CN111617084A - Preparation method and anti-tumor application of curcumin and fluorouracil co-loaded nano oral milk - Google Patents
Preparation method and anti-tumor application of curcumin and fluorouracil co-loaded nano oral milk Download PDFInfo
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Abstract
The invention discloses curcumin and fluorouracil co-loaded nano oral milk, and provides a preparation method and application thereof. Compared with the effect of the curcumin and the fluorouracil on tumor cells which are independently used, the effect of the nanoemulsion can be played on the basis of synergy, the anti-tumor effect of the drug is remarkably improved, the concentration of the drug in the cells is concentrated, and the oral bioavailability of the two drugs is remarkably improved.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to preparation of curcumin and fluorouracil co-loaded nano oral milk and anti-tumor application thereof.
Background
Tumor, a malignant disease that seriously threatens human survival and health. The global tumor morbidity is up to more than 20 percent, and the tumor mortality is high; current treatments for tumors are mainly focused on: surgery, chemotherapy, radiotherapy, immunotherapy and the like. Among them, chemotherapy is the mainstream of postoperative treatment because of its relatively strong targeting and relatively low treatment cost.
Combination drugs (comitant drugs) mean that two or more drugs are applied simultaneously or sequentially for better therapeutic purposes, mainly for increasing the therapeutic effect of the drugs or for alleviating the toxic and side effects of the drugs. In the chemotherapy of tumors, the combination is widely used. The current clinical commonly used combined medicines comprise western medicines combined with western medicines and western medicines combined with traditional Chinese medicines, the western medicines are mostly specific and nonspecific blocking medicines of cell cycles or small molecular target spot medicines, and the abnormal proliferation characteristics of tumor cells or the occurrence and development characteristics of different tumors are utilized to perform personalized treatment on the tumor cells. At present, some relevant literature reports about the combined application of curcumin and traditional chemotherapeutic drugs of fluorouracil exist, in the reports, curcumin and fluorouracil can act on colon cancer, gastric cancer, skin squamous cell carcinoma and the like in a synergistic manner, and research indicates that curcumin can reverse the cell drug resistance of FU chemotherapy through the regulation of a series of intracellular molecular signal pathways, and can achieve the synergistic effect through the combined application of curcumin and FU, reverse the drug resistance and reduce the dosage of FU, thereby reducing the toxic and side effects of the curcumin and the FU.
The nanoemulsion has the properties of both nano particles and emulsion, and can overcome blood brain barrier and reduce oral first pass effect according to literature reports. A nanoemulsion drug delivery system is established on the basis of CU combined FU, double advantages of combined drug delivery and the nanoemulsion drug delivery system are effectively integrated, the problem that the oral bioavailability of the drug is low, tumor cell toxicity is increased, and toxic and side effects are reduced is solved, and the establishment of a novel co-loading drug delivery system is the basis.
Disclosure of Invention
Aiming at the defects of the formula of the curcumin and fluorouracil composition, the invention strictly determines the combination of curcumin and fluorouracil in different proportions according to the sequence of cytotoxicity screening, cellular action mechanism exploration and pharmacokinetic experiment, provides a scientific and effective novel oral nanoemulsion loaded with curcumin and fluorouracil in a combined formula, and the oral nanoemulsion obtained by research can play a synergistic anticancer role in tumor cells, obviously increases the sensitivity of the cancer cells to the traditional chemotherapeutic drug fluorouracil and reduces toxic and side effects.
The first purpose of the invention is to provide curcumin and fluorouracil co-loaded nano oral milk.
The second purpose of the invention is to provide a preparation method of curcumin and fluorouracil co-loaded nano oral milk.
The third purpose of the invention is to discuss the action mechanism of curcumin and fluorouracil co-carried nano oral milk (CU-FU-LN) for improving tumor cytotoxicity, including apoptosis, laser confocal imaging or intracellular drug quantitative uptake. The invention also relates to pharmacokinetic behavior investigation of curcumin and fluorouracil co-loaded nano oral milk (CU-FU-LN) in an animal model.
