CN100525836C - Double-head radical lipid prodrug - Google Patents

Double-head radical lipid prodrug Download PDF

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CN100525836C
CN100525836C CNB2006100766533A CN200610076653A CN100525836C CN 100525836 C CN100525836 C CN 100525836C CN B2006100766533 A CNB2006100766533 A CN B2006100766533A CN 200610076653 A CN200610076653 A CN 200610076653A CN 100525836 C CN100525836 C CN 100525836C
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double
medicine
lipid prodrug
head radical
radical lipid
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CN1876187A (en
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金义光
佟丽
齐宁宁
陈书峰
辛瑞
陈大为
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Institute of Radiation Medicine of CAMMS
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Institute of Radiation Medicine of CAMMS
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Abstract

The disclosed dual-head lipid prodrug comprises structure as D1-R-D2 or D1-L1-R-L2-D2, wherein, D1, D2: medicinal group; R: aliphatic chain with 6-32 carbon atoms; L1, L2: any one of inorganic acyl, aliphatic group with 2-7 carbon atoms, and hydrophilic group. It also discloses the transfer system prepared by the dual-head lipid prodrug.

Description

Double-head radical lipid prodrug
Technical field
The present invention relates to chemistry and biomedicine field, particularly a kind of double-head radical lipid prodrug can be prepared the transmission system of high degree of dispersion by this chemical compound.
Background technology
Prodrug (Prodrugs) is important a kind of drug invention method and technology, utilization prodrug technology can change the physicochemical property of medicine, improve pharmacokinetics processes such as medicine absorption in vivo, distribution, transhipment, metabolism, improve bioavailability, increase the cellular uptake of medicine, raising is to the effect selectivity of target site, remove or the reduction toxic and side effects, improve the bad smell of medicine, (Bundagaard B.Design of prodrugs.Elsevier such as medicine sustained and controlled release, Amsterdam, The Netherlands, 1985).
The biomembrane permeability of medicine is except outside the Pass having with the character of biomembrane own and drug molecule amount, and the physicochemical properties of medicine are major influence factors.It is generally acknowledged, suitably increase the fat-soluble of medicine and can strengthen the biomembrane permeability.People increase drug bioavailability and cellular uptake with the method for synthetic fat dissolubility prodrug, and generally can improve the concentration of medicine in lymphsystem and brain.Prodrug can discharge former medicine and bring into play therapeutical effect (YatvinMB through effects such as enzyme catalysiss in cell or tissue, et al.Improved uptake and retention of lipophilic prodrug to improve treatmentof HIV.Adv Drug Del Rev, 1999,39:165).
Liposome (Liposomes) is a kind of vesicle that is made of phospholipid bilayer (Vesicles), is a kind ofly can be used as the carrier of a variety of medicines in the dispersive transmission system of aqueous solution camber.Its high dispersion makes it have effects such as targeting, slow release in vivo, oral have a lymph tropism, more portable medicine passes through blood brain barrier, enter (Lasic DD and Papahadjopoulos D.Liposomes revisited.Science in the cell by approach such as fusion, endocytosis easily, 1995,267:1275).The liposome that improvement phospholipid is formed also can have functions such as long circulation in the body, responsive to temperature, pH sensitivity, magnetic targeting, active targeting.The part of liposome (eye, nose, skin) administration also has good biocompatibility, promotes the effect of drug osmotic.Liposome still is a kind of transfection reagent that often uses in biochemistry and the molecular biology research field, present still a kind of important carrier (Kikuchi H of gene therapy, et al.Gene delivery using liposome technology.J ControlRelease, 1999,62:269).
The phospholipid bilayer film of liposome vesicle separates the water and the outside water of internal package, is hydrophobicity in the bilayer.Medicine is wrapped in respectively in interior water or the film according to the difference of its physicochemical properties.General water soluble drug is wrapped in aqueous phase in the liposome; Fat-soluble medicine is wrapped in the liposome rete.The preparation of liposome is the process of phospholipid molecule self assembly in water, and the volume ratio of inside and outside water has certain limit.These factors have determined the encapsulation ratio of most of water soluble drug lower (＜50%), sometimes also can very low (5%), and the medicine of parcel has the possibility that leaks into outer water, even easy to leak very in the environment in vivo and in vitro.Seepage or the free drug that does not wrap up just can't obtain liposome high degree of dispersion characteristics, have also lost characteristics such as liposome body internal target tropism.If the fat-soluble medicine molecule has proper fat-soluble group (as aliphatic chain), just can be inserted in the phospholipid bilayer, binding ratio is more firm, and drug molecule is not easy to take off, so the liposome rate of medicine is higher.Therefore in order to increase the encapsulation ratio of some polar medicine in liposome, people often prepare polar medicine fat-soluble prodrug (the Gulati M of growth aliphatic chain earlier, et al.Lipophilic drug derivatives in liposomes.Int J Pharm, 1998,165:129).Its Liposomal formulation has had simultaneously also that the aqueous solution camber disperses and fat-soluble prodrug easily penetrates into the characteristics (TongP of cell, et al.Preparation and in viro antiviral activity of liposomes of lipophilic esters ofacyclovir. Acta Pharmaceutica Sinica, 1991,27:15).
Non-ionic surface active agent vesicle (Niosomes) is meant that some non-ionic surface active agent (as sorbester p18) is self-assembled into vesicle structure, similar liposome under certain condition in water.It can be used as pharmaceutical carrier equally, has the inside and outside feature of similar liposome.It is nanoscale dispersed solids particle that nanoparticle (Nanoparticles) refers generally to, and high dispersion makes it that characteristics such as the drug bioavailability of raising, targeting, adhesion be arranged as pharmaceutical carrier.Solid lipid nanoparticle (SLN) adopts the compatible matrix material of human body to form nanoparticle as main adjuvant, has the characteristics of common nanoparticle and the characteristics of good biocompatibility.Microemulsion (Microemulsions) is meant the system that the emulsion droplet of particle diameter below 100nm formed, and fat-soluble medicine can be wrapped in the emulsion droplet.The high dispersion of microemulsion makes it that characteristics such as the drug bioavailability of raising, targeting be arranged as pharmaceutical carrier.
In sum,, and further be prepared into liposome, non-ionic surface active agent vesicle, nanoparticle, the dispersive transmission system of microemulsion equal altitudes, help bringing into play drug effect the medication preparation fat-soluble prodrug of aliphatic chain of growing up.
Drug combination is of long duration, and occupies critical role in clinical treatment.Except some pharmaceutical incompatibility situations, numerous disease needs the drug combination treatment, and can produce synergism, shortening treatment phase, the single medicine side effect of minimizing, the generation of minimizing drug resistance, particularly some adopts drug combination usually to treatments such as the more serious disease of human body infringement such as cardiovascular disease, tuberculosis, malaria, acquired immune deficiency syndrome (AIDS) (AIDS), cancers (Jia Gongfu, Xie Hui's democracy is compiled.Clinical medicine is newly used the coupling complete works.Beijing: People's Health Publisher, 1999).
In the anti-microbial infection disease treatment, antibiotic (aminoglycoside) coupling that sterilizes antibiotic (as penicillin, cephalosporin) and resting stage of sterilizing idiophase has synergism, quick-acting antibacterial antibiotic (as streptomycin, tetracycline, erythromycin) with imitate antibacterial (sulfonamides) coupling slowly summation action arranged.Antiviral drugs horse quinoline guanidine and antihistaminic coupling can strengthen the former curative effect, alleviate side effect.Couplings such as acyclovir and interferon, arabinose acyl glycosides, trifluorothymidine, foscarnet sodium, chloromethane cytosine arabinoside, levamisole, glucocorticoid, ketoconazole, amphotericin B, zidovudine have synergism.Amantadine and phenothiazine drug, antibiotic coupling, sulfamethoxazole and trimethoprim (TMP) coupling (title bactrim), rifampicin and TMP coupling, ampicillin and TMP coupling, norfloxacin and TMP coupling or the like all have potentiation.In addition, furazolidone and insulin coupling can strengthen and prolong the blood sugar reducing function of insulin, and it and stable coupling can reduce latter's consumption.Rifampicin and isoniazid coupling can delay the formation of Mycobacterium tuberculosis drug-resistant, improve curative effect.Rifampicin also can with the streptomycin coupling.Metronidazole and antibiotic coupling can strengthen infection scope and potentiation, improve curative effect.Because some antibacterial (as mycobacterium tuberculosis) easily produces drug resistance, drug combination has become necessary clinically.
In the parasiticide disease treatment, quinine and tetracycline, mefloquine, pyrimethamine, sulfonamides coupling can improve the malaria radical rate.Diethylcarbamazine and carbarsone coupling can improve the effect to filaricide.Because some parasite (as plasmodium) easily produces drug resistance, drug combination has become necessary clinically.
In central nervous system disease treatment, caffeine and morphine coupling can strengthen latter's analgesic activity, and slow down the latter and produce toleration and dependency.Naloxone has Detoxication to methadone.Clozapine can be treated chronic delusional syndrome due to the long reaction levodopa.Levodopa and glucocorticoid coupling can prevent hypotension.Chlorpromazine can promote that medicine passes through bacterial cell membrane.Chlorpromazine can be eliminated the central excitation effect of scopolamine.Phenobarbital can strengthen the papaverine coupling for the cerebral vasospasm disease, also can strengthen the cyclophosphamide effect.The nervus centralis medicine that has often has intensive side effect, must use some medicines that resist these side effect just can adhere to treatment.
For the peripheral nervous system medicine, but the muscarinic action of atropine antagonism neostigmine keeps its nicotinic action, and can eliminate and suffer from abdominal pain due to the neostigmine.But the central excitation effect of stable antagonism hyoscyami class medicine is used for the treatment of hyoscyami class drug intoxication.But tachycardia due to the propranolol antagonism atropine.
In treating cardiovascular disease, aspirin and persantin, verapamil have collaborative anti thrombotic action, and aspirin and sulphinpyrazone coupling can reduce incidence rate of myocardial infarction and mortality rate.Calcium channel blocker and clonidine coupling strengthen antihypertensive effect.Antihypertensive function can be more effectively brought into play in captopril and calcium channel blocker coupling.Depressor and diuretic coupling can strengthen the resisting hypertension effect.Aiselazine can reduce propranolol consumption 50%.Diuretic and nitrate esters coupling treatment congestive heart failure, evident in efficacy.Lignocaine and Propafenone coupling can reduce side effect.Clofibrate and neomycin coupling have collaborative effect for reducing fat, can be used for treating II type hyperlipidemia.
For antipyretic analgesic, indomethacin and amitriptyline coupling can strengthen analgesic effect, to late period carcinous obstinate pain effective.Indomethacin also can improve the curative effect of antimicrobial drug.Acetaminophen is in the amantadine coupling, and antipyretic effect quickens.Codeine also can strengthen the analgesic effect of acetaminophen.
For medicine for digestive system, banded bleb skin ulcer is treated in cimetidine and persantin coupling, can improve curative effect.The extrapyramidal system that trihexyphenidyl, diphenhydramine can be treated metoclopramide moves hyperfunction.
For treatment of cancer, reserpine, chlorpromazine can strengthen the anticancer effect of cyclophosphamide.The enzyme inhibition of interferon can reduce the clearance rate of fluorouracil, prolong half-life.Calcium leucovorin can be prevented and treated the toxicity of methotrexate.Levamisole can strengthen the cisplatin antitumaous effect.Cytosine arabinoside, vincristine, bleomycin and amycin coupling can heighten the effect of a treatment.Procarbazine, prednisone and vincristine coupling can improve treatment lymphosarcoma curative effect.Glutamic acid can reduce the toxic reaction of vincristine, also reduces antitumor and renders a service.Tiazofurine can strengthen antitumor action in the paclitaxel coupling.The cancer therapy drug compound preparation has the preparation of trade name Eloxatin.Cancer patient is through chemotherapy and radiation, and immunity is lower, often need use immunostimulant simultaneously, or uses antimicrobial drug to prevent and to treat infection.
For diuretic, hydrochlorothiazide and depressor coupling can strengthen antihypertensive effect, the compound preparation listing of existing at present more diuretic and depressor.Acetazolamide and antuepileptic coupling can be worked in coordination with the epilepsy effect.
For hormone medicine, the hydrogen phenothiazine drug can be eliminated edema due to the hormone.Methotrexate and prednisone coupling treatment hormone-dependent type asthma have synergism.Cimetidine and prednisone coupling treatment herpes zoster have synergism.
