CN102198085A - Triblock copolymer micelle and freeze-drying preparation loading taxane medicaments, and preparation method and application thereof - Google Patents
Triblock copolymer micelle and freeze-drying preparation loading taxane medicaments, and preparation method and application thereof Download PDFInfo
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- CN102198085A CN102198085A CN 201110139775 CN201110139775A CN102198085A CN 102198085 A CN102198085 A CN 102198085A CN 201110139775 CN201110139775 CN 201110139775 CN 201110139775 A CN201110139775 A CN 201110139775A CN 102198085 A CN102198085 A CN 102198085A
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Abstract
The invention belongs to the technical fields of medicament forms and preparation of nano medicaments, and relates to a triblock copolymer micelle and freeze-drying preparation loading taxane medicaments, and a preparation method and application thereof. In order to enable the micelle provided by the invention to be used clinically, the loading capacity, entrapment rate and stability of the preparation need to be guaranteed. The micelle is prepared from the following components in parts by weight: 1 part of taxane medicament and 1.5-99 parts of triblock copolymer polycaprolactone-polyethylene glycol-polycaprolactone, wherein the molecular weight ratio of polycaprolactone to polyethylene glycol in the triblock copolymer is 0.5-3. The micelle or freeze-drying preparation loading taxane medicaments can be used for treating patients with cancer, tumors, Kaposi sarcoma, malignant tumors, tissue dysfunction or hyperplasia secondary to tissue damage and any other disease capable of reacting with the taxane medicaments, and has especially obvious curative effects on hepatoma, liver metastasis, ovarian cancer and breast cancer.
Description
Technical field
The invention belongs to pharmaceutical dosage form and Nano medication preparing technical field, particularly relate to micelle, lyophilized formulations of a kind of triblock polymer load taxone and its production and application.
Background technology
Bearing taxanes is a big class natural product that obtains from plant, belongs to Diterpenes from textural classification, so claim the taxane diterpene again.Paclitaxel is a kind of important anticarcinogen that uses clinically as the star molecule in this compounds.Paclitaxel (Paclitaxel, commodity are called Taxol) is a kind of natural anti-cancer crude drug that extracts from Ramulus et folium taxi cuspidatae or Chinese yew, is white crystalline powder, and is water insoluble, easily dissolves in chloroform, acetone and other organic solvent.Docetaxel (Docetaxel, trade name: be taxotere Taxotere) by yew (Taxusbaccata, Europeanyew) the needle extract synthesizes the chemical compound of preparation through structural modification, be white or off-white color powdery solid, this product also belongs to the Ramulus et folium taxi cuspidatae series antineoplastic medicament, be fat-soluble compound, be insoluble in water (2.903 μ g/ml), be slightly larger than paclitaxel (0.25 μ g/ml～0.60 μ g/ml).This product antitumor mechanism is identical with paclitaxel, also is by inducing and impel tubulin polymerization to become microtubule, suppress the depolymerization of the microtubule that forms simultaneously, producing stable microtubule fasolculus.The normal dynamic regeneration of microtubule fasolculus is obstructed, and cell can not form normal mitosis spindle when mitosis, thereby has suppressed cell division and propagation.Its unique Anticancer Effect and Mechanism has unique therapeutical effect to breast carcinoma, ovarian cancer and non-small cell carcinoma etc., clinically as a line anticarcinogen and extensive use.But as other many anticarcinogens, taxone is all very low at water-soluble dissolubility, and the every ml of paclitaxel injection that uses clinically contains the Oleum Ricini (trade name of the rare modification of 6mg paclitaxel 527mg polyoxy second at present
EL) and in the mixed solution of 49.7% (V/V) dehydrated alcohol, before the injection with normal saline dilution 5-20 doubly.The solution that the Docetaxel injection also is made up of the Tween 80 and the ethanol of Docetaxel, clinic trial is somewhat similar with paclitaxel injection; But
EL, Tween 80 and ethanol tend to cause intensive side reaction, as allergy, haemolysis, nephrotoxicity, neurotoxicity and cardiac toxicity etc., may cause death when serious.And increase with dosage, toxic and side effects has the trend of increase.Therefore greatly limited the clinical practice of taxones such as paclitaxel.
Those skilled in the art are devoted to reduce toxic and side effects always, or improve its drug level at target organ, in the hope of better bringing into play curative effect, effectively solve the difficult problem that taxone runs into but still have at present when clinical antitumor.
