CN101658545A - Preparation method of tripterygium glycosides solid lipid nanoparticle - Google Patents

Preparation method of tripterygium glycosides solid lipid nanoparticle Download PDF

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CN101658545A
CN101658545A CN200910034968A CN200910034968A CN101658545A CN 101658545 A CN101658545 A CN 101658545A CN 200910034968 A CN200910034968 A CN 200910034968A CN 200910034968 A CN200910034968 A CN 200910034968A CN 101658545 A CN101658545 A CN 101658545A
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tripterygium glycosides
solid lipid
nanoparticle
preparation
tripterygium
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张陆勇
薛梅
江振洲
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

The invention relates to a preparation method of tripterygium glycosides solid lipid nanoparticle. The preparation method comprises the following steps: dissolving 1 portion of tripterygium glycosidesinto 5 to 15 portions of mixed lipid solution (wherein the ratio of lipin to lipid carrier is 1 to 5) to be used as oil phase; slowing adding the oil phase into a water phase containing 0.5 to 1.5 portions of surface active agent in equal temperature; keeping temperature and stirring; carrying out probe ultrasonography; naturally cooling to obtain primary dispersoid; and freezing and drying to obtain the tripterygium glycosides solid lipid nanoparticle. The nanoparticle is faint yellow, has stable quality with the partical size of 10-200 nm, and can be applied to various routes of administration, such as oral administration and intravenous injection. The preparation method is reliable, has simple and convenient operation and low energy consumption and is suitable for industrial production. Compared with tripterygium glycosides material, the prepared tripterygium glycosides solid lipid nanoparticle has higher dissolvability so as to improve the absorption, improve the bioavailability,enhance the drug action and reduce the toxicity.

Description

The preparation method of tripterygium glycosides solid lipid nanoparticle
Technical field
The present invention relates to field of traditional Chinese, specifically is the method for the effective site tripterygium glycosides of Chinese medicine Radix Tripterygii Wilfordii being made solid lipid nanoparticle.
Background technology
Radix Tripterygii Wilfordii is the Celastraceae tripterygium plant, have various active such as antiinflammatory, antitumor, immunosuppressant, the clinical treatment rheumatoid arthritis that is widely used in, chronic nephritis, lupus erythematosus and various dermatosis, but its oral absorption is bad, and gastrointestinal irritation is big, and untoward reaction is more, limited it and used, modified form is the effective ways of its efficacy enhancing and toxicity reducing.Wherein, tripterygium glycosides most widely used thinks that also tripterygium glycosides is main pharmacological component, mainly comprises one group of effective ingredient such as diterpenoid-lactone, alkaloid, triterpene, has the pharmacologically active of antiinflammatory, antitumor, immunosuppressant, anti HIV-1 virus.That nanometer Chinese medicine is meant is that the utilization nanotechnology is made, particle diameter is less than effective ingredient, effective site, former medicine and the compound preparation thereof of 200nm.Nanometer Chinese medicine has changed the physical state of medicine, and the activity and the bioavailability of medicine are greatly improved, and may produce new drug effect.The nanorize dosage form of the existing report of Radix Tripterygii Wilfordii has: CN01133514.9A nanometer Chinese medicine Radix Tripterygii Wilfordii Tripterygium hypoglaucum dosage form and preparation method thereof, CN02133332.7A discloses a kind of preparation method of thunder godvine nano particle, and CN200610104979.2A discloses a kind of Tripterygium glycosides nanoemulsion medicine and preparation method thereof.The above two mainly are at Radix Tripterygii Wilfordii alcohol extract and Radix Tripterygii Wilfordii extractum, rather than effective site, specific aim is not strong and method is simple, latter's administering mode only is confined to external, be restricted in the application, the invention discloses a kind of preparation technology of tripterygium glycosides solid lipid nanoparticle, by literature search, being made into this dosage form of solid lipid nanoparticle still belongs to the first time, (Solid lipid nanoparticles SLN) is a kind of novel administration nano-drug administration system of introducing the beginning of the nineties in last century to solid lipid nanoparticle.SLN has following advantage (Muhlen, 1998): 1. particle size is little, and mean diameter can be used for drug administration by injection at nanoscale; 2. good biocompatibility can not introduced poisonous residues such as poisonous polymer monomer in preparation process; 3. lipophilic drugs there are enough medicine carrying abilities, by the technology adjustment, all right encapsulating hydrophilic medicine; 4. have slow release characteristic, but prolong drug release reaches a couple of days to several weeks; 5. its aqueous dispersion can steady in a long-termly be preserved, and also can be made into pressed powder, good stability by lyophilization or spray drying; 6. modify by its surface being carried out feature, can have targeting with drug delivery to particular organization; 7. the large-scale industrial production of the supply the market mode that is enough to is arranged; 8. price is comparatively cheap.At present, be applied to the clinical tripterygium glycosides sheet that mainly contains, Triptolide ointment, Radix Tripterygii Wilfordii tablet etc., tripterygium glycosides are the effective site of Radix Tripterygii Wilfordii, clinical medicine is many as raw material, can improve its absorption after being made into this new dosage form of solid lipid nanoparticle, improve bioavailability, strengthen drug effect, reduce toxicity, and applicable to multiple route of administration.
