CN101352420B - Hydroxycamptothecin sustained-release microsphere and preparation method thereof - Google Patents
Hydroxycamptothecin sustained-release microsphere and preparation method thereof Download PDFInfo
- Publication number
- CN101352420B CN101352420B CN2008100717377A CN200810071737A CN101352420B CN 101352420 B CN101352420 B CN 101352420B CN 2008100717377 A CN2008100717377 A CN 2008100717377A CN 200810071737 A CN200810071737 A CN 200810071737A CN 101352420 B CN101352420 B CN 101352420B
- Authority
- CN
- China
- Prior art keywords
- chitosan
- microsphere
- solution
- hydroxycamptothecin
- polylactic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a hydroxycamptothecin slow-release microsphere and a preparation method thereof, relates to an anti-tumor pharmaceutical preparation and provides a hydroxycamptothecin slow-release microsphere and a preparation method thereof with long time of continuous drug release, stable drug release and high drug utilization; a carrier is polylactic acid, anti-cancer drug of hydroxycamptothecin is packed in the carrier and a modifying layer of water soluble derivative of chitosan is arranged on the surface of the carrier; the hydroxycamptothecin and the polylactic acid are dissolved in an organic solvent so as to obtain solution A; polyvinyl alcohol solution with the concentration of 0.5 percent to 5 percent is prepared and sodium dodecyl sulfate is added to prepare mixed solution B with the concentration of 0.5 percent to 1 percent; the solution A is transferred into a disperse phase container of a film emulsifier, the mixed solution B is added into a continuous phase container, a water suction pump is started to lead the continuous phase to be cycled, a mobile phase is collected, a certain pressure is maintained and a pressure indicating value which is operated to the film emulsifier is reduced to 0kPa. The collected mobile phase is centrifugated, precipitation is collected and freeze-dried to obtain the unmodified drug-carrying microsphere and then the surface modifying of the microsphere is carried out.
Description
Technical field
The present invention relates to a kind of anti-tumor medicinal preparation, especially relate to a kind of hydroxy camptothecin (hereinafter to be referred as HCPT) sustained-release micro-spheres and preparation method thereof at the malignant entity tumor postoperative recurrence.
Background technology
Hydroxy camptothecin (HCPT) antitumor spectrum is wider, does not have cross resistance with antitumor drug commonly used.Be mainly used in treatment hepatocarcinoma, colorectal cancer, pulmonary carcinoma and leukemia clinically, but this poison of drug side reaction is bigger, mainly shows as: bone marrow depression, leukopenia, gastrointestinal reaction and urinary tract stimulation etc.HCPT is a kind of topoisomerase I inhibitor, has the enzymatic activity effect that suppresses topoisomerase I, and it mainly acts on the DNA synthesis stage, to G
0The phase cell is effect not, to G
1, G
2With M phase cell slight lethality is arranged.HCPT is that water is insoluble, the fat insoluble drug, clinical used water soluble preparation is its sodium salt preparation, destroyed the Alpha-hydroxy lactonic ring of its anti-topoisomerase I active structure, anti-tumor activity reduces greatly, in addition, because hydroxy camptothecin pharmaceutical preparation targeting poor selectivity, serious adverse causes patients ' life quality to descend.
The film emulsion process (1, Gu Li, Li Xueming, Chen Guoguang, the application of film emulsifying technology in particulate delivery system, Chinese Journal of Pharmaceuticals, 2007,38 (11): 814-818) be current emerging pharmaceutical formulation techniques, it is a kind of emulsification method that was put forward in 1991 by Japanese scientist, and this method receives much concern in recent years having unique advantage aspect the various Emulsions of preparation, the microgranule.Conventional emulsification method such as colloid mill, mechanical agitation, ubiquity energy consumption such as ultrasonic is big, production efficiency is low, diameter of particle is big and have a very wide distribution, shortcoming such as system poor reproducibility, the achievement that obtains also mostly is in the laboratory research stage.And micropowder size homogeneous, envelop rate height, the good stability of film emulsion process preparation, the emulsion process energy consumption is lower, mild condition, favorable reproducibility.And particulate delivery system has the realization target administration; various kinds of drug such as protected protein, hormone, gene are not destroyed, delay and control the advantages such as release of medicine in gastrointestinal tract, reach purposes such as alleviating untoward reaction, raising bioavailability, prolongation administration cycle.
