CN104666308B - Chitosan microball simultaneously containing 5 fluorouracils and oleanolic acid derivate and preparation method thereof - Google Patents
Chitosan microball simultaneously containing 5 fluorouracils and oleanolic acid derivate and preparation method thereof Download PDFInfo
- Publication number
- CN104666308B CN104666308B CN201510115395.4A CN201510115395A CN104666308B CN 104666308 B CN104666308 B CN 104666308B CN 201510115395 A CN201510115395 A CN 201510115395A CN 104666308 B CN104666308 B CN 104666308B
- Authority
- CN
- China
- Prior art keywords
- chitosan
- solution
- fluorouracil
- oleanolic acid
- concentration
- 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.)
- Active
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of chitosan microball simultaneously containing 5 fluorouracils and oleanolic acid derivate and preparation method thereof.The chitosan microball for wrapping up 5 fluorouracils and Succinyl oleanolic acid (neat butyl ester) simultaneously is prepared using ionic cross-linking first, thus obtained microsphere, 5 fluorouracil envelop rates are 52.23 ± 1.76%, form rounding, surface is smooth, uniform particle sizes, and average grain diameter is 563 ± 101nm.The preparation method process stabilizing of the present invention is reliable, and gained chitosan microball has good slow release effect, and both synergistic antitumor effects can be played simultaneously.
Description
Technical field
The present invention relates to pharmaceutical technology field, more particularly to the shell containing 5 FU 5 fluorouracil and oleanolic acid derivate simultaneously
Glycan microballoon and preparation method thereof.
Background technology
Cancer is one of China's incidence of disease and fatal rate highest disease, seriously threatens health of people.Current cancer
Treatment means are limited primarily to operation, three kinds of methods of radiotherapy and chemotherapy.The chemotherapy of tumour is because with applicable surface, extensively, poison is secondary
The features such as acting on relatively small, critical role is occupied in the treatment of tumour.5 FU 5 fluorouracil (5-fluorouracil, 5-FU)
It is that a kind of important clinic commonly uses anti-metabolism antineoplastic, is widely used in treatment digestive system cancer, breast cancer and various
The treatment of solid tumor.Research shows that the half-life period about 10~20min of 5 FU 5 fluorouracil (5-FU) in vivo, oral absorption is not advised
Then, bioavilability is relatively low, it is necessary to frequent drug administration.The toxic side effect of 5 FU 5 fluorouracil mainly includes the alimentary canals such as diarrhoea, vomiting
The bone marrow suppression such as reaction symptom and leucocyte, decrease of platelet.Research shows that the antitumor action of 5 FU 5 fluorouracil is with it swollen
The local concentration at knurl position and action time are closely related.In order to extend drug effect, toxic side effect is reduced, domestic and foreign scholars are to 5- fluorine
The prodrug and formulation of uracil have carried out substantial amounts of research, develop and have listed Carmofur, Tegafur, fluridine and fludarabine
Deng pro-drug, while also studying various 5 FU 5 fluorouracil novel forms, including microballoon, liposome, nanoparticle etc..But it is existing
Mostly simply 5 FU 5 fluorouracil is prepared into suitable form of administration by research in technology, not the combination in view of medicine and collaboration effect
Should.
The content of the invention
The purpose of the present invention is while being encapsulated in one by 5 FU 5 fluorouracil (5-FU) and oleanolic acid (OA) or derivatives thereof
In individual chitosan microball, both synergistic antitumor effects are played.
To achieve these goals, the present invention is neat using the derivative that chemical synthesis process is prepared for oleanolic acid first
Pier tartaric acid succinate monoester (Succinyl oleanolic acid (SOA), neat butyl ester).Secondly, prepared using ionic cross-linking
Chitosan microball, using envelop rate and drugloading rate as index, the chitosan for preparing encapsulating 5 FU 5 fluorouracil and oleanolic acid simultaneously is micro-
Ball.
The technical solution adopted by the present invention is：Chitosan simultaneously containing 5 FU 5 fluorouracil and oleanolic acid derivate is micro-
Ball is by 5 FU 5 fluorouracil and oleanolic acid derivate while being encapsulated in chitosan, obtains chitosan microball.Described neat pier
Fruit acid derivative is oleanolic acid or neat butyl ester.
