CN104490772A - Liver targeting taxol nanometer suspension and preparation method thereof - Google Patents
Liver targeting taxol nanometer suspension and preparation method thereof Download PDFInfo
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- CN104490772A CN104490772A CN201510027805.XA CN201510027805A CN104490772A CN 104490772 A CN104490772 A CN 104490772A CN 201510027805 A CN201510027805 A CN 201510027805A CN 104490772 A CN104490772 A CN 104490772A
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Abstract
The invention discloses a liver targeting taxol nanometer suspension and a preparation method of the liver targeting taxol nanometer suspension. Taxol serves as therapeutic, poloxamer F127 modified by lactobionic acid serves as a stabilizer, the liver targeting taxol nanometer suspension is prepared with an ultrasonic coprecipitation united high pressure homogenizing method, the particle size ranges from 160 nm to 200 nm, and the polydispersity index is 0.2 +/- 0.012. According to the nanometer suspension, the galactose residue on the poloxamer F127 is acylated by lactobionic acid, asialoglycoprotein receptors on liver surface parenchyma cells are recognized, and the effect of liver targeted drug delivery is achieved.
Description
Technical field
The present invention relates to a kind of Liver targeting taxol nanosuspension and preparation method thereof, belong to field of medicaments.
Background technology
Paclitaxel (Paclitaxel, PTX) is Americanized scholar Wall and Wani a kind of tetracyclic diterpene series antineoplastic medicament that extracting and developing obtained from the bark of Taxus brevifolia in 1971.Horwitz equals its mechanism of action of 1979 annual reports.Due to mechanism of action and the curative effect of its uniqueness, since the nineties, successively independently be used for by U.S. FDA approval or combine the treatment for advanced ovarian cancer, metastatic breast cancer, nonsmall-cell lung cancer and the Kpaosi ｀ s tumor relevant with acquired immune deficiency syndrome (AIDS) with other medicine, showing wide application and development prospect.The molecular formula of paclitaxel is C
47h
51nO
14, molecular weight is 853.92, and structural formula is as follows:
The dissolubility of paclitaxel in water is very low, is about 4 μ g.mL
-1, oral administration biaavailability is poor, is therefore difficult to intravenously administrable.At present except the injection Paclitaxel liposome gone on the market (power is simple) (Jiangsu Province Medicine Primary Institute, Nanjing Sike Pharmaceutical Co., Ltd and Jiangsu Province's liposome medicament Engineering Technical Research Centre joint research and development) and obtained the albumin-bound paclitaxel nanoparticle injection suspension (research and development of American Bioscience company) that U.S. food Drug Administration ratifies listing, most domestic adds surfactant polyoxyethylene Oleum Ricini (Cremophor EL) in injection, namely with Cremophor EL/ dehydrated alcohol (50: 50, V/V) make for hydrotropy carrier and look for thick concentrated solution, said preparation paclitaxel concentration reaches 6mg.mL-1, with 5% glucose or normal saline dilution to 0.3 ~ 1.2mg.mL during use
-1.During clinical administration, preparation can produce precipitation when water dilutes, and during intravenous drip, use 0.22 μm of filtering with microporous membrane of still needing, uses inconvenience.Cause histamine release during Cremophor EL degradation in vivo in addition, cause serious anaphylaxis, Neutrophilic granulocytopenia reaches the toxicity 3 ~ 4 grades that WHO specifies.Have research display, although after pretreatment, anaphylactoid incidence rate still reaches 10% ~ 30%, greatly limit its Clinical practice.
Paclitaxel is due to the mechanism of action of its uniqueness, and the antitumor action of wide spectrum obtains to be paid close attention to widely, but the anaphylaxis caused due to solvent, clinical practice is restricted.The researcher of different subject all tries hard to seek the method for the dissolubility increasing paclitaxel, but because of the complexity of its molecular structure, changes pH value, salt forming method, cosolvent all can not solve its solubility well.At present, both at home and abroad all in the research actively developing paclitaxel nano preparation.Nanometer formulation can increase drug solubility and dissolution rate, and then improves bioavailability, and has long-acting in certain cancer target effect and body.
