CN107303263A - Tripterygium glycosides nano-emulsion gel and preparation method thereof - Google Patents
Tripterygium glycosides nano-emulsion gel and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to technical field of medicine, and in particular to a kind of tripterygium glycosides nano-emulsion gel and its preparation method and application.The invention discloses a kind of tripterygium glycosides nano-emulsion gel, main component is bulk drug tripterygium glycosides, oil phase, surfactant, cosurfactant, gel-type vehicle and deionized water.Tripterygium glycosides is mixed with oil phase, surfactant, cosurfactant, deionized water is added dropwise in mixed solution, tripterygium glycosides nano-emulsion is obtained under magnetic stirring, gel-type vehicle is subsequently added and tripterygium glycosides nano-emulsion gel is made.The present invention makees the carrier of its percutaneous dosing from O/W type nano-emulsions, prepares tripterygium glycosides nano-emulsion gel transdermal preparation, and a kind of new excellent effect pharmaceutical preparation is provided for tripterygium glycosides clinical practice.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of tripterygium glycosides nano-emulsion gel and preparation method thereof and
Using.
Background technology
Tripterygium wilfordii Tripterygium wilfordii Hook.f. systems Celastraceae Thunder God Calamus bejuco, its property
Bitter, very toxic, the effects such as stopping blooding with promoting blood circulation and removing blood stasis, clearing heat and detoxicating, dispersing swelling and dissipating binds, desinsection.Tripterygium glycosides is tripterygium wilfordii
Chief active position, with anti-inflammatory, analgesia, antitumor and immunological regulation etc. effect, be clinically usually used in treatment scytitis,
Immunosupress, malignant tumour etc..Tripterygium glycosides clinical therapeutic efficacy significantly, but because its oral absorption exist significantly " peak-
Paddy " phenomenon, easily causes larger toxic reaction, and the adverse reaction rate of its digestive system and urogenital system is respectively
35.8% and 22.8%.Simultaneously as tripterygium glycosides is insoluble in water, absorption difference, have impact on its druggability and biology in vivo
The raising of availability, seriously limits its clinical practice.Therefore, it is highly desirable to develop a kind of Thunder God of non-oral administration approach
The many glycosides formulations of rattan, to reduce the toxic side effect of tripterygium glycosides, improve the bioavilability of medicine and the compliance of patient medication,
A kind of new excellent effect pharmaceutical preparation is provided for the treatment of the immunity diseases such as clinical rheumatoid arthritis, psoriasis.
Tripterygium glycosides (Tripterygium glycoside), chemical structural formula is as follows：
The particle diameter that nano-emulsion is made up of aqueous phase, oil phase, surfactant and cosurfactant is in 10~100nm heating power
And the transparent or semitransparent system of dynamic stabilization.From structure, nano-emulsion can be divided into oil-in-water type (O/W), water-in-oil type
And bicontinuous (W/O).Nano-emulsion as new drug carrier, prepare it is simple, safe, the molten of insoluble drug can be increased
Xie Du, improves the stability of facile hydrolysis medicine, and it is sustained, targeting can improve the bioavilability of medicine, suitable for oral, injection
And percutaneous dosing.During as transdermal delivery system carrier, nano-emulsion is reduced because of its distinctive surface tension, it is easy to wet skin,
Change the physicochemical property of cutin Rotating fields, by very big concern in terms of the research of transdermal absorption formulation.
Transdermal delivery system can avoid the first pass effect and medicine of liver in the inactivation of intestines and stomach, and the absorption of medicine is not by stomach
The influence of intestinal factors.Constant effective blood drug concentration or physiological effect are maintained, the maintenance effect time is long, it is to avoid oral administration causes
The peak valley phenomenon of blood concentration, reduce toxicity, it is easy to use, patient can independently medication, medication can also be cancelled at any time
Deng.
Gel has smooth in appearance, and transparent exquisiteness, denseness, viscosity are suitable, it is easy to the advantages of being coated with, therefore by tripterygium wilfordii
Nano-emulsion gel, which is made, in many glycosides has good research and development value.
The content of the invention
It is an object of the invention to provide a kind of tripterygium glycosides nano-emulsion gel preparation, it is another object of the present invention to carry
For the preparation method of above-mentioned tripterygium glycosides nano-emulsion gel, the third object of the present invention is to provide above-mentioned tripterygium glycosides
Application of the nano-emulsion gel in the immunity disease medicines such as treatment rheumatoid arthritis, dermatitis and eczema, psoriasis.
