CN1306955C - Sodium ferulic acid albumin nano granular preparation and its preparing method - Google Patents
Sodium ferulic acid albumin nano granular preparation and its preparing method Download PDFInfo
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- CN1306955C CN1306955C CNB2004100664719A CN200410066471A CN1306955C CN 1306955 C CN1306955 C CN 1306955C CN B2004100664719 A CNB2004100664719 A CN B2004100664719A CN 200410066471 A CN200410066471 A CN 200410066471A CN 1306955 C CN1306955 C CN 1306955C
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Abstract
The present invention relates to a new preparation of sodium ferulate, namely sodium ferulate albumin nanoparticle preparation and a preparation method thereof, which belongs to the technical field of medicines. The sodium ferulate nanoparticle preparation prepared by the method of the present invention has the advantages of round and normal shape and narrow particle size distribution; the particle size range is from 50 to 250 nm, and the average particle size is 185 nm; the present invention can be prepared into freeze dried powder which can be prepared into an injection for intravenous injection while in use. After the sodium ferulate carried in albumin nanoparticle carriers enters systematic circulation, the nanometer particles are adsorbed by plasma opsonin proteins; macrophages in reticuloendothelial system of the liver, spleen, etc. specifically recognize and phagocytize the particles so that the sodium ferulate passively targeted to the liver; since most of the nanoparticles prepared by the method can penetrate through window-shaped small holes in a canaliculus endothelial cell layer of hepatic sinusoid and accumulate in the liver without entering systematic circulation to form a liver targeting administration system, the concentration of sodium ferulate at lesion sites is increased; thereby, the therapeutic effect of the medicine is increased, and the side effect of sodium ferulate on other organs of a human body is reduced.
Description
Technical field:
The present invention relates to medical technical field, is a kind of novel form of sodium ferulate---sodium ferulic acid albumin nano granular preparation and preparation method thereof.
Background technology:
Sodium ferulate is a clinical commonly used drug, find that after deliberation sodium ferulate has effect of anti hepatic fibrosis, and existing dosage form mostly is conventional tablet, powder and aqueous pharmaceutical etc., after medicine enters the interior whole body distribution of body, can't concentrate in liver performance curative effect, even outside liver, produce untoward reaction.
Albumin nano granular is as pharmaceutical carrier safety non-toxic, non-immunogenicity, biodegradable, good biocompatibility, and the unique targeting of tool, slow controlled capability and protection drug effect are one of biomedicine field focuses of attracting attention.After said targeting is meant that albumin nano granular preparation enters the body circulation, by blood plasma opsonin albumen (complement in the biological fluid, immunoglobulin) absorption, reticuloendothelial system can be by inherent biochemical action picked-up nanoparticle to by the microgranule of blood plasma opsonin protein adsorption the specific recognition ability being arranged.It is abundant that liver, spleen, bone marrow etc. are located reticuloendothelial system, and albumin nano granular is easily by the macrophage phagocytic at these several places, medicine concentrated locate in liver spleen etc., so tool organ targeting.But owing to only there be the nanoparticle of particle diameter between 70-200nm just can pass window shape aperture in the sinus hepaticus shape tubule endothelial layer, do not enter the body circulation in liver's accumulation, so preparation method must be able to be controlled size and surface nature just can make drug targeting in liver.And existing preparation albumin nano granular adopts thermal denaturation emulsification method, need with an organic solvent remove oiliness residue and surfactant, not only easily cause residual, for the purification of nanoparticle brings difficulty, and the difficult control of particle diameter, also unfavorable to the thermally labile medicine in addition.Another kind of wide, and need under salt-free condition, carry out the pH value adjustment with the prepared albumin nano granular particle size distribution of pH-coacervation, and as everyone knows under the high concentration protein existence condition, the reliability of measuring pH value with glass electrode is limited.
Summary of the invention:
The invention provides a kind of sodium ferulic acid albumin nano granular preparation and may command nanoparticle particle diameter is the preparation method of 50-250nm.
