CN1434730A - Polymer micelle as monolayer or layer-laminated surface - Google Patents
Polymer micelle as monolayer or layer-laminated surface Download PDFInfo
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- CN1434730A CN1434730A CN 00818177 CN00818177A CN1434730A CN 1434730 A CN1434730 A CN 1434730A CN 00818177 CN00818177 CN 00818177 CN 00818177 A CN00818177 A CN 00818177A CN 1434730 A CN1434730 A CN 1434730A
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Abstract
The present invention is directed to a coated biomedical device said micelle having a hydrophilic outer shell and a hydrophobic inner core, or a hydrophobic outer shell and a hydrophilic inner core said micelle comprised of a block copolymer having a HLB value ranging from about 1 to about 40. The medical device may have one coating thereon or multiple coatings. The present invention is also directed to the use of the micelle as a drug carrier.
Description
Invention field
The present invention relates to a kind of single or multiple lift polymer micelle and they purposes, especially biomedical devices as surface coating layer.
Background of invention
Micelle is to comprise hydrophilic and the two-part amphiphilic colloid aggregation thing of hydrophobic.In polarizable medium such as water, form micellar amphiphilic hydrophobic part and will partly will accumulate in polarity micelle water (solvent) interface and also be referred to as a polarity of the molecule of base away from the polarity part.On the other hand, micelle also can form in apolar medium, and as non-polar organic solvent, for example hexane wherein, is positioned at the center of system at little water droplet both sexes micelle on every side.In apolar medium, hydrophobic partly is exposed to apolar medium, and hydrophilic segment will be away from solvent and near water droplet.Be called as reverse micelle during being assembled with like this.These two kinds of aforementioned systems are represented oil-in-water and Water-In-Oil type system respectively.
A kind of micelle can have several forms, depends on the condition and the composition of system.For example, the little micelle in the weak solution under about critical micelle concentration (CMC) is generally considered to be spheric.Yet under other condition, they can be the sphere, dish of distortion, bar-shaped, lamellar or the like.
Micelle is to form down in critical micelle concentration (CMC), and this concentration depends on Several Factors, comprises amphiphilic type, solvent system, solute etc.Critical micelle concentration is meant the concentration when beginning to form micelle in the system that contains solvent, amphiphatic molecule, solute etc.CMC can adopt the mensuration that experimentizes of the standard technique in this area.For example, the CMC of surfactant can determine by performance is mapped as the function of surfactant concentration; Notice that performance generally is linear change with the concentration increase, be up to CMC, become non-linear at this point curve.Be used as the performance of measuring CMC and comprised these performances such as refraction index, light scattering, dialysis, surface tension and dye solution.
The micelle performance is affected by environment, and especially is subjected to the influence of specific change in the environment, as electrolyte in temperature, solvent, soluble constituent, the system etc.The micelle that performance has been studied has been described in the prior art.
For example, people's such as Kataoka United States Patent (USP) 5,929,177 has been described a kind of polymer molecule, wherein its useful as drug release vehicle.Micelle is formed by the block copolymer that all contains functional group at two ends, and it contains hydrophilic/hydrophobic segment.The terminated polymers functionality of block copolymer comprises amino, carboxyl and the sulfydryl of α end and hydroxyl, carboxyl, aldehyde radical and the vinyl of ω end.Hydrophilic segment comprises polyoxyethylene, and the hydrophobic segment is derived by lactide, lactone or (methyl) acrylate.
People's such as Kataoka United States Patent (USP) 5,925,720 provides a kind of different telechelic oligomer or polymer of following molecular formula:
Wherein, R
1And R
2C is represented in combination each other
1-10Alkoxyl, aryloxy group or aryl-C
1-3Alkoxyl or oxygen base (=O), or R
1And R
2Represent ethylenedioxy independently ,-O-CH (R
1)-CH
2-O-;
R
1Refer to hydrogen or C
1-6Alkyl;
L is
Or (CH
2)
rR
3And R
4Represent hydrogen, alkyl, aryl or aralkyl independently; R is 2-5; M is 2-10,000; N is 2-10,000;
P is 1-5;
Q is 0-20;
When q was 0, z referred to the amino propiono of H, alkali metal, acetyl group, acryloyl group, methacryl, cinnamoyl, p-toluenesulfonyl, 2-mercapto radical propionyl group or 2-or pi-allyl or ethenylphenyl,
When q was 1-20, z was C
1-6Alkoxy carbonyl group, carboxyl, sulfydryl or amino.
A kind of macromolecule micelle of this oligomer or polymer formation, it is stable and be useful to drug release as carrier in aqueous solvent.
In these lists of references, there is not one piece to be the micelle that is used as clad.
Yet the non-micellar copolymerization thing of other type has been used to clad surface.For example, the United States Patent (USP) 5,275,838 of Merrill disclose a kind of with the hydrogel layer form with fixed method of polyoxyethylene (PEO) star-shaped molecule and their product, it can be used for clad surface.It has been described and a kind of the polyoxyethylene star-shaped molecule has been fixed to the supporter surface, to form the method for clad on it, comprises the steps:
(a) a kind of organic solution that contains the polyoxyethylene star-shaped molecule is exposed to a kind of reagent so that the reagent group is fixed to terminal hydroxy group, each polyoxyethylene star-shaped molecule is made up of the terminal hydroxy group polyoxyethylene chain that is connected in a large number on the divinyl benzene nucleus basically, this reagent group allows by replacing amino or thiol group to be received the PEO end of the chain subsequently, therefore forms the activation polyoxyethylene star-shaped molecule that contains the active reaction end group;
(b) the activation polyoxyethylene star-shaped molecule that will contain the active reaction end group is separated from organic solvent;
(c) will activate the polyoxyethylene star-shaped molecule and be dissolved in aqueous solution; With
(d) solution of step (c) contact with the supporter surface of containing amino and/or mercapto, with the covalent bonding star-shaped molecule of end group that responds, so the star-shaped molecule that will react end group is fixed in the thick-layer on supporter surface.
This star-shaped molecule has a polymer core, and as divinylbenzene, a series of polyoxyethylene chains or side chain are from its growth.These star-shaped molecule are not micelles.They are block copolymer containing not, and its HLB value (hydrophile-lipophile balance) is 1-40.As described here, star-shaped molecule is formed by anionic polymerisation by divinylbenzene, oxygen ethylene and optional styrene.
Utilization of the present invention is different from those types of compounds and the clad technology that Merrill describes.Do not resemble Merrill, clad compositions of the present invention is made up of micelle.As illustrated subsequently, the used micelle of the present invention is that the block copolymer of 1-40 is formed by the HLB value.The inventor finds, brings several advantages with specific polymeric micelles clad surface among the present invention to cover surface.More detailed says, the inventor finds, contains the cover surface of the polymer micelle of following type, especially the multilamellar cover surface, strengthen the cover surface water holding capacity, stoped protein and greasy infiltration, and strengthened the drug release ability of cover surface.
The invention summary
Therefore, the present invention relates to a kind of supporter surface of coating, as biomedical devices, wherein clad contains a kind of lip-deep polymer micelle of this biomedical devices that is fixed at least, this micelle has hydrophilic outer shell and hydrophobic kernel or hydrophobic shell and hydrophilic kernel, and this micelle is that the block copolymer of about 1-about 40 is formed by the HLB value.The polymer micelle that is used for coating the supporter surface can exist with form of single sheet.Perhaps, they can be multilamellars, and wherein different layers is cross-linked with each other.In another embodiment, the multilamellar micelle contains two kinds of polymer micelles at least, the polyfunctionality low-molecular weight polymer chemical compound that they clip the heavy polymer chemical compound that contains many functional groups or contain two functional groups at least.
The accompanying drawing summary
Fig. 1 is for expression polymer-micelle laminated surface and according to lamination step sketch map of the present invention.
Fig. 2 is the AFM scintigram of a section part of laminated polymer micellar surface.
Fig. 3 illustrates in the polymer micelle laminated surface potential change as the pH function.
Fig. 4 illustrates the BSA absorbent properties that depend on polymer micelle lamination thing and the variation of zeta potential.In this figure, NH2/PP represents through plasma treated polypropylene; MCL-1 represents the NH2/PP that coated with the monolayer micelle; PAIAm-1 represents the MCL-1 that coats with PAH; MCL-2 represents the PAIAm-1 that coated with micelle; PAIAm-2 represents the MCL-2 that coated with PAH; MCL-3 represents the PAIAm-2 that coated with micelle.
The fluorescence intensity that Fig. 5 illustrates the silicon of handling with the ammonia plasma treatment of the bonded micelle coating of pyrene (APTS glass) changes.In the figure, use following legend:
-O-ML2????-■-3LE
-●-ML16??-▲-6LR
-□-3LO
The fluorescence intensity (I) that Fig. 6 illustrates APTS glass changes, and this glass micelle with 6 layers of polymer after being exposed to pyrene/micellar solution and water coats.
Fig. 7 has illustrated to see through the chamber of the films test dextran migration that coats with micelle, as described in example 3 above.
Fig. 8 represents to see through the dextran infiltration figure that micelle coats thin film, as described in example 6 above.In the drawings, used following legend:
PHEMA/ polypropylene film
The PHEMA/ polypropylene film that ■ coated with PEG-acetaldehyde (MW5000)
Zero monolayer micelle
● 3 layers of micelle
Detailed Description Of The Invention
As described here, the present invention relates to the supporter surface that coated with polymer micelle of the present invention.
As used herein, term " supporter surface " is to cause a kind of product of contacting with biofluid when using.Biofluid is meant the animal such as the mankind's body fluid, as tear, blood, urine, antiperspirant and saliva.Representational example comprises biomedical devices, as the experimental ware (as test tube, beaker etc.) that uses in the storage container of artificial organ (as artificial heart, artificial blood vessel, artificial bone, pacemaker etc.), contact lens, clamping plate, diagnostic instruments (as conduit), body fluid and the laboratory.Further, the supporter surface can be a film like structures, and it is by placing the intermediary high-molecular weight compounds of polymer micelle to form.Term " film like " is meant that it all is continuous films that base material needs not to be total.In addition, the supporter surface can be the medicine acceptable carrier.
The preferred support surface is a biomedical devices; Most preferably biomedical devices is contact lens and intraocular lens.
