CN103040791A - Asiatic acid lipid nanoparticle capable of stimulating oral absorption and preparation method thereof - Google Patents
Asiatic acid lipid nanoparticle capable of stimulating oral absorption and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an asiatic acid lipid nanoparticle capable of stimulating oral absorption and a preparation method thereof. The asiatic acid lipid nanoparticle is prepared by taking a lipid material as a carrier and asiatic acid as a main drug through a solvent diffusion method. The particle size of the obtained lipid nanoparticle is smaller than 700nm, the entrapment rate is 40-90% and the drug-loading rate is 7-11%. By utilizing the nanoparticle, the intestinal drug absorption can be increased, and the oral bioavailability is improved.
Description
Technical field
The present invention relates to technical field of medicine, relating in particular to a kind ofly can increase intestinal drug absorption, improves asiatic acid lipid nanoparticle of oral administration biaavailability and preparation method thereof.
Background technology
Herba Centellae is samphire Herba Centellae Centella asiatica(L.) dry herb or the whole herb with root of Urban., effect (Zhang Leilei with clearing away heat-damp and promoting diuresis, removing toxic substances and promoting subsidence of swelling, Deng. Herba Centellae chemical constitution study [J]. Chinese herbal medicine, 2005,36(12): 1761-1763.).Asiatic acid (Asiatic Acid) is one of Herba Centellae effective ingredient, belong to pentacyclic triterpene acid, have the effects such as treatment skin trauma and anti-liver, renal fibrosis, be usually used in the treating acne (Chen Jun relevant with beautifying skin, Deng. the bioactivity research overview [J] of asiatic acid and derivant thereof. Chinese herbal medicine, 2006,37 (3): 458-460.).The gastrointestinal absorption of asiatic acid is poor, and oral administration biaavailability is low.Bibliographical information, Oral Administration in Rats asiatic acid (1.25mg), blood peak concentration of drug (Cmax) are well below intravenous injection (being about 1/60), and behind the human oral asiatic acid (12mg), Cmax only is 0.098 μ gml
-1, 0-12h area under curve (AUC
0-12h) be 0.61 ± 0.25 μ ghmL
-1(Chasseaud L. F., et al.The metabolism of Asiatic Acid, Madecassic Acid and Asiaticoside in the Rat[J]. Drug Res., 1971,21:1379-1384; Rush W. R., et al.The comparative steady-state bioavailability of the active ingredients of madecassol[J] .Eur. J. Drug Metab. Pharmacokinet., 1993,18 (4): 323-326.).
Although asiatic acid has good biological activity, dissolubility is minimum in water, and intestinal absorption is relatively poor, and this brings certain difficulty to oral administration.People are devoted to improve the intestinal absorption of asiatic acid always, by being modified through chemical constitution, asiatic acid makes water solublity asiatic acid tromethane salt such as Liu Ying etc., make again the preparations such as microemulsion, microemulsion soft capsules, aerosol, hard capsule and tablet, although the oral administration biaavailability of asiatic acid increases (number of patent application: CN 102755333 A to some extent; CN 102755328 A; CN 102755329 A; CN 102755331 A; But because the chemical constitution of asiatic acid changes, whether safety and curative effect change remains further conclusive evidence CN 102755332 A).
Modern preparation technique can improve the oral absorption of medicine, magnify equality and adopt the self emulsifying technology, obtain the asiatic acid emulsion droplet, behind the gastric infusion, blood drug level obviously improves (number of patent application: CN 102784096 A) than the raw material group, but needs in the prescription to add a large amount of adjuvants such as emulsifying agent, co-emulsifier and antioxidant, may have potential safety hazard, and the formed drop size of self emulsifying is subject to the impact of gastrointestinal tract condition, thereby impact absorbs.
