WO2001032230A2 - A polymer micelle as monolayer or layer-laminated surface - Google Patents
A polymer micelle as monolayer or layer-laminated surface Download PDFInfo
- Publication number
- WO2001032230A2 WO2001032230A2 PCT/IB2000/001724 IB0001724W WO0132230A2 WO 2001032230 A2 WO2001032230 A2 WO 2001032230A2 IB 0001724 W IB0001724 W IB 0001724W WO 0132230 A2 WO0132230 A2 WO 0132230A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- micelle
- biomedical device
- denotes
- coated
- group
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/34—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/14—Eye parts, e.g. lenses, corneal implants; Implanting instruments specially adapted therefor; Artificial eyes
- A61F2/16—Intraocular lenses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
- A61K9/0051—Ocular inserts, ocular implants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2250/0014—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis
- A61F2250/0056—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis differing in wettability, e.g. in hydrophilic or hydrophobic behaviours
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
- A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
- A61L2300/604—Biodegradation
Definitions
- the present invention relates to a polymer micelle which is either in a single layer or in multilayers and to the use thereof as a coating on surfaces, especially biomedical devices.
- a micelle is a colloidal aggregate of amphipathic molecules containing both hydrophilic and hydrophobic moieties.
- polar media such as water
- the hydrophobic part of the amphiphile forming the micelle tends to locate away from the polar portion, while the polar portion of the molecule also known as the head group tends to locate at the polar micelle water (solvent) interface.
- micelles may also be formed in non-polar media, such as non-polar organic solvents, e.g., hexane, whereby the amphiphilic cluster around the small water droplets is in the center of the system.
- the hydrophobic moieties are exposed to the non-polar media, while the hydrophilic portion tends to locate away from the solvent and towards the water droplets.
- Such an assembly is sometimes referred to as a reversed micelle.
- a micelle may take several forms, depending on the conditions and the composition of the system. For example, small micelles in dilute solution at approximately the critical micelle concentration (CMC) are generally believed to be spherical. However, under other conditions, they may be in the shape of distorted spheres, disks, rods, lamellae, and the like.
- CMC critical micelle concentration
- Micelles are formed at a critical micelle concentration (CMC) which is dependent upon several factors, including the type of amphipathic molecule, the solvent system, solute and the like.
- the critical micelle concentration denotes the concentration at which micelles start to form in a system containing solvent, amphiphatic molecule, and solute and the like.
- the CMC can be determined experimentally using standard techniques in the art. For example, the CMC of a surfactant can be determined by plotting a property as a function of the concentration of the surfactant; it is noted that the property usually varies linearly with increasing concentration up to the CMC, at which point the curve becomes non- linear.
- Properties which have been used for the determination of the CMC include such properties as refractive index, light scattering, dialysis, surface tension and dye solution.
- Micellar properties are affected by the environment and more specifically changes in the environment, e.g., temperature, solvents, solubilized components, electrolytes in the system and the like. The prior art has described micelles whose properties have been exploited.
- U.S. Patent No. 5,929,177 to Kataoka, et al. describes a polymeric molecule which is usable as, inter alia, a drug delivery carrier.
- the micelle is formed from a block copolymer having functional groups on both of its ends and which comprises hydrophilic/hydrophobic segments.
- the polymer functional groups on the ends of the block copolymer include amino, carboxyl and mercapto groups on the - terminal and hydroxyl, carboxyl group, aldehyde group and vinyl group on the ⁇ - terminal.
- the hydrophilic segment comprises polyethylene oxide, while the hydrophobic segment is derived from lactide, lactone or (meth) acrylic acid ester.
- R 1 denotes hydrogen or C 1 . 6 alkyl
- R 3 and R 4 independently denote hydrogen, alkyl, aryl or arylalkyl; 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 denotes H, alkali metal, acetyl, acryloxyl, methacryloyl, cinnamoyl, p- toluenesulfonyl, 2- mercaptopropionyl or 2-aminopropionyl o allyl or vinyl - benzyl, when q is 1-20, Z is C x . 6 alkoxycarbonyl, carboxyl, mercapto or amino.
- This oligomer or polymer forms a high-molecular micelle which is stable in aqueous solvent and is useful as a carrier for drug delivery. In neither of these references was the micelle used as a coating.
- U.S. Patent No. 5,275,838 to Merrill discloses a method for immobilizing polyethylene oxide (PEO) star molecules in the form of hydrogel layers and the product thereof which can be used to coat surfaces. It describes a method for immobilizing polyethylene oxide star molecules to a support surface to form a layer thereon, comprising the steps of:
- step (d) contacting the solution of step (c) with a support surface containing amino and/or thiol groups to covalently bond the reagent terminated star molecules, thereby immobilizing the reagent terminated star molecules in a dense layer to the support surface.
- the star molecules have a polymeric core, such as divinyl benzene, from which a number of polyethylene oxide chains or arms are grown. These star molecules are not micelles. They are not comprised of block copolymers having HLB (hydrophilic -lipophilic balance) of 1-40. As described therein, the star molecules are synthesized by anionic polymerization from divinyl benzene, ethylene oxide and optionally styrene.
- HLB hydrophilic -lipophilic balance
- the present invention utilizes different 'types of compounds and coating technology than those described in Merrill.
- the coating composition of the present invention are comprised of micelles.
- the micelles utilized in the present invention are comprised of block copolymers having an HLB value ranging from 1-40.
- the present inventors have found coating a surface with specific polymeric micelles of the present invention imparts several advantages to the coated surface. More specifically, the present inventors have found that coated surfaces, especially multi -layered coated surfaces, with polymeric micelles of the type described hereinbelow enhances the ability of the coated surface to retain water, prevents penetration of proteins and lipids therethrough and enhances drug delivery capabilities of the coated surface.
- the present invention is directed to a coated support surface, such as a biomedical device, wherein the coating comprises at least one polymeric micelle immobilized on the surface of said biomedical device, said micelle having either a hydrophilic outer shell and an 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 polymer micelle used, to coat the support surface may be present as a monolayer. Alternatively, they may be multilayers in which the various layers are crosslinked to each other. In another embodiment, the multi -layer micelle contains at least two polymer micelles sandwiching either a high molecular weight polymer compound having a number of functional groups or a multi-functional low-molecular weight polymer compound having at least two functional groups.
- Fig. 1 is a schematic showing a polymer-micelle laminated surface and the lamination steps according to the present invention.
- Fig. 2 is the AFM scanning of a shaved portion of a laminated polymer micelle surface.
- Fig. 3 graphically depicts the change in potential as a function of pH in a polymer micelle laminated surface.
- Fig. 4 graphically depicts the change in BSA adsorption property and in ⁇ potential, depending on polymer micelle lamination.
- NH2/PP means plasma- treated polypropylene
- MCL-1 means NH2/PP which has been coated with single layer of micelle
- PAIAm-1 means MCL-1 which has been coated with polyallylamine
- MCL-2 means PAIAm-1 which has been coated with micelle
- PAIAm-2 means MCL-2 which has been coated with polyallylamine
- MCL-3 means PAIAm-2 which has been coated with micelle.
- Fig. 5 graphically depicts the change in fluorescence intensity of ammonia plasma treated silica (APTS glass) coated with pyrene- incorporated micelle.
- APTS glass ammonia plasma treated silica coated with pyrene- incorporated micelle.
- Fig. 6 graphically depicts the change in fluorescence intensity (I) of APTS glass coating with 6- layer of polymerized micelles after exposure to pyrene/micelle solution and water.
- Fig. 7 schematically depicts the chamber to test the migration of dextran through the film coated with micelle, as described in Example 3.
- Fig. 8 shows the plot of the permeation of dextran through the micelle coated films, as described in Example 6. In the graph, the following legend is utilized:
- the present invention relates to a support surface coated with the polymer micelle of the present invention.
- support surface is a product which is likely to be brought into contact with biological fluid when used.
- Biological fluid means a body fluid of animals like human being, such as tears, blood, urine, sweat and saliva.
- Representative examples include biomedical devices, such as artificial organs (e.g., artificial heart, artificial blood vessel, artificial bone, pacemaker, etc.), contact lens, stints, diagnostic instrument (e.g., catheter), storage vessel for body fluid, and experiment ware used in the laboratory (e.g., test tube, beaker, etc.).
- the support surface may be a film- like structure which is made of high-molecular weight compounds laying between polymer micelles.
- film- like means that the substrate does not necessarily need to be a continuous film all through the structure.
- the support surface may be a pharmaceutically acceptable carrier.
- the support surface is a biomedical device; the most preferred biomedical device is a contact lens and intraocular lens.