The film emulsion process be by the pressure official post decentralized photo of film both sides by microporous membrane, be dispersed in the form of droplet and form emulsion in the continuous phase.The decentralized photo and the continuous phase of microporous membrane both sides are insoluble, the dispersed phase drop forming process in two steps, at first decentralized photo is crossed film under pressure, form drop in opposite side micropore exit and grow up, when size droplet diameter arrives to a certain degree, will under the mobile shear action of continuous phase, come off, thereby be distributed in the continuous phase, reach emulsifying effectiveness preferably with the droplet form from film.Chitosan and soluble derivative thereof have excellent biological compatibility and biodegradability, also have multiple physiological activities such as broad-spectrum antiseptic, infection, promotion wound healing, blood lipid regulation, cholesterol reducing, enhance immunity and antitumor, some chitosan derivatives also has tumor-targeting, relevant field of medicaments than other synthetic material use more wide (2, Wang Hongchang, Sun Xiaofei, chitosan and derivant thereof are in the applied research progress of field of medicaments, Central-South pharmacy, 2007,5 (3): 258-262).Therefore,, be necessary the above various preparation technique advantages of comprehensive utilization, prepare a kind of novel hydroxy camptothecin microsphere for realizing targeting, the long-acting and stable release of medicine.
Summary of the invention
The object of the present invention is to provide hydroxycamptothecin sustained-release microsphere that a kind of lasting drug release time is long, drug release is stable and utilization ratio of drug is high and preparation method thereof, described hydroxycamptothecin sustained-release microsphere is with injection system administration in the tumor body, can realize target administration, reduce the whole body toxic and side effects, the control tumor recurrence.
Technical scheme of the present invention is to add polyvinyl alcohol (PVA) and sodium lauryl sulphate is made surfactant (needing flush away after making microsphere) in preparation process, modifies microsphere surface with water soluble derivatives of chitosan at last and prepares microsphere.
Hydroxycamptothecin sustained-release microsphere of the present invention is: carrier is polylactic acid (PLA), and parcel cancer therapy drug hydroxy camptothecin has the water soluble derivatives of chitosan decorative layer at carrier surface in the carrier.
The molecular weight of polylactic acid is preferably 5000～15000, and water soluble derivatives of chitosan preferably is selected from the N-succinyl-chitosan, N-succinyl-O-carboxymethyl chitosan, a kind of in N-lactose acidylate-O-carboxymethyl chitosan etc.The particle diameter of microsphere is preferably 2～3 μ m, and the drug loading of microsphere is preferably 5%～20%, and envelop rate is preferably 25%～50%.Press mass ratio, preferably the water soluble derivatives of chitosan decorative layer: carrier polylactic acid and cancer therapy drug hydroxy camptothecin=1: (10～20).
The preparation method of hydroxycamptothecin sustained-release microsphere of the present invention is carried out as follows:
1) hydroxy camptothecin and polylactic acid are dissolved in the organic solvent, get solution A, by volume, (hydroxy camptothecin and polylactic acid): organic solvent=1: (1～10), by the mass/volume ratio, the concentration of hydroxy camptothecin in mixed solution is 0.2～1mg/ml, presses mass ratio, hydroxy camptothecin: polylactic acid=1: (1～10);
2) by mass/volume percentage ratio, compound concentration be 0.5%～5% poly-vinyl alcohol solution greater than 200ml, add sodium lauryl sulphate (SDS) again, be mixed with concentration and be 0.5%～1% mixed solution B;
3) solution A is transferred in the membrane emulsifier decentralized photo container, charge into nitrogen to membrane emulsifier Pressure gauge and show that pressure is 30～50kPa, mixed solution B is added in the continuous phase container as continuous phase, open pulsating pump and make the continuous phase circulation, collect mobile phase, keep certain pressure, the pressure indicated value that moves to membrane emulsifier is reduced to 0kPa;
4) mobile phase of collecting is centrifugal, collecting precipitation, washing, lyophilizing gets the medicine carrying microballoons of unmodified;
5) medicine carrying microballoons with unmodified carries out the microsphere surface modification.
Organic solvent is N, the mixed solution of dinethylformamide and dichloromethane, or N, the mixed solution of N-dimethyl sulfoxide and dichloromethane.The centrifugal speed of mobile phase is preferably 1000～3000r/min.
