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WO1996037241A1 - Procedes de production de surfaces biocompatibles - Google Patents

Procedes de production de surfaces biocompatibles Download PDF

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Publication number
WO1996037241A1
WO1996037241A1 PCT/US1996/005893 US9605893W WO9637241A1 WO 1996037241 A1 WO1996037241 A1 WO 1996037241A1 US 9605893 W US9605893 W US 9605893W WO 9637241 A1 WO9637241 A1 WO 9637241A1
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WO
WIPO (PCT)
Prior art keywords
water soluble
primed
polyalkylene amine
contacting
molecular weight
Prior art date
Application number
PCT/US1996/005893
Other languages
English (en)
Inventor
Larry M. Sirvio
Original Assignee
Minnesota Mining And Manufacturing Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Minnesota Mining And Manufacturing Company filed Critical Minnesota Mining And Manufacturing Company
Priority to AU56307/96A priority Critical patent/AU5630796A/en
Publication of WO1996037241A1 publication Critical patent/WO1996037241A1/fr

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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
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005—Use of materials characterised by their function or physical properties
    • A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
    • A61L33/0029—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate using an intermediate layer of polymer
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
    • C08J7/04—Coating
    • C08J7/0427—Coating with only one layer of a composition containing a polymer binder
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
    • C08J7/04—Coating
    • C08J7/043—Improving the adhesiveness of the coatings per se, e.g. forming primers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2479/00—Characterised by the use of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing nitrogen with or without oxygen, or carbon only, not provided for in groups C08J2461/00 - C08J2477/00