- the term "support surface” refers to both the untreated surface on which the micelle is immobilized, as well as the surfaces which have been treated, coated or modified to enhance or promote an immobilization of the micelle thereon. It is preferred that the micelle is immobilized to the biomedical device through a covalent bond. For example, as illustrated hereinbelow, some surfaces may have hydroxy groups thereon, the micelle having carboxylic acid or carboxylic acid esters thereon can react under ester forming conditions to form an ester in which a covalent bond is formed between the oxygen atom on the surface with the acyl group of the micelle.
- the surface may be modified or treated to form a covalent bond with the micelle and the surface so treated is encompassed within the term "support surface".
- the support may be placed in a bath of an inert solvent, such as tetrahydrofuran, and tresyl chloride. The hydroxy groups on the surface are then tresylated. Once tresylated, the support surface may be animated in a water solution of ethylene diamine, which results in bonding the group -NH-CH-CH 2 -NH 2 to the carbon atom thereon which was bonded to the displaced hydroxy group thereon.
- Unreacted ' diamine is removed and then the surface so treated is reacted with the carboxylic acid groups thereon under amide forming conditions to form an amide so that a covalent bond is formed between the modified surface having the amino group and the aryl group of the micelle.
- the surface may be coated with a non-micelle coating that contains amino groups thereon, and the amino groups on the coat can react with the carboxylic acid groups of the micelle.
- a modification of the surface by placing a coating on the surface is included within the term "surface" when defining the immobilization and/or formation of a covalent bond between the support surface and the micelle.
- the immobilization between the support surface and the micelle is preferably a covalent bond linkage therebetween as described herein.
- the coating may be one layer or may be more than one layer or multi -layered.
- multilayer refers to two or more layers. If it is more than one layer, it is preferred that it contains at least two layers and more preferably 2-10 layers and even more preferably 2-6 layers. It is preferred that the coating comprises a multi -layered micelle.
- the polymer micelle forming the coat has a predetermined thickness regardless of whether a monolayer or a multilayer is utilized.
- the monolayer preferably has a thickness on the order of magnitude of greater than 0.05 microns and more preferably the thickness of the monolayer ranges from about 0.1 microns to about 0.5 microns and most preferably from about 0.1 microns to about 0.3 microns.
- each micelle layer may have the same or a different thickness than the other layers of the composite. Within each layer, however, the thickness is preferably uniform.
- the term "hydrogel” is a term of art and refers to a broad class of polymeric materials which are swollen extensively in water, but which do not dissolve in water.
- the thickness of each layer is usually determined by the various groups present in the micelle, such as the functional groups thereon, the high molecular polymer compound or the low molecular compound that may be present, the hydrophilic group and the like.
- the micelle is a monolayer, it may be comprised of one polymeric micelle or more than one polymeric micelle, although it is preferred that it is comprised of one polymeric micelle. If multilayered, the various layers may be comprised of one polymeric micelle or more than one polymeric micelle. Moreover, even within each layer, there may be one or a mixture of more than one polymeric micelles. However, it is preferred that each layer is comprised of one type of polymeric micelle.
- the present invention is capable of providing a surface which supports a hydrogel layer of desired thickness by means of choosing the number of lamination of polymer micelle layers. It is preferred that if laminated, there is no more than 10 layers on the support surface and more preferably up to and including 6 layers. Nevertheless, it is preferred that the thickness of each layer be greater than 0.05 microns and more preferably, the thickness of each layer in the multilayer embodiment ranges from about 0.05 microns to about 0.5 microns, and more preferably from about 0.05 microns to about 0.1 microns .
- the thickness of the polymer micelle monolayer or multilayer can be regulated by various techniques known in the art, such as doctor-blade spreading on a support web or centrifugal casting in tubes.
- the micelle has a outer hydrophilic shell and an inner hydrophobic core.
- the linkage between the support surface and the micelle is preferably a covalent bond between the hydrophilic shell and the support surface.
- the micelle may have a hydrophobic outer shell and a hydrophilic inner core, i.e., a reverse micelle.
- the linkage between the support surface and the micelle is, preferably, a covalent bond between the hydrophobic outer shell and the support surface.
- the micelle is a reverse micelle, it is preferred that a multilayered micelle is formed in which the reverse micelle layer with the outer hydrophobic shell sandwiches a normal micelle, i.e. one in which the outer layer is hydrophilic and the inner layer is hydrophobic. This forms a stable interaction between the various layers, since the hydrophilic inner cores of the reverse micelles face the hydrophilic outer shell of the normal micelle and do not face or interact with the hydrophobic inner core of the normal micelle.
- the term “micelle” shall include “normal micelle” and "reverse micelle”.
- the term "normal micelle” is a micelle in which the micelle has a hydrophilic outer shell and a hydrophobic inner core, while a reverse micelle has the opposite, i.e., a hydrophobic outer shell and a hydrophilic inner core.
- the present invention is directed 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, said micelle being immobilized on the support surface. It is preferred that the micelle is bonded to the support surface.
- the micelle has a hydrophilic outer shell which is covalently bonded to the surface of the biomedical device and a hydrophobic inner core, although reverse micelles in which the hydrophobic outer shell is covalently bonded to the support surface is also contemplated within the scope of the invention. Regardless whether a normal or reverse micelle is utilized, said micelle is comprised of a block copolymer having a HLB value ranging from about 1 to about 40.
- HLB hydrophilic -lipophilic balance
- HLB hydrophilic -lipophilic balance
- HLB numbers have been evaluated by other methods, e.g., cloud points, gas chromatography, critical micelle concentrations and NMR spectroscopy. It is preferred that the HLB value is calculated using the structural approach.
- a commonly used general formula for determining the HLB value of a nonionic material, including micelles, is: 20 X (M H )/(M H + M L ) EQ I
- M H is the formula weight of the hydrophilic segment and M L is the formula weight of the hydrophobic segment.
- a block copolymer utilized in the present invention having the formula:
- T and U are anchors to the support, has a
- HLB values referred to hereinabove refer to the HLB value obtained via a structural approach and more precisely by the calculation of EQI, as described hereinabove.
- the block copolymer utilized in the present invention has a HLB value ranging from about 4 to about 20.
- the block copolymer and the resulting micelle therefrom consists of a hydrophilic moiety (water soluble) and a hydrophobic moiety. It is preferred that the micelle has a hydrophilic outer shell and a hydrophobic inner core.
- the preferred water soluble (hydrophilic) region of the block copolymer and micelle consists of polyethylene glycol, polyethylene oxide, polyvinyl alcohol, polyacryiamide, polymethacrylamide, poly (vinylpyrrolidone) , and the like. It is most preferred that the hydrophilic moiety is polyethylene glycol, polyacryiamide, polymethacrylamide, poly (vinylpyrrolidone) or polyvinyl alcohol. The most preferred hydrophilic core is polyethylene glycol.
- the hydrophobic polymer segment is attached to the hydrophilic polymer by non-hydrolyzable chemical bonds, such as carbon -carbon bonds, by amide linkage, ether linkages, ester linkages, thio linkages, amino linkages, and the like.
- the hydrophobic polymer segment utilized herein may be derived from any polymer provided that the corresponding block copolymer forms a stable polymer micelle when dissolved or dispersed in a solvent which is capable of dissolving said hydrophobic polymer segment.
- the preferred hydrophobic polymer segments include poly ( -hydroxycarboxylic acids) which are derived from either glycolide or lactide; poly ( ⁇ -hydroxycarboxylic acids) which are derived from either y- lactone or ⁇ - lactone or e- lactone; or those derived from a copolymer of such poly ( ⁇ -hydroxycarboxylic acids) with such poly( ⁇ - hydroxycarboxylic acids) .
- the hydrophobic polymer segments may have an ethylenically unsaturated polymerizable group at one end which is opposite to the one at which the hydrophobic polymer segment is bonded to the hydrophilic polymer segment. Such a polymerizable group can be introduced from (meth) acrylic acid or vinylbenzyl chloride.
- such a polymerizable group may be subjected to a polymerization reaction after the formation of the polymer micelle, and is thus brought into a polymerized (crosslinked) state with the support surface. In such a state, the polymer micelle per se is more stable.
- the hydrophilic polymer segment has a functional group at an end opposite to the one at which it is bonded to the hydrophobic polymer segment.
- said functional group exists on the surface, or near the surface, of said polymer micelle, thereby forming a normal micelle.
- This functional group is preferably used to covalently bond the polymer micelle with the support surface and, when present, the high-molecular weight polymer compound or multi-functional low-molecular weight compounds lying between the polymer micelles.