In the clinical treatment field, drug combination is very general.The doctor leaves the prescription of different pharmaceutical combination often according to patient's situation.With reference to clinical treatment experience, also there is a large amount of compound preparations to be developed and to sell at present.But nearly all drug combination is the compound that adopts different pharmaceutical at present, and after these compound composite medicaments entered in the body, not constraint each other generally can only distribute in vivo according to the dynamic characteristic of each medicine own between the different pharmaceutical.Therefore the different pharmaceutical of drug combination can not arrive same position (as target cell) and obtain valid density simultaneously at synchronization under many circumstances.In some cases, owing to the medicine that toxicity is bigger is more in a certain site distribution, and the medicine of mithridatism is less in this site distribution, so have to increase the dosage of mithridatism medicine.So not only cause the ample resources waste, also may bring new side effect.
Highly active antiretroviral therapy (HAART) is almost all adopted in the treatment of AIDS at present, or title therapeuticcocktail of anti-retrovirals, be that two to three kinds of inverase is used simultaneously, produce to reduce drug resistance HIV, and the generation synergism strengthens drug effect (Parniak MA.HIV/AIDS after twenty-five years.Int J Biochem Cell Biol, 2004,36:1666; Sarafianos SG, et al.Designing anti-AIDS drugs targeting the major mechanism of HIV-1RTresistance to nucleoside analog drugs.Int J Biochem Cell Biol, 2004,36:1706).Also there is the anti-HIV medicine of compound recipe to sell in the market, as the preparation of commodity Combivir by name, Truvada, Epzicom, Kaletra.HIV sufferers is because immunocompetence is low, and also many other diseases that occur together simultaneously are as herpes simplex virus (HSV) infection, bacterial infection, mycobacterium tuberculosis infection, deep fungal infection, tumor.Therefore HIV sufferers is often taken the medicine of a large amount of anti-other diseases simultaneously.
Acquired immune deficiency syndrome (AIDS) is the pestilence of modern society.Whole world HIV (human immunodeficiency virus) (HIV) the infected was 4,000 ten thousand in 2004, dead 3,000,000,2005 newly-increased the infecteds 5,000,000.Official statistics result shows that the existing HIV the infected of China is about 650,000, wherein about 7.5 ten thousand, 2005 New Development the infecteds about 6～80,000 of acquired immune deficiency syndrome (AIDS) patient.Present China is in a HIV and infects quick build phase, and epidemic situation spreads to the general population from the high-risk group.Prevention, control and treatment that HIV infects are very urgent.
Macrophage (Microphages) is proved to be the important carrier of transfer in the HIV body, is the viral source in the AIDS pathogenesis, the carrier of virus diffusion, and the amplifier of immunologic function (Zhang Xingquan, Fan Jiang chief editor.HIV (human immunodeficiency virus) infection and acquired immune deficiency syndrome (AIDS).Beijing: People's Health Publisher, 1999:109; Aquaro S, et al.Macrophages and HIV infection:therapeutical approaches toward this strategic virus reservoir.Antivir Res, 2002,55:209).The half-life is short in present most of inverase body, cell membrane permeability is relatively poor, often dosage is big clinically, frequent (the Li X of administration number of times, Chan WK.Transport, metabolism and elimination mechanisms of anti-HIV agents.Adv Drug Del Rev, 1999,39:81).They nearly all do not have macrophage distribution specificity simultaneously, are difficult to the concentration of remaining valid for a long time in macrophage.Therefore need the inverase transmission system that finds energy targeting macrophage and controlled-release effect is arranged badly.Utilize the characteristics that microgranule in vivo can natural targeting mononuclear phagocyte system (MPS), someone is wrapped in liposome (Desormeaux A, Bergeron MG.Liposomes as drug deliverysystem:a strategicapproach for the treatment of HIV infection.J Drug Target.1998 with inverase; 1) or nanoparticle (Bender AR 6 (1):, et al.Efficiency of Nanoparticles as a carrier system for antivir alagents in humanimmunodeficiency virus-infected human monocytes/macrophages in vitro.Antimicrob AgentChemother, 1996,40:1467).But though these DDS targeting macrophages, they to water solublity be that main inverase encapsulation ratio is little, poor stability, drug loading be limited.
The administering mode of inverase (the oral or injection of ordinary preparation) is difficult to guarantee that two or more medicines in the therapeuticcocktail of anti-retrovirals arrive target cell simultaneously, and keeps valid density at present, does not promptly in fact play the effect of " compound recipe " treatment.Therefore how different inverases are transported to simultaneously target cell particularly the problem of macrophage need to be resolved hurrily.
Nearly 30 years, double end base amphiphile, amphiphilic molecule (Bolaamphiphiles) be subjected to gradually people pay close attention to (Lv Qing, etc.Double end base amphiphile, amphiphilic molecule progress.Chemical progress, 2001,13 (3): 161; FuhrhopJH, Wang T.Bolaamphiphiles.ChemRev, 2004,104:2901.).It is two polar groups by one or many special amphipathic molecules of the covalently bound class of hydrophobic chain, and wherein two polar groups can be identical or different.Bola is a kind of weapon of South America original inhabitant, refers to that the rope two ends are connected with two balls.Double end base amphiphile, amphiphilic molecule is similar to a kind of natural extinct plants and animal antibacterial archaeabacteria film fat molecular structure.This antibacterial can survive in harsh and unforgiving environments such as high temperature, high salinity, strong acid, just is being based on the unique double end base amphiphilic film fat molecule that aligns in its cell membrane.Therefore double end base amphiphile, amphiphilic molecule special physicochemical character has caused the very big interest of people.The single head base amphiphile, amphiphilic molecule (Chang Zuowei surfactant) that its complete different people knows, both character also has very big difference.Present various double end base amphiphile, amphiphilic molecule is synthesized, and is applied in aspects such as surfactant, simulation biomembrane, ordered molecular aggregation, nano material, but does not almost have its research as pharmaceutical carrier at present.The molecule self assembly can take place in the double end base amphiphile, amphiphilic molecule that satisfies the certain space structure, forms stable ordered aggregations such as micelle, monolayer, vesicle, nanotube.
The pharmaceutics research of 21st century has entered a New Times.To prepare pharmaceutical preparation safely and efficiently and to obtain the ideal medicament transmission is purpose, pharmaceutics research with the new techniques that utilize many basic subjects and related drugs subject more, biological example medicine new material, nanotechnology, hydrogel, organic synthesis, drug design, genome and protein science, cytobiology, molecular biology, pharmacokinetics, one of them important directions is at cellular level, micro-scale (comprising nanoscale) and molecular scale research pharmaceutical preparation, and preparation in vivo and in vitro with the interaction of other molecule and organism, finally obtain ideal drug delivery system (Drug delivery systems, DDS).
The research of microparticle formulation in the pharmaceutics (comprising nanometer formulation) has long historical.The high dispersion of microgranule makes it have the advantage that surmounts ordinary preparation, as dosage homogeneous, adhesion, targeting, controlled capability etc.Quiet notes back particle type DDS is mainly by monokaryon macrophage system (MPS, comprise liver spleen lung) engulf, has natural targeting, be called as targeted drug transmission system (Targeted drug delivery systems, TDDS) (Torchilin VP.Drug targeting.EurJ Pharm Sci, 2000,11:S81).To particle type DDS structure of modification or after adding some functional type compositions, can correspondingly obtain long circulating effect, can avoid MPS to engulf to a certain extent, and in blood, retain the long period, and acquisition be to the targeting of organ-tissues such as tumor, brain, kidney; In addition, also may obtain the effect of pH sensitivity, temperature sensitivity, photosensitivity, ultrasonic sensitive, radiosensitivity, magnetic targeting, active targeting (receptor-mediated).
The inventor once attempted nucleoside analog and aliphatic chain covalent bond are prepared the nucleoside analog lipid derivate, or nucleoside analog and cholesterol covalent bond are prepared Cholestrin derivative as nucleoside analog.They generally have amphipathic.If nucleoside analog is a medicine, can prepare the amphiphilic prodrug of single head base so.Can prepare the transmission system of high degree of dispersion easily by nucleoside analog lipid derivate or Cholestrin derivative as nucleoside analog, as liposome, non-ionic surface active agent vesicle, nanoparticle, microemulsion and self assembly transmission system.But related work referenced patent and article (Jin Yiguang, etc.Nucleoside analog lipid derivate and salt thereof.Chinese invention patent 03148546.4; Jin Yiguang, etc.Cholestrin derivative as nucleoside analog.Chinese invention patent 200410090653.X; Jin Yiguang, Hou Xinpo.Self assembly drug delivery system based on lipid prodrug.Chinese Journal of Pharmaceuticals, 2005,36 (3): 185; Yiguang Jin, et al.Self-assembled drug deliverysystems.1.Properties and in vitro/in vivo behavior of acyclovir selgf-assembled nanoparticles (SAN) .Int J Pharm, 2006,309 (1-2): 199).
Summary of the invention
The invention provides a kind of double-head radical lipid prodrug, it is characterized in that the structure of double-head radical lipid prodrug is:
D 1-R-D 2Or D 1-L 1-R-L 2-D 2
And satisfy:
(1) D 1And D 2It is pharmaceutical group;
(2) R is the aliphatic chain of 6～32 carbon atom length;
(3) L 1And L 2Be selected from inorganic acyl group, the fat group of 2～7 carbon atom length, hydrophilic radical.
Double-head radical lipid prodrug among the present invention, D wherein 1And D 2Can be identical, also can be different; L wherein 1And L 2Can be identical, also can be different.D 1, D 2, L 1, L 2And the connected mode between the R is without limits, but D preferably 1, D 2, L 1, L 2And connect with ester bond or amido link between the R.L 1And L 2On the basis of afore mentioned rules; inorganic acyl group is preferably from phosphoryl, phosphono, sulfonyl, pyrophosphoryl base, three phosphoryls, sulfonyl, boron acyl group; the fat group of 2～7 carbon atom length is preferably from two carboxyamino acid acyl groups of the fatty acyl group of 2～7 carbon atom length, 2～7 carbon atom length, the diamine base aminoacid amido of 2～7 carbon atom length; preferably from polyethylene glycol groups, polysaccharide base, poly-amino acid-based, wherein polyethylene glycol groups can be expressed as OCH to hydrophilic radical 2CH 2(OCH 2CH 2) nO, preferably the scope of n is 2～50.L 1And L 2It also can be the combination of these groups.Preferred L 1And L 2Be two carboxyamino acid acyl groups, the OCH of the fatty acyl group of phosphoryl, phosphono, sulfonyl, 2～7 carbon atom length, 2～7 carbon atom length 2CH 2(OCH 2CH 2) nThe combination of O base or these groups, wherein OCH 2CH 2(OCH 2CH 2) nThe scope of the n of O base is 2～50.To D 1And D 2The prototype molecular structure without limits, D preferably 1And D 2The prototype molecular structure in contain hydroxyl, amido or carboxyl.For D 1And D 2The prototype molecule properties without limits, polar molecule medicine preferably, more preferably dipole moment is greater than 0.5 polar molecule medicine, and further preferably dipole moment is greater than 1 polar molecule medicine, further preferably dipole moment greater than 2 polar molecule medicine.For D 1And D 2The prototype molecule the dissolubility aspect without limits, D preferably 1And D 2The dissolubility of prototype molecule in water greater than 0.01mg/ml, more preferably the dissolubility in water is greater than 0.1mg/ml, further preferably the dissolubility in water is greater than 1mg/ml.These dissolubility datas generally are meant the result who measures in the room temperature range (10～30 ℃).
Double-head radical lipid prodrug among the present invention, wherein D 1And D 2The prototype molecule can be selected from various medicines.The molecular weight that is applicable to medicine of the present invention can be a molecular weight greater than 10000 macromolecular drug without limits, also can be molecular weight less than 1000 medicine, and preferred molecular weight is less than 500 medicine, and more preferably molecular weight is less than 300 medicine.Be applicable to drug type of the present invention without limits, can be selected from medicine for central nervous system, the peripheral nervous system medicine, circulatory system drug, medicine for digestive system, medicine for respiratory system, the hormonal system medicine, the reproductive system medicine, the hemopoietic system medicine, the immune system medicine, medicine for urological system (comprising diuretic), anticarcinogen, ntipyretic analgesic medicine, antimicrobial agents, medicine for parasitic disease, hypoglycemic drug, hormonal medicaments, medicine for central nervous system preferably, circulatory system drug, anticarcinogen, ntipyretic analgesic medicine, antimicrobial agents, medicine for parasitic disease, hypoglycemic drug, more preferably anticarcinogen, antiviral drugs, anti-mycobacteria medicine, antimalarial.
Be applicable to concrete types of drugs of the present invention without limits, only need meet the structural requirement of double-head radical lipid prodrug.Enumerated some below applicable to variety classes medicine of the present invention, but scope of the present invention is not limited to this.
