CN100450549C - Solubilization carrier for drug, its preparation method and application - Google Patents
Solubilization carrier for drug, its preparation method and application Download PDFInfo
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- CN100450549C CN100450549C CNB200610037810XA CN200610037810A CN100450549C CN 100450549 C CN100450549 C CN 100450549C CN B200610037810X A CNB200610037810X A CN B200610037810XA CN 200610037810 A CN200610037810 A CN 200610037810A CN 100450549 C CN100450549 C CN 100450549C
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Abstract
The present invention discloses a solubilization carrier for medicines, and a preparation method and the application thereof. The carrier is prepared by separately inducting hydrophilic carboxymethyl or hydroxyethyl and hydrophobilic alkyl or alkyonyl on the 6th position and the 2th position of a chitosan framework to produce a chitosan derivative with amphipathicity for being combined into to nanomicelle naturally in water. The carrier has low critical gathering concentration, high medicine loading capacity, little toxicity, high medicine encapsulation ratio and stable nanomicelle. The solubilization carrier has the simple preparation method and mature technology, and is suitable for large-scale series production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relating to a kind of is the medicament solubilization carrier of raw material with the chitosan, the invention still further relates to the preparation method and the application thereof of this carrier.
Background technology
Nanotechnology and Biodegradable material all are hot research fields of current development drug delivery system.Both advantages are merged in polymer nano micelle research, and are promptly biodegradable, can form the medicament nano carrier again.Polymer nano micelle has following feature:
1, hydrophilic and pliability: polymer can spontaneous formation micelle in water, its hydrophobic part twines formation " kernel " mutually, outside hydrophilic parts then is looped around, form flexible hydrophilic " shell ", hydrophobic kernel provides a stabile microenvironment as the carrier or the bank of medicine for hydrophobic drug, hydrophilic shell nano-micelle can stably be present in the aqueous solution and body fluid in.
2, stability: polymer has lower critical aggregate concentration, and (Critical micelle concentrations is CMC) with higher glass transition temperature (T
g), make polymer have the thermodynamic stability and the dynamic stability of height, it is destroyed that thereby polymer micelle is difficult for below CMC, promptly has very high anti-dilution capacity, this diluting effect that is yet indicating blood can not impact the stability of polymer micelle, polymer micelle can circulate in blood with complete micellar structure, reaches the purpose of long circulation and targeting.
3, biocompatible polymer: can be degraded to monomer by hydrolysis or enzymolysis approach in vivo and excrete, can not produce depot action in vivo with biocompatibility.
4, slow releasing pharmaceutical characteristic: medicine generally discharges with passive diffusion way, because powerful cohesiveness between the rigid structure of copolymer nano micelle hydrophobic cores and lyophobic dust discharges slowly its rate of releasing drug.
5. targeting: polymer nano micelle has passive target, this mainly be because the molecular weight of (1) block copolymer micelle generally greater than 10
6So, can be by renal excretion; The particle size range of (2) 10～100nm and hydrophilic and flexible shell also descend its chance of being engulfed system (RES) identification and picked-up by RE greatly; (3) because the cell of normal structure is close-connected, so in the block copolymer micelle of macromolecule can't go into; (4) utilize distinctive high-permeability of tumor and the high property held back (enhanced permeability and retention effect, EPR effect), the capillary wall that nano level block copolymer micelle can penetrate tumor locus enters tumor tissues, again because the lymphsystem of tumor tissues is grown imperfection, can not micelle be discharged by lymphatic ducts, cause micelle in tumor locus savings and release, thereby reach the purpose of treatment tumor.Yoo (Yoo, H.S., J Control Release, 2001,70 (1-2), 63-70) grade has confirmed that tumor cell is higher more than 10 times than its crude drug to the intake of block copolymer micelle preparation.
Research to the biological degradation polyalcohol nano-micelle at present mainly concentrates on synthesized polymer material, mainly is amphipathic A-B block, A-B-A block copolymer or graft copolymer.A is a hydrophilic component, and B is a hydrophobic components.Owing to can supply copolymerization A, B component and biodegradable component less, when selecting, there is big difficulty, so hydrophobic components is confined to polylactone usually, (PLGA) or polyamino acid such as poly-aspartate, polyglutamic acid etc. as polylactide (PLA), poly-Acetic acid, hydroxy-, bimol. cyclic ester (PGA), poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester); Hydrophilic component then mostly is Polyethylene Glycol (PEG).Yet polyamino acid may cause immunoreation as hydrophobic section, and peptide bond is easy to by intravital enzymatic breaking, is not ideal selection to the control rate of releasing drug.Graft copolymer mainly is to introduce some hydrophobic group in hydrophilic chain such as PEG, polyacrylic acid side.Micelle can connect medicine by chemical coupling, and chemical coupling method difficulty when preparation particular functional group polymer is bigger, and safety is relatively poor.In addition, no matter the preparation of block copolymer or graft copolymer and characterize all more loaded down with trivial details, the working condition harshness.In addition, the high-molecular copolymer of synthetic also is not very good to the solubilising of hydrophobic drug, Zhang for example, Z. (Zhang, Z., Feng, S.S, Biomaterials, 2006,27 (2), synthetic poly (lactide)/VitaminE TPGS copolymer such as 262-70), the high drug load of its paclitaxel only is 5% (w/w).D.Le Garrec (Le Garrec, D., Gori, S., J Control Res, 99 (1), (D, L-lactide), the high drug load of its paclitaxel also only is 5% (w/w) 83-101) to have prepared poly (N-vinylpyrrolidone)-block-poly.
