CN105078879A - Preparation method for tegafur slow-release agent - Google Patents
Preparation method for tegafur slow-release agent Download PDFInfo
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- CN105078879A CN105078879A CN201510558466.8A CN201510558466A CN105078879A CN 105078879 A CN105078879 A CN 105078879A CN 201510558466 A CN201510558466 A CN 201510558466A CN 105078879 A CN105078879 A CN 105078879A
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Abstract
The invention provides a preparation method for a tegafur slow-release agent. The tegafur slow-release agent is prepared by selecting nanometer hollow titanium dioxide as a carrier for loading the anti-cancer drug tegafur; a PSM composite material coated with titanium dioxide is prepared according to a wet method of chemical sedimentation; nanometer hollow titanium dioxide is obtained after PSMs are removed; after being prepared according to a simple and effective impregnation method, the tegafur slow-release agent is put into a simulated body fluid, and the release rate of the tegafur slow-release agent is measured at scheduled time; the measurement results show that hollow titanium dioxide has a good effect of controlling the release of tegafur.
Description
Technical field
The present invention relates to a kind of preparation method of ftorafur slow releasing agent, belong to medicochemistry field.
Background technology
Ftorafur (Tegafur) is a kind of antimetabolite that tumor cell miazines nucleotide can be stoped to be formed, and is the derivant of antitumor drug 5-fluorouracil, is fluorouracil and working by the activation of liver in vivo.At present, ftorafur (Tegafur) is widely used in treatment gastric cancer, colorectal cancer, is clinically widely use and kinds of tumors had to the antitumor drug of good therapeutic effect.There are some researches show, the treatment of ftorafur to many solid tumors has obvious effect, compared with cancer therapy drug 5-FU important clinically, and the good absorbing of ftorafur.Safe and effective, toxic and side effects is little.
In recent years, titanium dioxide, because of its special character and wide market prospect, has become the focus of research.Titanium dioxide has good biocompatibility, can, as the carrier of local application, have scholar to attempt carrying out drug loading with this carrier.Result of study shows, nano titanium oxide not only has dissolution rate and the outstanding advantages such as absorbance, increase medicine stability that slow controlled release improves insoluble drug, can also inhibition tumor cell growth.Therefore, take hollow titanium dioxide as the carrier of ftorafur, not only can improve the drug loading of ftorafur, and can make that drug slow is constant to be discharged, single administration reaches the object of permanently effective treatment.
Summary of the invention
The present invention, in order to expand the application of ftorafur at medical domain, discloses a kind of preparation method of ftorafur slow releasing agent.
For achieving the above object, the present invention adopts following technical proposals to be achieved:
A preparation method for ftorafur slow releasing agent, comprises the steps
(1) hollow nano titanium dioxide is prepared;
(2) after evenly being soaked by the hollow nano titanium dioxide ftorafur alcoholic solution of step (1) gained, sealing is stirred, and then stirs in vacuum environment, dry, obtains ftorafur slow releasing agent.
In step (1), the preparation method of described hollow nano titanium dioxide comprises the steps:
The preparation of step a, polystyrylmethyl acrylic acid copolymer microsphere (PSM): by the refined styrene after distilling under reduced pressure, methacrylic acid is mixed homogeneously with distilled water, regulate bath temperature 70 ~ 85 DEG C, through nitrogen bubble effect deoxygenation, then the aqueous solution of potassium peroxydisulfate is added, after 10min, disconnected nitrogen is with initiated polymerization, after isothermal reaction 24h, obtains polystyrylmethyl acrylic acid copolymer microsphere PSM;
The preparation of step b, hollow nano titanium dioxide: copolymerization microsphere prepared by step (1) is placed in distilled water, the homodisperse suspension of ultrasonic acquisition, under the bath temperature of 75-90 DEG C, regulates PH to 2.0 with HCl solution; Under constantly stirring, drip TiCl simultaneously
4acid solution and NaOH solution maintain response system pH=2.0; After being added dropwise to complete, pH value maintains 2.0, stirs ageing, and washing is dry, and heating up from room temperature start program is heated to calcining heat, calcines to remove copolymerization microsphere.
