CN102579317A - Cantharidin vesicles and preparation thereof and preparation methods of cantharidin vesicles and preparation thereof - Google Patents
Cantharidin vesicles and preparation thereof and preparation methods of cantharidin vesicles and preparation thereof Download PDFInfo
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Abstract
The invention discloses cantharidin vesicles and a preparation method thereof, and a preparation containing the cantharidin vesicles and a preparation method thereof, and belongs to the field of pharmaceutical preparations. The cantharidin vesicles are prepared from cantharidin, a nonionic surfactant and an additive and are preferably prepared into an external gel preparation. A cantharidin percutaneous delivery external preparation has unique advantage over the medicament and is applied to a novel vesicle administration system, so that the percutaneous absorption of the medicament is increased, the clinical curative effect is enhanced, and the cantharidin percutaneous delivery external preparation can be used for treating cancer, specifically liver cancer, and has a liver targeting effect.
Description
Technical field
The present invention relates to cantharidin vesicle and preparation method thereof, contain preparation of cantharidin vesicle and preparation method thereof, belong to field of pharmaceutical preparations.
Background technology
Modern pharmacological research, human with the history in existing more than 2000 year of Mylabris treatment disease, Mylabris is the dry body of Meloidae insecticide south mylabris phalerata or yellow black mylabris cichorii.The big physician's Li Shizhen (1518-1593 A.D.) of the Ming Dynasty claims that in the Compendium of Material Medica monumental work Mylabris nature and flavor are hot, cold; Very toxic; Cure mainly cold and heat, tuberculosis handleless cup poison, scrofula, skin ulcer cellulitis, lose dead flesh, broken stone is infirmity, accumulation of blood, the flesh of hurting sb.'s feelings, control scabies, have an abortion, control scrofula, the tonneau water channel, treat drench disease, Fu's malignant boil fistula rots, controls hernia, separates the furuncle poison, controls effects such as rabies.Research to Mylabris in recent years mainly concentrates on the discussion to the anticancer mechanism of its effective ingredient cantharidin, the development of derivant and the exploitation aspect of novel form; Synthesized multiple cantharidin derivative in succession, like disodium cantharidinate, N-hydroxycantharidin, N-methylcantharidimide, norcantharidin etc.Modern clinical research confirms that Mylabris aspect some difficult miscellaneous diseases of treatment, has unique curative effect, like treatment rheumatalgia, neuralgia, globus hystericus, alopecia areata, cyclomastopathy, rhinitis, infectious warts, hepatitis, cancerous protuberance etc.
Contain compositions such as cantharidin, monoterpene class fat, resin, formic acid and pigment in the Mylabris, but active anticancer component is a cantharidin.Find in the pharmacological research that Mylabris has obvious inhibitory action to the kinds of experiments animal transplanting tumor; Cantharidin is to murine sarcoma-180Hela cell, and ascitic type skein cell tumor and ascitic type liver cancer have inhibitory action, because of synthesizing of protein and nucleic acid in the cantharidin interfere with cancer cells.In the clinical application, cantharidin and derivant thereof truly have better curative effect to hepatocarcinoma.According to statistics: with the cantharidin preparation is in the main treatment primary hepatocarcinoma, and effective percentage about 60% can improve the clinical symptoms of liver cancer patient, prolongs life cycle, and partly the case lump dwindles, and how leukocyte does not descend, and treating back 1 year survival rate is 12.7%.When also useful N-methylcantharidimide treatment II, III phase primary hepatocarcinoma; Half a year, above survival rate was organized apparently higher than 5-Fu; If the once used amount of N-methylcantharidimide is increased 5-10 doubly, half a year, above survival rate can be improved significantly (rising to 57.1% by 18.9%), and did not see obvious toxic-side effects.
The English Non-ionic surfactant based vesicles by name of nonionic surfactant vesicle (also having person to be the nonionic surfactant liposome) is called for short niosomes.It is to be carrier material with various non-ionic surface active agents, the miniature or multilamellar vesicles shape carrier of bilayer that forms through closed in itself.Thereby utilize that the nonionic surfactant vesicle packaging medicine can reduce that medicine is destroyed before reaching effective site, action time of the half-life prolong drug of prolong drug and reduce toxic and side effects; Change medicine distribution in vivo; Reach passive target effect etc., after adding suitable special adjuvant, also can reach the initiatively effect of targeting.Compare with liposome, the carrier material of nonionic surfactant vesicle does not contain phospholipid, has avoided the oxidative degradation of phospholipid, produces and store the neither specific condition that needs, and work simplification, cost are reduced, and is a kind of new drug carrier extremely likely.Because non-ionic surface active agent toxicity is less, has biocompatibility and degradability, does not dissociate, and oxydrolysis does not take place, be prone to mass production, and can design its structure according to purposes, therefore more and more to the people of its research in recent years.The vesicle technology has become one of focus in chemistry, pharmacy and the life science field.
Cantharidin is as effective ingredient in Chinese or composition, and clinical efficacy is remarkable, but toxic and side effects is very big; Dangerous, greatly limited it in Clinical Application, the percutaneous dosing external preparation has special advantages to this medicine; Use novel vesicle drug-supplying system, improve the Transdermal absorption of medicine, solve the toxic and side effects of medicine when oral and drug administration by injection; Increase clinical administration patient's compliance, will have broad application prospects, can produce good social benefit and considerable economic.
Summary of the invention
The object of the invention provides cantharidin vesicle and preparation method thereof, also has preparation of cantharidin vesicle gel and preparation method thereof.
The technical problem that the present invention solved, advantage of the present invention and technical advantage are:
Mylabris has the counteracting toxic substances phagedenoma; The effect of removing blood stasis eliminating stagnation, its effective ingredient cantharidin is an anticancer effective component, at aspects such as treatment hepatocarcinoma, breast carcinoma, pulmonary carcinoma, the esophageal carcinoma, colon cancer definite curative effect is arranged; External is smeared also has trichogenous function, can be used for treating alopecia.
Data shows; Human with the history in existing more than 2000 year of Mylabris treatment disease, its clinical practice did not wane in thousand, explained that it has significant curative effect; Be " severe and lingering illness has been apt in the violent agent of poison "; But simultaneously because it is " poison " simply, therapeutic dose and toxic dose are approaching, have seriously limited its clinical practice.
Targeting preparation be after generation ordinary preparation, secondary slow releasing preparation and precursor formulation, three generations's controlled release preparation the 4th generation preparation.Liposome is maximum target medicine carriers of research, but there is following shortcoming in the performance of liposome: 1. because its chemical instability, and preparation and storage difficulties, the not high and easy generation seepage of medicine encapsulation ratio and lose targeting property; 2. raw materials used phospholipid is difficult to purification, and easy oxidation deterioration and reduce membrane fluidity cause the being wrapped seepage of medicine; 3. the phospholipid of purification costs an arm and a leg; 4. often need logical noble gas in producing, preparation storage difficulty is bigger.Therefore, people have studied the carrier that chemical composition is confirmed, character is stable, can constitute liposome appearance vesicle widely.
