CN102093489A - Amphiphilic N-long chain alkyl-N-arginine chitosan derivative and preparation of derivative micelle - Google Patents
Amphiphilic N-long chain alkyl-N-arginine chitosan derivative and preparation of derivative micelle Download PDFInfo
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Abstract
The invention discloses natural and biodegradable N-long chain alkyl-N-arginine chitosan derivative and a preparation method of derivative micelle as well as a nano carrier used as an oral and indigestible medicament, namely polymer micelle. The micelle is prepared into conventional oral preparations in a form of conventional tablet, capsule and the like.
Description
Technical field
The present invention relates to a kind of natural and biodegradable amphipathic N-chain alkyl-N-arginine chitosan derivative and preparation method thereof, and, be used to prepare the polymer micelle of the extremely low medicine gastrointestinal absorption of short oral administration biaavailability as the medicament nano carrier.
Background technology
Chitosan is the unique alkaline polysaccharide of occurring in nature, it is a kind of cationic polymers, has bioadhesive, but prolong drug is in the residence time of biological mucous membrane surface, chitosan with the positive charge group also can interact with the electronegative cytolemma in surface, the reinforcing membrane permeability, thus the absorption of mucous membrane strengthened to medicine.The short effect of oozing of chitosan is very possible owing to its remarkably influenced to membranin, institute is positively charged to interact with the close-connected open architecture of iuntercellular, make cytoskeletal protein by thread become spherical, thereby make macromolecular drug stride film and absorb (van der Lubben IM by cell bypass, Verhoef JC, Borchard G, et al.Chitosan and its derivatives in mucosaldrug and vaccine delivery[J] .Eur J Pharm Sci.2001,14 (3): 201-207; Wang Zhiying opens strong. and penetration enhancer is to the short mechanism .Acta Pharmaceutica Sinica of effect, 2003,38 (12): 957-961 of oozing of many too tired medicine pulmonary administrations; Liu Mei, Chen Xiaoping. chitosan and derivative thereof are in the application of peptide class oral administration system. foreign medical science pharmacy fascicle, 2000,27 (6): 351-354).
In recent years, wearing the film peptide promotes the biomacromolecule oral absorption and promotes that the research of gene transfection is many.Wear the film peptide and be often referred to a class small peptide that has permeates cell membranes and transport medicine ability in the cell, often be less than 30 amino-acid residues, it is exactly all positively charged that these peptide sections have individual common characteristic, promptly generally is rich in basic aminoacids such as arginine or Methionin.The phosphatide of arginic guanidine radicals and lipid bilayer can form hydrogen bond. and the formation of hydrogen bond and the strong basicity of guanidine radicals (pKa～12.5) play important effect in control cell membrane transporter process, but short not clear at present (the Umezawa N of mechanism that oozes that arginine is detailed, Gelman M A, Haigis M C, et al.Translocation of a beta-peptide acrosscell membranes.J Am Chem Soc, 2002,124 (3): 368-369; Zhu Dun Anhui, Zhang Hailing, Bai Jingen, etc. the arginine beautify chitosan improves the gene transfection Study on Efficiency. Science Bulletin, and 2007,52:2199-2205).
Polymer micelle is the focus of pharmaceutics research at present, and it was both biodegradable, can form the medicament nano carrier again.Polymer micelle is to be that kernel, hydrophilic radical are the molecular assembly aggregate of shell with the hydrophobic grouping, but its solubilising hydrophobic drug, can help avoid the identification of reticuloendothelial system to the design of the particle diameter of polymer micelle and surface characteristic, extension body cycling time; Some have the polymer micelle of electric charge can protecting group because of the activity of, vaccine and pharmaceutical grade protein, can be used as the oral administration system of biopharmaceutical macromolecular drug.
Use for reference above result of study, a certain amount of arginine if can be introduced chitosan as wetting ability, and can introduce a certain amount of hydrophobic group simultaneously, formation has the polymer micelle of certain particle diameter and medicine carrying ability, because its hydrophilic group is to have with phospholipid bilayer to have fabulous affinity and the arginine of wearing film, so the nano drug-carrying micella and traditional polymer micellar phase ratio that are prepared from, it no longer only is a drug-loading system, had the good film effect of wearing simultaneously, this research thinking and invention achievement yet there are no document and patent report.
