CN102114246A - Amphiphilic polysaccharide derivative vector for specific medicine release in organism focusas well as preparation and application of pharmaceutical composition thereof - Google Patents
Amphiphilic polysaccharide derivative vector for specific medicine release in organism focusas well as preparation and application of pharmaceutical composition thereof Download PDFInfo
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Abstract
The invention relates to an amphiphilic polysaccharide derivative vector for specific medicine release in an organism focus. In derivatives, a hydrophobic group is introduced to a polysaccharide skeleton through a disulfide-bond-containing connecting arm which can be degraded specifically to make polysaccharide provided with amphiphilic characteristics, nano micelles can be self-assembled in an aqueous medium, a medicine can be coated through action of the hydrophobic group and the medicine, the disulfide-bond-containing connecting arm can be specifically degraded by high-concentration glutathione serving as a reducing substance in focus cells after the medicine is loaded to reach at the focus by the nano micelles, the medicine is quickly released from micelle cores to be acted on an efficacy part due to dropping of the hydrophobic group, thereby the concentration, the curative effect and the bioavailability of the free medicine in the focus can be obviously improved. An auxiliary material can be used as a vector of an organic medicine, a water-insoluble medicine, an insoluble medicine or an amphiphilic medicine and can be used for medicine administration in blood vessels or by intramuscular injection and oral intake. A preparation method disclosed by the invention has the advantages of simplicity and mature process and is suitable for continuous production on a large scale.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, the amphiphilic polysaccharide derivant that relates to a kind of organism lesions position specific drug release the invention still further relates to the preparation method and the application thereof of this carrier as pharmaceutical carrier.
Background technology
It is relatively poor that poorly water soluble drugs has oral absorption, and bioavailability is lower, is difficult to prepare the shortcoming of suitable formulations, therefore improves the dissolubility of medicine, and improving bioavailability of medicament is the urgency problem to be solved that medicine and pharmacology face.At present use surfactants or be prepared into liposome and clathrate increases the dissolubility of medicine.But because some low-molecular-weight surfactant critical micelle concentrations (CMC) higher (10
-2G/L), after the injection body is interior, by hemodilution, less stable, simultaneously a large amount of surfactants can produce certain toxic and side effects after injecting in the body, and liposome and clathrate exist that drug loading is lower, targeting distributes is undesirable, store in shortcomings such as stability is not good enough.
The amphipathy macromolecule material is the drug carrier material that development in recent years is got up, and has hydrophilic segment and hydrophobic segment in a part, can be in water self assembly form that kernel is hydrophobic, the hydrophilic core-shell type nano micelle of shell and self-assembled nanometer grain.Its outstanding advantage is: 1. the aggregation force of the hydrophobic segment of amphipathy macromolecule material in water is stronger, and hydrophobic inner core is more stable, and carrying medicine stability is high; 2. for hydrophobic drug provides hydrophobic microenvironment, it can be adsorbed onto drug molecule in its hydrophobic inner core by modes such as physically trapping, chemical bond and electrostatic interactions, significantly increases the solubility of dewatering medicament; 3. nanometer formulation has tendentiousness deposition (EPR effect), can make medicine in the diseased region enrichment, realizes " passive targeting " of pathological tissues present; 4. can reduce toxic and side effects at the lesions position rapid delivery of pharmaceuticals by specific enzyme or pH condition, improve bioavailability normal structure.The amphipathy macromolecule material becomes the focus of people's research with its unique advantage.
The amphipathy macromolecule material must satisfy and has excellent biological compatibility and biodegradability and avirulence and immunogenic condition.Most of synthetic high polymers all exist aspect defectives such as haemolysis, heat source response and permeability more or less; Various water soluble proteins are then easily by protease hydrolysis in the biomacromolecule, and degradation in vivo speed is very fast.Therefore, naturally occurring polysaccharide just shows its special advantages.
The natural polysaccharide wide material sources have lot of advantages as pharmaceutical polymers: 1. have good biocompatibility and degradability, in vivo can biodegradation for becoming micromolecule, final metabolite is CO
2, H
2O and carbamide etc.; 2. some polysaccharide materials have the broad-spectrum tumor targeting, and for example low-molecular-weight hyaluronic acid can be induced receptor-mediated cell internalizing.As the antitumor drug carrier, by combining, thereby antitumor drug is transferred between tumor cell in the matter with hyaluronic acid receptor CD44 that numerous tumor cell surface height are expressed; 3. contain a large amount of active groups in the polysaccharide structures,, provide enough reaction site for polysaccharide is carried out chemical modification as carboxyl, amino, hydroxyl, aldehyde radical etc.Now existing part amphiphilic polysaccharide derivant is in conceptual phase; but these derivants still exist significant disadvantages: the chemical bond that connects polysaccharide and hydrophobic segment mostly is amido link or ester bond; the body internal stability of these two kinds of chemical bonds is higher; make that coming off of hydrophobic segment is very slow; cause medicine to arrive thus can not in time discharging behind the drug effect position promptly being eliminated or metabolism, be unfavorable for the performance of curative effect.
At above problem, this patent is skeleton with the natural polysaccharide, the carboxyl of polysaccharide, through derivatization forms carboxyl, amino or the amino that forms through derivatization, hydroxyl or on the hydroxyl of derivatization formation, disulfide bond linking arm link (derivatization) polysaccharide and the hydrophobic group of the organism lesions position specific drug release that passes through, make it have amphipathic characteristic, but self assembly is a nano-micelle in aqueous medium, solubilize drugs.The amphiphilic polysaccharide derivant of new bio body lesions position specific drug release has following feature as pharmaceutical carrier: 1. polysaccharide derivates has amphipathic character, self assembly forms nano-micelle in aqueous solution, has avoided the use of organic solvent, surfactant, cross-linking agent or heating condition; 2. physics parcel insoluble drug under the hydrophobic bond active force significantly improves drug loading, and stabilization time is the prolongation of highly significant also; 3. the linking arm between polysaccharide and hydrophobic group contains disulfide bond, this disulfide bond environment in body circulates and be extracellular is stable, but can be degraded by the reducing substances glutathion of high concentration in the focus cell, at the specific rapid delivery of pharmaceuticals of lesions position, the medicine of having avoided being wrapped in the carrier fails to discharge, do not act on the shortcoming that the drug effect position promptly is eliminated, and can significantly improve bioavailability and drug effect.Introduce the formed organism lesions position of hydrophobic group specific drug release amphiphilic polysaccharide derivant by the linking arm that contains disulfide bond and do not see any document and patent report as yet.