Along with adipose membrane simulation CHEMICAL DEVELOPMENT; People find under study for action; Surfactant can be self-assembled into double seal structure and the similar vesicle of liposome structure at aqueous solution, all is hydrophilic groups inside and outside the shell; Empty center can hold aqueous medium, and being clipped in the two layers of hydrophilic group intermediary is hydrophobic group.Many surfactants all have the ability that oneself's assembling forms the vesicle structure; But because nonionic surfactant toxicity is less, have biocompatibility and degradability, do not dissociate; Oxydrolysis does not take place; Be prone to mass production, and can design its structure according to purposes, therefore comparatively deep to its research.
Nonionic surfactant vesicle (niosomes) also can be described as the nonionic surfactant liposome (because phospholipid also is a kind of surfactant; And liposomes is translated into liposome) always; It is the miniature or multilamellar vesicles carrier of bilayer that the non-ionic surface active agent closed in itself forms, and compares with liposome, and the carrier material of nonionic surfactant vesicle does not contain phospholipid; Avoided the oxidative degradation of phospholipid; Producing and store the neither specific condition that needs, work simplification, cost are reduced, is a kind of new drug carrier extremely likely.
The double membrane structure that vesicle had makes it become potential ideal drug disposition carrier; Both can carry water soluble drug (like aminoacid, polypeptide, protein medicaments), drug encapsulation in little water, also can have been carried oil-soluble medicine; With medicament solubilization in duplicature; Compare with micelle, microemulsion, the vesicle system has following characteristics as pharmaceutical carrier: big, the bigger solubilizing amount of (1) specific surface; (2) duplicature has stronger fastness and stability; (3) can regulate the size of particle diameter and the permeability of drug molecule through composition, pH, salt.Owing to form the height chemical stability of the surfactant of vesicle, vesicle is high more a lot of than the stability of liposome, and surfactant has well short osmosis again, therefore in transdermal delivery system, has special advantage.
At present, the method that the raising medicine sees through keratodermatitis comprises particulate carrier (vesicle, lipoid nanocapsule etc.), chemical promoter (azone, volatilization wet goods), the short technology (iontophoresis, electroporation, ultrasound wave etc.) of oozing of physics.The research of liposome percutaneous dosing is more; But traditional liposomal transdermal efficient is unsatisfactory; They tend on the keratodermatitis top layer, take place to merge and the generation cumulative action with skin, can't penetrate into deep skin; And the vesicle carrier is little with its toxicity, zest is little, skin is not damaged, and promotes various character medicines (fat-soluble, water solublity, macromole) transdermal horny layer, can reach blood circulation and enjoy and gaze at.
Vesicle is more stable than liposome, has the increase drug effect, reduces the advantage of toxic and side effects, and a kind of new drug carrier that can select use with liposome is provided.And vesicle is for the Chinese medicine especially research and development of the novel drug-supplying system of toxic traditional Chinese medicine transdermal targeting, significant than the good transdermal penetration performance of liposome.
Mylabris has removing blood stasis Xiao wei, and merit poison phagedenoma is drawn the effect of red foaming, is used for Zhi Liao WEIJIA lump; Stubborn dermatitis for many years, scrofula, wart, carbuncle are not burst; Diseases such as the dead flesh of malignant boil, determined curative effect, but its active component cantharidin therapeutic dose and toxic dose are approaching, have seriously limited clinical practice.This project selection vesicle can improve the concentration of local application position such as skin, joint part as the novel form of cantharidin percutaneous dosing, can bring into play the whole body therapeutic effect after the Transdermal absorption.
According to the characteristics of Mylabris treatment disease, because oral or drug administration by injection, topical remedy's substrate concentration is difficult for reaching, and has influenced therapeutic effect.And select the vesicle percutaneous dosing, because vesicle than the strong penetrance of liposome, is prone to reach deep skin; Can improve the concentration of topical remedy greatly; Simultaneously can form drug depot, keep stable blood drug level in the body, continue the effect of performance whole body therapeutic at local skin.
The cantharidin vesicle has also reduced the stimulation to skin, and is higher liver, spleen site concentration because the targeting property of vesicle microgranule self after vesicle reaches blood circulation, can avoid the infringement of cantharidin to organs such as the heart, kidneys, and drug safety is improved greatly.
The present invention accomplishes through following technical scheme:
Cantharidin vesicle of the present invention comprises following parts by weight of component:
Cantharidin 0.01-10 part
Non-ionic surface active agent 2.5-650 part
Additives 0.25-650 part.
Further be preferably:
Cantharidin 0.05-8 part
Non-ionic surface active agent 5-350 part
Additives 0.25-350 part.
Further be preferably:
Cantharidin 0.08-7 part
Non-ionic surface active agent 20-250 part
Additives 0.25-250 part.
Said cantharidin can also be one or more the mixture in disodium cantharidinate, N-hydroxycantharidin, N-methylcantharidimide, nor-Mylabris, the acrylic cantharidimide.
Said ionic surfactant pack is drawn together span; Tween; Polyoxyethylene fatty acid ester; Polyoxyethylene aliphatic alcohol ether; Polyglycerol alkyl ether; Crown ether; The glucose alkyl ether; Polyoxyethylene alkyl ether; Poloxamer; Sucrose ester; Fatty glyceride; Glyceryl monostearate; Polyethylene glycol fatty acid glyceride; The stearic glyceride of Polyethylene Glycol-4-; The Polyethylene Glycol glyceryl laurate ester; The sad certain herbaceous plants with big flowers acid glyceride of Polyethylene Glycol; One or more arbitrary proportion mixture in the poloxalkol.
Additives can be cholesterol, cholesterol polyethylene glycol polymer, stearmide (SA), two Cetyl Phosphates (DCP), 18-amine., sodium lauryl sulphate (SDS), Polyethylene Glycol (PEG), poloxamer 188 (F68), hydroxypropyl doubly its cyclodextrin, polyethylene glycol-lactic acid, Polyethylene Glycol-DSPE, N-palmityl-L-homocysteine, phosphatidylcholine, sodium palmitate, sodium stearate, Sodium myristate, sodium laurate, dodecylbenzene sodium sulfonate, sodium lauroylmethyl taurate, dodecyldimethylammonium hydroxide inner salt, one or more arbitrary proportion mixture of dodecanamide propyl betanin, and wherein Polyethylene Glycol (PEG) kind comprises one or more in 4000,6000,2000,400,300.
Span comprises span 20, span 40, sorbester p18, sorbester p38, sorbester p17, sorbester p37 etc. in the non-ionic surface active agent; Tween comprises polysorbas20, polysorbate40, polysorbate60, Tween 80, polysorbate85 etc.; Sucrose stearate comprises sucrose stearate S-3, sucrose stearate S-7, sucrose stearate S-11, sucrose stearate S-15 etc.; Polyoxyethylene fatty acid ester, another name Myrij (Myrij) is like polyoxyethylene 40 fatty acid esters (polyoxyl40stearate), polyoxyethylene 8 fatty acid esters, polyoxyethylene 50 fatty acid esters; Polyoxyethylene aliphatic alcohol ether, the another name Brij comprises Brij30, Brij35, Brij72, Brij721, cetomacrogol (Cetomacrogol), peregal 0 (Perogol 0), Ai Moerfu (Emlphor).
