CN105769817A - NLC (Nanostructured lipid carrier) with surface modified by TCS (thiolated chitosan) and preparation method of NLC - Google Patents

NLC (Nanostructured lipid carrier) with surface modified by TCS (thiolated chitosan) and preparation method of NLC Download PDF

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CN105769817A
CN105769817A CN201610134733.3A CN201610134733A CN105769817A CN 105769817 A CN105769817 A CN 105769817A CN 201610134733 A CN201610134733 A CN 201610134733A CN 105769817 A CN105769817 A CN 105769817A
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chitosan
nlc
glyceryl
lipid carrier
thiolated polymers
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刘丹丹
潘卫三
李金宇
吴庆银
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Liaoning Institute of Science and Technology
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Liaoning Institute of Science and Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
    • C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and discloses a novel synthetic method of a bio-adhesion TCS (thiolated chitosan) and a preparation method of the NLC (Nanostructured lipid carrier) with the surface modified by TCS. The preparation method comprises the steps as follows: firstly, a thiol donor and chitosan are adopted as starting materials, the thiol donor and a free amino group of a chitosan molecule are connected, and TCS is obtained; then based on an electrostatic adsorption principle, TCS with the positively charged surface is used for performing surface modification on NLC with the negatively charged surface, the NLC is endowed with more outstanding bio-adhesion and permeability, and accordingly, the mucosa adhesion, the bioavailability and the pharmaceutical efficacy of a drug delivery system are further improved. The drug delivery system is simple in preparation process and suitable for being produced in a large scale, and various drug delivery ways including eye delivery, gastrointestinal tract delivery, percutaneous delivery, nasal mucosa delivery, intravenous injection and the like can be achieved.

Description

A kind of Chitosan-Thiolated Polymers surface finish nano lipid carrier and preparation method thereof
Technical field:
The invention belongs to field of pharmaceutical preparations, relating to the synthesis of a kind of bioadhesive Chitosan-Thiolated Polymers and the preparation method of thio chitosan surface finish nano lipid carrier, this drug delivery system may be used for the multiple route of administration such as eye, gastrointestinal tract, percutaneous, nasal mucosa, intravenous injection.
Background technology:
Nano-lipid carrier (Nanostructuredlipidcarriers, NLC) is the nanometer medicine-carried system of new generation developed on solid lipid nanoparticle basis, liquid/solid mix lipid, surfactant and medicine and form.The addition of the fluid oil that character is widely different in Solid lipid, can upset the crystal formation arrangement of NLC skeleton lipid, make to form many lattice defect spaces in skeleton lipid, in order to hold more drug molecule.
NLC is as nano-medicament carrier, thus it is possible to vary film transporting mechanism, strengthens medicine to biomembranous permeability, is conducive to drug percutaneous or transmucosal to absorb and intracellular drug effect plays.NLC good biocompatibility, can Drug controlled release, it is to avoid drug degradation or leakage, has good targeting, can be used for multiple route of administration.But recent studies indicate that, for route of administration and administration purpose, NLC is carried out finishing, it is possible to improve NLC drug delivery effect further.
Chitosan-Thiolated Polymers (Thiolatedchitosan, TCS) be the amino on chitosan (CS) is reacted with compounds containing thiol groups and prepare there is free sulfhydryl groups and the better polymer of water solublity.Introducing of mercapto groups gives the more excellent biological nature of CS: 1. mucosa-adherent significantly improves: the free sulfhydryl groups of TCS can form disulfide bond with the cysteine on rete malpighii glycoprotein, and this covalent bond interaction strength is significantly larger than non-covalent bond.It is reported, compared with the CS of unmodified, the adhesiveness of TGA chitosan improves 5-10 times, and the adhesiveness of sulfydryl fourth amidine chitosan then can improve 140 times.2. Penetration enhancing effect: TCS can suppress tyrosine phosphatase activity, causes the structural rearrangement of compact siro spinning technology associated protein, regulates the flow between adhesion, and then increases the cell bypass absorbance of medicine.Moreover, owing to this process depends on easily oxidized glutathion, and TCS has reproducibility, it is possible to effectively protects glutathion, and then strengthens the permeability of medicine.3. P-gp inhibitory action: TCS can form covalent bond with the cysteine residues on the WalkerA consensus sequence being positioned at two ATP binding structural domains of P-gp, although the change of this body structure of cysteine residues has no effect on the performance of P-gp effect, but with the sterically hindered catalysis activity that can reduce P-gp produced after TCS covalent bond, thus suppressing the performance of its effect.All be there is inhibitory action in various degree by 4. CYP450 inhibitory action: TCS in CYP3A4 and the CYP2A6 in CYP3A metabolic enzyme family.5. biocompatibility improves further: compared with CS, and erythrocytic destruction is substantially weakened by TCS, almost without cytotoxicity, and can be degradable in human body.
The synthetic method of thio chitosan is usually what the group connected on the free amine group of chitosan containing sulfydryl realized.Research shows, the free sulfhydryl groups on TCS is to ensure that the key factor that its characteristic plays, and sulfhydryl content is more high, and the biopotency of TCS is more excellent.
Therefore, the present invention developed in the first the TCS synthetic method of a kind of improvement, to obtain the TCS copolymer with high-load free sulfhydryl groups, it is ensured that the performance of its biopotency；Then electrostatic absorption principle is passed through, the NLC of surface bear electricity is carried out finishing by the TCS utilizing surface lotus positive electricity, give bioadhesive more excellent for NLC and permeability, thus improving the mucosa-adherent of NLC drug delivery system, bioavailability and drug effect further.
Summary of the invention:
The technical problem to be solved is to build a kind of novel TCS surface finish nano lipid carrier, gives its more excellent bioadhesive, mucosal permeability and biocompatibility etc., to improve bioavailability and effect of medicine further.
The present invention is achieved through the following technical solutions:
Chitosan-Thiolated Polymers surface finish nano lipid carrier of the present invention comprises pharmacological active substance, matrix material, emulsifying agent, Chitosan-Thiolated Polymers, water, in 100mL nano-lipid carrier, the quality concentration expressed in percentage by volume (w/v) of each composition is: pharmacological active substance 0.001%～15%, matrix material 0.1%～30%, emulsifying agent 0.01%～30%, Chitosan-Thiolated Polymers 0.01%～15%, water surplus.
