CN102727445A - Sophocarpidine pH/ magnetic dual-sensitive hydrogel globule and preparation method thereof - Google Patents
Sophocarpidine pH/ magnetic dual-sensitive hydrogel globule and preparation method thereof Download PDFInfo
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- CN102727445A CN102727445A CN2012102428518A CN201210242851A CN102727445A CN 102727445 A CN102727445 A CN 102727445A CN 2012102428518 A CN2012102428518 A CN 2012102428518A CN 201210242851 A CN201210242851 A CN 201210242851A CN 102727445 A CN102727445 A CN 102727445A
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- matrine
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- sodium alginate
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Abstract
The invention relates to a sophocarpidine pH/ magnetic dual-sensitive hydrogel globule which is orally administrated and is used for treating digestive cancers and the preparation method of the sophocarpidine pH/ magnetic dual-sensitive hydrogel globule. The preparation method comprises the steps of: adding 0.3 to 0.7 g of CaCl to chitosan acetum; agitating to dissolve CaCl; preparing a 1.5 to 2.5% sodium alginate solution based on the mass to the volume concentration; weighing a proper amount of sophocarpidine and a proper amount of Fe3O4 nanoparticle respectively, and adding to the sodium alginate solution to obtain a suspension containing the sophocarpidine, the Fe3O4 nanoparticle and the sodium alginate; and weighing the suspension containing the sophocarpidine, the Fe3O4 nanoparticle and the sodium alginate, and dropping to the mixed solution of the chitosan and CaCl2 for crosslinking, and then filtering, washing, and then placing and naturally drying at room temperature so as to obtain the sophocarpidine pH/ magnetic dual sensitive hydrogel globule.
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 matrine pH/ magnetic of treatment digestive tract tumor and preparation method thereof.
Background technology
Matrine be from the leguminous plant Radix Sophorae Flavescentis (
Sophora flavescens Ait.), the leguminous plant root of subprostrate sophora (
Sophora subprosstratae) or Herba Sophorae alopecuroidis (
Sophora alopecuroides L.) in a kind of alkaloid of obtaining of extraction separation, belong to the Fourth Ring quinolizidine kind, have notable antitumor activity
[1]Research shows that the mechanism of action of its anti-tumor activity comprises inhibition tumor proliferation, induced tumor differentiation and apoptosis, inhibition is tumor-infiltrated and far-end shifts, ameliorate tumor brings out cachexia and inhibition drug resistance of tumor, inhibition telomerase activation etc.
In addition, matrine also has: calmness, analgesia, analgesic cooling, treatment cardiovascular disease, atherosclerosis, immunosuppressant effect, suppression of autoimmune responses, treatment hepatic disease, multiple pharmacological effect such as antiviral.
The new drug research bibliographical information, the matrine pharmaceutical formulation of listing has suppository, tablet, capsule and injection at present.With regard to present matrine common oral preparation,, need frequent drug administration because self dosage form mostly exists duration of efficacy shorter; And blood concentration fluctuation is bigger; Toxic and side effects and complication are more, and the patient is prone to produce drug resistance and adverse effect, and patient's compliance is low; Drug bioavailability is low, problems such as clinical efficacy difference.
Summary of the invention
The present invention aims to provide a kind of prior art deficiency that overcomes, and oral administration is administered for dual sensitive aqueous gel bead of matrine pH/ magnetic of treatment digestive tract tumor and preparation method thereof.Can prepare the dual sensitive aqueous gel bead of matrine pH/ magnetic by method of the present invention.
Method for preparing of the present invention is: prepare mass/volume concentration at first respectively and be 0.1～0.3% chitosan-acetic acid solution; The CaCl that in chitosan-acetic acid solution, adds 0.3g～0.7g again; Stirring makes the CaCl dissolving; Preparation mass/volume concentration is 1.5%～2.5% sodium alginate soln, takes by weighing the matrine of 1.25g～1.75g and the Fe of 0.05g～0.08g respectively
3O
4Nanoparticle adds among the aforesaid sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing matrine, Fe
3O
4The suspension of nanoparticle and sodium alginate is measured and is contained matrine, Fe
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, after carrying out washing treatment, room temperature is placed natural drying, obtains the dual sensitive aqueous gel bead of matrine pH/ magnetic.