Cantharidin vesicle of the present invention can be taked methods such as alcohol injection, film dispersion method, reverse phase evaporation, aquation method, extrusion molding, Mechanical Method, pH gradient method, preferred following method for preparing:
Get non-ionic surface active agent, additives, cantharidin and be dissolved in an amount of organic solvent, heating or ultrasonic dissolution, solution for standby; Water intaking or phosphate buffer under (15-80 ℃) constant temperature stirs, at the uniform velocity inject above-mentioned solution in addition, add continued and stir; Wave to the greatest extent to organic solvent, add water or phosphate buffer to full dose, ultrasonic or cross high pressure dispersing emulsification machine 1-3 time; Filter, fill or lyophilization promptly get.
Cantharidin vesicle method for preparing of the present invention also can for: get non-ionic surface active agent, additives, cantharidin and be dissolved in an amount of organic solvent, reduction vaporization is to dry film, and vacuum drying is removed remaining solvent; Add phosphate buffer then; (25-90 ℃) constant temperature hydration, hydration time 10-60 minute, supersound process after the hydration; Fill or lyophilization promptly get.
Cantharidin vesicle method for preparing of the present invention can also for: non-ionic surface active agent is added the dissolving of a spot of phosphate buffer; Add in the fused additives, stir, add cantharidin solution; Pour 25-85 ℃ phosphate buffer behind the mixing into; Water-bath was placed 5-30 minute, and fill or lyophilization promptly get.
Cantharidin vesicle method for preparing of the present invention can also for: non-ionic surface active agent, additives are added an amount of organic solvent dissolution, and solution adds the phosphate buffer below the 1/2 organic solvent amount, ultrasonic 2-20 minute; 25-65 ℃ rotates to colloidal state, adds cantharidin solution again, and 40-80 ℃ rotates to dried; Add phosphate buffer, rotated 10-30 minute, placed 1-12 hour; Fully hydration, fill or lyophilization promptly get.
Cantharidin vesicle method for preparing of the present invention can also for: get non-ionic surface active agent, additives are dissolved in an amount of organic solvent, heating or ultrasonic dissolution, solution for standby; Under 15-80 ℃ of constant temperature stirs, get above-mentioned solution and at the uniform velocity add the phosphate buffer that is added with cantharidin, add continued and stir, wave to the greatest extent to organic solvent, add an amount of alkali and regulate pH to 7, continue to stir 1h, fill or lyophilization promptly get.
Wherein said alkali is meant one or more in sodium hydroxide, ammonia, triethanolamine, triethylamine, sodium carbonate, the sodium bicarbonate.
Cantharidin vesicle method for preparing of the present invention can also for: get non-ionic surface active agent, additives are dissolved in an amount of organic solvent, heating or ultrasonic dissolution, solution for standby; Under 15-80 ℃ of constant temperature stirs, get above-mentioned solution and at the uniform velocity inject the solution that is added with ammonium salt, add continued and stir; Wave to the greatest extent to organic solvent,, add an amount of cantharidin solution through dialysing or crossing post and remove vesicle acid ion wherein; Continue to stir 0.5h; Filter, fill or lyophilization promptly get.
Wherein said ammonium salt is meant one or more in ammonium sulfate, ammonium carbonate, ammonium chloride, ammonium acetate, the Ammonium biphosphate.
In the freeze drying process; Can add an amount of mannitol, dextran, lactose makes lyophilizing solution weight ratio between 4%-25%; Cooling rate should be at per hour 5 ℃-6 ℃ in the freeze-drying process; In the first phase sublimation drying stage, products temperature should be lower than eutectic point, and programming rate is per hour about 5 ℃.
Additives dissolve in the organic solvent according to its deliquescent difference in the cantharidin vesicle method for preparing of the present invention, also in water soluble or the dissimilar buffer.
Phosphate buffer also can be ammonium sulfate buffer, the amino buffer of trihydroxy methyl, citrate buffer solution, tartaric acid buffer, water in the cantharidin vesicle method for preparing of the present invention; Organic solvent comprises dehydrated alcohol, methanol, acetone, dichloromethane, chloroform, the mixture of one or more arbitrary proportions of ether, isoamyl alcohol, ethyl acetate.
The cantharidin vesicle can be prepared as preparations such as peroral dosage forms such as injection, oral liquid, liquid capsule, external preparation, preferred external preparation, and further preferred gel, ointment, patch etc. further are preferably gel.
Cantharidin vesicle gel is made up of following parts by weight of component: cantharidin 0.01-10, non-ionic surface active agent 2.5-650, additives 0-650, thickening agent 0.1-125, wetting agent 1-1200, pH regulator agent 0-60, transdermal agent 0-70, antiseptic 0-300.
Can be preferably: cantharidin 0.05-8, non-ionic surface active agent 5-350, additives 0.25-350, thickening agent 0.1-100, wetting agent 1-1000, pH regulator agent 0-50, transdermal agent 0-50, antiseptic 0.5-250.
Thickening agent can be the cross-linked polypropylene resin class, comprises Carbopol 941, and 974,934P, 980,981 and cross-linked polypropylene resin different salt and derivant, also can be hydroxypropyl methylcellulose, xanthan gum.
Wetting agent can be one or more the mixture in glycerol, propylene glycol, isopropyl alcohol, the hyaluronic acid.
The pH regulator agent can be organic amine such as triethanolamine, triethylamine, diethylamine, also can be sodium hydroxide, sodium bicarbonate, sodium carbonate.
Transdermal agent can be one or more in azone, menthol, quintessence oil, dimethyl sulfoxide, propylene glycol, Semen Myristicae isopropyl acid esters, N-Methyl pyrrolidone, lauric acid polyethyleneglycol glyceride, polyglyceryl fatty acid ester, oleic acid polyethyleneglycol glyceride, the sad capric acid polyethyleneglycol glyceride.
Antiseptic can be one or more in potassium sorbate, sorbic acid, ethyl hydroxybenzoate, propyl hydroxybenzoate, methyl hydroxybenzoate, the phenol.
The method for preparing of cantharidin vesicle gel is:
Get thickening agent, wetting agent, transdermal agent, antiseptic, add distilled water, the pH regulator agent is processed gel-type vehicle and prepared cantharidin vesicle suspension and is mixed, and stirs, and promptly gets cantharidin vesicle gel.
The specific embodiment
Below come further to set forth the beneficial effect of compositions according to the invention through Test Example.
One, anticancer:
1, test material and method:
1.1 material:
Cantharidin vesicle gel of the present invention; People's hepatocarcinoma SMMC-7721 cell strain, calf serum, MTT, dimethyl sulfoxide, RPMI 1640 dehydrated mediums, trypsin, PI dyestuff.
1.2 instrument:
Fluorescence inverted microscope, CO
2Incubator, Bio-Rad ELIASA, flow cytometer.
2, method:
2.1 cell culture:
HCC adds the RPMI1640 high glucose medium contain 10% calf serum, puts 37 ℃, saturated humidity, 5%CO
2Cultivate in the incubator; Use 0.25% trypsinization behind the cell attachment, divide bottle to cultivate again, exponential phase to be got into is about when going down to posterity back 24h, abandons original fluid, the PBS flushing.
2.2 cell growth inhibition test
The trophophase cell of taking the logarithm is inoculated in 96 well culture plates, at 5%CO
2, cultivate the cantharidin vesicle gel that adds the preparation of 100ul variable concentrations culture fluid behind the 24h in the saturated humidity, 37 ℃ of incubators in advance, make that ultimate density is 10,50,100ug/ml, each dosage is established 5 multiple holes, continues to cultivate.Respectively at 24,48,72h carries out the MTT colorimetric test.ELIASA 570nm detects the absorbance A value.
