CN115778920A - Preparation method of 5-fluorouracil-loaded nanocapsule and rapidly separable microneedle thereof - Google Patents
Preparation method of 5-fluorouracil-loaded nanocapsule and rapidly separable microneedle thereof Download PDFInfo
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- 229960002949 fluorouracil Drugs 0.000 title claims abstract description 93
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 title claims abstract description 91
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- 238000000034 method Methods 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 18
- 229940079593 drug Drugs 0.000 claims abstract description 17
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 14
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
A preparation method of a 5-fluorouracil-loaded nanocapsule and a microneedle capable of being rapidly separated from the nanocapsule belongs to the field of pharmaceutical preparations, the selected drug is 5-fluorouracil, the nanocapsule takes polyvinyl alcohol, polylactic acid and the like as matrixes, preparation solvents of the nanocapsule are water and dichloromethane, and the preparation method of the nanocapsule is an ultrasonic emulsification method, wherein the concentrations of the drug, the polylactic acid and the polyvinyl alcohol are 0.6-1%,1-6% and 1-2% respectively. The rapidly separable microneedle takes chitosan, dextran, polyvinylpyrrolidone and the like as matrixes, and the preparation solvent of the rapidly separable microneedle is glacial acetic acid aqueous solution, water and absolute ethyl alcohol. The rapidly separable microneedle loaded with the 5-fluorouracil nanocapsule provided by the invention has the advantages of rapid separation property, no burst release phenomenon, simple preparation process, realization of sustained release of 5-fluorouracil and the like.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a 5-fluorouracil-loaded nanocapsule and preparation of a microneedle capable of being rapidly separated.
Background
5-Fluorouracil (5-FU) is a pyrimidine analog with antimetabolic activity that interferes with RNA and DNA synthesis and has also been shown to reduce fibroblast proliferation. Therefore, 5-FU is often used to treat diseases caused by the proliferation of malignant cells, such as various cancers, skin tumors, keloids, or hypertrophic scars. In the 70's of the 20 th century, 5-FU has been approved in the United states for use in the treatment of localized superficial cancers. 5-FU has a very short half-life of only a few minutes, while it is non-specific and easily causes systemic toxicity.
The surface characteristics of the nano carrier are easy to modify, and the release of the wrapped medicine can be slowed down, so that the stability of the nano carrier is improved. Studies have shown that combining microneedles with nanocarriers can provide surprising results in terms of slow controlled drug release, which is better than a single dosage form. The quickly separable microneedles can be broken on the skin briefly and painlessly and embedded into the biodegradable microneedles to release the drugs, so that the drugs can be well released into the skin, and the compliance of a human body can be improved. The idea provides a new idea for treating skin diseases, such as hypertrophic scars, keloids and superficial skin tumors.
The invention relates to 5-fluorouracil particles at home at present. For example, the magnetic nanoparticles are used as cores to prepare 5-fluorouracil-loaded sustained-release microspheres (CN 107890465A) so as to solve the problem of burst release caused by the loading of 5-fluorouracil on the simple magnetic nanoparticles, but the microspheres prepared by the method have the particle size of about 170 μm and cannot be used as injections. For another example, in order to reduce the problem of solvent residue caused by the multiple emulsion solvent evaporation method, patent CN 102525933A adopts supercritical carbon dioxide to evaporate and remove the organic solvent, and reduces the particle size of the prepared microspheres, but this method also needs supercritical equipment, and the preparation process is relatively complicated. At present, no invention of combining the nano-carrier and the micro-needle appears.
Disclosure of Invention
The invention aims to provide a preparation method of a 5-fluorouracil-loaded nano capsule, which realizes the slow release of 5-fluorouracil and has good stability.
The invention also aims to provide a preparation method of the rapidly separable microneedle loaded with the 5-fluorouracil nanocapsule. Not only solves the problem of drug burst release caused by the nano-carrier, but also realizes the slow release of the 5-fluorouracil, and has good biocompatibility.
