CN102600192A - Compound terbinafine nanomedicine for treating skin diseases and preparation method thereof - Google Patents
Compound terbinafine nanomedicine for treating skin diseases and preparation method thereof Download PDFInfo
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- CN102600192A CN102600192A CN2011102461136A CN201110246113A CN102600192A CN 102600192 A CN102600192 A CN 102600192A CN 2011102461136 A CN2011102461136 A CN 2011102461136A CN 201110246113 A CN201110246113 A CN 201110246113A CN 102600192 A CN102600192 A CN 102600192A
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Abstract
The invention discloses a compound terbinafine nanomedicine used for treating skin diseases. The grain size of the medicine is 1nm-10nm, and the compound terbinafine nanomedicine comprises the following components: 0.1%-10% of terbinafine, 0.1%-15% of eugenol, 0.1%-5% of erythromycin, 0.1%-10% of oil, 10%-40% of surfactant, 4%-20% of cosurfactant and the balance of distilled water, and the total percentage by weight of the components is 100%. The medicine disclosed by the invention has the advantages of small particle size, low viscosity, good liquidity, stable properties and better percutaneous permeability, and not only has a stronger curative effect on pet dermatomycosis, but also has a strong therapeutical effect on pet bacterial skin diseases and parasitic skin diseases. The compound terbinafine nanomedicine disclosed by the invention is easy to prepare, is low in energy consumption, and can be in mass production without special equipment. The compound terbinafine nanomedicine has wide application prospects in the aspect of pet skin disease treatment.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of compound medicine novel form, particularly a kind of method for preparing that is used to treat dermopathic compound terbinafine Nano medication of stable transparent.
Background technology
Terbinafine is broad-spectrum antifungal a new generation propylene amine drug, for white or off-white color crystalline powder, is insoluble in water, dissolves in organic solvent.Its outstanding advantage is that it has antibacterial and bacteriostatic dual function, and the main inhibition fungus Squalene Cycloxygenase that passes through causes Squalene to be assembled, and fat drips and is deposited in cell wall and the cytoplasm, causes that membranolysis reaches germ-resistant purpose; Secondly can cause the shortage of ergosterol, the growth of fungal cell membrane is disturbed, and fungus stops growing, and reaches the bacteriostatic purpose.Terbinafine has strong antibacterial action to clinical common fungus, does not have in the body and accumulates, and side reaction is low.
Eugenol is 4-pi-allyl-2-methoxyphenol, is the dulcet chemical compound of a kind of oily, is the effective ingredient in a lot of Chinese herbal medicine such as Flos Caryophylli, the Cortex Cinnamomi, and is water-soluble hardly, with ethanol, ether and wet goods can be miscible.The eugenol wide material sources are easy to preparation, are a kind of good plant source medicines, and pharmacological action is widely arranged, and it has and suppresses fungus, antibacterial more by force, kills effects such as removing acarid.
Erythromycin belongs to macrolide antibiotics, is the crystallization or the powder of white or off-white color, odorless, bitter in the mouth, little have draw moistly, character is stable, is insoluble in water, has been soluble in organic solvents such as methanol, ethanol.Gram positive bacteria is had powerful antibacterial action, and sensitive organism has staphylococcus, Streptococcus viridans, micrococcus scarlatinae, streptococcus pneumoniae etc.Gram-negative bacteria such as gonococcus, pylori, bordetella pertussis, Brucella etc. also there is inhibitory action.In addition, mycoplasma, actinomycetes, leptospira, rickettsia, chlamydia, slave's card bacterium, minority mycobacteria and ameba there is inhibitory action.Erythromycin toxicity is low, but zest is strong.Local inflammation can take place in intramuscular injection, should adopt the deep intramuscular injection.Quiet notes speed is wanted slowly should avoid simultaneously exposing outside the blood vessel.Symptoms such as dog, cat are taken orally and then can cause vomiting, suffer from abdominal pain, diarrhoea.
More than three kinds of medicine dissolution property relatively poor, physical instability can not prevent comprehensively and treat the pet skin that multiple reason causes sick, needing simultaneously, multiple dosing just can reach therapeutic effect.Treating the sick medicine of pet skin in the market has ivermectin, metronidazole, lincomycin, doractin etc., but the said goods function singleness is used inconvenience, and the drug use cycles such as ivermectin are longer, and are bigger for the house pet toxic and side effects.
