CN104666308A - Chitosan microsphere simultaneously containing 5-fluorouracil and oleanolic acid derivative and preparation method of chitosan microsphere - Google Patents
Chitosan microsphere simultaneously containing 5-fluorouracil and oleanolic acid derivative and preparation method of chitosan microsphere Download PDFInfo
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- CN104666308A CN104666308A CN201510115395.4A CN201510115395A CN104666308A CN 104666308 A CN104666308 A CN 104666308A CN 201510115395 A CN201510115395 A CN 201510115395A CN 104666308 A CN104666308 A CN 104666308A
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Abstract
The invention discloses a chitosan microsphere simultaneously containing 5-fluorouracil and an oleanolic acid derivative and a preparation method of the chitosan microsphere. The preparation method comprises the following steps: firstly adopting an ionic crosslinking method to prepare a chitosan microsphere simultaneously coating 5-fluorouracil and succinyl oleanolate, wherein the obtained microsphere is round in form, smooth in surface and uniform in particle size; the encapsulation efficiency of 5-fluorouracil is 52.23+/-1.76%; the average particle size is 563+/-101 nm. The preparation method disclosed by the invention is stable and reliable in process; the obtained chitosan microsphere is good in slow release effect and meanwhile can play the synergetic anti-tumor function of 5-fluorouracil and the oleanolic acid derivative.
Description
Technical field
The present invention relates to medical art, particularly relate to chitosan microball simultaneously containing 5-fluorouracil and oleanolic acid derivate and preparation method thereof.
Background technology
Cancer is one of the highest disease of China's sickness rate and fatality rate, and health of people in serious threat.The treatment means of current cancer is mainly limited to operation, radiotherapy and chemotherapy three kinds of methods.The chemotherapy of tumor is extensive owing to having applicable surface, and the features such as toxic and side effects is relatively little, occupy critical role in the treatment of tumor.5-fluorouracil (5-fluorouracil, 5-FU) is a kind of important clinical conventional anti-metabolism antitumor drug, is widely used in the treatment for the treatment of digestive tract cancer, breast carcinoma and various solid tumor.Research shows, 5-fluorouracil (5-FU) half-life about 10 ~ 20min in vivo, oral absorption is irregular, and bioavailability is lower, needs frequent drug administration.The toxic and side effects of 5-fluorouracil mainly comprises digestive tract reaction symptom and the bone marrow depression such as leukocyte, thrombocytopenia such as diarrhoea, vomiting.Research shows, the antitumor action of 5-fluorouracil and its local concentration at tumor locus and action time closely related.In order to extend drug effect, reduce toxic and side effects, Chinese scholars has carried out large quantifier elimination to the prodrug of 5-fluorouracil and dosage form, develop and the prodrug such as carmofur, ftorafur, floxuridine and fludarabine that gone on the market, simultaneously also at the various 5-fluorouracil novel form of research, comprise microsphere, liposome, nanoparticle etc.But in prior art, mostly just 5-fluorouracil is prepared into suitable form of administration by research, does not consider coupling and the cooperative effect of medicine.
Summary of the invention
The object of the invention is 5-fluorouracil (5-FU) and oleanolic acid (OA) or derivatives thereof to be encapsulated in a chitosan microball, the synergistic antitumor effect of both performances simultaneously.
To achieve these goals, the present invention, first adopts chemical synthesis process to prepare the derivant Succinyl oleanolic acid (Succinyl oleanolic acid (SOA), neat butyl ester) of oleanolic acid.Secondly, adopt ionic cross-linking to prepare chitosan microball, with envelop rate and drug loading for index, the chitosan microball of 5-fluorouracil and oleanolic acid is encapsulated in preparation simultaneously.
The technical solution used in the present invention is: the chitosan microball simultaneously containing 5-fluorouracil and oleanolic acid derivate, is 5-fluorouracil and oleanolic acid derivate are encapsulated in chitosan simultaneously, obtains chitosan microball.Described oleanolic acid derivate is oleanolic acid or neat butyl ester.