Medicine for central nervous system can be selected from barbiturates, the Benzodiazepines medicine, phenytoin Sodium, perphenazine, carbamazepine, propofol, sodium valproate, haloperidol, fluoxetine, Sertraline, clovoxamine, fluvoxamine, morphine, apomorphine, etorphine, dihydroetorphine, codeine, nalbuphine, naloxone, pentazocine, dezocine, tramadol, theophylline, amfetamine, pyritinol, modafinil, oxiracetam, ropinirole, bromocriptine, talipexole, cabergoline, pramipexole, budipine, tolcapone, entacapone, zopiclone, zolpidem, etomidate, Zaleplon, Escitalopram, varenicline, Lie Monaban, swell because of ground is general, Pa Lirui ketone, hydroxybutyric acid, memantine, acamprosate calcium, duloxetine, estazolam, the third oxygen sweet smell, adrafinil.Barbiturates can be selected from barbital, pentobarbital, quinalbarbitone, extra large rope barbital.The Benzodiazepines medicine can be selected from chlordiazepoxide, tavor, diazepam, oxazepam, temazepam, lorazepam.
The peripheral nervous system medicine can be selected from atropine, hyoscyami bases medicine, epinephrine, norepinephrine, isoproterenol, dopamine, ephedrine, albuterol, cetirizine, ecgonine.
Circulatory system drug can be selected from beta-blocker, calcium channel blocker, sodium channel inhibitor, potassium channel antagonists, angiotensin-convertion enzyme inhibitor, angiotensin ii receptor antagonist, NO donor medicine, cardiac tonic, lipid regulating agent, antithrombotic.Beta-blocker can be selected from Propranolol, alprenolol, oxprenolol, pindolol, nadolol, timolol, esmolol, flestolol, practolol, bisoprolol, acebutolol, atenolol, metoprolol, betaxolol, labetalol, celiprolol, arotinolol, bevantolol.Sodium channel inhibitor can be selected from quinidine, mexiletine, tocainide, Propafenone.Angiotensin-convertion enzyme inhibitor can be selected from captopril, alacepril, enalapril, lisinopril, training buttress Puli, ramipril, quinapril, delapril, cilazapril, benazepril, spirapril, trandolapril, moexipril, imidapril, fosinopril.Angiotensin ii receptor antagonist can be selected from losartan, eprosartan, telmisartan, valsartan.Lipid regulating agent can be selected from lovastatin, mevastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, nicotinic acid, nicotinyl alcohol, gemfibrozil, cerivastatin.Antithrombotic can be selected from aspirin, ozagrel, tirofiban, booth bundle heparin, argatroban.Other circulatory system drug also can be selected from clopidogrel, alfuzosin, Vardenafil, sldenafil, its Da Lafei, puerarin, ranolazine (ranolazine), amlodipine, nimodipine, troxerutin, buflomedil, diltiazem, Alprostadil.
Medicine for digestive system can be selected from famotidine, proglumide, rice Suo Qianlie acid, cisapride, metoclopramide, omeprazole, lansoprazole, pantoprazole.
Anticarcinogen can be selected from NSC-178248, mitobronitol, mitolactol, cisplatin, carboplatin, oxaliplatin, fluorouracil, doxifluridine, cytosine arabinoside, ancitabine, azacytidine, enocitabine, mercaptopurine, thioguanine, spray Si Tating, methotrexate, bleomycin, Bleomycin A5, peplomycin, amycin, daunorubicin, epirubicin, zorubicin, aklavine, mitoxantrone, mitomycin, hydroxy camptothecin, paclitaxel, Docetaxel, hydroxyurea, Soret is the Buddhist nun not, Avastin, letrozole, imatinib (trade name Gleevec), fulvestrant, zoledronic acid, ondansetron, palonosetron, granisetron, gefitinib, bortezomib, azacitidine (erlotinib, OSI-774), dacarbazine, pamidronic acid.
Ntipyretic analgesic medicine can be selected from aspirin, salicylic acid, acetaminophen, indomethacin, oxyphenbutazone, mefenamic acid, meclofenamic acid, piroxicam, meloxicam, diclofenac sodium, tolmetin, lonazolac, ibuprofen, flurbiprofen, naproxen, fenoprofen, ketoprofen, remifentanil.
Antimicrobial agents can be selected from Penicillin antibiotics, cephalosporins, beta-lactamase inhibitor, tetracycline antibiotics, aminoglycoside antibiotics, macrolide antibiotics, chloromycetin series antibiotics, quinolones, anti-mycobacteria medicine, sulfa drugs and Trimethoprim, antifungal drug, antiviral drugs.Quinolones can be selected from pipemidic acid, norfloxacin, enoxacin, ofloxacin, levofloxacin, ciprofloxacin, sparfloxacin, lomefloxacin, Pazufloxacin, Gatifloxacin.Anti-mycobacteria medicine can be selected from isoniazid, para-aminosalicylic acid, pyrazinamide, ethambutol, rifampicin, streptomycin, kanamycin.Sulfa drugs and Trimethoprim can be selected from sulfadiazine, sulfafurazole, sulfamethoxazole, trimethoprim.Antifungal drug is optional from Nystatin, amphotericin B, ciclopirox olamine.Antiviral drugs is optional from ribavirin, penciclovir, ganciclovir, acyclovir, famciclovir, valaciclovir, cidofovir, bent fluorothymidine, zidovudine, vidarabine, cytosine arabinoside, lamivudine, stavudine, Saquinavir, indinavir, ritonavir, viracept see nelfinaivr, zanamivir, Oseltamivir, amantadine, hydroxyurea, emtricitabine, imiquimod, zanamivir, tipranavir, Entecavir, dicaffeoyl quinic acid, atazanavir, fosamprenavir, efavirenz, pentafuside.
Medicine for parasitic disease is optional from anthelmintic medicine, antischistosomal, antimalarial, specifically is selected from quinine, quinidine, cinchonine, cinchonidine, mefloquine, LUMEFANTRINE, artelinic acid, dihydroartemisinine, artesunate, atovaquone, nitazoxanide, permethrin.
Hypoglycemic drug can be selected from metformin, glibornuride, acarbose, miglitol, pancreas opsonin.
Medicine for urological system (comprising diuretic) can be selected from etacrynic acid, bumetanide, ticrynafen, tolterodine, furosemide, solifenacin.
Hormone medicine can be selected from prostaglandin, chorionic gonadotrophin, glucagon, thyrotropin, levothyroxine, luteinising hormone-releasing hormo and analog thereof, growth hormone.
Other medicines also comprise paracodin, Mycophenolic Acid, cystamine, ambroxol, ferulic acid, neo-houttuyninum, garlicin, kurarinone, Antiradon, nor-Cantharidic acid., andrographolide, cetirizine, ritodrine, imipenum, cilastatin, ligustrazine, albuterol, triamterene, montelukast, Alendronic Acid, fexofenadine.
Double-head radical lipid prodrug among the present invention, wherein the prototype molecule of D1 and D2 also can be selected from polypeptide and protein medicaments, oligonucleotide drug, gene class medicine, polyose medicament.Polypeptide and protein medicaments can be selected from insulin and derivant thereof, calcitonin, various interferon, various interleukins, erythropoietin, hepatocyte growth-promoting factors, hepatocyte growth factor, hepatocyte forming agent (HPO), tumor necrosis factor, the metakentrin liberin, colony stimulating factor (comprises M-CSF, granulocyte macrophage colony stimulating factor, recombinant human granulocyte colony stimulating factor etc.), ADA Adenosine deaminase, asparaginase, superoxide dismutase, Defibrase, tissue-type plasminogen activator, the plasminogen activator of urokinase type, hirudin and analog thereof, ciclosporin, triptorelin, leuprorelin, alarelin, buserelin, the Gao She Rayleigh, nafarelin, glutathion, thymosin, neuropeptide, neurotensin (NT), endorphins and enkephalin derivant, serum thymic factor (FTS), pituitary adenylate cyclase activating peptide, antibacterial peptide, octreotide, Uropoly acid-peptide, various polypeptide antigens, the En Fuwei peptide, the Xi Fuwei peptide, brain natriuretic peptide (Nesiritide), ziconotide, the emol monoclonal antibody, the sharp former times monoclonal antibody (infliximab) of English, alemtuzumab, pegfilgrastim, abatacept.The oligonucleotides medicine can be selected from Fomivirsen, peptide nucleic acid(PNA), lock nucleic acid, siRNA.Polyose medicament can be selected from heparin and derivant thereof, chrondroitin, polyporusum bellatus, lentinan.
If D 1And D 2The prototype molecular structure in contain nitrogen heterocyclic ring, preferably nucleoside analog specifically can be selected from acyclovir, ganciclovir, famciclovir, penciclovir, valaciclovir, virazole, Sorivudine, ribavirin, vidarabine, zidovudine, lamivudine, didanosine, zalcitabine, stavudine, vidarabine, cidofovir, doxifluridine, cytosine arabinoside, azacitidine.
All are applicable to medicine of the present invention, and they can same medicine group form be positioned at the two ends of double-head radical lipid prodrug, also can be positioned at the two ends of double-head radical lipid prodrug with different pharmaceutical group form according to administration or Drug therapy needs.
R in the double-head radical lipid prodrug among the present invention, the structure of its prototype molecule on aforementioned regulation basis also without limits, can be preferably from the chemical compound that contains a plurality of reactive groups, reactive group can be selected from carboxyl, hydroxyl, amino, sulfydryl, acyl chlorides, also can be selected from chemical compound with reactivity, as anhydride, preferably dicarboxylic acid compound, diol compound, diamine compound, simultaneously contain the chemical compound of carboxyl and hydroxyl, contain the chemical compound of carboxyl and amido, the chemical compound of amino-contained and hydroxyl simultaneously simultaneously.The optional self-structure of prototype molecule of R is HOOCR 1COOH, HOR 2OH, H 2NR 3NH 2, HOOCR 4OH, HOOCR 5NH 2, HOR 3NH 2Chemical compound, preferably from fat diacid, aliphatic glycol, aliphatic diamine, wherein aliphatic chain is generally saturated carbon chains, also can be unsaturated carbon chains, preferred construction is that reactive group (carboxyl, hydroxyl, amido) is at the carbochain end.Saturated carbon chains is the linear paraffin base preferably.To the prototype molecular structure of R without limits, as long as can prepare as the double-head radical lipid prodrug structure among the present invention.The prototype molecule of concrete R can be selected from HOOCR 1COOH (R 1=(CH 2) n, n=4～30 wherein), HOR 2OH (R 2=(CH 2) n, n=6～32 wherein), H 2NR 3NH 2(R 3=(CH 2) n, n=6～32 wherein), HOOCR 4OH (R 4=(CH 2) n, n=5～31 wherein), HOOCR 5NH 2(R 5=(CH 2) n, n=5～31 wherein), HOR 3NH 2(R 6=(CH 2) n, n=6～32 wherein).
As previously mentioned, L in the double-head radical lipid prodrug 1And L 2Be selected from inorganic acyl group, the fat group of 2～7 carbon atom length, hydrophilic radical, also stipulated preferred range.In preparation double-head radical lipid prodrug process, introduce the basic L of connection 1And L 2Can relate to various reactions and reaction raw materials (is L 1And L 2The prototype molecule).Reaction raw materials can be selected from phosphoric acid, phosphonic acids, sulphuric acid, mineral acid and their derivants such as pyrophosphoric acid, comprise phosphoryl chloride phosphorus oxychloride, phosphonic chloride, chlorosulfuric acid, pyrophosphoryl chloride, also has fat diacid, the fat diacid acid anhydride, glutamic acid, aspartic acid, lysine, arginine, Polyethylene Glycol (PEG) and derivant thereof, polysaccharide, polyamino acid, wherein fat diacid can be selected from oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, 2-methyl-2-butene diacid, dimethyl succinic acid, hydroxyl succinic acid, oxalacetic acid (oxidation succinic acid), tartaric acid, 1,3-propanedicarboxylic acid, adipic acid, 2, the 2-dimethylated pentanedioic acid, 1,5-pentanedicarboxylic acid., phthalic acid, more preferably succinic acid, maleic acid, fumaric acid, glutamic acid, aspartic acid.The molecular weight of preferred polysaccharide, polyamino acid is below 5000.
