CN105147689B - Compound anti-malaria composition - Google Patents
Compound anti-malaria composition Download PDFInfo
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- CN105147689B CN105147689B CN201510496846.3A CN201510496846A CN105147689B CN 105147689 B CN105147689 B CN 105147689B CN 201510496846 A CN201510496846 A CN 201510496846A CN 105147689 B CN105147689 B CN 105147689B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
The present invention relates to a kind of compound anti-malaria composition.Specifically, the present invention relates to the compound anti-malaria composition containing Artesunate and Changshan B prime, compound antimalarial alcohol plastid composition and compound antimalarial Ethosomal gel paste more particularly to containing Artesunate alcohol plastid and Changshan B prime alcohol plastid, and its production and use.The compound antimalarial Ethosomal gel paste is made up of gel cream base matter, Artesunate alcohol plastid, Changshan B prime alcohol plastid, backing and adherent layer.The present invention utilizes the carrier enhancement characteristic of alcohol plastid, improves release and transdermal penetration performance, the antimalarial effect for enhancing medicine of antimalarial agent；In addition, the preparation technology of Ethosomal gel paste of the present invention is simple, without high-temperature heating in preparation process, and the use of harmful organic solvent is avoided.
Description
Technical field
The invention belongs to technical field of medicine, and in particular to the compound antimalarial group containing Artesunate and Changshan B prime
Compound, compound antimalarial alcohol plastid composition and Compound Resisting more particularly to containing Artesunate alcohol plastid and Changshan B prime alcohol plastid
Malaria Ethosomal gel paste, and its production and use.
Background technology
Malaria is a kind of insect-borne infectious disease propagated by bite by mosquitos.Data shows that the whole world in 2010 there are about 2.19
Hundred million people are infected with malaria, and death toll reaches 660,000[1].Malaria is still at present in world wide, especially it is tropical less-developedly
Area, threaten one of major disease of human health.The last century 70's, China pharmacy worker is from feverfew artemisia annua
Isolated a kind of Sesquiterpene lactones chemical combination with powerful plasmodium killing action in (Artemisiaannua L.)
Thing --- qinghaosu[2].With going deep into for research, people have synthesized a series of artemisine again on the basis of qinghaosu and spread out
Thing is penetrated, including：Artesunate, dihydroartemisinine and Artemether etc..
At present, the regular dosage form of artemisinin-based antimalarial drug mainly has tablet, injection, capsule and suppository etc..However, often
There is the problems such as drug metabolism in vivo speed is fast, bioavilability is low, first pass effect is obvious in use in rule artemisine preparation,
The administrations of continuous several times is needed to keep effective blood drug concentration[3,4], not only the compliance of patient is low, and have impact on the anti-of medicine
Malaria effect.In addition, by Clinical practice for many years, there is obvious plasmodium resistance phenomenon in folk prescription artemisinin-based drug, closely
As drug resistance problems are further severe over year, the World Health Organization (WHO) further provides comprehensively same using compound antimalarial
When forbid the requirement of folk prescription antimalarial.With reference to the requirement to compound antimalarial thing of development trend and WHO of antimalarial agent in the world,
Structure novel compound antimalarial preparation is very important.
The content of the invention
Identical with artemisia annua, Chinese medicine Changshan (Dichroa febrifuga Lour) is also used for controlling for malaria in folks of china
Treat.《Sheng Nong's herbal classic》Described in " Changshan, which has to draw, to tell, is desinsection, anti-malarial, antipyretic and other effects "[5].Modern study finds Changshan
B prime (febrifugine) is one of main active of Chinese medicine Changshan antimalarial[6], pharmacological research shows the anti-of Changshan B prime
Malaria effect is 50 times of quinine or so[7]。
It is of the invention by sweet wormwood amber with reference to the requirement of artemisinin-based antimalarial drug problems faced and WHO to compound antimalarial thing
Ester and Changshan B prime compatibility, and construct compound anti-malaria composition.
Therefore, first purpose of the invention is to provide a kind of compound anti-malaria composition, it is characterised in that includes sweet wormwood amber
Ester and Changshan B prime and pharmaceutically acceptable carrier；The content of wherein described Artesunate accounts for composition total weight
0.38-3.22%, the content of the Changshan B prime account for the 0.01-1.67 ‰ of composition total weight.
The invention further relates to a kind of compound antimalarial alcohol plastid composition, the alcohol plastid composition includes Artesunate
Alcohol plastid and Changshan B prime alcohol plastid, and pharmaceutically acceptable carrier.
Another object of the present invention is to provide a kind of compound antimalarial Ethosomal gel paste, it is characterised in that contain the back of the body
Lining, hydrophilic gel layer, adherent layer；The hydrophilic gel layer contains Artesunate alcohol plastid, Changshan B prime alcohol plastid and gel
Cream base matter.Weight ratio between the Artesunate alcohol plastid, Changshan B prime alcohol plastid and gel cream base matter is preferably：(sweet wormwood
Amber ester alcohol plastid+Changshan B prime alcohol plastid)：Gel cream base matter=1:9-2:3；Also, the Artesunate alcohol plastid and Changshan
The weight ratio of B prime alcohol plastid is preferably：3:1-29:1.The present invention compound Ethosomal gel paste using new transdermal carrier-
Alcohol plastid, to improve the percutaneous rate of compound medicine, strengthen the antimalarial effect of compound medicine percutaneous preparation.
Artesunate alcohol plastid of the present invention is counted using gross weight as 100%, and the Artesunate alcohol plastid composition is：
5-10% Artesunate, 10-20% phosphatide, 3-10% surfactant, 30-50% low mass molecule alcohol, 0.1-2%
The pure water of cholesterol, 0.1-1% antioxidant and 30-50%.
Changshan B prime alcohol plastid of the present invention is counted using gross weight as 100%, and the Changshan B prime alcohol plastid composition is：
0.3-2% Changshan B prime, 5-20% phosphatide, 5-10% surfactant, 30-50% low mass molecule alcohol, 0.1-2%
The pure water of cholesterol, 0.05-1% antioxidant and 30-50%.
The particle diameter of Artesunate alcohol plastid of the present invention is between 20-300nm, between preferably 20-30nm.
The particle diameter of Changshan B prime alcohol plastid of the present invention is between 20-300nm, between preferably 20-30nm.