Summary of the invention
The polysaccharide amphipathic derivatives carrier that the purpose of this invention is to provide a kind of hydrophobically modified of organism lesions position specific drug release.But the self assembly in aqueous medium of this carrier forms nanoparticle, can avoid the use of chemical cross-linking agent, a large amount of organic solvent, heating condition, and preparation technology is simple; And the hydrophobic cores physics solubilising insoluble drug that can utilize hydrophobic segment to form, significantly improve the dissolubility of medicine.In addition, this amphiphilic polysaccharide derivant can produce response to strong reducing property environment in the focus cell, its hydrophobic segment can be in the focus cell and the hydrophilic segment sharp separation, discharges medicine rapidly, improves remarkable focus endocellular liberation drug level, curative effect and bioavailability.This carrier has the feature of drug loading height, good stability, drug effect raising, toxic and side effects reduction.
Another object of the present invention provides the preparation method of above-mentioned carrier.
A further object of the invention provides the application of above-mentioned carrier in pharmacy.
For achieving the above object, the invention provides a kind of amphiphilic polysaccharide derivative carrier of organism lesions position specific drug release, its structure is shown in following chemical formula:
Wherein GLY is the polysaccharide molecule chain, and n+m is the contained alkylidene number of linking arm, and D is a hydrophobic group, and R is the number that hydrophobic group replaces on the polysaccharide molecule.
The amphiphilic polysaccharide derivative carrier of described organism lesions position specific drug release, the polysaccharide of wherein selecting for use comprise hyaluronic acid, unfraction heparin, low molecular weight heparin, desulfurization acidify heparin, chrondroitin, poly-sulfated chrondroitin, alginic acid, glucosan, fungus polysaccharide, chitosan and contain carboxyl, amino or hydroxy derivative.
The amphiphilic polysaccharide derivative carrier of described organism lesions position specific drug release, wherein linking arm contains the disulfide bond of lesions position specificity degraded, and the two ends reactive group is that amino or carboxyl or an end reactive group are that amino other end reactive group is a carboxyl, and linking arm alkylidene number is 2～16.
Described organism lesions position specific drug release amphiphilic polysaccharide derivative carrier, wherein hydrophobic group comprises C
2-18Fatty acid, deoxycholic acid, cholic acid, C
2-18Alkylamine and C
2-18Alkylol.
Described organism lesions position specific drug release amphiphilic polysaccharide derivative carrier, wherein the number that hydrophobic group replaces on the polysaccharide molecule chain is 2～600 integer.
Described organism lesions position specific drug release amphiphilic polysaccharide derivative carrier, wherein polysaccharide molecule links to each other by amido link or ester bond with linking arm one end, and the linking arm other end links to each other by amido link or ester bond with hydrophobic group.
The preparation method of the amphiphilic polysaccharide derivative carrier of described organism lesions position specific drug release comprises the following steps:
(1) carboxylic polysaccharide or the polysaccharide derivates that contains carboxyl are dissolved in the reaction dissolvent, employing contains disulfide bond and two ends are amino linking arm, with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and I-hydroxybenzotriazole (HOBt) is that activator carries out condensation reaction, and the amino reaction of an end of polysaccharide and linking arm obtains intermediate; Hydrophobic group fatty acid, deoxycholic acid, cholic acid are dissolved in the reaction dissolvent, with dicyclohexyl carbodiimide (DCC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) is activator, the carboxyl of hydrophobic group further with the intermediate linking arm on the amino condensation reaction of the other end, promptly get amphiphilic polysaccharide derivative carrier with organism lesions position specific drug release function.The gained polysaccharide derivates promptly has well amphipathic, can spontaneous formation nano-micelle in aqueous medium.
(2) polysaccharide derivates that will contain the polysaccharide of amino (hydroxyl) or contain amino (hydroxyl) is dissolved in the reaction dissolvent, employing contains disulfide bond and two ends are the linking arm of carboxyl, with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and I-hydroxybenzotriazole (HOBt) is that activator carries out condensation reaction, and an end carboxyl reaction of polysaccharide and linking arm obtains intermediate; Hydrophobic group alkylamine or alkylol are dissolved in the reaction dissolvent, with dicyclohexyl carbodiimide (DCC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) is activator, the amino of hydrophobic group or hydroxyl further with the intermediate linking arm on other end carboxyl condensation reaction, promptly get amphiphilic polysaccharide derivative carrier with organism lesions position specific drug release function.The gained polysaccharide derivates promptly has well amphipathic, can spontaneous formation nano-micelle in aqueous medium.
(3) carboxylic polysaccharide or carboxylic polysaccharide derivates are dissolved in the reaction dissolvent, employing contains disulfide bond and an end is amino linking arm for the carboxyl other end, with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and I-hydroxybenzotriazole (HOBt) is that activator carries out condensation reaction, and the amino reaction of an end of polysaccharide and linking arm obtains intermediate; Hydrophobic group alkylamine, alkylol are dissolved in the reaction dissolvent, with dicyclohexyl carbodiimide (DCC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) is activator, the amino of hydrophobic group, hydroxyl further with the intermediate linking arm on other end carboxyl condensation reaction, promptly get amphiphilic polysaccharide derivative carrier with organism lesions position specific drug release function.The gained polysaccharide derivates promptly has well amphipathic, can spontaneous formation nano-micelle in aqueous medium.
(4) polysaccharide derivates that will contain the polysaccharide of amino (hydroxyl) or contain amino (hydroxyl) is dissolved in the reaction dissolvent, employing contains disulfide bond and an end is amino linking arm for the carboxyl other end, with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and I-hydroxybenzotriazole (HOBt) is that activator carries out condensation reaction, and an end carboxyl reaction of polysaccharide and linking arm obtains intermediate; Hydrophobic group fatty acid, deoxycholic acid or cholic acid are dissolved in the reaction dissolvent, with dicyclohexyl carbodiimide (DCC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) is activator, the carboxyl of hydrophobic group further with the intermediate linking arm on the amino condensation reaction of the other end, promptly get amphiphilic polysaccharide derivative carrier with organism lesions position specific drug release function.The gained polysaccharide derivates promptly has well amphipathic, can spontaneous formation nano-micelle in aqueous medium.