In order to achieve the purpose, the invention adopts the following technical scheme:
the curcumin and fluorouracil co-carried nano oral milk comprises the following components in parts by mass: 0.96-2.53 parts of curcumin, 0.24-1.58 parts of 5-fluorouracil, 40037.49-37.95 parts of polyethylene glycol, 26.17-27.08 parts of medium-chain triglyceride, 10.13-12.28 parts of lecithin, 8015.98-17.06 parts of tween-ethanol, 0.002-0.009 parts of ethanol and 0.012-0.020 parts of purified water;
the curcumin and fluorouracil co-carried nano oral emulsion has the average particle size of 106.20 +/-3.93 nm, the Zeta potential of-9.71 +/-0.22 mV, the curcumin encapsulation rate of not less than 95.0% and the fluorouracil encapsulation rate of not less than 30.0%.
Further, the curcumin and fluorouracil co-loaded nano oral milk comprises the following components in parts by mass: 1.14 parts of curcumin, 0.33 part of 5-fluorouracil, 40037.80 parts of polyethylene glycol-medium chain triglyceride, 26.51 parts of lecithin, 8016.27 parts of tween-ethanol, 0.005 part of ethanol and 0.016 part of purified water.
Further, the preparation method of the curcumin and fluorouracil co-loaded nano oral milk comprises the following specific steps:
1) preparing a water phase: dissolving water-soluble auxiliary materials and 5-fluorouracil in purified water;
2) preparing an oil phase: dissolving curcumin powder in oil soluble adjuvant;
3) preparing an emulsion: uniformly mixing the oil phase and the water phase obtained in the step 1) and the step 2), and fully stirring and emulsifying under the condition of constant temperature sealing or pressurization to obtain the curcumin and fluorouracil co-carried nano oral emulsion.
Further, the preparation method of the curcumin and fluorouracil co-loaded nano oral milk comprises the steps of keeping the temperature at 40-80 ℃, stirring at the speed of 500-1500 r/min, and emulsifying for 5-40 min.
Further, the preparation method of the curcumin and fluorouracil co-carried nano oral milk comprises the following steps of 15.98-17.06 parts of tween-80 and 0.002-0.009 part of ethanol as water-soluble auxiliary materials, 26.17-27.08 parts of chain triglyceride, 37.49-37.95 parts of polyethylene glycol-400 and 10.13-12.28 parts of lecithin as oil-soluble auxiliary materials, and 0.012-0.020 part of purified water.
Further, the curcumin and fluorouracil co-loaded nano oral milk is applied to the aspect of tumor resistance.
The invention has the following advantages:
1. the invention provides a simple and repeatable curcumin and fluorouracil co-loaded nano oral emulsion, which can play a role of a nano emulsion on the basis of synergistic interaction, and obviously improve the anti-tumor effect of a medicament, wherein in liver cancer cells, by taking HepG2 as an example, after CU and FU are constructed by a molar ratio of 2: 1 and CU-FU-LN intervenes HepG2 cells for 24 hours, the half inhibitory concentration of CU is 78.12% of that of FU used alone, and the half inhibitory concentration of FU is 25.01% of that of FU used alone, so that the curcumin and fluorouracil combined anti-tumor application has obvious significance.
2. The invention discloses an effect of curcumin on improving related preparations of traditional chemotherapy drugs fluorouracil and cytotoxicity thereof, and compared with the single use of CU-FU-LN, drug fluorescence is in a state of aggregation to cell nucleus, and green fluorescence of CU-FU-LN group drugs is in a high-intensity aggregation state at the center position of the cell nucleus, which shows that CU-FU-LN can concentrate the concentration of drugs in cells.