Chitosan (Chitosan) is the product of chitin (Chitin) deacetylation, is the unique polysaccharide that has positive charge of nature, has advantages such as wide material sources, cheap, stable in properties, nontoxic, excellent biological compatibility and biodegradability.Have a large amount of active aminos and hydroxyl on the chitosan molecule chain, be easy to chemical modification and improve its physico-chemical property, as acidylate, Sulfation and oxidation, grafting and crosslinked, hydroxyethylation, methylolation etc.Chemical Modifications of Chitosan is a current very active both at home and abroad field, and its derivant has been widely used in various aspects such as food, medicine, daily-use chemical industry, environmental protection, agricultural, but the applied research in drug delivery system is also less.On the chitosan skeleton, introduce hydrophilic group and hydrophobic group respectively, form amphipathic nature polyalcohol, can spontaneous formation micelle in water, can be used as pharmaceutical carrier.Reported O-ethoxy-N-cholanic acid chitosan (Park, Jae Hyung, Kwon at present abroad, Seunglee, J ControlRelease, 95 (3), 579-588), O-ethoxy-N-deoxycholic acid chitosan (Kuen Yong Lee, Won Ho Jo, Macromolecules, 1998,31,378-383), O-ethoxy-N-quaternary ammonium palmityl chitosan (Uchegbu, I.F.Sadiq, L.Arastoo, M., Int J Pharm, 2001,224 (1-2), 185-99), N-alkyl-O-dodecyl-glucose-chitosan (Ngimhuang, Jerasak, Furukawa, Polymer, 45 (3), 837-841), but all do not have to be applied as insoluble drug or microsolubility pharmaceutical carrier.Dai Zhao etc. (Dai Zhao, Chinese herbal medicine, 2003,34 (2), 120-122) reported the cetyl water-soluble low molecular weight chitosan, the paclitaxel carried medicine amount is only up to 14.6% (w/w).CN 1439655 discloses a kind of novel chitosan derivant N-chain alkyl-O-sulfonic group chitosan, and reaction condition is comparatively harsh, and used chlorosulfonic acid is individual and active strong acid, and meeting water can explode, dangerous in the production, and sulfonation process needs at 10 ℃ of N
2Under carry out, haemolysis takes place during and micelle final concentration＞0.18mg/ml, critical micelle concentration is higher, be 450mg/L, the paclitaxel carried medicine amount is 25% (w/w), but dilution is unstable, 1.5h be can only stablize when being diluted to 0.67mg/ml, 0.6mg/ml then muddy immediately (Zhang, Can are diluted to, Qineng, Ping, et al.Colloids and Surfaces B:Biointerfaces, 2004,39 (1-2), 69-75).CN 1698899 discloses a kind of directly with hydrophobic carbochain beautify chitosan, can form micelle under suitable molecular weight and suitable substitution value in aqueous medium, but lower to the medicine drug loading, as paclitaxel 6.7% (w/w) only.(Miwa, Akio Ishibe, Atsuo such as AkioMiwa; Pharm Res, 1998,15 (12); 1844-1850) with the chitin be raw material, replace 140% carboxymethyl earlier, deacetylated; replace 90% dodecyl again; too high substitution value has brought certain difficulty to technology, and reaction condition is comparatively fierce, needs at 110 ℃ of reaction 2h as deacetylation; and strand ruptures in a large number when taking off acetyl, this micelle at 5mg/ml haemolysis up to 50%.
Summary of the invention
Purpose of the present invention provides a kind of chitosan with biodegradable natural origin as raw material at above-mentioned technical problem, modifies the medicament solubilization carrier that safety is good, drug loading is high that obtains by chemical constitution.
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.
The present invention is on existing technical foundation; improve synthesis technique; under comparatively gentle condition, introduce carboxymethyl or ethoxy as hydrophilic group; introduce alkanoyl or alkyl as hydrophobic group (〉=5C); select suitable chitosan molecule amount (5000～1,000,000), control the position of substitution (hydrophilic group mainly is substituted in 6 hydroxyls; hydrophobic group mainly is substituted in 2 bit aminos) and substitution value (hydrophilic group 50～120% and hydrophobic group 20～60%), select the chitosan polymer micelle of suitable medicine carrying prepared reaction condition gentleness, low toxicity, high drug load, high stability.
Purpose of the present invention can realize by following technical measures:
A kind of medicament solubilization carrier, this carrier are to introduce hydrophilic carboxymethyl or ethoxy and hydrophobic alkyl or alkanoyl respectively 6 on chitosan skeleton and 2, make it can be from being combined into the amphipathic chitosan derivatives of having of nano-micelle in water.
Described medicament solubilization carrier; wherein hydrophilic carboxymethyl or ethoxy replace 6 hydroxyls of chitosan and 2 bit aminos; based on 6 hydroxyls; total substitution value 50～120%; and hydrophobic alkyl or alkanoyl replace 6 hydroxyls of chitosan and 2 bit aminos; based on 2 bit aminos, total substitution value 20～60%.
Described medicament solubilization carrier, wherein the carbon number of hydrophobic alkyl or acyl group is not less than 5.
Described medicament solubilization carrier, the chitosan molecule amount of wherein selecting for use 5 * 10
3～1 * 10
6, deacetylation is＞70%.
The preparation method of described medicament solubilization carrier comprises the following steps:
Chitosan is scattered in isopropyl alcohol or the methanol, adopts 6 hydroxyls and 2 bit aminos on material that hydrophilic group is provided and the chitosan skeleton to carry out substitution reaction, 30～50 ℃ of stirring reaction 3～10h under alkali condition make it mainly 6 hydroxyls replacements; Adopt the material that hydrophobic group is provided to carry out substitution reaction with 2 bit aminos on the chitosan skeleton and 6 hydroxyls again, 40～70 ℃ are reacted 4～12h under the alkali condition, make it mainly be substituted in 2 bit aminos; The substitution reaction order of hydrophilic group and hydrophobic group can be put the cart before the horse; The control deacetylating degree of chitosan is＞70%, and the total substitution value of hydrophilic group is 50～120%, and the total substitution value of hydrophobic group is 20～60% to get final product.
Described preparation method, the material that hydrophilic group wherein is provided are monoxone, oxirane; The material that hydrophobic group is provided is that the carbon atom number average is not less than 5 halogenated hydrocarbons, alkyl aldehydes, fatty acid anhydride, fatty carboxylic acid halides.
