CN101138548B - Polyglycol derivatization phospholipid loaded vinorelbine nano-micelle preparations - Google Patents
Polyglycol derivatization phospholipid loaded vinorelbine nano-micelle preparations Download PDFInfo
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- CN101138548B CN101138548B CN2006101128883A CN200610112888A CN101138548B CN 101138548 B CN101138548 B CN 101138548B CN 2006101128883 A CN2006101128883 A CN 2006101128883A CN 200610112888 A CN200610112888 A CN 200610112888A CN 101138548 B CN101138548 B CN 101138548B
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- Prior art keywords
- vinorelbine
- phospholipid
- nano
- micelle
- polyglycol derivatization
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Abstract
The present invention provides a nanometer micelle of the vinorelbine preparation for the vein injection, which comprises the vinorelbine of effective amount, the polyethylene glycol-phospholipid and the adjuvant accepted in pharmacy. The nanometer micelle of the vinorelbine preparation for the vein injection is prepared by packaging the vinorelbine into the nanometer micelle. The nanometer micelles with uniform diameter are formed by the vinorelbine and the polyethylene glycol-phospholipid. In the micelle, the hydrophobic core of the vinorelbine is packaged by the carbowax molecule; therefore an inhibitory coating with hydrophilicity is formed. The contaction between the vinorelbine and the enzyme protein molecule in the blood is avoided. The vinorelbine is protected from identification and swallowing by the endothelial system. The circulating time of the medicine in the body is prolonged. In addition, the micelle improves the storing actability and the anti-tumor effect of the vinorelbine. The toxicity of the vinorelbine is reduced.
Description
Technical field
The present invention relates to can intravenous vinorelbine nano-micelle preparations and preparation method thereof.
Background technology
Catharanthus roseus alkaloids anti-tumor medicaments is the important antitumor drug of the effective broad-spectrum of a class, is widely used in the various cancers of treatment clinically, as leukemia, lymphoma, breast carcinoma, pulmonary carcinoma, hepatocarcinoma and multiple other solid tumors.This series antineoplastic medicament mainly comprises: vinblastine (Vinbastine, VLB), vincristine (Vincristine, VCR), vindesine (Vindesine, VDS), vinorelbine (Vinorelbine, VNR).Yet as other cell toxicant antitumor drug, this class medicine lacks the selectivity to tumor tissues, exists serious dose dependent acute toxicity, shows as clinically: feel sick, vomiting, alopecia, blood vessel irritation.Even more serious is: bone marrow depression and neurotoxicity are strong, and medication repeatedly causes severe complications.The toxic and side effects of catharanthus roseus alkaloids anti-tumor medicaments has seriously limited it and has been recycled and reused for tumor treatment clinically for a long time.
Tissue distribution and its selectivity to tumor tissues of raising of changing catharanthus roseus alkaloids anti-tumor medicaments can significantly reduce toxicity.The Liposomal formulation of catharanthus roseus alkaloids anti-tumor medicaments can reduce poisonous side effect of medicine, increase the distribution of medicine, thereby alleviate dose-dependent acute toxicity, carrying out clinical trial at tumor tissues, treat various types of cancers, and obtained clinical effectiveness preferably.In addition, the liposome product that has obtained the approval of national Bureau of Drugs Supervision in China has amphotericin liposome, taxol liposome.But the catharanthus roseus alkaloids anti-tumor medicaments liposome also exists many shortcomings.As: medicine is encapsulated in interior water, and medicine is very fast to be discharged from liposome, causes the preparation instability; The least limit particle diameter of liposome is 50nm, and liposome enters cell often by merging and the mechanism of endocytosis finishes, and common medicine is a little less than the more free medicine of cytotoxicity after the liposome; The preparation process complexity of liposome, compound (at least two kinds of lipid components) of the multiple lipid components of needs, particle diameter control needs special equipment and device; Easily flocculate in the storage process etc.