It is preferred that, the chitosan microball containing 5 FU 5 fluorouracil and oleanolic acid derivate simultaneously, 5 FU 5 fluorouracil and shell
The mass ratio of glycan is 1:10-30；The mass ratio of oleanolic acid derivate and chitosan is 1:10-30.
A kind of preparation method of chitosan microball simultaneously containing 5 FU 5 fluorouracil and oleanolic acid derivate, method is such as
Under：Chitosan is dissolved in acetum, chitosan-acetic acid solution is obtained；Oleanolic acid or neat butyl ester are dissolved in organic solvent
In, obtain solution A；5 FU 5 fluorouracil is dissolved in distilled water or cushioning liquid, solution B is obtained；, will be molten under rapid mixing conditions
Liquid A and solution B are added in chitosan-acetic acid solution, after stirring and emulsifying 15-45min, obtain solution C；Sodium tripolyphosphate is added dropwise molten
After liquid, completion of dropping, continue to stir 20-40min, produce targeted microspheres.
It is preferred that, the concentration of chitosan-acetic acid solution is 1.0-3.0%.
It is preferred that, the mass percentage concentration of oleanolic acid or neat butyl ester is 0.05-5.00% in solution A.Described is organic
Solvent is ethanol, acetone, dimethylformamide (DMF), dimethyl acetamide (DMA) or dimethyl sulfoxide (DMSO).
It is preferred that, in solution B, the concentration of 5 FU 5 fluorouracil is 100-300mg/ml.Described cushioning liquid is that pH is
2.0-8.0 phosphate buffer, acetate buffer or citrate buffer.
It is preferred that, the concentration of sodium tripolyphosphate (TPP) solution is 0.05-10.0%, sodium tripolyphosphate solution and solution C
Volume ratio is 1：10-100.
The beneficial effects of the invention are as follows：
1. by preparing the compound preparation of a chitosan microball, 5 FU 5 fluorouracil and neat butyl ester are encapsulated in one simultaneously
In chitosan microball, both synergistic antitumor effects are played.
2. the preparation method of the present invention is simple and reliable, process route is ripe, easily realizes industrialized production.
3. chitosan microball is a kind of novel targeted delivery system.The present invention encapsulates 5 FU 5 fluorouracil and neat butyl ester simultaneously
In a chitosan microball, chitosan microball is made, medicine stability is both improved, toxic side effect is reduced, life is improved
Thing availability, and method of administration is changed, increase the passive of medicine using the EPR effects near in-vivo tumour and inflammatory tissue
Targeting Performance.
4. the chitosan microball prepared using the method for the present invention, it is 563 ± 101nm, zeta current potentials as a result to show particle diameter
For 49.13 ± 1.99mv, the envelop rate of 5 FU 5 fluorouracil is good, and globulate is good.Pass through the release experiment of medicine, release in vitro research
Show, chitosan microball prepared by the present invention has certain slow releasing function in pH value is 7.40 buffer solution.
Brief description of the drawings
Fig. 1 is releasing result of the chitosan microball of the preparation of embodiment 3 in the buffer solution of different pH value.
Embodiment
It is prepared by the Succinyl oleanolic acid of embodiment 1 (neat butyl ester)
1.14g (2.5mmol) oleanolic acid, 1.25g (12.5mmol) succinic anhydride are added in there-necked flask respectively, with first
Benzene dissolving is complete, adds DMAP 1.53g (12.5mmol).65 DEG C of insulation, stirring reaction 3 hours, silica gel plate expansion detection is former
Shots disappearance (mobile phase：Ethyl acetate:Petroleum ether=3:1) reaction, is stopped.After solvent evaporated, ethyl acetate dissolving, using PH as
1 hydrochloric acid solution washing, then to distill water washing to neutrality, take ethyl acetate layer to be spin-dried for white powder product is target production
Thing, yield 95.0%.