Summary of the invention
The technical problem to be solved in the present invention is: with the chitosan in biodegradable natural rice source as raw material, carrying out chemical structure modifies, make its formation have amphipathic polymer molecule, promptly an end contains hydrophilic group, and this hydrophilic group is the arginine that has with cytolemma good affinity and penetrance; The other end contains the lipophilic group and the polymkeric substance of biodegrade in vivo still, forms nanometer polymer micelle to be suitable for the wrapping medicine carrying thing.
For solving the problems of the technologies described above, it is as follows to the invention provides technical solution.
Amphipathic N-chain alkyl-N-arginine chitosan derivative of representing by following general formula:
In the structural formula, k, m, n are the integer greater than zero in the structural formula, and n＞k 〉=m, R are the integer between 6～10.
Described amphipathic N-chain alkyl-N-arginine chitosan derivative, it is characterized in that: the molecular weight of chitosan is between 5000-50 in amphipathic N-chain alkyl-N-arginine chitosan derivative, 0000, the arginine substitution value is 1%～50%, and the chain alkyl substitution value is 1%～50%.
The preparation method of described amphipathic N-chain alkyl-N-arginine chitosan derivative is characterized in that making preparation with the following method:
1) get chitosan and add in the aqueous acetic acid, stirring at room, the chain alkyl aldehyde of 6～12 carbon of adding reacted after 3～6 hours, added NaBH
4The aqueous solution continues to stir 8～14 hours, makes the N-chain alkyl chitosan; The reaction solution that generates the N-chain alkyl chitosan neutralizes with sodium hydroxide solution, and suction filtration is with ethanol and water washing, drying;
2) getting the N-chain alkyl chitosan adds in the aqueous acetic acid, stirring at room, add arginine, NHS and EDC successively, react after 42～50 hours, generate N-chain alkyl-N-arginine chitosan, reaction solution is dialysed with dialysis tubing (MWCO 3500), and lyophilize obtains amphipathic N-chain alkyl-N-arginine chitosan powder.
3) getting the N-chain alkyl chitosan adds in the aqueous acetic acid; stirring at room; the arginine, NHS and the EDC that add the protection of BOC acid anhydrides successively; react after 42～50 hours; generate N-chain alkyl-N-arginine chitosan, add the trifluoroacetic acid deprotection of 5% above concentration, reaction solution is dialysed with dialysis tubing (MWCO 3500); lyophilize obtains amphipathic N-chain alkyl-N-arginine chitosan powder.
Described amphipathic N-chain alkyl-N-arginine chitosan derivative, its purposes are to wrap the medicine carrying thing and form micella, improve oral difficult absorptivity bioavailability of medicament simultaneously, thereby the clinical treatment that reaches medicine are required.
Described oral difficult absorptivity medicine is characterized in that it being Regular Insulin, Placenta caprae seu ovis element, vaccinia virus vaccine, Hepatitis B virus vaccine, influenza vaccines, bordetella pertussis vaccine, mycoplasma pneumonia vaccine, tetanus toxin, Protalbinic acid, bitter melon protein, interleukin-, diphtheria toxoid; Cis-platinum, taxol, Docetaxel, camptothecine, 10-hydroxycamptothecine, ciclosporin A, Zorubicin, 5 FU 5 fluorouracil, silymarin, methotrexate, vindesine, nimodipine, actinomycin, mitomycin, esperamicin, bleomycin.
The preparation method of described amphipathic N-chain alkyl-N-arginine chitosan carrier micelle, it is characterized in that: oral difficulty is absorbed the drug with after pharmaceutically acceptable solvent dissolves, described after the N-chain alkyl-the N-arginine chitosan mixes with claim 1～3, through the room temperature supersound process, lyophilize, making the particle diameter that contains treatment significant quantity medicine is the polymer micelle lyophilized powder of 50～800nm.
Described amphipathic N-chain alkyl-N-arginine chitosan carrier micelle is characterized in that the direct can of drug-carrying polymer micelle lyophilized powder in common gelatine capsule or the capsule that is prepared from the enteric coated capsule.
8. amphipathic N-chain alkyl according to claim 6-N-arginine chitosan carrier micelle, after it is characterized in that the drug-carrying polymer micelle lyophilized powder added the pharmacy acceptable auxiliary, can is in common gelatine capsule or the capsule that is prepared from the enteric coated capsule.
Described amphipathic N-chain alkyl-N-arginine chitosan carrier micelle is characterized in that directly suppressing the tablet that forms with after the drug-carrying polymer micelle lyophilized powder adding pharmacy acceptable auxiliary.
