CN110934826A - Preparation method of silymarin chitosan polymer micelle - Google Patents
Preparation method of silymarin chitosan polymer micelle Download PDFInfo
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- CN110934826A CN110934826A CN201910830661.XA CN201910830661A CN110934826A CN 110934826 A CN110934826 A CN 110934826A CN 201910830661 A CN201910830661 A CN 201910830661A CN 110934826 A CN110934826 A CN 110934826A
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Abstract
The invention discloses a method for preparing silymarin chitosan polymer micelle, which comprises the steps of firstly preparing pH sensitive water-soluble chitosan blank micelle by reacting chitosan, dimethyl sulfoxide and hexahydrophthalic anhydride; preparing the silymarin chitosan polymer micelle with silymarin, and encapsulating silymarin by using pH-sensitive water-soluble chitosan blank micelle, thereby effectively improving the water solubility of silymarin and solving the problem that the fat-soluble characteristic of silymarin is difficult to exert the anti-tumor effect; effectively enhances the anti-tumor property of the silymarin, and improves the bioavailability of the silymarin and the quality stability of a silymarin drug product.
Description
Technical Field
The invention relates to the field of preparation of chitosan polymer micelle, in particular to a preparation method of silymarin chitosan polymer micelle.
Background
Silymarin (Sillyurin) is a flavonolignan component prepared by condensing dihydroflavonol extracted from fruits and seeds of Silybum marianum (L) Gaenrt) which is a herb of Compositae and a phenylpropanoid derivative, and silymarin (trade names of Ligalon, Yiganling and Millk Thistle and the like) which is currently used in preparations internationally mainly contains four isomers of silybin, isosilybin, silychristin, Silibinin and Silibinin, wherein Silibinin has the highest content, has the effects of protecting liver, resisting oxidation and resisting tumors, but silymarin is a fat-soluble substance for a long time, has low bioavailability and has no obvious clinical anti-tumor effect. If the silymarin can be subjected to drug loading treatment, the water solubility of the silymarin is increased on the premise of keeping the anti-tumor efficacy, the anti-tumor property of the silymarin can be greatly enhanced, and the bioavailability of the silymarin and the quality stability of a silymarin product are improved.
Chitosan is popular as a medical high polymer material, and the entrapment of insoluble drugs by taking chitosan and derivatives thereof as carriers is a hotspot in the field of chitosan research at present. However, the application of chitosan is greatly limited due to high crystallinity and poor water solubility of chitosan. Therefore, the chitosan is modified to improve the water solubility of the chitosan, and the modified novel chitosan derivative is used as a drug carrier, so that the chitosan modified chitosan derivative provides a new drug delivery mode for insoluble drugs and has wide application prospects.
Disclosure of Invention
The purpose of the invention is as follows: in order to overcome the defects in the prior art, the invention provides a preparation method of silymarin chitosan polymer micelle, and the prepared drug-loaded micelle entraps silymarin, improves the water solubility of the silymarin, and enhances the anti-tumor property of the silymarin.
The technical scheme is as follows: in order to solve the technical problems, the technical scheme adopted by the invention is as follows: a method for preparing silymarin chitosan polymer micelle comprises the following steps:
1) preparing a pH sensitive water-soluble chitosan blank micelle: dissolving 15-20 g of chitosan in 30-40 g of dimethyl sulfoxide, and swelling for 1.5-2.5 h; stirring at room temperature, and adding 1-2 mmol hexahydrophthalic anhydride; heating to 70-80 ℃ and reacting for 20-26 h; after the reaction is finished, pouring 50-60 mL of water into the reaction solution, dropwise adding NaOH solution under the condition of ice-water bath until the pH of the reaction solution is 8-10, filtering to remove precipitates, dialyzing the obtained filtrate for 5-10 days, and performing freeze-drying operation to obtain a white flocculent solid product which is a pH-sensitive water-soluble chitosan blank micelle;
2) preparation of pH sensitive silymarin chitosan polymer micelle: dissolving the pH-sensitive water-soluble chitosan blank micelle prepared in the step 1) with the weight 5-10 times that of the silymarin into distilled water with the weight 1-5 times that of the silymarin, and stirring at room temperature for 1.5-2.5 h to obtain a solution A for later use; dissolving silymarin in 80% ethanol 2-5 times the weight of silymarin to obtain a solution B, dropwise adding the solution B into the solution A while stirring, dialyzing for 5-10 h, and filtering the formed micelle solution through a microporous filter membrane to finally obtain a pH-sensitive silymarin chitosan polymer micelle finished product.