In water, when the concentration of amphiphilic surpasses critical micelle concentration, can spontaneously assemble the formation micelle, utilize this character, with drug encapsulation in micellar hydrophobic core.The micellar preparation of medicine is used to be used for the solubilising of amphotericin B etc. as sodium deoxycholate in the clinical practice already.Kun etc. have delivered the article that is entitled as " polymer micelle: a kind of novel medicament carrier ", have summarized the application (Adv.Drug.Del.Rev., 21:107-116,1976) of micelle as the pharmaceutical carrier aspect.Recently, polymer micelle has caused people's very big concern as a kind of slow release, targeting, macrocyclic pharmaceutical carrier, and becomes the focus of drug-supplying system research.Yokoyama et al adopts and can form micellar polymer bag carrying anti-tumor medicine, studied its solid tumor resisting activity and cytotoxicity, and its macrocyclic characteristic (Cancerres.51:3229-3236 (1991) in blood.Polyethylene Glycol-phospholipid modified liposome had proved to have macrocyclic characteristics already in animal and human body, and was used for clinical treatment (Gregoriadis, G..TIBTECH, 13:527-537,1995) safely.With Polyethylene Glycol-phospholipid micelle as the carrier of insoluble drug be not studied the person carried out comparatively detailed summary (Torchilin, V.P.J.controlled Release, 73:137-172).
(polyethylene glycol PEG) is a kind of water-soluble polymer that can stable existence under physiological condition to Polyethylene Glycol.Because its space structure can stop the close of plasma protein, change phospholipid, protein medicaments character have been widely used in.Aspect particulate delivery system, PEG can form the hydrophilic protective layer on the surface of microgranule, prevents particles agglomerate, avoid by intravital reticuloendothelial system identification, engulf, thereby the retention time of prolong drug in blood circulation reaches macrocyclic purpose.
The advantage that not only has general nanoparticle based on the nano-micelle of PEG derivatization phospholipid preparation: particle diameter is little, substantially between 10nm～30nm, be a kind of system of dynamic stabilization, avoided for example liposome of other particulate delivery systems on the one hand, be easy to assemble agglomerating shortcoming; Be easier to go deep into diseased region on the other hand, improve drug distribution, improve the tumor tissues targeting of medicine.
Summary of the invention
The object of the present invention is to provide can intravenous catharanthus roseus alkaloids anti-tumor medicaments (vinorelbine) nano-micelle preparations, it is a kind of system of dynamic stabilization, has good stable, and has targeting in vivo, the distribution of medicine be can increase, thereby curative effect, reduction toxicity improved at tumor tissues.
Another object of the present invention provides the preparation method of nano-micelle preparations that can intravenous catharanthus roseus alkaloids anti-tumor medicaments (vinorelbine).
The invention provides can intravenous catharanthus roseus alkaloids anti-tumor medicaments nano-micelle preparations, it contains catharanthus roseus alkaloids anti-tumor medicaments (vinorelbine), polyglycol derivatization phospholipid and the pharmaceutically acceptable adjuvant for the treatment of effective dose.
Of the present invention to the effect that to utilize Polyethylene Glycol (PEG) derivatization phospholipid be main adjuvant, adopts the appropriate formulations section of learning to do to be prepared into catharanthus roseus alkaloids anti-tumor medicaments (vinorelbine) nano-micelle preparations.
Detailed Description Of The Invention
The invention provides a kind of nano-micelle preparations that can intravenous catharanthus roseus alkaloids anti-tumor medicaments (vinorelbine), comprise catharanthus roseus alkaloids anti-tumor medicaments (vinorelbine), polyglycol derivatization phospholipid and pharmaceutically acceptable adjuvant.
According to the present invention, wherein the mol ratio of catharanthus roseus alkaloids anti-tumor medicaments (vinorelbine) and polyglycol derivatization phospholipid (PEG2000-DSPE) is 1: 0.5 to 1: 10, preferred 1: 4 to 1: 6.
In the present invention, described catharanthus roseus alkaloids anti-tumor medicaments for one or more be selected from down the group medicine: vinblastine (Vinbastine, VLB), vincristine (Vincristine, VCR) and vindesine (Vindesine, VDS).