The invention realizes the above purposes through the following technical scheme:
a preparation method of a 5-fluorouracil-loaded nano capsule is realized by the following steps:
the method comprises the following steps: taking a certain amount of dichloromethane as O 1 (ii) a Adding oil-in-water type surfactant into 5-fluorouracil-loaded ZIF-8 solution, and mixing to obtain W 1 (ii) a Dissolving polylactic acid (PLA) in dichloromethane, adding water-in-oil type surfactant, stirring to obtain product O 2 (ii) a Dissolving polyvinyl alcohol (PVA) in water under heating, adding oil-in-water type surfactant, stirring to obtain W 2 ；
Step two: the obtained W 1 And O 1 Mixing, ultrasonic treating in ice bath to obtain O 1 /W 1 Primary emulsion;
step three: the obtained O 1 /W 1 Primary emulsion and O 2 Mixing, ultrasonic treating in ice bath to obtain O 1 /W 1 /O 2 Compounding milk;
step four: the obtained O is 1 /W 1 /O 2 Fast combining with W 2 Mixing, and performing ultrasonic treatment in ice bath to obtain a nano capsule solution;
step five: and centrifuging the obtained nano capsule solution, washing with water, volatilizing the solvent, and freeze-drying to obtain 5-fluorouracil-loaded nano capsule powder.
In the first step, the ZIF-8 is a metal-organic framework Material (MOF) and is synthesized by a one-pot method, and the specific synthesis method comprises the following steps: first, zn (NO) is dissolved in deionized water 3 ) 2 6H 2 O and 2-methylimidazole to prepare Zn (NO) 3 ) 2 6H 2 O solution and 2-methylimidazole solution; then adding Triethanolamine (TEA) dropwise into Zn (NO) 3 ) 2 6H 2 Stirring in the O solution; the 2-methylimidazole solution was then added dropwise to Zn (NO) 3 ) 2 6H 2 Stirring in the O solution; and centrifuging and washing the obtained product solution to obtain the ZIF-8 solution.
The ZIF-8 is used for entrapping 5-fluorouracil so as to further reduce the release rate of the 5-fluorouracil.
W is 1 The mass ratio of the medium 5-fluorouracil in the ZIF-8 solution is 0.6-1% (w/v) (6-10mg of 5-fluorouracil in 1mL of the ZIF-8 solution); the particle size of the ZIF-8 is 90-120nm; said O is 1 The mass ratio of the medium polylactic acid in the dichloromethane is 1-6% (w/v) (10-60 mg of polylactic acid to 1mL of dichloromethane); the W is 2 The mass ratio of the polyvinyl alcohol in the water is 1-2% (w/v) (10-20 mg polyvinyl alcohol to 1mL water).
The oil-in-water type surfactant is selected from one or more of Tween 80, tween 20, polyoxyethylene ether castor oil and PEG-40 hydrogenated castor oil; the water-in-oil surfactant is selected from one or more of span 80, span 60 and span 20.
The molecular weight of the polylactic acid is 1-10 ten thousand.
A5-fluorouracil-loaded nano-capsule is prepared by the preparation method.
A rapidly separable microneedle carrying 5-fluorouracil nanocapsules comprises a back lining, a needle body and a foaming layer, wherein the back lining and the needle body are prepared from one or more of chitosan, dextran, hyaluronic acid, hydroxypropyl beta cyclodextrin, polyvinyl alcohol and polyvinylpyrrolidone; the foaming principle of the foaming layer is that a substance containing bicarbonate reacts with acid to generate gas, and the acid is selected from one or more of citric acid, tartaric acid, sodium bicarbonate, potassium bicarbonate and the like.
A preparation method of a rapidly separable microneedle loaded with 5-fluorouracil nanocapsules comprises the following steps:
the method comprises the following steps: respectively dissolving chitosan and dextran in an acidic aqueous solution and water, mixing 1:1 (v/v) uniformly to obtain a microneedle matrix solution, and dissolving the prepared 5-fluorouracil-loaded nanocapsule in the microneedle matrix solution to obtain a drug-loaded microneedle matrix;
step two: dissolving polyvinylpyrrolidone, citric acid and sodium bicarbonate in absolute ethyl alcohol to obtain a microneedle backing solution;
step three: adding the drug-loaded microneedle matrix solution into a microneedle mould, centrifuging to uniformly fill the microneedle mould, removing the redundant matrix solution, standing at room temperature until the microneedle mould is dry, adding the microneedle backing solution, centrifuging to remove redundant bubbles, placing the microneedle in a drier for drying, and demoulding to obtain the rapidly-separable microneedle loaded with the 5-fluorouracil nanocapsule.
