CN104306335B - A kind of Fluconazole flexible nano lipid vesicle composition and its application - Google Patents
A kind of Fluconazole flexible nano lipid vesicle composition and its application Download PDFInfo
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- CN104306335B CN104306335B CN201410619117.8A CN201410619117A CN104306335B CN 104306335 B CN104306335 B CN 104306335B CN 201410619117 A CN201410619117 A CN 201410619117A CN 104306335 B CN104306335 B CN 104306335B
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Abstract
The invention discloses a kind of Fluconazole flexible nano lipid vesicle compositions, component including following weight part ratio: 1-10 parts of Fluconazole, 10-80 parts of vesica forming agent, 5-30 parts of vesica membrane fluidity regulator, 1-30 parts of vesica softening agent, and provide the method for preparing Fluconazole flexible nano lipid vesicle suspensions；Meanwhile also disclosing the application for being major ingredient in preparation for external application to skin using Fluconazole flexible nano lipid vesicle suspensions.Fluconazole flexible nano lipid vesicle percutaneous drug administration preparation provided by the invention, there can be the ability that drug penetrates cuticula that increases, drug is set to penetrate to the skin quickly interior, and it is trapped in epidermis and intradermal, epidermis and intradermal is set to form drug depot, become the drug delivery system that skin targets and has slow-releasing and controlled-releasing action, drug directly enduringly to local sick cell or can organize therapeutic effect, it is less by body absorption, thus systemic applications bring toxic side effect is reduced or avoided, to substantially increase therapeutic effect.
Description
Technical field
The present invention relates to a kind of externally applied drug combination preparation, specifically a kind of Fluconazole flexible nano lipid vesicle combination
Object and its application in preparation for external application to skin.
Background technique
Fluconazole (fluconazole) is the antifungal triazole developed by Pfizer Inc. (Pfizer) in 1980
Medicine, the mechanism of action, which mainly passes through, inhibits the cytochrome P-450 of fungi to make fungal cell's ergosterol dyssynthesis, thus
Achieve the effect that inhibition and kill fungi, has many advantages, such as has a broad antifungal spectrum.Fluconazole is in addition to for treating candidiasis, cryptococcus
Outside tissue organs infection caused by disease, coccidioidomycosis, blastomycosis and histoplasmosis etc., local patholoic change can also be treated
Such as monilial vaginitis, recalcitrant dermal fungal infection, Malassezia folliculits, onychomycosis.But with regard to existing market
Some Fluconazole tablets, capsule, powder-injection and several dosage forms of injection are only suitable for Formulations for systemic administration, and Formulations for systemic administration is used for treatment office
Portion's lesion, the dose that drug reaches local skin after transhipment in vivo, distribution and metabolism is limited, and part to be made to reach ideal
Therapeutic dose just inevitably causes the toxic side effect of whole body, such as: oral or intravenous administration after some patientss occur digestive tract reaction,
The adverse reactions such as allergic reaction, hepatotoxicity wind agitation.But according to the prior art, if Fluconazole is fabricated to outside common skin by we
With pharmaceutical preparation, due to the influence of drug nature and matrix, drug is more difficult to penetrate skin barrier, that is, cuticula, it is difficult to reach
Therapeutic effect.Even if using in industry in order to which the usual method physically or chemically of the curative effect for increasing external drug introduces a drug into
The therapentic part of body, such as using electro-ionic osmosis, ultrasound importing and electricity, heat, light skin pore physical method and transdermal suction
Receive the chemical methodes such as promotor, it is also difficult to reach ideal curative effect.Because though these methods can introduce a drug into better
Skin, but skin is increased to varying degrees to the acceleration permeability of drug, it accelerates drug and enters body blood circulation
Speed, increase the dosage that drug enters body, poor to skin drug effect persistence, this not only adds medical treatment costs, and
And it is also inevitably present some such as the problems such as transience skin lesion and potential cutaneous immunisation.Therefore, it develops a kind of suitable
It is that current pharmaceuticals industry is urgently to be resolved for local skin treatment and the Fluconazole external preparation of skin good absorbing, lasting medicine
The problem of.
Summary of the invention
It is an object of the invention to provide a kind of Fluconazole flexible nano lipid vesicle composition and its applications, existing to solve
There is the problem that Fluconazole percutaneous drug administration preparation skin absorption is poor, the residence time is short in skin, lasting medicine is poor.