Described medicament solubilization carrier is at the preparation indissoluble or be slightly soluble in application in the solubilized formulation of medicine of water; Wherein indissoluble or the medicine that is slightly soluble in water are the arbitrary material or derivatives thereofs in taxanes, ciclosporin class, camptothecin, flavonoid, dihydropyridines, Xiao Tiller bases, vinca, anthraquinone class, podophillotoxines antineoplastic agent or indissoluble or the NSAID (non-steroidal anti-inflammatory drug) that is slightly soluble in water; Be insoluble in the preferred taxanes antineoplastic agent of medicine of water.
The using method of this medicament solubilization carrier is to be that (preferred 5～20: 1000) dissolving obtains the amphiphilic chitosan derivative nano-micelle for 3～50: 1000 ratio by weight with described amphiphilic chitosan derivative and water; 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 chitosan derivative nano-micelle mixes, through supersound process, the solution molecular cut off is the dialysis of 12000～14000 bag filter, and it is that the polymer micelle of 10～1000nm gets final product that lyophilizing makes particle diameter.
Concrete scheme is as follows:
Introduce carboxymethyl or ethoxy is a hydrophilic group at 6 hydroxyls of chitosan and 2 bit aminos, wherein hydrophilic group replaces based on 6 hydroxyls; At 2 bit aminos with 6 hydroxyls are introduced alkanoyl or alkyl is hydrophobic group (carbon number is not less than 5), wherein hydrophobic group replaces based on 2 bit aminos.Chitosan is introduced hydrophilic group and hydrophobic group; it is become have amphipathic polymer molecule; in aqueous medium, can be assembled into micelle; hydrophobic relatively alkanoyl or alkyl are gathered into kernel; the chitosan that hydrophilic group is modified forms hydrophilic shell, has stable micelle, effectively hides the seizure of organism reticuloendothelial system and the effect of protein adsorption.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.This pharmaceutical carrier can be used in the blood vessel or intramuscular injection, oral, tract and external.This polymer 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.
The present invention is raw material with the chitosan, introduces carboxymethyl/hydrophobic alkyl, carboxymethyl/hydrophobic alkanoyl, ethoxy/hydrophobic alkyl respectively at chitosan, and ethoxy/hydrophobic alkanoyl makes amphiphilic chitosan derivative.Carboxymethyl, ethoxy are respectively monoxone, oxirane and 6 hydroxyls and the reaction of 2 bit aminos, mainly replace at 6 hydroxyls; Hydrophobic alkyl or hydrophobic alkanoyl are chitosan 2 bit aminos and 6 hydroxyls and halogenated hydrocarbons, alkyl aldehydes, fatty acid anhydride, fatty carboxylic acid halides (the C number all 〉=5) reaction, mainly are substituted in 2 bit aminos.The substitution reaction order of hydrophilic group and hydrophobic group can be put the cart before the horse.Elementary analysis, constant-current titration reach
1It is＞70% that H-NMR records its deacetylation; The total substitution value of carboxymethyl or ethoxy is 50～120%; The total substitution value of alkyl or alkanoyl is 20～60%.
Synthetic and the micelle preparation method of chitosan derivatives is described in detail as follows:
One, the preparation of 6-O-carboxymethyl-2-N-alkyl chitosan
1, connects hydrophilic group earlier and connect hydrophobic chain again
1.16-O-Preparation of Carboxymethylchitosan
Chitosan is suspended in the isopropyl alcohol, adds NaOH, and 30～50 ℃ are stirred 1～12h, add monoxone, 30～50 ℃ of reaction 3～10h, supernatant inclines, add suitable quantity of water, transfer pH6～8 with NaOH, add methanol or acetone precipitation, filter, filter cake concentration is 80～90% methanol or washing with alcohol, the sample vacuum drying promptly makes the 6-O-carboxymethyl chitosan, is faint yellow or white powder.
Graphical Synthetic Routes is as follows:
1.26-O-the preparation of carboxymethyl-2-N-alkyl chitosan
1.2.1 halogenated hydrocarbons
The 6-O-carboxymethyl chitosan is dispersed in the isopropyl alcohol, adds NaOH, and adding halogenated hydrocarbons is down stirred in 30～40 ℃ of alkalization, and 40～70 ℃ of reaction 4～12h transfer pH6～8, add methanol or acetone precipitation, filter the washing of filter cake ether, sample vacuum drying.
Graphical Synthetic Routes is as follows:
1.2.2 alkyl aldehydes
Get 6-O-carboxymethyl chitosan 1g, in sub-methanol of suspendible or the ethanol, add alkyl aldehydes, behind the reaction 1h, add NaBH
4Aqueous solution continue to stir 12h, and NaOH liquid is transferred pH7, and methanol or acetone precipitation filter, and filter cake concentration is that 80～90% methanol, acetone and normal hexane wash successively, and vacuum drying promptly gets 6-O-carboxymethyl-2-N-alkyl chitosan.
Graphical Synthetic Routes is as follows:
2, connect hydrophobic chain earlier and connect hydrophilic group again
2.12-N-the preparation of alkyl chitosan
Method is replaced the 6-O-carboxymethyl chitosan with chitosan and is got final product with 1.2 under " item one ".
2.26-O-the preparation of carboxymethyl-2-N-alkyl chitosan
Method is replaced chitosan with the 2-N-alkyl chitosan and is got final product with 1.1 under " item one ".
Two, the preparation method of 6-O-carboxymethyl-2-N-alkanoyl chitosan
1, connects hydrophilic group earlier and connect hydrophobic chain again
1.16-O-Preparation of Carboxymethylchitosan method:
Method is with 1.1 under " item one ".
1.26-O-the preparation of carboxymethyl-2-N-alkanoyl:
1.2.1 react with fatty acid anhydride
Fatty acid obtains anhydride by intermolecular dehydration.The 6-O-carboxymethyl chitosan is dispersed in the methanol; stir and drip fatty acid anhydride acetone soln (containing a small amount of pyridine) down; 25～70 ℃ of insulation reaction 5～15h; add acetone precipitation; filter; filter cake concentration is 80～90% methanol wash, and vacuum drying promptly gets 6-O-carboxymethyl 2-N-alkanoyl chitosan.
