CN1434730A - Polymer micelle as monolayer or layer-laminated surface - Google Patents

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

Polymer micelles as monolayers or laminated surfaces

field of invention

The present invention relates to single or multilayer polymer micelles and their use as surface coatings, especially for biomedical devices.

Background of the invention

Micelles are colloidal aggregates of amphiphilic molecules that contain both hydrophilic and hydrophobic parts. In a polar medium such as water, the hydrophobic portion of the amphiphilic molecules forming micelles will stay away from the polar portion, while the polar portion of the molecule, also known as the headgroup, will gather at the polar micellar water (solvent) interface. On the other hand, micelles can also be formed in non-polar media, such as non-polar organic solvents, such as hexane, where amphoteric micelles around small water droplets are located in the center of the system. In non-polar media, the hydrophobic part will be exposed to the non-polar medium, while the hydrophilic part will be away from the solvent and closer to the water droplet. Such assemblies are sometimes called reverse micelles. These two aforementioned systems represent oil-in-water and water-in-oil type systems, respectively.

A micelle can take several forms, depending on the conditions and composition of the system. For example, small micelles in dilute solutions at about the critical micelle concentration (CMC) are generally considered to be spherical. However, under other conditions, they may be distorted spheres, disks, rods, flakes, and the like.

Micelles are formed at a critical micelle concentration (CMC), which depends on several factors, including the type of amphiphile, solvent system, solute, etc. Critical micelle concentration refers to the concentration at which micelles start to form in a system containing solvent, amphiphile, solute, etc. CMC can be determined experimentally using standard techniques in the art. For example, the CMC of a surfactant can be determined by plotting the performance as a function of surfactant concentration; note that performance generally varies linearly with increasing concentration, up to the CMC, at which point the curve becomes nonlinear. Properties that have been used to measure CMC include such properties as refractive index, light scattering, dialysis, surface tension, and dye solution.

Micellar properties are influenced by the environment and especially by specific changes in the environment, such as temperature, solvents, soluble components, electrolytes in the system, etc. Micelles whose properties have been investigated have been described in the prior art.

For example, US Patent 5,929,177 to Kataoka et al. describes a polymer molecule in which it can be used as a drug delivery vehicle. Micelles are formed from block copolymers containing functional groups at both ends, and it contains hydrophilic/hydrophobic segments. The polymer functional groups at the end of the block copolymer chain include amino, carboxyl and mercapto groups at the α-terminal and hydroxyl, carboxyl, aldehyde and vinyl groups at the ω-terminal. The hydrophilic segment includes polyoxyethylene, while the hydrophobic segment is derived from lactide, lactone or (meth)acrylate.

其中，R¹和R²彼此相互结合，代表C_1-10烷氧基、芳氧基或芳基-C_1-3烷氧基或氧基(＝O)，或R¹和R²独立地代表乙二氧基，-O-CH(R¹)-CH₂-O-；U.S. Patent 5,925,720 to Kataoka et al. provides a heterotelechelic oligomer or polymer of the formula:

Wherein, R ¹ and R ² are combined with each other and represent C _1-10 alkoxy, aryloxy or aryl-C _1-3 alkoxy or oxy (=O), or R ¹ and R ² are independently Represents ethylenedioxy, -O-CH(R ¹ )-CH ₂ -O-;

R ¹ refers to hydrogen or C _1-6 alkyl;

或(CH₂)_r；R³和R⁴独立地代表氢、烷基、芳基或芳烷基；r为2-5；m为2-10,000；n为2-10,000；L is

Or (CH ₂ ) _r ; R ³ and R ⁴ independently represent hydrogen, alkyl, aryl or aralkyl; r is 2-5; m is 2-10,000; n is 2-10,000;

p is 1-5;

q is 0-20;

When q is 0, z refers to H, alkali metal, acetyl, acryloyl, methacryloyl, cinnamoyl, p-toluenesulfonyl, 2-mercaptopropionyl or 2-aminopropionyl or allyl or vinyl phenyl,

When q is 1-20, z is C _1-6 alkoxycarbonyl, carboxyl, mercapto or amino.

This oligomer or polymer forms a polymeric micelle that is stable in aqueous solvents and is useful as a vehicle for drug delivery.

In none of these references are micelles used as coatings.

However, other types of non-micelle polymers have been used to coat surfaces. For example, US Patent 5,275,838 to Merrill discloses a method of immobilizing polyoxyethylene (PEO) star molecules in a hydrogel layer and their products, which can be used to coat surfaces. It describes a method for immobilizing polyoxyethylene star molecules to the surface of a support to form a coating on it, comprising the following steps:

(a) exposing an organic solution containing polyoxyethylene star molecules, each of which essentially consists of a large number of divinyl groups attached to Hydroxyl-terminated polyoxyethylene chains on the benzene core, the reagent group allows the subsequent substitution of amino or thiol groups to the PEO chain ends, thus forming an activated polyoxyethylene star molecule with active reactive end groups;

(b) isolating the activated polyoxyethylene star molecules containing reactive end groups from the organic solvent;

(c) dissolving the activated polyoxyethylene star molecule in an aqueous solution; and

(d) contacting the solution of step (c) with the surface of a support containing amino groups and/or thiol groups to covalently bond the star molecules with reactive end groups, thereby immobilizing the star molecules with reactive end groups into a thick layer on the surface of the support.

The star molecule has a polymeric core, such as divinylbenzene, from which a series of polyoxyethylene chains or branches grow. These star molecules are not micelles. They do not contain block copolymers and have an HLB value (Hydrophile-Lipophile Balance) of 1-40. As described herein, star molecules are formed by anionic polymerization of divinylbenzene, oxyethylene, and optionally styrene.

The present invention utilizes compound types and coating techniques other than those described by Merrill. Unlike Merrill, the coating composition of the present invention consists of micelles. As explained later, the micelles used in the present invention consist of block copolymers having an HLB value of 1-40. The present inventors have found that coating a surface with the specific polymer micelles of the present invention brings several advantages to the coated surface. In more detail, the present inventors have found that coating surfaces, especially multi-layer coating surfaces, containing polymer micelles of the following type enhance the water retention capacity of the coating surface, prevent the formation of proteins and oils Penetrate and enhance the drug release ability on the coating surface.

Brief description of the invention

Accordingly, the present invention relates to a coated support surface, such as a biomedical device, wherein the coating comprises at least one polymeric micelle immobilized on the surface of the biomedical device, the micelle having a hydrophilic outer shell and a hydrophobic An aqueous core or a hydrophobic shell and a hydrophilic core, the micelles are composed of block copolymers having an HLB value of from about 1 to about 40. The polymeric micelles used to coat the surface of the support may exist in the form of a single layer. Alternatively, they may be multilayer, where the different layers are crosslinked to each other. In another embodiment, the multilayered micelles contain at least two types of polymeric micelles sandwiching a high molecular weight polymeric compound containing many functional groups or a multifunctional low molecular weight polymeric compound containing at least two functional groups.

Brief description of the drawings

Figure 1 is a schematic diagram showing a polymer-micelle laminated surface and the lamination steps according to the present invention.

Figure 2 is an AFM scan of a cross-sectional portion of the surface of a laminated polymer micelle.

Figure 3 illustrates the potential change as a function of pH in a polymeric micellar laminated surface.

Figure 4 illustrates the variation of BSA absorption properties and zeta potential depending on polymer micelle laminates. In this figure, NH2/PP represents plasma-treated polypropylene; MCL-1 represents NH2/PP that has been coated with monolayer micelles; PAIAm-1 represents polypropylene that has been coated with polyallylamine MCL-1; MCL-2 means PAIAm-1 that has been coated with micelles; PAIAm-2 means MCL-2 that has been coated with polyallylamine; MCL-3 means that it has been coated with micelles PAIAm-2.

Figure 5 graphically illustrates the change in fluorescence intensity of ammonia plasma-treated silicon (APTS glass) coated with pyrene-bound micelles. In this figure, the following legend is used:

-O-ML2 -■-3LE

-●-ML16 -▲-6LR

-□-3LO

Figure 6 illustrates the change in fluorescence intensity (I) of APTS glass coated with 6 layers of polymerized micelles after exposure to pyrene/micelle solution and water.

FIG. 7 is a schematic diagram of the chamber for testing the migration of dextran through a membrane coated with micelles, as described in Example 3. FIG.

Figure 8 shows a graph of the penetration of dextran through micellar coated films, as described in Example 6. In the figures, the following legends are used:

□PHEMA/polypropylene film

■PHEMA/PP film coated with PEG-Acetaldehyde (MW5000)

○Single-layer micelles

●3 layers of micelles

Detailed description of the invention

As described herein, the present invention relates to support surfaces coated with polymeric micelles of the present invention.

As used herein, the term "support surface" is a product that, when used, may come into contact with biological fluids. Biological fluids refer to bodily fluids of animals such as humans, such as tears, blood, urine, sweat and saliva. Representative examples include biomedical devices such as artificial organs (such as artificial hearts, artificial blood vessels, artificial bones, pacemakers, etc.), contact lenses, splints, diagnostic instruments (such as catheters), storage containers for body fluids, and laboratory The laboratory utensils used (such as test tubes, beakers, etc.). Furthermore, the support surface can be a film-like structure, which is composed of high molecular weight compounds placed in the middle of polymer micelles. The term "film-like" means that the substrate need not be a continuous film throughout the structure. Alternatively, the surface of the support may be a pharmaceutically acceptable carrier.

Preferred support surfaces are biomedical devices; most preferred biomedical devices are contact lenses and intraocular lenses.

As used herein, the term "support surface" refers to an untreated surface on which micelles are immobilized, and also refers to a surface that has been treated, coated or modified to enhance or enhance the immobilization of micelles thereon. Preferably the micelles are covalently immobilized on the biomedical device. For example, as described below, some micelles that may have hydroxyl groups on the surface and carboxylic acids or carboxylate esters on them can react under ester-forming conditions to form an ester in which the oxygen atoms on the surface and the glue The acyl groups of the bundle form a covalent bond. On the other hand, the surface may be modified or treated to form covalent bonds with the micelles, such treated surfaces are classified within the term "support surface". For example, if there are hydroxyl groups on the surface, the support can be placed in an inert solvent such as tetrahydrofuran, and chloroform. The hydroxyl groups of the surface are then tresylated, and once tresylated, the support surface can be aminated in an aqueous solution of ethylenediamine, which results in bonding the group -NH-CH- _CH2 - _NH2 to the carbon atom above it, the A carbon atom is bonded to a substituted hydroxyl group above it. Remove the unreacted diamine, and then react the surface thus treated with the carboxylic acid groups on it under amide-forming conditions to form amide compounds, so that the modified surface containing amino groups and the aryl groups of the micelles form a covalent bond between them. In addition, the surface can be coated with a non-micelle coating layer, which contains amino groups on the coating layer, and the amino groups on the coating layer can react with the carboxylic acid groups of the micelles. Thus, when defining the immobilization and/or formation of covalent bonds between the surface of the support and the micelles, the term "surface" includes surface modification by placing coatings on the surface.

