CN106860399B - Preparation of carbon nano tube doped fenbufen molecularly imprinted polymer controlled-release material - Google Patents
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Abstract
The invention relates to preparation of a carbon nanotube doped fenbufen molecularly imprinted polymer controlled-release material, in particular to a fenbufen controlled-release molecularly imprinted polymer material prepared by doping a single-walled carbon nanotube by taking ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate and a eutectic solvent) as a binary pore-foaming agent. The composition by mass is as follows: 0.67-0.76% of fenbufen, 0.03-0.06% of single-walled carbon nanotube, 2.41-2.75% of 4-vinylpyridine, 18.16-20.69% of ethylene glycol dimethacrylate, 18.37-48.39% of eutectic solvent, 30.06-57.08% of 1-butyl-3-methylimidazole tetrafluoroborate and 0.25-0.29% of azobisisobutyronitrile. The controlled-release effect of the invention is good, and the pharmacokinetics in vivo shows that compared with the peak reaching time of 1.5h and the bioavailability of 46.1 percent of the imprinted polymer without the carbon nano tube, the peak reaching time of the blood concentration in rats can reach 4 hours, the bioavailability is up to 140 percent compared with that of a commercial drug, and the performance is stable. The invention lays a foundation for the application of the molecular imprinting technology to a drug delivery system.
Description
Technical Field
The invention relates to preparation of a carbon nanotube doped fenbufen molecularly imprinted polymer controlled-release material, in particular to ionic liquid 1-Butyl-3-methylimidazolium tetrafluoroborate (1-Butyl-3-methylimidazolium terfenaoroborate, [ BMIM ]]BF4) With low co-lowThe in vivo pharmacokinetics shows that compared with the 1.5h peak reaching time and 46.1% bioavailability of the carbon nanotube-free imprinted polymer, the peak reaching time of the blood concentration in rats can reach 4 hours, and the bioavailability is up to 140% compared with that of a commercial drug.
Background
Fenbufen (Fenbufen, FB), chemical name: 1, 1' -biphenyl-gamma-oxobutyric acid, which is a novel nonsteroidal anti-inflammatory analgesic drug and has the characteristics of good anti-inflammatory effect, low side effect and the like. Fenbufen is a similar ibuprofen drug, is a long-acting non-steroidal anti-inflammatory analgesic, is a prodrug of ethyl biphenylate, has the effect of blocking inflammatory mediators, has weaker anti-inflammatory analgesic effect than indomethacin but stronger anti-inflammatory analgesic effect than aspirin, and has lower toxicity and smaller gastrointestinal reaction than indomethacin. Fenbufen is a precursor drug, is metabolized into felbinac in vivo, and the felbinac inhibits prostaglandin synthesis, thereby playing the roles of anti-inflammation and analgesia, and avoiding stimulation to gastrointestinal tracts. The blood concentration reaches the peak value t 2h after oral administration1/2Is 12-17 h. The combination rate of the medicine and plasma protein is up to more than 98%. After 4-8 h of taking fenbufen, the total concentration of fenbufen and its metabolites in the synovial fluid of breast milk and arthritis patients is about 1/3 of serum concentration. Fenbufen and its metabolites are mainly excreted by the kidney. However, their use is limited by the frequent occurrence of gastrointestinal and central nervous system side effects which lead to leukopenia and increased aminotransferases, but which can be alleviated if they are loaded into a solid material to slow their release rate in vivo. The research on the controlled and sustained release of fenbufen reported in the literature is few and few, so the invention prepares a fenbufen carbon nanotube doped molecular imprinting controlled and sustained release drug delivery system based on the basis.
Molecular Imprinting (MIT) is a technique developed based on the simulation of enzyme-substrate and receptor-antibody actions in nature to synthesize a stationary phase with preselectivity. One new area of application of molecularly imprinted polymers is as drug delivery systems. The controlled-release molecularly imprinted polymer is used as a carrier of a drug, can be used for the research of a drug delivery system as a special material, can delay the release process of the drug, has the advantage of high selectivity of the molecularly imprinted polymer, and has wide application range.