Gel cream base matter of the present invention is counted using gross weight as 100%, and the composition of gel cream base matter is：2-20%'s is poly-
PAA (sticky agent 1), 5-20% polyvinylpyrrolidone (sticky agent 2), 2-10% sodium carboxymethylcellulose (viscosity
Agent 3), 1-10% polyvinyl alcohol (sticky agent 4), 2-15% carbomer (sticky agent 5), 5-15% gelatin (sticky agent 6),
Crosslinking agent 0.0-2%, cross-linking regulator 0.0-1%, NMF 10%-40%, preservative 0.0-0.3%, pure water 20-40%.
Phosphatide of the present invention includes but is not limited to soybean lecithin, egg yolk lecithin, hydrogenated soy phosphatidyl choline, hydrogenation
One or more of mixtures of egg yolk lecithin.
Surfactant of the present invention include but is not limited to Tween 80, polysorbate60, polysorbas20, sorbester p17, sorbester p18,
Crodaret, sodium ursodexoxycholate, one or more of mixtures of PLURONICS F87.
Low mass molecule alcohol of the present invention include but is not limited to ethanol, propane diols, 1,3 butylene glycol it is one or more of
Mixture.
Antioxidant of the present invention includes but is not limited to vitamin C, vitamin E, 2,6- di-t-butyl -4- methylbenzenes
One or more of mixtures of phenol, natrium adetate.
Crosslinking agent of the present invention includes but is not limited to alum, aluminium hydroxide, Dihydroxyaluminium Aminoacetate, alchlor, calcium chloride, chlorine
Change one or more of mixtures of magnesium.
Cross-linking regulator of the present invention includes but is not limited to citric acid, tartaric acid, butanedioic acid, lactic acid, ethylenediamine tetraacetic
One or more of mixtures of acetic acid disodium.
NMF of the present invention includes but is not limited to one or more of mixtures of glycerine, propane diols, sorbierite.
Preservative of the present invention includes but is not limited to ethyl hydroxy benzoate, potassium sorbate, propylparaben, benzene first
One or more of mixtures of alcohol.
One kind that backing of the present invention includes but is not limited in non-woven fabrics, stretch fabric, flannel, clad aluminum foil；Institute
State one kind that adherent layer includes but is not limited in polyethylene film, separate paper, polypropylene screen.
The present invention further provides a kind of preparation method of compound antimalarial Ethosomal gel paste of the present invention, it is included
Following steps：
1) Artesunate alcohol plastid is prepared：
Each auxiliary material is weighed by recipe quantity, is first dissolved Artesunate and cholesterol with low mass molecule alcohol, and sequentially add antioxygen
Agent and surfactant, phosphatide is added after well mixed, pure water is slowly injected into above-mentioned low point after phosphatide is completely dissolved
In sub- alcoholic solution, 3-15 minutes are stirred at 25-40 DEG C, 800-1500 revs/min of mixing speed, the alcohol plastid of preparation are passed through
Filtering with microporous membrane, obtain the Artesunate alcohol plastid of uniform particle sizes；
2) Changshan B prime alcohol plastid is prepared：
Each auxiliary material is weighed by recipe quantity, is first dissolved Changshan B prime and cholesterol with low mass molecule alcohol, and sequentially add antioxygen
Agent and surfactant, phosphatide is added after well mixed, pure water is slowly injected into above-mentioned low point after phosphatide is completely dissolved
In sub- alcoholic solution, 3-15 minutes are stirred at 25-35 DEG C, 800-1500 revs/min of mixing speed, the alcohol plastid of preparation are passed through
Filtering with microporous membrane, obtain the Changshan B prime alcohol plastid of uniform particle sizes.
3) Ethosomal gel cream is prepared：
Each composition in gel cream base matter is weighed by recipe quantity, is mixed heating, by recipe quantity Artesunate alcohol after cooling
Plastid and Changshan B prime alcohol plastid are added in gel cream base matter and are well mixed in the lump, and Artesunate alcohol plastid/Changshan second is made
Plain Ethosomal gel paste.
The present invention further provides the compound anti-malaria composition of the present invention, compound antimalarial alcohol plastid composition or the present invention
Compound antimalarial Ethosomal gel paste is preparing the purposes in being used to treat the medicine of malaria.
" pharmaceutically acceptable " as described herein is that it has for preparing typically safety, the both toxicity on abiology
Again without other unwanted toxicity, and it is acceptable pharmaceutical composition to be used for animal doctor with human medicine use.
" carrier " as described herein refers to the diluent, adjuvant or excipient applied together with compound.It can pharmaceutically connect
The carrier received can be liquid, such as water and oil, including oil, animal, the oil of plant or synthesis source, such as peanut oil, soybean
Oil, mineral oil, rapeseed oil etc..Pharmaceutically acceptable carrier can also be physiological saline, gum arabic, gelatin, gelatinized corn starch, cunning
Stone flour, keratin, silica gel, urea etc..Furthermore it is also possible to use adjuvant, stabilizer, thickener, lubricant and colouring agent etc..
Compound antimalarial Ethosomal gel paste of the present invention is a kind of transdermal delivery system.Transdermal delivery system or warp
Skin absorbable preparation refers to sticks mode medication through skin, and medicine is absorbed into systemic blood circulation by skin and reaches effective blood medicine
Concentration, realize a kind of preparation of disease treatment or prevention.Transdermal drug delivery, which has, avoids liver and intestines and stomach first pass effect, drops
The features such as low poisonous side effect of medicine, medicament slow release conveying, reduces administration number of times, and patient medication compliance is good[8].Therefore, Changshan second
The structure of element/Artesunate compound transdermal drug-delivery system, help to stablize blood concentration, reduce administration number of times, improve antimalarial effect
Fruit, reduce the toxicity of medicine.
In terms of skin is overcome to the barrier action of medicine, the present invention uses the percutaneous delivery vehicles -ol plastid of newtype drug.
Alcohol plastid is a kind of novel flexible lipid for containing high concentration alcohol, having the imitated vesicle structure of lipid bilayer
Body[9], alcohol plastid has drug delivery and percutaneously rush oozes the advantage of aspect；Alcohol plastid has following special compared with conventional liposome
Point[10-13]：1. particle diameter is small, particle size distribution range is narrow；2. membrane flow is mutually strong, morphotropism is good, and cuticula transparency is strong, Ke Yijing
Skin enters blood；3. envelop rate is high, stability is good；4. skin irritation is low, although alcohol plastid contains larger amount of alcohol, its excitant
It is significantly less than the alcoholic solution of same concentrations；5. the intracellular delivery ability of alcohol plastid is strong.