Summary of the invention
For effectively utilizing taxone, the inventor once did multiple trial, wish to reduce toxic and side effects or improve its drug level at target organ, in the hope of better bringing into play curative effect, final the present inventor attempts providing a kind of novel form of triblock polymer load taxone to improve taxone application present situation clinically.
First technical problem solved by the invention provides a kind of micelle of load taxone, and is clinical in order to make that said preparation might be applied to, and needs to guarantee drug loading, envelop rate and the stability of preparation.
The novel form that the present invention is used for the load taxone is a micelle, and it is the micelle of being made by triblock polymer polycaprolactone-polyethylene glycol-polycaprolactone and taxone.
Wherein, triblock polymer polycaprolactone-polyethylene glycol-polycaprolactone belongs to biodegradable macromolecular material.Formulation system of the present invention can be controlled drug slow effectively and discharge, wherein biodegradable macromolecular material then can be degraded voluntarily, formed micelle particle diameter is between 10nm-200nm, according to the EPR effect, taxane anti-tumor medicament can effectively penetrate the damaged endotheliocyte of tumor and enter tumor tissues, and, reach the effect of passive target administration owing to removing obstacles and high concentration, accumulate in tumor tissues for a long time.Micelle of the present invention is the slow release nanometer micelle.
The weight proportion of taxone and triblock polymer polycaprolactone-polyethylene glycol-polycaprolactone is: 1 part of taxone, 1.5～99 parts of triblock polymer polycaprolactone-polyethylene glycol-polycaprolactones.
Further preferred, weight proportion is: 1 part of taxone, triblock polymer polycaprolactone-polyethylene glycol-polycaprolactone 1.5-90 part.
Further preferred, weight proportion is: 1 part of taxone, 1.5～49 parts of triblock polymer polycaprolactone-polyethylene glycol-polycaprolactones.
Wherein, taxone is selected from paclitaxel, Docetaxel, or derivatives thereof.A use can be selected, also use can be mixed.
The biodegradable macromolecular material of the present invention is selected from triblock polymer methoxy poly (ethylene glycol)-polycaprolactone, the molecular weight ratio of hydrophilic block and hydrophobic block wherein, and promptly the molecular weight ratio of polycaprolactone and Polyethylene Glycol is 0.5～3; Molecular weight ratio preferred 0.85.
Polycaprolactone in the polymer preferably adopts poly-(6-caprolactone), be triblock polymer be poly-(6-caprolactone)-polyethylene glycol-(6-caprolactone) (PCL-PEG-PCL), it is 0.5～3 with the di-block copolymer molecular weight ratio of Polyethylene Glycol (PEG) (PCL) that the molecular weight ratio of its hydrophilic block and hydrophobic block is selected from poly-(6-caprolactone); Molecular weight ratio preferred 0.85.
Micelle of the present invention, can adopt following method preparation:
A, polycaprolactone-polyethylene glycol-polycaprolactone and medicine are dissolved in organic solvent, obtain settled solution A;
B, remove the organic solvent of settled solution A, obtain gel B;
C, gel B is injected water (preferred water for injection), make it be the clear shape, filter, promptly get micelle C.
In the said method, used organic solvent is one or more the mixed solvent in ethanol, the tert-butyl alcohol, acetonitrile, dichloromethane, acetone, trifluoroethanol or the hexafluoroisopropanol.Preferred alcohol, the tert-butyl alcohol.
Gained micelle particle diameter is 10nm-200nm, and drug loading generally can reach 5-16%, envelop rate at least 95%, and stability is excellent.Selection process is handled to such an extent that can make particle diameter reach 10nm-100nm, and the clinical practice of being more convenient for, expectation can realize high concentration, accumulate in tumor tissues for a long time, reach the effect of passive target administration.
Above-mentioned micelle can adopt following method preparation according to production or laboratory equlpment:
A, Biodegradable polymer material and medicine are dissolved in organic solvent, fully, can adopt the mode of heated and stirred, obtain settled solution A for guaranteeing dissolving;
B, remove organic solvent and specifically can adopt the mode of revolving steaming, obtain being the gel B of transparence at last;
C, with the water for injection of preheating (being convenient to gel B dissolving), add gel B, under the condition of heated and stirred, make it clear, cross 0.22 μ m ultrafilter membrane, make particle diameter generally at the micelle C of 10nm-200nm.