To be peg molecule by covalent bond combine with active group on the phospholipid molecule polyglycol derivatization phospholipid of the present invention forms described active group such as nitrogenous base or hydroxyl.
Being used for phospholipid of the present invention is polyglycol derivatization phospholipid, the carbon number that the fatty acid of phospholipid moiety comprises in its structure is 10～24,12,14,16,18,20,22,24 carbon atoms preferably, fatty acid chain can be saturated, can be fractional saturation also, the fatty acid that it may be noted that especially be lauric acid (12 carbon), myristic acid (14 carbon), Palmic acid (16 carbon), stearic acid or oleic acid or linoleic acid (18 carbon), twenty acid (20 carbon), mountain Yu's acid (22 carbon), lignocerate (24 carbon).
Polyglycol derivatization phospholipid, its phospholipid moiety can be phosphatidyl ethanolamine (PE), phosphatidylcholine (PC), phosphatidylinositols (PI), phosphatidyl silk amino acid (PS), diphosphatidylglycerol, the sour phospholipid that contracts, lysophosphatidylcholine (LPC), haemolysis ethanolamine phospholipid (LPE) etc.
In the present invention, the phospholipid in the polyglycol derivatization phospholipid is preferably phosphatidyl ethanolamine, especially DSPE, two palmityl PHOSPHATIDYL ETHANOLAMINE, DOPE.
Polyglycol derivatization phospholipid, its molecular weight polyethylene glycol scope is 200～20000 (relevant with the quantity of ethyoxyl on the polyethylene glycol long chain), preferred molecular weight polyethylene glycol scope is 500～10000, preferred scope 1000～10000 (quantity of ethyoxyl is 22～220), most preferred molecular weight polyethylene glycol is 2000.
According to a preferred embodiment of the present invention, polyglycol derivatization phospholipid be Macrogol 2000 DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[poly (ethyleneglycol) 2000]) (PEG2000-DSPE).
The nano-micelle preparations of catharanthus roseus alkaloids anti-tumor medicaments involved in the present invention (vinorelbine) can be the solution form as required, also can be lyophilized form.
In the nano-micelle preparations of catharanthus roseus alkaloids anti-tumor medicaments of the present invention (vinorelbine), micellar particle size range is 5-100nm, preferred 10nm～50nm, most preferably 10nm～20nm.The consumption of catharanthus roseus alkaloids anti-tumor medicaments (vinorelbine) is the preparation of 1mg/ml～10mg/ml, preferred 1mg/ml～4mg/ml, and the consumption of polyglycol derivatization phospholipid is 1mg/ml～500mg/ml, preferred 10mg/ml～30mg/ml.
In the present invention, described polyglycol derivatization phospholipid is that peg molecule combines with phospholipid molecule by covalent bond and forms.
The nano-micelle preparations of catharanthus roseus alkaloids anti-tumor medicaments of the present invention (vinorelbine), be to adopt the PEG derivatization phospholipid as carrier, or be used with other phospholipid, by certain galenic pharmacy means, the vinorelbine of therapeutic dose is wrapped in the formed nano-micelle, adds certain antioxidant, osmotic pressure regulator, pH value regulator as required.
According to micellar preparation of the present invention, it contains vinorelbine, amphiphilic and pharmaceutically acceptable antioxidant, osmotic pressure regulator, pH value regulator.Described amphiphilic is PEG derivatization phospholipid and other phospholipid.Other phospholipid materials comprise phosphatidic acid, phosphatidylinositols, Phosphatidylserine, phosphatidyl glycerol, cuorin, soybean phospholipid, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, hydrolecithin etc.
In micellar preparation of the present invention, the molar ratio scope that the PEG derivatization phospholipid accounts for total phospholipid is 20%～100%, preferred 60%～100%.
The final preparation of micelle can be the solution form, contains the catharanthus roseus alkaloids anti-tumor medicaments of 1mg/ml～10mg/ml and the total phospholipids of 1mg/ml～500mg/ml.The concentration 0.01%～5% of other additives.
