CN102091034A - Preparation method of cholesterol derivative-based organic-inorganic composite nano vesicle - Google Patents
Preparation method of cholesterol derivative-based organic-inorganic composite nano vesicle Download PDFInfo
- Publication number
- CN102091034A CN102091034A CN200910073424XA CN200910073424A CN102091034A CN 102091034 A CN102091034 A CN 102091034A CN 200910073424X A CN200910073424X A CN 200910073424XA CN 200910073424 A CN200910073424 A CN 200910073424A CN 102091034 A CN102091034 A CN 102091034A
- Authority
- CN
- China
- Prior art keywords
- cholesterol
- cholesterol derivative
- organic
- silane
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Steroid Compounds (AREA)
Abstract
The invention discloses a preparation method of a cholesterol derivative-based organic-inorganic composite nano vesicle. The preparation method is characterized in that: the structure of an organic-inorganic composite cholesterol derivative is Si-L-Ch, wherein the Si is a silicane head group; the L is an aliphatic chain linking group; carbon number in the L is between 2 and 18; and the Ch is a cholesterol group or a cholesterol derivative group. The method comprises the following steps of: performing derivation on a hydroxy group of a cholesterol molecule to form a carboxyl; reacting the carboxyl and an amino of garma-aminopropyltriethoxysilane (APTES) under the condition of dehydration by using EDC as a dehydrating agent; and synthesizing the novel silicane head group-containing cholesterol derivative through covalent connection of an amido bond or by directly reacting the carboxyl on the cholesterol molecule and isocyanatopropyltriethoxysilane (IPTES). The cholesterol derivative-based organic-inorganic composite nano vesicle has excellent biocompatibility. The organic-inorganic composite cholesterol derivative can perform self assembly to form a highly dispersed system similar to a liposome and is applied to embedding, transferring and sustained release of various medicaments, such as hydrophilic medicaments, oleophylic medicaments, amphiphilic medicaments and the like. The method has a simple operation process and high repeatability, can be relatively widely applied to the synthesis of a plurality of organic-inorganic composite cholesterol derivatives and has a wide application prospect.
Description
Technical field
The present invention relates to a kind of preparation method of the organic and inorganic composite Nano vesicle based on cholesterol derivative.
Background technology
Malignant tumor is one of disease of serious harm human health, and at present, chemotherapy remains most common therapeutic method.Ideal Drug therapy should be that a specific cells to the host plays a role, and not to host's normal cell generation effect, the toxic and side effects that perhaps causes is very little, but the cancer therapy drug that uses at present has lethal effect equally to normal cell.Reduce toxic and side effects for increasing anticancer effect, research worker is is competitively researched and developed state-of-the art nano-medicament carrier material and technology, so that fundamentally change the situation of present cancer diagnosis, treatment and prevention.
Liposome is made up of bilayer as a kind of pharmaceutical carrier, because it has the class cellularity, makes liposome become a kind of effective drug carrier system.Liposome is as the carrier of antitumor drug, and is simple, nontoxic to body because of its making, can significantly reduce poisonous side effect of medicine and realize that easily advantages such as cancer target receive much concern.But just at present, yet there are some limitation such as poor stability.Liposome can interact with plasma protein, and these interactions have caused the instability of liposome to exist, and they were just removed from blood circulation before arriving target fast.Because shortcomings such as body internal stability and bin stability are not good enough, limited the clinical practice and the suitability for industrialized production of Liposomal formulation.Therefore, poor stability is a problem demanding prompt solution in the liposome commercialization process.
In recent years, research worker has been developed the inorganic/organic complex liposome with similar liposome structure of high stability, is called as " porcelain body ", and this complex liposome has been kept the substitutive characteristics of liposome, but stability significantly improves than traditional liposomal.Cholesterol is a kind of natural materials that is present on all animal cell membranes, and it is an important component of forming cell membrane, has therefore guaranteed the biological safety that it is used in biomedical sector.The present invention selects to have the hydrophobic part of the cholesterol or derivatives thereof of good biocompatibility as the organic/inorganic complex lipid, synthesized the compound cholesterol derivative vesicle of a kind of novel organic and inorganic (Fig. 1, Fig. 6), it had both possessed porcelain body good stable, have excellent biological compatibility again, can be used as a kind of good pharmaceutical carrier.