Lipid nanoparticle is to form through certain preparation process structure take matrix material as carrier, such as solid lipid nanoparticle (Solid Lipid Nanoparticles, SLN) and the made nano structured lipid carrier (Nanostructured Lipid Carriers, NLC) of ratio that changes liquid lipid in the matrix material.Such lipid nanoparticle mainly has following characteristics: after 1) oral, can enter the body circulation through the lymphatic channels absorption at gastrointestinal tract, this absorption alternative pathway can be avoided the first pass effect of liver, reduce drug loss (Hussain N., et al.Recent advances in the understanding of uptake of microparticulates across the gastrointestinal lymphatics[J] .Adv. Drug Deliv. Rev., 2001,50:107-142.).2) because the structure of lipid nanoparticle and the similarity of membrane structure have the penetrating ability of the cell membrane of enhancing.3) electronegative nanoparticle, has good bio-adhesive properties (Jung T., et al. Biodegradable nanoparticles for oral delivery of peptides:is there a role for polymers to affect mucosal uptake? [J]. Eur. J. Pharm. Biopharm., 2000,50 (1): 147-160.), can prolong the medicine carrying particle in the time of staying of absorption site, increase absorption, improve bioavailability.
Through retrieval, there is no at present patent application or bibliographical information that the asiatic acid lipid nanoparticle improves intestinal absorption.
Summary of the invention
The objective of the invention is for the deficiencies in the prior art, a kind of asiatic acid lipid nanoparticle and preparation method thereof is provided.
For achieving the above object, the present invention adopts following technical scheme: a kind of asiatic acid lipid nanoparticle that promotes oral absorption, the medicine of described nanoparticle parcel is asiatic acid, carrier is matrix material, described matrix material comprises solid-state lipid and liquid lipid, and the quality proportioning of solid-state lipid and liquid lipid is 80～100:0～20; Solid-state lipid is selected glyceryl monostearate or stearic acid, and liquid lipid is selected oleic acid or glycerol trioleate; The lipid nanoparticle particle diameter that obtains is less than 700nm, and envelop rate is 40～90%, and drug loading is 7～11%.
Described asiatic acid lipid nanoparticle prepares by following process:
(1) take dehydrated alcohol as solvent, add matrix material and chromatographic purity greater than 90% asiatic acid, in (70 ± 2) ℃ lower heating in water bath dissolving, and as organic facies, wherein asiatic acid and matrix material mass ratio are 1:7～11, and the solution concentration of matrix material is 7～11mg/mL;
(2) take water as decentralized photo, be heated to (70 ± 2) ℃;
(3) under the 400r/min mechanical agitation, organic facies is injected in the decentralized photo, the volume ratio of dehydrated alcohol and water is 1:10; Continue to stir 5min, must be with the turbid liquid of opalescence.This turbid liquid lets cool to room temperature, and is centrifugal with salt acid for adjusting pH to 1.2, and precipitation is used a small amount of deionized water wash, and centrifugal again, the tipping supernatant liquid gets the asiatic acid lipid nanoparticle.This nanoparticle can be scattered in the aqueous solution of PLURONICS F87 that mass volume ratio is 0.001g/mL, gets the lipid nanoparticle dispersion liquid of asiatic acid.
The invention has the beneficial effects as follows: simple, easy row, safe and effective is characteristics of the present invention.It is simple that " simply " refers to that prescription forms; " easily row " refers to that preparation technology is very simple, organic facies (dehydrated alcohol) is added to water gets final product, and need not high-speed stirred or HIGH PRESSURE TREATMENT, the favorable reproducibility of technique; " safe and effective ": refer to that prescription forms safety, do not add emulsifying agent and toxic solvent, carrier and the intestinal epithelial cell of nanoparticle are all lipid components, therefore are absorbed through intestinal easily.Gained asiatic acid lipid nanoparticle particle diameter of the present invention is less than 700nm, and envelop rate is 40～90%, and drug loading is 7～11%, and can effectively increase intestinal drug absorption, improves oral administration biaavailability.
Description of drawings
Fig. 1 is asiatic acid lipid nanoparticle transmission electron microscope photo among the embodiment 2;
Fig. 2 is asiatic acid lipid nanoparticle transmission electron microscope photo among the embodiment 5;
Fig. 3 is that asiatic acid lipid nanoparticle rat is at body intestinal perfusion model Chinese medicine PA curve;
Fig. 4 is bile asiatic acid excretion-time graph behind the asiatic acid lipid nanoparticle rat oral gavage.