Summary of the invention
To the shortcomings and deficiencies that exist in the prior art; The object of the invention is to provide a kind of sick compound terbinafine Nano medication of treatment pet skin that is suitable for clinical practice; This medicine can be treated the pet skin disease that reasons such as fungus, antibacterial, parasite cause simultaneously; And safe and effective, bioavailability is higher.
The technical scheme that realizes the foregoing invention purpose is the dermopathic compound terbinafine Nano medication of a kind of treatment, and the particle diameter of this medicine is 1nm～100nm, is made up of following raw materials by weight percentage:
Terbinafine 0.1%～10%, eugenol 0.1%～15%, erythromycin 0.1%～5%, oil phase 0.1%～10%, surfactant 10%～40%, cosurfactant 4%～20%, surplus are distilled water, and the mass percent sum of above-mentioned raw materials is 100%.
The formula optimization mass percent scope of preparation medicine of the present invention is: terbinafine 0.2%～8%, eugenol 0.2%～12%, erythromycin 0.2%～4.5%, oil phase 0.5%～8%, surfactant 15%～35%, cosurfactant 5%～15%, surplus are distilled water, and the mass percent sum of mentioned component is 100%.
Described surfactant is one or more the mixture in tween 80 (Tween-80), Tween-60 (Tween-60), tween 20 (Tween-20), polyoxyethylene (40) castor oil hydrogenated (RH-40), polyoxyethylene (40) Oleum Ricini (EL-40) and the Arlacel-80 (Span-80).
Described cosurfactant is dehydrated alcohol, ethylene glycol, 1, the mixture of one or more in 2-propylene glycol, glycerin, Macrogol 200 (PEG 200), PEG400 (PEG 400), the Macrogol 600 (PEG 600).
Described oil phase is one or more the mixture in isopropyl myristate, liquid paraffin, vitamin E oil, Jojoba oil, triacetyl glycerine, ethyl acetate, almond oil, Semen Tritici aestivi germ oil, olive oil, the Oleum Ricini.
On surfactant selection, the present invention selects the nonionic surfactant of avirulence and good biocompatibility for use.Nonionic surfactant is more stable in solution, is not subject to the influence of strong electrolyte, inorganic salts, also is not subject to the influence of soda acid, and good with the compatibility of other surfactants, haemolysis is less.In theory; The HLB value that the preparation of O/W type nanometer emulsion needs surfactant is between 8～18; Consider preparation technology's simplicity; Be the easy formation property of nano-emulsion and the stability of nano-emulsion, the present invention selects the liquid nonionic surfactant of HLB between 10～15 for use, and is perhaps composite with the nonionic surfactant of a kind of HLB＜10.Available surfactant has: the mixture of one or more among Tween-80, Tween-60, Tween-20, RH-40, EL-40 and the Span-80.
The present invention is according to when the HLB value of the required surfactant of emulsifying oil phase is close with surfactant; The principle that formed emulsion is stable, the oils and fats of selecting for use has: the mixture of one or more in isopropyl myristate, liquid paraffin, vitamin E oil, Jojoba oil, triacetyl glycerine, ethyl acetate, almond oil, Semen Tritici aestivi germ oil, olive oil, the Oleum Ricini.
The formation of most of nano-emulsion all need add cosurfactant, and its effect mainly contains: reduce interfacial tension between profit, the flowability that increases interfacial film, the HLB value of reconciliation statement surface-active agent etc.The cosurfactant that the present invention selects for use has: dehydrated alcohol, ethylene glycol, 1, the mixture of one or more among 2-propylene glycol, glycerin, PEG 200, PEG 400, the PEG 600.
A further object of the invention provides the method for preparing of the dermopathic compound terbinafine Nano medication of above-mentioned treatment, it is characterized in that, specifically comprises the following steps:
1) take by weighing terbinafine, eugenol, erythromycin, oil, surfactant, cosurfactant, distilled water, subsequent use;
2) terbinafine, eugenol, erythromycin are added dissolving fully in the cosurfactant;
3) oil is added step 2) preparation solution in stir;
4) again surfactant is added step 2) in the solution of preparation, stir, add down slowly distilled water at 20 ℃～25 ℃ and fully stir, until form clear, viscosity has mobile yellow or water white compound terbinafine nano-emulsion for a short time.