2.3 cell cycle and apoptosis rate are measured
The trophophase cell of taking the logarithm adds the cantharidin vesicle gel of variable concentrations culture fluid preparation, makes that ultimate density is 0,15,55,100ug/ml, continues to cultivate 24h.After the trypsinization, centrifugal abandoning adds sodium citrate buffer solution 2ml behind the supernatant, and room temperature is 20min fixedly, and the centrifugal again supernatant of abandoning adds 1.8ml trypsinization liquid, 1.5ml pancreatin inhibition liquid and 1.5ml propidium iodide successively.With cells were tested by flow cytometry cell cycle distribution and apoptosis rate.
2.4 statistical method
Using P EMS3.1 medical statistics software carries out data analysis, and the result representes with
.There is statistical significance P≤0.05 for difference.
3, result
3.1 cantharidin vesicle gel is to the growth inhibition test of human liver cancer cell SMMC-7721
15,55,100ug/ml cantharidin vesicle gelatification all obviously induces its apoptosis in human liver cancer cell SMMC-7721, acts on 24,48 respectively, behind the 72h, the SMMC-7721 cell receives inhibition in various degree, and is dosage and time dependence.See table 1.
Table 1 variable concentrations cantharidin vesicle gelatification is in the survival rate (%,
) of SMMC-7721 cell different time
3.2 cantharidin vesicle gel is to the influence of people's hepatocarcinoma SMMC-7721 cell cycle and apoptosis
Behind the cantharidin vesicle gelatification human liver cancer cell SMMC-7721, cell cycle all receives influence in various degree, and S phase cell proportion increases relatively, and S phase cell proportion significantly increases (P＜0.01) behind the various dose NCTD effect human liver cancer cell SMMC-7721; And G
0/ G
1Phase descends relatively.Prompting cantharidin vesicle gel blocks the growth that suppresses human liver cancer cell SMMC-7721 through the S phase.The apoptosis rate of dna content assay three dosage increases successively, and significant difference (P＜0.01) is relatively arranged in twos, and the apoptotic effect of prompting cantharidin vesicle gel pair cell is dose dependent.See table 2.
Table 2 cantharidin vesicle gel is to the influence (%,
) of SMMC-7721 cell cycle and apoptosis rate thereof
Annotate: compare * P＜0.05, P＜0.01 with matched group
4, conclusion
Cantharidin vesicle gelatification is behind people's hepatocarcinoma SMMC-7721 cell, and S phase cell proportion increases relatively, and cancerous cell is more is blocked the phase in S in prompting; G
0/ G
1The phase cell reduces, and prompting cantharidin vesicle gel has disturbed its cell cycle, has suppressed the propagation of cancerous cell.Continuation is carried out qualitative and quantitative analysis to cantharidin vesicle gel liver cancer apoptosis reducing; The result shows that cantharidin vesicle gel is liver cancer apoptosis reducing effectively, along with the increase of cantharidin vesicle gel dose; Apoptosis rate also obviously increases, and is dose dependent.
Two, promote hair growth:
1, materials and methods
1.1 test material
Anthology invention medicine, 30 of Wistar rats, body weight 200 ± 30g, male and female half and half.
1.2 modelling is tested with promoting hair growth
Be applied to the rat back same area after blended Colophonium/wax heating and melting with 1: 1, throw off after solidifying hardening, thereby reach the effect of depilation.Every mice depilation zone is about 3 * 3cm.
Lose hair or feathers next day, be divided into 2 groups at random, be respectively administration group and matched group.The administration group is smeared medicine 1ml of the present invention at every turn, administration every day 2 times, continuous 30 days; Matched group is smeared 70% ethanol 1ml at every turn, every day 2 times, continuous 30 days.
Cut new life's hair at the position of last time losing hair or feathers on the 31st day, the electronic balance precision is weighed.
2, experimental result
Show the influence of medicine of the present invention to rat depilation back hair growth
Annotate: compare * P＜0.05 with matched group
The result shows apparent, and medicine of the present invention has the effect of certain promotion depilation rat hair growth, and newborn gross weight amount is apparently higher than matched group.
Below come further to set forth preparation of compositions method according to the invention through embodiment.
Embodiment 1
Get cantharidin 0.3g, sorbester p18 2.8g, cholesterol 0.3g is dissolved in dehydrated alcohol; Rotary evaporation removes and to desolvate (60 ℃), adds pH and is in 6.8 the ammonium sulfate buffer, and 20 ℃ are stirred to ethanol and wave to the greatest extent; Supersound process 30min, room temperature leaves standstill cooling, promptly gets the vesicle suspension liquid of cantharidin.
Get HPMC (K-6000) 0.1g, glycerol 1g, potassium sorbate 0.5g adds purified water 100ml, makes blank gel-type vehicle, vesicle suspension and blank gel-type vehicle mixing, promptly gets the vesicle gel.
Embodiment 2
Get cantharidin 3g, sorbester p17 60g, hard amide 50g is dissolved in the ether; Rotary evaporation removes and to desolvate (60 ℃), and drying under vacuum overnight adds pH and is in 6.5 the ammonium sulfate buffer, 60 ℃ of hydration temperatures; Hydration time 30min handles with high pressure homogenizer, promptly gets the vesicle suspension of cantharidin.
Get carbomer 94112g, propylene glycol 120g, triethylamine 6g, menthol 6g, ethyl hydroxybenzoate 30g adds purified water 3000ml, makes blank gel-type vehicle, blank gel-type vehicle and vesicle suspension mixing, promptly gets the vesicle gel.
Embodiment 3
Get cantharidin 10g, span 40 300g, two Cetyl Phosphate 100g, 18-amine. 140g is dissolved in methanol; Rotary evaporation removes and desolvates (55 ℃), adds the purified water hydration, 65 ℃ of hydration temperatures; Hydration time 45min, supersound process 30 minutes promptly gets the vesicle suspension of cantharidin.
Embodiment 4
Get cantharidin 1g, sucrose stearate S-159g, sucrose stearate S-38g, sodium lauryl sulphate 15g is dissolved in acetone, at the uniform velocity injects purified water, and 80 ℃ of stirrings promptly get the vesicle suspension after removing and desolvating, but also supersound process 5-30 minute.
Embodiment 5
Get cantharidin 1g, sorbester p37 30g, span 20 20g, stearmide 47g is dissolved in the chloroform, injects pH and be 6.5 ammonium sulfate buffer, and 60 ℃ are stirred to ether and wave to the greatest extent, ultrasonic or handle with high pressure homogenizer, promptly get the vesicle suspension of cantharidin.
Embodiment 6
Getting sorbester p18 40g, to add a spot of pH be 6 phosphate buffers dissolvings; Add in fused 40gN-palmityl-L-homocysteine; Stir, add 1g cantharidin phosphate buffered saline (pH6), pour 55 ℃ phosphate buffer (pH6) behind the mixing into; Water-bath was placed 30 minutes, promptly got the vesicle suspension.
Embodiment 7
Get span 100g, two spermaceti phosphoric acid fat 110g add ether dissolution; Solution adds the 15g cantharidin phosphate buffer (pH6) of 1/5 ether amount, and ultrasonic 20 minutes, 65 ℃ of rotary evaporations were to colloidal state; The PBS (pH6) that adds again; 60 ℃ of hydrations were placed 12 hours, promptly got the vesicle suspension.