In 100mL nano-lipid carrier, mass percentage concentration (w/v) of each composition preferably ranges from: pharmacological active substance 0.01%～3%, matrix material 0.1%～8%, emulsifying agent 0.01%～5%, Chitosan-Thiolated Polymers 0.01%～3%, water surplus.
Described water is distilled water.
Described pharmacological active substance includes curcumin, flurbiprofen, ciclosporin, 5-fluorouracil, amphotericin B, bilobalide, silymarin, ibuprofen, dexamethasone acetate, carvedilol, vinpocetine, itraconazole, nimodipine, nitrendipine, Sorafenib, hydroxy camptothecin, paclitaxel, amycin, etoposide, docetaxel, rubescensine A, triamcinolone acetonide acetate, indomethacin, ubiquinone10Deng, but it is not limited to these medicines.
Described matrix material is made up of Solid lipid and liquid fatty substance, wherein one or more in glyceryl monostearate, glycerol distearate, glyceryl monolaurate, acetylation monoglyceride, Fructus Persicae resin, 18 alcohol, Glyceryl Behenate, cetyl palmitate, glyceryl palmitostearate, trilaurin, myristin, tripalmitin, glyceryl tristearate, stearylamine, stearic acid, stearyl alcohol, Palmic acid, lauric acid of Solid lipid；One or more in medium chain triglyceride, isopropyl myristate, caprylic/capric glyceride, glyceryl triacetate, ethyl sebacate, adipic acid diisopropyl ester, Dermol DIPS, lauric acid hexyl ester, 2-octyldodecanol, isopropyl palmitate fat, oleic acid, linoleic acid, vitamin E, liquid paraffin, soybean oil, Semen Maydis oil, Oleum Helianthi, olive oil, Oleum Arachidis hypogaeae semen of liquid fatty substance.The mass ratio of Solid lipid and liquid fatty substance is 1:10～10:1, it is preferred that the mass ratio of Solid lipid and liquid fatty substance is 2:5～2:1.
One or more in glyceryl monostearate, glycerol distearate, Glyceryl Behenate, cetyl palmitate, glyceryl palmitostearate, trilaurin, myristin, tripalmitin, glyceryl tristearate, stearylamine, stearic acid, stearyl alcohol, Palmic acid, lauric acid of currently preferred Solid lipid；One or more in medium chain triglyceride, isopropyl myristate, caprylic/capric glyceride, lauric acid hexyl ester, 2-octyldodecanol, isopropyl palmitate fat, oleic acid, linoleic acid, vitamin E, liquid paraffin, soybean oil, Semen Maydis oil, Oleum Helianthi, olive oil, Oleum Arachidis hypogaeae semen of preferred liquid fatty substance.Currently preferred matrix material is the mixture of Solid lipid and liquid fatty substance, it is preferred that compound mode is: Glyceryl Behenate-medium chain triglyceride；Glyceryl Behenate-caprylic/capric glyceride；Myristin, glyceryl monostearate-medium chain triglyceride；Glyceryl palmitostearate, Glyceryl Behenate-medium chain triglyceride, glycerol distearate-caprylic/capric glyceride.
Described emulsifying agent is selected from: one or more in sorbester p18, ten polyglycereol monolaurates, PEG-20 hexadecanol ether, PEG-2 hexadecanol ether, stearoylketene dilactic acid sodium and glyceryl stearate Fructus Citri Limoniae ester, Polyethylene Glycol-15-hydroxy stearic acid ester, polyoxyethylene castor oil, Gelucire 44/14, phospholipid, vitamin E, TPGS, OP emulsifying agent, Gelucire 44/14, tween, poloxamer, polyvinyl alcohol.
Preferred emulsifier of the present invention is: one or more in Polyethylene Glycol-15-hydroxy stearic acid ester, polyoxyethylene castor oil, Gelucire 44/14, phospholipid, vitamin E, TPGS, OP emulsifying agent, Gelucire 44/14, tween, poloxamer, polyvinyl alcohol.
Chitosan-Thiolated Polymers of the present invention is prepared via a method which:
First with sulfydryl donor and CS for initiation material, with 1-(3-dimethyl aminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCl) and 1-hydroxy benzo triazole (HOBT) for condensing agent, TCS is synthesized.
Described TCS synthetic method is as follows:
(1) sulfydryl donor, EDC HCl and HOBT are dissolved in inert organic solvents, within room temperature continuous stirring 3-6 hour, obtain activated thiol groups donor.
(2) being dissolved in by CS in 5～20% hydrochloric acid solutions, prepared concentration is the polymer solution of 0.8～1.25% (w/v).
(3) joining in the CS solution described in step (2) by the activated thiol groups donor described in step (1), after regulating pH value with NaOH, under room temperature, lucifuge is reacted 3-6 hour.
(4) for purified product, remove unreacted sulfydryl donor, the reactant liquor hydrochloric acid solution containing 1～5mmol/L is dialysed 1 time, dialyse twice with the hydrochloric acid (5mmol/L) containing 0.5～1.5%NaCl, dialyse 2 times with the hydrochloric acid solution containing 1～5mmol/L again, each dialysis time respectively 12 hours, whole dialysis procedure all carry out under 4 DEG C of lucifuges.To take out by solution after dialysis, and cross 0.8 μm of filter membrane and remove impurity, after lyophilization and get final product.
Sulfydryl donor described in step (1) can be the one in N-acetyl-L-cysteine, cysteine, TGA, 4-mercaptobutyl amidine.
Sulfydryl donor described in step (1), the ratio of the mole of EDC HCl and HOBT are 10～1:9～0.5:8～0.5, it is preferable that range for 8～3:6～1:6～1.
Inert organic solvents described in step (1) is the one in N,N-dimethylformamide, dehydrated alcohol, propylene glycol, dimethyl sulfoxide, oxolane, acetone, dichloromethane.
Chitosan described in step (2), deacetylation ranges for 60～100%, and molecular weight ranges is 10,000～1,000,000.