Described amphipathic N-chain alkyl-N-arginine chitosan carrier micelle is characterized in that the drug-carrying polymer micelle lyophilized powder is added the tablet that pharmacy acceptable auxiliary granulation back compacting forms.
The graphical Synthetic Routes of N-chain alkyl-N-arginine chitosan:
Description of drawings
Fig. 1 is the general formula of N-chain alkyl-N-arginine chitosan
Fig. 2 is the graphical Synthetic Routes of N-chain alkyl-N-arginine chitosan
Embodiment
The preparation of embodiment 1 different molecular weight low degree of substitution N-octyl group-N-arginine chitosan
Get chitosan (Mw 80000,100000,200000,500000) 1g and add in 100ml 1% aqueous acetic acid, stirring at room adds n-octaldehyde (0.5g), reacts after 4 hours, adds NaBH
4(0.18g) aqueous solution 1.8ml continues to stir 12 hours, transfers pH to 7 with 1M NaOH, and suction filtration, second alcohol and water alternately wash 4 times, and normal temperature vacuum-drying makes off-white powder N-octyl group chitosan 0.84g; Getting N-octyl group chitosan (0.5g) adds in 50ml 1% aqueous acetic acid, stirring at room, add a certain amount of arginine (3.00g), NHS (1.94) and EDC (7.8g) successively, react after 48 hours, dialysis tubing (MWCO 3500) dialysis, lyophilize gets oyster white floss 0.15g, i.e. N-octyl group-N-arginine chitosan after the drying.
FTIR:2926,2855,1435,1398,805cm
-1(octyl group), 1623,1137cm
1(arginine)
It is 86% that ultimate analysis records deacetylation, and the octyl group substitution value is 24%, and the arginine substitution value is 6%.
The preparation of embodiment 2 different molecular weight high substitution value N-octyl group-N-arginine chitosans
Get chitosan (Mw 80000,100000,200000,500000) 1g and add in 100ml 1% aqueous acetic acid, stirring at room adds n-octaldehyde (0.5g), reacts after 4 hours, adds NaBH
4(0.18g) aqueous solution 1.8ml continues to stir 12 hours, transfers pH to 7 with 1M NaOH, and suction filtration, second alcohol and water alternately wash 4 times, and normal temperature vacuum-drying makes off-white powder N-octyl group chitosan 0.84g; Getting N-octyl group chitosan (0.5g) adds in 50ml 1% aqueous acetic acid; stirring at room; add a certain amount of arginine (2.92g), NHS (1.94) and EDC (7.8g) successively through the protection of BOC acid anhydrides; react after 48 hours, add trifluoroacetic acid (0.8ml), stirring at room 3 hours; dialysis tubing (MWCO 3500) dialysis; lyophilize gets oyster white floss 0.25g, i.e. N-octyl group-N-arginine chitosan after the drying.
FTIR:2926,2855,1435,1398,805cm
-1(octyl group), 1623,1137cm
-1(arginine)
It is 86% that ultimate analysis records deacetylation, and the octyl group substitution value is 24%, and the arginine substitution value is 25%.
Embodiment 3N-octyl group-preparation of N-arginine chitosan micellar and particle size determination
Getting the 12mg substitution value is that 6%N-octyl group-N-arginine chitosan (Mw100000) is dissolved in 3ml water, 50 ℃ of stirring in water bath 30min, ultrasonic 30min under the room temperature, centrifugal (rpm3000) 15min, cross 0.45 μ m filter membrane, (UK) measuring the micella particle diameter is 100-200nm for MalvernInstruments, Malvern with Zetasizer 3000HS particle diameter instrument.
Embodiment 4N-octyl group-N-arginine chitosan Regular Insulin micellar preparation
1, comprises the N-octyl group-N-arginine chitosan micellar preparation of Regular Insulin
Getting the 12mg substitution value is that 6%N-octyl group-N-arginine chitosan (Mw100000) is dissolved in 3ml water, and 50 ℃ of stirring in water bath 30min dropwise add PBS solution (pH 7.4) 3ml of Regular Insulin (6mg), ultrasonic 30min under the room temperature, centrifugal (rpm3000) 15min crosses 0.45 μ m filter membrane, lyophilize.