Preferably, contain the chitosan microball of 5-fluorouracil and oleanolic acid derivate, the mass ratio of 5-fluorouracil and chitosan is 1:10-30 simultaneously; The mass ratio of oleanolic acid derivate and chitosan is 1:10-30.
Contain a preparation method for the chitosan microball of 5-fluorouracil and oleanolic acid derivate, method is as follows: be dissolved in by chitosan in acetum, obtain chitosan-acetic acid solution simultaneously; Oleanolic acid or neat butyl ester are dissolved in organic solvent, obtain solution A; 5-fluorouracil is dissolved in distilled water or buffer solution, obtains solution B; Under rapid mixing conditions, solution A and solution B are joined in chitosan-acetic acid solution, after stirring and emulsifying 15-45min, obtain solution C; Drip sodium tripolyphosphate solution, after dropwising, continue to stir 20-40min, obtain targeted microspheres.
Preferably, the concentration of chitosan-acetic acid solution is 1.0-3.0%.
Preferably, in solution A, the mass percentage concentration of oleanolic acid or neat butyl ester is 0.05-5.00%.Described organic solvent is ethanol, acetone, dimethyl formamide (DMF), dimethyl acetylamide (DMA) or dimethyl sulfoxine (DMSO).
Preferably, in solution B, the concentration of 5-fluorouracil is 100-300mg/ml.The phosphate buffer of described buffer solution to be pH be 2.0-8.0, acetate buffer or citrate buffer.
Preferably, the concentration of sodium tripolyphosphate (TPP) solution is 0.05-10.0%, and the volume ratio of sodium tripolyphosphate solution and solution C is 1:10-100.
The invention has the beneficial effects as follows:
1., by the compound preparation of a preparation chitosan microball, 5-fluorouracil and neat butyl ester are encapsulated in simultaneously in a chitosan microball, the synergistic antitumor effect of both performances.
2. preparation method of the present invention is simple and reliable, and process route is ripe, easily realizes suitability for industrialized production.
3. chitosan microball is a kind of novel targeted drug-supplying system.5-fluorouracil and neat butyl ester are encapsulated in a chitosan microball by the present invention simultaneously, make chitosan microball, both improve medicine stability, reduce toxic and side effects, improve bioavailability, and change route of administration, utilize the EPR effect near in-vivo tumour and inflammatory tissue to increase the passive target performance of medicine.
4. adopt chitosan microball prepared by method of the present invention, result display particle diameter is 563 ± 101nm, zeta current potential is 49.13 ± 1.99mv, and the envelop rate of 5-fluorouracil is good, and globulate is good.By the release experiment of medicine, release in vitro research shows, chitosan microball prepared by the present invention is have certain slow releasing function in the buffer of 7.40 at pH value.
Accompanying drawing explanation
Fig. 1 is the release result of chitosan microball in the buffer of different pH value prepared by embodiment 3.
Detailed description of the invention
Prepared by embodiment 1 Succinyl oleanolic acid (neat butyl ester)
Respectively 1.14g (2.5mmol) oleanolic acid, 1.25g (12.5mmol) succinic anhydride are added in there-necked flask, dissolve completely with toluene, then add DMAP 1.53g (12.5mmol).Be incubated 65 DEG C, stirring reaction 3 hours, silica gel plate launches to detect raw material point and disappears (mobile phase: ethyl acetate: petroleum ether=3:1), stopped reaction.After solvent evaporated, acetic acid ethyl dissolution, take PH as the hydrochloric acid solution washing of 1, then with distilled water wash to neutral, gets ethyl acetate layer and be spin-dried for white powder product is target product, yield 95.0%.