The optimization of the preparation process for chitosan microsphere condition of embodiment 2
Method：In the acetum that chitosan is dissolved in 1% (v/v), chitosan-acetic acid solution is obtained；Neat butyl ester is dissolved in
In ethanol, the solution A that neat butyl ester concentration is 0.5% (m/m) is obtained；5 FU 5 fluorouracil is dissolved in distilled water, 5- fluorine urine is obtained phonetic
Pyridine (5-Fu) concentration is 200mg/ml solution B；Under rapid mixing conditions, solution A and solution B are proportionally added into shell and gathered
In sweet and sour acid solution, after stirring and emulsifying, solution C is obtained；Sodium tripolyphosphate (TPP) solution, sodium tripolyphosphate solution and solution C is added dropwise
Volume ratio be 1:100, after completion of dropping, continue to stir 30min, produce targeted microspheres.G-50 exclusion chromatographies are surveyed:5- fluorine is urinated
The envelop rate of pyrimidine.
(1) influence of chitosan concentration
The mass ratio 1 of neat butyl ester and chitosan:20；The mass ratio 1 of 5-Fu and chitosan:20；TPP concentration is 0.20%
(m/m), the stirring and emulsifying time is 15min, when investigation chitosan-acetic acid solution concentration is respectively 1.0,2.0,3.0%, 5- fluorine urine
The envelop rate of pyrimidine, as a result such as table 1.
The influence of the chitosan concentration of table 1
From table 1, as chitosan concentration increases, encapsulating takes the lead in reducing after increase, and can be with from the product of preparation
Will become apparent from concentration for 3% when, microballoon is very uneven, and spheroid form is bad, the microspherulite diameter obtained when chitosan concentration is big
It is larger.
(2) influence that neat butyl ester is added
The concentration of chitosan-acetic acid solution is the mass ratio 1 of 2.0%, 5-Fu and chitosan:20；TPP concentration is
0.20% (m/m), the stirring and emulsifying time is 15min, and the mass ratio for investigating neat butyl ester and chitosan is 1:10,1:20,1:When 30,
The envelop rate of 5 FU 5 fluorouracil, as a result such as table 2.
The influence that the neat butyl ester of table 2 is added
From table 2, as a result show, in the range of investigation, the encapsulating of the increase of neat butyl ester addition to 5 FU 5 fluorouracil
Rate has certain influence, and 1:The envelop rate of 5 FU 5 fluorouracil when 20 is maximum.Now, the addition for being further added by neat butyl ester is led
The envelop rate reduction of 5 FU 5 fluorouracil is caused, reason is probably that neat butyl ester has exceeded the maximum suction that chitosan microball structure can bear
Attached amount, causes 5 FU 5 fluorouracil encapsulating decline.
(3) influence of the ratio of 5-Fu and chitosan
The concentration of chitosan-acetic acid solution is the mass ratio 1 of 2.0%, SOA and chitosan:20, TPP concentration is 0.20%
(m/m), the stirring and emulsifying time is 15min, and the mass ratio that 5-Fu and chitosan are investigated respectively is 1:10,1:20,1:When 30,5- fluorine
The envelop rate of uracil, as a result such as table 3.
The influence of the ratio of the 5-Fu of table 3 and chitosan
From table 3, in the range of investigation, with the increase of 5 FU 5 fluorouracil addition, envelop rate increase urinates phonetic in 5- fluorine
The mass ratio of pyridine and chitosan is 1:Envelop rate when 20 reaches maximum, with the increase again of 5 FU 5 fluorouracil, chitosan microball
All 5 FU 5 fluorouracils can not be coated, cause envelop rate to reduce.
(4) influence of emulsification times
The concentration of chitosan-acetic acid solution is the mass ratio 1 of 2.0%, SOA and chitosan:20,5-Fu and the matter of chitosan
Amount compares 1:20, TPP concentration is 0.20% (m/m), and emulsification times difference 15min, 30min, during 45min, 5- fluorine are investigated respectively
The envelop rate of uracil, as a result such as table 4.
The influence of the emulsification times of table 4
From table 4, experimental result is shown, in the range of investigation, and emulsification times have for the envelop rate of 5 FU 5 fluorouracil
Considerable influence.
(5) selection of TPP concentration
The concentration of chitosan-acetic acid solution is the mass ratio 1 of 2.0%, SOA and chitosan:20,5-Fu and the matter of chitosan
Amount compares 1:20, emulsification times 15min, when investigation TPP concentration is 0.05,0.10,0.20,0.30,1.0,5.0,10.0% respectively,
The envelop rate of 5 FU 5 fluorouracil, as a result such as table 5.