Adopt method of the present invention can prepare the dual sensitive aqueous gel bead of matrine pH/ magnetic.
Preparation of the present invention has pH sensitivity and magnetic targeting property; Can make matrine different pH environment position in digestive tract, press the pH gradient and discharge medicine, and can be under the guiding of externally-applied magnetic field; Realize targeting positioning release medicine characteristic; Reduce adverse effect and toxic and side effects, improve drug bioavailability, strengthen clinical therapeutic efficacy.
In order to achieve the above object, the dual sensitive aqueous gel bead of matrine pH/ magnetic of the present invention is made up of principal agent and pharmaceutic adjuvant.The principal agent matrine plays the anti-alimentary tract tumor effect, and pharmaceutic adjuvant is natural macromolecular material chitosan and sodium alginate, and cross-linking agent is CaCl
2, magnetisable material is Fe
3O
4Nanoparticle, solvent are purified water.
Chitosan among the present invention is a kind of deacetylated product of natural aminopolysaccharide chitin, contains amino group freely.Its source is abundant, cheap, has good biocompatibility and biological degradability; Bioadhesive and film property are good, nontoxic, non-stimulated, no anaphylaxis, environmental friendliness; Free from environmental pollution, be widely used in the fields such as medicine, chemical industry, food and water treatment.
Sodium alginate among the present invention is a kind of natural anionic polymer; Have the good characteristics of bio-compatible and biodegradation; 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 matrine pH/ magnetic and adding under the induced by magnetic field, the 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 matrine pH/ magnetic of the present invention's preparation has the release mechanism of pH sensitivity and the dual sensitivity of magnetic targeting property.At first, utilize its pH sensitivity, make matrine 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 gelled pill contains Fe
3O
4Nanoparticle has good magnetic responsiveness, externally-applied magnetic field capable of using induce performance; The dual sensitive aqueous gel bead of matrine pH/ magnetic orientation is transported to the target area, the medicine location is discharged, thereby realize targeting site-specific delivery of drugs digestive tract tumor; Increase the drug level of matrine, reduce the systemic drug level, reduce poisonous side effect of medicine and untoward reaction at the digestive tract tumor position; Improve drug bioavailability; Reduce drug administration number of times and dosage, strengthen patient's compliance, improve the clinical drug therapeutic effect.
Description of drawings
Fig. 1. the mode of appearance figure of the dual sensitive aqueous gel bead of matrine pH/ magnetic of embodiment 1 gained, among the figure: a figure is the wet dual sensitive aqueous gel bead of matrine pH/ magnetic digital photograph; B figure is the dual sensitive aqueous gel bead of a dry matrine pH/ magnetic digital photograph; C figure is the dual sensitive aqueous gel bead of the matrine pH/ magnetic stereoscan photograph of amplifying 45 multiples; D figure is the dual sensitive aqueous gel bead of the matrine pH/ magnetic stereoscan photograph of amplifying 800 multiples.
Fig. 2. the dual sensitive aqueous gel bead of the matrine pH/ magnetic infrared spectrogram of embodiment 1 gained.
Fig. 3. the X-ray diffraction spectrogram of the dual sensitive aqueous gel bead of matrine pH/ magnetic of embodiment 1 gained.
Fig. 4. the hysteresis graph of the dual sensitive aqueous gel bead of matrine pH/ magnetic of embodiment 1 gained, among the figure: be the dual sensitive aqueous gel bead of matrine pH/ magnetic; Be pure Fe
3O
4Nanoparticle.
Fig. 5. the swellbility figure of the dual sensitive aqueous gel bead of matrine pH/ magnetic in different pH environment of embodiment 1 gained.
Fig. 6. the matrine cumulative release curve chart of the dual sensitive aqueous gel bead of matrine 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
20.5g, add among above-mentioned 0.2% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, subsequent use.CaCl
2Concentration in chitosan solution is 2.5%.