Furthermore, the mass concentration of the sodium hydroxide solution dripped in the step 1) is 15-25%.
Further, the filtration mode in the step 1) is suction filtration.
Furthermore, the dialysis in the step 1) is carried out through a dialysis bag with the cut-off molecular weight of 8000-10000.
Furthermore, the dialysis in the step 2) is carried out through a dialysis bag with the cut-off molecular weight of 10000-14000.
Furthermore, the specification of the microporous filter membrane in the step 2) is 0.45-0.55 μm.
The principle of the silymarin chitosan polymer micelle for enhancing the anti-tumor effect is as follows: the pH value of the tumor cells is 5-6 under normal conditions, the chitosan is kept stable in the normal physiological environment (pH7.4) in the pH-sensitive polymer micelle carrying the medicine, when the condition that the tumor cells exist (the pH value is 5-6) and the pH value is obviously lower than that of the normal cells is reached, the micelle structure is destroyed, and the medicine is also released rapidly; thus, a large amount of silymarin can be released on tumor cells, so that the anti-tumor property of silymarin can be greatly enhanced, and the bioavailability of silymarin and the quality stability of silymarin products are improved.
Has the advantages that: the invention has the following advantages: (1) silymarin is entrapped by the pH sensitive water-soluble chitosan blank micelle, so that the water solubility of silymarin is effectively improved, and the problem that the anti-tumor effect is difficult to exert due to the fat-soluble characteristic of silymarin is solved; (2) effectively enhances the anti-tumor property of the silymarin, and improves the bioavailability of the silymarin and the quality stability of a silymarin drug product.
Drawings
FIG. 1 is a schematic representation of the infrared spectroscopic analysis of a product prepared in accordance with the present invention: wherein (1-a) is a pH-sensitive water-soluble chitosan blank micelle infrared spectroscopic analysis diagram, and (1-b) is a pH-sensitive silymarin chitosan polymer micelle finished product infrared spectroscopic analysis diagram;
FIG. 2 is a photograph showing the water solubility of the water-soluble chitosan blank micelle prepared by the present invention;
FIG. 3 is a photograph showing the water solubility of water-soluble chitosan blank micelles under various pH conditions;
fig. 4 is a graph showing the trend of the particle size and light transmittance of the water-soluble chitosan blank micelle under various pH conditions.
Detailed Description
The present invention will be described in further detail with reference to the following examples:
the sources of drug drugs used in the examples are as follows:
30 silymarin (HPLC content 80%, Jiangsu Zhongxing pharmaceutical Co., Ltd.)
Chitosan (deacetylation degree of 85% or more, national chemical group Co., Ltd.)
Dimethyl sulfoxide (DMSO)
Hexahydrophthalic anhydride (HHPA, Shanghai Aladdin Biochemical Co., Ltd.)
Dialysis bag (Shanghai golden ear biotechnology limited)
Infrared instrument (UV-1800, Nanjing Mei Banda Instrument Co., Ltd.)
