CN100558459C - Preparation of polymer microspheres using liposomes as microaggregators - Google Patents
Preparation of polymer microspheres using liposomes as microaggregators Download PDFInfo
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- CN100558459C CN100558459C CNB2007101510529A CN200710151052A CN100558459C CN 100558459 C CN100558459 C CN 100558459C CN B2007101510529 A CNB2007101510529 A CN B2007101510529A CN 200710151052 A CN200710151052 A CN 200710151052A CN 100558459 C CN100558459 C CN 100558459C
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- liposome
- soybean lecithin
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- polymer microspheres
- polymerization
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Abstract
一种以脂质体为微聚合器制备的聚合物微球。与以往高分子微球的制备方法不同，本发明提出了一种利用生物材料脂质体作为微型聚合器的高分子微球和制备方法。本发明以一种生物材料脂质体来限制聚合的空间，强制单体在脂质体内部微小的空间内进行聚合反应，形成聚合物，除去外层脂质体包覆后可得到与脂质体在尺度和形状上相似的高分子微球。利用脂质体强行限制聚合的空间，不仅克服了乳液和悬浮聚合的不稳定问题，而且可得到均一的高分子微球。A polymer microsphere prepared by using liposome as a micropolymer. Different from previous preparation methods of polymer microspheres, the present invention proposes a polymer microsphere and a preparation method using biomaterial liposomes as micro-aggregators. In the present invention, a biomaterial liposome is used to limit the polymerization space, and the monomer is forced to carry out polymerization reaction in the small space inside the liposome to form a polymer, which can be obtained after removing the outer liposome coating. Polymer microspheres that are similar in size and shape. Utilizing liposomes to forcibly limit the polymerization space not only overcomes the unstable problem of emulsion and suspension polymerization, but also obtains uniform polymer microspheres.
Description
[technical field]:
The present invention relates to the synthetic field of polymer microsphere, is as miniature polymerizer, by body or solution polymerization polymer microsphere with biomaterial.
[background technology]:
Traditional polymer microsphere is by emulsion polymerisation (Conti B.et al.J.Microencapsul.1997,14:303), emulsifier-free emulsion polymerization (Hoshino F.et al, Polym.J.1987,19:1157), micro-emulsion polymerization (Candau F.et al.Collloids Surface A:Physicochem.Eng.Aspects.1999,153:47), mini-emulsion polymerization (Erdem E.et al.J.Polym.Sci.Polym.Chem.2000,38:4419), suspension polymerisation (Omi S.etal.J.Microencapsulation 2001,18:749), dispersin polymerization (Nakamura K.et al.Collloids SurfaceA:Physicochem.Eng.Aspect.1999,153:195), (Kawaguchi et al.Polym.Int1993,30:225-231) etc. method makes precipitation polymerization.These methods can be prepared the microballoon of different size and performance, be widely used in pharmaceutical carrier (Veronese F.M.et al.J.Control.Release.1998,52:227), the immobilization of enzyme and cell (Bullock C.Sci.Progress 1995,78:119), the separation and purification of active material (Ma G.H.et al.J.Coll.Interf.Sci.1994,168:393), coating (Ishii K.et al.Collloids Surface A:Physicochem.Eng.Aspects.1999,153:591), (Okubo M.et al.J.Appl.Polym.Sci.1983 is 28:383) etc. in the field for adhesive.But said method all exists the more dispersion problem of reaction system amount stability problem and product size.This has caused the complexity of reaction process, and to the sensitivity of reaction condition fluctuation.
Liposome is a kind of by the vesica that phospholipid bilayer constituted, and two skins of film are hydrophilic region, are hydrophobic region between the bilayer.This biomembrane has good permeability, and hydrophily and lyophobic dust all can pass through rete and enter vesica inside.Therefore, liposome has obtained using widely (Langner M.﹠amp as the material of medicine release; Kral T.E.Pol.J.Pharmacol.1999,51:211).
[summary of the invention]:
The present invention seeks to utilize the extensive package action of biomaterial liposome to material, monomer is encapsulated in the liposome, as microreactor, initiated polymerization forms the crosslinking polymer microballoon similar to the liposome shape, that volume is slightly less than liposome therein with liposome.
Of the present inventionly be meant with the polymer microballoon of soybean lecithin liposome as the preparation of little polymerizer:
---the polyacrylamide or the polymethylacrylic acid that obtain with Raolical polymerizable;
---polymer microballoon forms in soybean lecithin vesica interior polymeric;
---polymer microballoon has the size and dimension similar to the soybean lecithin vesica.
The preparation method is for to be suspended in lecithin, cholesterol and vitamin E in the mixed solvent of ether and n-hexane, add monomer (acrylamide or methacrylic acid), crosslinking agent (N, N-methylene-bisacrylamide) and initator (ammonium persulfate and N, N, N ', N '-tetramethylethylenediamine).Decompression concentrates, and makes monomer, crosslinking agent and the initiator molecule outer surface attached to liposome.Add water, make partial monosomy, crosslinking agent and initiator molecule be brought into the inside of liposome vesicle, concentrate the monomer that the eccysis liposome vesicle is outer.Heated polymerizable under nitrogen protection.Destroy liposome membrane at last, obtain polymer microsphere.