The selection of the TPP concentration of table 5
From table 5, with the increase of TPP concentration, envelop rate is in gradually increase tendency substantially, but when concentration is more than
When 0.3%, the microballoon of preparation, particle diameter is big, and balling-up is uneven, occurs bonding situation.
(6) optimization of orthogonal test result
On the basis of single factor exploration, mass ratio, neat butyl ester and the shell of selection chitosan concentration, 5-Fu and chitosan are poly-
The mass ratio of sugar, four factors of emulsification times, design L9(34) orthogonal experiment, the preparation technology of further Optimization of Chitosan Microspheres.
As a result such as table 6.
The optimization of orthogonal test result of table 6
From table 6, it is 5-Fu and mass ratio, the chitosan of chitosan to influence the descending order of the factor of envelop rate
Concentration, the mass ratio of neat butyl ester and chitosan, emulsification times.It is final to determine that optimum experimental condition is chitosan concentration
The mass ratio 1 of 2.00%, SOA and chitosan:20；The ratio of 5 FU 5 fluorouracil and chitosan is 1:10, emulsifying temperature is 25 DEG C,
Emulsification times are 30min, and TPP concentration is 0.20%, and crosslinking temperature is 25 DEG C.
The chitosan microball containing 5 FU 5 fluorouracil and neat butyl ester simultaneously of embodiment 3
(1) preparation method
In the acetum that chitosan is dissolved in 1.0% (v/v), the chitosan acetic acid that concentration is 2.00% (m/m) is obtained molten
Liquid；Neat butyl ester is dissolved in ethanol, the solution A that neat butyl ester concentration is 0.5% (m/m) is obtained；5 FU 5 fluorouracil is dissolved in steaming
In distilled water, the solution B that 5 FU 5 fluorouracil concentration is 200mg/ml is obtained；In proportion, the mass ratio 1 of SOA and chitosan:20,5- fluorine
The mass ratio 1 of uracil and chitosan:10 take solution A and solution B, under rapid mixing conditions, and solution A and solution B are added
Into chitosan-acetic acid solution, after stirring and emulsifying 30min, solution C is obtained；0.20% sodium tripolyphosphate (TPP) solution, three is added dropwise
The volume ratio of polyphosphate sodium solution and solution C is 1:50, after completion of dropping, continue to stir 30min, produce targeted microspheres.
(2) testing result
G-50 exclusion chromatographies survey the envelop rate of 5 FU 5 fluorouracil, and the envelop rate of 5 FU 5 fluorouracil is 52.23 ± 1.76%,
5 FU 5 fluorouracil drugloading rate is the 20.0% of chitosan mass, and the drugloading rate of neat butyl ester is the 20.0% of chitosan mass.
Thus obtained microsphere is surveyed after appropriate dilution using laser particle analyzer (Nano-ZS 90, Malvern Instr Ltd.)
The particle mean size for obtaining microballoon is 563 ± 101nm, and thus obtained microsphere form rounding, surface is smooth, uniform particle sizes.
Thus obtained microsphere uses Nano-ZS 90 to determine its zetaz current potential for 49.13 ± 1.99mv, said after appropriate dilution
The bright system has larger positive charge, more stable.
(3) release in vitro of microballoon
Precision weighs appropriate chitosan microball, is placed in bag filter MwCO 8000, in pH value be respectively 1.4,7.4 phosphorus
In phthalate buffer, in 37 ± 0.5 DEG C of waters bath with thermostatic control, stirring, timing sampling investigates its release conditions.Calculate 5 FU 5 fluorouracil
Cumulative percentage release.As a result it is as shown in Figure 1.In pH value in 7.4 buffer solution, the microballoon has one to 5 FU 5 fluorouracil
Fixed slow release effect.Thus obtained microsphere has certain burst effect it can be seen from release test result.At 10 minutes of beginning
Interior, the burst size of medicine reaches 20% or so, and later stage release slows down.The quick release for starting appearance is foreign minister's medicine in microballoon
Quick release, diffusional resistance very little, rate of release is fast.After after foreign minister's medicine completely release, the medicine inside microballoon is due to microballoon
The retardance and suction-operated of carrier material cause slow release.Meanwhile, the strong electronegativity atom (O, N, F) in 5-Fu gathers with shell
- OH hydrogen atoms in glycan molecule form stronger hydrogen bond, or hydrogen atom and the oxygen in CS molecules in the-NH- in 5-Fu
Hydrogen bond is formd between atom and nitrogen-atoms, with the extension of release time, the hydrogen bond between 5-Fu and chitosan is destroyed, 5-
Fu is gradually slowly released from microballoon.In addition, rate of release of the microballoon in sour environment is than fast in neutral environment.