Described preparation method, wherein reaction dissolvent is water, methanol, N, the mixed solvent of dinethylformamide, oxolane, dimethyl sulfoxide or Methanamide, water and methanol, water and N, the mixed solvent of the mixed solvent of dinethylformamide, water and Methanamide or N, the mixed solvent of dinethylformamide and Methanamide.
The amphiphilic polysaccharide derivant of described organism lesions position specific drug release is as the application of pharmaceutical active or pharmacologically active molecular vehicle.Wherein this pharmaceutical active or pharmacologically active molecule mainly comprise: the arbitrary material or derivatives thereof in taxanes, ciclosporin class, camptothecin, flavonoid, dihydropyridines, XIAONIE bases, vinca, anthraquinone class, podophillotoxines antineoplastic agent, steroidal class or nonsteroidal anti-inflammatory drug, cardiovascular drugs, antibiotic, antifungal drug, antiviral drugs, the immunomodulator can be used in the blood vessel or intramuscular injection or oral, external.
The preparation method operating procedure of this medicament solubilization carrier is as follows: amphiphilic polysaccharide derivant and water are 1～50: 1000 ratio dissolving by weight, obtain the nano-micelle of polysaccharide derivates; With the indissoluble of treatment effective dose or the organic drug that is slightly soluble in water with after the acceptable solvent dissolving pharmaceutically, after described amphiphilic polysaccharide derivates nanometer micelle mixes, handle through ultrasonic or high pressure homogenize, solution is removed organic solvent and micromolecule with dialysis or ultrafiltration or post partition method, and lyophilizing makes the nano drug-carrying micelle that particle diameter is 10～1000nm.
Concrete scheme is as follows: but this carrier is to introduce hydrophobic group at the polysaccharide skeleton by the specificity degraded linking arm that contains disulfide bond, make polysaccharide have amphipathic characteristic, but self assembly is a nano-micelle in aqueous medium, after this nano-micelle carrying medicament arrives lesions position, its disulfide bond linking arm can be degraded by lesions position reducing substances glutathion specificity, coming off of hydrophobic group causes medicine to be discharged by the micelle kernel fast, act on lesions position, can significantly improve lesions position free drug concentration, curative effect and bioavailability
But introduce hydrophobic carbalkoxy or fatty acyl group or (deoxidation) cholic acid by the specificity degraded linking arm that contains disulfide bond at the amino of polysaccharide or carboxyl or hydroxyl; it is amphipathic that it is had; in aqueous medium, can be assembled into micelle; hydrophobic relatively carbalkoxy or fatty acyl group or (deoxidation) cholic acid are gathered into kernel; polysaccharide forms hydrophilic shell, has stable micelle, effectively hides the effect of the seizure of organism reticuloendothelial system.Therefore this family macromolecule material is the good pharmaceutical carrier of a class, especially is insoluble in the non-antitumor drug of water for insoluble anti-tumor medicament and other.After the carrier loaded medicine of this amphiphilic polysaccharide arrives lesions position, its disulfide bond linking arm can be by high concentration reducing substances glutathion specificity degraded in the focus cell, hydrophobic group is discharged by the micelle kernel fast with causing medicine separating of hydrophilic group fast, act on lesions position, can significantly improve lesions position free drug concentration, curative effect and bioavailability.This derivant is as pharmaceutical carrier, and particle diameter is controlled at 10～1000nm, smooth surface, and good evenness, regular particles does not have adhesion, and redispersibility is good, drug loading and envelop rate height.This pharmaceutical carrier can be used in the blood vessel or intramuscular injection, oral, tract and external.
Synthetic and the pharmacy or the physiologically active composition preparation method of organism lesions position specific drug release amphiphilic polysaccharide derivant are described in detail as follows:
One, organism lesions position specific drug release amphiphilic polysaccharide derivant is synthetic
1, the polysaccharide intermediate synthetic
(1) be amino linking arm reaction with two ends
A certain amount of carboxylic polysaccharide or carboxylic polysaccharide derivates are dissolved in the reaction dissolvent, adding excessive two ends is amino linking arm, with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and I-hydroxybenzotriazole (HOBt) is the activator reaction, use excessive acetone that polysaccharide precipitation is come out behind reaction 12h～24h, sucking filtration and separation and purification precipitate obtain the polysaccharide intermediate compound I.
Graphical Synthetic Routes is as follows:
(2) with two ends be the linking arm reaction of carboxyl
A certain amount of polysaccharide derivates that contains the polysaccharide of amino (hydroxyl) or contain amino (hydroxyl) is dissolved in the reaction dissolvent, adding excessive two ends is the linking arm of carboxyl, with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and I-hydroxybenzotriazole (HOBt) is the activator reaction, use excessive acetone that polysaccharide precipitation is come out behind reaction 12h～24h, sucking filtration and separation and purification precipitate obtain polysaccharide intermediate II, III.
Graphical Synthetic Routes is as follows:
(3) be amino linking arm reaction with an end for the carboxyl other end
With a certain amount of carboxyl (amino that contains, hydroxyl) polysaccharide or contain it and contain carboxyl (amino, hydroxyl) polysaccharide derivates is dissolved in the reaction dissolvent, adding an excessive end is amino linking arm for the carboxyl other end, with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and I-hydroxybenzotriazole (HOBt) is that activator reacts, use excessive acetone that polysaccharide precipitation is come out behind reaction 12h～24h, sucking filtration and separation and purification precipitate obtain the polysaccharide intermediate compound IV, V, VI.
Graphical Synthetic Routes is as follows:
2, the amphiphilic polysaccharide derivant is synthetic
(1) with the reaction of fatty acid
Method 1: fatty acid and intermediate compound I or V or VI are dissolved in the reaction dissolvent, are activator with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC), reaction 12h～24h.Reaction finishes the back and uses excessive acetone precipitation polysaccharide, and filtration and purification precipitate promptly get the polysaccharide derivates carrier that alkyl amide is modified.
Method 2: preparation fatty acid N-hydroxy-succinamide (NHS) active ester under dicyclohexyl carbodiimide (DCC) catalysis, the reactant liquor that adds intermediate compound I or V or VI, reaction 1h～24h, reaction finishes the back and uses excessive acetone precipitation polysaccharide, and filtration and purification precipitate promptly get the polysaccharide derivates carrier that alkyl amide is modified.
