CN104224787A - Compound antimalarial composition - Google Patents
Compound antimalarial composition Download PDFInfo
- Publication number
- CN104224787A CN104224787A CN201410437416.XA CN201410437416A CN104224787A CN 104224787 A CN104224787 A CN 104224787A CN 201410437416 A CN201410437416 A CN 201410437416A CN 104224787 A CN104224787 A CN 104224787A
- Authority
- CN
- China
- Prior art keywords
- ethosome
- artesunate
- prime
- gel
- radix dichroae
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to a compound antimalarial composition. Particularly, the invention relates to a compound antimalarial composition containing artesunate and febrifugine and in particular relates to a compound antimalarial ethosome composition containing artesunate ethosomes and febrifugine ethosomes, a compound antimalarial ethosome gel paste as well as a preparation method and an application of the compound antimalarial ethosome gel paste. The compound antimalarial ethosome gel paste is prepared from the following components including a gel paste matrix, the artesunate ethosomes, the febrifugine ethosomes, a backing and an antisticking layer. According to the compound antimalarial ethosome gel paste disclosed by the invention, by utilizing the carrier permeation enhancing property of the ethosomes, the percutaneous permeability of an antimalarial medicament and the antimalarial effect of the medicament are improved; in addition, with the adoption of the compound antimalarial ethosome gel paste, the preparation technology is simple, high-temperature heating is not needed in the preparation process, and a harmful organic solvent is avoided.
Description
Technical field
The invention belongs to technical field of medicine, be specifically related to the compound recipe anti-malaria composition containing artesunate and Radix Dichroae B prime, in particular to the compound recipe malaria ethosome compositions containing artesunate ethosome and Radix Dichroae B prime ethosome and compound recipe malaria Ethosomal gel unguentum, and its production and use.
Background technology
Malaria is a kind of arthropod borne infection being undertaken propagating by mosquito bite.Data shows the whole world in 2010 about has 2.19 hundred million people to be infected with malaria, and death toll reaches 660,000
[1].Malaria remains in world wide at present, especially tropical low developed area, threatens one of major disease of human health.Eighties of last century seventies, China pharmacy worker is separated and obtains a kind of sesquiterpene lactones compounds---arteannuin with powerful plasmodium killing action from feverfew Herba Artemisiae annuae (Artemisia annua L.)
[2].Along with going deep into of research, people have synthesized again a series of artemisine derivative on the basis of arteannuin, comprising: artesunate, dihydroarteannuin and Artemether etc.
At present, the regular dosage form of artemisinin-based antimalarial drug mainly contains tablet, injection, capsule and suppository etc.But in use there is the problems such as drug metabolism in vivo speed is fast, bioavailability is low, first pass effect is obvious in conventional artemisine preparation, needs the administration of continuous several times to blood drug level of remaining valid
[3,4], not only the compliance of patient is low, and have impact on the antimalarial effect of medicine.In addition, through Clinical practice for many years, there is obvious plasmodium drug resistance phenomenon in folk prescription artemisinin-based drug, in recent years along with drug resistance problems is further severe, World Health Organization (WHO) (WHO) further provides and adopts compound antimalarial to forbid the requirement of folk prescription antimalarial comprehensively simultaneously.In conjunction with the development trend of antimalarial agent in the world and WHO to the requirement of compound antimalarial thing, build novel compound malaria preparation and be very important.
Summary of the invention
Identical with Herba Artemisiae annuae, Chinese medicine Radix Dichroae (Dichroa febrifuga Lour) at folks of china also for the treatment of malaria.Record in Shennong's Herbal " Radix Dichroae have draw tell, parasite killing, malaria, the effect such as antipyretic "
[5].Modern study finds one of main active that Radix Dichroae B prime (febrifugine) is Chinese medicine Radix Dichroae malaria
[6], pharmacological research shows that the Antimalarial of Radix Dichroae B prime is about 50 times of quinine
[7].
In conjunction with artemisinin-based antimalarial drug problems faced and WHO to the requirement of compound antimalarial thing, the present invention by artesunate and Radix Dichroae B prime compatibility, and constructs compound recipe anti-malaria composition.
Therefore, first object of the present invention is to provide a kind of compound recipe anti-malaria composition, it is characterized in that comprising artesunate and Radix Dichroae B prime and pharmaceutically acceptable carrier; The content of wherein said artesunate accounts for the 0.38-3.22% of composition total weight, and the content of described Radix Dichroae B prime accounts for the 0.01-1.67 ‰ of composition total weight.
The invention further relates to a kind of compound recipe malaria ethosome compositions, described ethosome compositions comprises artesunate ethosome and Radix Dichroae B prime ethosome, and pharmaceutically acceptable carrier.
Another object of the present invention is to provide a kind of compound recipe malaria Ethosomal gel unguentum, it is characterized in that, containing backing layer, hydrophilic gel layer, adherent layer; Described hydrophilic gel layer contains artesunate ethosome, Radix Dichroae B prime ethosome and gel cream base matter.Described artesunate ethosome, weight ratio between Radix Dichroae B prime ethosome and gel cream base matter are preferably: (artesunate ethosome+Radix Dichroae B prime ethosome): gel cream base matter=1:9-2:3; Further, the weight ratio of described artesunate ethosome and Radix Dichroae B prime ethosome is preferably: 3:1-29:1.Compound recipe Ethosomal gel unguentum of the present invention utilizes novel transdermal carrier-ol plastid, improves the percutaneous rate of compound medicine, strengthens the antimalarial effect of compound medicine percutaneous preparation.
Artesunate ethosome of the present invention is in gross weight for 100%, and described artesunate ethosome consists of: the pure water of the surfactant of the artesunate of 5-10%, the phospholipid of 10-20%, 3-10%, the low mass molecule alcohol of 30-50%, the cholesterol of 0.1-2%, the antioxidant of 0.1-1% and 30-50%.
Radix Dichroae B prime ethosome of the present invention is in gross weight for 100%, and described Radix Dichroae B prime ethosome consists of: the pure water of the surfactant of the Radix Dichroae B prime of 0.3-2%, the phospholipid of 5-20%, 5-10%, the low mass molecule alcohol of 30-50%, the cholesterol of 0.1-2%, the antioxidant of 0.05-1% and 30-50%.
The particle diameter of artesunate ethosome of the present invention between 20-300nm, between preferred 20-30nm.
The particle diameter of Radix Dichroae B prime ethosome of the present invention between 20-300nm, between preferred 20-30nm.