Summary of the invention
The present invention is the preparation method of research tripterygium glycosides solid lipid nanoparticle, and purpose is to overcome the deficiency of existing dosage form, proposes a kind of new tripterygium glycosides solid lipid nanoparticle medicine, and method is simple, and production cost is low.Tripterygium glycosides solid lipid nanoparticle is characterized in that containing following component and ratio of weight and number:
Tripterygium glycosides 1
Mix lipid 5~15
Wherein mixing lipid is made up of by 1: 1~1: 5 weight ratio lipoid and lipid carrier
Surfactant 0.5~1.5
Tripterygium glycosides solid lipid nanoparticle of the present invention, can prepare by high temperature emulsifying-low-temperature setting, thin film-ultrasonic dispersion, the even method of high pressure breast, determine existing preparation method through testing repeatedly, because its stability, repeatability are all better, investigated different matrix materials, different medicine fat different proportion simultaneously than, lipid carrier and lipoid, with the influence of different surfactant, below be some datas to its quality:
The different matrix material of table 1 is to the influence of TWP-SLN quality
Figure G2009100349685D00021
The substrate of described nanoparticle is the matrix material of the biodegradable natural or synthetic lipoid of physiological compatibility, be lipid carrier and lipoid, lipid carrier can be phospholipid, glyceryl monostearate, glyceryl tristearate, myristin, caprylic/capric triglyceride or two or more mixture arbitrarily wherein.The preferred glyceryl monostearate in experiment back, glyceryl tristearate, myristin.Discover simultaneously, add a small amount of liquid lipid caprylic/capric glyceride, can improve nanoparticle stability, can delay solid-state lipid by the conversion of alpha crystalline form, can delay the leakage of medicine to beta-crystalline form because introduce liquid lipid.Adding emulsifying agent in the described nanoparticle, can play the effect of stable particle, mainly is phospholipid, can be lecithin, comprises soybean lecithin, Ovum Gallus domesticus Flavus lecithin; Or hydrogenated soy phosphatidyl choline, hydrogenated yolk lecithin, two Semen Myristicae phosphatidylcholine or distearyl phosphatidyl choline.Experiment back preferably soya lecithin and lecithin.The present invention adopts surfactant modified or is adsorbed in the lipid nanoparticle surface, so that lipid nanoparticle reaches the purpose of slow release.
The influence of the medicine fat comparison TWP-SLN quality that table 2 is different
Lipid carrier that table 3 is different and lipoid ratio are to the influence of TWP-SLN quality
Figure G2009100349685D00032
The effects the ratio of different lipids and lipid carrier and lipoid, determine that matrix material adopts solid and liquid mixing lipid, promptly adds micro-liquid lipid, and tripterygium glycosides: the ratio of matrix material is 1: 5~15, is lower than at 1: 5 o'clock, and the medicine parcel not exclusively, cause muddiness, be higher than at 1: 15 o'clock, particle size growth, lipid is easily separated out, lamination appears, the big more envelop rate of the consumption of lipid is good more, take all factors into consideration, medicine fat ratio be 1: 10 o'clock the most suitable.The ratio of lipoid and lipid carrier is 1~5 o'clock, and particle diameter, envelop rate are all better.