Graphical Synthetic Routes is as follows:
(2) with the reaction of (deoxidation) cholic acid
Method 1: (deoxidation) cholic acid and intermediate compound I or V or VI are dissolved in the reaction dissolvent, are activator with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC), reaction 12h～24h.Reaction finishes the back and uses excessive acetone precipitation polysaccharide, and filtration and purification precipitate promptly get the polysaccharide derivates carrier that (deoxidation) cholic acid is modified.
Method 2: preparation (deoxidation) cholic acid N-hydroxy-succinamide (NHS) active ester under dicyclohexyl carbodiimide (DCC) catalysis, add the reactant liquor that contains intermediate compound I or V or VI, reaction 1h～24h, reaction finishes the back and uses excessive acetone precipitation polysaccharide, and filtration and purification precipitate promptly get the polysaccharide derivates carrier that (deoxidation) cholic acid is modified.
Graphical Synthetic Routes is as follows:
(3) with the reaction of alkylamine
Method 1: alkylamine and intermediate II or III or IV are dissolved in the reaction dissolvent, are activator with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC), reaction 12h～24h.Reaction finishes the back and uses excessive acetone precipitation polysaccharide, and filtration and purification precipitate promptly get the polysaccharide derivates carrier that alkyl amide is modified.
Method 2: N-hydroxy-succinamide (NHS) active ester of preparation intermediate II or III or IV under dicyclohexyl carbodiimide (DCC) catalysis, add the reactant liquor that contains alkylamine, reaction 1h～24h, reaction finishes the back and uses excessive acetone precipitation polysaccharide, and filtration and purification precipitate promptly get the polysaccharide derivates carrier that alkyl amide is modified.
(4) with the reaction of alkylol
Method 1: alkylol and intermediate II or III or IV are dissolved in the reaction dissolvent, are activator with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC), reaction 12h～24h.Reaction finishes the back and uses excessive acetone precipitation polysaccharide, and filtration and purification precipitate promptly get the polysaccharide derivates carrier that alkyl amide is modified.
Method 2: N-hydroxy-succinamide (NHS) active ester of preparation intermediate II or III or IV under dicyclohexyl carbodiimide (DCC) catalysis, add the reactant liquor that contains alkylol, reaction 1h～24h, reaction finishes the back and uses excessive acetone precipitation polysaccharide, and filtration and purification precipitate promptly get the polysaccharide derivates carrier that alkyl amide is modified.
Two, the micellar preparation method of amphiphilic polysaccharide derivates nanometer
In the ratio of dissolving the amphiphilic polysaccharide derivant of 2～30mg in every 1ml water, the amphiphilic polysaccharide derivant that makes is soluble in water, handle through ultrasonic or high pressure homogenize, being prepared into particle diameter is the polysaccharide derivates micelle of 10～1000nm.
Three, with the amphiphilic polysaccharide derivant as carrier, preparation contains the pharmaceutical composition of insoluble medicine
Polysaccharide derivates is water-soluble, concentration 0.1%～5% (w/w) is dissolved insoluble drug such as paclitaxel with appropriate solvent, handle through ultrasonic or high pressure homogenize, method by dialysis or distilling under reduced pressure is removed organic solvent, makes the nano-micelle that particle diameter is 10～1000nm.So-called appropriate solvent refers to the solvent that can dissolve this medicine that pharmaceutically uses.
Four, adopt polysaccharide derivates as the preparing carriers pharmaceutical composition, can be to medicine payload.
Can use this amphiphilic polysaccharide derivant to have: paclitaxel as the medicine of carrier, ciclosporin, teniposide, hydroxy camptothecin, camptothecine, vindesine, etoposide, nimodipine, amycin, Docetaxel, breviscapine, bilobalide, silymarin, daunorubicin, mitomycin, methotrexate, indomethacin, ibuprofen, ketoprofen, naproxen, the different pear ester of nitre, dihydropyridine, nimodipine, fenofibrate, itraconazole, amphotericin B, bifendate, progesterone, dihydrotestosterone, haloperidol, Risperidone etc., but be not limited to these listed medicines.
Beneficial effect of the present invention:
One, the present invention introduces hydrophobic group with the linking arm that contains disulfide bond at the amino of polysaccharide or carboxyl or hydroxyl, this disulfide bond is stable higher in the environment in body circulates and be extracellular, but easily degraded by the reducing substances glutathion of high concentration in the focus cell, carrier micelle can be at the rapid delivery of pharmaceuticals of focus cell internal specific, the medicine of having avoided being wrapped in the carrier is failed to discharge, is failed to bring into play the shortcoming that drug effect promptly is eliminated, and can significantly improve bioavailability and drug effect.
Two, amphiphilic polysaccharide derivant provided by the invention has excellent biological compatibility and organism lesions position specific drug release, has also that critical micelle concentration is low, a good stability, the advantage of target tumor initiatively.
Three, amphiphilic polysaccharide derivant provided by the invention, can be in water spontaneous formation nano-micelle, to organic drug, water-insoluble or insoluble drug and amphipathic medicine have load preferably, for example, to the load of paclitaxel up to 32.4% (w/w), to the load of ciclosporin A up to 27.5% (w/w), to the load of itraconazole up to 28.2% (w/w), to the load of indomethacin up to 22.3% (w/w), to the load of nimodipine up to 20.3% (w/w), to the load of haloperidol up to 22.5% (w/w), to the load of azithromycin up to 18.5% (w/w).
Four, amphiphilic polysaccharide conjugate provided by the invention can be used for injection, oral, external or mucosa delivery.This derivant has tight security, and particle diameter can be controlled in 10～1000nm.
The specific embodiment
To the present invention's further instruction in addition, but following embodiment does not limit the interest field of this patent below by embodiment.
Embodiment 1: the hyaluronic preparation of caprylyl cystamine
0.1mmol hyaluronic acid, 1mmol cystamine, 0.2mmolEDC and 0.2mmolNHS are dissolved in the Methanamide, use acetone that the hyaluronic acid intermediate is precipitated out behind the reaction 24h, sucking filtration is also used distill water dialysis 3d (MWCO=3500), obtains the hyaluronic acid intermediate of a free end amino.
Sad and the 0.1mmol intermediate of 0.4mmol is dissolved in Methanamide, and 0.4mmolEDC is an activator, reaction 24h.Reaction finishes the back and uses excessive acetone precipitation, and filtration and vacuum drying promptly get the derivatives of hyaluronic acids carrier that the decoyl amido is modified.
