CN103263392B - A kind of Amoitone derivative long-circulation nanometer lipid carrier and preparation method thereof - Google Patents
A kind of Amoitone derivative long-circulation nanometer lipid carrier and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of Amoitone derivative long-circulation nanometer lipid carrier, main component is crude drug Amoitone B, polyglycol distearate, Solid lipid material, liquid fatty substance material, fat-soluble emulsifier, water soluble emulsifier and water for injection.Its preparation method is emulsifying evaporation-low temperature curing methods.Amoitone B long-circulating nanoliposome carrier prepared by the present invention has slow-release function in vivo, can the holdup time in the body of effective prolong drug, improves the bioavailability of medicine; There is comparatively high encapsulation rate and drug loading; Its particle diameter at about 200nm, can passive target in hepatic tissue, reduce the toxic and side effects of Amoitone B, and its good biocompatibility, easily to degrade, good stability, improves body toleration and patient compliance.
Description
Technical field
The present invention relates to a kind of Amoitone derivative long-circulation nanometer lipid carrier and preparation method thereof.
Background technology
Orphan receptor Nur77(also claim TR3, NGFI-B, TIS1 or NAK-1) be a kind of product of early gene at once, one of important member of orphan nuclear receptor subfamily NR4A, can by abduction deliverings such as nerve growth factor, PDGF, serum and epidermal growth factors, in various biological process, play vital effect, relate to the processes such as cell proliferation, metabolism, variation and apoptosis.The normal overexpression of Nur77 is in tumor cell, and as gastric cancer, pulmonary carcinoma, cancer of pancreas, colon cancer, ovarian cancer etc., having extremely important regulating and controlling effect to inhibition tumor cell growth, is the potential target spot for the treatment of relevant disease.
Cytospora bacterin B (cytosporone B; Csn-B) be belong to fungus HTF3 from Dothiorella ribis a kind of natural product extracted; it is natural Nur77 receptor stimulating agent; there is powerful affinity interaction with Nur77 and directly to be activated; it is made to transfer to mitochondrion from nucleus; it is made to be converted into lethal factor from the protective factors of tumor cell by changing the phenotype of Bcl-2, the release of ger cytochrome C and killing off tumor cells.But low extracted amount limits it and applies further, a series of Csn-B derivant is synthesized in succession.
Adriamycinone derivant Amoitone B is one of them, confirms that its anti-tumor activity is better than parent compound through pharmacologically active evaluation, is a kind of potential antitumor drug.Its chemistry Amoitone B by name, molecular formula is C
22h
44o
5, molecular weight is 378.50, and structural formula as shown in Figure 1, is a kind of off-white color crystalline powder, and odorless, tasteless is water insoluble, is soluble in ethanol, methanol, acetone, DMSO etc., in certain fat-soluble.
The water-fast character of Amoitone B makes its agent in vitro stripping poor, have a strong impact on its in vivo absorption distribution, reduce bioavailability, easily by liver metabolism, biological half-life is short, and unsatisfactory curative effect limits clinical practice.
CN102579373A discloses a kind of Amoitone B nano crystallization, and to improve its dissolubility and dissolution rate, but do not possess slow releasing function, in body, action time is short.
For Amoitone B, clinical needs one has slow releasing function, and circulation time in vivo is long, and administration number of times is few, good stability, bioavailability are high and preparation is simply easy to the preparation that patient uses.
Nanoparticle (nanoparticles) is made up of polymer substance, and medicine can dissolve, be wrapped in wherein or be adsorbed on the surface.The nanosphere (nanospheres) of skeleton solid type and the nanocapsule (nanocapsules) of putamina Drug Storage type can be divided into.
Nano-lipid carrier (nanostructured lipid carriers, NLC) is the new colloidal drug-supplying system developed by solid lipid nanoparticle (solid lipidnanoparticles, SLN).SLN is the nanoparticle made for framework material with the high-melting-point lipid of PHYSIOLOGICALLY COMPATIBLE, the structural limitations of its high-sequential Drug loading capacity, and can cause drug leakage.NLC adds liquid fatty substance in Solid lipid, thus the randomness of crystal is increased, and causes lattice defect, can hold more drug molecule.Therefore NLC has not only possessed that the advantage of SLN is as high in stability, good biocompatibility, bioavailability are high, sensitive medicaments is not degraded, Drug controlled release, passive targeting are good in protection; and envelop rate and the drug loading of medicine can be increased, delay drug leakage.Appropriate liquid fatty substance add the character that can not change nanoparticle solid kernel, therefore NLC still possesses slow controlled release characteristics.