Preferably the immobilization between the support surface and the micelles is a covalent linkage as described herein.

The cladding may be a single layer or may be more than one or more layers. The term "multilayer" as used herein means two or more layers. If more than one layer, preferably it contains at least two layers, more preferably 2-10 layers, more preferably 2-6 layers. Preferably the coating comprises multilayered micelles.

The polymer micelles forming the coating layer have a predetermined thickness regardless of whether a single layer or multiple layers are used. Monolayers preferably have thicknesses, in order of size, of greater than 0.05 microns, more preferably monolayers have thicknesses of from about 0.1 microns to about 0.5 microns, most preferably from about 0.1 microns to about 0.3 microns.

When multilayered, each micellar layer may be of the same or different thickness than the other layers of the composite. However, in each layer, the thickness is preferably uniform. The term "hydrogel" is a term of art and refers to a broad range of polymeric materials that are substantially swellable in water, but do not dissolve in water. However, the thickness of each layer is generally determined by the different groups present in the micelles, such as functional groups on it, high molecular polymer compounds or possibly low molecular compounds, hydrophilic groups, etc.

If the micelle is unilamellar it may consist of one polymeric micelle or more polymeric micelles, although preferably it consists of one polymeric micelle. If multilayered, the different layers may consist of one type of polymeric micelles or more types of polymeric micelles. In addition, even within each layer, there may be one type of polymeric micelles or a mixture of more types of polymeric micelles. However, it is preferred that each layer consists of one type of polymeric micelles.

In a preferred embodiment, the present invention can provide a surface that supports a desired thickness of the hydrogel layer by selecting the number of laminations of the polymeric micellar layers. Preferably, if laminated, there are no more than 10 layers on the surface of the support, more preferably up to and including 6 layers. Nonetheless, it is preferred that each layer is greater than 0.05 microns thick, more preferably in a multi-layer approach, each layer has a thickness from about 0.05 microns to about 0.5 microns, more preferably from about 0.05 microns to about 0.1 microns.

The thickness of the single or multiple layers of polymer micelles can be adjusted by various techniques known in the art, such as spreading on a support mesh with a surgical blade or centrifugal casting in a tube.

In a specific embodiment of the invention as described herein, the micelles have a hydrophilic outer shell and a hydrophobic inner core. Under these conditions, the link between the support surface and the micelles is preferably a covalent bond between the hydrophilic shell and the support surface.

Alternatively, micelles can have a hydrophobic outer shell and a hydrophilic inner core, ie reverse micelles. Under these conditions, preferably the connection between the support surface and the micelles is a covalent bond between the hydrophobic shell and the support surface. If the micelles are reverse micelles, it is preferred that the multilayered micelles are formed in such a way that the reverse micellar layer and the hydrophobic outer shell sandwich an ordinary micelle, that is, a glue with a hydrophilic outer layer and a hydrophobic inner layer. bundle. This creates a stable interaction between the different layers, since the hydrophilic inner core of the reverse micelles faces the hydrophilic outer shell of the normal micelles and does not face or interact with the hydrophobic inner cores of the normal micelles.

As used herein, the term "micelle" may include both "ordinary micelles" and "reverse micelles", unless indicated to the contrary. As noted herein, the term "ordinary micelle" is a micelle with a hydrophilic shell and a hydrophobic core, while reverse micelles are the opposite, ie a hydrophobic shell and a hydrophilic core.

As indicated above, the present invention relates to a coated support, preferably a coated biomedical device, wherein the coating comprises at least one polymeric micelle covalently bonded to the surface of the biomedical device, the The micelles are immobilized on the support surface. Preferably the micelles are bound to the support surface. It is also preferred that the micelles have a hydrophilic shell, which is covalently bonded to the surface of the biomedical device, and a hydrophobic core, although reverse micelles with a hydrophobic shell covalently bonded to the surface of the support are also contemplated. within the scope of the present invention. Whether normal or reverse micelles are used, the micelles are composed of block copolymers having an HLB value of from about 1 to about 40.

HLB (Hydrophile-Lipophile Balance) is a term of art which is quite familiar to those skilled in the art. It refers to the content of hydrophilic and lipophilic moieties in nonionic molecules. Its definition and application are described in "The HLB System" published by ICI Americas Corporation.

Surface-active block copolymers are classified according to the ratio of hydrophilic and lipophilic parts of the molecule. A number of commercial emulsifiers, such as surfactants, have been assigned a hydrophilic/lipophilic balance (HLB) number. In some cases this number was calculated from the molecular structure, in other cases it was calculated based on experimental emulsification data. In addition, HLB values have been determined by other methods such as fog point method, gas chromatography, critical micelle concentration and NMR spectroscopy. The HLB values are preferably calculated using structural methods. A common formula used to determine the HLB value of non-ionic substances, including micelles, is:

20 x (M _H )/(M _H +M _L ) Equation I where M _H is the molecular weight of the hydrophilic portion and _ML is the molecular weight of the hydrophobic portion. For example, a block copolymer used in the present invention has the formula:

T-[oxyethylene] ₃₅ -[methyl methacrylate] ₂₈ -U where T and U are the anchoring groups attached to the support, with

HLB=(20)[1540/(1540+2800)]=7.1.

Unless indicated to the contrary, the HLB values referred to above refer to HLB values obtained by the structural method, more precisely calculated according to Equation I as described above.

In a preferred embodiment, the block copolymers used in the present invention have an HLB value of from about 4 to about 20.

Block copolymers and micelles derived therefrom comprise a hydrophilic (water-soluble) portion and a hydrophobic portion. Preferably the micelles have a hydrophilic shell and a hydrophobic core.

Preferred water-soluble (hydrophilic) regions of block copolymers and micelles include polyethylene glycol, polyoxyethylene, polyvinyl alcohol, polyacrylamide, polymethacrylamide, polyvinylpyrrolidone, and the like. Most preferably the hydrophilic moiety is polyethylene glycol, polyacrylamide, polymethacrylamide, polyvinylpyrrolidone or polyvinyl alcohol. Most preferably the hydrophilic core is polyethylene glycol.

The hydrophobic polymer segment is connected to the hydrophilic polymer by means of amide bonds, ether bonds, ester bonds, sulfur bonds, amine bonds, etc. through non-hydrolyzable chemical bonds, such as carbon-carbon bonds.

The hydrophobic polymer segments used herein may be derived from any polymer provided that a stable polymer gel is formed when the corresponding block copolymer is dissolved or dispersed in a solvent capable of dissolving the hydrophobic polymer segment bundle. Preferred hydrophobic polymer segments include poly(alpha-hydroxycarboxylic acids) derived from glycolide or lactide; poly(alpha-hydroxycarboxylic acids) derived from gamma-lactone or delta-lactone or (ω-hydroxycarboxylic acids); or those derived from copolymers of poly(α-hydroxycarboxylic acids) and poly(ω-hydroxycarboxylic acids). The hydrophobic polymer segment may have an ethylenically unsaturated polymerizable group at one end opposite the end at which the hydrophobic polymer segment is bonded to the hydrophilic polymer segment. Such polymerizable groups can be introduced from (meth)acrylic acid or vinylbenzyl chloride. In addition, such polymerizable groups can be polymerized after the formation of polymer micelles, and thus lead to a polymerized (crosslinked) state with the surface of the support. In this state, the polymer micelles themselves are more stable.

On the other hand, the hydrophilic polymer segment has a functional group at one end opposite to the end bonded to the hydrophobic polymer segment. Thus, in a preferred embodiment, when the block copolymer forms polymer micelles, the functional groups are present at or near the surface of the polymer micelles, thus forming normal micelles. This functional group is preferably used to covalently bond the polymeric micelles to the support surface, and when present, the high molecular weight polymeric compound or multifunctional low molecular weight compound is located between the polymeric micelles. The hydrophilic and hydrophobic polymer segments on the micelles can have more than one type of functional group, which can be the same or different. Examples of functional groups present in the block copolymer include aldehyde groups, carboxyl groups, hydroxyl groups, mercapto groups, amino groups, and the like. If high molecular weight polymeric compounds or multifunctional low molecular weight compounds are present, they have functional groups, some of which can be bonded to the polymeric micelles. These various functional groups thereon may be the same or different, and they may be the same or different from the functional groups on the hydrophilic or hydrophobic part of the micelle.

Most preferably, the polymer micelles are formed from a block copolymer consisting of hydrophilic polymer segments and hydrophobic polymer segments, the hydrophilic polymer segments essentially comprising polyethylene glycol (hereinafter sometimes abbreviated for PEG). The phrase "substantially includes" means that PEG accounts for the main part of the hydrophilic polymer segment, and there may be a certain amount of some linking groups etc. between the PEG chain or between the hydrophilic and hydrophobic polymer segments, generally the linking The group has no effect on the hydrophilicity of the segment. However, it is preferred that the PEG chain consists only of PEG.

In U.S. Patents 5,925,720 to Kataoka et al., 5,412,072 to Sakarai et al., 5,410,016 to Kataoka et al., 5,929,177 to Kataoka et al., 5,693,751 to Sakurai et al., 5,449,513 to Yokoyama et al. Examples of block copolymers that can be used to prepare the micelles of the invention that can be used to coat the surface of a support are found in , the contents of all of which are incorporated by reference. Their modification by introducing suitable functional groups thereon, including ethylenically unsaturated polymerizable groups, are also examples of block copolymers from which the micelles of the present invention are preferably prepared. Preferred block copolymers are disclosed in those patents or international patent publications mentioned above. If the block copolymer has a sugar residue at one end of the hydrophilic polymer segment, as in the block copolymer of WO 96/32434, the sugar residue should preferably be subjected to Malaprade oxidation to form the corresponding aldehyde group.