Compound terbinafine Nano medication of the present invention has the function of treatment animal dermatomycosis, bacterial dermatosis, malis.
Usage: be coated with every day 1～2 time, continuous 1～2 week outside local.
The present invention detects through transmission electron microscope, and droplet diameter distribution is between 1～100nm, and outward appearance is yellow or colourless transparent liquid, has good stability:
1. light stability
Compound terbinafine Nano medication of the present invention is packed in the vial, and sealing places room temperature, and illumination 10d is in 1d, 3d, 5d, 7d, the 10d detection of taking a sample.The result shows that compound terbinafine nano-emulsion outward appearance is clear still, does not have phenomenons such as muddiness, layering, deposition, and particle diameter remains between 1nm ~ 100nm.
2. temperature stability
An amount of compound terbinafine Nano medication of the present invention is packed in the vial, and sealing places 4 ℃ respectively, 25 ℃ with 37 ℃ of three kinds of temperature conditions under keep sample and investigate 30d, every at a distance from 5d sampling observation.The result shows that this compound terbinafine Nano medication all keeps clear under these three kinds of temperature conditions, do not see layering, muddiness and sedimentary phenomenon.
3. anti-freeze-stable property
Compound terbinafine nano-emulsion of the present invention in-4 ℃ of one weeks of preservation, is returned to room temperature after the taking-up.This compound terbinafine Nano medication becomes solid in the time of-4 ℃, return to after the room temperature it and return to transparently, and places after a week still clear.
4. accelerated stability
Compound terbinafine Nano medication of the present invention is placed centrifuge tube, and in the centrifugal 20min of 15000rpm, observed result is found its not layering, still clear.
The dermopathic compound terbinafine Nano medication of treatment of the present invention compared with prior art has the following advantages:
1) thermodynamic stability is good, and bin stability is high, put for a long time not stratified, through centrifugal acceleration test layering not yet;
2) the invention belongs to nano-grade medicine, the outward appearance clear, the emulsion droplet dispersion is good, and bioavailability is high;
3) medicine of the present invention can be treated house pet fungoid, bacillary and malis simultaneously, and is easy to use, evident in efficacy.
4) preparation technology is simple, is fit to large-scale production.
Description of drawings
Fig. 1 is the transmission electron microscope picture of compound terbinafine Nano medication of the present invention.
The specific embodiment
Below further set forth the beneficial effect that the present invention narrates medicine through Test Example, these Test Example comprise the transmission electron microscope observation test of medicine of the present invention, the external test of pesticide effectiveness and clinical efficacy test.
Test Example 1Compound terbinafine Nano medication transmission electron microscopy observation of the present invention
Medicine of the present invention carries out microscopic pattern with transmission electron microscope to be observed; Fig. 1 is seen in result's demonstration; Fig. 1 is a compound terbinafine nano-emulsion transmission electron microscope photo, show that compound terbinafine nanometer emulsion droplet is spherical in shape and be evenly distributed, decentralized is good, particle diameter is all less than 100nm.
Test Example 2Compound terbinafine Nano medication antibacterial activity in vitro test of the present invention
Adopt micro-dilution method to measure MBC (MBC) and the minimum inhibitory concentration (MIC) of medicine to staphylococcus aureus, Staphylococcus intermedius, Hemolytic streptococcus (strain is all from moving medical college Microbiological Lab of Xibei Univ. of Agricultural & Forest Science & Technology).Compound terbinafine nano-emulsion group, erythromycin solution group, neomycin sulphate solution group are established in test.