It is an object of the invention to provide a kind of Fluconazole flexible nano lipid vesicle compositions, including following weight part ratio
Component: 1-10 parts of Fluconazole, 10-80 parts of vesica forming agent, 5-30 parts of vesica membrane fluidity regulator, vesica softening agent 1-30
Part；The vesica membrane fluidity regulator be cholesterol, the vesica softening agent be fatty glyceride, sucrose fatty ester,
Any one in sorbitan fatty acid ester, polysorbate, sodium taurocholate, deoxysodium cholate, ethyl alcohol or propylene glycol or two kinds
The mixture of arbitrary proportion.
Described the composition includes 1-10 parts of Fluconazole, and 10-80 parts of vesica forming agent, vesica membrane fluidity regulator 5-30
Part, 1-30 parts of vesica softening agent, 2-15 parts of antioxidant；The antioxidant is vitamin E, vitamin C, butylhydroxy fennel
Ether, 2,6 di tert butyl 4 methyl phenol, tea polyphenols, guaiac resin, sesamol or boldine, sodium pyrosulfite, sulfurous
The mixture of one or both of sour hydrogen sodium, sodium sulfite or sodium thiosulfate arbitrary proportion.
Described the composition includes 1-10 parts of Fluconazole, and 10-80 parts of vesica forming agent, vesica membrane fluidity regulator 5-30
Part, 1-30 parts of vesica softening agent, 2-15 parts of antioxidant, 2-20 parts of vesica stabilizer；It is preferred that 5-10 parts of Fluconazole, vesica is formed
50-70 parts of agent, 10-20 parts of vesica membrane fluidity regulator, 5-20 parts of vesica softening agent, 2-8 parts of antioxidant, vesica stabilizer
2-10 parts；The vesica stabilizer is any one or two kinds in povidone, crospovidone, polyethylene glycol or polyvinyl alcohol
The mixture of arbitrary proportion.
The vesica forming agent is soybean lecithin, egg yolk lecithin, dipalmitoylphosphatidylcholine, distearyl phosphatide
Phatidylcholine, dimyristoyl phosphatidyl choline, phosphatidyl-ethanolamine, phosphatidic acid, phosphatidyl glycerol, phosphatidylinositols, phosphatidyl
Serine, stearmide, oleoyl aliphatic amine derivative, cholesterol derivative, fatty acid esters of sorbitan, polyoxyethylene rouge
The mixing of one or both of fat acid esters, polyoxyethylene aliphatic alcohol ether or Pluronic F68 arbitrary proportion
Object.
The vesica softening agent is preferably fatty glyceride, sucrose fatty ester, sorbitan fatty acid ester or poly-
Any one in sorb ester, more preferable polysorbate.
In the use of the present invention, being first combined object is prepared as suspension, then using the suspension as major ingredient, it is equipped with and is suitable for
Paste is made in the appropriate amount of auxiliary materials of percutaneous dosing.
A kind of preparation method of its suspension the following steps are included:
(a) component needed for being weighed by above-mentioned weight part ratio；
(b) Fluconazole, vesica forming agent, vesica membrane fluidity regulator and Partial Antioxidation agent are mixed into postposition
In reactor；
(c) chloroform is added in the reactor to make it dissolve, evaporation under reduced pressure removed chloroform at being 48 DEG C in temperature；
Make to form uniform lipid film on the inner wall of reactor；
(d) remaining antioxidant, vesica softening agent and vesica stabilizer are dissolved in the phosphate buffer that pH is 7.0
In, it is added in the reactor and washes film, add several glass beads and be stirred aquation, in short-term ultrasonic vibration, microporous barrier
Filtering is to get Fluconazole flexible nano lipid vesicle suspensions.
Its described suspension, which can also be, to be prepared by the following method, step are as follows:
(a) component needed for being weighed by above-mentioned weight part ratio；
(b) it is dissolved in alcohol solvent, obtains after mixing the Fluconazole, vesica forming agent, vesica membrane fluidity regulator
Mixed liquor；
(c) vesica softening agent is dissolved in the phosphate buffer solution that pH value is 7 again, is injected into mixed liquor with syringe
Constant temperature is in 50 DEG C and the phosphate buffer that stirreds, and stirring, evaporative removal ethyl alcohol is to get Fluconazole flexible nano lipid capsule
Steep suspension.