Wherein the content of the first and second substances,
the mass-volume ratio of the 5-fluorouracil-loaded nanocapsules in the drug-loaded microneedle matrix to the microneedle matrix solution is (0.1-1) g:1mL (0.1-1 g of the 5-fluorouracil-loaded nanocapsules is loaded into 1mL of the microneedle matrix solution, and the 5-fluorouracil is contained in 1-10 mg). The mass ratio of chitosan to dextran in the microneedle matrix solution is 1; the acid solution is glacial acetic acid water solution, and the concentration is 1%.
The mass ratio of polyvinylpyrrolidone, citric acid and sodium bicarbonate in the microneedle backing solution is (20-30): 4:5.
The molecular weight of the chitosan is 300,000-400,000Da, and the molecular weight of the polyvinylpyrrolidone is 360,000-1300,000Da.
The centrifugal rotation speed of the microneedle substrate is 2500-3500rpm/min, and the centrifugal time is 10-20min; the centrifugal rotating speed of the microneedle backing solution is 1500-2500rpm/min, and the centrifugal time is 5-10min; the drying time of the microneedle substrate is 6-12h, and the drying time of the microneedle substrate is 24-48h.
The invention also provides application of the rapidly separable microneedle loaded with the 5-fluorouracil sustained-release nanocapsule in a sustained-release 5-fluorouracil and drug delivery system.
The invention has the beneficial effects that:
the invention provides a micro needle capable of being rapidly separated and loaded with 5-fluorouracil nano-capsules so as to realize slow release of 5-fluorouracil. The invention realizes the slow release of 5-fluorouracil. Compared with the nanocapsule alone, the preparation provided by the invention does not have the problem of burst release. In addition, the preparation provided by the invention can quickly realize the separation of the needle tip and the back lining, and the problem of poor human body compliance caused by long-time application on a human body does not exist.
The invention solves the burst release problem of single nano capsule and realizes the slow release of 5-fluorouracil. The average particle size of the prepared nanocapsule is 250nm, and the accumulative release amount of the nanocapsule within 168h can reach 70-80%. The 5-fluorouracil-loaded nanocapsule quick-separation microneedle can be quickly separated within 30s, the accumulated transdermal penetration amount of 24h is 26.95 +/-6.35%, and the accumulated transdermal penetration amount of the 5-fluorouracil-loaded quick-separation microneedle for 24h is 87.25 +/-8.61%, so that the release of 5-fluorouracil is remarkably slowed down.
Drawings
FIG. 1 scanning electron micrograph (a) and particle size (b) of fluorouracil nanocapsule.
Figure 2-release of fluorouracil nanocapsules.
Fig. 3 is a microscope picture of rapidly separable microneedles.
Fig. 4 separable performance evaluation of quickly separable microneedles.
Figure 5 transdermal permeation behavior of rapidly separable microneedles loaded with 5-fluorouracil nanocapsules.
FIG. 6 is a scanning electron micrograph (a), XRD pattern (b), IR pattern (c) and scheme (d) of ZIF-8.
FIG. 7 influence of ZIF-8 addition on 5-fluorouracil release.
Detailed Description
Hereinafter, the mode of the present invention will be described in detail. The invention is further illustrated by the following examples, which are not intended to limit the invention thereto.
Preparation method of 5-fluorouracil-loaded nano capsule
A certain amount of methylene chloride is taken as O 1 Adding 30mg of oil-in-water surfactant to the 5-fluorouracil-loaded ZIF-8 solution, and mixing well to obtain W 1 . Dissolving polylactic acid in dichloromethane, adding 90mg of water-in-oil type surfactant as O 2 Polyvinyl alcohol was dissolved in water in a heated state, and 150mg of an oil-in-water type surfactant was added as W 2 . The preparation method of the ZIF-8 solution comprises the following steps: 95mg of Zn (NO) was dissolved in 50mL of deionized water, respectively 3 ) 2 6H 2 O and 200mg 2-methylimidazole, preparation of Zn (NO) 3 ) 2 6H 2 O solution and 2-methylimidazole solution. Then, 0.5mL of TEA was added dropwise to Zn (NO) 3 ) 2 6H 2 In the O solution, stirring for 5min. The 2-methylimidazole solution was then added dropwise to Zn (NO) 3 ) 2 6H 2 The O solution is stirred for 1 hour. Centrifuging the obtained product solution at 13000rpm for 20min, and washing with water for 3 times to obtain the final product. The synthesis route, the scanning electron microscope image, the XRD image and the infrared image of the ZIF-8 are shown in figure 6.