The ratio of the activated thiol groups donor described in step (3) and the mole of CS is 20～0.2:1, it is preferable that range for 10～1:1.
PH value range of accommodation described in step (3) is 3～7.
The above-mentioned total sulfhydryl content of gained TCS can reach about 800 μm of ol/g, and free sulfhydryl groups content can reach 600 μm of ol/g, is namely successfully synthesized to the sulfydryl on chitosan, has 75% not oxidized, obtains higher free sulfhydryl groups yield, and the performance for usefulness provides guarantee.
The medicine carrying NLC of the present invention adopts melted emulsion process, high pressure homogenization method, ultrasonic dispersion or what solvent evaporation method was prepared from.
Described melted emulsion process is to melted as oil phase using the heating of medicine carrying matrix material, by the heated aqueous containing emulsifying agent to identical temperature and mix with this oil phase, stirs certain time, makes dispersion liquid, after ice bath cooling and get final product.
Described high pressure homogenization method is to be scattered in the emulsifier aqueous solution of heat to form colostrum by medicament-carrying lipoid fused mass, and colostrum forms nano-emulsion through high pressure homogenize at the temperature higher than lipoid fusing point, and under room temperature, nano-emulsion cooling curing forms medicine carrying NLC；First can also being solidified in liquid nitrogen or dry ice by medicament-carrying lipoid fused mass, grind to form the granule that particle diameter is about 50～100 μm, then be scattered in emulsifier aqueous solution and form colostrum, at room temperature namely high pressure homogenize obtains medicine carrying NLC.
Described ultrasonic dispersion is medicine and lipoid etc. to be dissolved in suitable organic solvent, and decompression removes organic solvent, forms one layer of lipid membrane, adds a certain amount of emulsifier aqueous solution, with Probe Ultrasonic Searching instrument ultrasonic disperse and get final product.
Described solvent evaporation method is lipophilic drugs and lipoid to be dissolved in and in the immiscible organic solvent of water, join emulsifying in the aqueous phase containing emulsifying agent, and after volatile organic solvent, lipoid precipitates formation NLC in aqueous phase.
TCS finishing NLC method, is be dissolved in distilled water by TCS, prepares into the polymer solution that mass concentration is 0.05%～5%, then is mixed with volume ratio 0.1:1～3:1 with medicine carrying NLC by polymer solution, is stirred at room temperature and hatches 0.5～3h and get final product.
TCS finishing NLC mean diameter of the present invention is 10～1000nm.
The method have the advantages that
1, the novel TCS finishing NLC nano structured lipid carrier constructed by the present invention is compared with common unmodified NLC, has higher Drug loading capacity, envelop rate and physical and chemical stability.
3, after modifying NLC with TCS, the much new biological nature of NLC can be given: 1) excellent bioadhesive, due to TCS in physiological conditions can with mucosa slime layer glycoprotein in rich in cysteine region formed disulfide bond, combine closely in mucosa with covalent bond, extend the medicine holdup time in vivo, improving the local concentration of medicine, promote drug absorption, this characteristic will play huge effect in eye, percutaneous, gastrointestinal tract and cavity/canal drug administration process.2) Penetration enhancing effect: TCS can suppress tyrosine phosphatase activity; cause the structural rearrangement of compact siro spinning technology associated protein; regulate the flow between adhesion; and then increase the cell bypass absorbance of medicine; moreover, owing to this process depends on easily oxidized glutathion, and TCS has reproducibility; can effectively protect glutathion, and then strengthen the permeability of medicine.3) charge reversal, TCS modifies after NLC, and the zeta current potential of NLC will take a turn for the worse, electronegative change positively charged into, and due to gastrointestinal tract epithelial cell, cornea etc. is all electronegative, and charge reversal would be even more beneficial to infiltration and the absorption of medicine.4) suppress Teat pipette that the outer row of medicine is acted on, improve the bioavailability of medicine further.
Accompanying drawing illustrates:
Fig. 1 is the structural representation of TCS finishing NLC；
Fig. 2 for synthesizing the reaction schematic diagram of chitosan-N-acetyl-L-cysteine (CS-NAC) according to embodiment 1.
Fig. 3 synthesizes CS-NAC's according to embodiment 11HNMR schemes
Fig. 4 is the X-ray diffractogram synthesizing CS-NAC according to embodiment 1
Fig. 5 is the means of differential scanning calorimetry figure synthesizing CS-NAC according to embodiment 1
Fig. 6 is the transmission electron microscope picture of (a) curcumin NLC and (b) CS-NAC finishing curcumin NLC according to embodiment 1 preparation
Fig. 7 is CS-NAC finishing curcumin NLC and unmodified NLC according to embodiment 1 preparation and the vitro cumulative release figure of curcumin eye drop
Fig. 8 is that the cornea of CS-NAC finishing curcumin NLC and unmodified NLC according to embodiment 1 preparation and curcumin eye drop is through figure
Fig. 9 is CS-NAC finishing curcumin NLC and unmodified NLC according to embodiment 1 preparation and small animal living body image (a) the curcumin eye drop of curcumin eye drop, (b) curcumin NLC, (c) CS-NAC finishing curcumin NLC.
Detailed description of the invention
Below in conjunction with example, the present invention is described in further detail, but the scope of the present invention is not limited to these examples.
The preparation of embodiment 1 chitosan-N-acetyl-L-cysteine (CS-NAC) finishing curcumin NLC
(1) synthetic method of CS-NAC
1) N-acetyl-L-cysteine (NAC), EDC HCl, HOBT (mol ratio is 4:1:1) that gross mass is 2g are dissolved in 10mLN, in dinethylformamide (DMF), under room temperature continuous stirring 3-6 hour to activate NAC.
2) being dissolved in by CS in 20% hydrochloric acid solution, prepared concentration is the polymer solution of 1.25% (w/v).
3) NAC of activation joins (mol ratio of NAC and CS is 4:1) in CS solution, and regulating pH with NaOH is after 5, and under room temperature, lucifuge is reacted 3-6 hour.