Gel cream base matter of the present invention in gross weight for 100%, the sodium carboxymethyl cellulose (sticky agent 3) of the sodium polyacrylate (sticky agent 1) of consisting of of gel cream base matter: 2-20%, the polyvinylpyrrolidone (sticky agent 2) of 5-20%, 2-10%, the polyvinyl alcohol (sticky agent 4) of 1-10%, the carbomer (sticky agent 5) of 2-15%, the gelatin (sticky agent 6) of 5-15%, cross-linking agent 0.0-2%, cross-linking regulator 0.0-1%, wetting agent 10%-40%, antiseptic 0.0-0.3%, pure water 20-40%.
Phospholipid of the present invention includes but not limited to the mixture of one or more of soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrogenated soy phosphatidyl choline, hydrogenated yolk lecithin.
Surfactant of the present invention includes but not limited to the mixture of one or more of Tween 80, polysorbate60, polysorbas20, sorbester p17, sorbester p18, polyoxyethylene hydrogenated Oleum Ricini, sodium ursodexoxycholate, PLURONICS F87.
Low mass molecule alcohol of the present invention includes but not limited to the mixture of one or more of ethanol, propylene glycol, 1,3 butylene glycol.
Antioxidant of the present invention includes but not limited to the mixture of one or more of vitamin C, vitamin E, 2,6-di-tert-butyl-4-methy phenols, disodium edetate.
Cross-linking agent of the present invention includes but not limited to the mixture of one or more of Alumen, aluminium hydroxide, dihydroxyaluminum aminoacetate, aluminum chloride, calcium chloride, magnesium chloride.
Cross-linking regulator of the present invention includes but not limited to the mixture of one or more of citric acid, tartaric acid, succinic acid, lactic acid, disodiumedetate.
Wetting agent of the present invention includes but not limited to the mixture of one or more of glycerol, propylene glycol, sorbitol.
Antiseptic of the present invention includes but not limited to the mixture of one or more of ethyl hydroxybenzoate, potassium sorbate, propyl p-hydroxybenzoate, benzyl alcohol.
Backing of the present invention includes but not limited to the one in non-woven fabrics, stretch fabric, flannel, clad aluminum foil; Described adherent layer includes but not limited to the one in polyethylene film, separate paper, polypropylene screen.
The present invention further provides a kind of preparation method of compound recipe malaria Ethosomal gel unguentum of the present invention, it comprises following steps:
1) artesunate ethosome is prepared:
Each adjuvant is taken by recipe quantity, first artesunate and cholesterol low mass molecule alcohol are dissolved, and add antioxidant and surfactant successively, phospholipid is added again after mix homogeneously, after phospholipid dissolves completely, pure water is slowly injected above-mentioned low mass molecule alcohol solution, at 25-40 DEG C, stir 3-15 minute, mixing speed 800-1500 rev/min, by the ethosome of preparation by filtering with microporous membrane, obtain the artesunate ethosome of uniform particle sizes;
2) Radix Dichroae B prime ethosome is prepared:
Each adjuvant is taken by recipe quantity, first Radix Dichroae B prime and cholesterol low mass molecule alcohol are dissolved, and add antioxidant and surfactant successively, phospholipid is added again after mix homogeneously, after phospholipid dissolves completely, pure water is slowly injected above-mentioned low mass molecule alcohol solution, at 25-35 DEG C, stir 3-15 minute, mixing speed 800-1500 rev/min, by the ethosome of preparation by filtering with microporous membrane, obtain the Radix Dichroae B prime ethosome of uniform particle sizes.
3) prepare Ethosomal gel cream: take each adjuvant by recipe quantity, carbomer, PVP-K30 are placed in beaker and add qs glycerin and water respectively, place and within 20-120 minute, make it fully swelling, obtained component A; Take gelatin by recipe quantity, sodium carboxymethyl cellulose, polyvinyl alcohol be placed in 50-100ml beaker and add suitable quantity of water and dissolve and stir 30-60 minute mix homogeneously, obtained B component; Take recipe quantity sodium polyacrylate be placed in beaker and add qs glycerin dispersion, obtained component C; Ethyl hydroxybenzoate, dihydroxyaluminum aminoacetate, citric acid are placed in 10ml cillin bottle and add suitable quantity of water and dissolve, obtained component D; Component A is mixed with B component and stirs, add D component subsequently to stir, add component C again, 40-120 minute is stirred at 50 DEG C, treat that gel cream substrate temperature is down to 20-40 DEG C after stopping heating, recipe quantity artesunate ethosome and Radix Dichroae B prime ethosome are joined mix homogeneously in gel cream base matter in the lump, obtained artesunate ethosome/Radix Dichroae B prime Ethosomal gel mastic; Get 5-15g above-mentioned pastille Ethosomal gel mastic, through coating, press mold, be cut into conventional GPC unguentum specification (long 10cm × wide 6cm or long 11cm × wide 7cm or long 12cm × wide 8cm), obtain artesunate ethosome/Radix Dichroae B prime Ethosomal gel unguentum finished product.
The present invention further provides compound recipe anti-malaria composition of the present invention, compound recipe malaria ethosome compositions or compound recipe malaria Ethosomal gel unguentum of the present invention purposes in the medicine for the preparation for the treatment of malaria.
" pharmaceutically acceptable " as herein described is that it has for the preparation of the toxicity on normally safety, not only abiology but also without other unwanted toxicity, and uses for veterinary and human medicine use is acceptable pharmaceutical composition.
" carrier " as herein described refers to diluent, adjuvant or the excipient used together with compound.Pharmaceutically acceptable carrier can be liquid, such as water and oil, comprises the oil that oil, animal, plant or synthesis are originated, such as Oleum Arachidis hypogaeae semen, soybean oil, mineral oil, Semen Allii Tuberosi wet goods.Pharmaceutically acceptable carrier also can be normal saline, Radix Acaciae senegalis, gelatin, gelatinized corn starch, Pulvis Talci, keratin, silica gel, carbamide etc.In addition, adjuvant, stabilizing agent, thickening agent, lubricant and coloring agent etc. can also be used.
Compound recipe malaria Ethosomal gel unguentum of the present invention is a kind of transdermal delivery system.Transdermal delivery system or transdermal formulation refer to stick mode medication through skin, and medicine is absorbed by skin and enters systemic blood circulation and reach effective blood drug concentration, realizes a class preparation of disease treatment or prevention.Transdermal drug delivery has avoids liver and gastrointestinal tract first pass effect, reduces poisonous side effect of medicine, and medicament slow release is carried, and reduces administration number of times, the features such as patient medication compliance is good
[8].Therefore, the structure of Radix Dichroae B prime/artesunate compound transdermal drug-delivery system, contributes to stabilised blood concentration, reduces administration number of times, improves antimalarial effect, reduces the toxicity of medicine.