The W is 1 The mass ratio of the medium 5-fluorouracil in the ZIF-8 solution is 0.6-1%; the particle size of the ZIF-8 is 90-120nm; said O is 2 The mass ratio of the polylactic acid in the dichloromethane is 1-6%; the W is 2 The mass ratio of the polyvinyl alcohol in the water is 1-2% (the concrete formulation of examples 1-4 is shown in Table 1).
The oil-in-water type surfactant is selected from one or more of tween 80, tween 20, polyoxyethylene hydrogenated castor oil and oleic acid, and the water-in-oil type surfactant is selected from one or more of span 80, span 60 and span 20.
Example 1
The preparation method of the 5-fluorouracil-loaded nanocapsule comprises the following specific operation steps:
the method comprises the following steps: 0.25mL of methylene chloride as O 1 0.75mL of a self-made 5-FU @ ZIF-8 solution (5-fluorouracil-loaded ZIF-8 solution) and 30mg of Tween 80 were mixed as W 1 .3mL of a solution of polylactic acid in methylene chloride and 90mg of span 80 as O 2 8mL of a polyvinyl alcohol solution, 150mg of TweenTemperature 80 as W 2 。
Step two: w obtained in the step one 1 And O 1 Mixing, performing ultrasonic treatment in 80% power ice bath for 20s to obtain O 1 /W 1 Primary emulsion.
Step three: quickly adding O into the primary emulsion obtained in the second step 2 50% power ice bath ultrasound for 2min to obtain O 1 /W 1 /O 2 And (4) compounding milk.
Step four: adding the multiple emulsion obtained in the third step into W rapidly 2 And carrying out ultrasonic treatment on 50% power ice bath for 7min to obtain the final nano capsule solution.
Step five: and (3) centrifuging the nano capsule solution obtained in the fourth step at 13000rpm for 10min, washing for 2 times, stirring the precipitated solution at room temperature for 6h to remove the organic solvent, and freeze-drying to obtain 5-fluorouracil-loaded nano capsule powder.
In vitro release experiments of nanocapsules:
the experiment was carried out in a constant temperature shaker using 8000-14000 cut-off dialysis bags at 37 ℃ and 95 rpm. Taking 10mL of phosphate buffer solution with pH7.4 as release medium, sampling 1mL at 0.5,1,2,4,6,8, 12, 24 and 48h, and supplementing the release medium with the same volume and temperature after sampling. 13000rpm for 5min, filtering the supernatant with 0.22 μm microporous membrane, and collecting the filtrate as the sample solution.
And (3) measuring the accumulative release amount of the 5-fluorouracil from the nanocapsule by using a high performance liquid chromatography. The calculation formula is as follows:
in the formula: q is the cumulative release of 5-FU,%; c i The concentration at the time of the ith sampling is μ g. Multidot.mL -1 ；V 0 Is the volume of release medium, 10mL; v e Is the release medium displacement volume, 1mL; m 0 The mass of 5-FU in the dialysis bag is μ g.
The conditions of the high performance liquid chromatography were as follows: a chromatographic column:
c18 (150X 4.6mm,5 μm); mobile phase: acetonitrile: water (85; column temperature: 25 ℃; detection wavelength: 265nm; flow rate: 1mL/min; sample introduction amount: 10 μ L.
And (3) stability investigation of the nanocapsule:
the prepared nanocapsule solution is placed in a closed glass test tube and is placed at 4 ℃ for 48h, and the 48h stability of the nanocapsule solution is inspected by taking the appearance, the particle size and PDI as indexes.
Preparation of nanocapsules
The influence of different matrix contents on the particle size, release and encapsulation efficiency of the nano-capsule.
The preparation method comprises the following steps: nanocapsules were prepared according to the recipe of table 1 below. The procedure and the raw materials used in examples 2 to 4 are the same as those in example 1 except that they are shown in Table 1.
