CN102813937A - Hydrophobic drug containing polyelectrolyte complex, its preparation method and application thereof - Google Patents
Hydrophobic drug containing polyelectrolyte complex, its preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a hydrophobic drug containing polyelectrolyte complex, its preparation method and an application thereof. The polyelectrolyte complex is formed by static compounding of polycation and electronegative nanoparticles formed by polyanion or its derivative entrapment or linkage of a hydrophobic drug. The particle size of the polyelectrolyte complex is 20-500 nm. The positive/negative charge ratio of the polycation to the polyanion is between 1.2 and 6.0. According to the drug-containing complex formed by static compounding, an external positive charge shell can protect stability of the complex in a gastric acidic environment, and in an intestinal alkaline environment, the complex disintegrates and releases the internal anion drug loaded nanoparticles so as to promote absorption of the drug through intestinal mucosa. In addition, the polycation shell has mucosa adhesiveness and retention time of the drug in gastrointestinal mucosa can be prolonged. Therefore, the complex is suitable for oral administration of hydrophobic drugs. Bioavailability of the hydrophobic drugs is increased, and pains caused by injection delivery can be minimized for patients.
Description
Technical field
The present invention relates to a kind of compound polyelectrolyte and method for preparing and application that contains hydrophobic drug, belong to the application technology of macromolecular material in pharmaceutical preparation.
Background technology
Oral administration can make things convenient for the patient, reduces the administration cost and promotes the enforcement of phase therapeutic scheme more how long.Medicine must be dissolved in earlier in the pipe intestinal digesting liquid before absorbing, and could get into blood circulation with mechanism of absorption such as passive diffusion or active transpories through gastrointestinal mucosal then.The stripping of insoluble drug in Digestive system is generally the rate-limiting step of its absorption.Therefore; The dissolubility and the dissolution rate that improve insoluble drug often become the first step that improves its oral administration bioavailability; Traditional pharmaceutics solubilising means are conceived to this more; In pharmaceutical manufacturing practice still by extensive employing, as selecting suitable drug crystal formation, superfine grinding, salify, interpolation solubilizing agent, cosolvent etc.; In addition, through changing the molecular structure of insoluble drug, selecting for use suitable carriers and preparation technique to improve its physicochemical property, improve itself and gastrointestinal tract mucous affinity and permeability etc., also is the effective way of its oral absorption of promotion.
But up to the present, the oral absorption problem of insoluble drug does not also fundamentally solve.The main barrier that the drug oral digestive tract absorbs mainly comes from the cell membrane of gastrointestinal epithelial cells.< nanoparticle of 500nm can realize that the complete gastrointestinal epithelial cells of nanoparticle absorbs through the mode of simulation Chylomicron to diameter.Through hydrophobic drug being bonded on the hydrophilic polymer or, can strengthening the water solublity of medicine, realize the efficient absorption of insoluble drug, but its preparation is mainly used in intravenous injection by means of the drug encapsulation technology of nanoparticulate carriers.Also have part polyester (PLGA) or the amphipathic copolymer of PEG-polyester to be used for the oral research of dewatering medicament, the nanoparticulate carriers mucoadhesive property that this base polymer forms is poor, and bioavailability is very low always aspect oral; Generally need to add the P-gp inhibitor and use together, these inhibitor can influence the human immune system, make human body produce drug resistance (D.R.Kalaria; G.Sharma, V.Beniwal, M.N.V.Ravi Kumar; Pharmaceutical Research, 2009,26:492-501).
The pH sensitive nanoparticles that utilizes chitosan and polyglutamic acid to be compounded to form through static is used for the oral research of hydrophilic medicaments such as insulin by broad research (Y.H.Lin, K.Sonaje, K.M.Lin; J.H.Juang, F.L.Mi, H.W.Yang; H.W.Sung, Journal of Controlled Release, 2008; 132:141-149); Two kinds of polyelectrolyte form nanoparticle pharmaceutical pack are rolled in nanoparticle inside under pH3.0-6.0, thereby the nanoparticle disintegrate discharges medicine under the pH7.4, but the release that utilizes the polyelectrolyte nanoparticle to be used for dewatering medicament rarely has report so far.And The present invention be directed to these insufficient local propose; The compound polyelectrolyte nanoparticle that contains hydrophobic drug; Not only can increase the water solublity of dewatering medicament; And can prolong drug in the time of staying of absorption site, improved the permeability of hydrophobic drug to gastrointestinal barrier, have novelty, creativeness and practicality.
