CN100367953C - Quercetin solid liposome nano particle preparation and its preparing method - Google Patents
Quercetin solid liposome nano particle preparation and its preparing method Download PDFInfo
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- CN100367953C CN100367953C CNB2006100444169A CN200610044416A CN100367953C CN 100367953 C CN100367953 C CN 100367953C CN B2006100444169 A CNB2006100444169 A CN B2006100444169A CN 200610044416 A CN200610044416 A CN 200610044416A CN 100367953 C CN100367953 C CN 100367953C
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Abstract
The present invention relates to a nanometer granule preparation of quercetin solid liposome and a preparing method thereof, which belongs to the technical field of medicine. The present invention takes quercetin as crude medicine, and uses the mixture of solid liposome, emulsifier and coemulsifier as a medicine carrier; the quercetin, the solid liposome and the emulsifier are dissolved in a n organic solvent to form an oil phase, and the oil phase is added in a isothermic primary water phase with the coemulsifier for emulsification; the primary water phase is added in a low temperature water phase with the coemulsifier to precipitate so that the suspension of the nanometer granules of quercetin solid liposome is obtained. The preparation of the present invention is simple; a cryodesiccation protective agent is added in the suspension for cryodesiccation after the suspension is filtered via a microporous filtering film with a certain granule diameter; the nanometer granules are uniformly distributed in carrier materials, and the stability of the preparation is greatly improved; the dissolution and the absorption of the medicine are greatly promoted.
Description
(1) technical field
The present invention relates to a kind of quercetin solid liposome nano particle preparation and preparation method thereof.
(2) background technology
(Quercetin QT) is a kind of natural flavone compound to Quercetin, chemistry pentahydroxyflavone by name, different name quercetin, Quercetin.Quercetin and derivant thereof extensively are present in vegetable, fruit, dry fruit, beverage and the Chinese herbal medicine, are a kind of important biological active substanceies of food and Chinese herbal medicine.Quercetin enters in the body and can interact with protein, has the expansion coronary vasodilator, blood fat reducing, antiplatelet aggregation, multiple biological activity and pharmacological actions such as anti-cancer and cancer-preventing, free radical resisting, anti-anemia, antiinflammatory, antiallergic, Quercetin and derivant thereof are with a wide range of applications in fields such as medicine, food, cosmetics.But, because Quercetin is water-soluble hardly, fat-soluble also very poor, limited it by biomembranous absorption, make its oral administration biaavailability lower.Therefore the oral absorption of improving Quercetin at present is to enlarge the Quercetin clinical practice, makes the bottleneck of its further large-scale production.
(solid lipid nanoparticles SLN) is the Performances of Novel Nano-Porous grain of rice drug-supplying system that a kind of particle diameter of growing up the nineties in 20th century is about 10～1000nm to solid lipid nanoparticle.It is a carrier with solid-state lipids (natural or synthetic), pharmaceutical pack is wrapped in the lipoid nuclear makes solid-state micelle, because of its carrier material that uses in the preparation at room temperature is a solid, make its both had physical stability height, the drug leakage of polymer nanocomposite ball and nanocapsule few, have slow-releasing and targeting, characteristics such as can sterilize, have the advantage that liposome toxicity is low, be easy to large-scale production again concurrently.High temperature emulsifying-low-temperature setting method is about to medicine and lipid, emulsifying agent and is dissolved in and constitutes oil phase in the organic solvent, with co-emulsifier formation water soluble in water, be heated to equality of temperature, under mechanical agitation with the first aqueous phase of oil phase impouring, continue to stir with organic solvent evaporation, the gained mixture is scattered in other low temperature aqueous phase fast, stirs promptly.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of quercetin solid liposome nano particle preparation and preparation method thereof is provided.
Quercetin solid liposome nano particle preparation of the present invention, as crude drug, the mixture that adopts solid lipid, emulsifying agent and co-emulsifier composition is as pharmaceutical carrier with Quercetin, and each component is as follows:
Quercetin 20～30mg, solid lipid 100～250mg, emulsifying agent 100～200mg contains 25%～35% alcoholic solution or the distilled water 50～60ml of 1800～3000mg hydrophilic co-emulsifier.