In addition described surfactant is screened, comprise poloxamer (Poloxamer, Pluronic), polyoxyethylene fatty acid ester (Myrij, Myrj), polyoxyethylene aliphatic alcohol ether (Bian Ze, Brij), Polysorbate (Polysorbate, tween, Tweens), fatty acid Pyrusussuriensis smooth (span, Spans), dehydrocholate, gum arabic powder.Preferred poloxamer, tween and dehydrocholate.
The preparation method of tripterygium glycosides solid lipid nanoparticle, it is characterized in that tripterygium glycosides is dissolved in the mixing lipid soln as oil phase, under stirring condition, oil phase is slowly joined the aqueous phase that equal temperature contains surfactant 0.5~1.5, insulated and stirred, ultrasonic, promptly get dispersion just behind the natural cooling, through lyophilization, get final product tripterygium glycosides solid lipid nanoparticle.Tripterygium glycosides solid lipid nanoparticle, it is characterized in that it stirs after, use the ultrasonic measure of probe, reduce the nanoparticle particle diameter.The tripterygium glycosides solid lipid nanoparticle that the present invention makes just dispersion outward appearance is transparent weak yellow liquid, particle diameter is between 10~200nm, potential value has reflected the mutual repulsive force between the particle,-20~-50mv better (seeing accompanying drawing 3,4 for details), redissolve after the lyophilization, particle diameter, several no changes of current potential, but long preservation after the lyophilizing.The blank nanoparticle of electron microscopic observation and the medicine carrying sodium grain of rice are rounded, form consolidation (seeing accompanying drawing 1,2 for details), envelop rate 67%, drug loading 0.2% is checked blank SLN sample and TWP-SLN sample peak basically identical through the X diffraction, illustrate that the nanoparticle crystal form does not change, more stable, the sample peak value is all greater than contrast, and the medicine into lipid (seeing accompanying drawing 5-7 for details) that has been wrapped is described.
The present invention wraps up medicine with above-mentioned material, makes solid lipid nanoparticle, can improve drug solubility and improve absorption, improves bioavailability, has certain slow releasing function, strengthens drug effect, reduces toxicity, is applicable to multiple route of administration.
Description of drawings:
Fig. 1 is blank solid lipid nanoparticle transmission electron microscope photo
Fig. 2 is the tripterygium glycosides solid lipid nanoparticle transmission electron microscope photo
Fig. 3 is tripterygium glycosides solid lipid nanoparticle potential measurement result
Fig. 4 is tripterygium glycosides solid lipid nanoparticle particle size determination result
Fig. 5 is a tripterygium glycosides raw material X diffraction pattern
Fig. 6 is blank SLN sample X diffraction pattern
Fig. 7 is a TWP-SLN sample X diffraction pattern
The specific embodiment:
Tripterygium glycosides can extract from the Chinese medicine Radix Tripterygii Wilfordii with literature method, also can buy.TWP-SLN is further specified technical scheme of the present invention by the following example, but protection scope of the present invention is not limited to this.
Particle diameter, potential measurement:
Adopt Zetasizer3000HS particle size determination instrument to measure.