Terminology used here " supporter surface " refers to the untreatment surface that micelle is fixed in the above, and also refers to handle, the surface of coating or modified, to strengthen or to improve micellar stationarity above it.Preferred micelle is fixed on the biomedical devices by covalent bond.For example, as described below, on some surfaces hydroxyl can be arranged, there is carboxylic acid or carboxylate micelle in the above under the condition that ester forms, to react, to form a kind of ester, wherein oxygen atom from the teeth outwards and micellar acyl group form covalent bond.On the other hand, the surface can modify or handle with micelle formation covalent bond, so surface treated is classified as in term " supporter surface " scope.For example, if there is hydroxyl on the surface, then supporter can be put into atent solvent, as oxolane and chloroform.Then with the hydroxyl tresylated on surface, in case tresylated, can be with supporter surface amination in the aqueous solution of ethylenediamine, this causes group-NH-CH-CH
2-NH
2Be bonded to the carbon atom above it, this carbon atom is bonded on the substituted hydroxyl above it.Remove unreacted diamidogen, the surface that will so handle and carboxylic acid group above it react under the condition that forms amide then, to form amide compound, like this contain amino group by modification of surfaces and micellar aryl between form covalent bond.In addition, can be with non-micelle clad clad surface, this contains amino above clad, the amino on the clad can with micellar carboxylic acid group's reaction.Therefore, when being defined in the fixing and/or formation of covalent bond between supporter surface and the micelle, term " surface " comprises by placing the finishing of clad from the teeth outwards.
Between preferred support surface and the micelle fixedly is that covalent bond as described herein connects.
Clad can be that monolayer maybe can surpass one or more layers.Terminology used here " multilamellar " refers to two-layer or more multi-layered.If surpass one deck, preferably its contain at least two-layer, more preferably 2-10 layer, more preferably 2-6 layer.Preferred clad comprises the multilamellar micelle.
The polymer micelle that forms clad has preset thickness, no matter whether use single or multiple lift.The monolayer preferred thickness is that above 0.05 micron, more preferably thickness in monolayer is about 0.1 micron-about 0.5 micron, most preferably about 0.1 micron to about 0.3 micron according to size order.
When being multilamellar, each micelle layer can have identical or different thickness with other layer of complex.Yet, in each layer, the preferred thickness unanimity.Term " hydrogel " is a term in this area, refer to can be in water abundant swelling, but be not dissolved in the polymeric material of the wide region in the water.Yet the thickness of each layer determines by the different groups that exist in micelle usually, the low molecular compound that maybe may exist as the functional group above it, high molecular polymerization compounds, hydrophilic group etc.
If micelle is a monolayer, it can be made up of a kind of polymer micelle or more kinds of polymer micelle, although preferably it is made up of a kind of polymer micelle.If multilamellar, different layers can be made up of a kind of polymer micelle or more kinds of polymer micelle.In addition, even in each layer, the mixture of a kind of polymer micelle or more kinds of polymer micelles can be arranged.Yet preferably each layer is made up of one type polymer micelle.
In preferred embodiments, the present invention can provide a surface, and it supports the hydrogel layer of desired thickness by the lamination number of selective polymer micelle layer.Preferably,, then on the supporter surface, be no more than 10 layers, more preferably mostly be most 6 layers, comprise 6 layers if laminated.However, preferred every layer thickness is greater than 0.05 micron, and more preferably every layer thickness is about 0.05 micron-about 0.5 micron in the multilamellar scheme, more preferably about 0.05 micron to about 0.1 micron.
Polymer micelle single or multiple lift thickness can be adjusted by various technology known in the art, as being tiled on the supporting network with knife blade or centrifugal casting in pipe.
In the specific embodiments as the present invention described herein, micelle has a hydrophilic outer shell and a hydrophobic kernel.Under these conditions, the connection between supporter surface and the micelle is preferably the covalent bond between hydrophilic outer shell and the supporter surface.
Perhaps, micelle can have a hydrophobic shell and hydrophilic kernel, i.e. a reverse micelle.Under these conditions, the connection between preferred support surface and the micelle is the covalent bond between hydrophobic shell and the supporter surface.If micelle is a reverse micelle, preferred multilamellar micelle is to form like this: reverse micelle layer and hydrophobic shell clip a common micelle, and promptly a skin is that hydrophilic layer, internal layer are the micelles of water-repellent layer.This forms a stable interaction between different layers because the hydrophilic kernel of reverse micelle is facing to common micellar hydrophilic outer shell, and not in the face of or with common micellar hydrophobic in nuclear interaction.
Here used, unless indication is opposite, term " micelle " can comprise " common micelle " and " reverse micelle ".As indicating here, term " common micelle " is the micelle that a hydrophilic outer shell and a hydrophobic kernel are arranged, and reverse micelle is then opposite, i.e. a hydrophobic shell and a hydrophilic kernel.
As noted above, the present invention relates to the supporter that a quilt coats, a preferred biomedical devices that quilt coats, wherein clad comprises a kind of polymer micelle that is covalently bound to the biomedical devices surface at least, this micelle is fixed on the supporter surface.Preferred micelle is bonded to the supporter surface.Same preferred micelle has a hydrophilic outer shell, and it is covalently bound to surface and a hydrophobic kernel of biomedical devices, also is considered within the scope of the invention although the hydrophobic shell is covalently bound to the reverse micelle on supporter surface.No matter use common or reverse micelle, this micelle is made up of block copolymer, and its HLB value is about 1-about 40.
HLB (hydrophile-lipophile balance) is a term of art, and it is quite familiar for those skilled in that art.It is meant the content of hydrophilic and oleophilic moiety in nonionic molecule.Its definition and application are described in " the HLB system " of ICI Americas company publication.
Having surface-active block copolymer classifies according to the ratio of the hydrophilic and oleophilic moiety in the molecule.A large amount of commercial emulsifying agents as surfactant, have been specified hydrophilic (HLB) number.In some cases, calculate this number, under the other situation, calculate based on experiment emulsifying data from molecular structure.In addition, the HLB value is determined by other method, as cloud point method, gas chromatogram, critical micelle concentration and NMR spectrum.Preferably use sodium hypochlorite oxidation of starch.One is used for determining nonionic, comprises that the common-used formula of micellar HLB value is:
20 * (M
H)/(M
H+ M
L) equation I wherein, M
HBe the molecular weight of hydrophilic segment, M
LIt is the molecular weight of hydrophobic part.For example, a block copolymer that uses in the present invention has following molecular formula:
T-[oxygen ethylene]
35-[methyl methacrylate]
28-U wherein T and U is that the anchor that is connected to supporter group, has
HLB＝(20)[1540/(1540+2800)]＝7.1。
Unless indication is opposite, the HLB value of above-mentioned indication is meant the HLB value that obtains by the structure method, and more accurate saying so got according to aforesaid equation I calculating.
In preferred specific embodiments, the HLB value of used in the present invention block copolymer is about 4-about 20.
Block copolymer and comprise hydrophilic (water miscible) part and hydrophobic part by the micelle of its gained.Preferred micelle has a hydrophilic outer shell and a hydrophobic kernel.
Block copolymer and micellar preferred water dissolubility (hydrophilic) zone comprise Polyethylene Glycol, polyoxyethylene, polyvinyl alcohol, polyacrylamide, PMAm, polyvinyl pyrrolidone etc.Most preferably hydrophilic segment is Polyethylene Glycol, polyacrylamide, PMAm, polyvinyl pyrrolidone or polyvinyl alcohol.Most preferably hydrophilic nuclear is Polyethylene Glycol.
Chemical bond by non-hydrolysable is received the hydrophobic polymer segment on the hydrophilic polymer this chemical bond such as carbon-carbon bond with connected modes such as amido link, ehter bond, ester bond, sulfide linkage, amine keys.
Here used hydrophobic polymer segment can be from any polymer-derived, and condition is: form the stable polymer micelle can dissolve the segmental solvent of this hydrophobic polymer the time when corresponding block copolymer is dissolved or dispersed in.Preferred hydrophobic polymer segment comprises by Acetic acid, hydroxy-, bimol. cyclic ester or lactide derives and next poly-(alpha-hydroxy carboxylic acid compounds); Derive and poly-('omega '-hydroxy carboxylic acid) that come by gamma lactone or delta-lactone or ε-lactone; Or those copolymers by poly-(alpha-hydroxy carboxylic acid compounds) class and poly-('omega '-hydroxy carboxylic acid) class are derived and are come.The hydrophobic polymer segment at one end can have an ethylenic unsaturated polymerizable group, and that end that it and hydrophobic polymer segment are bonded to the hydrophilic polymer segment is opposite.Can introduce this polymerizable groups from (methyl) acrylic acid or vinyl benzyl chloride.In addition, after polymer micelle forms, this polymerizable groups can be carried out polyreaction, and so cause polymerization (crosslinked) state with the supporter surface.In this state, polymer micelle itself is more stable.
On the other hand, the hydrophilic polymer segment at one end has functional group, and segmental that end of hydrophobic polymer is relative with being bonded to.Therefore, in a preferred embodiment, when block copolymer formed polymer micelle, this functional group was present in the surface or the approaching surface of this polymer micelle, thereby forms common micelle.This functional group preferably is used for polymer micelle is covalently bound to the supporter surface, and when existing, heavy polymer chemical compound or polyfunctionality low molecular weight compound are between polymer micelle.Hydrophilic and hydrophobic polymer segment on the micelle can have more than one functional groups, and these functional groups can be identical or different.The example that is present in the functional group in the block copolymer comprises aldehyde radical, carboxyl, hydroxyl, sulfydryl, amino etc.If heavy polymer chemical compound or multi-functional degree low molecular weight compound exist, they have functional group, and some in the middle of them can be bonded on the polymer micelle.The various functional groups of above it these can be identical or different, and they can be identical or different with the functional group on the micellar hydrophilic or hydrophobic part.
Most preferably polymer micelle is formed by a kind of block copolymer, and this copolymer is made up of hydrophilic polymer segment and hydrophobic polymer segment, and the hydrophilic polymer chains segment base originally comprises Polyethylene Glycol (being abbreviated as PEG later on sometimes).Phrase " comprises substantially " and is meant that PEG accounts for the major part of hydrophilic polymer segment, and at the PEG chain or some linking groups etc. of some can be arranged between hydrophilic and hydrophobic polymer segment, generally this linking group is to the not influence of this segmental hydrophilic.Yet preferred PEG chain only is made up of PEG.
United States Patent (USP) 5 people such as Kataoka, 925,720, people's such as Sakarai 5,412,072, people's such as Kataoka 5,410,016, people's such as Kataoka 5,929,177, people's such as Sakurai 5,693,751, people's such as Yokoyama 5,449,513, found the example that can be used for preparing the micellar block copolymer of the present invention among WO96/32434, WO96/33233 and the WO97/0623, this micelle can be used for coating the supporter surface, and the content of all these patents is merged in the list of references.By introducing suitable functional group (comprising ethylenic unsaturated polymerizable group) in the above their modification also be can be used as the example of block copolymer, micelle of the present invention is preferably by this block copolymer preparation.Open in patent that preferred block copolymer was mentioned on those or the international monopoly publication.If block copolymer has saccharide residue at hydrophilic polymer segment one end, the same with block copolymer among the WO96/32434, should preferably saccharide residue be carried out the Malaprade oxidation reaction, to form corresponding aldehyde radical.
