CN101422432B - Preparation method of tilmicosin nano-emulsion antibacterial drug - Google Patents
Preparation method of tilmicosin nano-emulsion antibacterial drug Download PDFInfo
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- CN101422432B CN101422432B CN2008101502921A CN200810150292A CN101422432B CN 101422432 B CN101422432 B CN 101422432B CN 2008101502921 A CN2008101502921 A CN 2008101502921A CN 200810150292 A CN200810150292 A CN 200810150292A CN 101422432 B CN101422432 B CN 101422432B
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Abstract
The invention discloses a Tilmicosin nano-emulsion antibacterial medicament, the grain diameter of which is between 1 and 100nm; the components and weight percentage thereof are as follows: 0.01 to 6.0 percent of Tilmicosin, 20.0 to 40.0 percent of surface active agent/cosurfactant, 2.2 to 10.0 percent of oil; the rest is distilled water; and the sum of the weight percentage of the components is 100 percent. The medicament is primrose, clear and transparent liquid in the appearance, is characterized by low viscidity, good stability, high dispersibility and quick absorption and the like, can improve the bioavailability of the medicament, prolong the half-life of the medicament in a body, enhance the curative effect, reduce the toxicity, and has the effects of sustained releasing and targeting; simultaneously, the preparation technique is simple; the energy consumption is low; and the toxicity is low, the safety is high and large production can be carried out without special devices.
Description
Technical field
The invention belongs to field of veterinary, relate to a kind of novel form of antibacterials for animals, particularly a kind of tilmicosin nano-emulsion antibacterial drug and preparation method thereof.
Background technology
Tilmicosin is the macrolide antibiotics of poultry special use, gram positive bacteria and part gram negative bacteria, Mycoplasma, spirillum etc. all there are inhibitory action, especially the strongest to Actinobacillus pleuropneumoniae, pasteurella haemolytica and the effect of poultry Mycoplasma.Because the main target organ of tilmicosin is lung and breast, therefore the drug level height is mainly used in livestock and poultry respiratory tract infection and mammitis of cow.But because tilmicosin is insoluble in water, the conventional formulation of present usefulness is a tilmicosin phosphate, and its back for oral administration, is absorbed not exclusively by stomach acids destroy because of easily, bioavailability is low, the interior half-life of body is short, and it has certain toxicity to heart in addition.Therefore, thus how to seek bioavailability, targeting, slow-releasing that a kind of suitable dosage form improves tilmicosin, prolong its in vivo the half-life, heightening the effect of a treatment becomes current urgent problem.
Summary of the invention
At the shortcomings and deficiencies of above-mentioned prior art, the object of the present invention is to provide a kind of bioavailability height, targeting and the good tilmicosin nano-emulsion antibacterial drug of slow-releasing.
The technical scheme that realizes the foregoing invention purpose is a kind of tilmicosin nano-emulsion antibacterial drug, and the particle diameter of this nano-emulsion antibacterial drug is between 1～100nm, and its composition and mass percent thereof are:
Tilmicosin 0.01%～6.0%, surfactants/cosurfactants 20.0%～40.0%, oil 2.2%～10.0%, surplus are distilled water, and the mass percent sum of above-mentioned composition is 100%.
According to the formation mechanism of nano-emulsion, when the required HLB value of hydrophile-lipophile balance (HLB) value and the oil of surfactant equates or be close, form the highly stable nano-emulsion of character easily.The present invention selects for use toxicity less relatively according to the method, is not subject to the influence of electrolyte, inorganic salts and soda acid and the polyoxyethylene ether good with the compatibility of other surfactants (40) castor oil hydrogenated (RH-40), tween 80 as surfactant.
Cosurfactant is to be used for the HLB value of reconciliation statement surface-active agent, makes the easier formation nano-emulsion of surfactant and oil.The present invention selects 1 for use, and 2-propylene glycol, dehydrated alcohol are regulated the HLB value as cosurfactant, and they also are the good solvents of tilmicosin.