The problem of percutaneous drug administration preparation most critical is the Transdermal absorption of medicine, therefore promotees pass of the saturating technology as production process
One of key technology.The present invention is in the preliminary experiment of gel preparation it has also been found that oil phase ratio, surfactant and cosurfactant
Ratio and aqueous phase to account for influence of the ratio of prescription total amount to transdermal test in vitro accumulation infiltration capacity very big.
Then, we are screened using Star point design-effect surface method to the prescription of tripterygium glycosides nano-emulsion gel, are adopted
Data are handled with Design-Expert softwares, the optimal prescription that is obtained by effect surface figure and binomial regression model and
Accumulative infiltration capacity and the deviation of measured value are smaller, show that institute's established model is predictive good.
The first aspect of the present invention, is to provide a kind of tripterygium glycosides nano-emulsion gel.
The weight percentage ratio of a kind of tripterygium glycosides nano-emulsion gel, its main ingredient and auxiliary material is：
Tripterygium glycosides 0.33%~3.30%,
Oil phase 10%~20%,
Surfactant 20%~40%,
Cosurfactant 10%~20%,
Gel-type vehicle 1%~5%,
Surplus is water.
Described gel-type vehicle is Acritamer 940.
Further, the tripterygium glycosides nano-emulsion gel, it is preferable that
Tripterygium glycosides 0.5%~3.3%,
Oil phase 15%~20%,
Surfactant 25%~35%,
Cosurfactant 12%~18%,
Gel-type vehicle Acritamer 940 1%~2%,
Surplus is water.
Described oil phase is Sefsol 218, Labraso, Emulsifier EL-60, three second
Acid glyceride, it is preferred that be Sefsol 218.
Described surfactant is OP-10 emulsifying agents, Tween-80, Sefsol 218, caprylic capric polyethylene glycol
Glyceride, it is preferred that be OP-10 emulsifying agents.
Described cosurfactant is 1,2-PD, Tween-80, Labraso, it is preferred that
It is 1,2- propane diols.
Described water is purified water, water for injection.
Further, the tripterygium glycosides nano-emulsion gel, it is preferable that
Tripterygium glycosides 1%~3.3%, optimal is 3%,
Sefsol 218 17%~19%, optimal is 18%,
OP-10 emulsifying agents 29%~31%, optimal is 30%,
1,2-PD 14%~16%, optimal is 15%,
Acritamer 940 1%~2%, optimal is 1.5%,
Surplus is water.
The second aspect of the present invention, is to provide the preparation method of above-mentioned tripterygium glycosides nano-emulsion gel.
The preparation method of the hydrochloric acid tripterygium glycosides is as follows：
A, tripterygium glycosides is first dissolved in Sefsol 218, OP-10 emulsifying agents and 1,2- mixed with propylene glycol solution
In, it is standby；
B, into above-mentioned solution purified water is added dropwise, stirs, obtain tripterygium glycosides nano-emulsion；
C, add appropriate deionization in being swelled overnight at 4 DEG C the Acritamer 940, obtain clear gel matrix；
D, tripterygium glycosides nano-emulsion is added in gel-type vehicle, stirs, produce.
Described mixing speed is 300rpm/min, and mixing time is 10~30min.
The transparent exquisiteness of tripterygium glycosides nanoemulsion gel prepared by the present invention, stickiness is suitable, it is easy to be coated with, to skin without
The features such as stimulation.In the aqueogel of the present invention, the saturating mechanism of rush of OP-10 and Sefsol 218 may be with upsetting cutin
The ordered structure of layer, the mobility of influence cell membrane are relevant, and 1,2-PD may be by improving medicine in cuticula
Dissolubility promotes the percutaneous absorbtion of medicine, and both play joint, collaboration and promote saturating effect.
Tripterygium glycosides nano-emulsion gel prepared by the present invention is in treatment rheumatoid arthritis, dermatitis and eczema, psoriasis
Tripterygium glycosides oral formulations not only convenient drug administration is substituted etc. immunity disease, it is to avoid liver first-pass effect, reduction tripterygium wilfordii is more
The toxic side effect of glycosides, and gel plays slow releasing function in skin formation drug depot, while improving the biological utilisation of medicine
The compliance of degree and patient medication.