The carbon nano tube is used as a novel functional material, has the characteristics of high chemical stability, high mass transfer rate, high specific surface area and the like, and is widely applied to gas chromatography and liquid chromatography stationary phases. Among them, the single-walled carbon nanotube is considered to be one of the most potential new materials at present because it has a unique structure and shows remarkable physical, chemical, electronic, mechanical and other excellent properties. However, the poor dispersibility in the solvent causes some difficulty in preparing the carbon nanotube composite having good properties.
Ionic Liquids (ILs) are composed mainly of relatively large-volume cations (mainly imidazolium cations) and different kinds of anions (Cl)-, BF4 -,PF6 -Etc.) a substance that is liquid at or near room temperature. The ionic liquid has the characteristics of wide liquid range, good dissolving capacity, good conductivity and the like, and is widely applied to the fields of extraction, organic synthesis, electrochemistry, analytical chemistry and the like.
As a novel green solvent, the eutectic solvent has unique physical and chemical properties of low vapor pressure, no toxicity, biodegradability, excellent solubility and conductivity, wide electrochemical stability window and the like, and the performance of the eutectic solvent can be adjusted by selecting proper components and proportions, so that the eutectic solvent has attractive application prospects in many fields.
Researches show that a binary solvent system consisting of the ionic liquid and the eutectic solvent can effectively disperse the carbon nano tube, and on the basis, the carbon nano tube doped molecular imprinting controlled-release nano composite material is prepared, so that a better drug controlled-release effect can be obtained compared with the effect of the carbon nano tube-free doped molecular imprinting controlled-release nano composite material.
Disclosure of Invention
The invention aims to provide a preparation method of a carbon nanotube doped fenbufen molecularly imprinted polymer controlled-release material, which is prepared by doping a single-walled carbon nanotube with a fenbufen carbon nanotube doped controlled-release molecularly imprinted polymer material by taking ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate and a eutectic solvent choline chloride/ethylene glycol (ChCl/EG) as binary pore-forming agents. According to the method, fenbufen and 4-vinylpyridine are added into the prepolymerization solution to be mixed by adopting a polymerization method, and the molecularly imprinted polymer with specific adsorption and drug controlled slow release performances is obtained after heating, and in vivo pharmacokinetics shows that compared with 1.5h peak reaching time and 46.1% bioavailability of the imprinted polymer without carbon nano tubes, the peak reaching time of blood drug concentration in rats can reach 4 hours, and the bioavailability is up to 140% compared with that of commercial drugs. The ionic liquid and the eutectic solvent are used as binary pore-foaming agents, so that the method has no pollution to the environment.
The carbon nanotube doped fenbufen molecularly imprinted polymer controlled-release material provided by the invention comprises the following raw materials in percentage by mass:
fenbufen 0.67-0.76%
0.03-0.06% of single-walled carbon nanotube
4-vinylpyridine 2.41-2.75%
18.16 to 20.69 percent of glycol dimethacrylate
Eutectic solvent 18.37-48.39%
1-butyl-3-methylimidazole tetrafluoroborate 30.06-57.08%
Azobisisobutyronitrile 0.25-0.29%
The sum of the mass compositions of the raw materials is 100 percent.
The eutectic solvent consists of choline chloride and ethylene glycol.