Embodiment 8
Get cantharidin 1g, polysorbas20 6g, poloxamer 2g, two spermaceti phosphoric acid fat 5g; Be dissolved in isoamyl alcohol, all speed injection pH is 6.5 citrate buffer solution, and 60 ℃ are stirred to isoamyl alcohol and wave to the greatest extent; Supersound process 30min, room temperature leaves standstill cooling, promptly gets the vesicle suspension of cantharidin.
Embodiment 9
Get cantharidin 2g, polysorbate60 10g, sucrose stearate S-724g, hydroxypropyl be its cyclodextrin 5g doubly; Cholesterol 3g, 18-amine. 2g is dissolved in methanol: chloroform (2: 1), rotary evaporation removes desolvate (65 ℃); Drying under vacuum overnight adds purified water, 60 ℃ of hydration temperatures; Hydration time 60min, supersound process 60 minutes promptly gets the vesicle suspension of cantharidin.
Embodiment 10
Get cantharidin 2g, Brij (Brij-35) 10g, sucrose stearate S-3 15g, cholesterol polyethylene glycol polymer 2g is dissolved in ether, at the uniform velocity injects purified water, and 60 ℃ of stirrings promptly get the vesicle suspension after removing and desolvating, but also supersound process 20 minutes.
Embodiment 11
With cantharidin 2g, polyoxyethylene (40) fatty acid ester 20g, sucrose stearate S-320g, stearmide 5g is dissolved in ethyl acetate, at the uniform velocity injects purified water, and 60 ℃ of stirrings promptly get the vesicle suspension after removing and desolvating;
Get carbomer 97450g, hyaluronic acid 480g, sorbic acid 10g, propyl hydroxybenzoate 15g, sodium hydroxide 28g adds purified water 5000ml, makes blank gel-type vehicle, blank gel-type vehicle and vesicle suspension mixing, promptly gets the vesicle gel.
Embodiment 12
Get cantharidin 8g, polyoxyethylene alkyl ether 150g, cholesterol 180g is dissolved in dichloromethane, at the uniform velocity injects and is dissolved in deionized water, and 60 ℃ of stirrings promptly get the vesicle suspension after removing and desolvating;
Get carbomer 934P 120g, propylene glycol 1000g, lauryl amine 50g, dimethyl sulfoxide 50g, ethyl hydroxybenzoate 200g, methyl hydroxybenzoate 50g adds purified water 6000ml, makes blank gel-type vehicle, blank gel-type vehicle and vesicle suspension mixing, promptly gets the vesicle gel.
Embodiment 13
Get cantharidin 2g, glucose alkyl ether 10g, polyglycerol alkyl ether 10g, two spermaceti phosphoric acid fat 13g are dissolved in ethanol, at the uniform velocity inject the tartaric acid buffer, and 25 ℃ of stirrings promptly get the vesicle suspension after removing and desolvating;
Get HPMC (K-6000) 80g, isopropyl alcohol 500g, phenol 30g adds purified water 9000ml, makes blank gel-type vehicle, blank gel-type vehicle and vesicle suspension mixing, promptly gets the vesicle gel.
Embodiment 14
Get cantharidin 2g, sucrose stearate S-79g, sucrose stearate S-118g, cholesterol 10g is dissolved in ethanol, at the uniform velocity injects the amino buffer (pH6.5) of trihydroxy methyl, and 70 ℃ of stirrings promptly get the vesicle suspension after removing and desolvating;
Get carbomer 934P 35g, glycerol 400g, methyl hydroxybenzoate 10g, propyl hydroxybenzoate 10g, sodium carbonate 21g adds purified water 6000ml, makes blank gel-type vehicle, blank gel-type vehicle and vesicle suspension mixing, promptly gets the vesicle gel.
Embodiment 15
Get cantharidin 1g, polyoxyethylene aliphatic alcohol ether 5g, cholesterol 0.25g is dissolved in dehydrated alcohol; Rotary evaporation removes and to desolvate (60 ℃), adds pH and is in 6.5 the ammonium sulfate buffer, and 60 ℃ are stirred to ethanol and wave to the greatest extent; Supersound process 30min, room temperature leaves standstill cooling, promptly gets the vesicle suspension liquid of cantharidin.
Embodiment 16
Get cantharidin 3g, sucrose stearate S-1125g, cholesterol polyethylene glycol polymer 1g is dissolved in ethanol, at the uniform velocity injects purified water, and 50 ℃ of stirrings promptly get the vesicle suspension after removing and desolvating.
Embodiment 17
Get cantharidin 5g, polyoxyethylene fatty acid ester 180g, cholesterol 200g is dissolved in chloroform, at the uniform velocity injects purified water, and 60 ℃ of stirrings promptly get the vesicle suspension after removing and desolvating.
Embodiment 18
With cantharidin 10g, poloxalkol 100g, cholesterol 300g is dissolved in isoamyl alcohol, at the uniform velocity injects purified water, and 40 ℃ of stirrings promptly get the vesicle suspension after removing and desolvating.
Embodiment 19
Get cantharidin 6g, sucrose stearate S-1136g, sucrose stearate S-360g, cholesterol 94g is dissolved in ethanol, at the uniform velocity injects the purified water that is dissolved with poloxamer 10g, and 60 ℃ of stirrings promptly get the vesicle suspension after removing and desolvating;
Get carbomer 934P 60g, propylene glycol 600g, ethyl hydroxybenzoate 10g, diethylamine 42g adds purified water 7000ml, makes blank gel-type vehicle, blank gel-type vehicle and vesicle suspension mixing, promptly gets the vesicle gel.
Embodiment 20
Get cantharidin 1g, Tween 80 15g, cholesterol 15g is dissolved in ethanol, at the uniform velocity injects the purified water that is dissolved with poloxamer 1g, and 60 ℃ of stirrings promptly get the vesicle suspension after removing and desolvating;
Get carbomer 94135g, HPMC (K-6000) 40g, glycerol 300g, hydroxypropyl methylcellulose 10g, sodium carbonate 18g adds purified water 6500ml, makes blank gel-type vehicle, blank gel-type vehicle and vesicle suspension mixing, promptly gets the vesicle gel.
Embodiment 21
Get cantharidin 5g, poloxamer 30g, two spermaceti phosphoric acid fat 15g are dissolved in ethanol, at the uniform velocity inject purified water, and 60 ℃ of stirrings promptly get the vesicle suspension after removing and desolvating;
Get carbomer 94140g, HPMC (K-4000) 20g, xanthan gum 15g, glycerol 300g, triethylamine 18g adds purified water 7000ml, makes blank gel-type vehicle, blank gel-type vehicle and vesicle suspension mixing, promptly gets the vesicle gel.
Embodiment 22
Get the vesicle suspension, be prepared into various oral solid formulations by conventional method.
Embodiment 23
Get the vesicle suspension, be prepared into ointment, patch, spray by conventional method.
Embodiment 24
Get span 40 100g, cholesterol 100g, sodium lauryl sulphate 20g; Ultrasonic or heating is dissolved in ethanol, under 30 ℃ of constant temperature stir, at the uniform velocity injects the 0.1mol/L aqueous citric acid solution that is dissolved with cantharidin 1g; Add continued and stir, wave to the greatest extent, add an amount of sodium carbonate and regulate pH to 7 to organic solvent; Continue to stir 1h, filter, promptly get.