Examples of block copolymers are represented by the following formulas (I), (II), (III):

其中，L代表下列分子式的化合物：

或 其中，R¹和R²独立地指氢原子、C_1-10烷基、芳基或芳基-C_1-3烷基；r指2-5的整数，和Molecular formula (I):

Wherein, L represents the compound of following molecular formula:

or Wherein, R ¹ and R ² independently refer to a hydrogen atom, C _1-10 alkyl, aryl or aryl-C _1-3 alkyl; r refers to an integer of 2-5, and

Wherein, m refers to an integer of 2-10,000;

n refers to an integer of 2-10,000;

p refers to an integer from 1 to 5; and

z refers to acetyl, acryloyl, methacryloyl, cinnamoyl, allyl or vinylbenzyl;

Or the following molecular formula (II):

Wherein, X refers to an alkyl group with 1-10 carbon atoms, which has an amino group, a carboxyl group or a mercapto group;

或

其中，R¹¹和R¹²独立地指氢原子或C_1-5烷基；Y refers to the group of following molecular formula:

or

Wherein, R ¹¹ and R ¹² independently refer to a hydrogen atom or a C _1-5 alkyl group;

R ³ refers to a hydrogen atom or a methyl group;

R ⁴ refers to C _1-5 alkyl substituted by hydroxy, which may be protected; and

q refers to an integer from 2 to 5, and

Wherein, z refers to acryloyl, methacryloyl, cinnamoyl, allyl or vinylbenzyl; m refers to an integer of 2-10,000;

And, n refers to an integer of 2-10,000;

其中，A指从有如下分子式的糖残基通过Malaprade氧化反应衍生而来的基团：其中，虚线(---)之一指单键，而另一个指氢原子；和Or the following molecular formula (III):

where A refers to a group derived from a sugar residue having the following molecular formula by Malaprade oxidation: Wherein, one of the dotted lines (---) refers to a single bond, and the other refers to a hydrogen atom; and

a and b independently refer to an integer of 0 or 1, and where

L1 refers to the linking group of the following molecular formula: or Wherein, R ⁵ and R ⁶ independently refer to a hydrogen atom, C _1-6 alkyl, aryl or C _1-3 alkaryl; and

Wherein, m refers to an integer of 2-10,000;

n refers to an integer from 2 to 10,000; and

z means acryloyl, methacryloyl, cinnamoyl, allyl, or vinylbenzyl.

As used herein, unless indicated to the contrary, alkyl when used alone or in combination with other groups refers to lower alkyl groups having 1 to 6 carbon atoms. Carbon atoms can be straight chain or branched. Examples include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl, pentyl, neopentyl, hexyl, and the like.

The term alkenyl when used alone or in combination with other groups refers to lower alkenyl groups containing 2 to 6 carbon atoms. Alkenyl groups may contain 1 or more carbon-carbon double bonds, up to 3; however, preferably contain 2 and more preferably 1 carbon-carbon double bond. Alkenyl groups can be straight chain or branched. Examples include vinyl, 1-propenyl, 2-propenyl, and the like.

As used herein alone or in combination with other groups, aryl refers to an aromatic moiety containing only ring carbon atoms and containing 2k+2 ring carbon atoms, where k is 1, 2, 3 or 4. An aryl group may be monocyclic, bicyclic, tricyclic or tetracyclic; if it contains more than one ring, these rings are fused to each other. Aryl groups may be substituted with lower carbon number alkyl groups. Thus, aryl groups may contain 6-18 ring carbon atoms and a total of 6-25 carbon atoms. Examples include phenyl, tolyl, xylyl, naphthyl, α-naphthyl, and the like.

Preferably the polymeric micelles are formed from the aforementioned block copolymers in which the terminal functional groups of the hydrophilic polymer segments are protected (e.g. in the case of aldehyde groups it is then acetalized or ketalized , in the case of an amino group, which is protected by an amino protecting group), and, followed by a deblocking reaction. When there is an ethylenically unsaturated polymerizable group at the end of the hydrophobic polymer segment, each block copolymer can undergo a polymerization crosslinking reaction through the polymerizable group after the polymer micelle is formed.

If the coating of the polymeric micelles is a single layer, it is preferred that it comprises the constituents of formulas I-III as described above. If the cladding is laminated, it is preferred that the cladding comprises at least a series of layers of two polymer micelles, formed from at least one polymer micelle of formulas I-III above.

Laminated layers of micelles can be cross-linked by carbon-carbon bonds. For example, micelles may contain internal carbon-carbon double bonds or their side chains may contain carbon-carbon double bonds. The micelles can be crosslinked together by exposing them to electron beam radiation, which generates free radicals. Then randomly couple to form layers. Generally, the solution is exposed to sufficient electron radiation to effect the formation of free radicals. For example, electron radiation may range from about 1 to about 10 Mrads. Alternatively, micelles can be crosslinked together by adding a photoinitiator to the micelles in an inert solution and exposing the solution to visible or ultraviolet light of sufficient wavelength to form free radicals. Then randomly couple to form layers. In general, the photoinitiator is exposed to light of sufficient wavelength to form free radicals, which then react within the micelles, especially the carbon-carbon double bond to effect the formation of free radicals within the micelles.

Alternatively, the layers can be covalently bonded to a high molecular weight polymeric compound that has one or more functional groups ("another kind of" functional groups) that can interact with functional groups on the block copolymers in the polymeric micelles. Covalently bonded, or bonded to a polyfunctional low molecular weight compound having at least 2, preferably 2 or 3, functional groups of the "other kind", the high molecular weight polymer compound and the polyfunctional low molecular weight compound Both are located in the middle of the 2 polymer micellar layers. The different layers are then bonded to each other via a covalent bond between one of the "another class" of functional groups of the high molecular weight polymer compound or the multifunctional low molecular weight compound described above and the functional groups on the block copolymer within the polymeric micelles combine. Alternatively, the outermost layer may be a layer of the above-mentioned high molecular weight compound, in which case it is bonded to the surface support at one end and covalently bonded to the micellar layer at the other end. There is reactivity between the functional groups on the surface of the support and the functional groups of the high molecular weight polymer, and a covalent bond is formed between the surface of the support and the high molecular weight polymer. In addition, the functional group on the micelle reacts with the functional group on the other end of the high molecular weight polymer, they become reactive and form a covalent bond between them.

Examples of functional groups to be substituted on high molecular weight compounds include amino groups covalently bondable to aldehydes (Schiff bases formed from aldehyde groups, and amino groups can be further reduced); hydroxyl and amino groups covalently bondable to carboxyl groups; A carboxyl group and a sulfo group covalently bondable to a hydroxyl group; or a mercapto group covalently bondable to an amino group. Such covalent bonds can be formed under known reaction conditions such as redox conditions, dehydration condensation conditions, addition conditions, and substitution (or displacement) conditions.

High molecular weight polymeric compounds are polymers having a molecular weight in excess of about 8,000 Daltons, more preferably in excess of about 10,000 Daltons, and having amino, carboxyl, thio, or sulfo functional groups. Preferably the high molecular weight polymer has a molecular weight of less than about 500,000 Daltons, more preferably less than about 300,000 Daltons.

The above-mentioned high molecular weight polymer compound is a natural product or a synthetic product. Examples of such amino groups include polyalkenylamines such as polyallylamine, polyvinylamine, etc.; basic amino acid polymers such as polylysine, chitin and polyethyleneimine. Examples of these high molecular weight polymers containing carboxyl groups include poly(meth)acrylic acid, polyacrylic acid, carboxymethyl cellulose, and alginic acid, etc. Examples of these high molecular weight polymers containing sulfonic acid groups (or sulfuric acid groups) include heparin and polystyrene sulfonic acid etc.

The low molecular weight compounds preferably have a molecular weight of no more than 200 Daltons, more preferably these compounds have a molecular weight in the range of about 17 to about 120 Daltons, both inclusive. Examples of polyfunctional low molecular weight compounds include lower alkylenediamines (such as ethylenediamine), glutaraldehyde, ethanedithiol, and the like.

Examples of functional groups to be substituted on low molecular weight compounds include amino groups covalently bondable to aldehydes (Schiff bases formed from aldehyde groups, and amino groups can be further reduced); hydroxyl and amino groups covalently bondable to carboxyl groups; A carboxyl group and a sulfonic acid group covalently bondable to a hydroxyl group; or a mercapto group covalently bondable to an amino group. Such covalent bonds can be formed under known reaction conditions such as redox conditions, dehydration condensation conditions, addition conditions, and substitution (or replacement) conditions.

The high or low molecular weight compounds are reacted with the block copolymers using techniques known in the art. The block copolymers have functional groups at their ends, such as hydroxyl, amino, carboxyl, thio, or may have leaving groups known in the art at their ends, such as halogens, sulfonate esters, such as mesylate , tosylate, p-brosylate, etc. High or low molecular weight compounds also have functional groups at their ends, such as hydroxyl, amino, carboxyl, thiol, or may have leaving groups known in the art at their ends, such as halogens, sulfonate esters, such as formazan Sulfonate, tosylate, brosylate, etc. Block copolymers and high or low molecular weight compounds react under effective conditions to form products. In this reaction, products can be formed by displacement (substitution), or can be formed under amide-forming conditions, ester-forming conditions, depending on the functionality on the block copolymer and the functionality on the high or low molecular weight compound.

For example, in one embodiment, a chemical reaction can be represented by the 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 ₂ Among them, (A ₁ -B ₁ -A ₁ -B ₁ ) is a block copolymer thing;

A ₁ is a hydrophilic segment;

B ₁ is a hydrophobic segment;

_X1 and _X2 are the same or different, and represent groups that can form covalent bonds with _Y2 and _Y1 respectively;

_Y1 and _Y2 are the same or different, and represent groups capable of forming covalent bonds with _X2 and _X1 respectively; and

_Rx is a low molecular weight or high molecular weight compound.

或 )键合到嵌段共聚物上。For example, with this technique, high or low molecular weight compounds can be passed through amides ( or ), or ester linkage (

or ) bonded to the block copolymer.

However, in a different example, only one of X (ie, _X1 and _X2 ) is a leaving group, while Y (ie, _Y1 and _Y2 ) is a functional group, such as hydroxyl, thio, amino, and the like. Under these circumstances, the response is 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 )-YR _x -Y ₂ wherein, A ₁ , B ₁ , R _x , Y ₁ and Y ₂ are the same as defined above, and X ₁ and X ₂ are isolated Go to the group.

For example, in this way, low molecular weight or high molecular weight compounds can be bonded to block copolymers via ether linkages, thio linkages, or hydrogen linkages.