Embodiment 2: dodecanoyl-3, the preparation of 3 '-dithio dipropyl acid chitosan
0.1mmol chitosan is water-soluble and methanol (v/v=1: mixed solvent 1), adding 1mmol3, the acid of 3 '-dithio dipropyl, 0.1mmolEDC and 0.1mmolHOBt, reaction 8h, rotary evaporation is removed methanol, distill water dialysis 3d (MWCO=3500) obtains the chitosan intermediate of a free end carboxyl.
With the 0.2mmol lauryl amine and 0.1mmol chitosan intermediate is water-soluble and methanol (v/v=1: mixed solvent 1), 0.2mmolEDC are activator, the reaction 24h.Rotary evaporation is removed methanol, distill water dialysis 3d (MWCO=3500), and lyophilizing promptly gets the chitosan derivatives carrier that the lauroyl amido is modified.
Embodiment 3: deoxycholic acid-cystamine Preparation of chondroitin sulfate
0.1mmol chondroitin sulfate, 2mmol cystamine, 0.4mmolEDC and 0.4mmolNHS are dissolved in the Methanamide, use acetone that the chondroitin sulfate intermediate is precipitated out behind the reaction 12h, sucking filtration is also used distill water dialysis 3d (MWCO=3500), obtains the chondroitin sulfate intermediate of a free end amino.
0.5mmol deoxycholic acid, 0.65mmol dicyclohexyl carbodiimide (DCC), 0.65mmol N-Hydroxysuccinimide (NHS) are dissolved in N, in N '-dimethyl formamide, ice bath reaction 30min rises to room temperature reaction 24h then.After reaction finished, the elimination precipitation with excessive oxolane precipitation, was filtered and is promptly obtained deoxycholic acid N-hydroxy-succinamide (NHS) active ester.
0.4mmol deoxycholic acid N-hydroxy-succinamide (NHS) active ester and 0.1mmol chondroitin sulfate intermediate are dissolved in Methanamide, reaction 12h.Reaction finishes the back and uses excessive acetone precipitation, and filtration and vacuum drying promptly get deoxycholic acid chondroitin sulfate derivative carrier.
Embodiment 4: cholic acid-aminoethyl-3, the preparation of 4-dithio propanoic acid chitosan
0.1mmol chitosan is water-soluble and dimethyl sulfoxine (v/v=1: mixed solvent 1), adding 2mmolS-aminoethyl-3,4-dithio propanoic acid, 0.4mmolEDC and 0.4mmolNHS, reaction 24h, distill water dialysis 3d (MWCO=3500) obtains the chitosan intermediate of a free end amino.
With the 0.4mmol cholic acid and 0.1mmol chitosan intermediate is water-soluble and methanol (v/v=1: mixed solvent 1), 0.4mmolEDC are activator, the reaction 24h.Rotary evaporation is removed methanol, distill water dialysis 3d (MWCO=3500), and lyophilizing promptly gets the chitosan derivatives font that cholic acid is modified.
Embodiment 5: hexadecyl ester base-3, the preparation of 3 '-dithio dipropyl hyaluromic acid
0.1mmol hyaluronic acid, 1mmol3, the acid of 3 '-dithio dipropyl, 0.3mmolEDC and 0.3mmolNHS are dissolved in the Methanamide, use acetone that the hyaluronic acid intermediate is precipitated out behind the reaction 24h, sucking filtration is also used distill water dialysis 3d (MWCO=3500), obtains the hyaluronic acid intermediate of a free end carboxyl.
0.3mmol hexadecanol and 0.1mmol intermediate are dissolved in Methanamide, and 0.3mmolEDC is an activator, reaction 24h.Reaction finishes the back and uses excessive acetone precipitation, and filtration and vacuum drying promptly get the derivatives of hyaluronic acids carrier that the hexadecyl ester base is modified.Embodiment 6: the preparation of polysaccharide derivates nano-micelle and sign
1, the preparation of amphiphilic polysaccharide derivates nanometer grain: polysaccharide derivates 30mg is dissolved in the 6ml water in stirring at room 1h, then under the ice bath behind the ultrasonic or high pressure homogenize, and 0.45 μ m membrane filtration, promptly.
2, particle diameter: (Malvern Instruments, Malvern UK) at 633nm, 25 ℃, He-Ne laser determination sample particle diameter, the results are shown in Table 1 to Zetasizer 3000HS instrument.
3, critical micelle concentration (CMC): adopt the most sensitive fluorescent probe method to measure CMC.With the pyrene is fluorescent probe, and pyrene is a kind of hydrophobicity aromatic, extremely responsive to environment polarity.When the concentration of amphipathic molecule is lower than CMC, can not form micelle in the solution, pyrene is dissolved in the polar water; Along with the concentration of amphipathic molecule is higher than CMC, micelle formation.The pyrene hydrophobic part of micelle kernel in opposite directions distributes, thereby enter nonpolar environment, then in its fluorescence wide spectrum, can observe a series of variations, to increase as fluorescence intensity, vibrating fine structure (the vibrational fine structure of theemission spectra) in the emission spectrum changes, (0,0) wave band red shift in the laser spectrum.Therefore, by with the I in the emission spectra of pyrene
1/ I
3Than (under fixed excitation wavelength, scanning I
1, I
3Represent respectively in the emission spectra first and the fluorescence intensity ratio at three strongest ones peak) or excitation spectrum in I
338/ I
333Mapping can obtain the apparent CMC of amphipathic molecule to the concentration of amphiphile, amphiphilic molecule than (the excitation spectrum medium wavelength is respectively the fluorescence intensity ratio of 338nm and 333nm), the results are shown in Table 1.
The micellar sign of table 1 amphiphilic polysaccharide derivates nanometer
Embodiment 7: comprise paclitaxel amphiphilic polysaccharide derivant self-assembled nanometer grain preparation of compositions and sign
1, preparation technology
(1) probe ultrasonic method:
Amphiphilic polysaccharide derivant 34mg is dissolved in the 6ml water in stirring at room 1h.Paclitaxel 20mg is dissolved in the ethanol (methanol, dichloromethane).The two solution mixes then, and behind the ice-bath ultrasonic 30min, with dialyse 12h or remove organic solvent under reduced pressure of bag filter (MWCO 3500) room temperature in distilled water, centrifugal 3000rpm 510min is with 0.45 μ m membrane filtration, lyophilization.