The medicine carrying microballoons of unmodified is carried out the microsphere surface modification, may further comprise the steps:
(1) by mass/volume percentage ratio, compound concentration is 0.1%～0.5% water soluble derivatives of chitosan phosphate buffered solution, and pH value is 5～9;
(2) get the medicine carrying microballoons of unmodified, under agitation add the water soluble derivatives of chitosan phosphate buffered solution, get mixed solution C, by the mass/volume ratio, the medicine carrying microballoons of unmodified: water soluble derivatives of chitosan phosphate buffered solution=(5～1): 1, coat 30min～1h;
(3) mixed solution C is centrifugal, collecting precipitation, washing places baking oven, in 40～60 ℃ of dry hydroxycamptothecin sustained-release microspheres that get of evacuation.Centrifugal speed is preferably 1000～3000r/min.
The hydroxy camptothecin medicine carrying microballoons productive rate that utilizes the present invention to prepare reaches more than 90%, preparation process does not only cause the loss of medicine and carrier material substantially, and the external drug release time in the modified back of microsphere surface prolongs, owing to the tumor-targeting of modification of chitosan and the particularity of tumor vivo medicine-feeding mode, can reach the effect of slow release and targeting simultaneously.In addition, hydroxy camptothecin keeps and suppresses the topoisomerase I active group, and antitumous effect is good; Used carrier material good biocompatibility, biodegradable; The release in vitro constant speed is stable, has the slow release effect; The hydroxy camptothecin dosage is little in the preparation, and cost is low; Preparation method is easy, good reproducibility.
Description of drawings
Fig. 1 is the composition sketch map of the hydroxy camptothecin microsphere of the embodiment of the invention.
Fig. 2 is the sem photograph of gained medicine carrying microballoons under the embodiment of the invention condition.
Fig. 3 is the external release curve of embodiment of the invention gained granular preparation.In Fig. 3, abscissa be the time (my god), vertical coordinate is drug accumulation release rate (%).
Fig. 4 is that different embodiment release behaviour in vitro compare.In Fig. 4, abscissa be the time (my god), vertical coordinate is cumulative release rate (%); From top to bottom, 4 curves are represented embodiment 1～4 successively.
The specific embodiment
Embodiment 1: take by weighing HCPT crude drug 30mg, molecular weight is 5000 polylactic acid (PLA) 300mg, puts in the beaker with 30ml DMF and the dissolving of CH2Cl2 mixed solution; With 5% polyvinyl alcohol (PVA) and 1% sodium lauryl sulphate (SDS) mixed aqueous solution is continuous phase, prepares the medicine carrying granule by membrane emulsifier; Gained Emulsion is with centrifugal under the 2000r/min rotating speed, and collecting precipitation and lyophilizing obtain modifying preceding medicine carrying microballoons; Take by weighing the 10mg medicine carrying microballoons again.Add 0.5%N-succinyl-chitosan PBS solution 10ml in the stirring, coat 1h, centrifugal back collecting precipitation is washed 3 times, places 40 ℃ of dry powder formulations that get of baking oven evacuation.Fig. 1 provides the composition sketch map of the hydroxy camptothecin microsphere of the embodiment of the invention, and carrier 2 is polylactic acid (PLA), and parcel cancer therapy drug hydroxy camptothecin 1 has water soluble derivatives of chitosan decorative layer 3 on carrier 2 surfaces in the carrier 2.Its sem photograph is referring to Fig. 2, and as can be seen from Figure 2 the microsphere monodispersity is good, and particle size distribution is more even, and the surface smoothing rounding shows that this method can successfully prepare medicine carrying microballoons.
Embodiment 2: take by weighing HCPT crude drug 20mg, molecular weight is 10000 polylactic acid (PLA) 400mg, puts in the beaker with 40ml DMF and CH
2Cl
2The mixed solution dissolving; With 0.5% polyvinyl alcohol (PVA) and 0.5% sodium lauryl sulphate (SDS) mixed aqueous solution is continuous phase, prepares the medicine carrying granule by membrane emulsifier; Gained Emulsion is with centrifugal under the 1800r/min rotating speed, and collecting precipitation and lyophilizing obtain modifying preceding medicine carrying microballoons; Take by weighing the 50mg medicine carrying microballoons again.Add 0.5%N-succinyl-O-carboxymethyl chitosan PBS solution 10ml in the stirring, coat 1h, centrifugal back collecting precipitation is washed 3 times, places 45 ℃ of dry powder formulations that get of baking oven evacuation.