The final preparation of micelle can be the lyophilized powder form, contains other additives of total phospholipids and 10%～90% (percentage by weight) of the catharanthus roseus alkaloids anti-tumor medicaments, 50%～95% (percentage by weight) of 0.02%～50% (percentage by weight).
Because catharanthus roseus alkaloids anti-tumor medicaments, phospholipid are all easily oxidized, as required, catharanthus roseus alkaloids anti-tumor medicaments micellar preparation of the present invention also contains antioxidant, as water solublity antioxidant (ascorbic acid, sodium sulfite, EDTA, amount ranges 0.01～1.0% (percentage by weight)) and fat-soluble antioxidant (tocopherol, BHA, propyl gallate, amount ranges 0.01～1.0% (percentage by weight)).
As required, micellar preparation of the present invention can add pH regulator agent (all kinds of buffer systems such as citric acid-sodium citrate, acetic acid-sodium acetate, phosphate or its combination etc.), amount ranges 1mM～100mM regulates medicinal liquid pH and is 3.0～8.0, the optimal pH scope is 6-7.5.
As required, micellar preparation of the present invention can add osmotic pressure regulator (sodium chloride, glucose, mannitol).Described osmotic pressure regulator refers to acceptablely on all kinds of pharmaceuticss be used to regulate isoosmotic salt and carbohydrate, regulates osmotic pressure to human body etc. and oozes or higher oozing (people's body fluid osmotic pressure scope 290-310mmol/L).
The present invention also provides the preparation method of the nano-micelle preparations of catharanthus roseus alkaloids anti-tumor medicaments (vinorelbine), comprise catharanthus roseus alkaloids anti-tumor medicaments (vinorelbine) is wrapped in the nano-micelle that polyglycol derivatization phospholipid forms, but be prepared into the nano-micelle preparations of the catharanthus roseus alkaloids anti-tumor medicaments (vinorelbine) of injection for intravenous.
Preparation method according to the nano-micelle preparations of catharanthus roseus alkaloids anti-tumor medicaments of the present invention (vinorelbine) specifically may further comprise the steps:
(1) vinorelbine and polyglycol derivatization phospholipid are dissolved in the mixture of organic solvent or organic solvent;
(2) remove organic solvent, make the polymer adipose membrane of vinorelbine;
(3) in the polymer adipose membrane that above-mentioned (2) obtain, add entry or buffer solution aquation, obtain wrapping the polyglycol derivatization phospholipid nano-micelle that carries vinorelbine.
In an embodiment of the inventive method, wherein the envelop rate of vinorelbine in described micelle is 90%～100%.
Described organic solvent in method step of the present invention (1) is methanol, ethanol, chloroform or their mixture.
In method step of the present invention (2), remove organic solvent and/or under vacuum condition, remove organic solvent by decompression.
Buffer solution in method step of the present invention (3) is citrate, acetate or phosphate buffer.
Method of the present invention in step (3) in 25 ℃-70 ℃, preferred 50 ℃-65 ℃ water-bath aquation 0.5～2 hour.
According to method of the present invention, further comprise with pH regulator agent (citric acid-sodium citrate, acetic acid-sodium acetate or phosphate) pH value of the micellar solution that obtains is adjusted to 3.0-8.0, preferred 6-7.5.
According to method of the present invention, further comprise the micellar solution lyophilization that will obtain, make the preparation of lyophilized form.
Particularly, micellar preparation of the present invention has adopted following preparation method to make: with catharanthus roseus alkaloids anti-tumor medicaments, polyglycol derivatization phospholipid, fat-soluble additive is dissolved in the organic solvent, place eggplant-shape bottle, utilize Rotary Evaporators, volatilize organic solvent, form thin and uniform adipose membrane on the eggplant-shape bottle surface, with water-soluble additives (water solublity antioxidant, osmotic pressure regulator, the pH value regulator) soluble in water, this aqueous solution is joined aquation in the eggplant-shape bottle, cross the filtering with microporous membrane degerming of 0.22 μ m, but be prepared into the catharanthus roseus alkaloids anti-tumor medicaments micellar preparation of injection for intravenous, the particle size range of formed nano-micelle is 10-50nm, preferred 10-30nm.Can adopt the solution form as required, also can be lyophilized form.