The preparation of embodiment 1 tripterygium glycosides solid lipid nanoparticle (1 recipe quantity)
Tripterygium glycosides 60mg
Glyceryl monostearate 360mg
Soybean phospholipid 360mg
Poloxamer 60mg
Preparation technology:
Get tripterygium glycosides, glyceryl monostearate adding acetone 8ml, in 80 ℃ of heating for dissolving; Soybean phospholipid adds ethanol 1ml, ultrasonic 10min dissolving; With above-mentioned two kinds of solution mixings as organic facies; Other gets poloxamer and is dissolved in the 20ml water as water, under the stirring condition organic facies is injected 80 ℃ of aqueous phases, insulated and stirred 4h with syringe needle, wave most organic solvent, this suspension is dispersed in 0~2 ℃ of 30ml water fast low-temperature setting 2h, 0.45um filtering with microporous membrane, promptly.Gained nanoparticle mean diameter is: 204.5nm, current potential :-6.8mv
The preparation of embodiment 2 tripterygium glycosides solid lipid nanoparticles (1 recipe quantity)
Tripterygium glycosides 60mg
Stearic acid 300mg
Soybean phospholipid 300mg
Poloxamer 60mg
Preparation technology:
Tripterygium glycosides, stearic acid, soybean phospholipid are dissolved in the dehydrated alcohol; The decompression rotary evaporation is removed organic solvent, forms one deck lipid membrane, and drying under reduced pressure spends the night, and then the poloxamer aqueous solution, slowly injects above-mentioned lipid membrane, ultrasonic 1h, and the 0.45um filtering with microporous membrane, promptly.Gained nanoparticle mean diameter is: 73.8nm current potential :-14.7mv
The preparation of embodiment 3 tripterygium glycosides solid lipid nanoparticles (1 recipe quantity)
Tripterygium glycosides 60mg
Glyceryl monostearate 300mg
Caprylin 200ul
Soybean phospholipid 60mg
Poloxamer 60mg
Preparation technology:
Tripterygium glycosides is joined in 80 ℃ of glyceryl monostearates, soybean phospholipid, the caprylin mixing lipid liquid; Again hot fat is distributed to mutually and obtains dispersion just in the poloxamer aqueous solution, 5~6 circulations of high pressure homogenization, 0~4 ℃ of crystallisation by cooling, promptly.Gained nanoparticle mean diameter is: 182.7nm current potential :-27.6mv
The preparation of embodiment 4 tripterygium glycosides solid lipid nanoparticles (1 recipe quantity)
Tripterygium glycosides 60mg
Glyceryl monostearate 300mg
Soybean phospholipid 60mg
Sodium dehydrocholate 20mg
Preparation technology:
Tripterygium glycosides, glyceryl monostearate are added acetone 8ml, in 80 ℃ of heating for dissolving; Soybean phospholipid adds ethanol 1ml, ultrasonic 10min dissolving; With above-mentioned two kinds of solution mixings as organic facies; Other removes the hydrogen sodium cholate and is dissolved in the 20ml water as water, under the stirring condition organic facies is injected 80 ℃ of aqueous phases, insulated and stirred 4h with syringe needle, wave most organic solvent, this suspension is dispersed in 0~2 ℃ of 30ml water fast low-temperature setting 2h, 0.45um filtering with microporous membrane, promptly.Gained nanoparticle mean diameter is: 198.9nm current potential :-19.4mv
The preparation of embodiment 5 tripterygium glycosides solid lipid nanoparticles (1 recipe quantity)
Tripterygium glycosides 60mg
Glyceryl tristearate 360mg
Tween 80 200ul
Poloxamer 30mg
Preparation technology:
Tripterygium glycosides is joined in 80 ℃ of glyceryl tristearates, the Tween 80 mixing lipid liquid; Again hot fat is distributed to mutually and obtains dispersion just in the poloxamer aqueous solution, 5~6 circulations of high pressure homogenization, 0~4 ℃ of crystallisation by cooling, promptly.Gained nanoparticle mean diameter is: 201nm current potential :-21.9mv
The preparation of embodiment 6 tripterygium glycosides solid lipid nanoparticles (1 recipe quantity)
Tripterygium glycosides 60mg
Myristin 360mg
Tween 80 200ul
Poloxamer 30mg
Preparation technology:
Tripterygium glycosides is joined in 80 ℃ of glyceryl laurate esters, the Tween 80 mixing lipid liquid; Again hot fat is distributed to mutually and obtains dispersion just in the poloxamer aqueous solution, 5~6 circulations of high pressure homogenization, 0~4 ℃ of crystallisation by cooling, promptly.Gained nanoparticle mean diameter is: 145.0nm current potential :-25.0mv
The preparation of embodiment 7 tripterygium glycosides solid lipid nanoparticles (1 recipe quantity)
Tripterygium glycosides 60mg
Glycerol stearic acid 360mg
Tween 80 200ul
Poloxamer 30mg
Preparation technology:
Tripterygium glycosides is joined in 80 ℃ of glycerol stearic acid, the Tween 80 mixing lipid liquid; Again hot fat is distributed to mutually and obtains dispersion just in the poloxamer aqueous solution, 5~6 circulations of high pressure homogenization, 0~4 ℃ of crystallisation by cooling, promptly.Gained nanoparticle mean diameter is: 127.3nm current potential :-23.4mv
The preparation of embodiment 8 tripterygium glycosides solid lipid nanoparticles (1 recipe quantity)
Tripterygium glycosides 60mg
Glyceryl monostearate 300mg
Lecithin 120mg
Caprylin 200ul
Poloxamer 30mg
Preparation technology:
Tripterygium glycosides is joined in 80 ℃ of glycerol stearic acid, the Tween 80 mixing lipid liquid; Again hot fat is distributed to mutually and obtains dispersion just in the poloxamer aqueous solution, 5~6 circulations of high pressure homogenization, 0~4 ℃ of crystallisation by cooling, promptly.Gained nanoparticle mean diameter is: 181.1nm current potential :-28.2mv
The preparation of embodiment 9 tripterygium glycosides solid lipid nanoparticles (1 recipe quantity)
Tripterygium glycosides 60mg
Glyceryl monostearate 300mg
Soybean phospholipid 300mg
Tween 80 200ul
Poloxamer 60mg
Preparation technology:
Tripterygium glycosides, glyceryl monostearate, soybean phospholipid, Tween 80 are dissolved in the dehydrated alcohol, and 80 ℃ of water-bath dissolvings are as oil phase; Poloxamer is dissolved in the 100ml water, under 80 ℃ of stirring conditions, oil phase slowly is injected into aqueous phase, insulated and stirred 1h, and 55 ℃ of vacuum rotary steam 30min, eliminating organic solvent, ultrasonic 40min, natural cooling, the 0.45um filtering with microporous membrane, promptly.Gained nanoparticle mean diameter is: 129.5nm current potential :-17.8mv
The preparation of embodiment 10 tripterygium glycosides solid lipid nanoparticles (1 recipe quantity)
Tripterygium glycosides 60mg
Glyceryl monostearate 300mg
Soybean phospholipid 300mg
Tween 80 200ul
Triethyl citrate 200ul
Poloxamer 60mg
Preparation technology:
Tripterygium glycosides, glyceryl monostearate, soybean phospholipid, Tween 80 are dissolved in the dehydrated alcohol, and 80 ℃ of water-bath dissolvings are as oil phase; Poloxamer is dissolved in the 100ml water, under 80 ℃ of stirring conditions, oil phase slowly is injected into aqueous phase, insulated and stirred 1h, and 55 ℃ of vacuum rotary steam 30min, eliminating organic solvent, ultrasonic 40min, natural cooling, the 0.45um filtering with microporous membrane, promptly.Gained nanoparticle mean diameter is: 165.8nm current potential :-23.9mv
The preparation of embodiment 11 tripterygium glycosides solid lipid nanoparticles (1 recipe quantity)
Tripterygium glycosides 60mg
Glyceryl monostearate 300mg
Soybean phospholipid 300mg
Tween 80 200ul
Caprylin 200ul
Poloxamer 60mg
Preparation technology:
Tripterygium glycosides, glyceryl monostearate, soybean phospholipid, caprylin, Tween 80 are dissolved in the dehydrated alcohol, and 80 ℃ of water-bath dissolvings are as oil phase; Poloxamer is dissolved in the 100ml water, under 80 ℃ of stirring conditions, oil phase slowly is injected into aqueous phase, insulated and stirred 1h, and 55 ℃ of vacuum rotary steam 30min, eliminating organic solvent, ultrasonic 40min, natural cooling, the 0.45um filtering with microporous membrane, promptly.Gained nanoparticle mean diameter is: 133.4nm current potential :-19.8mv
The preparation of embodiment 12 tripterygium glycosides solid lipid nanoparticles (1 recipe quantity)
Tripterygium glycosides 60mg
Glyceryl monostearate 300mg
Soybean phospholipid 300mg
Tween 80 200ul
Caprylin 200ul
Poloxamer 60mg
Preparation technology:
Tripterygium glycosides, glyceryl monostearate, soybean phospholipid, caprylin, Tween 80 are dissolved in the dehydrated alcohol, and 80 ℃ of water-bath dissolvings are as oil phase; Poloxamer is dissolved in the 100ml water, under 80 ℃ of stirring conditions, oil phase slowly is injected into aqueous phase, insulated and stirred 1h, 55 ℃ of vacuum rotary steam 30min, to eliminate organic solvent, pop one's head in ultrasonic (300W, 180 times), natural cooling, the 0.45um filtering with microporous membrane, promptly.Gained nanoparticle mean diameter is: 95.5nm current potential :-24.0mv

Claims (5)

1, a kind of tripterygium glycosides solid lipid nanoparticle is characterized in that containing following component and ratio of weight and number:
Tripterygium glycosides 1
Mix lipid 5~15
Wherein mixing lipid is made up of by 1: 1~1: 5 weight ratio lipoid and lipid carrier
Surfactant 0.5~1.5.