Concrete preparation process is:
---soybean lecithin liposome encapsulation monomer:
In the 50mL beaker, add 0.5～0.6g soybean lecithin, 0.1～0.12g cholesterol and 0.01～0.02g vitamin E, add the mixed organic solvents of ether and n-hexane again, wherein, and ether: n-hexane=9: 1, shake up, place the ice-bath ultrasonic device; Slowly inject 2.5～3g acrylamide or methacrylic acid, 0.4g N, the N-methylene-bisacrylamide, 15mg ammonium persulfate and 4mg N, N, N ', N '-tetramethylethylenediamine forms the aqueous solution of 10mL, ice-bath ultrasonic concussion 5min; Under 4 ℃, mixed liquor is evaporated to pasty state with Rotary Evaporators, adds 10mL water, and the rotary evaporation 30min that reduces pressure has again obtained having encapsulated the soybean lecithin liposome suspension of monomer;
---polymerization:
Under 4 ℃, the suspension of soybean lecithin liposome that had been encapsulated monomer the last step is 12, and supernatant is removed in centrifugal sedimentation under the 000rpm, washes with water 2 times; Under nitrogen protection, be heated to 60 ℃, keep reaction 2～3 hours, make the monomer polymerization in the liposome;
---the liposome rupture of membranes:
The soybean lecithin liposome that was encapsulated with polymer the last step places 5%TritonX-100 ethanolic solution, standing over night; 12, supernatant is removed in centrifugal sedimentation under the 000rpm, adds water, 3～5 times repeatedly, obtains polymer microballoon.
The monodispersity that the liposome particle diameter distributes is better, and average dimension is about 100nm.As miniature polymer reactor, monomer carries out simple polymerisation in bulk or polymerisation in solution therein with liposome, can avoid the stability problem that produces because of the micelle bonding in emulsion polymerisation and the suspension polymerisation.Simultaneously, can obtain particle diameter distribution polymer microsphere comparatively uniformly.This preparation method is applicable to the polymer that all can obtain with Raolical polymerizable.
Advantage of the present invention and good effect: different with the preparation method of polymer microsphere in the past, the present invention proposes a kind of polymer microsphere and preparation method who utilizes the biomaterial liposome as miniature polymerizer.The present invention comes the space of limit polymerization with a kind of biomaterial liposome, forces monomer to carry out polymerisation in the small space of liposome interior.Utilize liposome to impose restrictions on the space of polymerization, not only overcome the instability problem of emulsion and suspension polymerisation, and can obtain the polymer microsphere of homogeneous.
[specific embodiment]:
Embodiment 1
1, soybean lecithin liposome encapsulation monomer:
In the 50mL beaker, add 0.5～0.6g soybean lecithin, 0.1～0.12g cholesterol and 0.01～0.02g vitamin E, add the mixed organic solvents of ether and n-hexane again, wherein, and ether: n-hexane=9: 1, shake up, place the ice-bath ultrasonic device; Slowly inject 2.5～3g acrylamide, 0.4g N, the N-methylene-bisacrylamide, 15mg ammonium persulfate and 4mg N, N, N ', N '-tetramethylethylenediamine forms the aqueous solution of 10mL, ice-bath ultrasonic concussion 5min; Under 4 ℃, mixed liquor is evaporated to pasty state with Rotary Evaporators, adds 10mL water, and the rotary evaporation 30min that reduces pressure has again obtained having encapsulated the soybean lecithin liposome suspension of monomer;
2, polymerization:
Under 4 ℃, the suspension of soybean lecithin liposome that had been encapsulated monomer the last step is 12, and supernatant is removed in centrifugal sedimentation under the 000rpm, washes with water 2 times; Under nitrogen protection, be heated to 60 ℃, keep reaction 2～3 hours, make the monomer polymerization in the liposome;
3, liposome rupture of membranes:
The soybean lecithin liposome that was encapsulated with polymer the last step places 5%TritonX-100 ethanolic solution, standing over night; 12, supernatant is removed in centrifugal sedimentation under the 000rpm, adds water, 3～5 times repeatedly, obtains polymer microballoon.
Embodiment 2
1, soybean lecithin liposome encapsulation monomer:
In the 50mL beaker, add 0.5～0.6g soybean lecithin, 0.1～0.12g cholesterol and 0.01～0.02g vitamin E, add the mixed organic solvents of ether and n-hexane again, wherein, and ether: n-hexane=9: 1, shake up, place the ice-bath ultrasonic device; Slowly inject 2.5～3g methacrylic acid, 0.4g N, the N-methylene-bisacrylamide, 15mg ammonium persulfate and 4mg N, N, N ', N '-tetramethylethylenediamine forms the aqueous solution of 10mL, ice-bath ultrasonic concussion 5min; Under 4 ℃, mixed liquor is evaporated to pasty state with Rotary Evaporators, adds 10mL water, and the rotary evaporation 30min that reduces pressure has again obtained having encapsulated the soybean lecithin liposome suspension of monomer;
2, polymerization:
Under 4 ℃, the suspension of soybean lecithin liposome that had been encapsulated monomer the last step is 12, and supernatant is removed in centrifugal sedimentation under the 000rpm, washes with water 2 times; Under nitrogen protection, be heated to 60 ℃, keep reaction 2～3 hours, make the monomer polymerization in the liposome;
3, liposome rupture of membranes:
The soybean lecithin liposome that was encapsulated with polymer the last step places 5%TritonX-100 ethanolic solution, standing over night; 12, supernatant is removed in centrifugal sedimentation under the 000rpm, adds water, 3～5 times repeatedly, obtains polymer microballoon.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2007101510529A CN100558459C (en) | 2007-12-14 | 2007-12-14 | Preparation of polymer microspheres using liposomes as microaggregators |
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| CNB2007101510529A CN100558459C (en) | 2007-12-14 | 2007-12-14 | Preparation of polymer microspheres using liposomes as microaggregators |
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| CN101254450A CN101254450A (en) | 2008-09-03 |
| CN100558459C true CN100558459C (en) | 2009-11-11 |
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