CN107184551A - Double particle diameter distribution emulsions of a kind of Liranaftate and preparation method thereof - Google Patents
Double particle diameter distribution emulsions of a kind of Liranaftate and preparation method thereof Download PDFInfo
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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Abstract
A kind of double particle diameter distribution emulsions of Liranaftate, its active component is Liranaftate.The present invention also disclosed its preparation method simultaneously.The emulsion of the present invention not only solves the water insoluble problem of medicine, also makes drug transdermal good, and bioavilability is improved, security lifting, cost reduction.And, the emulsion of the invention is double particle diameter distributions, and due to small-size effect, medicine specific surface area is greatly increased, small particle medicine can quickly go deep into skin corium and directly fungi progress suppression is killed, large-grainsize medicine gos deep into that cortex is slower, but can persist and subcutaneously carrying out the slow release of medicine, extended treatment time, reduce administration number of times, the bioavilability of medicine is greatly improved on the whole, and the course for the treatment of shortens, and the paste prospect than in the market is more wide.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of double particle diameter distribution emulsions of Liranaftate and its preparation side
Method.
Background technology
Entitled N- (6- methoxyl group -2- the pyridine radicals)-N- methylaminos bamic acid of Liranaftate chemistry (5,6,7,8- tetra-
Hydrogen) -2- naphthalene esters, it is to compare a kind of new antifungal in recent years, by suppressing the squalene epoxidation reaction of fungal cell, resistance
Hold back the synthesis of cellularity composition ergosterol, so as to play antifungal activity.Clinical test shows, with conventional antifungal medicine phases
Than the effect of this product is more superior, and drug resistance is lower, still has to cureless pin Xian and body Xian disease and preferably controls curative effect
Really.Compared with traditional medicine Tolnaftate, 7 times of effect promoting, the therapeutic effect to tinea bacterium is better than clotrimazole, in coming years market part
Volume can be in the trend risen year by year.
But it is due to that Liranaftate is water insoluble, wants to make liquid preparation, it is necessary to is dissolved with substantial amounts of organic solvent, no
But costly, organic solvent also has certain detrimental effect to skin, and the liquid preparation that organic solvent is prepared into belongs to normal
Formulation is advised, is applied to after skin surface, due to the inhibition of skin natural horny layer, actually can penetrate subcutaneous medication amount simultaneously
Seldom, it is most of still to have stayed in skin surface, and the fungi overwhelming majority is bred in deep skin tissue after dermatophytid infection,
If medicine can not go deep into subcutaneous dermal layer, bioavilability can be limited, and curative effect is deteriorated, and disease is often repeatedly, it is difficult to thorough root
Control, in the market this medicine or the progress popularization and application by main application forms of paste.
The content of the invention
It is an object of the invention to provide a kind of double particle diameter distribution emulsions of Liranaftate, while it is this to provide its preparation method
The another goal of the invention of invention.
Based on above-mentioned purpose, the present invention is adopted the following technical scheme that：
A kind of double particle diameter distribution emulsions of Liranaftate, its active component is Liranaftate.
The percentage by weight of the Liranaftate is 0.01~5.0%.
The percentage by weight of the emulsion is constituted：Liranaftate 0.01~5.0%, oil phase 0.1~12.0%, the first table
Face activating agent 0.5~6.0%, second surface activating agent 15.0~30.0%, cosurfactant 0.1~8.0%, remaining is to go
Ionized water；The first surface activating agent is selected from polyoxyl 40 hydrogenated castor oil (RH-40), castor oil polyoxyethylene ether 40
(EL-40), one or both of emulsifier op-10, Tween 80, polysorbas20 mixture；The second surface activating agent is selected from
One or both of Si Ben -80, Si Ben -20, Tween-85 and triethanolamine oleate mixture.
The grease separation is from ethyl acetate, soybean oil, ethyl oleate, isopropyl myristate (IPM), corn oil, middle chain three
One or both of glyceride (MCT) and olive oil mixture.