Content for a better understanding of the present invention, we are explained as follows some technical terms.
" micelle " is meant when the concentration of amphiphilic in aqueous solution surpasses critical micelle concentration (CMC), and spontaneously polymerization forms micelle.MICELLAR STRUCTURE is different with liposome, does not have the architectural feature of lipid bilayer.In general, MICELLAR STRUCTURE is that hydrophobic part is inside, forms hydrophobic core, and hydrophilic segment outwards forms water-wetted surface.The micelle particle diameter is little, and mean diameter is about 10～20nm.Therefore, it is thermodynamic stable system still not, and is the dynamic stabilization system.In addition, the micelle granule is difficult for assembling layering, and bag carries the capacity height, promptly can wrap when low concentration and carry higher dose.
" phospholipid ", the molecular structure of phospholipid is similar with fat, and different is only is connected with two fatty acids on glycerol molecule, and the 3rd hydroxyl and phosphoric acid are combined into fat.This structure of phospholipid makes it become a kind of amphiphilic, and its phosphoric acid or phosphate ester one end are polar, and easy and water is inhaled, constitute the hydrophilic head of phospholipid molecule, and its fatty acid one end is nonpolar, does not inhale with water, constitutes the hydrophobicity afterbody of phospholipid molecule.Phospholipid involved in the present invention is mainly polyglycol derivatization phospholipid.In the present invention, polyglycol derivatization phospholipid also can be used with other phospholipid.
" treatment effective dose " is meant that catharanthus roseus alkaloids anti-tumor medicaments produces the consumption of therapeutic effect.According to the present invention, the unit dose of catharanthus roseus alkaloids anti-tumor medicaments is 1～50mg, preferred unit dosage 1～20mg, and optimum unit dose is 10mg, dosage will be adjusted according to the needs of each special entity.
The nano-micelle preparations of catharanthus roseus alkaloids anti-tumor medicaments of the present invention is a main matrix with Polyethylene Glycol (PEG) derivatization phospholipid; can protect nano-micelle not by intravital reticuloendothelial system phagocytic; prolong the retention time of nano-micelle in blood circulation; change the kinetic property that medicine distributes in vivo simultaneously, and then heighten the effect of a treatment, reduce toxicity.
As previously described, catharanthus roseus alkaloids anti-tumor medicaments exists serious dose dependent acute toxicity, and lacks the selectivity to tumor tissues.Common catharanthus roseus alkaloids anti-tumor medicaments injection causes serious bone marrow depression and neurotoxicity after injecting in the body.The toxic and side effects of catharanthus roseus alkaloids anti-tumor medicaments has seriously limited it and has been recycled and reused for tumor treatment clinically for a long time.Though the catharanthus roseus alkaloids anti-tumor medicaments liposome can reduce poisonous side effect of medicine, increase the distribution of medicine, thereby alleviate dose-dependent acute toxicity at tumor tissues.But the catharanthus roseus alkaloids anti-tumor medicaments liposome also exists many shortcomings.As: medicine is encapsulated in interior water, and medicine is very fast to be discharged from liposome, causes the preparation instability; The least limit particle diameter of liposome is 50nm, and liposome enters cell often by merging and the mechanism of endocytosis finishes, and therefore, common medicine is a little less than the more free medicine of cytotoxicity after the liposome but still have certain toxic and side effects; The preparation process complexity of liposome, compound (at least two kinds of lipid components) of the multiple lipid components of needs, particle diameter control needs special equipment and device; Easily flocculate in the storage process etc.