- the hydrophilic and hydrophobic polymer segments on the micelle may have more than one functional group and the 'functional groups may be the same or different.
- the functional groups present on the block copolymer include aldehyde groups, carboxyl groups, hydroxyl groups, mercapto groups, amino groups and the like. If the high molecular weight polymer compound or multi-function low molecular weight compound is present, they have functional groups, some of which may bind to the polymeric micelle. These various functional groups thereon may be the same o,r different and they may be the same or different from the functional groups present on the hydrophilic or hydrophobic portion of the micelle.
- the most preferred polymer micelle is formed from a block copolymer which is composed of both a hydrophilic polymer segment essentially comprising poly (ethyleneglycol) [hereinafter sometimes abbreviated as PEG] and a hydrophobic polymer segment.
- PEG poly (ethyleneglycol)
- hydrophobic polymer segment essentially comprising means that PEG occupies the main portion of the hydrophilic polymer segment, and that some linking group or the like which has essentially no influence on the hydrophilicity of said segment may be contained in some amount in the PEG chain or between hydrophilic and hydrophobic polymer segments.
- the PEG chain consists of PEG alone.
- Preferable block copolymers are those disclosed in the above-mentioned patents and or international patent publications. If the block copolymer has a sugar residue on 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 so that a corresponding aldehyde group may be formed.
- R 1 and R 2 independently denote hydrogen atom, C 1 . 10 alkyl, aryl or aryl-C 1 _ 3 alkyl; r denotes an integer of 2 - 5, and wherein m denotes an integer of 2 - 10,000; n denotes an integer of 2 - 10,000; p denotes an integer of 1 - 5; and
- Z denotes acetyl, acryloyl, methacryloyl, cinnamoyl, allyl or vinylbenzyl; or the following Formula (II) :
- X denotes an alkyl group having 1 to 10 carbon atoms which has an amino group, a carboxyl group or a mercapto group
- Y denotes groups of the following formula:
- R 11 and R 12 independently denote a hydrogen atom or a A. 5 alkyl
- R 3 denotes a hydrogen atom or a methyl group
- R 4 denotes a C ⁇ _ 5 alkyl substituted by a hydroxyl group which may be protected
- q denotes an integer of 2 - 5, and wherein
- Z denotes acryloyl, methacryloyl , cinnamoyl, allyl or vinylbenzyl; m denotes an integer of 2 - 10,000; and n denotes an integer of 2 - 10,000; or the following formula (III) :
- A denotes a group which is derived, by Malaprade oxidation, from a sugar residue having the following formula:
- one of the broken lines ( — ) denotes a single bond while the other denotes a hydrogen atom; and a and b independently denote an integer of 0 or 1, and wherein L-_ denotes linking groups of the following formula ;
- R 5 and R 6 independently denote a hydrogen atom, a C 1 . 6 alkyl, an aryl or a C 1 . i alkyl aryl; and wherein m denotes an integer of 2 - 10,000; n denotes an integer of 2 - 10,000; and Z denotes acryloyl, methyacryloyl, cinnamoyl, allyl or vinylbenzyl .
- alkyl group when used alone or in combination with another group refers to a lower alkyl which contains one to six carbon atoms.
- the carbon atoms may be straight- chained or branched. Examples include methyl, ethyl, propyl, isopropyl, butyl, sec -butyl, isobutyl - t -butyl , pentyl, neopentyl, hexyl and the like.
- alkenyl when used alone or in combination with other groups, refers to a loweralkenyl group containing 2-6 carbon atoms.
- the alkenyl group may contain 1 or more carbon- carbon double bonds up to a maximum of 3; however, it is preferred that it contains 2 and more preferably 1 carbon-carbon double bond.
- the alkenyl groups may be straight chained or branched.
- Examples include ethenyl, 1-propenyl, 2-propenyl and the like.
- Aryl when used herein, either alone or in combination with another group denotes an .aromatic moiety containing only ring carbon atoms and containing 2k + 2 ring carbon atoms, where k is 1, 2, 3 or 4.
- the aryl group may be monocyclic, bicyclic, tricyclic or tetracyclic; if it contains more than one ring, the rings are fused to one another.
- the aryl groups may be substituted by lower alkyl group.
- the aryl groups may contain 6-18 ring carbon atoms and a total of 6-25 carbon atoms. Examples include phenyl, tolyl, xyly ⁇ , naphthyl, ⁇ -naphthyl and the like.
- the polymer micelle is preferably formed where the functional group at the end of the hydrophilic polymer segment is protected (e.g., in the case of aldehyde group, it is acetalized or ketalized; in the case of an amino group, it is protected by an amino protecting group) , and, then is subjected to a deblocking reaction.
- each block copolymer may be subjected to polymerization-crosslinking via said polymerizable group after the polymer micelle is formed.
- the coating of the polymer micelle is a monolayer, then it preferably comprises the components of Formula I -III described hereinabove. If the coating is laminated, then the coating preferably comprises at least one set of layers composed of two polymer micelle layers, formed from at least one of the polymer micelles of Formula I -III described herein.
- the laminated layers of a micelle may be crosslinked by carbon-carbon bonds.
- the micelles may contain interior carbon-carbon double bonds or the side chains thereof may contain carbon-carbon double bonds.
- the micelles can be cross -linked together by exposing them to electron beam radiation which creates free radicals. Random coupling then results in the formation of a layer.
- the solution is exposed to sufficient electron radiation to effect free radical formation.
- the electron radiation may range from about one to about 10 megarads .
- the micelles may be cross -linked together by adding a , photoinitiator to the micelles in an inert solution, and exposing the solution to visible or UV light of sufficient wavelength to form a free radical. Random coupling then results in the formation of a layer.
- the photoinitiator is exposed to sufficient wavelength of light to form free radical which in turn reacts within the micelle, especially the carbon-carbon double bonding to effect free radical formation in the micelles .
- the layers may be covalently bonded either with a high-molecular weight polymer compound having one or more functional groups ("another species of" functional group) which groups are covalently bondable with the functional group in the block copolymer in the polymer micelle, or with a multi-functional low- molecular weight compound having at least two, preferably 2 or 3, of said "another species of" functional group, both of said high-molecular weight polymer compound and multi-functional low-molecular weight compound lying intermediate between said two polymer micelle layers.
- the various layers are, in turn, bonded to each other via a covalent bond between a functional group on the above- mentioned "another species of" functional group of the high-molecular weight polymer compound or multifunctional low-molecular weight compound, and the functional group of the block copolymer in the polymer micelle.
- the outermost layer may be a layer of the above-mentioned high-molecular compound and in this case, it is bonded to the surface support at one end and the micelle layer via a covalent bond at the other end.
- a functional group in the support surface is reactive with a functional group on the high molecular weight polymer and a covalent bond is formed between the support surface and the high molecular weight polymer.
- a functional group on the micelle reacts with a functional group at the opposite end of the high molecular weight polymer reactive therewith and forms a covalent bond therebetween.
- Examples of functional groups substituted on the high molecular weight compound include an amino group which is covalently bondable with aldehyde (Schiff base which is formed from aldehyde group and amino group may further be reduced) ; an hydroxyl group and an amino group which are covalently bondable with carboxyl group; a carboxyl group and a sulfo group which are covalently bondable with hydroxyl group; or a mercapto group which is covalently bondable with amino group.
- Such a covalent bond can be formed under known reaction condition such as oxidation- reduction conditions, dehydration condensation conditions, addition condition, and substitution (or displacement) conditions.
- the high molecular weight polymer compound is a polymer having a molecular weight greater than about 8000 daltons and more preferably greater than about 10,000 daltons having amino, carboxyl, thio or sulfo functional groups. It is preferable that the high molecular weight polymer has a molecular weight of less than about 500,000 daltons and more preferably less than about 300,000 daltons.
- the above-mentioned high-molecular weight polymer compound is either a natural product or a synthesized one.
- examples of those having an amino group include polyalkenylamine, such as polyallylamine, polyvinylamine and the like; polymers of basic aminp acids, such as polylysine; chitosan and polyethyleneimine.
- examples of those high molecular weight polymers having carboxyl groups include poly (meth) acrylic acid, polyacrylic acid carboxymethylcellulose and alginic acid and the like.
- high molecular weight polymers having sulfo group (or sulfate group) include heparin and polystyrene sulfonic acid and the like.
- the low molecular weight compounds preferably have a molecular weight not greater than 200 daltons .
- the molecular weight of these compounds ranges from about 17 to about 120 daltons, inclusive.
- multi-functional low-molecular weight compound include lower alkylene diamine (e.g., ethylene diamine), glutaraldehyde and ethanedithiol , and the like.