Its described suspension can be through the following steps that preparation:
(a) component needed for being weighed by above-mentioned weight part ratio；
(b) Fluconazole, vesica forming agent, vesica membrane fluidity regulator and Partial Antioxidation agent are placed in reactor
In；
(c) chloroform is added in the reactor to make it dissolve, evaporation under reduced pressure removed chloroform at being 48 DEG C in temperature；
Make to form lipid film on the inner wall of reactor；
(d) by volume it is to be added in reactor after 3:5 is mixed by chloroform and ether, makes it dissolve lipid film；
(e) vesica softening agent, remaining antioxidant and vesica stabilizer are dissolved in the phosphate buffer that pH is 7.0 again
In, and add it in the reactor, the mixture in ice-water bath ultrasound to reactor forms uniform w/o type emulsion；
(f) it is to be placed it is not stratified after, by the w/o type emulsion temperature be 20 DEG C at be evaporated under reduced pressure, remove organic solvent,
Obtain translucent gel；
(g) continuation is evaporated under reduced pressure at being 20 DEG C in temperature, until gel collapses to form aqueous suspension；
(h) the phosphate buffer aquation 30min that pH value is 7.0 is added to get Fluconazole flexible nano lipid vesicle
Suspension.
The present invention passes through the prescription for having selected specific raw material and proper proportion, and fluorine health is prepared under the conditions of ad hoc approach
Azoles flexible nano lipid vesicle suspensions, Fluconazole drug encapsulation has similar thin in class lipid bilayer in the suspension
The characteristic and function of born of the same parents' structure and biomembrane, have wherein upset bilayer due to joined vesica softening agent in composition
The sequence of phosphatidyl chain, so that sequence parameter is remarkably decreased, randomness increases, and vesica is provided with the deformability of height,
Under the action of transdermal aquation power, energy self extrusion passes through cutin interlayer region without causing the broken of vesica, and its vesica is straight
Front and back hardly happens variation to diameter herein, so being equipped with auxiliary material is prepared into Fluconazole flexible nano lipid vesicle percutaneous dosing
Preparation has and increases drug and penetrate the ability of cuticula, can make in drug penetrates to the skin quickly, and be trapped in epidermis and
Intradermal makes epidermis and intradermal form drug depot, becomes the drug delivery system that skin targets and has slow-releasing and controlled-releasing action, medicine
Object directly enduringly to local sick cell or can organize therapeutic effect, less by body absorption, thus be reduced or avoided
Systemic applications bring toxic side effect, to substantially increase therapeutic effect；And the Fluconazole of present composition preparation
Lipid vesicle suspensions uniform particle sizes, good dispersion, encapsulation rate are high, and it is highly stable to be experimentally confirmed its pharmacological property, are suitable for industry
Production and the popularization and application of field of medicaments.
Application of the Fluconazole flexible nano lipid vesicle composition of the present invention in preparation for external application to skin, specifically
Are as follows: using the Fluconazole flexible nano lipid vesicle of above-mentioned preparation as major ingredient, the gel substrate for being suitable for percutaneous dosing is auxiliary material,
It is 1ml:5-10mg preparation according to major ingredient and auxiliary material, can also adds the preparation of other auxiliary materials such as qs glycerin and be suitable for external preparation for skin system
Agent；The gelling agent is sodium alginate, sodium carboxymethylcellulose, low-substituted hydroxypropyl cellulose, hypromellose, methyl
Cellulose, carbopol 940, carbopol 941, any one or two kinds of arbitrary proportions in carbopol 934 mixture.It is prepared
Method are as follows: by gel-type vehicle plus it is water-swellable after, Fluconazole flexible nano lipid vesicle suspensions are added, lapping-in is uniformly to obtain the final product.
The usage of Fluconazole percutaneous drug administration preparation provided by the present invention is smeared mainly for the external preparation for skin of disease sites
In affected part, dosage is depending on gradient of infection of the different fungies to skin, and patient preferably follows the doctor's advice medication, general recommendations
Metering is 60-1000mg/ times (with effective meter of Fluconazole), 1-3 times daily.
Detailed description of the invention
Fig. 1 is the transmission electron microscope picture of Fluconazole flexible nano lipid vesicle suspensions prepared by embodiment 1.
Fig. 2 is Fluconazole flexible nano lipid vesicle grain size distribution prepared by embodiment 1.
Fig. 3 is Fluconazole flexible nano lipid vesicle percutaneous drug administration preparation cumulative in vitro drug release figure prepared by embodiment 6.