The specific embodiment
The present invention can promote that the medicine of the asiatic acid lipid nanoparticle parcel of oral absorption is asiatic acid, carrier is matrix material, asiatic acid and matrix material mass ratio are 1:7～11, described matrix material comprises solid-state lipid and liquid lipid, and the quality proportioning of solid-state lipid and liquid lipid is 80～100:0～20; Solid-state lipid is selected glyceryl monostearate or stearic acid, and liquid lipid is selected oleic acid or glycerol trioleate; The lipid nanoparticle particle diameter that obtains is less than 700nm, and envelop rate is 40～90%, and drug loading is 7～11%.
Above-mentioned asiatic acid lipid nanoparticle preparation method comprises following process:
1. take dehydrated alcohol as solvent, add matrix material and asiatic acid (chromatographic purity is greater than 90%), in (70 ± 2) ℃ lower heating in water bath dissolving, as organic facies, wherein asiatic acid and matrix material mass ratio are 1:7～11, and the solution concentration of matrix material is 7～11mg/mL.
2. take water as decentralized photo, be heated to (70 ± 2) ℃.
3. under the 400r/min mechanical agitation, organic facies is injected in the decentralized photo, the volume ratio of dehydrated alcohol and water is 1:10; Continue to stir 5min, must be with the turbid liquid of opalescence.This turbid liquid lets cool to room temperature, and is centrifugal with salt acid for adjusting pH to 1.2, and precipitation is used a small amount of deionized water wash, and centrifugal again, the tipping supernatant liquid gets the asiatic acid lipid nanoparticle.This nanoparticle can be scattered in the aqueous solution of PLURONICS F87 that mass volume ratio is 0.001g/mL, gets the lipid nanoparticle dispersion liquid of asiatic acid.
The below describes the present invention in detail with embodiment with reference to the accompanying drawings, and it is more obvious that purpose of the present invention and effect will become.
Embodiment 1: the preparation of asiatic acid glyceryl monostearate lipid nanoparticle (principal agent and matrix material mass ratio are 1:7)
Precision takes by weighing asiatic acid 5mg and glyceryl monostearate (commercially available, purity＞90%) 35mg, make under (70 ± 2) ℃ heating in water bath to be dissolved in the 5mL dehydrated alcohol, and as organic facies, the solution concentration of matrix material is 7mg/mL.Take water as decentralized photo, be heated to (70 ± 2) ℃.Under the 400rpm mechanical agitation, organic facies is injected in the 50mL decentralized photo, continues to stir 5min, must be with the turbid liquid of opalescence.This turbid liquid lets cool to room temperature, and is centrifugal with salt acid for adjusting pH to 1.2, and precipitation is used a small amount of deionized water wash, and centrifugal tipping supernatant liquid gets the asiatic acid lipid nanoparticle again.This nanoparticle can be scattered in the aqueous solution of PLURONICS F87 that mass volume ratio is 0.001g/mL, gets the lipid nanoparticle dispersion liquid of asiatic acid.
After measured, this lipid nanoparticle particle diameter is 214 ± 35nm(Ma Erwen Zetaszier Nano-S900);
Entrapment efficiency is the medication amount (mg)/dosage (mg) * 100% in 44.1 ± 4.8%(envelop rate=nanoparticle);
Drug loading is the medication amount (mg)/nanoparticle gross weight (freeze-dried powder, mg) * 100%) in 9.8 ± 0.5%(drug loading=nanoparticle.
Embodiment 2: the preparation of asiatic acid glyceryl monostearate lipid nanoparticle (principal agent and matrix material mass ratio are 1:9)
Precision takes by weighing asiatic acid 5mg and glyceryl monostearate (commercially available, purity＞90%) 45mg, (70
± 2) make under ℃ heating in water bath and be dissolved in the 5mL dehydrated alcohol, and as organic facies, the solution concentration of matrix material is 9mg/mL.Take water as decentralized photo, be heated to (70 ± 2) ℃, under the 400rpm mechanical agitation, organic facies is injected in the 50mL decentralized photo, continue to stir 5min, must be with the turbid liquid of opalescence.This turbid liquid lets cool to room temperature, and is centrifugal with salt acid for adjusting pH to 1.2, and precipitation is used a small amount of deionized water wash, and centrifugal again, the tipping supernatant liquid gets the asiatic acid lipid nanoparticle.This nanoparticle can be scattered in the aqueous solution of PLURONICS F87 that mass volume ratio is 0.001g/mL, gets the lipid nanoparticle dispersion liquid of asiatic acid.