The cosurfactant be selected from absolute ethyl alcohol, 1,2- propane diols, polyethylene glycol 200, triethylene glycol, isopropanol and
One kind in glycerine.
The preparation method of the double particle diameter distribution emulsions of described Liranaftate, comprises the following steps：
1) Liranaftate is added in oil phase and dissolved, obtain system I；
2) it is A, B two parts to divide system I, and allocation proportion is A:B=1:(3~10)；
3) mixing of first surface activating agent is added into part A, the deionized water for adding 2 times of A weight mixes to obtain system
A1；The mixing of second surface activating agent is added into part B, the deionized water for adding 2 times of B weight mixes to obtain system B1；Afterwards
By cosurfactant according to be added separately to mix in system A1 and system B1 after A, B allocation proportion distribution system II and
System III；
4) by system II and system III is respectively at ultrasound and emulsifies to observing two system transparent and homogeneous, without layering；
5) the system II after ultrasonic emulsification and system III is mixed, and adds the mixing of remaining deionized water i.e..
Step 4) in, the frequency of ultrasonic emulsification is 18KHZ, and the time of ultrasonic emulsification is more than 30min.
Double particle diameter distribution emulsions prepared by the present invention can also continue to add deionized water, to obtain diluter Liranaftate
Double particle diameter distribution emulsions.
The double particle diameter distribution emulsions of the Liranaftate of the present invention, small particle size distribution scope is in 1~30nm, big particle size distribution range
In 200~400nm scopes.
Regular dosage form is applied to after skin surface, due to the inhibition of skin natural horny layer, can actually be penetrated subcutaneous
Medication amount and few, it is most of still to have stayed in skin surface, and the fungi microbe overwhelming majority is all after dermatophytid infection
It is that, in the breeding of deep skin tissue, if medicine can not go deep into subcutaneous dermal layer, bioavilability can be limited, and not only cause treatment time
It is long, it can also trigger disease often repeatedly, it is difficult to thoroughly treat.The present invention uses nanometer emulsified technology, using to skin affinity
By force, safe oil phase, surfactant, cosurfactant and deionized water are major auxiliary burden, and medicine preparation is in pairs
The nano-emulsion liquid dosage form of particle diameter distribution, medicine is changed into after the emulsion of doubly-linked distributed mutually, not only solves medicine water insoluble
Problem, also makes drug transdermal good, and bioavilability is improved, security lifting, cost reduction.Moreover, the emulsion of the invention is
Double particle diameter distributions, due to small-size effect, medicine specific surface area is greatly increased, and it is direct that small particle medicine can quickly go deep into skin corium
Suppression is carried out to fungi to kill, large-grainsize medicine gos deep into that cortex is slower, but can persist and subcutaneously carrying out the slow release of medicine, prolong
Long treatment time, administration number of times is reduced, the bioavilability of medicine is greatly improved on the whole, the course for the treatment of shortens, than in the market
Paste prospect is more wide.
Specifically, technical scheme has following advantage：
(1) quick acting：Obtained double particle diameter distribution emulsion small particle size distributions are in 1~30nm, less than space between cells, and
Under Action of Surfactant, to skin compatibility more preferably, medicine interfacial surface tension reduction, it is easy to enter skin corium and it is right
Fungi carries out suppression and killed, quick acting；
(2) slow releasing function：Obtained double big particle diameter distributions of particle diameter distribution emulsion in 200~400nm, can enter cortex with
Under, because particle diameter is larger, rate of release is slower, adds slow releasing function effect again on the basis of quick acting, extends medicine
Action time, administration number of times is reduced, medication is more convenient；
(3) good water solubility：Water insoluble Liranaftate is become soluble in water, and can infinite dilution do not separate out, do not break
Breast, it is not stratified, do not precipitate, can store, be administered at any time, it is easy to use；
(4) present invention process simple possible, converts beneficial to large-scale industry, a kind of new Liranaftate is provided for market
Pharmaceutical dosage form, and than old formulation better efficacy, treatment cycle shortens, and cost is lower；
(5) medicine stability of the invention is strong, and temperature is not demulsified between -20~40 DEG C, not stratified, and medicine is not separated out,
Non-degradable, curative effect will not change.