Gel ointment is also known as cataplasm, is a kind of external plaster being made up of high molecular polymer for main host material
Agent[14].The major advantage of gel ointment includes：1) drugloading rate is high.It is reachable to the complicated traditional Chinese medicine powder of composition or extract, drugloading rate
More than 20%；2) lotion water content is high, up to more than 50%.High-moisture is that it is sticked comfortably, without no skin irritation and mistake
Quick property and aquation keratoderma promote the percutaneous penetrating key factor of active component；3) as used crosslinked matrix, it can be ensured that
Suitable lotion intensity (skin noresidue, absorption sweat be not tacky when taking off), suitable for the climatic environment of southern high-temperature, high humidity
Middle use.4) preparation technology can normal temperature coating-normal temperature crosslinked shaping, be not necessary to be heated at high temperature in preparation process, effectively avoid activity
Composition and moisture loss.
The features of the present invention is mainly：
(1) Artesunate/Changshan B prime is prepared into percutaneous drug administration preparation, medicament slow release conveying, stabilised blood can be reached
Concentration, administration number of times is reduced, reduce drug toxicity, enhancing compound medicine antimalarial effect and the purpose for improving patient's compliance.
(2) compared with ordinary gel paste, Ethosomal gel paste utilizes the carrier enhancement characteristic of alcohol plastid, hence it is evident that improves
Drug transdermal speed, enhance the antimalarial curative effect of medicine.
(3) specific surfactant is added in alcohol plastid prescription, can significantly reduce the particle diameter of alcohol plastid, contribute to
Improve the skin penetration rate for carrying medicine alcohol plastid.
(4) compound Ethosomal gel paste preparation technology of the invention is simple, in technique to use traditional mechanical agitation more,
Heating-up temperature is low, and energy consumption is low, and equipment requirement is not high；In terms of auxiliary material selection, the auxiliary material used in the present invention is in pharmaceutical preparation
Customary adjuvant, all had a clear superiority in cost savings and drug safety.
Brief description of the drawings
Fig. 1 shows the particle diameter test chart of the Artesunate alcohol plastid of gel ointment 8.
Fig. 2 shows the particle diameter test chart of the Changshan B prime alcohol plastid of gel ointment 8.
Fig. 3 shows the Zeta potential test chart of the Artesunate alcohol plastid of gel ointment 8.
Fig. 4 shows the Zeta potential test chart of the Changshan B prime alcohol plastid of gel ointment 8.
Fig. 5 shows the transmission electron microscope picture of the Artesunate alcohol plastid of gel ointment 8.
Fig. 6 shows the transmission electron microscope picture of the Changshan B prime alcohol plastid of gel ointment 8.
Fig. 7 shows the stability study figure of the Artesunate alcohol plastid of gel ointment 8.
Fig. 8 shows the stability study figure of the Changshan B prime alcohol plastid of gel ointment 8.
Fig. 9 shows Artesunate alcohol plastid/Changshan B prime Ethosomal gel paste 8 and common Artesunate/Changshan B prime
The Q-t of Artesunate in gel ointment1/2Drug release profiles comparison diagram.
Figure 10 shows Artesunate alcohol plastid/Changshan B prime Ethosomal gel paste 8 and common Artesunate/Changshan B prime
The Q-t of Changshan B prime in gel ointment1/2Drug release profiles comparison diagram.
Figure 11 shows Artesunate alcohol plastid/Changshan B prime Ethosomal gel paste 8 and common Artesunate/Changshan B prime
The transdermal curve comparison figures of the Q-t of Artesunate in gel ointment.
Figure 12 shows Artesunate alcohol plastid/Changshan B prime Ethosomal gel paste 8 and common Artesunate/Changshan B prime
The transdermal curve comparison figures of the Q-t of Changshan B prime in gel ointment.
Figure 13-A~L show Artesunate alcohol plastid/Changshan B prime Ethosomal gel paste 8 and common Artesunate/often
The percutaneous antimalarial effect of mountain B prime gel ointment (after each administration group is discontinued 5 days, representative mouse blood smear)；Wherein：
Figure 13-A show compound gel paste group C-A mouse blood smear；
Figure 13-B show compound Ethosomal gel paste group X-A mouse blood smear；
Figure 13-C show compound gel paste group C-B mouse blood smear；
Figure 13-D show compound Ethosomal gel paste group X-B mouse blood smear；
Figure 13-E show compound gel paste group C-C mouse blood smear；
Figure 13-F show compound Ethosomal gel paste group X-C mouse blood smear；
Figure 13-G show compound gel paste group C-D mouse blood smear；
Figure 13-H show compound Ethosomal gel paste group X-D mouse blood smear；
Figure 13-I show compound gel paste group C-E mouse blood smear；
Figure 13-J show compound Ethosomal gel paste group X-E mouse blood smear；
Figure 13-K show the mouse blood smear of blank control group；
Figure 13-L show the mouse blood smear of blank Ethosomal gel paste group.
Embodiment
Quote specific examples below and the accompanying drawing enclosed describe the present invention in detail, but it will be understood by those skilled in the art that with
Lower embodiment is only exemplary description, and it does not limit the scope of the present invention in any form.
Embodiment 1：The preparation of compound antimalarial Ethosomal gel paste of the present invention
The preparation of Artesunate alcohol plastid/Changshan B prime Ethosomal gel paste：
(1) preparation of Artesunate alcohol plastid：
Equipment and material
Magnetic stirring apparatus：C-MAG HS4 types magnetic stirring apparatus (German IKA companies)；Assay balance：BSA224S CW types electricity
Sub- assay balance (Sartorius AG)；Filter：One-shot injector formula filter (13,0.22 μm of Ф, polytetrafluoroethyl-ne
Alkene) (Tianjin Jin Teng experimental facilities Co., Ltd).
The each component of each recipe quantity is weighed, Artesunate and cholesterol are added in 25ml tool sieve triangular flasks first,
And whole recipe quantity low mass molecule alcohols are added into triangular flask, using magnetic stirrer (stirring condition：25-40 DEG C, 200-
800 revs/min), after Artesunate and cholesterol dissolving, antioxidant is added into low mass molecule alcohol solution, and stir in identical
Stirring makes antioxidant be completely dispersed (or dissolving) under the conditions of mixing；Surfactant is added into this low mass molecule alcohol solution again, is stirred
It is set to be completely dispersed (or dissolving)；Treat that surfactant is completely dispersed in (or dissolving) backward low mass molecule alcohol solution and continuously add phosphorus
Fat, and under above-mentioned identical stirring condition, it is completely dissolved phosphatide；Finally in the case where whipping temp is constant, it will stir
Speed is accelerated to 800-1500 revs/min, and pure water (injection rate is slowly injected into the low mass molecule alcohol solution：1.0-3.0ml/
Min), after pure water all adds, keep above-mentioned stirring condition to continue to stir 3-15 minutes, alcohol plastid is obtained, by the alcohol of preparation
Plastid filters by one-shot injector formula filter (13,0.22 μm of Ф, polytetrafluoroethylene (PTFE)), obtains the Artesunate of uniform particle sizes
Alcohol plastid.