Definitions

  • the present invention generally relates to an improved process for treating a surface in order to inhibit or prevent the surface from causing blood to clot or coagulate on or at the surface as well as novel compositions used in the practice of the improved process.
  • the present process is particularly adapted for coating polymeric or metallic surfaces which directly contact blood and blood products with heparin.
  • Surfaces of medical devices that are in direct contact with blood and blood products have been treated with surface modifying agents, such as heparin, in order to make such surfaces nonthrombogenic.
  • surface modifying agents such as heparin
  • the blood contacting surfaces of devices such as blood oxygenators, blood pumps, catheters, and tubing may be treated with heparin or heparin derivatives to prevent clotting or clot formation related to surface contact with blood or blood products.
  • U.S. Patent No. 4,565,740 reports a surface modified to include heparin where the substrate is first treated with a polymeric cationic surfactant and a dialdehyde crosslinker, then treated with an anionic compound and finally treated with diazotized heparin and sodium cyanoborohydride.
  • the cross linking agent is a dialdehyde having from 3-6 carbon atoms. From this group, glutaraldehyde is expressly identified. This process may be limited because of the use of reagents which may be toxic, hazardous or difficult to handle. For instance, glutaraldehyde is an irritant with a threshold limit value ceiling of 0.2 ppm in air.
  • U.S. Patent No. 5,049,403 reports a surface modified to include heparin where the surface is treated with a polyamine and then crosslinked with crotonaldehyde. Crotonaldehyde is also difficult to work with because it is a lacrimator which is highly irritating to eyes, skin, and mucous membranes. Thus, all of the methods referred to above employ agents that require special handling and care which may limit their general applicability. Further, U.S. Patent No. 4,326,532 reports a layered substrate coated with chitosan which is reacted with an antithrombotic agent such as heparin.
  • the heparin is added to a layer of chitosan which is applied to an acid oxidized or plasma etched hydrophobic surface and then, if needed, the heparin is bonded to the chitosan using sodium cyanoborohydride.
  • the need to etch or acid-oxidize the surface of the substrate also serves to inhibit the general applicability of this process.
  • a desirable process would allow the use of biologically active materials without degrading or otherwise altering the biological activity of the active material when it is used to modify the surface of a support.
  • the present invention provides a process to prepare a biocompatible surface which is treated by adding a biologically active or antithrombotic agent to the surface in order to inhibit or prevent blood coagulation.
  • This process includes a priming sequence of contacting a surface with a solution of a water soluble polyalkylene amine having an average molecular weight of between about 1,000-100,000 and a water soluble diepoxide of the general formula O
  • Ri is -O-(CH 2 ) a -O- and a is 2-3 or -(O-CH 2 -CH 2 )b-O-and b is 2-100 in a suitable buffer to give a first primed surface, and contacting the first primed surface with a buffered solution of an anionic compound such as dextran sulfate to give a second primed surface.
  • a biologically active or antithrombotic agent preferably heparin
  • a biologically active or antithrombotic agent is added to the surface by contacting the second primed surface with a polyalkylene amine having an average molecular weight of between about 1,000-100,000 in a suitable buffer to give a third primed surface and then contacting the third primed surface with a buffered solution of the biologically active or antithrombotic agent and a reducing agent to covalently bind the antithrombotic agent to the primed surface.
  • One embodiment of this invention includes: i) contacting a surface with a basic aqueous solution of about
  • the surface is thoroughly rinsed with deionized water between each of the above listed steps i-iv.
  • Steps i and ii may be repeated as needed.
  • the basic aqueous solutions in steps i and iii may be a basic buffer solution such as carbonate or borate which provides a pH of about 9.
  • a suitable basic buffer solution is 0.3 wt.% borate buffer at pH 9.
  • the acidic aqueous solutions in steps ii and iv may be an acidic buffer such as a phosphate or citrate buffer which provides a pH of about 3-4.2.
  • a suitable acidic buffer solution is 1 wt.% citrate buffer and 0.9 wt.% suitable sodium chloride at pH 3-4, preferably pH 3.9.
  • Surfaces which are particularly well suited for use in the present process include polymeric surfaces such as cellulose, poly(vinyl alcohol), poly(vinyl chloride), poly(methylmethacrylate), polycarbonate, polyurethane, polypropylene, polysulfone, poly(tetrafluoroethylene), silicone, and poly(ethylene terephthalate) as well as other surfaces typically used in medical devices such as glass and stainless steel.