Summary of the invention
The object of the present invention is to provide a kind of compound polyelectrolyte that contains hydrophobic drug, this compound polyelectrolyte that contains hydrophobic drug is applicable to the exploitation of multiple drug oral preparation, has application promise in clinical practice.
The present invention realizes through following technical scheme,
The described compound polyelectrolyte that contains hydrophobic drug; Be that polyanion or derivatives thereof bag carries or electronegative nanoparticle of keyed jointing hydrophobic drug formation and the compound polyelectrolyte that polycation static is compounded to form; Particle diameter is 20 ~ 500nm, and the positive and negative charge of polycation and polyanion is than between 1.2 ~ 6.0.
The polyanion nanoparticle that described electronegative nanoparticle is the keyed jointing medicine; To be the dewatering medicament that has hydroxyl, carboxyl, amino, a carbonyl functional group be keyed to number-average molecular weight through ester bond, amido link, hydrazone key to the polyanion of keyed jointing medicine is the product on 1000 ~ 100000 the polyanion; Anionic group on the described polyanion strand is carboxyl and salt thereof, and the mol ratio of drug molecule and anionic group is 0.1 ~ 0.6:1.
Described electronegative nanoparticle is to be that 1000 ~ 100000 amphipathic anion is carried the nanoparticle that dewatering medicament forms through the physical action bag by number-average molecular weight, and the drug loading amount in the nanoparticle is 0.1 ~ 14%.
Polycation is selected from chitosan and derivant thereof; Polylysine; Cationic starch derivative, PEI, polyamide, gelatin, cationic protein or polypeptide, cationic polyester, cation poly phosphate, polyvinyl pyrroles salt, N, the homopolymer and the copolymer of N-substituted (methyl) acrylic ester.
Polyanion is selected from polyglutamic acid, hyaluronic acid, sodium alginate, carboxy-modified cellulose and sodium salt thereof.
Described amphipathic anion is selected from the polyglutamic acid of glutamic acid/glutamic acid Bian ester copolymer, hydrophobically modified, the hyaluronic acid of hydrophobically modified, the sodium alginate of hydrophobically modified.
Dewatering medicament is selected from paclitaxel, Docetaxel, amycin, dexamethasone, hydroxy camptothecin, cisplatin, indomethacin, curcumin, arteannuin.
The described compound polyelectrolyte that contains hydrophobic drug can prepare through following method:
1) during the hydrophobic drug of formula ratio and polyanion are dissolved in the organic solvent; Pass through dicyclohexylcarbodiimide; The 4-dimethylamino naphthyridine is a catalyst, and room temperature reaction obtains the polyanion of ester bond keyed jointing medicine, or through 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride; N-hydroxy-succinamide catalysis room temperature reaction obtains the polyanion of amido link keyed jointing medicine; Or the reaction of polyanion side group and hydrazine hydrate holds amination, again with the medicine direct reaction that contains carbonyl, obtains the polyanion of hydrazone key keyed jointing medicine;
2) the gained product obtains the polyanion nanoparticle aqueous dispersions of keyed jointing medicine after solvent dialysis, deionized water dialysis, and lyophilizing obtains nano-granule freeze-dried powder;
3) 2) in the aqueous dispersions that forms in the water of polyanion nanoparticle aqueous dispersions or the nano-granule freeze-dried powder redispersion of the bonding medicine that obtains be added drop-wise in the aqueous solution that contains the formula ratio polycation; It is compound to carry out static; Make the aqueous dispersions of the compound polyelectrolyte nanoparticle that contains hydrophobic drug; Lyophilizing obtains lyophilized powder.Used solvent can be selected from dimethyl sulfoxide, dimethyl formamide, oxolane equal solvent.
Except that above-mentioned chemical bonding method, the described compound polyelectrolyte that contains hydrophobic drug also can be through the preparation of physical package package method, and method is following:
1) is dissolved into wiring solution-forming in the dimethyl sulfoxide to medicine and amphipathic anion by formula ratio, is put in the bag filter then and gives solvent, obtain wrapping the polyanion nanoparticle aqueous dispersions of medicine carrying thing through deionized water;
2) stir down, be added drop-wise to the polyanion nanoparticle aqueous dispersions that wraps the medicine carrying thing in the aqueous solution that contains the formula ratio polycation, it is compound to carry out static, contains the aqueous dispersions of the compound polyelectrolyte nanoparticle of hydrophobic drug, and lyophilizing obtains lyophilized powder.
