CN100486646C - Polyethylene glycol-phosphatidyl ethanolamine polymer or medicinal acid addition salt and application thereof in pharmacy - Google Patents
Polyethylene glycol-phosphatidyl ethanolamine polymer or medicinal acid addition salt and application thereof in pharmacy Download PDFInfo
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- CN100486646C CN100486646C CNB2007100193362A CN200710019336A CN100486646C CN 100486646 C CN100486646 C CN 100486646C CN B2007100193362 A CNB2007100193362 A CN B2007100193362A CN 200710019336 A CN200710019336 A CN 200710019336A CN 100486646 C CN100486646 C CN 100486646C
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Abstract
Polyethylene glycol-phospholipid choline polymeride or its medicinal acid salt and application in pharmacy belong to technology field of nanometer medicine preparation. Polyethylene glycol-phospholipid choline polymeride or its medicinal acid salt is indicated as the following general formula (I), namely methoxypolyethylene glycol and phospholipid choline is associative through link which is substituted methylene or ether substituted benzene methylene or oxalyl. The polymeride can be used as medicine carrier, especially in preparing antitumor liposome preparation, can thicken antitumor drug at tumour position. The invention provides the application of polymeride with general formula (I) or its medicinal acid salt in preparing medicine for treating tumour, cardio-cerebrovascular diseases, inflammation infection, and asthma.
Description
Technical field
The invention belongs to polymer, its medicinal acid addition salt of Polyethylene Glycol (PEG) and PHOSPHATIDYL ETHANOLAMINE, and preparation method thereof, and, belong to the technical field of Nano medication preparation as the application of pharmaceutical carrier in the preparation medicine.
Background technology
Liposome has targeting, the blood resides time of growing and higher organ distribution selectivity, can improve the curative effect of medicine and reduce toxic and side effects.
Liposome is mainly as the carrier of intravenously administrable medicine, yet reticuloendothelium (being called for short RES) cell can be removed liposome fast, has seriously limited its use range of choice as the vascular drug delivery carrier.After the general intravenous injection, the RES system can remove the liposome of 80%-95% within an hour, is higher than the picked-up speed of predetermined target site to it far away.Therefore, liposome to the treatment of pathological tissues by major limitation in treatment to the RES system of pathological changes.
Polyethyleneglycol modified long circulating liposomes has increased the blood circulation time of liposome, not only can escape catching of reticuloendothelial system, can also improve the passive targeting of liposome.Polyethylene Glycol is cheap and easy to get, can be mass-produced, and Polyethylene Glycol-phospholipid derivative is used in preparation, makes pharmaceutical preparation technology simple relatively, has become the research emphasis of macromolecule modified liposome at present.
Polyethyleneglycol modified liposomal doxorubicin (doxorubicin) goes on the market in the U.S. in nineteen ninety-five, commodity are called Doxil, be used for the treatment of the Kaposi sarcoma (KS) relevant with AIDS, the indication of other clinical researches has advanced breast cancer, uterus carcinoma, head-neck malignant tumor and small cell lung cancer.
Be between methoxy poly (ethylene glycol) (the MPEG molecular weight is about 2000) and the perhydro soybean lecithin choline (DSPE), link by carbonyl.PEG and DSPE are respectively the medicines dressing or the carriers of approved, by the carbonyl resulting product that links, at aspects such as toxic and side effects bigger reliability are arranged all in the middle of their, have established MPEG-DSPE finally by the material base of drugs approved by FDA.
Summary of the invention
Technical problem: the objective of the invention is for addressing the above problem, a class Polyethylene Glycol-phosphatidyl ethanolamine polymer or its medicinal acid addition salt and the application in pharmacy are provided.This polymer can be used as pharmaceutical carrier, when especially preparing the antitumor medicinal liposome preparation, antitumor drug is concentrated in tumor locus active or passive target.Another object of the present invention is to provide the polymer or the application of its medicinal acid addition salt in the medicine of diseases such as preparation treatment tumor, cardiovascular and cerebrovascular disease, inflammation infection, asthma of general formula (I).