Method: get aseptic microwell plate, the 1st hole adds 180 μ L 2 * 10
5The bacterium liquid of CFU/mL, all the other every Kong Jun add 100 μ L, add to 14 holes; In the 1st hole, adding concentration is the compound terbinafine nano-emulsion 20 μ L of 640 μ g/mL; Draw 100 μ L behind the piping and druming mixing and add in the 2nd hole, be diluted to the 13rd hole successively, discard 100 μ L with method; The 14th hole is the contrast of bacterium liquid, and the 15th hole only adds medicinal liquid and does the medicine contrast.Observed result behind 37 ℃ of cultivation 16～24h.Least concentration with no bacterial growth is MIC, in agar plate, pushes away evenly with the sterilization glass rod liquid subcultivation in all complete clear no bacterial growth holes, and through 37 ℃ of overnight incubation, the lowest drug concentration that clump count is no more than 5 flat board is the MBC of this medicine.Measure the MBC and the MIC of control drug erythromycin solution and neomycin sulphate solution with method.
The antibacterial activity in vitro test shows that the compound terbinafine nano-emulsion is respectively 0.0625 μ g/mL and 0.125 μ g/mL to MIC, the MBC of staphylococcus aureus, significantly is lower than erythromycin and polygynax; The staphylococcic MIC in centre, MBC are respectively 0.5 μ g/mL and 1 μ g/mL, and redder mould solution is little, and is suitable with neomycin sulphate solution; MIC, MBC to Hemolytic streptococcus are respectively 0.0156 μ g/mL and 0.0625 μ g/mL, significantly are lower than erythromycin and polygynax, show that compound terbinafine nano-emulsion vitro antibacterial activity is better than erythromycin and polygynax.The result sees table 1.
Table 1 MBC (MBC) and minimum inhibitory concentration (MIC) (unit: μ g/mL)
Test Example 3The demodicid mite test is killed in exsomatizing of compound terbinafine Nano medication of the present invention
Scrape the crust and the epidermis affected part scurf that cover with blood crusts in the rabbit auditory meatus of taking from right infection acarid, and place in the glass dish with the tweezers taking-up, the plate edge is coated with a small amount of acarid repellent agent, heats a little, is for experiment with choosing the active strong acarid of worm pin picking.Under anatomical lens, carry out the polypide evaluation, identify that it is psoroptes cuniculi and rabbit acaricide.
With separating pin picking acarid on the spill microscope slide; Drip and supply two of reagents, 8 of the acarids of selecting are placed medicinal liquid and add coverslip, under inverted microscope, continue to observe 24h; Every separated 5min observes once; Each observation 2min that continues observes until all death of 8 acarids, record acarid death time every group.It is 5 groups that test is divided into, and all the other four groups are respectively: the distilled water test group, kill demodicid mite Lingshui Spring solution group, ivermectin injection group and 1% eugenol solution group, and test method is with compound terbinafine nano-emulsion group.
Result of the test: different medicinal liquids are handled 24h result and shown that it is 3 ~ 4min that the compound terbinafine nano-emulsion kills the demodicid mite time, are lower than 600 times of dilutions and kill demodicid mite Lingshui Spring solution, and are suitable with the ivermectin miticidal effect, are better than 1% eugenol solution.The result sees table 2.
The table 2 miticidal effect comparative result that exsomatizes
Annotate :+expression has the acarid survival;-expression acarid all kills does not have recovery
Test Example 4The test of compound terbinafine nano-emulsion clinical efficacy
At hospital admission, it is sick to make a definite diagnosis the trouble mixed skin through check; After obtaining owner and agreeing, meet several 40 of the house pet of this experimental condition, as this object of study.Trial drug directly is applied to the affected part, and 14 d, are used continuously at every day twice in cleaning and dry affected part before the medication.The observed and recorded result of the test.Curative effect judging standard is the medicine effective percentage:
Recovery from illness: skin disappears fully or only stays pigmented spots, no gargalesthesia, and inflammation disappears;
Produce effects: skin disappears >=and 60%, the skin injury degree is light and osf density is lower, and gargalesthesia obviously alleviates;
Take a turn for the better: skin disappears 20%～60%, and gargalesthesia is lighter;
Invalid: skin disappears＜and 20% or continue to increase the weight of the same or aggravation of gargalesthesia.
