CN104027817A - Compound supermolecular evodiamine nanoparticles and preparation method thereof - Google Patents
Compound supermolecular evodiamine nanoparticles and preparation method thereof Download PDFInfo
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- CN104027817A CN104027817A CN201410271043.3A CN201410271043A CN104027817A CN 104027817 A CN104027817 A CN 104027817A CN 201410271043 A CN201410271043 A CN 201410271043A CN 104027817 A CN104027817 A CN 104027817A
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Abstract
The invention belongs to the field of the pharmaceutic preparations, and relates to a formula of compound supermolecular evodiamine nanoparticles and a preparation method of the nanoparticles. The bioavailability of the evodiamine is improved by use of the prepared compound supermolecular evodiamine nanoparticles, and the compound supermolecular evodiamine nanoparticles are used for treating tumors and inflammations.
Description
Technical field
The invention belongs to field of medicine preparations, the present invention relates to formula and the preparation method of composite supramolecular rutaecarpin nanoparticle.
Background technology
The Fructus Evodiae beginning is loaded in Shennong's Herbal, is rutaceae Fructus Evodiae stone tiger or the dry almost ripe fruit of dredging hair Fructus Evodiae.Rutaecarpin is the main alkaloid in this plant, research both at home and abroad shows that rutaecarpin has the fat-reducing of blood vessel dilating anti-inflammatory and antalgic, regulate body temperature, the pharmacological activities such as antitumor and anticancer transfer, but the water solublity extreme difference of rutaecarpin, bioavailability is low, and its Oral Administration in Rats bioavailability of rutaecarpin is only 0.1%.Phosphatide complexes, as Novel Drug Delivery Systems, can increase the oral absorption of active ingredient of Chinese herbs, improves its bioavailability.Document (Liu Shan, Tan Qunyou, Wang Hong, Liao Hong, open scape Qing. the preparation characterization of rutaecarpin phosphatide complexes and the research of anti tumor activity in vitro. Chinese Pharmaceutical Journal .2012,47 (4): 517-523) by rutaecarpin being prepared into rutaecarpin phosphatide complexes, can improve 3.4 times of drug solubilities, promote the absorption of medicine, be conducive to the raising of drug bioavailability.HP-β-CD is beta-cyclodextrin derivative, and inclusion compound is expected to improve by the stability of clathrate, water solublity and bioavailability.
That supermolecule medicine refers to is that two or more molecules form by non-covalent bond, for preventing, diagnose and treat the complex of disease.The phosphatide complexes of medicine and cyclodextrin clathrate all belong to supermolecule medicine.The compound rutaecarpin of phospholipid can be described as phospholipid composite supramolecular rutaecarpin.HP-β-CD enclose rutaecarpin can be described as HP-β-CD enclose supermolecule rutaecarpin (having not yet to see the research report of HP-β-CD enclose supermolecule rutaecarpin).
Through inquiry patent and document, have not yet to see the research report of the bioavailability that simultaneously adopts phospholipid complex technique and HP-β-CD inclusion technique to increase any medicine, more without adopt phospholipid complex technique and HP-β-CD inclusion technique to prepare the research report of the compound HP-β-CD enclose of rutaecarpin phospholipid nanoparticle (being composite supramolecular rutaecarpin nanoparticle) simultaneously, more this composite supramolecular rutaecarpin nanoparticle of no-trump, for increasing the bioavailability of rutaecarpin, improves the research report of active anticancer.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of composite supramolecular rutaecarpin nanoparticle and preparation method thereof.Composite supramolecular rutaecarpin nanoparticulate carriers has improved the dissolubility of medicine, has promoted the absorption of medicine, has increased the bioavailability of medicine, has improved active anticancer.Composite supramolecular rutaecarpin nanoparticle preparation technology provided by the invention is simple, and cost is lower, is easy to control, and is easy to suitability for industrialized production.
Composite supramolecular rutaecarpin nanoparticle provided by the invention, in preparation, each weight percentages of components is: rutaecarpin 1-4.2 part, hydroxy propyl-Beta-ring is stuck with paste 4.1-26.8 part, phospholipid 7-83.1 part, 790 parts of dehydrated alcohol.The preparation method of composite supramolecular rutaecarpin nanoparticle provided by the invention is as follows: rutaecarpin, HP-β-CD, the phospholipid of getting recipe quantity, be dissolved in dehydrated alcohol, after 60 DEG C of temperature constant magnetic stirring 5h reactions, rotary evaporation is removed dehydrated alcohol, vacuum drying is removed residual dehydrated alcohol, obtains composite supramolecular rutaecarpin nanoparticle.