Fig. 4 is that Fluconazole flexible nano lipid vesicle percutaneous drug administration preparation prepared by embodiment 6 accumulates releasing medicine through skin penetration figure.
Specific embodiment
Following example is for present invention be described in more detail, but the invention is not limited in any way.
Embodiment 1
Fluconazole bulk pharmaceutical chemicals 80mg, soybean lecithin 640mg, cholesterol 100mg and vitamin E 20mg is weighed to be placed in
In pear shape bottle, chloroform 25mL, which is added, to be made to dissolve, and (48 DEG C) removal chloroforms are evaporated under reduced pressure on a rotary evaporator, make
Uniform film layer is formed in bottle wall；Sodium taurocholate 100mg, vitamin C 20mg separately are taken, povidone 20mg is dissolved in the phosphorus of pH7.0
In phthalate buffer, it is added in pear shape bottle and washes film, if after adding bead dry granular stirring aquation 30min, ultrasound shake in short-term
2min is swung, to get Fluconazole flexible nano lipid vesicle suspensions after 0.45 μm of filtering with microporous membrane whole grain.
Embodiment 2
Weigh Fluconazole bulk pharmaceutical chemicals 100mg, fatty acid esters of sorbitan 800mg, cholesterol 300mg and vitamin E
75mg is placed in pear shape bottle, and chloroform 40mL, which is added, to be made to dissolve, and (48 DEG C) removal trichlorines are evaporated under reduced pressure on a rotary evaporator
Methane makes to form uniform film layer in bottle wall；Separately take fatty glyceride 300mg, vitamin C 75mg, povidone
200mg is dissolved in the phosphate buffer of pH7.0, is added in pear shape bottle and is washed film, if adding bead dry granular stirring aquation
After 30min, ultrasonic vibration 5min in short-term, to get Fluconazole flexible nano lipid vesicle after 0.45 μm of filtering with microporous membrane whole grain
Suspension.
Embodiment 3
Weigh Fluconazole bulk pharmaceutical chemicals 10mg, 100 mg of Distearoyl Phosphatidylcholine, cholesterol 50mg and vitamin E
25mg is placed in pear shape bottle, and chloroform 25mL, which is added, to be made to dissolve, and (48 DEG C) removal trichlorines are evaporated under reduced pressure on a rotary evaporator
Methane makes to form uniform film layer in bottle wall；Separately take sucrose fatty ester 100mg, vitamin C 30mg, povidone
50mg is dissolved in the phosphate buffer of pH7.0, is added in pear shape bottle and is washed film, if adding bead dry granular stirring aquation
After 30min, ultrasonic vibration 5min in short-term, to get Fluconazole flexible nano lipid vesicle after 0.45 μm of filtering with microporous membrane whole grain
Suspension.
Embodiment 4
Fluconazole bulk pharmaceutical chemicals 80mg, hydrogenated yolk lecithin 520mg and cholesterol 100mg are dissolved in 10mL ethyl alcohol jointly
In, it separately takes 10mg polyoxyethylene sorbitan monoleate to be dissolved in the phosphate buffer that the pH value of 20ml is 7.0, is delayed ethanol solution with syringe
In the slow phosphate buffer for being injected into 50 DEG C of constant temperature and stirred, continue to be stirred 1h removing ethyl alcohol with rotor to get Fluconazole
Flexible nano lipid vesicle suspensions.
Embodiment 5
Fluconazole bulk pharmaceutical chemicals 100mg, phosphatidylserine 800mg and cholesterol 300mg are dissolved in jointly in 50mL ethyl alcohol,
Sorbitan fatty acid ester 100mg is separately taken to be dissolved in the phosphate buffer that the pH value of 35ml is 7.0, with syringe by ethyl alcohol
Solution is slowly injected into 50 DEG C of constant temperature and in the phosphate buffer that stirreds, continue to be stirred with rotor 1h remove ethyl alcohol to get
Fluconazole flexible nano lipid vesicle suspensions.