A kind of sub-micrometer colloidal dispersion that nano suspension system adopts the pure drug particle of a small amount of surfactants stabilize to be formed.Nano suspension drug particles particle diameter is less than 1 μm, most within the scope of 150 ~ 800nm, and the relative surface area of medicine is large, substantially increases the dissolution rate of medicine, efficiently solves the problem that drug solubility is low.And in nano suspension, the content of surfactant is less, the zest that when greatly reducing drug administration by injection, surfactant causes and toxic and side effects.Compared with nano-drug transporter, nano suspension has following characteristics: (1), not by the restriction of envelop rate, drug dose adjusting range is wide, easily meets clinical demand.(2) dosage form variation, nanosuspension can be solidified further by spraying dry, lyophilization or fluid bed drying, is prepared into the injection types such as the solid preparation such as tablet, capsule or lyophilized powder.(3) nanometer particle size controllable precise, size is the important parameter of nanometer formulation, and due to medicine self nanorize, the particle diameter of actual measurement is the particle diameter of drug particle, truly can reflect the particle size of nanorize medicine.(3) to have versatility simple to operate for preparation method, and be easy to industrialized great production, conventional equipment such as high pressure homogenizer, high pressure microjet or wet milk all can prepare nanometer suspension agent medicine, and its preparation technology is simple, is suitable for large commercial production.
Hepatocarcinoma (HCC) is prevailing malignant primary liver neoplasm, HCC in most of population of US and European, not generally.But in many Asia and African country, be one of three large fatal cancers.Liver participates in removing toxic substances in body, and digestion and the many process hepatocyte of immunomodulating are mainly divided into hepatic parenchymal cells and liver non-parenchymal cell.Hepatic parenchymal cells is topmost cell in hepatocyte, is also to wait the main cell invaded and harassed, as hepatocarcinoma and hepatitis mainly occur in hepatic parenchymal cells by virus simultaneously.Asialoglycoprotein receptor is the efficient endocytic receptor of distinctive one on hepatic parenchymal cells film, with the carrier of narrow spectrum identification molecular end with galactose residue, and can combine with it, complex generation microscopic clusters collection, lysosome is swallowed to, release medicine after caving in.Asialoglycoprotein receptor is not degraded, and again transfers on cell membrane, participate in next round circulation, this research employing be poloxamer F127 end by chemical bond linkage galactose residue, make Liver targeting carrier, reach liver targeted drug delivery.
Summary of the invention
The present invention is directed to taxol solubility low, bioavailability is poor, existing preparation toxic and side effects is large, the problems such as intravenous administration cannot be used for, devise a kind of taxol nanosuspension of Liver targeting material settling out, utilize the asialoglycoprotein receptor specific recognition galactose part on hepatic parenchymal cells surface and receptor-mediated phagocytosis, medicine is transported to liver position, realizes target administration.
To the invention provides the stabilizing agent modified with lactobionic acid be targeting material taxol nanosuspension and preparation method thereof, concrete preparation process is:
(1) by medicine dissolution in the organic solvent of one of appropriate methanol, ethanol, acetone, chloroform, isopropyl alcohol, ethyl acetate, ethyl lactate or combination in any, magnetic agitation is to dissolving completely.
(2) be dissolved in the water by targeting stabilizing agent, magnetic agitation is to dissolving completely.
(3) under ice-bath ultrasonic condition, syringe drug solution is adopted slowly to be injected in the aqueous solution containing targeting stabilizing agent, ultrasonic 5-8 minute.
(4) 40 DEG C of rotary evaporations remove organic solvent, obtain thick nano suspension.
(5) by above-mentioned sample under condition of ice bath, adopt high pressure homogenization method process, obtain paclitaxel liver-targeted nanometer suspensoid.
Medicine is paclitaxel, but is not limited to this, and medicine can also be the other drug that can be used for the hepatic disease such as Hepatoma therapy, hepatitis.