Technical scheme: the present invention is an initiation material with common drug dressing Polyethylene Glycol and PHOSPHATIDYL ETHANOLAMINE, introduce principle of pro-drug and antitumor active targeting design (pH) principle and (utilize low, the acid stronger characteristics of the general normal cell of pH value of tumor cell, binding site in polyethylene glycol structures and PHOSPHATIDYL ETHANOLAMINE structure inserts acid-sensitive sense conjugated group, the facile hydrolysis under acid condition as acetal or ketal; Xi Fushi alkali is facile hydrolysis under acid condition), the chemical bond that changes between Polyethylene Glycol and the PHOSPHATIDYL ETHANOLAMINE connects mode, prepared Polyethylene Glycol-phosphatidyl ethanolamine polymer, mechanism of action is similar to MPEG-DSPE, after entering tumor cell, because sour pH environment, the chemical bond between Polyethylene Glycol and the PHOSPHATIDYL ETHANOLAMINE relatively easily ruptures, and antitumor drug discharges.And this chemical bond is relatively stable in normal tissue cell, and antitumor drug can not discharge, thereby reaches the purpose of antitumor drug targeting.
Purpose of the present invention can reach by following measure:
Polyethylene Glycol-phosphatidyl ethanolamine polymer of the present invention or its medicinal acid addition salt are represented by following general formula (I); promptly between methoxy poly (ethylene glycol) and PHOSPHATIDYL ETHANOLAMINE; link by connecting handle " link ", handle " link " is a substituted methylene or to oxygen ether substituted benzene methene base or oxalyl group:
Wherein, n is the integer of 10-100, and m or m1 are the integer of 3-20, and P is a phosphorus atoms.
Handle " link " is a substituted methylene, by following general formula (II) expression,
Wherein, R or R
1Be the alkyl of H or C1-C6 or continuous alkyl; N is the integer of 10-100; M or m1 are the integer of 3-20, and P is a phosphorus atoms.
Handle " link " is to oxygen ether substituted benzene methene base, is represented by following general formula (III):
Wherein, R is the alkyl of H or C1-C4 or the alkoxyl of C1-C4; N is the integer of 10-100; M or m1 are the integer of 3-20, and P is a phosphorus atoms.
Handle " link " is an oxalyl group, is represented by following general formula (IV):
Wherein, n is the integer of 10-100; M or m1 are the integer of 3-20, and P is a phosphorus atoms.
This polymer or its medicinal acid addition salt prepare medicinal liposome as pharmaceutical composition or pharmaceutical carrier.
When this polymer or its medicinal acid addition salt were used as the antitumor medicinal liposome preparation, antitumor drug was wrapped in the liposome, and mean diameter can make antitumor drug concentrate in tumor locus active or passive target between the 70-160 nanometer.
Polyethylene Glycol-phosphatidyl ethanolamine polymer of the present invention or the application of its medicinal acid addition salt in pharmacy have following several respects:
This polymer or its medicinal acid addition salt are used for preparing the application of the medicine for the treatment of tumor disease as pharmaceutical carrier;
This polymer or its medicinal acid addition salt are used for preparing the application of the medicine for the treatment of cardiovascular and cerebrovascular disease as pharmaceutical carrier.
This polymer or its medicinal acid addition salt are used for preparing the application of the medicine for the treatment of the inflammation infection disease as pharmaceutical carrier;
This polymer or its medicinal acid addition salt are used for preparing the application of the medicine for the treatment of asthma disease as pharmaceutical carrier;
The preparation method of Polyethylene Glycol of the present invention-phosphatidyl ethanolamine polymer general formula (II) or its medicinal acid addition salt adopts the conventional preparation method of acetal or ketal, and catalyst is Bronsted acid or lewis acid, and it is vital that anhydrous condition is controlled fine or notly.Shown in embodiment 1.
