CN104873456A - 5-fluorouracil corrosion inhibitor and preparation method thereof - Google Patents
5-fluorouracil corrosion inhibitor and preparation method thereof Download PDFInfo
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- CN104873456A CN104873456A CN201510229170.1A CN201510229170A CN104873456A CN 104873456 A CN104873456 A CN 104873456A CN 201510229170 A CN201510229170 A CN 201510229170A CN 104873456 A CN104873456 A CN 104873456A
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Abstract
The invention relates to a 5-fluorouracil corrosion inhibitor and a preparation method thereof, and belongs to the field of medical chemistry. The preparation method of a 5-fluorouracil anti-cancer medicine controlled-release agent comprises the following steps: slowly dropwise adding a 5-fluorouracil solution to soak nano-sized hydroxyapatite at a negative pressure, stirring, and drying. According to the 5-fluorouracil corrosion inhibitor disclosed by the invention, an adopted medicine controlled-release carrier namely nano-sized hydroxyapatite is a main inorganic component of hard tissues in the body of a mammal, has relatively high bioactivity, and is a treatment material with good biocompatibility and wide application; and in addition, nano-sized hydroxyapatite particle sols also have the effects of killing cancer cells, so that nano-sized hydroxyapatite can be taken as the controlled-release carrier of anti-cancer medicines namely 5-fluorouracil to play roles in reducing the side effects of the medicines and improving the bioavailability of the medicines.
Description
Technical field
The present invention relates to a kind of 5-fluorouracil corrosion inhibiter and preparation method thereof, belong to medicochemistry field.
Background technology
Hydroxyapatite is the main inorganic composition of vertebrate skeletal, tooth, and be a kind of common bioactive materials, hydroxyapatite has good biocompatibility, nontoxic, and specific surface is large, and bioadhesive is strong, can in conjunction with and transmission macromolecular drug; Research shows, will have different physicochemical properties when the size of hydroxyapatite reaches 1 ~ 100 nm compared with common hydroxyapatite, and as higher in dissolubility, surface energy is comparatively large, adsorptivity is stronger, biological activity is better; In addition, nano-grade hydroxy apatite has inhibitory action in various degree to growth of tumour cell, and on normal cell without impact, makes it be considered to have the pharmaceutical carrier of application prospect.
5-fluorouracil (5-fluorouracil, 5-Fu) is a kind of uracil antimetabolite of classics, can the growth of Tumor suppression, is widely used in digestive tract tumor, skin carcinoma, pulmonary carcinoma, the treatment of the malignant tumor such as bladder cancer;
In recent years hydroxyapatite antitumor action and it can be used as the research of antineoplastic drug carrier to become the focus of research.
Summary of the invention
The present invention, in order to expand the application of 5-fluorouracil at medical domain, discloses the method for a kind of 5-fluorouracil release.
For achieving the above object, the present invention adopts following technical proposals to be achieved:
A kind of 5-fluorouracil slow releasing agent, is characterized in that: described 5-fluorouracil anticancer medicine slow-release preparation containing is under negative pressure, slowly drips 5-fluorouracil solution wets nano-grade hydroxy apatite, stirs, dry obtained.
The concentration of the solution of the 5-fluorouracil used during load is all working concentration is use after the 5-fluorouracil solution dilution of 0.025g/mL, or directly uses; Due to drug loading smaller time, directly adding does not have the 5-FU solution diluted may not complete wetting hydroxyapatite, so will use after the 5-fluorouracil solution dilution of 0.025g/mL.
Described negative pressure refers to lower than 0.01 MPa.
The mass ratio of described 5-fluorouracil and hydroxyapatite is: 0.01 ~ 0.1:1.