Form mechanism according to nano-emulsion, oil is that the matching surface activating agent participates in forming the stabilized nanoscale breast, the HLB value of isopropyl myristate (IPM), ethyl acetate and the HLB value of tween 80 are approaching, easily form the stabilized nano breast, so the oil that the present invention selects for use is isopropyl myristate (IPM), ethyl acetate.
Surfactant and cosurfactant optimum quality ratio are 2: 1～4: 1 in the tilmicosin nano-emulsion antibacterial drug of the present invention.
In the tilmicosin nano-emulsion antibacterial drug of the present invention, surfactant and cosurfactant sum are 9: 1～7: 3 with the best in quality ratio of oil.
The present invention adopts the pseudo-ternary phase diagram method to filter out optimum formula to prepare tilmicosin nano-emulsion.When surfactant and cosurfactant mass ratio are 2: 1～4: 1, surfactant and cosurfactant sum are the nano-emulsion district maximum that formed at 9: 1～7: 3 o'clock with the mass ratio of oil, and the most stable, drug loading is the highest simultaneously.Polyoxyethylene ether (40) castor oil hydrogenated (RH-40), tween 80 toxicity used in the prescription are less relatively, are not subject to the influence of electrolyte, inorganic salts and soda acid; With 1, the nano-emulsion emulsifying capacity that 2-propylene glycol, dehydrated alcohol are done cosurfactant formation is strong, and it also is used for regulating the HLB value in addition, and they also are the good solvents of tilmicosin; The HLB value of isopropyl myristate (IPM), ethyl acetate and the HLB value of tween 80 are approaching, easily form the stabilized nano breast, their molecular weight is little in addition, the effect and the cosurfactant of micromolecule oil phase are similar, easily be embedded in the surfactant, form interfacial film with it jointly, solubilising power is greater than the macromole oil phase; The shared percentage ratio of water is high more in the nano-emulsion system, and the probability that forms nano-emulsion is big more.
Method is for choosing dehydrated alcohol or 1, the 2-propylene glycol is as the solvent (also it being used as cosurfactant) of tilmicosin crude drug, RH-40 or tween 80 are surfactant, isopropyl myristate (IPM) or ethyl acetate are oil phase, make surfactants/cosurfactants (km=2: 1～4: 1) with oil phase respectively according to 9: 1,8: 2,7: 3,6: 4,5: 5,4: 6,3: 7,2: 8,1: 9 ratio changes, find out the ratio that can form nano-emulsion, the result shows that the prescription of tilmicosin nano-emulsion is a tilmicosin 0.01%～6.0%, surfactants/cosurfactants (km=2: 1～4: 1) 20.0%～40.0%, IPM2.2%～10.0%, surplus is a distilled water.It is mixed to stir on the rearmounted constant temperature blender with magnetic force make that its formation is faint yellow, the O/W type microemulsion of clear by accurate respectively each component that takes by weighing of this prescription.
Tilmicosin nano-emulsion antimicrobial drug of the present invention is carried out high speed centrifugation and under-4 ℃, room temperature, 60 ℃ of conditions, carry out reserved sample observing and see its stability, whether have layering and crystallization to separate out.
1. the high speed centrifugation test is to the influence of nano-emulsion stability
The tilmicosin nano-emulsion antibacterial drug liquid of getting preparation is in right amount in centrifuge tube, 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 tilmicosin is separated out and the profit lamination.
2. reserved sample observing experiment
Get the part tilmicosin nano-emulsion, be sub-packed in several vials, placing respectively after the sealing keeps sample under refrigerator-4 ℃, 25 ℃, 60 ℃ conditions of room temperature investigates 60d, observes every the 5d sampling.The result shows that this nano-emulsion all keeps the outward appearance of clear under three kinds of temperature conditions, and breakdown of emulsion, layering and crystallization are not separated out.Transmission electron microscope is observed down, and the drop of tilmicosin nano-emulsion is spherical in shape, and its size is 1～100nm, and is evenly distributed, favorable dispersibility.
