CN102727572A - Dual pH/magnetism sensitive hydrogel bead of total alkaloids of sophora alopecuroides and preparation method thereof - Google Patents
Dual pH/magnetism sensitive hydrogel bead of total alkaloids of sophora alopecuroides and preparation method thereof Download PDFInfo
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- CN102727572A CN102727572A CN2012102428503A CN201210242850A CN102727572A CN 102727572 A CN102727572 A CN 102727572A CN 2012102428503 A CN2012102428503 A CN 2012102428503A CN 201210242850 A CN201210242850 A CN 201210242850A CN 102727572 A CN102727572 A CN 102727572A
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Abstract
The invention relates to a dual pH/magnetism sensitive hydrogel bead of total alkaloids of sophora alopecuroides, and a preparation method of the dual pH/magnetism sensitive hydrogel bead of total alkaloids of sophora alopecuroides, the dual pH/magnetism sensitive hydrogel bead is used for treating digestive system tumors by oral administration. The preparation method of the dual pH/magnetism sensitive hydrogel bead of total alkaloids of sophora alopecuroides comprises the following steps of: dissolving an appropriate amount of chitosan into an acetic acid solution, then adding an appropriate amount of CaCl2 into the chitosan solution, uniformly dispersing an appropriate amount of sodium alginate into purified water to obtain a sodium alginate solution, adding an appropriate amount of total alkaloids of sophora alopecuroides and Fe3O4 nanoparticles into the sodium alginate solution to obtain mixed suspension containing the total alkaloids of sophora alopecuroides, the Fe3O4 nanoparticles and the sodium alginate, and then dropping the mixed suspension into mixed solution of the chitosan and the CaCl2, filtering after finishing cross-linking reaction, washing by an appropriate amount of the purified water, and drying to obtain the dual pH/magnetism sensitive hydrogel bead of total alkaloids of sophora alopecuroides.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation, especially a kind of oral administration is administered for dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic of treatment digestive system carcinoma and preparation method thereof.The dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic of the present invention's preparation is that pH sensitivity and the dual release mechanism of magnetic targeting property are gathered the hydrogel bead of the dual release response that forms.
Background technology
Herba Sophorae alopecuroidis (
Sophora alopecuroidesL.) belonging to cassia leguminous plant, extensive growth is in the NORTHWEST CHINA area, and medicine resource is abundant, and effects such as heat-clearing and toxic substances removing and pain relieving parasite killing are arranged.Herba Sophorae alopecuroidis total alkali be its dry herb or seed extract and total alkaloids; Belong to quinolizidine kind alkaloid, its composition mainly comprises about 21 kinds of alkaloids such as matrine, oxymatrine, sophoridine, Oxysophoridine, sophocarpine, N-oxysophocarpine, sophoramine, lehmannine, wild pyridine alkali and aloperine.
Modern pharmacological research shows that Herba Sophorae alopecuroidis total alkali has following pharmacological action: the central nervous system acts on heart tonifying, arrhythmia and hypotensive effect, antiviral, antiinflammatory, antibiotic and immunoregulation effect, antitumor action.
At present, be that the dosage form that raw material is studied mainly contains the subsides of Herba Sophorae alopecuroidis chitosan oral ulcer, Herba Sophorae alopecuroidis suppository, Herba Sophorae alopecuroidis total alkali type of effervescent suppository, the matrix tablet of Herba Sophorae alopecuroidis total alkali, Herba Sophorae alopecuroidis total alkali micropill with the Herba Sophorae alopecuroidis total alkali.
Summary of the invention
The object of the present invention is to provide a kind of oral administration to be administered for dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic of treatment digestive system carcinoma and preparation method thereof; Said preparation has pH sensitivity release mechanism and magnetic targeting property release mechanism; Can make the digestive tract position of Herba Sophorae alopecuroidis total alkali, press the pH gradient and discharge medicine at different pH environment, and can be under the guiding of externally-applied magnetic field; Accumulate in tumor locus; Have the localized intelligent medicine releasing characteristic of targeting, thereby can improve the bioavailability of Herba Sophorae alopecuroidis total alkali, strengthen clinical therapeutic efficacy.