In step a, the volume ratio of described styrene and methacrylic acid is 3 ~ 6:1, and described distilled water and cinnamic volume ratio are 8 ~ 3:1; Volume ratio 1:1.2 ~ 2.8 of described methacrylic acid and potassium persulfate solution, wherein, the concentration of potassium persulfate solution is 12.5g/L.
In step b, described TiCl
4acid solution is by the TiCl of 9.7mL98%
4obtain to 100mL with HCl solution dilution; The concentration of HCl solution is 0.5mol/L; The concentration of NaOH solution is 2mol/L.
In step b, described digestion time is 3h; Baking temperature is 100 DEG C, and drying time is 24h; Calcining heat is 550 DEG C, and calcination time is 4h.
In step (2), in described ftorafur alcoholic solution, the concentration of ftorafur is 6.7 ~ 26.7g/L; The mass ratio of described ftorafur and hollow nano titanium dioxide is 0.05 ~ 0.2:1.
In step (2), the time that described sealing is stirred is 12h; The temperature of described vacuum stirring drying is 60 DEG C, and the time is 24h.
extracorporeal releasing experiment
The hollow titanium dioxide powder getting 3g load ftorafur is placed in 300mL simulated body fluid, measures its absorbance after 20min, 1h, 2h, 4h, 7h, 12h, 20h, 32h, 48h, 72h, 100h after sampling 4mL respectively, calculates its release percent, is designated as %.
Beneficial effect of the present invention is:
(1) preparation method of hollow nano titanium dioxide is simple to operation, reproducible.
(2) the hollow nano titanium dioxide prepared has regular pattern, and specific surface area is large, the advantages such as good biocompatibility.
(3) slow-released carrier being cancer therapy drug ftorafur with hollow nano titanium dioxide can make ftorafur slowly discharge enduringly, thus reduces dosage, reduces toxic and side effects, improves its bioavailability.
figure of description
The release profiles of hollow titanium dioxide in simulated body fluid when Fig. 1 ftorafur load capacity is 5%;
The release profiles of hollow titanium dioxide in simulated body fluid when Fig. 2 ftorafur load capacity is 10%;
The release profiles of hollow titanium dioxide in simulated body fluid when Fig. 3 ftorafur load capacity is 15%;
The release profiles of hollow titanium dioxide in simulated body fluid when Fig. 4 ftorafur load capacity is 20%.
Detailed description of the invention
Below by embodiment, the invention will be further described, and its object is only better understand research contents of the present invention but not limit the scope of the invention.
Embodiment 1
(1) preparation of polystyrylmethyl acrylic acid copolymer microsphere (PSM)
By the refined styrene after 8mL distilling under reduced pressure, 2mL methacrylic acid is mixed homogeneously with 64mL distilled water, regulate bath temperature 75 DEG C, through nitrogen bubble effect deoxygenation, then the aqueous solution of 2.4mL12.5g/L potassium peroxydisulfate is added, after 10min, disconnected nitrogen is with initiated polymerization, obtains polystyrylmethyl acrylic acid copolymer microsphere PSM after isothermal reaction 24h.
(2) preparation of hollow nano titanium dioxide
Copolymerization microsphere prepared by 2.5g step (1) is joined in 2000mL beaker, adds in 200mL distilled water, ultrasonic 30min, obtain homodisperse suspension.Regulate bath temperature 80 DEG C, drip the HCl solution adjust ph of 0.5mol/L.Under constantly stirring, drip 100mLTiCl simultaneously
4solution (9.7mLTiCl
4solution (98%), uses 0.5molL
-1hCl solution dilution is to 100mL) maintain response system pH=2.0 with 2mol/LNaOH solution.After dripping presoma, pH value maintains 2.0, after stirring ageing 3h, and washing, dry.Heat up from room temperature start program and be heated to 550 DEG C, in the hollow titanium dioxide that 550 DEG C keep 4h to obtain for ftorafur slow release to remove copolymerization microsphere.