Second technical problem solved by the invention is for guaranteeing micellar stability, be convenient to store and transportation that the inventor has been made into lyophilized formulations.This lyophilized powder adds the nanoscale micelle that the injection water will form automatically under the condition of giving heat before clinical use.The back particle diameter that redissolves still remains on 10nm-200nm, or even 10nm-100nm, has embodied good stable.
Use the micelle of taxone of the present invention or lyophilized formulations can be used for treating suffer from cancer, tumor, Kaposi sarcoma, malignant tumor, the tissue of imbalance that is secondary to tissue injury or hyperplasia and any other be to the patient of the disease of taxone reaction, especially effectively in the cancer types hepatocarcinoma regulating liver-QI metastatic tumor, ovarian cancer, breast carcinoma arranged in treatment.
In micelle of the present invention or its lyophilized formulations preparation method, taxone is made the gel that is transparence belong to solid dispersion technology, by solid dispersion technology and freeze drying technology micelle in conjunction with the load taxone of preparation, has preparation technology's advantage simple to operation, and the preparation that makes does not have any organic solvent, but long preservation, good stability.
Description of drawings
Fig. 1 is the character photo after paclitaxel micelle, lyophilized formulations, the lyophilized formulations redissolution.
Fig. 2 is a paclitaxel micelle particle diameter.
Fig. 3 is a paclitaxel micelle transmission electron microscope photo.
Fig. 4 is the X-diffracting spectrum of paclitaxel micelle freeze-drying preparation.
Fig. 5 is the behavior of paclitaxel micelle in the PBS buffer.
Wherein, the A bottle is a paclitaxel micelle before the lyophilizing among Fig. 1, and the B bottle is a paclitaxel micelle freeze-drying powder, and the C bottle gets the paclitaxel micelle for after redissolving.
The specific embodiment
Below be the Chinese name and the corresponding explanation that is called for short of material therefor among the present invention:
1, triblock polymer: triblock polymer: poly-(6-caprolactone)-polyethylene glycol-(6-caprolactone), be called for short PCL-PEG-PCL, or PCEC.
2, Polyethylene Glycol is called for short PEG.
3, poly-(6-caprolactone) is called for short PCL.
The micelle of triblock polymer load taxone of the present invention, it is characterized in that: it is to be made by biodegradable macromolecular material of triblock polymer polycaprolactone-polyethylene glycol-polycaprolactone and taxone, and its weight proportion is: 1 part of taxone, 1.5～99 parts of the degradable macromolecular materials of triblock polymer polycaprolactone-polyethylene glycol-polycaprolactone;
The molecular weight ratio of polycaprolactone and Polyethylene Glycol is 0.5～3 in the described triblock polymer; Molecular weight ratio preferred 0.85.
Weight proportion is preferred: 1 part of taxone, triblock polymer polycaprolactone-polyethylene glycol-polycaprolactone 1.5-90 part; Further preferred: 1 part of taxone, 1.5～49 parts of triblock polymer polycaprolactone-polyethylene glycol-polycaprolactones.
Triblock polymer is poly-(6-caprolactone)-polyethylene glycol-(6-caprolactone), PCL
m-PEG
n-PCL
m, wherein m and n represent the molecular weight of PCL and PEG respectively, and the molecular weight ratio of PCL and PEG then is 2m: n, and its molecular weight ratio is 0.5～3; The preferred molecular weight ratio is 0.85.
The crude drug taxone is selected from paclitaxel, Docetaxel, or derivatives thereof.A use can be selected, also use can be mixed.
Prove the beneficial effect of micelle, lyophilized formulations and the preparation method of triblock polymer load taxone of the present invention by following research process.
The Biodegradable polymer material that the present inventor uses is the micellar key point of the present invention.The inventor once attempted using above-mentioned triblock polymer and is used for hydrophobic drugs such as camptothecine, amphotericin B, coenzyme Q10 and prepares micelle, find after having investigated the block of various molecular weights ratio and different preparation method: all these medicines parcels can't be formed micelle.But the inventor finds that unexpectedly above-mentioned triblock polymer can wrap up the taxone that belongs to hydrophobic drug together the formation micelle, has good matching.So further relevant parameter, the preparation method of Biodegradable polymer material are investigated, in the hope of guaranteeing micellar drug loading, envelop rate and stability, it is clinical to make that said preparation might be applied to.