Brief description of the drawings
The transmission electron microscope picture (× 20000) of the tripterygium glycosides nano-emulsion of Fig. 1 present invention；
The tripterygium glycosides nano-emulsion particle diameter distribution map of Fig. 2 present invention；
Fig. 3 triptolide standard items HPLC chromatograms；
Tripterygium glycosides nano-emulsion (test sample) HPLC chromatogram of Fig. 4 present invention；
Fig. 5 tripterygium glycosides nano-emulsion cumulative in vitro transdermal penetrations amount-time plot；
The three-dismensional effect face figure (X of Fig. 6 influence factors and response1：Oil percentage (w/w) shared in oil phase；X2：Table
The ratio (w/w) of face activating agent and cosurfactant；X3：Water percentage (w/w) shared in nano-emulsion)；Wherein：a X1
(%) and X2(Km)；b X1(%) and X3(%)；c X2(Km) and X3(%)；
Two-dimentional circle of equal altitudes (the X of Fig. 7 influence factors and response1：Oil percentage (w/w) shared in oil phase；X2：Surface
The ratio (w/w) of activating agent and cosurfactant；X3：Water percentage (w/w) shared in nano-emulsion)；Wherein：a X1
(%) and X2(Km)；b X1(%) and X3(%)；c X2(Km) and X3(%).
Embodiment
The embodiment provided with reference to embodiment the present invention elaborates.
Material：
Tripterygium glycosides (Changsha Lu Yuan bio tech ltd)；
Triptolide standard items (lot number：120416, upper Hiroad standing grain Pharmaceutical Technology Co., Ltd)；
1,2-PD (lot number：20140503, forever magnificent chemical Science and Technology Ltd.)；
Azone (lot number：20131115, Chemical Reagent Co., Ltd., Sinopharm Group)；
Tween80 (lot numbers：20150121, Shanghai Ling Feng chemical reagent Co., Ltd)；
Sefsol 218 (lot number：150857, praise method lion)；
OP-10 (lot numbers：H1504057, Aladdin)；
Glyceryl triacetate (lot number：0050613, Beijing chemical reagents corporation)
Emulsifier EL-60 (lot number：A1506033, Aladdin)；
Methanol (lot number：14090703, TEDIA)；
SD rats, male, 20 ± 2g of body weight, by The 2nd Army Medical College, animal experimental center is provided.Experimental animal licensing
Number：SCXK (Shanghai) 2015-10-20.
Embodiment 1
0.6g tripterygium glycosideses are weighed, 3.63g Sefsol 218s, 5.94g OP-10,2.97g 1,2-PDs are stirred
Mix, mix, 7.46g purified waters are slowly added into the solution, tripterygium glycosides nano-emulsion is made in uniform stirring.
0.3g Acritamer 940s are weighed, plus appropriate purified water makes poloxamer there not to be below upstream face all, is positioned over 4 DEG C
In refrigerator, it is set fully to be swelled.
After 24h, the carbomer being swelled is taken out, tripterygium glycosides nano-emulsion is added while stirring, stirs, produces Huang
The transparent tripterygium glycosides nano-emulsion gel preparation of color.
Embodiment 2
0.6g tripterygium glycosideses are weighed, 3.63g Sefsol 218s, 5.94gOP-10,2.97g Tween 80s are stirred, mixed
It is even, 7.46g purified waters are slowly added into the solution, tripterygium glycosides nano-emulsion is made in uniform stirring.
0.3g Acritamer 940s are weighed, plus appropriate purified water makes poloxamer there not to be below upstream face all, is positioned over 4 DEG C
In refrigerator, it is set fully to be swelled.
After 24h, the carbomer being swelled is taken out, tripterygium glycosides nano-emulsion is added while stirring, stirs, produces Huang
The transparent tripterygium glycosides nano-emulsion gel preparation of color.
Embodiment 3
0.6g tripterygium glycosideses are weighed, 3.63g Sefsol 218s, 5.94g Tween 80s, 2.97g 1,2-PDs are stirred
Mix, mix, 7.46g purified waters are slowly added into the solution, tripterygium glycosides nano-emulsion is made in uniform stirring.
0.3g Acritamer 940s are weighed, plus appropriate purified water makes poloxamer there not to be below upstream face all, is positioned over 4 DEG C
In refrigerator, it is set fully to be swelled.