3. The research of the invention proves that the CU-FU-LN nanoemulsion has the characteristic of improving the oral bioavailability of two medicines, namely compared with the CU or FU single oral administration, the CU-FU-LN nanoemulsion has the advantages that the area under the curve (AUC) of the medicine time is increased to a certain extent by CU + FU (CU: FU is 2: 1, mol/mol), and the CU-FU-LN (CU: FU is 2: 1, mol/mol) further delays the retention time of the medicines in blood plasma on the basis of the combination of CU and FU, prolongs the half-life period (t1/2), improves the AUC and obviously improves the oral bioavailability of the two medicines.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention. The objectives and other advantages of the invention will be realized and attained by the structure particularly pointed out in the written description and claims hereof.
Drawings
FIG. 1 shows the intracellular distribution state of 24h colon cancer Caco2 under the action of drugs detected by laser scanning confocal microscope
FIG. 2 shows the intracellular distribution of 24h liver cancer HepG2 in the detection of drug action by confocal laser scanning microscopy
FIG. 3 is a graph of CU concentration-time in plasma of rats with oral CU-FU drug combination and CU-FU-LN group
FIG. 4 is a graph of concentration versus time of FU in plasma in rats treated with oral administration of a combination of CU-FU drug substances and CU-FU-LN group
Detailed Description
The present invention will now be described in detail with reference to the drawings and examples, which are not intended to limit the invention in any way, except as specifically stated, reagents, methods and apparatus are conventional in the art.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
Experiment 1: preparation of curcumin and fluorouracil co-loaded nano oral milk (CU-FU-LN):
product 1:
(1) experimental materials:
curcumin, 5-fluorouracil, polyethylene glycol-400, medium chain triglyceride, lecithin, tween-80, ethanol and purified water
(2) The test method comprises the following steps:
1) preparing a water phase: dissolving 0.901mmol of Tween-80, 0.002mmol of ethanol and 0.034mmol of 5-fluorouracil in 0.012mmol of purified water;
2) preparing an oil phase: dissolving 0.091mmol curcumin powder, 0.159mmol medium chain triglyceride, 2.893mmol polyethylene glycol-400 and 0.586mmol lecithin together to obtain oil phase;
3) preparing an emulsion: uniformly mixing the oil phase and the water phase prepared in the step 1) and the step 2), stirring and emulsifying at 70 ℃, wherein the emulsifying time is 10min, the stirring condition is a sealing or pressurizing condition, and the stirring speed is 850r/min, so as to obtain curcumin and fluorouracil co-carried nano oral emulsion (CU-FU-LN);
4) taking the curcumin and fluorouracil co-loaded nano oral milk (CU-FU-LN) prepared in the step 3), adding water to dilute to 1-3 times, measuring the encapsulation efficiency and the drug loading capacity by adopting HPLC, and analyzing the particle size and the dispersion coefficient by adopting a Marlven laser particle sizer.
(3) As a result:
the mean particle size of curcumin and fluorouracil co-loaded nano oral emulsion (CU-FU-LN) is 106.20 +/-3.93 nm, the Zeta potential is-9.71 +/-0.22 mV, the CU encapsulation rate is not lower than 95.0%, and the FU encapsulation rate is not lower than 30.0%.
Product 2:
(1) experimental materials:
curcumin, 5-fluorouracil, polyethylene glycol-400, medium chain triglyceride, lecithin, tween-80, ethanol and purified water
(2) The test method comprises the following steps:
1) preparing a water phase: dissolving 1.504mmol of Tween-80, 0.009mmol of ethanol and 0.125mmol of 5-fluorouracil in 0.020mmol of purified water;
2) preparing an oil phase: dissolving 0.244mmol curcumin powder, 0.198mmol medium chain triglyceride, 4.023mmol polyethylene glycol-400 and 0.804mmol lecithin together to obtain an oil phase;
3) preparing an emulsion: uniformly mixing the oil phase and the water phase prepared in the step 1) and the step 2), stirring and emulsifying at 70 ℃, wherein the emulsifying time is 10min, the stirring condition is a sealing or pressurizing condition, and the stirring speed is 850r/min, so as to obtain curcumin and fluorouracil co-carried nano oral emulsion (CU-FU-LN);
4) taking the curcumin and fluorouracil co-loaded nano oral milk (CU-FU-LN) prepared in the step 3), adding water to dilute to 1-3 times, measuring the encapsulation efficiency and the drug loading capacity by adopting HPLC, and analyzing the particle size and the dispersion coefficient by adopting a Marlven laser particle sizer.