2, the mensuration of insulin content in N-octyl group-N-arginine chitosan micella
(Japan) moving phase is acetonitrile: NaSO for LC-10AT, Shimadzu with HPLC
4Damping fluid (pH2.3)=30: 70 (v/v), chromatographic column is Lichrospher C
18(4.6 * 250mm, 5 μ m), flow velocity is 1.0ml/min, the detection wavelength be 214nm (SPD-10A, UVdetector, Shimadzu, Japan), column temperature is 30 ℃, sampling volume is 20 μ l.Record that insulin content is 560 μ g/ml in N-octyl group-N-arginine chitosan micella.
The experiment of embodiment 5N-octyl group-N-arginine chitosan pancreotropic hormone gastrointestinal absorption
After 15 Wistar rats are weighed, press 70mgkg
-1Dosage take by weighing STZ (streptozotocin), with 0.7ml citrate buffer solution (0.1molL
-1, pH4.4) dissolving, abdominal injection is in the rat body immediately.After raising 3d, survey blood sugar, blood glucose value is higher than 16.67mmolL
-1Rat can continue the experiment.Laboratory animal is divided into 3 groups at random, and fasting 12h before the administration can't help water.First group is the Regular Insulin control group, irritates stomach insulin solutions (30IU/kg); Second group is N-octyl group-N-arginine chitosan group, irritates the enteric coated capsule (30IU/kg) of the N-octyl group-N-arginine chitosan polymer micelle lyophilized powder of stomach insulin-containing; The 3rd group is the subcutaneous injection group, gives subcutaneous injection insulin solutions (2IU/kg).Respectively after administration 0,0.5,1,1.5,2,2.5,4, tail vein blood during 6h, survey blood glucose value, calculate the relative bioavailability of Regular Insulin.
The result: the oral administration biaavailability of N-octyl group-N-arginine chitosan group Regular Insulin is 18.9%, and the oral relative bioavailability of Regular Insulin control group Regular Insulin is 0, illustrates that N-octyl group-N-arginine chitosan can significantly promote the oral absorption of Regular Insulin.
Embodiment 5
1, comprises the N-octyl group-N-arginine chitosan micellar preparation of cis-platinum
Get 12mgN-octyl group-N-arginine chitosan and be dissolved in 3ml water, 50 ℃ of stirring in water bath 30min dropwise add the aqueous solution 5ml of cis-platinum (6mg), ultrasonic 30min under the room temperature, dialysis tubing (MWCO 14000) dialysed overnight, centrifugal (rpm3000) 15min, cross 0.45 μ m filter membrane, lyophilize.
2, cis-platinum Determination on content in N-octyl group-N-arginine chitosan micella
(Japan) moving phase is ethyl acetate-methyl alcohol-DMF (N, dinethylformamide)-water=25: 16: 5: 5 (v/v), chromatographic column is Lichrospher-NH for LC-10AT, Shimadzu with HPLC
2Post (4.6 * 250mm, 5 μ m), flow velocity is 1.0ml/min, the detection wavelength be 310nm (SPD-10A, UVdetector, Shimadzu, Japan), column temperature is a room temperature, sampling volume is 20 μ l.Record that cis-platinum content is 420 μ g/ml in N-octyl group-N-arginine chitosan micella.
The experiment of the short cis-platinum gastrointestinal absorption of embodiment 6N-octyl group-N-arginine chitosan
10 Wistar rats are divided into 2 groups at random.First group is the cis-platinum control group, irritates stomach cis-platinum physiological saline (8mg/kg); Second group is N-octyl group-N-arginine chitosan group, irritates the gelatine capsule (8mg/kg) that stomach contains the N-octyl group-N-arginine chitosan polymer micelle lyophilized powder of cis-platinum.Respectively after administration 10,20,40, the 60min eye socket gets blood, uses the concentration of cis-platinum in the HPLC methods analyst blood plasma of reliability conclusive evidence after blood sample is handled, and calculates the oral administration biaavailability of cis-platinum.
The result: the oral administration biaavailability of N-octyl group-N-arginine chitosan group cis-platinum is 34.3%, and the oral administration biaavailability of cis-platinum control group cis-platinum is 10.2%, illustrates that N-octyl group-N-arginine chitosan can significantly promote the oral absorption of cis-platinum.