Certain suitable reaction of general employing just can become double-head radical lipid prodrug with medication preparation.Be applicable to that response type of the present invention is unrestricted, as long as it is just passable to obtain double-head radical lipid prodrug.Concrete response type can be selected from addition, rearrangement, acidylate, hydrolysis, alcoholysis, ester exchange, oxidation, reduction, replacement, cyclisation, elimination, condensation, polymerization, alkylation, coupling, dehydration etc.; sometimes also need to introduce protecting group; deprotection also needs to activate certain group sometimes then.If former drug molecule, the prototype molecule of R, L 1And L 2The prototype molecule in do not have suitable reactive group; can introduce these molecules to some active group earlier by certain reaction; as hydroxyl, amino, carboxyl, sulfydryl, nitro, phosphoryl, phosphono, sulfonyl, acyl chlorides, N-hydroxy-succinamide etc., also can in reaction, directly obtain these groups.For designed double-head radical lipid prodrug molecule, this area professional and technical personnel can and utilize professional technique with reference to the pertinent literature method, just can design suitable reaction, and certain medication preparation is become double-head radical lipid prodrug.
Because two pharmaceutical groups of a double-head radical lipid prodrug molecule portability (can identical also can be different), so it plays dual release function in vivo, be that its two ends pharmaceutical group hydrolysis goes out two former medicine molecules, can only hydrolysis do not go out a former medicine molecule and do not resemble common single head base prodrug.If the two ends medicine is identical, double-head radical lipid prodrug is the double amount of single medicine carrying so, easily obtains the release of medicine high concentration and longer time at site of action.If two ends medicine difference, double-head radical lipid prodrug can also can claim two medicine carryings and two release in real " compound recipe " administration (drug combination) function of the three unities (in certain target cell) performance in vivo so.
After obtaining the double-head radical lipid prodrug among the present invention, can also it be prepared salify according to instructions for use.The salify position generally is in the pharmaceutical group position, the type of salt can be selected from sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, various ammonium salts, maleate, fumarate, succinate, benzoate, phthalate, benzene sulfonate, formates, acetate, propionate, oxalates, amino acid salts, malate, malonate, citrate, tartrate, lactate, nitrate, phosphate, dihydric phosphate, phosphoric acid hydrogen disalt, hydrochlorate, iodate, bromate, borate, sulfate, disulfate, preferably sodium salt, potassium salt, various ammonium salts, benzoate, benzene sulfonate, formates, acetate, amino acid salts, citrate, tartrate, lactate, dihydric phosphate, hydrochlorate, sulfate, disulfate.The method of the salt of preparation double-head radical lipid prodrug generally can be dissolved in identical or different organic solvent respectively with double-head radical lipid prodrug and corresponding acid or alkali earlier, organic solvent solution with them equates or almost equal mixed according to their molecule moles again, through suitably handling, at last mixed solution is volatilized, carry out suitable purification and separate, obtain the salt of double-head radical lipid prodrug.
The selectable scope of double-head radical lipid prodrug of the present invention is very extensive, and the described embodiment in back is a very small percentage, and the double-head radical lipid prodrug that the homologue among the embodiment and the medication preparation of same type obtain all belongs to the scope of the invention.
The form of administration and the route of administration of the double-head radical lipid prodrug among the present invention are not restricted yet, can be prepared into various dosage forms, as tablet, capsule, granule, drop pill, suspensoid, solution, Emulsion, gel, ointment, emulsifiable paste, suppository, membrane, liniment, aerosol, spray, implant, can certainly use various pharmaceutics technology such as solid dispersion, cyclodextrin inclusion compound, coating, microcapsule, microsphere, micropill, emulsifying, slow release, controlled release, magnetic targeting etc. it is prepared into various dosage forms.
The present invention also provides a kind of transmission system of high degree of dispersion especially, it is characterized in that it is made up of the double-head radical lipid prodrug among the present invention, is selected from liposome, non-ionic surface active agent vesicle, nanoparticle, microemulsion or self assembly transmission system.
Double-head radical lipid prodrug has fat-soluble.If contain suitable polar molecule pharmaceutical group, double-head radical lipid prodrug will have amphipathic, and can claim double end base amphiphilic prodrug this moment.These character make double-head radical lipid prodrug be fit to prepare the transmission system of high degree of dispersion.The transmission system of these high degree of dispersion can be selected from liposome, non-ionic surface active agent vesicle, nanoparticle, microemulsion or self assembly transmission system.As previously mentioned, the transmission system of high degree of dispersion is one of best form in drug delivery field, has characteristics such as dosage homogeneous, targeting, adhesion, slow-releasing.
Double-head radical lipid prodrug among the present invention or its salt have fat-soluble stronger aliphatic chain group, and may have amphipathicly, they can be prepared into easily the transmission system of above-mentioned high degree of dispersion.The transmission system of these high degree of dispersion can aqueous suspension form exist, also can become solid form by prepared such as lyophilization, spray dryinges, form aqueous suspension after adding water or aqueous solution.These average particle diameters that contain the high degree of dispersion transmission system of double-head radical lipid prodrug are generally less than 1 micron, preferably less than 0.5 micron, more preferably less than 0.2 micron.The preparation method of the transmission system of the high degree of dispersion of double-head radical lipid prodrug can be with reference to pertinent literature method and professional technique (New RRC ed.Liposome:a practicalapproach.Oxford:Oxford University Press, 1990; Uchegbu IF and Vyas SP.Non-ionicsurfactant based vesicles (niosomes) in drug delivery.Int J Pharm, 1998,172:33; CavalliR, et al.Sterilization and freeze-drying of drug-free and drug-loaded solid lipid nanoparticles.Int J Pharm, 1997,148:47; Lu Bin, Zhang Zhengquan.Study the formation condition of medicinal microemulsion with triangle phasor method.Acta Pharmaceutica Sinica, 2001,36:58; The Lu Bin chief editor.Novel pharmaceutical formulation and new technique.Beijing: People's Health Publisher, 1998).
The method for preparing the double-head radical lipid prodrug liposome can be selected from film dispersion method, reverse phase evaporation, injection method, freezing fusion method, multi-emulsion method, freeze-drying, surfactant facture, centrifuging, pro-liposome method, calcium fusion method, pressurization extrusion molding.Usually, if adopt film dispersion method to prepare liposome, liposome materials such as double-head radical lipid prodrug and phospholipid, cholesterol can be dissolved in organic solvent jointly, contain in the flask, the decompression rotary evaporation obtains thin film, adds entry or suitable buffer then, vibrate with ultrasonic, until forming uniform suspension.If ultrasonic time prolongs, can reduce the liposome particle diameter, may obtain nanometer liposome.If adopt reverse phase evaporation to prepare liposome, materials such as double-head radical lipid prodrug and phospholipid can be dissolved in organic solvent jointly, add entry or buffer, high-speed stirred or the ultrasonic Emulsion that is prepared into, the rotary evaporation that reduces pressure then obtains the gel state material, adds entry or suitable buffer or do not add then, continue the decompression rotary evaporation, until forming uniform liposome turbid liquor.Liposome turbid liquor can also be selected suitably to write out a prescription and carry out lyophilization or spray drying under proper condition, forms solid powdery, can guarantee stability of formulation like this, faces with the jolting of preceding adding aqueous solution to obtain liposome turbid liquor.The utilization similar techniques can obtain the non-ionic surface active agent vesicle of double-head radical lipid prodrug.
Nanoparticle can be divided into polymer nanoparticle and solid lipid nanoparticle (SLN) according to material.The optional self emulsifying polymerization of the preparation method of double-head radical lipid prodrug polymer nanoparticle, natural polymer method, intra-liquid desiccation method, automatic emulsified solvent diffusion method.Solid lipid nanoparticle (SLN) is suitable for the double-head radical lipid prodrug among the present invention.The preparation method of double-head radical lipid prodrug SLN can be selected from the even method of high pressure breast, solvent emulsion method, microemulsion method.The even method operating process of high pressure breast generally is that double-head radical lipid prodrug and room temperature are solid-state lipid down, as phospholipid, fatty acid, glyceride, common heating and melting, add entry or suitable buffer then, under heating state, in high pressure dispersing emulsification machine cocycle emulsifying repeatedly, form the emulsion droplet of nano-dispersed, rapidly cooling, make it to solidify, promptly obtain double-head radical lipid prodrug SLN.Double-head radical lipid prodrug nanoparticle suspension can also be selected suitably, and prescription also carries out lyophilization or spray drying under proper condition; form solid powdery; can guarantee stability of formulation like this, face with the jolting of preceding adding aqueous solution and can obtain the nanoparticle suspension.
The preparation of double-head radical lipid prodrug microemulsion can generally comprise medicine, emulsifying agent, co-emulsifier, cosolvent, oil phase, water with reference to common prescription.Generally after selecting suitable prescription, can easily form microemulsion.If select suitable prescription, generally comprise medicine, emulsifying agent, co-emulsifier, cosolvent, oil phase, can also form double-head radical lipid prodrug self-emulsifying microemulsion system.The latter can be dispersed into microemulsion voluntarily after adding suitable quantity of water or aqueous solution.
The transmission system of above-mentioned double-head radical lipid prodrug high degree of dispersion, comprise liposome, non-ionic surface active agent vesicle, nanoparticle, microemulsion, if contain special material, can obtain effects such as long cyclicity, pH sensitivity, temperature sensitivity, photosensitivity, ultrasonic sensitive, radiosensitivity, magnetic targeting, active targeting.
Except the transmission system of the high degree of dispersion of the above-mentioned double-head radical lipid prodrug that can obtain easily, the inventor also finds unexpectedly because the specific physical chemical property of the double-head radical lipid prodrug among the present invention, particularly have when amphipathic and (can be described as double end base amphiphilic prodrug this moment), by it self or add an amount of additive after the molecule self assembly can take place in water, form the self assembly transmission system of high degree of dispersion.When the ordered aggregation that the molecule self assembly forms high degree of dispersion may take place according to molecular characterization in double-head radical lipid prodrug in water, the nanoparticle form that obtains of the vesicle that obtains of monolayer, monolayer bending and monolayer stack for example.Sometimes in order to help double-head radical lipid prodrug to carry out the molecule self assembly or to improve the property of system, need to add certain quantity of additive.The present invention designs first and has prepared the self assembly transmission system of being formed or added the high degree of dispersion of an amount of additive by the double-head radical lipid prodrug among the present invention.
The preparation method of the self assembly transmission system of the high degree of dispersion of being made up of double-head radical lipid prodrug among the present invention and the preparation method of liposome equal altitudes disperse system are similar.Normally double-head radical lipid prodrug is dissolved in certain organic solvent, can adds suitable additives as required, disperse then.Concrete preparation method can be selected from film dispersion method, reverse phase evaporation, injection method, multi-emulsion method etc.In some cases, additive is optional, and this moment, transmission system all was made up of double-head radical lipid prodrug.In some cases, can not form good high degree of dispersion particle with double-head radical lipid prodrug separately, maybe need to regulate some physicochemical properties of self assembly transmission system, need this moment to add suitable additives, help its formation ordered structure or improve the property of system.Whether need to add additive according to the physicochemical properties of double-head radical lipid prodrug and the target decision that will reach, generally can infer by preliminary experiment.
To account for the molecule molar ratio of whole constituents be 50～100% to double-head radical lipid prodrug in the self assembly transmission system of the high degree of dispersion among the present invention, preferably 70～100%, more preferably 85～100%, and all the other compositions are additive.Additive can be selected from lipid molecular, surfactant.Lipid molecular can be selected from fatty acid, aliphatic alcohol, fatty amine, cholesterol again.Fatty acid comprises mono carboxylic fatty acid and two carboxylic fatty acids (fat diacid); Aliphatic alcohol also comprises monohydric aliphatic alcohols and two hydroxy fatty alcohols (aliphatic glycol); Aliphatic alcohol also comprises monoamine base fatty amine and diamine base fatty amine (aliphatic diamine); Their aliphatic chain can be 6～32 carbon atom length.Surfactant can be selected from anion surfactant, cationic surfactant, amphoteric surfactant, non-ionic surface active agent, natural surfactant, preferably from cholate, deoxycholate, phospholipid, polyhydric alcohol esters surfactant, polyoxyethylene surfactant, polyethyleneglycol lipid derivates, polysaccharide lipid derivate, polyamino acid lipid derivate, cholesterol monomester succinate, double end base Amphiphilic Surfactant.Phospholipid comprises synthetic phospholipid, semi-synthetic phospholipid, natural phospholipid.Synthetic phospholipid comprise again the phospholipid of modification such as polyglycol derivatization phospholipid, connect the phospholipid of monoclonal antibody.Polyhydric alcohol esters surfactant is sorbitan fatty acid ester preferably, and is concrete as sorbester p18, span 40, span 20.The polyoxyethylene surfactant is polyoxyethylene polyoxypropylene block copolymer (also claiming poloxamer) preferably, Polysorbate and polyoxyethylene aliphatic alcohol ether, concrete as poloxamer P188, Tween 80, polysorbate60, polysorbate40, polysorbas20, Brij35, Brij58.