After measured, this lipid nanoparticle particle diameter is 208 ± 24nm(Ma Erwen Zetaszier Nano-S900);
Entrapment efficiency is the medication amount (mg)/dosage (mg) * 100% in 67.6 ± 5.5%(envelop rate=nanoparticle);
Drug loading is the medication amount (mg)/nanoparticle gross weight (freeze-dried powder, mg) * 100%) in 8.6 ± 0.5%(drug loading=nanoparticle.
Embodiment 3: the preparation of asiatic acid glyceryl monostearate lipid nanoparticle (principal agent and matrix material mass ratio are 1:11)
Precision takes by weighing asiatic acid 5mg and glyceryl monostearate (commercially available, purity＞90%) 55mg, make under (70 ± 2) ℃ heating in water bath to be dissolved in the 5mL dehydrated alcohol, and as organic facies, the solution concentration of matrix material is 11mg/mL.Take water as decentralized photo, be heated to (70 ± 2) ℃.Under the 400rpm mechanical agitation, organic facies is injected in the 50mL decentralized photo, continues to stir 5min, must be with the turbid liquid of opalescence.This turbid liquid lets cool to room temperature, and is centrifugal with salt acid for adjusting pH to 1.2, and precipitation is used a small amount of deionized water wash, and centrifugal again, the tipping supernatant liquid gets the asiatic acid lipid nanoparticle.This nanoparticle can be scattered in the aqueous solution of PLURONICS F87 that mass volume ratio is 0.001g/mL, gets the lipid nanoparticle dispersion liquid of asiatic acid.
After measured, this lipid nanoparticle particle diameter is 217 ± 26nm(Ma Erwen Zetaszier Nano-S900);
Entrapment efficiency is the medication amount (mg)/dosage (mg) * 100% in 53.1 ± 3.9%(envelop rate=nanoparticle);
Drug loading is the medication amount (mg)/nanoparticle gross weight (freeze-dried powder, mg) * 100%) in 7.1 ± 0.9%(drug loading=nanoparticle.
Embodiment 4: the preparation of asiatic acid stearic acid lipid nanoparticle (principal agent and matrix material mass ratio are 1:9)
Precision takes by weighing asiatic acid 5mg and stearic acid (commercially available, purity＞90%) 45mg, make under (70 ± 2) ℃ heating in water bath to be dissolved in the 5mL dehydrated alcohol, and as organic facies, the solution concentration of matrix material is 9mg/mL.Take water as decentralized photo, be heated to (70 ± 2) ℃.Under the 400rpm mechanical agitation, organic facies is injected in the 50mL decentralized photo, continues to stir 5min, must be with the turbid liquid of opalescence.This turbid liquid lets cool to room temperature, and is centrifugal with salt acid for adjusting pH to 1.2, and precipitation is used a small amount of deionized water wash, and centrifugal again, the tipping supernatant liquid gets the asiatic acid lipid nanoparticle.This nanoparticle can be scattered in the aqueous solution of PLURONICS F87 that mass volume ratio is 0.001g/mL, gets the lipid nanoparticle dispersion liquid of asiatic acid.
After measured, this lipid nanoparticle particle diameter is 624 ± 29nm(Ma Erwen Zetaszier Nano-S900);
Entrapment efficiency is the medication amount (mg)/dosage (mg) * 100% in 53.6 ± 7.9%(envelop rate=nanoparticle);
Drug loading is the medication amount (mg)/nanoparticle gross weight (freeze-dried powder, mg) * 100%) in 7.5 ± 0.5%(drug loading=nanoparticle.