Embodiment 3: take by weighing HCPT crude drug 20mg, molecular weight is 15000 polylactic acid (PLA) 300mg, puts in the beaker with 40ml DMF and CH
2Cl
2The mixed solution dissolving; With 1% polyvinyl alcohol (PVA) and 0.5% sodium lauryl sulphate (SDS) mixed aqueous solution is continuous phase, prepares the medicine carrying granule by membrane emulsifier; Gained Emulsion is with centrifugal under the 2500r/min rotating speed, and collecting precipitation and lyophilizing obtain modifying preceding medicine carrying microballoons; Take by weighing the 30mg medicine carrying microballoons again.Add 0.2%N-lactose acidylate succinyl-chitosan PBS solution 20ml in the stirring, coat 1h, centrifugal back collecting precipitation is washed 3 times, places 50 ℃ of dry powder formulations that get of baking oven evacuation.
The medicine cumulative in vitro release profiles of embodiment 3 is seen Fig. 3, and as can be seen from Figure 3 the rate of release of microsphere is more steady.
Embodiment 4: take by weighing HCPT crude drug 30mg, molecular weight is 5000 polylactic acid (PLA) 300mg, puts in the beaker with 30ml DMSO and CH
2Cl
2The mixed solution dissolving; With 2.5% polyvinyl alcohol (PVA) and 0.5% sodium lauryl sulphate (SDS) mixed aqueous solution is continuous phase, prepares the medicine carrying granule by membrane emulsifier; Gained Emulsion is with centrifugal under the 2000r/min rotating speed, and collecting precipitation and lyophilizing obtain modifying preceding medicine carrying microballoons; Take by weighing the 25mg medicine carrying microballoons again.Add 0.2%N-lactose acidylate-O-carboxymethyl chitosan PBS solution 20ml in the stirring, coat 1h, centrifugal back collecting precipitation is washed 3 times, places 40 ℃ of dry powder formulations that get of baking oven evacuation.Fig. 4 provides different embodiment release behaviour in vitro relatively.
Embodiment 5: take by weighing HCPT crude drug 20mg, molecular weight is 15000 polylactic acid (PLA) 300mg, puts in the beaker with 40ml DMF and CH
2Cl
2The mixed solution dissolving; With 5% polyvinyl alcohol (PVA) and 0.5% sodium lauryl sulphate (SDS) mixed aqueous solution is continuous phase, prepares the medicine carrying granule by membrane emulsifier; Gained Emulsion is with centrifugal under the 1800r/min rotating speed, and collecting precipitation and lyophilizing obtain modifying preceding medicine carrying microballoons; Take by weighing the 25mg medicine carrying microballoons again.Add 0.5%N-lactose acidylate succinyl-chitosan PBS solution 20ml in the stirring, coat 45min, centrifugal back collecting precipitation is washed 3 times, places 45 ℃ of dry powder formulations that get of baking oven evacuation.
Embodiment 6: take by weighing HCPT crude drug 30mg, molecular weight is 5000 polylactic acid (PLA) 300mg, puts in the beaker with 30ml DMSO and CH
2Cl
2The mixed solution dissolving; With 2.5% polyvinyl alcohol (PVA) and 1% sodium lauryl sulphate (SDS) mixed aqueous solution is continuous phase, prepares the medicine carrying granule by membrane emulsifier; Gained Emulsion is with centrifugal under the 2000r/min rotating speed, and collecting precipitation and lyophilizing obtain modifying preceding medicine carrying microballoons; Take by weighing the 30mg medicine carrying microballoons again.Add 0.3%N-succinyl-chitosan PBS solution 20ml in the stirring, coat 1h, centrifugal back collecting precipitation is washed 3 times, places 55 ℃ of dry powder formulations that get of baking oven evacuation.