- Examples of functional groups substituted on the low molecular weight compound include an amino group which is covalently bondable with aldehyde (Schiff base which is formed from aldehyde group and amino group may further be reduced) ; an hydroxyl group and an amino group which are covalently bondable with carboxyl group; and carboxyl group and a sulfo group which are covalently bondable with hydroxyl group; or a mercapto group which is covalently bondable with amino group.
- Such a covalent bond can be formed under known reaction condition such as oxidation -reduction conditions, dehydration condensation conditions, addition conditions, and substitution (or displacement) conditions.
- the high or low molecular weight compounds are reacted with the block copolymers using art recognized techniques.
- the block copolymers have functional groups on their ends, such as hydroxy, amino, carboxy, thip or may have leaving groups known in the art on their ends, such as halo, sulfonic acid esters, e.g., mesylate, tosylates, brosylates and the like.
- the high or low molecular weight compounds also have functional groups on their ends, e.g., hydroxy, amino, carboxy, thio, or may have on their ends leaving groups known in the art, such as halo, sulfonic acid esters, such as tosylates, mesylates, brosylates, and the like.
- the block copolymer is reacted with the high or low molecular weight compound under conditions effective to form a product.
- the product may be formed by displacement (substitution) or it may be formed under amide forming conditions, ester forming conditions, and the like, depending upon the functional groups present on the block copolymer as well as on the high or low molecular weight compound .
- the chemistry can be represented by the following equation:
- B 1 is the hydrophobic segment
- X 1 and X 2 are the same or different and represent a group capable of forming a covalent bond with Y 2 and Y 1# respectively;
- Y 1 and Y 2 are the same or different and represent a group capable of forming a covalent bond with X 2 and X x respectively; and R x is a low or high molecular weight compound.
- the low or high molecular weight compounds can be bonded to the
- a 1# B 1# R x , Y : and Y 2 are as defined hereinabove, and X-_ and X 2 are leaving groups.
- the low or high molecular weight compounds can be bonded to the block copolymer through ether, thio, or amino bonds.
- X x and X 2 are functional groups and Y 1 and Y 2 are leaving groups, then the following product is obtained: Y 1 -R x -X 1 - (Ai-B -X 2 -R x -Y 2 , wherein
- a , B 1# and R x are as defined above.
- X 1# X 2 , Y 1# and Y 2 are leaving groups; in this way, carbon- carbon covalent bonds are formed between the block copolymer and the low or high molecular weight compounds:
- the support surface is made of e.g., glass, silicon wafer, polypropylene, etc. and it may also contain the above-mentioned functional groups.
- the support surface may be untreated or may be treated or modified as described herein.
- the support surface is coated with a micelle of the present invention.
- One layer of micelle may coat the support surface or it may be coated with more than one layer. If multi- layered, the micelle may contain a high molecular weight compound sandwiched between the layers. Alternatively, the micelle may contain a low molecular weight compound sandwiched between the layers. In another embodiment, the layers of the micelle may be crosslinked.
- the multi -level micelle may contain a combination of any of these embodiments.
- the support may be physically or chemically treated with a high-molecular weight polymer compound by a known method. An example of such a method is schematically illustrated in Figure 1.
- hydrogel refers to a broad class of polymeric materials which are swollen extensively in water but which do not dissolve in water.
- the polymer micelle of the present invention is produced by art recognized techniques or by using techniques described hereinabove or in any of the aforementioned patents and PCT applications, the contents of all of which are incorporated by reference.
- the coating is then applied to the support surface.
- the polymer micelle forms a covalent bond with the support surface. This may be effected by art recognized techniques such as by the following step:
- step A described hereinabove is still utilized.
- step A there are two additional steps also utilized in the process of coating the support surface:
- step (B) bringing the thus formed polymer micelle layer which has covalently been bonded with substrate into contact with a solution containing either a high- molecular weight polymer compound having a plural number of functional groups, as defined hereinabove or a multifunctional low-molecular weight compound having at least two, preferably two or three, functional groups as defined hereinabove, and accumulating on said polymer micelle layer either said high-molecular compound or said multi-functional low-molecular weight compound, and, then, reacting the functional group of the high molecular weight polymer compound or the low-molecular weight compound with the functional group on the polymer micelle of the product of step (A) under conditions effective to form a covalent bond, and, if necessary, removing unreacted high-molecular or low-molecular compound; and
- step (C) bringing the thus obtained laminate of step (B) in which the high-molecular weight polymer compound or low-molecular weight compound has covalently been bonded into further contact with the aforementioned dispersion of the polymer micelle, accumulating said polymer micelle on the layer of said high-molecular weight polymer compound or multi-functional low-molecular weight compound of said laminate, and, then, covalently bonding said high-molecular or low-molecular weight compound with polymer micelle, and, if necessary, removing unreacted polymer micelle, and if necessary, further repeating said steps (B) and (C) .
- the polymer micelle can be immobilized on a support surface of any geometry using free radical formation techniques such as electron beam radiation or UV or visible light in combination with a photoinitiator.
- the polymer micelles are . dissolved or suspended in an aqueous solution, preferably water, at a concentration sufficient to provide sufficient amount of polymer micelle to cover the support surface to the desired thickness.
- JA preferred concentration ranges from about 0.5 mg/mL to about 15 mg/mL, inclusive and more preferably from about Img ' /mL to about 5mg/mL, inclusive.
- the resulting solution is then deposited onto the support surface, using techniques known in the art such as by spraying, spreading, immersing the support in the micellular solution, and the like.
- the polymer micelle contains a polymerizable group, such as a carbon-carbon double bond, as in, for example, methacrylic acid, vinyl benzyl or ethylene, then the polymer micelle can be covalently bound to the support surface using techniques known to one of ordinary skill in the art.
- a polymerizable group such as a carbon-carbon double bond, as in, for example, methacrylic acid, vinyl benzyl or ethylene
- the surface of the support may be treated, prior to forming covalent linkages between the surface and the micelle.
- a plasma prepared from hydrogen and nitrogen gas such as 2 parts hydrogen gas and 1 part nitrogen gas, can be placed on the support as defined by the present invention.
- the plasma creates amino groups on the support surfaces.
- a polymer micelle having an aldehyde functionality can react with the surface under conditions of reductive amination to form a covalent bond with the support surface.
- Allylamine plasma is an alternative way to treat a substrate (or a medical device) surface to produce amine sites on the surface with which micelles can react.
- allylamine vapor is , introduced into the plasma chamber, and this creates amino groups on the support surfaces, which can react with an aldehyde or keto group under reductive amination conditions .
- the micelle has carboxy groups thereon, the polymer micelle can react with the surface having amino groups under amide forming conditions .
- Other functional groups may be placed on the substrate surface by coating the substrate with plasma containing said functional group.
- the substrate can be coated with a plasma containing carboxy groups.
- the plasma coated surface is reacted with the micelle under ester- forming condition to form an ester linkage between the micelle and the plasma coated surface.
- the micelle and the plasma coated surface react under amide forming conditions to form amide linkages between the micelle and the plasma coated surface.
- the carboxy groups may be placed on the surface by oxidizing the hydroxy groups thereon with oxidizing agents known to one skilled in the art to form carboxylic acids, which can then react with the hydroxy groups or amines on the micelles to form esters or amides, respectively, as described hereinabove.
- oxidizing agents known to one skilled in the art to form carboxylic acids, which can then react with the hydroxy groups or amines on the micelles to form esters or amides, respectively, as described hereinabove.
- the surface is activated to form a covalent bond with the micelle or (high molecular weight polymers or low molecular weight compound) .
- the micelle may be exposed to a reagent that affixes groups thereon which are reactive with the functional groups on the surfaces.
- the polymer micelles in solution can be crosslinked together and to the surface by subjecting them to conditions which form free radicals, such as electron beam radiation, or addition of a photoinitiator and subsequent exposure to light or UV light which creates free radicals on the micelles. Crosslinking between the free radicals forms a covalent bond.
- electron beam radiation is utilized, the solution containing the surface and polymer micelle is exposed to electron radiation in the range of between about one to about ten megarads, most preferably four megarads .
- Gamma radiation can be used as the radiation source but may result in the degradation of the polymer micelle unless oxygen is scrupulously excluded.
- a photoinitiator may be added to the solution and then the solution containing the photoinitiator and the polymer micelle are exposed to light or ultraviolet light of sufficient wavelength to form free radicals.
- Crosslinking via free radical coupling occurs randomly between the layers of the micelle and the surface.
- the micelle consists of the PEO arms. If the PEO arms contain et ylenically unsaturated groups, then crosslinking can be effected by the techniques described hereinabove.