Tilmicosin nano-emulsion antibacterial drug of the present invention is the liquid of faint yellow clear, does not have crystallization to separate out low temperature-4 ℃ long-term down a placement, does not also have muddy phenomenon under 60 ℃ of hot conditionss, as seen is a kind of stable pharmaceutical dosage form; And preparation method is simple, energy consumption is low, toxicity is little, safe, do not need special installation to can be used for producing in enormous quantities, thereby be used for the clinical treatment livestock and poultry.
Purposes: this medicine is mainly used in animals such as cattle, pig, chicken, sheep by the microbial infectious disease of sensitivity, livestock and poultry respiratory tract infection particularly, mycoplasma and animal Bacillus pasteurii disease as the disease of breathing of pig, contagious pleuropneumonia, chicken have good action to the main fungus strain of mammitis of cow simultaneously.
The concrete using method and the consumption of tilmicosin nano-emulsion of the present invention: mix drink, convert water 65Kg, freely drink logotype 3 days for poultry with this product 100ml (5%).Points for attention: this product only is used for drinking-water, and injectable not could use after must converting the water mixing, can not directly use, and laying cycle of laying hens is forbidden.
Compared with prior art, of the present invention having the following advantages:
1) has characteristics such as viscosity is low, good stability, dispersibility is strong, absorption is rapid, targeting drug release, and can improve bioavailability of medicament, prolong drug half-life, reduction toxic and side effects in vivo.
2) it also has the characteristics that surface tension is low, wellability is good, so medicine well is attached on the antibacterial, penetrates into its metabolism of antibacterial internal interference and brings into play antibacterial or bactericidal action.
Description of drawings
Fig. 1 is the transmission electron microscope photo figure of tilmicosin nano-emulsion antibacterial drug of the present invention.
Fig. 2 is the granularmetric analysis figure of tilmicosin nano-emulsion antibacterial drug of the present invention.
Fig. 3 is the granularmetric analysis examining report figure of tilmicosin nano-emulsion antibacterial drug of the present invention.
The specific embodiment
Below the result of use test example of the preparation method, formula for a product and the product that provide by the inventor further set forth the beneficial effect of medicine of the present invention.
1) take by weighing polyoxyethylene ether (40) castor oil hydrogenated (RH-40) 13.38g, isopropyl myristate (IPM) 2.43g, tilmicosin 0.01g, distilled water 84.18g, standby;
2) with polyoxyethylene ether (40) castor oil hydrogenated and tilmicosin stirring and evenly mixing, suitably ultrasonic emulsification is handled and is helped medicine dissolution, dissolves fully until tilmicosin; Add the isopropyl myristate stirring and evenly mixing again; The last distilled water that slowly drips constantly stirs in the time of dropping, until the system that forms homogeneous transparent, promptly gets drug level of the present invention and be 0.01% tilmicosin nano-emulsion antibacterial drug.
RH-40 9.0g
IPM 1.0g
Tilmicosin 0.03g
Distilled water 20.0g
Preparation method: with embodiment 1
1) take by weighing polyoxyethylene ether (40) castor oil hydrogenated (RH-40) 9.0g, isopropyl myristate (IPM) 1.0g, tilmicosin 0.3g, 1,2-propylene glycol 4.0g, distilled water 25.7g, standby;
2) earlier tilmicosin is dissolved in 1 fully, (can in 40 ℃ of water-baths, suitably heats and help dissolved substance) in the 2-propylene glycol, add then after RH-40 stirs, add the IPM stirring and evenly mixing again; The last distilled water that slowly drips constantly stirs in the time of dropping, and the system until forming homogeneous transparent promptly gets of the present invention 0.75% tilmicosin nano-emulsion antibacterial drug.
Embodiment 4 compounding pharmaceutical concentration are 1.37% tilmicosin nano-emulsion
Tilmicosin 0.5g
1,2-propylene glycol 3.27g
RH-40 9.81g
IPM 1.36g
Distilled water 21.47g
Preparation method: with embodiment 3
The preparation method of the tilmicosin nano-emulsion antibacterial drug of the present invention of embodiment 5-12:
1) it is standby to take by weighing tilmicosin, dehydrated alcohol, IPM, ethyl acetate, distilled water by following examples prescription;
2) earlier tilmicosin is dissolved in dehydrated alcohol (also can add an amount of phosphoric acid and make cosolvent) fully, adds then after tween 80 stirs, add IPM or ethyl acetate stirring and evenly mixing again; The last distilled water that slowly drips constantly stirs in the time of dropping, and the system until forming homogeneous transparent promptly gets tilmicosin nano-emulsion antibacterial drug of the present invention.