The screening experiment of triblock polymer and preparation method thereof
1, preparation method
After the molecular weight ratio through PEG and PCL among the preliminary investigation triblock polymer PCL-PEG-PCL, parameters such as selected envelop rate, drug loading, particle diameter, stability are PCL relatively preferably
850-PEG
2000-PCL
850Investigate the influence of different preparation methoies to taxone, raw materials used medicine is respectively paclitaxel and Docetaxel, and inventory is identical.Preparing micellar method is dialysis, solid dispersion method, direct lyophilization.
Table 1 (carrying paclitaxel) and table 2 (carrying docetaxel) micelle of making for different preparation methoies and the medicine carrying parameter of solid dispersion method lyophilized formulations.
Table 1 is with PCL
850-PEG
2000-PCL
850Adopt the medicine carrying situation (carrying paclitaxel) of different preparation methoies for carrier
Table 2 is with PCL
850-PEG
2000-PCL
850Adopt the medicine carrying situation (carrying docetaxel) of different preparation methoies for carrier
Remarks: directly lyophilization is to adopt paclitaxel or Docetaxel, carrier material are dissolved in the tert-butyl alcohol, and is directly freezing, and lyophilization then reaches medicine and is amorphous state and is distributed to purpose in the carrier material.Add water during use, under heating condition, be self-assembled into nano-micelle.
By table 1 and table 2 as seen: solid dispersion method and directly the parameters such as drug loading, envelop rate, yield of lyophilization obviously be better than dialysis, but directly lyophilization need be used the virose tert-butyl alcohol, therefore not as priority selection method.So the preferred solid dispersion method of the present invention is micellar preparation method.
2, triblock polymer (PCEC)
(1) adopt solid dispersion method to investigate the medicine carrying situation of different blocks (each block molecule amount difference), crude drug is respectively paclitaxel and Docetaxel, the results are shown in Table 3 and table 4.
The medicine carrying situation of the PCEC of the different blocks of table 3 (carrying paclitaxel)
The PCEC medicine carrying situation (carrying docetaxel) of the different blocks of table 4
Table 3 and 4 shows: PCL
2000-PEG
750-PCL
2000, PCL
2000-PEG
4000-PCL
2000And PCL
2000-PEG
2000-PCL
2000Can't wrap up taxone; But PCL
500-PEG
2000-PCL
500, PCL
850-PEG
2000-PCL
850, PCL
1000-PEG
4000-PCL
1000Can wrap up taxone, and drug loading, envelop rate are higher.But investigate the result from particle diameter and the coefficient of dispersion and stability of formulation and show PCL
850-PEG
2000-PCL
850More meet the preparation requirement.
Find in conjunction with the preliminary PCEC that investigates different blocks: the molecular weight ratio of polycaprolactone and Polyethylene Glycol is 0.5～3 o'clock in the triblock polymer, can realize effective parcel, and drug loading, envelop rate are higher; But preferred molecular weight is than the PCEC that is 0.85, as PCL after size and distribution situation, the stable integrated survey
850-PEG
2000-PCL
850
(2) through screening, PCL
850-PEG
2000-PCL
850Comprehensive parcel effect best, so further investigate its inventory and drug loading, envelop rate, particle diameter, the coefficient of dispersion, stability relationship.Crude drug is paclitaxel and Docetaxel, and preparation method is a solid dispersion method.The medicine carrying situation sees Table 5 and table 6.
Table 5PCL
850-PEG
2000-PCL
850 materialsThe medicine carrying situation of material (carrying paclitaxel)
Table 6PCL
850-PEG
2000-PCL
850The medicine carrying situation (carrying docetaxel) of material
Table 5 and 6 shows: PCL
850-PEG
2000-PCL
850The effect of parcel taxone is fine, and envelop rate is up to 94%, but along with the increase of inventory, the also corresponding increase of drug loading, the also corresponding increase of particle diameter and the coefficient of dispersion, corresponding, the significant reduction of stability.Therefore, when utilizing triblock polymer parcel taxone to prepare micelle, drug loading should not be pursued simply, drug loading, size and stability need be taken into account.
Below for adopting the example of PCEC parcel preparation micelle and lyophilized formulations, and the parameters such as drug loading, envelop rate, particle diameter, the coefficient of dispersion of having investigated each example are to illustrate beneficial effect of the present invention.