(2) preparation of Changshan B prime alcohol plastid：
Equipment and material
With the preparation of (1) Artesunate alcohol plastid.
The each component of each recipe quantity is weighed, Changshan B prime and cholesterol are added in 10ml tool sieve cillin bottles first,
And whole recipe quantity low mass molecule alcohols are added into cillin bottle, using magnetic stirrer (stirring condition：25-35 DEG C, 200-
800 revs/min), after Changshan B prime and cholesterol dissolving, antioxidant is added into low mass molecule alcohol solution, and stir in identical
Stirring makes antioxidant be completely dispersed (or dissolving) under the conditions of mixing；Surfactant is added into this low mass molecule alcohol solution again, is stirred
It is set to be completely dispersed (or dissolving)；Treat that surfactant is completely dispersed in (or dissolving) backward low mass molecule alcohol solution and continuously add phosphorus
Fat, and under above-mentioned identical stirring condition, it is completely dissolved phosphatide；Finally in the case where whipping temp is constant, it will stir
Speed is accelerated to 800-1500 revs/min, and pure water (injection rate is slowly injected into the low mass molecule alcohol solution：1.0-3.0ml/
Min), after pure water all adds, keep above-mentioned stirring condition to continue to stir 3-15 minutes, alcohol plastid is obtained, by the alcohol of preparation
Plastid filters by one-shot injector formula filter (13,0.22 μm of Ф, polytetrafluoroethylene (PTFE)), obtains the Changshan B prime of uniform particle sizes
Alcohol plastid.
(3) preparation of Ethosomal gel cream：
Equipment and material
Agitator：Z92-BD universal mixers (Tianjin Li Hua instrument plants)；Assay balance：BSA224S CW types electronics point
Analyse balance (Sartorius AG).
Preparation method：Each auxiliary material is weighed by recipe quantity, carbomer, PVP-K30 are placed in 50-200ml beakers and added respectively
Enter 1-6g glycerine, 2-6ml water, placement 20-120 minutes make it fully be swelled, and component A is made；Gelatin, carboxylic first are weighed by recipe quantity
Base sodium cellulosate, polyvinyl alcohol, which are placed in 50-100ml beakers, plus 2-5ml water dissolves and stir 30-60 minutes is well mixed, and stirs
Speed 50-100rpm is mixed, component B is made；Recipe quantity Sodium Polyacrylate is weighed to be placed in 25-50ml beakers and add 1-6g glycerine
It is scattered, component C is made；Ethyl hydroxy benzoate, Dihydroxyaluminium Aminoacetate, citric acid are placed in 10ml cillin bottles and add the dissolving of 2-6ml water, is made
Component D；Component A and B component are mixed and stirred for uniformly, D components is then added and stirs, add component C, stirred at 50 DEG C
Mix 40-120 minutes, mixing speed 30-100rpm, treat that gel cream substrate temperature is down to 20-40 DEG C after stopping heating, by recipe quantity
Artesunate alcohol plastid and Changshan B prime alcohol plastid are added in gel cream base matter and are well mixed in the lump, mixing speed 50-
100rpm, mixing time 20-70 minutes, 20-40 DEG C of whipping temp, Artesunate alcohol plastid/Changshan B prime alcohol plastid is made and coagulates
Glue lotion；The above-mentioned drug containing Ethosomal gel lotions of 5-15g are taken, coated, press mold, are cut into conventional GPC paste specification (length
10cm × wide 6cm or long 11cm × wide 7cm or long 12cm × wide 8cm), obtain Artesunate alcohol plastid/Changshan B prime alcohol plastid
Gel ointment finished product.
Embodiment 2：The sign of Artesunate alcohol plastid and Changshan B prime alcohol plastid
(1) test of Artesunate alcohol plastid and Changshan B prime alcohol plastid particle diameter
Test equipment
Zetasizer Nano ZS nano particle sizes instrument (Malvern company of Britain)；DTS0012 sample cells.
Test object
In embodiment 1, for preparing the Artesunate alcohol plastid and Changshan B prime alcohol plastid of gel ointment 8.
Method of testing
1ml Artesunates alcohol plastid and Changshan B prime alcohol plastid stoste are added to DTS0012 sample cells respectively, and by sample
Product pond, which is positioned in Zetasizer Nano ZS nano particle sizes instrument, tests the particle diameter of the two.
Test result
In embodiment 1, for preparing the Artesunate alcohol plastid of gel ointment 8 and the particle diameter difference of Changshan B prime alcohol plastid
For：26.48 ± 0.12nm and 28.58 ± 0.24nm (see Fig. 1 and Fig. 2).
Using above-mentioned identical method, the Artesunate alcohol plastid and often of other gel ointments 1~7 and 9~10 is tested
The particle diameter of mountain B prime alcohol plastid, its result is in the range of 20~30nm.
(2) test of Artesunate alcohol plastid and Changshan B prime alcohol plastid Zeta potential
Test equipment
Zetasizer Nano ZS nano particle sizes instrument (Malvern company of Britain)；DTS1060 sample cells.
Test object
In embodiment 1, for preparing the Artesunate alcohol plastid and Changshan B prime alcohol plastid of gel ointment 8.
Method of testing
Artesunate alcohol plastid to be measured and Changshan B prime each 0.2ml of alcohol plastid stoste are taken, it is with pure water that the two dilution is appropriate
Multiple, dilution are added separately in DTS1060 sample cells, and sample cell is positioned over into Zetasizer Nano ZS nano particle sizes
The Zeta potential of the two is tested in instrument.
Test result
In embodiment 1, for preparing the Artesunate alcohol plastid of gel ointment 8 and the Zeta potential of Changshan B prime alcohol plastid
Respectively：- 28.0 ± 1.6mv and -28.8 ± 1.68mv (see Fig. 3 and Fig. 4).
Using above-mentioned identical method, the Artesunate alcohol plastid and often of other gel ointments 1~7 and 9~10 is tested
The Zeta potential of mountain B prime alcohol plastid, its result is in the range of -25~-35mv.
(3) morphologic observation of Artesunate alcohol plastid and Changshan B prime alcohol plastid
Test equipment
JEM 2200FS types transmission electron microscope (Japanese JEOL companies).
Test object
The Artesunate alcohol plastid and Changshan B prime alcohol plastid prepared by the prescription in the gel ointment 8 of embodiment 1.