The example of block copolymer is represented by following molecular formula (I), (II), (III):
Molecular formula (I):
Wherein, L represents the chemical compound of following molecular formula:
Or
Wherein, R
1And R
2Refer to hydrogen atom, C independently
1-10Alkyl, aryl or aryl-C
1-3Alkyl; R refer to 2-5 integer and
Wherein, m refers to 2-10,000 integer;
N refers to 2-10,000 integer;
P refers to the integer of 1-5; With
Z refers to acetyl group, acryloyl group, methacryl, cinnamoyl, pi-allyl or vinyl benzyl;
Or following molecular formula (II):
Wherein, X refers to have the alkyl of 1-10 carbon atom, and it has an amino, a carboxyl or a sulfydryl;
Y refers to the group of following molecular formula:
Or
Wherein, R
11And R
12Refer to hydrogen atom or C independently
1-5Alkyl;
R
3Refer to hydrogen atom or methyl;
R
4The C that finger is replaced by hydroxyl
1-5Alkyl, this hydroxyl can be protected; With
Q refers to the integer of 2-5, and
Wherein, z refers to acryloyl group, methacryl, cinnamoyl, pi-allyl or vinyl benzyl; M refers to 2-10,000 integer;
And n refers to 2-10,000 integer;
Or following molecular formula (III):
Wherein, A refers to the group of deriving and by the Malaprade oxidation reaction from the saccharide residue that following molecular formula is arranged:
Wherein, one of dotted line (---) refers to singly-bound, and another refers to hydrogen atom; With
A and b refer to 0 or 1 integer independently, and wherein
L1 refers to the linking group of following molecular formula:
Or
Wherein, R
5And R
6Refer to hydrogen atom, C independently
1-6Alkyl, aryl or C
1-3Alkaryl; And
Wherein, m refers to 2-10,000 integer;
N refers to 2-10,000 integer; With
Z refers to acryloyl group, methacryl, cinnamoyl, pi-allyl or vinyl benzyl.
As used herein, unless indication is opposite, when independent use or and other group in conjunction with the time, alkyl refers to contain the low alkyl group of 1-6 carbon atom.Carbon atom can be straight chain or branching.Example comprises methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl, isobutyl group, the tert-butyl group, amyl group, neopentyl, hexyl etc.
When independent use or and other group in conjunction with the time, the term alkenyl refers to contain the low-grade alkenyl of 2-6 carbon atom.Alkenyl can contain one or more carbon-to-carbon double bonds, maximum 3; Yet, preferably contain 2 and more preferably 1 carbon-to-carbon double bond.Alkenyl can be straight chain or branching.Example comprises vinyl, 1-acrylic, 2-acrylic etc.
When here use separately or and other group in conjunction with the time, aryl refers to the aromatic portion that only contains ring carbon atom and contain 2k+2 ring carbon atom, wherein k is 1,2,3 or 4.Aryl can be monocycle, dicyclo, three ring or Fourth Rings; If it contains more than one ring, these rings merge mutually.Aryl can be replaced by the alkyl than low carbon atom number.Therefore, aryl can contain 6-18 ring carbon atom and add up to 6-25 carbon atom.Example comprises phenyl, tolyl, xylyl, naphthyl, Alpha-Naphthyl etc.
The preferred polymers micelle is to be formed by the above-mentioned block copolymer of mentioning; wherein the functional end-group of hydrophilic polymer segment is protected (for example; under the situation of aldehyde radical; then it is by acetalation or ketalization; under the situation of amino; it is protected by the amido protecting group), and, carry out the deblocking reaction then.When the segmental end of hydrophobic polymer has ethylenic unsaturated polymerizable group, after polymer micelle formed, each block copolymer can carry out the polymerization crosslinking reaction by this polymerizable groups.
If the clad of polymer micelle is a monolayer, then preferred it comprises the composition of molecular formula I-III recited above.If clad is laminated, then preferred clad comprises the series of layers of being made up of two kinds of polymer micelle layers at least, is formed by the polymer micelle of at least a above-mentioned molecular formula I-III.
Micellar lamination layer can be crosslinked by carbon-carbon bond.For example, micelle can contain inner carbon-to-carbon double bond or their side chain can contain carbon-to-carbon double bond.Can be they are crosslinked together by micelle is exposed to electron beam irradiation, radiation can produce free radical.Coupling cambium layer at random then.Usually, solution is exposed to enough electron radiations, to realize the formation of free radical.For example, the electron radiation scope can be about about 10 Megarads of 1-.Perhaps, can add light trigger by the micelle by in inertia solution, and solution is exposed to the visible light of enough wavelength or ultraviolet light to form free radical, micelle is crosslinked together.Coupling cambium layer at random then.Usually, the light that light trigger is exposed to enough wavelength is to form free radical, and it then reacts in micelle, and especially carbon-to-carbon double bond is to realize the formation of free radical in the micelle.
Perhaps, each layer can with heavy polymer chemical compound covalent bonding, this chemical compound has one or more functional groups (" another kind " functional group), this functional group can with the functional group's covalent bonding on the intrafascicular block copolymer of polymer latex, or and polyfunctionality low molecular weight compound bonding, this chemical compound has at least 2 kinds, preferred 2 or 3 kind should " another kind " functional group, this heavy polymer chemical compound and polyfunctionality low molecular weight compound all are positioned in the middle of the described 2 strata compound micelle layers.Then, different layers is by the mutual bonding of covalent bond between the functional group on the block copolymer in a kind of and polymer micelle in " another kind " functional group of above-mentioned heavy polymer chemical compound or polyfunctionality low molecular weight compound.Perhaps, outermost layer can be one deck of above-mentioned high-molecular weight compounds, in this case, its end and surface support thing bonding, and by covalent bond at the other end and micelle layer bonding.Have reactivity between the functional group of lip-deep functional group of supporter and heavy polymer, and between supporter surface and heavy polymer, form covalent bond.In addition, the functional group reactions of the functional group on the micelle and the heavy polymer other end has reactivity and form covalent bond between them between them.
The example of substituted functional group comprises and the amino of aldehyde covalent bonding but (the Schiff alkali that is formed by aldehyde radical, and amino can further be reduced) on high-molecular weight compounds; But hydroxyl and amino with the carboxyl covalent bonding; But carboxyl and sulfo group with the hydroxyl covalent bonding; But or and the sulfydryl of amino covalent bonding.Can under following known reaction condition, form this covalent bond, as oxidoreduction condition, dehydrating condensation condition, addition condition and replacement (or replacement) condition.
The heavy polymer chemical compound is that molecular weight surpasses about 8000 dalton, more preferably surpasses about 10,000 daltonian polymer, and has amino, carboxyl, thio group or sulfo group functional group.Preferred heavy polymer molecular weight is less than about 500,000 dalton, more preferably less than about 300,000 dalton.
Above-mentioned heavy polymer chemical compound is natural prodcuts or sintetics.These contain amino example and comprise polyalkenyl amine, as PAH, polyvinylamine etc.; The basic amino acid polymer is as polylysin, chitin and polymine.These examples that contain the heavy polymer of carboxyl comprise poly-(methyl) acrylic acid, polyacrylic acid, carboxymethyl cellulose and alginic acid etc., and these examples that contain the heavy polymer of sulfonic group (or sulfate) comprise heparin and polystyrolsulfon acid etc.
The low molecular weight compound preferred molecular weight is no more than 200 dalton, and more preferably the molecular weight ranges of these chemical compounds is about 120 dalton of about 17-, and the both is included.The example of polyfunctionality low molecular weight compound comprises low-grade alkylidene diamidogen (as ethylenediamine), glutaraldehyde, dithioglycol etc.
The example of substituted functional group comprises and the amino of aldehyde covalent bonding but (the Schiff alkali that is formed by aldehyde radical, and amino can further be reduced) on low molecular weight compound; But hydroxyl and amino with the carboxyl covalent bonding; But carboxyl and sulfonic group with the hydroxyl covalent bonding; But or and the sulfydryl of amino covalent bonding.Can under following known reaction condition, form this covalent bond, as oxidoreduction condition, dehydrating condensation condition, addition condition and replacement (or replacement) condition.
With technology known in the art high or low compound molecular weight and block copolymer are reacted.Block copolymer has functional group at its end, as hydroxyl, amino, carboxyl, thio group, or can have leaving group known in the art at its end, as halogen, sulphonic acid ester, as methanesulfonates, tosylate, brosylate etc.High molecular or low molecular weight compound also have functional group at its end, as hydroxyl, amino, carboxyl, thio group, or can have leaving group known in the art at its end, as halogen, sulphonic acid ester, as methanesulfonates, tosylate, brosylate etc.Block copolymer and high molecular or low molecular weight compound react under condition for validity to form product.In this reaction, product can form by displacement (replacements), or can form product under the condition of the condition that forms amide, formation ester, depends on functional group on the block copolymer and the functional group on high molecular or the low molecular weight compound.
For example, in one embodiment, chemical reaction can be represented with following equation:
X
1-(A
1-B
1)-X
2+Y
1-R
x-Y
2???→
Y
1-R
x-Y
2-X
1-(A
1-B
1)-X
2-Y
1-R
x-Y
2Wherein, (A
1-B
1-A
1-B
1) be block copolymer;
A
1It is hydrophilic segment;
B
1It is the hydrophobic segment;
X
1And X
2Identical or different, and represent energy and Y
2And Y
1Form the group of covalent bond respectively;
Y
1And Y
2Identical or different, and represent energy and X
2And X
1Form the group of covalent bond respectively; And
R
xBe low-molecular-weight or high-molecular weight compounds.
For example, use this technology, high molecular or low molecular weight compound can pass through amide (
Or
), or the ester bond connection (
Or
) be bonded on the block copolymer.
Yet in a different example, X (is X
1And X
2) in have only one to be leaving group, and Y (is Y
1And Y
2) be functional group, as hydroxyl, thio group, amino etc.Under these environment, react as follows:
X
1-(A
1-B
1)-X
2+Y
1-R
x-Y
2??→
Y
1-R
x-Y
2-(A
1-B
1)-Y-R
x-Y
2Wherein, A
1, B
1, R
x, Y
1And Y
2The same with above-mentioned definition, X
1And X
2Be leaving group.
For example, in this way, low-molecular-weight or high-molecular weight compounds can pass through ehter bond, sulfo-key or ammonia key and block copolymer bonding.
Similar, if X
1And X
2Be functional group, Y
1And Y
2Be leaving group, then obtain following product:
X
1-(A
1-B
1)-X
2+Y
1-R
x-Y
2???→
Y
1-R
x-X
1-(A
1-B
1)-X
2-R
x-Y
2Wherein, A
1, B
1With Rx as above-mentioned definition.