In order to overcome the shortcoming of above-mentioned preparation, it is main carrier that the present invention adopts polyglycol derivatization phospholipid, or be aided with other phospholipid, and preparation catharanthus roseus alkaloids anti-tumor medicaments (vinorelbine) micellar preparation, the envelop rate of vinorelbine in described micelle is 90%～100%.Major technique advantage of the present invention is to utilize polyglycol derivatization phospholipid can form the very nano-micelle of homogeneous of particle diameter automatically in aqueous solution, and the particle size range of nano-micelle reaches 10-30nm.In the micelle, peg molecule forms the hydrophilic protective layer outside the hydrophobic core of bag medicine carrying thing, avoids medicine contact and discerned, engulf by reticuloendothelial system in the body, prolongation micelle circulation time in vivo with protein moleculars such as enzyme in the blood; In the hydrophobic core of drug encapsulation in micelle, can make medicine avoid the destruction of extraneous factor (water, oxygen, light), improve the stability of medicine in storage process greatly, in addition, micellar preparation can change the kinetic property that medicine distributes in vivo, increase the distribution of medicine, and then improve curative effect, reduction toxicity at tumor tissues.
The accompanying drawing summary
Fig. 1 is that different medicine fat are than the micellar release of VNR-PEG2000-DSPE.
Fig. 2 is the micellar release of different batches VNR-PEG2000-DSPE.
Fig. 3 is the influence that F-VNR and M-VNR grow to mice lung cancer Lewis.
The specific embodiment
Following examples mainly are to be used to further specify the present invention, rather than limit the scope of the invention.
The micellar encapsulation efficiency of embodiment 1VNR-PEG2000-DSPE
The micellar encapsulation efficiency of table 1 VNR-PEG2000-DSPE
| Medicine fat is than (mol/mol) | Aquation solution | Envelop rate (%) |
| 1∶1.25 | Water for injection | 72.2 |
| 1∶2.5 | Water for injection | 96.7 |
| 1∶4 | Water for injection | 99.7 |
| 1∶5 | Water for injection | 99.9 |
| 1∶6 | Water for injection | 100 |
Preparation technology: by above-mentioned prescription Chinese medicine fat ratio, take by weighing VNR and be dissolved in (2mg/ml) in the chloroform, take by weighing the PEG2000-DSPE (available from Chinese Shanghai Dong Shang company) that is purchased, be dissolved in an amount of chloroform, place the 100ml eggplant-shape bottle.Put Rotary Evaporators, eliminate organic solvent, form thin and uniform immobilized artificial membrane on the eggplant-shape bottle surface.Water for injection is joined in the eggplant-shape bottle, 50 ℃ of vibration aquations 1 hour, nitrogen protection, the filtering with microporous membrane degerming of 0.22 μ m, but make the vinorelbine micellar preparation of injection for intravenous.The gained sample appearance is the solution of achromatism and clarity, and mean diameter 15nm is between particle size distribution 10nm～20nm.
Embodiment 2 different medicine fat are than the micellar release of VNR-PEG2000-DSPE
Method: the VNR-PEG2000-DSPE micelle 0.5ml (3mg/1ml) that gets different medicine fat ratios, put (12-14kD) in the bag filter, in volume is (phosphoric acid normal saline buffer solution) in the 40ml release medium, 37 ℃ of constant temperature shaking table vibrations (100rpm), timing sampling is measured the content of VNR in the release medium with high performance liquid chromatogram, calculate the release percentage rate, release profiles is seen accompanying drawing 1.
By the research of sample at medium (phosphate buffer pH 7.4) releasing properties, the result shows that medicine fat is than slowly discharging (48 hours, the medication amount of release is less than 30%) and do not have burst effect at 1: 5～6 o'clock VNR.
The micellar release of embodiment 3 different batches VNR-PEG2000-DSPE
Method: 1: 5 the VNR-PEG2000-DSPE micelle 0.5ml (3mg/1ml) that gets three batches of different batches, put (12-14kD) in the bag filter, in volume is (phosphoric acid normal saline buffer solution) in the 40ml release medium, 37 ℃ of constant temperature shaking table vibrations (100rpm), timing sampling is measured the content of VNR in the release medium with high performance liquid chromatogram, calculate the release percentage rate, release profiles is seen accompanying drawing 2.