Embodiment 5: the preparation of asiatic acid glyceryl monostearate-oleic acid lipid nanoparticle (principal agent and matrix material mass ratio are 1:9)
Precision take by weighing asiatic acid 5mg, glyceryl monostearate (commercially available, purity＞90%) 36mg and liquid lipid oleic acid 9mg(commercially available, purity＞95%; The mass ratio that oleic acid accounts for matrix material is 20%), make under (70 ± 2) ℃ heating in water bath to be dissolved in the 5mL dehydrated alcohol, and as organic facies, the solution concentration of matrix material is 9mg/mL.Take water as decentralized photo, be heated to (70 ± 2) ℃.Under the 400rpm mechanical agitation, organic facies is injected in the 50mL decentralized photo, continues to stir 5min, must be with the turbid liquid of opalescence.This turbid liquid lets cool to room temperature, and is centrifugal with salt acid for adjusting pH to 1.2, and precipitation is used a small amount of deionized water wash, and centrifugal again, the tipping supernatant liquid gets the asiatic acid lipid nanoparticle.This nanoparticle can be scattered in the aqueous solution of PLURONICS F87 that mass volume ratio is 0.001g/mL, gets the lipid nanoparticle dispersion liquid of asiatic acid.
After measured, this lipid nanoparticle particle diameter is 310 ± 11nm(Ma Erwen Zetaszier Nano-S900);
Entrapment efficiency is the medication amount (mg)/dosage (mg) * 100% in 77.9 ± 4.8%(envelop rate=nanoparticle);
Drug loading is the medication amount (mg)/nanoparticle gross weight (freeze-dried powder, mg) * 100%) in 8.8 ± 0.7%(drug loading=nanoparticle.
Embodiment 6: the preparation of asiatic acid glyceryl monostearate-glycerol trioleate lipid nanoparticle (principal agent and matrix material mass ratio are 1:9)
Precision take by weighing asiatic acid 5mg, glyceryl monostearate (commercially available, purity＞90%) 36mg and liquid lipid glycerol trioleate 9mg(commercially available, purity＞95%; The mass ratio that glycerol trioleate accounts for matrix material is 20%), make under (70 ± 2) ℃ heating in water bath to be dissolved in the 5mL dehydrated alcohol, and as organic facies, the solution concentration of matrix material is 9mg/mL.Take water as decentralized photo, be heated to (70 ± 2) ℃.Under the 400rpm mechanical agitation, organic facies is injected in the 50mL decentralized photo, continues to stir 5min, must be with the turbid liquid of opalescence.This turbid liquid lets cool to room temperature, and is centrifugal with salt acid for adjusting pH to 1.2, and precipitation is used a small amount of deionized water wash, and centrifugal again, the tipping supernatant liquid gets the asiatic acid lipid nanoparticle.This nanoparticle can be scattered in the aqueous solution of PLURONICS F87 that mass volume ratio is 0.001g/mL, gets the lipid nanoparticle dispersion liquid of asiatic acid.
After measured, this lipid nanoparticle particle diameter is 293 ± 9nm(Ma Erwen Zetaszier Nano-S900);
Entrapment efficiency is the medication amount (mg)/dosage (mg) * 100% in 63.3 ± 5.7%(envelop rate=nanoparticle);
Drug loading is the medication amount (mg)/nanoparticle gross weight (freeze-dried powder, mg) * 100%) in 8.2 ± 0.4%(drug loading=nanoparticle.
Embodiment 7: the rat of lipid nanoparticle absorbs at body intestinal perfusion model Chinese medicine to be investigated
By the literature method compound concentration be 20 μ g/ml phenol red solution (Wu Peisheng, etc. intestine in rats is to the absorption difference research [J] of rotundine and raceme thereof. Acta Pharmaceutica Sinica, 2007,42 (5): 534-537.).It is an amount of that precision pipettes the lipid nanoparticle dispersion liquid of embodiment 2 and embodiment 5, redispersion is in phenol red solution, preparing respectively asiatic acid concentration is the nanoparticle intestinal perfusate of 30 μ g/mL, simultaneously organize in contrast (liquor strength 30 μ g/mL with the asiatic acid raw material, the phenol red solution preparation), transfer the usefulness of purchasing for 37 ℃.