  • polymeric surfaces such as cellulose, poly(vinyl alcohol), poly(vinyl chloride), poly(methylmethacrylate), polycarbonate, polyurethane, polypropylene, polysulfone, poly(tetrafluoroethylene), silicone, and poly(ethylene terephthalate) as well as other surfaces typically used in medical devices such as glass and stainless steel.
  • the above described process is particularly suited to add a novel four part biocompatible coating composition to surfaces that will contact blood or blood products.
  • the coating composition includes a water soluble polyalkylene amine crosslinked with a water soluble diepoxide, an anionic compound such as dextran sulfate, a polyalkylene amine, and a biologically active or antithrombotic agent.
  • preferred polyalkylene amines have an average molecular weight of between about 1,000-100,000 and, more preferably, between about 20,000-60,000.
  • a particularly preferred polyalkylene amine is polyethylene imine having an average molecular weight of about 50,000-60,000.
  • Preferred diepoxides are selected from compounds of the general formula
  • a particularly preferred diepoxide is ethylene glycol diglycidyl ether.
  • Preferred biologically active or antithrombotic agents include biologically active oligo or polysaccharides containing glucosamine or galactosamine subgroups such as heparin, heparan sulfate, hyaluronic acid, dermatan sulfate, chitosan and active derivatives of these polysaccharides.
  • a particularly preferred antithrombotic agent is heparin or a derivative thereof.
  • the present coating composition When the present coating composition is compared with other coating compositions that use aldehyde-containing crosslinking agents, it was unexpectedly found that the present composition provides a surface which is smoother and more uniform than the aldehyde-cross linked compositions.
  • a smoother, more uniform surface may be desirable because smooth, uniform surfaces are less likely to promote blood clot or coagulation as compared to a rough, irregular surface of the same material.
  • Figure 1 is a scanning electron microscope photomicrograph of a polycarbonate surface treated with a coating composition of the present invention.
  • Figure 2 is a scanning electron microscope photomicrograph of a poly(methylmethacrylate) surface treated with a coating composition of the present invention.
  • Figure 3 is a scanning electron microscope photomicrograph of a polycarbonate surface treated with a coating composition containing a glutaraldehyde cross linking agent.
  • Figure 4 is a scanning electron microscope photomicrograph of a poly(methylmethacrylate) surface treated with a coating composition containing a glutaraldehyde cross linking agent.
  • Figure 5 is a scanning electron microscope photomicrograph of a polycarbonate surface treated with a coating composition containing a crotonaldehyde cross linking agent.
  • Figure 6 is a scanning electron microscope photomicrograph of a poly(methylmethacrylate) surface treated with a coating composition containing a crotonaldehyde cross linking agent.
  • a "biocompatible or blood compatible surface” is a treated surface which, when in contact with a patient's blood, plasma, or other body fluids, does not cause an adverse physiological reaction.
  • Treated surfaces preferably include a "biologically active or nonthrombotic agent” is a material which, when in contact with a patient's blood, plasma, or other body fluids under physiological conditions, exhibits biological activity.
  • heparin is biologically active or nonthrombogenic in the sense that it acts as an anti-coagulant in the presence of blood.
  • both hydrophobic and hydrophilic surfaces are first contacted with a mixture of a polyalkylene amine such as polyethylene imine and a diepoxide crosslinking agent such as ethylene glycol diglycidyl ether to give a surface having an outer layer which is both wettable and positively charged.
  • a polyalkylene amine such as polyethylene imine
  • a diepoxide crosslinking agent such as ethylene glycol diglycidyl ether
  • an anionic compound or negatively charged agent such as dextran sulfate is added to the positively charged surface to give an outer layer which further increases the wettability of the surface and also allows the addition of another layer of polyamine to the surface.
  • the surface is treated or primed by the sequential treatment with three agents: i) polyalkylene amine and crosslinker, ii) dextran sulfate, and iii) polyalkylene amine.
  • an antithrombotic agent such as heparin in the presence of sodium cyanoborohydride which covalently binds the agent to the polyalkylene amine.
  • the covalent binding of the biologically active or antithrombotic agent to the polyalkylene amine most likely occurs when a reactive terminal aldehyde group of the antithrombotic agent reacts with a primary amino group of the polyamine.
  • the initial Schiffs base intermediate is readily reduced to a secondary amine in the presence of a reducing agent such as sodium cyanoborohydride.
  • the treated surface may be contacted a biologically active or nonthrombotic agent having free aldehyde groups (generated, e.g., by periodate oxidation) in the presence of a reducing agent such as sodium cyanoborohydride which also covalently binds the agent to the polyalkylene amine.
