CN101756899A - Valnemulin nano-emulsion antibacterial medicine preparation - Google Patents
Valnemulin nano-emulsion antibacterial medicine preparation Download PDFInfo
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- CN101756899A CN101756899A CN200910254646A CN200910254646A CN101756899A CN 101756899 A CN101756899 A CN 101756899A CN 200910254646 A CN200910254646 A CN 200910254646A CN 200910254646 A CN200910254646 A CN 200910254646A CN 101756899 A CN101756899 A CN 101756899A
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Abstract
The invention discloses a valnemulin nano-emulsion antibacterial medicine preparation with the grain diameter between 1 and 100 nm. The valnemulin nano-emulsion antibacterial medicine preparation is prepared from the following ingredients in mass percent: 0.1 to 10.0 percent of valnemulin, 20.0 to 40.0 percent of surface active agents, 0 to 25.0 percent of accessory surface active agents, 1.0 to 12.0 percent of oil and the balance distilled water, and the sum of the mass percent of the ingredients is 100 percent. The medicine has the appearance of faint yellow clear transparent liquid, has the characteristics of high stability, low viscosity, strong dispersivity, fast absorption and the like, and can improve the bioavailability of the medicine, so the half-life of the medicine in the body is prolonged, the curative effect is enhanced, and the medicine has the slow release and targeting effects. At the same time, the invention has the advantages of simple preparation process, low energy consumption, low toxicity and high safety, and can realize the mass production without special equipment.
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 valnemulin nano-emulsion antibacterial medicine preparation.
Background technology
Valnemulin (Valnemulin) is pleuromutilin of new generation (pleuromu.tilin) class semisynthetic antibiotics, belongs to two terpenes, is the similar medicine of taimulin.1984, the Bemer of Switzerland Sandoz company etc. utilized pleuromutilin to take the lead in synthesizing successfully.1999, pre-mixing agent was made with it by Switzerland Norvatis company, and trade name Econor now in the listing of a plurality of countries, is mainly used in control livestock and poultry mycoplasma and intestinal spirochaete infection.Because valnemulin has safety, efficient, low toxicity, be difficult for producing characteristics such as drug resistance, present many countries are widely-used.But the valnemulin bitter in the mouth, hygroscopicity is extremely strong, and zest is big, and stability is relatively poor relatively, is difficult for preserving.Also there is certain palatability problem in the external valnemulin product (pre-mixing agent) of exploitation at present, because valnemulin is insoluble in water.Therefore, thus how to seek stability that a kind of suitable dosage form improves valnemulin, reduce zest, improve palatability, 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 good stability, zest is little and the valnemulin nano-emulsion antibacterial medicine preparation of good palatability.
The technical scheme that realizes the foregoing invention purpose is a kind of valnemulin nano-emulsion antibacterial medicine preparation, and the particle diameter of this nano-emulsion antibacterial drug is between 1～100nm, and its composition and mass percent thereof are:
Valnemulin 0.1%～10.0%, surfactant 20.0%～40.0%, cosurfactant 0～25.0%, oil 1.0%～12.0%, surplus are distilled water, and the mass percent sum of above-mentioned composition is 100%;
Described surfactant is tween 80 or polyoxyethylene ether (40) castor oil hydrogenated (RH-40);
Described cosurfactant is a dehydrated alcohol;
Described oil is isopropyl myristate (IPM) or liquid paraffin.
The preferred mass percentage ratio of preparation valnemulin nano-emulsion antibacterial medicine of the present invention is:
Valnemulin 0.5%～8.0%, surfactant 22.0%～35.0%, cosurfactant 0.5～20.0%, oil 2.0%～10.0%, surplus are distilled water.
Nearly step preferred mass percentage ratio of preparation valnemulin nano-emulsion antibacterial medicine of the present invention is:
Valnemulin 1.5%～6.0%, surfactant 25.0%～30.0%, cosurfactant 1.0～18.0%, oil 2.5%～8.0%, surplus are distilled water.
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 for use dehydrated alcohol to regulate the HLB value as cosurfactant, and they also are the good solvents of valnemulin.
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 valnemulin nano-emulsion antibacterial medicine of the present invention.
In the valnemulin nano-emulsion antibacterial medicine 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 valnemulin 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 this medicine 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 valnemulin; The HLB value of isopropyl myristate (IPM), liquid paraffin 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 valnemulin crude drug, RH-40 or tween 80 are surfactant, isopropyl myristate (IPM) or liquid paraffin 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 valnemulin nano-emulsion is a valnemulin 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.
Valnemulin 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 valnemulin nano-emulsion antibacterial medicine 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 valnemulin is separated out and the profit lamination.
2. reserved sample observing experiment
Get the part valnemulin 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 valnemulin nano-emulsion is spherical in shape, and its size is 1～100nm, and is evenly distributed, favorable dispersibility.
Valnemulin nano-emulsion antibacterial medicine 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 present domestic pig of only using.
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.
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.
Embodiment 1
Tween 80 9.0g
IPM 1.0g
Valnemulin 0.03g
Distilled water 19.97g
1) take by weighing tween 80, isopropyl myristate (IPM), valnemulin, the distilled water of recipe quantity, standby;
2) with tween 80 and valnemulin stirring and evenly mixing, suitably ultrasonic emulsification is handled and is helped medicine dissolution, dissolves fully until valnemulin; 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% valnemulin nano-emulsion antibacterial medicine.