The described compound polyelectrolyte that contains hydrophobic drug can be used for the oral formulations of hydrophobic drug; The described compound polyelectrolyte that contains hydrophobic drug is distributed to the aqueous humour that forms in the aqueous medium with the nanoparticle state; Or lyophilized powder is loaded in the capsule; Or be prepared into tablet, as oral drug preparation.Described aqueous humour comprises normal saline, deionized water, glucose injection and other water-bearing media.
Advantage of the present invention is the complex of the drug that is compounded to form through static; Outside positive charge shell can protect complex under the stomach acidity environment stability, and complex is solved a problem and is discharged inner anion drug-carrying nanometer particle under the alkaline environment of intestinal, the promotion medicine is through the absorption of intestinal mucosa; And the polycation shell has mucoadhesive property; Can prolong drug in the time of staying of gastrointestinal mucosa, therefore, be applicable to the dewatering medicament oral administration; Increase the bioavailability of hydrophobic drug, reduce injection and give the misery that to bring to the patient.
Description of drawings
Fig. 1 is the infrared spectrum of L-polyglutamic acid (L-PGA) and L-PGA-DOX (I-12), the infrared disappearance and 2800 in 1700cm place among the L-PGA, and the appearance at 2900cm methyl peak proves keyed jointing amycin (DOX) success.
Chitosan under Fig. 2 pH1.2 (CS) and L-PGA-DOX positive and negative charge are than being the tem analysis of 2:1 nanoparticle (II-1).
Chitosan under Fig. 3 pH5.0 (CS) and L-PGA-DOX positive and negative charge are than being the tem analysis of 2:1 nanoparticle (II-1).
Chitosan under Fig. 4 pH7.4 (CS) and L-PGA-DOX positive and negative charge prove that than being the tem analysis of 2:1 nanoparticle (II-1) form of polyelectrolyte prodrug is influenced by pH value.
Fig. 5 chitosan (CS) and the particle size distribution figure that wraps glutamic acid/glutamic acid Bian ester copolymer composite nano-granule (II-16) aqueous dispersions that carries paclitaxel prove that its particle diameter is approximately 360nm.
Fig. 6 H460 cell was to endocytosis ability (concentration 0.5ug/mL) incubation time of free amycin 2 hours.
Fig. 7 H460 cell was to endocytosis ability (concentration 0.5ug/mL) incubation time of I-12 nanoparticle 2 hours.It is thus clear that H460 is higher than free amycin far away to the endocytosis ability of I-12 nanoparticle.
Fig. 8 DOX and I-12 nanoparticle are to the cytotoxicity (incubation time 48 hours) of H460 cell.I-12 has fine cytotoxicity to H460.
Fig. 9 is that paclitaxel (PTX) and bag carry the cytotoxicity (incubation time 48 hour) of glutamic acid/glutamic acid Bian ester copolymer (I-27) of PTX to the HepG-2 cell.I-27 has fine cytotoxicity to HepG-2.
The oral back of Figure 10 amycin tissue distribution figure
The oral back of Figure 11 II-1 tissue distribution.It is thus clear that II-1 is higher than DOX far away in the abundance of intestinal, and the medicament contg of II-1 group in tumor also is higher than the DOX group.
After Figure 12 is the different preparation lumbar injections of amycin and oral (filling stomach) administration, the mouse tumor growth curve.The negative matched group of normal saline (Saline); With the positive matched group of DOX clinical preparation lumbar injection; L-glutamic acid (L-PGA) (number-average molecular weight 6500Da) is blank (PGA/CS) with the chitosan composite nano-granule; PEC is oral not to have any antitumous effect, and tumor growth is obvious; The administration group can obviously suppress growth of tumor.In three groups of treatment groups, the direct oral group of antitumous effect of DOX solution is the poorest, explains that the direct oral administration biaavailability of DOX solution is very low, and the DOX lumbar injection can to a certain degree suppress the growth of tumor.Oral group of II-1 complex nanometer granule and DOX lumbar injection group compare, and the II-1 complex nanometer granule can significantly suppress the growth of gross tumor volume, presents better anti-tumor activity.
Mice survival rate after the different preparation lumbar injections of Figure 13 amycin and oral (filling stomach) administration.Because doxorubicin hydrochloride has very strong toxicity, each administration finishes all has animal dead, and amycin solution is oral to be reduced than injection toxicity, still has toxicity.II-1 complex nanometer granule group experimental session does not have animal dead, and this proof can effectively reduce its toxicity through chemical bond keyed jointing DOX, prolongs the time-to-live of animal.