Example 1:
a method for preparing silymarin chitosan polymer micelle comprises the following steps:
1) preparing a pH sensitive water-soluble chitosan blank micelle: dissolving 15g of chitosan in 30g of dimethyl sulfoxide (DMSO), and swelling for 1.5 h; stirring at room temperature, and adding 1mmol hexahydrophthalic anhydride; heating to 70 ℃ for reaction for 20h, pouring 50mL of water into the reaction solution after the reaction is finished, then dropwise adding 15% (mass concentration) NaOH solution under the condition of ice-water bath until the pH of the reaction solution is 8, removing precipitates by suction filtration, dialyzing the obtained filtrate for 5d by a dialysis bag (molecular weight cut-off: 8000), and finally performing freeze-drying operation to obtain a white flocculent solid product which is a pH-sensitive water-soluble chitosan blank micelle;
2) preparation of pH sensitive silymarin chitosan polymer micelle: dissolving pH sensitive water soluble chitosan blank micelle 5 times the weight of silymarin in distilled water 1 times the weight of silymarin, and stirring at room temperature for 1.5h to obtain solution A;
dissolving silymarin in 80% ethanol 2 times the weight of silymarin to obtain solution B, adding dropwise the solution B into the solution A while stirring, dialyzing distilled water for 5h in dialysis bag (molecular weight cut-off: 10000), and filtering the formed micelle solution with 0.45 μm microporous membrane to remove residual drug to obtain pH sensitive silymarin chitosan micelle.
Example 2:
a method for preparing silymarin chitosan polymer micelle comprises the following steps:
1) preparing a pH sensitive water-soluble chitosan blank micelle: dissolving 17g of chitosan in 34g of dimethyl sulfoxide (DMSO), and swelling for 2.0 h; stirring at room temperature, and adding 1.5mmol hexahydrophthalic anhydride; heating to 75 ℃ for reaction for 24 hours, pouring 55mL of water into the reaction solution after the reaction is finished, then dropwise adding the poured 55mL of water under the condition of ice-water bath, then dropwise adding 17% (mass concentration) of NaOH solution under the condition of ice-water bath until the pH of the reaction solution is 9, removing precipitates by suction filtration, dialyzing the obtained filtrate for 7 days by a dialysis bag (cut-off molecular weight: 10000), and finally performing freeze-drying operation to obtain a white flocculent solid product which is a pH-sensitive water-soluble chitosan blank micelle;
2) preparation of pH sensitive silymarin chitosan polymer micelle: dissolving the pH sensitive water-soluble chitosan blank micelle 7 times the weight of the silymarin in distilled water 3 times the weight of the silymarin, and stirring at room temperature for 2.0h to obtain a solution A;
dissolving silymarin in 80% ethanol 5 times the weight of silymarin to obtain solution B, adding dropwise the solution B into the solution A while stirring, dialyzing distilled water in a dialysis bag (cut-off molecular weight: 12000) for 10h, and filtering the formed micelle solution with a 0.50 μm microporous membrane to remove residual drug to obtain pH sensitive silymarin chitosan micelle.
Example 3:
a method for preparing silymarin chitosan polymer micelle comprises the following steps:
1) preparing a pH sensitive water-soluble chitosan blank micelle: dissolving 20g of chitosan in 40g of dimethyl sulfoxide (DMSO), and swelling for 2.5 h; stirring at room temperature, and adding 2.0mmol hexahydrophthalic anhydride; heating to 80 ℃ for reaction for 26h, pouring 60mL of water into the reaction solution after the reaction is finished, then dropwise adding the poured 60mL of water under the condition of ice-water bath, then dropwise adding 20% (mass concentration) NaOH solution under the condition of ice-water bath until the pH of the reaction solution is 10, removing precipitates by suction filtration, dialyzing the obtained filtrate for 10d by a dialysis bag (cut-off molecular weight: 14000), and finally performing freeze-drying operation to obtain a white flocculent solid product which is a pH-sensitive water-soluble chitosan blank micelle;
2) preparation of pH sensitive silymarin chitosan polymer micelle: dissolving pH sensitive water soluble chitosan blank micelle 10 times the weight of silymarin in distilled water 5 times the weight of silymarin, and stirring at room temperature for 2.5h to obtain solution A;
dissolving silymarin in 80% ethanol 5 times the weight of silymarin to obtain solution B, adding dropwise the solution B into the solution A while stirring, dialyzing distilled water in dialysis bag (molecular weight cutoff: 14000) for 10 hr, and filtering the formed micelle solution with 0.55 μm microporous membrane to remove residual drug to obtain pH sensitive silymarin chitosan micelle.