After 24h, the carbomer being swelled is taken out, tripterygium glycosides nano-emulsion is added while stirring, stirs, produces Huang
The transparent tripterygium glycosides nano-emulsion gel preparation of color.
Embodiment 4
Weigh 0.6g tripterygium glycosideses, 3.63g Sefsol 218s, 5.94g Emulsifier EL-60s, 2.97g1,2-
Propane diols stirring, mixing, 7.46g purified waters are slowly added into the solution, and tripterygium glycosides nanometer is made in uniform stirring
Breast.
0.3g Acritamer 940s are weighed, plus appropriate purified water makes poloxamer there not to be below upstream face all, is positioned over 4 DEG C
In refrigerator, it is set fully to be swelled.
After 24h, the carbomer being swelled is taken out, tripterygium glycosides nano-emulsion is added while stirring, stirs, produces Huang
The transparent tripterygium glycosides nano-emulsion gel preparation of color.
Embodiment 5
Weigh 0.6g tripterygium glycosideses, 3.63g glyceryl triacetates, 5.94g Sefsol 218s, 2.97g1,2- third
Glycol stirring, mixing, 7.46g purified waters are slowly added into the solution, and tripterygium glycosides nano-emulsion is made in uniform stirring.
0.3g Acritamer 940s are weighed, plus appropriate purified water makes poloxamer there not to be below upstream face all, is positioned over 4 DEG C
In refrigerator, it is set fully to be swelled.
After 24h, the carbomer being swelled is taken out, tripterygium glycosides nano-emulsion is added while stirring, stirs, produces Huang
The transparent tripterygium glycosides nano-emulsion gel preparation of color.
Embodiment 6
Weigh 0.6g tripterygium glycosideses, 3.63g Sefsol 218s, 5.94g Labrasos,
The stirring of 2.97g 1,2-PDs, mixing, 7.46g purified waters are slowly added into the solution, and tripterygium wilfordii is made in uniform stirring
Many glycosides nano-emulsions.
0.3g Acritamer 940s are weighed, plus appropriate purified water makes poloxamer there not to be below upstream face all, is positioned over 4 DEG C
In refrigerator, it is set fully to be swelled.
After 24h, the carbomer being swelled is taken out, tripterygium glycosides nano-emulsion is added while stirring, stirs, produces Huang
The transparent tripterygium glycosides nano-emulsion gel preparation of color.
Embodiment 7
Weigh 0.6g tripterygium glycosideses, 3.63g glyceryl triacetates, 5.94g OP-10 emulsifying agents, 2.97g 1,2- the third two
Alcohol stirring, mixing, 7.46g purified waters are slowly added into the solution, and tripterygium glycosides nano-emulsion is made in uniform stirring.
0.3g Acritamer 940s are weighed, plus appropriate purified water makes poloxamer there not to be below upstream face all, is positioned over 4 DEG C
In refrigerator, it is set fully to be swelled.After 24h, the carbomer being swelled is taken out, tripterygium glycosides nano-emulsion is added while stirring, is stirred
Mix uniform, produce the tripterygium glycosides nano-emulsion gel preparation of yellow transparent.
Embodiment 8：Percutaneous penetration
The preparation of isolated skin：SD rat abdomens are lost hair or feathers, rest 1d, it is ensured that skin of abdomen not damaged, after execution immediately
Its complete belly depilation skin is taken, superabundant fats on skin is scraped off, after tissue, is cleaned up with physiological saline, in being soaked at 4 DEG C
Steep in fresh physiological saline.
Carried out using Franz diffusion cells method：It is with 32 DEG C of waters bath with thermostatic control, the PBS at the uniform velocity stirred (containing 20% absolute ethyl alcohol)
Reception liquid.The cuticula for the isolated skin handled well is fixed on Franz diffusion cells upward, 0.1g preparations are uniformly coated with
Tripterygium glycosides nano-emulsion gel (prepared by embodiment 1), is sealed with sealed membrane.1ml is taken when 1,2,3,4,6,8,12h
Reception liquid carries out content detection, and synthermal addition 1ml PBS in reception tank.
The calculating of transdermal test in vitro accumulation infiltration capacity：
ByThe accumulation infiltration capacity of unit of account area medicine.Wherein, Q is single
The drug accumulation transdermal penetration amount of plane product, drug concentration when Cn is the sample point in reception liquid, V is reception liquid volume,
Accumulative drug concentration during for the 1st sample point to last sample point in reception liquid, S is effective transdermal area of medicine.