After Figure 14 is the different intravenous injections of paclitaxel and oral (filling stomach) administration, the mouse tumor growth curve.The negative matched group of normal saline (Saline); With the positive matched group of PTX clinical preparation intravenous injection; L-glutamic acid (L-PGA) (number-average molecular weight 6500Da) is blank (CS/HA/PLA with the chitosan composite nano-granule; CS/I-36), PEC is oral not to have any antitumous effect, and tumor growth is obvious; The administration group can obviously suppress growth of tumor.In three groups of treatment groups, the direct oral group of antitumous effect of PTX solution is the poorest, explains that the direct oral administration biaavailability of PTX solution is very low, and the PTX intravenous injection can to a certain degree suppress the growth of tumor.Oral group of II-20 complex nanometer granule and PTX intravenous injection group compare, and the II-20 complex nanometer granule can significantly suppress the growth of gross tumor volume, presents better anti-tumor activity.
The specific embodiment
With embodiment the present invention is further explained again below.
Embodiment 1 (I-1):
Polyanion is connected with the medicine ester bond:
In the dry reaction bottle, add 0.1g L-glutamic acid (L-PGA) (number-average molecular weight 6500Da); 0.13g paclitaxel (PTX) and 82.52mg dicyclohexylcarbodiimide (DCC); Dimethyl formamide (DMF) dissolving adds 48.87mg 4-dimethylamino naphthyridine (DMAP) at last.Evacuation, inflated with nitrogen.At room temperature react 24h.The reactant liquor 24h that in DMF, dialyses then at distill water dialysis 24h, afterwards with product lyophilization 24h, obtains the polyglutamic acid target product L-PGA-PTX (being called for short I-1) of ester bond bonding medicine.
Embodiment 2 ~ 10: press embodiment 1 method, change the kind and the medicine keyed jointing amount of polyanion, medicine, (I-2 ~ I-11), concrete parameter is as shown in table 1 can to obtain the polyanion of multiple bonding medicine.
The polyanion of table 1 ester bond bonding medicine
| Embodiment | Drug-PA | Polyanion | M n | Medicine/N 0 | N | NPs(nm) |
| 1 | I-1 | L-PGA | 6500 | PTX/0.4 | 0.2 | 50 |
| 2 | I-2 | L-PGA | 6500 | PTX/0.6 | 0.3 | 75 |
| 3 | I-3 | γ-PGA | 100000 | Docetaxel/0.8 | 0.4 | 170 |
| 4 | I-4 | γ-PGA | 20000 | Curcumin/0.8 | 0.4 | 210 |
| 5 | I-5 | HA | 100000 | Curcumin/0.9 | 0.5 | 20 |
| 6 | I-6 | HA | 15000 | DEX/0.8 | 0.4 | 100 |
| 7 | I-7 | HA | 20000 | DEX/0.2 | 0.1 | 180 |
| 8 | I-8 | SA | 5000 | Hydroxy camptothecin/0.5 | 0.3 | 150 |
| 9 | I-9 | L-PGA | 20000 | PTX/1.0 | 0.6 | 100 |
| 10 | I-10 | PAC | 20000 | Docetaxel/0.4 | 0.2 | 300 |
| 11 | I-11 | L- |
1000 | Cisplatin/0.7 | 0.5 | 200 |
Drug-PA: the polyanion of bonding medicine; M
n: the number average relative molecular mass of polyanion; N
0: the anionic group mol ratio of medicine that drops in the reaction and polyanion; N: the anionic group mol ratio of product Chinese medicine and polyanion; γ-PGA: gamma-polyglutamic acid-; HA: hyaluronic acid; SA: sodium alginate; PAC: carboxy-modified cellulose; PTX: paclitaxel; DEX: dexamethasone; NPs: the polyanion nanoparticle of drug
The polyanion of embodiment 11 ester bond keyed jointing cisplatin
The 30mg cisplatin is dissolved in the 20mL deionized water, contains the aqueous solution of 100mg L-PGA respectively with 10mL, at 37 ℃ of lucifuge stirring reaction 24h.With the reactant liquor 2d that dialyses, lyophilization obtains the white powder 97mg of HA-CDDP macromolecule anticancer drug, productive rate 74.6%.
Embodiment 12 (I-12):
Polyanion is connected with the medicine amido link:
In the dry reaction bottle, add 0.1g L-glutamic acid (L-PGA) (number-average molecular weight 6500Da); 0.11g amycin (DOX) and 90.5mg 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC); Dimethyl formamide (DMF) dissolving adds 50.6mgN-HOSu NHS (NHS) at last.Evacuation, inflated with nitrogen.At room temperature react 24h.The reactant liquor 24h that in DMF, dialyses then at distill water dialysis 24h, afterwards with product lyophilization 24h, obtains the polyglutamic acid target product ester bond L-PGA-DOX (being called for short I-12) of amido link bonding medicine.