This is probably that the amino of hydrogen ion and microsphere surface in strong acid environment combines to form ammonium salt quickly, makes microsphere surface comparatively fast molten
Swollen, macromolecular chain stretches, and cross-linked network aperture increases, medicine and medium molecule easily pass in and out and discharge medicine, therefore cause medicine
The release of thing is very fast.
Influence of the different organic solvents of embodiment 4 to 5 FU 5 fluorouracil chitosan microball envelop rate
Method be the same as Example 3, replaces organic solvent.As a result such as table 7.
The influence of the organic solvent of table 7
The envelop rate of 5 FU 5 fluorouracil chitosan microball in the different cushioning liquid of embodiment 5
Method be the same as Example 3, cushioning liquid is replaced with by distilled water.As a result such as table 8.
The envelop rate of 5 FU 5 fluorouracil chitosan microball in the different cushioning liquid of table 8
Claims (2)
1. the chitosan microball containing 5 FU 5 fluorouracil and oleanolic acid derivate simultaneously, it is characterised in that：By 5 FU 5 fluorouracil
It is encapsulated in simultaneously in chitosan with oleanolic acid derivate, obtains chitosan microball；Described oleanolic acid derivate is neat pier
Tartaric acid or Succinyl oleanolic acid；The mass ratio of 5 FU 5 fluorouracil and chitosan is 1: 10-30；Oleanolic acid derives
The mass ratio of thing and chitosan is 1: 10-30.
2. a kind of preparation method of chitosan microball simultaneously containing 5 FU 5 fluorouracil and oleanolic acid derivate, it is characterised in that
Method is as follows：Chitosan is dissolved in acetum, chitosan-acetic acid solution is obtained；By oleanolic acid or oleanolic acid succinic acid list
Ester is dissolved in organic solvent, obtains solution A；5 FU 5 fluorouracil is dissolved in distilled water or cushioning liquid, solution B is obtained；Fast
Under fast stirring condition, solution A and solution B are added in chitosan-acetic acid solution, after stirring and emulsifying 15-45 min, solution is obtained
C；It is added dropwise after sodium tripolyphosphate solution, completion of dropping, continues to stir 20-40 min, produce targeted microspheres；Chitosan-acetic acid solution
Concentration be 1.0-3.0 %；In solution A, the mass percentage concentration of oleanolic acid or Succinyl oleanolic acid is 0.05-
5.00 %；Described organic solvent is ethanol, acetone, dimethylformamide, dimethyl acetamide or dimethyl sulfoxide；In solution B,
The concentration of 5 FU 5 fluorouracil is 100-300 mg/ml；Described cushioning liquid is the phosphate buffer that pH is 2.0-8.0, vinegar
Phthalate buffer or citrate buffer；The concentration of sodium tripolyphosphate solution be 0.05-10.0 %, sodium tripolyphosphate solution with
The volume ratio of solution C is 1：10-100.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510115395.4A CN104666308B (en) | 2015-03-16 | 2015-03-16 | Chitosan microball simultaneously containing 5 fluorouracils and oleanolic acid derivate and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510115395.4A CN104666308B (en) | 2015-03-16 | 2015-03-16 | Chitosan microball simultaneously containing 5 fluorouracils and oleanolic acid derivate and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104666308A CN104666308A (en) | 2015-06-03 |
| CN104666308B true CN104666308B (en) | 2017-08-29 |
Family
ID=53302248
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510115395.4A Active CN104666308B (en) | 2015-03-16 | 2015-03-16 | Chitosan microball simultaneously containing 5 fluorouracils and oleanolic acid derivate and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104666308B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112618550A (en) * | 2021-01-15 | 2021-04-09 | 中国医学科学院医药生物技术研究所 | Antineoplastic uracil compound and lipid composition thereof |