Graphical Synthetic Routes is as follows:
2RCOOH→(RCO)
2O
1.2.2 react with fatty carboxylic acid halides:
A kind of reaction in fatty acid and thionyl chloride, Phosphorous chloride., phosphorus pentachloride, phosphorus tribromide, the phosphorus pentabromide makes fatty carboxylic acid halides.The 6-O-carboxymethyl chitosan is scattered in the dimethyl sulfoxine (contains a small amount of pyridine), stir and drip fatty carboxylic acid halides down, 40～70 ℃ of reaction 5～12h; add acetone precipitation, filter the filter cake washing with acetone; vacuum drying promptly gets 6-O-carboxymethyl 2-N-alkanoyl chitosan.
Graphical Synthetic Routes is as follows:
RCOOH+SOCl
2→RCOCl
2, connect hydrophobic chain earlier and connect hydrophilic group again
2.12-N-the preparation of alkanoyl chitosan:
Method replaces the 6-O-carboxymethyl chitosan to get final product with 1.2 under " item two " with chitosan.
2.26-O-the preparation of carboxymethyl 2-N-alkanoyl chitosan:
Method replaces chitosan to get final product with 1.1 under " item one " with 2-N-alkanoyl chitosan.
The preparation of three 6-O-ethoxy-2-N-alkyl chitosan
1, connects hydrophilic group earlier and connect hydrophobic chain again
1.16-O-the preparation of hydroxyethyl chitosan:
Chitosan is suspended in the isopropyl alcohol, add NaOH, 30～50 ℃ are stirred 1～12h, and ice bath adds oxirane down, and ice bath stirs 2～6h, be warming up to 30～50 ℃ and continue reaction 3～10h, the supernatant that inclines adds certain water gaging, transfers pH6～8 with NaOH, with bag filter (MWCO 12000～14000) room temperature dialysis 72h in distilled water, the dialysis solution lyophilizing promptly makes the high 6-O-hydroxyethyl chitosan that replaces.
Graphical Synthetic Routes is as follows:
1.26-O-the preparation of ethoxy-2-N-alkyl chitosan:
Method replaces the 6-O-carboxymethyl chitosan to get final product with in " one " 1.2 with the 6-O-hydroxyethyl chitosan.
2, connect hydrophobic chain earlier and connect hydrophilic group again
2.12-N-the preparation of alkyl chitosan:
Method replaces the 6-O-carboxymethyl chitosan to get final product with 1.2 under " item two " with chitosan.
2.26-O-the preparation of ethoxy-2-N-alkyl chitosan:
Method replaces chitosan to get final product with 1.1 under " item three " with the 2-N-alkyl chitosan.
The preparation of four 6-O-ethoxy-2-N-alkanoyl chitosan
1, connects hydrophilic group earlier and connect hydrophobic chain again
1.16-O-the preparation of hydroxyethyl chitosan:
Method is with 1.1 under " item three ".
1.26-O-the preparation of ethoxy-2-N-alkanoyl chitosan:
Method replaces the 6-O-carboxymethyl chitosan to get final product with 1.2 under " item two " with the 6-O-hydroxyethyl chitosan.
2, connect hydrophobic chain earlier and connect hydrophilic group again
2.12-N-the preparation of alkanoyl chitosan:
Method replaces the 6-O-carboxymethyl chitosan to get final product with 1.2 under " item two " with chitosan.
2.26-O-the preparation of ethoxy-2-N-alkanoyl chitosan:
Method replaces chitosan to get final product with 1.1 under " item three " with 2-N-alkanoyl chitosan.
Five, amphiphilic chitosan derivative micelle preparation method
In the ratio of dissolving the amphiphilic chitosan derivative of 3～20mg in every 1ml water, the amphiphilic chitosan derivative that makes is soluble in water, (frequency of supersound process and processing time all are that those of ordinary skills are known through supersound process, down together), being prepared into particle diameter is the chitosan micelle of 10～1000nm.
Six, with amphiphilic chitosan derivative as carrier, preparation contains the pharmaceutical composition of insoluble medicine
After amphiphilic chitosan derivative is water-soluble, insoluble drug such as paclitaxel are dissolved with appropriate solvent,,, make the polymer micelle that particle diameter is 10～1000nm through supersound process with the amphiphilic chitosan derivative aqueous solution.So-called appropriate solvent refers to the solvent that can dissolve this medicine that pharmaceutically uses.
Seven, adopt amphiphilic chitosan derivative as the preparing carriers pharmaceutical composition, can solubilization be arranged insoluble drug.
Can use this amphiphilic chitosan derivative to have: paclitaxel as the insoluble medicine of carrier, ciclosporin, teniposide, hydroxy camptothecin, camptothecine, vindesine, etoposide, nimodipine, amycin, Docetaxel, breviscapine, bilobalide, silymarin, daunorubicin, mitomycin, methotrexate, indomethacin, ibuprofen, naproxen, especially to paclitaxel, teniposide, hydroxy camptothecin, camptothecine, vindesine, etoposide, nimodipine, amycin, Docetaxel has solubilizing effect, but is not limited to these listed medicines.
Beneficial effect of the present invention:
One, this amphiphilic chitosan derivative micelle has better solubilization to above medicine, especially paclitaxel there is tangible solubilizing effect, when 6-O-carboxymethyl-when 2-N-octyl group chitosan derivatives concentration of aqueous solution is 0.57% (w/v), carrier is 1.7: 1 o'clock with the administration of medication ratio, and drug loading is 34.40% (w/w), and envelop rate is 89.90%, further increasing carrier compares to 1.7: 1.2 with administration of medication, drug loading further increases, and is 37.65% (w/w), and envelop rate is 80.52%.The 6-O-ethoxy-when 2-N-octyl group chitosan derivatives concentration of aqueous solution was 0.57% (w/v), carrier was 1.7: 0.8 o'clock with the administration of medication ratio, and drug loading is 26.99% (w/w), and envelop rate is 76.23%.Replace alkyl with alkanoyl, medicine carrying is similar.