- the terminal hydroxyl groups remain available for subsequent activation, such as for coupling affinity ligands to the PEO arms.
- Crosslinking enhances the stability of the micelle.
- the polymer micelle can be covalently immobilized to a support surface by tresylation of the terminal hydroxyl groups .
- the following embodiment is illustrative for a PEO hydrophilic group, but it is to be understood that this is only exemplary, and the techniques described hereinbelow are applicable to other hydrophilic groups.
- the support surface and the polymer micelles are each pretreated prior to immobilization.
- the support surface should contain active functional groups for immobilizing tresylated polymer micelles thereto, such as amino and/or thiol groups.
- the polymer micelles are tresylated in an appropriate solvent prior to contacting with the support surface. Tresylation is particularly convenient for the PEO hydrophilic groups, since the PEO is solvated by media appropriate to tresyl chloride (e.g., dichloromethane, chloroform) . This method results in a monolayer coating of the hydrogel over the support surface.
- an organic solvent such as dichloromethane
- tresyl chloride under conditions effective to affix the tresyl groups to the hydroxy- terminal on the PEO of the polymer micelle.
- the resulting tresylated PEO polymeric micelles are then precipitated and recovered, ultimately as a dry active product.
- the tresylated PEO polymeric micelles are dissolved in an aqueous solution at a pH of ten or above, so as to favor reaction with amino and/or thiol groups already present on the support surface.
- the pH-adjusted solution is contacted with a support surface that contains amino and/or thiol groups, under conditions whereby the polymeric micelle become covalently bound in a dense layer to the support surface.
- reagents can be used to react with the terminal hydroxyl groups on the PEO chains .
- These reagents include tosyl chloride (p- toluene sulfonyl chloride), mesyl chloride (methane sulfonyl chloride) , epichlorohydrin, cyanuric chloride (C 3 N 3 CI 3 ) , carbonyl diimidazole (CDI) and a mixture of succinic anhydride and succinimide.
- the hydroxy- terminated polyethylene oxide is reacted with tosyl chloride or mesyl chloride to form a tosylated or mesylated polymer micelle, respectively.
- the activated PEO arms can be reacted with any molecule containing an amino or thiol group.
- By-products liberated by the reaction of the amino or thiol containing compound with the activated PEO arms include tresyl, mesyl or tosyl sulfonic acid, HC1 (reaction of cyanuric chloride) , imidazole (reaction of CDI) , or N- hydroxylsuccinimide (reaction of succinic anhydride and succinimide) . There is no by-product liberated in the epichlorhydrin reaction.
- any molecule containing an amino or thiol group for example can become covalently attached to a tresylated, tosylated or mesylated polyethylene oxide chain by the formation of the stable NC or SC bond, with the elimination of the respective sulfonic acid, tresyl, tosyl or mesyl.
- the hydrophilic group may have carboxy groups thereon and the surface pretreated to form thereon amino or hydroxy groups. Then the surface and the polymer micelle are reacted under amide or ester forming conditions to form the corresponding amide or ester. Similarly, the surface may be modified to have free carboxy groups thereon, and the functional groups on the end of the polymer may be amino or hydroxy groups. Again, the micelle and the surface are reacted under amide or ester forming conditions to form the corresponding amide or ester, respectively. Moreover, the surface may be pretreated to have free hydroxy, amino or thiol groups.
- the polymer micelle has on its ends a leaving group, such as halide or sulfonic esters, e.g., brosylate, tosylate or mesylate and the like.
- the polymer micelle and the surface are reacted under displacement or substitution conditions to form the corresponding ether, a ine or thio bonds.
- crosslinking may be effected by free radical reactions, using the techniques described herein. In this way, using common techniques in the art, the hydrophilic or hydrophobic core is bonded to the surface
- the biomedical device is substantially free of contaminants, especially proteins.
- the micelles repel proteins, thereby keeping the surface of the biomedical device free of contaminants. This is especially useful when the biomedical device is inserted into' the body of an animal, preferably mammal, such as dog, cat, cow, horse, and especially human. As a result, there is less contamination and less risk of infection when the inserted biomedical device is coated with the micelles described herein.
- This invention provides a stable surface wherein the thickness of the hydrogel layer comprising polymer micelle is controlled within a range from several tens of nanometers to more than 100 nanometers.
- the polymer micelle is useful as a carrier for guest systems, e.g. molecules.
- the polymer micelle having a hydrophilic outer shell and a hydrophobic inner core can be a carrier in its interior with hydrophobic drugs which can then be released when the biomedical device is inserted into or placed into the body of the patient.
- the polymer micelle can be charged in its interior with the drug when said surface is contacted with said hydrophobic drugs in an aqueous solvent at an elevated temperature.
- the drugs are present in pharmaceutically effective amounts. Such drugs can slowly be released in an aqueous medium at ambient temperature.
- the present inventors have found that the rate of drug release is controlled by utilizing multi -layered micelle.
- the present micelle sys.tem is capable at effecting controlled release of the drug.
- drug charging may also be conducted by laminating a polymer micelle which has previously been charged with drug. It is preferably that the drug is adsorbed on the surface of the support. Regardless, the linkage of the drug to the surface of the support is biodegradable, that is, it is easily removed when inserted into the body of an animal. If the drug is covalently bonded to the surface, the covalent bond is such that it is hydrolyzed by the enzymes in the animal.
- drug includes medicaments, therapeutics, vitamins, nutritional supplements, and the like.
- the inventors have found that by coating the surface with the micelles described herein, the method provides a surface which exhibits excellent bioaffinity.
- Any pharmaceutical drug can be utilized such as, for example, anti cancer drugs, drug for central nerves, drugs for peripheral nerve, drugs for allergy, drugs for circulatory organs, drugs for respiratory organs, drugs for digestive organs, hormone drugs, antibiotics, drugs for chemotherapy, vitamins, food supplements and the like.
- the polymer micelles described herein are in the manufacture of contact lenses, especially contact lenses described in U.S. Patent Nos. 4,680,336 to Larsen, et al., 4,889,664 to Kindt-Larsen, et al. and 5,039,459 to Kindt-Larsen, et al., the contents of all of which is incorporated herein by reference.
- the contact lens prepared in accordance with the procedures of 'any of the aforementioned patents may be coated with the polymer micelle described herein. It may be coated with 1 layer or more than one layer.
- the polymer micelle can be covalently bound onto a suitable art recognized contact lens material such as a polyHEMA hydrogel contact lens described in U.S.
- the contact lens material can be immersed in a solution containing the polymer micelle and exposed to conditions forming free radicals ionizing radiation, as described hereinabove, to covalently bound the polymer micelle onto the contact lens surface.
- the surface of the contact lens material can be modified by creating amino or thiol groups on its surface. The modified lens material may then be exposed to an activated polymer micelle, such as the tresylated derivatives described hereinabove.
- the contact lens material coated with the polymer micelle of the present invention has several advantages relative to those contact lens which are not coated with the micelles used herein. More specifically, due to the properties of the polymer micelle, absorption of proteineous deposits from natural enzymatic secretions of the eye by the coated lens material is substantially reduced or eliminated. Thus, the coated lenses will not become clouded or opaque because of lowered protein absorption.
- the micelle of the present invention has the ability to reduce microbial, including bacterial contamination.
- the coated contact lenses have a greater ability to retain water and thus are less likely to dry out.
- the contact lens so coated may be used as a carrier for guest molecules, such as a drug, in which the drug is covalently bound to the coated contact lens in accordance with the procedure described herein and then released from the contact lens through the eye into the body.
- guest molecules such as a drug
- the guest molecule e.g., drug
- the drug is entrapped in the biomedical device.
- the drug is incorporated into the material from which the biomedical device is prepared.
- the biomedical device is a contact lens or an intraocular lens
- the guest molecule e.g., the drug is incorporated into the monomer mix, and cured into the lens in accordance with the procedure described in U.S. Patent Nos.
- the drug is then released therefrom after insertion into the body of the animal, e.g., eye.
- the guest molecule may be associated with or entrapped inside the micelle or it may be covalently linked to the micelle. If entrapped in the micelle, the entrapped guest molecule is released after the insertion into the body of the animal. If covalently linked, just like as in case of the drug being covalently linked to the biomedical device, it is released by enzymatic cleavage (hydrolysis) . Moreover, the release of drug molecules can be controlled, especially if multi- layers are utilized. Regardless, the guest molecule is present in amounts effective for its function.
- the guest molecule is a drug
- the micelles described, hereinabove can be used as a carrier for drugs to treat eye diseases.