Sodium ferulic acid albumin nano granular preparation of the present invention is that sodium ferulate, albumin are dissolved in aqueous solvent or neutral salt solution (as 10mM NaCl etc.) by a certain percentage, control pH value 6-11, stirring state continues to add a certain amount of dehydrant (as ethanol, methanol, acetone etc.) down, after forming sodium ferulic acid albumin nano granular, add an amount of cross-linking agent (as glutaraldehyde, methyl polyethylene-dextran) or stabilizing agent lactic acid, continuous stirring is impelled the nanoparticle crosslinking curing more than 12 hours.Gained sodium ferulic acid albumin nano granular colloidal suspension slight fever (about 37 ℃, down together) is spent the night, get final product with lyophilizing after removing ethanol.Add proper amount of surfactant (as poloxamer etc.) in the preparation and can improve nanoparticle envelop rate and carrying drug ratio.
Above-mentioned gained sodium ferulic acid albumin nano granular particle diameter 50-250nm, mean diameter is 185nm.
The preparation method of sodium ferulic acid albumin nano granular preparation of the present invention is an a kind of desolvation and physics parcel absorption method, have fast and convenient, characteristics such as cost is low, and is workable, and particle size distribution is narrower, concrete grammar is:
1. fill a prescription and proportioning:
Sodium ferulate 5～200mg
Albumin 5～600mg
Solvent 1～4ml
Dehydrant 3～30ml
Cross-linking agent 1～800 μ l
Stabilizing agent lactic acid 0～800 μ l
Surfactant poloxamer 0～800 μ l
Wherein dehydrant is selected from a kind of in ethanol, methanol, the acetone; Cross-linking agent is selected from a kind of in glutaraldehyde, the methyl polyethylene-dextran; Solvent is selected from distilled water or the 10mM NaCl solution a kind of.
Preferably:
Sodium ferulate 12.5～100mg
White egg 12.5～200mg
Distilled water or 10mM NaCl 2～4ml
95% ethanol (dehydrants such as acetone, methanol), 4～25ml
Glutaraldehyde or methyl polyethylene-dextran 3～200 μ l
Stabilizing agent lactic acid 0～600 μ l
Surfactant poloxamer 0～600 μ l
Preferred especially:
Sodium ferulate 12.5～50mg
Albumin 25～100mg
Distilled water or 10mM NaCl 4ml
95% ethanol, 4～12ml
Glutaraldehyde or methyl polyethylene-dextran 3～120 μ l
Stabilizing agent lactic acid 0～400 μ l
Surfactant poloxamer 0～400 μ l
2. preparation sodium ferulic acid albumin nano granular preparation
(1) preparation sodium ferulic acid albumin solution is dissolved in albumin, sodium ferulate aqueous solvent or neutral salt solution (as 10mM NaCl etc.) by a certain percentage, and pH is adjusted to 6-11, also can add the proper amount of surfactant poloxamer and stir fully dissolving.
(2) preparation sodium ferulic acid albumin nano granular colloidal suspension continues a certain amount of dehydrant (as ethanol, acetone, methanol etc.) to add in the solution that (1) make with 0.1-5.0ml/min speed under stirring state.
(3) crosslinked stablizing with purification adds a certain amount of cross-linking agent (as glutaraldehyde, methyl polyethylene-dextran etc.) or stabilizing agent lactic acid in the sodium ferulic acid albumin nano granular colloidal suspension that (2) make, and stirs more than 12 hours, impels the nanoparticle crosslinking curing.Gained colloidal suspension slight fever is spent the night, remove ethanol or acetone, methanol, lyophilization can make the nanoparticle lyophilized formulations of sodium ferulate.The nanoparticle particle diameter is 50-250nm, and mean diameter is 185nm.