Adopt rat single pass perfusion model in situ absorbing model, investigate the absorbing state of rat small intestine section.Namely take from the SD rat of overnight fasting under the right conditions of water drinking, body weight (200 ± 20) g is divided into 3 groups at random, 5 every group.The anesthesia of lumbar injection pentobarbital sodium, the back is fixed.Open the abdominal cavity along ventrimeson, careful separation goes out little intestinal segment.Behind the otch of small intestinal section two ends, with being preheated to 37 ℃ of normal saline intestinal contents is rinsed well, with air that normal saline is emptying again, intubate and ligation connect constant flow pump.After washing 50 min with the intestinal perfusate of having prepared (being preheated to 37 ℃) with the flow velocity of 1.0 mL/min, flow velocity is adjusted into 0.2 mL/min, the beginning timing, respectively at 15～30,30～45,45～60,60～75,75～90,90～105,105～120,120～135 minutes collection perfusates, measure respectively the asiatic acid of each time point and phenol red concentration, and calculate asiatic acid raw material and lipid nanoparticle thereof in the drug absorption percentage rate (PA=absorbtivity of each time point
/ initial amount * 100%).By the enteric cavity effective absorption coefficient (
P Eff ), absorption rate constant (
K a ) and drug absorption dosage mark (
f a ) estimate the absorption characteristic (table 1) of medicine.Result's demonstration, two kinds of lipid nanoparticles
P Eff With
f a All have significant difference (P＜0.05) with raw material, prepared lipid nanoparticle can obviously improve the transmitance of intestinal Chinese medicine.
Table 1: different lipid nanoparticle rat small intestines
P Eff ,
K a With
f a (n=5)
| ? | P eff /×10 -4·cm - 1·s - 1 | K a /×10 -3·s - 1 | f a % |
| Asiatic acid | 0.48±0.04 | 0.34±0.06 | 52.50±3.08 |
| Lipid nanoparticle (glyceryl monostearate) | 0.57±0.03 * | 0.41±0.03 | 62.06±3.97 * |
| Lipid nanoparticle (glyceryl monostearate-oleic acid) | 0.66±0.10 * | 0.45±0.07 * | 67.64±6.51 * |
*Compare with asiatic acid raw material group P＜0.05.
Embodiment 8: the Oral Administration in Rats of lipid nanoparticle absorbs to be investigated
Its main metabolites was glucuronidation and sulfate conjugates (glucuronidation and the about 4:1 of sulfate conjugates ratio) after asiatic acid was oral, and drained as main take the bile approach.The gastrointestinal absorption of asiatic acid is poor, and oral administration biaavailability is very low.This medicine of Oral Administration in Rats (1.25mg), blood peak concentration of drug (Cmax) is well below intravenous injection (being about 1/60); Behind the human oral asiatic acid (12mg), Cmax only is 0.098
μ gml
-1, 0-12h area under curve (AUC
0-12h) be 0.61 ± 0.25 μ ghmL
-1(Chasseaud L. F., et al.The metabolism of Asiatic Acid, Madecassic Acid and Asiaticoside in the Rat[J]. Drug Res., 1971,21:1379-1384; Rush W. R., et al.The comparative steady-state bioavailability of the active ingredients of madecassol[J] .Eur. J. Drug Metab. Pharmacokinet., 1993,18 (4): 323-326.).Cross low oral administration biaavailability and also bring larger difficulty for estimating drug absorption by detection blood drug level.Because bile is the main excretion pathway of asiatic acid metabolite, and higher being convenient to of relative concentration detected.The present invention estimates the oral absorption characteristic of nanoparticle by detecting asiatic acid total concentration in the different time rat bile (comprise the asiatic acid main metabolites---asiatic acid glucuronidation and sulfate conjugates).
Healthy SD rat (body weight (200 ± 20) g) is divided into 3 groups at random, and 5 every group, overnight fasting (can't help water), pentobarbital sodium anesthesia is opened the abdominal cavity along ventrimeson, cystic duct cannula, and ligation fixes, and collects blank bile.After rat is clear-headed, gavage gives lipid nanoparticle (the asiatic acid lipid nanoparticle that is prepared by embodiment 2 and embodiment 5 respectively, make to be scattered in the aqueous solution of PLURONICS F87 that mass volume ratio is 0.001g/mL, drug level is 5mg/mL), organize in contrast with the asiatic acid raw material simultaneously that (gavage gives suspension, prepare with 0.5%CMC-Na, drug level is 5mg/mL), dosage is 50mg/kg, 0～1h after the collection administration, 1～2h, 2～3h, 3～4h, 4～5h, 5～6h, 6～8h, 8～10h, 10～12h, the bile sample of 12～24h, and record bile volume.