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 matrine 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 matrine, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned matrine, 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 matrine 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
20.5g, add among above-mentioned 0.2% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, subsequent use.CaCl
2Concentration in chitosan solution is 2.5%.
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 matrine 1.25g, Fe respectively
3O
4Nanoparticle 0.05g adds among above-mentioned 1.5% the sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing matrine, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned matrine, 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 matrine 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
20.5g, add among above-mentioned 0.2% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, subsequent use.CaCl
2Concentration in chitosan solution is 2.5%.
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 matrine 1.25g, Fe respectively
3O
4Nanoparticle 0.05g adds among above-mentioned 2.0% the sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing matrine, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned matrine, 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 matrine 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
20.5g, add among above-mentioned 0.2% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, subsequent use.CaCl
2Concentration in chitosan solution is 2.5%.
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 matrine 1.25g, Fe respectively
3O
4Nanoparticle 0.06g adds among above-mentioned 2.5% the sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing matrine, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned matrine, 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 matrine 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
20.5g, add among above-mentioned 0.2% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, subsequent use.CaCl
2Concentration in chitosan solution is 2.5%.
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 matrine 1.25g, Fe respectively
3O
4Nanoparticle 0.08g adds among above-mentioned 2.5% the sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing matrine, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned matrine, 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 matrine pH/ magnetic.
Embodiment 6:
1) take by weighing chitosan 0.02g, evenly be sprinkled among 1% the acetum 20ml, placement is spent the night, and is stirred to dissolving fully, obtains concentration and be 0.1% chitosan solution, and is subsequent use.
2) take by weighing CaCl
20.5g, add among above-mentioned 0.1% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, subsequent use.CaCl
2Concentration in chitosan solution is 2.5%.
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 matrine 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 matrine, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned matrine, 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 matrine pH/ magnetic.
Embodiment 7:
1) take by weighing chitosan 0.06g, 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
20.5g, add among above-mentioned 0.3% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, subsequent use.CaCl
2Concentration in chitosan solution is 2.5%.
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 matrine 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 matrine, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned matrine, 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 matrine pH/ magnetic.
Embodiment 8:
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 the above-mentioned 0.2% chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, subsequent use.CaCl
2Concentration in chitosan solution is 1.5%.
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 matrine 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 matrine, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned matrine, 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 matrine pH/ magnetic.
Embodiment 9:
1) get 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, subsequent use.CaCl
2Concentration in chitosan solution is 3.5%.
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 matrine 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 matrine, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned matrine, 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 matrine 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
20.5g, add among above-mentioned 0.2% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, subsequent use.CaCl
2Concentration in chitosan solution is 2.5%.
3) take by weighing sodium alginate 0.25g, evenly be sprinkled in the 10ml purified water, placement is spent the night, and stirs to make dissolving fully, obtains concentration and be 2.5% sodium alginate soln, and is subsequent use.
4) take by weighing matrine 1.50g, 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 matrine, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned matrine, 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 matrine 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
20.5g, add among above-mentioned 0.2% the chitosan solution 20ml, stir and make dissolving, obtain chitosan and CaCl
2Mixed solution, subsequent use.CaCl
2Concentration in chitosan solution is 2.5%.
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 matrine 1.75g, 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 matrine, Fe
3O
4The suspension of nanoparticle and sodium alginate, subsequent use.
5) measure above-mentioned matrine, 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 matrine pH/ magnetic.
The mode of appearance of the dual sensitive aqueous gel bead of matrine pH/ magnetic is observed:
It is an amount of to take by weighing the wet dual sensitive aqueous gel bead of matrine pH/ magnetic with dried embodiment 1 gained respectively, 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 matrine pH/ magnetic.Before the observation, all samples need metal spraying to handle, and the control accelerating potential is 30 kV, and amplification is 40 and 800 times.As can beappreciated from fig. 1, the wet dual sensitive aqueous gel bead of matrine pH/ magnetic is spherical in shape, and sepia, form be rule, and smooth surface, average diameter are 2.5 ~ 4.0mm (a); Room temperature still keeps its spherical morphology after placing natural drying, but volume-diminished, diameter is about 2mm (b).(c d) can find out, and is still spherical in shape, and form is rule, and the surface becomes comparatively coarse to this gelled pill because dry back gel network structure dewaters, and has hole ditch and fold by Fig. 1 SEM picture.