The optimization of embodiment 2 preparation process for chitosan microsphere condition
Method: chitosan is dissolved in the acetum of 1% (v/v), obtains chitosan-acetic acid solution; Neat butyl ester is dissolved in ethanol, obtains the solution A that neat butyl ester concentration is 0.5% (m/m); Be dissolved in by 5-fluorouracil in distilled water, obtaining 5-fluorouracil (5-Fu) concentration is the solution B of 200mg/ml; Under rapid mixing conditions, solution A and solution B are joined in chitosan-acetic acid solution in proportion, after stirring and emulsifying, obtains solution C; Drip sodium tripolyphosphate (TPP) solution, the volume ratio of sodium tripolyphosphate solution and solution C is 1:100, after dropwising, continues to stir 30min, obtains targeted microspheres.G-50 gel chromatography is surveyed: the envelop rate of 5-fluorouracil.
(1) impact of chitosan concentration
The mass ratio 1:20 of neat butyl ester and chitosan; The mass ratio 1:20 of 5-Fu and chitosan; The concentration of TPP is 0.20% (m/m), and the stirring and emulsifying time is 15min, and when investigation chitosan-acetic acid solution concentration is respectively 1.0,2.0,3.0%, the envelop rate of 5-fluorouracil, result is as table 1.
The impact of table 1 chitosan concentration
From table 1, along with chitosan concentration increase, encapsulating take the lead in increasing rear reduction, and as apparent from preparation product can concentration be 3% time, microsphere is very uneven, and spheroid form is bad, and the microspherulite diameter obtained when chitosan concentration is large is also larger.
(2) impact that adds of neat butyl ester
The concentration of chitosan-acetic acid solution is the mass ratio 1:20 of 2.0%, 5-Fu and chitosan; The concentration of TPP is 0.20% (m/m), and the stirring and emulsifying time is 15min, and when the mass ratio investigating neat butyl ester and chitosan is 1:10,1:20,1:30, the envelop rate of 5-fluorouracil, result is as table 2.
The impact that the neat butyl ester of table 2 adds
From table 2, result shows, and within the scope of investigation, the envelop rate of increase to 5-fluorouracil of neat butyl ester addition has certain influence, and the envelop rate of 5-fluorouracil when 1:20 is maximum.Now, then the addition increasing neat butyl ester causes the envelop rate of 5-fluorouracil to reduce, and reason may be the maximal absorptive capacity that neat butyl ester has exceeded chitosan microball structure and can bear, and causes 5-fluorouracil to be encapsulated and declines.
(3) impact of the ratio of 5-Fu and chitosan
The concentration of chitosan-acetic acid solution is 2.0%, the mass ratio 1:20 of SOA and chitosan, the concentration of TPP is 0.20% (m/m), the stirring and emulsifying time is 15min, when the mass ratio of investigation 5-Fu and chitosan is 1:10,1:20,1:30 respectively, the envelop rate of 5-fluorouracil, result is as table 3.
The impact of the ratio of table 3 5-Fu and chitosan
From table 3, in the scope investigated, increase with 5-fluorouracil addition, envelop rate increases, envelop rate when the mass ratio of 5-fluorouracil and chitosan is 1:20 reaches maximum, with the increase again of 5-fluorouracil, chitosan microball can not coated all 5-fluorouracil, cause envelop rate to reduce.
(4) impact of emulsification times
The concentration of chitosan-acetic acid solution is the mass ratio 1:20 of 2.0%, SOA and chitosan, the mass ratio 1:20 of 5-Fu and chitosan, the concentration of TPP is 0.20% (m/m), investigates emulsification times 15min, 30min respectively respectively, during 45min, the envelop rate of 5-fluorouracil, result is as table 4.
The impact of table 4 emulsification times
From table 4, experimental result shows, and within the scope of investigation, emulsification times has considerable influence for the envelop rate of 5-fluorouracil.
(5) selection of TPP concentration
The concentration of chitosan-acetic acid solution is the mass ratio 1:20 of 2.0%, SOA and chitosan, the mass ratio 1:20 of 5-Fu and chitosan, emulsification times 15min, investigating TPP concentration is respectively 0.05,0.10,0.20,0.30,1.0,5.0,10.0% time, the envelop rate of 5-fluorouracil, result is as table 5.