4) for purified product, remove unreacted NAC, the reactant liquor hydrochloric acid solution containing 5mmol/L is dialysed 1 time, dialyse twice with the hydrochloric acid (5mmol/L) containing 1%NaCl, dialyse 2 times with the hydrochloric acid solution containing 5mmol/L again, each dialysis time respectively 12 hours, whole dialysis procedure all carry out under 4 DEG C of lucifuges.To take out by solution after dialysis, and cross 0.8 μm of filter membrane and remove impurity, after lyophilization and get final product.
Under 412nm, these polymer lyophilized product being measured, total sulfhydryl content is 600.2 ± 28.8 μm of ol/g, and free content is: 496.7 ± 17.1 μm of ol/g, and disulfide bond content is: 103.5 ± 19.4 μm of ol/g.
(2) preparation method of CS-NAC finishing curcumin NLC
Prescription: curcumin 6mg, CS-NAC10mg, glyceryl monostearate 112mg, medium chain triglyceride 69mg, Polyethylene Glycol-15-hydroxy stearic acid ester 89mg, Gelucire 44/14 10mg.
Preparation technology: glyceryl monostearate, Polyethylene Glycol-15-hydroxy stearic acid ester, medium chain triglyceride and curcumin are added heat fusing in 75 DEG C, then the Gelucire 44/14 aqueous solution that the identical temperature of 10mL is fully dissolved it is added dropwise over, 75 DEG C are sufficiently stirred for 3～10min, and in ice bath, namely cooling curing obtains curcumin NLC；CS-NAC is substantially soluble in 10mL deionized water；CS-NAC aqueous solution is added dropwise in curcumin NLC, is stirred at room temperature and hatches after 30min and get final product.The nano structured lipid carrier mean diameter of gained is 88.6nm, current potential 22.5mv, envelop rate 96.6%, and drug loading is 3.2%, and stability is more than 15 days.
For screening prescription scope, the present invention adopts Star point design-effect surface optimization contrived experiment, and data is processed and matching, obtains best prescription scope.On the basis of experiment of single factor, select preparation nature is affected the total amount (X of significant glyceryl monostearate and medium chain triglyceride1), the mass ratio (X of glyceryl monostearate and medium chain triglyceride2), Polyethylene Glycol-15-hydroxy stearic acid ester (X3) three factors are for investigating object；With particle diameter (Y1), polydispersity coefficient (Y2), Zeta potential (Y3) and envelop rate (Y4) for inspection target.According to Star point design principle, each factor arranges 5 levels, its code respectively 0, ± 1, ± α, α=1.682
Each factor value end points level is determined according to experiment of single factor result.The factor of Star point design and level are in Table 1, and specific experiment arrangement and result are in Table 2.
Table 1 Star point design factor and water-glass
Testing according to table 1, specific experiment arrangement, in Table 2, adopts Design-Expert software that data carry out linear and quadratic polynomial models fitting respectively, sets up based on Star point design, it is recommended that optimal fitting on the basis of secondary model.
Table 2 Star point design prescription composition and result
Predictive value under optimal conditions and the deviation of observation, be used to evaluate the quality of the predictability of model of fit.As shown in table 3, deviation value (%) is all in the scope of ± 10%, it was shown that this model of fit predictability is better.
The comparison of the predictive value under table 3 optimal conditions and observation
Deviation (%)=(actual value-predictive value)/-predictive value × 100；Index Y1: mean diameter；
Y2: polydispersity coefficient；Y3: zeta current potential；Y4: envelop rate；Observation: average., n=3.
Thus, lipid concentration (X can be drawn1) preferably range from 160～230mg, solid-liquid lipid proportions (X2) preferably range from 0.4:1～0.7:1, emulsifier (X3) preferably range from 100～150mg.
The preparation of embodiment 2 chitosans-TGA (CS-TGA) finishing curcumin NLC
(1) synthetic method of CS-TGA
1) by the TGA (TGA) that gross mass is 2g, EDC HCl, HOBT (mol ratio is 10:0.5:8) are dissolved in 10mLN, in dinethylformamide (DMF), under room temperature continuous stirring 3-6 hour to activate TGA.
2) being dissolved in by CS in 20% hydrochloric acid solution, prepared concentration is the polymer solution of 1.25% (w/v).
3) TGA of activation joins (mol ratio of TGA and CS is 10:1) in CS solution, and regulating pH with NaOH is after 5, and under room temperature, lucifuge is reacted 3-6 hour.
4) for purified product, remove unreacted TGA, the reactant liquor hydrochloric acid solution containing 5mmol/L is dialysed 1 time, dialyse twice with the hydrochloric acid (5mmol/L) containing 1%NaCl, dialyse 2 times with the hydrochloric acid solution containing 5mmol/L again, each dialysis time respectively 12 hours, whole dialysis procedure all carry out under 4 DEG C of lucifuges.To take out by solution after dialysis, and cross 0.8 μm of filter membrane and remove impurity, after lyophilization and get final product.
Under 412nm, these polymer lyophilized product being measured, total sulfhydryl content is 186.7 ± 21.6 μm of ol/g, and free content is: 118.7 ± 17.5 μm of ol/g, and disulfide bond content is: 68.0 ± 13.2 μm of ol/g.
(2) preparation method of CS-TGA finishing curcumin NLC
Prescription: curcumin 6mg, CS-TGA15mg, Glyceryl Behenate 60mg, medium chain triglyceride 120mg, polyoxyethylene castor oil 30mg, Polyethylene Glycol-15-hydroxy stearic acid ester 80mg, Gelucire 44/14 aqueous solution 5mg, phosphatidase 5 mg.
Preparation technology: Glyceryl Behenate, polyoxyethylene castor oil, Polyethylene Glycol-15-hydroxy stearic acid ester, medium chain triglyceride and curcumin are added heat fusing in 75 DEG C, then Gelucire 44/14/phospholipid aqueous solution that the identical temperature of 15mL is fully dissolved it is added dropwise over, 75 DEG C are sufficiently stirred for 3～10min, and in ice bath, namely cooling curing obtains curcumin NLC；CS-TGA is substantially soluble in 5mL deionized water；CS-TGA aqueous solution is added dropwise in curcumin NLC, is stirred at room temperature and hatches after 30min and get final product.The nano structured lipid carrier mean diameter of gained is 97.2nm, current potential 31.5mv, envelop rate 94.5%, and drug loading is 6.75%, and stability is 10 days.
