CN101011581A - Sulfated PEG lipid derivative and its preparing process and application - Google Patents

Sulfated PEG lipid derivative and its preparing process and application Download PDF

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CN101011581A
CN101011581A CNA200710010226XA CN200710010226A CN101011581A CN 101011581 A CN101011581 A CN 101011581A CN A200710010226X A CNA200710010226X A CN A200710010226XA CN 200710010226 A CN200710010226 A CN 200710010226A CN 101011581 A CN101011581 A CN 101011581A
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peg
sulfated
sulfonic acid
esterification
lipid derivative
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CN101011581B (en
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邓意辉
陈国良
王绍宁
徐晖
金圣煊
李�杰
周欣羽
毕殿洲
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Shenyang Pharmaceutical University
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Abstract

The invention relates to a method for preparing sulfuric (sulfonic acid) esterification PEG liposome derivate, and relative application in drug transmitter, especially the application of novel polyethylene glycol dimethyl ether cholesterol sulfate derivate in medical aera. The inventive sulfuric (sulfonic acid) esterification PEG liposome derivate is sulfuric (sulfonic acid) esterification PEG cholesterol, sulfuric (sulfonic acid) esterification PEG sterol, sulfuric (sulfonic acid) esterification PEG tocofecol, sulfuric (sulfonic acid) esterification PEG vitamin D, sulfuric (sulfonic acid) esterification PEG phosphatide, or sulfuric (sulfonic acid) esterification PEG-DSPE. And the drug transmitter comprises a gel beam, a nanometer gel beam, an emulsifier, a micro emulsifier, a nanometer emulsion, a liposome, and nanometer particles. The invention esterificates and connects the PEG sulfuric (sulfonic acid) with cholesterol to prepare derivate, to protect drug, reduce degradation, and prolong the circulation time in body, and realize the combination with gp120 specificity at the surface of HIV, to transmit drug targeted.