Summary of the invention
The preparation method that the purpose of this invention is to provide a kind of organic and inorganic composite Nano vesicle based on cholesterol derivative.
Method of the present invention comprises following step:
1) carboxylic cholesterol derivative is synthetic: with cholesterol, succinic anhydrides and catalyst dissolution are in organic solvent.With said mixture 35 ℃-65 ℃ backflow 3-10 days.Solvent is removed under vacuum condition.The residue that removes solvent is dissolved in ethanol, pours into then in the cold NaCl solution.With acid the pH value of suspension is adjusted to pH＜7.Product filters and is extremely neutral with deionized water wash.With solid product recrystallization in ethanol/ethyl acetate mixed solvent.
2) product is dissolved in the exsiccant organic solvent the activation of reactant: with 1), adds dehydrant (EDC) then, activation 0.5-2h.
3) add silane reagent: silane reagent is joined in the mixture, stir 4-24h under the room temperature.
4) remove solvent: solvent is removed under vacuum condition.
5) purification of products: by the silicagel column purification, developing solvent is an ethyl acetate/dichloromethane, obtains white solid at last with product.
6) product the preparation of organic and inorganic composite vesicles: with 5) is dissolved in organic solvent, is injected in the aqueous solution under ultrasound condition, and until forming milky suspension, ultrasonic time is 1-30min.
Among the present invention, the solvent that synthetic carboxylic cholesterol derivative uses is dichloromethane, chloroform, ether, benzene, toluene, DMF or their mixture.
Among the present invention, being used for the activatory dehydrant of reactant is EDC, DCC or their mixture.
Among the present invention, silane reagent is meant gamma-aminopropyl-triethoxy-silane, γ-An Bingjisanjiayangjiguiwan, methyl (γ-aminopropyl) diethoxy silane, N-β-aminoethyl-γ-An Bingjisanjiayangjiguiwan, N-β-aminoethyl-gamma-aminopropyl-triethoxy-silane, N-β-aminoethyl-γ-aminopropyl dimethoxy silane, N-β-aminoethyl-γ-aminopropyl diethoxy silane, methyl (N-β-aminoethyl-γ-aminopropyl) dimethoxy silane, the phenylamino MTES, the phenylamino MTMS, N, N '-two (β-aminoethyl)-γ-An Bingjisanjiayangjiguiwan, Carbimide. propyl-triethoxysilicane, perhaps their mixture.
Among the present invention, cholesterol and cholesterol derivative can select for use cholesterol, cholesterol monomester succinate and other to contain a kind of or its mixture in carboxyl or the amino cholesterol derivative.
Among the present invention, the method for the compound cholesterol derivative of synthesizing organic-inorganic (Si-L-Ch), L part carbon chain lengths is 2-18.
Among the present invention, preparation organic and inorganic composite vesicles, the employed organic solvent of lysate is an ethanol, methanol, a kind of or its mixture among dichloromethane, chloroform, ether, benzene, toluene, the DMF.
In the inventive method step 1), the preferred dichloromethane of organic solvent, preferred 55 ℃ of reflux temperature, preferred 3 days of return time is adjusted to the preferred pH 2 of final pH value.
The inventive method step 2) in, the preferred dichloromethane of organic solvent, the preferred EDC of dehydrant, the preferred 0.5h of soak time.
In the inventive method step 3), the preferred gamma-aminopropyl-triethoxy-silane of silane reagent, the preferred 4h of mixing time.
In the inventive method step 6), organic solvent preferred alcohol, the preferred 10min of ultrasonic time.
The inventive method has following advantages:
(1) the compound cholesterol derivative of organic and inorganic can self assembly forms the drug delivery system of similar liposome under certain condition, compare with traditional aliphatic chain afterbody, cholesterol and derivant thereof have stronger hydrophobic-hydrophobic interaction, and easier self assembly forms the transmission system of high degree of dispersion.
(2) the liposome analog of Xing Chenging improves its stability because the surface has the covalent networks structure of Si-O-Si greatly.