In another different embodiment, X
1, X
2, Y
1And Y
2Be leaving group; In this manner, between block copolymer and low-molecular-weight or high-molecular weight compounds, form the carbon-to-carbon covalent bond:
X
1-(A
1-B
1)-X
2+Y
1-R
x-Y
2??→
Y
1-R
x-(A
1-B
1)-R
x-Y
2
As noted above, all these are reflected under the condition that is enough to form required product carries out.
Carry out similar reaction with the surface, as described below.
The supporter surface is made by glass, silicon wafer, polypropylene etc., and it also can contain above-mentioned functional group.The supporter surface can not add to be handled or handles or modify by method described here.The supporter surface coats with micelle of the present invention.One deck micelle can coat the supporter surface and maybe can coat with the micelle that surpasses one deck.If be multiwalled, micelle can contain the high-molecular weight compounds that is clipped between the layer.Perhaps, micelle can contain the low molecular weight compound that is clipped between the layer.In another scheme, micellar layer can be crosslinked.In addition, if coat the supporter surface by surpassing two-layer micelle, the multilamellar micelle can contain any combination in these schemes.Further, supporter can carry out physical or chemical treatment with the heavy polymer chemical compound by known method.The example of this method illustrative in Fig. 1.
When polymer micelle of the present invention is placed in the water, form hydrogel.Term " hydrogel " is meant the polymeric material of wide region, and it is abundant swelling in water, but is not dissolved in the water.
Can by technology known in the art or by using any technology in above-mentioned technology or the patent of mentioning in the past and the PCT application to produce polymer micelle of the present invention, the content of all these be drawn and is list of references.
Then clad is applied to the supporter surface.Fix preferred polymers micelle and supporter surface formation covalent bond in order to guarantee clad.This can realize by technology known in the art, for example as follows:
(A) surface being contained the polymer micelle dispersion of functional group and supporter surface that other functional group is contained on the surface contacts, the lip-deep functional group of supporter can be intrafascicular with polymer latex functional group reactions, allow corresponding functional group on supporter surface and the polymer micelle at the conditioned response that can effectively form covalent bond then, and, if necessary, from the covalent bonding material that forms thus, remove unreacted polymer micelle.
If the multilamellar clad is applied to the supporter surface, then still use above-mentioned steps A.Yet under the situation of multilamellar clad, in the technology that coats the supporter surface, also use 2 additional steps.
What (B) will form thus contacts with a kind of solution with the polymer micelle layer of base covalent bonding, this solution contains the heavy polymer chemical compound of a large amount of above-mentioned functional groups or has 2 kinds at least, the polyfunctionality low molecular weight compound of preferred 2 kinds or 3 kinds above-mentioned functional groups, and this high-molecular weight compounds or this polyfunctionality low molecular weight compound accumulate on the described polymer micelle layer, and, then, functional group on the polymer micelle of the functional group of heavy polymer chemical compound or low molecular weight compound and steps A product is reacted under the condition that can effectively form covalent bond, and, if necessary, remove unreacted high molecular or low molecular weight compound; With
(C) the lamination thing of the step that will obtain thus (B) further contacts with foregoing polymer micelle dispersion, heavy polymer chemical compound or low molecular weight compound covalent bonding in this lamination thing, polymer micelle is accumulated on the heavy polymer chemical compound or polyfunctionality low molecular weight compound layer of this lamination thing, and, then, with this high molecular or low molecular weight compound and polymer micelle covalent bonding, and, if necessary, remove unreacted polymer micelle, and if necessary, further repeat this step (B) and (C).
These reactions among above-mentioned B and the C are carried out as mentioned above.
Adopt free radical to form technology and polymer micelle can be fixed on the supporter surface of any geometry, as with the bonded electron beam irradiation of light trigger or UV or visible light.According to this method, polymer micelle the polymer micelle that is enough to provide capacity cover the supporter surface with the concentration that reaches desired thickness under dissolving or be suspended in the aqueous solution preferred water.Preferred concentration range for is the about 15mg/mL of about 0.5mg/mL-, and two includes interior, and more preferably about about 5mg/mL of 1mg/mL-, and two includes interior.Then with the gained solution deposition on the supporter surface, adopt technology known in the art, as spraying, blade coating, that supporter is immersed micellar solution is medium.If polymer micelle contains polymerizable groups,, then can polymer micelle be covalently bound to the supporter surface by the known method of those skilled in the art as the carbon-to-carbon double bond in methacrylic acid, vinyl benzyl or ethylene.
In addition, before forming covalently bound between surface and the micelle, can handle the supporter surface.
Below illustrate technology.For example, as herein defined, the plasma by hydrogen and nitrogen preparation can be applied on the defined supporter of the present invention as 2 parts of hydrogen and 1 part of nitrogen.This plasma produces amino on the supporter surface.Polymer micelle with aldehyde radical degree of functionality can be under the condition of reductive amination and surface reaction, to form covalent bond with the supporter surface.The allyl amine plasma is an another kind of method of handling base (or Medical Equipment) surface, can react with micelle in generation amido site, surface and it.Except the mixture that uses hydrogen and nitrogen, in plasma reactor, to introduce the allyl amine steam, and produce amino on the supporter surface, it can react under the reductive amination condition with aldehyde radical or ketone group.
Perhaps, if carboxyl is arranged on the micelle, polymer micelle can and contain amino surface reaction under the condition that forms amide.
By coating base, other functional group can be received on the substrate surface with the plasma that contains described functional group.For example, can coat base with the plasma that contains carboxyl.Therefore, if micelle contains hydroxyl, surface that plasma coats and micelle react under the condition that forms ester, connect to form ester bond between the surface of micelle and plasma coating.Perhaps, if micelle contains amino, react under the condition that forms amide on the surface that micelle and plasma coat, and connects to form amido link between the surface of micelle and plasma coating.
It is pointed out that the hydroxyl that can come with the oxidant that those skilled in that art know on the oxidized surface forms carboxylic acid so that carboxyl is received on the surface, it can react with hydroxyl or the amido on the micelle then, to form aforesaid ester or amide respectively.Therefore, by the surface being exposed to a kind of reagent, be fixed with on this reagent can with the group of radical reaction of (or high molecular or low-molecular weight polymer or low molecular weight compound) on the micelle, activating surface with and micelle (or heavy polymer or low molecular weight compound) form covalent bond.Perhaps, micelle can be exposed to a kind of reagent, be fixed with on this reagent can with the group of lip-deep functional group reactions.Polymer micelle in the solution can be crosslinked together, and can be linked on the surface by being placed under the condition that forms free radical, form condition such as the electron beam irradiation or the adding light trigger of free radical and be exposed to light or UV light subsequently, it can produce free radical on micelle.Be cross-linked to form covalent bond between the free radical.Usually, if use electron beam irradiation, the solution that contains surface and polymer micelle is exposed to the electron ray that strength range is about 10 Megarads of about 1-, most preferably 4 Megarads.Gamma-rays can be used as radiation source, but may cause the degraded of polymer micelle, unless remove oxygen carefully.Perhaps, can add light trigger in solution, the solution that will contain light trigger and polymer micelle then is exposed to the light or the ultraviolet light of enough wavelength, to form free radical.Take place at random between micelle layer and surface by the crosslinked of free radical coupling.For example, in preferred embodiments, micelle is made up of the PEO side chain.If the PEO side chain contains the ethylenic unsaturated group, then adopt the crosslinked realization of above-mentioned technology.Because PEO contains several hydroxyls, so the remaining end hydroxyl is to be used for follow-up priming reaction, as affinity ligand is coupled on the PEO side chain.The micellar stability of crosslinked increase.
In another embodiment, polymer micelle can pass through the tresylation Covalent Immobilization of terminal hydroxy group to the supporter surface.Following embodiment has illustrative to the PEO hydrophilic group, but should be understood that this is illustrative, and following technology also is suitable for other hydrophilic group.
Supporter surface and polymer micelle are all pretreated before fixing.Like this, the active function groups of face that the tresylated polymer micelle is fixed to the upper should be contained in the supporter surface, as amino and/or thio group.Similar, with before the supporter surface contacts with polymer micelle tresylated in suitable solvent.To the PEO hydrophilic group, tresylation is especially convenient, and this is because PEO is dissolved into (for example dichloromethane, chloroform) in the tresyl chlorine by suitable medium.The method causes forming monolayer hydrogel clad on the supporter surface.
According to the method, contain the organic solvent of polymer micelle, under the condition on the PEO terminal hydroxy group that can effectively the tresyl group be fixed to polymer micelle, be exposed to tresyl chlorine as dichloromethane.Tresylated PEO polymer micelle with gained precipitates and recovery then, finally as exsiccant activated product.Before use just, with tresylated PEO polymer micelle be dissolved in pH value be 10 or higher aqueous solution in, to promote and the reaction that has been present in the amino and/or the thio group on supporter surface.Be covalently bound at polymer micelle under the condition of thick-layer on the supporter surface, the solution behind the pH regulator is contacted with the supporter surface of containing amino and/or thio group.
Except tresyl chlorine, also can use the terminal hydroxy group reaction of other reagent and PEO chain.These reagent comprise toluene sulfochloride (paratoluensulfonyl chloride), mesyl chloride (methane sulfonyl chloride), chloropropylene oxide, cyanuric chloride, (C
3N
3Cl
3), the mixture of carbonyl dimidazoles (CDI) and succinic anhydrides and succimide.Harris has described these reactions prevailingly, and " laboratory of polyethyleneglycol derivative is synthetic ",
J.Macromolecular Sci.Reviews in Macro. Chem.Phys.,C25 (3), 325-373 (1985), its content is merged in list of references.For example, the reaction of terminal hydroxy group polyoxyethylene and toluene sulfochloride or mesyl chloride generates polymer micelle tosylation or methylsulfonylization respectively.In both cases, activatory PEO side chain can with any molecular reaction that contains amino or thio group.The by-product that the chemical compound that contains amino or thio group and activation PEO chain reaction discharge comprises the reaction or the N-maloyl imines (reaction of succinic anhydrides and succimide) of tresyl, methanesulfonic acid or toluenesulfonic acid, HCl (reaction of cyanuric chloride), imidazoles (CDI).In the reaction of chloropropylene oxide, do not discharge by-product.Therefore; the any molecule that contains amino or thio group; for example can be covalently bound to the polyoxyethylene chain of tresylated, tosylation or methylsulfonylization by forming stable NC or SC key, remove corresponding sulfonic acid, tresyl, tosyl or mesyl.