Method of testing
A drop Artesunate alcohol plastid is taken, is added dropwise on the copper grid of 400 mesh, unnecessary Artesunate alcohol is sucked with filter paper
Plastid, this sample is placed and dried at room temperature, and carry out transmission electron microscope observing.A drop Changshan B prime alcohol plastid is taken, is added dropwise
On the copper grid of 400 mesh, unnecessary Changshan B prime alcohol plastid is sucked with filter paper, this sample is placed and dried at room temperature, is gone forward side by side
Row transmission electron microscope observing
Test result
The Artesunate alcohol plastid and Changshan B prime alcohol plastid, outward appearance prepared by the prescription in the gel ointment 8 of embodiment 1 is equal
In relatively regular spheroidal (see Fig. 5 and Fig. 6).
(4) estimation of stability of Artesunate alcohol plastid and Changshan B prime alcohol plastid
Test equipment
Zetasizer Nano ZS nano particle sizes instrument (Malvern company of Britain)；DTS0012 sample cells.
Test object
Artesunate alcohol plastid and Changshan B prime alcohol matter are prepared by the prescription in the gel ointment 8 of embodiment 1 and preparation method
Body.
Evaluation method
Respectively at the same day (the 0th day) prepared by Artesunate alcohol plastid and Changshan B prime alcohol plastid, prepare after the 7th day,
15th day, the 30th day, the 60th day and the 90th day, determine the particle diameter and polydispersion of Artesunate alcohol plastid and Changshan B prime alcohol plastid
Coefficient (closed after Artesunate alcohol plastid and the preparation of Changshan B prime alcohol plastid to refrigerate in 4 DEG C of refrigerators).
Particle Size Determination Method
1ml Artesunates alcohol plastid and Changshan B prime alcohol plastid stoste are added to DTS0012 sample cells respectively, and by sample
Product pond, which is positioned in Malvern Zetasizer Nano ZS nano particle sizes instrument, tests the particle diameter and polydispersity coefficient of the two.
Test result
The estimation of stability result of Artesunate alcohol plastid is shown in Fig. 7, and the estimation of stability result of Changshan B prime alcohol plastid is shown in
Fig. 8.As a result show, Artesunate alcohol plastid and Changshan B prime alcohol plastid have good stability at 4 DEG C.
Embodiment 3：The medicine-releasing performance of compound antimalarial Ethosomal gel paste of the present invention
Under identical drugloading rate, Artesunate alcohol plastid of the present invention/Changshan B prime Ethosomal gel paste 8 and common sweet wormwood amber
The medicine-releasing performance comparative study of ester/Changshan B prime gel ointment.
The preparation of sample
(1) preparation of Artesunate/Changshan B prime gel ointment
Gel ointment Matrix formulation procedure according to gel ointment 8 in embodiment 1 prepares gel cream base matter；According to gel cream
Artesunate alcohol plastid prescription and Changshan B prime alcohol plastid prescription weigh each auxiliary material and medicine in agent 8, but without alcohol plastid
Preparation process, only each auxiliary material (including medicine) is mixed with gel cream base matter, coagulated so as to which common Artesunate/Changshan B prime be made
Glue paste.
(2) preparation of Artesunate alcohol plastid/Changshan B prime Ethosomal gel paste
Prescription and preparation method according to gel ointment 8 in embodiment 1 prepare Artesunate alcohol plastid/Changshan B prime alcohol matter
Body gel ointment.
Equipment and material
(2487 type dual wavelength ultraviolet detectors, 1515 type high pressure pumps, 717 types are certainly for Waters high performance liquid chromatographs
Dynamic injector, Waters, US)；Chromatographic column Diamonsil C18 (2) (4.6mm × 250mm, 5 μm) (Beijing enlightening equine
Skill Co., Ltd)；Fisher trifluoroacetic acid aqueous solutions (Thermo Fischer Scient Inc.)；One-shot injector formula filter (Ф 13,0.22
μm, polytetrafluoroethylene (PTFE)) (Tianjin Jin Teng experimental facilities Co., Ltd).
Drug release studies
Experiment is using formula Franz diffusion cell (volumes of hanging down：18ml, diffusion area：2.92cm2)；Temperature：32.5±0.5℃；
Rotating speed：350r/min；By (area：2.92cm2, containing Artesunate about 3mg, Changshan B prime about 0.02mg) and compound Ethosomal gel
Paste or compound gel paste are fixed on device, and reception liquid (water of 30% ethanol -70%) is filled in receiving chamber.Respectively at
0.5th, 1,2,4,8,12,24 hour, the reception liquid in receiving chamber is all poured out and (adds the fresh reception liquid of same volume), sample warp
After 0.22 μm of filtering with microporous membrane, enter high performance liquid chromatograph, (liquid of Artesunate is wherein determined according to corresponding liquid-phase condition
Phase condition is：Mobile phase：The phosphoric acid of acetonitrile -0.1% (compound method of 0.1% phosphoric acid：It will be added in 0.1% phosphate aqueous solution
Alkaline matter, adjust a kind of buffer salt solution in prepared by pH value is to 3.0) (40:60), flow velocity 1.0ml/min, 30 DEG C of column temperature,
Detection wavelength 210nm；Measure Changshan B prime liquid-phase condition be：Mobile phase：The phosphoric acid of acetonitrile -0.1% (match somebody with somebody by 0.1% phosphoric acid
Method processed：Alkaline matter will be added in 0.1% phosphate aqueous solution, adjusts a kind of buffer salt solution in prepared by pH value is to 3.0)
(9:91), flow velocity 1.0ml/min, 30 DEG C of column temperature, Detection wavelength 225nm), Artesunate in sample is determined in each reception liquid respectively
With the content of Changshan B prime.
Compound gel paste and compound Ethosomal gel paste, respectively with the unit area of Artesunate and Changshan B prime
Cumulative release amount Q is to time t1/2Mapping, as a result as shown in Figures 9 and 10；With the cumulative release amount Q of unit area to t1/2Progress side
Journey is fitted, and the results are shown in Table 3；24 hours Cumulative release amounts and release are shown in Table 4.
Table 3：Compound Ethosomal gel paste of the present invention or the Higuchi equations of common compound gel paste medicine release are intended
Close result
Table 4：24 hours accumulative releasing degrees of compound Ethosomal gel paste of the present invention or common compound gel paste medicine
As a result：
As shown in Fig. 9, Figure 10 and table 3, table 4, Artesunate of the invention alcohol plastid/Changshan B prime Ethosomal gel paste
Compared with common Artesunate/Changshan B prime gel ointment, medicine has faster rate of release, and alcohol plastid coagulates in the unit interval
The release amount of medicine of glue paste is significantly improved.