The transmission system of the high degree of dispersion of double-head radical lipid prodrug comprises the self assembly transmission system; if the double-head radical lipid prodrug molecule contains itself, transmission system prescription has in forming or the transmission system surface adsorption has the molecule or the molecule segment of highly-hydrophilic; just can form the hydrophilic protective layer in external environment or internal milieu, so block interparticle polymerization or in vivo the retardance conditioning turn into and obtain long circulating effect.Hydrophilic molecule or molecule segment commonly used are Polyethylene Glycol (PEG), polysaccharide, polyamino acid.The transmission system of high degree of dispersion that can adopt the method for materials such as the phospholipid that adds polyglycol derivatization, polyoxyethylene surfactant, polyethyleneglycol lipid derivates, polysaccharide lipid derivate, polyamino acid lipid derivate, polyethylene glycol type double end base amphiphile, amphiphilic molecule to prepare the double-head radical lipid prodrug of surface hydrophilic in the present invention comprises its self assembly transmission system.
The method of the transmission system of the high degree of dispersion of above-mentioned preparation double-head radical lipid prodrug is without changing or through after adjusting a little, all applicable to the salt of double-head radical lipid prodrug.
Description of drawings
Fig. 1. the transmission electron microscope photo of the two zidovudine ester self assembly transmission systems of 15 carbon diacid.
Fig. 2. the transmission electron microscope photo of two succinyl acyclovir dodecane diester self assembly transmission systems.
The specific embodiment
1. pairs of succinyl acyclovirs of embodiment dodecane diester
This product is that dodecanediol two terminal hydroxy groups are connected with the carboxyl of succinyl acyclovir respectively, English name disuccinylacyclovir dodecanediol ester, be called for short DSAD, standard name succinic acid 12-{3-[2-(2-amino-6-oxo-1,6-dihydro-purin-9-ylmethoxy)-ethoxycarbonyl]-propanoyloxy}-dodecyl ester, the Chinese full name is a succinic acid 12-[3-[2-(2-amino-6-oxygen-1,6-dihydro purine-9-base methoxy)-carbethoxyl group]-propionyloxy]-dodecyl ester, molecular formula is C 36H 52N 10O 12, molecular weight 817.Get acyclovir (4.5g, 0.02mol), succinic anhydrides (10g, 0.1mol), 4-dimethylaminopyridine (DMAP, 0.244g, 2mmol), add 100ml N, dinethylformamide (DMF), charge into nitrogen, airtight, room temperature reaction 2 days, the reactant liquor reduction vaporization is removed most of solvent, and remaining liq is poured in the frozen water, gets white suspension, regulate pH to 2, sucking filtration, water washing with 1mol/L hydrochloric acid, drying obtains succinyl acyclovir (SACV, C 12H 15N 5O 6). 1H NMR data: 2.61 (4H, OCCH 2CH 2CO), 3.75 (2H, CH 2OCO), 4.22 (2H, OCH 2), 5.40 (2H, NCH 2O), 6.86 (3H, NH 2, COOH), 7.76 (1H, NCHN), 10.59 (1H, OCNHC).Elementary analysis value C (44.22%), H (4.68%), N (21.69%), theoretical value C (44.31%), H (4.65%), N (21.53%).The synthesis step of other pair carboxyl fatty acyl acyclovir such as maleoyl acyclovir, fumaroyl acyclovir, glutaryl acyclovir, Radix Asparagi acyl acyclovir, glutamy acyclovir is close with the succinyl acyclovir.
Get SACV (1.6g, 5mmol), dodecanediol (3.1g, 15mmol), dicyclohexylcarbodiimide (DCC, 1.1g, 5.5mmol), add 30ml DMF, airtight, stirring at room 2 days is filtered, and filtrate is poured in the saturated NaHCO3 aqueous solution, filter, filter residue and drying is used the isopropyl alcohol recrystallization, obtains DSAD.TLC shows a speckle. 1H NMR data: 10.59 (H, CONHCO), 6.41 (4H, 2NH 2), 5.35 (4H, 2NCH 2), 4.08 (4H, 2NCH 2OCH 2), 3.78 (4H, 2CH 2OCO), 1.28～1.30 (16H, (CH 2) 8).Elementary analysis value C (53.02%), H (6.75%), N (16.96%), theoretical value C (52.93%), H (6.42%), N (17.15%).
Two succinyl acyclovir dodecane diester (DSAD) also can be prepared into basic salt, as its sodium salt (DSAD-Na), molecular formula C 36H 50N 10O 12Na 2(0.817g 1mmol) is dissolved in the 5ml chloroform, adds the methanol solution that contains 1mmol NaOH, and jolting is ultrasonic, and decompression volatilizes solvent, and recrystallizing methanol obtains DSAD-Na to get DSAD.TLC shows a speckle.Other alkali salt such as potassium salt, calcium salt, magnesium salt preparation method are close.DSAD also can be prepared into acid salt, as its acetate, molecular formula C 40H 60N 10O 16(0.817g 1mmol) is dissolved in the 5ml chloroform, adds the acetone soln that contains 1mmol acetic acid, and jolting is ultrasonic, and decompression volatilizes solvent, and the isopropyl alcohol recrystallization obtains C to get DSAD 40H 60N 10O 16TLC shows a speckle.Other acid salt of DSAD such as formates, oxalates, maleate preparation method are close with acetate.
With the molecule of DSAD structural similarity, as the length and the interval base that change aliphatic chain, their synthesis step is close with it.Pharmaceutical group is changed to other nucleoside analog, as ganciclovir, famciclovir, penciclovir, valaciclovir, virazole, Sorivudine, ribavirin, vidarabine, zidovudine, lamivudine, didanosine, zalcitabine, stavudine, vidarabine, cidofovir, doxifluridine, cytosine arabinoside, azacitidine, can adopt similar synthetic method.Can also prepare salify for some double-head radical lipid prodrug.
The two zidovudine esters of embodiment 2. ten five carbon diacid
Figure C200610076653D00181
This product is that 15 carbon diacid two ends carboxyls are connected with the zidovudine hydroxyl respectively, English name pentadecanedioic aciddi-zidovudine ester, be called for short PDZ, standard is called pentadecanedioic acid bis-[3-azido-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-and tetrahydro-furan-2-ylmethyl] ester, Chinese 15 carbon diacid two by name-[3-nitrine-5-(5-methyl-2,4-dioxy-3,4-dihydro-2H-1-pyrimidine radicals)-and tetrahydrochysene-furan-2-methyl] ester, molecular formula C 35H 50N 10O 10, molecular weight 771.Get 15 carbon diacid (2.7g 10mmol) adds 20ml dichloromethane and 5ml thionyl chloride, reflux 3h, solvent evaporated promptly gets 15 carbon diacid chlorides (PDC).(AZT, 4.45g 16.7mmol), add 30ml dichloromethane and 4ml Et to get zidovudine 3The N dissolving, the dichloromethane solution of adding PDC, room temperature reaction 2h filters, and evaporated under reduced pressure gets semi-solid, and the silicagel column separation and purification gets PDZ.TLC shows a speckle. 1H NMR data: 9.02 (2H, 2NH), 7.26 (2H, 2AZT-pyrimidine-CH), 2.18～2.50 (8H, 2CH 2CO, 2CHCH 2CH), 1.94 (6H, 2CH 3), 1.62～1.66 (4H, 2CH 2CH 2CO), 1.23～1.28 (18H, (CH 2) 9).Elementary analysis value C (54.22%), H (6.93%), N (18.28%), theoretical value C (54.54%), H (6.54%), N (18.17%).
With the molecule of PDZ structural similarity, as the length and the interval base that change aliphatic chain, their synthesis step is close with it.Pharmaceutical group is changed to other nucleoside analog, as acyclovir, ganciclovir, famciclovir, penciclovir, valaciclovir, virazole, Sorivudine, ribavirin, vidarabine, lamivudine, didanosine, zalcitabine, stavudine, vidarabine, cidofovir, doxifluridine, cytosine arabinoside, azacitidine, can adopt similar synthetic method.
Embodiment 3. benazepril succinyl hydralazine hexadecane diester
Figure C200610076653D00191
This product is that hexadecane glycol two terminal hydroxy groups are connected with the carboxyl of benazepril with the succinyl hydralazine respectively, English name benazepril succinyl hydralazine hexadecanediol ester (being called for short BSHH), standard is called ethyl2-[(2-oxo-1-{2-oxo-2-[(16-{[4-oxo-4-(2-phthalazin-l-ylhydrazino) butanoyl] oxy}hexadecyl) oxy] ethyl}-2,3,4,5-tetrahydro-1H-l-benzazepin-3-yl) amino]-4-phenyl butanoate, molecular formula C 52H 70N 6O 8, molecular weight 907.Close with SACV synthetic method among the embodiment 1, synthetic obtain succinyl hydralazine (SH).Get the hexadecane glycol (2.58g, 10mmol), DCC/DMAP is an amount of, adds 30ml DMF heating for dissolving, (10h is continued to stir in the back that finishes of progressively increasing, and filters for 0.26g, DMF solution 1mmol), and filtrate is poured saturated NaHCO into to drip SH 3In the aqueous solution, filter, filter residue and drying is used acetone recrystallization, and separates through silicagel column, obtains succinyl hydralazine hexadecane diol monoester (SHH, C 28H 44N 4O 4).TLC shows a speckle.
Get SHH (0.5g 1mmol) is dissolved in THF, with benazepril (1.27g, 3mmol) DMF solution mixes, and adds an amount of DCC, DMAP, room temperature reaction 2 days filters, and filtrate is poured in the 15% NaCl aqueous solution, filters, filter residue and drying is used the isopropyl alcohol recrystallization, separates through silicagel column, obtains BSHH.TLC shows a speckle. 1H NMR data: 3.96 (H, OCH 2-1) ,～1.27 (24H, (CH 2) 12), 1.56 (4H, CH 2-2,15), 7.03 (3H, hydralazine-NHNH, benazepril-NH), 9.33 (H, hydralazine-N-CH-C), 7.89 (H, hydralazine-CH-23), 7.73 (H, hydralazine-CH-24), 7.49 (H, hydralazine-CH-25), 7.38 (H, hydralazine-CH-26), 2.41,2.81 (4H, succinyl-(CH 2) 2), 4.49 (2H, benazepril-OCOCH 2), 4.18 (2H, benazepril-CH2O).Elementary analysis value C (68.57%), H (7.52%), N (9.08%), theoretical value C (68.85%), H (7.78%), N (9.26%).
With the molecule of BSHH structural similarity, as changing aliphatic chain length or basic at interval, their synthesis step is close with it.Pharmaceutical group is changed to other Puli's class and piperazine class medicine in the wrong,, also can adopts similar synthetic method as dihydralazine, cadralazine, budralazine, captopril, enalapril, training buttress Puli.
The two insulin amide of embodiment 4. thapsic acids
Figure C200610076653D00201
This product is that thapsic acid two ends carboxyl is connected with the intermediary amido of insulin B chain, and English name hexadecanedioic aciddi-insulin amide is called for short HDI.Earlier with the serine amino of 29 on the glutamic acid amino of 1 on special fourth oxygen carbonyl oxygen base (t-Boc) protection INSULIN A chain and B chain.In addition thapsic acid is activated into thapsic acid N-hydroxy-succinamide ester, with the protection insulin response of front, slough protecting group at last again, obtain HDI.Structure is determined by NMR and MS.
Polypeptide or albumen that other pair carboxyl fatty acyl replaces can obtain by similar reaction.
Embodiment 5. methotrexate succinyl amycin 12 carbon two acyl polyethylene glycol 1500 esters
Figure C200610076653D00202
This product is that methotrexate is connected with the hydroxyl terminal of succinyl amycin c-terminus with 12 carbon, two acyl polyethylene glycol 1500 esters, English name methotrexate succinyl adriamycin decanedioicyl polyethylene glycol 1500 ester are called for short MSADP.Get amycin (1.09g, 2mmol), succinic anhydrides (1g, 10mmol), DMAP is an amount of, add 20ml DMF, airtight, room temperature reaction 1 day, the reactant liquor reduction vaporization is removed most of solvent, and remaining liq is poured in the frozen water, gets suspension, reuse 0.1mol/L hydrochloric acid is regulated pH to 3, filter washing, filter residue and drying, obtain succinyl amycin (SA, C 31H 33NO 14).But the synthetic method of single head base fatty acyl Polyethylene Glycol prepares in 12 carbon, the two acyl polyethylene glycol 1500 lists of references, mainly comprises activated carboxylic and esterif iotacation step.Get 12 carbon, two acyl polyethylene glycol 1500s (1.7g ,～1mmol), DCC (0.103g, 0.5mmol), DMAP adds 10ml DMF heating for dissolving in right amount, the SA that progressively increases (0.322g, DMF solution 0.5mmol), progressively increasing finishes afterwards continues to stir 5h, filters, and filtrate is poured saturated NaHCO into 3In the aqueous solution, filter, filter residue and drying is used acetone recrystallization, separates through silicagel column, obtains succinyl amycin 12 carbon two acyl polyethylene glycol 1500 monoesters (SADP).Get SADP (0.47g ,～0.2mmol) be dissolved in THF, (DMF solution 0.5mmol) mixes, and adds an amount of DCC, DMAP for MXT, 0.227g, and room temperature reaction 2 days filters, and filtrate is poured saturated NaHCO into methotrexate 3In the aqueous solution, filter, filter residue and drying is used the isopropyl alcohol recrystallization, and separates through silicagel column, obtains MSADP.Structure is determined by NMR, MS.