The long-circulating nanoliposome carrier of PEGization is due to the existence of its hydrophilic group, opsonin and its combination can be stoped, thus avoid the phagocytosis of reticuloendothelial system mononuclear phagocyte, can in blood circulation stable existence, the prolong drug half-life, increase action time in medicine body.
In sum, Amoitone B is made long-circulating nanoliposome carrier, expection can reach action time in prolong drug body, changes drug distribution, improves the objects such as bioavailability.Although medicine being made nano-lipid carrier is conventional technological means, but develop a kind of long circulating, release be controlled, good effect, good stability, toxicity are little, the preparation not a duck soup of good biocompatibility, need repeatedly to grope condition, pay a large amount of creative work.
Summary of the invention
For above-mentioned prior art, the invention provides a kind of Amoitone derivative long-circulation nanometer lipid carrier, said preparation can improve Amoitone B dissolubility, there is slow releasing function, can circulation time in vivo be extended, improve bioavailability, good biocompatibility, patient compliance is good, realizes passive targeting, increases stability.Present invention also offers its preparation method, preparation method is simple, is easy to large-scale production.
The present invention is achieved by the following technical solutions:
A kind of Amoitone derivative long-circulation nanometer lipid carrier, composed of the following components: crude drug Amoitone B0.03 ~ 0.5wt%, polyglycol distearate 0.1 ~ 4wt%, Solid lipid material 0.1 ~ 4wt%, liquid fatty substance material 0.05 ~ 2wt%, fat-soluble emulsifier 0.3 ~ 5wt%, water soluble emulsifier 0.3 ~ 5wt%, surplus is water.
Preferably, composed of the following components: crude drug Amoitone B0.03 ~ 0.2wt%, polyglycol distearate 0.85 ~ 3wt%, Solid lipid material 0.85 ~ 3wt%, liquid fatty substance material 0.2 ~ 1wt%, fat-soluble emulsifier 0.5 ~ 2wt%, water soluble emulsifier 0.4 ~ 2wt%, surplus is water.
Described polyglycol distearate is PEG (10) stearate or PEG (40) stearate, or their combination, preferred PEG (40) stearate.
Described Solid lipid material is a kind of or several arbitrarily combination in glyceryl monostearate, stearic acid, behenic acid, Palmic acid, tripalmitin, cholesterol or spermol cetylate, preferred glyceryl monostearate or stearic acid.
Described liquid fatty substance material is a kind of or several arbitrarily combination in oleic acid, linoleic acid, vitamin E, median chain triglyceride oil, olive oil, Oleum Arachidis hypogaeae semen or liquid paraffin, preferred median chain triglyceride oil.
Described fat-soluble emulsifier is a kind of or several arbitrarily combination in lecithin, soybean phospholipid or Span60.
Described water soluble emulsifier is a kind of or several arbitrarily combination in PLURONICS F87, Tween80, Myrij, Brij or sodium lauryl sulphate.
For being suitable for intravenous administration better, the combination of described fat-soluble emulsifier and the preferred soybean phospholipid of water soluble emulsifier and PLURONICS F87.
The preparation method of described Amoitone derivative long-circulation nanometer lipid carrier, comprises the following steps:
(1) Amoitone B, polyglycol distearate, Solid lipid material, liquid fatty substance material and fat-soluble emulsifier are dissolved in organic solvent, are heated to 70 ~ 80 DEG C and dissolve completely, form organic facies;
(2) water soluble emulsifier is dissolved in the water, is heated to 70 ~ 80 DEG C and dissolves completely, form aqueous phase;
(3) under temperature 70 ~ 80 DEG C, mixing speed 800 ~ 1400r/min condition, organic facies is injected in aqueous phase, stirs 2.5h ~ 6h, organic facies is volatilized completely, obtains colostrum;
(4) poured into by colostrum in the water of 0 ~ 2 DEG C, under rotating speed 800 ~ 1400r/min condition, ice bath stirs 1.5h ~ 4h, obtains Amoitone derivative long-circulation nanometer lipid carrier (Amoitone B nano-lipid carrier).
Described organic solvent is a kind of or several arbitrarily combination in ethanol, acetone, chloroform or isopropyl alcohol.
The preparation method of described Amoitone derivative long-circulation nanometer lipid carrier, further comprising the steps of: in obtained Amoitone derivative long-circulation nanometer lipid carrier, to add freeze drying protectant, make lyophilized formulations; Specifically be operable as: the freeze drying protectant of 3 ~ 9wt% is dissolved in Amoitone derivative long-circulation nanometer lipid carrier, be then sub-packed in cillin bottle, put pre-freeze 24h in the ultra cold storage freezer of-80 DEG C; take out; in rapid immigration freezer dryer, lyophilizing 48h, jumps a queue and seals.