(2) high pressure homogenization method:
Amphiphilic polysaccharide derivant 34mg is dissolved in the 6ml water in stirring at room 1h.Paclitaxel 30mg is dissolved in the ethanol (methanol, dichloromethane).The two solution mixes then, high pressure homogenize, and with dialyse 12h or remove organic solvent under reduced pressure of bag filter (MWCO 3500) room temperature in distilled water, centrifugal 3000rpm 10min is with 0.45 μ m membrane filtration, lyophilization.
(3) solvent evaporation method:
Amphiphilic polysaccharide derivant 34mg is dissolved in the 6ml water in stirring at room 1h.Paclitaxel 30mg is dissolved in the chloroform, and both solution mix then, continues to stir and spends the night, and makes the chloroform volatilization, and centrifugal 3000rpm 10min is with 0.22 μ m membrane filtration, lyophilization.
2, the mensuration of content of taxol in the amphiphilic polysaccharide derivant self-assembled nanometer grain
(Japan) method is carried out assay for LC-2010C, Shimadzu with HPLC.Mobile phase is methanol: water=75: 25 (v/v), chromatographic column are Lichrospher C
18(150 * 4.6mm), the pillar particle diameter is 5 μ m.Flow velocity is 1.0mL/min, the detection wavelength be 227nm (SPD-10A, UV detector, Shimadzu, Japan), column temperature is 30 ℃, the injected sample volume is 20 μ l.Drug loading with formula (1) calculation sample.
3, (Malvern Instruments, Malvern is UK) at 633nm, 25 ℃, He-Ne laser determination sample particle diameter with Zetasizer 3000HS instrument.
The amphiphilic polysaccharide derivant self-assembled nanometer grain physicochemical property that embodiment 1～5 is loaded with paclitaxel sees Table 2.
Table 2 is loaded with the sign of the amphiphilic polysaccharide derivant self-assembled nanometer grain of paclitaxel
Embodiment 8: comprise ciclosporin A amphiphilic polysaccharide derivant self-assembled nanometer grain preparation of compositions and sign
1, preparation technology
Amphiphilic polysaccharide derivant 34mg is dissolved in the 6ml water in stirring at room 1h.Ciclosporin A 20mg is dissolved in the ethanol (methanol, acetonitrile, chloroform).The two solution mixes then, and behind the ice-bath ultrasonic 30min, with dialyse 12h or remove organic solvent under reduced pressure of bag filter (MWCO 3500) room temperature in distilled water, centrifugal 3000rpm 10min is with 0.45 μ m membrane filtration, lyophilization.
2, ciclosporin A Determination on content in the amphiphilic polysaccharide derivant self-assembled nanometer grain
(Japan) method is carried out assay for LC-2010C, Shimadzu with HPLC.Mobile phase is acetonitrile: methanol: water: isopropyl alcohol=900: 450: 50: 0.5 (v/v), chromatographic column is Lichrospher C
18(150 * 4.6mm), the pillar particle diameter is 5 μ m.Flow velocity is 1.0mL/min, the detection wavelength be 225nm (SPD-10A, UV detector, Shimadzu, Japan), column temperature is 60 ℃, the injected sample volume is 20 μ l.Drug loading with formula (1) calculation sample.
3, (Malvern Instruments, Malvern is UK) at 633nm, 25 ℃, He-Ne laser determination sample particle diameter with Zetasizer 3000HS instrument.
The physicochemical property that embodiment 1～5 is loaded with the amphiphilic polysaccharide derivant self-assembled nanometer grain of ciclosporin A sees Table 3.
Table 3 is loaded with the sign of the amphiphilic polysaccharide derivant self-assembled nanometer grain of ciclosporin A
Embodiment 9: comprise itraconazole amphiphilic polysaccharide derivant self-assembled nanometer grain preparation of compositions and sign
1, preparation technology
Amphiphilic polysaccharide derivant 34mg is dissolved in the 6ml water in stirring at room 1h.Itraconazole 20mg is dissolved in the ethanol (methanol, acetonitrile).The two solution mixes then, and behind the ice-bath ultrasonic 30min, with dialyse 12h or remove organic solvent under reduced pressure of bag filter (MWCO 3500) room temperature in distilled water, centrifugal 3000rpm 10min is with 0.45 μ m membrane filtration, lyophilization.
2, itraconazole Determination on content in the amphiphilic polysaccharide derivant self-assembled nanometer grain
(Japan) method is carried out assay for LC-2010C, Shimadzu with HPLC.Mobile phase is methanol: water=75: 25 (v/v), chromatographic column are Lichrospher C
18(150 * 4.6mm), the pillar particle diameter is 5 μ m.Flow velocity is 1.0mL/min, the detection wavelength be 263nm (SPD-10A, UV detector, Shimadzu, Japan), column temperature is 25 ℃, the injected sample volume is 20 μ l.Drug loading with formula (1) calculation sample.
3, (Malvern Instruments, Malvern is UK) at 633nm, 25 ℃, He-Ne laser determination sample particle diameter with Zetasizer 3000HS instrument.
The physicochemical property that embodiment 1～5 is loaded with the amphiphilic polysaccharide derivant self-assembled nanometer grain of itraconazole sees Table 4.
Table 4 is loaded with the sign of the amphiphilic polysaccharide derivant self-assembled nanometer grain of itraconazole
Embodiment 10: comprise indomethacin amphiphilic polysaccharide derivant self-assembled nanometer grain preparation of compositions and sign
1, preparation technology
Amphiphilic polysaccharide derivant 34mg is dissolved in the 6ml water in stirring at room 1h.Indomethacin 20mg is dissolved in the ethanol (methanol, acetonitrile).The two solution mixes then, and behind the ice-bath ultrasonic 30min, with dialyse 12h or remove organic solvent under reduced pressure of bag filter (MWCO 3500) room temperature in distilled water, centrifugal 3000rpm 10min is with 0.45 μ m membrane filtration, lyophilization.
2, indomethacin Determination on content in the amphiphilic polysaccharide derivant self-assembled nanometer grain
(Japan) method is carried out assay for LC-2010C, Shimadzu with HPLC.Mobile phase is methanol: water: acetic acid=75: 25: 0.1 (v/v), chromatographic column are Lichrospher C
18(150 * 4.6mm), the pillar particle diameter is 5 μ m.Flow velocity is 1.0mL/min, the detection wavelength be 260nm (SPD-10A, UV detector, Shimadzu, Japan), column temperature is 25 ℃, the injected sample volume is 20 μ l.Drug loading with formula (1) calculation sample.