Embodiment 1
(1) with poly-(6-caprolactone)-polyethylene glycol-(6-caprolactone) triblock copolymer (PCL of 92mg
850-PEG
2000-PCL
850) and the 8mg paclitaxel be dissolved in the 2ml dehydrated alcohol, heated and stirred to fully the dissolving, obtain settled solution A;
(2) with settled solution A under heating condition, revolve and boil off organic solvent, make it to be clear gel B;
(3) with the 5ml water for injection of preheating, add gel B, under the condition of heated and stirred, make it clear, cross 0.22 μ m filter membrane, make the micelle C of particle diameter at 10nm-100nm;
(4), promptly obtain final stabilized nano medicament freeze-drying powder D with micelle C lyophilizing.
This lyophilized powder adds the nanoscale micelle that the injection water will form automatically under the condition of giving heat before clinical use.
Resulting micelle C, lyophilized powder D and the final micelle that redissolves are seen Fig. 1.Average diameter is seen Fig. 2 at 28.9nm; Transmission electron microscope photo is seen Fig. 3; The micelle medicine carrying amount of gained is 8.0%, and envelop rate is 98.8%; The X diffracting spectrum of its carrier micelle lyophilized powder is seen Fig. 4, can see no paclitaxel characteristic peak on carrier micelle figure, illustrates that paclitaxel is wrapped in the material; Release behavior in the pH7.4 of 0.5% Tween 80 phosphate buffer is seen Fig. 5.
Embodiment 2
(1) with poly-(6-caprolactone)-polyethylene glycol-(6-caprolactone) triblock copolymer (PCL of 92mg
850-PEG
2000-PCL
850) and the 8mg Docetaxel be dissolved in the 2ml dehydrated alcohol, heated and stirred to fully the dissolving, obtain settled solution A;
(2) with settled solution A under heating condition, revolve and boil off organic solvent, make it to be clear gel B;
(3) with the 5ml water for injection of preheating, add gel B, under the condition of heated and stirred, make it clear, cross 0.22 μ m filter membrane, make the micelle C of particle diameter at 10nm-100nm;
(4), promptly obtain final stabilized nano medicament freeze-drying powder D with micelle C lyophilizing; This lyophilized powder adds the nanoscale micelle that the injection water will form automatically under the condition of giving heat before clinical use.
The nano-micelle drug loading of gained is 8.2%, and envelop rate is the trend of the nano-micelle of 97.8% resulting micelle C, lyophilized powder D and final redissolution with Fig. 1; Release behavior in the pH7.4 of 0.5% Tween 80 phosphate buffer is with the trend of Fig. 5.
Embodiment 3
(1) with poly-(6-caprolactone)-polyethylene glycol-(6-caprolactone) triblock copolymer (PCL of 92mg
850-PEG
2000-PCL
850) and the 15.4mg Docetaxel be dissolved in the 2ml dehydrated alcohol, heated and stirred to fully the dissolving, obtain settled solution A;
(2) with settled solution A under heating condition, revolve and boil off organic solvent, make it to be clear gel B;
(3) with the 5ml water for injection of preheating, add gel B, under the condition of heated and stirred, make it clear, cross 0.22 μ m filter membrane, make the micelle C of particle diameter at 10nm-100nm;
(4), promptly obtain final stabilized nano medicament freeze-drying powder D with micelle C lyophilizing; This lyophilized powder adds the nanoscale micelle that the injection water will form automatically under the condition of giving heat before clinical use.
The nano-micelle drug loading of gained is 15.1%, and envelop rate is 98.1%; Resulting micelle C, lyophilized powder D and the final nano-micelle that redissolves are with the trend of Fig. 1; Release behavior in the pH7.4 of 0.5% Tween 80 phosphate buffer is with the trend of Fig. 5.
To sum up, micelle of the present invention all can be used as or is called the slow release nanometer micelle.
Claims (12)
1. the micelle of triblock polymer load taxone, it is characterized in that: it is to be made by triblock polymer polycaprolactone-polyethylene glycol-polycaprolactone and taxone, and its weight proportion is: 1 part of taxone, 1.5～99 parts of triblock polymer polycaprolactone-polyethylene glycol-polycaprolactones;
Weight proportion is preferred: 1 part of taxone, triblock polymer polycaprolactone-polyethylene glycol-polycaprolactone 1.5-90 part;
Weight proportion is further preferred: 1 part of taxone, 1.5～49 parts of triblock polymer polycaprolactone-polyethylene glycol-polycaprolactones;
The molecular weight ratio of polycaprolactone and Polyethylene Glycol is 0.5～3 in the described triblock polymer; Molecular weight ratio preferred 0.85.