Description

Sulfated PEG lipid derivative and its production and application
Technical field:
The invention belongs to medical technical field, relate to sulfated PEG lipid derivative and preparation method thereof and the application in drug delivery system, more specifically relate to of the application of a kind of novel adjuvant poly glycol monomethyl ether cholesterol sulfate derivative in medical technical field.
Background technology:
Generally speaking, drug delivery system, in blood, all can suffer multiple factor as Emulsion, microemulsion, nano-emulsion, liposome, nanoparticle etc., it mainly is the destruction of opsonin (opsonin), major part turns round to the abundant position of mononuclear phagocyte systems such as liver and spleen (MPS), in order to reduce the intake of MPS, prolong circulation time, the PEGization carrier has appearred.Comparatively common PEG lipid derivate is PEG-DSPE at present, and wherein PEG2000-DSPE (PEG2000-PHOSPHATIDYL ETHANOLAMINE) has become pharmaceutic adjuvant, is used for Evacet DOXI L.Because the PEG that adopted is a monomethyl ether, there is metabolism/produce corresponding antibody in vivo, thereby quickens the problem of the removing of carrier.
Acquired immune deficiency syndrome (AIDS) be acquired immune deficiency syndrome (AIDS) (Acquired ImmunodeficiencySyndrome, AIDS), its cause of disease be HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) (HIV (human immunodeficiency virus), HumanImmunodeficiency Virus, HIV).HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) can be destroyed people's immune system, makes the ability of human body forfeiture opposing various diseases.Acquired immune deficiency syndrome (AIDS) is wreaked havoc in the whole world so far from discovery, becomes one of the most dangerous infectious disease of harm humans.Claim in the popular situation report of global acquired immune deficiency syndrome (AIDS) in 2004 according to UNAIDS and World Health Organization (WHO) (UNAIDS/WHO), HIV number of the infected by existing work in the end of the year 2004 reaches 3,940 ten thousand, the new number that infects was 4,900,000 in 2004, and death toll reaches 3,100,000.
Haseltine etc. studies show that the cell surface that HIV infects expresses gp120, the CD4 that can and not infect equally +Cell surface CD4 receptors bind is induced plasmodial formation, causes the lymphocytic exhaustion of HIV sufferers T4.Thereby DS can block virus infected cell on the one hand competitively; Cell that can suppress to have infected and normal cell form syncytium on the other hand.(Haseltine WA.Replication and pathogenesis of the AIDS virus.J AIDS 1988；1：217-240.)
In addition, there is article to point out to studies show that in a large number that controlling sulfate polyoses such as DS can suppress the cytopathy of HIV, prevent that the inductive syncytium of HIV (giant cell) from forming, effectively block HIV duplicating in cultured cell, and synergism [Nakashima H is arranged with antiviral drugs such as AZT, Kido Y, Kobayashi N, et al.Antiretroviral activity in a marine red alga:reverse transcriptase inhibition by an aqueous extract ofSchizymenia pacifica.J Cancer Res Clin Oncol 1987; 113:413-416.Baba M, Pauwels R, Balzarini J, et al.mechanism of inhibitory effectof dextran sulfate and heparin on replication of humanimmunodeficiency virus in vitro.Proc Natl Acad Sci USA 1988; 85:6132-6136.Baba M, Schols D, Pauwels R, et al.Sulfatedpolysaccharides as potent inhibitors of HIV-induced syncytiumformation:a new strategy towards AIDS chemotherapy.J AIDS 1990; 3:493-499.Mitsuya H, Looney DJ, kuno S, et al.Dextran sulfatesuppression of virus es in the HIV family:inhibition of virionbinding to CD4 +Cells.Science 1988; 240:646-649.Piret J, Lamontagne J, Bestman Smith J, et al.In vitro and in vivo evalutionsof sodium lauryl sulfate and dextran sulfate as microbicides againstherpes simplex and human immunodeficiency viruses.J Clin Microbiol2000; 38:110-119.].Its mechanism of action is electronegative Sulfation group, can be with the last critical function district of HIV outer membrane protein gp120---V3 ring (positively charged) combines.Utilize the HIV neutralizing antibody to prove the critical function of V3 ring, and be referred to as main in and determinant (PND).Mutation and antibody competition experiment showed, that the gp120 of disappearance V3 ring can combine with CD4 is normal, but can not be in conjunction with CCR5/CXCR4, can't with cell fusion.
Summary of the invention:
Based on above-mentioned basis, we have designed and synthesized the preparation of sulphuric acid (sulfonic acid) esterification PEG lipid derivate and the application in drug delivery system thereof.Said lipid derivate comprises " sulphuric acid (sulfonic acid) esterification PEG cholesterol ", " sulphuric acid (sulfonic acid) esterification PEG sitoesterol ", " sulphuric acid (sulfonic acid) esterification PEG tocopherol ", " sulphuric acid (sulfonic acid) esterification PEG vitamin D ", " sulphuric acid (sulfonic acid) esterification PEG phospholipid " or " sulphuric acid (sulfonic acid) esterification PEG-DSPE ".Wherein " sulphuric acid (sulfonic acid) esterification PEG cholesterol " has following structural formula:
Figure A20071001022600041
Advantage of the present invention: PEG metabolic pathway in vivo is sulphuric acid (sulfonic acid) esterification; PEG sulphuric acid (sulfonic acid) esterification is connected the preparation derivant with cholesterol; both can protect medicine; reduce degraded; the extension body internal recycle time; also can realize combining, realize the purpose of targeting drug delivery with the gp120 specificity on HIV surface.This type of does not appear in the newspapers as yet.The Preliminary experiment results explanation, with synthetic derivant drug-loaded liposome is modified, vitro inhibition HIV activity is significantly improved, main cause is that sulfate group in the PEG sulfuric ester cholesterol molecule and the positively charged V3 loops of HIV outer membrane protein gp120 close, specificity suppresses the absorption of virus to sensitive cells in conjunction with free HIV, stops virus to enter cell, simultaneously drug targeting is delivered to the HIV infection cell, suppresses the HIV propagation in the infection cell.Sulfated PEG lipid derivative can combine with the gp120 binding site of HIV, realizes the HIV targeting drug delivery.