Targeting stabilizing agent is the stabilizing agent that lactobionic acid is modified, and what be specially the modification of the lactobionic acid acidylate poloxamer (GLC-Pluronic) of synthesis, lactobionic acid phospholipid or other lactobionic acids has surface-active stabilizing agent.
Organic solvent is selected from the organic solvent of one of methanol, ethanol, acetone, chloroform, isopropyl alcohol, ethyl acetate, ethyl lactate or combination in any, nano suspension particle diameter obtained by integrated survey, the factors such as the toxicity of organic solvent, the present invention finally determines to adopt methanol to be organic solvent.
Aqueous solution can be selected from deionized water, 0.9% sodium-chloride water solution or phosphate buffer any one.
The mass ratio of prescription Chinese medicine and stabilizing agent is 1: 1 ~ 1: 10, and be preferably 1: 4, the mass volume ratio of medicine and organic solvent is 50: 1 ~ 1: 20, is preferably 8: 1.
The ultrasound intensity of ultrasonic cell disintegration instrument is 200 ~ 800w, and ultrasonic time is 1 ~ 10min, is preferably the ultrasonic 5min of 400w.
The homogenization pressure of high pressure homogenizer is 200 ~ 1500bar, and homogenization cycles is 5 ~ 25 times, is more preferably 800bar homogenizing 15 times.
The invention has the advantages that:
1) dissolubility of paclitaxel in water is very low, and bioavailability is poor, is difficult to pass through intravenous administration.The present invention adopts ultrasonic-co-precipitation high pressure homogenization method preparation.The recrystallization process of medicine carries out under ultrasound condition, ensures that the particle diameter obtained is more even.With directly adopt compared with homogenizing method, reach same particle size require needed for homogenization pressure lower, cycle-index is less, less to the degree of wear of instrument.
2) preparation method of the present invention is less demanding to instrument and equipment, and technical process is simple, can carry out amplification suitability for industrialized production, have a good application prospect.
3) the present invention adopts lactobionic acid acidylate poloxamer F127 to be stabilizing agent; improve the stability of prepared nano suspension, galactose residue can active targeting liver, improves the dose in liver; reduce the toxic and side effects of medicine to other organs, improve the therapeutic effect of medicine.
Accompanying drawing explanation
Fig. 1 is lactobionic acid acidylate poloxamer F127 synthetic schemes.
Fig. 2 is lactobionic acid poloxamer F127 Infrared Characterization figure.
Fig. 3 is the transmission electron microscope photo of suspension freeze-dried dose of paclitaxel liver-targeted nanometer prepared by embodiment 2.
Fig. 4 is the grain size distribution of suspension freeze-dried dose of paclitaxel liver-targeted nanometer prepared by embodiment 3.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated, but protection scope of the present invention, be not limited to this.
Embodiment 1:
The synthesis of lactobionic acid acidylate poloxamer F127 (GLC-F127): 5g poloxamer F127 is dissolved in 50mL acetone by (1); then the normal hexane of 60mL pre-cooling is added; poloxamer F127 is separated out, and filter, vacuum drying obtains the poloxamer F127 of purification.Poloxamer F127 and 0.24gNaH after 0.63g purification is dissolved in 15mL anhydrous chloroform, separately by 0.1g 2-bromine ethamine hydrobromic acid (BrCH
2cH
2nH
3br) be dissolved in appropriate chloroform, then by BrCH
2cH
2nH
3the chloroformic solution of Br, under the condition of nitrogen protection, is slowly added drop-wise in above-mentioned solution, room temperature magnetic agitation 24h in 1h.After reaction terminates, deionized water dialysis 24h, namely vacuum lyophilization obtain F127-NH
21.136g lactobionic acid, 0.3gNHS, 0.42gEDCHCl and 0.03gDMAP are dissolved in the anhydrous DMSO of 10mL, and add 0.1mL triethylamine, nitrogen protection by white crystalline powder (2), and under lucifuge condition, room temperature magnetic agitation 12h activates.By 2g poloxamer F127-NH
2be dissolved in the anhydrous DMSO of 10mL, then add 0.1mL triethylamine, magnetic agitation is slowly added drop-wise to poloxamer F127-NH to the reactant liquor dissolving above-mentioned activation completely
2anhydrous DMSO solution in, under nitrogen protection condition, room temperature magnetic agitation reaction 24h.After reaction terminates; 15mL deionized water is slowly added in reactant liquor; then to be placed in bag filter (MWCO7000) and to change a release medium with dialyse 3d, every 6h of deionized water, namely dialysis solution lyophilization obtains lactobionic acid acidylate poloxamer F127 material.Be Pluronic F127-GLC through Infrared Characterization product.