Embodiment 13 ~ 21: press embodiment 12 methods, change the kind and the drug dose of polyanion, polycation, medicine, (I-13 ~ I-21), concrete parameter is as shown in table 2 can to obtain the polyanion of multiple amide linkage medicine.
The polyanion of table 2 amido link bonding medicine
| Embodiment | ?Drug-PA | Polyanion | M n | Medicine/N 0 | N | NPs(nm) |
| 12 | ?I-12 | L-PGA | 6500 | DOX/0.4 | 0.3 | 60 |
| 13 | ?I-13 | L-PGA | 6500 | DOX/0.5 | 0.4 | 80 |
| 14 | ?I-14 | L-PGA | 100000 | DOX/0.5 | 0.4 | 150 |
| 15 | ?I-15 | L-PGA | 20000 | DOX/0.8 | 0.6 | 100 |
| 16 | ?I-16 | γ-PGA | 40000 | DOX/0.3 | 0.2 | 250 |
| 17 | ?I-17 | HA | 20000 | DOX/0.2 | 0.1 | 300 |
| 18 | ?I-18 | SA | 5000 | DOX/0.4 | 0.3 | 230 |
| 19 | ?I-19 | L- |
1000 | DOX/0.3 | 0.2 | 15 |
M
n: the number average relative molecular mass of polyanion; N: medicine and polyanion repetitive mol ratio; DOX: amycin.
Embodiment 20 (I-20):
Polyanion is connected with medicine hydrazone key:
In the dry reaction bottle, add 0.1g L-glutamic acid (L-PGA) (number-average molecular weight 6500Da); 90.5mg 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC); 50.6mg N-hydroxy-succinamide (NHS); Add 182 μ L hydrazine hydrates, dimethyl formamide (DMF) dissolving.Evacuation, inflated with nitrogen.At room temperature react 24h.The reactant liquor 24h that in DMF, dialyses then at distill water dialysis 24h, afterwards with product lyophilization 24h, obtains the polyglutamic acid of diazanylization.The polyglutamic acid of 50mg diazanylization; 42mg doxorubicin hydrochloride (DOX) is dissolved in 5mL DMF, drips a trifluoroacetic acid; Room temperature reaction 24h; Reactant liquor is added 20 μ L triethylamines, pour bag filter into and place the distilled water 24h that dialyses, lyophilization gets the L-PGA-DOX (being called for short I-20) that the hydrazone key connects.
Embodiment 21 ~ 26: press embodiment 20 methods, change the kind and the medication amount of polyanion, medicine, (I-23 ~ I-31), concrete parameter is as shown in table 3 can to obtain the polyanion of multiple hydrazone key bonding medicine.
The polyanion of table 3 hydrazone bonding medicine
| Embodiment | ?Drug-PA | Polyanion | M n | Medicine/N 0 | N | NPs(nm) |
| 20 | ?I-20 | L-PGA | 6500 | DOX/0.3 | 0.2 | 60 |
| 21 | ?I-21 | L-PGA | 20000 | DOX/0.4 | 0.3 | 100 |
| 22 | ?I-22 | L-PGA | 100000 | DOX/0.7 | 0.5 | 170 |
| 23 | ?I-23 | γ-PGA | 20000 | DOX/0.8 | 0.6 | 250 |
| 24 | ?I-24 | HA | 20000 | DOX/0.15 | 0.1 | 110 |
| 25 | I-25 | ?SA | 5000 | DOX/0.4 | 0.3 | 240 |
| 26 | I-26 | ?PAC | 20000 | DOX/0.3 | 0.2 | 260 |
Embodiment 27
1g glutamic acid/(hydrophilic unit accounts for mass percent 40% to glutamic acid Bian ester copolymer; Number-average molecular weight 20000) is dissolved into wiring solution-forming among the 10ml DMF, installs in the bag filter (molecular cut off 3500) then with the 22mg paclitaxel; Spend PBS (pH7.4) dialysis 48h, centrifugal glutamic acid/glutamic acid Bian ester copolymer nanoparticle (I-27) aqueous dispersions that obtains wrapping year paclitaxel.
Embodiment 28 ~ 35: adopt embodiment 27 methods, change amphipathic anion, drug kinds and pharmaceutical pack carrying capacity, prepare the polyanion nanoparticle of different physical package medicine carrying things, like table 4.