The preparation of embodiment 3 chitosans-N-acetyl-L-cysteine (CS-NAC) finishing flurbiprofen NLC
(1) synthetic method of CS-NAC
1) NAC, EDC HCl, HOBT (mol ratio is 8:3:2) that gross mass is 1.3g are dissolved in DMF (DMF), under room temperature continuous stirring 3-6 hour to activate NAC.
2) being dissolved in by CS in 20% hydrochloric acid solution, prepared concentration is the polymer solution of 1.25% (w/v).
3) NAC of activation joins (mol ratio of NAC and CS is 6:1) in CS solution, and regulating pH with NaOH is after 5, and under room temperature, lucifuge is reacted 3-6 hour.
4) for purified product, remove unreacted NAC, the reactant liquor hydrochloric acid solution containing 5mmol/L is dialysed 1 time, dialyse twice with the hydrochloric acid (5mmol/L) containing 1%NaCl, dialyse 2 times with the hydrochloric acid solution containing 5mmol/L again, each dialysis time respectively 12 hours, whole dialysis procedure all carry out under 4 DEG C of lucifuges.To take out by solution after dialysis, and cross 0.8 μm of filter membrane and remove impurity, after lyophilization and get final product.
Under 412nm, these polymer lyophilized product being measured, total sulfhydryl content is 778.7 ± 39.3 μm of ol/g, and free content is: 575.1 ± 30.3 μm of ol/g, and disulfide bond content is: 203.6 ± 17.9 μm of ol/g.
(2) preparation method of CS-NAC finishing flurbiprofen NLC
Prescription: flurbiprofen 8mg, CS-NAC40mg, Glyceryl Behenate 140mg, caprylic/capric glyceride 90mg, Polyethylene Glycol-15-hydroxy stearic acid ester 90mg, tween 80 40mg, Gelucire 44/14 aqueous solution 15mg.
Preparation technology: Glyceryl Behenate, caprylic/capric glyceride, Polyethylene Glycol-15-hydroxy stearic acid ester and flurbiprofen are added heat fusing in 85 DEG C, then Gelucire 44/14/tween 80 aqueous solution that the identical temperature of 5mL is fully dissolved it is added dropwise over, 85 DEG C are sufficiently stirred for 3～10min, obtain colostrum.Then by first dispersion liquid Probe Ultrasonic Searching 3min (ultrasonic 3s, interval 3s) under the power of 300W, then in ice bath, namely cooling curing obtains flurbiprofen NLC；CS-NAC is substantially soluble in 15mL deionized water；CS-NAC aqueous solution is added dropwise in flurbiprofen NLC, is stirred at room temperature and hatches after 30min and get final product.The nano structured lipid carrier mean diameter of gained is 108.8nm, current potential 19.5mv, envelop rate 84.8%, and drug loading is 2.95%, and stability is 12 days.
The preparation of embodiment 4 chitosan-4-sulfydryl fourth amidine (CS-TBA) finishing vinpocetine NLC
(1) synthetic method of CS-TBA
1) by the 4-sulfydryl fourth amidine that gross mass is 1.3g, EDC HCl, HOBT (mol ratio is 1:9:8) are dissolved in dehydrated alcohol, under room temperature continuous stirring 3-6 hour to activate 4-sulfydryl fourth amidine.
2) being dissolved in by CS in 20% hydrochloric acid solution, prepared concentration is the polymer solution of 1.25% (w/v).
3) the 4-sulfydryl fourth amidine of activation joins in CS solution (mol ratio of 4-sulfydryl fourth amidine and CS is 0.2:1), and regulating pH with NaOH is after 7, and under room temperature, lucifuge is reacted 3-6 hour.
4) for purified product, remove unreacted 4-sulfydryl fourth amidine, the reactant liquor hydrochloric acid solution containing 5mmol/L is dialysed 1 time, dialyse twice with the hydrochloric acid (5mmol/L) containing 1%NaCl, dialyse 2 times with the hydrochloric acid solution containing 5mmol/L again, each dialysis time respectively 12 hours, whole dialysis procedure all carry out under 4 DEG C of lucifuges.To take out by solution after dialysis, and cross 0.8 μm of filter membrane and remove impurity, after lyophilization and get final product.
Under 412nm, these polymer lyophilized product being measured, total sulfhydryl content is 76.7 ± 9.3 μm of ol/g, and free content is: 48.4 ± 5.6 μm of ol/g, and disulfide bond content is: 28.3 ± 7.2 μm of ol/g.
(2) preparation method of CS-TBA finishing vinpocetine NLC
Prescription: vinpocetine 12mg, CS-TBA20mg, glycerol distearate 210mg, caprylic/capric glyceride 112mg, Polyethylene Glycol-15-hydroxy stearic acid ester 90mg, TPGS 60mg, Gelucire 44/14 aqueous solution 100mg.
Preparation technology: glycerol distearate, caprylic/capric glyceride, Polyethylene Glycol-15-hydroxy stearic acid ester and flurbiprofen vinpocetine are added heat fusing in 85 DEG C, then Gelucire 44/14/TPGS aqueous solution that the identical temperature of 10mL is fully dissolved it is added dropwise over, 85 DEG C are sufficiently stirred for 10min, obtain colostrum.Being placed in high pressure homogenizer by colostrum 800bar pressure homogenizing 8 times, then in ice bath, namely cooling curing obtains vinpocetine NLC；CS-TBA is substantially soluble in 10mL deionized water；CS-TBA aqueous solution is added dropwise in vinpocetine NLC, is stirred at room temperature and hatches after 30min and get final product.The nano structured lipid carrier mean diameter of gained is 133.4nm, current potential 17.6mv, envelop rate 89.3%, and drug loading is 3.33%, and stability is 10 days.
The preparation of embodiment 5 chitosans-N-acetyl-L-cysteine (CS-NAC) finishing Sorafenib NLC
(1) synthetic method of CS-NAC
1) NAC, EDC HCl, HOBT (mol ratio is 3:1:1) that gross mass is 2g are dissolved in 10mLN, in dinethylformamide (DMF), under room temperature continuous stirring 3-6 hour to activate NAC.