Embodiment
With reference to specific embodiment the present invention will be further described, it is necessary to explanation, unless otherwise noted, this hair
Bright preparation method is to operate at room temperature, and the room temperature described in the invention refers to 15-25 DEG C.
Embodiment 1-10
To make specification briefly, each specific embodiment is provided in the form of a list below, so as to be done further to the present invention
Explanation.
The embodiment 1-10 of table 1 each component composition
By taking embodiment 1 as an example, the preparation method of the double particle diameter distribution emulsions of Liranaftate is described in detail, comprised the following steps：
1) 8.0g olive oil and 2.0g IPM are added in a container, are well mixed as oil phase, by 2.0g Liranaftates
Add in oil phase, stirring and dissolving obtains system I；
2) it is A, B two parts to divide system I, and allocation proportion is A:B=1:5, i.e. part A are 2g, and part B is 10g；
3) first surface activating agent RH-40 4.0g and Tween-80 1.5g are added in part A, 4.0g deionizations are added
Water and 1.0g1,2- propane diols, are uniformly mixed, and obtain system II；Second surface activating agent Si Ben -20 is added in part B
25g, adds 20.0g deionized waters and 5.0g 1,2-PDs, is uniformly mixed, and obtains system III；
4) system II and system III are respectively placed in more than ultrasonic emulsification 30min under 18KHZ supersonic frequency, side ultrasound
Side is stirred, until observing two system transparent and homogeneous, no layering, no precipitation；
5) system II and system III is mixed, adds deionized water 27.5g, gross mass is reached 100g, be stirred for mixing
Uniformly produce.
Embodiment 2-10 preparation method be the same as Example 1, difference is, in embodiment 2, and allocation proportion is A:B=
1:3；In embodiment 3, allocation proportion is A:B=1:10.
The stability experiment of embodiment 11
It is stable that Example 1-10 double particle diameter distribution emulsion products carry out test of time, accelerated test, anti-freezing respectively
Property experiment and dewatering ability experiment, the stability of the double particle diameter distribution emulsions of the observation present invention, be confirmed whether to have layering, demulsification or
The wild effects such as medicine precipitation occur.
1st, test of time
Example 1-10 double particle diameter distribution emulsions are stored 12 months under the conditions of room temperature natural trend, investigate double grains footpath
The character and changes of contents of emulsion are distributed, is as a result shown, the lasting clear of outward appearance, do not find to be layered, be demulsified or medicine precipitation
Occur etc. wild effect, illustrate that ageing stability is good.
2nd, accelerated test
Embodiment 1-10 double particle diameter distribution emulsions are sub-packed in 100ml vials, 40 DEG C of temperature is placed in after sealing,
60d is stored in the accelerated test case of relative humidity 75%, samples and observes every 10d.As a result show, embodiment 1-10 double grains footpath
Distribution emulsion do not found to be layered, be demulsified or medicine is separated out etc., and wild effect occurs, and illustrates that accelerated stability is good.
3rd, anti-freezing stability
Embodiment 1-10 double particle diameter distribution emulsions are sub-packed in 100ml vials, it is continuous at a temperature of -20 DEG C of refrigerator
January is preserved, is during which taken out every 10d, recovers to thaw at RT to observe.As a result show, embodiment 1-10 double particle diameter distributions
Emulsion do not found to be layered, be demulsified or medicine is separated out etc., and wild effect occurs, and shows that freezing-resistance is good.
4th, dewatering ability
Embodiment 1-10 double particle diameter distribution emulsions are placed in centrifuge tube, seals, 30 is centrifuged under 3000r/min rotating speed
Observed after minute, do not find to be layered after examining through dilution, be demulsified or medicine is separated out etc. that wild effect occurs, show that centrifugation is stable
Property is good.
Peace of the medicine of the present invention to animal is expanded on further below by way of drug safety experiment and the test of pesticide effectiveness
Full property and its drug effect.