The molecule of other and MSADP structural similarity as changing aliphatic chain length or adopting methotrexate and the amycin double-head radical lipid prodrug molecule of the PEG of different polymerization degree, can prepare with reference to this method.
Embodiment 6. succinyl arteannuin glutamy LUMEFANTRINE hexadecane diester
Figure C200610076653D00211
This product is that artesunate (succinyl arteannuin) is connected with hexadecane glycol hydroxyl end with glutamy LUMEFANTRINE c-terminus, English name artesunate glutamyl lumefantrine hexadecanediol ester (being called for short AGLH), standard name 5-{2-(dibutylamino)-1-[(9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl] ethyl}1-(16-{[3-({ [(3R, 5aS, 6R, 8aS, 9R, 10R, 12R, 12aR)-3,6,9-trimethyldecahydro-3,12-epoxy[1,2] dioxepino[4,3-i] isochromen-10-yl] carbonyl}oxy) propanoyl] oxy}hexadecyl) glutamate, molecular formula is C 70H 97Cl 3N 2O 12, molecular weight 1265.Get LUMEFANTRINE (0.529g, 1mmol), glutamic acid (0.735g, 5mmol), DCC/DMAP is an amount of, adds 10ml DMSO, airtight, reacting by heating 18h, reactant liquor pour in the frozen water, suspension, sucking filtration, filter residue and drying obtains glutamy LUMEFANTRINE (GL, C 35H 39Cl 3N 2O 4).Get the hexadecane glycol (1.29g, 5mmol), DCC (0.206g, 1mmol), DMAP adds 15ml THF in right amount, heating for dissolving, (2h continue to be stirred in the progressively increasing back that finishes to the GL that progressively increases, and filters for 0.658g, DMSO solution 1mmol), and filtrate is poured saturated NaHCO into 3In the aqueous solution, filter, filter residue and drying is used ethyl alcohol recrystallization, and separates through silicagel column, obtains glutamy LUMEFANTRINE hexadecane diol monoester (GLH).Get GLH (0.9g 1mmol) is dissolved in THF, with artesunate (0.768g, 2mmol) THF solution mixes, and adds an amount of DCC/DMAP, room temperature reaction 2 days filters, and filtrate is poured in the 15% NaCl aqueous solution, filters, filter residue and drying is used the isopropyl alcohol recrystallization, and separates through silicagel column, obtains AGLH.TLC shows a speckle. 1H NMR data: 0.88 (6H, lumefantrine-2CH 3), 0.96 (3H, artesunate-cyclohexane-CH 3), 1.09 (3H, artesunate-tetrahydropyran-CH 3), 1.27 (24H, 12CH 2), 1.42 (3H, artesunate-CH3), 6.39 (H, lumefantrine-OCH), 5.08 (H, lumefantrine-H-31), 8.10 (H, artesunate-H-43), 7.91 (H, artesunate-H-52), 4.10 (2H, glutamyl-NH 2).Elementary analysis value C (66.95%), H (7.66%), Cl (8.10%), N (1.91%), theoretical value C (66.47%), H (7.73%), Cl (8.41%), N (2.21%).
The molecule of other and AGLH structural similarity as changing aliphatic chain length or the artesunate and the LUMEFANTRINE double-head radical lipid prodrug molecule of base (as Radix Asparagi acyl, succinyl, maleoyl) at interval, can prepare with reference to this method.
Embodiment 7. tetracosa carbon diacid Oseltamivir ribavirin esters
Figure C200610076653D00221
This product is that tetracosa carbon diacid c-terminus is connected with Oseltamivir aminoterminal and ribavirin hydroxyl terminal, English name tetracosanedioic acid oseltamivirribavirin ester, be called for short TOR, standard name 1-[5-O-(24-{[(1R, 5S, 6S)-and 6-(acetylamino)-3-(ethoxycarbonyl)-5-(1-ethylpropoxy) cyclohex-3-en-l-yl] amino}-24-oxotetracosaoyl)-b-D-ribofuranosyl]-1H-1,2,4-triazole-3-carboxamide, molecular formula C 48H 82N 6O 11, molecular weight 919.Get the tetracosa carbon diacid (2g, 5mmol), DCC/DMAP adds in 25ml THF and the 10ml DMF mixed solvent in right amount, heating for dissolving drips Oseltamivir (0.312g, DMSO solution 1mmol), dropwise the back and continue to stir 5h, filter, filtrate is poured in the water, filters, filter residue and drying, use ethyl alcohol recrystallization, and separate, obtain tetracosa carbon diacid Oseltamivir monoesters (TO) through silicagel column.Get TO (0.7g 1mmol) is dissolved in THF, with ribavirin (0.5g, 2mmol) DMF solution mixes, and adds an amount of DCC/DMAP, room temperature reaction 18h filters, and filtrate is poured in the 15% NaCl aqueous solution, filters, filter residue and drying is used acetone recrystallization, and separates through silicagel column, obtains TOR.TLC shows a speckle. 1H NMR data: 0.86 (6H, oseltamivir-2CH 3), 1.24-1.39 (40H, 20CH 2), 1.90 (3H, oseltamivir-NCOCH 3), 7.69 (2H, ribavirin-NH 2), 8.88 (H, ribavirin-NCHN).Elementary analysis value C (62.34%), H (8.58%), N (9.46%), theoretical value C (62.72%), H (8.99%), N (9.14%).
The molecule of other and TOR structural similarity, Oseltamivir and ribavirin double-head radical lipid prodrug molecule as the different length aliphatic chain can prepare with reference to this method.
Embodiment 8. succinyls zidovudine-12-oxygen-dodecoic acid didanosine ester
Figure C200610076653D00222
This product is that the hydroxyl terminal of ω-hydroxyl dodecanoic acid is connected with didanosine with the succinyl zidovudine respectively with c-terminus.English name succinyl zidovudine 12-oxy-dodecanic acid didanosine ester, be called for short SZODD, standard name 1-[2,3-dideoxy-5-O-{4-[(12-{[5-(6-hydroxy-4,5-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl] methoxy}-12-oxododecyl) oxy]-4-oxobutanoyl}-3-(2 λ 5-triaz-1-en-2-yp-1-yl) pentofuranosyl]-5-methylpyrimidine-2,4 (1H, 3H)-dione, molecular formula C 36H 51N 9O 11, molecular weight 786.Synthetic similar with SACV among the embodiment 1, the synthetic succinyl zidovudine (SAZT) that obtains.Get ω-hydroxyl dodecanoic acid (0.2g, 1mmol), SAZT (0.7g, 2mmol), DMAP and DCC are an amount of, are dissolved in the DMF/THF mixed solvent, and be airtight, room temperature reaction 24h filters, filtrate is poured saturated NaHCO into 3In the aqueous solution, filter, filter residue and drying, use glacial acetic acid: chloroform (1: 5) recrystallization obtains succinyl zidovudine-12-oxygen-dodecoic acid (SZOD).Get SZOD (0.28g, 0.5mmol), didanosine (0.476g, 2mmol), DMAP and DCC are an amount of, be dissolved in the DMF/THF mixed solvent, airtight, room temperature reaction 2 days filters, and filtrate is poured in the 15% NaCl aqueous solution, filter, filter residue and drying is used the isopropyl alcohol recrystallization, obtains SZODD.TLC shows a speckle. 1H NMR data: 11.29 (H, zidovudine-CONHCO), 9.94 (H, didanosine-OH), 8.59 (H, didanosine-N=CHN), 7.64 (H, didanosine-NCH=N), 6.29 (H, zidovudine-OCHN), 5.45 (H, didanosine-NCH (C) N), 4.90 (H, CCHC=N), 3.94 (2H, OCH 2), 2.77 (2H, zidovudine-CH 2), 2.63,2.46 (4H, COCH 2CH 2CO), 2.33 (4H, 2CH 2CO), 1.80 (3H, CH 3), 1.28～1.54 (18H, (CH 2) 9).Elementary analysis value C (55.23%), H (6.87%), N (16.31%), theoretical value C (55.02%), H (6.54%), N (16.04%).
With the molecule of SZODD structural similarity, as succinyl zidovudine-22-oxygen-behenic acid didanosine ester, maleoyl zidovudine-6-oxygen-caproic acid didanosine ester synthesis step is close with it.Pharmaceutical group is changed to other nucleoside analog, as acyclovir, ganciclovir, famciclovir, penciclovir, valaciclovir, virazole, Sorivudine, ribavirin, vidarabine, lamivudine, zalcitabine, stavudine, vidarabine, cidofovir, doxifluridine, cytosine arabinoside, azacitidine, can adopt similar synthetic method.
9. pairs of glutamy lovastatins of embodiment, 15 carbon, two acyl Macrogol 200 esters
Figure C200610076653D00231
This product is that 15 carbon, two acyl Macrogol 200s, two terminal hydroxy groups are connected with glutamy lovastatin c-terminus respectively.English name diglutamyllovastatin pentadecanedioicyl polyethylene glycol 200 ester are called for short DGLPP, and molecular formula can be write as C 91H 146N 2O 26, molecular weight is about 1684.Get 15 carbon diacid (2.7g, 10mmol), 20ml thionyl chloride, reflux 1h, evaporated under reduced pressure, add PEG200 (4.4g, 22mmol), 0.4ml Et3N adds the 50ml dichloromethane, stirring at room 2h filters, and evaporated under reduced pressure gets 15 carbon, two acyl Macrogol 200s (PP).Get lovastatin (0.4g, 1mmol), glutamic acid (0.74g, 5mmol), (0.2g 1mol), adds the 10ml dichloromethane to DCC, ice bath reaction 12h, filter, filtrate is poured in the frozen water, is adjusted to pH4.5 with 0.1mol/L hydrochloric acid, filters to obtain glutamy lovastatin (GL).Get GL (0.53g, 1mmol), DCC and DMAP are an amount of, PP (0.65g, 1mmol), use the THF/DMF mixed solvent, stirring at room 2 days is filtered, and filtrate is poured in the saturated NaHCO3 aqueous solution, filter, filter residue and drying, the isopropyl alcohol recrystallization, the silicagel column separation and purification obtains DGLPP. 1H NMR data: 4.10 (4H, 2NH 2), 4.35,3.60 (32H, 8OCH 2CH 2O), 3.18 (2H, 2CHNH 2), 2.26 (4H, 2CH 2CO), 1.28～1.57 (22H, (CH 2) 11).
10. pairs of ibuprofen of embodiment, 15 carbon, two acyl PEG200 esters
Figure C200610076653D00241
This product is that 15 carbon, two acyl PEG200, two terminal hydroxy groups are connected with the ibuprofen carboxyl, English name di-ibuprofenpentadecanedioicyl polyethylene glycol 200ester, be called for short DIPP, chemical name bis[14-(4-isobutylphenyl)-13-oxo-3,6,9,12-tetraoxapentadec-1-yl] pentadecanedioate, molecular formula can be write as C 57H 92O 14, molecular weight is about 1001.Get ibuprofen (0.9g, 2.2mmol), DCC and DMAP are an amount of, 15 carbon, two acyl PEG200 (with embodiment 9 preparation, 0.65g, 1mmol), DMF makees solvent, room temperature reaction 12h filters, filtrate is poured NaHCO into 3In the aqueous solution, filter, filter residue and drying is used the isopropyl alcohol recrystallization, obtains DIPP through the silicagel column separation and purification. 1H NMR data: 4.08 (4H, 2COOCH 2) 4.05 (4H, 2CH 2OCOCHCH 3), 3.60 (16H, 2 (OCH 2CH 2OCH 2CH 2O)), 3.56 (2H, 2OC HCH 3) 2.46 (4H, 2CH 2CH (CH 3) 2), 2.30 (4H, 2CH 2CO), 1.85 (2H, 2CH (CH) 3), 1.25～1.58 (16H, (CH 2) 8).With the molecule of DIPP similar, as changing the aliphatic chain length or the PEG degree of polymerization, synthesis step is similar with it.