Show that by accompanying drawing 2 the micellar release characteristics of the VNR-PEG2000-DSPE of different batches does not have significant change and do not have burst effect, and micellar stable preparation process is described.
The micellar stability of embodiment 4VNR-PEG2000-DSPE
Get VNR-PEG2000-DSPE micelle 1ml (3mg/1ml) and put in the 250ml flask, add 100ml pH 7.0 phosphate buffers, 2h in 37 ℃ of waters bath with thermostatic control.Sample thief 300 μ l put in the centrifugal filtration pipe (molecular sieve: 30kD), 10000 rev/mins centrifugal 10 minutes, high performance liquid chromatogram is measured the content of vinorelbine in the filtrate, calculates the envelop rate of micelle dilution.Micelle preparation back is placed in 4 ℃ and was measured the total vinorelbine and the content of free vinorelbine in 30 days respectively, investigates stability.
The micellar stability of table 2 VCR-PEG2000-DSPE
| Medicine fat than (1: 5, mol/mol), VCR (1mg/ml) | Content (%) | Envelop rate (%) |
| 0 day | 100 | 99.9 |
| Envelop rate before the dilution | 99.9 | |
| Dilution back envelop rate (100 times) | 99.4 | |
| 30 days | 98.6 | 99.4 |
The anti-tumor in vivo effect of embodiment 5 vinorelbine micellar preparations
(ATCC is CRL-1642) by 1 * 10 with fresh Lewis lung cancer cell
7/ ml, it is subcutaneous only to be inoculated in Balb/c mice right fore armpit with 0.2ml/.(17-19g, female) is divided into 3 groups at random with the mice behind the inoculated tumour, i.e. matched group, free vinorelbine group (F-VNR) and vinorelbine micelle group (M-VNR), 6 every group.Inoculation back administration next day, F-VNR and M-VNR dosage are 5mg/kg (drug level 0.5mg/ml), iv volume 0.1ml/10g body weight, the normal saline of matched group iv 0.1ml/10g body weight.Administration is 1 time weekly, continuous 3 weeks (administration in the 1st, 8,15 day), wherein in the 7th, 10,14,17,21 day with vernier caliper measurement tumor major diameter (a) and wide footpath (b), press gross tumor volume (Volume) V=a * b
2/ 2 calculate gross tumor volume.The result shows F-VNR to the Lewis lung cancer nearly unavailable, and M-VNR has all significantly suppressed growth of tumor in the different measuring time, and suppression ratio is in the scope of 65-70%.
Table 3.F-VNR and M-VNR are to the influence of mice lung cancer Lewis growth
Claims (16)
- One kind can intravenous vinorelbine nano-micelle preparations, it is characterized in that, described preparation comprises vinorelbine, polyglycol derivatization phospholipid, and pharmaceutically acceptable adjuvant, the mol ratio of described vinorelbine and polyglycol derivatization phospholipid is 1: 0.5 to 1: 10, to be peg molecule by nitrogenous base on covalent bond and the phospholipid molecule or hydroxyl combine described polyglycol derivatization phospholipid forms, the fatty acid chain of phospholipid moiety is the fatty acid chain saturated or fractional saturation that comprises 10-24 carbon atom in the described polyglycol derivatization phospholipid, and the molecular weight polyethylene glycol scope in the described polyglycol derivatization phospholipid structure is 200～20000.
- 2. according to the nano-micelle preparations of claim 1, wherein the mol ratio of vinorelbine and polyglycol derivatization phospholipid is 1: 4 to 1: 6.
- 3. nano-micelle preparations according to claim 1, the fatty acid chain of phospholipid moiety is lauric acid, myristic acid, Palmic acid, stearic acid or oleic acid or linoleic acid, twenty acid, mountain Yu's acid or lignocerate in the wherein said polyglycol derivatization phospholipid.