The N-octyl group N-arginine chitosan micellar preparation of embodiment 7 taxols
1, comprises the N-octyl group-N-arginine chitosan micellar preparation of taxol
Get 12mgN-octyl group-N-arginine chitosan and be dissolved in 3ml water, 50 ℃ of stirring in water bath 30min, dropwise drip ethanolic soln (30mg/ml) the 330 μ l of taxol, ultrasonic 30min under the room temperature, dialysis tubing (MWCO 14000) dialysed overnight, centrifugal (rpm3000) 15min crosses 0.45 μ m filter membrane, lyophilize.
2, the mensuration of content of taxol in N-octyl group-N-arginine chitosan micella
With HPLC (LC-10AT, Shimadzu, Japan) moving phase is methanol-water=75: 25 (v/v), chromatographic column is Lichrospher C18 post (4.6 * 250mm, 5 μ m), flow velocity is 1.0ml/min, and the detection wavelength is 227nm (SPD-10A, UVdetector, Shimadzu, Japan), column temperature is 30 ℃, and sampling volume is 20 μ l.Record that content of taxol is 2340 μ g/ml in N-octyl group-N-arginine chitosan micella.
The experiment of the short taxol gastrointestinal absorption of embodiment 8N-octyl group-N-arginine chitosan
Choose 12 of the healthy SD rats of body weight 200 ± 20g, fasting 12h is divided into 2 groups at random, every group of male and female half and half.First group is commercially available taxol control group, irritates stomach Taxol (20mg/kg); Second group is N-octyl group-N-arginine chitosan group, irritates N-octyl group-N-arginine chitosan polymer micelle solution (20mg/kg) that stomach contains taxol.Respectively after administration 0.25,0.5,1,2,4,8,12,24,48h gets blood in the eyeground vein clump.Use the concentration of taxol in the HPLC methods analyst blood plasma of reliability conclusive evidence after blood sample is handled, calculate the oral relative bioavailability of taxol.
The result: with the Taxol contrast, the oral relative bioavailability of N-octyl group-N-arginine chitosan group taxol is 283%, illustrates that N-octyl group-N-arginine chitosan can significantly promote the oral absorption of taxol.
The N-octyl group of embodiment 9 silymarins-N-arginine chitosan micellar preparation
1, comprises the N-octyl group-N-arginine chitosan micellar preparation of silymarin
Get 12mgN-octyl group-N-arginine chitosan and be dissolved in 3ml water, 50 ℃ of stirring in water bath 30min, dropwise drip ethanolic soln (15mg/ml) 1ml of silymarin, ultrasonic 30min under the room temperature, dialysis tubing (MWCO 14000) dialysed overnight, centrifugal (rpm3000) 15min crosses 0.45 μ m filter membrane, lyophilize.
2, silymarin Determination on content in N-octyl group-N-arginine chitosan micella
With HPLC (LC-10AT, Shimadzu, Japan) moving phase is methyl alcohol-phosphate buffered saline buffer (0.1mol/L pH 3.0)=49: 51 (v/v), chromatographic column is Lichrospher C18 post (4.6 * 250mm, 5 μ m), flow velocity is 1.0ml/min, and the detection wavelength is 288nm (SPD-10A, UVdetector, Shimadzu, Japan), column temperature is 40 ℃, and sampling volume is 20 μ l.Record that silymarin content is 1320 μ g/ml in N-octyl group-N-arginine chitosan micella.
The experiment of the short silymarin gastrointestinal absorption of embodiment 10N-octyl group-N-arginine chitosan
Choose 12 of the healthy SD rats of body weight 250～300g, fasting 12h is divided into 2 groups at random, every group of male and female half and half.First group is the silymarin control group, irritates stomach silymarin solution (30mg/kg); Second group is N-octyl group-N-arginine chitosan group, irritates the moisture gelatine capsule (30mg/kg) that flies the N-octyl group-N-arginine chitosan polymer micelle lyophilized powder of silibin of stomach.Respectively after administration 0.17,0.33,0.5,1,2,4,6,8,12h gets blood in the eyeground vein clump.Use the concentration of silymarin in the HPLC methods analyst blood plasma of reliability conclusive evidence after blood sample is handled, calculate the oral relative bioavailability of silymarin.
The result: compare with the silymarin control group, the relative oral administration biaavailability of N-octyl group-N-arginine chitosan group silymarin is 483%, illustrates that N-octyl group-N-arginine chitosan can significantly promote the oral absorption of silymarin.
Claims (10)
1. amphipathic N-chain alkyl-N-arginine chitosan derivative of representing by following general formula:
N in the structural formula
1, n
2, n
3For greater than zero integer, A is L-arginine and pharmaceutical salts thereof, and B is the chain alkyl of 6～12 carbon.