Overcoming skin in the barrier action of medicine, the present invention adopts newtype drug percutaneous delivery vehicles-ol plastid.
Ethosome is a kind of containing high concentration alcohol, has the novel flexible liposome of the imitated vesicle structure of lipid bilayer
[9], ethosome has the advantage that drug conveying and percutaneous urge to ooze aspect; Ethosome has following features compared with conventional liposome
[10-13]: 1. particle diameter is little, particle size distribution range is narrow; 2. membrane flow is strong mutually, and morphotropism is good, and horny layer transparency is strong, can enter blood by percutaneous; 3. high, the good stability of envelop rate; 4. skin irritation is low, although ethosome is containing relatively large alcohol, its zest is significantly less than the alcoholic solution of same concentrations; 5. the intracellular delivery ability of ethosome is strong.
Gel ointment, also known as cataplasma, be a kind of is the external patch unguentum that main matrix material forms by high molecular polymer
[14].The major advantage of gel ointment comprises: 1) drug loading is high.The Chinese medicine powder complicated to composition or extract, drug loading can reach more than 20%; 2) mastic water content is high, can reach more than 50%.High-moisture be its stick comfortable, promote without no skin irritation and anaphylaxis and aquation keratodermatitis the key factor that active component percutaneous is penetrating; 3) as adopted crosslinked substrate, the mastic intensity (skin noresidue when taking off, absorption perspiration are not clamminess) be suitable for can be guaranteed, be applicable to use in the climatic environment of southern high-temperature, high humidity.4) preparation technology can room temperature coating-normal temperature crosslinked molding, must high-temperature heating in preparation process, effectively avoids active component and moisture loss.
Feature of the present invention is mainly:
(1) artesunate/Radix Dichroae B prime is prepared into percutaneous drug administration preparation, medicament slow release conveying can be reached, stabilised blood concentration, reduce administration number of times, reduce drug toxicity, strengthen compound medicine antimalarial effect and the object improving patient's compliance.
(2) compared with ordinary gel unguentum, Ethosomal gel unguentum utilizes the carrier enhancement characteristic of ethosome, significantly improves drug transdermal speed, enhances the malaria curative effect of medicine.
(3) in ethosome prescription, add specific surfactant, significantly can reduce the particle diameter of ethosome, contribute to the skin penetration rate improving medicine carrying ethosome.
(4) compound recipe Ethosomal gel unguentum preparation technology of the present invention is simple, the mechanical agitation that in technique, many employings are traditional, and heating-up temperature is low, and energy consumption is low, and equipment requirements is not high; Adjuvant selection aspect, the present invention's adjuvant used is the customary adjuvant in pharmaceutical preparation, and cost savings and drug safety all have clear superiority.
Accompanying drawing explanation
Fig. 1 shows the particle diameter test pattern of gel ointment 8 artesunate ethosome.
Fig. 2 shows the particle diameter test pattern of gel ointment 8 Radix Dichroae B prime ethosome.
Fig. 3 shows the Zeta potential test pattern of gel ointment 8 artesunate ethosome.
Fig. 4 shows the Zeta potential test pattern of gel ointment 8 Radix Dichroae B prime ethosome.
Fig. 5 shows the Q-t transdermal curve comparison figure of artesunate in artesunate ethosome/Radix Dichroae B prime Ethosomal gel unguentum 8 and common artesunate/Radix Dichroae B prime gel ointment.
Fig. 6 shows the Q-t transdermal curve comparison figure of Radix Dichroae B prime in artesunate ethosome/Radix Dichroae B prime Ethosomal gel unguentum 8 and common artesunate/Radix Dichroae B prime gel ointment.
Fig. 7-A ~ L shows the percutaneous antimalarial effect (drug withdrawal of each administration group after 5 days, representative mouse blood smear) of artesunate ethosome/Radix Dichroae B prime Ethosomal gel unguentum 8 and common artesunate/Radix Dichroae B prime gel ointment; Wherein:
Fig. 7-A shows the mouse blood smear of compound gel unguentum group C-A;
Fig. 7-B shows the mouse blood smear of compound recipe Ethosomal gel unguentum group X-A;
Fig. 7-C shows the mouse blood smear of compound gel unguentum group C-B;
Fig. 7-D shows the mouse blood smear of compound recipe Ethosomal gel unguentum group X-B;
Fig. 7-E shows the mouse blood smear of compound gel unguentum group C-C;
Fig. 7-F shows the mouse blood smear of compound recipe Ethosomal gel unguentum group X-C;
Fig. 7-G shows the mouse blood smear of compound gel unguentum group C-D;
Fig. 7-H shows the mouse blood smear of compound recipe Ethosomal gel unguentum group X-D;
Fig. 7-I shows the mouse blood smear of compound gel unguentum group C-E;
Fig. 7-J shows the mouse blood smear of compound recipe Ethosomal gel unguentum group X-E;
Fig. 7-K shows the mouse blood smear of blank group;
Fig. 7-L shows the mouse blood smear of blank Ethosomal gel unguentum group.
Detailed description of the invention
Quote following specific embodiment and describe the present invention in detail with the accompanying drawing of enclosing, but it will be understood by those skilled in the art that following examples are only exemplary descriptions, it does not limit the scope of the invention in any form.
Embodiment 1: the preparation of compound recipe malaria Ethosomal gel unguentum of the present invention
The preparation of artesunate ethosome/Radix Dichroae B prime Ethosomal gel unguentum:
(1) preparation of artesunate ethosome:
Equipment and material
Magnetic stirring apparatus: C-MAG HS4 type magnetic stirring apparatus (German IKA company); Analytical balance: BSA224S CW type electronic analytical balance (Sartorius AG); Filter: one-shot injector formula filter (Ф 13,0.22 μm, politef) (Tianjin Jin Teng experimental facilities company limited).
Take each component of each recipe quantity, first artesunate and cholesterol are joined in 25ml tool sieve triangular flask, and in triangular flask, add whole recipe quantity low mass molecule alcohol, adopt magnetic stirrer (stirring condition: 25-40 DEG C, 200-800 rev/min), after artesunate and cholesterol dissolve, in low mass molecule alcohol solution, add antioxidant, and stirring makes antioxidant disperse completely (or dissolving) under identical stirring condition; In this low mass molecule alcohol solution, add phospholipid again, stir and make it dissolve completely; Treat that phospholipid dissolves backward low mass molecule alcohol solution for continuous and adds surfactant, and under above-mentioned identical stirring condition, surfactant is disperseed (or dissolving) completely; It is last when whipping temp is constant, mixing speed is accelerated to 800-1500 rev/min, pure water (injection rate: 1.0-3.0ml/min) is slowly injected in this low mass molecule alcohol solution, after pure water all adds, keep above-mentioned stirring condition to continue to stir 3-15 minute, obtain ethosome, by the ethosome of preparation through one-shot injector formula filter (Ф 13,0.22 μm, politef) filter, obtain the artesunate ethosome of uniform particle sizes.