The infrared spectrum analysis of the dual sensitive aqueous gel bead of matrine pH/ magnetic:
Dual sensitive aqueous gel bead of blank pH/ magnetic and the dual sensitive aqueous gel bead of matrine pH/ magnetic of take by weighing chitosan, sodium alginate, matrine respectively, executing routine 1 gained are an amount of; 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.Be placed in the sample light path of infrared spectrometer; Record infrared spectrogram; Compare the infrared spectrogram of chitosan, sodium alginate, matrine, the dual sensitive aqueous gel bead of blank pH/ magnetic and the dual sensitive aqueous gel bead of matrine pH/ magnetic, the result sees Fig. 2.Visible by Fig. 2, the characteristic absorption peak of chitosan is positioned at 3444,2877,1655,1598,1095 and 1033cm
-1The place.The characteristic absorption peak of sodium alginate is positioned at 1626,1427 and 1029cm
-1The place.In the infrared spectrum of the dual sensitive aqueous gel bead of blank pH/ magnetic, the characteristic absorption peak 1419,1087 and the 1032cm of chitosan and sodium alginate
-1Still exist, explain in the hydrogel bead for preparing and contain spectral studies.In the matrine infrared spectrogram, characteristic absorption peak is positioned at 2929,1651,1440,1338,1252cm
-1The place.In the infrared spectrogram of the dual sensitive aqueous gel bead of matrine pH/ magnetic, the characteristic absorption peak of matrine occurred, explained that matrine successfully is written in the dual sensitive aqueous gel bead of the matrine pH/ magnetic network structure.
The X-diffraction analysis of the dual sensitive aqueous gel bead of matrine pH/ magnetic:
Take by weighing chitosan, sodium alginate, matrine, Fe respectively
3O
4Nanoparticle, dual sensitive aqueous gel bead of blank pH/ magnetic and the dual sensitive aqueous gel bead of matrine pH/ magnetic of executing routine 1 gained are an amount of, put in the agate mortar to grind, and go up machine testing after evenly spreading cloth, relatively chitosan, sodium alginate, matrine, Fe
3O
4The crystal form of nanoparticle, the dual sensitive aqueous gel bead of blank pH/ magnetic and the dual sensitive aqueous gel bead of matrine pH/ magnetic, selecting the scope of scanning angle 2 θ is 10 ° ~ 90 °, the result sees Fig. 3.Visible by Fig. 3; The dual sensitive aqueous gel bead of matrine pH/ magnetic; The diffraction maximum position of the position of its main diffraction maximum and the dual sensitive aqueous gel bead of blank pH/ magnetic is in full accord; The part diffraction maximum of matrine disappears; And change has taken place in residual part matrine diffraction peak intensity, shows that most of matrine successfully is written in the dual sensitive aqueous gel bead of the matrine pH/ magnetic network structure, has only a small amount of matrine possibly be attached on the dual sensitive aqueous gel bead of matrine pH/ magnetic surface.
The magnetic property of the dual sensitive aqueous gel bead of matrine pH/ magnetic is measured:
Take by weighing Fe respectively
3O
4Nanoparticle and to execute the dual sensitive aqueous gel bead of the matrine pH/ magnetic powder of routine 1 gained an amount of, in room temperature condition down with vibrating specimen magnetometer (VSM) mensuration Fe
3O
4The B-H loop of nanoparticle and the dual sensitive aqueous gel bead of matrine pH/ magnetic is investigated the magnetic response characteristic of this gelled pill.The result shows Fe
3O
4Nanoparticle 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 matrine pH/ magnetic is about 4emu/g, and coercivity is zero, and this character can make the magnetic gel bead can not produce gathering in vivo, after magnetic field disappears, can disperse again fast again.The result sees Fig. 4.Hence one can see that, when the dual sensitive aqueous gel bead of the matrine pH/ magnetic administered through oral administration of executing routine 1 gained, during the approach gastrointestinal tract environment; Its drug release behavior can be under the guiding of gastrointestinal tract externally-applied magnetic field; Be positioned the tumor target area, performance location release action is concentrated in lesions position medicine; Reduced the Chinese medicine concentration of other normal structures, reduced infringement normal structure.Thereby can effectively bring into play the magnetic susceptibility medicine controlled releasing effect of this gelled pill, improve drug bioavailability, strengthen clinical therapeutic efficacy, also can reduce the anti-and complication of adverse drug simultaneously, reduce poisonous side effect of medicine, improve the compliance that the patient takes medicine.