Experimental result：In the cumulative in vitro transdermal penetration amount such as accompanying drawing 6 of different sample points.
From accompanying drawing 6 as can be seen that the transdermal test in vitro effect of the tripterygium glycosides nano-emulsion external-use gel preparation of the present invention is good
It is good, skin barrier can be passed through well, to provide a kind of novel medicine feeding preparation for tripterygium glycosides clinical practice.And drug release
Time is longer, and administration number of times is less.
Embodiment 9：Pharmacodynamic experiment
Rat is grouped intraperitoneal injection of anesthesia at random.The depilation of rat recipient site is handled after anesthesia.Adapt to after raising 3 days,
Rat is anaesthetized again, in rat toe position setting-out mark to be measured.Normal toes before the detection rat modeling of toes capacity measurer
Volume.The tripterygium glycosides nano-emulsion gel that after detection prepared by Example 1, blank nano-emulsion gel (being not added with medicine), vinegar
Sour each 0.5g of dexamethasone and physiological saline smears rat toe position, 10/group.
Next day starts modeling.Rat chloraldurate 300mg/kg intraperitoneal injection of anesthesia.1ml syringes are drawn Freund and helped completely
It it is 0.1ml/ to scorching volume in agent injection rat foot pad skin, pressing pin hole 20s prevents adjuvant from overflowing.It is each after 10min
Tested group of rat toe position smears corresponding test medicine.It is administered after 24h, rat is anaesthetized again, the detection of toes capacity measurer
Toes volume after rat to inflammation.
Experimental animal model of CFA induced adjuvant arthritis in rats experimental result is shown in Table 1.Before rat to inflammation, average level 1.80ml or so with just
Normal toes volume relatively, receives after Freund's complete adjuvant to inflammation, obvious tumefaction, matrix control group swelling occur in rat toes
Degree reaches 41.4%.Positive controls swelling degree reaches 18.4%, less than matrix control group, difference highly significant (p ＜
0.001).Tripterygium wilfordii gel delivery group swelling degree reaches 29.7%, is compared with matrix control group, significant difference (p ＜ 0.05).
Understand that tripterygium glycosides nano-emulsion gel has the effect for the treatment of rat assist agent arthritis from experimental result.
The influence (n=10) of the tripterygium wilfordii gel on adjuvant arthritis in rats of table 1
* P ＜ 0.05***P ＜ 0.001VS model control groups
Embodiment 10：Star point design-effect surface method is optimized to the prescription of Propranolol Hydrochloride gel
The foundation of 1 content assaying method
1.1 Chromatography/Mass Spectrometry conditions
Chromatographic column：ZORBAX Extend-C18 posts (2.1mm × 100mm, 3.5um)；Mobility is methanol：0.1% (v/
V) aqueous formic acid=60：40；Flow velocity is 0.3ml/min；Ultraviolet detection wavelength is 280nm；Sample size 3ul；Column temperature is 40 DEG C.
Mass Spectrometry Conditions：Ion gun is ESI sources；Cation mode is detected；Scan mode is multiple-reaction monitoring (MRM)；For
The ion of quantitative analysis is m/z=361.3/105.2；Internal standard removes m/z=361.3/147；Capillary voltage 4000V；Dry
Gas velocity 8L/min；Dry 350 DEG C of temperature degree；Nebulizer pressure 33psi；Cracker voltage 168eV；Collision energy is 41.
The preparation of 1.2 solution
Precision weighs the close triptolide standard items 1mg that weighs of triptolide reference substance in 100ml volumetric flasks, uses first
Alcohol dissolves constant volume, and 1ml solution constant volume into 50ml volumetric flasks is pipetted after mixing, shakes up, produces triptolide standard items mark
Quasi- product solution.
Accurate tripterygium glycosides nano-emulsion 0.1g, into 10ml volumetric flasks, adds proper amount of methanol ultrasound 20min demulsifications, after
Plus methanol constant volume, shake up, shake up, produce tripterygium glycosides need testing solution.
Triptolide standard solution and tripterygium glycosides need testing solution are through 0.45 μm of filtering with microporous membrane, 1.1
The spectrogram obtained under the conditions of item Chromatography/Mass Spectrometry is shown in Fig. 4, Fig. 5.From the triptolide in standard items and gel knowable to spectrogram
Peak shape is good, and absorption of the other compositions in gel to tripterygium glycosides is noiseless.