(2) preparation of Radix Dichroae B prime ethosome:
Equipment and material
With the preparation of (1) artesunate ethosome.
Take each component of each recipe quantity, first Radix Dichroae B prime and cholesterol are joined in 10ml tool sieve cillin bottle, and in cillin bottle, add whole recipe quantity low mass molecule alcohol, adopt magnetic stirrer (stirring condition: 25-35 DEG C, 200-800 rev/min), after Radix Dichroae B prime and cholesterol are dissolved, in low mass molecule alcohol solution, add antioxidant, and stirring makes antioxidant disperse completely (or dissolving) under identical stirring condition; In this low mass molecule alcohol solution, add phospholipid again, stir and make it dissolve completely; Treat that phospholipid dissolves backward low mass molecule alcohol solution for continuous and adds surfactant, and under above-mentioned identical stirring condition, surfactant is disperseed (or dissolving) completely; It is last when whipping temp is constant, mixing speed is accelerated to 800-1500 rev/min, pure water (injection rate: 1.0-3.0ml/min) is slowly injected in this low mass molecule alcohol solution, after pure water all adds, keep above-mentioned stirring condition to continue to stir 3-15 minute, obtain ethosome, by the ethosome of preparation through one-shot injector formula filter (Ф 13,0.22 μm, politef) filter, obtain the Radix Dichroae B prime ethosome of uniform particle sizes.
(3) preparation of Ethosomal gel cream:
Equipment and material
Agitator: Z92-BD universal mixer (Tianjin Li Hua instrument plant); Analytical balance: BSA224S CW type electronic analytical balance (Sartorius AG).
Preparation method: take each adjuvant by recipe quantity, is placed in 50-200ml beaker adds 1-6g glycerol, 2-6ml water respectively by carbomer, PVP-K30, place and within 20-120 minute, make it fully swelling, obtained component A; Take gelatin by recipe quantity, sodium carboxymethyl cellulose, polyvinyl alcohol be placed in 50-100ml beaker and add 2-5ml water dissolution and stir 30-60 minute mix homogeneously, obtained B component; Take recipe quantity sodium polyacrylate be placed in 25-50ml beaker and add the dispersion of 1-6g glycerol, obtained component C; Ethyl hydroxybenzoate, dihydroxyaluminum aminoacetate, citric acid are placed in 10ml cillin bottle and add 2-6ml water dissolution, obtained component D; Component A is mixed with B component and stirs, add D component subsequently to stir, add component C again, 40-120 minute is stirred at 50 DEG C, treat that gel cream substrate temperature is down to 20-40 DEG C after stopping heating, recipe quantity artesunate ethosome and Radix Dichroae B prime ethosome are joined mix homogeneously in gel cream base matter in the lump, obtained artesunate ethosome/Radix Dichroae B prime Ethosomal gel mastic; Get 5-15g above-mentioned pastille Ethosomal gel mastic, through coating, press mold, be cut into conventional GPC unguentum specification (long 10cm × wide 6cm or long 11cm × wide 7cm or long 12cm × wide 8cm), obtain artesunate ethosome/Radix Dichroae B prime Ethosomal gel unguentum finished product.
Embodiment 2: the sign of artesunate ethosome and Radix Dichroae B prime ethosome
(1) test of artesunate ethosome and Radix Dichroae B prime ethosome particle diameter
Testing equipment
Zetasizer Nano ZS nano particle size instrument (Malvern company of Britain); DTS0012 sample cell.
Tested object
In embodiment 1, for the preparation of artesunate ethosome and the Radix Dichroae B prime ethosome of gel ointment 8.
Method of testing
Respectively 1ml artesunate ethosome and Radix Dichroae B prime ethosome stock solution are joined DTS0012 sample cell, and sample cell is positioned over the particle diameter of both Zetasizer Nano ZS nano particle size instrument build-in tests.
Test result
In embodiment 1, be respectively for the preparation of the artesunate ethosome of gel ointment 8 and the particle diameter of Radix Dichroae B prime ethosome: 26.48 ± 0.12nm and 28.58 ± 0.24nm (see Fig. 1 and Fig. 2).
Adopt above-mentioned identical method, test the artesunate ethosome of other gel ointment 1 ~ 7 and 9 ~ 10 and the particle diameter of Radix Dichroae B prime ethosome, its result is all in the scope of 20 ~ 30nm.
(2) test of artesunate ethosome and Radix Dichroae B prime ethosome Zeta potential
Testing equipment
Zetasizer Nano ZS nano particle size instrument (Malvern company of Britain); DTS1060 sample cell.
Tested object
In embodiment 1, for the preparation of artesunate ethosome and the Radix Dichroae B prime ethosome of gel ointment 8.
Method of testing
Get artesunate ethosome to be measured and each 0.2ml of Radix Dichroae B prime ethosome stock solution, with pure water, the two is diluted suitable multiple, diluent joins in DTS1060 sample cell respectively, sample cell is positioned over the Zeta potential of both Zetasizer Nano ZS nano particle size instrument build-in tests.
Test result
In embodiment 1, be respectively for the preparation of the artesunate ethosome of gel ointment 8 and the Zeta potential of Radix Dichroae B prime ethosome :-28.0 ± 1.6mv and-28.8 ± 1.68mv (see Fig. 3 and Fig. 4).
Adopt above-mentioned identical method, test the artesunate ethosome of other gel ointment 1 ~ 7 and 9 ~ 10 and the Zeta potential of Radix Dichroae B prime ethosome, its result is all in the scope of-25 ~-35mv.
Embodiment 3: the percutaneous abilities research of compound recipe malaria Ethosomal gel unguentum of the present invention
Under identical drug loading, the drug transdermal performance comparison research of artesunate ethosome/Radix Dichroae B prime Ethosomal gel unguentum and artesunate/Radix Dichroae B prime gel ointment.