The composite supramolecular rutaecarpin nanoparticle mean diameter making with the present invention is about 180.8nm (Fig. 1).After Oral Administration in Rats administration, in body, pharmacokinetics investigation result shows, with respect to rutaecarpin, rutaecarpin hydroxypropyl-beta-cyclodextrin inclusion and rutaecarpin phosphatide complexes, the area under curve of composite supramolecular rutaecarpin nanoparticle increases, peak concentration increases, and bioavailability in vivo obviously increases.The area under curve AUC of composite supramolecular rutaecarpin nanoparticle
0-∞(μ g/L*h) is (4085.86 ± 17.21), is approximately respectively rutaecarpin (870.3 ± 8.87), rutaecarpin hydroxypropyl-beta-cyclodextrin inclusion (2166.72 ± 25.06) and rutaecarpin phosphatide complexes (2280.43 ± 13.69) 4.7,1.9,1.8 times.Composite supramolecular rutaecarpin nanoparticle bioavailability is respectively 469%, 188%, 180% of rutaecarpin, rutaecarpin hydroxypropyl-beta-cyclodextrin inclusion and rutaecarpin phosphatide complexes.
Oral Administration in Rats gastric infusion composite supramolecular rutaecarpin nanoparticle, rutaecarpin, rutaecarpin hydroxypropyl-beta-cyclodextrin inclusion and rutaecarpin phosphatide complexes, dosage is 250mg/kg.Get blood respectively at different time eye socket rear vein beard after administration, be placed in heparinization test tube, mix, centrifugal (12000r/min) 5min, separates upper plasma, in-20 DEG C of refrigerators, saves backup.The preparation of plasma sample: draw plasma sample 150 μ L, add interior mark working solution (20 μ gml
-1) 10 μ L, vortex 30s, adds ammonia 75 μ L, and vortex 30s adds ether 750 μ L, vortex 3min (after vortex 1min, leave standstill 30s, then vortex 1min, three times like this, total vortex time is 3min), 4000rmin
-1vortex 5min, gets supernatant 600 μ L to centrifuge tube, and 40 DEG C of water-baths volatilize after ether, adds methanol 100 μ L vortex 1min, 12000rmin
-1centrifugal 10min, gets supernatant 40 μ L sample detection.Result substitution regression equation calculation blood drug level, curve while obtaining medicine, is shown in Fig. 2.
This patent is different from the preparation of the nano-carrier of the medicine of common research report.The present invention adopts phospholipid complex technique and HP-β-CD inclusion technique to prepare composite supramolecular rutaecarpin nanoparticle (being the compound HP-β-CD enclose of rutaecarpin phospholipid nanoparticle) first simultaneously, obviously promote rutaecarpin absorption in vivo, increased the bioavailability of rutaecarpin.First passage of the present invention utilizes pharmaceutic adjuvant phospholipid and HP-β-CD simultaneously, adopt phospholipid complex technique and HP-β-CD inclusion technique simultaneously, be prepared into the compound HP-β-CD enclose of rutaecarpin phospholipid nanoparticle, i.e. composite supramolecular rutaecarpin nanoparticle.This novel delivery system has had the advantage of phosphatide complexes and cyclodextrin clathrate concurrently, on the one hand due to the existence of HP-β-CD, has obviously improved the solubility property of rutaecarpin; The existence of phospholipid on the other hand, has promoted rutaecarpin to be transferred to lipophilic environment from hydrophilic environment better, can effectively improve interior absorption of body of rutaecarpin.Composite supramolecular rutaecarpin nanoparticle, merge HP-β-CD and phospholipid and improved rutaecarpin water solublity, sorbefacient advantage, greatly improve the bioavailability of rutaecarpin, extend drug treating time, in the body of the compound HP-β-CD enclose of rutaecarpin phospholipid nanoparticle (being composite supramolecular rutaecarpin nanoparticle), bioavailability is apparently higher than free rutaecarpin, the phospholipid composite supramolecular rutaecarpin that adopts phospholipid complex technique to obtain separately, the HP-β-CD enclose supermolecule rutaecarpin that adopts HP-β-CD inclusion technique to obtain separately, the novel drug-loading system that composite supramolecular rutaecarpin nanoparticle provides a kind of bioavailability obviously to improve for rutaecarpin, significant.
