CN102813938A - Llex A-cyclodextrin polymer medicine composition for preventing and curing atherosclerosis and preparation method thereof - Google Patents
Llex A-cyclodextrin polymer medicine composition for preventing and curing atherosclerosis and preparation method thereof Download PDFInfo
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- CN102813938A CN102813938A CN2012103420119A CN201210342011A CN102813938A CN 102813938 A CN102813938 A CN 102813938A CN 2012103420119 A CN2012103420119 A CN 2012103420119A CN 201210342011 A CN201210342011 A CN 201210342011A CN 102813938 A CN102813938 A CN 102813938A
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- cyclodextrin polymer
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Abstract
The invention provides a novel llex A-cyclodextrin polymer (llex A-CDP) medicine composition for preventing and curing atherosclerosis (AS) and in particular relates to a preparation method of the novel water-soluble llex A-CDP medicine composition which takes CDP as the host molecule and llex A as the guest molecule. The invention obviously enhance the water-solubility of llex A and has regulating effect for dyslipidemia related to AS and inbibitional effect for inflammatory cell factor in vessel atheromatous plaque. The preparation method comprises the following steps: cyclodextrin polymer is taken as the raw material and is crosslinked with epoxy chloropropane under the condition of strong basicity to generate cyclodextrin polymer; the cyclodextrin polymer is taken as the host molecule, the llex A is taken as the guest molecule and water is taken as the reaction solvent to prepare the water-soluble llex A-CDP medicine composition by supermolecular reaction.
Description
Technical field
The invention belongs to the preparation of supermolecule technical field water solublity organic material; It is host molecule that special design relates to the cyclodextrin polymer clathrate; Ilicin A is that the method for preparing and the atherosclerosis thereof of the new type water-solubility ilicin A/ cyclodextrin polymer clathrate (IlexA-CDP) of guest molecule used, and this IlexA-CDP can produce the effect that prevention atheromatous plaque deposition is prevented and treated atherosclerosis (AS) through blood lipid regulation, inflammation-inhibiting cytokine.
Background technology
The inflammation immunity of AS and oxidative damage mechanism think that AS shows the high oxidation stress state; With blood vessel wall inner lipid deposition and lipoprotein oxidation is characteristic; The oxidized formation oxidized low-density lipoprotein of low density lipoprotein, LDL (LDL) (ox-LDL); The macrophage scavenger receptor is engulfed ox-LDL and is caused vicious cycle such as foam cell formation, quickens the incidence and development of AS.Ilicin A is a kind of monomeric compound that mainly is present in the plant Folium Ilicis hainanensis; Water insoluble; Become water-soluble substances IlexA-CDP through preparation; Can significantly alleviate the vascular inflammation reaction and the inflammatory cytokine secretion of mice AS model, regulate lipid metabolic disorder, alleviate the calm course of disease progress of preventing or significantly delaying AS of AS speckle.Known ilicin A tool is transferred the fat effect, but water insoluble because of it, influences bioavailability, biological activity and becomes the property of medicine.Based on cyclodextrin (CDP) is one type of super molecular compound of cyclodextrin molecular being gone into macromolecular structure with chemical bonding or physics compounding method group; It is the beta cyclodextrin (product that β-CD) obtains with the branching chain extending reaction of epoxychloropropane; At present; After small-molecule drug and this base polymer is compound, can realize increasing medicine dissolubility, improve its stability, improve biological activity, reduce toxic and side effects, improve functions such as pharmacokinetics characteristic.But because there is very big-difference in the different pharmaceutical structure, so can certain concrete medicine by enclose, and whether water solublity can improve behind the enclose, can clathrate be realized the drug effect identical with principal agent? These all can't be expected; Remaining further, research solves.
Summary of the invention
The objective of the invention is to prepare the pharmaceutical composition of a kind of water miscible control AS.
The pharmaceutical composition of the said control of the present invention AS is a kind of water miscible ilicin A/ cyclodextrin polymer clathrate (IlexA-CDP).
Described water miscible ilicin A/ cyclodextrin polymer clathrate (IlexA-CDP) is to be host molecule with the cyclodextrin polymer, and ilicin A is a guest molecule, and water is reaction dissolvent, and the generation supermolecule reacts and obtains.
Wherein said cyclodextrin polymer synthetic, the present invention recommend to use cyclodextrin under strong alkaline condition and epoxychloropropane crosslinked generation cyclodextrin polymer takes place.