Embodiment 4：The percutaneous abilities research of compound antimalarial Ethosomal gel paste of the present invention
Under identical drugloading rate, Artesunate alcohol plastid of the present invention/Changshan B prime Ethosomal gel paste 8 and common sweet wormwood amber
The drug transdermal performance comparison research of ester/Changshan B prime gel ointment.
The preparation of sample
(1) preparation of Artesunate/Changshan B prime gel ointment
Gel ointment Matrix formulation procedure according to gel ointment 8 in embodiment 1 prepares gel cream base matter；According to gel cream
Artesunate alcohol plastid prescription and Changshan B prime alcohol plastid prescription weigh each auxiliary material and medicine in agent 8, but without alcohol plastid
Preparation process, only each auxiliary material (including medicine) is mixed with gel cream base matter, coagulated so as to which common Artesunate/Changshan B prime be made
Glue paste.
(2) preparation of Artesunate alcohol plastid/Changshan B prime Ethosomal gel paste
Prescription and preparation method according to gel ointment 8 in embodiment 1 prepare Artesunate alcohol plastid/Changshan B prime alcohol matter
Body gel ointment.
Equipment and material
High performance liquid chromatograph (2487 type dual wavelength ultraviolet detectors, 1515 type high pressure pumps, 717 type auto injections
Device, Waters, US)；Chromatographic column Diamonsil C18 (2) (4.6mmX250mm, 5 μm) (the limited public affairs of Beijing enlightening equine skill
Department)；Fisher trifluoroacetic acid aqueous solutions (Thermo Fischer Scient Inc.)；Depilatory cream NairTMLotion with Aloe&Lanolin
(CHURCH&DWIGHT CO.,INC)；One-shot injector formula filter (13,0.22 μm of Ф, polytetrafluoroethylene (PTFE)) (is risen in Tianjin Tianjin
Experimental facilities Co., Ltd).
The processing of animal skin
Male Kun Ming mice (20-25g) (is purchased from Beijing Military Medical Science Institute Experimental Animal Center, animal license
Card number：SCXK- (army) -2012-004), mouse is broken after neck execution, is lost hair or feathers with depilatory cream, peels off skin of abdomen, removes fat deposit,
It is standby after normal saline flushing.
Transdermal test in vitro is studied
Experiment is using formula Franz diffusion cell (volumes of hanging down：18.0ml diffusion area：2.92cm2)；Temperature：32.5±0.5
℃；Rotating speed：350 revs/min；By (area：2.92cm2, containing Artesunate about 3mg, Changshan B prime about 0.02mg) and compound alcohol matter
Body gel ointment or compound gel paste are closely affixed on mouse skin cuticula side, are fixed on device, are noted in receiving chamber
Full reception liquid (water of 30% ethanol -70%).Respectively at 1,2,4,8,12,24 hour, the reception liquid in receiving chamber is all poured out
(adding the fresh reception liquid of same volume), sample filter through one-shot injector formula filter, enter high performance liquid chromatograph, according to corresponding
Liquid-phase condition (wherein determine Artesunate liquid-phase condition be：Mobile phase：The phosphoric acid of acetonitrile -0.1% (match somebody with somebody by 0.1% phosphoric acid
Method processed：Alkaline matter will be added in 0.1% phosphate aqueous solution, adjusts a kind of buffer salt solution in prepared by pH value is to 3.0)
(40:60), flow velocity 1.0ml/min, 30 DEG C of column temperature, Detection wavelength 210nm；Measure Changshan B prime liquid-phase condition be：Mobile phase：
The phosphoric acid of acetonitrile -0.1% (compound method of 0.1% phosphoric acid：Alkaline matter will be added in 0.1% phosphate aqueous solution, adjusts pH value
Prepared by 3.0 a kind of buffer salt solution) (9:91), flow velocity 1.0ml/min, 30 DEG C of column temperature, Detection wavelength 225nm), respectively
Determine in each reception liquid the content of Artesunate and Changshan B prime in sample.
Respectively with the transdermal amount Q of the accumulation of Artesunate and the unit area of Changshan B prime to time t1/2Mapping, as a result as schemed
Shown in 11 and 12；With the transdermal amount Q of the accumulation of unit area to t1/2Equation model is carried out, it the results are shown in Table 5；24 hours medicines
Accumulative transit dose and skin permeation rate are shown in Table 6.
Table 5：The transdermal zero level equation model result of compound gel paste and the compound Ethosomal gel paste of the present invention
Table 6：Compound gel paste and 24 hours accumulative transmitances of compound Ethosomal gel paste of the present invention
As a result：
As shown in Figure 11, Figure 12 and table 5, table 6, Artesunate of the invention alcohol plastid/Changshan B prime Ethosomal gel cream
Agent is compared with common Artesunate/Changshan B prime gel ointment, and medicine has faster percutaneous rate, alcohol plastid in the unit interval
The drug transdermal amount of gel ointment is significantly improved.
In addition, testing the percutaneous abilities of other gel ointments 1~7 and 9~10 using the above method, the display of its result is single
The drug transdermal amount of more corresponding ordinary gel paste is significantly improved in the time of position.
Embodiment 5：The pharmacodynamic study of compound antimalarial Ethosomal gel paste of the present invention
Artesunate alcohol plastid/Changshan B prime Ethosomal gel paste and common Artesunate/Changshan B prime gel ointment
Percutaneous antimalarial active and anti-resume combustion situation contrast (Artesunate and Changshan B prime purity>98%).
The preparation of sample
(1) preparation of compound gel paste
According to the dose requirements of each dosage group, according to the gel ointment matrix preparation side of gel ointment 8 in embodiment 1
Method prepares gel cream base matter, and is weighed according to Artesunate alcohol plastid prescription in gel ointment 8 and Changshan B prime alcohol plastid prescription
Each auxiliary material (dosage of Artesunate and Changshan B prime weighs according to the dosage of different dosing dosage group), but without alcohol plastid
Preparation process, only each auxiliary material (including medicine) is mixed with gel cream base matter, so as to which compound gel paste be made.
(2) preparation of compound Ethosomal gel paste
According to the dose requirements of each dosage group, according to the gel ointment matrix preparation side of gel ointment 8 in embodiment 1
Method prepares gel cream base matter；Weighed respectively according to Artesunate alcohol plastid prescription in gel ointment 8 and Changshan B prime alcohol plastid prescription
Auxiliary material (dosage of Artesunate and Changshan B prime weighs according to the dosage of different dosing dosage group), and according to sweet wormwood amber of the present invention
Ester alcohol plastid and Changshan B prime alcohol plastid preparation method prepare alcohol plastid；Finally according to the preparation method system of Ethosomal gel paste
Standby compound Ethosomal gel paste.