- 4. nano-micelle preparations according to claim 3, the phospholipid in the wherein said polyglycol derivatization phospholipid are phosphatidyl ethanolamine, phosphatidylcholine, phosphatidylinositols, phosphatidyl silk amino acid, diphosphatidylglycerol, the sour phospholipid that contracts, haemolysis cholinphospholipide or haemolysis ethanolamine phospholipid.
- 5. nano-micelle preparations according to claim 4, the phospholipid in the wherein said polyglycol derivatization phospholipid are DSPE, two palmityl PHOSPHATIDYL ETHANOLAMINE, DOPE.
- 6. nano-micelle preparations according to claim 1, the molecular weight polyethylene glycol scope in the wherein said polyglycol derivatization phospholipid structure is 500～10000.
- 7. nano-micelle preparations according to claim 6, the molecular weight polyethylene glycol in the wherein said polyglycol derivatization phospholipid structure is 2000.
- 8. nano-micelle preparations according to claim 1, wherein said polyglycol derivatization phospholipid are the Macrogol 2000 DSPE.
- 9. nano-micelle preparations according to claim 1, wherein said micellar preparation are solution form or lyophilized form.
- 10. nano-micelle preparations according to claim 1, wherein said pharmaceutically acceptable adjuvant are pharmaceutically acceptable antioxidant, osmotic pressure regulator or pH value regulator.
- 11. one kind prepare according among the claim 1-10 any one can intravenous vinorelbine the method for nano-micelle preparations, comprise vinorelbine is wrapped in the nano-micelle that polyglycol derivatization phospholipid forms, but make the nano-micelle preparations of the vinorelbine of injection for intravenous.
- 12. the method according to claim 11 may further comprise the steps:(1) vinorelbine and polyglycol derivatization phospholipid are dissolved in the mixture of organic solvent or organic solvent;(2) remove organic solvent, make the polymer adipose membrane of vinorelbine;(3) in the polymer adipose membrane that above-mentioned (2) obtain, add entry or buffer solution aquation, obtain wrapping the polyglycol derivatization phospholipid nano-micelle that carries vinorelbine.
- 13. according to the method for claim 12, wherein this method comprises one of following feature in addition:Described organic solvent in step (1) is methanol, ethanol, chloroform, DMSO etc. or their mixture;In step (2), remove organic solvent and/or under vacuum condition, remove organic solvent by decompression;Buffer solution in step (3) is citrate, acetate or phosphate buffer; WithIn step (3) in 25 ℃-70 ℃ water-bath aquation 0.5～2 hour.
- 14. according to the method for claim 13, wherein in step (3) in 50 ℃-65 ℃ water-bath aquation 0.5～2 hour.
- 15., further comprise with the pH regulator agent pH value of the micellar solution that obtains is adjusted to 6-7.5 according to the method for claim 14.
- 16. according to the method for claim 15, further comprise the micellar solution lyophilization that to obtain, make the preparation of lyophilized form.
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| PCT/CN2006/002327 WO2007028341A1 (en) | 2005-09-09 | 2006-09-08 | Nano anticancer micelles of vinca alkaloids entrapped in polyethylene glycolylated phospholipids |
| JP2008529454A JP2009507049A (en) | 2005-09-09 | 2006-09-08 | Nanomicelle formulation of vinca alkaloid anticancer drug encapsulated in polyethylene glycol derivative of phospholipid |
| US12/066,066 US8765181B2 (en) | 2005-09-09 | 2006-09-08 | Nano anticancer micelles of vinca alkaloids entrapped in polyethylene glycolylated phospholipids |
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| 林宏英.长春新碱PEG-PE胶束的制备及其对乳腺癌细胞生长的抑制.生物化学与生物物理进展33 8.2006,33(8),第770页1.2方法. |
| 林宏英.长春新碱PEG-PE胶束的制备及其对乳腺癌细胞生长的抑制.生物化学与生物物理进展33 8.2006,33(8),第770页1.2方法. * |
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