The preparation method of Polyethylene Glycol of the present invention-phosphatidyl ethanolamine polymer general formula (III) or its medicinal acid addition salt is to replace the aldehyde radical of hydroxy benzaldehyde and the amino partial dehydration formation Xi Fushi alkali imines of PHOSPHATIDYL ETHANOLAMINE earlier, again under the effect of strong acid acid anhydride (preferred trifluoromethanesulfanhydride anhydride), organic or inorganic alkali is as catalyst or acid binding agent, replace the phenolic hydroxyl group of hydroxy benzaldehyde and the alcoholic extract hydroxyl group dehydration of Polyethylene Glycol and form the phenylate key, make the polymer of general formula (III) simultaneously.Shown in embodiment 2.
The preparation method of Polyethylene Glycol of the present invention-phosphatidyl ethanolamine polymer general formula (IV) or its medicinal acid addition salt has two kinds; a kind of is that oxalic anhydride and Polyethylene Glycol reaction obtain the Polyethylene Glycol oxalate; the latter is under chlorinating agent (preferred thionyl chloride) effect; make acyl chlorides; acylation reaction takes place in acyl chlorides again on the amino of PHOSPHATIDYL ETHANOLAMINE, make the polymer of general formula (IV).Shown in embodiment 3 methods one.Another kind is that amidatioon PHOSPHATIDYL ETHANOLAMINE again makes the polymer of general formula (IV) with oxalyl chloride elder generation esterification Polyethylene Glycol.Shown in embodiment 3 method twos.
When Polyethylene Glycol-phosphatidyl ethanolamine polymer of the present invention or its medicinal acid addition salt prepared medicinal liposome as pharmaceutical composition or pharmaceutical carrier, the composition of this liposome comprised:
Medicine (preferred antitumor drug); Polyethylene Glycol-phosphatidyl ethanolamine polymer of the present invention or its medicinal acid addition salt; Lecithin or soybean lecithin; Cholesterol; Vitamin E; Histidine; Citric acid; Sodium citrate; Natrium carbonicum calcinatum; Ammonium sulfate; Trehalose or sucrose; Water for injection.
Be wrapped in the preferred anthraquinone series antineoplastic medicament of medicine such as amycin, epirubicin etc. in the liposome; Platinum series antineoplastic medicament such as cisplatin, JM-216 etc.
Be wrapped in medicine in the liposome and can select cardiovascular medicament such as nimodipine, amlodipine, felodipine, verapamil, Valsartan, Losartan etc.
The medicine that is wrapped in the liposome also can be selected antibiotic such as amphotericin B, vancomycin, acyclovir, fluconazol, penicillins, cephalosporins etc.
The preferred for preparation method of this liposome is:
This liposome is made into the liposome of size between the 70-160 nanometer of homogeneous.Liposome in this scope can pass blood vessel and enter tumor tissues, is suitable for medicine transmission in vivo, also is suitable for Entkeimung.Can pass blood vessel easily less than the liposome of 70 nanometers and enter tissue, but the ability of its packaging medicine is too poor; The upper limit 160 nanometers are not the out to out that can pass the blood vessel vesicle, but the maximum upper limit size that the filtration sterilization step requires before the injection.
The method of control liposome size is with the overstocked polycarbonate membrane by the pore size homogeneous of the water slurry of liposome.Pore size is generally between the 30-200 nanometer, and common have 50,80,100 nanometers.The pore size of film and the about consistent size of the maximum of the liposome that passes through this film.Also can use high pressure extrusion and liposome homogenization method.
Sealing of medicine can be adopted passive and active method.
Passive method rule method for preparing lipidosome as usual.
Active method is to prepare liposome in the ammonium sulfate of higher concentration.After the size of " reduction " good liposome, produce from inside to outside ammonium concentration gradient on the film surface of liposome thereby handle liposome suspension with ammonium sulfate.The dialysis or the diafiltration of the medium (as isoosmotic glucose medium) by not containing ammonium, or the method for gel chromatography (the SG-50 post that the NaCl of 0.15M or KCl are saturated) produces the ammonium ion gradient.Can displace the ammonium sulfate on top layer like this with sodium ion or potassium ion or non-electrolyte.Perhaps, also can so also can reduce the ammonium concentration on surface with the solution dilution liposome suspension that does not contain ammonium ion.The ammonium concentration of liposome interior is than at least 10 times greatly of the concentration of outside, and best has 100-1000 doubly.