The polyanion nanoparticle of table 4 physical package medicine carrying thing
P (GA/GAE): glutamic acid/glutamic acid Bian ester copolymer; PLA/PGA: polylactic acid grafted polyglutamic acid;
PLA/HA: polylactic acid grafting hyaluronic acid; PLA/SA: polylactic acid grafting alginic acid
Embodiment 39 (II-1):
Contain the preparation of the compound polyelectrolyte of hydrophobic drug:
5mg CS (50000Da) is dissolved in the acetum of 5mLpH5.0 (0.01M); (pH7.4 0.01M), dropwise joins in the CS solution with 2mLI-12 nanoparticle aqueous dispersions; Dropwise and stir 1h, get adriamycin bonded compound polyelectrolyte (II-1)
Table 4 contains the compound polyelectrolyte of hydrophobic drug
| Embodiment | Complex | Polyanion | Polycation/M n | The positive and negative charge ratio | Particle diameter (nm) |
| 37 | II-1 | I-12 | CS/50000 | 2:1 | 100 |
| 38 | II-2 | I-12 | CS/50000 | 4:1 | 150 |
| 39 | II-3 | I-1 | CS/100000 | 6:1 | 200 |
| 40 | II-4 | I-2 | PL/30000 | 5:1 | 378 |
| 41 | II-5 | I-3 | CS/150000 | 2:1 | 289 |
| 42 | II-6 | I-4 | PL/50000 | 3:1 | 216 |
| 43 | II-7 | I-5 | PDMAEMA/50000 | 4.0:1 | 350 |
| 44 | II-8 | I-6 | PL/100000 | 3.5:1 | 335 |
| 45 | II-9 | I-6 | PEI/5000 | 4.0:1 | 443 |
| 46 | II-10 | I-7 | PEI/60000 | 4.5:1 | 267 |
| 47 | II-11 | I-9 | CS/1000000 | 5.5:1 | 130 |
| 48 | II-12 | I-15 | Gelatin/100000 | 6.0:1 | 150 |
| 49 | II-13 | I-19 | CS/100000 | 5.0:1 | 20 |
| 50 | II-14 | I-26 | CS/1000000 | 2.5:1 | 110 |
| 51 | II-15 | I-28 | CS/50000 | 1.2:1 | 205 |
| 52 | II-16 | I-27 | CS/50000 | 2.5:1 | 360 |
| 53 | II-17 | I-30 | Poly arginine/100000 | 3.5:1 | 190 |
| 54 | II-18 | I-32 | PL/2000 | 3:1 | 110 |
| 55 | II-19 | I-33 | PDMAM/50000 | 5.0:1 | 500 |
| 56 | II-20 | I-36 | CS/10000 | 3.0:1 | 70 |
| 57 | II-21 | I-20 | PVPs/2000 | 1.2:1 | 420 |
| 58 | II-22 | I-26 | Lipofectamine?2000 | 3.0:1 | 90 |
| 59 | II-23 | I-11 | SD/45000 | 4.0:1 | 150 |
| 60 | II-24 | I-19 | PMSC/40000 | 3.0:1 | 240 |
CS: chitosan; PL: polylysine; PDMAEMA: polymethylacrylic acid N, N-dimethylaminoethyl; PEI: PEI; SD: cationic starch; PDMAM: gather N, the N-dimethylmethacryl amide; PVPs: polyvinyl pyrroles hydrochlorate; PMSC: gather (N-methyl-diethyl-amine base sebacate)
Embodiment 61:
Press embodiment 2 preparation II-1 nanoparticles, II-1 nanoparticle solution is transferred to pH3.0,5.0,7.4 respectively with hydrochloric acid or NaOH.Different pH mixed liquors drip on the copper mesh, and with transmission electron microscope observation polyelectrolyte particle shape, the result is shown in Fig. 2-4.
Embodiment 62:
To contain l0% hyclone (FBS; BiochromAg, DMEM Germany) (Sigma-Aldrich USA) is basic culture solution, with cell (H460, radiological study institute of Chinese medicine institute) with 1 * 10
5Individual/mL cell concentration is inoculated in 96 orifice plates, places 37 ° of C, 5%CO
2, cultivate under the saturated humidity condition.Normal saline (control), DOX and II-1 solution dilute with DMEM, obtain the solution of concentration at 10～100ng/ml.The above-mentioned solution of getting 100 each concentration of μ L is added to respectively and substitutes original fluid in the orifice plate of inoculating cell.The cell of cultivation in DMEM is as matched group.After cultivating a period of time respectively; Take out culture plate; Detect the endocytosis ability of cell with inverted fluorescence microscope and flow cytometer to material, the toxicity of mtt assay test material, it is as shown in Figure 3 to breed percentage rate RGR (Relative Growth Rate) result relatively by formula 3 calculating cells.