(3) blank Ethosomal gel paste
Gel ointment Matrix formulation procedure according to gel ointment 8 in embodiment 1 prepares gel cream base matter；According to gel cream
Artesunate alcohol plastid prescription and Changshan B prime alcohol plastid prescription only weigh each auxiliary material in agent 8, without weighing corresponding medicine, press
According to the preparation method of Artesunate alcohol plastid in embodiment 1 and Changshan B prime alcohol plastid, two kinds of blank alcohol plastids are prepared respectively, and
Two kinds of blank alcohol plastids are mixed with gel cream base matter, so as to which Blank gel paste be made.
Test method：
Equipment and animal
Microscope：OLYMPUS-BX51.
Experimental animal：120 male Kun Ming mices (18-22g) (have purchased from Beijing dimension tonneau China experimental animal technology
Limit company, licensing numbering：SCXK (capital) 2012-0001)；Animal week old：From 7 week old animals, after adaptability is raised 1 day
Start to give tested material；Animal requires：Without special pathogen.
Rearing conditions：Barrier system, 20~23 DEG C of temperature, relative humidity are 40~70%, all-fresh air.Take artificial light
According to 12 hours light and shade cycles.Animal feeding is in makrolon mice rearing cage, per 10 mouse of cage.
Group：Compound gel paste group, compound Ethosomal gel paste group, blank Ethosomal gel paste group, blank pair
According to group (i.e. without the group of any processing after mouse inoculation plasmodium).
Pharmacodynamics test is carried out according to chemicals technological guidance principle.Every mouse peritoneal quantification inoculation contains
The red blood cell of 10000000 infected mice plasmodiums, inoculum concentration 0.2ml.The same day is inoculated with, 120 mouse are by blank control group, blank
The compound Ethosomal gel paste group of Ethosomal gel paste group, compound gel paste group and the present invention, mouse is randomly divided into
12 groups (animal packet and dosage are shown in Table 7), every group 10, according to the daily cutaneous penetration of group once, successive administration 4 days,
It is about 2 × 3cm that area, which is administered,2, the 5th day afterbody takes blood, smear, the dyeing of Giemsa staining method, micro- Microscopic observation every after drug withdrawal
Individual dosage group plasmodium negative conversion rate and resume combustion situation.1 month smear time is tested in anti-resume combustion.Result of the test is shown in Table 8 and Figure 13.
Table 7：Pharmacodynamics test animal packet and dosage situation
Table 8：The warp of Artesunate/Changshan B prime Ethosomal gel cream and common Artesunate/Changshan B prime gel ointment
Skin antimalarial result (n=10)
As a result：
As shown in table 8 and Figure 13, Artesunate/Changshan B prime Ethosomal gel paste coagulates with Artesunate/Changshan B prime
Glue paste is compared, and antimalarial effect is strengthened.
The present invention uses alcohol plastid Transfer Technology, and comprehensively utilizes the advantage of compound antimalarial and percutaneous antimalarial, constructs
The compound alcohol plastid antimalarial gel ointment of efficient antimalarial.Load medicine alcohol plastid particle diameter prepared by the present invention is small, and the circle of rule is presented
Spherical-like morphology, this alcohol plastid be advantageous in preparation carry medicine fast strikethrough skin, play drug effect.In drug effect contrasts research
In, compound antimalarial gel ointment can make Infected With Plasmodium animal quickly turn out cloudy, and only have after being discontinued in compound gel paste group
The a small amount of animal of relatively low dosage group resume combustion (being shown in Table 8) occurs；Compound medicine is respectively adopted into alcohol plastid technology to be included,
Ethosomal gel paste is made again, recrudescence rate can further be reduced, even up to be discontinued after zero resume combustion therapeutic effect (see
Table 8).Galenic pharmacy evaluation display：Compound gel paste and the release in vitro of Ethosomal gel paste and transdermal kinetic parameter are special
Sign is consistent with above-mentioned pharmacodynamic result, i.e.,：Antimalarial agent Ethosomal gel paste has and released faster compared with gel ointment
Put and percutaneous rate, concrete outcome are shown in Table 3-6 and Fig. 9-12.
The studies above demonstrates the antimalarial high efficiency of compound antimalarial Ethosomal gel paste, it is shown that alcohol plastid technology is carrying
Outstanding role in high medicine antimalarial effect；Meanwhile under the support of alcohol plastid technology, make percutaneous preparation in antimalarial application
Prospect it is more wide.
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Claims (20)
1. a kind of compound anti-malaria composition, it is characterised in that include Artesunate and Changshan B prime and pharmaceutically acceptable load
Body, wherein the content of the Artesunate accounts for the 0.38-3.22% of composition total weight, the content of the Changshan B prime accounts for combination
The 0.01-1.67 ‰ of thing gross weight.
A kind of 2. compound antimalarial alcohol plastid composition, it is characterised in that comprising Artesunate alcohol plastid and Changshan B prime alcohol plastid,
And pharmaceutically acceptable carrier, wherein the content of the Artesunate accounts for the 0.38-3.22% of composition total weight, it is described
The content of Changshan B prime accounts for the 0.01-1.67 ‰ of composition total weight.
3. compound antimalarial alcohol plastid composition according to claim 2, wherein the Artesunate alcohol plastid and/or Changshan
The particle diameter of B prime alcohol plastid is between 20-300nm.
4. compound antimalarial alcohol plastid composition according to claim 3, wherein the Artesunate alcohol plastid and/or Changshan
The particle diameter of B prime alcohol plastid is between 20-30nm.
5. the compound antimalarial alcohol plastid composition according to any one of claim 2 to 4, wherein with the Artesunate alcohol
Plastid gross weight is 100% meter, and the Artesunate alcohol plastid composition is：5-10% Artesunate, 10-20% phosphatide,
3-10% surfactant, 30-50% low mass molecule alcohol, 0.1-2% cholesterol, 0.1-1% antioxidant and 30-
50% pure water.
6. compound antimalarial alcohol plastid composition according to claim 5, wherein, the phosphatide is soybean lecithin, yolk
Lecithin, hydrogenated soy phosphatidyl choline, one kind of hydrogenated yolk lecithin；The surfactant is Tween 80, polysorbate60, tween
20th, sorbester p17, sorbester p18, Crodaret, sodium ursodexoxycholate, the one or more of of PLURONICS F87 mix
Compound；The low mass molecule alcohol is ethanol, propane diols, one or more of mixtures of 1,3 butylene glycol；The antioxidant is dimension
Raw plain C, vitamin E, 2,6 di tert butyl 4 methyl phenol, one or more of mixtures of natrium adetate.