Similarly, if _X1 and _X2 are functional groups and _Y1 and _Y2 are leaving groups, the following products are obtained:

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 ₂ wherein A ₁ , B ₁ and Rx are as defined above.

In yet another variant, _X1 , _X2 , _Y1 , and _Y2 are leaving groups; in this manner, carbon-carbon copolymers are formed between the block copolymer and the low or high molecular weight compound. Price key:

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 indicated above, all of these reactions are carried out under conditions sufficient to form the desired product.

Reacts in the same way with surfaces, as described below.

The support surface is made of glass, silicon wafer, polypropylene, etc., and it may also contain the above-mentioned functional groups. The support surface can be untreated or treated or modified as described herein. The surface of the support is coated with the micelles of the present invention. One layer of micelles may coat the support surface or it may be coated with more than one layer of micelles. If multilayered, the micelles may contain high molecular weight compounds sandwiched between layers. Alternatively, micelles may contain low molecular weight compounds sandwiched between layers. In another approach, the layers of micelles can be crosslinked. Additionally, if the support surface is coated by more than two layers of micelles, the multilayered micelles may contain any combination of these schemes. Further, the support can be physically or chemically treated with a high molecular weight polymer compound by known methods. An example of this approach is schematically illustrated in Figure 1.

When the polymer micelles of the present invention are placed in water, hydrogels are formed. The term "hydrogel" refers to a broad range of polymeric materials that are sufficiently swellable in water but insoluble in water.

The polymeric micelles of the present invention may be produced by techniques known in the art or by using any of the techniques described above or in the previously mentioned patents and PCT applications, the contents of which are all incorporated by reference.

The coating is then applied to the surface of the support. In order to ensure the immobilization of the coating, it is preferred that the polymer micelles form a covalent bond with the surface of the support. This can be accomplished by techniques known in the art, for example by the following steps:

(A) Contact the polymer micelle dispersion containing functional groups on the surface with the support surface containing other functional groups on the surface, the functional groups on the surface of the support can react with the functional groups in the polymer micelles, and then let the surface of the support and the polymer The corresponding functional groups on the micelles react under conditions effective to form a covalent bond and, if necessary, remove unreacted polymer micelles from the covalently bonded species thus formed.

If multiple coating layers are applied to the surface of the support, step A above is still used. In the case of multilayer cladding, however, 2 additional steps are used in the process of cladding the surface of the support.

(B) contacting the thus-formed polymer micelle layer covalently bonded to the substrate with a solution containing a high molecular weight polymer compound containing a large amount of the above-mentioned functional groups or at least 2, preferably 2 or 3 kinds of multifunctional low molecular weight compounds of the above-mentioned functional groups, and the high molecular weight compound or the multifunctional low molecular weight compound is aggregated on the polymer micelle layer, and, then, the high molecular weight polymer compound or the low molecular weight compound and the functional groups on the polymer micelles of the product of step A react under conditions effective to form a covalent bond and, if necessary, remove unreacted high molecular weight or low molecular weight compounds; and

(C) further contacting the thus obtained laminate of step (B) with the aforementioned polymer micelle dispersion, in which the high molecular weight polymer compound or the low molecular weight compound has been covalently bonded, to polymerize The micelles are aggregated on the high molecular weight polymeric compound or multifunctional low molecular weight compound layer of the laminate, and, then, the high molecular weight or low molecular weight compound and the polymeric micelles are covalently bonded, and, if If necessary, unreacted polymer micelles are removed, and if necessary, the steps (B) and (C) are further repeated.

These reactions in B and C above are carried out as described above.

Polymer micelles can be immobilized on any geometrically shaped support surface using free radical formation techniques, such as electron beam radiation or UV or visible light in combination with photoinitiators. According to the method, the polymeric micelles are dissolved or suspended in an aqueous solution, preferably water, at a concentration sufficient to provide sufficient polymeric micelles to cover the surface of the support to achieve the desired thickness. A preferred concentration range is about 0.5 mg/mL to about 15 mg/mL, both inclusive, and more preferably about 1 mg/mL to about 5 mg/mL, both inclusive. The resulting solution is then deposited on the surface of the support using techniques known in the art, such as spraying, knife coating, dipping the support into the micellar solution, and the like. If the polymeric micelles contain polymerizable groups, such as carbon-carbon double bonds in methacrylic acid, vinylbenzyl, or ethylene, the polymeric micelles can be co-polymerized by methods well known to those of ordinary skill in the art. bonded to the surface of the support.

Additionally, the support surface can be treated prior to the formation of covalent linkages between the surface and micelles.

The process is set forth below. For example, a plasma prepared from hydrogen and nitrogen, such as 2 parts hydrogen and 1 part nitrogen, as defined herein, can be applied to a support as defined herein. This plasma generates amino groups on the support surface. Polymer micelles with aldehyde functionality can react with the surface under reductive amination conditions to form covalent bonds with the support surface. Allylamine plasma is another method of treating the surface of a substrate (or medical device) to generate amine-based sites on the surface and which can react with micelles. In addition to using a mixture of hydrogen and nitrogen, allylamine vapor is introduced into the plasma reactor and amino groups are generated on the support surface, which can react with aldehyde or ketone groups under reductive amination conditions.

Alternatively, if carboxyl groups are present on the micelles, the polymeric micelles can react with amino-containing surfaces under amide-forming conditions.

Additional functional groups can be attached to the substrate surface by coating the substrate with a plasma containing said functional groups. For example, a substrate may be coated with a carboxyl-containing plasma. Thus, if the micelles contain hydroxyl groups, the plasma-coated surface and the micelles react under ester-forming conditions to form an ester linkage between the micelles and the plasma-coated surface. Alternatively, if the micelles contain amino groups, the micelles and the plasma-coated surface are reacted under amide-forming conditions to form amide linkages between the micelles and the plasma-coated surface.

It should be pointed out that the hydroxyl group on the surface can be oxidized with an oxidizing agent well known to those skilled in the art to attach the carboxyl group to the surface to form a carboxylic acid, which can then react with the hydroxyl or amine group on the micelle to form the above The ester or amide. Thus, by exposing the surface to a reagent that has immobilized groups that can react with groups on the micelles (or high or low molecular weight polymers or low molecular weight compounds), the surface is activated to interact with the micelles ( or high molecular weight polymers or low molecular weight compounds) to form covalent bonds. Alternatively, the micelles can be exposed to a reagent that has immobilized groups that can react with functional groups on the surface. Polymer micelles in solution can be crosslinked together and can be crosslinked to surfaces by subjecting them to free radical forming conditions, such as electron beam irradiation or addition of photoinitiators and subsequent exposure to Light or UV light, which can generate free radicals on the micelles. Crosslinks between free radicals form covalent bonds. Generally, if electron beam radiation is used, the solution containing the surface and polymer micelles is exposed to electron beams at an intensity in the range of about 1 to about 10 Mrads, most preferably 4 Mrads. Gamma rays can be used as a radiation source but may cause degradation of polymer micelles unless oxygen is carefully removed. Alternatively, a photoinitiator can be added to the solution and the solution containing the photoinitiator and polymer micelles exposed to light or ultraviolet light of sufficient wavelength to form free radicals. Crosslinking via radical coupling occurs randomly between the micellar layer and the surface. For example, in a preferred embodiment the micelles consist of PEO branches. If the PEO branches contain ethylenically unsaturated groups, crosslinking is achieved using the techniques described above. Since PEO contains several hydroxyl groups, the terminal hydroxyl groups are reserved for subsequent activation reactions, such as coupling of affinity ligands to PEO branched chains. Crosslinking increases the stability of micelles.

In another embodiment, polymeric micelles can be covalently immobilized on the support surface by tresylation of terminal hydroxyl groups. The following embodiments are illustrative of PEO hydrophilic groups, but it is understood that this is illustrative only and that the techniques described below are applicable to other hydrophilic groups as well.

Both the support surface and the polymer micelles were pretreated before immobilization. Thus, the surface of the support should contain reactive functional groups, such as amino and/or thio groups, on which the tresylated polymer micelles can be anchored. Similarly, the polymeric micelles are tresylated in a suitable solvent before contacting the support surface. Tresylation is especially convenient for PEO hydrophilic groups, since PEO is dissolved in tresyl chloride through a suitable medium (eg dichloromethane, chloroform). This method results in the formation of a monolayer hydrogel coating on the surface of the support.

According to this method, an organic solvent containing polymer micelles, such as dichloromethane, is exposed to tresyl chloride under conditions effective to fix tresyl groups to the PEO terminal hydroxyl groups of the polymer micelles. The resulting tresylated PEO polymer micelles were then precipitated and recovered, finally as a dry active product. Just before use, the tresylated PEO polymer micelles are dissolved in an aqueous solution with a pH of 10 or higher to facilitate the reaction with amino and/or thio groups already present on the support surface. The pH-adjusted solution is brought into contact with the support surface containing amino and/or thio groups under conditions where the polymer micelles are covalently bonded to the support surface in a thick layer.

In addition to tresyl chloride, other reagents can be used to react with the terminal hydroxyl groups of the PEO chains. These reagents include toluenesulfonyl chloride (p-toluenesulfonyl chloride), methanesulfonyl chloride (methanesulfonyl chloride), epichlorohydrin, cyanuric chloride, (C ₃ N ₃ Cl ₃ ), carbonyldiimidazole (CDI), and succinic anhydride with butyl A mixture of diimides. These reactions are described generally by Harris, "Laboratory Synthesis of Polyethylene Glycol Derivatives", J. Macromolecular Sci. Reviews in Macro. Chem. Phys., C25(3), 325-373 (1985), in which Incorporated by reference. For example, hydroxyl-terminated polyoxyethylene reacts with tosyl chloride or methanesulfonyl chloride to form tosylated or mesylated polymer micelles, respectively. In both cases, the activated PEO branches can react with any molecule containing amino or thio groups. The by-products released by the reaction of compounds containing amino or thio groups with activated PEO branches include tresyl, methanesulfonic acid or toluenesulfonic acid, HCl (reaction of cyanuric chloride), imidazole (CDI) reaction, or N-hydroxybutyrate Diimides (reaction of succinic anhydride with succinimide). No by-products are released in the reaction of epichlorohydrin. Thus, any molecule containing an amino or thio group, for example, can be covalently attached to a tresylated, tosylated or mesylated polyoxyethylene chain by forming a stable NC or SC bond, scavenging the corresponding sulfonic acid , tresyl, tosyl or methylsulfonyl.