- the drug is incorporated, as described hereinabove, onto the contact lens by techniques known in the art, and the contact lens so treated is coated with the micelle polymer described hereinabove.
- the contact lens with the coating and the drug is inserted into the eye. If controlled release is desired, the contact lens may be coated with a laminated micelle.
- the enzymes present in the eye can cleave the micelle containing the drug, whereby the drug is delivered to the desired site.
- the micelle coating is useful as a carrier for treating dry eye syndrome.
- ocular fluid forms a thin layer approximately 7-10 micrometers thick that covers the corneal and conjunctival epithelium.
- This ultra thin layer provides a smooth optical surface to the cornea by abolishing minute surface irregularities of its epithelium, wets the surface of the corneal and conjunctival epithelium, thereby preventing damage to the epithelial cells, and inhibits the growth of . microorganisms on the conjunctiva in the cornea by mechanical flushing.
- the tear film normally includes a three layer structure.
- the outermost layer is a lipid layer derived from the secretions of the meibomian glands and thought to retard evaporation of the aqueous layer.
- the middle aqueous layer is provided by the major and minor lacrimal glands, and contains water-soluble substances.
- the innermost mucinous layer is composed of glycoprotein ⁇ mucin and overlies the corneal and conjunctival epithelial cells.
- the epithelial cell membranes are composed of lipoproteins and are thus generally hydrophobic.
- the mucin plays an important role in wetting the surface, as the aqueous tears to spread out on and the surface is wetted by a lowering of the tears' surface tension.
- mucin is provided by goblet cells of the conjunctiva and is also provided from the lacrimal gland.
- the tear film components When any of the tear film components is deficient, the tear film will break up, and dry spots will form on the corneal and the conjunctival epithelium. Deficiency of any of the three components (aqueous, mucin or lipid) may result in dryness of the eye.
- keratoconjunctivitis sica There are many forms of the disease known as keratoconjunctivitis sica. Those connected with rheumatoid arthritis or other connective tissue disease are referred to as Sjogren's syndrome .
- the linkage between the drug and the contact lens is biodegradable.
- the mucin type products e.g., polyglycolic acid or polylactides are hydrophobic and are thus soluble in the hydrophobic portion of the micelle.
- the drug is easily removed from the contact lens by biological processes and the micelles hold the mucin-like material, which serves to wet the eye.
- other mucin like material such as collagen or gelatin can be adsorbed onto the contact lens, which is then coated with the micelle described hereinabove.
- the collagen and gelatin is also soluble in the micelle.
- the micelle of the present invention reduces microbial infection.
- the biomedical device is a contact lens or intraocular lens and if it is coated with the micelles of the present invention, the contact lens will have reduced microbial contamination.
- the micelle is present as a coating on the biomedical device in an amount sufficient to retard or prevent substantially contamination by the microbe.
- the biomedical device or the micelle may be associated with an anti -microbial agent.
- the anti -microbial agent may be entrapped in the micelle or biomedical device, by, for example, being mixed in with material used to prepare the biomedical device.
- the biomedical device is a contact lens
- the anti -microbial agent may be mixed in with the monomer e.g., polyHEMA, in accordance with the procedure described in U.S. Patent Nos. 4,680,336, 5,039,459 and 4,889,664.
- it may be covalently bound to the biomedical device or micelle, using the techniques described herein.
- the micelle or biomedical device contains an anti -microbial agent
- there the contamination of the biomedical device, e.g., contact lens or intraocular lens, by microbes, e.g., bacteria is reduced relative to a contact lens wherein the antimicrobial agent is absent.
- the anti -microbial agent is present on the coating device or in the micelle in an amount sufficient to retard and/or substantially prevent contamination by the microbe.
- the present invention offers several advantages, especially when the hydrophilic moiety is PEG.
- One of the most important advantages is that a high density coating of a hydrophilic moiety, e.g., PEG can readily be obtained through simple micelle coating. This is not easy to achieve by PEG grafting to the surfaces. Without wishing to be bound, it is believed that this is attributable to the number of PEG chains in the micelle.
- the present system prevents the flip flop of grafted PEG. This is a great advantage to keep the surface constant even in drastic change in the environment, for example, if the surface dries up. This migration of grafted chain into the sample interior upon drying is often a problem, especially for the treatment of surfaces with high mobility, including silicone.
- the coating of the present invention avoids this problem.
- polyethylene glycol (PEG) segment, polylactide (PLA) and block copolymer had each a molecular weight of 5800, 4000 and 9800.
- Example 2 In 40 ml of dimethyl acetamide (DMAc) , there was dissolved 280 mg of the block copolymer which had been obtained in Example 1. The resultant solution was dialyzed against water (2 t : for 2 hours, 5 hours and 8 hours) using a dialysis membrane having a fractional molecular weight of 12-14000. To the resultant dialyzate, 1N-HC0 was added to adjust the dialyzate 'to pH 2, and the resultant mixture was stirred for two hours. The resultant solution was adjusted to pH 7 by the addition of an aqueous solution of 0.1 N-NaOH.
- DMAc dimethyl acetamide
- the resultant solution was dialyzed against water for 24 hours using a dialysis membrane having a fractional molecular weight of 12-14000.
- the thus obtained dialyzate was transferred into a flask in an argon atmosphere, and, then 1.8 (w/w) % per micelle of potassium persulfate was added, and, after deaeration, the resultant mixture was allowed to react at 50 °C for 24 hours.
- the measurement of the dynamic light scattering (DLS) of the product indicated that the particle size and the indication ⁇ / T 2 of polydispersion degree of the polymer micelle before and after the polymerization reaction were (35.5 nm, 0.094) and (41.0 nm, 0.125), respectively. Almost no change was seen in particle size between before and after the polymerization reaction.
- the base plate there was used a strip which is mainly made of slide glass, silicon wafer or polypropylene.
- Slide glass or silicon wafer was cut into a suitable size, and was subjected to ultrasonic cleaning, and, thereafter, was further cleaned in a mixed liquid at about 100 °C which was composed of 30% H 2 S0 4 and H 2 0 (at a volume ratio of 1:1), and was then rinsed fully with pure water.
- the thus treated fragment of slide glass or silicon wafer was dried in vacuum at normal temperature for 16 hours, and, then was dipped in a toluene solution of 3 -ammopropyltriethoxysilane for 3 to 4 hours, and, thereafter, was dried in vacuum at 160 °C.
- the amino group was thereby introduced onto the surface of said fragment.
- the amino group was introduced onto the surface of the base plate by means of a treatment (Samco International; Model BP-1; 75 W; 30 minutes) with plasma derived from N 2 :H 2 (at a volume ratio of 1:2) .
- Silicon wafer (made by Mitsubishi Material Co.) supporting an amino group on its surface which had been prepared in Comparative Example 3 was dipped, at a normal temperature for two hours, in a solution of a polymer micelle which had been obtained in accordance with the procedure of Example 2, having a concentration of about 1 mg/mC dissolved in 0.04 M HEPES [said solution containing 0.0032 (w/v) % NaCNBH 3 ] .
- a laminated type micelle-gel membrane was constructed (See: Figure 1) .
- NaCNBH 3 was used at a concentration of 0.25 %.
- micelle coat laminated membrane
- the thickness was about 20 nm in single coat, while it changed to 40-45 nm in the two-layer coat, and was 80-90 nm in the three-layer coat.
- three- layer micelle coat it was observed that the area shaved in the contact mode had decreased as time progressed. Without wishing to be bound, it is believed that in the laminated membrane on the surface, the micelle and polyallylamine had been crosslinked by a chemical bond; hence, the membrane which had been cut and compressed by cantilever gradually restored, resulting in the decrease of shaved area.
- a surface is coated with a hydrogel such as the above-mentioned micelle coat, in .particular when the micelle is the outermost surface layer, it is expected that protein adsorption is inhibited.
- a surface of propylene base plate to which an amino group had been introduced in the above- mentioned way was coated with a micelle- laminated gel prepared in Example 1 and the adsorption of protein (bovine serum albumin: BSA) onto the micelle surface and polyallylamine surface was compared.
- BSA bovine serum albumin
- the hydrogel membrane is formed from the micelle prepared hereinabove.
- the hydrogel membrane contains a hydrophobic core membrane.
- the release of the drug from the polymer micelle will be controlled release.
- Pyrene was used as a model drug.
- a solution of pyrene in acetone was put in a flask, so that pyrene might be accumulated on the interior surface of flask.
- the flask was charged with polymer micelle solution according to Example 2, which was stirred at 60 °C for four hours. After the temperature of the solution returned to a normal one, insoluble matters were then removed by a filter of 0.4 ⁇ m.