Embodiment 63:
The nude mice of inoculation anthropogenic pulmonary carcinoma tumor, fasting 12 hours is irritated stomach (doxorubicin concentration: 74ug/mL) with amycin aqueous solution and II-1 nanoparticle solution respectively; After 4 hours; It is deadly to use heavy dose of pentobarbital sodium solution to anaesthetize mice, then mice is dissected, and the mouse heart after the dissection, liver, spleen, lung, kidney, stomach, small intestinal, colon, tumor are separated; Be placed on the sample panel according to from left to right order then, carry out fluorescence imaging and observe, take pictures.Mice is bought from Beijing dimension tonneau China laboratory animal company limited, and all is male, is 4-6 age in week.In the zoopery process, mice is all raised the environment at SPF, and manages and operate in strict accordance with " zoopery management rules ".
Embodiment 64:
Get healthy Bab/c mice, female, body weight 19 ± 2g; Adopt the tumor strain animal of going down to posterity; Take out ascites cells, ascites cells and normal saline are diluted in the 1:3 ratio, under aseptic condition, inoculate fast; In mice right rear leg subcutaneous injection glucagonoma liquid 0.2mL/ only, cell concentration is 5.0 * 10
6/ only.After tumor liquid was inoculated a week, gross tumor volume reached 100mm
3(V=1/2 (a * b
2)) time, mice is divided into 5 groups at random, i.e. normal saline matched group (lumbar injection 4 times, per injection 300 μ L); DOX lumbar injection group (being equivalent to 15mgDOX/Kg, lumbar injection 4 times, per injection 300 μ L); Blank nanoparticle matched group (the compound nanoparticle of L-PGA and chitosan) (irritating stomach 4 times, each 300 μ L), DOX (is equivalent to 15mgDOX/Kg for oral group; Irritate stomach 4 times, each 300 μ L), II-1 nanoparticle solution (is equivalent to 15mg DOX/Kg for oral group; Irritate stomach 4 times, each 300 μ L), after the administration animal tracking is observed.Investigate the variation of 28 days gross tumor volumes of administration and the survival condition of mice, gross tumor volume is through vernier caliper measurement, according to V=1/2 (a * b
2) calculate, a represents the length of tumor here, and b represents the wide of tumor, when diabrosis appears in tumor, stops to observe.Result such as Figure 12 and 13.
Embodiment 65:
Get healthy Bab/c mice, female, body weight 19 ± 2g; Adopt the tumor strain animal of going down to posterity; Take out ascites cells, ascites cells and normal saline are diluted in the 1:3 ratio, under aseptic condition, inoculate fast; In mice right rear leg subcutaneous injection glucagonoma liquid 0.2mL/ only, cell concentration is 5.0 * 10
6/ only.After tumor liquid was inoculated a week, gross tumor volume reached 100mm
3(V=1/2 (a * b
2)) time, mice is divided into 5 groups at random, i.e. normal saline matched group (lumbar injection 4 times, per injection 300 μ L); PTX intravenous injection group (being equivalent to 15mg PTX/Kg, intravenous injection 4 times, per injection 300 μ L); Blank nanoparticle matched group (the compound nanoparticle of I-36 and chitosan) (irritating stomach 4 times, each 300 μ L), PTX (is equivalent to 15mg PTX/Kg for oral group; Irritate stomach 4 times, each 300 μ L), II-20 nanoparticle solution (is equivalent to 15mg PTX/Kg for oral group; Irritate stomach 4 times, each 300 μ L), after the administration animal tracking is observed.Investigate the variation of 14 days gross tumor volumes of administration, gross tumor volume is through vernier caliper measurement, according to V=1/2 (a * b
2) calculate, a represents the length of tumor here, and b represents the wide of tumor, when diabrosis appears in tumor, stops to observe.Result such as Figure 14.
Claims (10)
1. compound polyelectrolyte that contains hydrophobic drug; It is characterized in that it being that polyanion or derivatives thereof bag carries or electronegative nanoparticle of keyed jointing hydrophobic drug formation and the compound polyelectrolyte that polycation static is compounded to form; Particle diameter is 20 ~ 500nm, and the positive and negative charge of polycation and polyanion is than between 1.2 ~ 6.0.