2. the micelle of triblock polymer load taxone according to claim 1 is characterized in that: described polycaprolactone-polyethylene glycol-polycaprolactone is poly-(6-caprolactone)-polyethylene glycol-(6-caprolactone).
3. the micelle of triblock polymer load taxone according to claim 2 is characterized in that: poly-(6-caprolactone) is 0.5～3 with the molecular weight ratio of Polyethylene Glycol in described poly-(6-caprolactone)-polyethylene glycol-(6-caprolactone); Molecular weight ratio preferred 0.85.
4. the micelle of triblock polymer load taxone according to claim 1 is characterized in that: taxone is selected from paclitaxel, Docetaxel, or derivatives thereof.
5. the micelle of triblock polymer load taxone according to claim 4 is characterized in that: paclitaxel, Docetaxel, or derivatives thereof adopt the mode of using or mixing use of selecting.
6. according to the micelle of each described triblock polymer load taxone of claim 1-5, it is characterized in that: the micelle particle diameter is 10nm-200nm; The preferred 10nm-100nm of micelle particle diameter.
7. the micelle freeze-drying preparation of triblock polymer load taxone is characterized in that: with the micelle of each described triblock polymer load taxone of claim 1-6, adopt freeze-drying method commonly used to prepare lyophilized formulations.
8. the micellar preparation method of the described triblock polymer load of claim 1 taxone is characterized in that: it is by following method preparation:
A, triblock polymer polycaprolactone-polyethylene glycol-polycaprolactone and medicine are dissolved in organic solvent, obtain settled solution A;
B, remove the organic solvent of settled solution A, obtain gel B;
C, gel B is injected water, make it be the clear shape, filter, promptly get micelle C;
The preferred water for injection of the described water of step C.
9. the micellar preparation method of triblock polymer load taxone according to claim 8 is characterized in that: described organic solvent is one or more the mixed solvent in ethanol, the tert-butyl alcohol, acetonitrile, dichloromethane, acetone, trifluoroethanol or the hexafluoroisopropanol; Organic solvent preferred alcohol, the tert-butyl alcohol.
10. the preparation method of the micelle freeze-drying preparation of triblock polymer load taxone is characterized in that: after adopting claim 8 or 9 described preparation methoies to make micelle, make lyophilized formulations according to the lyophilization processing method that pharmaceutics is commonly used.
11. the micelle freeze-drying preparation of the micelle of each described triblock polymer load taxone of claim 1-6 or the described triblock polymer load of claim 7 taxone preparation treatment cancer, tumor, Kaposi sarcoma, malignant tumor, be secondary to tissue injury imbalance tissue or hyperplasia and any other is to the application in the medicine of the disease of taxone reaction.
12. the application of the micelle freeze-drying preparation of the micelle of each described triblock polymer load taxone of claim 1-6 or the described triblock polymer load of claim 7 taxone in the medicine of preparation treatment hepatocarcinoma regulating liver-QI metastatic tumor, ovarian cancer, breast carcinoma.
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| CN102423302A (en) * | 2011-11-21 | 2012-04-25 | 中国药科大学 | Picropodophyllin-carrying nano micelle preparation and picropodophyllin-carrying nano micelle freezing and drying preparation and preparation method thereof |
| CN103990135B (en) * | 2014-05-13 | 2017-02-01 | 广东众生药业股份有限公司 | Micelle composed of taxane drug-loaded di-block polymer, and preparation method and application thereof |
| CN104224735B (en) * | 2014-09-30 | 2017-01-18 | 济南康和医药科技有限公司 | Cleviprex polymeric micelle freeze-drying preparation and preparation process thereof |
| CN106800641B (en) * | 2016-06-29 | 2019-03-12 | 四川省人民医院 | A kind of mPEG-b-PCL diblock polymer polymer and its application and preparation |
| CN108837157A (en) * | 2018-09-10 | 2018-11-20 | 成都医学院 | A kind of double polymer nanoparticles and preparation method thereof for carrying the pure and mild flavone compound of Taxotere |
| CN111035617A (en) * | 2018-10-11 | 2020-04-21 | 四川大学 | A method for preparing multi-molecule micro-core-loaded artemisinin (DHA, ARM, ARS) for treating cancer and its application |
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| CN1214818C (en) * | 1995-09-21 | 2005-08-17 | 株式会社三养社 | Copolymeric micelle drug compsn. and method for the prepn. thereof |
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