The foundation precision of 1.3 standard curves draw 1.2 Plays product solution 0.1ml, 0.25ml, 0.5ml, 1.0ml,
2.0ml, 4.0ml, 5.0ml, with methanol dilution and constant volume, obtain series concentration, shaken up, by 1.1 chromatograms into 10ml volumetric flasks
Condition sample introduction, determines peak area (A), makees linear regression to concentration (C) with A, obtain regression equation：A=22.487C ﹢ 10.586,
(R2=0.9993).The concentration range of linearity of tripterygium glycosides is 2-100ng/ml.
1.4 precision tests take the standard solution in 1.2, repeat sample introduction 6 times by 1.1 chromatographic conditions, and record
Peak area, measurement result is shown in Table 2, as a result shows that the precision of instrument test is good.
In table 2 days, day to day precision measurement result
1.5 stability tests take the standard solution in 1.2, by 1.1 chromatographic conditions respectively at 0h, 1h, 2h, 4h,
6h, 8h sample introduction determine sample introduction, record peak area value, measurement result is shown in Table 3, as a result show that test sample is substantially steady in 8h after treatment
It is fixed.
The study on the stability result of table 3
1.6 average recoveries are tested in the tripterygium glycosides gel (sample prepared by embodiment 1) of 9 parts of known contents
It is separately added into the accurate reference substance solution measured appropriate, 3 parts are 1 group, plus proper amount of methanol dissolution filter, by 1.1 chromatographic conditions
Sample introduction, records peak area, and measurement result is shown in Table 4.As a result show that this method rate of recovery is good, other compositions are to tripterygium wilfordii in preparation
The assay of A prime is noiseless.
The average recovery experimental result of table 4
1.7 assays take 3 batches of 3% tripterygium glycosides nano-emulsion gels, prepare sample solution by 1.2 methods, press
1.1 chromatographic condition sample introductions, record peak area, according to the content of tripterygium glycosides in linear regression calculated for gel agent.In table 5
Measurement result show that the assay method meets the requirement of assay.
53 batches of tripterygium glycosides nano-emulsion gel sample assay results of table
2 tripterygium glycosides nano-emulsion Process for preparing hydrogels
2.1 composition tripterygium glycosides 0.6g, the Sefsol 218 3.63g of tripterygium glycosides nano-emulsion gel,
OP-10 emulsifying agent 5.94g, 1,2-PD 2.97g, plus Purified Water q. s are to 20g.
The preparation of 2.2 Propranolol Hydrochloride gels first by triptolide and Sefsol 218, OP-10 emulsifying agents,
1,2-PD is mixed, dispersed with stirring, then purified water is added dropwise, and is stirred, is obtained tripterygium glycosides nano-emulsion；By carbomer
940 add appropriate purified water in being swelled overnight at 4 DEG C, obtain clear gel matrix；Tripterygium glycosides nano-emulsion is added to gel base
In matter, stir, produce the gel preparation of yellow transparent.The pH 7.0~7.4 of the gel preparation is made.
3 percutaneous penetrations
SD rat abdomens are lost hair or feathers in the preparation of 3.1 isolated skins, it is ensured that skin of abdomen not damaged.Mouse is put to death after 1d,
Its complete belly depilation skin is taken immediately, is scraped off superabundant fats on skin, after tissue, is cleaned, soaked with physiological saline, in 4
Short-term preservation at DEG C, it is standby.
3.2 percutaneous penetrations are carried out using Franz diffusion cells method.Equipment therefor is Franz diffusion cells and homemade
Skin diffusion instrument, effectively diffusion internal diameter 0.9cm, reception building volume is 5ml, with PBS (containing 20% absolute ethyl alcohol) for reception liquid, in 32
At the uniform velocity stirred in DEG C water bath with thermostatic control.The isolated skin handled well under 3.1 is taken, moisture unnecessary on surface is blotted with filter paper, will
Cuticula is fixed on Franz diffusion cells upward, and 0.1g Propranolol Hydrochloride gel is equably coated on rat skin, is used
Sealed membrane is sealed.1ml reception liquids, and synthermal addition 1ml PBS in reception tank are taken when 1,2,3,4,6,8,12h.