Embodiment 2
Valnemulin 0.5g
Ethanol 3.27g
RH-40 9.81g
IPM 1.36g
Distilled water 21.47g
Embodiment 3
Valnemulin 0.9g
Dehydrated alcohol 5.0g
Tween 80 15.0g
IPM 5.0g
Distilled water 34.1g
Embodiment 4
Valnemulin 1.0g
Dehydrated alcohol 5.0g
Tween 80 7.5g
IPM 1.4g
Distilled water 15.0g
Embodiment 5
Valnemulin 1.0g
Dehydrated alcohol 4.0g
Tween 80 6.0g
IPM 1.1g
Distilled water 15.0g
Embodiment 6
Valnemulin 1.2g
Dehydrated alcohol 5.0g
Tween 80 7.5g
IPM 1.4g
Distilled water 15.0g
Embodiment 7
Valnemulin 1.3g
Dehydrated alcohol 4.0g
Tween 80 6.0g
Liquid paraffin 1.1g
Distilled water 9.4g
Embodiment 8
Valnemulin 8.0g
Dehydrated alcohol 20.0g
Tween 80 30.0g
Liquid paraffin 12.0g
Distilled water 30.0g
Embodiment 9
Valnemulin 10.0g
Dehydrated alcohol 18.0g
Tween 80 38.0g
Liquid paraffin 10.0g
Distilled water 34.0g
The in-vitro antibacterial result of the test of test example 1 medicine of the present invention
With valnemulin solution, tylosin tartrate is contrast, and medicine of the present invention is as described below to the antibacterial effect of streptococcus agalactiae, staphylococcus aureus, Escherichia coli:
MIC and measurement result see Table 1.As shown in Table 1, valnemulin nano-emulsion is 1/2 times of a valnemulin solution to the MIC of streptococcus agalactiae, 1/4 times of tylosin tartrate; To the MIC of staphylococcus aureus is 1/2 times of valnemulin solution, is 1/8 times of tylosin tartrate; To the MIC of Escherichia coli is 1/2 times of valnemulin solution, 1/4 times of tylosin tartrate; The result shows that the external fungistatic effect of valnemulin nano-emulsion is better than valnemulin solution, and to compare fungistatic effect remarkable with tylosin tartrate.The result is as follows:
Table 1 minimum inhibitory concentration (MIC) (unit: μ g/ml)
Claims (3)
1. a valnemulin nano-emulsion antibacterial medicine preparation is characterized in that, the particle diameter of this nano-emulsion antibacterial drug is between 1～100nm, and its composition and mass percent thereof are:
Valnemulin 0.1%～10.0%, surfactant 20.0%～40.0%, cosurfactant 0～25.0%, oil 1.0%～12.0%, surplus are distilled water, and the mass percent sum of above-mentioned composition is 100%;
Described surfactant is tween 80 or polyoxyethylene ether 40 castor oil hydrogenated;
Described cosurfactant is a dehydrated alcohol;
Described oil is isopropyl myristate or liquid paraffin.
2. nano-emulsion antibacterial medicine preparation according to claim 1 is characterized in that, its composition and mass percent thereof are:
Valnemulin 0.5%～8.0%, surfactant 22.0%～35.0%, cosurfactant 0.5～20.0%, oil 2.0%～10.0%, surplus are distilled water.
3. nano-emulsion antibacterial medicine preparation according to claim 1 is characterized in that, its composition and mass percent thereof are:
Valnemulin 1.5%～6.0%, surfactant 25.0%～30.0%, cosurfactant 1.0～18.0%, oil 2.5%～8.0%, surplus are distilled water.
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| CN200910254646A CN101756899A (en) | 2009-12-31 | 2009-12-31 | Valnemulin nano-emulsion antibacterial medicine preparation |
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| CN200910254646A CN101756899A (en) | 2009-12-31 | 2009-12-31 | Valnemulin nano-emulsion antibacterial medicine preparation |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101947203A (en) * | 2010-10-14 | 2011-01-19 | 郑州后羿制药有限公司 | Valnemulin hydrochloride emulsion for animals and preparation method thereof |
| CN102415996A (en) * | 2011-12-13 | 2012-04-18 | 齐鲁动物保健品有限公司 | Valnemulin hydrochloride self-emulsified oral nano emulsion for veterinary use and preparation method thereof |
| CN102764252A (en) * | 2012-08-07 | 2012-11-07 | 湖北龙翔药业有限公司 | Application of valnemulin hydrochloride |
| CN105878176A (en) * | 2016-04-06 | 2016-08-24 | 山东胜利生物工程有限公司 | Valnemulin hydrochloride injection in-situ gel preparation and preparation method thereof |
-
2009
- 2009-12-31 CN CN200910254646A patent/CN101756899A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101947203A (en) * | 2010-10-14 | 2011-01-19 | 郑州后羿制药有限公司 | Valnemulin hydrochloride emulsion for animals and preparation method thereof |
| CN102415996A (en) * | 2011-12-13 | 2012-04-18 | 齐鲁动物保健品有限公司 | Valnemulin hydrochloride self-emulsified oral nano emulsion for veterinary use and preparation method thereof |
| CN102415996B (en) * | 2011-12-13 | 2013-06-05 | 齐鲁动物保健品有限公司 | Valnemulin hydrochloride self-emulsified oral nano emulsion for veterinary use and preparation method thereof |
| CN102764252A (en) * | 2012-08-07 | 2012-11-07 | 湖北龙翔药业有限公司 | Application of valnemulin hydrochloride |
| CN105878176A (en) * | 2016-04-06 | 2016-08-24 | 山东胜利生物工程有限公司 | Valnemulin hydrochloride injection in-situ gel preparation and preparation method thereof |
| CN105878176B (en) * | 2016-04-06 | 2019-01-08 | 山东胜利生物工程有限公司 | A kind of valnemulin hydrochloride injection in-situ gel preparation and preparation method thereof |
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Application publication date: 20100630 |