The preparation method of the carbon nanotube doped fenbufen molecularly imprinted polymer controlled-release material provided by the invention specifically comprises the following steps:
1) according to the measurement, the template molecule fenbufen, the initiator azobisisobutyronitrile and the single-walled carbon nanotube are mixedMixing and adding [ BMIM ]]BF4Ultrasonically dissolving and uniformly mixing with ChCl/EG at room temperature, adding 4-vinylpyridine and ethylene glycol dimethacrylate, continuously ultrasonically mixing, removing oxygen in the mixed reaction liquid, sealing, and reacting in a water bath at 60 ℃ for 14 hours;
2) the molecularly imprinted polymer obtained above was pulverized in a mortar, and first subjected to soxhlet extraction with methanol/acetic acid of v/v =9:1 for 48 to 72 hours to remove unreacted residual impurities and washed to remove fenbufen until fenbufen is not detected by uv spectrophotometry. Soxhlet extracting with methanol for 24-48 hr, and eluting residual acetic acid; the obtained fenbufen molecularly imprinted polymer is dried at room temperature.
The synthesis of the fenbufen molecularly imprinted polymer without the carbon nanotube is performed in the same manner as above except that the carbon nanotube is not added.
The synthesis of the non-imprinted polymer was performed as described above except that the template molecule fenbufen was not added.
The invention provides a controlled-release material of a carbon nanotube doped fenbufen molecularly imprinted polymer, which is characterized in that a dispersant of a single-walled carbon nanotube is 1-butyl-3-methylimidazolium tetrafluoroborate, a solvent of an imprinting system is choline chloride/ethylene glycol, and an adopted functional monomer is 4-vinylpyridine; the special proportion of choline chloride and glycol required by the fenbufen nano composite material and the special proportion of 1-butyl-3-methylimidazolium tetrafluoroborate and choline chloride/glycol required by the fenbufen nano composite material.
The invention provides a carbon nano tube doped fenbufen molecularly imprinted polymer controlled-release material (carbon nano tube doped fenbufen controlled-release molecularly imprinted framework material), which takes ionic liquid and eutectic solvent as pore-forming agent, is a single-walled carbon nano tube doped molecularly imprinted controlled-release drug carrier and a preparation method thereof, and is prepared by adjusting the proportion of ChCl and EG in the eutectic solvent and [ BMIM ] in a binary pore-forming agent]BF4The ratio of the molecular imprinted polymer to ChCl/EG and the content of SWCNTs in the polymer synthesize the fenbufen molecular imprinted polymer with specific recognition performance. The preparation method has the advantages of less reagent, easy operation and simple preparation process. Synthetic fenbufen molecularly imprinted polyThe compound has specific adsorption and obvious imprinting effect on fenbufen (imprinting factor = 3.97); the in vivo pharmacokinetics shows that compared with the material without the carbon nano tube, the material has the advantages that the peak reaching time of the blood concentration in the rat body can reach 4 hours, and the bioavailability is as high as 140%. The invention has stable physical and chemical properties, and is suitable for the research of a drug delivery system as a special drug carrier material.
Drawings
FIG. 1 shows the change of the ratio of ChCl to EG in the eutectic solvent and [ BMIM ] in the binary porogen in the optimization of the preparation conditions of the present invention]BF4The ratio of ChCl/EG and the content of SWCNTs in the polymer have the influence on the retention factor and the imprinting factor of fenbufen.
Fig. 2 is a release curve chart of in vitro drug release experiments for preparing different types of fenbufen molecularly imprinted polymers according to the invention.
Fig. 3 is a graph showing the time-dependent change of the pharmacokinetic blood concentration of different types of fenbufen molecularly imprinted polymers prepared by the method.
Detailed Description
The present invention will be described in further detail with reference to the following examples. The experimental methods in the examples, in which specific conditions are not specified, are generally performed under the conditions described in the manual and the conventional conditions, or under the conditions recommended by the manufacturer; general equipment, materials, reagents and the like used are commercially available unless otherwise specified.