The specific embodiment:
Below in conjunction with embodiment (the fat prodrug azidothymidine palmitate (AZTP) with zidovudine (AZT) is a model drug) the present invention is done further detailed description, but method not only is confined to given embodiment.
Note: HPLC chromatographic condition
Chromatographic column: Betasil C18 post (200mm * 4.6mm 5 μ m, Diamonsil, Dikma, USA);
Guard column: Fusion-RP (4 * 3.0mm, AJO-7557, Phenomenex, USA);
Mobile phase: methanol (35: 65);
Flow velocity: 1.0mL min -1
Column temperature: 40 ℃;
Detect wavelength: 266nm;
Sample size: 20 μ L.
Embodiment 1: the preparation of cholesterol Polyethylene Glycol sulfuric ester
The method of preparation I compound, these methods have: concentrated sulphuric acid method, sulfur trioxide-pyridine method, chlorosulfonic acid-pyridine method, sulfur trioxide-dimethyl formamide method etc.
The chlorosulfonic acid method:
The 2mL pyridine is joined in the 2 5mL three-necked bottles, under the ice bath, drip the 0.2mL chlorosulfonic acid, 5 ℃ of following stirring reactions added 0.2g cholesterol Macrogol 2000 (the PEG end contains hydroxyl) after 30 minutes, 60 ℃ of stirring reactions 1 hour, be poured in the frozen water, stir and separated out precipitation in 30 minutes, filter, be washed to pH value neutrality, dry that white solid 0.23 restrains.IR(KBr)(cm -1)：1287，1172，851(ROSO 3H)。
Molecular weight be can prepare with method and 300 or 30000 PEG sulfuric ester cholesterol derivative and salt thereof are respectively.
Embodiment 2: increase the stability to degradation of AZTP in rat plasma
According to conventional method, with AZTP/SPC 4/V EThe ratio of (1: 10: 0.1) prepares liposome; With AZTP/SPC 4/V E(1: 10: 0.1: ratio 0.1) prepared the coating liposome to/Compound I.Equally, prepare submicronized emulsion and coating submicronized emulsion according to conventional method.
Different liposome group (conventional liposome, the solid coating liposome of Polyethylene Glycol alcohol sulfuric ester gallbladder), the different submicron emulsion group (common submicron emulsion, Polyethylene Glycol sulfuric ester cholesterol coating submicron emulsion) of zidovudine (AZT) solution and fat prodrug azidothymidine palmitate (AZTP) are placed 10% rat plasma respectively, hatch for 37 ℃, take a sample in different time points, measure the concentration of zidovudine in the blood plasma, the t of solution group, conventional liposome group, coating liposome group 1/218 times and 171 times of the solution group respectively, the t of common submicron emulsion group, coating submicron emulsion group 1/2Be respectively 8 times and 120 times of solution group, concrete numerical value sees attached list 1.The result shows: medicine is subjected to the protection of coating material, and stability improves greatly in blood plasma, the interior holdup time of body that this has not only prolonged medicine, has increased the targeting chance, and can reach the purpose of prolong half-life, slow release long-acting.
The apparent first order kinetics speed constant and the half-life of each degraded of liposome group in mice plasma of subordinate list 1.AZT solution and AZTP
Experimental group AZT solution group AZTP liposome group AZTP submicron emulsion group AZTP coating liposome group AZTP coating submicron emulsion group
K obs/min -1 0.3480 0.0198 0.0073 0.0038 0.0036
t 1/2/min 1.99 35.01 94.95 180.32 192.54
Embodiment 3: the Injectable liposomal of preparation Polyethylene Glycol sulfuric ester cholesterol derivative coating, investigate its distribution situation in each tissue of mice.
With female medicine zidovudine (AZT) solution and fat prodrug azidothymidine palmitate (AZTP) liposome group (Polyethylene Glycol sulfuric ester cholesterol coating liposome (PEG-CH-S group)) mouse tail vein administration, investigate the distribution situation of zidovudine in different tissues of mice.Compare with the AZT solution, the distribution of liposome Chinese medicine in the heart, liver, spleen, lung, brain all has increase, and uptake ratio (re) is all greater than 1 relatively, and concrete numerical value sees attached list 2, illustrate that the lipid physical ability increases the targeting of medicine at these tissues, wherein with brain Chinese medicine concentration improve the most remarkable.Compare with the solution group, the distribution of liposome group in kidney obviously reduces, and helps reducing the nephrotoxicity of zidovudine.
After subordinate list 2. mouse tail vein injection AZT solution and each liposome group of AZTP, AUC0-60 and the targeting efficient (re) of AZT in each tissue
Tissue (μ gmin/g) The heart Liver Spleen Lung Kidney Brain
AUC r e AUC r e AUC r e AUC r e AUC r e AUC r e
AZT-Sol 216.2 145.4 231.4 216.8 637.0 46.7
PEG-CH-S 378.4 1.75 262.1 1.80 378.2 1.63 453.8 2.09 555.4 0.87 98.1 2.1
After subordinate list 3. mouse tail vein injection AZT solution and each liposome group of AZTP, the half-life t of AZT in the blood 1/2/ min
Experimental group AZT solution group AZTP liposome group Through the AZTP of DSPE-PEG coating liposome group Through the AZTP of PEG-CH-S coating liposome group
t 1/2/min 11.0 18.1 21.7 21.1
The preparation of embodiment 4 micelles/precursor micelle
Micelle: AZT myristinate (AZTM)/PEG 30000Sulfuric ester cholesterol derivative or its salt (the PEG mean molecule quantity is 30000) (1: 100) use earlier an amount of dissolve with ethanol, and decompression eliminates ethanol, add entry be micelle.Add an amount of freeze drying protectant on this basis,, carry out lyophilization and promptly get the solid micelle as 5%-15% mannitol or 5%-15% lactose or 5%-15% trehalose or any two or three combinations in them.
Precursor micelle: AZT myristinate (AZTM)/PEG 10000Sulfuric ester cholesterol derivative or its salt (the PEG mean molecule quantity is 10000) (1: 80) are used an amount of dissolve with ethanol, promptly get precursor micelle.Face time spent adding retarder thinner and can form micelle.
The preparation of embodiment 5 nanoparticles
Increase PEG at prescription 300-30000(1%-30% w/w), prepares nanoparticle according to conventional method and gets final product for sulfuric ester cholesterol derivative or its salt.