The preparation of sample
(1) preparation of artesunate/Radix Dichroae B prime gel ointment
Gel cream base matter is prepared according to the gel ointment Matrix formulation procedure of gel ointment 8 in embodiment 1; Each adjuvant and medicine is taken according to artesunate ethosome prescription in gel ointment 8 and Radix Dichroae B prime ethosome prescription, but do not carry out the preparation process of ethosome, only each adjuvant (comprising medicine) is mixed with gel cream base matter, thus obtained common artesunate/Radix Dichroae B prime gel ointment.
(2) preparation of artesunate ethosome/Radix Dichroae B prime Ethosomal gel unguentum
Artesunate ethosome/Radix Dichroae B prime Ethosomal gel unguentum is prepared according to the prescription of gel ointment 8 in embodiment 1 and preparation method.
Equipment and material
High performance liquid chromatograph (2487 type dual wavelength ultraviolet detectors, 1515 type high pressure pumps, 717 type automatic samplers, Waters, US); Chromatographic column Diamonsil C18 (2) (4.6mmX250mm, 5 μm) (Beijing Di Ma Science and Technology Ltd.); Fisher trifluoroacetic acid aqueous solution (Thermo Fischer Scient Inc.); Depilatory cream Nair
tMlotion with Aloe & Lanolin (CHURCH & DWIGHT CO., INC); One-shot injector formula filter (Ф 13,0.22 μm, politef) (Tianjin Jin Teng experimental facilities company limited).
Zoodermic process
Male Kun Ming mice (20-25g) is (purchased from Beijing Military Medical Science Institute Experimental Animal Center, animal credit number: SCXK-(army)-2012-004), mice is broken after neck execution, lose hair or feathers with depilatory cream, peel off skin of abdomen, remove fat deposit, for subsequent use after normal saline flushing.
Transdermal test in vitro is studied
Test adopts hang down formula Franz diffusion cell (volume: 18.0ml, diffusion area: 2.92cm
2); Temperature: 32.5 ± 0.5 DEG C; Rotating speed: 350 revs/min; By (area: 2.92cm
2, containing artesunate 3mg, Radix Dichroae B prime 0.02mg) and compound recipe Ethosomal gel unguentum or compound gel unguentum be closely affixed on mouse skin horny layer side, and be fixed on device, in receiving chamber, fill receiving liquid (30% ethanol-70% water).Respectively at 1,2,4,8,12,24 hour, receiving liquid in receiving chamber is all poured out (adding the fresh receiving liquid of same volume), sample is through one-shot injector formula metre filter, enter high performance liquid chromatograph, according to corresponding liquid-phase condition, (liquid-phase condition wherein measuring artesunate is: mobile phase: acetonitrile-0.1% phosphoric acid (42:68), flow velocity 1.0ml/min, column temperature 30 DEG C, determined wavelength 210nm; The liquid-phase condition measuring Radix Dichroae B prime is: mobile phase: acetonitrile-0.1% phosphoric acid (9:91), flow velocity 1.0ml/min, column temperature 30 DEG C, determined wavelength 225nm), measure the content of artesunate and Radix Dichroae B prime in sample in each receiving liquid respectively.
Respectively with the accumulation transdermal amount Q of the unit are of artesunate and Radix Dichroae B prime to time t
1/2mapping, result is as illustrated in Figures 5 and 6; With the accumulation transdermal amount Q of unit are to t
1/2carry out equation model, it the results are shown in Table 3; The accumulative skin permeation rate of 24 Hours drug is in table 4.
Table 3: the transdermal zero level equation model result of compound gel unguentum and compound recipe Ethosomal gel unguentum of the present invention
Table 4: compound gel unguentum and compound recipe Ethosomal gel unguentum of the present invention 24 hours accumulative transmitances
Result:
As shown in Fig. 5, Fig. 6 and table 3, table 4, artesunate ethosome of the present invention/Radix Dichroae B prime Ethosomal gel unguentum is compared with common artesunate/Radix Dichroae B prime gel ointment, medicine has percutaneous rate faster, and in the unit interval, the drug transdermal amount of Ethosomal gel unguentum is significantly improved.
In addition, adopt said method to test the percutaneous abilities of other gel ointment 1 ~ 7 and 9 ~ 10, in its result unit of display time, the drug transdermal amount of all more corresponding ordinary gel unguentum is significantly improved.
Embodiment 4: the pharmacodynamic study of compound recipe malaria Ethosomal gel unguentum of the present invention
Percutaneous antimalarial active and the anti-resume combustion situation of artesunate ethosome/Radix Dichroae B prime Ethosomal gel unguentum and common artesunate/Radix Dichroae B prime gel ointment contrast (artesunate and Radix Dichroae B prime purity >98%).
The preparation of sample
(1) preparation of compound gel unguentum
According to the dose requirements of each dosage group, gel cream base matter is prepared according to the gel ointment Matrix formulation procedure of gel ointment 8 in embodiment 1, and take each adjuvant (consumption of artesunate and Radix Dichroae B prime takes according to the consumption of different dosing dosage group) according to artesunate ethosome prescription in gel ointment 8 and Radix Dichroae B prime ethosome prescription, but do not carry out the preparation process of ethosome, only each adjuvant (comprising medicine) is mixed with gel cream base matter, thus obtained compound gel unguentum.
(2) preparation of compound recipe Ethosomal gel unguentum
According to the dose requirements of each dosage group, prepare gel cream base matter according to the gel ointment Matrix formulation procedure of gel ointment 8 in embodiment 1; Take each adjuvant (consumption of artesunate and Radix Dichroae B prime takes according to the consumption of different dosing dosage group) according to artesunate ethosome prescription in gel ointment 8 and Radix Dichroae B prime ethosome prescription, and prepare ethosome according to artesunate ethosome of the present invention and Radix Dichroae B prime ethosome preparation method; Finally prepare compound recipe Ethosomal gel unguentum according to the preparation method of Ethosomal gel unguentum.
(3) blank Ethosomal gel unguentum
Gel cream base matter is prepared according to the gel ointment Matrix formulation procedure of gel ointment 8 in embodiment 1; Each adjuvant is only taken according to artesunate ethosome prescription in gel ointment 8 and Radix Dichroae B prime ethosome prescription, and do not take corresponding medicine, according to the preparation method of artesunate ethosome in embodiment 1 and Radix Dichroae B prime ethosome, prepare two kinds of blank ethosome respectively, and two kinds of blank ethosome are mixed with gel cream base matter, thus obtained Blank gel unguentum.
Test method:
Equipment and animal
Microscope: OLYMPUS-BX51.
Experimental animal: 120 male Kun Ming mice (18-22g) (purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., number: SCXK (capital) 2012-0001) by licence; Age in animal week: select animal in 7 week age, adaptability starts to give tested material after raising 1 day; Animal requires: without special pathogen.