(3) As a result:
the mean particle size of curcumin and fluorouracil co-loaded nano oral emulsion (CU-FU-LN) is 106.20 +/-3.93 nm, the Zeta potential is-9.71 +/-0.22 mV, the CU encapsulation rate is not lower than 95.0%, and the FU encapsulation rate is not lower than 30.0%.
Product 3:
(1) experimental materials:
curcumin, 5-fluorouracil, polyethylene glycol-400, medium chain triglyceride, lecithin, tween-80, ethanol and purified water
(2) The test method comprises the following steps:
1) preparing a water phase: dissolving 0.979mmol of Tween-80, 0.005mmol of ethanol and 0.061mmol of 5-fluorouracil in 0.016mmol of purified water;
2) preparing an oil phase: dissolving 0.122mmol curcumin powder, 0.175mmol medium chain triglyceride, 3.750mmol polyethylene glycol-400, and 0.699mmol lecithin as oil phase;
3) preparing an emulsion: uniformly mixing the oil phase and the water phase prepared in the step 1) and the step 2), stirring and emulsifying at 70 ℃, wherein the emulsifying time is 10min, the stirring condition is a sealing or pressurizing condition, and the stirring speed is 850r/min, so as to obtain curcumin and fluorouracil co-carried nano oral emulsion (CU-FU-LN);
4) taking the curcumin and fluorouracil co-loaded nano oral milk (CU-FU-LN) prepared in the step 3), adding water to dilute to 1-3 times, measuring the encapsulation efficiency and the drug loading capacity by adopting HPLC, and analyzing the particle size and the dispersion coefficient by adopting a Marlven laser particle sizer.
(3) As a result:
the mean particle size of curcumin and fluorouracil co-loaded nano oral emulsion (CU-FU-LN) is 106.20 +/-3.93 nm, the Zeta potential is-9.71 +/-0.22 mV, the CU encapsulation rate is not lower than 95.0%, and the FU encapsulation rate is not lower than 30.0%.
Experiment 2: the effect of curcumin and fluorouracil co-loaded nano oral milk (CU-FU-LN) on liver cancer cell proliferation:
(1) experimental materials:
1) test drugs: curcumin (CU), Fluorouracil (FU), curcumin and fluorouracil co-loaded nano oral milk (CU-FU-LN) obtained from product 3 in experiment 1: comprises tween-80 0.979mmol, ethanol 0.005mmol, 5-fluorouracil 0.061mmol, purified water 0.016mmol, curcumin powder 0.122mmol, medium-chain triglyceride 0.175mmol, polyethylene glycol-400 3.750mmol, and lecithin 0.699mmol
2) A subject: liver cancer cell (human liver cancer cell SMMC-7721, HepG2)
(2) The experimental method comprises the following steps:
taking HepG2 liver cancer cells in logarithmic growth phase and adding 5 × 104The cells were plated at a concentration of one/ml in 96-well cell culture plates. Test zero-adjusting group (without drug), control group: 6.25 mu mol CU +3.125 mu mol FU bulk drug combination group (CU: FU is 2: 1), 3.125 mu mol CU +3.125 mu mol FU bulk drug combination group (CU: FU is 1: 1), 3.125 mu mol CU +6.25 mu mol FU bulk drug combination group (CU: FU is 1: 2), 3.125 mu mol CU +12.5 mu mol FU bulk drug combination group (CU: FU is 1: 4), 3.125 mu mol CU +18.75 mu mol FU bulk drug combination groupEach set of 5 complex wells was prepared using CU-FU-LN nanoemulsion set (CU: FU ═ 1: 6) and 6.25 μmol CU +3.125 μmol FU (CU: FU ═ 2: 1), CU-FU-LN nanoemulsion set (CU: FU ═ 1: 1) of 3.125 μmol CU +3.125 μmol FU), CU-FU-LN nanoemulsion set (CU: FU ═ 1: 2) of 3.125 μmol CU +6.25 μmol FU, CU-FU-LN nanoemulsion set (CU: FU ═ 1: 4) of 3.125 μmol CU +12.5 μmol FU, and CU-FU-LN nanoemulsion set (CU: FU ═ 1: 6) of 3.125 μmol +18.75 μmol FU. After incubation for 24 hours at 37 deg.C, 5% C02 and saturated humidity (divided by the action time) according to the dry condition of each group, the supernatant was discarded and 150. mu.L of dimethyl sulfoxide was added, and the mixture was placed on a shaker and shaken at low speed for 10min to dissolve the crystals sufficiently. Measuring the absorbance (OD) of each well at 570nm of an ELISA detector; calculating the inhibition rate and calculating the median Inhibitory Concentration (IC)50)。
(3) As a result:
TABLE 1 IC of CU-FU-LN acting on hepatoma cell HepG250(24h)
Significant differences between P < 0.05 compared with CU and FU
As can be seen from Table 1, in the hepatoma cells, CU-FU-LN can remarkably increase the anti-proliferation effect of the drug, and taking HepG2 as an example, after CU-FU-LN constructed by CU and FU in a molar ratio of 2: 1 intervenes HepG2 cells for 24h, the half inhibitory concentration of CU is 78.12% of that of FU when used alone, and the half inhibitory concentration of FU is 25.01% of that of FU when used alone.
Experiment 3: curcumin and fluorouracil co-loaded nano oral milk (CU-FU-LN) increases the distribution of the drug in cancer cells:
(1) experimental materials:
1) test drugs and reagents: curcumin (CU), Fluorouracil (FU), 3 curcumin and fluorouracil co-loaded nano oral milk (CU-FU-LN) obtained in experiment 1: comprises 0.979mmol Tween-80, 0.005mmol ethanol, 0.061mmol 5-fluorouracil, 0.016mmol purified water, 0.122mmol curcumin powder, 0.175mmol medium chain triglyceride, 3.750mmol polyethylene glycol-400, 0.699mmol lecithin, DAPI staining solution, anti-fluorescence attenuation tablet, and 4% paraformaldehyde solution
2) A subject: liver cancer cell (human liver cancer cell SMMC-7721, HepG2)
(2) The experimental method comprises the following steps:
placing 24-well professional glass slide (thickness of 0.17mm) in 24-well plate, dripping 500 μ L of tumor cell liquid with concentration of 5 × 104/mL onto the slide at 37 deg.C and 5% CO2Culturing in an incubator. After the adhesion, 500 μ L of prepared CU (20 μmol/L), FU (10 μmol/L), CU + FU bulk drug (20 μmol/L CU +10 μmol/L FU) (CU-FU-sink) and CU-FU-LN nanoemulsion (20 μmol/LCU +10 μmol/L FU) drug solutions were added to each well, and the administration concentration was determined to be FU of 10 μmol/L (CU: FU of 2: 1, mol/mol) according to the MTT experiment, and an administration-free blank control group was set. After administration, the cell plates were placed at 37 ℃ with 5% CO2In the incubator, the action time of the medicine is 24 hours. After 24h of administration, the drug-containing medium in each well was removed and washed 2 times with PBS solution; adding 500 mu L of 4% paraformaldehyde into each well, and fixing for 15 min; sucking out the fixing solution, and washing with PBS solution for 2 times; adding 100 μ L of DAPI solution into each well, and dyeing for 5min in dark; discarding the staining solution, and washing with PBS solution for 4 times; taking out the slide, sealing, and observing the distribution state of the medicine in Caco2 cell of colon cancer and HepG2 cell of liver cancer under laser scanning confocal microscope (388/448nm ultraviolet light excitation).