As a concrete scheme, step is following:
(1) cyclodextrin polymer is synthetic
Sodium hydroxide 20g, cyclodextrin 25g and water 40mL stirring at normal temperature to solid are all dissolved, then add epoxychloropropane 1mL, stirring at room 24h; Question response finishes, and solution is dialysed, and shows neutral until the solution pH value; Solution is rotated evaporation, steams to thick, add acetone and separate out white solid, filter, 50 ℃ of vacuum drying 24h obtain cyclodextrin polymer;
(2) water solublity ilicin A/ cyclodextrin polymer clathrate is synthetic
With cyclodextrin polymer 4g, ilicin A1g and water 100mL stirring at normal temperature 24h, leave standstill; After question response finishes,, get milk yellow solution with the inclusion complex in solution sucking filtration; In solution, add 100mL acetone, solid is separated out, the sucking filtration solid, filter cake is used absolute ethanol washing, then 50 ℃ of vacuum dryings of solid is obtained water solublity ilicin A/ cyclodextrin polymer super molecule inclusion compound.
The present invention adopts cyclodextrin that ilicin A is carried out enclose, and characterizes and the enclose percentage rate through infrared, ultraviolet, its clathrate of nuclear magnetic resonance measuring, and IlexA-CDP is different from IlexA; Can be water-soluble fully; And make accent fat biological activity significantly strengthen, and inflammatory cell of inhibition hyperlipemia model mice and cytokine effect thereof and antioxidant activity, inhibition ox-LDL produce, and its effect all is better than ilicin A itself; Therefore, control AS is respond well.
Find that in experiment the IlexA-CDP preparation parameter forms clathrate has influence, the present invention selects process conditions of the present invention through testing sieve, and operational approach of the present invention is easy, and condition is prone to control, is easy to industrialization.The ilicin A/ cyclodextrin polymer clathrate good water solubility of preparation, Stability Analysis of Structures is not destroyed the structure of ilicin A.This pharmaceutical composition oral administration can suppress the inflammatory reaction of AS, regulates the serum lipids level, prevents or improve the pathological change of AS.This is to be theoretical basis with inflammation-inhibiting reaction, accents fat, and the present invention has found that IlexA-CDP is to the adjustment of AS relevant cell factor and the effect of inhibition AS speckle inflammation.Having broken traditional is single traditional method of treatment of target spot with " blood lipid regulation ", has set up and has prevented and treated the new way of atherosclerosis with " putting prevention first ", thereby opened up new way for prevention of AS.
Description of drawings
Fig. 1 is the infrared spectrogram of IlexA-CDP.
The specific embodiment
In order to make the object of the invention, technical scheme and advantage clearer, the present invention is at length explained below in conjunction with embodiment.Used cyclodextrin polymer adopts cyclodextrin and the crosslinked acquisition of epoxychloropropane among the present invention; Ilicin A can buy from market.
Synthesizing of embodiment 1 cyclodextrin polymer
In the 250mL there-necked flask, add sodium hydroxide (20g), cyclodextrin (25g) and water (40mL).Stirring at normal temperature to solid all dissolves, and then adds epoxychloropropane (1mL), stirring at room 24h.
Question response finishes, and solution is dialysed, and shows neutral until the solution pH value.Solution is rotated evaporation, steams, add acetone and separate out white solid, filter 50 ℃ of vacuum drying 24h to thick.Obtain cyclodextrin polymer (15g) at last.
Synthesizing of embodiment 2 water solublity ilicin A/ cyclodextrin polymer clathrates
In the 250mL round-bottomed flask, add cyclodextrin polymer (4g), ilicin A (1g) and water (100mL).Stirring at normal temperature 24h leaves standstill 12h.
After question response finishes,, get milk yellow solution with the inclusion complex in solution sucking filtration.In solution, add 100mL acetone, solid is separated out, the sucking filtration solid, filter cake is used absolute ethanol washing, then with 50 ℃ of vacuum drying 24h of solid, obtains solid (3g), i.e. water solublity ilicin A/ cyclodextrin polymer clathrate.Its infrared spectrogram is seen Fig. 1.
Embodiment 3 ilicin A/ cyclodextrin polymer clathrate blood lipid regulation biological activitys (seeing table 1).
Table 1.Ilex A-CDP is to the influence (x ± s, n=8) of hyperlipemia in mice serum lipids
1. Ilex A-CDP to the influence of hyperlipemia model blood fat respectively per os give Ilex A-CDP and IlexA intervenes ApoE
-/-The mice hyperlipemia model through detecting serum lipids, finds that Ilex A-CDP can significantly reduce TC, TG, LDL-C, rising HDL-C, and apo A1, downward modulation apo B, and be dose dependent, and effect is superior to principal agent Ilex A.
2. Ilex A-CDP is to the influence of atherosclerosis coefficient, cardiovascular disease danger coefficient
The hyperlipidemia model mice detects serum lipids; Calculate AS coefficient (AI), cardiovascular disease danger coefficient (CRF); Find that IlexA-CDP can significantly reduce AI and increase CRF; And the CRF of IlexA-CDP is 1.71 ± 0.33, and effect is superior to principal agent IlexA (CRF=1.32 ± 0.29), and difference has significance (P＜0.05).