(3) a kind of preparation of ftorafur slow releasing agent
Add ftorafur solution (0.2g ftorafur is dissolved in 30mL dehydrated alcohol) in the 100mL flask of rotor and make its uniform wet 4g hollow nano titanium dioxide, prevent ethanol from volatilizing with preservative film sealing, after stirring 12h, evacuation, stir, drying, obtains the hollow titanium dioxide that ftorafur load capacity is 5%.
(4) extracorporeal releasing experiment
The hollow titanium dioxide powder getting 3g load ftorafur is placed in 300mL simulated body fluid, measures its absorbance after 20min, 1h, 2h, 4h, 7h, 12h, 20h, 32h, 48h, 72h, 100h after sampling 4mL respectively, calculates its release percent, is designated as %.As can be seen from Figure 1, from 20min to 100h, the release percent of ftorafur is raised to 92.1% from 45.6%.Experimental result shows: hollow nano titanium dioxide is that the carrier of ftorafur can make ftorafur slowly discharge enduringly, thus reduces toxic and side effects, improves its bioavailability.
Embodiment 2
(1) preparation of polystyrylmethyl acrylic acid copolymer microsphere (PSM)
By the refined styrene after 6mL distilling under reduced pressure, 2mL methacrylic acid is mixed homogeneously with 36mL distilled water, regulate bath temperature 70 DEG C, through nitrogen bubble effect deoxygenation, then the aqueous solution of 4.8mL12.5g/L potassium peroxydisulfate is added, after 10min, disconnected nitrogen is with initiated polymerization, obtains polystyrylmethyl acrylic acid copolymer microsphere PSM after isothermal reaction 24h.
(2) preparation of hollow nano titanium dioxide
Copolymerization microsphere prepared by 2.5g step (1) is joined in 2000mL beaker, adds in 200mL distilled water, ultrasonic 30min, obtain homodisperse suspension.Regulate bath temperature 90 DEG C, drip the HCl solution adjust ph of 0.5mol/L.Under constantly stirring, drip 100mLTiCl simultaneously
4solution (9.7mLTiCl
4solution (98%), uses 0.5molL
-1
HCl solution dilution is to 100mL) maintain response system pH=2.0 with 2mol/LNaOH solution.After dripping presoma, pH value maintains 2.0, after stirring ageing 3h, and washing, dry.Heat up from room temperature start program and be heated to 550 DEG C, in the hollow titanium dioxide that 550 DEG C keep 4h to obtain for ftorafur slow release to remove copolymerization microsphere.
Getting hollow titanium dioxide powder prepared by 4g adds in the 100mL flask with rotor, add ftorafur solution (0.4g ftorafur is dissolved in 30mL dehydrated alcohol) and make its uniform wet, prevent ethanol from volatilizing with preservative film sealing, after stirring 12h, evacuation, stir, dry, obtain the hollow titanium dioxide that ftorafur load capacity is 10%.The hollow titanium dioxide powder getting 3g load ftorafur is placed in 300mL simulated body fluid, measures its absorbance after 20min, 1h, 2h, 4h, 7h, 12h, 20h, 32h, 48h, 72h, 100h after sampling 4mL respectively, calculates its release percent, is designated as %.As can be seen from Figure 2, from 20min to 100h, the release percent of ftorafur is raised to 89.2% from 40.5%.