Above-mentioned solid lipid is selected from one of following or their combination: glyceryl monostearate, glycerol distearate, glyceryl tristearate, trilaurin, tripalmitin, Rikemal B 200, behenic acid are single, double, the mixture of triglyceride, myristin, stearic acid, Palmic acid, capric acid, cholesterol, paraffin, spermol 16 esters, citric acid glyceride.
Above-mentioned emulsifying agent is selected from one of following or their combination: soybean phospholipid, egg yolk lecithin, lecithin, poloxamer 188, poloxamer 182, poloxamer 407, poloxamer 908, Tai Luoshamu, sodium cholate, sodium glycocholate, Bile Salts, deoxidation Bile Salts, sodium lauryl sulphate, sodium stearyl sulfate, dodecylbenzene sodium sulfonate, polyethylene glycols.
Above-mentioned co-emulsifier is selected from one of following or their combination: ethanol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polyoxyethylene sorbitan monoleate, polysorbate 85, isopropyl alcohol, 1,2-propylene glycol, n-butyl alcohol, n-octyl alcohol, n-heptanol, glycerol, butanoic acid, polyoxyethylene (400) monolaurate, polyoxyethylene (400) monostearate, PEG400.
The preparation method of quercetin solid liposome nano particle preparation of the present invention is as follows:
Quercetin, solid lipid and emulsifying agent be dissolved in constitute oil phase in the organic solvent, join the first aqueous phase emulsifying that contains co-emulsifier of equality of temperature, again it is joined the low temperature aqueous phase precipitation that contains co-emulsifier, promptly get the quercetin solid liposome nano particle suspension.
After above-mentioned quercetin solid liposome nano particle suspension is carried out filtering with microporous membrane, add the freeze drying protectant lyophilizing again and promptly get lyophilized formulations.
The employed organic solvent of the preparation method of quercetin solid liposome nano particle preparation is selected from one of following or their combination among the present invention: ethyl acetate, acetone, chloroform, dichloromethane, methanol.
The preparation method of quercetin solid liposome nano particle preparation more detailed steps is as follows:
1, take by weighing Quercetin, solid lipid adds in the organic solvent, dissolving constitutes oil phase A.
2, it is an amount of to measure 25%～35% alcoholic solution or distilled water, adds co-emulsifier and constitutes aqueous phase B just.
3, it is an amount of to get 25%～35% alcoholic solution or distilled water in addition, adds co-emulsifier of the same race, constitutes water C, and cold preservation is stand-by.
4, with above-mentioned oil phase A and first aqueous phase B heating in water bath to 70～80 ℃, after A is dissolved as clear liquid fully, stir down among the A impouring B, constant temperature stirred 50～80 minutes, and organic solvent is volatilized fully, faint yellow Emulsion D.
5, among the water C (putting ice bath) with faint yellow Emulsion D impouring step 3, stirred under the condition of ice bath 50～80 minutes, get the tangible faint yellow suspension E of opalescence.
6, use solution to be settled to 50ml faint yellow suspension E, promptly get the quercetin solid liposome nano particle suspension with water C same system.
The preparation lyophilized formulations, continue following steps:
7, above-mentioned quercetin solid liposome nano particle suspension is carried out filtering with microporous membrane after, add the freeze drying protectant lyophilizing again and promptly get lyophilized formulations.Freeze drying protectant can be chosen wantonly, as mannitol.