The swellability test of the dual sensitive aqueous gel bead of matrine pH/ magnetic:
Precision takes by weighing the dual sensitive aqueous gel bead of the matrine pH/ magnetic 10mg that executes routine 1 gained; Immerse respectively in the serial PBS of simulated gastric fluid hydrochloric acid solution and pH 2.5, pH 5.0, pH 6.8, pH 7.4 and pH 8.0 of 10ml pH1.5; The swelling medium temperature is 37 ± 0.5 ° of C; Take out at preset time; Weigh after blotting the bead surface moisture with filter paper, calculate the swellbility (SR) of bead, investigate the swelling behavior of the matrine dual sensitive aqueous gel bead of pH/ magnetic in the PBS environment 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 matrine pH/ magnetic swelling, W
0Be the quality (g) before the dual sensitive aqueous gel bead of the dry matrine pH/ magnetic swelling.The result shows that the dual sensitive aqueous gel bead of matrine pH/ magnetic swellbility in different pH value environment has evident difference.This gelled pill swelling hardly in pH1.5 and pH2.5 phosphate buffer; PH6.8, pH8.0 alkalescence buffer solution in, show sensitivity preferably, reach the maximum swelling degree in the time of 90 minutes, be respectively 24.0 and 22.6.Surpass after 90 minutes, bead begins to break gradually, and swelling curve has a declining tendency in the drawings.Above result shows that the dual sensitive aqueous gel bead of matrine pH/ magnetic is difficult for swelling and breaks under simulated gastric fluid pH value condition; Be unfavorable for drug release; And have good swellability in small intestinal, colon position, and help drug release, have tangible pH sensitivity; Be that the low more swellbility of environment pH is more little, environment pH high swelling degree more is big more.The result sees Fig. 5.
The release behavior test of the dual sensitive aqueous gel bead of matrine pH/ magnetic in different pH environment:
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 the dual sensitive aqueous gel bead of the matrine pH/ magnetic 50mg that executes routine 1 gained; The accurate title, decide; Different pH value PBS 500ml with pH2.5, pH5.0, pH6.8, pH7.4, pH8.0 are dissolution medium respectively, and the control rotating speed is that per minute 100 changes, and temperature is 37.0 ± 0.5
oC measured, in 0.5,1,2,4,8,12,18,24 hour in accordance with the law; The precision of fixing a point is respectively measured release medium 1ml, and replenishes 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, the accumulative total release profiles drawn according to measuring the result.Chromatographic condition is: be filler with the octadecylsilane chemically bonded silica, methanol: 0.1% phosphate aqueous solution (70:30, it is 6.0 that triethylamine is transferred pH) is mobile phase, and the detection wavelength is 220nm, and flow velocity is 1.0ml/min, and column temperature is 30
oC, sample size are 5 μ l, and theoretical cam curve is not less than 2000 by the matrine peak.Drug accumulation release degree (%)=[R
t/ L] * 100, wherein, Rt representes the medicine accumulative total burst size in the t time, L representes the medicine total amount that is written at first.Fig. 6 is the cumulative release curve of the dual sensitive aqueous gel bead of matrine pH/ magnetic in different pH environment.As shown in the figure, the release behavior of matrine in the phosphate buffer of different pH value has notable difference.The release amount is lower in the acid solution of pH2.5, discharges approximately 26% in 2 hours, and drug release is slower behind this time point, only discharges 34.90% in 8 hours; And the release amount is bigger in the weakly alkaline solution of pH6.8, discharged about 77% in 2 hours, and release is very fast, and release in 8 hours reaches 97.11%.Above result shows that this gelled pill has tangible pH sensitivity, and this is also consistent with the swelling experimental result, and promptly environment pH is low more, and drug release is few more, and environment pH is high more, and drug release is many more.The result sees Fig. 6.Hence one can see that, and when the dual sensitive aqueous gel bead of the matrine pH/ magnetic administered through oral administration of executing routine 1 gained, during the approach gastrointestinal tract environment, its drug release behavior can be with gastrointestinal tract pH graded, and produces the different drug burst size.Be that environment pH is low more, the gelled pill swelling is more little, and drug release is just few more; Environment pH is high more, and the gelled pill swelling is big more, and drug release is just many more.Thereby can
Effectively the pH sensitive drug controlled-release function of this gelled pill of performance improves drug bioavailability, strengthens clinical therapeutic efficacy, also can reduce the anti-and complication of adverse drug simultaneously, reduces poisonous side effect of medicine, improves the compliance that the patient takes medicine.