Embodiment 11. penicillin clavulanic acid docosane diester
Figure C200610076653D00242
This product is that docosane glycol two ends are connected with the clavulanic acid carboxyl with the penicillin carboxyl respectively, English name is benzylpenicillin clavulanic acid docosanediol ester, be called for short BCD, standard name is 22-[({3,3-dimethyl-7-oxo-6-[(phenylacetyl) amino]-4-thia-1-azabicyclo[3.2.0] hept-2-yl}carbonyl) oxy] docosyl (3E)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0] heptane-2-carboxylate, molecular formula C 46H 69N 3O 95, molecular weight is 840.Penicillin (3.34g, 11mmol), the docosane glycol (3.4g, 10mmol), DCC/DMAP is an amount of, adds DMF/THF (1:1) 50ml, and stirring at room 2 days is filtered, and filtrate is poured in the water, filters, and drying gets penicillin docosane diol monoester (BD).(3.2g, 5mmol), (2.2g 11mmol), adds DMF/THF (1:1) 30ml to clavulanic acid, and room temperature reaction 12h filters, and filtrate is poured NaHCO into to get BD 3In the aqueous solution, filter filter residue and drying, ethyl alcohol recrystallization.TLC shows a speckle. 1H NMR data; 4.38 (H, NH), 4.07,4.09 (4H, 2COOCH 2), 3.64 (2H, CH 2CO), 1.43,1.46 (6H, C (CH 3) 2), 1.27～1.61 (40H, (CH 2) 20).Elementary analysis value C (65.55%), H (8.10%), N (5.21%), S (3.44%), theoretical value C (65.76%), H (8.28%), N (5.00%), S (3.82%).Synthesizing of other antibiotic double-head radical lipid prodrug is close with BCD.
Embodiment 12. norfloxacins-12-oxygen-dodecoic acid metronidazole ester
Figure C200610076653D00251
This product is that the hydroxyl terminal of ω-hydroxyl dodecanoic acid is connected with metronidazole with norfloxacin respectively with c-terminus, English name is norfloxacin 12-oxy-dodecanicyl metronidazole ester, be called for short NODM, standard is called 12-[2-(2-methyl-5-nitro-1H-imidazol-1-yl) ethoxy]-12-oxododecyl-1-ethyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydroquinoline-3-carboxylate, molecular formula C 34H 47FN 6O 7, molecular weight 671.ω-hydroxyl dodecanoic acid (2g, 10mmol), the 10ml that adds methylene chloride, thionyl chloride 0.5ml, reflux 0.5h, evaporated under reduced pressure solvent get ω-hydroxyl lauroyl chloride, add an amount of dichloromethane and metronidazole (2g, 10mmol), 1.6ml Et 3N, ice bath reaction 2h filters, and the evaporated under reduced pressure solvent gets ω-hydroxyl lauroyl metronidazole ester (ODM), continuation adding norfloxacin (3.5g, 11mmol), DCC/DMAP is an amount of, adds 30ml DMF, and room temperature reaction 12h filters, and filtrate is poured NaHCO into 3In the aqueous solution, filter, filter residue and drying is used the isopropyl alcohol recrystallization.TLC shows a speckle. 1H NMR data: 8.08 (1H, C=CHN), 4.52,4.50 (4H, NCH 2CH 2O), 4.47 (2H, CH 3CH 2), 4.18 (2H, CH 2OCO), 4.07 (1H, NH), 2.51 (3H, N=CCH 3), 2.29 (2H, OCOCH 2), 1.26～1.52 (18H, (CH 2) 9).
The two zidovudine esters of embodiment 13. oneself two phosphinylidynes
Figure C200610076653D00252
This product is that oneself two phosphoryl two ends are connected with the zidovudine hydroxyl respectively, and English name hexanediol phosphyldi-zidovudine is called for short HPDZ, molecular formula C 26H 38N 10O 14P 2, molecular weight 777.Get POCl 3(2.2ml), (0.118g 1mmol), adds the 20ml dichloromethane to hexanediol, and ice bath reaction 10h obtains oneself two phosphoryl chloride phosphorus oxychlorides (HPC).Get zidovudine (0.255g, 1mmol), 0.4ml Et 3N, the dichloromethane solution of add methylene chloride 20ml and HPC, ice bath reaction is filtered, most of solvent is removed in decompression, water washing repeatedly, the organic facies evaporate to dryness gets semi-solid, obtains HPDZ through the silicagel column separation and purification.TLC shows a speckle. 1H NMR data: 11.29 (2H, 2NH), 4.38 (4H, 2CH 2O) 4.15,4.22 (4H, 2OCH 2), 1.80 (6H, 2CH 3).
Molecule with the HPDZ structural similarity, as change aliphatic chain length, or pharmaceutical group is changed to other nucleoside analog, as acyclovir, ganciclovir, famciclovir, penciclovir, valaciclovir, virazole, Sorivudine, ribavirin, vidarabine, lamivudine, didanosine, zalcitabine, stavudine, vidarabine, cidofovir, doxifluridine, cytosine arabinoside, azacitidine, can adopt similar synthetic method.
Embodiment 14. ten two carbon diamidogen tetrahydrochysene-2H-1,3,5-thiadiazine-2-thioketone isoniazid
Figure C200610076653D00261
This product is that 12 carbon diamidogen two ends amidos are connected with isoniazid by annulation, English name N, and N '-[dodecane-1, and 12-diylbis (6-thioxo-1,3,5-thiadiazinane-5,3-diyl)] diisonicotinamide, be called for short DTHTI, molecular formula C 30H 42N 8O 2S 4, molecular weight 675.(2g 10mmol) adds 5.6ml KOH solution (20mmol, 20%), stirs a moment, Dropwise 5 ml CS to get 12 carbon diamidogen 2, reaction 4h adds formaldehyde 44mmol, reaction 2h, and reactant liquor is added dropwise to isoniazid, and (2.74g reacts 6h in PBS 20mmol) (5ml)/ethanol (10ml) mixed solution, adds 5% hydrochloric acid 5ml reaction 1h, filters filtering residue chloroform/methanol recrystallization.
Embodiment 15. glutamy isoniazid para-aminosalicylic acid dodecane diester
Figure C200610076653D00262
This product is that dodecanediol two terminal hydroxy groups are connected with the para-aminosalicylic acid carboxyl with glutamy isoniazid carboxyl respectively, and English name glutamylisoniazid aminosalicylic acid dodecanediol ester is called for short GIASD, molecular formula C 30H 43N 5O 7, molecular weight 586.Synthetic similar with glutamy LUMEFANTRINE among the embodiment 6, the synthetic earlier glutamy isoniazid (GI) that obtains, GI elder generation and dodecanediol generate monoesters then, and the latter generates dibasic acid esters (GIASD) with para-aminosalicylic acid again. 1H NMR data: 8.69 (2H, isoniazid-CH-N-CH), 7.61 (2H, isoniazid-2CH), 7.52,6.45 (2H, AS-2CH), 6.87 (7H, 2NH, 2NH 2, OH), 6.05 (H, AS-H 2NCC HCOH), 4.34 (2H, CH 2OCO), 4.03 (2H, CH 2OCO).
The two naloxone esters of embodiment 16. ten five carbon diacid
This product is that 15 carbon, two acid molecule two ends carboxyls are connected with the naloxone hydroxyl respectively, English chemical name pentadecanedioicacid di-naloxone ester, be called for short PDN, standard name (5a)-17-allyl-14-hydroxy-6-oxo-4,5-epoxymorphinan-3-yl (5b, 9a, 13a, 14a)-17-allyl-14-hydroxy-6-oxo-4,5-epoxymorphinan-3-ylpentadecanedioate-(5a)-17-allyl-3,14-dihydroxy-4,5-epoxymorphinan-6-one (1:1), molecular formula C 53H 66N 2O 10, molecular weight 891.Get 15 carbon diacid (5.1g, 20mmol) and acetic anhydride (3.78ml, 40mmol), backflow 10h removes excess reactant, 15 carbon dicarboxylic anhydrides.Get anhydride (1.5g, 6mmol), naloxone (1.3g, 4mmol), DMAP is dissolved in 20ml DMF/THF (1:1) in right amount, reacting by heating 2 days, decompression removes most of solvent, and remaining liq is poured in the 15% NaCl aqueous solution, filter, use the isopropyl alcohol recrystallization after the filter residue and drying, get PND. 1H NMR data: 6.81 (2H, 2CH-18,42), 6.72 (2H, 2CH-14,38), 5.20 (2H, 2OH), 4.73 (2H, 2OCHCO), 2.56 (4H, OCCH 2).Elementary analysis value C (71.23%), H (7.51%), N (2.97%), theoretical value C (71.44%), H (7.47%), N (3.14%).
17. pairs of own diester of succinyl atropine of embodiment
Figure C200610076653D00272
This product is that hexanediol two terminal hydroxy groups are connected with succinyl atropine carboxyl respectively, and English name di-succinyl atropinehexanediol ester is called for short DSAH, standard name bis[(3-endo)-and 8-methyl-8-azabicyclo[3.2.1] oct-3-yl] 5,8,17,20-tetraoxo-2,23-diphenyl-4,9,16,21-tetraoxatetracosane-1,24-dioate, molecular formula C 48H 64N 2O 12, molecular weight 861.Similar with succinyl acyclovir among the embodiment 1, synthetic obtain succinyl atropine (SA), obtain DSAH with the hexanediol esterification then. 1H NMR data :～7.3 (10H, bezene-CH), 5.03 (2H, CH), 2.48,2.59 (8H, succinyl-4CH 2).Elementary analysis value C (66.65%), H (7.51%), N (3.01%), theoretical value C (66.96%), H (7.49%), N (3.25%).
The two Radix Asparagi acyl norepinephrine 12 carbon two acyl Macrogol 200 esters of embodiment 1R.
Figure C200610076653D00281
This product is that 12 carbon, two acyl PEG200, two terminal hydroxy groups are connected with Radix Asparagi acyl norepinephrine carboxyl, and English name di-aspartylnoradrenaline dodecanedioicyl polyethylene glycol 200ester is called for short DANDP, and molecular formula can be write as C 52H 82N 4O 22, molecular weight is about 1115.Synthetic similar with glutamy LUMEFANTRINE among the embodiment 6, earlier synthetic Radix Asparagi acyl norepinephrine is reacted into DANDP with 12 carbon, two acyl PEG200 again.
Embodiment 19. succinyl Propranolol furosemide 12 carbon two acyl polyethylene glycol 1500 esters
Figure C200610076653D00282
This product is that 12 carbon, two acyl polyethylene glycol 1500s, two terminal hydroxy groups are connected with the carboxyl of succinyl Propranolol, furosemide respectively, English name succinyl propranolol furosemide dodecanedioicyl polyethylene glycol 1500 ester, be called for short SPFDP, molecular weight is about 4400.With reference to preceding embodiment, first ambroin acyl Propranolol (SP) and 12 carbon, two acyl polyethylene glycol 1500 esters (DP), DP obtains SPFDP with SP and furosemide reaction respectively then.
Embodiment 20. tetracosa carbon diacid Oseltamivir ribavirin ester liposomes
Get tetracosa carbon diacid Oseltamivir ribavirin ester (TOR, 10mg), soybean phospholipid (100mg) is in the 300ml flask, with the dissolving of 25ml dichloromethane, the decompression rotary evaporation, obtain one deck alicyclic organic soluble film, add the phosphate buffer 1 0ml of pH7.4, vibration, most of film comes off, 60 ℃ ultrasonic, until obtaining even suspension, microscopically is observed, most of particle diameter is the TOR liposome less than 1 micron.
The preparation of embodiment 21. tetracosa carbon diacid Oseltamivir ribavirin ester long circulating liposomess
Get tetracosa carbon diacid Oseltamivir ribavirin ester (TOR, 20mg), soybean phospholipid (150mg), PEGization DSPE (PEG-DSPE) are (10mg) in flask, use the 30ml chloroform: diisopropyl ether (1:1) dissolving, add an amount of distilled water, ultrasonicly make it become Emulsion, the decompression rotary evaporation, obtain the gel state material, add low amounts of water, continue the decompression rotary evaporation, the gel state material comes off and is dispersed into even suspension, and microscopically is observed, most of particle diameter is the TOR long circulating liposomes less than 1 micron.