Described freeze drying protectant is a kind of or several arbitrarily combination in mannitol, lactose, glucose or trehalose.
The present invention has the following advantages:
(1) Amoitone B long-circulating nanoliposome carrier dissolubility of the present invention is high, has slow-releasing, and circulation time in vivo extends, and bioavailability improves.
(2) Amoitone B long-circulating nanoliposome carrier stability of the present invention is high, good biocompatibility, high-efficiency low-toxicity, good patient compliance.
(3) Amoitone B long-circulating nanoliposome carrier particle diameter of the present invention is at about 200nm, can passive target in hepatic tissue, reduce heart nephrotoxicity.
(4) Amoitone B long-circulating nanoliposome carrier of the present invention is to mix lipid as carrier material, adding of liquid fatty substance, destroys the crystal formation of material to a certain extent, improves drug loading and envelop rate.
(5) Amoitone B long-circulating nanoliposome carrier preparation technology of the present invention is simple, and cost is low, is easy to large-scale production.
Accompanying drawing explanation
Fig. 1 is Amoitone B chemical structural formula.
Fig. 2 is Amoitone B long-circulating nanoliposome carrier transmission electron microscope picture.
Fig. 3 is Amoitone B long-circulating nanoliposome carrier grain size distribution, wherein, and abscissa: particle diameter (diameter), vertical coordinate: percentage rate (%intensity).
Fig. 4 is the cumulative release percentage rate-time graph schematic diagram of Amoitone B long-circulating nanoliposome carrier release in vitro.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.
Embodiment 1 prepares Amoitone B long-circulating nanoliposome carrier
Step is as follows:
Get Amoitone B10mg, PEG (40) stearate 70mg, stearic acid 100mg, oleic acid 40mg, soybean phospholipid 200mg are dissolved in 5ml acetone, be heated to 75 DEG C and dissolve completely, form organic facies;
Get PLURONICS F87 250mg to be dissolved in 10ml water for injection, be heated to 75 DEG C and dissolve completely, form aqueous phase;
Be 75 DEG C in temperature, mixing speed is under 1000r/min condition, organic facies is injected in aqueous phase, stirs 2.5h, organic facies is volatilized completely, obtains colostrum;
Poured into by colostrum in DEG C water of 25ml0 ~ 2, under rotating speed is 1000r/min condition, ice bath stirs 2h, obtains Amoitone B long-circulating nanoliposome carrier.
Embodiment 2 prepares Amoitone B long-circulating nanoliposome carrier
Step is as follows:
Get Amoitone B10mg, PEG (40) stearate 80mg, glyceryl monostearate 80mg, median chain triglyceride oil 40mg, soybean phospholipid 150mg are dissolved in 5ml ethanol, be heated to 80 DEG C and dissolve completely, form organic facies;
Get PLURONICS F87 200mg to be dissolved in 15ml water for injection, be heated to 80 DEG C and dissolve completely, form aqueous phase;
Be 80 DEG C in temperature, mixing speed is under 1200r/min condition, organic facies is injected in aqueous phase, stirs 3h, organic facies is volatilized completely, obtains colostrum;
Poured into by colostrum in DEG C water of 20ml0 ~ 2, under rotating speed is 1200r/min condition, ice bath stirs 2h, obtains Amoitone B long-circulating nanoliposome carrier.
After dilute with water, with its form of H-7000 type transmission electron microscopy observation, as shown in Figure 2.As shown in Figure 2, gained Amoitone B long-circulating nanoliposome carrier size is homogeneous, form rounding, and particle diameter is at about 200nm.
Embodiment 3 prepares Amoitone B long-circulating nanoliposome carrier
Step is as follows:
Get Amoitone B30mg, PEG (40) stearate 250mg, glyceryl monostearate 250mg, oleic acid 100mg, lecithin 250mg are dissolved in 10ml ethanol, be heated to 75 DEG C and dissolve completely, form organic facies;
Get sodium lauryl sulphate 300mg to be dissolved in 20ml water for injection, be heated to 75 DEG C and dissolve completely, form aqueous phase;
Be 75 DEG C in temperature, mixing speed is under 1000r/min condition, organic facies is injected in aqueous phase, stirs 4h, organic facies is volatilized completely, obtains colostrum;
Poured into by colostrum in DEG C water of 20ml0 ~ 2, under rotating speed is 1000r/min condition, ice bath stirs 4h, obtains Amoitone B long-circulating nanoliposome carrier.
