a large scale.
Compared with prior art, compound nanometer emulsion of the present invention has the following advantages:
1) compound nanometer emulsion of the present invention safely, efficient, drug resistance is low;
2) compound nanometer emulsion of the present invention absorbs rapidly, and bioavailability is high; Targeting drug release, side effect is low; Particle diameter is little and even, the permeable membrane good absorbing;
3) compound nanometer emulsion viscosity of the present invention is low, and pain is little during injection;
4) compound nanometer emulsion of the present invention has and has good stability, but filtration sterilization is easy to preserve.
The specific embodiment
The present invention is described in further detail by the following examples, but protection scope of the present invention is not limited to this.
Embodiment 1
A kind of compound recipe trimethoprim and doxycycline hydrochloride nano-emulsion preparation, this nano-emulsion preparation is by 0.003g trimethoprim, 0.012g doxycycline hydrochloride, 9.0g surfactant EL-40,3.0g cosurfactant PG, 1.2g IPM, and the 12g distilled water is made.
The preparation method of described compound recipe trimethoprim and doxycycline hydrochloride nano-emulsion preparation, it may further comprise the steps:
1) takes by weighing respectively in proportion each raw material; The trimethoprim crude drug is added mix homogeneously in the cosurfactant (PG), and suitably then ultrasonic emulsification adds surfactant (EL-40) and oil (IPM) until trimethoprim dissolves fully, and stirring and evenly mixing gets system a, and is for subsequent use;
2) the doxycycline hydrochloride crude drug is dissolved in distilled water, gets solution b, for subsequent use;
3) under the room temperature solution b slowly is added drop-wise among the system a, constantly stirs simultaneously, until form the system of homogeneous transparent, namely get the nano-emulsion preparation that particle diameter is 1～100 nm, appearance transparent.
Embodiment 2
A kind of compound recipe trimethoprim and doxycycline hydrochloride nano-emulsion preparation, this nano-emulsion preparation is by 0.03g trimethoprim, 0.12g doxycycline hydrochloride, 3.0g surfactant tween 80,1.0g cosurfactant ethanol, 0.44g IPM, and the 8.0g distilled water is made.
The preparation method of described compound recipe trimethoprim and doxycycline hydrochloride nano-emulsion preparation is with reference to embodiment 1.
Embodiment 3
A kind of compound recipe trimethoprim and doxycycline hydrochloride nano-emulsion preparation, this nano-emulsion preparation is by 0.4g trimethoprim, 1.6g doxycycline hydrochloride, 6.0g surfactant EL-40,2.0g cosurfactant ethanol, 0.88g ethyl acetate, and the 12g distilled water is made.
The preparation method of described compound recipe trimethoprim and doxycycline hydrochloride nano-emulsion preparation is with reference to embodiment 1.
Embodiment 4
A kind of compound recipe trimethoprim and doxycycline hydrochloride nano-emulsion preparation, this nano-emulsion preparation is by 0.4g trimethoprim, 1.8g doxycycline hydrochloride, 6.0g surfactant tween 80,3.0g cosurfactant ethanol, 1.0g IPM, and the 15g distilled water is made.
The preparation method of described compound recipe trimethoprim and doxycycline hydrochloride nano-emulsion preparation is with reference to embodiment 1.
Test example 1The stability test of compound recipe trimethoprim and doxycycline hydrochloride nano-emulsion
1) centrifugal acceleration test
Get the nanoemulsions of the present invention's preparation, centrifugal with 20 000 r/min, observe the nanoemulsions outward appearance behind 10 min: still keep clear, the profit lamination do not occur.
2) photo-stability testing
Nanoemulsions of the present invention is packed in the vial in right amount, after the sealing under (4500 ± 500) lx illumination condition room temperature place, respectively at 0 d, 5 d, the 10 d observation of taking a sample.The result shows, emulsion keeps the clear outward appearance, has no the phenomenons such as layering and breakdown of emulsion.
3) temperature stability test
Nanoemulsions of the present invention is sub-packed in the vial, and placing respectively after the sealing keeps sample under 4 ℃, 25 ℃, 37 ℃, the 60 ℃ conditions investigates 3 months, observes every 10 d sampling.The result shows, emulsion all keeps the clear outward appearance under these four kinds of temperature conditions, have no the phenomenons such as layering and breakdown of emulsion.Observe under the transmission electron microscope, the drop of nano-emulsion of the present invention is spherical in shape, and its size is 1～100nm, and is evenly distributed, favorable dispersibility.
Test example 2The associating drug sensitive test of compound recipe trimethoprim and doxycycline hydrochloride nano-emulsion
1) single medicinal chart sheet is put up a bridge and is tested
The trimethoprim drug sensitive test paper of preparation contains trimethoprim 5 μ g/ sheets, and the doxycycline hydrochloride drug sensitive test paper contains trimethoprim 30 μ g/ sheets.Test strain is staphylococcus aureus ATCC
25923With escherichia coli ATCC
25922
Be that the bacterium liquid of 1/2 Maxwell standard opacity tube is inoculated on the MHA culture medium with concentration, then each one of above-mentioned two kinds of drug sensitive test paper be attached to respectively the MHA media surface, spacing 2～3 mm, 35 ℃ cultivate 18 h after, observe antibacterial circle diameter and form between two scraps of paper.The result shows, two kinds of antibacterials are to staphylococcus aureus ATCC
25923With escherichia coli ATCC
25922Angle, inhibition zone boundary straight, expression trimethoprim and doxycycline hydrochloride are synergetic antibacterial effect.