-O-，-S-， 和CH₂CH₂.In another embodiment, the hydrophilic groups may have carboxyl groups on them, and the surface may be pretreated to form amino or hydroxyl groups on them. The surface and polymeric micelles are then reacted under amide or ester forming conditions to form the corresponding amide or ester. Similarly, the surface can be modified to have free carboxyl groups on it, and the functional groups at the end of the polymer can be amino or hydroxyl groups. Alternatively, the micelles and the surface react under amide- or ester-forming conditions to form the corresponding amide or ester, respectively. In addition, the surface can be pretreated to have free hydroxyl, amino or thio groups. The polymer micelle has a leaving group at its end, such as a halide or a sulfonate, such as brosylate, tosylate, or mesylate. The polymer micelles and the surface react under displacement or substitution conditions to form the corresponding ether linkages, amine linkages or thiolation linkages. In another embodiment, if the surface contains carbon-carbon double bonds and the polymer micelles have carbon-carbon double bonds at the ends, crosslinking can occur via free radical reactions using the techniques described here. In this manner, hydrophilic or hydrophobic cores are bonded to the surface of the biomedical device by covalent bonds selected from the following using techniques commonly used in the art:

-O-, -S-, and CH ₂ CH ₂ .

By coating supports, such as biomedical devices, with micelles (the micelles are composed of block copolymers with HLB values ranging from about 1 to about 40), according to the present invention, biomedical devices are substantially free of contaminants, especially protein. Although not bound by theory, it is believed that the micelles repel proteins, thus keeping the surface of the biomedical device free of contaminants. This is especially useful when inserting biomedical devices into animals, preferably mammals, such as dogs, cats, cows, horses, and especially humans. As a consequence, there is less contamination and less risk of infection when inserted biomedical devices are coated with the micelles described herein.

The present invention provides a stable surface in which the thickness of the hydrogel layer containing polymer micelles is controlled in the range of tens of nanometers to over 100 nanometers.

Polymer micelles can be used as guest systems, such as carriers for molecules. For example, a polymeric micelle with a hydrophilic outer shell and a hydrophobic inner core could be a carrier with a hydrophobic drug inside that can be released when a biomedical device is inserted or placed in a patient. When the surface and the hydrophobic drug are contacted in an aqueous solvent at elevated temperature, the interior of the polymeric micelles can become impregnated with drug. The drug is present in a pharmaceutically effective amount. The drug is slowly released into aqueous media at room temperature. The present inventors have found that the rate of drug release can be controlled by employing multilayered micelles. In more detail, they found that the more layers of micelles, the slower the drug release. Therefore, the micellar system can effectively control drug release. It should be noted that drug loading can also be performed by laminating polymeric micelles that have been previously filled with drug. Preferably the drug is adsorbed to the surface of the support. Regardless, the drug attachment to the surface of the support is biodegradable, ie, easily removed when inserted into the animal. If a drug is covalently bonded to a surface, the covalent bond is such that it is hydrolyzed by enzymes in the animal's body.

The term drug as used herein includes pharmaceuticals, therapeutics, vitamins, nutritional supplements and the like.

The inventors have found that by coating the surface with the micelles described herein, the present method provides a surface that exhibits excellent bioaffinity.

Any preparation drugs such as, for example, anticancer drugs, central nervous drugs, peripheral nerve drugs, allergy drugs, circulatory organ drugs, respiratory organ drugs, digestive organ drugs, hormonal drugs, antibiotics, chemotherapy drugs, vitamins, food supplements, etc. can be used .

Another use of the polymeric micelles described herein is in the production of contact lenses, especially as described in U.S. Patents 4,680,336 to Larsen et al., 4,889,664 to Kindt-Larsen et al., and 5,039,459 to Kindt-Larsen et al. Contact lenses, all of which are hereby incorporated by reference. For example, contact lenses prepared according to the processes of any of the aforementioned patents can be coated with the polymeric micelles described herein. There can be one layer or more than one layer. Using the techniques described herein, polymeric micelles can be covalently bonded to suitable contact lens materials well known in the art, such as the polyHEMA hydrogel contact lenses described in US Pat. For example, a contact lens material can be immersed in a solution containing polymeric micelles and exposed to the radical-forming ionizing radiation conditions described above to covalently bond the polymeric micelles to the surface of the contact lens. Alternatively, the surface of the contact lens material can be modified by generating amino or thio groups on the surface. The modified lens material is then exposed to activated polymer micelles, such as the tresylated derivatives described above.

Contact lens materials coated with the polymer micelles of the present invention have several advantages over contact lenses not coated with the micelles herein. In more detail, due to the properties of the polymeric micelles, the use of coated lens materials substantially reduces or eliminates the adsorption of protein deposits from the eye's natural enzyme secretions. Thus, the coated lens will not become dull or cloudy due to reduced protein adsorption.

In addition, the micelles of the present invention have the ability to reduce microbial contamination, including bacterial contamination.

Also, coated contact lenses have a better ability to retain water and are therefore less likely to dry out.

Furthermore, according to the present invention, such coated contact lenses can be used as carriers of guest molecules, such as drugs, wherein the drugs are covalently bonded to the coated contact lenses according to the processes described herein, and the drugs are then passed through the contact lenses. The eye is released into the body. Alternatively, guest molecules, such as drugs, are embedded in biomedical devices. For example, the incorporation of drugs into materials used to make biomedical devices. Thus, for example, if the biomedical device is a contact lens or an intraocular lens, a guest molecule, such as a drug, is added to the monomer mixture, which is then cured in the lens according to the processes described in US Pat. Then, the drug is released from the animal after it is inserted into the body, such as the eye. Alternatively, the guest molecule can be incorporated or entrapped within the micelle or it can be covalently bonded to the micelle. If embedded in micelles, the entrapped guest molecules are released after insertion into the animal. In the case of covalent bonding, it is released by enzymatic cleavage (hydrolysis) as is the case when the drug is covalently bonded to a biomedical device. Furthermore, the release of drug molecules can be controlled, especially if multiple layers are used. Regardless, the amount of guest molecule used is such that it is effective to perform its function. For example, if the guest molecule is a drug, it is used in a therapeutically effective amount in relation to its function.

Thus, for example, the above-mentioned micelles can be used as drug carriers for the treatment of eye diseases. As described above, the drug is incorporated into the contact lens by techniques known in the art, and the contact lens is coated with the polymeric micelles described above. A contact lens with coating and medication is inserted into the eye. If controlled release is desired, contact lenses can be coated with layered micelles. When inserted into the eye, enzymes present in the eye can cut the drug-containing micelles, thereby delivering the drug to the desired location.

Additionally, when the drug is mucin or mucin-like structures, such as polylactide or polyglycolic acid, the micellar coating is useful as a vehicle for the treatment of dry eye syndrome.

Under normal conditions, ocular fluid forms a thin layer approximately 7-10 microns thick that covers the corneal and conjunctival epithelium. This ultrathin layer provides the cornea with a smooth visual surface by clearing away microscopic surface irregularities of its epithelium, wets the surface of the corneal and conjunctival epithelium, thus preventing damage to the epithelium, and prevents conjunctiva in the cornea by mechanical scouring. growth of microorganisms.

The tear film generally consists of three layers. The outermost layer is a lipid layer derived from the secretions of the alkaloid glands and is thought to prevent the evaporation of the aqueous layer. The middle aqueous layer is supplied by the primary and secondary lacrimal glands and contains water-soluble substances. The innermost mucus layer is composed of glycoproteins and mucins and overlies the epithelial cells of the cornea and conjunctiva. Epithelial cell membranes are composed of lipoproteins and are therefore generally hydrophobic. Mucins play an important role in wetting surfaces, allowing aqueous tears to spread on them, and by lowering the surface tension of the tears to wet the surface. Under normal conditions, mucin is supplied by the goblet cells of the conjunctiva and can also be supplied from the lacrimal gland.

When any tear film component is deficient, the tear film will rupture and dry spots will form on the corneal and conjunctival epithelium. Deficiencies in any of the three components (water, mucin or lipids) can lead to dry eyes. There are various forms of eye diseases such as keratoconjunctivitis. Those combined with rheumatoid arthritis or other connective tissue diseases are known as Sjogren's syndrome.

The link between the drug and the contact lens is degradable. Mucin-like products such as polyglycolic acid or polylactide are hydrophobic and therefore soluble in the hydrophobic part of the micelles. So when a contact lens containing a drug and micelles is put into the eye, the drug can be easily removed from the contact lens by biological means, and the micelles hold the mucin-like substance, which serves to moisten the eye.

In addition to polylactide and polyglycolic acid, other mucinous substances such as collagen or gelatin can be adsorbed to contact lenses and then coated with the micelles described here. Collagen and gelatin can also be dissolved in micelles. When placed in the eye, the collagen or gelatin is released from the contact lens and moistens the surface of the eye.

Mucinous materials such as polyglycolic acid, polylactide, collagen and gelatin are present in effective amounts in the coating.

As mentioned above, the micelles of the present invention reduce microbial infection. For example, if the biomedical device is a contact lens or an intraocular lens, and is coated with the micelles of the invention, the contact lens will reduce microbial contamination. The micelles are present in an amount substantially sufficient to delay or prevent microbial contamination as a coating for a biomedical device.

However, to further reduce microbial (eg, bacterial) contamination, biomedical devices or micelles can be combined with antimicrobial agents. For example, antimicrobial agents can be embedded in micelles or biomedical devices by incorporation into materials used to make biomedical devices. For example, if the biomedical device is a contact lens, the antimicrobial agent is incorporated into a monomer, such as polyHEMA, according to the processes described in US Patent Nos. 4,680,336, 5,039,459, and 4,889,664. Alternatively, it can be covalently bonded to biomedical devices or micelles using techniques described here. In this case, if the micelles or biomedical devices contain antimicrobial agents, the contamination of biomedical devices such as contact lenses or intraocular lenses by microorganisms such as bacteria can be reduced compared to contact lenses without antimicrobial agents. The antimicrobial agent is present in the coated device or micelles in an amount sufficient to delay and/or substantially prevent microbial contamination.

The present invention offers several advantages, especially when the hydrophilic moiety is PEG. One of the most important advantages is that a high density of hydrophilic moieties such as PEG coating can be easily obtained by simple micellar coating. However, it is not easy to achieve this goal by grafting PEG to the surface. While not being bound by theory, it is believed that this is due to the number of PEG chains in the micelles.