  • a reducing agent such as sodium cyanoborohydride which also covalently binds the agent to the polyalkylene amine.
  • the covalent binding of the biologically active agent to the polyalkylene amine most likely occurs when a reactive aldehyde group of the biologically active agent reacts with a primary amino group of the polyalkylene amine.
  • the Schiffs' base initially formed as a result is readily reduced to a secondary amine in the presence of the sodium cyanoborohydride.
  • covalent binding of the biologically active or nonthrombotic agent may also be accomplished using a carbodiimide coupling agent, rather than sodium cyanoborohydride, in which case it is not necessary to use periodate oxidation to generate free aldehyde groups.
  • the surface-bound concentration of heparin may be measured by a thrombin inhibition assay.
  • the inhibition assay exploits the observation that thrombin enzymatically cleaves a synthetic substrate (S-2238) to yield a product whose concentration is proportional to its absorbance at 405 ran, and the concentration of product is therefore proportional to the thrombin concentration. Decreased amounts of product reflect inhibition of thrombin by heparin in the presence of excess amounts of antithrombin-III.
  • the assay is performed by adding, in the following sequence, the listed materials to test tubes: an unknown sample and 0.05 ml of buffer (where the sample has unknown concentration of heparin on the surface), or 0.05 ml of a standard heparin solution, 1.0 ml of 0.3 mM S-2238, 0.1 ml of antithrombin-III (5 units/ml), and 0.1 ml of thrombin (0.1 units/ml).
  • the standard heparin solutions (50 microliters) contain, for example, 0.08, 0.04, 0.02, 0.01 and 0.0 micrograms of heparin.
  • the assay is carried out at 37°C with overnight incubation in a water bath, with continuous mixing. Measurements are made on 0.20 ml aliquots taken from the unknown and standard solutions using microtiter plates and optical density at 405 nm is recorded. The optical density values are related to heparin concentration using the heparin standard solutions.
  • the assay procedure is a modification of Chandler et al., J. Biomed Mater. Res., 22:497-508 (1988) which uses the following reagents.
  • Antithrombin-HI is reconstituted to 5 units/ml with 10 ml deionized distilled water and refrigerated at 4°C.
  • S-2238 is reconstituted to 0.3 mM using 133 ml of buffer stock solution of PBS (phosphate buffered saline) with 1 mg/ml BSA (bovine serum albumin, Cat. No. A7838, Sigma Chemical Company, St. Louis, MO) and 1 mg/ml polyethylene glycol (8000 MW, Cat. No. P2139, Sigma Chemical Company, St. Louis, MO) and stored at 4°C.
  • Thrombin is reconstituted to 10 units/ml with 10 ml Hanks' phosphate buffered saline and stored at -20°C in 1 ml aliquots. A 1 : 100 dilution of thrombin is used in the assay.
  • Standard heparin solutions are prepared from the 10 units/ml stock solution by serial dilution. Each new batch of thrombin and/or heparin must be tested to insure maximum sensitivity. Representative values of standard heparin solutions are listed in the following table.
  • 0.05 ml of appropriate standards as well as an unknown sample having a measured surface area together with PBS/BSA buffer are dispensed into tubes.
  • the following reagents are added to each of the tubes, 0.1 ml antithrombin-III, 1.0 ml S-2238 and 0.1 ml thrombin, all tubes are vortexed and then incubated overnight at 37°C. After incubation, 0.2 ml from each tube is added to a well of a microtiter plate in duplicate for each tube and optical density readings are taken at 405 nM (All standards and samples are run in duplicate, with duplicate optical density readings at 405 nM.)
  • Polycarbonate (PC, HYZOD, Sheffield Plastics Inc., Sheffield, MA) sheets were treated with polyethylene imine having an average molecular weight of 50,000 (PEI, 500 mg, Aldrich Chemical Company, Milwaukee, WI) and ethylene glycol diglycidyl ether (EGDE, 500 mg, Aldrich Chemical Company, Milwaukee, WI) in 0.3% borate buffer at pH 9 for fifteen minutes at room temperature and were then treated with a solution of dextran sulfate (100 mg, 500,000 MW, Sigma Chemical Company, St. Louis, MO) in 1% citrate buffer and 0.9 wt.% sodium chloride at pH 3 for five minutes at 50°C.
  • the treated sheets stained purple with toluidine blue which indicates the presence of the dextran sulfate.
  • thrombin inhibition assay (described above). The thrombin inhibition assay data is also listed in Table 2.
  • a Sarns/3M adult membrane oxygenator made of polypropylene, polycarbonate, and stainless steel, Model 16310, Sams/3 M, Ann Arbor, MI
  • the related centrifugal pump made of polycarbonate and poly(methyl methacrylate), Model 7850, Sarns/3M, Ann Arbor, MI
  • reservoir bag and tubing both made of poly(vinyl chloride), Sarns/3M, Ann Arbor, MI
  • the complete system was rinsed with phosphate buffered saline (pH 7) for two hours at 37° to remove ionically bound heparin. Without this step, it was found that ionically bound heparin was eluted into the circulating blood during testing.
  • pH 7 phosphate buffered saline