In another embodiment, hydrophilic group can have carboxyl in the above, and can carry out pretreatment to form amino or hydroxyl in the above to the surface.Under the condition that forms amide or ester, surface and polymer micelle are reacted then, to form corresponding amide or ester.Similarly, can carry out modification to the surface, so that free carboxyl is arranged above it, can be amino or hydroxyl in the functional group of polymer ends.In addition, micelle and surface react under the condition that forms amide or ester, to form corresponding amide or ester respectively.In addition, can carry out pretreatment, so that it has free hydroxyl group, amino or thio group to the surface.Polymer micelle has a leaving group at its end, as halogenide or sulphonic acid ester, as, brosylate, tosylate or methanesulfonates etc.Polymer micelle and surface react under displacement or replacement condition, to form corresponding ehter bond, amine key or sulfo-key.In another embodiment, if carbon-to-carbon double bond is contained on the surface and the polymer micelle end has carbon-to-carbon double bond, then can adopt technology described herein to take place crosslinked by radical reaction.In this manner, adopt common technology in this area, by being selected from the surface that following covalent bond is incorporated into hydrophilic or hydrophobic nuclear bond biomedical devices:
-O-,-S-,
And CH
2CH
2.
By coating supporter with micelle, as biomedical devices (this micelle is that the block copolymer of about 1-about 40 is formed by HLB value scope), according to the present invention, biomedical devices does not have pollutant, especially protein basically.Although binding isotherm does not think that micelle can repel protein, therefore keep the surface of biomedical devices not have pollutant.When inserting biomedical devices in the animal body, preferred mammal, as Canis familiaris L., cat, cattle, horse, especially people, this is particularly useful.As consequence, when the biomedical devices that inserts coats with micelle described here, still less pollution and still less infected danger are just arranged.
The invention provides a kind of stable surface, the thickness range of wherein controlling the hydrogel layer that contains polymer micelle arrives in tens nanometers and surpasses 100 nanometers.
Polymer micelle can be used as system of object, as the carrier of molecule.For example, when biomedical devices being inserted or put into the patient body, the polymer micelle with hydrophilic outer shell and hydrophobic kernel can be a carrier, and the hydrophobic medicine that can discharge is contained in portion within it.When this surface and this hydrophobic medicine when in aqueous solvent, contacting under the intensification condition, can charge into medicine in polymer micelle inside.Medicine exists with the effective quantity of materia medica.At ambient temperature, this medicine can slow release in aqueous medium.The inventor finds, can come control drug release speed by adopting the multilamellar micelle.In more detail, they find that the micelle layer is many more, and drug release is slow more.Therefore, the effective control drug release of this micellar system.It is pointed out that also can carry out medicine by the polymer micelle lamination that will fill medicine before fills.Preferred agents is adsorbed to the supporter surface.In any case, it is biodegradable that the medicine on supporter surface connects, that is, be easy in the time of in being inserted into animal body remove.If medicine is covalently bound to the surface, then covalent bond is such: it is by the enzyme hydrolysis in the animal body.
The terminology used here medicine comprises medicament, therapeutic agent, vitamin, supplementary etc.
The inventor finds to pass through with micelle clad surface described here, and this method provides a surface that demonstrates outstanding bioaffinity.
Can use any preparation medicine as, for example, anticarcinogen, nervus centralis medicine, peripheral nervous medicine, allergic drug, causing circulatory medicine, respiratory apparatus medicine, digestive organs medicine, hormone medicine, antibiotic, chemotherapeutics, vitamin, food supplement etc.
Another purposes of polymer micelle described here is in the production of contact lens, especially at people's such as Larsen United States Patent (USP) 4,680,336, people's such as Kindt-Larsen 4,889,664 and people such as Kindt-Larsen 5,039, contact lens described in 459, all these contents all are merged in list of references here.For example, the contact lens according to the prepared of any aforementioned patent can coat with polymer micelle described here.Can coat one deck or surpass one deck.Adopt technology described here polymer micelle can be covalently bound on the suitable contact lens material well known in the art, as United States Patent (USP) 4,680,336,5,039,459,4,889, the poly-HEMA hydrogel contact lens described in 664.For example, contact lens material can be immersed and contain the solution of polymer micelle, and be exposed under the ionizing radiation condition of above-mentioned formation free radical, so that polymer micelle is covalently bound to contact lens surface.Perhaps, can be by modification being carried out on the contact lens material surface at its surface generation amino or thio group.Then the lens material that is modified is exposed to the activated polymer micelle, as above-mentioned tresylated derivant.
Compare with the contact lens that the micelle of not using here coats, the contact lens material that coats with polymer micelle of the present invention has several advantages.In more detail, because the performance of polymer micelle is used the lens material that is coated, reduced or eliminated the absorption of protein deposit in the native enzyme secretions of eyes basically.Therefore, owing to reduced protein adsorption, it is dull or fuzzy that the lens that coated will can not become.
In addition, micelle of the present invention has minimizing microbial contamination, comprises the ability of germ contamination.
And the contact lens that is coated has better water holding capacity, and therefore unlikely parches.
In addition, according to the present invention, the contact lens of Bao Fuing can be used as guest molecule like this, as the carrier of medicine, wherein according to technology described here medicine is covalently bound to the contact lens that is coated, and medicine is discharged in the body by eyes from contact lens then.Perhaps, with guest molecule, be embedded in the biomedical devices as pharmaceutical pack.For example, medicine is mixed in the material of preparation biomedical devices.Therefore, for example,,, add monomer mixture as medicine with guest molecule if biomedical devices is contact lens or intraocular lens, then according at United States Patent (USP) 4,680,336,5,039,459 and 4,889, the technology described in 664 is solidificated in them in lens.Then, in inserting animal body, as behind the eyes with medicine from wherein discharging.Perhaps, guest molecule can be attached to or be embedded in the micelle and maybe it can be covalently bound on the micelle.If be embedded in the micelle, in inserting animal body after, discharge by the guest molecule of embedding.If covalent bonding, situation about being covalently bound on the biomedical devices with medicine is the same, cuts off (hydrolysis) with its release by enzymolysis.In addition, can control the release of drug molecule, if especially use multilamellar.In any case, the consumption of guest molecule is a degree of effectively bringing into play its function.For example, if guest molecule is a medicine, then its consumption for relevant with its function to treating effective amount.
Therefore, for example, above-mentioned micelle can be as pharmaceutical carrier with the treatment ophthalmic.As mentioned above, medicine is added contact lens, and coat contact lens with above-mentioned polymer micelle by technology known in the art.The contact lens that will have clad and medicine inserts eyes.If wish controllable release, can coat contact lens with the lamination micelle.When inserting eyes, the enzyme that exists in the eyes can cut off the micelle that contains medicine, thereby medicine is sent to desired location.
In addition, when medicine was mucin or mucin shape structure, as polylactide or polyglycolic acid, the micelle clad was useful as the carrier of treatment dry eye syndrome.
Under usual conditions, ocular fluid forms the thin layer of about 7-10 micron thickness, and it has covered cornea and conjunctival epithelium.This superthin layer provides a slick visual surface by the small surface imperfection thing of disposing its epithelium for cornea, the surface of moistening cornea and conjunctival epithelium, therefore prevent epithelial damage, and stop in the cornea microbial growth on the conjunctiva by mechanical erosion.
Tear film generally includes three-decker.Outermost layer is the deutero-lipid layer of secretions by alkali plate gland, and is considered to stop the evaporation of water layer.Middle water layer is provided by main and less important lachrymal gland, and contains water-soluble substances.Rete malpighii is made up of glycoprotein and mucin, and is positioned at cornea and above the conjunctival epithelial cell.Epithelial cell membrane is made up of lipoprotein, generally is hydrophobic therefore.Mucin plays an important role to wetting surface, allows above the aqueous tear spread over, and comes wetting surface by the surface tension that reduces tear.Under household condition, mucin is provided by the goblet cell of conjunctiva, also can provide mucin from lachrymal gland.
When any tear film component is not enough, tear film will break, and will form dry spot on cornea and conjunctival epithelium.Any deficiency can cause eyes dry and astringent in three kinds of components (water, mucin or lipid).Ophthalmic such as keratoconjunctivitis that various ways is arranged.Those and rheumatic arthritis or the bonded disease of other connective tissue disease are known as this Jaeger logical sequence syndrome.
Connection between medicine and the contact lens is degradable.Mucin class product is hydrophobic as polyglycolic acid or polylactide, therefore dissolves in the hydrophobic part in the micelle.Therefore in the time will containing medicine and micellar contact lens and put into eyes, can at an easy rate medicine be removed from contact lens by biological method, and micelle keeping mucin class material, it is used for wetting eye.
Except polylactide and polyglycolic acid, other mucin class material can be adsorbed on the contact lens as collagen or gelatin, coats with micelle described here then.Collagen and gelatin also can be dissolved in micelle.When putting into eyes, collagen or gelatin discharge from contact lens, and the wetting eye surface.
Mucin class material exists with effective dose in clad as polyglycolic acid, polylactide, collagen and gelatin.
As mentioned above, micelle of the present invention reduces infected by microbes.For example, if biomedical devices is contact lens or intraocular lens, and coat with micelle of the present invention, contact lens will reduce microbial contamination.Micelle postpones or prevents that the clad of the amount effect biomedical devices of microbial contamination from existing being enough to basically.
Yet, polluting in order further to reduce microorganism (as antibacterial), biomedical devices or micelle can be used in combination with antibacterial.For example, be used for preparing in the material of biomedical devices, antibacterial can be embedded in micelle or the biomedical devices by sneaking into.For example, if biomedical devices is a contact lens, according to United States Patent (USP) 4,680,336,5,039,459 and 4,889, the technology described in 664 is sneaked into antibacterial in the monomer, as poly-HEMA.Perhaps, utilize technology described here that it is covalently bound on biomedical devices or the micelle.In this case,,, can reduce microorganism if micelle or biomedical devices contain antibacterial with respect to the contact lens that does not have antibacterial, as antibacterial to biomedical devices, as the pollution of contact lens or intraocular lens.Antibacterial delays and/or prevents that basically the amount of microbial contamination is present in coating equipment or the micelle being enough to.
The invention provides several advantages, especially when hydrophilic segment is PEG.One of most important advantage is and easily to obtain highdensity hydrophilic segment by simple micelle coating, as the PEG clad.And be not easy to reach this purpose by PEG being grafted to the surface.Although binding isotherm is not thought this number owing to PEG chain in the micelle.
In addition, body series has prevented that the triggering of grafting PEG is mobile.This in addition great change takes place at environment, when for example the surface was dry, also keeping surface-stable was a very big advantage.Grafted chain especially to the processing on high animal migration surface, comprises siloxanes to the normally individual problem of the migration of sample interior when drying.Yet clad of the present invention has been avoided this problem.
In the following embodiments the present invention there is more detailed explanation.Yet these embodiment do not limit the present invention.