Embodiment 22. penicillin clavulanic acid docosane diester non-ionic surface active agent vesicles
Get penicillin clavulanic acid docosane diester (BCD, 20mg), sorbester p18 (100mg) in the 300ml flask, with the dissolving of 30ml dichloromethane, the decompression rotary evaporation, obtain one deck alicyclic organic soluble film, the phosphate buffer 1 0ml that adds pH7.4, vibration, most of film comes off, ultrasonic at 50 ℃, until the even suspension that obtains BCD non-ionic surface active agent vesicle, the laser light scattering Particle Size Analyzer detects, and mean diameter is 450 nanometers.
Embodiment 23. methotrexate succinyl amycin 12 carbon two acyl polyethylene glycol 1500 ester solid lipid nanoparticles
Get methotrexate succinyl amycin 12 carbon two acyl polyethylene glycol 1500 ester (MSADP, 200mg), glyceryl monostearate (1g), Tween 80 (0.03g) are heated to 80 ℃ in beaker, add the 80 ℃ of water (10ml) that contain sodium lauryl sulphate (10mg) gradually, keep temperature-resistant, be transparency liquid.Again it is injected in 0 ℃ of water of high-speed stirred with syringe, is transparency liquid.TEM shows the particle that mostly is below 100 nanometers.But this MSADP solid lipid nanoparticle suspension room temperature is placed and was not seen that precipitation separated out in 10 days.This solid lipid nanoparticle suspension is lyophilized into pressed powder after adding due care agent, face with before adding entry, jolting MSADP solid lipid nanoparticle suspension.
Embodiment 24. succinyl arteannuin glutamy LUMEFANTRINE hexadecane diester microemulsion
Get succinyl arteannuin glutamy LUMEFANTRINE hexadecane diester (AGLH, 30mg) be dissolved in 3ml ethanol, and mix, under agitation splash into then in the 5ml water with 2ml propylene glycol, 0.4g triglycerin decanoin, 0.6g polyoxyethylene hydrogenated Oleum Ricini, form clear solution, be the AGLH microemulsion.
The two zidovudine ester self assembly transmission systems of embodiment 25. ten five carbon diacid
Get the methanol solution (5% of the two zidovudine esters (PDZ) of 15 carbon diacid, w/w), slowly be injected into syringe in the water of stirring, to obtaining even little suspension, decompression can be flung to organic solvent, can concentrate under the heating condition, product negative staining transmission electron microscope observing, be ball-type vesicle structure, particle diameter is about 150nm, is PDZ self assembly transmission system (seeing Figure of description 1).Reduction vaporization can be removed organic solvent.
26. pairs of succinyl acyclovirs of embodiment dodecane diester self assembly transmission system
Get two succinyl acyclovir dodecane diester (DSAD) (5%, w/w) and poloxamer P188 (0.5%, w/w) tetrahydrofuran solution slowly is injected into syringe in the water of stirring, to obtaining even little suspension, decompression can be flung to organic solvent, can concentrate under the heating condition, product negative staining transmission electron microscope observing is ball-type vesicle structure, the particle diameter major part is DSAD self assembly transmission system (seeing Figure of description 2) less than 200nm.Reduction vaporization can be removed organic solvent.
The two naloxone ester self assembly transmission systems of embodiment 27. ten five carbon diacid
Get the two naloxone ester (PDN of 15 carbon diacid, 50mg) and embodiment 10 in 15 carbon, two acyl PEG200 (20mg), heating is dissolved in the 3ml isopropyl alcohol, slowly be injected in the water of stirring, to obtaining even little suspension, transmission electron microscope observing is ball-type vesicle structure, particle diameter is PDN self assembly transmission system less than 1 micron.

Claims (34)

1. double-head radical lipid prodrug is characterized in that the structure of double-head radical lipid prodrug is:
D 1-R-D 2Or D 1-L 1-R-L 2-D 2
And satisfy:
(1) D 1And D 2It is pharmaceutical group;
(2) R is the aliphatic chain of 6～32 carbon atom length;
(3) L 1And L 2Be selected from inorganic acyl group, the fat group of 2～7 carbon atom length, hydrophilic radical;
(4) reaction that obtains above-mentioned double-head radical lipid prodrug is selected from addition, rearrangement, acidylate, hydrolysis, alcoholysis, ester exchange, oxidation, reduction, replacement, cyclisation, elimination, condensation, polymerization, alkylation, coupling, dehydration.
2. double-head radical lipid prodrug as claimed in claim 1, D 1, D 2, L 1, L 2And connect with ester bond or amido link between the R.
3. double-head radical lipid prodrug as claimed in claim 1, D 1And D 2Identical.
4. double-head radical lipid prodrug as claimed in claim 1, D 1And D 2Different.
5. double-head radical lipid prodrug as claimed in claim 1, L 1And L 2Identical.
6. double-head radical lipid prodrug as claimed in claim 1, L 1And L 2Different.
7. double-head radical lipid prodrug as claimed in claim 1, L 1And L 2Be selected from two carboxyamino acid acyl groups, the OCH of the fatty acyl group of phosphoryl, phosphono, sulfonyl, 2～7 carbon atom length, 2～7 carbon atom length 2CH 2(OCH 2CH 2) nThe combination of O base or these groups, wherein OCH 2CH 2(OCH 2CH 2) nThe scope of the n of O base is 2～50.
8. double-head radical lipid prodrug as claimed in claim 1, wherein D 1And D 2The prototype molecular structure in contain hydroxyl, amido or carboxyl.
9. double-head radical lipid prodrug as claimed in claim 1, wherein D 1And D 2The prototype molecule be the polar molecule medicine.
10. double-head radical lipid prodrug as claimed in claim 1, wherein D 1And D 2The prototype molecule be dipole moment greater than 0.5 polar molecule medicine.
11. double-head radical lipid prodrug as claimed in claim 1, wherein D 1And D 2The prototype molecule be dipole moment greater than 1 polar molecule medicine.
12. double-head radical lipid prodrug as claimed in claim 1, wherein D 1And D 2The prototype molecule be dipole moment greater than 2 polar molecule medicine.
13. double-head radical lipid prodrug as claimed in claim 1, wherein D 1And D 2The dissolubility of prototype molecule in water greater than 0.01mg/ml.
14. double-head radical lipid prodrug as claimed in claim 1, wherein D 1And D 2The dissolubility of prototype molecule in water greater than 0.1mg/ml.
15. double-head radical lipid prodrug as claimed in claim 1, wherein D 1And D 2The dissolubility of prototype molecule in water greater than 1mg/ml.
16. double-head radical lipid prodrug as claimed in claim 1, wherein D 1And D 2The prototype molecule be molecular weight less than 1000 medicine.
17. double-head radical lipid prodrug as claimed in claim 1, wherein D 1And D 2The prototype molecule be molecular weight less than 500 medicine.
18. double-head radical lipid prodrug as claimed in claim 1, wherein D 1And D 2The prototype molecule be molecular weight less than 300 medicine.
19. double-head radical lipid prodrug as claimed in claim 1, wherein D 1And D 2The prototype molecule be selected from medicine for central nervous system, peripheral nervous system medicine, circulatory system drug, medicine for digestive system, medicine for respiratory system, hormonal system medicine, reproductive system medicine, hemopoietic system medicine, immune system medicine, medicine for urological system, anticarcinogen, ntipyretic analgesic medicine, antimicrobial agents, medicine for parasitic disease, hypoglycemic drug, hormonal medicaments, preferably medicine for central nervous system, circulatory system drug, anticarcinogen, ntipyretic analgesic medicine, antimicrobial agents, medicine for parasitic disease, hypoglycemic drug.
20. double-head radical lipid prodrug as claimed in claim 1, wherein D 1And D 2The prototype molecule be selected from anticarcinogen, antiviral drugs, anti-mycobacteria medicine, antimalarial.
21. double-head radical lipid prodrug as claimed in claim 1, wherein D 1Be selected from polypeptide and protein medicaments, oligonucleotide drug, gene class medicine, polyose medicament with the prototype molecule of D2.
22. double-head radical lipid prodrug as claimed in claim 1, wherein D 1And D 2The prototype molecule be nucleoside analog.
23. double-head radical lipid prodrug as claimed in claim 1, wherein D 1And D 2The prototype molecule be selected from acyclovir, ganciclovir, famciclovir, penciclovir, valaciclovir, virazole, Sorivudine, ribavirin, vidarabine, zidovudine, lamivudine, didanosine, zalcitabine, stavudine, vidarabine, cidofovir, doxifluridine, cytosine arabinoside, azacitidine.
24. double-head radical lipid prodrug as claimed in claim 1, also its salt be can be prepared into, and sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, various ammonium salt, maleate, fumarate, succinate, benzoate, phthalate, benzene sulfonate, formates, acetate, propionate, oxalates, amino acid salts, malate, malonate, citrate, tartrate, lactate, nitrate, phosphate, dihydric phosphate, phosphoric acid hydrogen disalt, hydrochlorate, iodate, bromate, borate, sulfate, disulfate are selected from.
25. double-head radical lipid prodrug as claimed in claim 1, also its salt be can be prepared into, and sodium salt, potassium salt, various ammonium salt, benzoate, benzene sulfonate, formates, acetate, amino acid salts, citrate, tartrate, lactate, dihydric phosphate, hydrochlorate, sulfate, disulfate are selected from.
26. double-head radical lipid prodrug as claimed in claim 1, also can be prepared into its various dosage forms, and be selected from tablet, capsule, granule, drop pill, suspensoid, solution, Emulsion, gel, ointment, emulsifiable paste, suppository, membrane, liniment, aerosol, spray, implant.
27. the transmission system of a high degree of dispersion is characterized in that it comprises the double-head radical lipid prodrug of claim 1, and is selected from liposome, non-ionic surface active agent vesicle, nanoparticle, microemulsion or self assembly transmission system.
28. as the transmission system of the high degree of dispersion of claim 27, wherein particle diameter is less than 1 micron.
29. as the transmission system of the high degree of dispersion of claim 27, wherein the single particle average diameter is less than 0.5 micron.
30. as the transmission system of the high degree of dispersion of claim 27, the molecule molar ratio that the amount of the double-head radical lipid prodrug of claim 1 accounted for whole constituents during the particle of wherein self assembly transmission system was formed is between 50～100%, all the other are additive.
31. as the transmission system of the high degree of dispersion of claim 27, the molecule molar ratio that the amount of the double-head radical lipid prodrug of claim 1 accounted for whole constituents during the particle of wherein self assembly transmission system was formed is between 70～100%, all the other are additive.
32. as the transmission system of the high degree of dispersion of claim 27, the molecule molar ratio that the amount of the double-head radical lipid prodrug of claim 1 accounted for whole constituents during the particle of wherein self assembly transmission system was formed is between 85～100%, all the other are additive.
33. as the transmission system of the high degree of dispersion of claim 27, the particle of wherein self assembly transmission system all is made up of the double-head radical lipid prodrug of claim 1.
34. as the transmission system of claim 30,31, any one high degree of dispersion of 32, additive wherein is selected from cholate, deoxycholate, phospholipid, polyhydric alcohol esters surfactant, polyoxyethylene surfactant, polyethyleneglycol lipid derivates, polysaccharide lipid derivate, polyamino acid lipid derivate, cholesterol monomester succinate.
CNB2006100766533A 2006-04-28 2006-04-28 Double-head radical lipid prodrug Expired - Fee Related CN100525836C (en)

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CN101732251B (en) * 2009-12-25 2012-09-26 海南美兰史克制药有限公司 Oxiracetam liposome injection
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CN107670048B (en) 2017-08-30 2019-04-26 南京明臻医药科技有限公司 With the active intermediate drug of Synergistic anti-cancer and polyethylene glycol conjugation Synergistic anti-cancer drug, and its preparation method and application
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1566130A (en) * 2003-07-03 2005-01-19 中国人民解放军军事医学科学院放射医学研究所 Nucleoside analogue lipid derivative and salt thereof
CN1634969A (en) * 2004-11-11 2005-07-06 中国人民解放军军事医学科学院放射医学研究所 Cholestrin derivative as nucleoside analog

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1566130A (en) * 2003-07-03 2005-01-19 中国人民解放军军事医学科学院放射医学研究所 Nucleoside analogue lipid derivative and salt thereof
CN1634969A (en) * 2004-11-11 2005-07-06 中国人民解放军军事医学科学院放射医学研究所 Cholestrin derivative as nucleoside analog

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
双头基两亲分子研究进展. 吕庆，贡浩飞，刘鸣华.化学进展，第13卷第3期. 2001 *
基于脂质前药的自组装药物传递系统. 金义光，侯新朴.中国医药工业杂志，第36卷第3期. 2005 *

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