Claims (2)
1. hydroxycamptothecin sustained-release microsphere, it is characterized in that carrier is a polylactic acid, parcel cancer therapy drug hydroxy camptothecin in the carrier, at carrier surface the water soluble derivatives of chitosan decorative layer is arranged, described water soluble derivatives of chitosan is selected from the N-succinyl-chitosan, N-succinyl-O-carboxymethyl chitosan, a kind of in N-lactose acidylate-O-carboxymethyl chitosan;
The molecular weight of described polylactic acid is 5000～15000;
The particle diameter of described microsphere is 2～3 μ n, and the drug loading of microsphere is 5%～20%, and envelop rate is 25%～50%;
Press mass ratio, the water soluble derivatives of chitosan decorative layer: carrier polylactic acid and cancer therapy drug hydroxy camptothecin=1: 10～20;
The concrete preparation method of described hydroxycamptothecin sustained-release microsphere is as follows:
1) hydroxy camptothecin and polylactic acid are dissolved in the organic solvent, get solution A, by volume, hydroxy camptothecin and polylactic acid: organic solvent=1: 1～10, by the mass/volume ratio, the concentration of hydroxy camptothecin in mixed solution is 0.2～1mg/ml, presses mass ratio, hydroxy camptothecin: polylactic acid=1: 1～10, described organic solvent is N, the mixed solution of dinethylformamide and dichloromethane, or N, the mixed solution of N-dimethyl sulfoxide and dichloromethane;
2), be that 0.5%～5% poly-vinyl alcohol solution and concentration are that 0.5%～1% sodium lauryl sulphate mixed aqueous solution is continuous phase B with concentration by mass/volume percentage ratio;
3) solution A is transferred in the membrane emulsifier decentralized photo container, charge into nitrogen to membrane emulsifier Pressure gauge and show that pressure is 30～50kPa, continuous phase B is added in the continuous phase container, open pulsating pump and make the continuous phase circulation, collect mobile phase, keep certain pressure, the pressure indicated value that moves to membrane emulsifier is reduced to 0kPa;
4) mobile phase of collecting is centrifugal, collecting precipitation, washing, lyophilizing gets the medicine carrying microballoons of unmodified;
5) medicine carrying microballoons with unmodified carries out the microsphere surface modification, and concrete steps are as follows:
(1) by mass/volume percentage ratio, compound concentration is 0.1%～0.5% water soluble derivatives of chitosan phosphate buffered solution, and pH value is 5～9;
(2) get the medicine carrying microballoons of unmodified, under agitation add the water soluble derivatives of chitosan phosphate buffered solution, get mixed solution C, by the mass/volume ratio, the medicine carrying microballoons of unmodified: water soluble derivatives of chitosan phosphate buffered solution=5～1: 1, coat 30min～1h;
(3) mixed solution C is centrifugal, collecting precipitation, washing places baking oven, and in 40～60 ℃ of dry hydroxycamptothecin sustained-release microspheres that get of evacuation, described centrifugal speed is 1000～3000r/min.
2. hydroxycamptothecin sustained-release microsphere as claimed in claim 1 is characterized in that the centrifugal speed of mobile phase is 1000～3000r/min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100717377A CN101352420B (en) | 2008-09-08 | 2008-09-08 | Hydroxycamptothecin sustained-release microsphere and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100717377A CN101352420B (en) | 2008-09-08 | 2008-09-08 | Hydroxycamptothecin sustained-release microsphere and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101352420A CN101352420A (en) | 2009-01-28 |
| CN101352420B true CN101352420B (en) | 2011-01-26 |
Family
ID=40305596
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008100717377A Expired - Fee Related CN101352420B (en) | 2008-09-08 | 2008-09-08 | Hydroxycamptothecin sustained-release microsphere and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101352420B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102309762B (en) * | 2011-09-06 | 2013-02-13 | 薛万江 | Preparation method for lactosaminated carboxymethyl chitosan magnetic nano-particle gene vector |
| CN103004859A (en) * | 2011-09-26 | 2013-04-03 | 中国农业科学院植物保护研究所 | Preparation method and application of sustained-release nanoparticle preparation for preventing and treating grape ulcer |
| CN102908318B (en) * | 2012-10-31 | 2014-08-27 | 中山大学 | 10-hydroxycamptothecine nanometer microsphere and preparation method thereof |