(3) As a result:
as can be seen from FIGS. 1 and 2, the distribution of the drugs in HepG2 cells of liver cancer and Caco2 cells of colon cancer was examined by confocal laser scanning microscopy, and in each fluorescence image, the blue fluorescence of DAPI-stained cell nuclei was shown on the left, the green fluorescence of the drugs was shown in the middle, and the complex fluorescence of DAPI-stained cells and drugs was shown on the right. The nuclei of the liver cancer HepG2 cell and the colon cancer Caco2 cell are dyed blue by the DAPI dye and respectively act on CU, FU, CU-FU and CU-FU-LN for 24 hours, and except for FU (the fluorescence excitation wavelength of FU exceeds the minimum wavelength range of an instrument), the green fluorescence of the medicine appears in other medicine groups, which indicates that the medicine mainly enters the cancer cell to play an anticancer role. Meanwhile, green fluorescence of free raw material medicines is distributed in a dispersion mode, the fluorescence intensity is scattered, the combined medicine group can see the state that the fluorescence of the medicines is gathered to cell nucleus, particularly the CU-FU-LN group, the green fluorescence of the medicines is gathered in a high-intensity mode at the center position of the cell nucleus, the main action position of CU is shown to be in the cell nucleus, and the nano drug delivery system can improve the permeability of the medicines to cell membranes, increase the concentration in the cell nucleus and improve the anticancer activity.
Experiment 4: curcumin and fluorouracil co-loaded nano oral milk (CU-FU-LN) improves oral bioavailability:
(1) experimental materials:
1) test drugs: curcumin (CU), Fluorouracil (FU), 3 curcumin and fluorouracil co-loaded nano oral milk (CU-FU-LN) obtained in experiment 1: comprises tween-80 0.979mmol, ethanol 0.005mmol, 5-fluorouracil 0.061mmol, purified water 0.016mmol, curcumin powder 0.122mmol, medium-chain triglyceride 0.175mmol, polyethylene glycol-400 3.750mmol, and lecithin 0.699mmol
2) A subject: SD rat, 180-
(2) The experimental method comprises the following steps:
20 rats were randomly divided into 4 groups of 5 rats each. Administered by intragastric administration, wherein group A is 50mg/kg CU; group B is 8.9mg/kg FU; group C is 50mg/kg CU +8.9mg/kg FU; group D was CU-FU-LN (50 mg/kg CU +8.9mg/kg FU loading equal doses). Blood was taken at 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, 24h and 48h after administration. The whole blood (0.3mL) was placed in a centrifuge tube containing heparin sodium, centrifuged for 3min (5000rpm/min), and plasma samples were taken for HPLC detection after treatment.
(3) As a result:
TABLE 2 pharmacokinetic statistical moment parameters for CU and FU, respectively
As can be seen from fig. 3 and 4, CU + FU (CU: FU 2: 1, mol/mol) increases the area under the curve (AUC) to some extent when taking medicine compared with CU or FU alone, whereas CU-FU-LN (CU: FU 2: 1, mol/mol) further delays the retention time of the drug in plasma based on CU + FU combination, prolongs the half-life (t1/2), increases the AUC, and significantly increases the oral availability of the drug. As shown in Table 2, the pharmacokinetic statistical moment parameters fitted by DAS software analysis also demonstrate these advantages of CU-FU-LN.
Finally, the description is as follows: although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art will understand that various changes, modifications and substitutions can be made without departing from the spirit and scope of the invention as defined by the appended claims. Any modification, equivalent replacement, or improvement made without departing from the spirit and principle of the present invention shall fall within the protection scope of the present invention.