Get carbomer 94125g, HPMC (K-4000) 30g, glycerol 280g adds purified water 6000ml, fully mixes swelling, adds sodium bicarbonate adjusting pH of latex gel to 7.0 and makes blank gel-type vehicle, blank gel-type vehicle and vesicle suspension mixing, promptly gets the vesicle gel.
Embodiment 25
Get polyoxyethylene (40) fatty acid ester 100g, cholesterol 98g, the ultrasonic or heating of sodium stearate 18g is dissolved in isopropyl alcohol; Under 50 ℃ of constant temperature stir, at the uniform velocity inject the 0.15mol/L aqueous citric acid solution that is dissolved with cantharidin 8g, add continued and stir; Wave to the greatest extent to organic solvent, add an amount of sodium carbonate and regulate pH to 7, continue to stir 1h; Filter, promptly get.
Get carbomer 980120g, glycerol 450g, propylene glycol 100g; Propyl hydroxybenzoate 3g adds purified water 7000ml, fully mixes swelling; Add triethanolamine adjusting pH of latex gel to 7.0 and make blank gel-type vehicle,, promptly get the vesicle gel blank gel-type vehicle and vesicle suspension mixing.
Embodiment 26
Get polyoxyethylene (50) fatty acid ester 100g, cholesterol 100g, sodium stearate 18g; Ultrasonic or heating is dissolved in acetone, under 45 ℃ of constant temperature stir, at the uniform velocity injects the 0.3mol/L aqueous citric acid solution that is dissolved with cantharidin 5g; Add continued and stir, wave to the greatest extent, add an amount of sodium carbonate and regulate pH to 7 to organic solvent; Continue to stir 1h, filter, promptly get.
Get carbomer 93430g, glycerol 360g, propylene glycol 100g, azone 10g; Ethyl hydroxybenzoate 1g adds purified water 6000ml, fully mixes swelling; Add sodium carbonate adjusting pH of latex gel to 7.0 and make blank gel-type vehicle,, promptly get the vesicle gel blank gel-type vehicle and vesicle suspension mixing.
Embodiment 27
Get sorbester p18 100g, cholesterol 100g, the ultrasonic or heating of sodium lauryl sulphate 20g is dissolved in ether; Under 40 ℃ of constant temperature stir, get above-mentioned solution and at the uniform velocity inject the solution that pH is 6.5 ammonium sulfate, add continued and stir; Wave to the greatest extent to organic solvent,, add in the water of dissolving cantharidin 3g through dialysing or crossing post and remove vesicle sulfate radical wherein; Continue to stir 0.5h, filter, promptly get.
Get carbomer 981100g, glycerol 400g, isopropyl myristate 12g; Sorbic acid 1g adds purified water 6000ml, fully mixes swelling; Add triethanolamine adjusting pH of latex gel to 7.0 and make blank gel-type vehicle,, promptly get the vesicle gel blank gel-type vehicle and vesicle suspension mixing.
Embodiment 28
Get polyoxyethylene (40) fatty acid ester 100g, cholesterol 150g, sodium stearate 25g; Ultrasonic or heating is dissolved in ethyl acetate, under 55 ℃ of constant temperature stir, at the uniform velocity injects the 0.2mol/L aqueous citric acid solution that is dissolved with cantharidin 4g; Add continued and stir, wave to the greatest extent, add proper amount of sodium hydroxide and regulate pH to 7 to organic solvent; Continue to stir 1h, filter, promptly get.
Get carbomer 981180g, glycerol 200g, azone 10g; Ethyl hydroxybenzoate 12g adds purified water 6000ml, fully mixes swelling; Add sodium hydroxide adjusting pH of latex gel to 7.0 and make blank gel-type vehicle,, promptly get the vesicle gel blank gel-type vehicle and vesicle suspension mixing.
Embodiment 29
Get Brij721100g, cholesterol 120g, the ultrasonic or heating of sodium lauryl sulphate 20g is dissolved in dichloromethane; Under 48 ℃ of constant temperature stir, get above-mentioned solution and at the uniform velocity inject the solution that pH is 6.5 ammonium sulfate, add continued and stir; Wave to the greatest extent to organic solvent,, add in the water of dissolving cantharidin 6g through dialysing or crossing post and remove vesicle sulfate radical wherein; Continue to stir 0.5h, filter, promptly get.
Get carbomer 941150g, glycerol 250g, oleic acid polyethyleneglycol glyceride 20g, propylene glycol 8g; Phenol 5g adds purified water 6000ml, fully mixes swelling; Add sodium hydroxide and regulate pH of latex gel to 7.0 white gel of having leisure,, promptly get the vesicle gel blank gel-type vehicle and vesicle suspension mixing.
Embodiment 30
Get polyoxyethylene (8) fatty acid ester 100g, cholesterol 115g, sodium stearate 20g; Ultrasonic or heating is dissolved in chloroform, under 50 ℃ of constant temperature stir, at the uniform velocity injects the 0.2mol/L aqueous citric acid solution that is dissolved with cantharidin 4g; Add continued and stir, wave to the greatest extent, add an amount of sodium carbonate and regulate pH to 7 to organic solvent; Continue to stir 1h, filter, promptly get.
Get carbomer 980120g, glycerol 360g, Semen Myristicae isopropyl acid esters 50g; Methyl hydroxybenzoate 3g adds purified water 6000ml, fully mixes swelling; Add sodium carbonate adjusting pH of latex gel to 7.0 and make blank gel-type vehicle,, promptly get the vesicle gel blank gel-type vehicle and vesicle suspension mixing.
Embodiment 31
Get Brij72150g, cholesterol 125g, the ultrasonic or heating of sodium lauryl sulphate 25g is dissolved in methanol; Under 35 ℃ of constant temperature stir, get above-mentioned solution and at the uniform velocity inject the solution that pH is 6.5 ammonium carbonate, add continued and stir; Wave to the greatest extent to organic solvent,, add in the water of dissolving cantharidin 10g through dialysing or crossing post and remove vesicle carbonate wherein; Continue to stir 0.5h, filter, promptly get.
Get carbomer 941350g, glycerol 350g, azone 30g, polyglyceryl fatty acid ester 20g; Ethyl hydroxybenzoate 2g adds purified water 7000ml, fully mixes swelling; Add sodium hydroxide and regulate pH of latex gel to 7.0 white gel of having leisure,, promptly get the vesicle gel blank gel-type vehicle and vesicle suspension mixing.
Embodiment 32
Get span 20 200g, cholesterol 100g, the ultrasonic or heating of sodium lauryl sulphate 20g is dissolved in ethanol; Under 60 ℃ of constant temperature stir, get above-mentioned solution and at the uniform velocity inject the solution that pH is 6.5 ammonium acetates, add continued and stir; Wave to the greatest extent to organic solvent,, add in the water of dissolving cantharidin 7g through dialysing or crossing post and remove vesicle acetate wherein; Continue to stir 0.5h, filter, promptly get.