In argon atmosphere, in a reactor, add 30ml THF, 0.147g 3, the THF solution of the naphthalene potassium of 3-diethoxy propanol and 3.0ml 0.34mol/l at room temperature stirred 10 minutes.Therefore form 3, the potassium compound of 3-diethoxy propanol.In gained solution, add 7.04g oxirane, under room temperature and 1 atmospheric pressure, stir the gained mixture.With gained solution reaction 2 days, then, add the THF solution of the DL-lactide of 26.0ml 1.92mol/l, the gained mixture is continued to stir 2 hours.Then, add the 3.1g methacrylic anhydride, the gained mixture was at room temperature stirred 2 days.Pour gained solution into cold 2-propanol, and precipitate the polymer that forms thus.By the lyophilization precipitate that the purification centrifugalize obtains from benzene, productive rate is 11.48g (79.4%).According to GPC and
1H-NMR, the molecular weight of Polyethylene Glycol (PEG) segment, polylactide (PLA) and block copolymer is respectively 5800,4000 and 9800.
The micellar preparation of Acet-PEG-PLA and to the micellar transformation of aldehyde radical PEG-PLA
The block copolymer that makes among the 280mg embodiment 1 is dissolved in the 40ml dimethyl acetylamide (DMA).The dialyser that with the classification molecular weight is 12-14000 carries out dialysis against the current (2 liters: 2 hours, 5 hours and 8 hours) with gained solution.Adding 1N-HCl in the gained dialysate, is 2 with the pH value of regulating dialysate, and the gained mixture was stirred 2 hours.The pH value of regulating gained solution by adding 0.1N-NaOH aqueous solution is 7.Then, be that the dialyser of 12-14000 carried out dialysis against the current 24 hours with gained solution with the classification molecular weight.Thus obtained dialysate is moved in the flask of argon atmosphere, add the potassium peroxydisulfate of every micelle 1.8 (W/W) % then, after the degassing, the gained mixture was reacted 24 hours down at 50 ℃.The indication μ of the polydispersity of the dynamic light scattering of product (DLS) test shows particle size and polymer micelle/Γ 2 is respectively (35.5nm, 0.094) and (41.0nm, 0.125) before and after polyreaction.Before and after polyreaction, almost do not find change in particle size.
The aqueous solution (20g/l) that respectively adds the 1ml sodium lauryl sulphate in the product solution before and after the polyreaction of 2ml, and, carry out the DLS test then with gained solution stirring 24 hours.Found that,, keeping the indication μ/Γ 2 of particle size and polydispersity to be 47.2nm and 0.106 at reaction post polymerization thing micelle although almost completely disappear at reaction prepolymer micelle.This shows that polymer micelle is so stable after reaction, to such an extent as to even with not decomposing after the surfactant processing.Micelle is cryodesiccated before and after polyreaction, carries out in heavy chloroform
1The H-NMR test.The deutero-peak of terminal olefine (the 5.6 and 6.2ppm) complete obiteration that discovery observes before by reaction, this shows that polymerization efficiency is very high.In this case, the polymerization at the methacryl of polylactide end generates highly stable micelle.
The preparation of base (or chassis)
For the chassis, use the thin slice of mainly making by wave carrier piece, silicon chip or polypropylene.Wave carrier piece or silicon chip are cut into suitable dimensions, and carry out ultrasonic waves for cleaning, then under about 100 ℃, use by 30%H
2SO
4And H
2The mixing material of O (volume ratio is 1: 1) further cleans, and cleans fully with pure water then.With the wave carrier piece handled thus or silicon chip fragment vacuum drying 16 hours at normal temperatures, then it was soaked 3-4 hour in the toluene solution of 3-aminopropyltriethoxywerene werene, follow at 160 ℃ of following vacuum dryings.By this way, the amino surface that therefore is introduced into this fragment.On the other hand, when polypropylene is used as the material on chassis, by using N
2: H
2Cement Composite Treated by Plasma (the Samco International that (volume ratio is 1: 2) makes; The BP-1 type; 75W; 30 minutes) mode amino is introduced the surface on chassis.
The zeta potential measurement being carried out on the surface of handling thus shown, is positive polarity at low pH value scope inner surface.Therefore, confirmed the existence of surface amino groups.
The polymer micelle lamination coats
At normal temperatures, to there be amino silicon chip (manufacturing of MitsubishiMaterial company) in polymer micelle solution, to soak 2 hours by the surface of preparation among the embodiment 3, this micelle is dissolved in the NaCNBH that this solution of 0.04M HEPES[contains 0.0032 (w/v) % according to the prepared of embodiment 2
3], concentration is approximately 1mg/ml.By after removing unconjugated polymer micelle with the pure water washing, further be repeatedly dipped into polymer micelle solution and washing step, therefore constituted laminate-type micelle-gel film (see figure 1).By the way, in final micelle clad, NaCNBH
3Consumption concentration be 0.25%.
Embodiment 5 Laminate film (polymer micelle layer; Be called the micelle clad later on) property test(a) atomic force microscope (AFM) test
Thickness with the micelle clad of preparation in the AFM test implementation example 4.For configuration of surface, under the situation of monolayer, obtained an images, wherein micelle itself be fixed on lip-deep.Yet, when the clad number increased, variation had taken place, scrambling has also become obviously.Cutting away an area with the brute force of cantilever from the surface that coats with the multilamellar micelle under contact mode is 1 * 1 μ m
2The zone, then, under the pattern of patting, check cross section.Fig. 2 has shown the variation of thickness, and it is to observe according to the number of clad.Thickness is approximately 20nm in monolayer, and it changes to 40-45nm at the double-coating layer, is 80-90nm in three layers of clad.
About three layers of micelle clad, observe the area cut off in the contact mode incision having reduced in time.Although binding isotherm is not thought in the laminate film on surface, micelle and PAH are crosslinked by chemical bond; Therefore, recover gradually, cause cutting the decline of area with the laminate film of cantilever cutting with compression.
On the other hand, when the unpolymerized micelle of the kernel polymer micelle of polyreaction (or do not carry out) is as the AFM test three layers when coating, in coating thin film, observe and break.Although binding isotherm is not thought that the tension force that produces causes the destruction of the unpolymerized thin film of its kernel, thereby has been caused disruptive formation in the thin film of multilamellar clad.By the way, in polymeric micelle, do not find such breaking.
(b) test of zeta potential
Measure the zeta potential of the micellar surface of above-mentioned micelle clad in the sodium chloride solution of 7.5mM, the pH value scope is 2-11.Fig. 3 is a sketch map.When micellar surface is outermost layer, low the reaching ± 5mV of variation of the zeta potential that causes by the variation of pH value.On the other hand, when PAH during, be 8 o'clock along with pH value increases to pH at outermost layer, zeta potential is higher, and still, when increasing pH value and surpass pH=8, zeta potential finally drops to 0.On micellar surface and PAH surface, when clad mostly was 3 layers most, no matter the lamination number how, zeta potential remained unchanged.As shown in Figure 2, the repetition thickness with the lamination number increases.As shown in Figure 3, although the zeta potential between micelle layer and the PAH layer is widely different, only there is small difference to cause by the lamination number.This shows, although the thickness increase owing to lamination, micelle layer and PAH layer do not mix mutually, but exist with the form of lamination shape layer.
(c) protein adsorption
When as above stating the micelle clad with hydrogel and come clad surface, especially when micelle is the outmost surface layer, wish to stop absorption of proteins.In order to confirm, the propylene chassis surface of amino having been introduced coated with said method with the micelle lamination gel pack of preparation among the embodiment 1, and the protein (bovine serum albumin: BSA) absorption on micellar surface and PAH surface relatively.The sample that micelle is coated immerses the BSA solution of 45 μ g/ml, keeps 1 hour.Behind rinsing sample gently, remove the protein of adsorbed close with surfactant (sodium lauryl sulphate), and measure the BSA (analytical biochemistry, 1985,150,76) that removes thus by the BCA method of measuring BSA absorption in the per unit volume.The result as shown in Figure 4.This has proved, when micelle during at outermost layer, has suppressed absorption of proteins.When PAH during, observed high protein adsorption at outermost layer.Although binding isotherm is not thought this phenomenon owing to the existence of sample surfaces positive charge, it has caused the electrostatic interaction of PROTEIN B SA, and interaction has taken place on the positive charge surface of this BSA and PAH.Yet when with the micelle clad surface, the minimizing of BSA absorption shows that this surface is covered by micelle fully, and micelle has shielded the variation of PAH effectively.
Generally speaking, data show that clearly micellar multilamellar clad repels protein adsorption effectively on the positive charge surface, and the PAH surface is slight hydrophobic.
(d) adding of the intrafascicular pyrene of polymer latex and release
Micelle formation hydrogel thin film by method for preparing.Therefore, hydrogel thin film contains the hydrophobic inner membrance.As follows, be possible to introducing the hydrophobic medicine by the kernel of micelle formation gel surface.Shown in following data, the intrafascicular drug release of polymer latex will be a controllable release.
Pyrene is as model drug.Pyrene the acetone soln of pyrene added flask, so that can accumulate in the inwall of flask.Behind bone dry, the polymer micelle solution among the embodiment 2 is added flask, and stirred 4 hours down at 60 ℃.After solution temperature is got back to room temperature, remove insoluble matter with the filter of 0.4 μ m.Then, according to the technology of embodiment 3, coat the polymer micelle that pyrene is housed that obtains thus with the product clad of the embodiment 1 of varying number, number of plies scope is the 1-6 layer.Described in the concrete clad such as following table:
Table 1. micelle is to the coating of amination glass surface
* the coating time that coats for the third time is a whole night.
| Sample | Coat the number of plies | The coating condition |
| ML2 | ?1 | NaH at 0.01M 2PO 4In ,～1mg/ml micelle and 0.25% (w/v) NaCNBH 3，25℃，2h |
| ML16 | ?1 | NaH at 0.01M 2PO 4In ,～1mg/ml micelle and 0.25% (w/v) NaCNBH 3，25℃，16h |
| 3LO | ?3 | 1. in 0.4M HEPES (pH6.7),～1mg/ml micelle, 25 ℃, |
| 3LE | ?3 | 1. in 0.04M HEPES (pH6.7) ,～1mg/ml micelle and 0.016% (w/v) NaCNBH
3, 25 ℃, |
| 6LE * | ?6 | 1. in 0.04M HEPES (pH6.7) ,～1mg/ml micelle and 0.016% (w/v) NaCNBH
3, 25 ℃, |
Each lamination thing is immersed in the water, and measure the fluorescence intensity that produces by the pyrene on the chassis in time.The result as shown in Figure 5.
Shown in data, initial fluorescence intensity depends on the coating number of plies.The fluorescence intensity that coats (3LO, 3LE) for 3 times is once 2 times of coating (ML2, ML16) intensity, and the intensity of 6 coatings (6LE) is approximately more than 10 times.This result shows that by the coating under the described condition of table 1, micellar multilamellar can be connected to the surface, and this multilamellar has increased the surperficial quantity that goes up pyrene.