The reception liquid of taking-up is through 0.45 μm of filtering with microporous membrane, by 1.1 chromatographic condition sample introductions, records peak area.
The calculating of 3.3 vitro cumulative infiltration capacities Propranolol Hydrochloride in regression equation calculation different time points reception tank
Content, byThe accumulation infiltration capacity of unit of account area medicine.Wherein, Q is unit
The drug accumulation transdermal penetration amount of area, drug concentration when Cn is the sample point in reception liquid, V is reception liquid volume,For
Accumulative drug concentration during the 1st sample point to last sample point in reception liquid, S is effective transdermal area of medicine.
4 Star point designs-effect surface method optimization formulation
4.1 Star point design
Designed using Box-Behnken-effect surface method optimizes its prescription.On the basis of pre-stage test, select to nanometer
Milkiness matter influences 3 more significant factors, i.e. X1：Oil is in oil and the percentage (w/w) of emulsifying agent gross mass, X2：Surface-active
The ratio (w/w) of agent and cosurfactant, X3：Water percentage (w/w) shared in nano-emulsion, is carried out in 3 levels
Optimizing research, basic, normal, high three level of each factor is denoted as -1,0 ,+1 respectively, is pacified with accumulative transmitance (K) for evaluation index
Row's experiment, factor level is set and experiment Star point design is shown in Table 6, table 7.
The Box-Behnken experimental factor levels of table 6
The Star point design of table 7 tests table and result
4.2 effect surface methods optimize
Regression analysis is carried out using Design-Expert softwares (8.0.5b masters), is judged using confidence level (P) as model
Standard, set up quadratic polynomial regression model：
Y=A0+A1X1+A2X2+A3X3+A4X1X2+A5X2X3+A6X1X3+A7X1 2+A8X2 2+A9X3 2
By effect surface figures of modeling rendering X1, X2 and the X3 obtained by fitting to each evaluation index, from the effect of each index
Face figure can reflect effect tendency of each dependent variable to response, from effect value with determining that preferably optimization is joined in investigating factor relation
Number.
According to the accumulation infiltration rate (being shown in Table 6) of each factor level, obtained quadratic polynomial regression equation is：Y=-
14.08331+0.98805X1+1.49515X2+0.60686X3-0.098629X1X2+8.73102E-003X1X3-
0.013432X2X3-0.023179X12-2.29345X22-8.42670E-003X32.Three are drawn out by Polynomical regressive equation
Effect surface and two-dimentional contour map are tieed up, Fig. 7, Fig. 8 is seen.
Actual prescription ratio after optimization is：Oil phase accounts for prescription total amount 18.15%, and S/CO-S accounts for prescription total amount 44.54%,
Distilled water accounts for prescription total amount 37.31%.
4.3 optimal prescription checkings
3 batches of tripterygium glycosides nano-emulsion gels are prepared according to optimal prescription, are carried out according to percutaneous penetration method transdermal
Experiment, cumulative in vitro transdermal penetration amount is calculated by formula.The predictive whether good index of institute's established model, deviation are used as using deviation
(%)=(measured value-predicted value)/predicted value × 100%, by the average accumulated transdermal penetration rate (15.612 of this 3 batches of preparations
μg.cm-2.h-1) and predicted value (16.486 μ g.cm-2.h-1) substitute into the deviation formula and obtain the deviation for 5.3%.It is indicated above this
The predictability of experiment is good.Refer to table 8.
The prescription the result of table 8
Test result indicates that：When the optimal proportion of tripterygium glycosides nano-emulsion is Sefsol 218 18.15%, OP-
10 emulsifying agents 29.69%, 1,2-PD 14.85%, 12h accumulation transdermal penetration rate is 15.612 μ g.cm-2.h-1, it is and pre-
Measured value has good compatibility.
The preferred embodiment to the invention is illustrated above, but the invention be not limited to it is described
Embodiment, those skilled in the art can also make a variety of equivalent on the premise of without prejudice to the invention spirit
Modification or replacement, these equivalent modifications or replacement are all contained in the application claim limited range.
Claims (10)
1. a kind of tripterygium glycosides nano-emulsion gel, is made up of by weight percentage following component：
Tripterygium glycosides 0.33%~3.30%,
Oil phase 10%~20%,
Surfactant 20%~40%,
Cosurfactant 10%~20%,
Gel-type vehicle 1%~5%,
Surplus is water；
Described gel-type vehicle is Acritamer 940.
2. a kind of tripterygium glycosides nano-emulsion gel according to claim 1, it is characterised in that by following component by weight
Percentage is constituted：
Tripterygium glycosides 0.5%~3.0%,
Oil phase 15%~20%,
Surfactant 25%~35%,
Cosurfactant 12%~18%,
Acritamer 940 1%~2%,
Surplus is water.
3. tripterygium glycosides nano-emulsion gel according to claim 1 or 2, it is characterised in that described oil phase is the third two
Alcohol list caprylate, Labraso, Emulsifier EL-60 or glyceryl triacetate.
4. tripterygium glycosides nano-emulsion gel according to claim 1 or 2, it is characterised in that described surfactant
For OP-10 emulsifying agents, Tween-80, Sefsol 218 or Labraso.
5. tripterygium glycosides nano-emulsion gel according to claim 1 or 2, it is characterised in that described helps surface-active
Agent is 1,2- propane diols, Tween-80 or Labraso.
6. tripterygium glycosides nano-emulsion gel according to claim 1, it is characterised in that described tripterygium glycosides nanometer
Curdling glue, is made up of by weight percentage following component：
7. a kind of preparation method of tripterygium glycosides nano-emulsion gel as claimed in claim 1, described preparation method includes
Following steps：
A, tripterygium glycosides and oil phase, surfactant and cosurfactant mixed in proportion, stirred, it is standby；
B, into above-mentioned solution deionized water is added dropwise, stirs, obtain tripterygium glycosides nano-emulsion；
C, add appropriate deionization in being swelled overnight at 4 DEG C the Acritamer 940, obtain clear gel matrix；
D, tripterygium glycosides nano-emulsion is added in gel-type vehicle, stirs, produce.
8. the preparation method of tripterygium glycosides nano-emulsion gel according to claim 7, it is characterised in that in step B and D
Mixing speed be 100~500rpm/min, mixing time be 10~30min.
9. the tripterygium glycosides nano-emulsion gel as described in any one of claim 1 to 6 is preparing treatment immunity disease medicine
In application.
10. tripterygium glycosides nano-emulsion gel according to claim 9 answering in treatment immunity disease medicine is prepared
With, it is characterised in that described immunity disease is rheumatoid arthritis, dermatitis and eczema or psoriasis.
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| CN110200833A (en) * | 2019-06-03 | 2019-09-06 | 五邑大学 | A kind of phloretin nano-emulsion preparation and its preparation method and application |
| CN110327285A (en) * | 2019-07-15 | 2019-10-15 | 张正华 | The preparation method of Statins ointment and its application in treatment porokeratosis of Mibelli |
| CN110859842A (en) * | 2019-12-13 | 2020-03-06 | 澳门大学 | Tetrandrine composition, preparation method thereof, tetrandrine external preparation, preparation method and application thereof |
| CN113244167A (en) * | 2021-05-20 | 2021-08-13 | 河北科技大学 | Lidocaine hydrochloride gel and preparation method thereof |
| CN115252626A (en) * | 2022-08-17 | 2022-11-01 | 泰州市中医院 | Pharmaceutical composition containing glucocorticoid and application thereof |
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| CN110200833A (en) * | 2019-06-03 | 2019-09-06 | 五邑大学 | A kind of phloretin nano-emulsion preparation and its preparation method and application |
| CN110327285A (en) * | 2019-07-15 | 2019-10-15 | 张正华 | The preparation method of Statins ointment and its application in treatment porokeratosis of Mibelli |
| CN110859842A (en) * | 2019-12-13 | 2020-03-06 | 澳门大学 | Tetrandrine composition, preparation method thereof, tetrandrine external preparation, preparation method and application thereof |
| CN113244167A (en) * | 2021-05-20 | 2021-08-13 | 河北科技大学 | Lidocaine hydrochloride gel and preparation method thereof |
| CN113244167B (en) * | 2021-05-20 | 2022-11-29 | 河北科技大学 | Lidocaine hydrochloride gel and preparation method thereof |
| CN115252626A (en) * | 2022-08-17 | 2022-11-01 | 泰州市中医院 | Pharmaceutical composition containing glucocorticoid and application thereof |
| CN115252626B (en) * | 2022-08-17 | 2024-04-02 | 泰州市中医院 | Pharmaceutical composition containing glucocorticoid and application thereof |
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