Example 1
In order to obtain an optimal synthesis formula of a fenbufen carbon nanotube doped controlled-release molecularly imprinted polymer, the synthesis formula of a fenbufen imprinted monolithic column is optimized, and the specific operation steps are as follows:
the preparation method of the fenbufen molecular imprinting monolithic column doped with the single-walled carbon nanotube by using the ionic liquid and the eutectic solvent as binary pore-forming agents comprises the following steps:
a. mixing template molecule fenbufen 0.75% (mass percentage), initiator azodiisobutyronitrile 0.29%, and single-walled carbon nanotube 0.06%, and adding BMIM 54.03%]BF4And 21.76 percent of ChCl (choline chloride)/EG (ethylene glycol) by mass fractionGlycol) is dissolved and mixed by ultrasound (40 KHz, 10 min) at room temperature, then 4-vinylpyridine with the mass fraction of 2.71 percent and ethylene glycol dimethacrylate with the mass fraction of 20.40 percent are added to continue the ultrasound to be mixed uniformly, oxygen in the mixed reaction liquid is removed, the mixture is arranged in a stainless steel pipe column (100 mm multiplied by 4.6 mm I.D.), two ends are sealed by polytetrafluoroethylene tapes, and the mixture is put into a 60 ℃ water bath kettle to react for 14 h;
b. the resulting fully reacted monolith was taken out and connected to a high pressure pump, washed with acetonitrile to remove unreacted porogen, washed through at a flow rate of 0.1 mL/min, washed to about 100 mL at a flow rate of 0.6 mL/min, and then replaced with a methanol/acetic acid (9/1, v/v) mixture to remove template molecules, washing to a volume of 150 mL.
The synthesis of the non-imprinted monolithic column was performed as described above except that the template molecule fenbufen was not added.
Examination of production conditions:
(1) and (3) investigating the ratio of ChCl to EG in the eutectic solvent: according to the above preparation method, while keeping the amounts of the other components unchanged, the molar ratio of ChCl to EG was changed, and a blotting monolith was prepared from 1:2 to 1:4, and subjected to chromatographic evaluation by HPLC, and the results are shown in FIG. 1.
(2) In binary porogenic agent [ BMIM ]]BF4Investigation of the ratio to ChCl/EG: according to the preparation method, the molar ratio of ChCl to EG is kept to be 1:3, the total volume of the binary pore-foaming agent is not changed, and the ChCl/EG and [ BMIM ] are changed]BF4The blotting monolith was prepared from 1:1 to 1:5, and the results were shown in FIG. 1 by HPLC.
(3) And investigating the content of SWCNTs in the formula: maintaining the molar ratio of ChCl to EG at 1:3, ChCl/EG to [ BMIM ]]BF4The volume ratio of SWCNTs in the synthesis formula is changed from 0 to 1.5mg/mL, a blotting monolithic column is prepared, and the result is shown in FIG. 1 by HPLC chromatography evaluation.
Example 2
Drug release experiments a model for the kinetics of drug release from fenbufen molecularly imprinted polymers was studied. In order to examine the release model of the drug, the total amount of the drug released by the fenbufen molecularly imprinted polymer and the non-imprinted polymer in a certain period of time was determined. The specific operation steps are as follows:
a. mixing template molecule fenbufen 0.75% (mass percentage), initiator azodiisobutyronitrile 0.29%, and single-walled carbon nanotube 0.06%, and adding BMIM 54.03%]BF4Ultrasonically dissolving and uniformly mixing with ChCl/EG (mol/mol, 1: 3) with the mass fraction of 21.76 percent at room temperature, adding 4-vinylpyridine with the mass fraction of 2.71 percent and ethylene glycol dimethacrylate with the mass fraction of 20.40 percent, continuously ultrasonically mixing, removing oxygen in a mixed reaction solution, sealing, and reacting in a water bath at 60 ℃ for 14 hours;
b. the molecularly imprinted polymer obtained above was pulverized in a mortar, and first subjected to Soxhlet extraction with methanol/acetic acid (v/v, 9:1) for 48 hours to remove unreacted residual impurities and washed to remove fenbufen until fenbufen was not detected by UV spectrophotometry. Soxhlet extracting with methanol for 24 hr to elute residual acetic acid; the obtained fenbufen imprinted polymer was dried at room temperature.