Embodiment 6
Weigh Fluconazole bulk pharmaceutical chemicals 80mg, egg yolk lecithin 640mg, cholesterol 160mg and butylated hydroxy anisole
10mg is placed in pear shape bottle, and chloroform 25mL, which is added, to be made to dissolve, and (48 DEG C) removal trichlorines are evaporated under reduced pressure on a rotary evaporator
Methane makes to form uniform film layer on bottle；Mixed liquor (volume ratio 3:5) solubilizing lipids of 12mL chloroform and ether are added
Film, then the vitamin C of 10mg, the polyethylene glycol 400 of 50mg and the polysorbate of 50mg are dissolved in the pH value of 4mL for 7.0 phosphoric acid
Salt buffer is added in pear shape bottle, and ice-water bath ultrasound to mixture forms uniform w/o type cream in water-bath type Ultrasound Instrument
It is not stratified can to place 30min for agent；W/o type emulsion is evaporated under reduced pressure to (20 DEG C) removal organic solvents on a rotary evaporator to having
Translucent gel-forming；Continue that 5min is evaporated under reduced pressure, gel piece is collapsed to form aqueous suspension i.e. vesicle suspension, be added
The phosphate buffer aquation 30min that a small amount of pH value is 7.0 is to get Fluconazole flexible nano lipid vesicle suspensions.
Embodiment 7
Weigh Fluconazole bulk pharmaceutical chemicals 100mg, phosphatidyl glycerol 800mg, cholesterol 260mg and 2,6- di-t-butyl -4-
Methylphenol 20mg is placed in pear shape bottle, and chloroform 35mL, which is added, to be made to dissolve, and (48 DEG C) are evaporated under reduced pressure on a rotary evaporator
Chloroform is removed, makes to form uniform film layer on bottle；The mixed liquor (volume ratio 3:5) of 18mL chloroform and ether is added
The pH value that solubilizing lipids film, then by the vitamin C of 20mg, the crospovidone of 50mg and the polysorbate of 200mg are dissolved in 4mL is
7.0 phosphate buffers, are added in pear shape bottle, and ice-water bath ultrasound to mixture forms uniform W/ in water-bath type Ultrasound Instrument
It is not stratified can to place 30min for O-shaped emulsion；W/o type emulsion is evaporated under reduced pressure to (20 DEG C) removal organic solvents on a rotary evaporator
To there is translucent gel-forming；Continuing that 5min is evaporated under reduced pressure, gel piece collapses to form aqueous suspension i.e. vesicle suspension, then
The phosphate buffer aquation 30min that a small amount of pH value is 7.0 is added to get Fluconazole flexible nano lipid vesicle suspensions.
Embodiment 8
Weigh Fluconazole bulk pharmaceutical chemicals 10mg, polyoxyethylene fatty acid ester 100mg, cholesterol 100mg and tea polyphenols 10mg
It being placed in pear shape bottle, chloroform 25mL, which is added, to be made to dissolve, (48 DEG C) removal chloroforms are evaporated under reduced pressure on a rotary evaporator,
Make to form uniform film layer on bottle；Mixed liquor (volume ratio 3:5) solubilizing lipids film of 12mL chloroform and ether is added, then
By the vitamin C of 30mg, the pH value that the polyvinyl alcohol of 50mg and the polysorbate of 20mg are dissolved in 4mL is 7.0 phosphate buffers,
It is added in pear shape bottle, ice-water bath ultrasound to mixture forms uniform w/o type emulsion in water-bath type Ultrasound Instrument, can place
30min is not stratified；It is translucent solidifying to having that w/o type emulsion is evaporated under reduced pressure to (20 DEG C) removal organic solvents on a rotary evaporator
Glue is formed；Continue that 5min is evaporated under reduced pressure, gel piece collapses to form aqueous suspension i.e. vesicle suspension, and adding a small amount of pH value is
7.0 phosphate buffer aquation 30min is to get Fluconazole flexible nano lipid vesicle suspensions.
Embodiment 9
It weighs Fluconazole bulk pharmaceutical chemicals 80mg, egg yolk lecithin 640mg and cholesterol 160mg to be placed in pear shape bottle, be added
Chloroform 25mL makes to dissolve, and (48 DEG C) removal chloroforms are evaporated under reduced pressure on a rotary evaporator, makes to be formed on bottle uniform
Film layer；Mixed liquor (volume ratio 3:5) solubilizing lipids film of 12mL chloroform and ether is added, then by the polyethylene glycol of 50mg
The pH value that the polysorbate of 400 and 50mg is dissolved in 4mL is 7.0 phosphate buffers, is added in pear shape bottle, in water-bath type ultrasound
Ice-water bath ultrasound to mixture forms uniform w/o type emulsion on instrument, and it is not stratified can to place 30min；W/o type emulsion is being rotated
(20 DEG C) removal organic solvents are evaporated under reduced pressure on evaporimeter to there is translucent gel-forming；Continue that 5min, gel is evaporated under reduced pressure
Block collapses to form aqueous suspension i.e. vesicle suspension, adds the phosphate buffer aquation 30min that a small amount of pH value is 7.0,
Up to Fluconazole flexible nano lipid vesicle suspensions.