2) being dissolved in by CS in 20% hydrochloric acid solution, prepared concentration is the polymer solution of 1.25% (w/v).
3) NAC of activation joins (mol ratio of NAC and CS is 5:1) in CS solution, and regulating pH with NaOH is after 4, and under room temperature, lucifuge is reacted 3-6 hour.
4) for purified product, remove unreacted NAC, the reactant liquor hydrochloric acid solution containing 5mmol/L is dialysed 1 time, dialyse twice with the hydrochloric acid (5mmol/L) containing 1%NaCl, dialyse 2 times with the hydrochloric acid solution containing 5mmol/L again, each dialysis time respectively 12 hours, whole dialysis procedure all carry out under 4 DEG C of lucifuges.To take out by solution after dialysis, and cross 0.8 μm of filter membrane and remove impurity, after lyophilization and get final product.
Under 412nm, these polymer lyophilized product being measured, total sulfhydryl content is 526.6 ± 33.3 μm of ol/g, and free content is: 442.3 ± 28.7 μm of ol/g, and disulfide bond content is: 84.3 ± 15.1 μm of ol/g.
(2) preparation method of CS-NAC finishing Sorafenib NLC
Prescription: Sorafenib 10mg, CS-NAC10mg, glyceryl palmitostearate 50mg, Glyceryl Behenate 80mg, medium chain triglyceride 85mg, Polyethylene Glycol-15-hydroxy stearic acid ester 75mg, Gelucire 44/14 5mg, PLURONICS F87 5mg.
Preparation technology: glyceryl palmitostearate, Glyceryl Behenate, Polyethylene Glycol-15-hydroxy stearic acid ester, medium chain triglyceride and Sorafenib are added heat fusing in 80 DEG C, then Gelucire 44/14/PLURONICS F87 aqueous solution that the identical temperature of 18mL is fully dissolved it is added dropwise over, 80 DEG C are sufficiently stirred for 10min, obtain colostrum.Being placed in high pressure homogenizer by colostrum 1000bar pressure homogenizing 10 times, then in ice bath, namely cooling curing obtains Sorafenib NLC；CS-NAC is substantially soluble in 2mL deionized water；CS-NAC aqueous solution is added dropwise in Sorafenib NLC, is stirred at room temperature and hatches after 30min and get final product.The nano structured lipid carrier mean diameter of gained is 78.9nm, current potential 38.6mV, envelop rate 94.6%, and drug loading is 4.40%, and stability is more than 15 days.
The preparation of embodiment 6CS-TGA finishing itraconazole NLC
(1) synthetic method of CS-TGA
1) TGA, EDC HCl, HOBT (mol ratio is 5:2:3) that gross mass is 2g are dissolved in 10mLN, in dinethylformamide (DMF), under room temperature continuous stirring 3-6 hour to activate TGA.
2) being dissolved in by CS in 20% hydrochloric acid solution, prepared concentration is the polymer solution of 1.25% (w/v).
3) TGA of activation joins (mol ratio of TGA and CS is 1:1) in CS solution, and regulating pH with NaOH is after 3, and under room temperature, lucifuge is reacted 3-6 hour.
4) for purified product, remove unreacted TGA, the reactant liquor hydrochloric acid solution containing 5mmol/L is dialysed 1 time, dialyse twice with the hydrochloric acid (5mmol/L) containing 1%TGA, dialyse 2 times with the hydrochloric acid solution containing 5mmol/L again, each dialysis time respectively 12 hours, whole dialysis procedure all carry out under 4 DEG C of lucifuges.To take out by solution after dialysis, and cross 0.8 μm of filter membrane and remove impurity, after lyophilization and get final product.
Under 412nm, these polymer lyophilized product being measured, total sulfhydryl content is 219.1 ± 19.8 μm of ol/g, and free content is: 132.6 ± 22.3 μm of ol/g, and disulfide bond content is: 86.5 ± 10.9 μm of ol/g.
(2) preparation method of CS-NAC finishing itraconazole NLC
Prescription: itraconazole 20mg, CS-NAC20mg, myristin 30mg, glyceryl monostearate 90mg, medium chain triglyceride 150mg, Polyethylene Glycol-15-hydroxy stearic acid ester 45mg, phosphatidase 3 0mg, PLURONICS F87 5mg, OP emulsifying agent 5mg.
Preparation technology: myristin, glyceryl monostearate, Polyethylene Glycol-15-hydroxy stearic acid ester, medium chain triglyceride, OP emulsifying agent and itraconazole are added heat fusing in 85 DEG C, then phospholipid/PLURONICS F87 aqueous solution that the identical temperature of 10mL is fully dissolved it is added dropwise over, 85 DEG C are sufficiently stirred for 10min, obtain colostrum.Being placed in high pressure homogenizer by colostrum 600bar pressure homogenizing 10 times, then in ice bath, namely cooling curing obtains itraconazole NLC；CS-NAC is substantially soluble in 10mL deionized water；CS-NAC aqueous solution is added dropwise in itraconazole NLC, is stirred at room temperature and hatches after 30min and get final product.The nano structured lipid carrier mean diameter of gained is 205.9nm, current potential 16.6mV, envelop rate 93.5%, and drug loading is 6.93%, and stability is 9 days.
The preparation method of embodiment 7CS-TBA finishing carvedilol NLC
(1) synthetic method of CS-TBA
1) by the 4-sulfydryl fourth amidine that gross mass is 1.3g, EDC HCl, HOBT (mol ratio is 10:6:3) are dissolved in dehydrated alcohol, under room temperature continuous stirring 3-6 hour to activate 4-sulfydryl fourth amidine.
2) being dissolved in by CS in 20% hydrochloric acid solution, prepared concentration is the polymer solution of 1.25% (w/v).
3) the 4-sulfydryl fourth amidine of activation joins in CS solution (mol ratio of 4-sulfydryl fourth amidine and CS is 2:1), and regulating pH with NaOH is after 6, and under room temperature, lucifuge is reacted 3-6 hour.