Get carbomer 981130g, glycerol 400g, lauric acid polyethyleneglycol glyceride 12g; Ethyl hydroxybenzoate 1g adds purified water 7000ml, fully mixes swelling; Add triethanolamine adjusting pH of latex gel to 7.0 and make blank gel-type vehicle,, promptly get the vesicle gel blank gel-type vehicle and vesicle suspension mixing.
Embodiment 33
Get sorbester p17 110g, cholesterol 95g, the ultrasonic or heating of sodium lauryl sulphate 20g is dissolved in ethanol; Under 65 ℃ of constant temperature stir, get above-mentioned solution and at the uniform velocity inject the solution that pH is 6.5 Ammonium biphosphates, add continued and stir; Wave to the greatest extent to organic solvent,, add in the water of dissolving cantharidin 5g through dialysing or crossing post and remove vesicle dihydrogen phosphate wherein; Continue to stir 0.5h, filter, promptly get.
Get carbomer 980200g, glycerol 200g, oleic acid polyethyleneglycol glyceride 10g; Potassium sorbate 3g adds purified water 6000ml, fully mixes swelling; Add triethanolamine adjusting pH of latex gel to 7.0 and make blank gel-type vehicle,, promptly get the vesicle gel blank gel-type vehicle and vesicle suspension mixing.
Claims (43)
1. cantharidin vesicle is characterized in that being processed by the following weight proportion raw material:
Cantharidin 0.01-10 part
Non-ionic surface active agent 2.5-650 part
Additives 0.25-650 part.
2. according to the vesicle of claim 1, it is characterized in that processing by the following weight proportion raw material:
Cantharidin 0.05-8 part
Non-ionic surface active agent 5-350 part
Additives 0.25-350 part.
3. according to the vesicle of claim 1, it is characterized in that processing by the following weight proportion raw material:
Cantharidin 0.08-7 part
Non-ionic surface active agent 20-250 part
Additives 0.3-300 part.
4. according to vesicle any among the claim 1-3; It is characterized in that described non-ionic surface active agent is one or more arbitrary proportion mixture in span, tween, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether, polyglycerol alkyl ether, crown ether, glucose alkyl ether, polyoxyethylene alkyl ether, poloxamer, sucrose ester, fatty glyceride, glyceryl monostearate, polyethylene glycol fatty acid glyceride, the stearic glyceride of Polyethylene Glycol-4-, Polyethylene Glycol glyceryl laurate ester, the sad certain herbaceous plants with big flowers acid glyceride of Polyethylene Glycol, the poloxalkol.
5. according to the vesicle of claim 4, it is characterized in that described non-ionic surface active agent is the Tweens non-ionic surface active agent.
6. according to the vesicle of claim 5, it is characterized in that described non-ionic surface active agent is a polysorbas20, polysorbate40, polysorbate60, Tween 80, polysorbate85.
7. according to the vesicle of claim 4, it is characterized in that described non-ionic surface active agent is a polyoxyethylene fatty acid ester class non-ionic surface active agent.
8. according to the vesicle of claim 7, it is characterized in that described non-ionic surface active agent is polyoxyethylene (40) fatty acid ester, polyoxyethylene (8) fatty acid ester, polyoxyethylene (50) fatty acid ester.
9. according to the vesicle of claim 4, it is characterized in that described non-ionic surface active agent is a polyoxyethylene aliphatic alcohol ether class non-ionic surface active agent.
10. according to the vesicle of claim 9, it is characterized in that described non-ionic surface active agent is Brij30, Brij35, Brij72, Brij721, cetomacrogol (Cetomacrogol), peregal 0 (Perogol 0), Ai Moerfu (Emlphor).
11. the vesicle according to claim 4 is characterized in that, described non-ionic surface active agent is the sucrose ester non-ionic surface active agent.
12. the vesicle according to claim 11 is characterized in that, described non-ionic surface active agent is sucrose stearate S-3, sucrose stearate S-7, sucrose stearate S-11, sucrose stearate S-15.
13. the vesicle according to claim 4 is characterized in that, described non-ionic surface active agent is the spans non-ionic surface active agent.
14. the vesicle according to claim 13 is characterized in that, described non-ionic surface active agent is span 20, span 40, sorbester p18, sorbester p38, sorbester p17, sorbester p37.
15. the vesicle according to claim 14 is characterized in that, described non-ionic surface active agent is span 20, span 40, sorbester p18, sorbester p17.
16. according to vesicle any among the claim 1-3; It is characterized in that described additives are cholesterol, cholesterol polyethylene glycol polymer, stearmide (SA), two Cetyl Phosphates (DCP), 18-amine., sodium lauryl sulphate (SDS), Polyethylene Glycol (PEG), poloxamer 188 (F68), hydroxypropyl doubly its cyclodextrin, polyethylene glycol-lactic acid, Polyethylene Glycol-DSPE, N-palmityl-L-homocysteine, phosphatidylcholine, sodium palmitate, sodium stearate, Sodium myristate, sodium laurate, dodecylbenzene sodium sulfonate, sodium lauroylmethyl taurate, dodecyldimethylammonium hydroxide inner salt, one or more arbitrary proportion mixture of dodecanamide propyl betanin.
17. the vesicle according to claim 16 is characterized in that, described additives are cholesterol.
18. the method for preparing of the vesicle of claim 1 is characterized in that, gets non-ionic surface active agent, additives, cantharidin and is dissolved in an amount of organic solvent, heating or ultrasonic dissolution, solution for standby; Stir down at 15-80 ℃ of constant temperature, get above-mentioned solution and at the uniform velocity inject phosphate buffer, add continued and stir, wave to the greatest extent, add phosphate buffer to full dose to organic solvent, ultrasonic or cross high pressure dispersing emulsification machine 1-3 time, filtration, fill or lyophilization promptly get.
19. the method for preparing of the vesicle of claim 1 is characterized in that, gets non-ionic surface active agent, additives, cantharidin and is dissolved in an amount of organic solvent; Reduction vaporization is to dry film, and vacuum drying removes remaining solvent, adds phosphate buffer then; 25-90 ℃ of constant temperature hydration, hydration time 10-60 minute, supersound process after the hydration; Fill or lyophilization promptly get.
20. the method for preparing of the vesicle of claim 1 is characterized in that, non-ionic surface active agent is added a spot of phosphate buffer dissolving; Add in the fused additives, stir, add cantharidin solution; Pour 25-85 ℃ phosphate buffer behind the mixing into; Water-bath was placed 5-30 minute, and fill or lyophilization promptly get.
21. the method for preparing of the vesicle of claim 1 is characterized in that, non-ionic surface active agent, additives are added an amount of organic solvent dissolution, solution adds the phosphate buffer below the 1/2 organic solvent amount; Ultrasonic 2-20 minute, 25-65 ℃ rotated to colloidal state, adds cantharidin solution again, and 40-80 ℃ rotates to dried; Add phosphate buffer, rotated 10-30 minute, placed 1-12 hour; Fully hydration, fill or lyophilization promptly get.
22. the method for preparing according to the vesicle of claim 1 is characterized in that, gets non-ionic surface active agent, additives are dissolved in an amount of organic solvent, heating or ultrasonic dissolution, solution for standby; Under 15-80 ℃ of constant temperature stirs, get above-mentioned solution and at the uniform velocity add the phosphate buffer that is added with cantharidin, add continued and stir, wave to the greatest extent to organic solvent, add an amount of alkali and regulate pH to 7, continue to stir 1h, fill or lyophilization promptly get.