2) meat soup dilution chessboard test
According to measured single medicine trimethoprim and doxycycline hydrochloride nano-emulsion to staphylococcus aureus ATCC
25923With escherichia coli ATCC
25922Minimum inhibitory concentration MIC value, adopt micro-meat soup dilution chessboard method to carry out the associating antibacterial tests of medicine.
Preparation method according to compound recipe trimethoprim of the present invention and doxycycline hydrochloride nano-emulsion prepares respectively trimethoprim nanoemulsions and doxycycline hydrochloride nanoemulsions, and become a series of concentration with the MHB doubling dilution respectively, then two kinds of antibacterials with variable concentrations design by chessboard method, in twos combination adds in the 96 hole flat boards, every kind of antibacterials are got 50 μ L, again with 1.5 * 10
5The bacterium liquid 100 μ L of CFU/mL add in the hand-hole, hatch 24 h for 37 ℃.MIC when recording two prescriptions and solely using, and separately MIC during two medicine drug combinations, and calculate the FIC index.Process of the test repeats 5 times, and getting mode is the MIC value, the results are shown in Table 1.
As shown in Table 1, trimethoprim and doxycycline hydrochloride are to staphylococcus aureus ATCC
25923When the MIC during coupling is respectively alone 1/16 and 1/4 times is to escherichia coli ATCC
25922MIC during coupling all is 1/8 times when alone, and the two coupling is to staphylococcus aureus ATCC
25923With escherichia coli ATCC
25922The FIC index all be not more than 0.5.The result shows: compound recipe trimethoprim and doxycycline hydrochloride nano-emulsion can improve the antibacterial activity of trimethoprim, doxycycline hydrochloride, medicament curative effect enhancement, thus can reduce dosage, reduce drug residue, delay or reduce bacterial resistance.
Claims (4)
1. a compound recipe trimethoprim and doxycycline hydrochloride nano-emulsion preparation, it is characterized in that, this nano-emulsion preparation is oil-in-water type, particle diameter is between 1～100 nm, raw material by following weight percentage ratio is made: trimethoprim 0.01～1.75%, doxycycline hydrochloride 0.04～6.99%, surfactant 21.8～35.7%, cosurfactant 7.94～11.9%, oil 3.49～4.76%, surplus is distilled water.
2. compound recipe trimethoprim as claimed in claim 1 and doxycycline hydrochloride nano-emulsion preparation is characterized in that, described surfactant is tween 80 or castor oil polyoxyethylene ether, and described cosurfactant is ethanol or 1,2-PD; Described oil is isopropyl myristate or ethyl acetate.
3. compound recipe trimethoprim according to claim 1 and doxycycline hydrochloride nano-emulsion preparation is characterized in that, described surfactant and cosurfactant mass ratio are 2-3:1.
4. a method for preparing the arbitrary described compound recipe trimethoprim of claims 1 to 3 and doxycycline hydrochloride nano-emulsion preparation is characterized in that, specifically may further comprise the steps:
1) takes by weighing respectively in proportion each raw material; Trimethoprim is dissolved in the cosurfactant, then adds surfactant and oil, mixing gets system a, and is for subsequent use;
2) doxycycline hydrochloride is dissolved in distilled water, gets solution b, for subsequent use;
3) under the room temperature solution b is joined among the system a, constantly stir simultaneously, until form the system of homogeneous transparent, namely get the nano-emulsion preparation of appearance transparent.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104274404A (en) * | 2014-10-21 | 2015-01-14 | 河南牧翔动物药业有限公司 | Compound doxycycline antibacterial medicine |
| JP2020015695A (en) * | 2018-07-26 | 2020-01-30 | エア・ウォーター株式会社 | Dental oral composition |
| WO2020047197A1 (en) * | 2018-08-29 | 2020-03-05 | Ocugen, Inc. | Ophthalmic compositions and methods of use |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101972226A (en) * | 2010-10-13 | 2011-02-16 | 郑州后羿制药有限公司 | Veterinary doxycycline hydrochloride injection and preparation method thereof |
| CN102076333A (en) * | 2008-06-26 | 2011-05-25 | 安特里奥公司 | Dermal delivery |
-
2012
- 2012-10-30 CN CN2012104232564A patent/CN102895245A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102076333A (en) * | 2008-06-26 | 2011-05-25 | 安特里奥公司 | Dermal delivery |
| CN101972226A (en) * | 2010-10-13 | 2011-02-16 | 郑州后羿制药有限公司 | Veterinary doxycycline hydrochloride injection and preparation method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104274404A (en) * | 2014-10-21 | 2015-01-14 | 河南牧翔动物药业有限公司 | Compound doxycycline antibacterial medicine |
| JP2020015695A (en) * | 2018-07-26 | 2020-01-30 | エア・ウォーター株式会社 | Dental oral composition |
| JP7050612B2 (en) | 2018-07-26 | 2022-04-08 | エア・ウォーター株式会社 | Dental Oral Composition |
| WO2020047197A1 (en) * | 2018-08-29 | 2020-03-05 | Ocugen, Inc. | Ophthalmic compositions and methods of use |
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Application publication date: 20130130 |