Testing of finished products:
firstly, analyzing pH sensitivity of chitosan blank micelle:
the white flocculent solid product prepared by the method of the step (1) in the embodiment 2 is fully dissolved in water to prepare a proper amount of water-soluble chitosan blank micelle solution with the concentration of 10mg/mL, as shown in figure 2, the blank micelle treated by the method is completely dissolved in the water, is clear and transparent, and completely meets the water-solubility requirement.
1mL of the above water-soluble chitosan blank micelle solution was added dropwise to 8mL of phosphate buffer solution having pH of 7.4, 7.0, 6.5, 6.0, 5.5, 5.0, 4.5, respectively, and then the transmittance at 500nm was measured by an ultraviolet spectrophotometer, and the pH sensitivity of the water-soluble chitosan blank micelle was observed by the transmittance.
As shown in fig. 3 and 4, it can be seen from the clear state of micelles in the multiple pH environments of fig. 3 that the solution is clear and transparent at pH 5.5 in each pH environment; the water-soluble chitosan blank micelle prepared by the method can be quickly dissolved when the pH value is 5.5.
As can be seen from fig. 4, the transmittance of the blank micelle in the buffer solution with pH 5.5 decreases rapidly, while the particle size of the micelle solution gradually increases with decreasing pH, and at pH 5.5, the particle size increases significantly, which is consistent with the results obtained from the subsequent transmittance test.
From the analysis results, the water solubility of the modified chitosan blank micelle prepared by the method is greatly improved.
Secondly, analyzing the stability of the medicine:
the pH-sensitive water-soluble chitosan blank micelle prepared in the step 1) of the example 2 and the pH-sensitive silymarin chitosan polymer micelle finished product prepared in the step 2) are subjected to infrared spectrum analysis, and the analysis conditions are as follows: an appropriate amount of 10mg/mL water-soluble chitosan blank micelle solution is prepared, 1mL of the water-soluble chitosan blank micelle solution is respectively added dropwise into phosphate buffer solutions with the pH values of 8mL and 7.4, 7.0, 6.5, 6.0, 5.5, 5.0 and 4.5, and then the light transmittance of the water-soluble chitosan blank micelle solution at 500nm is measured by an ultraviolet spectrophotometer, and the light transmittance is obviously increased when the pH value reaches 5.5. The silymarin chitosan polymer micelle is detected by the same method, and the peak value difference is found to be small.
The results of the analysis are shown in FIG. 1: wherein (1-a) is a pH-sensitive water-soluble chitosan blank micelle infrared spectroscopic analysis diagram, and (1-b) is a pH-sensitive silymarin chitosan polymer micelle finished product infrared spectroscopic analysis diagram; the comparison of the two infrared spectrograms shows that the chitosan micelle after carrying the medicine has the medicine stability. The peak value does not vary much.
Thirdly, analyzing anti-tumor characteristics:
due to the abnormal proliferation and metabolism of tumor cells, oxygen supply at the tumor site is insufficient, so that a large amount of ATP hydrolysate and lactic acid generated by the metabolism of the tumor cells are accumulated at the tumor site. The tumor tissue is generally in a slightly acidic environment. The pH sensitive polymer micelle introduces pH sensitive chemical bonds such as amide groups, hydrazone bonds, ester bonds and the like to a block copolymer of the polymer micelle, or directly connects medicines by using the pH sensitive chemical bonds, thereby achieving the aim of site-specific administration. The pH sensitive polymer micelle carrying the medicine is kept stable in a normal physiological environment (pH7.4), and when the pH is obviously lower than that of a normal cell when a tumor (pH5-6) is reached, the micelle structure is destroyed, and the medicine is rapidly released. Therefore, when the silymarin chitosan polymer micelle prepared in the embodiment 1-3 of the invention reaches the condition that tumor cells exist (pH is 5-6), and the pH is obviously lower than that of the normal cell environment, the micelle structure is destroyed, and the drug is also released rapidly; thus, a large amount of silymarin can be released on tumor cells, so that the anti-tumor property of silymarin can be greatly enhanced, and the bioavailability of silymarin and the quality stability of silymarin products are improved.