Embodiment 10
Weigh Fluconazole bulk pharmaceutical chemicals 80mg, dipalmitoylphosphatidylcholine 640mg, cholesterol 160mg and butylhydroxy
Anisole 10mg is placed in pear shape bottle, and chloroform 25mL, which is added, to be made to dissolve, and (48 DEG C) are evaporated under reduced pressure on a rotary evaporator and go
Except chloroform, make to form uniform film layer on bottle；The mixed liquor (volume ratio 3:5) that 12mL chloroform and ether is added is molten
Lipid film is solved, then the polysorbate of the vitamin C of 10mg and 50mg is dissolved in the pH value of 4mL for 7.0 phosphate buffers, is added
Into pear shape bottle, ice-water bath ultrasound to mixture forms uniform w/o type emulsion in water-bath type Ultrasound Instrument, can place 30min
It is not stratified；W/o type emulsion is evaporated under reduced pressure to (20 DEG C) removal organic solvents on a rotary evaporator to there is translucent gel shape
At；Continue that 5min is evaporated under reduced pressure, gel piece collapses to form aqueous suspension i.e. vesicle suspension, and adding a small amount of pH value is 7.0
Phosphate buffer aquation 30min to get Fluconazole flexible nano lipid vesicle suspensions.
Embodiment 11
Weigh Fluconazole bulk pharmaceutical chemicals 80mg, soybean lecithin 300mg and phosphatidyl glycerol 340mg, cholesterol 160mg and
Butylated hydroxy anisole 10mg is placed in pear shape bottle, and chloroform 25mL, which is added, to be made to dissolve, and is evaporated under reduced pressure on a rotary evaporator
(48 DEG C) removal chloroforms, make to form uniform film layer on bottle；Mixed liquor (the volume ratio of 12mL chloroform and ether is added
For 3:5) solubilizing lipids film, then by the poly- mountain of the vitamin C of 10mg, the polyethylene glycol 400 of 20mg, 30mg povidone and 25mg
The pH value that the sucrose fatty ester of pear ester and 25mg are dissolved in 4mL is 7.0 phosphate buffers, is added in pear shape bottle, in water-bath
Ice-water bath ultrasound to mixture forms uniform w/o type emulsion in type Ultrasound Instrument, and it is not stratified can to place 30min；By w/o type emulsion
(20 DEG C) removal organic solvents are evaporated under reduced pressure on a rotary evaporator to there is translucent gel-forming；Continue to be evaporated under reduced pressure
5min, gel piece collapse to form aqueous suspension i.e. vesicle suspension, add the phosphate buffer water that a small amount of pH value is 7.0
Change 30min to get Fluconazole flexible nano lipid vesicle suspensions.
Embodiment 12
Fluconazole flexible nano lipid vesicle suspension made from above-described embodiment and its be equipped with auxiliary material gelling agent be made
External preparation for skin paste performance and effect verifying.
1, the microstate experiment of Fluconazole flexible nano lipid vesicle suspension
Experimental method:
By taking 1 gained Fluconazole flexible nano lipid vesicle suspension of embodiment as an example, with transmitted electron sem observation partial size capsule
Blister state, measures its partial size and dispersibility with laser particle analyzer, measures its encapsulation rate with sephadex column chromatography.
Measurement result:
Partial size is more uniform spherical or nearly spherical vesica with being viewed as under transmission electron microscope, as shown in Figure 1；Glucan
It is 55.02% that gel filtration chromatography method, which measures its encapsulation rate, and the result that laser particle analyzer measures is shown in that Fig. 2, the partial size of vesica are
199.6nm, polydispersity coefficient 0.231.The result of other embodiments and the result are substantially similar.
2, the stability experiment of Fluconazole flexible nano lipid vesicle suspension
Experimental method:
By taking 4 gained Fluconazole flexible nano lipid vesicle suspension of embodiment as an example, with sedimentation volumn, when stability is joined
Number measures the stability of the drug.