Embodiment 3
(1) preparation of polystyrylmethyl acrylic acid copolymer microsphere (PSM)
By the refined styrene after 12mL distilling under reduced pressure, 2mL methacrylic acid is mixed homogeneously with 36mL distilled water, regulate bath temperature 85 DEG C, through nitrogen bubble effect deoxygenation, then the aqueous solution of 5.6mL12.5g/L potassium peroxydisulfate is added, after 10min, disconnected nitrogen is with initiated polymerization, obtains polystyrylmethyl acrylic acid copolymer microsphere PSM after isothermal reaction 24h.
(2) preparation of hollow nano titanium dioxide
Copolymerization microsphere prepared by 2.5g step (1) is joined in 2000mL beaker, adds in 200mL distilled water, ultrasonic 30min, obtain homodisperse suspension.Regulate bath temperature 75 DEG C, drip the HCl solution adjust ph of 0.5mol/L.Under constantly stirring, drip 100mLTiCl simultaneously
4solution (9.7mLTiCl
4solution (98%), uses 0.5molL
-1hCl solution dilution is to 100mL) maintain response system pH=2.0 with 2mol/LNaOH solution.After dripping presoma, pH value maintains 2.0, after stirring ageing 3h, and washing, dry.Heat up from room temperature start program and be heated to 550 DEG C, in the hollow titanium dioxide that 550 DEG C keep 4h to obtain for ftorafur slow release to remove copolymerization microsphere
Getting hollow titanium dioxide powder prepared by 4g adds in the 100mL flask with rotor, add ftorafur solution (0.6g ftorafur is dissolved in 30mL dehydrated alcohol) and make its uniform wet, prevent ethanol from volatilizing with preservative film sealing, after stirring 12h, evacuation, stir, dry, obtain the hollow titanium dioxide that ftorafur load capacity is 15%.The hollow titanium dioxide powder getting 3g load ftorafur is placed in 300mL simulated body fluid, measures its absorbance after 20min, 1h, 2h, 4h, 7h, 12h, 20h, 32h, 48h, 72h, 100h after sampling 4mL respectively, calculates its release percent, is designated as %.As can be seen from Figure 3, from 20min to 100h, the release percent of ftorafur is raised to 84.7% from 36.9%.
Embodiment 4
The hollow titanium dioxide powder getting 4g example 3 preparation adds in the 100mL flask with rotor, add ftorafur solution (0.8g ftorafur is dissolved in 30mL dehydrated alcohol) and make its uniform wet, prevent ethanol from volatilizing with preservative film sealing, after stirring 12h, evacuation, stir, dry, obtain the hollow titanium dioxide that ftorafur load capacity is 20%.The hollow titanium dioxide powder getting 3g load ftorafur is placed in 300mL simulated body fluid, measures its absorbance after 20min, 1h, 2h, 4h, 7h, 12h, 20h, 32h, 48h, 72h, 100h after sampling 4mL respectively, calculates its release percent, is designated as %.As can be seen from Figure 4, from 20min to 100h, the release percent of ftorafur is raised to 76.6% from 30.4%.
Described embodiment is preferred embodiment of the present invention; but the present invention is not limited to above-mentioned embodiment; when not deviating from flesh and blood of the present invention, any apparent improvement that those skilled in the art can make, replacement or modification all belong to protection scope of the present invention.
Claims (7)
1. a preparation method for ftorafur slow releasing agent, is characterized in that, comprises the steps
(1) hollow nano titanium dioxide is prepared;
(2) after evenly being soaked by the hollow nano titanium dioxide ftorafur alcoholic solution of step (1) gained, sealing is stirred, and then stirs in vacuum environment, dry, obtains ftorafur slow releasing agent.