3. Ilex A-CDP improves the morphosis of liver fat lesion
IlexA-CDP can improve the hepatocyte fatty infiltration, accidental lipochondrion, and the hepatocyte form is normal, and the lobules of liver boundary is clear, and liver cell plate is radial arrangement, does not see obvious lipoid degeneration; Effect is superior to principal agent IlexA.
Claims (5)
1. the atherosclerotic pharmaceutical composition of control is characterized in that this pharmaceutical composition is water miscible ilicin A/ cyclodextrin polymer super molecule inclusion compound.
2. the atherosclerotic pharmaceutical composition of control according to claim 1; It is characterized in that making: be host molecule with the cyclodextrin polymer through following method; Ilicin A is a guest molecule; Water is reaction dissolvent, the supermolecule reaction takes place generate water solublity ilicin A/ cyclodextrin polymer super molecule inclusion compound.
3. prevent and treat atherosclerotic preparation of drug combination method for one kind; It is characterized in that, be to be host molecule with the cyclodextrin polymer, and ilicin A is a guest molecule; Water is reaction dissolvent, the supermolecule reaction takes place generate water solublity ilicin A/ cyclodextrin polymer super molecule inclusion compound.
4. method for preparing according to claim 3 is characterized in that said cyclodextrin polymer is that cyclodextrin takes place crosslinked with epoxychloropropane and generates under strong alkaline condition.
5. method for preparing according to claim 4 is characterized in that step is following:
(1) cyclodextrin polymer is synthetic
Sodium hydroxide 20 g, cyclodextrin 25 g and water 40 mL stirring at normal temperature to solids are all dissolved, then add epoxychloropropane 1 mL, stirring at room 24 h; Question response finishes, and solution is dialysed, and shows neutral until the solution pH value; Solution is rotated evaporation, steams to thick, add acetone and separate out white solid, filter, 50 ℃ of vacuum drying 24h obtain cyclodextrin polymer;
(2) water solublity ilicin A/ cyclodextrin polymer clathrate is synthetic
With cyclodextrin polymer 4 g, ilicin A1 g and water 100 mL stirring at normal temperature 24 h, leave standstill; After question response finishes,, get milk yellow solution with the inclusion complex in solution sucking filtration; In solution, add 100 mL acetone, solid is separated out, the sucking filtration solid, filter cake is used absolute ethanol washing, then 50 ℃ of vacuum dryings of solid is obtained water solublity ilicin A/ cyclodextrin polymer super molecule inclusion compound.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104546867A (en) * | 2014-12-30 | 2015-04-29 | 扬州大学 | Application of ilicin A to preparation of lipid-regulating drug preparation |
| CN104546958A (en) * | 2014-12-25 | 2015-04-29 | 扬州大学 | Application of ilex hainanensis merr total triterpenes and weight-reducing and lipid-regulating pharmaceutical preparation taking ilex hainanensis merr total triterpenes as raw materials |
| CN105267975A (en) * | 2015-10-10 | 2016-01-27 | 扬州大学 | Preparation method of poly gamma cyclodextrin-paclitaxel supermolecular anticancer drug |
| CN106581007A (en) * | 2016-12-22 | 2017-04-26 | 扬州大学 | Application of ilexgenin A in preparation of anti-atherosclerosis drugs |
| CN109806264A (en) * | 2019-04-10 | 2019-05-28 | 江苏海钥医药科技有限公司 | Pharmaceutical composition and its application |
| CN115887469A (en) * | 2022-09-23 | 2023-04-04 | 中国药科大学 | Application of ilicin A as ACSS2 nuclear translocation inhibitor |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104546958A (en) * | 2014-12-25 | 2015-04-29 | 扬州大学 | Application of ilex hainanensis merr total triterpenes and weight-reducing and lipid-regulating pharmaceutical preparation taking ilex hainanensis merr total triterpenes as raw materials |
| CN104546867A (en) * | 2014-12-30 | 2015-04-29 | 扬州大学 | Application of ilicin A to preparation of lipid-regulating drug preparation |
| CN105267975A (en) * | 2015-10-10 | 2016-01-27 | 扬州大学 | Preparation method of poly gamma cyclodextrin-paclitaxel supermolecular anticancer drug |
| CN106581007A (en) * | 2016-12-22 | 2017-04-26 | 扬州大学 | Application of ilexgenin A in preparation of anti-atherosclerosis drugs |
| CN109806264A (en) * | 2019-04-10 | 2019-05-28 | 江苏海钥医药科技有限公司 | Pharmaceutical composition and its application |
| CN115887469A (en) * | 2022-09-23 | 2023-04-04 | 中国药科大学 | Application of ilicin A as ACSS2 nuclear translocation inhibitor |
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