7. the compound antimalarial alcohol plastid composition according to any one of claim 2 to 4, wherein with the Changshan B prime alcohol
Plastid gross weight is 100% meter, and the Changshan B prime alcohol plastid composition is：0.3-2% Changshan B prime, 5-20% phosphatide,
5-10% surfactant, 30-50% low mass molecule alcohol, 0.1-2% cholesterol, 0.05-1% antioxidant and 30-
50% pure water.
8. compound antimalarial alcohol plastid composition according to claim 7, wherein, the phosphatide is soybean lecithin, yolk
Lecithin, hydrogenated soy phosphatidyl choline, one kind of hydrogenated yolk lecithin；The surfactant is Tween 80, polysorbate60, tween
20th, sorbester p17, sorbester p18, Crodaret, sodium ursodexoxycholate, the one or more of of PLURONICS F87 mix
Compound；The low mass molecule alcohol is ethanol, propane diols, one or more of mixtures of 1,3 butylene glycol；The antioxidant is dimension
Raw plain C, vitamin E, 2,6 di tert butyl 4 methyl phenol, one or more of mixtures of natrium adetate.
9. a kind of compound antimalarial Ethosomal gel paste, it is characterised in that contain back sheet, hydrophilic gel layer, adherent layer；It is described
Hydrophilic gel layer contains Artesunate alcohol plastid, Changshan B prime alcohol plastid and gel cream base matter；Wherein, the Artesunate alcohol
The weight ratio of plastid and Changshan B prime alcohol plastid is：3:1-29:1；Wherein using the Artesunate alcohol plastid gross weight as 100%
Meter, the Artesunate alcohol plastid contain 5-10% Artesunate；Using the Changshan B prime alcohol plastid gross weight as 100%
Meter, the Changshan B prime alcohol plastid contain 0.3-2% Changshan B prime.
10. compound antimalarial Ethosomal gel paste according to claim 9, wherein, the Artesunate alcohol plastid, Changshan
Weight ratio between B prime alcohol plastid and gel cream base matter is：(Artesunate alcohol plastid+Changshan B prime alcohol plastid)：Gel cream base
Matter=1:9-1:2.
11. the compound antimalarial Ethosomal gel paste according to claim 9 or 10, wherein with the Artesunate alcohol plastid
Gross weight is 100% meter, and the Artesunate alcohol plastid composition is：5-10% Artesunate, 10-20% phosphatide, 3-
10% surfactant, 30-50% low mass molecule alcohol, 0.1-2% cholesterol, 0.1-1% antioxidant and 30-50%
Pure water.
12. compound antimalarial Ethosomal gel paste according to claim 11, wherein, the phosphatide be soybean lecithin,
Egg yolk lecithin, hydrogenated soy phosphatidyl choline, one kind of hydrogenated yolk lecithin；The surfactant be Tween 80, polysorbate60,
Polysorbas20, sorbester p17, sorbester p18, Crodaret, sodium ursodexoxycholate, the one or more of PLURONICS F87
Mixture；The low mass molecule alcohol is ethanol, propane diols, one or more of mixtures of 1,3 butylene glycol；The antioxidant
For vitamin C, vitamin E, 2,6 di tert butyl 4 methyl phenol, natrium adetate one or more of mixtures.
13. the compound antimalarial Ethosomal gel paste according to claim 9 or 10, wherein with the Changshan B prime alcohol plastid
Gross weight is 100% meter, and the Changshan B prime alcohol plastid composition is：0.3-2% Changshan B prime, 5-20% phosphatide, 5-
10% surfactant, 30-50% low mass molecule alcohol, 0.1-2% cholesterol, 0.05-1% antioxidant and 30-50%
Pure water.
14. compound antimalarial Ethosomal gel paste according to claim 13, wherein, the phosphatide be soybean lecithin,
Egg yolk lecithin, hydrogenated soy phosphatidyl choline, one kind of hydrogenated yolk lecithin；The surfactant be Tween 80, polysorbate60,
Polysorbas20, sorbester p17, sorbester p18, Crodaret, sodium ursodexoxycholate, the one or more of PLURONICS F87
Mixture；The low mass molecule alcohol is ethanol, propane diols, one or more of mixtures of 1,3 butylene glycol；The antioxidant
For vitamin C, vitamin E, 2,6 di tert butyl 4 methyl phenol, natrium adetate one or more of mixtures.
15. the compound antimalarial Ethosomal gel paste according to claim 9 or 10, wherein the gross weight with gel cream base matter
For 100% meter, the composition of gel cream base matter is：2-20% Sodium Polyacrylate, 5-20% polyvinylpyrrolidone, 2-10%
Sodium carboxymethylcellulose, 1-10% polyvinyl alcohol, 2-15% carbomer, 5-15% gelatin, crosslinking agent 0.0-2%,
Cross-linking regulator 0.0-1%, NMF 10%-40%, preservative 0.0-0.3%, pure water 20-40%.
16. compound antimalarial Ethosomal gel paste according to claim 15, wherein, the crosslinking agent is alum, hydrogen-oxygen
Change aluminium, Dihydroxyaluminium Aminoacetate, alchlor, calcium chloride, one or more of mixtures of magnesium chloride；The cross-linking regulator is lemon
Acid, tartaric acid, butanedioic acid, lactic acid, one or more of mixtures of disodium ethylene diamine tetraacetate；The NMF be glycerine,
One or more of mixtures of propane diols, sorbierite；The preservative is ethyl hydroxy benzoate, potassium sorbate, P-hydroxybenzoic acid
One or more of mixtures of propyl ester, phenmethylol.
17. the compound antimalarial Ethosomal gel paste according to claim 9 or 10, wherein the backing is：Non-woven fabrics, bullet
One kind in power cloth, flannel, clad aluminum foil；The adherent layer is：One kind in polyethylene film, separate paper, polypropylene screen.
18. compound anti-malaria composition according to claim 1 is preparing the purposes in being used to treat the medicine of malaria.
19. the compound antimalarial alcohol plastid composition according to any one of claim 2 to 8 is being prepared for treating malaria
Purposes in medicine.
20. the compound antimalarial Ethosomal gel paste according to any one of claim 9 to 17 is being prepared for treating malaria
Purposes in the medicine of disease.
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| CN105147689A (en) | 2015-12-16 |
| CN104224787A (en) | 2014-12-24 |
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