3, (Malvern Instruments, Malvern is UK) at 633nm, 25 ℃, He-Ne laser determination sample particle diameter with Zetasizer 3000HS instrument.
The physicochemical property that embodiment 1～5 is loaded with the amphiphilic polysaccharide derivant self-assembled nanometer grain of indomethacin sees Table 5.
Table 5 is loaded with the sign of the amphiphilic polysaccharide derivant self-assembled nanometer grain of indomethacin
Embodiment 11: comprise nimodipine amphiphilic polysaccharide derivant self-assembled nanometer grain preparation of compositions and sign
1, preparation technology
Amphiphilic polysaccharide derivant 34mg is dissolved in the 6ml water in stirring at room 1h.Nimodipine 20mg is dissolved in the ethanol (methanol, acetonitrile).The two solution mixes then, and behind the ice-bath ultrasonic 30min, with dialyse 12h or remove organic solvent under reduced pressure of bag filter (MWCO 3500) room temperature in distilled water, centrifugal 3000rpm 10min is with 0.45 μ m membrane filtration, lyophilization.
2, nimodipine Determination on content in the amphiphilic polysaccharide derivant self-assembled nanometer grain
(Japan) method is carried out assay for LC-2010C, Shimadzu with HPLC.Mobile phase is methanol: water=65: 35 (v/v), chromatographic column are Lichrospher C
18(150 * 4.6mm), the pillar particle diameter is 5 μ m.Flow velocity is 1.0mL/min, the detection wavelength be 237nm (SPD-10A, UV detector, Shimadzu, Japan), column temperature is 25 ℃, the injected sample volume is 20 μ l.Drug loading with formula (1) calculation sample.
3, (Malvern Instruments, Malvern is UK) at 633nm, 25 ℃, He-Ne laser determination sample particle diameter with Zetasizer 3000HS instrument.
The physicochemical property that embodiment 1～5 is loaded with the amphiphilic polysaccharide derivant self-assembled nanometer grain of nimodipine sees Table 6.
Table 6 is loaded with the sign of the amphiphilic polysaccharide derivant self-assembled nanometer grain of nimodipine
Embodiment 12: comprise haloperidol amphiphilic polysaccharide derivant self-assembled nanometer grain preparation of compositions and sign
1, preparation technology
Amphiphilic polysaccharide derivant 34mg is dissolved in the 6ml water in stirring at room 1h.Haloperidol 20mg is dissolved in the chloroform.The two solution mixes then, and behind the ice-bath ultrasonic 30min, with dialyse 12h or remove organic solvent under reduced pressure of bag filter (MWCO 3500) room temperature in distilled water, centrifugal 3000rpm 10min is with 0.45 μ m membrane filtration, lyophilization.
2, haloperidol Determination on content in the amphiphilic polysaccharide derivant self-assembled nanometer grain
(Japan) method is carried out assay for LC-2010C, Shimadzu with HPLC.Mobile phase is acetonitrile: methanol: 0.025mol/L potassium dihydrogen phosphate=45: 5: 50 (v/v), chromatographic column are Lichrospher C
18(150 * 4.6mm), the pillar particle diameter is 5 μ m.Flow velocity is 1.0mL/min, the detection wavelength be 248nm (SPD-10A, UV detector, Shimadzu, Japan), column temperature is 25 ℃, the injected sample volume is 20 μ l.Drug loading with formula (1) calculation sample.
3, (Malvern Instruments, Malvern is UK) at 633nm, 25 ℃, He-Ne laser determination sample particle diameter with Zetasizer 3000HS instrument.
The physicochemical property of the amphiphilic polysaccharide derivant self-assembled nanometer grain of 1～5 year haloperidol of embodiment sees Table 7.
Table 7 is loaded with the sign of the amphiphilic polysaccharide derivant self-assembled nanometer grain of haloperidol
Embodiment 13: comprise azithromycin amphiphilic polysaccharide derivant self-assembled nanometer grain preparation of compositions and sign
1, preparation technology
Amphiphilic polysaccharide derivant 34mg is dissolved in the 6ml water in stirring at room 1h.Azithromycin 20mg is dissolved in the chloroform.The two solution mixes then, and behind the ice-bath ultrasonic 30min, with dialyse 12h or remove organic solvent under reduced pressure of bag filter (MWCO 3500) room temperature in distilled water, centrifugal 3000rpm 10min is with 0.45 μ m membrane filtration, lyophilization.
2, the mensuration of potency of azithromycin in the amphiphilic polysaccharide derivant self-assembled nanometer grain
(Japan) method is carried out assay for LC-2010C, Shimadzu with HPLC.Mobile phase is acetonitrile: 0.1% triethylamine aqueous solution=30: 70 (v/v), regulate pH to 4.0 with phosphoric acid, and chromatographic column is Lichrospher C
18(150 * 4.6mm), the pillar particle diameter is 5 μ m, and flow velocity is 1.2mL/min, the detection wavelength be 205nm (SPD-10A, UV detector, Shimadzu, Japan), column temperature is 40 ℃, the injected sample volume is 20 μ l.Drug loading with formula (1) calculation sample.
3, (Malvern Instruments, Malvern is UK) at 633nm, 25 ℃, He-Ne laser determination sample particle diameter with Zetasizer 3000HS instrument.
The physicochemical property of the amphiphilic polysaccharide derivant self-assembled nanometer grain of 1～5 year azithromycin of embodiment sees Table 8.
Table 8 is loaded with the sign of the amphiphilic polysaccharide self-assembled nanometer grain of azithromycin
Claims (11)
1. the amphiphilic polysaccharide derivative carrier of an organism lesions position specific drug release, it is characterized in that but this carrier is to introduce hydrophobic group at the polysaccharide skeleton by the specificity degraded linking arm that contains disulfide bond, make polysaccharide have amphipathic characteristic, but self assembly is a nano-micelle in aqueous medium, after this nano-micelle carrying medicament arrives lesions position, its disulfide bond linking arm can be degraded by the reducing substances glutathion specificity of high concentration in the focus cell, coming off of hydrophobic group causes medicine to be discharged by the micelle kernel fast, act on lesions position, can significantly improve lesions position free drug concentration, curative effect and bioavailability, this carrier structure is shown in following chemical formula:
Wherein GLY is the polysaccharide molecule chain, and n+m is the contained alkylidene number of linking arm, and D is a hydrophobic group, and R is the number that hydrophobic group replaces on the polysaccharide molecule.