Tilmicosin 0.9g
Dehydrated alcohol 5.0g
Tween 80 15.0g
IPM 2.2g
Distilled water 36.9g
Embodiment 6 compounding pharmaceutical concentration are 1.5% tilmicosin nano-emulsion
Tilmicosin 0.9g
Dehydrated alcohol 5.0g
IPM 5.0g
Distilled water 34.1g
Tilmicosin 0.9g
Dehydrated alcohol 5.0g
IPM 1.4g
Distilled water 18.5g
Tilmicosin 1.0g
Dehydrated alcohol 5.0g
IPM 1.4g
Distilled water 15.0g
Embodiment 9 compounding pharmaceutical concentration are 3.7% tilmicosin nano-emulsion
Tilmicosin 1.0g
Dehydrated alcohol 4.0g
IPM 1.1g
Distilled water 15.0g
Tilmicosin 1.2g
Dehydrated alcohol 5.0g
IPM 1.4g
Distilled water 15.0g
Embodiment 11 compounding pharmaceutical concentration are 4.4% tilmicosin nano-emulsion
Tilmicosin 1.2g
Dehydrated alcohol 4.0g
IPM 2.5g
Distilled water 13.6g
Embodiment 12 compounding pharmaceutical concentration are 6.0% tilmicosin nano-emulsion
Tilmicosin 1.3g
Dehydrated alcohol 4.0g
Ethyl acetate 1.1g
Distilled water 9.4g
Test example 1 medicine of the present invention carries out microscopic pattern with transmission electron microscope and observes (JEM1230 type transmission electron microscope, FDAC electronics corporation produces), the result shows and to see Fig. 1, and this nano-emulsion drop be spherical as can be seen from Figure 1, size is equal-and be evenly distributed, favorable dispersibility.
Fig. 2, Fig. 3 are nano-emulsion of the present invention Particle Size Analyzer measurement result figure (Zetasizer Nano ZS type laser particle size analyzer, Britain Malvern Instrument company), nano-emulsion particle diameter＞10nm particle accounts for 95% as can be seen from Figure 2,＞20nm accounts for 15%, particle size distribution accounts for 80% at 10～20nm, and particle size distribution range is narrow, and size ratio is more even, mean diameter is 14.6nm, and Fig. 3 is the granularmetric analysis examining report of tilmicosin nano-emulsion antibacterial drug.
The in-vitro antibacterial result of the test of test example 2 medicines of the present invention
With tilmicosin solution, tylosin tartrate is contrast, and medicine of the present invention is as described below to the antibacterial effect of pathogenic pasteurellosis bacillus, streptococcus agalactiae, staphylococcus aureus, Escherichia coli, Salmonella:
The measurement result of MIC and MBC sees Table 1.As shown in Table 1, tilmicosin nano-emulsion is 2 times of tilmicosin solution to the MIC of pasteurellosis bacillus, 5 times of tylosin tartrate; To the MIC of streptococcus agalactiae, staphylococcus aureus, Escherichia coli is respectively 2 times of tilmicosin solution, 6 times of tylosin tartrate; Tilmicosin nano-emulsion is 2 times of tilmicosin solution to the MIC of Salmonella, 8 times of tylosin tartrate.The result shows that the external fungistatic effect of tilmicosin nano-emulsion is better than tilmicosin solution, and to compare fungistatic effect remarkable with tylosin tartrate.The result is as follows:
Table 1 minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) (unit: μ g/ml)
Nano-emulsion can improve the dissolubility of insoluble drug as a kind of novel medicament carrier, has advantages such as slow release and targeting and raising oral administration biaavailability.The small-size effect that medicine occurs in the nanometer magnitude range, skin effect also help drug effect and strengthen.This result of the test shows that tilmicosin nano-emulsion all has stronger inhibition and killing action to pasteurellosis bacillus, streptococcus agalactiae, staphylococcus aureus, Escherichia coli, Salmonella.The bacteriostasis of