The preparation method of described 5-fluorouracil anticancer medicine slow-release preparation containing, is characterized in that carrying out in the steps below:
(1) preparation of nano-grade hydroxy apatite
The 500 mL there-necked flasks being furnished with magnetic stir bar are placed in water-bath, add the calcium nitrate solution of equal-volume 1.0 mol/L and the phosphoric acid solution of 0.6 mol/L, stir; In there-necked flask, dripping sodium hydroxide solution or ammonia with constant flow peristaltic pump regulates pH to continue stirring reaction 5 hours under 9,25 DEG C ~ 45 DEG C water-baths; Product and mother solution are transferred in politef hydrothermal reaction kettle, 100 DEG C ~ 150 DEG C hydrothermal crystallizing 6 ~ 24 h, sucking filtration, filter cake distilled water wash, 60 DEG C of dry 24 h of evacuation obtain nanometer hydroxyapatite.
(2) preparation of load 5-fluorouracil slow releasing agent
Under negative pressure, slowly drip 5-fluorouracil solution and make its uniform wet nano-grade hydroxy apatite, stir and obtain mixed solution, stir, dry, obtain the hydroxyapatite for 5-fluorouracil slow release.
The present invention compared with prior art has following features:
The slow releasing carrier of medication nanometer hydroxyapatite that the present invention uses is the main inorganic composition of sclerous tissues in mammalian body, and having higher biological activity, is the broad-spectrum treatment material of a kind of good biocompatibility; In addition, nano-grade hydroxy apatite colloidal sol also has the effect of killing cancerous cell, therefore nano-grade hydroxy apatite can be reduced side effects of pharmaceutical drugs as the slow-released carrier of cancer therapy drug 5-FU, improves the bioavailability of medicine.
Accompanying drawing explanation
Fig. 1 is the XRD figure spectrum of hydroxyapatite prepared by the present invention; Only there is the diffraction maximum of hydroxyapatite in sample as can be seen from Figure 1, illustrates that the sample of preparation is pure hydroxyapatite.
Fig. 2 is hydroxyapatite nitrogen adsorption-desorption curve prepared by the present invention; As can be seen from Figure 2, this sample is porous material.
Fig. 3 is hydroxyapatite transmission electron microscope (TEM) figure prepared by the present invention; The hydroxyapatite prepared as can be seen from Figure 3 is the rod-shpaed particle that particle diameter is less than 100 nm, and can see the duct of sample, illustrates that the sample of preparation is mesoporous hydroxyapatite.
Detailed description of the invention
Be below preferred embodiment of the present invention, can understand the present invention better, but embodiments of the invention be not limited thereto, shown in it, data do not represent the restriction to characteristic range of the present invention simultaneously.
Embodiment 1
(1) preparation of nano-grade hydroxy apatite
The 500 mL there-necked flasks being furnished with magnetic stir bar are placed in 45 DEG C of water-baths, add 100 mL 1.0 mol/L calcium nitrate solutions and 100 mL 0.6mol/L phosphoric acid solutions, stir; In there-necked flask, dripping 2 mol/L sodium hydroxide solutions with constant flow peristaltic pump regulates pH to 9, continues stirring reaction 5 h under 45 DEG C of water-baths; Product and mother solution are transferred in politef hydrothermal reaction kettle, 90 DEG C of hydrothermal crystallizing 12 h, sucking filtration, filter cake distilled water wash, 60 DEG C of dry 24h of evacuation obtain nanometer hydroxyapatite.
(2) 5-fluorouracil load capacity is the preparation of the anticancer sustained-release agent of 1%
Under the negative pressure of 0.005MPa, the hydroxyapatite of slow dropping 5 mL 5-fluorouracil solution (1 mL concentration is that the 5-FU solution dilution of 25 g/L is to 5 mL) uniform wet 2.5 g example 1 preparation, make its uniform wet 5-fluorouracil solution, stir ultrasonic after obtain mixed solution, evacuation, stir, dry, 5-fluorouracil load capacity is the anticancer sustained-release agent of 1 %.
(3) extracorporeal releasing test
Get powder prepared by 1.0 g and be placed in 50 mL simulated body fluids, after the the the 4th, 6,10,12 h, sample 1mL standardize solution respectively measure absorbance to the volumetric flask of 50mL; Again be placed in 50 mL simulated body fluids of replacing after measurement, sampling 1mL standardize solution measures absorbance to the volumetric flask of 50mL; Thus obtain accumulative 5-fluorouracil burst size, be designated as mg/L; From 4 h to the 12nd h, the release percentage ratio of 5-fluorouracil is from 30.8 % to 78 %; The biological half-life of 5-fluorouracil is 10-20 minute, and the release time of 5-fluorouracil is extended to 12h by the slow releasing agent of this 5-fluorouracil, reaches to allow the object of medicament slow release, and improves the bioavailability of medicine.
Embodiment 2 5-fluorouracil load capacity is the preparation of 3 % anticancer sustained-release agents
The same method of embodiment 1 is adopted to prepare nano-grade hydroxy apatite, under the negative pressure of 0.005MPa, hydroxyapatite prepared by slow dropping 5 ml 5-fluorouracil solution (3 ml concentration are that the 5-fluorouracil solution dilution of 25 g/L is to 5 ml) uniform wet 2.5 g, make its uniform wet 5-fluorouracil solution, stir ultrasonic after obtain mixed solution, evacuation, stir, drying, 5-fluorouracil load capacity is 3 % anticancer sustained-release agents; Get powder prepared by 1.0 g and be placed in 50 mL simulated body fluids, the concentration of 5-fluorouracil in sampling and measuring simulated body fluid respectively after the the the 4th, 6,10,12 h, thus obtain accumulative 5-fluorouracil burst size, be designated as mg/L; From 4h to the 12nd h, the release percentage ratio of 5-fluorouracil is from 28.6 % to 73 %.
Embodiment 3 5-fluorouracil load capacity is the preparation of 5 % anticancer sustained-release agents
The same method of embodiment 1 is adopted to prepare nano-grade hydroxy apatite, under the negative pressure of 0.005MPa, hydroxyapatite prepared by slow dropping 5 ml 5-fluorouracil solution (concentration is 25 g/L) uniform wet 2.5 g, make its uniform wet 5-fluorouracil solution, stir ultrasonic after obtain mixed solution, evacuation, stir, drying, 5-fluorouracil load capacity is 5 % anticancer sustained-release agents; Get powder prepared by 1.0 g and be placed in 50 mL simulated body fluids, the concentration of 5-fluorouracil in sampling and measuring simulated body fluid respectively after the the the 4th, 6,10,12 h, thus obtain accumulative 5-fluorouracil burst size, be designated as mg/L; From 4 h to the 12nd h, the release percentage ratio of 5-fluorouracil is from 25.4 % to 69.8 %.
Embodiment 4 5-fluorouracil load capacity is the preparation of 7 % anticancer sustained-release agents
The same method of embodiment 1 is adopted to prepare nano-grade hydroxy apatite, under the negative pressure of 0.005MPa, hydroxyapatite prepared by slow dropping 7 ml 5-fluorouracil solution (concentration is 25 g/L) uniform wet 2.5 g, make its uniform wet 5-fluorouracil solution, stir ultrasonic after obtain mixed solution, evacuation, stir, drying, 5-fluorouracil load capacity is 7 % anticancer sustained-release agents; Get powder prepared by 1.0 g and be placed in 50 mL simulated body fluids, the concentration of 5-fluorouracil in sampling and measuring simulated body fluid respectively after the the the 4th, 6,10,12 h, thus obtain accumulative 5-fluorouracil burst size, be designated as mg/L; From 4 h to the 12nd h, the release percentage ratio of 5-fluorouracil is from 20.1 % to 60.4 %.
Embodiment 5 5-fluorouracil load capacity is the preparation of 10 % anticancer sustained-release agents
The same method of embodiment 1 is adopted to prepare nano-grade hydroxy apatite, under negative pressure, hydroxyapatite prepared by slow dropping 10 mL 5-fluorouracil solution (concentration is 25 g/L) uniform wet 2.5 g, make its uniform wet 5-fluorouracil solution, stir ultrasonic after obtain mixed solution, evacuation, stir, drying, 5-fluorouracil load capacity is 10 % anticancer sustained-release agents; Get powder prepared by 1.0 g and be placed in 50 mL simulated body fluids, the concentration of 5-fluorouracil in sampling and measuring simulated body fluid respectively after the the the 4th, 6,10,12 h, thus obtain accumulative 5-fluorouracil burst size, be designated as mg/L; From 4 h to the 12nd h, the release percentage ratio of 5-fluorouracil is from 20.2 % to 66.9 %.