2. the amphiphilic polysaccharide derivative carrier of organism lesions position specific drug release as claimed in claim 1 is characterized in that described polysaccharide comprises hyaluronic acid, unfraction heparin, low molecular weight heparin, desulfurization acidify heparin, chrondroitin, poly-sulfated chrondroitin, alginic acid, glucosan, fungus polysaccharide, chitosan and contains carboxyl, amino or hydroxy derivative.
3. the amphiphilic polysaccharide derivative carrier of organism lesions position specific drug release as claimed in claim 1, it is characterized in that linking arm contains the disulfide bond of lesions position specificity degraded, and the reactive group at two ends is that amino or carboxyl or an end reactive group are that amino other end reactive group is a carboxyl, and linking arm alkylidene number is 2～16.
4. the amphiphilic polysaccharide derivative carrier of organism lesions position specific drug release as claimed in claim 1 is characterized in that described hydrophobic group D comprises C
2-18Fatty acid, deoxycholic acid and cholic acid, C
2-18Alkylamine, C
2-18Alkylol.
5. the amphiphilic polysaccharide derivative carrier of organism lesions position specific drug release as claimed in claim 1, the number P that hydrophobic group replaces on the polysaccharide molecule are 2～600 integer.
6. the amphiphilic polysaccharide derivative carrier of organism lesions position specific drug release as claimed in claim 1 is characterized in that polysaccharide molecule links to each other by amido link or ester bond with linking arm, and linking arm links to each other by amido link or ester bond with hydrophobic group.
7. the preparation method of the amphiphilic polysaccharide derivative carrier of the described organism lesions position of claim 1 specific drug release is characterized in that comprising the following steps:
(1) carboxylic polysaccharide or the polysaccharide derivates that contains carboxyl are dissolved in the reaction dissolvent, employing contains disulfide bond and two ends are amino linking arm, with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and I-hydroxybenzotriazole (HOBt) is that activator carries out condensation reaction, and the amino reaction of an end of polysaccharide and linking arm obtains intermediate; Hydrophobic group fatty acid, deoxycholic acid, cholic acid are dissolved in the reaction dissolvent, with dicyclohexyl carbodiimide (DCC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) is activator, the carboxyl of hydrophobic group further with the intermediate linking arm on the amino condensation reaction of the other end, promptly get amphiphilic polysaccharide derivative carrier with organism lesions position specific drug release function.
(2) polysaccharide derivates that will contain the polysaccharide of amino (hydroxyl) or contain amino (hydroxyl) is dissolved in the reaction dissolvent, employing contains disulfide bond and two ends are the linking arm of carboxyl, with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and I-hydroxybenzotriazole (HOBt) is that activator carries out condensation reaction, and an end carboxyl reaction of polysaccharide and linking arm obtains intermediate; Hydrophobic group alkylamine or alkylol are dissolved in the reaction dissolvent, with dicyclohexyl carbodiimide (DCC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) is activator, the amino of hydrophobic group or hydroxyl further with the intermediate linking arm on other end carboxyl condensation reaction, promptly get amphiphilic polysaccharide derivative carrier with organism lesions position specific drug release function.
(3) carboxylic polysaccharide or carboxylic polysaccharide derivates are dissolved in the reaction dissolvent, employing contains disulfide bond and an end is amino linking arm for the carboxyl other end, with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and I-hydroxybenzotriazole (HOBt) is that activator carries out condensation reaction, and the amino reaction of an end of polysaccharide and linking arm obtains intermediate; Hydrophobic group alkylamine, alkylol are dissolved in the reaction dissolvent, with dicyclohexyl carbodiimide (DCC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) is activator, the amino of hydrophobic group, hydroxyl further with the intermediate linking arm on other end carboxyl condensation reaction, promptly get amphiphilic polysaccharide derivative carrier with organism lesions position specific drug release function.
(4) polysaccharide derivates that will contain the polysaccharide of amino (hydroxyl) or contain amino (hydroxyl) is dissolved in the reaction dissolvent, employing contains disulfide bond and an end is amino linking arm for the carboxyl other end, with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and I-hydroxybenzotriazole (HOBt) is that activator carries out condensation reaction, and an end carboxyl reaction of polysaccharide and linking arm obtains intermediate; Hydrophobic group fatty acid, deoxycholic acid or cholic acid are dissolved in the reaction dissolvent, with dicyclohexyl carbodiimide (DCC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) is activator, the carboxyl of hydrophobic group further with the intermediate linking arm on the amino condensation reaction of the other end, promptly get amphiphilic polysaccharide derivative carrier with organism lesions position specific drug release function.
8. the preparation method of the amphiphilic polysaccharide derivative carrier of claim 6 described organism lesions position specific drug releases, it is characterized in that described reaction dissolvent is water, methanol, N, the mixed solvent of dinethylformamide, oxolane, dimethyl sulfoxide, Methanamide, water and methanol, water and N, the mixed solvent of the mixed solvent of dinethylformamide, water and Methanamide or N, the mixed solvent of dinethylformamide and Methanamide.
9. the application of the amphiphilic polysaccharide derivative carrier of the described organism lesions position of claim 1 specific drug release is characterized in that being used in the blood vessel or intramuscular injection or oral, the pharmaceutical active of external or the carrier of pharmacologically active molecule.
10. application according to claim 8 is characterized in that described pharmaceutical active or pharmacologically active molecule are selected from: the arbitrary material or derivatives thereof in taxanes, ciclosporin class, camptothecin, flavonoid, dihydropyridines, XIAONIE bases, vinca, anthraquinone class, podophillotoxines antineoplastic agent, steroidal class or nonsteroidal anti-inflammatory drug, cardiovascular drugs, antibiotic, antifungal drug, antiviral drugs, the immunomodulator.
11. application according to claim 8 is characterized in that the preparation method of this medicament solubilization carrier may further comprise the steps: amphiphilic polysaccharide derivant and water are 1～50: 1000 ratio dissolving by weight, obtain the nano-micelle of polysaccharide derivates; With the indissoluble of treatment effective dose or the organic drug that is slightly soluble in water with after the acceptable solvent dissolving pharmaceutically, after described amphiphilic polysaccharide derivates nanometer micelle mixes, handle through ultrasonic or high pressure homogenize, solution is removed organic solvent and micromolecule with dialysis or ultrafiltration or post partition method, and lyophilizing makes the nano drug-carrying micelle that particle diameter is 10～1000nm.
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