On the other hand, the rate dependent of fluorescence intensity decline is in coating condition and coating number.Initial fluorescence intensity looks with to coat number closely related.Yet, the different variations that cause the fluorescence fall off rate in different and Sciff alkali (3LO and the 3LE) method of reducing of coating number of times (ML2 and ML16), as shown in Figure 5.It should be noted that 6 layers of coating have shown high initial intensity, and the loaarithmic curve of intensity and temperature retention time shows that pyrene is more controlled from the release on surface.Although binding isotherm is not thought in diffusion process, medicine may take place to be re-assigned in the micelle by multilamellar rubber alloy bundle layer, make and realize that with controlled manner dilator discharges.
(e) pyrene coats micellar filling and release from the surface
In order to determine that medicine can be repeated to be filled into micelle coats in the sample, has studied the filling that coats back hydrophobic reagent at micelle equally.For this purpose, the micelle that will prepare in embodiment 1 coats sample and is exposed in the micellar solution or water that contains pyrene.Under the condition identical, will there be the micellar solution of pyrene to be coated on the on glass of APTS with 6LE.It is on glass under the condition identical with 6LE micellar solution to be coated to APTS.Then micelle is coated sample and be exposed in the micellar solution that is filled with pyrene, kept 12 hours.Wash this sample then with water, and under room temperature (～22 ℃) and 4 ℃, in excessive water, preserved 12 hours.During preservation, the fluorescence of periodic measurement sample.Preservation in water is exposed to sample in the micellar solution that is filled with pyrene after finishing, and keeps 12 hours, then in water.Fig. 6 has shown the curve (λ ex=336.2nm, λ em=375nm) of fluorescence intensity.
Fluorescence intensity after being exposed to the micelle that is filled with pyrene is almost identical with the initial intensity of 6LE among Fig. 5.(release-filling, 24h) afterwards, fluorescence intensity returns to base level in circulation for the first time.Circulation for the second time too.Discharge (0-12h) for the first time and shown identical intensity decreases with release (24-36h) for the second time.These results show that the micelle clad is stable, and can repeat to fill and discharge pyrene.Exposing (48-60h) for the third time is in 4 ℃ water.Suppression ratio the first two times of fluorescence intensity discharges (being exposed to 22 ℃ water) and wants slow.Although the segmental activeness of PLA also may influence pyrene (hydrophobic medicine) from micellar release, temperature may influence the diffusion coefficient of pyrene in micelle equally.If the molecule that the packing ratio pyrene is bigger, rate of release may be lower.
Embodiment 6
In order to estimate the ability that the micelle layer stops the molecule free permeation, adopt polypropylene film (25 micron thickness, 45% hole, 0.25 micron pore size), promptly PP is as base.With hemacol PHEMA cover film, by methanol solution with polypropylene film immersion 10%, and drying at room temperature, carry out Cement Composite Treated by Plasma described here subsequently.Coat this amidized sample with the monolayer micelle of embodiment 1 noted earlier and the multilamellar micelle of embodiment 4.Test dextran infiltration to sample thin film from a side of thin film to the diffusion of opposite side by measuring fluorescein isothiocyanate (FiTC) dextran (buying) from Sigma Aldrich company.Used instrument (4) as shown in Figure 7.Sample thin film (1) separates a side and the opposite side of container, and the one side is equipped with PBS solution (2), and opposite side is equipped with the FITC dextran solution (3) of 0.1% (weight/volume) in PBS solution.The temperature of container is set in 25 ℃.The PBS solution of per 24 hours sampling 3.0ml, and the infiltration rate of dextran is measured in the variation by fluorescent intensity.
Fig. 8 has shown that the dextran infiltration coats the curve of thin film by micelle.As a comparison, shown coating under the same terms the permeability of the thin film of handling to the permeability of PP (polypropylene) thin film that PHEMA is arranged and with PEG-acetaldehyde that PHEMA is arranged equally with micelle.When coating the PHEMA/PP thin film with PEG, the permeability of dextran increases.This is owing to the erosion on PHEMA surface.Compensate this erosion by multilamellar micelle clad.The micelle clad has covered the surface effectively.Under the situation of 3 layers of micelle coatings, owing to micelle, PAH (PAIAm; Weight average molecular weight is 10,000, can buy from Tokyo Nittobo chemical company) network that forms and the increase of layer thickness, obviously stoped infiltration rate.
Above preferred embodiment and embodiment are used for illustrating scope of the present invention and spirit.These embodiments and embodiment will make those those skilled in that art know other embodiment and embodiment in addition.Other embodiment and embodiment are also in desired extent of the present invention.
Therefore, the present invention is only limited by claims.
Claims (72)
1. biomedical devices that quilt coats, wherein clad comprises at least a polymer micelle that is fixed on described biomedical devices surface, described micelle has a hydrophilic kernel and hydrophobic shell or a hydrophobic kernel and a hydrophilic outer shell, and the block copolymer that described micelle is about 1-about 40 by a kind of HLB value scope is formed.
2. the quilt according to claim 1 coats biomedical devices, and the HLB value scope of wherein said block copolymer is about 4-about 20.
3. according to the biomedical devices that coated of claim 1, wherein micelle has an outside hydrophilic shell and an inner hydrophobic nuclear.
4. according to the biomedical devices that coated of claim 1, wherein micelle has an outside hydrophobic shell and an inner hydrophilic nuclear.
5. the quilt according to claim 1 coats biomedical devices, and wherein micelle is covalently bound to the surface of biomedical devices.
6. according to the biomedical devices that coated of claim 5, wherein the covalent bonding of micelle by being selected from following group is to the surface of biomedical devices:
-O-,-S-,
With
7. the quilt according to claim 1 coats biomedical devices, and wherein micelle has a hydrophilic outer shell and a hydrophobic kernel, and hydrophilic outer shell is covalently bound to the surface of biomedical devices.
8. the quilt according to claim 1 coats biomedical devices, and wherein micelle has a hydrophobic shell and a hydrophilic kernel, and the hydrophobic shell is covalently bound to the surface of described biomedical devices.
9. the quilt according to claim 7 coats biomedical devices, and wherein hydrophilic outer shell is made up of Polyethylene Glycol, polyacrylamide, PMAm, polyvinyl pyrrolidone or polyvinyl alcohol basically.
10. the quilt according to claim 9 coats biomedical devices, and wherein hydrophilic outer shell is a Polyethylene Glycol.
11. according to the biomedical devices that coated of claim 7, wherein the hydrophobic kernel is methyl methacrylate, siloxanes, poly-(alpha-hydroxy carboxylic acid compounds) or poly-('omega '-hydroxy carboxylic acid).
12. according to the biomedical devices that coated of claim 11, wherein the hydrophobic kernel comprises poly-(alpha-hydroxy carboxylic acid compounds) or poly-('omega '-hydroxy carboxylic acid) or methyl methacrylate.
13. the quilt according to claim 1 coats biomedical devices, wherein the hydrophobic kernel has a free radical activity group at its end.
14. the quilt according to claim 13 coats biomedical devices, wherein said hydrophobic shell has an ethylenic polymerizable groups at its end.
15. the quilt according to claim 14 coats biomedical devices, wherein ethylenic unsaturated polymerizable group is a kind of free radical activity polymerizable acrylic ester, free radical activity polymerizable styryl, free radical activity polymerizable methacrylate or free radical activity polymerizable vinyl ethylether.
16. the quilt according to claim 1 coats biomedical devices, wherein said hydrophilic kernel has a free radical activity group at its end.
17. the quilt according to claim 16 coats biomedical devices, wherein said hydrophilic outer shell has an ethylenic unsaturated polymerizable group at its end.
18. the quilt according to claim 17 coats biomedical devices, wherein ethylenic unsaturated polymerizable group is a kind of free radical activity polymerizable acrylic ester, free radical activity polymerizable styryl, free radical activity polymerizable methacrylate or free radical polymerizable vinyl ethylether.
19. according to the biomedical devices that coated of claim 1, wherein biomedical devices coats with the described micelle of monolayer.
20. according to the biomedical devices that coated of claim 1, wherein biomedical devices coats with the described micelle of multilamellar.
21. according to the biomedical devices that coated of claim 20, wherein biomedical devices coats with maximum 6 layers of described micelle.
22. the quilt according to claim 20 coats biomedical devices, wherein multilamellar comprises that at least one cover is clipped in the covalent bonding layer that their intermediary second polymer are formed by two layers of polymers micelle and one deck, the molecular weight of described second polymer is greater than 8000 dalton, has above it to be selected from amino, carboxyl and sulfonic functional group in a large number.
23. according to the biomedical devices that coated of claim 22, wherein second polymer is PAH, polyvinylamine, polylysin, chitin, polymine, poly-(methyl) acrylic acid, carboxymethyl cellulose, alginic acid, heparin or polystyrolsulfon acid.
24. the quilt according to claim 20 coats biomedical devices, wherein at least two micelle layers are cross-linked with each other.
25. the quilt according to claim 20 coats biomedical devices, wherein biomedical devices coats with the multiple layer polymer micelle, wherein multilamellar comprises at least one cover by two layers of polymers micelle and be clipped in the covalent bonding layer that their intermediary a kind of low-molecular-weight molecules are formed, and low-molecular-weight molecule is selected from low-grade alkylidene diamidogen, glutaraldehyde and ethane two mercaptan.
26. the quilt according to claim 1 coats biomedical devices, wherein the block copolymer formula is as follows:
Wherein, L is meant the part of following molecular formula:
Or
Wherein, R
1And R
2Refer to hydrogen atom, C independently
1-10Alkyl, aryl or aryl-C
1-3Alkyl; R refer to 2-5 integer and
Wherein, m refers to 2-10,000 integer;
N refers to 2-10,000 integer;
P refers to the integer of 1-5; With
Z refers to acetyl group, acryloyl group, methacryl, cinnamoyl, pi-allyl or vinyl benzyl.
27. the quilt according to claim 1 coats biomedical devices, wherein the block copolymer formula is as follows:
Wherein, X is meant the alkyl of 1-10 carbon atom, and it has amino, carboxyl or a sulfydryl; Y is meant the part of following molecular formula:
Or
Wherein, R
11And R
12Refer to hydrogen atom or C independently
1-5Alkyl;
R
3Refer to hydrogen atom or methyl;
R
4The C that finger is replaced by hydroxyl
1-5Alkyl, this hydroxyl can be protected; With
Q refers to the integer of 2-5, and
Wherein, z refers to acryloyl group, methacryl, cinnamoyl, pi-allyl or vinyl benzyl; M refers to 2-10,000 integer;
And n refers to 2-10,000 integer.
