CN103495175A - Preparation method of thermo-sensitive drug sustained and controlled release mesoporous composite - Google Patents
Preparation method of thermo-sensitive drug sustained and controlled release mesoporous composite Download PDFInfo
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- CN103495175A CN103495175A CN201310477059.5A CN201310477059A CN103495175A CN 103495175 A CN103495175 A CN 103495175A CN 201310477059 A CN201310477059 A CN 201310477059A CN 103495175 A CN103495175 A CN 103495175A
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Abstract
The invention belongs to the technical field of polymer chemistry and inorganic synthesis, and relates to a preparation method of a thermo-sensitive drug sustained and controlled release mesoporous composite. Mesoporous SiO2 microspheres are taken as carriers, and in-situ polymerization is adopted for preparing the mesoporous composite with thermosensitivity. The method includes adding an amides polymerization monomer, a crosslinking agent and an initiating agent into an acetone solvent until being completely dissolved, then adding the mesoporous SiO2 microsphere activated in advance into the mixture, heating in the atmosphere of nitrogen at the temperature of 60 DEG C for 12 hours prior to cooling to the room temperature, and performing suction filtration, washing and vacuum drying to obtain the thermo-sensitive mesoporous composite; adding the thermo-sensitive mesoporous composite into an organic solvent containing a drug, regulating the concentration of the drug, stirring at the temperature of 45 DEG C for 48 hours prior to filtering and washing to obtain a solid, and dying the solid in vacuum at the temperature of 40-60 DEG C. The method has the advantages of simple process, convenience in operation and the like, and the obtained thermo-sensitive drug sustained and controlled release mesoporous composite has the advantages of stable structure, high drug loading capacity, good thermosensitivity, stable drug release rate and the like and can be applied to the field of drug controlled release.
Description
Technical field
The present invention relates to a kind of preparation method of Thermo-sensitive medicine sustained and controlled release mesoporous composite material, specifically temperature sensing polymer poly-N-isopropyl acrylamide or poly-N-isopropyl acrylamide hydrophilic copolymers are loaded to mesoporous SiO
2formed a kind of organic and inorganic mesoporous composite material on microsphere surface, thereby for the gentle controlled release application of the loading of medicine.
Background technology
From Mobil company (Nature.1992,359:710～712 in 1992; J.Am.Chem.Soc.1992,114:10834～10843) since develop goes out mesoporous M41S family, because it has large specific surface area and pore volume, pattern is controlled, surface is the advantage such as functionalization and regular pore structure easily, relevant mesoporous material synthetic and apply and become one of study hotspot of people.Poly-N-isopropyl acrylamide (PNIPAAm) is a kind of typical temperature sensitive type poly compound, from within 1969, it is found that its have can intellectuality to the variation of ambient temperature reply and reversible response performance after (J Macromol Sci Chem, 1969,2:1441), this base polymer and derivant thereof are widely used in macromole and separate, and enzyme is fixing controls the numerous areas such as release with medicine.
In recent years, the composite organic-inorganic material prepared by above-mentioned mesoporous material and temperature sensitive type poly compound combined together gets more and more people's extensive concerning in fields such as surface chemistry and medicine controlled releasings.
Chinese patent CN10337072B has reported the mesoporous SiO of dual model
2material is as the preparation method of sustained and controlled release medicine material, and this invention has the drug loading amount that Stability Analysis of Structures, physiology are nontoxic and high and the advantage such as pharmaceutical release time is long, rate of release is stable.But the method can only play the slow releasing function to medicine, can not play good controlled-release function to medicine, and temperature is not had to sensitivity.
Chinese patent CN101085422A and CN102010488A have reported the preparation method of temperature sensitive nano microcapsule and micro-hydrogel, have investigated the application potential at aspects such as medicine and protein loading and releases simultaneously.But, because its surface area is very little, make drug loading lower.
For the problems referred to above, effective method is exactly by mesoporous SiO
2high medicine carrying and the temperature sensitive performance of polymer combine, the stability of integrated silicon based mesoporous material, high medicine carrying and the polymer response to temperature, build the newtype drug controlled release durg delivery system.
Chinese patent CN101941705A has reported that a kind of temperature sensing polymer structure directing agent prepares mesoporous SiO
2method, the advantage of this invention is to remove structure directing agent without the method for high-temperature calcination and organic solvent extraction, is a kind of environment-friendly preparation method thereof cheaply, but the building-up process more complicated.
The art of this patent is on original patented technology (CN10337072B) basis, will have the PNIPAAm of temperature-sensing property and the hydrophilic copolymers of derivant thereof and load to mesoporous SiO
2on microsphere, make it not only have Stability Analysis of Structures, drug loading is high, and has temperature-sensing property, and loading and the controlled release of medicine played to remarkable improvement, and preparation technology is simple, easy to operate simultaneously.
The mesoporous SiO that this patent is related
2microsphere is to have the SiO that the mesoporous and 10～30nm of 3～5nm piles up hole
2the hud typed hollow SiO that nano-particle or internal diameter are 260～300nm left and right
2nanoparticle.
Summary of the invention
The purpose of this invention is to provide a kind of mesoporous SiO of organic and inorganic with Thermo-sensitive characteristic and high drug load
2the preparation method of composite.
The present invention includes following steps:
A kind of preparation method of Thermo-sensitive medicine sustained and controlled release mesoporous composite material, is characterized in that, comprises the following steps:
(1) by mesoporous SiO
2microsphere activates 5 hours under 120-150 ℃, after being placed in exsiccator and naturally cooling to room temperature, and airtight preservation.
(2) preparation of Thermo-sensitive mesoporous composite material
By amide-type polymerization single polymerization monomer and cross-linking agent and initiator, be 1:(0.016～0.032 in mass ratio): (0.01～0.022) joins in acetone solvent to after dissolving fully, then gets the above-mentioned mesoporous SiO activated
2microsphere adds wherein, and mesoporous microsphere and amide-type polymerization single polymerization monomer mass ratio are 0.5～2, finally under nitrogen protection 60 ℃ the heating 12h and be cooled to room temperature after, through sucking filtration, the washing, vacuum drying obtains the Thermo-sensitive mesoporous composite material.
(3) get and contain the hexane solution that drug level is 20mg/mL～40mg/mL and mix according to the ratio of 30mL:0.3g with prepared Thermo-sensitive mesoporous composite material, after stirring 48h under 45 ℃, filter, washing, and obtain having Thermo-sensitive medicine sustained and controlled release mesoporous composite material after vacuum drying.
Further, mesoporous SiO
2microsphere is to have the SiO that the mesoporous and 10～30nm of 3～5nm piles up hole
2the hud typed hollow SiO that nano-particle or internal diameter are 260～300nm left and right
2nanoparticle.
Further, the amide-type polymerization single polymerization monomer is NIPA or NIPA hydrophilic copolymers.The NIPA hydrophilic copolymers is NIPA-co-acrylic acid or NIPA-co-acrylamide.
Further, cross-linking agent is N, N '-methylene-bisacrylamide, and initiator is azodiisobutyronitrile.
Further, medicine is water soluble drug aspirin or microsolubility medicine ibuprofen.
The present invention has following characteristics:
1. preparation technology is simple, easy to operate.
2. prepared mesoporous composite material has Stability Analysis of Structures, and drug loading is high, and has temperature-sensing property, and loading and the controlled release of medicine played to remarkable improvement.
The accompanying drawing explanation:
Fig. 1 is the control releasing curve diagram in the example 1 intermediary hole composite phosphate buffered solution that to load after ibuprofen in temperature be 45 ℃ and 25 ℃.
The specific embodiment:
Below in conjunction with accompanying drawing, the present invention is described in further detail.
Embodiment 1
Compound experiment: by mesoporous SiO
2nano-particle activates 5 hours under 120 ℃, after being placed in exsiccator and naturally cooling to room temperature, and airtight preservation.By the NIPA of 0.15g, 0.0024g N, N '-methylene-bisacrylamide, the 0.0033g azodiisobutyronitrile is dissolved in 3mL acetone wiring solution-forming, gets the mesoporous SiO that 0.15g has activated
2nano-particle adds wherein, finally under nitrogen protection 60 ℃ the heating 12h and be cooled to room temperature after, through sucking filtration, the washing, vacuum drying obtains the Thermo-sensitive mesoporous composite material.
Drug absorbability: 1.2g microsolubility medicine ibuprofen is dissolved in the 30mL normal hexane, gets the synthetic mesoporous composite material of 0.3g and join in above-mentioned solution, filter after stirring 48h under 45 ℃, washing, will filter gained solid vacuum drying afterwards, obtain sample after medicine carrying.
Medicine sustained and controlled release experiment: get 0.05g sample tabletting, be placed in pH=7.4, in the phosphate buffered solution that temperature is 45 ℃ (PBS), take out at regular intervals 1mL solution, ultraviolet determination solution medicine absorbance, simultaneously at once toward the buffer that adds equivalent in buffer system.Same method, by 0.05g sample tabletting, be placed in pH=7.4, carries out drug release in the PBS that temperature is 25 ℃.
Result is known: the medicine charging ratio of this mesoporous composite material reaches 29.2%, discharge after 5 hours, 45 ℃ of buffer solution Chinese medicine release rates reach 45%, and 25 ℃ of Chinese medicine release rates are only 25% left and right, discharge after 12 hours, it is 39% that 45 ℃ of buffer solution Chinese medicine release rates reach 50%, 25 ℃ of Chinese medicine release rate, and this mesoporous composite material has shown good temperature-sensing property.
This preparation method one-step method is synthetic, and all experimental apparatus and equipment is all the laboratory apparatus & equipment in common use, and the operation of employing is also the chemical field common operation, so preparation method is simple to operate.
Compound experiment: by mesoporous SiO
2nano-particle activates 5 hours under 120 ℃, after being placed in exsiccator and naturally cooling to room temperature, and airtight preservation.By the NIPA of 0.15g, 0.0024g N, N '-methylene-bisacrylamide, the 0.0017g azodiisobutyronitrile is dissolved in 3mL acetone wiring solution-forming, gets the mesoporous SiO that 0.15g has activated
2nano-particle adds wherein, finally under nitrogen protection 60 ℃ the heating 12h and be cooled to room temperature after, through sucking filtration, the washing, vacuum drying obtains the Thermo-sensitive mesoporous composite material.
Drug absorbability: 1.2g microsolubility medicine ibuprofen is dissolved in the 30mL normal hexane, gets the synthetic mesoporous composite material of 0.3g and join in above-mentioned solution, filter after stirring 48h under 45 ℃, washing, will filter gained solid vacuum drying afterwards, obtain sample after medicine carrying.
The sensitivity of carrying out ibuprofen in the phosphate buffered solution of the pH=7.4 that its medicine-carried system is 45 ℃ and 25 ℃ in temperature respectively discharges.
Embodiment 3
Compound experiment: by mesoporous SiO
2nano-particle activates 5 hours under 120 ℃, after being placed in exsiccator and naturally cooling to room temperature, and airtight preservation.By the NIPA of 0.15g, 0.0048g N, N '-methylene-bisacrylamide, the 0.0033g azodiisobutyronitrile is dissolved in 3mL acetone wiring solution-forming, gets the mesoporous SiO that 0.15g has activated
2nano-particle adds wherein, finally under nitrogen protection 60 ℃ the heating 12h and be cooled to room temperature after, through sucking filtration, the washing, vacuum drying obtains the Thermo-sensitive mesoporous composite material.
Drug absorbability: 1.2g microsolubility medicine ibuprofen is dissolved in the 30mL normal hexane, gets the synthetic mesoporous composite material of 0.3g and join in above-mentioned solution, filter after stirring 48h under 45 ℃, washing, will filter gained solid vacuum drying afterwards, obtain sample after medicine carrying.
The sensitivity of carrying out ibuprofen in the phosphate buffered solution of the pH=7.4 that its medicine-carried system is 45 ℃ and 25 ℃ in temperature respectively discharges.
Example 2 and example 3 experimental results: after discharging 5 hours, 45 ℃ of Chinese medicine release rates are 40%～45%, and 25 ℃ of Chinese medicine release rates are in 20%～25% scope, after discharging 12 hours, 45 ℃ of buffer solution Chinese medicine release rates are that 50%～55%, 25 ℃ of Chinese medicine release rates are in 35%～40% scope.
Compound experiment: by mesoporous SiO
2nano-particle activates 5 hours under 120 ℃, after being placed in exsiccator and naturally cooling to room temperature, and airtight preservation.By the NIPA of 0.15g, 0.0024g N, N '-methylene-bisacrylamide, the 0.0033g azodiisobutyronitrile is dissolved in 3mL acetone wiring solution-forming, gets the mesoporous SiO that 0.15g has activated
2nano-particle adds wherein, finally under nitrogen protection 60 ℃ the heating 12h and be cooled to room temperature after, through sucking filtration, the washing, vacuum drying obtains the Thermo-sensitive mesoporous composite material.
Drug absorbability: 0.6g microsolubility medicine ibuprofen is dissolved in the 30mL normal hexane, gets the synthetic mesoporous composite material of 0.3g and join in above-mentioned solution, filter after stirring 48h under 45 ℃, washing, will filter gained solid vacuum drying afterwards, obtain sample after medicine carrying.
Experimental result: the medicine charging ratio is on the low side (approximately 15%), and the method proof drug level affects the charging ratio of medicine.After its medicine-carried system discharges 5 hours, the release rate of medicine in 45 ℃ of PBS buffer is 40% left and right, and the release rate in 25 ℃ of PBS buffer is about 25%.
Embodiment 5
Compound experiment: by mesoporous SiO
2nano-particle activates 5 hours under 120 ℃, after being placed in exsiccator and naturally cooling to room temperature, and airtight preservation.By the NIPA of 0.15g, 0.0024g N, N '-methylene-bisacrylamide, the 0.0033g azodiisobutyronitrile is dissolved in 3mL acetone wiring solution-forming, gets the mesoporous SiO that 0.07g has activated
2nano-particle adds wherein, finally under nitrogen protection 60 ℃ the heating 12h after and be cooled to room temperature after, through sucking filtration, the washing, vacuum drying obtains the Thermo-sensitive mesoporous composite material.
Drug absorbability: 1.2g microsolubility medicine ibuprofen is dissolved in the 30mL normal hexane, gets the synthetic mesoporous composite material of 0.3g and join in above-mentioned solution, filter after stirring 48h under 45 ℃, washing, will filter gained solid vacuum drying afterwards, obtain sample after medicine carrying.
The sensitivity of carrying out ibuprofen in the phosphate buffered solution of the pH=7.4 that its medicine-carried system is 45 ℃ and 25 ℃ in temperature respectively discharges.
Result is known: the medicine charging ratio is 20% left and right, and after its medicine-carried system discharges 5 hours, the release rate of medicine in 45 ℃ of PBS buffer is 40% left and right, and the release rate in 25 ℃ of PBS buffer is about 25%.
Compound experiment: by mesoporous SiO
2nano-particle activates 5 hours under 120 ℃, after being placed in exsiccator and naturally cooling to room temperature, and airtight preservation.By the NIPA of 0.15g, 0.0024g N, N '-methylene-bisacrylamide, the 0.0033g azodiisobutyronitrile is dissolved in 3mL acetone wiring solution-forming, gets the mesoporous SiO that 0.30g has activated
2nano-particle adds wherein, and finally under nitrogen protection after 60 ℃ of heating 12h and after being cooled to room temperature, for products therefrom continues, acetone soaks 12 hours, then through sucking filtration, and washing, vacuum drying obtains the Thermo-sensitive mesoporous composite material.
Drug absorbability: 1.2g microsolubility medicine ibuprofen is dissolved in the 30mL normal hexane, gets the synthetic mesoporous composite material of 0.3g and join in above-mentioned solution, filter after stirring 48h under 45 ℃, washing, will filter gained solid vacuum drying afterwards, obtain sample after medicine carrying.
Medicine sustained and controlled release experiment: get 0.05g sample tabletting, be placed in pH=7.4, in the PBS that temperature is 45 ℃, take out at regular intervals 1mL solution, ultraviolet determination solution medicine absorbance, simultaneously at once toward the buffer that adds equivalent in buffer system.Same method, by 0.05g sample tabletting, be placed in pH=7.4, in the PBS buffer that temperature is 25 ℃, carries out drug release.
Result is known: the medicine charging ratio is 29% left and right, and after discharging 5 hours, the release rate of medicine in 45 ℃ of PBS buffer is 45% left and right, and the release rate in 25 ℃ of PBS buffer is 27%.This preparation method is by telomerized polymer and mesoporous SiO
2the addition of microsphere, thus carrying drug ratio and the temperature-sensing property of nano composite material can well be controlled.
Claims (6)
1. the preparation method of a Thermo-sensitive medicine sustained and controlled release mesoporous composite material, is characterized in that, comprises the following steps:
(1) by mesoporous SiO
2microsphere activates 5 hours under 120-150 ℃, after being placed in exsiccator and naturally cooling to room temperature, and airtight preservation;
(2) preparation of Thermo-sensitive mesoporous composite material
By amide-type polymerization single polymerization monomer and cross-linking agent and initiator, be 1:(0.016～0.032 in mass ratio): (0.01～0.022) joins in acetone solvent to after dissolving fully, then gets the above-mentioned mesoporous SiO activated
2microsphere adds wherein, mesoporous SiO
2microsphere and amide-type polymerization single polymerization monomer mass ratio are 0.5～2, finally under nitrogen protection 60 ℃ the heating 12h and be cooled to room temperature after, through sucking filtration, the washing, vacuum drying obtains the Thermo-sensitive mesoporous composite material;
(3) get and contain the hexane solution that drug level is 20mg/mL～40mg/mL and mix according to the ratio of 30mL:0.3g with prepared Thermo-sensitive mesoporous composite material, after stirring 48h under 45 ℃, filter, washing, and obtain having Thermo-sensitive medicine sustained and controlled release mesoporous composite material after vacuum drying.
2. preparation method as claimed in claim 1, is characterized in that: mesoporous SiO
2microsphere is to have the SiO that the mesoporous and 10～30nm of 3～5nm piles up hole
2the hud typed hollow SiO that nano-particle or internal diameter are 260～300nm left and right
2nanoparticle.
3. preparation method as claimed in claim 1, it is characterized in that: the amide-type polymerization single polymerization monomer is NIPA or NIPA hydrophilic copolymers.
4. preparation method as claimed in claim 3, it is characterized in that: the NIPA hydrophilic copolymers is NIPA-co-acrylic acid or NIPA-co-acrylamide.
5. preparation method as claimed in claim 1, it is characterized in that: cross-linking agent is N, N '-methylene-bisacrylamide, initiator is azodiisobutyronitrile.
6. preparation method as claimed in claim 1, it is characterized in that: medicine is water soluble drug aspirin or microsolubility medicine ibuprofen.
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Cited By (5)
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| CN103768605A (en) * | 2014-01-17 | 2014-05-07 | 东华大学 | Method for preparing organic/inorganic hybrid nanofiber drug-carrying microsphere |
| CN104587474A (en) * | 2015-02-02 | 2015-05-06 | 国家纳米科学中心 | Gold-core-composite nano-carrier as well as preparation method and application thereof |
| CN105670791A (en) * | 2016-01-26 | 2016-06-15 | 广东中烟工业有限责任公司 | Method for increasing content of aroma in cigarette smoke |
| CN108624005A (en) * | 2017-03-24 | 2018-10-09 | 华东理工大学 | Double factor slow-released system based on POC and meso-porous nano microballoon |
| CN114259605A (en) * | 2021-11-16 | 2022-04-01 | 陕西科技大学 | Preparation method and application of acellular pig dermal matrix temperature-sensitive antibacterial conductive scaffold |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103768605A (en) * | 2014-01-17 | 2014-05-07 | 东华大学 | Method for preparing organic/inorganic hybrid nanofiber drug-carrying microsphere |
| CN104587474A (en) * | 2015-02-02 | 2015-05-06 | 国家纳米科学中心 | Gold-core-composite nano-carrier as well as preparation method and application thereof |
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| CN108624005A (en) * | 2017-03-24 | 2018-10-09 | 华东理工大学 | Double factor slow-released system based on POC and meso-porous nano microballoon |
| CN108624005B (en) * | 2017-03-24 | 2021-10-29 | 华东理工大学 | Double-factor slow release system based on POC and mesoporous nano-microspheres |
| CN114259605A (en) * | 2021-11-16 | 2022-04-01 | 陕西科技大学 | Preparation method and application of acellular pig dermal matrix temperature-sensitive antibacterial conductive scaffold |
| CN114259605B (en) * | 2021-11-16 | 2022-07-22 | 陕西科技大学 | Preparation method and application of acellular pig dermal matrix temperature-sensitive antibacterial conductive scaffold |
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Application publication date: 20140108 |