Embodiment 2:
The preparation of Liver targeting taxol nanosuspension: precision takes 4mg paclitaxel, is dissolved in 2mL methanol, and magnetic agitation, to dissolving completely, obtains solution A.Precision takes 16mg poloxamer F127-GLC and is dissolved in 48mL water, and magnetic agitation, to dissolving completely, obtains B solution.Under ice-bath ultrasonic condition, with syringe just solution A be slowly injected in B solution, the ultrasonic 5min of 400W.40 DEG C of rotary evaporations remove methanol, and thick for gained nano suspension is placed in high pressure homogenizer, 0 DEG C, under 800bar pressure condition, homogenizing 15 times, obtains Liver targeting taxol nanosuspension.Size is 179.1nm, and polydispersity coefficient is 0.19.
Embodiment 3:
The preparation of Liver targeting taxol nanosuspension: precision takes 16mg paclitaxel, is dissolved in 2mL methanol, and magnetic agitation, to dissolving completely, obtains solution A.Precision takes 64mg poloxamer F127-GLC and is dissolved in 48mL water, and magnetic agitation, to dissolving completely, obtains B solution.Under ice-bath ultrasonic condition, with syringe just solution A be slowly injected in B solution, the ultrasonic 5min of 400W.40 DEG C of rotary evaporations remove methanol, and thick for gained nano suspension is placed in high pressure homogenizer, 0 DEG C, under 800bar pressure condition, homogenizing 15 times, obtains Liver targeting taxol nanosuspension.Size is 182.3nm, and polydispersity coefficient is 0.21.
Embodiment 4:
The preparation of Liver targeting taxol nanosuspension: precision takes 16mg paclitaxel, is dissolved in 2mL methanol, and magnetic agitation, to dissolving completely, obtains solution A.Precision takes 64mg poloxamer F127-GLC and is dissolved in 48mL water, and magnetic agitation, to dissolving completely, obtains B solution.Under ice-bath ultrasonic condition, with syringe just solution A be slowly injected in B solution, the ultrasonic 5min of 400W.40 DEG C of rotary evaporations remove methanol, and thick for gained nano suspension is placed in high pressure homogenizer, 0 DEG C, under 1000bar pressure condition, homogenizing 15 times, obtains Liver targeting taxol nanosuspension.Size is 181.7nm, and polydispersity coefficient is 0.22.
Claims (8)
1. Liver targeting taxol nanosuspension and preparation method thereof, is characterized in that: this targeted nano suspensoid prescription comprises medicine, common stable agent, the stabilizing agent (targeting stabilizing agent) that lactobionic acid is modified and water for injection; Preparation technology comprises: medicine dissolution in organic solvent, is slowly injected the aqueous solution containing targeting stabilizing agent, ultrasonic a period of time by a under ice-bath ultrasonic condition; B rotary evaporation removes organic solvent;
cthick for gained in b suspensoid is adopted high pressure homogenization method process, obtains Liver targeting taxol nanosuspension.
2. a kind of Liver targeting taxol nanosuspension and preparation method thereof according to claim 1, it is characterized in that: medicine is paclitaxel, but is not limited to this, medicine can also be the other drug that can be used for the hepatic disease such as Hepatoma therapy, hepatitis.