4) for purified product, remove unreacted 4-sulfydryl fourth amidine, the reactant liquor hydrochloric acid solution containing 5mmol/L is dialysed 1 time, dialyse twice with the hydrochloric acid (5mmol/L) containing 1%NaCl, dialyse 2 times with the hydrochloric acid solution containing 5mmol/L again, each dialysis time respectively 12 hours, whole dialysis procedure all carry out under 4 DEG C of lucifuges.To take out by solution after dialysis, and cross 0.8 μm of filter membrane and remove impurity, after lyophilization and get final product.
Under 412nm, these polymer lyophilized product being measured, total sulfhydryl content is 456.9 ± 15.3 μm of ol/g, and free content is: 323.4 ± 11.2 μm of ol/g, and disulfide bond content is: 133.5 ± 21.4 μm of ol/g.
(2) preparation method of CS-TBA finishing carvedilol NLC
Prescription: carvedilol 15mg, CS-TBA10mg, Glyceryl Behenate 215mg, caprylic/capric glyceride 100mg, Polyethylene Glycol-15-hydroxy stearic acid ester 100mg, tween 80 40mg, poloxamer F127 aqueous solution 20mg, polyvinyl alcohol 5mg.
Preparation technology: Glyceryl Behenate, caprylic/capric glyceride, Polyethylene Glycol-15-hydroxy stearic acid ester and carvedilol are added heat fusing in 85 DEG C, then tween 80/poloxamer F127/ polyvinyl alcohol water solution that the identical temperature of 10mL is fully dissolved it is added dropwise over, 85 DEG C are sufficiently stirred for 10min, obtain colostrum.Then by first dispersion liquid Probe Ultrasonic Searching 5min (ultrasonic 3s, interval 3s) under the power of 300W, then in ice bath, namely cooling curing obtains carvedilol NLC；CS-TBA is substantially soluble in 10mL deionized water；CS-TBA aqueous solution is added dropwise in carvedilol NLC, is stirred at room temperature and hatches after 30min and get final product.The nano structured lipid carrier mean diameter of gained is 152.5nm, current potential 9.6mv, envelop rate 83.6%, and drug loading is 2.76%, and stability is 3 days.
The preparation of embodiment 8 chitosans-N-acetyl-L-cysteine (CS-NAC) finishing docetaxel NLC
(1) synthetic method of CS-NAC
1) NAC, EDC HCl, HOBT (mol ratio is 4:3:2) that gross mass is 2g are dissolved in 10mLN, in dinethylformamide (DMF), under room temperature continuous stirring 3-6 hour to activate NAC.
2) being dissolved in by CS in 20% hydrochloric acid solution, prepared concentration is the polymer solution of 1.25% (w/v).
3) NAC of activation joins (mol ratio of NAC and CS is 4:1) in CS solution, and regulating pH with NaOH is after 5, and under room temperature, lucifuge is reacted 3-6 hour.
4) for purified product, remove unreacted NAC, the reactant liquor hydrochloric acid solution containing 5mmol/L is dialysed 1 time, dialyse twice with the hydrochloric acid (5mmol/L) containing 1%NaCl, dialyse 2 times with the hydrochloric acid solution containing 5mmol/L again, each dialysis time respectively 12 hours, whole dialysis procedure all carry out under 4 DEG C of lucifuges.To take out by solution after dialysis, and cross 0.8 μm of filter membrane and remove impurity, after lyophilization and get final product.
Under 412nm, these polymer lyophilized product being measured, total sulfhydryl content is 433.2 ± 53.5 μm of ol/g, and free content is: 334.3 ± 36.1 μm of ol/g, and disulfide bond content is: 19.7 ± 6.7 μm of ol/g.
(2) preparation method of CS-NAC finishing docetaxel NLC
Prescription: docetaxel 3mg, CS-NAC25mg, Glyceryl Behenate 95mg, medium chain triglyceride 100mg, PLURONICS F87 70mg, phosphatidase 2 5mg.
Preparation technology: in 80 DEG C, Glyceryl Behenate, phospholipid, medium chain triglyceride and docetaxel are added heat fusing, is then added dropwise over the PLURONICS F87 aqueous solution that the identical temperature of 10mL is fully dissolved, and 80 DEG C are sufficiently stirred for 10min, obtain colostrum.Being placed in high pressure homogenizer by colostrum 1000bar pressure homogenizing 10 times, then in ice bath, namely cooling curing obtains docetaxel NLC；CS-NAC is substantially soluble in 10mL deionized water；CS-NAC aqueous solution is added dropwise in docetaxel NLC, is stirred at room temperature and hatches after 30min and get final product.The nano structured lipid carrier mean diameter of gained is 69.4nm, current potential 23.7mV, envelop rate 91.7%, and drug loading is 1.4%, and stability is 12 days.

Claims (10)

1. a Chitosan-Thiolated Polymers surface finish nano lipid carrier, it is characterized in that, comprise pharmacological active substance, matrix material, emulsifying agent, Chitosan-Thiolated Polymers, water, in 100mL nano-lipid carrier, the quality concentration expressed in percentage by volume (w/v) of each composition is: pharmacological active substance 0.001%～15%, matrix material 0.1%～30%, emulsifying agent 0.01%～30%, Chitosan-Thiolated Polymers 0.01%～15%, water surplus.
2. Chitosan-Thiolated Polymers surface finish nano lipid carrier as claimed in claim 1, it is characterized in that, in 100mL nano-lipid carrier, the percent mass volumetric concentration (w/v) of each composition is: pharmacological active substance 0.01%～3%, matrix material 0.1%～8%, emulsifying agent 0.01%～5%, Chitosan-Thiolated Polymers 0.01%～3%, water surplus.
3. Chitosan-Thiolated Polymers surface finish nano lipid carrier as claimed in claim 1 or 2, it is characterized in that, described matrix material is made up of Solid lipid and liquid fatty substance, wherein Solid lipid is selected from glyceryl monostearate, glycerol distearate, glyceryl monolaurate, acetylation monoglyceride, Fructus Persicae resin, 18 alcohol, Glyceryl Behenate, cetyl palmitate, glyceryl palmitostearate, trilaurin, myristin, tripalmitin, glyceryl tristearate, stearylamine, stearic acid, stearyl alcohol, Palmic acid, one or more in lauric acid；One or more in medium chain triglyceride, isopropyl myristate, caprylic/capric glyceride, glyceryl triacetate, ethyl sebacate, adipic acid diisopropyl ester, Dermol DIPS, lauric acid hexyl ester, 2-octyldodecanol, isopropyl palmitate fat, oleic acid, linoleic acid, vitamin E, liquid paraffin, soybean oil, Semen Maydis oil, Oleum Helianthi, olive oil, Oleum Arachidis hypogaeae semen of liquid fatty substance.