(1) measurement of sedimentation volumn ratio: by vesicle suspension room temperature 3 months, results of regular determination settling height used formula
F=H/H0Sedimentation volumn ratio is calculated, F is sedimentation volumn ratio in formula, and H0 be the height of suspension before settling, and H is to settle after settling
The height in face；
(2) measurement of stability parameter: by freshly prepd a small amount of Fluconazole flexible nano lipid vesicle suspensions be placed in from
CENTRIFUGAL ACCELERATING experiment is carried out in heart pipe, with 2000rmin-1Revolving speed be centrifuged 15min, it is accurate respectively to measure the vesica not being centrifuged
The supernatant 0.5mL of vesicle suspension after suspension and centrifugation, is diluted to 10mL with phosphate buffer, uses spectrophotometer
The variation of vesica centrifugation front and back absorbance at 500nm is measured, and according to formula Ke=(A0-A)/A0Computational stability parameter Ke.
Wherein A0For the absorbance value before vesica centrifugation, A is the absorbance value after vesica centrifugation.
Experimental result:
(1) measurement result of sedimentation volumn ratio is as shown in table 1, illustrates that vesica keeps stablizing in suspension, does not assemble
Sedimentation.
The stability of 1 Fluconazole flexible nano lipid vesicle suspensions of table
(2) measurement result of stability parameter shows Ke=0.066；Stability parameter Ke is as evaluation Vesicle stability
Index, Ke is smaller to illustrate that change of size is smaller, illustrates that vesica is just more stable.As it can be seen that its stability of suspension prepared by the present invention
Very well.
The result of other embodiments and the result are substantially similar.
3, Fluconazole flexible nano lipid vesicle suspensions release in vitro performance test
Experimental method:
For the Fluconazole flexible nano lipid vesicle suspensions made from the embodiment 6, Fluconazole made from embodiment 6 is soft
Property nano-lipid vesica partial size be 202.1nm, vitro release measuring method is as follows: it is flexible that precision draws 10mL Fluconazole
Nano-lipid vesicle suspension (containing about Fluconazole main ingredient 32mg), is transferred in the bag filter pre-processed completely, drains sky
Gas tightens sack, is fixed on the agitating paddle of digestion instrument, and the pH7.0 phosphate buffer with 250mL containing 30% ethyl alcohol is to release
Medium is put, (37 ± 0.5) DEG C circulator bath, 100rmin-1Constant speed stirring, respectively at 20min, 40min, 1h, 2h, 3h, 5h,
7h, 9h and 12h timing sampling 1mL are measured with sample introduction after 0.22 μm of filtering with microporous membrane, and the release of equivalent constant temperature are replenished in time
Medium.
Control experiment: precision measures 10mL Fluconazole pH7.4 phosphate solution (containing about Fluconazole main ingredient 32mg), is placed in pre-
In the bag filter first handled well, according to releasing in vitro for above-mentioned Fluconazole vesica vitro release measuring method measurement Fluconazole solution
Degree of putting.
Experimental result: release measurement result is shown in Fig. 3, as seen from the figure in Fluconazole flexible nano lipid vesicle suspensions
Drug release is slow, which can play long-acting slow-release effect.
4, the performance test that is transdermal and being detained storage drug of Fluconazole flexible nano lipid vesicle percutaneous drug administration preparation
For the Fluconazole flexible nano lipid vesicle suspensions made from the embodiment 6, Fluconazole flexible nano lipid is taken
Vesicle suspension 20mL (contains Fluconazole 64mg), and 0.1g carbopol 941,0.3g glycerol, 1molL is added-1Sodium hydroxide solution
About 1mL is ground well, and is prepared into gelling agent.
(1) transdermal experiment of drug isolated mouse skin: the hair on the skin of back of mice two sides is cut short with scissors, uses cotton
Flower dips depilatory agent and loses hair or feathers in right amount, allow mouse survive the pessimal stimulation to eliminate epilation operation to mouse skin for 24 hours.It is transdermal
Before absorption experiment, be anesthetized with ether and put to death mouse, remove the skin of back two sides, with scalpel remove subcutaneous fat and fascia it
Afterwards, clean with normal saline flushing.
Using vertical two-chamber osmotic disperser to Fluconazole vesica gel and non-bladder foaming gel (by Fluconazole in example 6
Flexible nano lipid vesicle suspensions are substituted for Fluconazole pH7.4 phosphate solution, remaining ingredient is used in medicament contg and prescription
Measure identical) carry out transdermal test in vitro Release behavior.The mouse skin handled well is clipped between sample cell and reception tank, back side skin
Connect with receiving liquid.Fluconazole vesica gel and non-bladder foaming gel are uniformly smeared into about 1g in skin front, area is
1.77cm2.Reception tank with phosphate buffer (pH=7.0)-ethyl alcohol (7:3, v/v) be medium, volume 17mL, temperature 37
DEG C, rotor mixing speed is 130rmin-1.In for 24 hours at preset timed intervals point (0.5,1,2,3,4,6,8,12, for 24 hours) sampling
1mL (and the fresh reception medium of 1mL is replenished in time) measures the content of wherein Fluconazole after 0.22 μm of filtering with microporous membrane.