Show that with the cell experiment that composite supramolecular rutaecarpin nanoparticle provided by the invention carries out composite supramolecular rutaecarpin nanoparticle can obviously improve the ability (seeing Fig. 3) that rutaecarpin kills tumor cell, the drug level that composite supramolecular rutaecarpin nanoparticle and rutaecarpin suppress 50% tumor cell is about respectively 1.25 μ M and 20 μ M, and the half-inhibition concentration of composite supramolecular rutaecarpin nanoparticle is about rutaecarpin 1/16.Show to there is obvious tumor-targeting and tumor killing effect after nude mice intravenous injection with the zoopery that composite supramolecular rutaecarpin nanoparticle provided by the invention carries out.
Brief description of the drawings
Fig. 1 is the particle diameter of the composite supramolecular rutaecarpin nanoparticle that makes of the present invention.
Composite supramolecular rutaecarpin nanoparticle mean diameter is 180.8nm.
Fig. 2 is curve chart when medicine in body after the Oral Administration in Rats gastric infusion of the composite supramolecular rutaecarpin nanoparticle that makes of the present invention.Vertical coordinate is drug level, and abscissa is the time.
The composite supramolecular rutaecarpin nanoparticle that the present invention prepares has larger area under curve compared with rutaecarpin, rutaecarpin hydroxypropyl-beta-cyclodextrin inclusion, rutaecarpin phosphatide complexes, and extended the time of having acted on, composite supramolecular rutaecarpin nanoparticle bioavailability is respectively 469%, 188%, 180% of rutaecarpin, rutaecarpin hydroxypropyl-beta-cyclodextrin inclusion and rutaecarpin phosphatide complexes.Its bioavailability is not only compared with free drug, and the rutaecarpin hydroxypropyl-beta-cyclodextrin inclusion of preparing with respect to monotechnics, rutaecarpin phosphatide complexes are all significantly improved.
Fig. 3 is the survival condition of 48 hours after the composite supramolecular rutaecarpin nanoparticle that gives respectively pulmonary carcinoma H446 cell equivalent, free rutaecarpin, blank nanoparticle.Vertical coordinate is the survival rate of tumor cell, and abscissa is the drug level in the preparation giving.The drug level that composite supramolecular rutaecarpin nanoparticle and rutaecarpin suppress 50% tumor cell is about respectively 1.25 μ M and 20 μ M, the half-inhibition concentration that is composite supramolecular rutaecarpin nanoparticle is about rutaecarpin 1/16, illustrates that composite supramolecular rutaecarpin nanoparticle can obviously improve rutaecarpin and kill the ability of tumor cell.
Detailed description of the invention
In order to further illustrate the present invention and advantage thereof, provide following specific embodiment, should understand these embodiment only has in illustrating instead of as the restriction of the scope of the invention.
Embodiment 1:
The weight ratio of components of the each component containing in formula is: 1.1 parts of rutaecarpins, 4.6 parts of HP-β-CD, 0.3 part of phosphatidase 11,410 parts of dehydrated alcohol.
Preparation method comprises the following steps: to get rutaecarpin, HP-β-CD, the phospholipid of recipe quantity, be dissolved in dehydrated alcohol, after 60 DEG C of temperature constant magnetic stirring 5h reactions, rotary evaporation is removed dehydrated alcohol, vacuum drying is removed residual dehydrated alcohol, obtains composite supramolecular rutaecarpin nanoparticle.
Embodiment 2:
The weight ratio of components of the each component containing in formula is: 1.5 parts of rutaecarpins, 12.1 parts of HP-β-CD, 6.8 parts of phosphatidase 11s, 600 parts of dehydrated alcohol.
Preparation method is substantially with embodiment 1.
Embodiment 3:
The weight ratio of components of the each component containing in formula is: 1.8 parts of rutaecarpins, 16.7 parts of HP-β-CD, 2 parts of phosphatidase 11s, 790 parts of dehydrated alcohol.
Preparation method is substantially with embodiment 1.
Embodiment 4:
The weight ratio of components of the each component containing in formula is: 2.1 parts of rutaecarpins, 5.3 parts of HP-β-CD, 5.7 parts of phosphatidase 11s, 800 parts of dehydrated alcohol.