Claims (9)
1. The curcumin and fluorouracil co-carried nano oral milk is characterized by comprising the following components in parts by mass: 0.96-2.53 parts of curcumin, 0.24-1.58 parts of 5-fluorouracil, 40037.49-37.95 parts of polyethylene glycol, 26.17-27.08 parts of medium-chain triglyceride, 10.13-12.28 parts of lecithin, 8015.98-17.06 parts of tween-ethanol, 0.002-0.009 parts of ethanol and 0.012-0.020 parts of purified water;
the curcumin and fluorouracil co-carried nano oral emulsion has the average particle size of 106.20 +/-3.93 nm, the Zeta potential of-9.71 +/-0.22 mV, the curcumin encapsulation rate of not less than 95.0% and the fluorouracil encapsulation rate of not less than 30.0%.
2. The curcumin and fluorouracil co-carried nano oral milk as claimed in claim 1, which comprises the following components in parts by mass: 1.14 parts of curcumin, 0.33 part of 5-fluorouracil, 40037.80 parts of polyethylene glycol-medium chain triglyceride, 26.51 parts of lecithin, 8016.27 parts of tween-ethanol, 0.005 part of ethanol and 0.016 part of purified water.
3. The preparation method of curcumin and fluorouracil co-carried nano oral milk as claimed in claim 1, which is characterized by comprising the following specific steps:
1) preparing a water phase: dissolving water-soluble auxiliary materials and 5-fluorouracil in purified water;
2) preparing an oil phase: dissolving curcumin powder in oil soluble adjuvant;
3) preparing an emulsion: uniformly mixing the oil phase and the water phase obtained in the step 1) and the step 2), and fully stirring and emulsifying under the condition of constant temperature sealing or pressurization to obtain the curcumin and fluorouracil co-carried nano oral emulsion.
4. The preparation method of curcumin and fluorouracil co-carried nano oral milk as claimed in claim 3, wherein the constant temperature condition is 40-80 ℃, the stirring speed is 500r/min-1500r/min, and the emulsifying time is 5-40 min.
5. The method for preparing curcumin and fluorouracil co-carried nano oral milk as claimed in claim 3, wherein the water-soluble auxiliary materials are 15.98-17.06 parts of tween-80 and 0.002-0.009 parts of ethanol, the oil-soluble auxiliary materials are 26.17-27.08 parts of chain triglyceride, 37.49-37.95 parts of polyethylene glycol-400 and 10.13-12.28 parts of lecithin, and the purified water is 0.012-0.020 part.
6. The method for preparing curcumin and fluorouracil co-carried nano oral milk according to claim 5, wherein curcumin 1.14 parts, 5-fluorouracil 0.33 parts, polyethylene glycol-40037.80 parts, medium chain triglyceride 26.51 parts, lecithin 11.36 parts, tween-8016.27 parts, ethanol 0.005 parts, and purified water 0.016 parts, the constant temperature is 70 ℃, the stirring speed is 850r/min, and the emulsification time is 10 min.
7. The curcumin and fluorouracil co-loaded nano oral milk as claimed in claim 1 or 2, for use in anti-tumor.
8. The use of the curcumin and fluorouracil co-loaded nano oral milk as claimed in claim 1 or 2 for increasing the distribution of drugs in cancer cells.
9. The use of the curcumin and fluorouracil co-loaded nano oral milk as claimed in claim 1 or 2 for improving oral bioavailability.
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| CN107028883A (en) * | 2017-04-20 | 2017-08-11 | 东北农业大学 | Deliver the preparation method of curcumin nano breast |
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| KR20030066927A (en) * | 2002-02-06 | 2003-08-14 | 구자영 | Anticancer drug made of curcumin and 5-fluorouracil, and its clinical uses |
| CN105997875A (en) * | 2016-07-19 | 2016-10-12 | 重庆医科大学 | Water-in-oil type nano-emulsion capable of obviously improving bioavailability of poorly water-soluble drugs and preparation method of water-in-oil type nano-emulsion |
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