The method for preparing of the dual sensitive aqueous gel bead of a kind of Herba Sophorae alopecuroidis total alkali pH/ magnetic of the present invention is, it is among 1% the acetum 20ml, with 0.3g～0.7g CaCl that chitosan 0.04g～0.08g is dissolved in volume ratio
2Add among the aforementioned chitosan solution 20ml,, evenly be sprinkled into the 10ml purified water and obtain sodium alginate aqueous solution, Herba Sophorae alopecuroidis total alkali 1.0g～1.5g, Fe with sodium alginate 0.15g～0.25g
3O
4Nanoparticle 0.04g～0.07g adds among the aforesaid sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing Herba Sophorae alopecuroidis total alkali, Fe
3O
4The suspension of nanoparticle and sodium alginate is measured aforementioned Herba Sophorae alopecuroidis total alkali, the Fe of containing
3O
4The suspension 10ml of nanoparticle and sodium alginate under slowly stirring, is added drop-wise to chitosan and the CaCl of 20ml
2Mixed solution in, cross-linking reaction 20 minutes, reaction finishes after-filtration, with an amount of purified water washing 3 times, room temperature placement natural drying obtains the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic.
The dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic that can make according to the method for preparing of the dual sensitive aqueous gel bead of a kind of Herba Sophorae alopecuroidis total alkali pH/ magnetic of the present invention.
Chitosan among the present invention is a kind of natural linear macromolecule alkalescence polysaccharide, contains amino group freely.Its source is abundant, cheap, has good biocompatibility and biological degradability; Nontoxic, non-stimulated, no anaphylaxis, adhesion, film property are good, environmental friendliness; Free from environmental pollution, be widely used in fields such as medicine, chemical industry, food, be one to have the pharmaceutic adjuvant of development prospect.
Sodium alginate among the present invention is a kind of natural anionic polymer; Have better biocompatibility and biological degradability; Carboxyl in its structure can form the polyeletrolyte complex with the amino cation generation ionic reaction in the chitosan molecule; High temperature and the covalent bond in the chemical crosslinking process that this process does not relate in the heat cross-linking process form, and the character of bag loading is not had influence, and therefore the carrier as medicine, biological product, vaccine and cell has great superiority.
Fe among the present invention
3O
4Nanoparticle is as magnetisable material; Have toxicity low, be easy to get, characteristics such as saturation magnetization height; Help the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic and adding under the induced by magnetic field, the tumor locus targeting location in digestive tract is after drug release finishes; Self can excrete with feces, can not cause accumulate poisoning in vivo or influence body function.
The dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic of the present invention's preparation has the dual release response characteristic of pH sensitivity release mechanism and magnetic targeting property release mechanism.At first, utilize its pH sensitivity, make Herba Sophorae alopecuroidis total alkali at stomach, duodenum, small intestinal, the digestive tract position of different pH environment such as colon is pressed the pH gradient and is discharged.In addition, this hydrogel bead contains Fe
3O
4Nanoparticle has good magnetic responsiveness, externally-applied magnetic field capable of using induce performance; Hydrogel bead orientation is transported to the target area, the Herba Sophorae alopecuroidis total alkali location is discharged, thereby realize dual-target site-specific delivery of drugs digestive tract tumor; Increase the drug level of Herba Sophorae alopecuroidis total alkali, reduce systemic drug concentration, can reduce poisonous side effect of medicine and untoward reaction at the digestive tract tumor position; Improve drug bioavailability; Strengthen clinical therapeutic efficacy, reduce drug administration number of times and dosage, increase patient's compliance.
The present invention is a main component with the active component Herba Sophorae alopecuroidis total alkali in the natural drug Herba Sophorae alopecuroidis, is main pharmaceutic adjuvant with natural macromolecular material chitosan and sodium alginate, CaCl
2Be cross-linking agent, Fe
3O
4Nanoparticle is a magnetisable material, and solvent is a purified water, adopts ion gelatine method, through relevant pharmaceutical technology research, is prepared into the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic with good Release Performance.This preparation has pH sensitivity and the dual sensitivity of magnetic targeting property; Herba Sophorae alopecuroidis total alkali location targeting is discharged, thereby can realize dual target position targeted delivery of drugs, improve drug bioavailability digestive tract tumor; Strengthen the clinical drug therapeutic effect; Reduce adverse effect and toxic and side effects, reduce administration number of times and dosage, improve patient's compliance.
Description of drawings
Fig. 1. the mode of appearance figure of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic of embodiment 1 gained, among the figure: a. is the wet dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic digital photograph; B is the dual sensitive aqueous gel bead of a dry Herba Sophorae alopecuroidis total alkali pH/ magnetic digital photograph; C does. amplify the stereoscan photograph of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic of 65 multiples; D does. amplify the stereoscan photograph of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic of 400 multiples.
Fig. 2 is the dual sensitive aqueous gel bead of the Herba Sophorae alopecuroidis total alkali pH/ magnetic infrared spectrogram of embodiment 1 gained, and among the figure: A is a chitosan; B is a sodium alginate; C is the dual sensitive aqueous gel bead of blank pH/ magnetic; D is the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic; E is a Herba Sophorae alopecuroidis total alkali.