- the thus obtained pyrene -charged polymer micelle was then coated with different amounts of layers of the product of Example 1, ranging from one layer to six layers, in accordance with the procedure of Example 3.
- the specific coating is depicted in the following table:
- the initial fluorescence intensity depends upon the number of coatings.
- the fluorescence of 3 - time coating (3LO, 3LE) was twice as intense as the single coating (ML2 , ML16) , and 6-time coating (6LE) was about 10 times higher in intensity. This result indicates that by coating under the condition described in Table 1, the multi -layer of micelle could be attached to the surface and the multi -layer increased the amount of pyrene on the surface.
- the rate of fluorescence decline depends upon the coating condition as well as the number of coatings.
- the initial fluorescence intensity seems to be closely correlated to the number of coatings.
- the differences in coating time (ML2 and ML16) and the differences in the reduction process of Schiff base (3LO and 3LE) resulted in a change in a decline rate of fluorescence as seen in Figure 5.
- the 6 -layer coating showed high initial intensity and the log-plot of intensity versus incubation time indicates a more controlled release of pyrene from the surface.
- the loading of hydrophobic reagents after the coating of micelle was also investigated to determine if drugs can be reloaded repetitively into the micelle coated sample.
- the micelle coated sample prepared in Example 1 was exposed to pyrene containing micelle solution and water alternatively.
- the pyrene- free micelle solution was coated on APTS -glass under the same condition as 6LE.
- the micelle solution was coated on the APTS-glass under the same condition as 6LE.
- the micelle coated sample was then exposed to the pyrene-loaded micelle solution for 12 h. Then the sample was rinsed with water and stored in excess amount of water at room temperature (-22°C) and at 4 °C for 12 h. During the storage, the fluorescence of the sample was measured periodically.
- the fluorescence intensity after the exposure to pyrene- loaded micelle is almost identical to the initial intensity of 6LE in Figure 5.' After the first cycle (release- loading, 24 h) , the fluorescence intensity was recovered to the initial level. The same was true with the second cycle. The first release (0-12 h) and the second release (24-36 h) showed similar decline in intensity. These results indicate that the micelle coating is stable and can load and release pyrene repetitively. The third exposure (48-60 h) was to 4 °C water. The decline in fluorescence intensity was slower than the first two releases (exposure to 22 °C water) .
- PLA segment may also affect the release of pyrene (hydrophobic drug) from the micelle
- temperature also may have also affected the diffusion coefficient of pyrene in the micelle. If the larger molecule than pyrene is loaded, the release rate is expected to be slower.
- a polypropylene film 25 micron thick, 45% pore, ⁇ 0.25 micron pore size
- the film was covered with poly (hydroxyethyl methacrylate) , PHEMA, by dipping the polypropylene film into a 10% solution in methanol and drying in ambient followed by the plasma treatment described herein.
- the aminated sample was coated with the monolayer micelle of Example 1 and the multi layered micelle of Example 4 as previously described.
- a permeation of dextran through the sample film was tested by measuring the diffusion of fluorescein isothiocyanate (FiTC) dextran (commercially available from Sigma Aldrich) from one side of the film through ⁇ the other.
- the apparatus (4) utilized is shown in Figure 7.
- the sample film (1) separates one side of the chamber filled with PBS solution (2) and the other side of the chamber which is filled with 0.1% (weight/volume) FITC dextran solution in PBS solution (3) .
- the temperature of the chamber was set at 25 °C. 3.0 mL of solution of the PBS was sampled every 24 hours and the rate of dextran permeation was determined by the change in its fluorescence intensity.
- Figure 8 shows the plot of the permeation of dextran through the micelle coated films.
- PEG the permeation of dextran increased. This is due to erosion of the PHEMA surface. The erosion is compensated by the monolayer micelle coating. The micelle coating effectively covered the surface. In the case of 3 layers of micelle coating, the permeation rate was remarkably prevented due to the formed network of micelle, polyallylamine (PAIAm; 10,000 MW, commercially available from Nittobo Chemical Company, Tokyo, Japan) and the increased thickness of the layer.
- PAIAm polyallylamine
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Transplantation (AREA)
- Ophthalmology & Optometry (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Biomedical Technology (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Surgery (AREA)
- Cardiology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Dispersion Chemistry (AREA)
- Materials For Medical Uses (AREA)
- Polyesters Or Polycarbonates (AREA)
- Medicinal Preparation (AREA)
- Macromonomer-Based Addition Polymer (AREA)
- Treatments Of Macromolecular Shaped Articles (AREA)
- Laminated Bodies (AREA)
- Paints Or Removers (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP31346399A JP2001131271A (en) | 1999-11-04 | 1999-11-04 | Surface on which polymer-micell layer is laminated and its preparation process |
JP31345799A JP2001131092A (en) | 1999-11-04 | 1999-11-04 | Laminar structure for controlling passage of medicine |
CA002389917A CA2389917A1 (en) | 1999-11-04 | 2000-11-03 | A polymer micelle as monolayer or layer-laminated surface |
EP00974727A EP1225929A2 (en) | 1999-11-04 | 2000-11-03 | A polymer micelle as monolayer or layer-laminated surface |
JP2001534434A JP2003527890A (en) | 2000-11-03 | 2000-11-03 | Polymer micelles as single layer or laminated surface |
AU12941/01A AU1294101A (en) | 1999-11-04 | 2000-11-03 | A polymer micelle as monolayer or layer-laminated surface |
PCT/IB2000/001724 WO2001032230A2 (en) | 1999-11-04 | 2000-11-03 | A polymer micelle as monolayer or layer-laminated surface |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9911010 | 1999-11-04 | ||
JP31346399A JP2001131271A (en) | 1999-11-04 | 1999-11-04 | Surface on which polymer-micell layer is laminated and its preparation process |
JP31345799A JP2001131092A (en) | 1999-11-04 | 1999-11-04 | Laminar structure for controlling passage of medicine |
PCT/IB2000/001724 WO2001032230A2 (en) | 1999-11-04 | 2000-11-03 | A polymer micelle as monolayer or layer-laminated surface |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2001032230A2 true WO2001032230A2 (en) | 2001-05-10 |
WO2001032230A3 WO2001032230A3 (en) | 2001-12-20 |
Family
ID=27270231
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2000/001724 WO2001032230A2 (en) | 1999-11-04 | 2000-11-03 | A polymer micelle as monolayer or layer-laminated surface |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1225929A2 (en) |
JP (2) | JP2001131271A (en) |
AU (1) | AU1294101A (en) |
WO (1) | WO2001032230A2 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1518568A1 (en) * | 2003-09-25 | 2005-03-30 | Wageningen Universiteit, Agrotechnologie en Voedingswetenschappen | Complex coacervate core micelles as anti-fouling agents |
JP2005538767A (en) * | 2002-09-11 | 2005-12-22 | ノバルティス アクチエンゲゼルシャフト | LbL-coated medical device and method of manufacturing the same |
CN1299116C (en) * | 2001-05-30 | 2007-02-07 | 株式会社三菱化学药得论 | Core-shell type particle having signal-generating susbstance enclosed therein and process for producing the same |
US7329415B2 (en) | 2002-03-13 | 2008-02-12 | Novartis Ag | Materials containing multiple layers of vesicles |
CN102887992A (en) * | 2012-09-28 | 2013-01-23 | 天津大学 | Polyester/polyethylene glycol block copolymer containing side cinnamoyl group and application thereof |
US9310627B2 (en) | 2013-11-15 | 2016-04-12 | Ocular Dynamics, Llc | Contact lens with a hydrophilic layer |
US9395468B2 (en) | 2012-08-27 | 2016-07-19 | Ocular Dynamics, Llc | Contact lens with a hydrophilic layer |
US10525170B2 (en) | 2014-12-09 | 2020-01-07 | Tangible Science, Llc | Medical device coating with a biocompatible layer |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001131271A (en) * | 1999-11-04 | 2001-05-15 | Kazunori Kataoka | Surface on which polymer-micell layer is laminated and its preparation process |