(3) hydrophobic part adopts naturally occurring cholesterol or derivatives thereof in the animal cell membrane, has overcome shortcomings such as traditional hydrophobic ingredient biocompatibility is not good enough.
(4) based on the composite vesicles of cholesterol derivative can be used for hydrophilic, oleophylic and various types of medicines such as amphipathic embedding, transmit gentle controlled release, have a good application prospect.
Description of drawings
The dehydration of figure-1 gamma-aminopropyl-triethoxy-silane (APTES) and cholesterol monomester succinate.
The reaction of figure-2 cholesterol and Carbimide. propyl-triethoxysilicane.
The compound cholesterol derivative self assembly of figure-3 organic and inorganics forms vesicle, and transmission electron microscope (a), laser particle analyzer (b), scanning electron microscope (c) and EDS (d) characterize.
The stability contrast of the vesicle that figure-4 traditional liposomal DPPC, cholesterol monomester succinate (CHS) and the compound cholesterol derivative of organic and inorganic (CSS) self assembly form.
The release in vitro performance of the 6-CF of figure-5 free 6-CF 5(6)-Carboxyfluorescein (6-CF), DPPC parcel and the 6-CF of the compound cholesterol derivative of organic and inorganic (CSS) parcel.
The figure compound cholesterol derivatives of-6 organic and inorganics (CSS) vesicle is to the effect of HUVEc and Hela cell.
The specific embodiment mode
Following examples further specify this patent.
Embodiment one
Synthesizing of cholesterol monomester succinate: cholesterol (1eq.), succinic anhydrides (3eq.) and DMAP (0.1eq.) are dissolved in dichloromethane, reflux 3 days in 55 ℃.Vacuum condition removes down and desolvates.Residue is poured in the cold 15%NaCl solution after being dissolved in ethanol.The suspension that obtains is adjusted to pH 2 with 1M HCl.Filter and wash with neutral water.(10: 1, v/v), productive rate was near 100% with ethanol/re-crystallizing in ethyl acetate for exsiccant solid.
Synthesizing of the compound cholesterol derivative of organic and inorganic (1): be dissolved in exsiccant dichloromethane as scheming shown in-1, EDC (1.2eq.) being mixed with cholesterol monomester succinate (1.2eq.), behind the 30min, add APTES (1.2eq.), stirring at room 4h.Solvent removed in vacuo, crude product separates with silicagel column, with ethyl acetate/dichloromethane (1: be developing solvent 3v/v), obtain white solid, productive rate about 40%.It is 96.5～98.2 ℃ that the fusing point instrument records its fusing point; Its R of thin-layer chromatographic analysis
fValue is 0.43 (ethyl acetate/dichloromethane 1: 3); The following δ of nuclear-magnetism result=: 0.61 (t, 2H, SiCH
2), 1.22 (t, 9H, SiOCH
2CH
3), 1.62 (m, 2H, SiCH
2CH
2), 3.83 (q, 6H, SiOCH
2), 3.24 (q, 2H, SiCH
2CH
2CH
2NH), 5.90 (t, 1H, CH
2NHCO), and 0.65-2.31 (43H, cholesteryl), 4.62 (m, 1H, OCH cholesteryl), 5.37 (d, 1H, CCHCH
2), 2.45,2.64 (m, 4H, OCCH
2CH
2CO).