Additionally, the present system prevents triggered flow of the grafted PEG. This is a great advantage for keeping the surface stable even when there are major changes in the environment, such as drying out of the surface. Migration of grafted chains into the sample interior during drying is often a problem, especially with highly migratory surface treatments, including siloxanes. However, the coating of the present invention avoids this problem.

The invention is illustrated in more detail in the following examples. However, these examples do not limit the present invention.

The production of the polyethylene glycol-polylactide block copolymer (Acet-PEG-PLA) of embodiment 1 acetal termination

In an argon atmosphere, 30 ml of THF, 0.147 g of 3,3-diethoxypropanol and 3.0 ml of a THF solution of 0.34 mol/l potassium naphthalide were added to a reactor, and stirred at room temperature for 10 minutes. Thus the potassium compound of 3,3-diethoxypropanol is formed. To the resulting solution was added 7.04 g of ethylene oxide, and the resulting mixture was stirred at room temperature under 1 atmosphere. The resulting solution was reacted for 2 days, then, 26.0 ml of a 1.92 mol/l THF solution of DL-lactide was added, and the resulting mixture was further stirred for 2 hours. Then, 3.1 g of methacrylic anhydride was added, and the resulting mixture was stirred at room temperature for 2 days. The resulting solution was poured into cold 2-propanol, and the polymer thus formed was precipitated. The precipitate obtained by centrifugation was purified from benzene by lyophilization in a yield of 11.48 g (79.4%). According to GPC and ¹ H-NMR, the molecular weights of polyethylene glycol (PEG) segments, polylactide (PLA) and block copolymers were 5800, 4000 and 9800, respectively.

Example 2

Preparation of Acet-PEG-PLA Micelles and Its Transformation to Aldehyde PEG-PLA Micelles

280 mg of the block copolymer prepared in Example 1 was dissolved in 40 ml of dimethylacetamide (DMA). The resulting solution was subjected to reverse water dialysis (2 liters: 2 hours, 5 hours and 8 hours) using a dialysis membrane with a fractional molecular weight of 12-14000. To the obtained dialyzate was added 1N-HCl to adjust the pH of the dialyzate to 2, and the resulting mixture was stirred for 2 hours. The pH of the resulting solution was adjusted to 7 by adding 0.1 N-NaOH aqueous solution. Then, the obtained solution was subjected to reverse water dialysis for 24 hours by using a dialysis membrane with a fractional molecular weight of 12-14000. The dialyzate thus obtained was transferred into an argon atmosphere flask, then 1.8 (W/W)% potassium persulfate per micelle was added, and after degassing, the resulting mixture was reacted at 50° C. for 24 hours. The dynamic light scattering (DLS) test of the product shows that the particle size and the polydispersity of the polymer micelles are (35.5nm, 0.094) and (41.0nm, 0.125) respectively before and after polymerization. Little change in particle size was found before and after polymerization.

1 ml of an aqueous solution of sodium lauryl sulfate (20 g/l) was added to 2 ml of the product solution before and after the polymerization reaction, and the resulting solution was stirred for 24 hours, followed by DLS testing. It was found that, although the polymer micelles almost completely disappeared before the reaction, the polymer micelles kept the particle size and polydispersity with μ/Γ2 of 47.2nm and 0.106 after the reaction. This suggests that the polymeric micelles are so stable after the reaction that they do not disintegrate even after treatment with surfactants. The micelles were freeze-dried before and after polymerization, and were tested by ¹ H-NMR in heavy chloroform. It was found that the peaks (5.6 and 6.2 ppm) derived from terminal olefins observed before the reaction completely disappeared, indicating that the polymerization efficiency was high. In this case, the polymerization of the methacryloyl groups at the polylactide terminals produces very stable micelles.

Example 3

Preparation of the base (or chassis)

For the chassis, thin sheets mainly made of slides, silicon wafers or polypropylene are used. Cut the slide or silicon wafer into a suitable size, and perform ultrasonic cleaning, and then further clean it with a mixed liquid of 30% H ₂ SO ₄ and H ₂ O (volume ratio 1:1) at about 100°C, and then Rinse thoroughly with pure water. The thus-treated slide or silicon wafer fragments were vacuum-dried at room temperature for 16 hours, then soaked in a toluene solution of 3-aminopropyltriethoxysilane for 3-4 hours, and then vacuum-dried at 160°C. In this way, amino groups are thus introduced to the surface of the fragment. On the other hand, when polypropylene is used as the material of the chassis, by plasma treatment (Samco International; type BP-1; 75W; 30 minutes) made with N ₂ :H ₂ (volume ratio 1:2) way to introduce amino groups to the surface of the chassis.

Zeta potential measurements on the surfaces thus treated showed positive polarity of the surface in the low pH range. Thus, the presence of surface amino groups was confirmed.

Example 4

Polymer Micellar Lamination Coating

At normal temperature, the silicon chip (manufactured by MitsubishiMaterial Company) with amino groups on the surface prepared in Example 3 was immersed in the polymer micelle solution for 2 hours. The micelle was prepared according to the process of Example 2 and dissolved in 0.04M HEPES[ The solution contained 0.0032 (w/v) % NaCNBH ₃ ] at a concentration of approximately 1 mg/ml. After removing unbound polymer micelles by washing with pure water, the steps of soaking into the polymer micelles solution and washing were further repeated, thus constituting a layered type micelle-gel film (see FIG. 1 ). Incidentally, NaCNBH ₃ was used at a concentration of 0.25% in the final micellar coating.

Example 5 Special Performance Test of Laminated Film (Polymer Micellar Layer; hereinafter referred to as Micellar Coating) (a) Atomic Force Microscope (AFM) Test

The thickness of the micellar coating prepared in Example 4 was tested by AFM. For surface morphology, in the case of monolayers, an image is obtained in which the micelles themselves are anchored to the surface. However, when the number of coating layers was increased, changes occurred and irregularities became apparent. Use the force of the cantilever in contact mode to excise a 1 × ¹ μm area from the surface coated with multilayered micelles, then examine the cross-section in tap mode. Figure 2 shows the thickness variation, which is observed according to the number of cladding layers. In a single layer the thickness is about 20 nm, while in a double clad it varies to 40-45 nm and in a triple clad it is 80-90 nm.

Regarding the three-layer micellar coating, it was observed that the area under cleavage in contact mode decreased with time. Although not bound by theory, it is believed that in the laminated film at the surface, the micelles and polyallylamine have been cross-linked by chemical bonds; thus, the laminated film cut and compressed by the cantilever recovers gradually, resulting in a decrease in the cut area.

On the other hand, when unpolymerized micelles with inner cores (or unpolymerized polymer micelles) were used as three-layer coatings for AFM testing, rupture was observed within the coating film. While not being bound by theory, it is believed that the tension generated in the multilayer clad film leads to the breakdown of the unpolymerized film in its inner core, leading to the formation of cracks. By the way, no such ruptures were found in the polymerized micelles.

(b) Measurement of zeta potential

The zeta potential of the micellar surface of the above-mentioned micellar coating layer was measured in 7.5 mM sodium chloride solution, the pH range was 2-11. Figure 3 is a schematic diagram. When the micelle surface is the outermost layer, the change in zeta potential caused by the change in pH is as low as ±5 mV. On the other hand, when polyallylamine is the outermost layer, the zeta potential is higher as the pH increases up to pH 8, however, when increasing the pH beyond pH = 8, the zeta potential eventually drops to 0 . On the surface of micelles and polyallylamine, the zeta potential remains unchanged when the coating layer is up to 3 layers, regardless of the number of layers. As shown in Figure 2, the repeat thickness increases with the number of laminations. As shown in Figure 3, although the zeta potential difference between the micellar layer and the polyallylamine layer is large, only a small difference is caused by the lamination number. This indicates that despite the increase in thickness due to lamination, the micellar layer and the polyallylamine layer are not mixed with each other but exist in the form of laminated layers.

(c) Protein adsorption

When coating a surface with a hydrogel such as the micellar coating described above, especially when micelles are the outermost surface layer, it is desirable to prevent protein adsorption. In order to confirm, use the micelle lamination gel prepared in Example 1 to coat the surface of the acrylic chassis into which the amino group has been introduced by the above method, and compare the proteins on the micelle surface and the polyallylamine surface (bovine serum albumin: BSA) adsorption. The micelle-coated samples were immersed in 45 μg/ml BSA solution for 1 hour. After gently rinsing the sample, the tightly bound proteins were removed with a surfactant (sodium lauryl sulfate), and the BSA thus removed was measured by the BCA method measuring BSA adsorption per unit volume (Analytical Biochemistry , 1985, 150, 76). The result is shown in Figure 4. This demonstrates that protein adsorption is inhibited when the micelles are in the outermost layer. High protein adsorption was observed when polyallylamine was the outermost layer. While not being bound by theory, it is believed that this phenomenon is due to the presence of a positive charge on the sample surface, which results in an electrostatic interaction of the protein BSA, which interacts with the positively charged surface of the polyallylamine. However, when the surface was coated with micelles, the decrease in BSA adsorption indicated that the surface was completely covered by micelles, which effectively shielded the polyallylamine changes.

Altogether, the data clearly demonstrate that the multilayer coating of micelles effectively repels protein adsorption on positively charged surfaces, and that polyallylamine surfaces are slightly hydrophobic.

(d) Incorporation and release of pyrene in polymer micelles

The micelles prepared by the above method form hydrogel films. Thus, hydrogel films contain a hydrophobic inner membrane. As shown below, it is possible to introduce hydrophobic drugs into the inner core of the gel surface formed by micelles. As shown by the data below, drug release from polymer micelles will be controlled release.