Embodiment 4 prepares Amoitone B long-circulating nanoliposome carrier
Step is as follows:
Get Amoitone B20mg, PEG (40) stearate 150mg, glyceryl monostearate 100mg, Palmic acid 50mg, median chain triglyceride oil 60mg, soybean phospholipid 250mg be dissolved in 7ml ethanol, be heated to 70 DEG C dissolve completely, form organic facies;
Get PLURONICS F87 250mg to be dissolved in 20ml water for injection, be heated to 70 DEG C and dissolve completely, form aqueous phase;
Be 70 DEG C in temperature, mixing speed is under 1400r/min condition, organic facies is injected in aqueous phase, stirs 4h, organic facies is volatilized completely, obtains colostrum;
Poured into by colostrum in DEG C water of 25ml0 ~ 2, under rotating speed is 1400r/min condition, ice bath stirs 3h, obtains Amoitone B long-circulating nanoliposome carrier.
After dilute with water, measure particle size distribution with Zetasizer3000HS type laser fineness gage, recording mean diameter is 234.9nm, and polydispersity coefficient is 0.302, as shown in Figure 3.
Embodiment 5 prepares Amoitone B long-circulating nanoliposome carrier
Step is as follows:
Get Amoitone B30mg, PEG (40) stearate 200mg, stearic acid 250mg, Palmic acid 50mg, olive oil 100mg, soybean phospholipid 300mg be dissolved in 10ml acetone-ethanol (volume ratio 1:1), be heated to 75 DEG C dissolve completely, form organic facies;
Get PLURONICS F87 300mg to be dissolved in 10ml water for injection, be heated to 75 DEG C and dissolve completely, form aqueous phase;
Be 75 DEG C in temperature, mixing speed is under 1000r/min condition, organic facies is injected in aqueous phase, stirs 4h, organic facies is volatilized completely, obtains colostrum;
Poured into by colostrum in DEG C water of 25ml0 ~ 2, under rotating speed is 1000r/min condition, ice bath stirs 2h, obtains Amoitone B long-circulating nanoliposome carrier.
The drug release of Amoitone B long-circulating nanoliposome carrier, realized by dialysis: the accurate Amoitone B long-circulating nanoliposome carrier 1.5ml that draws is in bag filter, being placed in containing 200mlpH is that the PBS(of 7.4 is containing 15% ethanol) little stripping rotor, design temperature is 37 DEG C, and rotating speed of agitator is 100r/min.After 0.22um membrane filtration, sample introduction 20ul carries out HPLC mensuration, calculate cumulative release percentage rate, as shown in Figure 4, Amoitone B long-circulating nanoliposome carrier release in vitro is double dynamical as seen from the figure, namely be slow release after being initially prominent releasing, and the increase rate of release accounting for TL ratio along with liquid fatty substance material is accelerated.
Embodiment 6 prepares Amoitone B long-circulating nanoliposome carrier
Step is as follows:
Get Amoitone B40mg, PEG (40) stearate 300mg, glyceryl monostearate 300mg, median chain triglyceride oil 200mg, soybean phospholipid 350mg be dissolved in 10ml acetone-ethanol (volume ratio 1:1), be heated to 80 DEG C dissolve completely, form organic facies;
Get PLURONICS F87 400mg to be dissolved in 25ml water for injection, be heated to 80 DEG C and dissolve completely, form aqueous phase;
Be 80 DEG C in temperature, mixing speed is under 1000r/min condition, organic facies is injected in aqueous phase, stirs 5h, organic facies is volatilized completely, obtains colostrum;
Poured into by colostrum in DEG C water of 25ml0 ~ 2, under rotating speed is 1000r/min condition, ice bath stirs 4h, obtains Amoitone B long-circulating nanoliposome carrier.Lyophilizing.
Its freeze-dry process is: be dissolved in by the mannitol of 5wt% in Amoitone B long-circulating nanoliposome carrier aqueous dispersion, be then sub-packed in cillin bottle, put pre-freeze 24h in the ultra cold storage freezer of-80 DEG C, take out, in rapid immigration freezer dryer, lyophilizing 48h, jumps a queue and seals.
The drug release of Amoitone B long-circulating nanoliposome carrier, realized by dialysis: the accurate Amoitone B long-circulating nanoliposome carrier lyophilizing dispersant 1.5ml that draws is in bag filter, being placed in containing 200mlpH is that the PBS(of 7.4 is containing 15% ethanol) little stripping rotor, design temperature is 37 DEG C, and rotating speed of agitator is 100r/min.After 0.22um membrane filtration, sample introduction 20ul carries out HPLC mensuration, calculates cumulative release percentage rate, as shown in Figure 4.