The test method comprises the following steps: the particle size, encapsulation efficiency, and in vitro release rate of examples 1-4 were determined and calculated according to the in vitro release assay and assay methods described above for examples 1-4. And (4) inspecting the stability of the prepared nanocapsules according to the nanocapsule stability inspection method.
Particle size results are shown in table 2 and fig. 1, in vitro release results are shown in fig. 2, and stability results are shown in table 3.
TABLE 1
5-FU (W/v,%) means W 1 The mass ratio of the medium 5-fluorouracil in the ZIF-8 solution; PLA (w/v,%) represents O 2 The mass ratio of the polylactic acid in the dichloromethane; PVA (W/v,%) represents W 2 The mass ratio of polyvinyl alcohol in water. w/v:1g was dissolved in 100mL of solvent.
TABLE 2
TABLE 3
The results show that the increase of the matrix concentration has no significant influence on the encapsulation efficiency and the in vitro release behavior, and only the particle size of the nanocapsules is enlarged. The stability results show that the prepared nano-capsule solution is stable within 48 hours.
Investigation of the Effect of ZIF-8 addition on nanocapsule Release
The preparation method comprises the following steps: according to the formulation of the matrix of example 2 and the procedure of example 1, a nanocapsule containing ZIF-8 (example 7) and a nanocapsule not containing ZIF-8 (example 8) were prepared, respectively (both drug loading was the same).
The test method comprises the following steps: the in vitro release degrees of examples 7-8 were calculated according to the in vitro release assay and assay methods described above.
The in vitro release results are shown in figure 7. The results show that the addition of ZIF-8 reduces the release rate of 5-fluorouracil to some extent.
Preparation of 5-fluorouracil-loaded nanocapsule capable of quickly separating microneedle
Example 5
A preparation method of a rapidly separable microneedle loaded with 5-fluorouracil nanocapsules comprises the following specific operation steps:
the method comprises the following steps: respectively dissolving chitosan and dextran in 1% glacial acetic acid water solution and water to obtain 5% chitosan solution and 50% dextran solution. The two are uniformly mixed according to the volume ratio of 1:1 to be used as the microneedle matrix solution. And (3) adding 1.5mL of the prepared microneedle matrix solution into 1g of the 5-fluorouracil-loaded nanocapsule prepared in the example 2, and dissolving to prepare the drug-loaded microneedle matrix.
Step two: polyvinylpyrrolidone (25%, w/v), citric acid (4%, w/v) and sodium bicarbonate (5%, w/v) were dissolved in anhydrous ethanol to obtain microneedle backing solution.
Step three: and (3) adding the drug-loaded microneedle matrix obtained in the step one into a microneedle mould, centrifuging at 3000rpm for 15min to uniformly fill the drug-loaded microneedle matrix, scraping off redundant matrix solution, standing at room temperature to dry, adding microneedle backing solution, centrifuging at 2000rpm for 10min to remove redundant bubbles, placing the microneedle in a dryer to dry for 48h, and demolding to obtain the rapidly separable microneedle loaded with the 5-fluorouracil nanocapsule.
Transdermal penetration Performance examination of microneedles
Adopts a vertical double-chamber diffusion cell (the effective diffusion area is 0.95 cm) 2 ) The transdermal permeability of the prepared drug-loaded microneedle is studied. The rabbit skin in vitro is thawed and washed by normal saline, and wiped dry by filter paper. Pressing the microneedle on the skin for 1min, fixing the skin between diffusion cells, allowing the dermis side to face a receiving cell, allowing a patch with a certain area to be pasted on the cuticle side, adding 9mL of receiving medium into the receiving cell, continuously stirring, and circulating water bath at 37 +/-1 ℃ to ensure that the interlayer of the water bath has no bubbles. 2mL of the sample is sampled at 0.5,1,2,4,6,8, 12 and 24 hours respectively, then an equal amount of receiving solution is added into the receiving pool, the receiving solution is centrifuged at 13000rpm for 5min, supernatant is taken, and 10 mu L of the sample is precisely measured and injected into HPLC. And calculating the 24h cumulative permeation amount.