3. a kind of Liver targeting taxol nanosuspension and preparation method thereof according to claim 1, it is characterized in that: stabilizing agent can be the poloxamer of various model, phospholipid, tween, sodium lauryl sulphate, polyvinylpyrrolidone etc. have surface-active stabilizing agent.
4. a kind of Liver targeting taxol nanosuspension and preparation method thereof according to claim 1; it is characterized in that: the stabilizing agent that lactobionic acid is modified, what be specially the modification of the lactobionic acid acidylate poloxamer (GLC-Pluronic) of synthesis, lactobionic acid phospholipid or other lactobionic acids has surface-active stabilizing agent.
5. a kind of Liver targeting taxol nanosuspension and preparation method thereof according to claim 1, it is characterized in that: the mass ratio of prescription Chinese medicine and stabilizing agent is 1: 1 ~ 1: 10, be preferably 1: 4, the mass volume ratio of medicine and organic solvent is 50: 1 ~ 1: 20, is preferably 8: 1.
6. a kind of Liver targeting taxol nanosuspension and preparation method thereof according to claim 1, it is characterized in that: the organic solvent in preparation technology a can be one of methanol, ethanol, acetone, chloroform, isopropyl alcohol, ethyl acetate, ethyl lactate or combination in any, be preferably methanol.
7. a kind of Liver targeting taxol nanosuspension and preparation method thereof according to claim 1, is characterized in that: the ultrasound intensity in preparation technology a is 200 ~ 800w, and be preferably 400w, ultrasonic time is 1 ~ 10min, is more preferably 5min.
8. a kind of Liver targeting taxol nanosuspension and preparation method thereof according to claim 1, is characterized in that: the high pressure homogenize pressure in preparation technology c is 200 ~ 1500bar, is more preferably 800bar, and homogenization cycles is 5 ~ 25 times, is more preferably 15 times.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105456188A (en) * | 2015-11-30 | 2016-04-06 | 广东中盛药物研究院有限公司 | Targeted paclitaxel nano preparation and preparation method thereof |
| EP3795139A1 (en) * | 2019-09-23 | 2021-03-24 | CAPNOMED GmbH | Composition with drug micro-nano particles of an anti-cancer agent |
| CN112778389A (en) * | 2019-12-31 | 2021-05-11 | 嘉应学院医学院 | Targeting ligand molecule, preparation method thereof and drug loading system |
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| CN101843582A (en) * | 2010-05-18 | 2010-09-29 | 南京工业大学 | Taxol nanosuspension and preparation method thereof |
| CN104274401A (en) * | 2014-07-25 | 2015-01-14 | 中国医学科学院药用植物研究所 | High drug-loading content nano suspension for camptothecin medicine based on HCPT-PEG (hydroxycamptothecin-polyethylene glycol) and preparation method of high drug-loading content nano suspension |
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2015
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101843582A (en) * | 2010-05-18 | 2010-09-29 | 南京工业大学 | Taxol nanosuspension and preparation method thereof |
| CN104274401A (en) * | 2014-07-25 | 2015-01-14 | 中国医学科学院药用植物研究所 | High drug-loading content nano suspension for camptothecin medicine based on HCPT-PEG (hydroxycamptothecin-polyethylene glycol) and preparation method of high drug-loading content nano suspension |
Non-Patent Citations (1)
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105456188A (en) * | 2015-11-30 | 2016-04-06 | 广东中盛药物研究院有限公司 | Targeted paclitaxel nano preparation and preparation method thereof |
| EP3795139A1 (en) * | 2019-09-23 | 2021-03-24 | CAPNOMED GmbH | Composition with drug micro-nano particles of an anti-cancer agent |
| WO2021058423A1 (en) * | 2019-09-23 | 2021-04-01 | CAPNOMED GmbH | Composition with drug micro-nano particles of an anti-cancer agent |
| CN112778389A (en) * | 2019-12-31 | 2021-05-11 | 嘉应学院医学院 | Targeting ligand molecule, preparation method thereof and drug loading system |
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