Embodiment two
Synthesizing of the compound cholesterol derivative of organic and inorganic (2): shown in figure-2; cholesterol (0.5mmol) is dissolved in the exsiccant dichloromethane of 20mL; under nitrogen protection, add Carbimide. propyl-triethoxysilicane (IPTES then; 0.5mmol) and dibutyl tin laurate (0.1mmol); reactant mixture stirs 24h, the carrying out of TLC monitoring reaction in 50 ℃ under nitrogen protection.After reaction was finished, down except that desolvating, crude product separated with silicagel column, with ethyl acetate/normal hexane (1: 5v/v) be developing solvent, obtain white solid, productive rate about 75% in vacuum condition.It is 81-82 ℃ that the fusing point instrument records its fusing point; The nuclear-magnetism result is as follows:
1H NMR (CDCl
3, 400MHz) δ: 0.63 (t, J=8.0Hz, 2H, NHCH
2CH
2CH
2Si), 0.67 (s, 3H, CH
3), 0.85～0.87 (m, 6H, CH
3), 0.90～0.92 (m, 3H, CH
3), 1.00 (s, 3H, CH
3), 1.02～1.21 (m, 6H), 1.22～1.35 (m, 9H), 1.35～1.47 (m, 3H), 1.48～1.53 (m, 9H), 1.63～1.87 (m, 3H), 1.90～2.03 (m, 2H, CH
2CH=CCH
2), 2.20～2.40 (m, 2H, HC=CCH
2CHO), 3.15～3.17 (m, 2H, NHCH
2), 3.70～3.85 (m, 6H, SiOCH
2CH
3), 4.42～4.51 (m, 1H, COOCH), 5.37 (d, J=5.2Hz, 1H, C=CH).
Embodiment three
The compound cholesterol derivative of synthetic organic and inorganic (1) is dissolved in ethanol, then in ultrasound condition is made a bet aqueous solution, make it carry out self assembly, prepare vesicle with liposome similar structures, DLS result shows, its granule size is about 100-200nm, conforms to TEM, SEM result.EDX result shows that its surface contains C, O, Si element, illustrates that the vesicle surface has the structure of Si-O-Si (figure-3), has proved the formation of its surface silica dioxide shell.
The change of size of CSS vesicle is measured in adding by Triton X-100, has measured its stability.The result shows (figure-4), after TritonX-100 joins in DPPC and the CHS liposome suspension, begins to cause that the particle diameter increase of vesicle reduces suddenly then, and this has illustrated that vesicle is destroyed.By contrast, CSS vesicle size does not but have to change because of the adding of Triton X-100, and this explanation is compared with traditional liposome, and the existence of the silica shell on the surface of CSS vesicle improves its stability greatly.In addition, the CHS vesicle has better more stable than traditional DPPC liposome, and this is because the cholesterol group has the hydrophobic interaction stronger than common alkyl chain.
The 6-CF 5(6)-Carboxyfluorescein has been simulated a kind of hydrophilic medicament, is loaded in the liquid phase of CSS vesicle.Figure-5 has shown the release in vitro performance of 6-CF 5(6)-Carboxyfluorescein.Compare with traditional liposome DPPC, the CSS vesicle has the performance that continues to discharge medicine more, and this is because its surperficial silica shell has hindered medicine and oozed out from vesicle.
Vesicle and Human umbilical vein endothelial cells (HUVEc) and two kinds of cell interaction 24h of human cervical carcinoma cell (Hela) with the compound cholesterol derivative preparation of organic and inorganic, under the vesicle effect of high concentration, two kinds of cells still have good vigor, show that this vesicle has good biocompatibility; And this vesicle can promote the propagation of HUVEc significantly, and to the effect of Hela cell then not obvious (figure-6), this mechanism wherein may have facilitation with the nanoparticle on cell proliferation and CSS vesicle excellent biological compatibility is relevant.The new thinking that this provides for its potential application in biomedical sector from now on.
Claims (6)
1. the method that silane reagent is connected the compound cholesterol derivative of synthesizing organic-inorganic (Si-L-Ch) with the cholesterol molecule comprises following step:
1) carboxylic cholesterol derivative is synthetic: with cholesterol, succinic anhydrides and DMAP are dissolved in the dichloromethane.Said mixture was refluxed 3 days.Solvent is removed under vacuum condition.The residue that removes solvent is dissolved in ethanol, pours into then in the cold NaCl solution.With hydrochloric acid the pH value of suspension is adjusted to pH 2.0.Product filters and is extremely neutral with deionized water wash.With solid product recrystallization in ethanol/ethyl acetate mixed solvent;
2) product is dissolved in the exsiccant solvent the activation of reactant: with 1), adds dehydrant then, activation a period of time;
3) add silane reagent: silane reagent is joined in the mixture, stir a period of time under the room temperature;
4) remove solvent: solvent is removed under vacuum condition;
5) purification of products: by the silicagel column purification, developing solvent is ethyl acetate/dichloromethane (1: 3), obtains white solid at last with product.