JP4728093B2 (en) * | 2005-03-02 | 2011-07-20 | 独立行政法人科学技術振興機構 | Single-crystal noble metal ultra-thin film nanoparticles formed by using an adsorption micelle film formed at a solid / liquid interface as a reaction field, and a method for producing the same |
JP4992090B2 (en) * | 2005-05-02 | 2012-08-08 | 国立大学法人 東京大学 | Electrostatic coupling type polymer vesicle |
AU2019226030A1 (en) * | 2018-02-21 | 2020-10-08 | Aron H. BLAESI | Expanding structured dosage form |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4749585A (en) * | 1986-04-11 | 1988-06-07 | University Of Medicine And Dentistry Of New Jersey | Antibiotic bonded prosthesis and process for producing same |
WO1996038726A1 (en) * | 1995-05-30 | 1996-12-05 | Ecole Polytechnique Federale De Lausanne (Epfl) | Covalently immobilized phospholipid bilayers on solid surfaces |
EP0822217A1 (en) * | 1995-04-19 | 1998-02-04 | Kazunori Kataoka | Heterotelechelic block copolymers and process for producing the same |
EP0844269A1 (en) * | 1995-08-10 | 1998-05-27 | Kazunori Kataoka | Block polymer having functional groups at both ends |
WO1999026665A2 (en) * | 1997-11-26 | 1999-06-03 | Ranier Limited | Reticulated polymeric coatings |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2087125A1 (en) * | 1992-01-23 | 1993-07-24 | Mridula Nair | Chemically fixed micelles |
US5702754A (en) * | 1995-02-22 | 1997-12-30 | Meadox Medicals, Inc. | Method of providing a substrate with a hydrophilic coating and substrates, particularly medical devices, provided with such coatings |
JP2001131271A (en) * | 1999-11-04 | 2001-05-15 | Kazunori Kataoka | Surface on which polymer-micell layer is laminated and its preparation process |
-
1999
- 1999-11-04 JP JP31346399A patent/JP2001131271A/en active Pending
- 1999-11-04 JP JP31345799A patent/JP2001131092A/en active Pending
-
2000
- 2000-11-03 WO PCT/IB2000/001724 patent/WO2001032230A2/en not_active Application Discontinuation
- 2000-11-03 AU AU12941/01A patent/AU1294101A/en not_active Abandoned
- 2000-11-03 EP EP00974727A patent/EP1225929A2/en not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4749585A (en) * | 1986-04-11 | 1988-06-07 | University Of Medicine And Dentistry Of New Jersey | Antibiotic bonded prosthesis and process for producing same |
EP0822217A1 (en) * | 1995-04-19 | 1998-02-04 | Kazunori Kataoka | Heterotelechelic block copolymers and process for producing the same |
WO1996038726A1 (en) * | 1995-05-30 | 1996-12-05 | Ecole Polytechnique Federale De Lausanne (Epfl) | Covalently immobilized phospholipid bilayers on solid surfaces |
EP0844269A1 (en) * | 1995-08-10 | 1998-05-27 | Kazunori Kataoka | Block polymer having functional groups at both ends |
WO1999026665A2 (en) * | 1997-11-26 | 1999-06-03 | Ranier Limited | Reticulated polymeric coatings |
Non-Patent Citations (2)
Title |
---|
EMOTO KAZUNORI ET AL: "Coating of surfaces with stabilized reactive micelles from poly(ethylene glycol)-poly(DL-lactic acid) block copolymer" LANGMUIR, ACS, WASHINGTON DC, USA, vol. 15, no. 16, 2 July 1999 (1999-07-02), pages 5212-5218, XP002172102 * |
EMOTO KAZUNORI ET AL: "Core-shell structured hydrogel thin layer on surfaces by lamination of a poly(ethylene glycol)-b-poly(D,L-lactide) micelle and polyallylamine" LANGMUIR; ACS, WASHINGTON, DC, USA, vol. 16, no. 13, June 2000 (2000-06), pages 5738-5742, XP002172103 * |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1299116C (en) * | 2001-05-30 | 2007-02-07 | 株式会社三菱化学药得论 | Core-shell type particle having signal-generating susbstance enclosed therein and process for producing the same |
US7329415B2 (en) | 2002-03-13 | 2008-02-12 | Novartis Ag | Materials containing multiple layers of vesicles |
US7901706B2 (en) | 2002-03-13 | 2011-03-08 | Novartis Ag | Materials containing multiple layers of vesicles |
JP2005538767A (en) * | 2002-09-11 | 2005-12-22 | ノバルティス アクチエンゲゼルシャフト | LbL-coated medical device and method of manufacturing the same |
WO2005030282A1 (en) * | 2003-09-25 | 2005-04-07 | Rhodia Chimie | Complex coacervate core micelles as surface modification or surface treatment |
EP1518568A1 (en) * | 2003-09-25 | 2005-03-30 | Wageningen Universiteit, Agrotechnologie en Voedingswetenschappen | Complex coacervate core micelles as anti-fouling agents |
US10451896B2 (en) | 2012-08-27 | 2019-10-22 | Tangible Science, Llc | Contact lens with a hydrophilic layer |
US11181754B2 (en) | 2012-08-27 | 2021-11-23 | Tangible Science, Llc | Contact lens with a hydrophilic layer |
US9395468B2 (en) | 2012-08-27 | 2016-07-19 | Ocular Dynamics, Llc | Contact lens with a hydrophilic layer |
CN102887992A (en) * | 2012-09-28 | 2013-01-23 | 天津大学 | Polyester/polyethylene glycol block copolymer containing side cinnamoyl group and application thereof |
US10330951B2 (en) | 2013-11-15 | 2019-06-25 | Tangible Science, Llc | Contact lens with a hydrophilic layer |
US9310627B2 (en) | 2013-11-15 | 2016-04-12 | Ocular Dynamics, Llc | Contact lens with a hydrophilic layer |
US11433628B2 (en) | 2013-11-15 | 2022-09-06 | Tangible Science, Inc. | Contact lens with a hydrophilic layer |
US10525170B2 (en) | 2014-12-09 | 2020-01-07 | Tangible Science, Llc | Medical device coating with a biocompatible layer |
US11260150B2 (en) | 2014-12-09 | 2022-03-01 | Tangible Science, Inc. | Medical device coating with a biocompatible layer |
Also Published As
Publication number | Publication date |
---|---|
EP1225929A2 (en) | 2002-07-31 |
WO2001032230A3 (en) | 2001-12-20 |
AU1294101A (en) | 2001-05-14 |
JP2001131271A (en) | 2001-05-15 |
JP2001131092A (en) | 2001-05-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7674478B2 (en) | Polymer micelle as monolayer or layer-laminated surface | |
CA2354060C (en) | Apparatus and method for control of tissue/implant interactions | |
JP5118281B2 (en) | Amphiphilic polymer vesicles | |
US20030099682A1 (en) | Apparatus and method for control of tissue/implant interactions | |
Martin et al. | The release of model macromolecules may be controlled by the hydrophobicity of palmitoyl glycol chitosan hydrogels | |
Jagur-Grodzinski | Biomedical application of functional polymers | |
US20120082717A1 (en) | Complex, multilayer using the same, and device coated with the multilayer | |
WO2001032230A2 (en) | A polymer micelle as monolayer or layer-laminated surface | |
EP1434571A1 (en) | Particle immobilized coatings and uses thereof | |
US20050003016A1 (en) | Controlled release polymersomes | |
Kim et al. | Design and development of pH-responsive polyurethane membranes for intravaginal release of nanomedicines | |
JP2001181924A (en) | Polymer having biologically active agent | |
US20050084513A1 (en) | Nanocoating for improving biocompatibility of medical implants | |
US10682309B2 (en) | Hydrogel microparticle scaffold with gradients of degradability and methods thereof | |
Athar et al. | Cellulose nanocrystals and PEO/PET hydrogel material in biotechnology and biomedicine: current status and future prospects | |
US6284375B1 (en) | Lipid vesicle system | |
JP3308010B2 (en) | Coating-stabilized liposome and method for producing the same | |
Abbaszadeh et al. | Emerging strategies to bypass transplant rejection via biomaterial-assisted immunoengineering: Insights from islets and beyond | |
JP2003527890A (en) | Polymer micelles as single layer or laminated surface | |
Nakajima et al. | Fusogenic activity of various water-soluble polymers | |
Vladkova | Surface modification of silicone rubber with poly (ethylene glycol) hydrogel coatings | |
EP1152774A2 (en) | Biocompatible material with a novel functionality | |
CN1434730A (en) | Polymer micelle as monolayer or layer-laminated surface | |
JP6564983B2 (en) | Drug sustained release device | |
Englert et al. | Synthetic Evolution of a Supramolecular Harpooning Mechanism to Immobilize Vesicles at Antifouling Interfaces |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2389917 Country of ref document: CA |
|
ENP | Entry into the national phase in: |
Ref country code: JP Ref document number: 2001 534434 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2000974727 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 008181772 Country of ref document: CN |
|
WWP | Wipo information: published in national office |
Ref document number: 2000974727 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2000974727 Country of ref document: EP |