The selection of table 5 TPP concentration
From table 5, with the increase of TPP concentration, envelop rate is increase tendency gradually substantially, but when concentration is greater than 0.3%, the microsphere of preparation, particle diameter is large, and balling-up is uneven, occurs bonding situation.
(6) optimization of orthogonal test result
On the basis of single factor exploration, select mass ratio, emulsification times four factors of the mass ratio of chitosan concentration, 5-Fu and chitosan, neat butyl ester and chitosan, design L
9(3
4) orthogonal experiment, the preparation technology of further Optimization of Chitosan Microspheres.Result is as table 6.
Table 6 optimization of orthogonal test result
From table 6, affect mass ratio, the emulsification times of mass ratio, the concentration of chitosan, neat butyl ester and the chitosan that the descending order of the factor of envelop rate is 5-Fu and chitosan.Finally determine that optimum experimental condition is the mass ratio 1:20 of chitosan concentration 2.00%, SOA and chitosan; The ratio of 5-fluorouracil and chitosan is 1:10, and emulsifying temperature is 25 DEG C, and emulsification times is 30min, TPP concentration is 0.20%, and crosslinking temperature is 25 DEG C.
Embodiment 3 contains the chitosan microball of 5-fluorouracil and neat butyl ester simultaneously
(1) preparation method
Chitosan is dissolved in the acetum of 1.0% (v/v), obtains the chitosan-acetic acid solution that concentration is 2.00% (m/m); Neat butyl ester is dissolved in ethanol, obtains the solution A that neat butyl ester concentration is 0.5% (m/m); 5-fluorouracil is dissolved in distilled water, obtains the solution B that 5-fluorouracil concentration is 200mg/ml; In proportion, the mass ratio 1:20 of SOA and chitosan, the mass ratio 1:10 of 5-fluorouracil and chitosan gets solution A and solution B, under rapid mixing conditions, joins in chitosan-acetic acid solution by solution A and solution B, after stirring and emulsifying 30min, obtains solution C; Drip sodium tripolyphosphate (TPP) solution of 0.20%, the volume ratio of sodium tripolyphosphate solution and solution C is 1:50, after dropwising, continues to stir 30min, obtains targeted microspheres.
(2) testing result
G-50 gel chromatography surveys the envelop rate of 5-fluorouracil, and the envelop rate of 5-fluorouracil is 52.23 ± 1.76%, and 5-fluorouracil drug loading is 20.0% of chitosan mass, and the drug loading of neat butyl ester is 20.0% of chitosan mass.
Thus obtained microsphere is after suitably diluting, and the particle mean size adopting laser particle analyzer (Nano – ZS 90, Malvern Instr Ltd.) to record microsphere is 563 ± 101nm, thus obtained microsphere form rounding, smooth surface, uniform particle sizes.
Thus obtained microsphere is after suitably diluting, and adopting Nano-ZS 90 to measure its zetaz current potential is 49.13 ± 1.99mv, illustrates that this system has larger positive charge, more stable.
(3) release in vitro of microsphere
Precision takes appropriate chitosan microball, is placed in bag filter MwCO 8000, is respectively in the phosphate buffer of 1.4,7.4 in pH value, and in 37 ± 0.5 DEG C of waters bath with thermostatic control, stir, its release conditions investigated by timing sampling.Calculate the cumulative percentage release of 5-fluorouracil.Result as shown in Figure 1.Be that in the buffer of 7.4, this microsphere has certain slow release effect to 5-fluorouracil at pH value.As can be seen from release test result, thus obtained microsphere has certain burst effect.In 10 minutes that start, the burst size of medicine reaches about 20%, and later stage release slows down.The quick release starting to occur is that the foreign minister's medicine in microsphere discharges fast, and diffusional resistance is very little, and rate of release is fast.After foreign minister's medicine discharges completely, the medicine of microsphere inside causes slow releasing due to the retardance of microspherical carrier material and adsorption.Simultaneously, strong electronegativity atom (O, N, F) in 5-Fu defines stronger hydrogen bond with the-OH hydrogen atom in chitosan molecule, or define hydrogen bond between the oxygen atom in the-NH-in 5-Fu in hydrogen atom and CS molecule and nitrogen-atoms, along with the prolongation of release time, hydrogen bond between 5-Fu and chitosan is destroyed, and 5-Fu slowly releases gradually from microsphere.In addition, fast than in neutral environment of the rate of release of microsphere in sour environment.This may be that hydrion is combined very soon with the amino of microsphere surface and forms ammonium salt in strong acid environment, make microsphere surface comparatively fast swelling, macromolecular chain stretches, and cross-linked network aperture increases, medicine and medium molecule easily pass in and out and discharge medicine, therefore cause the release of medicine very fast.