2, the tripterygium glycosides solid lipid nanoparticle of claim 1 is characterized in that described lipid carrier is glyceryl monostearate, glyceryl tristearate, myristin, caprylic/capric glyceride or two or more mixture arbitrarily wherein; Lipoid is soybean phospholipid and lecithin; Surfactant is poloxamer, Tween 80 or dehydrocholate.
3, the tripterygium glycosides solid lipid nanoparticle of claim 1 is characterized in that particle size distribution is at 10~200nm.
4, the preparation method of tripterygium glycosides solid lipid nanoparticle, it is characterized in that tripterygium glycosides is dissolved in the mixing lipid soln as oil phase, under stirring condition, oil phase is slowly joined the aqueous phase that equal temperature contains surfactant 0.5~1.5, insulated and stirred, ultrasonic, promptly get dispersion just behind the natural cooling, through lyophilization, get final product tripterygium glycosides solid lipid nanoparticle.
5, the preparation method of the tripterygium glycosides solid lipid nanoparticle of claim 1 after it is characterized in that stirring, is used the ultrasonic measure of probe, effectively reduces the nanoparticle particle diameter.
CN200910034968A 2009-09-16 2009-09-16 Preparation method of tripterygium glycosides solid lipid nanoparticle Pending CN101658545A (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102949375A (en) * 2012-11-28 2013-03-06 厦门大学附属第一医院 Berberine hydrochloride solid lipid nano preparation and preparation method thereof
CN103622935A (en) * 2013-11-26 2014-03-12 福建省医学科学研究院 Preparation method of triptolide nano coating agent
CN108635338A (en) * 2018-05-15 2018-10-12 复旦大学附属肿瘤医院 A kind of external application triptolide lipid nano particle and preparation method
CN113940919A (en) * 2021-10-22 2022-01-18 江苏集萃新型药物制剂技术研究所有限公司 Solid nano-particles and preparation method thereof, transdermal patch drug delivery system and preparation method thereof, and application of transdermal patch drug delivery system as medicament for treating neurological diseases
CN114711288A (en) * 2022-03-01 2022-07-08 珠海科技学院 Cinnamyl aldehyde solid lipid nanoparticle with high stability and preparation method thereof

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102949375A (en) * 2012-11-28 2013-03-06 厦门大学附属第一医院 Berberine hydrochloride solid lipid nano preparation and preparation method thereof
CN102949375B (en) * 2012-11-28 2015-04-08 厦门大学附属第一医院 Berberine hydrochloride solid lipid nano preparation and preparation method thereof
CN103622935A (en) * 2013-11-26 2014-03-12 福建省医学科学研究院 Preparation method of triptolide nano coating agent
CN103622935B (en) * 2013-11-26 2015-10-28 福建省医学科学研究院 The preparation method of Radix Tripterygii Wilfordii lactone alcohol nano-film coating agent
CN108635338A (en) * 2018-05-15 2018-10-12 复旦大学附属肿瘤医院 A kind of external application triptolide lipid nano particle and preparation method
CN108635338B (en) * 2018-05-15 2020-07-31 复旦大学附属肿瘤医院 Triptolide lipid nanoparticle for external use and preparation method thereof
CN113940919A (en) * 2021-10-22 2022-01-18 江苏集萃新型药物制剂技术研究所有限公司 Solid nano-particles and preparation method thereof, transdermal patch drug delivery system and preparation method thereof, and application of transdermal patch drug delivery system as medicament for treating neurological diseases
CN114711288A (en) * 2022-03-01 2022-07-08 珠海科技学院 Cinnamyl aldehyde solid lipid nanoparticle with high stability and preparation method thereof

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