The safety testing of embodiment 12
Following safety testing is carried out using the double particle diameter distribution emulsions of Liranaftate made from embodiment 1 as sample.
Safety testing：The Kunming small white mouse that 30 body weight are 20g or so is randomly divided into three groups, every group 10, male and female
Half and half, wherein first group is blank control group, second group is healthy skin group, and the 3rd group is damaged skin group.By three groups of little Bai
The skin of abdomen of mouse is smeared with 8% sodium sulfide solution respectively to lose hair or feathers, size about 2.0cm*2.0cm, while by the 3rd group
" well " word is drawn with sterile needle at mouse depilation skin, using micro, slight oozing of blood to spend, first group and second group of mouse do not make any processing.
12h is observed after being disposed, starts experiment after the performance without exception of each group mouse, first group of mouse embrocates depilation with physiological saline
Place, second group and the 3rd group of mouse embrocate the emulsion of embodiments of the invention 1, are used as healthy skin and damaged skin test group.
Daily once in the morning and once at night, it is used in conjunction 3, then observes 3 again, during which observes the stimulation situation of skin, mouse behavior expression and dead
Situation is died, and performs record.
It is that sample carries out safety to the double particle diameter distribution emulsions of Liranaftate made from other embodiment using this test method
Property experiment.
Result of the test：Each group mouse skin is normal, at the medication skin of second group and the 3rd group mouse and the first group pair
According to group compared to simultaneously indifference, behavior expression and health status are normal, and no death condition occurs.2 are randomly selected to each group mouse
Indifference between cut open inspection observation, each internal organs also lesion without exception, each group is only carried out, shows double particle diameter distribution emulsion liquid peaces of the invention
Full property is good.
The test of pesticide effectiveness of embodiment 13
The drug effect of dermatophytid infection treatment is carried out as sample using the double particle diameter distribution emulsions of Liranaftate made from embodiment 1
Experiment.
The test of pesticide effectiveness：By 40 body weight for 2kg or so, the rabbit with skin depilatory tinea (dermatophytid infection), at random
It is divided into 4 groups, every group 10, male and female half and half.1st group is control group, and cropping, not medication are only carried out at psoriasis；2nd and 3 group is removed
At psoriasis outside cropping, the most frequently used cream of formulation 2% in market of embrocating Liranaftate in affected area respectively, the 2nd group is daily
Timing is embrocated once, and the 3rd group is embrocated 3 times daily；The 4th group of double particle diameter distribution emulsions of the Liranaftate for embrocating the invention of embodiment 1, often
Day once, each group mouse needs continuous use 7d, observes the rehabilitation situation at psoriasis position afterwards, Continuous Observation again after experiment is finished
15d, sees whether there is recurrence, is judged according to result, during which performs detailed test data sheet.
Rehabilitation situation standard：
Illing skin incrustation comes off, and exposes new granulation tissue, and grows virgin wool again for rehabilitation；
Illing skin incrustation is not completely fallen off, and affected part has been restrained, and there is growth sign in new granulation tissue to lapse to；
Pars affecta skin incrustation becomes big, local moist or bleeding, rabbit still have grab sting skin show as it is invalid；
It is efficient=(rehabilitation number+lapse to number)/sum * 100%
The double particle diameter distribution emulsions of the Liranaftate of table 2 are to rabbit psoriasis test of pesticide effectiveness result
| Group | Rabbit sum (/ only) | Rehabilitation number (/ only) | Lapse to number (/ only) | Invalid number (/ only) | It is efficient | Recurrence number (/ only) |
| 1st group | 10 | 0 | 1 | 9 | 10% | --- |
| 2nd group | 10 | 2 | 3 | 5 | 50% | 1 |
| 3rd group | 10 | 6 | 2 | 2 | 80% | 2 |
| 4th group | 10 | 7 | 2 | 1 | 90% | 0 |
As a result show：
1. in the case of not medication, by the self-healing rate of rabbit itself resistance skin depilatory tinea disease only 10%；2. adopt
After being treated with Liranaftate, effective percentage is significantly improved, and shows that Liranaftate has therapeutic action to rabbit skin depilatory tinea disease；
3. under same dosage conditions, the 2nd group is compared with the 4th group of result, same administrated method and medicine frequency, profit draws naphthalene
The double particle diameter distribution emulsion effects of ester are higher by 40% than common paste effective percentage, show that this emulsion curative effect is better than traditional paste；
4. under same dosage conditions, the 3rd group is compared with the 4th group of result, the daily medication of traditional paste 3 times, and curative effect is final
It is suitable with double particle diameter distribution emulsions daily medication effect of 1 time, show that the present invention has significant slow releasing function, administration time can be reduced
Number, time saving and energy saving, medication also more facilitates.