When doing therapeutic evaluation, the case of will fully recovering and produce effects case add up to effective case, calculate effective percentage, and formula is following:
Effective percentage (%)=(recovery from illness case load+produce effects case load)/treat total case load * 100
The effective percentage of two kinds of medicines of table 3
The clinical efficacy result of the test shows; Compound terbinafine nanoemulsion medicine effective percentage is 95%; And the clean effective percentage of clinical commonly used drug tinea demodicid mite is 85%, and it is clean that the clinical therapeutic efficacy that the compound terbinafine nano-emulsion is described is superior to the tinea demodicid mite, and safety; Untoward reaction is few, has broad prospect of application aspect the treatment of pet skin disease.
Below the embodiment that provides through the inventor method for preparing of coming further to set forth compound terbinafine nano-emulsion of the present invention.
Embodiment 1
1) 0.02g terbinafine, 0.02g eugenol, 0.01g erythromycin are added dissolving fully in the 0.6g ethylene glycol;
2) stir in the solution with the preparation of 0.8g ethyl acetate adding step 1);
3) again 3g Tween-80 is added step 2) in the solution of preparation, stir, slowly add the 5.55g distilled water down at 20 ℃ and fully stir, until form clear, viscosity has mobile yellow or water white compound terbinafine nano-emulsion for a short time.
Embodiment 2
Terbinafine 0.6g, eugenol 0.1g, erythromycin 0.1g, triacetyl glycerine 0.2g, Tween-80 2g, dehydrated alcohol 1g, distilled water 6g.
Embodiment 3
Terbinafine 0.05g, eugenol 1.2g, erythromycin 0.05g, ethyl acetate 0.2g, Tween-80 1g, dehydrated alcohol 1g, distilled water 6.5g.
Embodiment 4
Terbinafine 0.1g, eugenol 0.1g, erythromycin 0.3g, Oleum Ricini 0.1g, RH-40 4g, dehydrated alcohol 0.8g, distilled water 4.6g.
Embodiment 5
Terbinafine 0.2g, eugenol 0.2g, erythromycin 0.1g, Jojoba oil 0.1g, Tween-80 2g, dehydrated alcohol 0.4g, distilled water 7g.
Embodiment 6
Terbinafine 0.1g, eugenol 0.1g, erythromycin 0.08g, liquid paraffin 0.01g, olive oil 0.01g, Tween-80 2g, dehydrated alcohol 0.75g, 1,2-propylene glycol 0.25g, distilled water 6.7g.
Embodiment 7
Terbinafine 0.2g, eugenol 0.1g, erythromycin 0.05g, almond oil 0.02g, Semen Tritici aestivi germ oil 0.03g, Tween-80 2g, Tween-60 1g, dehydrated alcohol 0.4g, PEG400 0.2g, distilled water 6g.
Embodiment 8
Terbinafine 0.1g, eugenol 0.1g, erythromycin 0.1g, ethyl acetate 0.2g, Tween-80 2g, Tween-20 1g, glycerin 1.5g, 1,2-propylene glycol 0.5g, distilled water 4.5g.
Embodiment 9
Terbinafine 0.05g, eugenol 0.1g, erythromycin 0.1g, isopropyl myristate 0.05g, Tween-80 3.5g, Span-80 0.5g, PEG200 0.3g, PEG600 0.3, distilled water 5.1g.
Embodiment 10
Terbinafine 0.2g, eugenol 0.3g, erythromycin 0.1g, vitamin E oil 0.2g, EL-40 2g, dehydrated alcohol 1g, distilled water 6.2g.
Claims (9)
1. treat dermopathic compound terbinafine Nano medication for one kind, it is characterized in that the particle diameter of this medicine is 1nm～100nm, is made up of following raw materials by weight percentage:
Terbinafine 0.1%～10%, eugenol 0.1%～15%, erythromycin 0.1%～5%, oil 0.1%～10%, surfactant 10%～40%, cosurfactant 4%～20%, surplus are distilled water, and the mass percent sum of above-mentioned raw materials is 100%;
Said surfactant is one or more the mixture among Tween-80, Tween-60, Tween-20, RH-40, EL-40 and the Span-80;
Said cosurfactant is dehydrated alcohol, ethylene glycol, 1, the mixture of one or more among 2-propylene glycol, glycerin, PEG 200, PEG 400, the PEG 600;
Said oil is one or more the mixture in isopropyl myristate, liquid paraffin, vitamin E oil, Jojoba oil, triacetyl glycerine, ethyl acetate, almond oil, Semen Tritici aestivi germ oil, olive oil, the Oleum Ricini.