And (3) measuring the accumulative release amount of the 5-fluorouracil from the nanocapsule by using a high performance liquid chromatography. The calculation formula is as follows:
in the formula: q is 5-FU cumulative permeation volume,%; c i The concentration at the time of the ith sampling is μ g. Multidot.mL -1 ；V 0 Is the volume of release medium, 9mL; v e Is the release medium displacement volume, 2mL; m 0 Is the mass of 5-FU in the microneedle, μ g; a is the effective diffusion area, 0.95cm 2 。
The conditions of the high performance liquid chromatography were as follows: a chromatographic column:
c18 (150X 4.6mm,5 μm); mobile phase: acetonitrile: water (85; column temperature: 25 ℃; detection wavelength: 265nm; flow rate: 1mL/min; sample introduction amount: 10 μ L.
Examination of separability of microneedles
A drop of water is dropped on the root of the microneedle array, and then the separation condition of the rapidly separable microneedles is recorded by a camera.
A micrograph of the prepared microneedle is shown in fig. 3, and the separability is shown in fig. 4.
Example 6
A preparation method of a separable microneedle carrying 5-fluorouracil comprises the following operation steps:
the preparation method comprises the following steps: the 5-fluorouracil-loaded separable microneedle is prepared according to the method of the embodiment 5, and the 5-fluorouracil nanocapsule is only required to be replaced by 5-fluorouracil with equal drug content.
The test method comprises the following steps: the transdermal permeation amounts of examples 5 and 6 were analyzed according to the transdermal permeation performance examination method of the microneedles and the analysis method described above.
The 24-h transdermal permeation amounts of examples 5 and 6 are shown in fig. 5, and the results show that the rapidly separable microneedle loaded with the 5-fluorouracil nanocapsule can realize the sustained release of 5-fluorouracil.
In conclusion, the microneedle loaded with the 5-fluorouracil nanocapsule and capable of being rapidly separated has the advantages of high separation speed, no burst release phenomenon, simple preparation process, capability of realizing slow release of 5-fluorouracil and the like.
Claims (10)
1. A preparation method of a 5-fluorouracil-loaded nano capsule is characterized by comprising the following steps:
the method comprises the following steps: taking a certain amount of dichloromethane as O 1 (ii) a Adding oil-in-water type surfactant into 5-fluorouracil-loaded ZIF-8 solution, and mixing to obtain W 1 (ii) a Dissolving polylactic acid in dichloromethane, adding water-in-oil type surfactant, stirring to obtain product O 2 (ii) a Dissolving polyvinyl alcohol in water under heating, adding oil-in-water type surfactant, stirring to obtain W 2 ；
The synthesis method of the ZIF-8 solution comprises the following steps: first, zn (NO) is dissolved in deionized water 3 ) 2 6H 2 O and 2-methylimidazole to prepare Zn (NO) 3 ) 2 6H 2 O solution and 2-methylimidazole solution; then dropping triethanolamineBy addition of Zn (NO) 3 ) 2 6H 2 Stirring in the O solution; the 2-methylimidazole solution was then added dropwise to Zn (NO) 3 ) 2 6H 2 Stirring in the O solution; centrifuging the obtained product solution, and washing with water to obtain a ZIF-8 solution;
step two: the obtained W 1 And O 1 Mixing, ultrasonic treating in ice bath to obtain O 1 /W 1 Primary emulsion;
step three: the obtained O 1 /W 1 Primary emulsion and O 2 Mixing, ultrasonic treating in ice bath to obtain O 1 /W 1 /O 2 Compounding milk;
step four: the obtained O 1 /W 1 /O 2 Fast combining with W 2 Mixing, performing ice bath ultrasound to obtain a nano capsule solution;
step five: and centrifuging the obtained nano capsule solution, washing with water, volatilizing the solvent, and freeze-drying to obtain 5-fluorouracil-loaded nano capsule powder.
2. The method for preparing 5-fluorouracil-loaded nanocapsules according to claim 1, wherein W is 1 The mass ratio of the medium 5-fluorouracil in the ZIF-8 solution is 0.6-1%; the particle size of the ZIF-8 is 90-120nm; said O is 1 The mass ratio of the polylactic acid in the dichloromethane is 1-6%; the W is 2 The mass ratio of polyvinyl alcohol in water is 1-2%.