2. the method for the compound cholesterol derivative of synthesizing organic-inorganic according to claim 1 is characterized in that used dry solvent is dichloromethane, chloroform, ether, benzene, toluene, DMF or their mixture.
3. the method for the compound cholesterol derivative of synthesizing organic-inorganic according to claim 1 is characterized in that used dehydrant is EDC, DCC or their mixture.
4. the method for the compound cholesterol derivative of synthesizing organic-inorganic according to claim 1, it is characterized in that the used silane reagent of Si part is a gamma-aminopropyl-triethoxy-silane, γ-An Bingjisanjiayangjiguiwan, methyl (γ-aminopropyl) diethoxy silane, N-β-aminoethyl-γ-An Bingjisanjiayangjiguiwan, N-β-aminoethyl-gamma-aminopropyl-triethoxy-silane, N-β-aminoethyl-γ-aminopropyl dimethoxy silane, N-β-aminoethyl-γ-aminopropyl diethoxy silane, methyl (N-β-aminoethyl-γ-aminopropyl) dimethoxy silane, the phenylamino MTES, the phenylamino MTMS, N, N '-two (β-aminoethyl)-γ-An Bingjisanjiayangjiguiwan, Carbimide. propyl-triethoxysilicane or their mixture.
5. the method for the compound cholesterol derivative of synthesizing organic-inorganic according to claim 1 is characterized in that cholesterol that the Ch part is used or its derivant can be cholesterol, cholesterol monomester succinate, other contains a kind of or its mixture in carboxyl or the amino cholesterol derivative.
6. the method for the compound cholesterol derivative of synthesizing organic-inorganic according to claim 1 (Si-L-Ch) is characterized in that L part carbon chain lengths is 2-18.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910073424XA CN102091034A (en) | 2009-12-15 | 2009-12-15 | Preparation method of cholesterol derivative-based organic-inorganic composite nano vesicle |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910073424XA CN102091034A (en) | 2009-12-15 | 2009-12-15 | Preparation method of cholesterol derivative-based organic-inorganic composite nano vesicle |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102091034A true CN102091034A (en) | 2011-06-15 |
Family
ID=44124415
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910073424XA Pending CN102091034A (en) | 2009-12-15 | 2009-12-15 | Preparation method of cholesterol derivative-based organic-inorganic composite nano vesicle |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102091034A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102266564A (en) * | 2011-07-20 | 2011-12-07 | 哈尔滨工业大学 | Nano-carrier with anti-leukemia activity |
| CN102391446A (en) * | 2011-09-05 | 2012-03-28 | 同济大学 | Method for preparing biocompatible polymer nano-vesicle in pure water |
| CN102443034A (en) * | 2011-09-23 | 2012-05-09 | 南开大学 | Cholesterol hybrid compound of molybdenum-containing polyoxometallate and preparation method of cholesterol hybrid compound |
| CN103720656A (en) * | 2012-10-15 | 2014-04-16 | 北京大学 | Oral and injection dual-effect protein or polypeptide drug controlled-release vesicle and preparation method thereof |
| CN104684575A (en) * | 2012-08-02 | 2015-06-03 | 遗传工程与生物技术中心 | Vesicles which include epidermal growth factor and compositions that contain same |
| CN104840421A (en) * | 2014-02-18 | 2015-08-19 | 北京大学 | Long-circulating cholesterol composite liposome and preparation method thereof |
| CN105016347A (en) * | 2015-07-13 | 2015-11-04 | 陕西师范大学 | W/O/W multiphase emulsion and method for preparing hierarchical pore SiO2 microspheres using W/O/W multiphase emulsion as formwork |
-
2009
- 2009-12-15 CN CN200910073424XA patent/CN102091034A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102266564A (en) * | 2011-07-20 | 2011-12-07 | 哈尔滨工业大学 | Nano-carrier with anti-leukemia activity |
| CN102391446A (en) * | 2011-09-05 | 2012-03-28 | 同济大学 | Method for preparing biocompatible polymer nano-vesicle in pure water |
| CN102443034A (en) * | 2011-09-23 | 2012-05-09 | 南开大学 | Cholesterol hybrid compound of molybdenum-containing polyoxometallate and preparation method of cholesterol hybrid compound |