2. the described compound polyelectrolyte that contains hydrophobic drug of claim 1; It is characterized in that; The polyanion nanoparticle that described electronegative nanoparticle is the keyed jointing medicine; To be the dewatering medicament that has hydroxyl, carboxyl, amino, a carbonyl functional group be keyed to number-average molecular weight through ester bond, amido link, hydrazone key to the polyanion of keyed jointing medicine is the product on 1000 ~ 100000 the polyanion; Anionic group on the described polyanion strand is carboxyl and salt thereof, and the mol ratio of drug molecule and anionic group is 0.1 ~ 0.6:1.
3. the described compound polyelectrolyte that contains hydrophobic drug of claim 1; It is characterized in that described electronegative nanoparticle is is that 1000 ~ 100000 amphipathic anion is carried the nanoparticle that dewatering medicament forms through the physical action bag by number-average molecular weight, the drug loading amount in the nanoparticle is 0.1 ~ 14%.
4. the described compound polyelectrolyte that contains hydrophobic drug of claim 1; It is characterized in that; Polycation is selected from chitosan and derivant thereof; Polylysine, cationic starch derivative, PEI, polyamide, gelatin, cationic protein or polypeptide, cationic polyester, cation poly phosphate, polyvinyl pyrroles salt, N, the homopolymer and the copolymer of N-substituted (methyl) acrylic ester; The number average relative molecular mass of polycation is 2000 ~ 1000000.
5. the described compound polyelectrolyte that contains hydrophobic drug of claim 2 is characterized in that, polyanion is selected from polyglutamic acid, hyaluronic acid, sodium alginate, carboxy-modified cellulose and sodium salt thereof.
6. the described compound polyelectrolyte that contains hydrophobic drug of claim 3; Be characterised in that described amphipathic anion is selected from the polyglutamic acid of glutamic acid/glutamic acid Bian ester copolymer, hydrophobically modified, the hyaluronic acid of hydrophobically modified, the sodium alginate of hydrophobically modified.
7. claim 2 or the 3 described compound polyelectrolytes that contain hydrophobic drug is characterized in that dewatering medicament is selected from paclitaxel, Docetaxel, amycin, dexamethasone, hydroxy camptothecin, cisplatin, indomethacin, curcumin, arteannuin.
8. the described method for preparing that contains the compound polyelectrolyte of hydrophobic drug of claim 1 is characterized in that the polyanion of described keyed jointing medicine and nanoparticle thereof prepare through following method:
1) hydrophobic drug of formula ratio and polyanion are dissolved in the organic solvent, and through dicyclohexylcarbodiimide, the 4-dimethylamino naphthyridine is a catalyst, and room temperature reaction obtained the polyanion of ester bond keyed jointing medicine in 24 hours;
Or through 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide catalysis room temperature reaction obtained the polyanion of amido link keyed jointing medicine in 24 hours;
Or the reaction of polyanion side group and hydrazine hydrate holds amination, obtains the polyanion of hydrazone key keyed jointing medicine again in 24 hours with the medicine direct reaction that contains carbonyl;
2) step 1) gained product obtains the polyanion nanoparticle aqueous dispersions of keyed jointing medicine after solvent dialysis, deionized water dialysis, and lyophilizing obtains nano-granule freeze-dried powder;
3) stir down; 2) in the aqueous dispersions that forms in the water of polyanion nanoparticle aqueous dispersions or the nano-granule freeze-dried powder redispersion of the bonding medicine that obtains be added drop-wise in the aqueous solution that contains the formula ratio polycation; It is compound to carry out static; Make the aqueous dispersions of the compound polyelectrolyte nanoparticle that contains hydrophobic drug, lyophilizing obtains lyophilized powder.
9. the described method for preparing that contains the compound polyelectrolyte of hydrophobic drug of claim 3 is characterised in that through following method preparation:
1) is dissolved into wiring solution-forming in the dimethyl sulfoxide to medicine and amphipathic anion by formula ratio, is put in the bag filter then and gives solvent, obtain wrapping the polyanion nanoparticle aqueous dispersions of medicine carrying thing through deionized water;
2) stir down, be added drop-wise to the polyanion nanoparticle aqueous dispersions that wraps the medicine carrying thing in the aqueous solution that contains the formula ratio polycation, it is compound to carry out static, contains the aqueous dispersions of the compound polyelectrolyte nanoparticle of hydrophobic drug, and lyophilizing obtains lyophilized powder.
10. the described application that contains the compound polyelectrolyte of hydrophobic drug of claim 1; Be characterised in that described complex is distributed to the aqueous humour that forms in the aqueous medium with the nanoparticle state; Or lyophilized powder is loaded in the capsule, or is prepared into tablet, as oral drug preparation.
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