Preparation method is substantially with embodiment 1.
Embodiment 5:
The weight ratio of components of the each component containing in formula is: 1.9 parts of rutaecarpins, 5.1 parts of HP-β-CD, 7 parts, phospholipid, 850 parts of dehydrated alcohol.
Preparation method is substantially with embodiment 1.
Embodiment 6:
The weight ratio of components of the each component containing in formula is: 2.5 parts of rutaecarpins, 13.7 parts of HP-β-CD, 0.6 part of phosphatidase 11,1200 parts of dehydrated alcohol.
Preparation method is substantially with embodiment 1.
Embodiment 7:
The weight ratio of components of the each component containing in formula is: 3 parts of rutaecarpins, 13.9 parts of HP-β-CD, 2.1 parts of phosphatidase 15s, 1350 parts of dehydrated alcohol.
Preparation method is substantially with embodiment 1.
Embodiment 8:
The weight ratio of components of the each component containing in formula is: 3.1 parts of rutaecarpins, 4.1 parts of HP-β-CD, 9 parts, phospholipid, 1400 parts of dehydrated alcohol.
Preparation method is substantially with embodiment 1.
Embodiment 9:
The weight ratio of components of the each component containing in formula is: 3.5 parts of rutaecarpins, 26.8 parts of HP-β-CD, 7.5 parts of phosphatidase 13s, 1800 parts of dehydrated alcohol.
Preparation method is substantially with embodiment 1.
Embodiment 10:
The weight ratio of components of the each component containing in formula is: 4.1 parts of rutaecarpins, 11.5 parts of HP-β-CD, 4.8 parts of phosphatidase 13s, 2100 parts of dehydrated alcohol.
Preparation method is substantially with embodiment 1.
Embodiment 11:
The weight ratio of components of the each component containing in formula is: 4.0 parts of rutaecarpins, 26.7 parts of HP-β-CD, 83 parts, phospholipid, 2000 parts of dehydrated alcohol.
Preparation method is substantially with embodiment 1.
Embodiment 12:
The weight ratio of components of the each component containing in formula is: 4.2 parts of rutaecarpins, 11.6 parts of HP-β-CD, 5.6 parts of phosphatidase 11s, 2400 parts of dehydrated alcohol.
Preparation method is substantially with embodiment 1.
Claims (2)
1. a composite supramolecular rutaecarpin nanoparticle, is characterized in that: in preparation, each weight percentages of components is:
2. the preparation method of composite supramolecular rutaecarpin nanoparticle according to claim 1: rutaecarpin, HP-β-CD, the phospholipid of getting recipe quantity, be dissolved in dehydrated alcohol, after 40-60 DEG C of reaction in temperature constant magnetic stirring 3-5 hour, rotary evaporation is removed dehydrated alcohol, vacuum drying is removed residual dehydrated alcohol, obtains composite supramolecular rutaecarpin nanoparticle.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108904504A (en) * | 2018-06-20 | 2018-11-30 | 暨南大学 | Application of the rutaecarpin in the drug of preparation enhancing NLRP3 inflammation corpusculum activation |
| CN113599538A (en) * | 2021-08-19 | 2021-11-05 | 重庆医科大学 | Teriparatide supermolecule slow-release nanoparticle and preparation method thereof |
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| CN1475205A (en) * | 2002-08-15 | 2004-02-18 | 刘云清 | Medicine conveying system--preparation method of solid nano medicine |
| CN103284947A (en) * | 2012-02-23 | 2013-09-11 | 重庆医科大学 | Evodiamine nanoemulsion |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1475205A (en) * | 2002-08-15 | 2004-02-18 | 刘云清 | Medicine conveying system--preparation method of solid nano medicine |
| CN103284947A (en) * | 2012-02-23 | 2013-09-11 | 重庆医科大学 | Evodiamine nanoemulsion |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108904504A (en) * | 2018-06-20 | 2018-11-30 | 暨南大学 | Application of the rutaecarpin in the drug of preparation enhancing NLRP3 inflammation corpusculum activation |
| CN113599538A (en) * | 2021-08-19 | 2021-11-05 | 重庆医科大学 | Teriparatide supermolecule slow-release nanoparticle and preparation method thereof |
| CN113599538B (en) * | 2021-08-19 | 2024-02-09 | 重庆医科大学 | Teriparatide supermolecule slow-release nanoparticle and preparation method thereof |
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