Claims (6)
1. A method for preparing silymarin chitosan polymer micelle is characterized by comprising the following steps:
1) preparing a pH sensitive water-soluble chitosan blank micelle: dissolving 15-20 g of chitosan in 30-40 g of dimethyl sulfoxide, and swelling for 1.5-2.5 h; stirring at room temperature, and adding 1-2 mmol hexahydrophthalic anhydride; heating to 70-80 ℃ and reacting for 20-26 h; after the reaction is finished, pouring 50-60 mL of water into the reaction solution, dropwise adding NaOH solution under the condition of ice-water bath until the pH of the reaction solution is 8-10, filtering to remove precipitates, dialyzing the obtained filtrate for 5-10 days, and performing freeze-drying operation to obtain a white flocculent solid product which is a pH-sensitive water-soluble chitosan blank micelle;
2) preparation of pH sensitive silymarin chitosan polymer micelle: dissolving the pH-sensitive water-soluble chitosan blank micelle prepared in the step 1) with the weight 5-10 times that of the silymarin into distilled water with the weight 1-5 times that of the silymarin, and stirring at room temperature for 1.5-2.5 h to obtain a solution A for later use; dissolving silymarin in 80% ethanol 2-5 times the weight of silymarin to obtain a solution B, dropwise adding the solution B into the solution A while stirring, dialyzing for 5-10 h, and filtering the formed micelle solution through a microporous filter membrane to finally obtain a pH-sensitive silymarin chitosan polymer micelle finished product.
2. The method for preparing silymarin chitosan polymeric micelle as claimed in claim 1, wherein: the mass concentration of the sodium hydroxide solution dripped in the step 1) is 15-25%.
3. The method for preparing silymarin chitosan polymeric micelle as claimed in claim 1, wherein: the filtration mode in the step 1) is suction filtration.
4. A method for preparing silymarin chitosan polymeric micelle as in claim 1, characterized in that: the dialysis in the step 1) is carried out through a dialysis bag with the cut-off molecular weight of 8000-10000.
5. The method for preparing silymarin chitosan polymeric micelle as claimed in claim 1, wherein: the dialysis in the step 2) is carried out by a dialysis bag with the cut-off molecular weight of 10000-.
6. The method for preparing silymarin chitosan polymeric micelle as claimed in claim 1, wherein: the specification of the microporous filter membrane in the step 2) is 0.45-0.55 μm.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040138152A1 (en) * | 2001-08-18 | 2004-07-15 | Kwon Ick Chan | Anticancer drug-chitosan complex forming self-aggregates and preparation method thereof |
| CN101831005A (en) * | 2010-04-27 | 2010-09-15 | 中国药科大学 | PH sensitive type chitosan derivant and application thereof in pharmaceutics |
| CN106420611A (en) * | 2016-11-11 | 2017-02-22 | 天津城建大学 | PH-sensitive chitosan drug-carrying micelle with targeting and fluorescent characteristics and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040138152A1 (en) * | 2001-08-18 | 2004-07-15 | Kwon Ick Chan | Anticancer drug-chitosan complex forming self-aggregates and preparation method thereof |
| CN101831005A (en) * | 2010-04-27 | 2010-09-15 | 中国药科大学 | PH sensitive type chitosan derivant and application thereof in pharmaceutics |
| CN106420611A (en) * | 2016-11-11 | 2017-02-22 | 天津城建大学 | PH-sensitive chitosan drug-carrying micelle with targeting and fluorescent characteristics and preparation method thereof |
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Application publication date: 20200331 |