4. right wants the Chitosan-Thiolated Polymers surface finish nano lipid carrier as described in 3, it is characterized in that, one or more in glyceryl monostearate, glycerol distearate, Glyceryl Behenate, cetyl palmitate, glyceryl palmitostearate, trilaurin, myristin, tripalmitin, glyceryl tristearate, stearylamine, stearic acid, stearyl alcohol, Palmic acid, lauric acid of Solid lipid；One or more in medium chain triglyceride, isopropyl myristate, caprylic/capric glyceride, lauric acid hexyl ester, 2-octyldodecanol, isopropyl palmitate fat, oleic acid, linoleic acid, vitamin E, liquid paraffin, soybean oil, Semen Maydis oil, Oleum Helianthi, olive oil, Oleum Arachidis hypogaeae semen of liquid fatty substance；Preferred Solid lipid and liquid fatty substance compound mode be: Glyceryl Behenate-medium chain triglyceride;Glyceryl Behenate-caprylic/capric glyceride;Myristin, glyceryl monostearate-medium chain triglyceride;Glyceryl palmitostearate, Glyceryl Behenate-medium chain triglyceride and glycerol distearate-caprylic/capric glyceride.
5. the Chitosan-Thiolated Polymers surface finish nano lipid carrier as described in claim 3 or 4, it is characterised in that the mass ratio of Solid lipid and liquid fatty substance is 1:10～10:1, it is preferred to 2:5～2:1.
6. Chitosan-Thiolated Polymers surface finish nano lipid carrier as claimed in claim 1 or 2, it is characterized in that, described emulsifying agent is sorbester p18, ten polyglycereol monolaurates, PEG-20 hexadecanol ether, PEG-2 hexadecanol ether, stearoylketene dilactic acid sodium and glyceryl stearate Fructus Citri Limoniae ester, Polyethylene Glycol-15-hydroxy stearic acid ester, polyoxyethylene castor oil, Gelucire 44/14, phospholipid, vitamin E, TPGS, OP emulsifying agent, Gelucire 44/14, tween, poloxamer, one or more in polyvinyl alcohol.
7. Chitosan-Thiolated Polymers surface finish nano lipid carrier as claimed in claim 1 or 2, it is characterized in that, described pharmacological active substance includes curcumin, flurbiprofen, ciclosporin, 5-fluorouracil, amphotericin B, bilobalide, silymarin, ibuprofen, dexamethasone acetate, carvedilol, vinpocetine, itraconazole, nimodipine, nitrendipine, Sorafenib, hydroxy camptothecin, paclitaxel, amycin, etoposide, docetaxel, rubescensine A, triamcinolone acetonide acetate, indomethacin, coenzyme Q10.
8. the Chitosan-Thiolated Polymers surface finish nano lipid carrier as described in claim 1-7 any one, it is characterised in that described Chitosan-Thiolated Polymers is prepared via a method which:
(1) sulfydryl donor, EDC HCl and HOBT are dissolved in inert organic solvents, within room temperature continuous stirring 3-6 hour, obtain activated thiol groups donor；
(2) being dissolved in by CS in 5～20% hydrochloric acid solutions, prepared concentration is 0.8～1.25%(w/v) polymer solution；
(3) joining in the CS solution described in step (2) by the activated thiol groups donor described in step (1), after regulating pH value with NaOH, under room temperature, lucifuge is reacted 3-6 hour；
(4) reactant liquor hydrochloric acid solution containing 1～5mmol/L is dialysed 1 time, dialyse twice with the hydrochloric acid containing 0.5～1.5%NaCl, dialyse 2 times with the hydrochloric acid solution containing 1～5mmol/L again, each dialysis time respectively 12 hours ］ solution after dialysis is taken out, cross 0.8 μm of filter membrane and remove impurity, lyophilization；
Wherein, described sulfydryl donor is the one in N-acetyl-L-cysteine, cysteine, TGA, 4-mercaptobutyl amidine.
9. the surface modification method of a Chitosan-Thiolated Polymers surface finish nano lipid carrier, it is characterized in that, Chitosan-Thiolated Polymers is dissolved in distilled water, prepare into the polymer solution that mass concentration is 0.05%～5%, again polymer solution is mixed with volume ratio 0.1:1 ~ 3:1 with medicine carrying NLC, be stirred at room temperature and hatch 0.5～3h and get final product.
10. the surface modification method of a kind of Chitosan-Thiolated Polymers surface finish nano lipid carrier as claimed in claim 9, it is characterised in that described medicine carrying NLC adopts melted emulsion process, high pressure homogenization method, ultrasonic dispersion or solvent evaporation method to be prepared from.
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CN111848833A (en) * 2019-04-30 2020-10-30 苏州大学 Application of cationic polymer modified by fluorine-containing compound in preparation of eye medicine
CN111848834A (en) * 2019-04-30 2020-10-30 苏州大学 Application of cationic polymer modified by fluorine-containing compound in preparing transmucosal drug delivery of drug
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CN111920782A (en) * 2019-05-13 2020-11-13 中国医学科学院药物研究所 Composite lipid nanocapsule composition and preparation method and application thereof
CN113893355A (en) * 2021-11-03 2022-01-07 辽宁大学 Metal organic framework modified by sulfhydryl chitosan surface as oral drug carrier, preparation method and application thereof
CN114504565A (en) * 2022-03-15 2022-05-17 扬州大学 Intelligent chitosan arsenic-loaded nanoparticle with tumor microenvironment responsiveness and preparation method thereof
CN115869286A (en) * 2022-11-10 2023-03-31 海南卓泰制药有限公司 Amsacrine-containing encapsulating composition and preparation method thereof
CN115869286B (en) * 2022-11-10 2023-08-18 海南卓泰制药有限公司 Encapsulation composition containing amsacrine and preparation method thereof
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