Rearing conditions: barrier system, temperature 20 ~ 23 DEG C, relative humidity is 40 ~ 70%, all-fresh air.Take artificial lighting, 12 hours light and shade cycles.Animal feeding in Merlon Mouse feeder cage, every cage 10 mices.
Group: compound gel unguentum group, compound recipe Ethosomal gel unguentum group, blank Ethosomal gel unguentum group, blank group (namely not carrying out the group of any process after mouse inoculation plasmodium).
Pharmacodynamics test is carried out according to chemical drugs technological guidance principle.Every mouse peritoneal quantification inoculation contains 1,000 ten thousand plasmodial erythrocyte of infected mice, inoculum concentration 0.2ml.Inoculate the same day, 120 mices press blank group, blank Ethosomal gel unguentum group, compound gel unguentum group and compound recipe Ethosomal gel unguentum group of the present invention, mice is divided at random 12 groups (animal grouping and dosage are in tables 5), often organize 10, according to group transdermal administration every day once, successive administration 4 days, administration area is about 2 × 3cm
2, after drug withdrawal, the 5th day afterbody gets blood, smear, the dyeing of Giemsa staining method, basis of microscopic observation each dosage group plasmodium negative conversion rate and resume combustion situation.Anti-resume combustion 1 month smear time of experiment.Result of the test is in table 6 and Fig. 7.
Table 5: the grouping of pharmacodynamics test animal and dosage situation
Table 6: the percutaneous malaria result (n=10) of artesunate/Radix Dichroae B prime Ethosomal gel cream and common artesunate/Radix Dichroae B prime gel ointment
Result:
As shown in table 6 and Fig. 7, artesunate/Radix Dichroae B prime Ethosomal gel unguentum is compared with artesunate/Radix Dichroae B prime gel ointment, and antimalarial effect obtains enhancing.
The present invention adopts ethosome Transfer Technology, and fully utilizes the advantage of compound recipe malaria and percutaneous malaria, constructs the compound recipe ethosome malaria gel ointment of efficient malaria.In drug effect comparative study, compound recipe malaria gel ointment can make Infected With Plasmodium animal turn out cloudy fast, and only has the lower dosage group a small amount of animal generation resume combustion (see table 4) in compound gel unguentum group after drug withdrawal; Adopted by compound medicine ethosome technology to carry out enclose respectively, then make Ethosomal gel unguentum, recrudescence rate can be reduced further, even reach the therapeutic effect (see table 4) of zero resume combustion after drug withdrawal.Galenic pharmacy evaluation shows: release in vitro and the transdermal kinetic parameter feature of compound gel unguentum and Ethosomal gel unguentum are consistent with above-mentioned pharmacodynamic result, that is: antimalarial agent Ethosomal gel unguentum is compared with gel ointment, have percutaneous rate faster, concrete outcome is in Table 1-2,4 and Fig. 3,4.Known by testing, compound recipe malaria gel ointment is to the antimalarial treatments Be very effective of malaria model Mus, and recrudescence rate is low, and toxic and side effects is little.
Above-mentioned research demonstrates the malaria high efficiency of compound recipe malaria Ethosomal gel unguentum, shows ethosome technology and is improving the outstanding role in medicine antimalarial effect; Meanwhile, under the support of ethosome technology, make the prospect of percutaneous preparation in malaria application more wide.
List of references:
[1] Wang Yingxin, Yang Henglin. the chemotherapeutical present Research of malaria [J]. Medical review, 2013,19 (22): 4151-4153.
[2] Lu Yiqin. the discovery of arteannuin and progress [J]. life science, 2012,16 (3): 260-265.
[3] Li Chao. artemisinin-based antimalarial drug animal Internal pharmacokinetics and In vitro metabolism research [D]. Mountain Western Medicine S University, tutor: Zhang Shuqiu, 2011.
[4] Chen Zhixi, Lin Ping Liu, Li Guoqiao, Li Zhiqiang, Chen Jinyan. the pharmacokinetic of artesunate tablet in Canis familiaris L. body [J]. radioimmunology magazine, 1996,9 (2): 77-79.
[5] Li Yan, Liu Mingchuan, Jin Linhong, Hu Deyu, Yang Song. Radix Dichroae chemical composition and bioactivity research progress [J]. Chemical Industry in Guangzhou, 2011,39 (9): 7-9.
[6]Chou,T.Q.,Fu,F.Y.,Kao,Y.S.Antimalarial?constituents?of?Chinese?drug,ch'ang?shan,Dichroa?febrifuga?Lour.[J].J.Amer.Chem.Soc.,1948,70(5):1765-1767.
[7] prosperous Shao is opened, Huang Qizhang, the pharmacology [J] of orixine. Journal of physiology, 1956,20 (1): 30-36.
[8] Hua Xiaodong, a core popular form of narrative literature flourishing in the Tang Dynasty. the progress [J] of transdermal delivery system. modern medicines and clinical, 2009,24 (5): 282-285.
[9] Zhang Hong, Wang Yunshan, Zhang Xiaochun, Zhang Fuming. the preparation of curcumin ethosome and quality evaluation [J] thereof. Chinese pharmacists, 2012 (8) 15:1063-1067.
[10] An Keyao, Sun Yong. the progress [J] of ethosome. China Dispensary, 2011,22 (5): 463-465.
[11] Zhu Weiwei, Zhai Guangxi, Zhao Jun. the progress [J] of ethosome. food and pharmaceutical, 2007,9 (1): 46-49.
[12]Godin?B,Touitou?E.Mechanism?of?bacitracin?permeation?enhancement?through?the?skin?and?cellular?membranes?from?an?ethosomal?carrier[J].Journal?of?Controlled?Release,2004,94(2-3):365-379.
[13]Touitou?E.,Godin?B.Dermal?drug?delivery?with?ethosomes:therapeutic?potential[J].Therapy,2007,4(4):465-472.
[14] Japanese official compendium association. the 12 corrects Pharmacopeia of Japan solution tells a story [M]. Tokyo: Guang Chuan bookstore, 1991.A136-141.
Claims (12)
1. a compound recipe anti-malaria composition, is characterized in that comprising artesunate and Radix Dichroae B prime and pharmaceutically acceptable carrier.
2. compound recipe anti-malaria composition according to claim 1, the content of wherein said artesunate accounts for the 0.38-3.22% of composition total weight, and the content of described Radix Dichroae B prime accounts for the 0.01-1.67 ‰ of composition total weight.
3. a compound recipe malaria ethosome compositions, is characterized in that, comprises artesunate ethosome and Radix Dichroae B prime ethosome, and pharmaceutically acceptable carrier.