In order to improve the oral absorption of Quercetin, improve its bioavailability, the present invention selects the mixture of solid lipid, emulsifying agent and co-emulsifier composition as pharmaceutical carrier.The solid lipid that is adopted, emulsifying agent, co-emulsifier and freeze drying protectant are the pharmaceutical necessities of extensive use on the pharmaceutics, have nontoxic, nonirritant, good biocompatibility characteristic.But because solid lipid nanoparticle is particularly suitable for the preparation of fat-soluble medicine preferably, and Quercetin belongs to insoluble drug, and very difficult compatible with water solublity or fat-soluble adjuvant, therefore preparation gets up to acquire a certain degree of difficulty.In order to obtain satisfied result, the organic solvent that the present invention selects mostly is the mixed solvent of two or more different solvent composition of solubility property, and add the emulsifying agent that Quercetin is had short molten effect therein, so both can improve the dissolubility of Quercetin in oil phase, make oil phase and water that certain intersolubility is arranged again, help preparing the high colostrum of content of dispersion.Simultaneously, the present invention has also added one or more emulsifying agents or the co-emulsifier that Quercetin is had certain solubility property at aqueous phase.In the process that forms solid lipid nanoparticle; because the character of Quercetin makes it easily be gathered in the surface of nanoparticle; at this moment; the emulsifying agent of aqueous phase and co-emulsifier can form one deck emulsifying film on the surface of nanoparticle; Quercetin is held wherein; stop separating out of medicine, make the solid lipid nanoparticle of preparation have unique protective effect of drug and sustained release characteristic.By prescription screening and optimization, when various ratio of adjuvant are suitable, can make comparatively ideal quercetin solid liposome nano particle with high temperature emulsifying-low-temperature setting method, envelop rate is 45%～50%, particle diameter is between 10～300nm, this big or small microgranule is very easily in gastrointestinal absorption, and the cohesiveness that nano-particle has can significantly improve bioavailability of medicament, and the absorption that increases medicine also reduces its irregular absorption.
Rat is in the body test for intestinal absorption: the test liquid of 50ml constant temperature (37 ± 0.5) ℃ is added in the beaker of circulating device; test liquid (1): Quercetin surfactant micella solution (the containing Quercetin 40mg) 100ml+2mg of Krobs-Ringer test solution preparation is phenol red, test liquid (2): quercetin solid liposome nano particle suspension (the containing Quercetin 40mg) 100ml+2mg of Krobs-Ringer test solution preparation is phenol red.After the fasting male rat anesthesia at one night, open the abdominal cavity, respectively insert the glass intubate of diameter 0.5cm from duodenal cap and colon bottom, tighten, wash down intestinal contents with 37 ℃ of normal saline, intubate is connected peristaltic pump, test liquid is circulated in intestinal, regularly remove sample and add phenol red solution (every ml Krobs-Ringer test solution contains phenol red 20 μ g).Measure the content of Quercetin in the sample liquid, calculate the absorbtivity of Quercetin.The result shows: Quercetin surfactant micella solution small intestinal absorbtivity is (27.4 ± 2.8) %; quercetin solid liposome nano particle suspension (prescription is as embodiment 4) small intestinal absorbtivity is (58.7 ± 1.3) %, and the absorption of solid lipid nanoparticle obviously is better than micellar solution.
The preparation of quercetin solid liposome nano particle suspension is simple; with it by behind the filtering with microporous membrane of a certain size particle diameter; add freeze drying protectant; lyophilization; can make nanoparticle homodisperse in carrier material; improve stability of formulation greatly, can better promote the dissolving and the absorption of medicine.
(4) description of drawings
Fig. 1 is the quercetin solid liposome nano particle electromicroscopic photograph of the embodiment of the invention 4, amplifies 36000 times.
(5) specific embodiment
Embodiment 1:
Precision takes by weighing Quercetin 20mg, stearic acid 200mg, and lecithin 100mg adds in the mixed solvent of the chloroform of 1: 1 proportioning of 20ml and acetone, and dissolving constitutes oil phase A.Measure 20ml 30% alcoholic solution, add 0.8g poloxamer 188 constitution system B.Other gets the alcoholic solution of 30ml 30%, adds 1.2g poloxamer 188 and constitutes water C, and cold preservation is stand-by.A, B heating in water bath to 70 ℃, after A is dissolved as clear liquid fully, stir down among the A impouring B, constant temperature stirs 1h, and organic solvent is volatilized fully, faint yellow Emulsion D.In D impouring C (putting ice bath), stir 1h under the condition of ice bath, get the tangible faint yellow suspension E of opalescence, use solution to be settled to 50ml E with the C same system, promptly get the quercetin solid liposome nano particle suspension.