Said method provided by the invention also can prepare other medicine carrying albumin nano granular preparations.Certainly, also can select for use the other biological degradation material to prepare sodium ferulic acid nano grain preparation, hand over fat (PLA), poly-own fat (PGA), poly-own lactone (PCL), PMMA, polystyrene (PS), cellulose, cellulose-polyethylene, poly-hydracrylic acid fat, the gelatin etc. handed over as poly-third as nano-medicament carrier.
The specific embodiment:
Now in conjunction with the embodiments, the present invention is described in detail
Embodiment 1 preparation sodium ferulic acid albumin nano granular preparation
Precision takes by weighing the 25.0mg albumin, is dissolved in the 4.0ml 10mM NaCl aqueous solution, and pH value is 8.3.Precision takes by weighing sodium ferulate 12.5mg and is dissolved in the albumin aqueous solution again, and (300 rev/mins) continue to add 11.0ml 95% ethanol with the speed of 0.5ml/min under the stirring at room, can form sodium ferulic acid albumin nano granular.Add 8% glutaraldehyde water solution, 29 μ l again and make microgranule crosslinked, stir more than the 12h simultaneously in the cross-linking process.Detect through laser light scattering instrument, gained sodium ferulic acid albumin nano granular particle diameter is 181.0nm, and particle size distribution is 86.3%.Observe visible nanoparticle form under the Electronic Speculum than rounding, particle size distribution is narrower.Gained nanoparticle colloidal suspension slight fever is spent the night,, adopt the conventional method lyophilization can obtain the sodium ferulic acid albumin nano granular lyophilized formulations to remove ethanol.
Embodiment 2
Precision takes by weighing the 50.0mg albumin, is dissolved in the 4.0ml distilled water, and pH value is 8.3.Precision takes by weighing sodium ferulate 12.5mg and is dissolved in the albumin aqueous solution again, and (300 rev/mins) continue to add 8.0ml 95% ethanol with the speed of 0.5ml/min under the stirring at room, can form sodium ferulic acid albumin nano granular.Add 8% glutaraldehyde water solution, 27 μ l again and make microgranule crosslinked, stir more than the 12h simultaneously in the cross-linking process.Detect through laser light scattering instrument, gained sodium ferulic acid albumin nano granular particle diameter is 191.4nm, and particle size distribution is 86.8%.Observe visible nanoparticle form under the Electronic Speculum than rounding, particle size distribution is narrower.Gained nanoparticle colloidal suspension slight fever is spent the night,, adopt the conventional method lyophilization can obtain the sodium ferulic acid albumin nano granular lyophilized formulations to remove ethanol.
Albumin and sodium ferulate be with other proportionings, as albumin 200mg, and sodium ferulate 50mg; Albumin 100mg, sodium ferulate 50mg; Albumin 100mg, sodium ferulate 12.5mg; Albumin 12.5mg, sodium ferulate 12.5mg; Albumin 12.5mg, sodium ferulate 50mg or albumin 50mg, sodium ferulate 100mg etc. adopt the method identical with embodiment 1 to be prepared, and can obtain sodium ferulic acid albumin nano granular preparation equally.
The sodium ferulic acid nano grain preparation form that the inventive method makes is rounding comparatively, and narrower particle size distribution, particle size range are 50～250nm, and mean diameter is 185nm.Available freeze-drying makes lyophilized preparation, can be made into the injection intravenous injection during use.Sodium ferulate is after the albumin nano granular carrier is written into the body circulation, nanoparticle is by blood plasma opsonin protein adsorption, liver, spleens etc. are located the macrophage specific recognition of reticuloendothelial system and are engulfed these microgranules, make the sodium ferulate passive target in liver, because the nanoparticle overwhelming majority of this method preparation can pass the window shape aperture in the sinus hepaticus shape tubule endothelial layer, do not enter the body circulation in liver's accumulation, become hepatic-targeted delivery system, thereby improved the concentration of sodium ferulate at diseased region, improved curative effect of medication, also reduced the side effect of sodium ferulate other position of health.