Wherein said alkali is meant one or more in sodium hydroxide, ammonia, triethanolamine, triethylamine, sodium carbonate, the sodium bicarbonate.
23. the method for preparing according to the vesicle of claim 1 is characterized in that, gets non-ionic surface active agent, additives are dissolved in an amount of organic solvent, heating or ultrasonic dissolution, solution for standby; Under 15-80 ℃ of constant temperature stirs, get above-mentioned solution and at the uniform velocity inject the solution that is added with ammonium salt, add continued and stir; Wave to the greatest extent to organic solvent,, add an amount of cantharidin solution through dialysing or crossing post and remove vesicle acid ion wherein; Continue to stir 0.5h; Filter, fill or lyophilization promptly get.
Wherein said ammonium salt is meant one or more in ammonium sulfate, ammonium carbonate, ammonium chloride, ammonium acetate, the Ammonium biphosphate.
24. method for preparing according to any described vesicle of claim 18-23; It is characterized in that; Additives are according to its deliquescent difference; Dissolve in the organic solvent, also a kind of in the amino buffer of water soluble, phosphate buffer, ammonium sulfate buffer, trihydroxy methyl, citrate buffer solution, the tartaric acid buffer; Cantharidin dissolves in organic solvent, or a kind of cantharidin solution of processing in water-soluble, the phosphate buffer, ammonium sulfate buffer, the amino buffer of trihydroxy methyl, citrate buffer solution, tartaric acid buffer.
25. method for preparing according to any described vesicle of claim 18-23; It is characterized in that organic solvent is meant the mixture of one or more arbitrary proportions of dehydrated alcohol, methanol, acetone, dichloromethane, chloroform, ether, isoamyl alcohol, ethyl acetate; Phosphate buffer also can be ammonium sulfate buffer, the amino buffer of trihydroxy methyl, citrate buffer solution, tartaric acid buffer, water.
26. contain the preparation of the cantharidin vesicle of claim 1, it is characterized in that, be peroral dosage form or external preparation.
27. the preparation according to the cantharidin vesicle of claim 26 is characterized in that, is external preparation.
28. the preparation according to the cantharidin vesicle of claim 27 is characterized in that said external preparation is gel, ointment, patch, spray.
29. the preparation according to the cantharidin vesicle of claim 28 is characterized in that, is gel.
30. the preparation according to the cantharidin vesicle of claim 29 is characterized in that said gel is made up of following components by part by weight:
Cantharidin 0.01-10, non-ionic surface active agent 2.5-650, additives 0-650, thickening agent 0.1-125, wetting agent 1-1200, pH regulator agent 0-60, transdermal agent 0-70, antiseptic 0-300.
31. the preparation according to the cantharidin vesicle of claim 30 is characterized in that said gel is made up of following components by part by weight:
Cantharidin 0.05-8, non-ionic surface active agent 5-350, additives 0.25-350, thickening agent 0.1-100, wetting agent 1-1000, pH regulator agent 0-50, transdermal agent 0-50, antiseptic 0.5-250.
32. the preparation of the cantharidin vesicle of claim 29 or 30 is characterized in that, said thickening agent is cross-linked polypropylene resin class, cross-linked polypropylene resin variety classes salt and derivant or hydroxypropyl methylcellulose, one or more mixture of xanthan gum.
33. the preparation according to the cantharidin vesicle of claim 32 is characterized in that said cross-linked polypropylene resin class thickening agent comprises Carbopol 941,974, and 934P, 980,981.
34. the preparation according to the cantharidin vesicle of claim 29 or 30 is characterized in that said wetting agent is one or more mixture in glycerol, propylene glycol, isopropyl alcohol, the hyaluronic acid.
35. the preparation according to the cantharidin vesicle of claim 30 or 31 is characterized in that said pH regulator agent is an organic amine, or sodium hydroxide, sodium bicarbonate, sodium carbonate.
36. the preparation according to the cantharidin vesicle of claim 35 is characterized in that said organic amine is triethanolamine, triethylamine, diethylamine, lauryl amine.
37. preparation according to the cantharidin vesicle of claim 30 or 31; It is characterized in that said transdermal agent is azone, menthol, quintessence oil, dimethyl sulfoxide, propylene glycol, Semen Myristicae isopropyl acid esters, N-Methyl pyrrolidone, lauric acid polyethyleneglycol glyceride, polyglyceryl fatty acid ester, oleic acid polyethyleneglycol glyceride, sad capric acid polyethyleneglycol glyceride.
38. the preparation according to the cantharidin vesicle of claim 30 or 31 is characterized in that said antiseptic can be one or more mixture in potassium sorbate, sorbic acid, ethyl hydroxybenzoate, propyl hydroxybenzoate, methyl hydroxybenzoate, the phenol.
39. the preparation of claim 30 or 31 cantharidin vesicles is characterized in that, the method for preparing of said cantharidin vesicle gel is:
Get thickening agent, wetting agent, transdermal agent, antiseptic, add entry, the pH regulator agent is processed gel-type vehicle and prepared cantharidin vesicle suspension and is mixed, and stirs, and promptly gets cantharidin vesicle gel.
40. among the claim 18-23 in the freeze drying process; Can add an amount of mannitol, dextran, lactose makes lyophilizing solution weight ratio between 4%-25%; Cooling rate should be at per hour 5 ℃-6 ℃ in the freeze-drying process; In the first phase sublimation drying stage, products temperature should be lower than eutectic point, and programming rate is per hour about 5 ℃.
41., it is characterized in that cantharidin can also be disodium cantharidinate, N-hydroxycantharidin, N-methylcantharidimide, nor-Mylabris, acrylic cantharidimide according to claim 1 or 2 or 3 or 30 or 31 described preparations.
42., it is characterized in that described preparation is used for preparing the particularly application of liver-cancer medicine of treatment cancer according to claim 1 or 2 or 3 or 30 or 31 described preparations.
43. according to claim 1 or 2 or 3 or 30 or 31 described preparations, it is characterized in that described preparation has trichogenous effect, can be used for treating alopecia.
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| CN103169141A (en) * | 2013-03-18 | 2013-06-26 | 北京林业大学 | Preparation method of encapsulating carotenoid by niosomes |
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| CN104274494A (en) * | 2013-07-05 | 2015-01-14 | 陈光健 | America periplaneta external preparation and preparation method thereof |
| CN105311638A (en) * | 2014-06-13 | 2016-02-10 | 上海中医药大学 | Drug-carrying precursor vesicle, preparation method and application thereof |
| CN105311638B (en) * | 2014-06-13 | 2019-01-01 | 上海中医药大学 | A kind of medicine carrying precursor vesica and its preparation method and application |
| CN105748437A (en) * | 2014-12-17 | 2016-07-13 | 北京盈科瑞药物研究院有限公司 | Vesicle and vesicle preparation, and preparation methods thereof |
| CN107320716A (en) * | 2017-06-27 | 2017-11-07 | 珠海亿胜生物制药有限公司 | Basic fibroblast growth factor vesica and preparation method thereof |
| CN107320716B (en) * | 2017-06-27 | 2019-03-05 | 珠海亿胜生物制药有限公司 | Basic fibroblast growth factor vesica and preparation method thereof |
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Application publication date: 20120718 |