4. compound recipe malaria ethosome compositions according to claim 3, the particle diameter of wherein said artesunate ethosome and/or Radix Dichroae B prime ethosome between 20-300nm, between preferred 20-30nm.
5. a compound recipe malaria Ethosomal gel unguentum, is characterized in that, containing backing layer, hydrophilic gel layer, adherent layer; Described hydrophilic gel layer contains artesunate ethosome, Radix Dichroae B prime ethosome and gel cream base matter.
6. gel ointment according to claim 5, wherein, described artesunate ethosome, weight ratio between Radix Dichroae B prime ethosome and gel cream base matter are: (artesunate ethosome+Radix Dichroae B prime ethosome): gel cream base matter=1:9-1:2; Wherein, the weight ratio of preferred described artesunate ethosome and Radix Dichroae B prime ethosome is: 3:1-29:1.
7. the ethosome compositions according to claim 3 or 4 or the gel ointment according to claim 5 or 6, wherein in described artesunate ethosome gross weight for 100%, described artesunate ethosome consists of: the pure water of the surfactant of the artesunate of 5-10%, the phospholipid of 10-20%, 3-10%, the low mass molecule alcohol of 30-50%, the cholesterol of 0.1-2%, the antioxidant of 0.1-1% and 30-50%; Wherein, described phospholipid is preferably the one of soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrogenated soy phosphatidyl choline, hydrogenated yolk lecithin; Described surfactant is preferably the mixture of one or more of Tween 80, polysorbate60, polysorbas20, sorbester p17, sorbester p18, polyoxyethylene hydrogenated Oleum Ricini, sodium ursodexoxycholate, PLURONICS F87; Described low mass molecule alcohol is preferably the mixture of one or more of ethanol, propylene glycol, 1,3 butylene glycol; Described antioxidant is preferably the mixture of one or more of vitamin C, vitamin E, 2,6-di-tert-butyl-4-methy phenols, disodium edetate.
8. the ethosome compositions according to claim 3 or 4 or the gel ointment according to claim 5 or 6, wherein in described Radix Dichroae B prime ethosome gross weight for 100%, described Radix Dichroae B prime ethosome consists of: the pure water of the surfactant of the Radix Dichroae B prime of 0.3-2%, the phospholipid of 5-20%, 5-10%, the low mass molecule alcohol of 30-50%, the cholesterol of 0.1-2%, the antioxidant of 0.05-1% and 30-50%; Wherein, described phospholipid is preferably the one of soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrogenated soy phosphatidyl choline, hydrogenated yolk lecithin; Described surfactant is preferably the mixture of one or more of Tween 80, polysorbate60, polysorbas20, sorbester p17, sorbester p18, polyoxyethylene hydrogenated Oleum Ricini, sodium ursodexoxycholate, PLURONICS F87; Described low mass molecule alcohol is preferably the mixture of one or more of ethanol, propylene glycol, 1,3 butylene glycol; Described antioxidant is preferably the mixture of one or more of vitamin C, vitamin E, 2,6-di-tert-butyl-4-methy phenols, disodium edetate.
9. the gel ointment according to any one of claim 5 ~ 8, wherein in the gross weight of gel cream base matter for 100%, the carbomer of the sodium carboxymethyl cellulose of the sodium polyacrylate of consisting of of gel cream base matter: 2-20%, the polyvinylpyrrolidone of 5-20%, 2-10%, the polyvinyl alcohol of 1-10%, 2-15%, the gelatin of 5-15%, cross-linking agent 0.0-2%, cross-linking regulator 0.0-1%, wetting agent 10%-40%, antiseptic 0.0-0.3%, pure water 20-40%; Wherein, described cross-linking agent is preferably the mixture of one or more of Alumen, aluminium hydroxide, dihydroxyaluminum aminoacetate, aluminum chloride, calcium chloride, magnesium chloride; Described cross-linking regulator is preferably the mixture of one or more of citric acid, tartaric acid, succinic acid, lactic acid, disodiumedetate; Described wetting agent is preferably the mixture of one or more of glycerol, propylene glycol, sorbitol; Described antiseptic is preferably the mixture of one or more of ethyl hydroxybenzoate, potassium sorbate, propyl p-hydroxybenzoate, benzyl alcohol.
10. gel ointment according to claim 5, wherein said backing is: the one in non-woven fabrics, stretch fabric, flannel, clad aluminum foil; Described adherent layer is: the one in polyethylene film, separate paper, polypropylene screen.
The preparation method of 11. 1 kinds of compound recipe malaria Ethosomal gel unguentum according to any one of claim 5 ~ 10, it comprises following steps:
1) artesunate ethosome is prepared:
Each adjuvant is taken by recipe quantity, first artesunate and cholesterol low mass molecule alcohol are dissolved, and add antioxidant and surfactant successively, phospholipid is added again after mix homogeneously, pure water is slowly injected the low mass molecule alcohol solution of above-mentioned adjuvant after phospholipid dissolves completely, stir 3-15 minute at 25-40 DEG C, mixing speed 800-1500 rev/min, by the ethosome of preparation by filtering with microporous membrane, obtain the artesunate ethosome of uniform particle sizes;
2) Radix Dichroae B prime ethosome is prepared:
Each adjuvant is taken by recipe quantity, first Radix Dichroae B prime and cholesterol low mass molecule alcohol are dissolved, and add antioxidant and surfactant successively, phospholipid is added again after mix homogeneously, pure water is slowly injected the low mass molecule alcohol solution of above-mentioned adjuvant after phospholipid dissolves completely, stir 3-15 minute at 25-35 DEG C, mixing speed 800-1500 rev/min, by the ethosome of preparation by filtering with microporous membrane, obtain the Radix Dichroae B prime ethosome of uniform particle sizes;
3) Ethosomal gel cream is prepared:
Take each adjuvant by recipe quantity, carbomer, PVP-K30 are added qs glycerin, water respectively, place and within 20-120 minute, make it fully swelling; Take gelatin by recipe quantity, sodium carboxymethyl cellulose, polyvinyl alcohol be dissolved in water and stir 30-60 minute mix homogeneously; Take recipe quantity sodium polyacrylate and add qs glycerin dispersion; Take ethyl hydroxybenzoate, dihydroxyaluminum aminoacetate, citric acid add suitable quantity of water and dissolve; By each several part adjuvant mix homogeneously in order, 40-120 minute is stirred at 50 DEG C, treat that gel cream substrate temperature is down to 20-40 DEG C after stopping heating, recipe quantity artesunate ethosome and Radix Dichroae B prime ethosome are joined mix homogeneously in gel cream base matter in the lump, obtained artesunate ethosome/Radix Dichroae B prime Ethosomal gel mastic; Get 5-15g above-mentioned pastille Ethosomal gel mastic, through coating, press mold, be cut into conventional GPC unguentum specification, obtain artesunate ethosome/Radix Dichroae B prime Ethosomal gel unguentum finished product.
