CN103239727B - Method for preparing material of controlled-release drug - Google Patents
Method for preparing material of controlled-release drug Download PDFInfo
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- CN103239727B CN103239727B CN201310138685.1A CN201310138685A CN103239727B CN 103239727 B CN103239727 B CN 103239727B CN 201310138685 A CN201310138685 A CN 201310138685A CN 103239727 B CN103239727 B CN 103239727B
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Abstract
The invention relates to a method for preparing a material of a controlled-release drug, and in particular relates to a method for preparing a polymer-wrapped mesoporous SiO2 controlled-release drug which can be sensitive under the condition of different pH values. The method comprises the steps of preparing a double bond-containing pH sensitive polymer modified by a silane coupling agent by utilizing the principle of free radical polymerization, and adding to absolute ethyl alcohol according to a certain ratio together with SiO2, refluxing and stirring for 8-24 hours at 70 DEG C, and obtaining solid powder of polymer-wrapped mesoporous SiO2 after filtering, washing and drying. The preparation method is simple to operate due to the fact that only two steps of modifying the polymer and wrapping mesoporous SiO2 by the polymer are included; in addition, by adopting the preparation method, the result of the method can be well controlled just by changing the adding amount of the polymer and mesoporous SiO2; and meanwhile, the method does not include the step of synthesizing mesoporous silica beads, and the result of the method is only affected by the two influencing factors of the adding mount of the polymer and mesoporous SiO2, so that the grafting amount of the polymer on the surface of mesoporous SiO2 is easily controlled.
Description
Technical field
The present invention relates to a kind of preparation method of controlling the material of drug release, be specifically related to a kind of with the mesoporous SiO of polymer wrapped
2the preparation method of controlled release drug that can be responsive under different pH condition.
Background technology
Since the reported first ordered mesoporous material M41S of Mobil company in 1992 (J.Am.Chem.Soc., 1992,27 (114): 10834-10843), mesoporous SiO
2material has higher specific surface area, preferably bio-compatibility and the feature such as have no side effect, and after organo-functional group is modified, has been considered to one of optimal slow releasing carrier of medication.As Chinese patent CN101020058A, CN101337072B, CN200710061610.2 and CN201110052824.X have reported the application of a kind of pure silicon based monodisperse spherical mesoporous molecular sieve in medicament slow release, and these materials have higher drug loading, and have good sustained drug release effect.US Patent No. 2007/0160639A1 is to SiO
2mesopore molecular sieve surface carries out, after oxidative function processing drug loading, also having obtained good sustained drug release effect.The above results shows by playing the slow releasing function to medicine-carried system to mesoporous regulation and control and finishing, but will reach control in certain pH value solution, discharges still difficult.
It is reported, polymer has certain response function according to the heterogeneity of its segment to pH value, therefore can be used as pharmaceutical carrier and by principle packaging medicines such as chemistry, physics and electrostatic interactions, can realize medicine to the responsive controlled-release effect of pH value.But because its specific surface area is less, Adsorption is less simultaneously, makes the drug loading of polymer very low, can only reach 5% left and right (modern chemical industry, 2007,27 (10): 69-74).At present, for the problems referred to above, effective method is exactly by mesoporous SiO
2high medicine carrying and the pH stimuli responsive performance of polymer combine, the stability of integrated silicon based mesoporous material, high medicine carrying and the response of polymer to pH value, build novel pH value controlled release drug delivery system, thereby realize medicine to the responsive object discharging of controlling of pH value.(the Angew Chem such as Shi, 2005,117 (32): 5213-5217) (Micropor Mesopor Mater., 2007,103 (1-2): 243-249) utilize the hollow core of medium hole hollow ball and the through hole of mesoporous shell and polyelectrolyte to there is the features such as environment pH value response, by layer-by-layer, make to be wrapped in the outer field polyelectrolyte of medium hole hollow ball and pH value is produced to the response of structural behaviour, thereby play, medicine is controlled to " switch " effect discharging; But due to this kind of method complex process and complex operation, thereby limited its application.(the Microporous and Mesoporous Mater.2005 such as Zhu, 85,75-81) (Angew.Chem.Int.Ed.2005,44,5083-5087) by in-situ method, high molecular polymer is wrapped up to the nanosphere after medicine carrying, utilize the difference of high molecular polymer dissolubility in different pH medium, the rate of release of regulating drug molecule; Although simple to operate, the grafting amount of polymer on nanosphere surface is not easy to control and influence factor's more complicated.(the J.Phys.Chem.C.2009 such as Xu, 113,12753-12758) adopt grafting, in the building-up process of mesoporous silicon sphere, pH sensitive polymer is wrapped in to mesoporous silicon sphere surface, utilize the diastole/contractility of polymer in alkalescence and acid solution, realized the object of the responsive controllable release of medicine pH; Yet, because encapsulation process is carried out with synthetic the synchronizeing of mesoporous silicon sphere, therefore to the research of building-up process and the influence factor's more complicated to polymer wrapped performance.
We once reported a kind of preparation method (CN101337072B) of sustained and controlled release medicine material, but prepared medicine-carried system does not have the responsive feature discharging of controlling of environment pH value.The art of this patent is on this patented technology basis, and comprehensive the problems referred to above adopt grafting to prepare pH value sensitive polymer and wrap up mesoporous SiO
2, further report a kind of mesoporous SiO of polymer wrapped for the responsive controlled release drug of pH value
2preparation method.
Summary of the invention
For the weak point of above-mentioned technology, the invention provides the preparation method that a kind of simple to operate, rate of charge holds the material of the controlled release drug manageable, influence factor is less.
A preparation method for the material of controlled release drug, comprises the following steps:
1) Organic substance that contains two keys and carboxyl is carried out to modification
Silane coupler and the Organic substance that contains two keys and carboxyl are dissolved in dehydrated alcohol according to the volume ratio of 0-100%, and logical nitrogen added initiator after two hours, at 70 ℃ after sustained response 4-48 hour, then by n-hexane extraction, made polymer, was labeled as P;
2) above-mentioned polymer P is wrapped up to mesoporous SiO by grafting
2
By polymer P and mesoporous SiO
2according to the mass ratio of 1-80%, add in dehydrated alcohol, the 8-24 hour that refluxes at 70 ℃, finally by filtering and washing, and at 60-80 ℃ dry 5-10 hour, obtain polymer P and wrap up mesoporous SiO
2pressed powder, be labeled as B.
Preferably, described silane coupler is VTES, vinyltrimethoxy silane, 3-(methacryloxypropyl) propyl trimethoxy silicane, 3-(methacryloxypropyl) propyl-triethoxysilicane.
Preferably, described in contain two keys and carboxyl Organic substance be acrylic acid or derivatives thereof, first-selected methacrylic acid and methyl methacrylate.
Preferably, described initiator is organic peroxide class, azo and inorganic peroxy class initiator, the preferred dibenzoyl peroxide of organic peroxide initiator, the preferred azodiisobutyronitrile of azo-initiator, the preferred persulfate of inorganic peroxy class initiator.
Preferably, described mesoporous SiO
2be two meso-hole structures, wherein the large bore dia of two meso-hole structures is 15-30nm, and hole diameter is 2-3nm, and particle diameter is 20-1000nm.
Further, the medicine that sample B loads can be water soluble drug gentamycin etc., microsolubility medicine aspirin etc. or insoluble drug ibuprofen etc.
Further, after sample B drug loading, the delivery systme at different pH value can be citric acid buffer system, phosphate buffer, simulated gastric fluid, simulated body fluid, dilute hydrochloric acid, weak ammonia etc.
Beneficial effect of the present invention is, this preparation method is owing to only having the mesoporous SiO of polymer modification and polymer wrapped
2two steps, and all experimental apparatus and equipment is all laboratory apparatus & equipment in common use, the operation of employing is also chemical field common operation, so preparation method is simple to operate; In addition, this preparation method only need to change polymer and mesoporous SiO
2addition, can well control inventive result; The present invention does not simultaneously have synthetic this step of mesoporous silicon sphere, has and only have polymer and mesoporous SiO
2these two influence factors of addition impact result of the present invention, easily control polymer at mesoporous SiO
2the grafting amount on surface; In addition, in the present invention, Organic substance used contains carboxyl, can realize the control to medicine under different acidity or alkali condition, i.e. the control of different pH value to medicine.
Accompanying drawing explanation
Fig. 1 is flow chart of the present invention;
Fig. 2 be in example 1 sample B to load after ibuprofen at pH value be the control releasing curve diagram in 2.0 and 7.4 phosphate buffered solution.
The specific embodiment
Below in conjunction with accompanying drawing, the present invention is described in further detail.
Embodiment 1
A preparation method for the material of controlled release drug, as shown in Figure 1, comprises the following steps:
1) Organic substance that contains two keys and carboxyl is carried out to modification
Silane coupler and the Organic substance that contains two keys and carboxyl are dissolved in dehydrated alcohol according to the volume ratio of 0-100%, and logical nitrogen added initiator after two hours, at 70 ℃ after sustained response 4-48 hour, then by n-hexane extraction, made polymer, was labeled as P;
2) above-mentioned polymer P is wrapped up to mesoporous SiO by grafting
2
By polymer P and mesoporous SiO
2according to the mass ratio of 1-80%, add in dehydrated alcohol, the 8-24 hour that refluxes at 70 ℃, finally by filtering and washing, and at 60-80 ℃ dry 5-10 hour, obtain polymer P and wrap up mesoporous SiO
2pressed powder, be labeled as B.
The medicine that sample B loads can be water soluble drug gentamycin etc., microsolubility medicine aspirin etc. or insoluble drug ibuprofen etc., further, after sample B drug loading, the delivery systme at different pH value can be citric acid buffer system, phosphate buffer, simulated gastric fluid, simulated body fluid, dilute hydrochloric acid, weak ammonia etc.
Embodiment 2
8mL vinyl-triethoxysilane and 80mL methacrylic acid are dissolved in dehydrated alcohol to logical N
2after two hours, add rapidly a certain amount of initiator azodiisobutyronitrile (AIBN), sustained response, after 24 hours, obtains solid matter by n-hexane extraction at 70 ℃, and by dissolve with ethanol/n-hexane extraction process repeatedly, makes polymer, is labeled as P.
0.25g P and 0.5g are had to couple SiO of mesoporous (large hole diameter is respectively 21.0nm and 2.7nm)
2add in dehydrated alcohol, reflux 12 hours at 70 ℃, finally by filtration washing, and dryly at 70 ℃ obtain pressed powder, be labeled as B.
Above-mentioned sample B is used for loading ibuprofen, and carrying drug ratio is 25.1%, and the sensitivity that its medicine-carried system carries out respectively ibuprofen in pH value is 2.0 and 7.4 phosphate buffered solution discharges, and its controlled-release effect as shown in Figure 2.
Embodiment 3
8mL vinyl-triethoxysilane and 80mL methacrylic acid are dissolved in dehydrated alcohol to logical N
2after two hours, add rapidly a certain amount of initiator azodiisobutyronitrile (AIBN), sustained response, after 24 hours, obtains solid matter by n-hexane extraction at 70 ℃, and by dissolve with ethanol/n-hexane extraction process repeatedly, makes polymer, is labeled as P.
0.05g P and 0.5g are had to couple SiO of mesoporous (large hole diameter is respectively 21.0nm and 2.7nm)
2add in dehydrated alcohol, reflux 12 hours at 70 ℃, finally by filtration washing, and dryly at 70 ℃ obtain pressed powder, be labeled as B.
Above-mentioned sample B is used for loading ibuprofen, and carrying drug ratio is 26.7%, and the sensitivity that its medicine-carried system carries out respectively ibuprofen in pH value is 2.0 and 7.4 phosphate buffered solution discharges.
Embodiment 4
8mL vinyl-triethoxysilane and 80mL methacrylic acid are dissolved in dehydrated alcohol, logical N2 adds rapidly a certain amount of initiator azodiisobutyronitrile (AIBN) after two hours, at 70 ℃, sustained response is after 24 hours, by n-hexane extraction, obtain solid matter, and by dissolve with ethanol/n-hexane extraction process repeatedly, make polymer, be labeled as P.
0.1g P and 0.5g are had to couple SiO of mesoporous (large hole diameter is respectively 21.0nm and 2.7nm)
2add in dehydrated alcohol, reflux 12 hours at 70 ℃, finally by filtration washing, and dryly at 70 ℃ obtain pressed powder, be labeled as B.
Above-mentioned sample B is used for loading ibuprofen, and carrying drug ratio is 35.9%, and the sensitivity that its medicine-carried system carries out respectively ibuprofen in pH value is 2.0 and 7.4 phosphate buffered solution discharges.
This preparation method is owing to only having the mesoporous SiO of polymer modification and polymer wrapped
2two steps, and all experimental apparatus and equipment is all laboratory apparatus & equipment in common use, the operation of employing is also chemical field common operation, so preparation method is simple to operate.
Embodiment 5
8mL vinyl-triethoxysilane and 80mL methacrylic acid are dissolved in dehydrated alcohol to logical N
2after two hours, add rapidly a certain amount of initiator azodiisobutyronitrile (AIBN), sustained response, after 24 hours, obtains solid matter by n-hexane extraction at 70 ℃, and by dissolve with ethanol/n-hexane extraction process repeatedly, makes polymer, is labeled as P.
0.4g P and 0.5g are had to couple SiO of mesoporous (large hole diameter is respectively 21.0nm and 2.7nm)
2add in dehydrated alcohol, reflux 12 hours at 70 ℃, finally by filtration washing, and dryly at 70 ℃ obtain pressed powder, be labeled as B.
Above-mentioned sample B is used for loading ibuprofen, and carrying drug ratio is 24.6%, and the sensitivity that its medicine-carried system carries out respectively ibuprofen in pH value is 2.0 and 7.4 phosphate buffered solution discharges.
Embodiment 6
10mL vinyl-trimethoxy silane and 80mL methacrylic acid are dissolved in dehydrated alcohol to logical N
2after two hours, add rapidly a certain amount of initiator azodiisobutyronitrile (AIBN), sustained response, after 10 hours, obtains solid matter by n-hexane extraction at 70 ℃, and by dissolve with ethanol/n-hexane extraction process repeatedly, makes polymer, is labeled as P.
2.0g P and 0.5g are had to couple SiO of mesoporous (large hole diameter is respectively 15nm and 2nm)
2add in dehydrated alcohol, reflux 24 hours at 70 ℃, finally by filtration washing, and dryly at 80 ℃ obtain pressed powder, be labeled as B.
Above-mentioned sample B is used for loading ibuprofen, and the sensitivity that its medicine-carried system carries out respectively ibuprofen in pH value is 2.0 and 7.4 phosphate buffered solution discharges.In the present invention, Organic substance used contains carboxyl, can realize the control to medicine under different acidity or alkali condition, i.e. the control of different pH value to medicine.
Embodiment 7
40mL vinyl-triethoxysilane and 40mL methyl methacrylate are dissolved in dehydrated alcohol to logical N
2after two hours, add rapidly a certain amount of initiator dibenzoyl peroxide, sustained response, after 48 hours, obtains solid matter by n-hexane extraction at 70 ℃, and by dissolve with ethanol/n-hexane extraction process repeatedly, makes polymer, is labeled as P.
2.0g P and 0.5g are had to couple SiO of mesoporous (large hole diameter is respectively 30nm and 3nm)
2add in dehydrated alcohol, reflux 24 hours at 70 ℃, finally by filtration washing, and dryly at 80 ℃ obtain pressed powder, be labeled as B.
Above-mentioned sample B is used for loading ibuprofen, and the sensitivity that its medicine-carried system carries out respectively ibuprofen in pH value is 2.0 and 7.4 phosphate buffered solution discharges.
Embodiment 8
80mL methacrylic acid is dissolved in dehydrated alcohol to logical N
2after two hours, add rapidly a certain amount of initiator sodium peroxydisulfate, sustained response, after 4 hours, obtains solid matter by n-hexane extraction at 70 ℃, and by dissolve with ethanol/n-hexane extraction process repeatedly, makes polymer, is labeled as P.
0.005g P and 0.5g are had to couple SiO of mesoporous (large hole diameter is respectively 18nm and 2nm)
2add in dehydrated alcohol, reflux 8 hours at 70 ℃, finally by filtration washing, and dryly at 60 ℃ obtain pressed powder, be labeled as B.
Above-mentioned sample B is used for loading ibuprofen, and the sensitivity that its medicine-carried system carries out respectively ibuprofen in pH value is 2.0 and 7.4 phosphate buffered solution discharges.
Embodiment 9
20mL3-(methacryloxypropyl) propyl trimethoxy silicane and 80mL methacrylic acid are dissolved in dehydrated alcohol to logical N
2after two hours, add rapidly a certain amount of initiator azodiisobutyronitrile (AIBN), sustained response, after 12 hours, obtains solid matter by n-hexane extraction at 70 ℃, and by dissolve with ethanol/n-hexane extraction process repeatedly, makes polymer, is labeled as P.
1.5g P and 0.5g are had to couple SiO of mesoporous (large hole diameter is respectively 25nm and 3nm)
2add in dehydrated alcohol, reflux 24 hours at 70 ℃, finally by filtration washing, and dryly at 80 ℃ obtain pressed powder, be labeled as B.
Above-mentioned sample B is used for loading ibuprofen, and the sensitivity that its medicine-carried system carries out respectively ibuprofen in pH value is 2.0 and 7.4 phosphate buffered solution discharges.
The present invention does not have synthetic this step of mesoporous silicon sphere, has and only have polymer and mesoporous SiO
2these two influence factors of addition impact result of the present invention, easily control polymer at mesoporous SiO
2the grafting amount on surface.
Embodiment 10
50mL3-(methacryloxypropyl) propyl-triethoxysilicane and 80mL methacrylic acid are dissolved in dehydrated alcohol to logical N
2after two hours, add rapidly a certain amount of initiator azodiisobutyronitrile (AIBN), sustained response, after 24 hours, obtains solid matter by n-hexane extraction at 70 ℃, and by dissolve with ethanol/n-hexane extraction process repeatedly, makes polymer, is labeled as P.
0.8g P and 0.5g are had to couple SiO of mesoporous (large hole diameter is respectively 30nm and 2nm)
2add in dehydrated alcohol, reflux 10 hours at 70 ℃, finally by filtration washing, and dryly at 70 ℃ obtain pressed powder, be labeled as B.
Above-mentioned sample B is used for loading ibuprofen, and the sensitivity that its medicine-carried system carries out respectively ibuprofen in pH value is 2.0 and 7.4 phosphate buffered solution discharges.
This preparation method only need to change polymer and mesoporous SiO
2addition, can well control inventive result.
The foregoing is only preferred embodiment of the present invention, in order to limit the present invention, within the spirit and principles in the present invention not all, any modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (7)
1. a preparation method for the material of controlled release drug, is characterized in that, comprises the following steps:
1) Organic substance that contains two keys and carboxyl is carried out to modification
Silane coupler and the Organic substance that contains two keys and carboxyl are dissolved in dehydrated alcohol according to the volume ratio of 0-100%, and logical nitrogen added initiator after two hours, at 70 ℃ after sustained response 4-48 hour, then by n-hexane extraction, made polymer, was labeled as P;
Described silane coupler is VTES, vinyltrimethoxy silane, 3-(methacryloxypropyl) propyl trimethoxy silicane or 3-(methacryloxypropyl) propyl-triethoxysilicane;
The described Organic substance that contains two keys and carboxyl is acrylic acid, methacrylic acid or methyl methacrylate;
2) above-mentioned polymer P is wrapped up to mesoporous SiO by grafting
2
By polymer P and mesoporous SiO
2according to the mass ratio of 1-80%, add in dehydrated alcohol, the 8-24 hour that refluxes at 70 ℃, finally by filtering and washing, and at 60-80 ℃ dry 5-10 hour, obtain polymer P and wrap up mesoporous SiO
2pressed powder, be labeled as B.
2. preparation method according to claim 1, is characterized in that: described initiator is organic peroxide class, azo and inorganic peroxy class initiator.
3. preparation method according to claim 2, is characterized in that: described organic peroxide initiator is dibenzoyl peroxide.
4. preparation method according to claim 2, is characterized in that: described azo-initiator is azodiisobutyronitrile.
5. preparation method according to claim 2, is characterized in that: described inorganic peroxy class initiator is persulfate.
6. preparation method according to claim 1, is characterized in that: described mesoporous SiO2 is two meso-hole structures, and particle diameter is 20-1000nm.
7. preparation method according to claim 6, is characterized in that: the large bore dia of described pair of meso-hole structure is 15-30nm, and hole diameter is 2-3nm.
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