Claims (7)

1, sulfated PEG lipid derivative is characterized in that: it is the sulfated PEG cholesterol, and its structural formula is as follows:
Figure A2007100102260002C1
N=5～500 (the PEG molecular weight is 300～30000), R is SO 2OH, SO 2H, and its esters.
2, sulfated PEG lipid derivative according to claim 1, it is characterized in that: sulfated PEG lipid derivative also comprises the sulfated PEG sitoesterol, the sulfated PEG tocopherol, sulfated PEG vitamin D, sulfated PEG phospholipid or sulfated PEG-DSPE.
3, the application of sulfated PEG lipid derivative in the preparation drug delivery system.
4, the application of sulfated PEG lipid derivative according to claim 3 in the preparation drug delivery system, it is characterized in that: described delivery system comprises micelle, nano-micelle, Emulsion, microemulsion, nano-emulsion, liposome, nanoparticle.
5, the application of sulfated PEG lipid derivative according to claim 3 in the preparation drug delivery system, it is characterized in that: sulfated PEG lipid derivative can combine with the gp120 binding site of HIV, realizes the HIV targeting drug delivery.
6, a kind of preparation method of sulfated PEG lipid derivative as claimed in claim 1 is characterized in that: as follows with chlorosulfonic acid-pyridine method preparation process, pyridine is joined in the three-necked bottle, under the ice bath, drip chlorosulfonic acid, 5 ℃ of following stirring reactions are after 30 minutes, adding cholesterol, end contain the hydroxyl Macrogol 2000,60 ℃ of stirring reactions 1 hour are poured in the frozen water, stir and separate out precipitation in 30 minutes, filter, be washed to pH value neutrality, dry white solid, IR (the KBr) (cm of getting -1): 1287,1172,851 (ROSO 3H).
7, the preparation method of sulfated PEG lipid derivative according to claim 6 is characterized in that: chlorosulfonic acid-pyridine method can use concentrated sulphuric acid method, sulfur trioxide-pyridine method, sulfur trioxide-dimethyl formamide method to substitute.
CN200710010226XA 2007-01-31 2007-01-31 Sulfated PEG lipid derivative and its preparing process and application Expired - Fee Related CN101011581B (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102558166A (en) * 2011-12-22 2012-07-11 江西天新药业有限公司 Preparation method of 3-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-5-(2-sulfonyl oxy ethyl)-4-methylthiazole
CN104163915A (en) * 2013-05-16 2014-11-26 沈阳药科大学 Cholesterol-poloxamer-cholesterol triblock copolymer, preparation method and application thereof
CN110559263A (en) * 2019-10-10 2019-12-13 中国海洋大学 Delta 5-cholest sulfate compound liposome and preparation method thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102558166A (en) * 2011-12-22 2012-07-11 江西天新药业有限公司 Preparation method of 3-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-5-(2-sulfonyl oxy ethyl)-4-methylthiazole
CN104163915A (en) * 2013-05-16 2014-11-26 沈阳药科大学 Cholesterol-poloxamer-cholesterol triblock copolymer, preparation method and application thereof
CN104163915B (en) * 2013-05-16 2016-09-28 沈阳药科大学 Cholesterol-poloxamer-cholesterol triblock copolymer and its preparation method and application
CN110559263A (en) * 2019-10-10 2019-12-13 中国海洋大学 Delta 5-cholest sulfate compound liposome and preparation method thereof

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