-
2015
- 2015-03-16 CN CN201510115395.4A patent/CN104666308B/en active Active
Non-Patent Citations (4)
| Title |
|---|
| 5-氟尿嘧啶 /壳聚糖载药纳米微球的制备及性能;杨培慧等;《化学研究与应用》;20090131;第21卷(第1期);第42-46页 * |
| Oleanolic acid potentiates the antitumor activity of 5-fluorouracil in pancreatic cancer cells;JIANTENG WEI等;《ONCOLOGY REPORTS》;20121231;第28卷;第1339-1345页 * |
| Synthesis and cytotoxicity evaluation of oleanolic acid derivatives;Jia Hao等;《Bioorganic & Medicinal Chemistry Letters》;20130208;第23卷;第2074–2077页 * |
| 离子交联法制备氟尿嘧啶壳聚糖微球;杨春梅等;《华东理工大学学报（自然科学版）》;20100831;第36卷(第4期);第546-549页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104666308A (en) | 2015-06-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Xu et al. | Microwave responsive nanoplatform via P-selectin mediated drug delivery for treatment of hepatocellular carcinoma with distant metastasis | |
| CN110859826B (en) | Brain tumor targeted bionic drug-loaded nanoparticle and preparation method and application thereof | |
| CN107149592B (en) | Biological self-assembly nano-crystalline injection and preparation method with lympha targeted function | |
| US9624237B2 (en) | Oridonin functionalized selenium nanoparticles and method of preparation thereof | |
| CN104530256B (en) | Hyaluronic acid-vitamin E succinate polymer as well as preparation and application thereof | |
| CN107737348B (en) | Preparation method of lung cancer targeted self-assembly nanoparticles | |
| CN106083769A (en) | A kind of reduce response prodrugs of paclitaxel and prepare nano-micelle carrier method | |
| CN104013968B (en) | A kind of modified with folic acid cholesterol hydrophobically modified sodium alginate self-assembled nanometer grain and its preparation method and application | |
| Hu et al. | Chitooligosaccharides-modified PLGA nanoparticles enhance the antitumor efficacy of AZD9291 (Osimertinib) by promoting apoptosis | |
| Yan et al. | In vivo biodistribution for tumor targeting of 5-fluorouracil (5-FU) loaded N-succinyl-chitosan (Suc-Chi) nanoparticles | |
| CN101708337B (en) | Preparation method of human serum albumin nano granules coated with oxaliplatin | |
| CN105106176A (en) | Degradable organic silicon nanocapsule drug carrier as well as preparation method and application thereof | |
| CN105944108B (en) | PH sensitivity modifier of liposome containing menthone ketal and paclitaxel-curcumin compound liposome preparation | |
| CN104666308B (en) | Chitosan microball simultaneously containing 5 fluorouracils and oleanolic acid derivate and preparation method thereof | |
| CN104666247A (en) | Heparin-modified cleavable adriamycin liposome preparation and preparation method thereof | |
| Zhou et al. | A deep tumor penetration nanoplatform for glycolysis inhibition and antimetastasis of breast cancer | |
| CN103655484A (en) | Method for preparing paclitaxel sustained-release microspheres by use of self-assembly technology and product thereof | |
| CN108524951A (en) | A kind of Sorafenib nanometer formulation with liver tumour targeting | |
| CN105919935B (en) | Sorafenib medicine lipid nano suspension and preparation method thereof | |
| CN112741828B (en) | Drug combination and preparation method and application thereof | |
| Arulanandraj et al. | NANOTECHNOLOGICAL APPROACH TO ENHANCE THE STABILITY AND BIOAVAILABILITY OF THE HERBAL DRUG" MURVA" | |
| CN107735108A (en) | A kind of PEGylation vitamin E periplocymarin conjugate nanoparticle and its preparation method and purposes | |
| Miao et al. | Preparation of DOX/BSANP and its antitumor effect on bel-7404 liver cancer cells in vitro and in vivo | |
| CN105693544B (en) | Small molecule material and preparation method and application for antineoplastic delivering | |
| CN103263671A (en) | Preparation and application of anti-tumor activator nanostructure lipid carrier |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |