CN104873456B - A kind of 5 fluorouracil corrosion inhibiter and preparation method thereof - Google Patents
A kind of 5 fluorouracil corrosion inhibiter and preparation method thereof Download PDFInfo
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- CN104873456B CN104873456B CN201510229170.1A CN201510229170A CN104873456B CN 104873456 B CN104873456 B CN 104873456B CN 201510229170 A CN201510229170 A CN 201510229170A CN 104873456 B CN104873456 B CN 104873456B
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- fluorouracil
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Abstract
The present invention relates to a kind of 5 fluorouracil corrosion inhibiter and preparation method thereof, belong to Iatrochemistry field.5 described fluorouracil anticancer medicine slow-release preparation containings are under negative pressure, 5 fluorouracil solution to be slowly added dropwise and soak nano-grade hydroxy apatite, stirring, dry and are made.The slow releasing carrier of medication nanometer hydroxyapatite that the present invention uses is the main inorganic composition of mammal Ti Nei sclerous tissueses, has higher bioactivity, is a kind of widely used treatment material of good biocompatibility；In addition, nano-grade hydroxy apatite colloidal sol also has the function that to kill cancer cell, therefore side effects of pharmaceutical drugs can be reduced using nano-grade hydroxy apatite as the slow-released carrier of cancer therapy drug 5-FU, improve the bioavilability of medicine.
Description
Technical field
The present invention relates to a kind of 5 FU 5 fluorouracil corrosion inhibiter and preparation method thereof, belong to Iatrochemistry field.
Background technology
Hydroxyapatite is the main inorganic composition of vertebrate skeletal, tooth, is a kind of common bioactivity material
Material, hydroxyapatite has good biocompatibility, nontoxic, and bigger than surface, bioadhesive is strong, can combine and transmit big point
Sub- medicine；Research shows will have not compared with common hydroxyapatite when the size of hydroxyapatite reaches 1 ~ 100 nm
Same physicochemical property, as solubility is higher, surface energy is larger, adsorptivity is stronger, bioactivity is more preferable；In addition, nano-grade hydroxy
Apatite has different degrees of inhibitory action to growth of tumour cell, and on normal cell without influence, it is considered as pole to make it
Has the pharmaceutical carrier of application prospect.
5 FU 5 fluorouracil (5-fluorouracil, 5-Fu) is a kind of classical uracil antimetabolite, can be suppressed
The growth of tumour, it is widely used in the treatment of the malignant tumours such as tumor in digestive tract, cutaneum carcinoma, lung cancer, carcinoma of urinary bladder；
The antitumor action of hydroxyapatite and the research as antineoplastic drug carrier have become in recent years
The focus of research.
The content of the invention
The present invention discloses a kind of side of 5 FU 5 fluorouracil release to expand application of the 5 FU 5 fluorouracil in medical domain
Method.
For achieving the above object, the present invention is achieved using following technical proposals：
A kind of 5 FU 5 fluorouracil sustained release agent, it is characterised in that：Described 5 FU 5 fluorouracil anticancer medicine slow-release preparation containing is negative
Pressure, is slowly added dropwise 5 FU 5 fluorouracil solution and soaks nano-grade hydroxy apatite, stirs, and dries and is made.
The concentration of the solution of the 5 FU 5 fluorouracil used during load, all it is that the 5- fluorine urine that concentration is 0.025g/mL is phonetic
Use after the dilution of pyridine solution, or directly use；Due to drug loading it is smaller when, directly plus without dilution 5 fluorine urine it is phonetic
Pyridine solution may not complete wetting hydroxyapatite, so will 0.025g/mL 5 FU 5 fluorouracil solution dilution after use.
The negative pressure refers to less than 0.01 MPa.
The mass ratio of the 5 FU 5 fluorouracil and hydroxyapatite is：0.01~0.1:1.
The preparation method of described 5 FU 5 fluorouracil anticancer medicine slow-release preparation containing, it is characterized in that carry out in the steps below：
（1）The preparation of nano-grade hydroxy apatite
The 500 mL three-necked flasks equipped with magnetic stir bar are placed in water-bath, add isometric 1.0 mol/L nitre
The phosphoric acid solution of sour calcium solution and 0.6 mol/L, stirs；It is molten that sodium hydroxide is added dropwise into three-necked flask with constant flow peristaltic pump
Liquid or ammoniacal liquor regulation pH are to continue stirring reaction under 9,25 DEG C ~ 45 DEG C water-baths 5 hours；Reaction product and mother liquor are transferred to
In polytetrafluoroethylene (PTFE) hydrothermal reaction kettle, 100 DEG C ~ 150 DEG C h of hydrothermal crystallizing 6 ~ 24, filter, filter cake distillation water washing, 60
DEG C vacuumize and to dry 24 h and obtain nanometer hydroxyapatite.
（2）Load the preparation of 5 FU 5 fluorouracil sustained release agent
Under negative pressure, 5 FU 5 fluorouracil solution, which is slowly added dropwise, makes its uniform wet nano-grade hydroxy apatite, and stirring obtains
Mixed solution, stir, dry, obtain the hydroxyapatite for 5 FU 5 fluorouracil sustained release.
The present invention has following features compared with prior art：
The slow releasing carrier of medication nanometer hydroxyapatite that the present invention uses is the host inorganic of mammal Ti Nei sclerous tissueses
Composition, there is higher bioactivity, be a kind of widely used treatment material of good biocompatibility；In addition, nano-grade hydroxy
Hydroxyapatite particles colloidal sol also has the function that to kill cancer cell, therefore is urinated nano-grade hydroxy apatite as the fluorine of cancer therapy drug 5
The slow-released carrier of pyrimidine can reduce side effects of pharmaceutical drugs, improve the bioavilability of medicine.
Brief description of the drawings
Fig. 1 is the XRD spectrum of hydroxyapatite prepared by the present invention；Only there is hydroxy-apatite in sample as can be seen from Figure 1
The diffraction maximum of stone, the sample for illustrating to prepare is pure hydroxyapatite.
Fig. 2 is hydroxyapatite nitrogen adsorption-desorption curve prepared by the present invention；From figure 2 it can be seen that the sample
For porous material.
Fig. 3 is hydroxyapatite transmission electron microscope prepared by the present invention（TEM）Figure；The hydroxyl phosphorus prepared as can be seen from Figure 3
Lime stone is the rod-shpaed particle that particle diameter is less than 100 nm, and can see the duct of sample, and the sample for illustrating to prepare is mesoporous
Hydroxyapatite.
Embodiment
It is below presently preferred embodiments of the present invention, better understood when the present invention, but embodiments of the invention are not limited to
This, while its shown data does not represent the limitation to feature of present invention scope.
Embodiment 1
（1）The preparation of nano-grade hydroxy apatite
The 500 mL three-necked flasks equipped with magnetic stir bar are placed in 45 DEG C of water-baths, add the mol/ of 100 mL 1.0
L calcium nitrate solutions and 100 mL 0.6mol/L phosphoric acid solutions, stir；2 are added dropwise into three-necked flask with constant flow peristaltic pump
Mol/L sodium hydroxide solutions adjust pH to 9, continue the h of stirring reaction 5 under 45 DEG C of water-baths；Reaction product and mother liquor are transferred to
In polytetrafluoroethylene (PTFE) hydrothermal reaction kettle, 90 DEG C of h of hydrothermal crystallizing 12, filter, filter cake distillation water washing, 60 DEG C vacuumize drying
24h obtains nanometer hydroxyapatite.
（2）5 FU 5 fluorouracil load capacity is the preparation of 1% anticancer sustained-release agent
Under 0.005MPa negative pressure, 5 mL 5 FU 5 fluorouracil solution are slowly added dropwise（1 mL concentration is the 5 of 25 g/L
Fluorouracil solution is diluted to 5 mL）Hydroxyapatite prepared by the g examples 1 of uniform wet 2.5, urinate its uniform wet 5- fluorine
Pyrimidine solution, mixed solution is obtained after stirring is ultrasonic, is vacuumized, is stirred, is dried, 5 FU 5 fluorouracil load capacity is 1 % anticancer
Sustained release agent.
（3）Extracorporeal releasing test
The powder for taking 1.0 g to prepare is placed in 50 mL simulated body fluids, the separately sampled 1mL constant volumes after the 4th, 6,10,12 h
Volumetric flask to 50mL determines absorbance；It is replaced in after measurement in 50 mL simulated body fluids of replacing, sampling 1mL constant volumes arrive
50mL volumetric flask measure absorbance；So as to obtain accumulative 5 FU 5 fluorouracil burst size, mg/L is designated as；From 4 h to the 12nd h, 5-
The release percentage of fluorouracil is from 30.8 % to 78 %；The biological half-life of 5 FU 5 fluorouracil is 10-20 minutes, this 5- fluorine urine
The release time of 5 FU 5 fluorouracil is extended to 12h by the sustained release agent of pyrimidine, has been reached and has been allowed the purpose of medicament slow release, and has improved
The bioavilability of medicine.
The 5 FU 5 fluorouracil load capacity of embodiment 2 is the preparation of 3 % anticancer sustained-release agents
Nano-grade hydroxy apatite is prepared using the same method of embodiment 1, under 0.005MPa negative pressure, is slowly added dropwise
5 ml 5 FU 5 fluorouracil solution（3 ml concentration are that 25 g/L 5 FU 5 fluorouracil solution is diluted to 5 ml）Uniform wet 2.5
Hydroxyapatite prepared by g, make its uniform wet 5 FU 5 fluorouracil solution, obtain mixed solution after stirring ultrasound, vacuumize, stir
Mix, dry, 5 FU 5 fluorouracil load capacity is 3 % anticancer sustained-release agents；The powder for taking 1.0 g to prepare is placed in 50 mL simulated body fluids,
The concentration of 5 FU 5 fluorouracil, phonetic so as to obtain accumulative 5- fluorine urine in separately sampled measure simulated body fluid after the 4th, 6,10,12 h
Pyridine burst size, is designated as mg/L；From 4h to the 12nd h, the release percentage of 5 FU 5 fluorouracil is from 28.6 % to 73 %.
The 5 FU 5 fluorouracil load capacity of embodiment 3 is the preparation of 5 % anticancer sustained-release agents
Nano-grade hydroxy apatite is prepared using the same method of embodiment 1, under 0.005MPa negative pressure, is slowly added dropwise
5 ml 5 FU 5 fluorouracil solution（Concentration is 25 g/L）Hydroxyapatite prepared by the g of uniform wet 2.5, makes its uniform wet 5-
Fluorouracil solution, mixed solution is obtained after stirring is ultrasonic, is vacuumized, is stirred, is dried, 5 FU 5 fluorouracil load capacity is that 5 % resist
Cancer sustained release agent；The powder for taking 1.0 g to prepare is placed in 50 mL simulated body fluids, the separately sampled measure mould after the 4th, 6,10,12 h
Intend the concentration of 5 FU 5 fluorouracil in body fluid, so as to obtain accumulative 5 FU 5 fluorouracil burst size, be designated as mg/L；From 4 h to the 12nd h,
The release percentage of 5 FU 5 fluorouracil is from 25.4 % to 69.8 %.
The 5 FU 5 fluorouracil load capacity of embodiment 4 is the preparation of 7 % anticancer sustained-release agents
Nano-grade hydroxy apatite is prepared using the same method of embodiment 1, under 0.005MPa negative pressure, is slowly added dropwise
7 ml 5 FU 5 fluorouracil solution（Concentration is 25 g/L）Hydroxyapatite prepared by the g of uniform wet 2.5, makes its uniform wet 5-
Fluorouracil solution, mixed solution is obtained after stirring is ultrasonic, is vacuumized, is stirred, is dried, 5 FU 5 fluorouracil load capacity is that 7 % resist
Cancer sustained release agent；The powder for taking 1.0 g to prepare is placed in 50 mL simulated body fluids, the separately sampled measure mould after the 4th, 6,10,12 h
Intend the concentration of 5 FU 5 fluorouracil in body fluid, so as to obtain accumulative 5 FU 5 fluorouracil burst size, be designated as mg/L；From 4 h to the 12nd h,
The release percentage of 5 FU 5 fluorouracil is from 20.1 % to 60.4 %.
The 5 FU 5 fluorouracil load capacity of embodiment 5 is the preparation of 10 % anticancer sustained-release agents
Nano-grade hydroxy apatite is prepared using the same method of embodiment 1, under negative pressure, 10 mL 5- fluorine are slowly added dropwise
Uracil solution（Concentration is 25 g/L）Hydroxyapatite prepared by the g of uniform wet 2.5, makes its uniform wet 5 FU 5 fluorouracil
Solution, mixed solution is obtained after stirring is ultrasonic, is vacuumized, is stirred, is dried, 5 FU 5 fluorouracil load capacity is 10 % anticancer slow-releases
Agent；The powder for taking 1.0 g to prepare is placed in 50 mL simulated body fluids, the separately sampled measure simulated body fluid after the 4th, 6,10,12 h
The concentration of middle 5 FU 5 fluorouracil, so as to obtain accumulative 5 FU 5 fluorouracil burst size, it is designated as mg/L；From 4 h to the 12nd h, 5- fluorine urine
The release percentage of pyrimidine is from 20.2 % to 66.9 %.
Claims (5)
- A kind of 1. 5 FU 5 fluorouracil sustained release agent, it is characterised in that：Described 5 FU 5 fluorouracil sustained release agent is under negative pressure, slowly to drip Add 5 FU 5 fluorouracil solution to soak porous nano level hydroxyapatite, stir, dry and be made.
- A kind of 2. 5 FU 5 fluorouracil sustained release agent as claimed in claim 1, it is characterised in that：The solution of the 5 FU 5 fluorouracil used Concentration, be all concentration be 0.025g/mL 5 FU 5 fluorouracil solution dilution after use, or directly use；Concentration with Energy complete wetting porous nano level hydroxyapatite is defined.
- A kind of 3. 5 FU 5 fluorouracil sustained release agent as claimed in claim 1, it is characterised in that：The negative pressure refers to less than 0.01MPa.
- A kind of 4. 5 FU 5 fluorouracil sustained release agent as claimed in claim 1, it is characterised in that：The 5 FU 5 fluorouracil is received with porous The mass ratio of meter level hydroxyapatite is：0.01~0.1:1.
- A kind of 5. 5 FU 5 fluorouracil sustained release agent as claimed in claim 1, it is characterised in that：Porous nano level hydroxyapatite Preparation method is as follows：500mL three-necked flasks equipped with magnetic stir bar are placed in water-bath, add isometric 1.0mol/L's The phosphoric acid solution of calcium nitrate solution and 0.6mol/L, stirs；Sodium hydroxide is added dropwise into three-necked flask with constant flow peristaltic pump Solution or ammoniacal liquor regulation pH are to continue stirring reaction under 9,25 DEG C~45 DEG C water-baths 5 hours；Reaction product and mother liquor are shifted Into polytetrafluoroethylene (PTFE) hydrothermal reaction kettle, 100 DEG C~150 DEG C 6~24h of hydrothermal crystallizing, filter, filter cake distillation water washing, 60 DEG C vacuumizing dry 24h obtains porous nanometer hydroxyapatite.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20080241256A1 (en) * | 2007-03-30 | 2008-10-02 | Liisa Kuhn | Targeted active agent delivery system based on calcium phosphate nanoparticles |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
|---|
| "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";吴占敖等;《中国组织工程研究与临床康复》;20080701;第12卷(第27期);第5296页右栏倒数第2段、第5298页左栏第1段 * |
| "多孔载体负载农药缓释剂的制备及缓释性能的研究";江熠辉;《中国优秀硕士学位论文全文数据库 (工程科技I辑)》;20150331;正文第21页第2.3节 * |
| "纳米羟基磷灰石作为药物载体材料的研究进展";赵欣等;《材料导报：综述篇》;20101231;第24卷(第12期);摘要、第116页左栏最后1段至右栏第1段、第118页右栏倒数第2段 * |
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