  • the surface treated oxygenator was replaced with an oxygenator that had no surface treatment.
  • the entire system was disassembled and visually examined for the presence of thrombi.
  • the surface treated oxygenator showed no signs of thrombi except for a few small thrombi on the stainless steel heat exchanger in the oxygenator.
  • the substantially identical oxygenator that had not been treated as described above exhibited massive thrombi formation on all parts of the untreated oxygenator.
  • An INSYTE twenty gauge polyurethane catheter (Deseret Medical Inc./Becton Dickenson and Company, Sandy, UT) was treated with the reagents listed in Table 2 for a polyurethane substrate using the listed times and temperatures with the exception that the catheter was treated with the buffered solution of sodium heparin and sodium cyanoborohydride for four hours. Upon completion of the surface treatment process, the catheter was thoroughly rinsed with water. The presence of heparin on the catheter surface was determined by staining with toluidine blue.
  • polycarbonate and poly(methylmethacrylate) surfaces were primed with three different coating compositions according to the procedures generally described in Example 2 except that polyethylene imine alone and heparin were not added.
  • a polycarbonate or poly(methyl methacrylate) surface was primed or treated using a three step process.
  • the surface was contacted with a buffered solution of polyethylene imine and a cross linking agent, then with a buffered solution of dextran sulphate and finally with a second buffered solution of polyethylene imine and cross linking agent.
  • Three different cross linking agent were used, ethylene glycol diglycidyl ether (EGDE), glutaraldehyde (GA, see U.S. Patent 4,565,740)), or crotonaldehyde (CTA, see U.S. Patent 5,049,403). Reaction times, buffers and concentrations are listed in Table 3.
  • Figs. 2-6 The photomicrographs indicate that using EGDE as a cross linking agent provided a surface which was different when compared with the surfaces provided when GA or CTA were used as cross linking agents.
  • the EGDE-containing surface was smoother and more uniform compared to the other surfaces. It is believed that the paniculate material observed in the photomicrographs of GA-containing or CTA-containing polycarbonate or poly(methylmethacrylate) surfaces is related to a suspension polymerization phenomena. Both GA and CTA react rapidly with amines and may also self-polymerize which may result in the formation of reactive paniculate material in the buffered solutions. The paniculate material is then deposited on the surface. In a similar experiment polycarbonate surfaces were contacted with the above solutions for five minutes.
  • the substrates were then immersed in a citrate buffer solution (ll.O g citric acid monohydrate and 9.0 g sodium chloride in one liter water, adjusted to pH 3.0 with 5N sodium hydroxide) of dextran sulfate (0.15 g/ 500 ml citrate buffer, molecular weight 500,000, Sigma Chemical Company, St. Louis, MO) for five minutes and then again rinsed thoroughly with water.
  • a citrate buffer solution ll.O g citric acid monohydrate and 9.0 g sodium chloride in one liter water, adjusted to pH 3.0 with 5N sodium hydroxide
  • dextran sulfate (0.15 g/ 500 ml citrate buffer, molecular weight 500,000, Sigma Chemical Company, St. Louis, MO
  • the substrates then immersed in in an aqueous PEI solution (PEI 0.40 g/400 ml distilled water, average molecular weight 60,000, Aldrich Chemical Company, Milwaukee, WI) for fifteen minutes at room temperature. Following a thorough rinsing with water, the substrates were immersed in a solution containing 0.04% by weight periodate oxidized heparin and 0.004% by weight sodium cyanoborohydride (Aldrich Chemical Co., Milwaukee, WI) in the above-described citrate buffer for two hours at 50°C.
  • PEI solution PEI 0.40 g/400 ml distilled water, average molecular weight 60,000, Aldrich Chemical Company, Milwaukee, WI
  • Periodate oxidized heparin was prepared by dissolving sodium heparin (15 g, Diosynth Inc., Chicago, IL) and sodium periodate (1.5 g) in phosphate buffered saline (450 ml, pH 7), and then stirring the solution in the dark for one hour. Glycerin (15 g) was then added to quench the unreacted periodate, after which the mixture was stirred for one hour and then dialyzed against water (4 times, using a total of 4 liters of water) using 1000 MWCO dialysis tubing. The dialyzed solution was then lyophilized to yield about 8 g of periodate oxidized heparin.
  • Example 3 An oxygenator circuit as described in Example 3 was treated using the procedure described in Example 6 except that the rinse was 25% saline solution was omitted. This oxygenator circuit was tested as in Example 3. During this time no heparin was administered to the animal and no heparin eluted from the oxygenator circuit as determined by monitoring coagulation times of the animal's blood during the experiment. At the end of the three hour period the surface treated oxygenator and heat exchanger were nearly thrombus free. The remaining parts of the circuit were thrombus free.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
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Abstract