2. according to claim 1, it is characterized in that: in amphipathic N-chain alkyl-N-arginine chitosan derivative the molecular weight of chitosan between 5000-50,0000, the arginine substitution value is 1%～50%, the chain alkyl substitution value is 1%～50%.
3. the preparation method of amphipathic N-chain alkyl according to claim 1-N-arginine chitosan derivative is characterized in that making preparation with the following method:
1) get chitosan and add in the aqueous acetic acid, stirring at room, the chain alkyl aldehyde of 6～12 carbon of adding reacted after 3～6 hours, added NaBH
4The aqueous solution continues to stir 8～14 hours, makes the N-chain alkyl chitosan; The reaction solution that generates the N-chain alkyl chitosan neutralizes with sodium hydroxide solution, and suction filtration is with ethanol and water washing, drying;
2) getting the N-chain alkyl chitosan adds in the aqueous acetic acid, stirring at room, add arginine, NHS and EDC successively, react after 42～50 hours, generate N-chain alkyl-N-arginine chitosan, reaction solution is dialysed with dialysis tubing (MWCO 3500), and lyophilize obtains amphipathic N-chain alkyl-N-arginine chitosan powder.
3) getting the N-chain alkyl chitosan adds in the aqueous acetic acid; stirring at room; the arginine, NHS and the EDC that add the protection of BOC acid anhydrides successively; react after 42～50 hours; generate N-chain alkyl-N-arginine chitosan, add the trifluoroacetic acid deprotection of 5% above concentration, reaction solution is dialysed with dialysis tubing (MWCO 3500); lyophilize obtains amphipathic N-chain alkyl-N-arginine chitosan powder.
4. according to the described amphipathic N-chain alkyl of claim 1～2-N-arginine chitosan derivative, its purposes is to wrap the medicine carrying thing and forms micella, improve oral difficult absorptivity bioavailability of medicament simultaneously, thereby the clinical treatment that reaches medicine is required.
5. oral difficult absorptivity medicine according to claim 4 is characterized in that it being Regular Insulin, Placenta caprae seu ovis element, vaccinia virus vaccine, Hepatitis B virus vaccine, influenza vaccines, bordetella pertussis vaccine, mycoplasma pneumonia vaccine, tetanus toxin, Protalbinic acid, bitter melon protein, interleukin-, diphtheria toxoid; Cis-platinum, taxol, Docetaxel, camptothecine, 10-hydroxycamptothecine, ciclosporin A, Zorubicin, 5 FU 5 fluorouracil, silymarin, methotrexate, vindesine, nimodipine, actinomycin, mitomycin, esperamicin, bleomycin.
6. the preparation method of N-chain alkyl according to claim 4-N-arginine chitosan carrier micelle, it is characterized in that: oral difficulty is absorbed the drug with after pharmaceutically acceptable solvent dissolves, described after the N-chain alkyl-the N-arginine chitosan mixes with claim 1～3, through the room temperature supersound process, lyophilize, making the particle diameter that contains treatment significant quantity medicine is the polymer micelle lyophilized powder of 50～800nm.
7. amphipathic N-chain alkyl according to claim 6-N-arginine chitosan carrier micelle is characterized in that the direct can of drug-carrying polymer micelle lyophilized powder in common gelatine capsule or the capsule that is prepared from the enteric coated capsule.
8. amphipathic N-chain alkyl according to claim 6-N-arginine chitosan carrier micelle, after it is characterized in that the drug-carrying polymer micelle lyophilized powder added the pharmacy acceptable auxiliary, can is in common gelatine capsule or the capsule that is prepared from the enteric coated capsule.
9. amphipathic N-chain alkyl according to claim 6-N-arginine chitosan carrier micelle is characterized in that directly suppressing the tablet that forms with after the drug-carrying polymer micelle lyophilized powder adding pharmacy acceptable auxiliary.
10. amphipathic N-chain alkyl according to claim 6-N-arginine chitosan carrier micelle is characterized in that the drug-carrying polymer micelle lyophilized powder is added the tablet that pharmacy acceptable auxiliary granulation back compacting forms.
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| EP3822292A4 (en) * | 2018-07-11 | 2022-04-06 | Josho Gakuen Educational Foundation | Polymer compound and promoter for introducing compound into cells using same |
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