(2) retardation assay of the drug in body mouse skin: the hair on the skin of back of mice two sides is cut short with scissors, uses cotton
Flower dips depilatory agent and loses hair or feathers in right amount, allow mouse survive the pessimal stimulation to eliminate epilation operation to mouse skin for 24 hours.Experiment
When beginning, Fluconazole vesica and each 1g of non-bladder foaming gel are respectively coated on the skin to have lost hair or feathers at left and right sides of back of mice,
Spreading area is consistent.Be administered 12h and for 24 hours after, be anesthetized with ether put to death mouse, the gel on skin is wiped off, removing carry on the back
The skin of portion two sides is rinsed with the phosphate buffer that pH value is 7.0, and filter paper suck dry moisture is simultaneously weighed.Skin is shredded, is added few
Amount pH7.0 phosphate buffer is ground to chyle shape, adds methanol ultrasonic extraction, 4000rmin-1It is centrifuged 15min, takes supernatant,
Residue methanol repeats to extract once, merges supernatant, is settled in 25mL measuring bottle, after 0.22 μm of filtering with microporous membrane,
HPLC sample introduction measures medicament contg.
Testing result:
(1) as shown in figure 4, Fluconazole flexible nano lipid vesicle gel external preparation is far below through the amount of mouse skin
The transit dose of drug in non-bladder foaming gel illustrates that the drug in vesica can be stored in skin, less to enter blood through skin
Liquid circulation.
(2) as the result is shown: percutaneous drug delivery 12h and for 24 hours after, Fluconazole flexible nano lipid vesicle gel preparation it is intradermal stagnant
Allowance is 123.2 ± 9.1 and 162.5 ± 15.5 μ gcm-2(n=3), the intradermal hold-up of non-bladder foaming gel drug be 36.7 ±
5.4 and 48.9 ± 6.3 μ gcm-2(n=3), compare through two sample t-tests, the medicaments intradermal hold-up of Fluconazole vesica gel
Significantly greater than non-bladder foaming gel (P < 0.05).
The result of other embodiments and the result are substantially similar.
Claims (2)
1. a kind of Fluconazole flexible nano lipid vesicle composition, which is characterized in that the composition is by following weight part ratio group
Divide and constitutes: 8 parts of Fluconazole, 64 parts of egg yolk lecithin, 16 parts of cholesterol, 1 part of butyl anisole, 1 part of vitamin C, poly- second two
5 parts of alcohol, 5 parts of polysorbate.
2. a kind of Fluconazole flexible nano lipid vesicle composition described in claim 1 is in being used to prepare preparation for external application to skin
Application.
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Citations (2)
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| CN101273971A (en) * | 2008-05-09 | 2008-10-01 | 绍兴文理学院 | Ethosomes preparation of antimycotics pharmaceutical and method for preparing the same |
| WO2013057208A1 (en) * | 2011-10-18 | 2013-04-25 | Targeted Delivery Technologies Limited | Compositions and methods for reducing the proliferation and viability of microbial agents |
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2014
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101273971A (en) * | 2008-05-09 | 2008-10-01 | 绍兴文理学院 | Ethosomes preparation of antimycotics pharmaceutical and method for preparing the same |
| WO2013057208A1 (en) * | 2011-10-18 | 2013-04-25 | Targeted Delivery Technologies Limited | Compositions and methods for reducing the proliferation and viability of microbial agents |
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| Effect of Surfactants on the Characteristics of Fluconazole Niosomes for Enhanced Cutaneous Delivery;Madhu Gupta, et al;《Artificial Cells, Blood Substitutes, and Biotechnology》;20111231;第39卷;第377页右栏第3段"Preparation of Niosomes"；第382页左栏"表2"以及第383页左栏第1段 * |
| 氟康唑脂质体及脂质体凝胶的研制;赵珊珊;《中国优秀硕士学位论文全文数据库》;20071215(第6期);正文第38页第3段 * |
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