| CN104684575A (en) * | 2012-08-02 | 2015-06-03 | 遗传工程与生物技术中心 | Vesicles which include epidermal growth factor and compositions that contain same |
| CN104684575B (en) * | 2012-08-02 | 2018-07-31 | 遗传工程与生物技术中心 | Including the vesica of epidermal growth factor and the composition containing the vesica |
| CN103720656A (en) * | 2012-10-15 | 2014-04-16 | 北京大学 | Oral and injection dual-effect protein or polypeptide drug controlled-release vesicle and preparation method thereof |
| CN104840421A (en) * | 2014-02-18 | 2015-08-19 | 北京大学 | Long-circulating cholesterol composite liposome and preparation method thereof |
| CN105016347A (en) * | 2015-07-13 | 2015-11-04 | 陕西师范大学 | W/O/W multiphase emulsion and method for preparing hierarchical pore SiO2 microspheres using W/O/W multiphase emulsion as formwork |
| CN105016347B (en) * | 2015-07-13 | 2017-01-18 | 陕西师范大学 | W/O/W multiphase emulsion and method for preparing hierarchical pore SiO2 microspheres using W/O/W multiphase emulsion as formwork |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102091034A (en) | Preparation method of cholesterol derivative-based organic-inorganic composite nano vesicle | |
| JP2022028904A (en) | Silicon based drug conjugates and methods of using same | |
| CN102949728A (en) | Meso-porous silicon nano-drug carrier with both reduction responsiveness and targeting ability and preparation method thereof | |
| CN106220641B (en) | Containing the indoles volution compound and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure | |
| TW200300078A (en) | Method of treating disorder related to high cholesterol concentration | |
| CN102139112A (en) | Drug carrier raw material and preparation method and application thereof | |
| CA2522874A1 (en) | Prodrugs of selective androgen receptor modulators and methods of use thereof | |
| CN102260356A (en) | Chitosan derivative used as gene vector, and preparation method and application thereof | |
| CN111012919A (en) | PEGylated ICD inducer-IDO inhibitor nanoconjugate, and preparation method and application thereof | |
| CN105732381A (en) | Compounds from antrodia camphorata, method for preparing the same and use thereof | |
| CN101822841A (en) | Application of organic amine derivatives as brain-targeting modification group of small-molecule drug | |
| CN106632272A (en) | Synthesis and applications of an albumin bounding type 5-fluorouracil prodrug | |
| US20110015372A1 (en) | Methods and compositions for improved uptake of biological molecules | |
| KR20220029728A (en) | Design and Efficient Synthesis of Lipid-Fluorescein Conjugates for CAR-T Cell Therapy | |
| CN107496937A (en) | A kind of pre-targeting drug delivery system and its preparation method and application | |
| CN107216362A (en) | A kind of cytarabine amphipathic small molecules prodrug and its preparation method and application | |
| CN110251685A (en) | Taxol-berberine Nano medication synthetic method and application | |
| CN102898433A (en) | Tetrandrine gallate and drug composition, preparation method and applications thereof | |
| CN107233314A (en) | It is a kind of that there are double target areas to pass composite phospholipid thermal sensitive liposome of drug effect fruit and its preparation method and application simultaneously | |
| WO1994021667A1 (en) | Compound for inhibiting bone resorption and accelerating osteogenesis | |
| WO2021213492A1 (en) | Drug-carrying macromolecule and preparation method therefor | |
| WO2021175275A1 (en) | Hydrophobically modified albumin, preparation method therefor, and application thereof | |
| WO2017156959A1 (en) | Micromolecular lung-targeting drug | |
| CN114163479A (en) | Platinum compounds for treating cancer and preparation method thereof | |
| CN101564538B (en) | 3, 5-dihydroxy-4-isopropyl diphenyl ethylene-butanedioic anhydride-polyoxyethylene compound and synthetic method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20110615 |