The synthesis of the fenbufen molecularly imprinted polymer without the carbon nanotube is performed in the same manner as above except that the carbon nanotube is not added.
The synthesis of the non-imprinted polymer was performed as described above except that the template molecule fenbufen was not added.
c. Placing the synthesized carbon-containing nanotubes, the fenbufen molecularly imprinted polymer and the non-imprinted polymer which do not contain the carbon nanotubes, and the single carbon nanotubes in a fenbufen acetonitrile solution, soaking for three days, airing for 24 hours at room temperature, then washing twice with absolute ethyl alcohol, and airing at room temperature; accurately weighing the materials carrying the drugs, respectively placing the materials into acetonitrile solution, stirring at room temperature, and carrying out 50 rp/min; at regular intervals, 3.00 mL of the assay sample was taken, the amount of drug released was measured using a UV-vis spectrophotometer, and the sample removed was poured back into the release medium.
The release curve of the drug is drawn by plotting the cumulative released drug quantity against time, the drug release model is in accordance with a zero-order release model, the controlled release effect of the molecularly imprinted polymer carrier is good, and the stable release of the aesculin can reach more than 6 hours (figure 2) compared with the release time (2.5 hours) of the non-imprinted polymer drug and the release time (1.5 hours) of the imprinted polymer without the carbon nano tube. Proves that the fenbufen molecularly imprinted polymer doped with the single-walled carbon nanotube has good controlled release effect on fenbufen by taking the ionic liquid and the eutectic solvent as binary pore-forming agents.
Example 3
Pharmacokinetic experiments study the change of the blood concentration of fenbufen molecularly imprinted polymer in rats with time. In order to examine the controlled release effect of the drug in rats, the plasma concentration of rats in a certain time after different types of fenbufen carrier materials are orally taken by the rats is measured.
The specific operation steps are as follows:
a. the molecularly imprinted polymer containing carbon nanotubes and the molecularly imprinted polymer containing no carbon nanotubes, and the non-imprinted polymer containing carbon nanotubes were synthesized in the same manner as described above (example 2).
b. The reference group commercial drug fenbufen tablet (Zhejiang is kang pharmaceutical Co., Ltd.) was purchased from big pharmacy linkage Co., Ltd of common people in Tianjin; single-walled carbon nanotubes were purchased from Nanjing Xiancheng nanotechnology, Inc.
c. Soaking the prepared material in an acetonitrile solution of fenbufen, washing twice with acetonitrile, and drying at room temperature; accurately weighing a carbon nanotube-containing molecularly imprinted polymer and a carbon nanotube-free molecularly imprinted polymer which carry medicines, and suspending a carbon nanotube-containing non-imprinted polymer, a fenbufen commercial medicine and a single-walled carbon nanotube in physiological saline; another 5 healthy male rats with weight of about 200g are administered by intragastric administration at dosage of 1mg/kg, numbered 1, 2, 3, 4 and 5. Blood is collected in orbit at 30, 60, 90, 120, 150, 180, 240, 360, 420 and 480min after gastric lavage for 200ul, and the blood sample is anticoagulated by heparin and centrifuged at 13000r/min to prepare plasma.
f. Taking 50ul of plasma supernatant, adding 150ul of acetonitrile, mixing uniformly, centrifuging again for 5min at the rotating speed of 13000r/min, taking 150ul of supernatant, naturally volatilizing, adding 50ul of mobile phase after volatilizing, ultrasonically dissolving and mixing uniformly, taking 20ul of sample, and measuring the drug release amount by using HPLC.