2. the dermopathic compound terbinafine Nano medication of treatment according to claim 1 is characterized in that, is made up of following raw materials by weight percentage:
Terbinafine 0.2%～8%, eugenol 0.2%～12%, erythromycin 0.2%～4.5%, oil 0.5%～8%, surfactant 15%～35%, cosurfactant 5%～15%, surplus are distilled water, and the mass percent sum of above-mentioned raw materials is 100%.
3. the dermopathic compound terbinafine Nano medication of treatment is characterized in that, is made up of following raw materials by weight percentage:
Terbinafine 2%, eugenol 3%, erythromycin 1%, oil 2%, surfactant 20%, cosurfactant 10%, distilled water 62%.
4. the dermopathic compound terbinafine Nano medication of treatment is characterized in that, is made up of following raw materials by weight percentage:
Terbinafine 0.2%, eugenol 0.2%, erythromycin 0.1%, ethyl acetate 8%, Tween-80 are 30%, ethylene glycol 6%, distilled water 55.5%.
5. the dermopathic compound terbinafine Nano medication of treatment is characterized in that, is made up of following raw materials by weight percentage:
Terbinafine 6%, eugenol 1%, erythromycin 1%, triacetyl glycerine 2%, Tween-80 are 20%, dehydrated alcohol 10%, distilled water 60%.
6. the dermopathic compound terbinafine Nano medication of treatment is characterized in that, is made up of following raw materials by weight percentage:
Terbinafine 0.5 %, eugenol 12%, erythromycin 0.5%, ethyl acetate 2%, Tween-80 are 10%, dehydrated alcohol 10%, distilled water 65%.
7. the dermopathic compound terbinafine Nano medication of treatment is characterized in that, is made up of following raw materials by weight percentage:
Terbinafine 1%, eugenol 1%, erythromycin 3%, Oleum Ricini 1%, RH-40 are 40%, dehydrated alcohol 8%, distilled water 46%.
8. the dermopathic compound terbinafine Nano medication of treatment is characterized in that, is made up of following raw materials by weight percentage:
Terbinafine 2%, eugenol 2%, erythromycin 1%, Jojoba oil 1%, Tween-80 are 20%, dehydrated alcohol 4%, distilled water 70%.
9. the method for preparing of the dermopathic compound terbinafine Nano medication of the said treatment of claim 1 is characterized in that, specifically comprises the following steps:
1) take by weighing terbinafine, eugenol, erythromycin, oil, surfactant, cosurfactant, distilled water, subsequent use;
2) terbinafine, eugenol, erythromycin are added dissolving fully in the cosurfactant;
3) oil is added step 2) preparation solution in stir;
4) again surfactant is added step 2) in the solution of preparation, stir, add down slowly distilled water at 20 ℃～25 ℃ and fully stir, until form clear, viscosity has mobile yellow or water white compound terbinafine nano-emulsion for a short time.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103975921A (en) * | 2014-04-25 | 2014-08-13 | 浙江大学 | Pre-harvest sprouting inhibitor and method for inhibiting pre-harvest sprouting of rice |
| CN114981379A (en) * | 2019-10-08 | 2022-08-30 | 哈尔卢克斯股份有限公司 | Compositions and methods for treating onychomycosis |
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2011
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103975921A (en) * | 2014-04-25 | 2014-08-13 | 浙江大学 | Pre-harvest sprouting inhibitor and method for inhibiting pre-harvest sprouting of rice |
| CN103975921B (en) * | 2014-04-25 | 2016-04-13 | 浙江大学 | A kind of method that fringe is sprouted inhibitor and suppressed Rice Panicle to be sprouted |
| CN114981379A (en) * | 2019-10-08 | 2022-08-30 | 哈尔卢克斯股份有限公司 | Compositions and methods for treating onychomycosis |
| CN114981379B (en) * | 2019-10-08 | 2024-05-14 | 哈尔卢克斯股份有限公司 | Compositions and methods for treating onychomycosis |
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Application publication date: 20120725 |