Embodiment 2:
Precision takes by weighing Quercetin 30mg, stearic acid 200mg, and sodium cholate 100mg adds 20ml1: in the chloroform and ethanol mixed solvent of 1 proportioning, dissolving constitutes oil phase A.Measure the 20ml distilled water, add polyoxyethylene sorbitan monoleate 1g constitution system B.Other gets the 30ml distilled water, adds polyoxyethylene sorbitan monoleate 2g, constitutes water C, and cold preservation is stand-by.A, B heating in water bath to 70 ℃, after A is dissolved as clear liquid fully, stir down among the A impouring B, constant temperature stirs 1h, and organic solvent is volatilized fully, faint yellow Emulsion D.In D impouring C (putting ice bath), stir 1h under the condition of ice bath, get the tangible faint yellow suspension E of opalescence, use solution to be settled to 50ml E with the C same system, promptly get the quercetin solid liposome nano particle suspension.
Embodiment 3:
Precision takes by weighing Quercetin 20mg, glyceryl monostearate 100mg, and soybean phospholipid 200mg adds in the mixed solvent of the chloroform of 1: 1 proportioning of 20ml and methanol, and dissolving constitutes oil phase A.Measure 20ml 25% alcoholic solution, add poloxamer 1880.8g constitution system B.Other gets the alcoholic solution of 30ml20%, adds poloxamer 1881.6g, constitutes water C, and cold preservation is stand-by.A, B heating in water bath to 90 ℃, after A is dissolved as clear liquid fully, stir down among the A impouring B, constant temperature stirs 1h, and organic solvent is volatilized fully, faint yellow Emulsion D.In D impouring C (putting ice bath), stir 1h under the condition of ice bath, get the tangible faint yellow suspension E of opalescence, use solution to be settled to 50ml E with the C same system, promptly get the quercetin solid liposome nano particle suspension.
Embodiment 4:
Precision takes by weighing Quercetin 20mg, stearic acid 150mg, and lecithin 200mg adds to 20ml1: in the chloroform of 1 proportioning and the mixed solvent of acetone, dissolving constitutes oil phase A.Measure 20ml 35% alcoholic solution, add polyoxyethylene sorbitan monoleate 0.6g constitution system B.Other gets the alcoholic solution of 30ml35%, adds polyoxyethylene sorbitan monoleate 1.2g, constitutes water C, and cold preservation is stand-by.A, B heating in water bath to 75～80 ℃, after A is dissolved as clear liquid fully, stir down among the A impouring B, constant temperature stirs 1h, and organic solvent is volatilized fully, faint yellow Emulsion D.In D impouring C (putting ice bath), stir 1h under the condition of ice bath, get the tangible faint yellow suspension E of opalescence, use solution to be settled to 50ml E with the C same system, promptly get the quercetin solid liposome nano particle suspension.
It is an amount of to get the above-mentioned suspension that makes, 0.8 μ m filtering with microporous membrane, and in 1 part of ratio that adds 40 portions of mannitol, lyophilized powder is made in dissolving back lyophilizing.
It is an amount of to get suspension, drips on copper mesh, and (pH4.47) carries out negative staining with 2% Salkowski's solution, observe down at transmission electron microscope (TEM) behind the natural drying, be the class spherical entity particle of rounding, smooth surface, particle diameter is between 10～300nm, and mean diameter is 217.3nm.Size and form according to particle can judge that said preparation is a solid lipid nanoparticle.