The blood concentration is plotted against time to draw a drug time curve (see figure 3), and as can be seen from the graph, the peak time of the blood concentration of the carbon nanotube-containing molecularly imprinted polymer can reach 4h compared with 1h of the molecularly imprinted polymer without the carbon nanotube and 2h of the carbon nanotube-containing non-imprinted polymer. The carbon nanotube-containing molecularly imprinted polymer is proved to have a certain controlled release effect on the release of fenbufen in a rat body. In addition, the bioavailability of the carbon nanotube-containing molecularly imprinted polymer relative to a commercial drug is up to 140%, while the bioavailability of the carbon nanotube-free molecularly imprinted polymer and the carbon nanotube-containing non-imprinted polymer is only 46.1% and 42.6% respectively.
Claims (3)
1. A carbon nanotube doped fenbufen molecularly imprinted polymer controlled-release material is characterized by comprising the following raw materials in parts by mass:
fenbufen 0.67-0.76%
0.03-0.06% of single-walled carbon nanotube
4-vinylpyridine 2.41-2.75%
18.16 to 20.69 percent of glycol dimethacrylate
Eutectic solvent 18.37-48.39%
1-butyl-3-methylimidazole tetrafluoroborate 30.06-57.08%
Azobisisobutyronitrile 0.25-0.29%
The sum of the mass compositions of the raw materials is 100 percent;
the eutectic solvent consists of choline chloride and ethylene glycol in a mass ratio of: 1: 2-4; the volume ratio of the 1-butyl-3-methylimidazole tetrafluoroborate to the choline chloride to the ethylene glycol is as follows: 1: 1-5;
the preparation method comprises the following steps:
1) proportionally mixing template molecule fenbufen, initiator azobisisobutyronitrile and single-wall carbon nanotube, adding BMIM]BF4Ultrasonically dissolving and uniformly mixing with ChCl/EG at room temperature, adding 4-vinylpyridine and ethylene glycol dimethacrylate, continuously ultrasonically mixing, removing oxygen in the mixed reaction liquid, sealing, and reacting in a water bath at 60 ℃ for 14 hours;
2) grinding the obtained molecular imprinting polymer in a mortar, performing Soxhlet extraction for 48-72 hours by using methanol and acetic acid with v/v =9:1, removing unreacted residual impurities and washing to remove the fenbufen until the fenbufen cannot be detected by using an ultraviolet spectrophotometry, performing Soxhlet extraction for 24-48 hours by using methanol, eluting residual acetic acid, and drying at room temperature.
2. The carbon nanotube-doped fenbufen molecularly imprinted polymer controlled-release material according to claim 1, characterized in that the material comprises the following raw materials by mass:
0.75 percent of fenbufen,
0.06 percent of single-walled carbon nanotube
4-vinylpyridine 2.71%
Ethylene glycol dimethacrylate 20.40%
Choline chloride and ethylene glycol 21.76%
1-butyl-3-methylimidazolium tetrafluoroborate 54.03%
Azobisisobutyronitrile 0.29%.
3. The preparation method of the carbon nanotube-doped fenbufen molecularly imprinted polymer controlled-release material according to claim 1, characterized by comprising the following steps:
1) proportionally mixing template molecule fenbufen, initiator azobisisobutyronitrile and single-wall carbon nanotube, adding BMIM]BF4Ultrasonically dissolving and uniformly mixing with ChCl/EG at room temperature, adding 4-vinylpyridine and ethylene glycol dimethacrylate, continuously ultrasonically mixing, removing oxygen in the mixed reaction liquid, sealing, and reacting in a water bath at 60 ℃ for 14 hours;
the volume ratio of the 1-butyl-3-methylimidazole tetrafluoroborate to the choline chloride to the ethylene glycol is as follows: 1: 1-5;
2) grinding the obtained molecular imprinting polymer in a mortar, performing Soxhlet extraction for 48-72 hours by using methanol and acetic acid with v/v =9:1, removing unreacted residual impurities and washing to remove the fenbufen until the fenbufen cannot be detected by using an ultraviolet spectrophotometry; soxhlet extracting with methanol for 24-48 hr, eluting residual acetic acid, and air drying at room temperature.
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