2. the preparation method of a kind of ftorafur slow releasing agent according to claim 1, is characterized in that, in step (1), the preparation method of described hollow nano titanium dioxide comprises the steps:
The preparation of step a, polystyrylmethyl acrylic acid copolymer microsphere (PSM): by the refined styrene after distilling under reduced pressure, methacrylic acid is mixed homogeneously with distilled water, regulate bath temperature 70 ~ 85 DEG C, through nitrogen bubble effect deoxygenation, then the aqueous solution of potassium peroxydisulfate is added, after 10min, disconnected nitrogen is with initiated polymerization, after isothermal reaction 24h, obtains polystyrylmethyl acrylic acid copolymer microsphere PSM;
The preparation of step b, hollow nano titanium dioxide: copolymerization microsphere prepared by step (1) is placed in distilled water, the homodisperse suspension of ultrasonic acquisition, under the bath temperature of 75-90 DEG C, regulates PH to 2.0 with HCl solution; Under constantly stirring, drip TiCl simultaneously
4acid solution and NaOH solution maintain response system pH=2.0; After being added dropwise to complete, pH value maintains 2.0, stirs ageing, and washing is dry, and heating up from room temperature start program is heated to calcining heat, calcines to remove copolymerization microsphere.
3. the preparation method of a kind of ftorafur slow releasing agent according to claim 2, is characterized in that, in step a, the volume ratio of described styrene and methacrylic acid is 3 ~ 6:1, and described distilled water and cinnamic volume ratio are 8 ~ 3:1; Volume ratio 1:1.2 ~ 2.8 of described methacrylic acid and potassium persulfate solution, wherein, the concentration of potassium persulfate solution is 12.5g/L.
4. the preparation method of a kind of ftorafur slow releasing agent according to claim 2, is characterized in that, in step b, and described TiCl
4acid solution is by the TiCl of 9.7mL98%
4obtain to 100mL with HCl solution dilution; The concentration of HCl solution is 0.5mol/L; The concentration of NaOH solution is 2mol/L.
5. the preparation method of a kind of ftorafur slow releasing agent according to claim 2, is characterized in that, in step b, described digestion time is 3h; Baking temperature is 100 DEG C, and drying time is 24h; Calcining heat is 550 DEG C, and calcination time is 4h.
6. the preparation method of a kind of ftorafur slow releasing agent according to claim 1, is characterized in that, in step (2), in described ftorafur alcoholic solution, the concentration of ftorafur is 6.7 ~ 26.7g/L; The mass ratio of described ftorafur and hollow nano titanium dioxide is 0.05 ~ 0.2:1.
7. the preparation method of a kind of ftorafur slow releasing agent according to claim 1, is characterized in that, in step (2), the time that described sealing is stirred is 12h; The temperature of described vacuum stirring drying is 60 DEG C, and the time is 24h.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101423249A (en) * | 2007-10-29 | 2009-05-06 | 中国科学院理化技术研究所 | Monodisperse pure rutile type or rutile type and anatase type composite phase titanic oxide hollow sub-micron ball and preparation method |
| CN101785860A (en) * | 2009-12-01 | 2010-07-28 | 青岛科技大学 | Tegafur/layered duplex metal hydroxide nanometer hybrid and preparation method thereof |
| CN103359782A (en) * | 2013-07-24 | 2013-10-23 | 南京理工大学 | Preparation method of hollow titanium dioxide microspheres |
| CN104743607A (en) * | 2013-06-26 | 2015-07-01 | 华东理工大学 | Preparing method of cube titanium dioxide vacant shell |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101423249A (en) * | 2007-10-29 | 2009-05-06 | 中国科学院理化技术研究所 | Monodisperse pure rutile type or rutile type and anatase type composite phase titanic oxide hollow sub-micron ball and preparation method |
| CN101785860A (en) * | 2009-12-01 | 2010-07-28 | 青岛科技大学 | Tegafur/layered duplex metal hydroxide nanometer hybrid and preparation method thereof |
| CN104743607A (en) * | 2013-06-26 | 2015-07-01 | 华东理工大学 | Preparing method of cube titanium dioxide vacant shell |
| CN103359782A (en) * | 2013-07-24 | 2013-10-23 | 南京理工大学 | Preparation method of hollow titanium dioxide microspheres |
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