Two, adjuvant of the present invention also can be used in the blood vessel or the carrier of intramuscular injection and oral organic drug, water-insoluble or insoluble drug and amphipathic medicine.As the intravenously administrable system, its hemolytic reaction meets intravenous injection pharmaceutic adjuvant standard.With 6-O-carboxymethyl-2-N-octyl group chitin carrier material is that example is examined or check its hemolytic.
1 experimental technique: get human blood 4ml, normal saline centrifugal (2500rpm, 10min) wash to supernatant colourless.Pipette the volumetric flask of the hemocyte suspension of 2ml to 100ml, normal saline is settled to 100ml, gets 2% hemocyte suspension.Prepare the blank micelle (micelles) of Tween 80 (tween80), 6-O-carboxymethyl 2-N-octyl group chitosan, the polyoxyethylene castor oil (Cremophore EL) of 10mg/ml respectively, obtain the sample solution of final concentration difference 0.2,0.4,0.6,0.8,1.0,1.5,2,4mg/ml by table 1 preparation, after shaking up, put in 37 ℃ of waters bath with thermostatic control.No. 9 pipes and No. 10 pipes are respectively 0% haemolysis and 100% haemolysis.37 ℃ hatch 3h after, the centrifugal 10min of 3000rpm gets supernatant, measures its absorption value in the 416nm ultraviolet spectrophotometer, is contrast with the blank sample.Calculate haemolysis percent by following formula.
The design of table 1 hemolytic experiment
2. experimental result
With the final concentration of sample in test tube is abscissa, is vertical coordinate with haemolysis percent, obtains the haemolysis curve, sees Fig. 1.
Amphipathic nature polyalcohol has the similar structure of low-molecular-weight surfactant, and low-molecular-weight surfactant has injury effect to the hemocyte film, so we have investigated the injury situation of chitosan amphipathic derivatives to the hemocyte film.Tween80 and Cremophore EL be the most frequently used two kinds can intravenous low-molecular-weight surfactant, we compare the chitosan amphipathic derivatives with it.From Fig. 1 we as can be seen the blank micellar hemolytic of 6-O-carboxymethyl 2-N-octyl group chitosan well below tween80, when 2mg/mL (pipe 7), the blank micelle of 6-O-carboxymethyl 2-N-octyl group chitosan is haemolysis 2.3% only, and tween80 haemolysis 47.4%, when concentration is 4mg/mL (pipe 8), tween80 haemolysis reaches 68.5%, and the blank micelle haemolysis of 6-O-carboxymethyl 2-N-octyl group chitosan only 5.1%.As seen the hemolytic of chitosan derivatives is far superior to tween80.Cremophore EL slightly is better than chitosan derivatives, there is no significant difference.But according to reported in literature, Cremophore EL has higher sensitization, and its every day, intravenous maximum tolerated dose was 75mg only, and tween80 is 500mg.The report that chitosan sensitization and other side effect are not also arranged at present.Other chitosan derivatives haemolysis situation is similar to 6-O-carboxymethyl-2-N-octyl group chitosan derivatives among the present invention.Therefore, for tween80 and Cremophor EL, chitosan derivatives be good can intravenous pharmaceutic adjuvant.
Three, (Critical micelle concentrations CMC) measures the critical micelle concentration of chitosan amphipathic derivatives.
Adopt the most sensitive fluorescent probe method.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 the emission 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
333Can obtain the apparent CMC of amphiphile, amphiphilic molecule to the concentration mapping of amphiphile, amphiphilic molecule than (the excitation spectrum medium wavelength is respectively the fluorescence intensity ratio of 338nm and 333nm).The CMC of chitosan derivatives all in 3～20mg/L scope, indicates that it has fabulous dilution stability among the embodiment 1～16.
Four, medicine carrying chitosan polymer micelle study on the stability
Generally speaking, medicine carrying is high more, and stability is poor more.The present invention is that the 6-O-carboxymethyl 2-N-octyl group chitosan micelle of 34.40% (w/w) is an example with drug loading, with commercial preparation paclitaxel injection (Taxol
) be contrast, investigate dilution and temperature to the influence of medicine carrying chitosan micelle, the results are shown in Table 2.
The dilution stability of table 2 paclitaxel chitosan micelle
As seen, the chitosan polymer micelle not only has high drug loading, also has very superior stability.
In sum; the present invention with the chitosan of biodegradable natural origin as raw material; carrying out chemical constitution modifies; introduce carboxymethyl/hydrophobic alkyl, carboxymethyl/hydrophobic acyl, ethoxy/hydrophobic alkyl; ethoxy/hydrophobic acyl; spontaneous formation nanoscale micelle in aqueous medium; have excellent biological compatibility, biodegradability and dilution stability in vivo; insoluble drug there is solubilization preferably, but can be used as the pharmaceutical carrier that toxicity is little, can not produce the intravenous administration of hemolytic reaction.
The amphipathic chitosan derivatives of the present invention's research, can be in water spontaneous formation nanoscale micelle, the solubilising and the parcel that not only can be used for insoluble medicine, control drug release, and because the nano-micelle structure that its hydrophilic shell and hydrophobic nuclear are formed, can the extension body internal recycle, reduce engulfing of reticuloendothelial cell, increase cancer target, reach the minimizing toxic and side effects, increase the purpose of curative effect.
The critical aggregate concentration of amphiphilic chitosan derivative provided by the invention is low, drug loading height, entrapment efficiency height, and nano-micelle is stable.The carrier that this adjuvant toxicity is little, can be used as the slightly solubility organic drug is used for injection, oral, tract and external with the nanoscale dispersion.Preparation method of the present invention is simple, and technical maturity is suitable for large-scale continuous production.
Description of drawings
Fig. 1: Tween 80, the blank micelle of 6-O-carboxymethyl 2-N-octyl group chitosan, polyoxyethylene castor oil haemolysis curve.