Claims (5)
1. a 5-fluorouracil slow releasing agent, is characterized in that: described 5-fluorouracil anticancer medicine slow-release preparation containing is under negative pressure, slowly drips 5-fluorouracil solution wets nano-grade hydroxy apatite, stirs, dry obtained.
2. a kind of 5-fluorouracil slow releasing agent as claimed in claim 1, is characterized in that: the concentration of the solution of the 5-fluorouracil of use, be all working concentration is use after the 5-fluorouracil solution dilution of 0.025g/mL, or directly uses; Concentration is being as the criterion by complete wetting hydroxyapatite.
3. a kind of 5-fluorouracil slow releasing agent as claimed in claim 1, is characterized in that: described negative pressure refers to lower than 0.01 MPa.
4. a kind of 5-fluorouracil slow releasing agent as claimed in claim 1, is characterized in that: the mass ratio of described 5-fluorouracil and hydroxyapatite is: 0.01 ~ 0.1:1.
5. a kind of 5-fluorouracil slow releasing agent as claimed in claim 1, it is characterized in that: the preparation method of nano-grade hydroxy apatite is as follows: the 500 mL there-necked flasks being furnished with magnetic stir bar are placed in water-bath, add the calcium nitrate solution of equal-volume 1.0 mol/L and the phosphoric acid solution of 0.6 mol/L, stir; In there-necked flask, dripping sodium hydroxide solution or ammonia with constant flow peristaltic pump regulates pH to continue stirring reaction 5 hours under 9,25 DEG C ~ 45 DEG C water-baths; Product and mother solution are transferred in politef hydrothermal reaction kettle, 100 DEG C ~ 150 DEG C hydrothermal crystallizing 6 ~ 24 h, sucking filtration, filter cake distilled water wash, 60 DEG C of dry 24 h of evacuation obtain nanometer hydroxyapatite.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080241256A1 (en) * | 2007-03-30 | 2008-10-02 | Liisa Kuhn | Targeted active agent delivery system based on calcium phosphate nanoparticles |
| CN101756908A (en) * | 2010-01-25 | 2010-06-30 | 沈阳药科大学 | Hydroxyapatite micro-sphere with polyester coating and preparation method thereof |
| CN101804032A (en) * | 2010-04-09 | 2010-08-18 | 华南理工大学 | Preparation method of 5-fluorouracil-wrapped biodegradable polylactic acid/nano-hydroxyapatite compound microspheres |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080241256A1 (en) * | 2007-03-30 | 2008-10-02 | Liisa Kuhn | Targeted active agent delivery system based on calcium phosphate nanoparticles |
| CN101756908A (en) * | 2010-01-25 | 2010-06-30 | 沈阳药科大学 | Hydroxyapatite micro-sphere with polyester coating and preparation method thereof |
| CN101804032A (en) * | 2010-04-09 | 2010-08-18 | 华南理工大学 | Preparation method of 5-fluorouracil-wrapped biodegradable polylactic acid/nano-hydroxyapatite compound microspheres |
Non-Patent Citations (3)
| Title |
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| 吴占敖等: ""反应温度和有机修饰剂对医用纳米羟基磷灰石尺寸的影响"", 《中国组织工程研究与临床康复》 * |
| 江熠辉: ""多孔载体负载农药缓释剂的制备及缓释性能的研究"", 《中国优秀硕士学位论文全文数据库 (工程科技I辑)》 * |
| 赵欣等: ""纳米羟基磷灰石作为药物载体材料的研究进展"", 《材料导报：综述篇》 * |
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