Embodiment 4 different organic solvents is on the impact of 5-fluorouracil chitosan microball envelop rate
Method, with embodiment 3, replaces organic solvent.Result is as table 7.
The impact of table 7 organic solvent
The envelop rate of 5-fluorouracil chitosan microball in the different buffer solution of embodiment 5
Distilled water, with embodiment 3, is replaced with buffer solution by method.Result is as table 8.
The envelop rate of 5-fluorouracil chitosan microball in the different buffer solution of table 8
Claims (10)
1. contain the chitosan microball of 5-fluorouracil and oleanolic acid derivate simultaneously, it is characterized in that: 5-fluorouracil and oleanolic acid derivate are encapsulated in chitosan simultaneously, obtain chitosan microball.
2. the chitosan microball simultaneously containing 5-fluorouracil and oleanolic acid derivate as claimed in claim 1, is characterized in that: described oleanolic acid derivate is oleanolic acid or Succinyl oleanolic acid.
3. the chitosan microball simultaneously containing 5-fluorouracil and oleanolic acid derivate as claimed in claim 1, is characterized in that: the mass ratio of 5-fluorouracil and chitosan is 1:10-30; The mass ratio of oleanolic acid derivate and chitosan is 1:10-30.
4. contain a preparation method for the chitosan microball of 5-fluorouracil and oleanolic acid derivate simultaneously, it is characterized in that method is as follows: be dissolved in by chitosan in acetum, obtain chitosan-acetic acid solution; Oleanolic acid or Succinyl oleanolic acid are dissolved in organic solvent, obtain solution A; 5-fluorouracil is dissolved in distilled water or buffer solution, obtains solution B; Under rapid mixing conditions, solution A and solution B are joined in chitosan-acetic acid solution, after stirring and emulsifying 15-45min, obtain solution C; Drip sodium tripolyphosphate solution, after dropwising, continue to stir 20-40min, obtain targeted microspheres.
5. method as claimed in claim 4, is characterized in that: the concentration of chitosan-acetic acid solution is 1.0-3.0%.
6. method as claimed in claim 4, it is characterized in that: in solution A, the mass percentage concentration of oleanolic acid or Succinyl oleanolic acid is 0.05-5.00%.
7. method as claimed in claim 4, is characterized in that: described organic solvent is ethanol, acetone, dimethyl formamide, dimethyl acetylamide or dimethyl sulfoxine.
8. method as claimed in claim 4, it is characterized in that: in solution B, the concentration of 5-fluorouracil is 100-300mg/ml.
9. method as claimed in claim 4, is characterized in that: the phosphate buffer of described buffer solution to be pH be 2.0-8.0, acetate buffer or citrate buffer.
10. method as claimed in claim 4, it is characterized in that: the concentration of sodium tripolyphosphate solution is 0.05-10.0%, the volume ratio of sodium tripolyphosphate solution and solution C is 1:10-100.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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| JIA HAO等: "Synthesis and cytotoxicity evaluation of oleanolic acid derivatives", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| JIANTENG WEI等: "Oleanolic acid potentiates the antitumor activity of 5-fluorouracil in pancreatic cancer cells", 《ONCOLOGY REPORTS》 * |
| 杨培慧等: "5-氟尿嘧啶 /壳聚糖载药纳米微球的制备及性能", 《化学研究与应用》 * |
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Cited By (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 |
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