Claims (3)
1. quercetin solid liposome nano particle preparation as crude drug, adopts mixture that solid lipid, emulsifying agent and co-emulsifier form as pharmaceutical carrier with Quercetin, and each component is as follows:
Quercetin 20～30mg, solid lipid 100～250mg, emulsifying agent 100～200mg contains 25%～35% alcoholic solution of 1800～3000mg hydrophilic co-emulsifier;
Described solid lipid is stearic acid or glyceryl monostearate;
Described emulsifying agent is lecithin, soybean phospholipid or sodium cholate;
Described co-emulsifier is that ethanol is or/and polyoxyethylene sorbitan monoleate;
Make by the following method:
Quercetin, solid lipid and emulsifying agent be dissolved in constitute oil phase in the organic solvent, join the first aqueous phase emulsifying that contains co-emulsifier of equality of temperature, again it is joined the low temperature aqueous phase precipitation that contains co-emulsifier, promptly get the quercetin solid liposome nano particle suspension;
After gained quercetin solid liposome nano particle suspension carried out filtering with microporous membrane, add the lyophilizing of freeze drying protectant mannitol again and promptly get lyophilized formulations.
2. quercetin solid liposome nano particle preparation as claimed in claim 1 is characterized in that described organic solvent is the mixed solvent of chloroform and acetone or alcohol.
3. quercetin solid liposome nano particle preparation as claimed in claim 1 is characterized in that the preparation process of described quercetin solid liposome nano particle suspension is as follows:
(1) take by weighing Quercetin, solid lipid adds in the organic solvent, dissolving constitutes oil phase A,
(2) it is an amount of to measure 25%～35% alcoholic solution or distilled water, adds co-emulsifier aqueous phase B just,
(3) it is an amount of to get 25%～35% alcoholic solution or distilled water in addition, adds co-emulsifier of the same race, constitutes water C, and cold preservation is stand-by,
(4) with above-mentioned oil phase A and first aqueous phase B heating in water bath to 70～80 ℃, after A is dissolved as clear liquid fully, stir down among the A impouring B, constant temperature stirred 50～80 minutes, and organic solvent is volatilized fully, faint yellow Emulsion D,
(5) among the water C with faint yellow Emulsion D impouring step 3, stirred under the condition of ice bath 50～80 minutes, get the tangible faint yellow suspension E of opalescence,
(6) use solution to be settled to 50ml faint yellow suspension E, promptly get the quercetin solid liposome nano particle suspension with water C same system.
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| CN102469816A (en) * | 2009-08-10 | 2012-05-23 | 斯托克里-丰康普公司 | Method for suspending a flavonoid in a beverage |
| CN102327226B (en) * | 2011-07-14 | 2012-12-19 | 海南美大制药有限公司 | Solid cefprozi lipid nanoparticle preparation |
| CN103315977B (en) * | 2013-06-28 | 2015-07-08 | 山东大学 | Folic acid modified quercetin lipid nano-capsule preparation and preparation method thereof |
| CN104172184A (en) * | 2014-08-15 | 2014-12-03 | 东南大学 | Quercetin nanostructured lipid carrier and preparation method thereof |
| CN104224752A (en) * | 2014-09-18 | 2014-12-24 | 暨南大学 | Psoralen-quercetin composite solid lipid nanoparticle preparation and preparation thereof |
| PL3654938T3 (en) * | 2017-07-17 | 2022-12-27 | Indena S.P.A. | Powder solid dispersions comprising quercetin, process for their preparation and formulations thereof |
| CN108904814A (en) * | 2018-07-12 | 2018-11-30 | 浙江大学 | With difunctional matrix material and prepare application in anti-tumor drug |
| CN111264860A (en) * | 2020-01-19 | 2020-06-12 | 上海海洋大学 | Solid self-microemulsion microcapsule containing astaxanthin and quercetin and preparation method and application thereof |
| CN113304109A (en) * | 2021-06-08 | 2021-08-27 | 内蒙古大唐药业股份有限公司 | A flavone acetylsalicylate solid lipid nanoparticle dispersion and its preparation method |
| CN115282084A (en) * | 2022-04-25 | 2022-11-04 | 深圳市萱嘉生物科技有限公司 | Preparation method and application of supramolecular ionic liquid bacteriostatic and aroma-extending composition for oral products |
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