Claims (5)
1. the preparation method of a sodium ferulic acid albumin nano granular preparation, prescription is as follows with proportioning:
Sodium ferulate 5～200mg
Albumin 5～600mg
Solvent 1～4ml
Dehydrant 3～30ml
Cross-linking agent 1～800 μ l
Stabilizing agent lactic acid 0～800 μ l
Surfactant poloxamer 0～800 μ l
Wherein dehydrant is selected from a kind of in ethanol, methanol, the acetone; Cross-linking agent is selected from a kind of in glutaraldehyde, the methyl polyethylene-dextran; Solvent is selected from distilled water or the 10mMNaCl solution a kind of;
Concrete steps are:
(1) preparation sodium ferulic acid albumin solution
By proportioning albumin and sodium ferulate are dissolved in solvent, pH is adjusted to 6-11, adds or do not add surfactant;
(2) preparation sodium ferulic acid albumin nano granular colloidal suspension
Under stirring state, in proportion dehydrant continue is added in the solution that (1) make with 0.1-5.0ml/min speed;
(3) crosslinked stable and purification
Add cross-linking agent or stabilizing agent in proportion in the colloidal suspension that (2) make, stir and impel the nanoparticle crosslinking curing more than 12 hours, slight fever is spent the night and is flung to dehydrant again, and lyophilization gets lyophilized formulations.
2. by the preparation method of the described sodium ferulic acid albumin nano granular preparation of claim 1, it is characterized in that prescription and proportioning are as follows:
Sodium ferulate 12.5～100mg
Albumin 12.5～200mg
Distilled water or 10mM NaCl 2～4ml
Acetone or methanol or 95% ethanol, 4～25ml
Glutaraldehyde or methyl polyethylene-dextran 3～200 μ l
Stabilizing agent lactic acid 0～600 μ l
Surfactant poloxamer 0～600 μ l
3. by the preparation method of the described sodium ferulic acid albumin nano granular preparation of claim 2, it is characterized in that prescription and proportioning are as follows:
Sodium ferulate 12.5～50mg
Albumin 25～100mg
Distilled water or 10mMNaCl 4ml
95% ethanol, 4～12ml
Glutaraldehyde or methyl polyethylene-dextran 3～120 μ l
Stabilizing agent lactic acid 0～400 μ l
Surfactant poloxamer 0～400 μ l
4. the sodium ferulic acid albumin nano granular preparation that makes of claim 1 or 2 or 3 described methods.
5. the application of the described sodium ferulic acid albumin nano granular preparation of claim 4 in preparation treatment hepatic fibrosis medicines.
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| CNB2004100664719A CN1306955C (en) | 2004-09-17 | 2004-09-17 | Sodium ferulic acid albumin nano granular preparation and its preparing method |
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| CN1306955C true CN1306955C (en) | 2007-03-28 |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1302808C (en) * | 2005-11-03 | 2007-03-07 | 中国人民解放军第二军医大学 | Nanometer granule prepn of cinobufagin toxoprotein and its prepn process |
| CN1302809C (en) * | 2005-11-03 | 2007-03-07 | 中国人民解放军第二军医大学 | Nanometer granule prepn of bufanin albumin and its prepn process |
| CN102415999A (en) * | 2011-12-07 | 2012-04-18 | 中国药科大学 | Breviscapine albumin nanoparticles prepared by adsorbing breviscapine through albumin nanoparticles |
| CN103356485B (en) * | 2012-04-10 | 2019-06-07 | 青岛大学附属医院 | Hirudin albumin nano granular and preparation method thereof |
| CN102940621B (en) * | 2012-11-27 | 2014-08-13 | 桂林医学院 | Application of methyl ferulic acid in preparation of medicine for preventing and curing hepatic fibrosis |
| CN110384679A (en) * | 2018-04-16 | 2019-10-29 | 广州铠宝蕊医药科技有限公司 | Cabazitaxel albumin nano granular preparation and the preparation method and application thereof |
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