Pyrene was used as a model drug. A solution of pyrene in acetone was added to the flask so that pyrene could accumulate on the inner wall of the flask. After complete drying, the polymer micelle solution in Example 2 was added to the flask and stirred at 60° C. for 4 hours. After the solution temperature returned to normal temperature, insoluble matter was removed with a 0.4 μm filter. Then, according to the process of Example 3, the obtained polymer micelles loaded with pyrene are coated with different numbers of product coating layers of Example 1, and the number of layers ranges from 1 to 6 layers. The specific cladding layers are described in the table below:

Table 1. Coating of micelles on the surface of aminated glass sample Coating Coating condition ML2 1 ~1 mg/ml micelles and 0.25% (w/v) NaCNBH ₃ in 0.01M NaH ₂ PO ₄ , 25°C, 2h ML16 1 ~1 mg/ml micelles and 0.25% (w/v) NaCNBH ₃ in 0.01M NaH ₂ PO ₄ , 25°C, 16h 3LO 3 1. In 0.4M HEPES (pH6.7), ~1 mg/ml micelles, 25°C, 2h 2. In 0.04M HEPES (pH6.7), 0.6% (w/v) polyallylamine, 25 ℃, 20min. 3. Repeat 1 and 2 3 times 4. In 0.04M HEPES (pH6.7), ~1mg/ml micelles and 0.025% (w/v) NaCNBH ₃ , 25℃, 40h 3LE 3 1. In 0.04M HEPES (pH6.7), ~1mg/ml micelles and 0.016% (w/v) NaCNBH ₃ , 25°C, 2h2. In 0.04M HEPES (pH6.7), 0.6% (w /v) Polyallylamine and 0.25% (w/v) NaCNBH ₃ , 25°C, 2h3. Repeat 1 and 24. In 0.04M HEPES (pH 6.7), ~1 mg/ml micelles and 0.025% ( w/v) NaCNBH ₃ , 25°C, 40h 6LE ^* 6 1. In 0.04M HEPES (pH6.7), ~1mg/ml micelles and 0.016% (w/v) NaCNBH ₃ , 25°C, 2h2. In 0.04M HEPES (pH6.7), 0.6% (w /v) Polyallylamine and 0.25% (w/v) NaCNBH ₃ , 25°C, 2h 3. Repeat 1 and 2 3 times 4. ~1 mg/ml micelles in 0.04M HEPES (pH 6.7) and 0.025% (w/v) NaCNBH ₃ , 25°C, 16h *Wrap time for the third coat is overnight.

Each laminate was immersed in water, and the intensity of fluorescence produced by pyrene on the chassis was measured over time. The result is shown in Figure 5.

As shown by the data, the onset fluorescence intensity is dependent on the coating layer number. The fluorescence intensity of 3 times of coating (3LO, 3LE) is twice that of 1 times of coating (ML2, ML16), and the intensity of 6 times of coating (6LE) is about 10 times more. This result indicates that by coating under the conditions described in Table 1, multiple layers of micelles can be attached to the surface and that this multiple layers increase the amount of pyrene on the surface.

On the other hand, the rate at which the fluorescence intensity decreases depends on the coating conditions and the number of coatings. The onset fluorescence intensity appears to be closely related to the number of coats. However, the difference in the number of coatings (ML2 and ML16) and the reduction method of Sciff base (3LO and 3LE) lead to changes in the rate of fluorescence decline, as shown in Figure 5. It should be noted that the 6-layer coating showed high initial strength, and the logarithmic curve of strength versus incubation time indicated a more controllable release of pyrene from the surface. While not being bound by theory, it is believed that during diffusion, drug redistribution into the micelles through multilayered micelle layers may have occurred such that extended drug release is achieved in a controlled manner.

(e) Filling and release of pyrene from surface-coated micelles

To determine whether drugs can be refilled into micelles-coated samples, the filling of hydrophobic reagents after micelles coating was also investigated. For this purpose, micellar coated samples prepared in Example 1 were exposed to pyrene-containing micellar solutions or water. Under the same conditions as 6LE, micellar solutions without pyrene were coated on APTS glass. The micellar solution was coated onto APTS glass under the same conditions as 6LE. The micellar coated samples were then exposed to the pyrene-filled micellar solution for 12 hours. The samples were then washed with water and stored in excess water for 12 hours at room temperature (-22°C) and 4°C. During storage, periodically measure the fluorescence of the samples. After the storage in water was completed, the samples were exposed to the micellar solution filled with pyrene for 12 hours and then in water. Fig. 6 shows the curves of fluorescence intensity (λex=336.2nm, λem=375nm).

The fluorescence intensity after exposure to pyrene-filled micelles was almost the same as the initial intensity of 6LE in FIG. 5 . After the first cycle (release-fill, 24h), the fluorescence intensity returned to the initial level. The same goes for the second loop. The first release (0-12h) and the second release (24-36h) showed the same decrease in intensity. These results suggest that the micellar coating is stable and can repeatedly fill and release pyrene. The third exposure (48-60h) was in water at 4°C. The decrease in fluorescence intensity was slower than the first two releases (exposure to water at 22°C). Although the mobility of the PLA segment may also affect the release of pyrene (hydrophobic drug) from the micelles, the temperature may also affect the diffusion coefficient of pyrene in the micelles. If filled with molecules larger than pyrene, the release rate may be lower.

Example 6

In order to evaluate the ability of the micellar layer to prevent the free penetration of molecules, a polypropylene film (25 μm thick, 45% porosity, 0.25 μm pore size), ie PP, was used as the substrate. Films were covered with polyhydroxyethyl methacrylate PHEMA by dipping polypropylene films into a 10% methanol solution and drying at room temperature, followed by plasma treatment as described here. The aminated sample was coated with the monolamellar micelles of Example 1 and the multilamellar micelles of Example 4 described above. The penetration of dextran into the sample films was tested by measuring the diffusion of fluorescein isothiocyanate (FiTC) dextran (purchased from Sigma Aldrich) from one side of the film to the other. The apparatus ( 4 ) used is shown in FIG. 7 . A sample film (1) separates one side of the container from the other, with one side containing a PBS solution (2) and the other side containing a 0.1% (w/v) FITC dextran solution in PBS solution (3). The temperature of the vessel was set at 25°C. 3.0ml of PBS solution was sampled every 24 hours, and the penetration rate of dextran was determined by the change of fluorescence intensity of the sample.

Figure 8 shows the profile of dextran permeation through micellar coated films. As a comparison, the permeability to PP (polypropylene) films with PHEMA and the films with PHEMA treated with PEG-acetaldehyde under the same conditions as for micellar coating are also shown. When the PHEMA/PP film was coated with PEG, the permeability of dextran increased. This is attributed to the erosion of the PHEMA surface. This erosion is compensated by multiple layers of micellar coating. A micellar coating effectively covers the surface. In the case of micelles covering 3 layers, the network formed by micelles, polyallylamine (PAIAm; weight-average molecular weight 10,000, available from Nittobo Chemical Co., Tokyo, Japan) and the increase in layer thickness significantly prevented penetration rate.

The above preferred embodiments and examples illustrate the scope and spirit of the invention. These embodiments and examples will make it apparent to those skilled in the art that there are still other embodiments and examples. Other embodiments and examples are also within the contemplated scope of the invention.

Accordingly, the invention is limited only by the claims.

Claims (72)

1. A coated biomedical device, wherein the coating comprises at least one polymeric micelle immobilized on the surface of said biomedical device, said micelle having a hydrophilic inner core and a hydrophobic outer shell or a With a hydrophobic inner core and a hydrophilic outer shell, the micelles consist of a block copolymer having an HLB value ranging from about 1 to about 40. 2. The coated biomedical device according to claim 1, wherein said block copolymer has an HLB value in the range of about 4 to about 20. 3. The coated biomedical device according to claim 1, wherein the micelles have an outer hydrophilic shell and an inner hydrophobic core. 4. The coated biomedical device according to claim 1, wherein the micelles have an outer hydrophobic shell and an inner hydrophilic core. 5. The coated biomedical device according to claim 1, wherein the micelles are covalently bonded to the surface of the biomedical device. 6. The coated biomedical device according to claim 5, wherein the micelles are covalently bonded to the surface of the biomedical device by a group selected from the group consisting of:

-O-, -S-,

and

7. The coated biomedical device according to claim 1, wherein the micelles have a hydrophilic shell and a hydrophobic core, and the hydrophilic shell is covalently bonded to the surface of the biomedical device. 8. The coated biomedical device according to claim 1, wherein the micelles have a hydrophobic shell and a hydrophilic core, and the hydrophobic shell is covalently bonded to the surface of said biomedical device. 9. A covered biomedical device according to claim 7, wherein the hydrophilic shell consists essentially of polyethylene glycol, polyacrylamide, polymethacrylamide, polyvinylpyrrolidone or polyvinyl alcohol. 10. A coated biomedical device according to claim 9, wherein the hydrophilic shell is polyethylene glycol. 11. The coated biomedical device according to claim 7, wherein the hydrophobic inner core is methyl methacrylate, silicone, poly(alpha-hydroxycarboxylic acid), or poly(omega-hydroxycarboxylic acid). 12. A coated biomedical device according to claim 11, wherein the hydrophobic inner core comprises poly(alpha-hydroxycarboxylic acid) or poly(omega-hydroxycarboxylic acid) or methyl methacrylate. 13. The coated biomedical device according to claim 1, wherein the hydrophobic inner core has a radically active group at its terminus. 14. A coated biomedical device according to claim 13, wherein said hydrophobic shell has an ethylenically polymerizable group at its terminus. 15. The coated biomedical device according to claim 14, wherein the ethylenically unsaturated polymerizable group is a free radically reactive polymerizable acrylate, a free radically reactive polymerizable styryl, a free radically reactive polymerizable formazan radical acrylates or free radically reactive polymerizable vinyl ethyl ethers. 16. The coated biomedical device according to claim 1, wherein said hydrophilic inner core has a radically active group at its terminus. 17. A coated biomedical device according to claim 16, wherein said hydrophilic shell has an ethylenically unsaturated polymerizable group at its terminus. 18. The coated biomedical device according to claim 17, wherein the ethylenically unsaturated polymerizable group is a free radically reactive polymerizable acrylate, a free radically reactive polymerizable styryl, a free radically reactive polymerizable formazan acrylates or free radically polymerizable vinyl ethyl ethers. 19. The coated biomedical device according to claim 1, wherein the biomedical device is coated with a single layer of said micelles. 20. The coated biomedical device according to claim 1, wherein the biomedical device is coated with multiple layers of said micelles. 21. The coated biomedical device according to claim 20, wherein the biomedical device is coated with up to 6 layers of said micelles. 22. The coated biomedical device according to claim 20, wherein the multilayer comprises at least one covalently bonded layer consisting of two layers of polymeric micelles and a second polymer sandwiched between them, said The second polymer has a molecular weight greater than 8000 Daltons and has a large number of functional groups selected from amino, carboxyl and sulfonic acid groups thereon. 23. The coated biomedical device according to claim 22, wherein the second polymer is polyallylamine, polyvinylamine, polylysine, chitin, polyethyleneimine, poly(meth)acrylic acid, Carboxymethylcellulose, alginic acid, heparin, or polystyrenesulfonic acid. 24. The coated biomedical device according to claim 20, wherein at least two micellar layers are cross-linked to each other. 25. The coated biomedical device according to claim 20, wherein the biomedical device is coated with multiple layers of polymer micelles, wherein the multiple layers comprise at least one set of two layers of polymer micelles and one of them sandwiched between them. A covalently bonded layer of low molecular weight molecules selected from the group consisting of lower alkylenediamines, glutaraldehyde and ethaneedithiol. 26. The coated biomedical device according to claim 1, wherein the block copolymer has the formula: Wherein, L refers to the part of following molecular formula:

or Wherein, R ¹ and R ² independently refer to a hydrogen atom, C _1-10 alkyl, aryl or aryl-C _1-3 alkyl; r refers to an integer of 2-5, and Wherein, m refers to an integer of 2-10,000; n refers to an integer of 2-10,000; p refers to an integer from 1 to 5; and z refers to acetyl, acryloyl, methacryloyl, cinnamoyl, allyl or vinylbenzyl. 27. The coated biomedical device according to claim 1, wherein the block copolymer has the formula:

Wherein, X refers to the alkyl group that has 1-10 carbon atoms, and it has an amino, carboxyl or mercapto group; Y refers to the part of following molecular formula:

or

Wherein, R ¹¹ and R ¹² independently refer to a hydrogen atom or a C _1-5 alkyl group; R ³ refers to a hydrogen atom or a methyl group; R ⁴ refers to C _1-5 alkyl substituted by hydroxy, which may be protected; and q refers to an integer from 2 to 5, and Wherein, z refers to acryloyl, methacryloyl, cinnamoyl, allyl or vinylbenzyl; m refers to an integer of 2-10,000; And, n means an integer of 2-10,000. 28. The coated biomedical device according to claim 1, wherein the block copolymer has the formula:

where A refers to a group derived from a sugar residue having the following molecular formula by Malaprade oxidation: Wherein, one of the dotted lines (---) refers to a single bond, and the other refers to a hydrogen atom; and a and b independently refer to an integer of 0 or 1, and where L ₁ refers to the linking group of the following molecular formula:

or

Wherein, R ⁵ and R ⁶ independently refer to a hydrogen atom, C _1-6 alkyl, aryl or C _1-3 alkaryl; and Wherein, m refers to an integer of 2-10,000; n refers to an integer from 2 to 10,000; and z means acryloyl, methacryloyl, cinnamoyl, allyl, or vinylbenzyl. 29. The encapsulated biomedical device according to any one of claims 1-28, wherein the biomedical device is a contact lens or an intraocular lens. 30. A method for reducing protein contamination of a biomedical device after insertion into an animal body, said method comprising encapsulating the surface of said biomedical device with an effective amount of protein adsorption inhibiting polymer micelles Covering the biomedical device, the micelles have a hydrophilic shell and a hydrophobic core or a hydrophobic shell and a hydrophilic core, the micelles being copolymerized with blocks having an HLB value ranging from about 1 to about 40 composition. 31. The method according to claim 30, wherein said block copolymer has an HLB value in the range of about 4 to about 20. 32. The method according to claim 30, wherein the micelles have a hydrophilic outer shell and a hydrophobic inner core. 33. The method according to claim 30, wherein the micelles have a hydrophobic outer shell and a hydrophilic inner core. 34. The method according to claim 30, wherein the micelles are covalently bonded to the surface of the biomedical device. 35. The coated biomedical device according to claim 34, wherein the hydrophilic inner core is bonded to the surface of the biomedical device by a covalent bond selected from the group consisting of:

-O-, -S-,

and 36. The method according to claim 30, wherein the micelles have a hydrophilic shell and a hydrophobic core, and the hydrophilic shell is covalently bonded to the surface of the biomedical device. 37. The method according to claim 30, wherein the micelles have a hydrophobic shell and a hydrophilic core, and the hydrophobic shell is covalently bonded to the surface of said biomedical device. 38. The method according to claim 36, wherein the hydrophilic shell consists essentially of polyethylene glycol, polyacrylamide, polymethacrylamide, polyvinylpyrrolidone, polyvinyl alcohol or polymethacrylate or polyacrylate . 39. A method according to claim 38, wherein the hydrophilic shell is polyethylene glycol. 40. The method according to claim 36, wherein the hydrophobic inner core is methyl methacrylate, silicone, poly(alpha-hydroxycarboxylic acid), poly(omega-hydroxycarboxylic acid). 41. The method according to claim 40, wherein the hydrophobic inner core comprises poly(alpha-hydroxycarboxylic acid), poly(omega-hydroxycarboxylic acid), or methyl methacrylate. 42. A method according to claim 33, wherein the hydrophobic shell has a radically active group at its terminus. 43. A method according to claim 42, wherein said hydrophobic shell has an ethylenically unsaturated polymerizable group at its terminus. 44. The method according to claim 43, wherein said ethylenically unsaturated polymerizable group is a free radically reactive polymerizable acrylate, a free radically reactive polymerizable styryl, a free radically reactively polymerizable methacrylate or a free radically reactive polymerizable group. based polymerizable vinyl ethyl ether. 45. The method according to claim 32, wherein said hydrophilic shell has a radically active group at its terminus. 46. The method according to claim 45, wherein said hydrophilic shell has an ethylenically unsaturated polymerizable group at its terminus. 47. The method according to claim 46, wherein the ethylenically unsaturated polymerizable group is a free radically reactive polymerizable acrylate, a free radically reactive polymerizable styryl, a free radically reactively polymerizable methacrylate or a free radically reactive Polymerized vinyl ethyl ether. 48. The method according to claim 30, wherein the biomedical device is coated with a layer of micelles. 49. The method according to claim 30, wherein the biomedical device is coated with multiple layers of polymeric micelles. 50. The method according to claim 49, wherein the biomedical device is coated with up to 6 layers of polymeric micelles. 51. according to the method for claim 49, wherein multilayer comprises at least one set of covalently bonded layer that is made of two layers of polymeric micelles and a second polymer sandwiched between them, the second polymer's The molecular weight is greater than 8000 Daltons, and it has a large number of functional groups selected from amino, carboxyl and sulfonic acid groups. 52. The method according to claim 51, wherein the second polymer is polyallylamine, polyvinylamine, polylysine, chitin, polyethyleneimine, poly(meth)acrylic acid, carboxymethylcellulose , alginic acid, heparin or polystyrene sulfonic acid. 53. The method according to claim 49, wherein the biomedical device is coated with multiple layers of polymer micelles, wherein the multiple layers include at least one set of polymer micelles and a low molecular weight molecule sandwiched between them. Covalently bonded layer, low molecular weight molecules selected from lower alkylenediamines, glutaraldehyde and ethaneedithiol. 54. The method according to claim 30, wherein the biomedical device is a contact lens or an intraocular lens. 55. The method according to claim 30, wherein the block copolymer has the formula:

Wherein, L refers to the part of following molecular formula: or Wherein, R ¹ and R ² independently refer to a hydrogen atom, C _1-10 alkyl, aryl or aryl-C _1-3 alkyl; r refers to an integer of 2-5, and Wherein, m refers to an integer of 2-10,000; n refers to an integer of 2-10,000; p refers to an integer from 1 to 5; and z refers to acetyl, acryloyl, methacryloyl, cinnamoyl, allyl or vinylbenzyl. 56. The method according to claim 30, wherein the block copolymer has the formula: Wherein, X refers to the alkyl group that has 1-10 carbon atoms, and it has an amino group, carboxyl group or mercapto group; Y refers to a moiety having the following molecular formula:

or

Wherein, R ¹¹ and R ¹² independently refer to a hydrogen atom or a C _1-5 alkyl group; R ³ refers to a hydrogen atom or a methyl group; R ⁴ refers to C _1-5 alkyl substituted by hydroxy, which may be protected; and q refers to an integer from 2 to 5, and Wherein, z refers to acryloyl, methacryloyl, cinnamoyl, allyl or vinylbenzyl; m refers to an integer of 2-10,000; And, n means an integer of 2-10,000. 57. The method according to claim 30, wherein the block copolymer has the formula:

where A refers to a group derived from a sugar residue having the following molecular formula by Malaprade oxidation: Wherein, one of the dotted lines (---) refers to a single bond, and the other refers to a hydrogen atom; and a and b independently refer to an integer of 0 or 1, and where L ₁ refers to the linking group of the following molecular formula: or Wherein, R ⁵ and R ⁶ independently refer to a hydrogen atom, C _1-6 alkyl, aryl or C _1-3 alkaryl; and Wherein, m refers to an integer of 2-10,000; n refers to an integer from 2 to 10,000; and z means acryloyl, methacryloyl, cinnamoyl, allyl, or vinylbenzyl. 58. A method according to any one of claims 30-57, wherein the biomedical device is a contact lens or an intraocular lens. 59. A method of releasing a guest molecule into an animal, comprising (a) binding said guest molecule to the surface of a biomedical device or micelle, or into a biomedical device or micelle, (b) using The biomedical device is coated with at least one polymeric micelle immobilized on the surface of the biomedical device, said micelle comprising a hydrophobic shell and a hydrophilic core or comprising a hydrophilic shell and a hydrophobic core, said The micelles are composed of a block copolymer having an HLB value ranging from about 1 to about 40, and (c) inserting said biomedical device into said animal. 60. The method according to claim 59, wherein the guest molecule is a drug. 61. The method according to claim 59, wherein the biomedical device is a contact lens or an intraocular lens. 62. The method according to claim 60, wherein the biomedical device is a contact lens and the drug is an agent useful for treating an eye disease. 63. The method according to claim 60, wherein the connection of the drug to the biomedical device is biodegradable. 64. The method according to claim 62, wherein the eye condition is dry eye syndrome. 65. The method according to claim 59, wherein the micelles are laminated. 66. The method according to claim 65, wherein the drug release is tapered. 67. A method for reducing microbial contamination of a biomedical device after insertion into an animal, the method comprising coating said biomedical device with an effective amount of an antimicrobial polymer micelle, said micelle having an affinity Water shell and a hydrophobic core or a hydrophobic shell and a hydrophilic core, the micelles are composed of a block copolymer having an HLB value ranging from about 1 to about 40. 68. The method according to claim 67, wherein said block copolymer has an HLB value in the range of about 4 to about 20. 69. The method according to claim 67, wherein an antimicrobial agent is additionally present on the biomedical device. 70. The method according to claim 58, wherein the biomedical device is a contact lens. 71. The method according to claim 70, wherein the contact lens is composed of polyhydroxyethyl methacrylate. 72. A coated biomedical device according to claim 1 which substantially prevents the penetration thereof by dextran.

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