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 preparation of 6-O-carboxymethyl-2-N-octyl group chitosan (connect hydrophilic group earlier and connect hydrophobic group again)
1,6-O-Preparation of Carboxymethylchitosan
The 1g chitosan is suspended in the isopropyl alcohol, add 5g NaOH, 30 ℃ of stirring alkalization 12h, add the chloroacetic aqueous isopropanol of 6g, 35 ℃ of reaction 5h, supernatant inclines, add certain water gaging, transfer pH7, methanol extraction with the NaOH aqueous solution, filter, 90% washing with alcohol vacuum drying promptly makes the high 6-O-carboxymethyl chitosan that replaces, and is faint yellow or white powder.
2, the preparation of 6-O-carboxymethyl-2-N-octyl group chitosan
A and alkyl halide reaction
1g 6-O-carboxymethyl chitosan is dispersed in the isopropyl alcohol, adds 2g NaOH, and the positive hot chlorine of adding is down stirred in 35 ℃ of alkalization, 30 ℃ of reaction 8h transfer pH7, add acetone precipitation, filter, the washing of filter cake ether, the sample vacuum drying promptly gets 6-O-carboxymethyl-2-N-octyl group chitosan.
It is 91.5% that elementary analysis records degree of deacetylation, and degree of substitution by carboxymethyl is 90%, and the octyl group substitution value is 45%.
B and alkyl aldehydes reaction
Get 6-O-carboxymethyl chitosan 1g, be suspended in methanol or the ethanol, add the 1.02g n-octaldehyde, behind the reaction 1h, add NaBH
4Aqueous solution continue to stir 12h, and NaOH liquid is transferred pH7, and methanol extraction filters, and filter cake concentration is that 80～90% methanol, acetone and normal hexane wash successively, and vacuum drying promptly gets 6-O-carboxymethyl-2-N-octyl group chitosan.
It is 91.5% that elementary analysis records degree of deacetylation, and degree of substitution by carboxymethyl is 90%, and the octyl group substitution value is 48%.
Embodiment 2:
The preparation of 6-O-carboxymethyl-2-N-octyl group chitosan (connect hydrophobic group earlier and connect hydrophilic group again)
1, the preparation of 2-N-octyl group chitosan
Method replaces the 6-O-carboxymethyl chitosan with among the embodiment 12 with chitosan.
2, the preparation of 6-O-carboxymethyl-2-N-octyl group chitosan
Method replaces chitosan with among the embodiment 11 with 2-N-octyl group chitosan
It is 91.5% that elementary analysis records degree of deacetylation, and degree of substitution by carboxymethyl is 95%, and the octyl group substitution value is 48%.
The preparation of 6-O-carboxymethyl-2-N-decyl chitosan
With positive last of the ten Heavenly stems chlorine, n-capric aldehyde replace positive hot chlorine, n-octaldehyde among the embodiment 1,2, preparation method is with embodiment 1,2.
It is 91.5% that elementary analysis records degree of deacetylation, and degree of substitution by carboxymethyl is 98%, and the decyl substitution value is 40%.
The preparation of 6-O-carboxymethyl-2-N-dodecyl chitosan
Replace positive hot chlorine, n-octaldehyde among the embodiment 1,2 with dodecyl chloride, dodecyl aldehyde, preparation method is with embodiment 1,2.
It is 91.5% that elementary analysis records degree of deacetylation, and the succinyl group substitution value is 96%, and the dodecyl substitution value is 39%.
Embodiment 5:
The preparation of 6-O-carboxymethyl-2-N-caprylyl chitosan (connect hydrophilic group earlier and connect hydrophobic group again)
1,6-O-Preparation of Carboxymethylchitosan
Preparation method is with 1 among the embodiment 1.
2, the preparation of 6-O-carboxymethyl-2-N-caprylyl chitosan
A and anhydride reaction
3.6g caprylic acid (0.05mol) splashes into the 4ml acetic anhydride, 120 ℃ steam acetic acid, obtain the caprylic acid acid anhydride.1g is dispersed in the methanol with the 6-O-carboxymethyl chitosan, stirs to drip the caprylic acid acid anhydride down, and 40 ℃ of reaction 8h add acetone precipitation, filter, and filter cake 80% methanol wash, vacuum drying promptly gets 6-O-carboxymethyl-2-N-caprylyl chitosan.
B and carboxylic acid halides reaction
2.88g caprylic acid (0.02mol), thionyl chloride 6ml, 50 ℃ of back flow reaction 3h, excessive dimethyl sulfoxine is removed in distilling under reduced pressure, and it is stand-by to add a small amount of absolute ether.1g carboxylic 6-O-methyl chitosan is dispersed in the dimethyl sulfoxine (containing a small amount of pyridine), stirs and drip caprylyl chloride down, 60 ℃ of reaction 10h add acetone precipitation, filter, and the filter cake washing with acetone, vacuum drying promptly gets 6-O-carboxymethyl-2-N-caprylyl chitosan.
Embodiment 6
The preparation of 6-O-carboxymethyl-2-N-caprylyl chitosan (connect hydrophobic group earlier and connect hydrophilic group again)
1, the preparation of 2-N-caprylyl chitosan
Method replaces the 6-O-carboxymethyl chitosan with 2 among the embodiment 5 with chitosan.
2, the preparation of 6-O-carboxymethyl-2-N-caprylyl chitosan
Method replaces chitosan with 1 among the embodiment 1 with 2-N-caprylyl chitosan.
It is 91.5% that elementary analysis records degree of deacetylation, and degree of substitution by carboxymethyl is 100%, and the caprylyl substitution value is 47%.
Embodiment 7
The preparation of 6-O-carboxymethyl-2-N-capryl chitosan
Method is with embodiment 5,6, replaces positive caprylyl chloride, caprylic acid acid anhydride among the embodiment 5,6 respectively with positive decanoyl chloride, n-capric acid acid anhydride.
It is 91.5% that elementary analysis records degree of deacetylation, and degree of substitution by carboxymethyl is 95%, and the capryl substitution value is 42%.
Embodiment 8
The preparation of 6-O-carboxymethyl-2-N-lauroyl chitosan
Preparation method is with embodiment 5,6, replaces positive caprylyl chloride, caprylic acid acid anhydride among the embodiment 5,6 respectively with lauroyl chloride, lauric anhydride.