The ammonium sulfate concentrations gradient of liposome has produced a kind of chemical gradient, makes it be easy to catch unionized amine, and medicine is just caught by the aqueous favoring of liposome interior like this.With the aqueous solution of the liposome suspension and the medicine of 20-200mg/ml concentration, stir and made it even in several hours.Temperature can remain between room temperature to 60 degree (depending on that lipid is converted to the required phase inversion temperature of liposome).
Conventional method in common is to be that the liposome suspension of 50 μ mol/ml mixes at the medicine of 5-8mg/ml mutually with the concentration with volume with concentration.At last, remove free medicine.Preferably by ion exchange resin, as Dowex 50 wx-4, it can combine with free medicine the method for removing free medicine, but does not combine with liposomal encapsulated medicine.
The medicinal liposome envelop rate that makes is more than 90%.The medicinal liposome that makes (below 8 ℃) is at low temperatures preserved.
Use the optimizing prescriptions of the liposomal encapsulated amycin of preparing carriers of the present invention as follows:
Amycin 20 grams, polymer of the present invention (II) (m=m1=12, n=45, R=R1=H) 3.4 grams, soybean lecithin 9.5 grams, cholesterol 3.2 grams, 8 milligrams of vitamin Es, ammonium sulfate 2 grams, histidine 3 grams, sucrose 80 grams, water for injection 1000ml, regulating pH with HCl and NaOH is 6.5.
The method that the employing ammonium sulphate gradient prepares above-mentioned Evacet is as follows:
Rotation vacuum evaporation forms transparent adipose membrane;
After the adipose membrane aquation, form the thick suspension of liposome;
Squeezing and pressing method makes the liposome of greater particle size become liposome than small particle diameter;
Dialysis makes the inside and outside ammonium sulphate gradient that forms of liposome membrane;
Blank liposome loads amycin.
After the Evacet lyophilizing of the present invention's preparation, constant product quality.
Beneficial effect: the Evacet of the present invention's preparation is used for the treatment of the zoopery of tumor:
100 of mices are weighed, be divided into 10 groups at random, 10 every group; H22 extracts out from the mouse peritoneal that goes down to posterity, and counting is diluted to 5 * 10
6Individual ml
-1, be inoculated in subcutaneous (0.2ml of right side of mice axil
-1).For the purpose of parallel control, Evacet of the present invention, amycin conventional liposome and common doxorubicin injection (positive control drug) all use same dose, are 5mgkg
-1, the blank group is injected isopyknic normal saline.Administration number of times is a single-dose.Administration time was respectively the inoculation back the 2nd day and inoculated back the 5th day.Medicine-feeding part is the tail vein injection administration.After inoculating for two weeks, mice is broken cervical vertebra put to death, peel off the tumor body, weigh.
The result:
Gave Evacet 5mgkg of the present invention behind the tumor cell inoculation on the 2nd day
-1Dosage treatment, the heavy suppression ratio of its tumor reaches 67%, is significantly higher than conventional liposome and common amycin administration group; The heavy suppression ratio of tumor of conventional liposome administration group is about 43%, is significantly higher than the heavy suppression ratio (31%) of tumor of common amycin administration group.Evacet treatment group of the present invention is compared with blank group and common amycin treatment group, and the tumor of mice heavily has significant difference between two groups; Compare with conventional liposome treatment group, the tumor of two groups of mices heavily has significant difference.
Gave Evacet 5mgkg of the present invention behind the tumor cell inoculation on the 5th day
-1Dosage treatment, the heavy suppression ratio of its tumor reaches 70%, is significantly higher than the heavy suppression ratio (57%) of tumor of conventional liposome administration group; Be significantly higher than the heavy suppression ratio (37%) of tumor of common amycin administration group.Evacet treatment group of the present invention is compared respectively with blank group, common amycin treatment group, and the tumor of mice heavily has significant difference between two groups: compare with conventional liposome treatment group, the tumor of two groups of mices heavily has significant difference.
Result of study shows that pharmaceutical carrier of the present invention can obviously improve the concentration of medicine at tumor locus, obviously improves the antineoplaston effect of medicine.