5. using in the rabbit of Liranaftate therapy rehabilitation, after drug withdrawal 15d, the 2nd group and the 3rd group has recurrence, and
Double particle diameter distribution emulsions of the present invention occur without recurrence, thorough treatment.
Claims (7)
1. a kind of double particle diameter distribution emulsions of Liranaftate, its active component is Liranaftate.
2. the double particle diameter distribution emulsions of Liranaftate as claimed in claim 1, it is characterised in that in emulsion, the Liranaftate
Percentage by weight be 0.01~5.0%.
3. the double particle diameter distribution emulsions of Liranaftate as claimed in claim 2, it is characterised in that the percentage by weight of the emulsion
Constitute and be：Liranaftate 0.01~5.0%, oil phase 0.1~12.0%, first surface activating agent 0.5~6.0%, second surface are lived
Property agent 15.0~30.0%, cosurfactant 0.1~8.0%, remaining is deionized water；The first surface activating agent is selected from poly-
The rilanit special of oxygen ethene 40 (RH-40), castor oil polyoxyethylene ether 40（EL-40）, emulsifier op-10, Tween 80, polysorbas20
One or both of mixture；The second surface activating agent is selected from Si Ben -80, Si Ben -20, Tween-85 and oily triethylenetetraminehexaacetic acid
One or both of hydramine mixture.
4. the double particle diameter distribution emulsions of Liranaftate as claimed in claim 3, it is characterised in that the grease separation from ethyl acetate,
Soybean oil, ethyl oleate, isopropyl myristate（IPM）, corn oil, one kind in medium chain triglycerides (MCT) and olive oil
Or two kinds of mixtures.
5. the double particle diameter distribution emulsions of Liranaftate as claimed in claim 3, it is characterised in that the cosurfactant is selected from
One kind in absolute ethyl alcohol, 1,2- propane diols, polyethylene glycol 200, triethylene glycol, isopropanol and glycerine.
6. the preparation method of the double particle diameter distribution emulsions of any described Liranaftates of claim 3-5, it is characterised in that including with
Lower step：
1）Liranaftate is added in oil phase and dissolved, system I is obtained；
2）By system, I points are A, B two parts, and allocation proportion is A:B=1:（3~10）；
3）The mixing of first surface activating agent is added into part A, the deionized water for adding 2 times of A weight mixes to obtain system A1；To
The mixing of second surface activating agent is added in part B, the deionized water for adding 2 times of B weight mixes to obtain system B1；Table will be helped afterwards
Face activating agent is added separately in system A1 and system B1 mix to obtain system II and system after distributing according to A, B allocation proportion
III；
4）By system II and system III respectively at ultrasonic emulsification to observing two system transparent and homogeneous, without layering；
5）System II and system III after ultrasonic emulsification is mixed at room temperature, and adds the mixing of remaining deionized water and is produced.
7. the preparation method of the double particle diameter distribution emulsions of Liranaftate as claimed in claim 6, it is characterised in that step 4）In,
The frequency of ultrasonic emulsification is 18KHZ, and the time of ultrasonic emulsification is more than 30min.
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| CN101422434A (en) * | 2008-12-11 | 2009-05-06 | 扬子江药业集团有限公司 | Liranaftate cream preparation method |
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