It is 91.5% that elementary analysis records degree of deacetylation, and degree of substitution by carboxymethyl is 96%, and N-lauroyl substitution value is 40%.
Embodiment 9
The preparation of 6-O-ethoxy-2-N-octyl group chitosan---connect hydrophilic group earlier, after connect hydrophobic group
1, the preparation of 6-O-hydroxyethyl chitosan
The 1g chitosan is suspended in the isopropyl alcohol, add 5gNaOH, 30 ℃ of stirring alkalization 12h, ice bath adds 7ml oxirane down, room temperature reaction 2h, 40 ℃ of reaction 5h add certain water gaging, transfer pH7 with the NaOH aqueous solution, with bag filter (MWCO 12000～14000) room temperature dialysis 72h in distilled water, to filter, the filtrate lyophilizing promptly makes the high 6-O-hydroxyethyl chitosan that replaces.
2, the preparation of 6-O-ethoxy-2-N-octyl group chitosan
Method replaces the 6-O-carboxymethyl chitosan with 2 among the embodiment 1 with the 6-O-hydroxyethyl chitosan.
It is 91.5% that elementary analysis records degree of deacetylation, and the ethoxy substitution value is 91%, and the substitution value that the octyl group substitution value is is 39%.
Embodiment 10
The preparation of 6-O-ethoxy-2-N-octyl group chitosan---connect hydrophobic group earlier, connect hydrophilic group again
1, the preparation of 2-N-octyl group chitosan
Method is with among the embodiment 21.
2, the preparation of 6-O-ethoxy-2-N-octyl group chitosan
Method replaces chitosan with among the embodiment 91 with 2-N-octyl group chitosan.
It is 91.5% that elementary analysis records degree of deacetylation, and the ethoxy substitution value is 87%, and the octyl group substitution value is 35%.
Embodiment 11
The preparation of 6-O-ethoxy-2-N-decyl chitosan
With positive last of the ten Heavenly stems chlorine, n-capric aldehyde replace positive hot chlorine, n-octaldehyde among the embodiment 9,10, preparation method is with embodiment 9,10.
It is 91.5% that elementary analysis records degree of deacetylation, and the ethoxy substitution value is 90%, and N-decyl substitution value is 30%.
Embodiment 12
The preparation of 6-O-ethoxy-2-N-dodecyl chitosan
Replace positive hot chlorine, n-octaldehyde among the embodiment 9,10 with Laurel chlorine, dodecyl aldehyde, preparation method is with embodiment 9,10.
It is 91.5% that elementary analysis records degree of deacetylation, and the ethoxy substitution value is 92%, and the dodecyl substitution value is 32%.
Embodiment 13
Preparation---the method one of 6-O-ethoxy-2-N-caprylyl chitosan
1, the preparation of 6-O-hydroxyethyl chitosan
Method is with 1 of embodiment 9.
2, the preparation of 6-O-ethoxy-2-N-caprylyl chitosan
Method replaces the 6-O-carboxymethyl chitosan with 2 of embodiment 5 with the 6-O-hydroxyethyl chitosan.
It is 91.5% that elementary analysis records degree of deacetylation, and the ethoxy substitution value is 95%, and the caprylyl substitution value is 35%.
Embodiment 14
Preparation---the method two of 6-O-ethoxy-2-N-caprylyl chitosan
1, the preparation of 2-N-caprylyl chitosan
Method replaces the 6-O-carboxymethyl chitosan with 2 of embodiment 5 with chitosan.
2, the preparation of 6-O-ethoxy-2-N-caprylyl chitosan
Method replaces chitosan with 1 of embodiment 9 with the caprylyl chitosan.
It is 91.5% that elementary analysis records degree of deacetylation, and the ethoxy substitution value is 92%, and the caprylyl substitution value is 40%.
Embodiment 15
The preparation of 6-O-ethoxy-2-N-capryl chitosan
Method is with embodiment 13,14, replaces caprylyl chloride, caprylic anhydride among the embodiment 13,14 respectively with decanoyl chloride, capric anhydride.
It is 91.5% that elementary analysis records degree of deacetylation, and the ethoxy substitution value is 92%, and the capryl substitution value is 32%.
Embodiment 16
The preparation of 6-O-ethoxy-2-N-lauroyl chitosan
Method is with embodiment 13,14, with lauroyl chloride, lauric anhydride, replace positive caprylyl chloride, caprylic acid acid anhydride among the embodiment 13,14 respectively.
It is 91.5% that elementary analysis records degree of deacetylation, and the ethoxy substitution value is 89%, and the lauroyl substitution value is 38%.
Embodiment 17
Micellar preparation of amphiphilic chitosan derivative and micelle particle size determination
Amphiphilic chitosan derivative 40mg is dissolved in the 7ml water in 50 ℃ of stirring 2h; then under the ice bath behind the ultrasonic 30min; with Zetasizer 3000 HS instrument (Malvern Instruments; Malvern; UK) at 633nm; 25 ℃; the He-Ne laser determination; embodiment 1～16 derivant particle diameter is at 150～300nm; as 6-O-carboxymethyl-2-N-octyl group chitosan micelle particle diameter is 175nm; 6-O-carboxymethyl-2-N-caprylyl chitosan micelle particle diameter is 167nm, and 6-O-ethoxy-2-N-octyl group chitosan micelle particle diameter is 188nm, 6-O-ethoxy-2-N-caprylyl chitosan micelle particle diameter 206nm.
Embodiment 18
1, comprises the micellar preparation of paclitaxel amphiphilic chitosan derivative
(1). dialysis:
Amphiphilic chitosan derivative 51mg is dissolved in the 9ml water and stirs 2h in 50 ℃.Paclitaxel 30mg is dissolved in the 1ml ethanol (methanol, acetonitrile).The two solution mixes then, and behind the ice-bath ultrasonic 30min, with bag filter (MWCO12000～14000) room temperature dialysis 12h in distilled water, centrifugal 3000rpm 5min is with 0.45 μ m membrane filtration, lyophilization.With Zetasizer 3000 HS instrument (Malvern Instruments, Malvern, UK) at 633nm, 25 ℃, He-Ne laser determination 6-O-carboxymethyl-2-N-octyl group chitosan micelle particle diameter is 238nm, and Zeta potential is-25mV that it is 2.968mg/mL that HPLC records solution concentration, drug loading is 34.40% (w/w), and envelop rate is 89.90%.6-O-ethoxy-2-N-octyl group chitosan micelle particle diameter is 203nm, and Zeta potential is+18mV, and it is 2.060mg/mL that HPLC records solution concentration, and drug loading is 26.67% (w/w), and envelop rate is 76.23%.