tilmicosin nano-emulsion is stronger than conventional formulation, and its reason has three: the one, and the particle diameter of nano-emulsion is at 1～100nm, and medicine and carrier very permeable thereof are crossed the cell wall of antibacterial, thereby antibacterial is had stronger inhibitory action; The 2nd, blank nano-emulsion has self-antimicrobial ability, and bacillus pyocyaneus, staphylococcus aureus etc. is all had stronger killing action; The 3rd, hydrophilic decentralized photo particle diameter is a nanoscale in the nano-emulsion, and much smaller than the volume of antibacterial, and continuous phase is nonpolar, and microorganism also is difficult to growth.Because the stronger antibacterial activity of tilmicosin nano-emulsion, can be used for the treatment of the respiratory tract infection of animals such as cattle, pig, chicken, sheep clinically, as mycoplasma and the poultry Bacillus pasteurii disease of the disease of breathing of pig, contagious pleuropneumonia, chicken, also can be used for the treatment of mammitis of cow simultaneously.
Claims (1)
1. the preparation method of a tilmicosin nano-emulsion antibacterial drug is characterized in that, comprises the following steps:
1) take by weighing polyoxyethylene ether (40) castor oil hydrogenated 9.0g, isopropyl myristate 1.0g, tilmicosin 0.3g, 1,2-propylene glycol 4.0g, distilled water 25.7g, standby;
2) earlier tilmicosin is dissolved in 1 fully, adds polyoxyethylene ether (40) castor oil hydrogenated in the 2-propylene glycol then and stir;
3) add the isopropyl myristate stirring and evenly mixing again;
4) the last distilled water that slowly drips constantly stirs in the time of dropping, and the system until forming homogeneous transparent promptly gets tilmicosin nano-emulsion antibacterial drug.
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Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102000105B (en) * | 2010-10-11 | 2012-05-23 | 西北农林科技大学 | Compound timicosin oral liquid and preparation method thereof |
| CN101983632A (en) * | 2010-10-11 | 2011-03-09 | 西北农林科技大学 | Compound Tilmicosin nanoemulsion antibacterial agent and preparation method thereof |
| CN102397237B (en) * | 2011-11-23 | 2012-11-28 | 河南牧翔动物药业有限公司 | Tilmicosin micelle preparation and preparation method thereof |
| MX364800B (en) * | 2014-02-18 | 2019-04-26 | Univ Mexico Nac Autonoma | Improved long-acting tilmicosin and use thereof in the treatment of bovine respiratory disease complex (brdc) and in the dry cow period. |
| CN105012332A (en) * | 2015-07-02 | 2015-11-04 | 河北科恒生物科技有限公司 | Compound tilmicosin phosphate-ambroxol nanoemulsion preparation |
| CN105640883A (en) * | 2016-01-21 | 2016-06-08 | 陈小媚 | Tilmicosin emulsion and preparation method thereof |
| CN105640887A (en) * | 2016-04-08 | 2016-06-08 | 山东畜牧兽医职业学院 | Compound nanoemulsion for preventing and treating MGI (mycoplasma gallisepticum infection) and preparation method |
| CN106667909A (en) * | 2016-12-31 | 2017-05-17 | 河南牧翔动物药业有限公司 | Venenum bufonis total lactone nanoemulsion and preparation method thereof |
| WO2019032057A1 (en) * | 2017-08-11 | 2019-02-14 | Vet Products Research And Innovation Center Company Limited | Method for preparing nano-particle of tilmicosin and product thereof |
| CN108042491B (en) * | 2018-01-23 | 2021-02-09 | 山东迅达康兽药有限公司 | Tilmicosin nanoemulsion and preparation method thereof |
| CN110251481A (en) * | 2019-07-17 | 2019-09-20 | 华中农业大学 | A kind of veterinary tilmicosin taste masking slow-releasing granules and its preparation process |
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