La présente invention concerne un procédé amélioré permettant de traiter une surface dans le but d'empêcher cette surface de provoquer une coagulation du sang ou une formation de caillots sanguins à son contact ainsi que de nouvelles compositions utilisées pour mettre en pratique ledit procédé. Ce procédé convient particulièrement bien au dépôt de revêtements sur des surfaces polymères qui sont en contact direct avec le sang ou avec des produits sanguins. Ce procédé consiste à mettre séquentiellement la surface en contact avec (i) une amine polyalkylène soluble dans l'eau et un diépoxyde soluble dans l'eau, avec (ii) un composé anionique et avec (iii) une amine polyalkylène soluble dans l'eau de façon à obtenir une surface recouverte d'une couche de fond. Cette surface recouverte d'une couche de fond est ensuite mise en contact avec un agent antithrombotique et un agent réducteur de façon à lier par covalence l'agent antithrombotique à ladite surface recouverte de la couche de fond.
PCT/US1996/005893 1995-05-25 1996-04-25 Procedes de production de surfaces biocompatibles WO1996037241A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU56307/96A AU5630796A (en) 1995-05-25 1996-04-25 Process for producing biocompatible surfaces

Applications Claiming Priority (2)

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US45072095A 1995-05-25 1995-05-25
US08/450,720 1995-05-25

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WO1996037241A1 true WO1996037241A1 (fr) 1996-11-28

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US6309660B1 (en) 1999-07-28 2001-10-30 Edwards Lifesciences Corp. Universal biocompatible coating platform for medical devices
US6340465B1 (en) 1999-04-12 2002-01-22 Edwards Lifesciences Corp. Lubricious coatings for medical devices
US6451871B1 (en) 1998-11-25 2002-09-17 Novartis Ag Methods of modifying surface characteristics
US6719929B2 (en) 2000-02-04 2004-04-13 Novartis Ag Method for modifying a surface
US6793973B2 (en) 2000-02-04 2004-09-21 Novartis Ag Single-dip process for achieving a layer-by-layer-like coating
US6827966B2 (en) 2001-05-30 2004-12-07 Novartis Ag Diffusion-controllable coatings on medical device
US6852353B2 (en) 2000-08-24 2005-02-08 Novartis Ag Process for surface modifying substrates and modified substrates resulting therefrom
US6858248B2 (en) 2001-05-30 2005-02-22 Novartis Ag Method for applying a coating to a medical device
US6893685B2 (en) 2000-08-24 2005-05-17 Novartis Ag Process for surface modifying substrates and modified substrates resulting therefrom
US6896926B2 (en) 2002-09-11 2005-05-24 Novartis Ag Method for applying an LbL coating onto a medical device
US6926965B2 (en) 2002-09-11 2005-08-09 Novartis Ag LbL-coated medical device and method for making the same
DE102008003271A1 (de) 2008-01-02 2009-07-09 Friedrich-Schiller-Universität Jena Verfahren zur Herstellung und Verwendung niedrig schmelzender, biokompatibler Dextranfettsäureester
US8044112B2 (en) 2006-03-30 2011-10-25 Novartis Ag Method for applying a coating onto a silicone hydrogel lens
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US8460743B2 (en) 2008-03-18 2013-06-11 Novartis Ag Coating process for ophthalmic lenses
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US9005700B2 (en) 2011-10-12 2015-04-14 Novartis Ag Method for making UV-absorbing ophthalmic lenses
US9052442B2 (en) 2006-10-30 2015-06-09 Novartis Ag Method for applying a coating onto a silicone hydrogel lens
US9272246B2 (en) 2011-03-28 2016-03-01 3M Innovative Properties Company Ligand functional substrates
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US9708087B2 (en) 2013-12-17 2017-07-18 Novartis Ag Silicone hydrogel lens with a crosslinked hydrophilic coating
US10338408B2 (en) 2012-12-17 2019-07-02 Novartis Ag Method for making improved UV-absorbing ophthalmic lenses
US10449740B2 (en) 2015-12-15 2019-10-22 Novartis Ag Method for applying stable coating on silicone hydrogel contact lenses
US10830923B2 (en) 2017-12-13 2020-11-10 Alcon Inc. Method for producing MPS-compatible water gradient contact lenses
US11002884B2 (en) 2014-08-26 2021-05-11 Alcon Inc. Method for applying stable coating on silicone hydrogel contact lenses
CN116211776A (zh) * 2023-04-23 2023-06-06 广州睿晞生化科技有限公司 一种含植物雌激素的护肤化妆品组合物、化妆品及其制备方法
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US12016978B2 (en) 2018-03-09 2024-06-25 Carmeda Ab Processes for immobilising biological entities

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