Fig. 3. the X-ray diffraction spectrogram of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic of embodiment 1 gained, among the figure: a is a chitosan; B is a sodium alginate; C is Fe
3O
4Nanoparticle; D is a Herba Sophorae alopecuroidis total alkali; E is the dual sensitive aqueous gel bead of blank pH/ magnetic; F is the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic.
Fig. 4. the hysteresis graph of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic of embodiment 1 gained, among the figure: A is the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic; B is Fe
3O
4Nanoparticle.
Fig. 5. the swellbility figure of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic in different pH environment of embodiment 1 gained.
Fig. 6. be the drug accumulation releasing curve diagram of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic in different pH environment of embodiment 1 gained.
The specific embodiment
Be embodiments of the invention below, but the present invention is not limited only to embodiment.
Embodiment 1:
1) take by weighing chitosan 0.04g, evenly be sprinkled among 1% the acetum 20ml, placement is spent the night, and is stirred to dissolving fully, obtains concentration and be 0.2% chitosan solution, and is subsequent use.
2) take by weighing CaCl
20.3g, add among above-mentioned 0.2% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, CaCl
2Concentration in chitosan solution is 1.5%, and is subsequent use.
3) take by weighing sodium alginate 0.25g, evenly be sprinkled in the 10ml purified water, placement is spent the night, and is stirred to fully dissolving, obtains concentration and be 2.5% sodium alginate soln, and is subsequent use.
4) take by weighing Herba Sophorae alopecuroidis total alkali 1.25g, Fe respectively
3O
4Nanoparticle 0.04g adds among above-mentioned 2.5% the sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing Herba Sophorae alopecuroidis total alkali, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned Herba Sophorae alopecuroidis total alkali, the Fe of containing
3O
4The suspension 10ml of nanoparticle and sodium alginate under slowly stirring, is added drop-wise to chitosan and the CaCl of 20ml through the 5ml syringe
2Mixed solution in, cross-linking reaction 20 minutes, reaction finishes after-filtration, with an amount of purified water washing 3 times, room temperature placement natural drying obtains the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic.
Embodiment 2:
1) take by weighing chitosan 0.04g, evenly be sprinkled among 1% the acetum 20ml, placement is spent the night, and is stirred to dissolving fully, obtains concentration and be 0.2% chitosan solution, and is subsequent use.
2) take by weighing CaCl
20.3g, add among above-mentioned 0.2% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, CaCl
2Concentration in chitosan solution is 1.5%, and is subsequent use.
3) take by weighing sodium alginate 0.15g, evenly be sprinkled in the 10ml purified water, placement is spent the night, and is stirred to fully dissolving, obtains concentration and be 1.5% sodium alginate soln, and is subsequent use.
4) take by weighing Herba Sophorae alopecuroidis total alkali 1.25g, Fe respectively
3O
4Nanoparticle 0.04g adds among above-mentioned 1.5% the sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing Herba Sophorae alopecuroidis total alkali, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned Herba Sophorae alopecuroidis total alkali, the Fe of containing
3O
4The suspension 10ml of nanoparticle and sodium alginate under slowly stirring, is added drop-wise to chitosan and the CaCl of 20ml through the 5ml syringe
2Mixed solution in, cross-linking reaction 20 minutes, reaction finishes after-filtration, with an amount of purified water washing 3 times, room temperature placement natural drying obtains the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic.
Embodiment 3:
1) take by weighing chitosan 0.04g, evenly be sprinkled among 1% the acetum 20ml, placement is spent the night, and is stirred to dissolving fully, obtains concentration and be 0.2% chitosan solution, and is subsequent use.
2) take by weighing CaCl
20.3g, add among above-mentioned 0.2% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, CaCl
2Concentration in chitosan solution is 1.5%, and is subsequent use.
3) take by weighing sodium alginate 0.20g, evenly be sprinkled in the 10ml purified water, placement is spent the night, and is stirred to fully dissolving, obtains concentration and be 2.0% sodium alginate soln, and is subsequent use.
4) take by weighing Herba Sophorae alopecuroidis total alkali 1.25g, Fe respectively
3O
4Nanoparticle 0.04g adds among above-mentioned 2.0% the sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing Herba Sophorae alopecuroidis total alkali, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned Herba Sophorae alopecuroidis total alkali, the Fe of containing
3O
4The suspension 10ml of nanoparticle and sodium alginate under slowly stirring, is added drop-wise to chitosan and the CaCl of 20ml through the 5ml syringe
2Mixed solution in, cross-linking reaction 20 minutes, reaction finishes after-filtration, with an amount of purified water washing 3 times, room temperature placement natural drying obtains the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic.
Embodiment 4:
1) take by weighing chitosan 0.04g, evenly be sprinkled among 1% the acetum 20ml, placement is spent the night, and is stirred to dissolving fully, obtains concentration and be 0.2% chitosan solution, and is subsequent use.
2) take by weighing CaCl
20.3g, add among above-mentioned 0.2% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, CaCl
2Concentration in chitosan solution is 1.5%, and is subsequent use.
3) take by weighing sodium alginate 0.25g, evenly be sprinkled in the 10ml purified water, placement is spent the night, and is stirred to fully dissolving, obtains concentration and be 2.5% sodium alginate soln, and is subsequent use.
4) take by weighing Herba Sophorae alopecuroidis total alkali 1.25g, Fe respectively
3O
4Nanoparticle 0.05g adds among above-mentioned 2.5% the sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing Herba Sophorae alopecuroidis total alkali, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned Herba Sophorae alopecuroidis total alkali, the Fe of containing
3O
4The suspension 10ml of nanoparticle and sodium alginate under slowly stirring, is added drop-wise to chitosan and the CaCl of 20ml through the 5ml syringe
2Mixed solution in, cross-linking reaction 20 minutes, reaction finishes after-filtration, with an amount of purified water washing 3 times, room temperature placement natural drying obtains the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic.
Embodiment 5:
1) take by weighing chitosan 0.04g, evenly be sprinkled among 1% the acetum 20ml, placement is spent the night, and is stirred to dissolving fully, obtains concentration and be 0.2% chitosan solution, and is subsequent use.
2) take by weighing CaCl
20.3g, add among above-mentioned 0.2% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, CaCl
2Concentration in chitosan solution is 1.5%, and is subsequent use.
3) take by weighing sodium alginate 0.25g, evenly be sprinkled in the 10ml purified water, placement is spent the night, and is stirred to fully dissolving, obtains concentration and be 2.5% sodium alginate soln, and is subsequent use.
4) take by weighing Herba Sophorae alopecuroidis total alkali 1.25g, Fe respectively
3O
4Nanoparticle 0.07g adds among above-mentioned 2.5% the sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing Herba Sophorae alopecuroidis total alkali, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned Herba Sophorae alopecuroidis total alkali, the Fe of containing
3O
4The suspension 10ml of nanoparticle and sodium alginate under slowly stirring, is added drop-wise to chitosan and the CaCl of 20ml through the 5ml syringe
2Mixed solution in, cross-linking reaction 20 minutes, reaction finishes after-filtration, with an amount of purified water washing 3 times, room temperature placement natural drying obtains the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic.
Embodiment 6:
1) take by weighing chitosan 0.04g, evenly be sprinkled among 1% the acetum 20ml, placement is spent the night, and is stirred to dissolving fully, obtains concentration and be 0.2% chitosan solution, and is subsequent use.
2) take by weighing CaCl
20.5g, add among above-mentioned 0.2% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, CaCl
2Concentration in chitosan solution is 2.5%, and is subsequent use.
3) take by weighing sodium alginate 0.25g, evenly be sprinkled in the 10ml purified water, placement is spent the night, and is stirred to fully dissolving, obtains concentration and be 2.5% sodium alginate soln, and is subsequent use.
4) take by weighing Herba Sophorae alopecuroidis total alkali 1.25g, Fe respectively
3O
4Nanoparticle 0.04g adds among above-mentioned 2.5% the sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing Herba Sophorae alopecuroidis total alkali, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned Herba Sophorae alopecuroidis total alkali, the Fe of containing
3O
4The suspension 10ml of nanoparticle and sodium alginate under slowly stirring, is added drop-wise to chitosan and the CaCl of 20ml through the 5ml syringe
2Mixed solution in, cross-linking reaction 20 minutes, reaction finishes after-filtration, with an amount of purified water washing 3 times, room temperature placement natural drying obtains the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic.
Embodiment 7:
1) take by weighing chitosan 0.04g, evenly be sprinkled among 1% the acetum 20ml, placement is spent the night, and is stirred to dissolving fully, obtains concentration and be 0.2% chitosan solution, and is subsequent use.
2) take by weighing CaCl
20.7g, add among above-mentioned 0.2% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, CaCl
2Concentration in chitosan solution is 3.5%, and is subsequent use.
3) take by weighing sodium alginate 0.25g, evenly be sprinkled in the 10ml purified water, placement is spent the night, and is stirred to fully dissolving, obtains concentration and be 2.5% sodium alginate soln, and is subsequent use.
4) take by weighing Herba Sophorae alopecuroidis total alkali 1.25g, Fe respectively
3O
4Nanoparticle 0.04g adds among above-mentioned 2.5% the sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing Herba Sophorae alopecuroidis total alkali, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned Herba Sophorae alopecuroidis total alkali, the Fe of containing
3O
4The suspension 10ml of nanoparticle and sodium alginate under slowly stirring, is added drop-wise to chitosan and the CaCl of 20ml through the 5ml syringe
2Mixed solution in, cross-linking reaction 20 minutes, reaction finishes after-filtration, with an amount of purified water washing 3 times, room temperature placement natural drying obtains the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic.
Embodiment 8:
1) take by weighing the 0.06g chitosan, evenly be sprinkled among 1% the acetum 20ml, placement is spent the night, and is stirred to dissolving fully, obtains concentration and be 0.3% chitosan solution, and is subsequent use.
2) take by weighing CaCl
20.3g, add among above-mentioned 0.3% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, CaCl
2Concentration in chitosan solution is 1.5%, and is subsequent use.
3) take by weighing sodium alginate 0.25g, evenly be sprinkled in the 10ml purified water, placement is spent the night, and is stirred to fully dissolving, obtains concentration and be 2.5% sodium alginate soln, and is subsequent use.
4) take by weighing Herba Sophorae alopecuroidis total alkali 1.25g, Fe respectively
3O
4Nanoparticle 0.04g adds among above-mentioned 2.5% the sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing Herba Sophorae alopecuroidis total alkali, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned Herba Sophorae alopecuroidis total alkali, the Fe of containing
3O
4The suspension 10ml of nanoparticle and sodium alginate under slowly stirring, is added drop-wise to chitosan and the CaCl of 20ml through the 5ml syringe
2Mixed solution in, cross-linking reaction 20 minutes, reaction finishes after-filtration, with an amount of purified water washing 3 times, room temperature placement natural drying obtains the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic.
Embodiment 9:
1) take by weighing chitosan 0.08g, evenly be sprinkled among 1% the acetum 20ml, placement is spent the night, and is stirred to dissolving fully, obtains concentration and be 0.4% chitosan solution, and is subsequent use.
2) take by weighing CaCl
20.3g, add among above-mentioned 0.4% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, CaCl
2Concentration in chitosan solution is 1.5%, and is subsequent use.
3) take by weighing sodium alginate 0.25g, evenly be sprinkled in the 10ml purified water, placement is spent the night, and is stirred to fully dissolving, obtains concentration and be 2.5% sodium alginate soln, and is subsequent use.
4) take by weighing Herba Sophorae alopecuroidis total alkali 1.25g, Fe respectively
3O
4Nanoparticle 0.04g adds among above-mentioned 2.5% the sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing Herba Sophorae alopecuroidis total alkali, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned Herba Sophorae alopecuroidis total alkali, the Fe of containing
3O
4The suspension 10ml of nanoparticle and sodium alginate under slowly stirring, is added drop-wise to chitosan and the CaCl of above-mentioned 20ml through the 5ml syringe
2Mixed solution in, cross-linking reaction 20 minutes, reaction finishes after-filtration, with an amount of purified water washing 3 times, room temperature placement natural drying obtains the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic.
Embodiment 10:
1) take by weighing chitosan 0.04g, evenly be sprinkled among 1% the acetum 20ml, placement is spent the night, and is stirred to dissolving fully, obtains concentration and be 0.2% chitosan solution, and is subsequent use.
2) take by weighing CaCl
20.3g, add among above-mentioned 0.2% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, CaCl
2Concentration in chitosan solution is 1.5%, and is subsequent use.
3) take by weighing sodium alginate 0.25g, evenly be sprinkled in the 10ml purified water, placement is spent the night, and is stirred to fully dissolving, obtains concentration and be 2.5% sodium alginate soln, and is subsequent use.
4) take by weighing Herba Sophorae alopecuroidis total alkali 1.0g, Fe respectively
3O
4Nanoparticle 0.04g adds among above-mentioned 2.5% the sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing Herba Sophorae alopecuroidis total alkali, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned Herba Sophorae alopecuroidis total alkali, the Fe of containing
3O
4The suspension 10ml of nanoparticle and sodium alginate under slowly stirring, is added drop-wise to chitosan and the CaCl of 20ml through the 5ml syringe
2Solution in, cross-linking reaction 20 minutes, reaction finishes after-filtration, with an amount of purified water washing 3 times, room temperature placement natural drying obtains the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic.
Embodiment 11:
1) take by weighing chitosan 0.04g, evenly be sprinkled among 1% the acetum 20ml, placement is spent the night, and is stirred to dissolving fully, obtains concentration and be 0.2% chitosan solution, and is subsequent use.
2) take by weighing CaCl
20.3g, add among above-mentioned 0.2% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, CaCl
2Concentration in chitosan solution is 1.5%, and is subsequent use.
3) take by weighing sodium alginate 0.25g, evenly be sprinkled in the 10ml purified water, placement is spent the night, and is stirred to fully dissolving, obtains concentration and be 2.5% sodium alginate soln, and is subsequent use.
4) take by weighing Herba Sophorae alopecuroidis total alkali 1.5g, Fe respectively
3O
4Nanoparticle 0.04g adds among above-mentioned 2.5% the sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing Herba Sophorae alopecuroidis total alkali, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned Herba Sophorae alopecuroidis total alkali, the Fe of containing
3O
4The suspension 10ml of nanoparticle and sodium alginate under slowly stirring, is added drop-wise to chitosan and the CaCl of above-mentioned 20ml through the 5ml syringe
2Mixed solution in, cross-linking reaction 20 minutes, reaction finishes after-filtration, with an amount of purified water washing 3 times, room temperature placement natural drying obtains the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic.
The mode of appearance of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic is observed:
Take by weighing the wet and an amount of metal spraying processing of the dual sensitive aqueous gel bead of dried Herba Sophorae alopecuroidis total alkali pH/ magnetic of embodiment 1 gained respectively, the control accelerating potential is 30kV, and amplification is 65 and 400 times.Under room temperature condition with the naked eye and scanning electron microscope (SEM) observe the configuration of surface and the microstructure of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic.As can beappreciated from fig. 1 be the sphere than rounding before the dual sensitive aqueous gel bead of the Herba Sophorae alopecuroidis total alkali pH/ magnetic drying, shape is rule, pitchy, and smooth surface, average diameter are 3mm (a); Room temperature still keeps its spherical morphology after placing natural drying, but volume-diminished, diameter is about 1mm (b).(c d) can find out, this hydrogel bead is the sphere than rounding, and shape is rule, but because the gelled pill network structure is dewatered and to be made rough surface, and has hole ditch and fold, and the result sees Fig. 1 by the SEM picture.
The infrared spectrum analysis of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic:
It is an amount of to take by weighing chitosan, sodium alginate, the dual sensitive aqueous gel bead of blank pH/ magnetic, the embodiment 1 dual sensitive aqueous gel bead of gained Herba Sophorae alopecuroidis total alkali pH/ magnetic and Herba Sophorae alopecuroidis total alkali respectively; Grind back and the mixed of KBr fine powder, in agate mortar, be ground to evenly the compression mold of packing into 1:100; Evenly behind the cloth of shop; Pressurization is kept pressure 5min during to the about 20MPa of pressure while bleeding, and obtains the transparent KBr sample strip of thick about 1mm; Place the sample light path of infrared spectrometer, record infrared spectrogram.Relatively the infrared spectrogram of chitosan, sodium alginate, the dual sensitive aqueous gel bead of blank pH/ magnetic, the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic and Herba Sophorae alopecuroidis total alkali can be found out; The characteristic absorption peak of chitosan is positioned at 1095,1033,1598,1655,2877 and 3444 cm
-1The place.The characteristic absorption peak of sodium alginate is positioned at 1029,1427 and 1626cm
-1The place.Sodium alginate and chitosan form after the compound polyelectrolyte, respectively 1609,1416,1094 and 1032cm
-1The characteristic absorption peak of chitosan and sodium alginate has appearred in the place, explains in blank and the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic of gained to contain spectral studies simultaneously.Visible in dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic and the dual sensitive aqueous gel bead of blank pH/ magnetic, Fe
3O
4The characteristic absorption peak of nanoparticle appears at 561cm
1The place.In the infrared spectrogram of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic, the characteristic absorption peak 2928cm of Herba Sophorae alopecuroidis total alkali has appearred
-1, explain that Herba Sophorae alopecuroidis total alkali successfully is written in this hydrogel bead network structure.The result sees Fig. 2.
The X-diffraction analysis of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic:
Take by weighing chitosan, sodium alginate, Fe respectively
3O
4Nanoparticle, Herba Sophorae alopecuroidis total alkali, the dual sensitive aqueous gel bead of blank pH/ magnetic and the dual sensitive aqueous gel bead of embodiment 1 gained Herba Sophorae alopecuroidis total alkali pH/ magnetic are an amount of; Put in the agate mortar and grind; Evenly go up machine testing behind the cloth of shop, selecting the scope of scanning angle 2 θ is 10 ° ~ 90 °.Compare chitosan, sodium alginate, Fe
3O
4The crystal form of nanoparticle, Herba Sophorae alopecuroidis total alkali, the dual sensitive aqueous gel bead of blank pH/ magnetic and the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic is visible; The angle of diffraction of chitosan is 20 °, and the angle of diffraction of sodium alginate is 19 °, 28 °, 29.5 °, 32.5 °, 34.5 °.And both form that the angle of diffraction of chitosan and sodium alginate all disappears behind the hydrogel, and this is because intermolecular interaction has destroyed the hydrogen bond between two kinds of materials.And, Fe
3O
4The angle of diffraction of nanoparticle is 35.9 ° and 43.45 °, and visible its angle of diffraction is explained Fe in the hydrogel bead
3O
4Crystal configuration does not take place nanoparticle changes, and stably is present in this hydrogel bead.The principal character crystal diffraction angle of Herba Sophorae alopecuroidis total alkali is 11 °, 15 ° and 18.5 °.And do not see the characteristic crystal diffraction maximum of Herba Sophorae alopecuroidis total alkali in the dual sensitive aqueous gel bead of the pH/ magnetic of Herba Sophorae alopecuroidis total alkali, explain that Herba Sophorae alopecuroidis total alkali is not with crystal form but is written into molecular forms in the hydrogel bead.The result sees Fig. 3.
The magnetic property of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic is measured:
Take by weighing Fe respectively
3O
4Nanoparticle and the dual sensitive aqueous gel bead of embodiment 1 gained Herba Sophorae alopecuroidis total alkali pH/ magnetic powder are an amount of, measure Fe with vibrating specimen magnetometer (VSM) down in room temperature condition
3O
4The B-H loop of nanoparticle and the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic is investigated the magnetic response characteristic of this hydrogel bead.The result shows Fe
3O
4Magnetic nano particle has higher saturation magnetization, can reach 58.57emu/g; Remanent magnetization and coercivity all are zero, show typical superparamagnetism, can not produce gathering when using in vivo.The saturation magnetization of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic is about 5.02emu/g, and coercivity is zero, and this character can make the hydrogel bead can not produce gathering in vivo, after magnetic field disappears, can disperse again fast again.The result sees Fig. 4.
The swellability test of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic:
Precision takes by weighing dual each 30mg of sensitive aqueous gel bead of embodiment 1 gained Herba Sophorae alopecuroidis total alkali pH/ magnetic; Place the simulated gastric fluid hydrochloric acid solution of pH1.5 and PBS liquid pH5.0, pH6.8, pH7.4, the pH8.0 of different pH value respectively; Temperature is 37 ± 0.5 ℃; Fixed point is taken out at the fixed time; Weigh after blotting surface moisture with filter paper, investigate the swelling behavior of the Herba Sophorae alopecuroidis total alkali dual sensitive aqueous gel bead of pH/ magnetic in the phosphate buffer of simulated gastric fluid pH1.5 and different pH value.Calculate swellbility: SR=(W – W by following formula
0)/W
0Wherein W is the gross mass (g) after the dual sensitive aqueous gel bead of the Herba Sophorae alopecuroidis total alkali pH/ magnetic swelling, W
0Be the quality (g) before the dual sensitive aqueous gel bead of the dry Herba Sophorae alopecuroidis total alkali pH/ magnetic swelling.The result shows that this hydrogel bead swellbility in different pH value environment has evident difference.In the sour environment of pH1.5, the swellbility of this hydrogel bead is very little, is about 1.0; And along with the increase of solution pH value, swellbility obviously increases, and in the PBS of pH6.8, the swellbility of this hydrogel bead can be up to about 28.Above result shows that the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic has lower swellability under simulated gastric fluid pH value condition; And under small intestinal, colon position pH value condition, has good swellability; Therefore this hydrogel bead can be used as the pharmaceutical preparation of anti-alimentary tract tumor targeting site-specific delivery of drugs, has tangible pH sensitivity, and promptly environment pH is low more; Swellbility is more little, and drug release is less; Environment pH is high more, and swellbility is big more, helps drug release.The result sees Fig. 5.
The release behavior test of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic:
Carrying out the cumulative release degree by first law regulation in two appendix drug release determinations of Pharmacopoeia of the People's Republic of China version in 2010 method measures.Take by weighing 5 parts of the dual sensitive aqueous gel beads of embodiment 1 gained Herba Sophorae alopecuroidis total alkali pH/ magnetic; Every part of 2.0g; The accurate title, decide; PBS 500ml with the different pH value of pH1.5, pH5.0, pH6.8, pH7.4, pH8.0 is a dissolution medium respectively, is that per minute 100 changes at rotating speed, and temperature is 37.0 ± 0.5
oMeasure under the C condition, respectively at the stipulated time spot sampling, each precision is measured release medium 1ml in accordance with the law; And add the blank release medium 1ml of uniform temp, equal volume simultaneously, with 0.22 μ m filtering with microporous membrane, discard filtrating just; Precision is measured subsequent filtrate 5 μ l, injects high performance liquid chromatograph (Agilent 1200 types, the U.S.); Measure the peak area of matrine in the 220nm wavelength, and substitution standard curve Equation for Calculating cumulative release degree, release profiles drawn according to measuring the result.Chromatographic condition is: chromatographic column is the ZORBAX Eclipse XDB-C of U.S. Agilent company
18(250mm * 4.6mm, 5 μ m); Mobile phase is methanol: 0.1% phosphoric acid (it is 6.8 that triethylamine is transferred pH)=55:45; Column temperature is 30 ℃; Flow velocity is 1.0mlmin
-1The detection wavelength is 220nm; Sample size is 5 μ l.Theoretical cam curve is not less than 2000 by the matrine peak.Drug accumulation release degree (%)=[R
t/ L] * 100, wherein, Rt representes the accumulative total burst size of medicine in the t time, L representes the medicine total amount that is written at first.The result shows that the release behavior of matrine in different pH value PBSs has notable difference.Visible by the drug accumulation releasing curve diagram of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic in different pH environment, the release amount is lower in the acid solution of pH1.5, discharged 49.17% in 2 hours, and drug release is slower behind this time point; And the release amount is bigger in the weakly alkaline solution of pH6.8, discharged 87.43% in 2 hours, and release is very fast.Above result shows that the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic has tangible pH sensitivity, and this is also consistent with the swelling experimental result, and promptly environment pH is low more, and the hydrogel bead is difficult for swelling and breaks, and drug release is few more; Environment pH is high more, and the hydrogel bead is easy to swelling and breaks, and drug release is many more.The result sees Fig. 6.
The dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic release dynamics:
Adopt the peppas equation that the releasing mechanism of the dual sensitive aqueous gel bead of embodiment 1 gained Herba Sophorae alopecuroidis total alkali pH/ magnetic is inquired into.The peppas equation is: Mt/M ∞=kt
nMt/M ∞ representes medicine cumulative release mark (representing with %) at a time; T is release time; K is a speed constant; N is a dropout value, is the characteristic parameter that characterizes releasing mechanism in the peppas equation, when 0.43<n<0.85 the time, the releasing mechanism of medicine is non-Fick diffusion, by drug diffusion and bulk erosion combined effect; Work as n<0.43 the time, be the Fick diffusion; As n>0.85 the time, be bulk erosion mechanism.The result sees table 1.
The releasing mechanism of the table 1 embodiment 1 dual sensitive aqueous gel bead of gained Herba Sophorae alopecuroidis total alkali pH/ magnetic in different pH environment
| pH | n | k | r | Releasing mechanism |
| 1.5 | 0.5233 | 0.15918 | 0.9388 | Non-Fick diffusion |
| 5.0 | 0.5225 | 0.24502 | 0.9284 | Non-Fick diffusion |
| 6.8 | 0.4072 | 1.50661 | 0.8252 | The Fick diffusion |
| 7.4 | 0.3972 | 1.71751 | 0.8340 | The Fick diffusion |
| 8.0 | 0.3343 | 4.14572 | 0.8101 | The Fick diffusion |
Claims (2)
1. the method for preparing of the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic is characterized in that it is among 1% the acetum 20ml, with 0.3g～0.7g CaCl that chitosan 0.04g～0.08g is dissolved in volume ratio
2Add among the aforementioned chitosan solution 20ml,, evenly be sprinkled into the 10ml purified water and obtain sodium alginate aqueous solution, Herba Sophorae alopecuroidis total alkali 1.0g～1.5g, Fe with sodium alginate 0.15g～0.25g
3O
4Nanoparticle 0.04g～0.07g adds among the aforesaid sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing Herba Sophorae alopecuroidis total alkali, Fe
3O
4The suspension of nanoparticle and sodium alginate is measured aforementioned Herba Sophorae alopecuroidis total alkali, the Fe of containing
3O
4The suspension 10ml of nanoparticle and sodium alginate under slowly stirring, is added drop-wise to chitosan and the CaCl of 20ml
2Mixed solution in, cross-linking reaction 20 minutes, reaction finishes after-filtration, with an amount of purified water washing 3 times, room temperature placement natural drying obtains the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic.
2. the dual sensitive aqueous gel bead of Herba Sophorae alopecuroidis total alkali pH/ magnetic of the method for preparing of the dual sensitive aqueous gel bead of the described a kind of Herba Sophorae alopecuroidis total alkali pH/ magnetic of claim 1 preparation.
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