The specific embodiment
Polyethylene Glycol-phosphatidyl ethanolamine polymer of the present invention or its medicinal acid addition salt are represented by following general formula (I); promptly between methoxy poly (ethylene glycol) and PHOSPHATIDYL ETHANOLAMINE; link by connecting handle " link ", handle " link is a substituted methylene or to oxygen ether substituted benzene methene base or oxalyl group:
Wherein, n is the integer of 10-100, and m or m1 are the integer of 3-20, and P is a phosphorus atoms.
Handle " link " is a substituted methylene, is represented by following general formula (II):
Wherein, R or R
1Be the alkyl of H or C1-C6 or continuous alkyl; N is the integer of 10-100; M or m1 are the integer of 3-20, and P is a phosphorus atoms.
Handle " link " is to oxygen ether substituted benzene methene base, is represented by following general formula (III):
Wherein, R is the alkyl of H or C1-C4 or the alkoxyl of C1-C4; N is the integer of 10-100; M or m1 are the integer of 3-20, and P is a phosphorus atoms.
Handle " link " is an oxalyl group, is represented by following general formula (IV):
Wherein, n is the integer of 10-100; M or m1 are the integer of 3-20, and P is a phosphorus atoms.
This polymer or its medicinal acid addition salt useful as drug compositions or pharmaceutical carrier prepare medicinal liposome.
When this polymer and medicinal acid addition salt thereof were used as the antitumor medicinal liposome preparation, antitumor drug was wrapped in the liposome, and mean diameter can make antitumor drug concentrate in tumor locus active or passive target between the 70-160 nanometer.
Embodiment 1
Method is led in the preparation of Polyethylene Glycol-phosphatidyl ethanolamine polymer general formula (II)
In the 1000ml three-necked bottle, add MPEG-2000 (20g; 0.01mol), DSPE (0.01mol) and chloroform 500ml, (3g 0.1mol), stirs down to add paraformaldehyde again, reflux, slowly splash into concentrated hydrochloric acid 10ml, continue reaction, TLC monitoring reaction process, developing solvent is 2-butanone/acetic acid/water=40/25/5, v/v/v, the iodine colour developing, the Rf value of DSPE is 0.68, after 10 hours, DSPE major part reacts completely, and with the reactant liquor evaporate to dryness, residue dissolves with the 10ml dichloromethane, carry out the tonsure column chromatography, eluent is dichloromethane and methanol.Merge the product component, concentrate 11g colourless wax shape methoxy poly (ethylene glycol) 2000-methylene-DSPE.
Embodiment 2
Method is led in the preparation of Polyethylene Glycol-phosphatidyl ethanolamine polymer general formula (III)
In the 1000ml three-necked bottle, add cephalin (0.01mol), hydroxy benzaldehyde (1.22g, 0.01mol) and dry toluene 300ml, the band water that refluxes is to the toluene clarification that steams, TLC monitoring reaction process is stand-by.
In the 500ml three-necked bottle, add MPEG-1900 (19g; 0.01mol) and anhydrous chloroform 300ml, bathe cooling with cryosel, slowly add triethylamine 10ml and trifluoromethanesulfanhydride anhydride 3ml, inert gas shielding, stirring is spent the night.Slowly splash into reactant liquor in the above-mentioned reactant liquor next day, and heating up gradually boils off chloroform, and in 110 ℃ of reactions 16 hours, with the reactant liquor evaporate to dryness, residue carried out the tonsure column chromatography with the dissolving of 10ml dichloromethane, and eluent is dichloromethane and methanol.Merge the product component, concentrate 3g colourless wax shape methoxy poly (ethylene glycol) 1900-oxygen base benzene methene-cephalin.
Embodiment 3
Method is led in the preparation of Polyethylene Glycol-phosphatidyl ethanolamine polymer general formula (IV)
Method one:
In the 500ml three-necked bottle, add MPEG-1500 (15g; 0.01mol) and anhydrous benzene 300ml, stir down, (1.4g 0.02mol), continued back flow reaction 4 hours slowly to splash into oxalic anhydride, be cooled to room temperature, add the new thionyl chloride 10ml that steams, continued back flow reaction 4 hours, heating up gradually, it is dried to be evaporated to, add anhydrous benzene band acid 3 times, stand-by with anhydrous benzene 300ml dissolving.