28. the quilt according to claim 1 coats biomedical devices, wherein the block copolymer formula is as follows:
Wherein, A refers to the group of deriving and by the Malaprade oxidation reaction from the saccharide residue that following molecular formula is arranged:
Wherein, one of dotted line (---) refers to singly-bound, and another refers to hydrogen atom; With
A and b refer to 0 or 1 integer independently, and wherein
L
1The linking group that refers to following molecular formula:
Or
Wherein, R
5And R
6Refer to hydrogen atom, C independently
1-6Alkyl, aryl or C
1-3Alkaryl; And
Wherein, m refers to 2-10,000 integer;
N refers to 2-10,000 integer; With
Z refers to acryloyl group, methacryl, cinnamoyl, pi-allyl or vinyl benzyl.
29. coat biomedical devices according to the quilt of any one among the claim 1-28, wherein biomedical devices is contact lens or intraocular lens.
30. method that is used to reduce the protein contamination of biomedical devices after inserting animal body, described method comprises that the polymer micelle that adsorbs with a kind of Profilin matter that is fixed on effective quantity on described biomedical devices surface coats this biomedical devices, described micelle has a hydrophilic outer shell and hydrophobic kernel or a hydrophobic shell and a hydrophilic kernel, and the block copolymer that this micelle is about 1-about 40 by a kind of HLB value scope is formed.
31. according to the method for claim 30, the HLB value scope of wherein said block copolymer is about 4-about 20.
32. according to the method for claim 30, wherein micelle has a hydrophilic outer shell and a hydrophobic kernel.
33. according to the method for claim 30, wherein micelle has a hydrophobic shell and a hydrophilic kernel.
34. according to the method for claim 30, wherein micelle is covalently bound to the surface of biomedical devices.
35. the quilt according to claim 34 coats biomedical devices, wherein hydrophilic kernel is by being selected from the surface of following covalent bonding to biomedical devices:
-O-,-S-,
With
36. according to the method for claim 30, wherein micelle has a hydrophilic outer shell and a hydrophobic kernel, and hydrophilic outer shell is covalently bound to the surface of biomedical devices.
37. according to the method for claim 30, wherein micelle has a hydrophobic shell and a hydrophilic kernel, and the hydrophobic shell is covalently bound to the surface of described biomedical devices.
38. according to the method for claim 36, wherein hydrophilic outer shell is made up of Polyethylene Glycol, polyacrylamide, PMAm, polyvinyl pyrrolidone, polyvinyl alcohol or polymethacrylates or polyacrylate basically.
39. according to the method for claim 38, wherein hydrophilic outer shell is a Polyethylene Glycol.
40. according to the method for claim 36, wherein the hydrophobic kernel is methyl methacrylate, siloxanes, poly-(alpha-hydroxy carboxylic acid compounds), poly-('omega '-hydroxy carboxylic acid).
41. according to the method for claim 40, wherein the hydrophobic kernel comprises poly-(alpha-hydroxy carboxylic acid compounds), poly-('omega '-hydroxy carboxylic acid) or methyl methacrylate.
42. according to the method for claim 33, wherein the hydrophobic shell has a free radical activity group at its end.
43. according to the method for claim 42, wherein said hydrophobic shell has an ethylenic unsaturated polymerizable group at its end.
44. according to the method for claim 43, wherein said ethylenic unsaturated polymerizable group is free radical activity polymerizable acrylic ester, free radical activity polymerizable styryl, free radical activity polymerizable methacrylate or free radical polymerizable vinyl ethylether.
45. according to the method for claim 32, wherein said hydrophilic outer shell has a free radical activity group at its end.
46. according to the method for claim 45, wherein said hydrophilic outer shell has an ethylenic unsaturated polymerizable group at its end.
47. according to the method for claim 46, wherein ethylenic unsaturated polymerizable group is free radical activity polymerizable acrylic ester, free radical activity polymerizable styryl, free radical activity polymerizable methacrylate or free radical polymerizable vinyl ethylether.
48. according to the method for claim 30, wherein biomedical devices coats with one deck micelle.
49. according to the method for claim 30, wherein biomedical devices coats with the multiple layer polymer micelle.
50. according to the method for claim 49, wherein biomedical devices coats with maximum 6 strata compound micelles.
51. method according to claim 49, wherein multilamellar comprises that at least one cover is clipped in the covalent bonding layer that their intermediary second polymer are formed by two layers of polymers micelle and one deck, the molecular weight of described second polymer is greater than 8000 dalton, has above it to be selected from amino, carboxyl and sulfonic functional group in a large number.
52. according to the method for claim 51, wherein second polymer is PAH, polyvinylamine, polylysin, chitin, polymine, poly-(methyl) acrylic acid, carboxymethyl cellulose, alginic acid, heparin or polystyrolsulfon acid.
53. method according to claim 49, wherein biomedical devices coats with the multiple layer polymer micelle, wherein multilamellar comprises at least one cover by two layers of polymers micelle and be clipped in the covalent bonding layer that their intermediary a kind of low-molecular-weight molecules are formed, and low-molecular-weight molecule is selected from low-grade alkylidene diamidogen, glutaraldehyde and ethane two mercaptan.
54. according to the method for claim 30, wherein biomedical devices is contact lens or intraocular lens.
55. according to the method for claim 30, wherein block copolymer has following molecular formula:
Wherein, L is meant the part of following molecular formula:
Or
Wherein, R
1And R
2Refer to hydrogen atom, C independently
1-10Alkyl, aryl or aryl-C
1-3Alkyl; R refer to 2-5 integer and
Wherein, m refers to 2-10,000 integer;
N refers to 2-10,000 integer;
P refers to the integer of 1-5; With
Z refers to acetyl group, acryloyl group, methacryl, cinnamoyl, pi-allyl or vinyl benzyl.
56. according to the method for claim 30, wherein block copolymer has following molecular formula:
Wherein, X is meant the alkyl of 1-10 carbon atom, and it has amino, carboxyl or a sulfydryl;
Y is meant the part of following molecular formula:
Or
Wherein, R
11And R
12Refer to hydrogen atom or C independently
1-5Alkyl;
R
3Refer to hydrogen atom or methyl;
R
4The C that finger is replaced by hydroxyl
1-5Alkyl, this hydroxyl can be protected; With
Q refers to the integer of 2-5, and
Wherein, z refers to acryloyl group, methacryl, cinnamoyl, pi-allyl or vinyl benzyl; M refers to 2-10,000 integer;
And n refers to 2-10,000 integer.
57. according to the method for claim 30, wherein block copolymer has following molecular formula:
Wherein, A refers to the group of deriving and by the Malaprade oxidation reaction from the saccharide residue that following molecular formula is arranged:
Wherein, one of dotted line (---) refers to singly-bound, and another refers to hydrogen atom; With
A and b refer to 0 or 1 integer independently, and wherein
L
1The linking group that refers to following molecular formula:
Or
Wherein, R
5And R
6Refer to hydrogen atom, C independently
1-6Alkyl, aryl or C
1-3Alkaryl; And
Wherein, m refers to 2-10,000 integer;
N refers to 2-10,000 integer; With
Z refers to acryloyl group, methacryl, cinnamoyl, pi-allyl or vinyl benzyl.
58. according to any one method among the claim 30-57, wherein biomedical devices is contact lens or intraocular lens.
59. one kind is discharged into the intravital method of animal with guest molecule, it comprises that (a) is attached to described guest molecule on biomedical devices or the micellar surface, or enter in biomedical devices or the micelle, (b) coat this biomedical devices with at least a lip-deep polymer micelle of biomedical devices that is fixed on, described micelle comprises a hydrophobic shell and a hydrophilic kernel or comprises a hydrophilic outer shell and a hydrophobic kernel, the block copolymer that described micelle is about 1-about 40 by a kind of HLB value scope is formed, and (c) described biomedical devices is inserted in the described animal body.
60. according to the method for claim 59, wherein guest molecule is a kind of medicine.
61. according to the method for claim 59, wherein biomedical devices is contact lens or intraocular lens.
62. according to the method for claim 60, wherein biomedical devices is a contact lens, medicine is to the useful medicament of treatment ophthalmic.
63. according to the method for claim 60, the connection that its Chinese medicine is linked on the biomedical devices is biodegradable.
64. according to the method for claim 62, wherein ophthalmic is a dry eye syndrome.
65. according to the method for claim 59, wherein micelle is a lamination.
66. according to the method for claim 65, wherein drug release is weak gradually.
67. method that is used to reduce the microbial contamination of biomedical devices after in inserting animal body, this method comprises that the antimicrobial polymer micelle with effective quantity coats described biomedical devices, described micelle has a hydrophilic outer shell and hydrophobic kernel or a hydrophobic shell and a hydrophilic kernel, and the block copolymer that described micelle is about 1-about 40 by a kind of HLB value scope is formed.
68. according to the method for claim 67, the HLB value scope of wherein said block copolymer is about 4-about 20.
69., wherein additionally on biomedical devices have a kind of antimicrobial according to the method for claim 67.
70. according to the method for claim 58, wherein biomedical devices is a contact lens.
71. according to the method for claim 70, wherein contact lens is made of hemacol.
72. the quilt according to claim 1 coats biomedical devices, it stops the infiltration of dextran to it basically.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP313463/1999 | 1999-11-04 | ||
| JP31346399A JP2001131271A (en) | 1999-11-04 | 1999-11-04 | Surface on which polymer-micell layer is laminated and its preparation process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1434730A true CN1434730A (en) | 2003-08-06 |
Family
ID=34179415
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 00818177 Pending CN1434730A (en) | 1999-11-04 | 2000-11-03 | Polymer micelle as monolayer or layer-laminated surface |
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| CN (1) | CN1434730A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101137700B (en) * | 2005-03-09 | 2012-07-18 | 东丽株式会社 | Microparticle and pharmaceutical composition |
| CN101516413B (en) * | 2006-09-15 | 2013-11-13 | 东丽株式会社 | Substrate and method for production thereof |
| CN104956256A (en) * | 2012-08-27 | 2015-09-30 | 视觉力学有限责任公司 | Contact lens with a hydrophilic layer |
-
2000
- 2000-11-03 CN CN 00818177 patent/CN1434730A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101137700B (en) * | 2005-03-09 | 2012-07-18 | 东丽株式会社 | Microparticle and pharmaceutical composition |
| CN101516413B (en) * | 2006-09-15 | 2013-11-13 | 东丽株式会社 | Substrate and method for production thereof |
| CN103071192B (en) * | 2006-09-15 | 2016-04-27 | 东丽株式会社 | Base material and manufacture method thereof |
| CN104956256A (en) * | 2012-08-27 | 2015-09-30 | 视觉力学有限责任公司 | Contact lens with a hydrophilic layer |
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