Embodiment 7 prepares Amoitone B long-circulating nanoliposome carrier
Step is as follows: get Amoitone B10mg, PEG (40) stearate 100mg, glyceryl monostearate 60mg, olive oil 40mg, lecithin 250mg are dissolved in 5ml chloroform, is heated to 70 DEG C and dissolves completely, forms organic facies;
Get PLURONICS F87 250mg to be dissolved in 15ml water for injection, be heated to 70 DEG C and dissolve completely, form aqueous phase;
Be 70 DEG C in temperature, mixing speed is under 800r/min condition, organic facies is injected in aqueous phase, stirs 4h, organic facies is volatilized completely, obtains colostrum;
Poured into by colostrum in DEG C water of 20ml0 ~ 2, under rotating speed is 800r/min condition, ice bath stirs 2h, obtains Amoitone B long-circulating nanoliposome carrier.
Claims (7)
1. an Amoitone derivative long-circulation nanometer lipid carrier, is characterized in that: composed of the following components:
Amoitone B20mg, PEG (40) stearate 150mg, glyceryl monostearate 100mg, Palmic acid 50mg, median chain triglyceride oil 60mg, soybean phospholipid 250mg, PLURONICS F87 250mg, water 45ml.
2. an Amoitone derivative long-circulation nanometer lipid carrier, is characterized in that: composed of the following components:
Amoitone B10mg, PEG (40) stearate 80mg, glyceryl monostearate 80mg, median chain triglyceride oil 40mg, soybean phospholipid 150mg, PLURONICS F87 200mg, water 35ml.
3. an Amoitone derivative long-circulation nanometer lipid carrier, is characterized in that: composed of the following components:
Amoitone B30mg, PEG (40) stearate 200mg, stearic acid 250mg, Palmic acid 50mg, olive oil 100mg, soybean phospholipid 300mg, PLURONICS F87 300mg, water 35ml.
4. an Amoitone derivative long-circulation nanometer lipid carrier, is characterized in that: composed of the following components:
Amoitone B40mg, PEG (40) stearate 300mg, glyceryl monostearate 300mg, median chain triglyceride oil 200mg, soybean phospholipid 350mg, PLURONICS F87 400mg, water 50ml.
5. the preparation method of the Amoitone derivative long-circulation nanometer lipid carrier according to any one of Claims 1 to 4, is characterized in that: comprise the following steps:
(1) Amoitone B, polyglycol distearate, Solid lipid material, liquid fatty substance material and fat-soluble emulsifier are dissolved in organic solvent, are heated to 70 ~ 80 DEG C and dissolve completely, form organic facies;
(2) water soluble emulsifier is dissolved in the water, is heated to 70 ~ 80 DEG C and dissolves completely, form aqueous phase;
(3) under temperature 70 ~ 80 DEG C, mixing speed 800 ~ 1400r/min condition, organic facies is injected in aqueous phase, stirs 2.5h ~ 6h, organic facies is volatilized completely, obtains colostrum;
(4) poured into by colostrum in the water of 0 ~ 2 DEG C, under rotating speed 800 ~ 1400r/min condition, ice bath stirs 1.5h ~ 4h, obtains Amoitone derivative long-circulation nanometer lipid carrier.
6. the preparation method of Amoitone derivative long-circulation nanometer lipid carrier according to claim 5, is characterized in that: described organic solvent is a kind of or several arbitrarily combination in ethanol, acetone, chloroform or isopropyl alcohol.
7. the preparation method of Amoitone derivative long-circulation nanometer lipid carrier according to claim 5; it is characterized in that: further comprising the steps of: in obtained Amoitone derivative long-circulation nanometer lipid carrier, add freeze drying protectant; make lyophilized formulations: be dissolved in Amoitone derivative long-circulation nanometer lipid carrier by the freeze drying protectant of 3 ~ 9wt%; put pre-freeze 24h in the ultra cold storage freezer of-80 DEG C; take out; in rapid immigration freezer dryer, lyophilizing 48h, to obtain final product.
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| CN1883455A (en) * | 2006-07-07 | 2006-12-27 | 中国科学院上海药物研究所 | A long-circulating nanoliposome carrier of hydroxycamptothecine and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1883455A (en) * | 2006-07-07 | 2006-12-27 | 中国科学院上海药物研究所 | A long-circulating nanoliposome carrier of hydroxycamptothecine and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| Studies on the preparation, characterization and pharmacokinetics of Amoitone B nanocrystals;Leilei Hao etal;《International Journal of Pharmaceutics》;20120511;第433卷;第157-164页 * |
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