In the 1000ml three-necked bottle, add DSPE or cephalin (0.01mol), triethylamine 10ml and anhydrous benzene 300ml, stir down, cryosel slowly drips above-mentioned solution in bathing, drip and finish, continued back flow reaction 6 hours, with the reactant liquor evaporate to dryness, residue dissolves with the 10ml dichloromethane, carry out the tonsure column chromatography, eluent is dichloromethane and methanol.Merge the product component, get 8g colourless wax shape methoxy poly (ethylene glycol) 1500-oxalyl-cephalin or 5g colourless wax shape methoxy poly (ethylene glycol) 1500-oxalyl-DSPE.
Method two:
In the 1000ml three-necked bottle, add oxalyl chloride (1.26g; 0.01mol) and anhydrous benzene 100ml, cryosel slowly splashes into MPEG-1500 (15g in bathing; 0.01mol) at the solution of anhydrous benzene 200ml, drip and finish, continued room temperature reaction 1 hour, slowly splash into the solution of cephalin (0.01mol) again at anhydrous benzene 200ml, continued back flow reaction 2 hours, with the reactant liquor evaporate to dryness, residue dissolves with the 10ml dichloromethane, carry out the tonsure column chromatography, eluent is dichloromethane and methanol.Merge the product component, get 2g colourless wax shape methoxy poly (ethylene glycol) 1500-oxalyl-cephalin.
Embodiment 4
The preparation one of Evacet:
In 500ml ground pyriform bottle, precision takes by weighing lecithin, cholesterol and Polyethylene Glycol-phosphatidyl ethanolamine polymer of the present invention or its medicinal acid addition salt (mol ratio is 1: 0.18: 0.15) is dissolved in chloroform 200ml, in the water bath with thermostatic control, Rotary Evaporators removes the organic solvent chloroform under reduced pressure, form even class membrane of lipoprotein, be cooled to room temperature, the 150ml that adds diethyl ether dissolving makes the class lipoprotein solution.Amycin 0.2g is dissolved among the dehydrated alcohol 10ml, add the class lipoprotein solution, and then add the phosphate buffer of pH6.8, ultra-sonic dispersion, constant temperature reduces pressure down for 35 ℃ and removes organic solvent, add an amount of hydration medium, ultrasonic 3min, 100nm filtering with microporous membrane granulate, with SephadexG50 sephadex chromatography separated free medicine, divide to install in the cillin bottle, lyophilization promptly gets Evacet finished product of the present invention.
The preparation two of Evacet:
In 500ml ground pyriform bottle, precision takes by weighing lecithin, Polyethylene Glycol-phosphatidyl ethanolamine polymer of the present invention or its medicinal acid addition salt (mol ratio is 1: 0.18: 0.15) and is dissolved in chloroform 200ml, in the water bath with thermostatic control, Rotary Evaporators removes the organic solvent chloroform under reduced pressure, form even class membrane of lipoprotein, being cooled to room temperature, is 100mmolL with concentration
-1(NH
4)
2SO
4Solution 200ml adds in the lipid membrane, ultrasonic 10min, blank liposome turbid liquor, the filtering with microporous membrane granulate that this suspension is suitable excessively promptly gets the blank liposome of particle diameter 70-160nm.Blank liposome is put in the bag filter dialysis 3 times, dialysis solution is 5% glucose solution, is reentered into after the taking-up in the 500ml ground pyriform bottle, and precision takes by weighing amycin 0.2g in addition, soluble in water, this solution is added to the blank liposome suspension, places 30min, jolting frequently in 60 ℃, with SephadexG50 sephadex chromatography separated free medicine, divide to install in the cillin bottle, lyophilization promptly gets Evacet finished product of the present invention.The preparation of conventional liposome does not only add Polyethylene Glycol-phosphatidyl ethanolamine polymer of the present invention or its medicinal acid addition salt with the preparation one or two of Evacet in the film material.