The dual sensitive aqueous gel bead of matrine pH/ magnetic release dynamics:
Adopt the peppas equation that the releasing mechanism of the dual sensitive aqueous gel bead of matrine pH/ magnetic of executing routine 1 gained 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.This hydrogel bead release degree in the pH2.5 environment is less, and the release degree is bigger in the environment of pH5.0 ~ 8.0, and the releasing mechanism of matrine from the hydrogel bead is the Fick diffusion.The result sees table 1.
The releasing mechanism of the dual sensitive aqueous gel bead of table 1 matrine pH/ magnetic in different pH environment
PH n k * 10 r releases mechanism
2.5 0.2475 2.2951 0.9303 Fick diffusion
5.0 0.2727 4.5814 0.9977 Fick diffusion
6.8 0.1129 7.2728 0.9906 Fick diffusion
7.4 0.0907 7.8127 0.9894 Fick diffusion
8.0 0.1126 7.2210 0.9836 Fick diffusion.
Claims (2)
1. the method for preparing of the dual sensitive aqueous gel bead of matrine pH/ magnetic; It is characterized in that: prepare mass/volume concentration at first respectively and be 0.1～0.3% chitosan-acetic acid solution; The CaCl that in chitosan-acetic acid solution, adds 0.3g～0.7g again; Stirring makes the CaCl dissolving, and preparation mass/volume concentration is 1.5%～2.5% sodium alginate soln, takes by weighing the matrine of 1.25g～1.75g and the Fe of 0.05g～0.08g respectively
3O
4Nanoparticle adds among the aforesaid sodium alginate soln 10ml, and supersound process 30 minutes stirs, and obtains containing matrine, Fe
3O
4The suspension of nanoparticle and sodium alginate is measured and is contained matrine, Fe
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, after carrying out washing treatment, room temperature is placed natural drying, obtains the dual sensitive aqueous gel bead of matrine pH/ magnetic.
2. the dual sensitive aqueous gel bead of matrine pH/ magnetic of the described method of claim 1 preparation.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113040937A (en) * | 2021-03-10 | 2021-06-29 | 西安交通大学医学院第一附属医院 | Magnetic tracer for palpation negative breast nodule marking and positioning |
| CN113143537A (en) * | 2021-04-12 | 2021-07-23 | 西安交通大学医学院第一附属医院 | Magnetic control device for treating female stress urinary incontinence |
| CN113413881A (en) * | 2021-06-17 | 2021-09-21 | 兰州大学 | BWO/Fe3O4Preparation method and application of @ cBC chitosan gel beads |
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2012
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113040937A (en) * | 2021-03-10 | 2021-06-29 | 西安交通大学医学院第一附属医院 | Magnetic tracer for palpation negative breast nodule marking and positioning |
| CN113143537A (en) * | 2021-04-12 | 2021-07-23 | 西安交通大学医学院第一附属医院 | Magnetic control device for treating female stress urinary incontinence |
| CN113413881A (en) * | 2021-06-17 | 2021-09-21 | 兰州大学 | BWO/Fe3O4Preparation method and application of @ cBC chitosan gel beads |
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