Precision pipettes different time points bile 50 μ L, and respectively through β-Artogicurol enzyme and sulfatase enzymolysis, liquid-liquid extraction is by the total concentration of asiatic acid in the HPLC method detection bile.Fig. 4 is bile asiatic acid excretion-time graph, and the result shows that two kinds of nanoparticles take lipid as carrier all can improve the excretion of drug amount, and the excretion of drug peak value is significantly higher than the raw material matched group, and (carrier is that glyceryl monostearate nanoparticle group is with single stearic
Acid glyceride-oleic acid nanoparticle group is respectively 1.6 times and 1.8 times of raw material matched group, P＜0.05), point out two kinds of lipid nanoparticles can obviously improve the bioavailability of asiatic acid.
The present invention is principal agent with slightly solubility asiatic acid (commercially available, chromatographic purity is greater than 90%), adopts advanced lipid nanometer preparation technique, prepares a kind of asiatic acid lipid nanoparticle that promotes drug absorption with physical means.Preparation technology of the present invention is simple, easy suitability for industrialized production, and also solvent only relates to three a small amount of kind solvent dehydrated alcohol (removing) and water in subsequent technique; Adjuvant in the prescription forms also simple, is conventional matrix material only, does not relate to emulsifying agent.The lipid nanoparticle that adopts this formulation and technology to obtain, it is less than the emulsion droplet of self emulsifying affected by gastrointestinal, absorbs more regular.
Claims (2)
1. asiatic acid lipid nanoparticle that can promote oral absorption, it is characterized in that the medicine of described nanoparticle parcel is asiatic acid, carrier is matrix material, described matrix material comprises solid-state lipid and liquid lipid, and the quality proportioning of solid-state lipid and liquid lipid is 80～100:0～20; Solid-state lipid is selected glyceryl monostearate or stearic acid, and liquid lipid is selected oleic acid or glycerol trioleate; The lipid nanoparticle particle diameter that obtains is less than 700nm, and envelop rate is 40～90%, and drug loading is 7～11%.
2. the preparation method of an asiatic acid lipid nanoparticle claimed in claim 1 is characterized in that, the method may further comprise the steps:
(1) take dehydrated alcohol as solvent, add matrix material and chromatographic purity greater than 90% asiatic acid, in (70 ± 2) ℃ lower heating in water bath dissolving, and as organic facies, wherein asiatic acid and matrix material mass ratio are 1:7～11, and the solution concentration of matrix material is 7～11mg/mL;
(2) take water as decentralized photo, be heated to (70 ± 2) ℃;
(3) under the 400r/min mechanical agitation, organic facies is injected in the decentralized photo, the volume ratio of dehydrated alcohol and water is 1:10; Continue to stir 5min, must be with the turbid liquid of opalescence; This turbid liquid lets cool to room temperature, and is centrifugal with salt acid for adjusting pH to 1.2, and precipitation is used a small amount of water washing, and centrifugal again, the tipping supernatant liquid gets the asiatic acid lipid nanoparticle; This nanoparticle can be scattered in the aqueous solution of PLURONICS F87 that mass volume ratio is 0.001g/mL, gets the lipid nanoparticle dispersion liquid of asiatic acid.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105477001A (en) * | 2014-10-10 | 2016-04-13 | 上海现代药物制剂工程研究中心有限公司 | Asiatic acid tromethamine salt lipid nanoparticle preparation and preparation method thereof |
| CN105477001B (en) * | 2014-10-10 | 2020-05-19 | 上海现代药物制剂工程研究中心有限公司 | Asiatic acid tromethamine salt lipid nanoparticle preparation and preparation method thereof |
| CN111920760A (en) * | 2020-07-28 | 2020-11-13 | 长沙医学院 | Madecassic acid solid lipid nanoparticle gel |
| CN111920760B (en) * | 2020-07-28 | 2024-02-27 | 长沙医学院 | Hydroxy snowmobile solid lipid nanoparticle gel |
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