Claims (10)
1. a Polyethylene Glycol-phosphatidyl ethanolamine polymer or its medicinal acid addition salt; it is characterized in that this polymer or its medicinal acid addition salt represented by following general formula (I); promptly between methoxy poly (ethylene glycol) and PHOSPHATIDYL ETHANOLAMINE; link by connecting handle " link ", handle " link " is a substituted methylene or to oxygen ether substituted benzene methene base or oxalyl group:
Wherein, n is the integer of 10-100, and m or m1 are the integer of 3-20, and P is a phosphorus atoms.
2. Polyethylene Glycol-phosphatidyl ethanolamine polymer according to claim 1 or its medicinal acid addition salt is characterized in that handle " link " is substituted methylene, is represented by following general formula (II):
Wherein, R or R
1Alkyl for H or C1-C6; N is the integer of 10-100; M or m1 are the integer of 3-20, and P is a phosphorus atoms.
3. Polyethylene Glycol-phosphatidyl ethanolamine polymer according to claim 1 or its medicinal acid addition salt is characterized in that handle " link " is to oxygen ether substituted benzene methene base, is represented by following general formula (III):
Wherein, R is the alkyl of H or C1-C4 or the alkoxyl of C1-C4; N is the integer of 10-100; M or m1 are the integer of 3-20, and P is a phosphorus atoms.
4. Polyethylene Glycol-phosphatidyl ethanolamine polymer according to claim 1 or its medicinal acid addition salt is characterized in that handle " link " is oxalyl group, is represented by following general formula (IV):
Wherein, n is the integer of 10-100; M or m1 are the integer of 3-20, and P is a phosphorus atoms.
5. according to claim 1 or 2 or 3 or 4 described Polyethylene Glycol-phosphatidyl ethanolamine polymer or its medicinal acid addition salts, it is characterized in that this polymer or its medicinal acid addition salt are as the preparation of pharmaceutical compositions medicinal liposome.
6. according to claim 1 or 2 or 3 or 4 described Polyethylene Glycol-phosphatidyl ethanolamine polymer or its medicinal acid addition salts, when it is characterized in that this polymer and medicinal acid addition salt thereof as the antitumor medicinal liposome preparation, antitumor drug is wrapped in the liposome, this liposome mean diameter can make antitumor drug concentrate in tumor locus active or passive target between the 70-160 nanometer.
7. one kind as claim 1 or 2 or 3 or 4 described Polyethylene Glycol-phosphatidyl ethanolamine polymers or the application of its medicinal acid addition salt in pharmacy, it is characterized in that this polymer or its medicinal acid addition salt are used for preparing the application of the medicine for the treatment of tumor disease as pharmaceutical carrier.
8. one kind as claim 1 or 2 or 3 or 4 described Polyethylene Glycol-phosphatidyl ethanolamine polymers or the application of its medicinal acid addition salt in pharmacy, it is characterized in that this polymer or its medicinal acid addition salt are used for preparing the application of the medicine for the treatment of cardiovascular and cerebrovascular disease as pharmaceutical carrier.
9. one kind as claim 1 or 2 or 3 or 4 described Polyethylene Glycol-phosphatidyl ethanolamine polymers or the application of its medicinal acid addition salt in pharmacy, it is characterized in that this polymer or its medicinal acid addition salt are used for preparing the application of the medicine of treatment inflammation infection disease as pharmaceutical carrier.
10. one kind as claim 1 or 2 or 3 or 4 described Polyethylene Glycol-phosphatidyl ethanolamine polymers or the application of its medicinal acid addition salt in pharmacy, it is characterized in that this polymer or its medicinal acid addition salt are used for preparing the application of the medicine for the treatment of asthma disease as pharmaceutical carrier.
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| CN103965463B (en) * | 2014-04-28 | 2016-09-21 | 苏州岸谷纳米材料科技有限公司 | A kind of preparation method of mPEG2000-DSPE |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103626993A (en) * | 2013-11-05 | 2014-03-12 | 南京理工大学 | Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative and preparation thereof |
| CN103626993B (en) * | 2013-11-05 | 2016-01-20 | 南京理工大学 | Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative and preparation thereof |
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