(2). solvent evaporation method:
Amphiphilic chitosan derivative 51mg is dissolved in the 9ml water in 50 ℃ and stirs 2h, and paclitaxel 30mg is dissolved in the 1mL chloroform.Under stirring at room the two solution is mixed then, continue to stir and spend the night, make the chloroform volatilization, centrifugal (3000rpm) 5min is with 0.22 μ m membrane filtration, lyophilization.It is 0.8310mg/ml that HPLC records 6-O-carboxymethyl-2-N-octyl group chitosan micelle solution concentration, and drug loading is 12.78% (w/w), and envelop rate is 24.93%; 6-O-ethoxy-2-N-octyl group chitosan micelle, solution concentration is 0.67mg/ml, and drug loading is 10.57% (w/w), and envelop rate is 20.10%.
2, the mensuration of content of taxol in the amphiphilic chitosan derivative micelle
(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.
Claims (8)
1, a kind of medicament solubilization carrier is characterized in that this carrier is to introduce hydrophilic ethoxy and hydrophobic alkyl or alkanoyl respectively 6 on chitosan skeleton and 2, makes it can be from being combined into the amphipathic chitosan derivatives of having of nano-micelle in water;
Wherein: hydrophilic ethoxy replaces 6 hydroxyls of chitosan and 2 bit aminos; based on 6 hydroxyls, total substitution value 50～120%, and hydrophobic alkyl or alkanoyl replacement 6 hydroxyls of chitosan and 2 bit aminos; based on 2 bit aminos, total substitution value 20～60%.
2, medicament solubilization carrier according to claim 1 is characterized in that the carbon number of hydrophobic alkyl or acyl group is not less than 5.
3, medicament solubilization carrier according to claim 1 is characterized in that selected chitosan molecule amount 5 * 10
3～1 * 10
6, deacetylation is＞70%.
4, the preparation method of the described medicament solubilization carrier of claim 1 is characterized in that comprising the following steps:
Chitosan is scattered in isopropyl alcohol or the methanol, adopts 6 hydroxyls and 2 bit aminos on material that hydrophilic group is provided and the chitosan skeleton to carry out substitution reaction, 30～50 ℃ of stirring reaction 3～10h under alkali condition make it mainly 6 hydroxyls replacements; Adopt the material that hydrophobic group is provided to carry out substitution reaction with 2 bit aminos on the chitosan skeleton and 6 hydroxyls again, 40～70 ℃ are reacted 4～12h under the alkali condition, make it mainly be substituted in 2 bit aminos; Perhaps the substitution reaction of hydrophilic group and hydrophobic group is put the cart before the horse in proper order; The control deacetylating degree of chitosan is＞70%, and the total substitution value of hydrophilic group is 50～120%, and the total substitution value of hydrophobic group is 20～60%;
Wherein: the material that hydrophilic group is provided is monoxone, oxirane; The material that hydrophobic group is provided is that the carbon atom number average is not less than 5 halogenated hydrocarbons, alkyl aldehydes, fatty acid anhydride, fatty carboxylic acid halides.
5, the described medicament solubilization carrier of claim 1 is at the preparation indissoluble or be slightly soluble in application in the solubilized formulation of medicine of water.
6, application according to claim 5, the medicine that it is characterized in that described indissoluble or be slightly soluble in water are the arbitrary material or derivatives thereofs in taxanes, ciclosporin class, camptothecin, flavonoid, dihydropyridines, XIAONIE bases, vinca, anthraquinone class, podophillotoxines antineoplastic agent or indissoluble or the NSAID (non-steroidal anti-inflammatory drug) that is slightly soluble in water.
7, application according to claim 6 is characterized in that the described medicine that is insoluble in water is the taxanes antineoplastic agent.
8, application according to claim 5, the using method that it is characterized in that this medicament solubilization carrier are to be 3～50: 1000 ratio dissolving by weight with described amphiphilic chitosan derivative and water, obtain the amphiphilic chitosan derivative nano-micelle; After treating the indissoluble of effective dose or being slightly soluble in the dissolution with solvents of organic drug with pharmaceutically permission of water, after described amphiphilic chitosan derivative nano-micelle mixes, through supersound process, the solution molecular cut off is 12000～14000 bag filter dialysis, and lyophilizing makes the polymer micelle that particle diameter is 10～1000nm.
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| CN102585036A (en) * | 2012-03-05 | 2012-07-18 | 中国药科大学 | Amphiphilic chitosan derivative, its preparation method and its application in medicinal preparation |
| CN107163165B (en) * | 2017-06-14 | 2020-01-31 | 山东师范大学 | O-carboxymethyl-N, N-double-chain long alkylated chitosan oligosaccharide and preparation method and application thereof |
| CN107383357B (en) * | 2017-08-22 | 2019-08-20 | 山东省医学科学院药物研究所 | A kind of preparation method and application of racemosus shape block polyether |
| CN109221178B (en) * | 2018-10-08 | 2021-01-26 | 江苏省农业科学院 | Dissolving method and application of zinc thiazole raw medicine |
| CN109925515A (en) * | 2019-03-05 | 2019-06-25 | 上海珑欣生物医学科技有限公司 | For treating microRNA nano-complex and its preparation and the application of colon cancer |
| CN110251687B (en) * | 2019-07-10 | 2023-09-22 | 大连医科大学 | Charge reversal oral chitosan nano-drug preparation and preparation method thereof |
| CN116396414A (en) * | 2023-04-10 | 2023-07-07 | 华侨大学 | Preparation method and solubilization method of chitosan-based pesticide solubilizing agent |
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