The purposes of 12. compound recipe anti-malaria composition, compound recipe malaria ethosome compositions or compound recipe malaria Ethosomal gel unguentum according to any one of claim 1 ~ 10 in the medicine for the preparation for the treatment of malaria.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410437416.XA CN104224787A (en) | 2014-08-29 | 2014-08-29 | Compound antimalarial composition |
| CN201510496846.3A CN105147689B (en) | 2014-08-29 | 2015-08-13 | Compound anti-malaria composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410437416.XA CN104224787A (en) | 2014-08-29 | 2014-08-29 | Compound antimalarial composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104224787A true CN104224787A (en) | 2014-12-24 |
Family
ID=52214272
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410437416.XA Pending CN104224787A (en) | 2014-08-29 | 2014-08-29 | Compound antimalarial composition |
| CN201510496846.3A Active CN105147689B (en) | 2014-08-29 | 2015-08-13 | Compound anti-malaria composition |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510496846.3A Active CN105147689B (en) | 2014-08-29 | 2015-08-13 | Compound anti-malaria composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN104224787A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104586768A (en) * | 2014-12-30 | 2015-05-06 | 亚邦医药股份有限公司 | Linezolid-containing anti-infection pharmaceutical composition and preparation method thereof |
| CN105147689A (en) * | 2014-08-29 | 2015-12-16 | 中国中医科学院中药研究所 | Compound antimalarial composition |
| CN106727327A (en) * | 2016-12-31 | 2017-05-31 | 河南牧翔动物药业有限公司 | A kind of orixine liposome and preparation method thereof |
| CN114099474A (en) * | 2021-09-17 | 2022-03-01 | 杭州上禾健康科技有限公司 | Flurbiprofen gel, preparation process of gel plaster and coating machine |
| CN114617859A (en) * | 2022-03-28 | 2022-06-14 | 烟台大学 | Tropisetron hydrochloride ethosome gel plaster and preparation method thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108721604B (en) * | 2018-08-21 | 2021-03-02 | 山东大学 | Thymosin beta-4 ethosome and preparation process thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104224787A (en) * | 2014-08-29 | 2014-12-24 | 中国中医科学院中药研究所 | Compound antimalarial composition |
-
2014
- 2014-08-29 CN CN201410437416.XA patent/CN104224787A/en active Pending
-
2015
- 2015-08-13 CN CN201510496846.3A patent/CN105147689B/en active Active
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105147689A (en) * | 2014-08-29 | 2015-12-16 | 中国中医科学院中药研究所 | Compound antimalarial composition |
| CN105147689B (en) * | 2014-08-29 | 2017-11-10 | 中国中医科学院中药研究所 | Compound anti-malaria composition |
| CN104586768A (en) * | 2014-12-30 | 2015-05-06 | 亚邦医药股份有限公司 | Linezolid-containing anti-infection pharmaceutical composition and preparation method thereof |
| CN106727327A (en) * | 2016-12-31 | 2017-05-31 | 河南牧翔动物药业有限公司 | A kind of orixine liposome and preparation method thereof |
| CN114099474A (en) * | 2021-09-17 | 2022-03-01 | 杭州上禾健康科技有限公司 | Flurbiprofen gel, preparation process of gel plaster and coating machine |
| CN114099474B (en) * | 2021-09-17 | 2023-12-15 | 杭州上禾健康科技有限公司 | Flurbiprofen gel, gel plaster preparation process and coating machine |
| CN114617859A (en) * | 2022-03-28 | 2022-06-14 | 烟台大学 | Tropisetron hydrochloride ethosome gel plaster and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105147689A (en) | 2015-12-16 |
| CN105147689B (en) | 2017-11-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104224787A (en) | Compound antimalarial composition | |
| Fanun | Microemulsions as delivery systems | |
| Sankhyan et al. | Recent Trends in Niosome as Vesicular DrugDelivery System | |
| CN102225205B (en) | Tripterine nano structure lipid carrier and preparation method and application thereof | |
| TW201114766A (en) | Pharmaceutical composition for a hepatitis C viral protease inhibitor | |
| CN101862306A (en) | New type slightly soluble oral medicine self-emulsification preparation and preparation method thereof | |
| CN101028274A (en) | Ursodeoxycholic acid preparation in treatment of hepatobiliary diseases and its making method | |
| Sharma et al. | Advancement in novel drug delivery system: niosomes | |
| CN106619588A (en) | Self-microemulsion nutrient composition containing coenzyme Q10 and preparation method and application | |
| CN1887270A (en) | Nanometer berberine hydrochloride emulsion and its prepn process | |
| CN102379862B (en) | Spirosal-containing hydrophilic cataplasm | |
| Lu et al. | Characterization and evaluation of an oral microemulsion containing the antitumor diterpenoid compound ent-11alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid | |
| WO2020103832A1 (en) | Method for preparing flexible lipidosome | |
| CN103690483A (en) | Dl-praeruptorin A microemulsion and preparation method thereof | |
| CN107412699A (en) | A kind of Chinese medicine compound prescription micro emulsion gel emplastrum and its production and use | |
| CN101147735A (en) | Pharmaceutical composition for injection and its medicine box | |
| CN102379850B (en) | Targeted administration liposome passing through mucus barriers of human bodies | |
| CN101756886A (en) | Imiquimod micro emulsion gels for local skin and preparation method thereof | |
| Zanutto et al. | Semisynthetic derivative of Artemisia annua-loaded transdermal bioadhesive for the treatment of uncomplicated malaria caused by Plasmodium falciparum in children | |
| Zhang et al. | Panax quinquefolium saponin liposomes prepared by passive drug loading for improving intestinal absorption | |
| CN108743534B (en) | Tripterine or tripterine derivative vesicle and preparation method thereof | |
| CN103690482B (en) | Take phosphatide complexes as glycyrrhizic acid self-emulsifiable preparation concentrated solution and the preparation method of intermediate | |
| CN102614116B (en) | Self-emulsifying substrate and application thereof | |
| CN102784102A (en) | Tetraodotoxin oral liquid state preparation and preparation method thereof | |
| CN107281163B (en) | Application of carboxyl compound in aspect of promoting oral absorption of drug-loaded nanoparticle microspheres |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20141224 |