3. The method for preparing the 5-fluorouracil-loaded nanocapsule according to claim 1, wherein the oil-in-water surfactant is one or more selected from the group consisting of tween 80, tween 20, polyoxyethylene castor oil, and PEG-40 hydrogenated castor oil; the water-in-oil surfactant is selected from one or more of span 80, span 60 and span 20.
4. A 5-fluorouracil-loaded nanocapsule characterized by being prepared by the preparation method of any one of claims 1 to 3.
5. A preparation method of a rapidly separable microneedle loaded with 5-fluorouracil nanocapsules is characterized by comprising the following steps:
the method comprises the following steps: respectively dissolving chitosan and dextran in an acidic aqueous solution and water, uniformly mixing according to a volume ratio of 1:1 to obtain a microneedle matrix solution, and dissolving the 5-fluorouracil-loaded nanocapsule of claim 4 in the microneedle matrix solution to obtain a drug-loaded microneedle matrix;
step two: dissolving polyvinylpyrrolidone, citric acid and sodium bicarbonate in absolute ethyl alcohol to obtain a microneedle backing solution;
step three: adding the drug-loaded microneedle matrix solution into a microneedle mould, centrifuging to uniformly fill the microneedle mould, removing the redundant matrix solution, standing at room temperature until the microneedle mould is dry, adding the microneedle backing solution, centrifuging to remove redundant bubbles, placing the microneedle in a drier for drying, and demoulding to obtain the rapidly-separable microneedle loaded with the 5-fluorouracil nanocapsule.
6. The preparation method of the 5-fluorouracil nanocapsule-loaded rapid separable microneedle according to claim 5, wherein the mass-to-volume ratio of the 5-fluorouracil nanocapsule-loaded microneedle matrix to the microneedle matrix solution in the drug-loaded microneedle matrix is (0.1-1) g:1mL; the mass ratio of chitosan to dextran in the microneedle matrix solution is 1; the acid solution is glacial acetic acid water solution, and the concentration is 1%.
7. The method for preparing the rapidly separable microneedle carrying the 5-fluorouracil nanocapsule according to claim 5, wherein the mass ratio of polyvinylpyrrolidone, citric acid and sodium bicarbonate in the microneedle backing solution is (20-30): 4:5.
8. The method for preparing a rapidly separable microneedle carrying 5-fluorouracil nanocapsules according to claim 5, wherein the microneedle substrate is centrifuged at 2500-3500rpm/min for 10-20min; the centrifugal rotating speed of the microneedle backing solution is 1500-2500rpm/min, and the centrifugal time is 5-10min; the drying time of the microneedle substrate is 6-12h, and the drying time of the microneedle is 24-48h.
9. A rapidly separable microneedle carrying 5-fluorouracil nanocapsules, characterized by being prepared by the preparation method according to any one of claims 5 to 8.
10. Use of the 5-fluorouracil-loaded nanocapsule of claim 4 or the rapidly separable microneedle of the 5-fluorouracil-loaded sustained release nanocapsule of claim 9 in a sustained release 5-fluorouracil and drug delivery system.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017133419A1 (en) * | 2016-02-03 | 2017-08-10 | 三捷生物科技（北京）有限公司 | Drug-loaded microsphere and preparation method and use thereof |
| CN111465387A (en) * | 2017-10-11 | 2020-07-28 | 乔治亚州技术研究公司 | Separable microneedle array for sustained release of drug |
| WO2021097194A1 (en) * | 2019-11-14 | 2021-05-20 | Board Of Regents, The University Of Texas System | Compositions and methods for controlled delivery and protection of therapeutic agents |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017133419A1 (en) * | 2016-02-03 | 2017-08-10 | 三捷生物科技（北京）有限公司 | Drug-loaded microsphere and preparation method and use thereof |
| CN111465387A (en) * | 2017-10-11 | 2020-07-28 | 乔治亚州技术研究公司 | Separable microneedle array for sustained release of drug |
| WO2021097194A1 (en) * | 2019-11-14 | 2021-05-20 | Board Of Regents, The University Of Texas System | Compositions and methods for controlled delivery and protection of therapeutic agents |
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| QIUXIANG WANG等: "Synthesis and modification of ZIF-8 and its application in drug delivery and tumor therapy", RSC ADV., vol. 10, 12 October 2020 (2020-10-12), pages 37600 - 37620, XP055965505, DOI: 10.1039/D0RA07950B * |
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