| CN103251573B (en) * | 2013-05-13 | 2014-10-29 | 李伟 | Protein micro/nano sphere carrying antitumor chemotherapeutic medicine and preparation method of protein micro/nano sphere |
| CN103800294B (en) * | 2013-12-26 | 2015-12-30 | 厦门大学 | A kind of broom shape carries hydroxycamptothecin sustained-release particle and preparation method thereof |
| CN105748413B (en) * | 2016-03-10 | 2018-06-29 | 华南理工大学 | Hydroxycamptothecin nano crystal load microballoon and preparation method thereof |
| CN110302171A (en) * | 2019-07-12 | 2019-10-08 | 山东大学 | A kind of intratumor injection SN-38-PLGA sustained-release micro-spheres and its preparation method and application |
| CN114870029A (en) * | 2022-06-02 | 2022-08-09 | 平顶山学院 | Hydroxycamptothecin malignant tumor targeted microsphere and preparation method and application thereof |
-
2008
- 2008-09-08 CN CN2008100717377A patent/CN101352420B/en not_active Expired - Fee Related
Non-Patent Citations (4)
| Title |
|---|
| Aiping Zhu et. al.."Synthesis and aggregation behavior of N–succinyl-O- carboxymethylchitosan in aqueous solutions".《Colloid. Polym. Sci. 》.2007,第285卷(第14期),1535. |
| Aiping Zhu et. al.."Synthesis and aggregation behavior of N-succinyl-O-carboxymethylchitosan in aqueous solutions".《Colloid. Polym. Sci. 》.2007,第285卷(第14期),1535. * |
| 仵文英等.乳糖化羧甲基壳聚糖包覆苦参碱脂质体在大鼠体内组织分布研究.《中国药学杂志》.2008,第43卷(第6期), * |
| 王银松等.不同分子量N-琥珀酰壳聚糖的制备及其与K562肿瘤细胞间亲和性的初步探讨.《高分子学报》.2004,第2004年卷(第3期),378. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101352420A (en) | 2009-01-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101352420B (en) | Hydroxycamptothecin sustained-release microsphere and preparation method thereof | |
| Ribeiro-Costa et al. | In vitro and in vivo properties of usnic acid encapsulated into PLGA-microspheres | |
| CN105030795B (en) | A kind of nano medicament carrying system and its preparation method and application | |
| CN103435718B (en) | The hyaluronic acid cholesteryl ester that PEG modifies | |
| CN101940792B (en) | PCL-b-PEG-b-PCL carried hydrophobic medicine polymer vesica as well as preparation method and application thereof | |
| CN105617394A (en) | Self-assembled nano-system of unsaturated fatty acid-anti-tumor drug conjugates as well as preparation method and application thereof | |
| US9474715B2 (en) | Polymeric drug-delivery material, method for manufacturing thereof and method for delivery of a drug-delivery composition | |
| US9283190B2 (en) | Highly efficient and long-acting slow-release formulation of poorly soluble drugs and preparation method thereof | |
| CN103330680A (en) | Nano drug transdermal preparation and preparation method thereof | |
| CN103006539A (en) | Polymeric micelle medicine composition and preparation method thereof | |
| CN104163915A (en) | Cholesterol-poloxamer-cholesterol triblock copolymer, preparation method and application thereof | |
| US8962017B2 (en) | Formulation of silymarin with high efficacy and prolonged action and the preparation method thereof | |
| CN105287382A (en) | Preparation method of folic acid-chitosan modified curcumin nano-liposome | |
| CN102357075A (en) | Docetaxel nano preparation and preparation method thereof | |
| CN103585113B (en) | Apigenin polylactic acid sustained release microsphere and preparation method thereof | |
| CN103316352A (en) | Graphene oxide nano-drug carrier and anti-tumor drug as well as preparation method of anti-tumor drug | |
| CN103655484A (en) | Method for preparing paclitaxel sustained-release microspheres by use of self-assembly technology and product thereof | |
| CN104288093A (en) | Application of nano-drug transdermal preparation in tumors | |
| CN106620714B (en) | 7-ethyl-10-hydroxycamptothecin-polymer coupling drug and preparation method of nano preparation thereof | |
| CN102225204A (en) | Anti-tumour pH sensitive slow release implant and preparation method thereof | |
| CN105037739B (en) | Reduction sensitive polymer with arginine membrane penetration effect and preparation method and application | |
| CN107137350A (en) | A kind of taxol polymer micelle and preparation method thereof | |
| CN101317823B (en) | Implantation type antineoplastic drug of 10-hydroxycamptothecin dual-sustained-release particle formulation and preparation method thereof | |
| CN101549272A (en) | Method of preparing S/O/W of 5-fluorouracil biodegradable polymer microspheres | |
| CN112121028B (en) | Simvastatin solid nanoparticle preparation and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110126 Termination date: 20130908 |